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WO2008019309A1 - Novel inhibitors of fructose 1,6-bisphosphatase - Google Patents

Novel inhibitors of fructose 1,6-bisphosphatase Download PDF

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Publication number
WO2008019309A1
WO2008019309A1 PCT/US2007/075159 US2007075159W WO2008019309A1 WO 2008019309 A1 WO2008019309 A1 WO 2008019309A1 US 2007075159 W US2007075159 W US 2007075159W WO 2008019309 A1 WO2008019309 A1 WO 2008019309A1
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Prior art keywords
group
alkyl
compound
aryl
optionally substituted
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PCT/US2007/075159
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French (fr)
Inventor
Raja K. Reddy
Mark D. Erion
Qun Dang
Original Assignee
Metabasis Therapeutics, Inc.
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Publication of WO2008019309A1 publication Critical patent/WO2008019309A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention is directed towards novel nucleoside analogs, including deazapurine nucleoside analogs that are potent inhibitors of fructose 1,6-bisphosphatase (FBPase).
  • FBPase fructose 1,6-bisphosphatase
  • the invention is directed toward phosphonic acids and prodrugs thereof.
  • the present invention is directed to the preparation and the clinical use of these FBPase inhibitors as a method of treatment or prevention of diseases responsive to inhibition of gluconeogenesis and in diseases responsive to lower blood glucose levels.
  • the compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as metabolic disordersincluding hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.
  • Diabetes mellitus is one of the most prevalent diseases in the world today. Diabetic patients have been divided into two classes, namely type 1 and type 2 diabetes. Type 2 accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in the U. S. alone (6.6% of the population). Type 2 diabetes is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels. Type 2 diabetes is associated with a variety of long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models demonstrate a causal relationship between long term hyperglycemia and complications.
  • Gluconeogenesis from pyruvate and other 3-carbon precursors is a highly regulated biosynthetic pathway requiring eleven enzymes. Seven enzymes catalyze reversible reactions and are common to both gluconeogenesis and glycolysis. Four enzymes catalyze reactions unique to gluconeogenesis, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose- 1,6-bisphosphatase and glucose-6-phosphatase. Overall flux through the pathway is controlled by the specific activities of these enzymes, the enzymes that catalyzed the corresponding steps in the glycolytic direction, and by substrate availability.
  • Dietary factors (glucose, fat) and hormones (insulin, glucagon, glucocorticoids, epinephrine) coordinatively regulate enzyme activities in the gluconeogenesis and glycolysis pathways through gene expression and post-translational mechanisms.
  • nucleosides can lower blood glucose in the whole animal through inhibition of FBPase. These compounds exert their activity by first undergoing phosphorylation to the corresponding monophosphate (EP 0427 799 Bl).
  • Patent 6,054,587 described novel indole and azaindole compounds containing a phosphonate group that are inhibitors of FBPase. Dang et al., U.S. Patent 6,284,748, described novel purine compounds containing a phosphonate group that are inhibitors of FBPase. Bookser et al., U.S. Patent 6,919,322, described novel aryl phosphonate compounds that are inhibitors of FBPase. Kasibhatla, et al., U.S. Patnent No. 6,399,782, described benzimidazole compounds containing a phosphonate group that are inhibitors of FBPase.
  • the present invention relates to compounds and pharmaceutical compositions of Formula I-III and IX-XIII, including pharmaceutically acceptable salts, co-crystals and prodrugs thereof.
  • Acyl refers to -C(O)R S where R s is alkyl, heterocycloalkyl, or aryl.
  • Acylalkyl refers to an alkyl-C(O)-alk-, wherein “alk” is alkylene.
  • Acylamino refers to and R W C(O)-NR W -, wherein R w is -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Acyloxy refers to the ester group -0-C(O)R 1 , where R 1 is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
  • Alicyclic refers to a cyclic group or compound which combines the properties of aliphatic and cyclic compounds and include cycloalkyl and bridged cycloalkyl compounds.
  • the cyclic compound includes heterocycles. Cyclohexenylethyl, cyclohexanylethyl, and norbornyl are suitable alicyclic groups. Such groups may be optionally substituted.
  • Alkanoyl refers to the group alkyl-C(O)-.
  • Alkenyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups included alkenylene and alkynylene. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1-alkenyl” refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, it is attached at the first carbon.
  • Alkylaminoalkyl- refers to the group -alk-NR u -alk- wherein “alk” is alkylene, and R u is H or lower alkyl.
  • Lower alkylaminoalkyl- refers to groups where the alkyl and the alkylene group are lower alkyl and alkylene, respectively.
  • Alkylaminoalkylcarboxy refers to the group alkyl-NR u -alk-C(O)-O- where "alk” is an alkylene group, and R u is a H or lower alkyl.
  • Alk is an alkylene group
  • R u is a H or lower alkyl.
  • Alkylaminoaryl- refers to the group alkyl-NR vl -aryl- wherein “aryl” is a divalent group and R v! is -H, alkyl, aralkyl, or heterocycloalkyl. In “lower alkylaminoaryl-", the alkyl group is lower alkyl.
  • Alkylaminocarbonyl refers to the group alk-NR-C(O)- where R is a H or lower alkyl, and "alk” is an alkyl group. "-Alkylaminocarbonyl-” refers to same group, except when “alk” is alkylene. When X is - alkylaminocarbonyl- the alkyl portion is attached to M and the carbonyl portion to Gg.
  • alkylcarbonylamino- refers to the group -alk-C(O)-NR- where "alk” is an alkylene group, and R is a H or lower alkyl.
  • alk is an alkylene group
  • R is a H or lower alkyl.
  • Alkoxy- or alkyloxy- refers to the group alkyl-O.
  • -Alkoxy- or -alkyloxy- refers to the group -alkylene-O-.
  • X is -alkoxy- or - alkyloxy-, the alkyl portion is attached to M.
  • Alkoxyalkyl- or “alkyloxyalkyl-” refers to the group alkyl-O-alk- wherein “alk” is an alkylene group.
  • X is -alkoxyalkyl-" or “-alkyloxyalkyl-” then the terms refer to -alk-O-alk- wherein “alk” is an alkylene group.
  • lower alkoxyalkyl- each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • Alkoxyaryl- refers to an aryl group substituted with an alkyloxy group. In “lower alkyloxyaryl-”, the alkyl group is lower alkyl.
  • Alkoxycarbonyloxy- refers to alky 1-0-C(O)-O-.
  • Alkyl refers to a straight or branched chain or cyclic chain hydrocarbon radical with only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted. Alkyl groups are Ci-C 12 .
  • Alkylaryl- refers to alkyl-arylene-.
  • -Alkylaryl- refers to -alkylene- arylene-.
  • X alkylaryl
  • the alkylene is attached to M and the arylene is attached to G 8 .
  • “Lower alkylaryl-” refers to such groups where alkyl is lower alkyl.
  • Alkylene-aryl- refers to a divalent aklylene substituted aryl group, with one valency on the aryl group and one valency on the alkylene group.
  • Lower alkylaryl- refers to such groups where alkyl is lower alkyl.
  • Alkylene refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene chain contains up to and including 6 atoms. In a further aspect the alkylene groups contains up to and including 4 atoms. The alkylene group can be either straight, branched chain or cyclic.
  • Alkylthio- refers to the group alkyl-S- and -alkylthio- refers to - alkylene-S-.
  • X is -alkylthio-, the alkyl group is attached to M.
  • Alkylthioalkyl- refers to the group alkyl-S-alk- wherein “alk” is an alkylene group.
  • -Alkylthioalkyl- refers to -alkylene-S-alkylene-.
  • lower alkylthioalkyl- each alkyl and alkylene is lower alkyl and alkylene, respectively.
  • Alkylthiocarbonyloxy- refers to alkyl-S-C(O)-O-.
  • Alkynyl refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1 -alkynyl” refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
  • Amino refers to -NR xl R xl wherein each R xl is independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H aarree ooppttiionally substituted, or wherein both R xl together form a cyclic ring system.
  • Aminocarbonylamino refers to - NR ⁇ C(O)-NR'-, where R' is selected from a bond, -H, alkyl, aryl, aralkyl, and heterocycloalkyl
  • Aminoalkyl refers to the group NRVaIk- wherein “alk” is an alkylene group and R* is selected from a bond, -H, alkyl, aryl, aralkyl, and heterocycloalkyl .
  • aminocarboxamidoalkyl refers to the group
  • Animal includes birds and mammals, in one embodiment a mammal, including a dog, cat, cow, horse, goat, sheep, pig or human. In one embodiment the animal is a human. In another embodiment the animal is a male. In another embodiment the animal is a female.
  • Alkyl refers to aryl -alkylene-. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. "-Aralkyl-” refers to -arylene-alkylene-. When X is aralkyl, the arylene is attached to M and the alkylene is attached to G 8 .
  • Alkyloxyalkyl- refers to the group aryl-alk-O-alk- wherein “alk” is an alkylene group. "Lower aralkyloxyalkyl-” refers to such groups where the alkylene groups are lower alkylene.
  • Aroyl refers to the group aryl-C(O)-.
  • Aryl refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl, bicylic aryl (e.g., naphthyl) and biaryl groups (e.g., biphenyl), all of which may be optionally substituted.
  • Arylamino refers to the group aryl-NH-.
  • Alkylamino refers to the group -NR-alk- wherein “alk” is alkylene and R is a H or lower alkyl. When X is alkylamino, the alkylene group is attached to M and the amino group to G 8 .
  • Alk refers to the group -NR-alk-aryl wherein “alk” is alkylene.
  • Arylene refers to divalent aromatic ring systems which have 5-14 atoms and at least one ring having a conjugated pi electron system and includes carbocyclic arylene, heterocyclic arylene and biarylene groups, all of which may be optionally substituted.
  • Arylaminoalkyl- refers to the group aryl-N(R w )-alk- wherein “alk” is an alkylene group and R w is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • R w is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • the alkylene group is lower alkylene.
  • Aryloxy refers to aryl-O-.
  • Aryloxyalkyl- refers to an alkyl group substituted with an aryloxy group.
  • Aryloxycarbonyl refers to the group aryl-O-C(O)-.
  • Aryloxycarbonyloxy- refers to ary 1-0-C(O)-O-.
  • Atherosclerosis refers to a condition characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries wherein such deposits provoke fibrosis and calcification. Atherosclerosis raises the risk of angina, stroke, heart attack, or other cardiac or cardiovascular conditions.
  • Biaryl represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
  • Binding means the specific association of the compound of interest to the target of interest, .e.g., a receptor.
  • C 2 - 6 -perfluoroalkyl refers to a 2 to 6 carbon alkyl group where all of the carbon atoms are exhaustively substituted with fluorine.
  • Non limiting examples include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, pentafluorocyclopropyl, and the like.
  • C 4 _ 8 -cycloalkenyl refers to a non-aromatic, carbocyclic group having 4 to 8 carbon atoms and containing at least one double bond.
  • C 3 _ 8 -cycloalkyloxy refers to -O-C ⁇ g-cycloalkyl where Cv 8 - cycloalkyl is an aliphatic carbocyclic group having 3 to 8 carbon atoms
  • C 3 - 8 -cycloalkylthio refers to -S-C 3 -g-cycloalkyl where Cv 8 - cycloalkyl is a 3 to 8 aliphatic carbocyclic group having 3 to 8 carbon atoms
  • Carboxylamido or “carboxamido” refer to NR W 2 -C(0)-, wherein each R w include -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carboxamidoalkylaryl refers to NR w 2 -C(O)-alk-aryl- where “alk” is alkyl and R w includes H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carboxamidoaryl refers to NR w -C(O)-aryl- wherein “alk” is alkylene and R w include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
  • Carbocyclic aryl groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
  • Carbonylalkyl refers to -C(O)-alk-, where “alk” is alkylene.
  • X is carbonylalkyl
  • the carbonyl is attached to M and the alkylene is attached to G 8 .
  • Carboxy esters refers to -C(O)OR Z where R z is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, each optionally substituted.
  • Carboxyl refers to -C(O)OH.
  • Cyclic alkyl or “cycloalkyl” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and, in one aspect, are 3 to 6 carbon atoms.
  • the cycloalkyl groups include fused cyclic, bridged cyclic and spirocyclic groups.
  • cyclic alkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalin, bicycle[3.1.1]heptane, bycyclo[2.2.1]heptane, bycyclo[2.2.2]octane, bicycle[3.2.2]nonane, spiro[2.5]octane, spiro[3.5]nonane, adamantyl and the like. Such groups may be substituted.
  • Cycloalkyloxy refers to the group cycloalkyl-O-.
  • Cycloalkylalkoxy refers to the group cycloalkyl-alkyl-O-.
  • Co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature that are H-bonded.
  • Coronary heart disease or “coronary disease” refers to an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. "Diabetes” refers to a heterogeneous group of disorders that share glucose intolerance in common.
  • Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision.
  • the vast majority of cases of diabetes fall into two broad etiopathogenetic categories.
  • type 1 diabetes the cause is an absolute deficiency of insulin secretion.
  • Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers.
  • type 2 diabetes the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response.
  • a degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected.
  • this asymptomatic period it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load.
  • Criteria for the diagnosis of diabetes include: 1. Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl (11.1 mmol/1). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss; or
  • FPG 126 mg/dl (7.0 mmol/1). Fasting is defined as no caloric intake for at least 8 h; or
  • Etiologic classification of diabetes mellitus are as follows:
  • Type 1 diabetes ⁇ -cell destruction, usually leading to absolute insulin deficiency
  • Type 2 diabetes may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance
  • III Other specific types
  • GDM Gestational diabetes mellitus
  • Energy expenditure means basal or resting metabolic rate as defined by Schoeller et al, J Appl Physiol. ;53(4):955-9 (1982). Increases in the resting metabolic rate can be also be measured using increases in O 2 consumption and/or CO 2 efflux and/or increases in organ or body temperature.
  • Enhanced oral bioavailability refers to an increase of at least 50% of the absorption of the dose of the parent drug, unless otherwise specified. In an additional aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100% (at least a doubling of the absorption). Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drag metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following systemic administration of the compound administered orally.
  • “Enhancing” refers to increasing or improving a specific property.
  • the term “perhalo” refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include -CF3 and -CFCI 2 .
  • Haloalkyl refers to an alkyl group substituted with one halo (halogen group).
  • Halogen or "halo” refers to -F, -Cl, -Br and -I.
  • Heteroalicyclic refers to an alicyclic group or compound having 1 to 4 heteroatoms selected from nitrogen, sulfur, phosphorus and oxygen.
  • Heteroarylalkyl refers to an alkylene group substituted with a heteroaryl group.
  • Heteroarylene refers to a divalent, aromatic, heterocyclic ring containing 5-14 ring atoms wherein 1 to 4 heteroatoms in the aromatic ring are ring atoms and the remainder of the ring atoms being carbon atoms.
  • Heteroarylene refers to a divalent heterocyclic aryl or heteroaryl group.
  • Heterocyclic or “heterocyclyl” refer to cyclic groups of 3 to 10 atoms or cyclic groups of 3 to 6 atoms. These groups contain at least one heteroatom, and in some aspects contain 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or carbon atom in the ring. Heterocyclic and heterocyclyl cyclic groups include, e.g., heterocyclic alkyl or heterocycloalkyl groups. The heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
  • Heterocyclic aryl or “heteroaryl groups” are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, and the like, all optionally substituted.
  • Hydroalkyl refers to an alkyl group substituted with one -OH.
  • “Hypercholesterolemia” refers to presence of an abnormally large amount of cholesterol in the cells and plasma of the circulating blood.
  • Hyperinsulinemia refers to a patient with a fasting serum insulin concentration of at least 12 uU/mL.
  • Hydrolipemia refers to the presence of an abnormally large amount of lipids in the circulating blood.
  • Insulin resistance is defined clinically as the impaired ability of a known quantity of exogenous or endogenous insulin to increase whole body glucose uptake and utilization.
  • IGT Internet glucose tolerance
  • IGT refers to a condition known to precede the development of overt Type 2 diabetes. It is characterized by abnormal blood glucose excursions following a meal. The current criteria for the diagnosis of IGT are based on 2-h plasma glucose levels post a 75g oral glucose test (144-199 mg/dL). Although variable from population to population studied, IGT progresses to full-blown NIDDM at a rate of 1.5 to 7.3% per year, with a mean of 3-4% per year. Individuals with IGT are believed to have a 6 to 10-fold increased risk in developing Type 2 diabetes. IGT is an independent risk factor for the development of cardiovascular disease.
  • “Increased or enhanced liver specificity” refers to an increase in the liver specificity ratio in animals treated with a compound of the present invention and a control compound.
  • One aspect of this invention provides organic radicals or compounds as containing up to and including 6 carbon atoms.
  • Yet another aspect of the invention provides organic radicals or compounds that contain one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
  • Liver refers to the liver organ.
  • Liver specificity refers to the ratio:
  • the ratio can be determined by measuring tissue levels at a specific time or may represent an AUC based on values measured at three or more time points.
  • Methodabolic disease includes diseases and conditions such as obesity, diabetes and lipid disorders such as hypercholesterolemia, hyperlipidemia, hypertriglyceridemia as well as disorders that are associated with abnormal levels of lipoproteins, lipids, carbohydrates and insulin such as metabolic syndrome X, diabetes, impaired glucose tolerance, atherosclerosis, coronary heart disease, cardiovascular disease.
  • lipid disorders such as hypercholesterolemia, hyperlipidemia, hypertriglyceridemia as well as disorders that are associated with abnormal levels of lipoproteins, lipids, carbohydrates and insulin such as metabolic syndrome X, diabetes, impaired glucose tolerance, atherosclerosis, coronary heart disease, cardiovascular disease.
  • Methods or “Metabolic Syndrome X” to a condition identified by the presence of three or more of these components:
  • Obsity refers to the condition of being obese. Being obese is defined as a BMI of 30.0 or greater; and extreme obesity is defined at a BMI of 40 or greater.
  • “Overweight” is defined as a body mass index of 25.0 to 29.9.
  • Perhalo refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group.
  • Non-linking examples of perhaloalkyl groups include -CF 3 and -CFCl 2 .
  • “Pharmaceutically acceptable salt” includes salts of compounds of the invention derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include acetic acid, adipic acid, benzenesulfonic acid,
  • Patient means an animal. In one embodiement a patient is a mammal. In one embodiment a patient is a human.
  • Preventing includes a slowing of the progress or development of a disease before onset or precluding onset of a disease.
  • Prodrug refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each.
  • Standard prodrugs are formed using groups attached to functionality, e.g., HO-, HS-, HOOC-, .NHR, associated with the drug, that cleave in vivo.
  • Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • the groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of the invention, fall within this scope. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
  • the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc.
  • Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
  • Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992.
  • “Significant” or “statistically significant” means a result (i.e. experimental assay result) where the p-value is ⁇ 0.05 (i.e. the chance of a type I error is less than 5%) as determined by an art-accepted measure of statistical significance appropriate to the experimental design.
  • Substituted or “optionally substituted” includes groups substituted by one to six substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower -carboxamidoalkylaryl, lower -carboxamido
  • Substituted aryl and “substituted heteroaryl” refers to aryl and heteroaryl groups substituted with 1-3 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.
  • “Sulphonate” or “sulfonate” refers to -SO 2 OR", where R w is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
  • “Sulphonyl” or “sulfonyl” refers to -SO 2 R W , where R w is alkyl, aryl, aralkyl, or heterocycloalkyl.
  • “Therapeutically effective amount” means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.
  • Treating" or “treatment” of a disease includes a slowing of the progress or development of a disease after onset or actually reversing some or all of the disease affects. Treatment also includes palliative treatment.
  • Type 1 diabetes (formerly known as “childhood,” “juvenile,” “insulin-dependent” diabetes) is a form of diabetes characterized by an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. Type 1 diabetes may be caused by immune mediated beta-cell destruction, usually leading to absolute insulin deficiency or may be idiopathic, having no known etiologies.
  • Type 2 diabetes refers to a heterogeneous disorder characterized by impaired insulin secretion by the pancreas and insulin resistance in tissues such as the liver, muscle and adipose tissue.
  • the manifestations of the disease include one or more of the following: impaired glucose tolerance, fasting hyperglycemia, glycosuria, decreased levels of insulin, increased levels of glucagon, increased hepatic glucose output, reduced hepatic glucose uptake and glycogen storage, reduced whole body glucose uptake and utilization, dyslipidemia, fatty liver, ketoacidosis, microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease.
  • Phosphonate, phosphonic acid monoester and phosphinate prodrug refers to compounds that break down chemically or enzymatically to a phosphonic acid or phosphinc acid group in vivo.
  • the term includes, but is not limited to, the following groups and combinations of these groups:
  • acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).
  • alkyloxycarbonyloxymethyl esters as shown in formula A, where R a is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino; each R c is independently -H, alkyl, aryl, alkylaryl, or heterocycloalkyl have been studied in the area of ⁇ -lactam antibiotics (Nishimura et al., J. Antibiotics, 40(1): 81-90 (1987); for a review see Ferres, H., Drugs of Today, 19: 499 (1983)). More recently Cathy, M. S., et al.
  • R a and R c are independently H, alkyl, aryl, alkylaryl, and alicyclic; (see WO 90/08155; WO 90/10636) and R b , for e.g., is selected from -OH, -CH 3 , -H, -0-CH 3 or monoester prodrug moiety.
  • acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed such as shown in formula B. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).
  • R d is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl.
  • Aryl esters have also been used as phosphonate prodrugs (e.g., DeLambert et al., J. Med. Chem. 37(7): 498-511 (1994); Serafinowska et al., J. Med. Chem. 38(8): 1372-9 (1995). Phenyl as well as mono and poly- substituted phenyl proesters have generated the parent phosphonic acid in studies conducted in animals and in man (Formula C). Another approach has been described where R e is a carboxylic ester ortho to the phosphate (Khamnei et al., J. Med. Chem. 39: 4109-15 (1996)).
  • R e is -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, or heterocycloalkyl and R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety.
  • Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using substituents at the para-position can accelerate the hydrolysis.
  • R and R 8 are independently -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; R is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety, as described therein.
  • R h and R 1 are independently -H, alkyl, aryl, alkylaryl, halogen, or cyclic alkyl.
  • Thio-containing phosphonate proesters may also be useful in the delivery of drugs to hepatocytes. These proesters contain a protected thioethyl moiety as shown in formula E. One or more of the oxygens of the phosphonate can be esterified. Since the mechanism that results in de- esterification requires the generation of a free thiolate, a variety of thiol protecting groups are possible. For example, the disulfide is reduced by a reductase-mediated process (Puech et al., Antiviral Res. 22: 155-174 (1993)). Thioesters will also generate free thiolates after esterase-mediated hydrolysis Benzaria, et al., J. Med. Chem., 39(25): 4958-65 (1996)). Cyclic analogs are also possible and were shown to liberate phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below has not been previously described and is novel.
  • R J is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio and R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety.
  • prodrugs include proester classes exemplified by Biller and Magnin (U.S. 5,157,027); Serafinowska et al., J. Med. Chem,. 38(8): 1372-9 (1995); Starrett et al., J. Med. Chem, 37: 1857 (1994); Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59: 1853 (1994); and EP 0 632048 Al.
  • R m is -H, alkyl, cycloalkyl, or heterocycloalkyl
  • R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH 3 or monoester prodrug moiety
  • R k is - H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, heterocycloalkyl, or alkoxy carbonyl.
  • the prodrugs of Formula E6 are an example of "optionally substituted heterocycloalkyl where the cyclic moiety contains a carbonate or thiocarbonate.”
  • Propyl phosphonate proesters can also be used to deliver drugs into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in formula F2.
  • the R n and R p groups can form a cyclic ring system as shown in formula F2.
  • One or more of the oxygens of the phosphonate can be esterified.
  • R n is alkyl, aryl, or heteroaryl
  • R p is alkylcarbonyloxy, or alkyloxycarbonyloxy
  • R b is selected, for e.g., from -OH, -CH 3 , -H, -O-CH3 or monoester prodrug moiety ;
  • R q is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, or amino.
  • Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g., McGuigan et al., J. Med. Chem., 42: 393 (1999) and references cited therein) as shown in Formula G and H, wherein R r , for example.is lower alkyl, lower aryl, lower aralkyl, and as described therein..
  • Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates (e.g., Starrett et al., J. Med. Chem., 37: 1857 (1994)).
  • prodrugs are possible based on literature reports such as substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al., Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al., Bioorg. Med. Chem. Lett. 7:99-104 (1997).
  • V and W defined herein
  • cyclic phosphonate ester of 1,3-propane diol refers to the following:
  • the structure shown above (left) has an additional 3 carbon atoms that forms a five member cyclic group. Such cyclic groups must possess the listed substitution to be oxidized.
  • the structure above has an acyloxy substituent that is three carbon atoms from a Y, and an optional substituent, -CH 3 , on the new 6-membered ring.
  • the phrase "together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl” includes the following:
  • V aryl, and a spiro-fused cyclopropyl group for W and W.
  • cyclic phosphon(amid)ate refers to:
  • trans stereochemistry for the same moiety refers to the spatial relationship of the V group and the carbon, attached to the phosphorus atom, on the six-membered ring.
  • the formula below shows a trans- stereochemistry.
  • R-configuration refers to the absolute configuration R of carbon C .
  • R-isomer refers to the absolute configuration R of carbon C .
  • R-prodrug refers to the absolute configuration R of carbon C .
  • the formula below shows the R-stereochemistry.
  • percent enantiomeric excess refers to optical purity. It is obtained by using the following formula:
  • enantioenriched or “enantiomerically enriched” refers to a sample of a chiral compound that consists of more of one enantiomer than the other. The extent to which a sample is enantiomerically enriched is quantitated by the enantiomeric ratio or the enantiomeric excess.
  • the present invention relates to compounds of general Formulas I- III and IX-XIII and pharmaceutically acceptable salts, co-crystals and prodrugs thereof, and methods of making and using the same.
  • One aspect of the present invention provides for compounds of general Formulas I-III:
  • Gi, G 2 , G 3 , G 6 , G 7 and G 9 are each independently selected from the group consisting of C and N;
  • A is selected from the group consisting of absent, -H, -NR 8 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -SO 2 R 9 , guanidine, -C(NH)NR 5 2 , - NHSO 2 R 20 , -SO 2 NR 5 2 , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Q-Csalkyl, C ⁇ Csalkenyl, C 2 -C 5 alkynyl, and lower alicyclic;
  • L is selected from the group consisting of absent, -H, -NR 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -SO 2 R 9 , guanidine, -C(NH)NR 5 2 , - NHSO 2 R 20 , -SO 2 NR 5 2 , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-Csalkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, and lower alicyclic; or together A and L form a cyclic group;
  • E is selected from the group consisting of absent, -H, -NR 8 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -SO 2 R 9 , guanidine, -C(NH)NR 5 2 , - NHSO 2 R 20 , -SO 2 NR 5 2 , -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-Csalkyl, C 2 -Csalkenyl, C 2 -Csalkynyl, and lower alicyclic; or together E and J form a cyclic group; or
  • J is selected from the group consisting of absent, -H, -NR 2 , -NO 2 , - OR 7 , -SR 7 , -C(O)NR 5 2 , halo, -C(O)R 11 , -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl; or together J and D form a cyclic group;
  • D is selected from the group consisting of absent, -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R 9 , -S(O) 2 R 9 , -C(O)R 11 ,-C(O)-OR 9 , -CONHR 9 , -NR 2 2 , and -OR 9 , each, except H, optionally substituted; or together D and X form a cyclic group;
  • X is selected from the group consisting of -alkylamino-, - alkylene(hydroxy)-, -alkylene(carboxyl)-, -alkylene(phosphonate)-, -alkylene-, -alkenylene-, -alkynylene-, -alkylene(sulfonate)-, -arylene-, -carbonylalkyl-, - (l,l-dihalo)alkylene-, -aminocarbonylamino-, -alkylaminoalkyl-, - alkoxyalkyl-, -alkylthioalkyl-, -alkylthio-, - alkylaminocarbonyl -, - alkylcarbonylamino-, -alicyclic-, -aralkyl-, and -alkylaryl-, each optionally substituted; or together X and D form a cyclic group; M is -P
  • Y and Y' are each independently selected from the group consisting of -0-, and -NR V -; when Y and Y' are both -0-, R 21 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R 52 ) 2 OC(O)NR 52 2 , -NR 52 -C(O)-R 53 , -C(R 52 ) 2 -OC(O)R 5 ⁇ -C(R 52 ) 2 -O-C(O)OR 53 , -C(R 52 ) 2 OC(O)S R 53 , -alkyl-S-C(O)R 53 , -alkyl-S-S-alkyl
  • R 21 attached to -NR V - is independently selected from the group consisting of -H, -[C(R 52 ) 2 ] P -COOR 53 , -C(R X ) 2 COOR 53 , -[C(R 52 ) 2 ] P -C(O)SR 53 , and -cycloalkylene-COOR 53 ; wherein if both R 21 are alkyl, at least one is higher alkyl; or when Y and Y' are independently selected from -O- and -NR V -, then R 21 and R 21 together form a cyclic group comprising -alkyl-S-S-alkyl-, or R 21 and R 21 together are the group:
  • V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; and
  • Z is selected from the group consisting of - CHR 52 OH, -CHR 52 OC(O)R 53 ,
  • W and W are as defined above and together V and Z are connected via (a) an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon, optionally substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus, or (b) an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, wherein said cyclic group is fused to an aryl group at the beta and gamma position to a Y or Y that is attached to the phosphorus; or
  • W and Z are as defined above and together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon ring atoms optionally substituted with one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy, said substituent attached to one of said carbon ring atoms that is three atoms from a Y or Y' that is attached to the phosphorus; or
  • W is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon; or
  • Z is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together W and W are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining ring atoms are carbon;
  • R 52 is selected from the group consisting of R 53 and -H;
  • R 53 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
  • R x is independently selected from the group consisting of -H, and alkyl, or together R x and R x form a cycloalkyl group;
  • R v is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; p is an integer 2 or 3;
  • R is selected from the group consisting of R and -H;
  • R is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
  • R is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and -C(O)R 10 ;
  • R 8 is selected from the group consisting of -H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R 10 , or together they form a bidentate alkyl;
  • R 9 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
  • R is selected from the group consisting of -H, lower alkyl, -NH 2 , lower aryl, and lower perhaloalkyl;
  • R is selected from the group consisting of alkyl, aryl, -OH, -NH 2 and
  • R 2 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; wherein, a) V, Z, W, W are not all -H, b) when Z is -R 52 , then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl, and, c) said compound of Formula I-III is not a compound of Formulas IV-VIII as represented by
  • Formula VIII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof.
  • the present invention provides for compounds of Formulas IX or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula IX, wherein the substituents (Gi-G ⁇ , G7-G9, L, E, J, D, X and M) are as defined above; B is C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 - C 5 alkynyl, lower alicyclic or aralkyl; and, X " is Cl “ or Br " :
  • the present invention provides for compounds of Formula X or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula X, wherein the substituents (G7-G9, L, E, J, D, X and M) are as defined above:
  • the present invention provides for compounds of Formula XI or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XI, wherein the substituents (Gi, G 2 , Ge 5 G 7 -Gg, A, L, E, D, X and M) are as defined above; B is C r C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, lower alicyclic or aralkyl; and, X " is Cl " or Br "
  • the present invention provides for compounds of Formula XII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XII, wherein the substituents (Gi, G 2 , G 6 , G 7 -G9, A, L, E, D, X and M) are as defined above.
  • the present invention provides for compounds of Formula XIII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XIII, wherein the substituents (G7-G 9 , A, L, E,D, X and M) are as defined above:
  • A, L, and E are independently selected from the group consisting of absent-H, -NR 2 , -NO 2 , hydroxy, alkylaminocarbonyl, halogen, - OR 7 , -SR 7 , lower perhaloalkyl, and C)-C 5 alkyl.
  • L and E are independently selected from the group consisting of absent -NR 8 2 , -H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower alkyl.
  • A is selected from the group consisting of absent - NR 8 2 , -H, halogen, lower perhaloalkyl, and lower alkyl.
  • L and E are independently selected from the group consisting of absent -H, lower alkoxy, lower alkyl, and halogen.
  • J is selected from the group consisting of absent -H, halogen, lower alkyl, lower hydroxylalkyl, -NR 8 2 , lower R 8 2 N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic.
  • J is selected from the group consisting of absent -H, halogen, and lower alkyl-, lower hydroxyalkyl-, -NR 8 2 , lower R 8 2 N-alkyl-, lower haloalkyl, lower alkenyl, alicyclic, and aryl.
  • J is selected from the group consisting of alicyclic and lower alkyl.
  • a and L together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • L and E together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • E and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • D and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • D and X together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
  • X is selected from the group consisting of -alkylene-, -alkynylene-, -arylene-, -alkoxyalkyl-, -alkylthio-, -alkylaminocarbonyl-, - alkylcarbonylamino-, -(l,l-dihalo)alkylene, -carbonylalkyl-, -alkylene(OH)-, and -alkylene(sulfonate)-.
  • X is selected from the group consisting of - heteroarylene-, -alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, - alkylene(sulfonate)-, and -alkoxyalkyl-.
  • X is selected from the group consisting of - heteroarylene-, -alkylaminocarbonyl-, and -alkoxyalkyl-.
  • X is selected from the group consisting of - methylaminocarbonyl-, - methoxymethyl-, and furan-2,5-diyl.
  • X is not substituted with a phosphonic acid or ester.
  • X when X is -arylene- or -alkylaryl-, X does not link Gs and M through position 1 and 4 a 6-membered aromatic ring.
  • X is Furan-2,5-diyl, Pyridin-2,6-diyl, Oxazol-2,5- diyl, -C(O)-OCH2-, -C(O)-NHCH2-, -C(O)-SOE-, -C(0)-N(Me)CH2-, - NHC(0)-CH2-, -CH2 ⁇ CH2-, wherein the direction of X is from G 8 to M.
  • R 20 and R 7 are independently selected from the group consisting of -H, and lower alkyl.
  • L, and E are independently selected from the group consisting of absent -H, lower alkyl, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and -NR 8 2 ;
  • X is selected from the group consisting of - arylene-, -alkoxyalkyl-, -alkylene-, -alkylthio-, -(l,l-dihalo)alkylene-, - carbonyl-, -alkylene-, -alkylene(hydroxy)-, -alkylene(sulfonate)-, - alkylaminocarbonyl-, and -alkylcarbonylamino-; and each R 5 and R 7 is independently -H, or lower alkyl.
  • L, and E are independently selected from the group consisting of absent -H, lower alkyl, halogen, and -NR 8 2 ;
  • J is selected from the group consisting of -H, halogen, haloalkyl, hydroxyalkyl, R 2 N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic, or together with D forms a cyclic group;
  • X is selected from the group consisting of -heteroarylene-, - alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, and -alkoxyalkyl-.
  • A is selected from the group consisting of -H, -NH 2 , - F, and -CH 3 ;
  • L is selected from the group consisting of -H, -F, -OCH 3 , -Cl, and -CH 3 ;
  • E is selected from the group consisting of -H and -Cl;
  • J is selected from the group consisting of -H, halo, C 1 -C 5 hydroxyalkyl, C1-C5 haloalkyl, R 8 2 N- Ci-Csalkyl, Q-Csalicyclic, and Q-Csalkyl;
  • X is selected from the group consisting Of -CH 2 OCHi- and furan-2,5-diyl; and, D is lower alkyl.
  • M is selected from the group consisting of -P(O)[-OCR 52 2 OC(O)R 53 ] 2 , -P(O)[-OCR 52 2 OC(O)OR"] 2 , -P(O)[-N(H)CR 52 2 C(O)OR 53 ] 2 , -P(O)[-N(H)CR 52 2 C(O)OR 53 ][-OR ⁇ ], -P(O) [-OCH(V)CH 2 CH 2 O-], -P(O)(OH)(OR 11 ), -P(O)(OR e )(OR e ), -P(O)[-OCR 52 2 OC(O)R 53 ](OR e ), -P(O)[-OCR 52 2 OC(O)OR 53 ](OR e ), and -P(O)[-N(H)CR 52 2 C(O)OR 53 ](OR e ); wherein:
  • V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl;
  • R e is selected from the group consisting of optionally substituted -C 1 -C 12 alkyl, optionally substituted -C 2 -Ci 2 alkenyl, optionally substituted -C 2 -Ci 2 alkynyl, optionally substituted -(CR 57 2 ) n aryl, optionally substituted -(CR 57 2 ) n cycloalkyl, and optionally substituted -(CR 57 2 ) n heterocycloalky 1 ; n is an integer from 1 to 3; each R 57 is independently selected from the group consisting of hydrogen, optionally substituted -Q-C 4 alkyl, halogen, optionally substituted -0-Ci-C 4 alkyl, -OCF 3 , optionally substituted -S-Ci-C 4 alkyl, -NR 58 R 59 , optionally substituted -C 2 -C 4 alkenyl, and optionally substituted -C 2 -C 4 alky
  • R 58 is selected from hydrogen and optionally substituted -Ci-C 4 alkyl; and, R 59 is selected from the group consisting of hydrogen and optionally substituted -Q-C 4 alkyl, optionally substituted -C(O)-Ci-C 4 alkyl and -C(O)H.
  • the asymmetric carbon of alpha-amino esters is of the L-configuration.
  • M is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCR 52 2 OC(O)R 53 ] 2 , -P(O)[-OCR 52 2 OC(O)OR 53 ] 2 , -P(O)[-N(H)CR 52 2C(O)OR"]2, -P(O)[-N(H)CR 52 2 C(O)OR 53 ][-OR ⁇ ], -P(O) [-OCH(V)CH 2 CH 2 O-], , -P(O)(OR e XOR e ), -P(O)[-OCR 52 2 OC(O)R 53 ](OR e ), -P(O)[-OCR 52 2 OC(O)OR 53 ](OR e ), -P(O)[-OCR 52 2 OC(O)OR 53 ](OR e ), -P(O)[-N(H)CR 52 2 C
  • M is selected from the group consisting of -PO 3 H 2 , -P(O)[-OCH 2 OC(O)-r-butyl] 2 , -P(O)[-OCH 2 OC(O)O-i-propyl] 2 , -P(O)[-N(H)CH(CH 3 )C(O)O CH 2 CH 3 ] 2 , -P(O)[-N(H)C(CH 3 ) 2 C(O)OCH 2 CH 3 ] 2 , -P(0)[-N(H)CH (CH 3 )C(O)OCH 2 CH 3 ][3,4-methylenedioxyphenyl], -P(O)[-N(H)C (CH 3 ) 2 C(O)OCH 2 CH 3 ] [3,4-methylenedioxyphenyl] , -P(0)[-0CH (3-chlorophenyl)CH 2 CH 2 O-], -P(O)[-OCH 2 CH
  • M is selected from wherein Y and Y' are each independently selected from -O- and -NR V -; together R 2 ' and R 21 are the group:
  • V is substituted aryl or substituted heteroaryl.
  • Z is selected from hydrogen, W is hydrogen, and W is hydrogen.
  • V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl and 3,5-dichlorophenyl.
  • Another aspect provides for the use of a compound of the invention for the manufacture of a medicament for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which an FBPase inhibitor(s) is indicated.
  • Another aspect provides for the use of a compound of the invention for the manufacture of a medicament for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels, the method comprising the step of administering to a patient a therapeutically effective amount a compound of the invention, or a pharmaceutically acceptable salt or prodrugs thereof.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type I diabetes, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type II diabetes, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of impaired glucose tolerance, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of insulin resistance, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of hyperglycemia, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset of or reducing the risk for the development or progression accelerated gluconeogenesis, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for methods for treating, preventing, delaying the time to onset of or reducing the risk for the development or progression increased or excessive (greater than normal levels) hepatic glucose output, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
  • Another aspect provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically exceptable excipient.
  • compositions comprising a salt or co-crystal of a compound of Formula I-III or IX-XIII and a pharmaceutically exceptable excipient.
  • compounds of the invention are administered in a total daily dose of 0.01 to 2500 mg. In one aspect the range is about 1 mg to about 1000 mg. In one aspect the range is about 1 mg to about 500 mg. In one aspect the range is about 10 mg to about 500 mg.
  • the dose may be administered in as many divided doses as is convenient or necessary.
  • compounds of the invention are administered in a unit dose of a range between 0.01 to 1000 mg. In one aspect the range is about 0.1 mg to about 500 mg. In one aspect the range is about 0.1 mg to about 100 mg. In one aspect the range is about 1 mg to about 1000 mg. In one aspect the range is about 1 mg to about 500 mg. In one aspect the range is about 1 mg to about 100 mg. In one aspect the range is about 1 mg to about 10 mg. In one aspect the range is about 10 mg to about 1000 mg. In one aspect the range is about 10 mg to about 500 mg. In one aspect the range is about 10 mg to about 100 mg. In one aspect, the unit dose is 10 mg. In one aspect, the unit dose is 25 mg. In one aspect, the unit dose is 50 mg.
  • the unit dose is 75 mg. In one aspect, the unit dose is 100 mg. In one aspect, the unit dose is 150 mg. In one aspect, the unit dose is 200 mg. In one aspect, the unit dose is 250 mg. In one aspect, the unit dose is 300 mg. In one aspect, the unit dose is 400 mg. In one aspect, the unit dose is 500 mg. In one aspect, the unit dose is 600 mg. In one aspect, the unit dose is 700 mg. In one aspect, the unit dose is 800 mg. In one aspect, the unit dose is 900 mg. In one aspect, the unit dose is 1000 mg.
  • the compound is administered QD (once a day). In another aspect the compound is administered BID (twice a day). In another aspect the compound is administered TID (three times a day). In another aspect the compound is administered QID (four times a day). In one aspect the compound is administered before a meal. In one aspect the compound is administered after a meal. In one aspect the compound is administered in the morning hours. In one aspect the compound is administered upon awaking in the morning. In one aspect the compound is administered in the evening hours. In one aspect the compound is administered at bedtime in the evening. Compounds of this invention may be used in combination with other pharmaceutical agents. The compounds may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid).
  • Administration of the compound may occur at or near the time in which the other pharmaceutical agent is administered or at a different time.
  • the compounds of this invention may be used in a multidrug regimen, also known as combination or 'cocktail' therapy, wherein, multiple agents may be administered together, may be administered separately at the same time or at different intervals, or administered sequentially.
  • the compounds of this invention may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy by another agent in a treatment program.
  • the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters. Intravenous administration is generally preferred.
  • Pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucoranate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, subsalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • One aspect relates to the administration of a pharmaceutically acceptable composition of the present invention by controlled- or delayed-release means. Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts.
  • a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the crystalline forms of the invention. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598, 123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5, 639,476; 5,354,556; 5,733,566; and 6,365,185; each of which is incorporated herein by reference.
  • dosage forms can be used to provide delayed or controlled- release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS, Alza Corporation, Mountain View, Calif. USA), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • ion exchange materials can be used to prepare immobilized, adsorbed co-crystals and thus effect controlled delivery of the drug. Examples of specific anion exchangers include, but are not limited to, Duolite A568 and Duolite AP143 (Rohm & Haas, Spring House, PA, USA).
  • One aspect of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable composition comprising a crystalline form of a compound of the present invention and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition, medicament or dosage forms is formulated for controlled-release.
  • the dosage form utilizes an osmotic drug delivery system.
  • OROS osmotic drug delivery system
  • This technology can readily be adapted for the delivery of compounds and compositions of the invention.
  • Various aspects of the technology are disclosed in U.S. Pat. Nos. 6, 375, 978; 6,368,626 ; 6,342,249; 6,333,050; 6,287,295; 6, 283,953; 6,270,787; 6,245,357; and 6,132,420; each of which is incorporated herein by reference.
  • OROS that can be used to administer compounds and compositions of the invention
  • OROS include, but are not limited to, the OROS; Push- PuIl, Delayed Push-Pull, Multi-Layer Push- Pull, and Push-Stick Systems, all of which are well known. See, e.g., http://www. alza.com.
  • Additional OROS systems that can be used for the controlled oral delivery of compounds and compositions ofthe invention include OROS- CT and L-OROS (Id.; see also, Delivery Times, vol. II, issue II (Alza Corporation).
  • OROS oral dosage forms are made by compressing a drug powder (e.g. a crystalline form selected from Forms A-D) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser).
  • a drug powder e.g. a crystalline form selected from Forms A-D
  • Kim Cherug-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, PA: 2000).
  • the advantage of such dosage forms is that the delivery rate of the drug is not influenced by physiological or experimental conditions. Even a drug with a pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium. But because these advantages are provided by a build-up of osmotic pressure within the dosage form after administration, conventional OROS drug delivery systems cannot be used to effectively deliver drugs with low water solubility. Id. at 234.
  • a specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drug layer located within the cavity adjacent to the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer interposed between the inner surface of the wall and at least the external surface of the drag layer located within the cavity, wherein the drug layer comprises a crystalline form of a compound of the present invention. See U.S. Pat. No. 6,368,626, the entirety of which is incorporated herein by reference.
  • Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises a crystalline form of a compound of the present invention. See U. S. Pat. No. 6,342,249, the entirety of which is incorporated herein by reference.
  • a pharmaceutical composition or medicament comprising a crystalline form of a compound of the present invention is administered transdermally.
  • TD transdermal
  • a "pill-and-patch" strategy can be taken, where only a fraction of the daily dose is delivered through the skin to generate basal systemic levels, onto which oral therapy is added.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monoo
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachid oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of the invention when such compounds are susceptible to acid hydrolysis.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations suitable for parenteral administration may be administered in a continuous infusion manner via an indwelling pump or via a hospital bag.
  • Continuous infusion includes the infusion by an external pump.
  • the infusions may be done through a Hickman or PICC or any other suitable means of administering a formulation either parenterally or i.v.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
  • Synthesis of the compounds encompassed by the present invention typically includes some or all of the following general steps: (1) synthesis of the prodrug ; (2) phosphonate deprotection; (3) substitution of the heterocycle; (4) substitution or modification of 2-substituent; (5) cyclization to generate bicyclic base ring system; (6) synthesis of the linker-PO ⁇ ; and (7) synthesis of the monocyclic base precursor. A detailed discussion of each step is given below.
  • Prodrugs can be introduced at different stages of the synthesis. Most often these prodrugs are made from the phosphonic acids of compounds of the invention because of their lability.
  • Phosphonic acids of compounds of the invention can be alkylated with electrophiles such as alkyl halides and alkyl sulfonates under nucleophilic substitution conditions to give phosphonate esters.
  • compounds of invention wherein YR 21 is an acyloxyalkyl group can be prepared by direct alkylation of compounds of invention with an appropriate acyloxyalkyl halide (e.g., Cl, Br, I; Phosphorus Sulfur 54:143 (1990); Synthesis 62 (1988)) in the presence of a suitable base (e.g., pyridine, TEA, diisopropylethylamine) in suitable solvents such as DMF (J. Med. Chem. 37:1875 (1994)).
  • the carboxylate component of these acyloxyalkyl halides includes but is not limited to acetate, propionate, isobutyrate, pivalate, benzoate, carbonate and other carboxylates.
  • Dimethylformamide dialkyl acetals can also be used for the alkylation of phosphonic acids (Collect. Czech Chem. Comma. 59:1853 (1994)).
  • Compounds of invention wherein YR 21 is a cyclic carbonate, a lactone or a phthalidyl group can also be synthesized by direct alkylation of the free phosphonic acids with appropriate halides in the presence of a suitable base such as NaH or diisopropylethylamine (/. Med. Chem. 38:1372 (1995); J. Med. Chem. 57:1857 (1994); J. Pharm. ScL 76:180 (1987)).
  • these phosphonate prodrugs can be synthesized by the reactions of the corresponding dichlorophosphonates and an alcohol (Collect Czech Chem. Commun. 59:1853 (1994)).
  • a dichlorophosphonate is reacted with substituted phenols and arylalkyl alcohols in the presence of a base such as pyridine or TEA to give the compounds of of the invention wherein YR 21 is an aryl group (J. Med. Chem. 39:4109 (1996); J. Med. Chem. 38:1372 (1995); J. Med. Chem. 37:498 (1994)) or an arylalkyl group (J. Chem. Soc. Perkin Trans.
  • the disulfide-containing prodrugs can be prepared from a dichlorophosphonate and 2-hydroxyethyldisulfide under standard conditions. Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs.
  • treatment of a dichlorophosphonate with ammonia gives both a monophosphonamide and a diphosphonamide
  • treatment of a dichlorophosphonate with l-amino-3- propanol gives a cyclic 1 ,3-propylphosphonamide
  • treatment of a chlorophosphonate monophenyl ester with an amino acid ester in the presence of a suitable base gives a substituted monophenyl monophosphonamidate.
  • Such reactive dichlorophosphonates can be generated from the corresponding phosphonic acids with a chlorinating agent (e.g., thionyl chloride, J. Med. Chem. 1857 (1994); oxalyl chloride, Tetrahedron Lett. 37:3261 (1990); phosphorous pentachloride, Synthesis 490 (1974)).
  • a dichlorophosphonate can be generated from its corresponding disilyl phosphonate esters (Synth. Comma. 17:107 '1 (1987)) or dialkyl phosphonate esters (Tetrahedron Lett. 24:4405 (1983); Bull. Soc. CMm. 750:485 (1993)).
  • compounds of the invention can be mixed phosphonate ester (e.g., phenyl and benzyl esters, or phenyl and acyloxyalkyl esters) including the chemically combined mixed esters such as phenyl and benzyl combined prodrugs reported in Bioorg. Med. Chem. Lett. 7:99 (1997).
  • mixed phosphonate ester e.g., phenyl and benzyl esters, or phenyl and acyloxyalkyl esters
  • Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs.
  • a dichlorophosphonate with an amine e.g. an amino acid alkyl ester such as L- alanine ethyl ester
  • a suitable base e.g. triethylamine, pyridine, etc.
  • treatment of a dichlorophosphonate with l-amino-3-propanol gives a cyclic 1,3- propylphosphonamide
  • treatment of a chlorophosphonate monophenyl ester with an amino acid ester in the presence of a suitable base gives a substituted monophenyl monophosphonamidate.
  • the SATE (5-acetyl thioethyl) prodrugs can be synthesized by the coupling reaction of the phosphonic acids of compounds of the invention and S-acyl-2-thioethanol in the presence of DCC, EDCI or PyBOP (J. Med. Chem. 59:1981 (1996)).
  • Cyclic phosphonate esters of substituted 1 ,3-propane diols can be synthesized by either reactions of the corresponding dichlorophosphonate with a substituted 1,3-propanediol or coupling reactions using suitable coupling reagents (e.g., DCC, EDCI, PyBOP; Synthesis 62 (1988)).
  • the reactive dichlorophosphonate intermediates can be prepared from the corresponding acids and chlorinating agents such as thionyl chloride (J. Med. Chem. 1857 (1994)), oxalyl chloride (Tetrahedron Lett. 57:3261 (1990)) and phosphorus pentachloride (Synthesis 490 (1974)).
  • these dichlorophosphonates can also be generated from disilyl esters (Synth. Commun. 77:1071 (1987)) and dialkyl esters (Tetrahedron Lett. 24:4405 (1983); Bull. Soc. Chim. Fr., 750:485 (1993)).
  • these cyclic phosphonate esters of substituted 1,3- propane diols are prepared from phosphonic acids by coupling with diols under Mitsunobu reaction conditions (Synthesis 1 (1981); J.Org. Chem. 52:6331 (1992)), and other acid coupling reagents including, but not limited to, carbodiimides (Collect. Czech. Chem. Commun.
  • Phosphonic acids also undergo cyclic prodrug formation with cyclic acetals or cyclic ortho esters of substituted propane-l,3-diols to provide prodrugs as in the case of carboxylic acid esters (HeIv. Chim. Acta. 48:1746 (1965)).
  • cyclic sulfites or sulfates are also suitable coupling precursors to react with phosphonic acid salts. These precursors can be made from the corresponding diols as described in the literature.
  • cyclic phosphonate esters of substituted 1,3-propane diols can be synthesized by trans esterification reaction with substituted 1,3- propane diol under suitable conditions.
  • Mixed anhydrides of parent phosphonic acids generated in situ under appropriate conditions react with diols to give prodrugs as in the case of carboxylic acid esters (Bull. Chem. Soc. Jpn. 52:1989 (1979)).
  • Aryl esters of phosphonates are also known to undergo transesterification with alkoxy intermediates (Tetrahedron Lett. 38:2597 (1997); Synthesis 968 (1993)).
  • One aspect of the present invention provides methods to synthesize and isolate single isomers of prodrugs of phosphonic acids of compounds of the invention. Because phosphorus is a stereogenic atom, formation of a prodrug with a substituted- 1,3-propane-diol will produce a mixture of isomers. For example, formation of a prodrug with a racemic l-(V)-substituted- 1,3-propane diol gives a racemic mixture of cis-prodrugs and a racemic mixture of trans- prodrags.
  • the use of the enantioenriched substituted- 1,3- propane diol with the R-configuration gives enantioenriched R-cis-and R- trans-prodrugs.
  • These compounds can be separated by a combination of column chromatography and/or fractional crystallization.
  • YR 21 can also be introduced at an early stage of the synthesis.
  • compounds of the invention where R 21 is phenyl can be prepared by phosphorylation of 2-furanyl bicyclic base subjected to a strong base (e.g. LDA) and chlorodiphenyl phosphonate.
  • such compounds can be prepared by alkylation of lithiated furfuraldehyde followed by ring closure to the bicyclic base.
  • compounds of the invention can be mixed phosphonate esters (e.g. phenyl benzyl phosphonate esters, phenyl acyloxyalkyl phosphonate esters, phenyl aminoacid esters etc).
  • phosphonate esters e.g. phenyl benzyl phosphonate esters, phenyl acyloxyalkyl phosphonate esters, phenyl aminoacid esters etc.
  • the chemically combined phenyl-benzyl prodrugs are reported by Meier, et al. Bioorg. Med. Chem. Lett, 1997, 7: 99.
  • the substituted cyclic propyl phosphonate esters of compounds of the invention can be synthesized by reaction of the corresponding dichlorophosphonate and the substituted 1,3-propane diol. The following are some methods to prepare the substituted 1,3-propane diols.
  • This step includes various synthetic methods for the preparation of the following types of propane- 1,3-diols: i) 1 -substituted; ii) 2- substituted; and iii) 1,2- or 1 ,3-annulated.
  • Different groups on the prodrug part of the molecule i.e., on the propane diol moiety can be introduced or modified either during the synthesis of the diols or after the synthesis of the prodrugs.
  • 1 ,3-Propanediols useful in the synthesis of compounds in the present invention can be prepared using various synthetic methods. As described in Scheme A, additions of an aryl Grignard to a l-hydroxy-propan-3-al give 1-aryl-substituted 1 ,3-propanediols (path a). This method is suitable for the conversion of various aryl halides to l-arylsubstituted-l,3-propanediols (J. Org. Chem. 1988, 55, 911).
  • Conversions of aryl halides to 1-substituted 1,3-propanediols can also be achieved using Heck reactions (e.g., couplings with a 1 ,3-diox-4-ene) followed by reductions and subsequent hydrolysis reactions (Tetrahedron Lett. 1992, 33, 6845).
  • Various aromatic aldehydes can also be converted to 1-substituted- 1,3-propanediols using alkenyl Grignard addition reactions followed by hydroboration-oxidation reactions (path b).
  • A OR, NR(R) 1 wherein each R is independently selected from groups including alkyl and aralkly(e.g., Bn);
  • R' is a protecting group such as Bn, Si(R")(R")-, wherein each R" is independently alkyl or aryl, or -C-O-Me.
  • Aldol reactions between an enolate (e.g., lithium, boron, tin enolates) of a carboxylic acid derivative (e.g., tert-butyl acetate) and an aldehyde (e.g., the Evans's aldol reactions) are especially useful for the asymmetric synthesis of enantioenriched 1 ,3-propanediols.
  • reaction of a metal enolate of f-butyl acetate with an aromatic aldehyde followed by reduction of the ester gives a 1,3-propanediol (J. Org. Chem. 1990, 55 4744).
  • epoxidation of cinnamyl alcohols using known methods e.g., Sharpless epoxidations and other asymmetric epoxidation reactions
  • reduction reactions e.g., using Red- Al
  • Enantioenriched 1 ,3-propanediols can be obtained via asymmetric reduction reactions (e.g., enantioselective borane reductions) of 3-hydroxy-ketones (Tetrahedron Lett. 1997, 38761).
  • resolution of racemic 1,3-propanediols using various methods e.g., enzymatic or chemical methods
  • Propan-3-ols with a 1-heteroaryl substituent e.g., a pyridyl, a quinolinyl or an isoquinolinyl
  • a 1-heteroaryl substituent e.g., a pyridyl, a quinolinyl or an isoquinolinyl
  • a variety of 2-substituted 1 ,3-propanediols useful for the synthesis of compounds of Formula I can be prepared from various other 1 ,3-propanediols (e.g., 2-(hydroxymethy I)- 1,3-propanediols) using conventional chemistry (Comprehensive Organic Transformations, VCH, New York, 1989).
  • 1 ,3-propanediols e.g., 2-(hydroxymethy I)- 1,3-propanediols
  • reductions of a trialkoxycarbonylmethane under known conditions give a triol via complete reduction (path a) or a bis(hydroxymethyl)acetic acid via selective hydrolysis of one of the ester groups followed by reduction of the remaining two other ester groups.
  • Nitrotriols are also known to give triols via reductive elimination (path b) (Synthesis 1987, 8, 742). Furthermore, a 2-(hydroxy methyl)- 1,3-propanediol can be converted to a mono acylated derivative (e.g., acetyl, methoxycarbonyl) using an acyl chloride or an alkyl chloroformate (e.g., acetyl chloride or methyl chloroformate) (path d) using known chemistry (Protective Groups In Organic Synthesis ; Wiley, New York, 1990).
  • a mono acylated derivative e.g., acetyl, methoxycarbonyl
  • an alkyl chloroformate e.g., acetyl chloride or methyl chloroformate
  • Prodrugs of formula I where V - Z or V - W are fused by three carbons are made from cyclohexane diol derivatives.
  • Commercially available cis, cis- 1,3,5-cyclohexane triol can be used for prodrug formation.
  • This cyclohexanetriol can also be modified as described in the case of 2-substituted propan-l,3-diols to give various analogues. These modifications can either be made before or after formation of prodrugs.
  • Various 1 ,3-cyclohexane diols can be made by Diels- Alder methodology using pyrone as the diene (Posner, et.
  • Cyclohexyl diol derivatives are also made by nitrile oxide olefin-additions (Curran, et. al., J. Am. Chem. Soc, 1985, 107, 6023).
  • cyclohexyl precursors can be made from quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32, 547.)
  • Compounds of formula 6, may be prepared from phosphonate esters of formula 5, using known phosphate and phosphonate ester cleavage conditions.
  • silyl halides have been used to cleave the various phosphonate esters, followed by mild hydrolysis of the resulting silyl phosphonate esters to give the desired phosphonic acids.
  • acid scavengers such as 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc.
  • Such silyl halides include, chlorotrimethylsilane (Rabinowitz, J. Org.
  • phosphonate esters can be cleaved under strong acid conditions, (e.g HBr, HCl, etc.) in polar solvents, preferably acetic acid (Moffatt, et al, U.S. Patent 3,524,846, 1970) or water.
  • esters can also be cleaved via dichlorophosphonates, prepared by treating the esters with halogenating agents e.g. phosphorus pentachloride, thionyl chloride, BBr 3 , etc.(Pelchowicz, et al, J. Chem. Soc, 1961, 238) followed by aqueous hydrolysis to give phosphonic acids.
  • halogenating agents e.g. phosphorus pentachloride, thionyl chloride, BBr 3 , etc.
  • Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al, J. Med.
  • the bicyclic base ring system of formula 4 may require further elaboration to provide desired compounds of formula 5.
  • Substitution of the 6-membered Ring Electrophilic and nucleophilic substitution reactions enable inco ⁇ oration of the desired substitutions encompassed by the formula 5.
  • G6 is C
  • A is NH 2
  • L and J are hydrogens
  • Compounds of formula 5, where A is NO 2 , L and/or J are alkenyl, alkynyl, alkyl, or aryl groups, and Y is H or alkyl, may be prepared from compounds of formula 4, where A is NO 2 , R is H or alkyl, and L and/or J are halogens, preferably bromide or iodide, through Stille coupling (Stille, Angew. Chem. Int. Ed. Engl. 1986, 25: 508- 524). Treatment of the compounds of formula 4, where A is NO 2 , and L and/or J are bromides, with a coupling reagent (e.g.
  • the compounds thus obtained can be modified as needed.
  • vinyl or propargyl alcohol derivatives can be hydrogenated to give the ethyl or propyl alcohol derivatives respectively.
  • These alcohols can be further modified as required via alkyl halides (ref. Wagner et al.
  • alkyl sulfonates etc. to a number of substituted alky Is such as amino alkyl compounds by subjecting them to nucleophilic substitution reactions (March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 293- 500). Alternatively, these substitutions can also be done by metal exchange followed by quenching with an appropriate nucleophile (Jerry March, Advanced Organic Chemistry , Wiley-Interscience, 1992, 606-609). Nucleophilic addition reactions can also be useful in preparing compounds of formula 5. For example, when A is NO 2 , L and/or J are halogens, nucleophiles such as alkoxides, thiols, amines, etc.
  • these substituted compounds can be further modified to the desired products.
  • reduction of the NO 2 to NH 2 may be done in many different ways, e.g. Pd/C, H 2 , aq. Na 2 S 2 O 4 , etc. (Larock, Comprehensive Organic Transformations , VCH, 412-415).
  • These primary aromatic amines can also be modified as needed.
  • N-acetyl derivatives can be prepared by treatment with acetyl chloride or acetic anhydride in the presence of a base such as pyridine.
  • the mono- or di- alkylamines can be synthesized by direct alkylation, using a base such as NaH in polar solvents such as DMF or by reductive alkylation methods (ref. Abdel- Magid et al. Tetrahedron Lett. 1990, 31, 5595; also see ref. March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 898-900 for more methods).
  • deaza-purine analogs can be prepared from corresponding diaminoprecursors.
  • Diaminoprecursors of variety of nitrogen heterocycles, such as pyridyl, pyrazinyl and pyridazinyl bases can be further transformed into bicyclic systems as shown in the following synthesis of 1- deaza analogs. These compounds may be functionalized as shown below by activation to N-oxide.
  • the resulting phosphonate substituted bicyclic systems may be further transformed to alpha-haloamines via nitration (Wanner, et al, Nucleosides, Nucleotides & Nucleic Acids 2004, 23: 1313, Cristalli, et al., J. Med. Chem., 1987, 30: 1686)
  • Alkylation of the bicyclic base ring system of formula 4 is achieved by treatment of an alcohol, triphenylphosphine and dialkylazodicarboxylate with heterocycle and a non-nucleophilic base such as Hunigs base in polar solvents such as CH 3 CN (Zwierzak et al, Liebigs Ann. Chem. 1986, 402). b) Base Alkylation
  • the bicyclic base ring system of formula 4 can be deprotonated with a suitable base, preferably cesium carbonate in a polar aprotic solvent such as DMF, and the resulting anion is alkylated with an appropriate electrophilic component Y-L' , where L' is a leaving group preferably bromide or iodide.
  • a heterosubstituted methyl phosphonates can also be prepared by displacement reactions on phosphonomethyl halides or sulfonates (Phillion et al, Tetrahedron Lett., 1986, 27: 1477.) with an appropriate nucleophile e.g. 2-hydroxylmethylbicyclic base compound which can be prepared using a variety of methods, including oxidation of the substituted 2-methylbicyclic bases.
  • compounds of formula 1, where X is carboxypropyl or sulfonopropyl can be prepared from the reaction of 2-(2-iodoethyl) bicyclic base and corresponding phosphonomethylcarboxylate or phosphonomethylsulfonate (Carretero et al., Tetrahedron, 1987, 43, 5125) in the presence of base such as NaH in polar aprotic solvents such as DMF.
  • the substituted 2-(2-iodoethyl) bicyclic base can be prepared from condensation of the corresponding substituted diamine and 3-halopropanaldehyde. Also see ref. Magnin, D. R. et al. J. Med. Chem. 1996, 39, 657 for the preparation of ⁇ - phosphosulfonic acids.
  • the componds of formula 4 where X is all carbon e.g. -(CH 2 ) 3 - can be prepared by Stille coupling (Stille Angew. Chem. Int. Ed. Engl. 1986, 25: 508- 524) of the dialkylphosphopropenyl tributylstanne (J. Org. Chem. 1993, 58: 6531.) and appropriate 2-bromobicyclic base (Misery, et al, Tetrahedron Lett., 1986, 27: 1051).
  • the componds of formula 4 where X is an amide linker e.g. -CONHCH 2 - can be synthesized using the following two steps.
  • Treatment of the appropriate 1,2-1,2-diamine with trihalomethylacetamidate preferably trichloromethylacetamidate in polar solvent such as acetic acid followed by hydrolysis of the trihalomethyl group with strong aqueous base (e.g. KOH) gives the bicyclic base-2-carboxylic acid (Eur. J. Med. Chem., 1993, 28: 71).
  • Condensation of the acid with an amino phosphonate e.g. diethyl(aminomethyl)phosphonate in presence of a coupling agent (e.g. pyBOP) in a polar solvent such as methylene chloride provides the amide linked phosphonate.
  • a coupling agent e.g. pyBOP
  • the componds of formula 4 where X is an amide linker e.g. -NHCOCH 2 - can be synthesized using the following two steps.
  • Treatment of the appropriate 1 ,2-diamine with cyanogenbromide Johnson, et al, J. Med. Chem., 1993, 36: 3361
  • polar solvent such as MeOH
  • Condensation of the 2-aminobicyclic base with a carboxylic acid e.g. diethyl(carboxymethyl)phosphonate using standard coupling conditions (Klausner, et al, Synthesis, 1972, 453) provides the amide linked phosphonate.
  • the 2-aminobicyclic bases can also be prepared from the 2- bromobicyclic base via the 2-azidobicyclic base using known methods (Chem. Rev. 1988, SS: 297).
  • the bicyclic base ring systems of formula 4 is preferably assembled by condensation of substituted 1,2-diamines with an aldehyde (RCHO, where R is e.g. aliphatic, heteroaliphatic, aromatic or heteroaromatic etc.) using known methods; (a) in presence of Fe 3+ salts, preferably FeCl 3 , in polar solvents such as DMF, EtOH etc., (b) reflux in non-polar solvents such as toluene followed by oxidation, preferably with iodine (Bistocchi et al, Collect. Czech. Chem.
  • RCHO aldehyde
  • the first condensation can be achieved in the presence of a dilute inorganic acid, preferably 10 % H 2 SO 4 , in polar solvents such as THF, followed by oxidation with I 2 .
  • a dilute inorganic acid preferably 10 % H 2 SO 4
  • polar solvents such as THF
  • these bicyclic base ring systems can be constructed using solid phase synthesis (ref: Phillips et al. Jet. Lett., 1996, 37: 4887; Lee et al, Tet. Lett, 1998: 35: 201.
  • Aryl functionalized phosphonate linkers can be prepared by lithiation of an aromatic ring using methods well described in literature (Gschwend, Org. React. 1979, 26, 1; Durst, Comprehensive Carbanion Chemistry, Vol. 5, Elsevier, New York, 1984) followed by addition of phosphorylating agents (e.g. ClPO 3 R 2 ). Phosphonate esters are also introduced by Arbuzov-Michaelis reaction of primary halides (Brill, T. B., Chem Rev., 1984, 84: 577). Aryl halides undergo Ni 2+ catalysed reaction with trialkylphosphites to give aryl phosphonate containing compounds (Balthazar, et al, J. Org.
  • Aromatic triflates are known to result in phosphonates with ClPO 3 R 2 in the presence of a palladium catalyst (Petrakis, et al, J. Am. Chem. Soc, 1987, 109: 2831; Lu, et al, Synthesis, 1987, 726).
  • aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel, et al, Synthesis, 1991, 691).
  • arylphosphate esters, where X is aryloxy can also be made.
  • N-Alkoxy aryl salts with alkali metal derivatives of dialkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers (Redmore, J. Org. Chem., 1970, 55: 4114).
  • aldehyde, ketone, or carboxylic acid functionalities can also be introduced after the phosphonate ester is formed.
  • a lithiation reaction can be used to incorporate the aldehyde or ketone functionalities, although other methods known to generate aromatic aldehydes or ketones can be envisioned as well (e.g. Vilsmeier-Hack reaction, Reimar-Teimann reaction etc.; Pizey, Synthetic reagents, 1974, 7: 1; Wynberg, H., et al, Org. React. 1982, 28: 1; palladium catalyzed coupling reaction of acid halides and organotin compounds).
  • the lithiated aromatic ring can be treated with reagents that directly generate the aldehyde (e.g. DMF, HCOOR, efc.)(Einchorn, J., et al, Tetrahedron Lett., 1986, 27: 1791), or the ketone (e.g. Weinreb's amide, RCOOR').
  • the lithiated aromatic ring can also be treated with reagents that lead to a group that is subsequently transformed into the aldehyde or ketone group using known chemistry (synthesis of aldehyde and ketone from alcohol, ester, cyano, alkene, etc.).
  • the sequence of these reactions can be reversed, i.e. the aldehyde and ketone moieties can be incorporated first, followed by the phosphorylation reaction.
  • the order of the reaction will depend on reaction conditions and protecting groups. Prior to the phosphorylation it is also envisioned that it may be advantageous to protect the aldehyde or ketone using well-known methods (acetal, aminal, hydrazone, ketal, etc.), and then the aldehyde or ketone is unmasked after phosphorylation. (Protective groups in Organic Synthesis, Greene, T. W., 1991, Wiley, New York).
  • heteroaryl linkers e.g. pyridine, furan, thiophene etc.
  • Ar(Z)alkyl phosphonates can be prepared from the reaction of substituted aryls e.g. salicylaldehyde with an appropriate phosphonate electrophile [L(CfO) n PO 3 R 2 , L is a leaving group, preferably iodine; Walsh et al, J. Am. Chem. Soc, 1956, 78, 4455.] in the presence of a base, preferably K 2 CO 3 or NaH, in a polar aprotic solvent, such as DMF or DMSO.
  • a base preferably K 2 CO 3 or NaH
  • a polar aprotic solvent such as DMF or DMSO.
  • linkers of formula 3, where X is alkyloxymethyl can be synthesized through direct alkylation of the hydroxymethyl phosphonate ester, with the desired alkyl halide [L(CH2) n CH(OMe)2, L is a leaving group, preferably bromine or iodine] in the presence of a base, preferably NaH, in a polar aprotic solvent, such as DMF or DMSO.
  • L alkyl halide
  • L is a leaving group, preferably bromine or iodine
  • substituted heteroarylhalides F,Cl,Br,I
  • nucleophilic addition e.g. NH 3 , NH 2 OH, etc
  • Diamines of formula 2 R is alkyl, can be produced using alkylamine displacement of alpha-haloheterocycles. Such resulting alpha- alkylamino heterocycles can then be transformed to nitro-amines via nitration. The nitro group can be reduced with number of reagents preferably sodium dithionite to provide the corresponding diamine. This diamine is then subjected to cyclization.
  • diamines of formula 2 where R is not H are prepared by reductive alkylation of the amino substituted pyridine, pyrimidine or pyrazines with various aldehydes(e.g. akyl, aryl etc.) in the presence of a reducing agent preferably NaB(OAc) 3 followed by reduction (e.g. Na 2 S 2 O 4 ; Pd/C, H 2 etc.) of the nitro group (Magid et al Tetrahedron Lett. 1990, 31: 5595).
  • a reducing agent preferably NaB(OAc) 3 followed by reduction (e.g. Na 2 S 2 O 4 ; Pd/C, H 2 etc.) of the nitro group (Magid et al Tetrahedron Lett. 1990, 31: 5595).
  • Alkylation precursor was made as described in steps A and B of example 1.
  • Example 3 Compounds of example 3 were made starting from commercially available 3,4-diamino-pyridine following steps A-D of example 2.
  • Step A General procedure of alkylamine substitution of alpha-halopyridine:
  • Step B Preparation of 1,2-diamines via dithionite reduction:
  • Steps C and D were carried-out as described in example steps B and C of example 1.
  • Example 2.1 was made as described in steps A-C.
  • example 2.1 420 mg, 1.1 mmol
  • acetic acid 1 mL
  • 30% hydrogen peroxide 0.25 mL
  • the reaction mixture was then evaporated to dryness and azeotroped with toluene (2 X 10 mL).
  • the crude product was chromatographed with 5% MeOH-CH 2 Cl 2 to give 150 mg of N-oxide.
  • step A Diamine obtained in step A was coupled and cyclized with 2-Furaldehyde-5- diethylphosphonate utilizing the procedure described in step B of example 1.
  • N-oxide was made as described in step E of example 5.
  • Step G To a solution of amino compound (30 mg, 0.076 mmol) in methanol (2 mL) was added N-chlorosuccinimide. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated upon completion of the reaction and the crude product was chromatographed using 2% to 5% MeOH-dichloromethane to provide the pure chlorinated product (23 mg).
  • step B Diamine obtained in step B was coupled and cyclized with 2-Furaldehyde-5- diethylphosphonate utilizing the procedure described in step B of example 1.
  • Example 8 7-Methyl-6-chloro-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine-N4-ethyl bromide.
  • Examples of use of the method of the invention includes the following. Examples A and E were actually performed. The remaining examples are prophetic. It will be understood that these examples are exemplary and that the method of the invention is not limited solely to these examples. Besides the following Examples, assays that may be useful for identifying compounds which inhibit gluconeogenesis include the following animal models of diabetes: i. Animals with pancreatic beta-cells destroyed by specific chemical cytotoxins such as Alloxan or Streptozotocin (e.g. the Streptozotocin-treated mouse, rat, dog, and monkey).
  • specific chemical cytotoxins such as Alloxan or Streptozotocin (e.g. the Streptozotocin-treated mouse, rat, dog, and monkey).
  • mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob, and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and others such as Yellow Obese, T-KK, and New Zealand Obese.
  • Example A Inhibition of Human Liver FBPase.
  • E. coli strain BL21 transformed with a human liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook.
  • hlFBPase was typically purified from 10 liters of E. coli culture as described (M. Gidh-Jain et al., The Journal of Biological Chemistry 1994, 269, 27732-27738).
  • Enzymatic activity was measured spectrophotometrically in reactions that coupled the formation of product (fructose 6-phosphate) to the reduction of dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP and phenazine methosulfate (PMS) , using phosphoglucose isomerase and glucose 6-phosphate dehydrogenase as the coupling enzymes.
  • Reaction mixtures (200 ⁇ L) were made up in 96-well microtitre plates, and consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl2, 0.2 mM NADP, 1 mg/mL BSA, 1 mM MTT, 0.6 mM PMS, 1 unit/mL phosphoglucose isomerase, 2 units/mL glucose 6- phosphate dehydrogenase, and 0.150 mM substrate (fructose 1 ,6- bisphosphate). Inhibitor concentrations were varied from 0.01 ⁇ M to 10 ⁇ M.
  • Example B In vitro Inhibition of Rat Liver and Mouse Liver FBPase.
  • Inhibitors of FBPase may also be identified by assaying rat and mouse liver FBPase.
  • E. coli strain BL21 transformed with a rat liver FBPase-encoding plasmid is purified as described in El-Maghrabi, M.R., and Pilkis, SJ. Biochem. Biophys. Res. Commun. 1991, 776, 137-144.
  • Mouse liver FBPase is obtained by homogenizing freshly isolated mouse liver in 100 mM Tris-HCl buffer, pH 7.4, containing 1 mM EGTA, and 10 % glycerol. The homogenate is clarified by centrifugation, and the 45-75 % ammonium sulfate fraction prepared.
  • rat liver and mouse liver FBPase are assayed as described for human liver FBPase. Generally, as reflected by the higher IC50 values, the rat and mouse liver enzymes are less sensitive to inhibition by the compounds tested than the human liver enzyme.
  • the enzyme is incubated with radiolabeled AMP in the presence of a range of test compound concentrations.
  • the reaction mixtures are incubated with radiolabeled AMP in the presence of a range of test compound concentrations.
  • AMP bound to FBPase is separated from unbound AMP by means of a centrifugal ultrafiltration unit ("Ultrafree-MC", Millipore) used according to the instructions of the manufacturer.
  • Ultrafree-MC centrifugal ultrafiltration unit
  • the radioactivity in aliquots (100 ⁇ L) of the upper compartment of the unit (the retentate, which contains enzyme and label) and the lower compartment (the filtrate, which contains unbound label) are quantified using a Beckman liquid scintillation counter.
  • the amount of AMP bound to the enzyme is estimated by comparing the counts in the filtrate (the unbound label) to the total counts in the retentate.
  • Adenosine Kinase Human adenosine kinase is purified from an E. coli expression system as described by Spychala et al. (Spychala, J., Datta, N.S., Takabayashi, K., Datta, M., Fox, I.H., Gribbin, T., and Mitchell, B.S. Proc. Natl. Acad. Sci. USA 1996, 93, 1232-1237). Activity is measured essentially as described by Yamada et al. (Yamada, Y., Goto, H., Ogasawara, N. Biochim. Biophys. Acta 1988, 660, 36-43.) with a few minor modifications.
  • Assay mixtures contain 50 mM TRIS-maleate buffer, pH 7.0, 0.1 % BSA, 1 mM ATP 1 mM MgCl2, 1.0 ⁇ M [U- 14 C] adenosine (400-600 mCi/mmol) and varying duplicate concentrations of inhibitor.
  • C-AMP is separated from unreacted C-adenosine by absorption to anion exchange paper (Whatman) and quantified by scintillation counting.
  • Porcine heart AMPDA is purified essentially as described by Smiley et al. (Smiley, K.L., Jr, Berry, AJ., and Suelter, CH. J. Biol. Chem. 1967, 242, 2502-2506) through the phosphocellulose step. Inhibition of AMPDA activity is determined at 37 0 C in a 0.1 mL assay mixture containing inhibitor, -0.005U AMPDA, 0.1 % bovine serum albumin, 10 mM ATP, 250 mM KCl, and 50 mM MOPS at pH 6.5. The concentration of the substrate AMP is varied from 0.125 - 10.0 mM.
  • Catalysis is initiated by the addition of enzyme to the otherwise complete reaction mixture, and terminated after 5 minutes by injection into an HPLC system. Activities are determined from the amount of IMP formed during 5 minutes. IMP is separated from AMP by HPLC using a Beckman Ultrasil- SAX anion exchange column (4.6 mm x 25 cm) with an isocratic buffer system (12.5 mM potassium phosphate, 30 mM KCl, pH 3.5) and detected spectrophotometrically by absorbance at 254 nm.
  • Phosphofructokinase Enzyme (rabbit liver) is purchased from Sigma. Activity is measured at 30 0 C in reactions in which the formation of fructose 1 ,6-bisphosphate is coupled to the oxidation of NADH via the action of aldolase, triosephosphate isomerase, and ⁇ -glycerophosphate dehydrogenase. Reaction mixtures (200 ⁇ L) are made up in 96-well microtitre plates and are read at 340 nm in a Molecular Devices Microplate Reader.
  • the mixtures consist of 200 mM Tris-HCl pH 7.0, 2 mM DTT, 2 mM MgC12, 0.2 mM NADH, 0.2 mM ATP, 0.5 mM Fructose 6-phosphate, 1 unit aldolase/mL, 3 units/mL triosephosphate isomerase, and 4 units/mL ⁇ -glycerophosphate dehydrogenase.
  • Test compound concentrations range from 1 to 500 ⁇ M. Reactions are started by the addition of 0.0025 units of phosphofructokinase and are monitored for 15 minutes.
  • Glycogen Phosphorylase Enzyme (rabbit muscle) is purchased from Sigma. Activity is measured at 37 0 C in reactions in which the formation of glucose 1 -phosphate is coupled to the reduction of NADP via phosphoglucomutase and glucose 6-phosphate dehydrogenase. Assays are performed on 96-well microtitre plates and are read at 340 nm on a Molecular Devices Microplate Reader.
  • Reaction mixtures consist of 20 mM imidazole, pH 7.4, 20 mM MgCl2, 150 mM potassium acetate, 5 mM potassium phosphate, 1 mM DTT, 1 mg/mL BSA, 0.1 mM NADP, 1 unit/mL phosphoglucomutase, 1 unit/mL glucose 6-phosphate dehydrogenase, 0.5 % glycogen. Test compound concentrations range from 1 to 500 ⁇ M. Reactions are started by the addition of 17 ⁇ g enzyme and are monitored for 20 minutes. Adenylate Kinase: Enzyme (rabbit muscle) is purchased from Sigma.
  • Activity is measured at 37 0 C in reaction mixtures (100 ⁇ L) containing 100 mM Hepes, pH 7.4, 45 mM MgCl2, 1 mM EGTA, 100 mM KCl, 2 mg/mL BSA, 1 mM AMP and 2 mM ATP. Reactions are started by addition of 4.4 ng enzyme and terminated after 5 minutes by addition of 17 ⁇ L perchloric acid. Precipitated protein is removed by centrifugation and the supernatant neutralized by addition of 33 ⁇ L 3 M KOH/3 M KH2CO3.
  • the neutralized solution is clarified by centrifugation and filtration and analyzed for ADP content (enzyme activity) by HPLC using a YMC ODS AQ column (25 X 4.6 cm). A gradient is run from 0.1 M KH2PO4, pH 6, 8 mM tetrabutyl ammonium hydrogen sulfate to 75 % acetonitrile. Absorbance is monitored at 254 nM.
  • Example E Inhibition of GIuconeogenesis in Rat Hepatocytes
  • Hepatocytes were prepared from overnight fasted Sprague-Dawley rats (250-300 g) according to the procedure of Berry and Friend (Berry, M.N., Friend, D.S., J. Cell. Biol. 1969, 43, 506-520) as modified by Groen (Groen, A.K., Sips, H.J., Vervoorn, R.C., Tager, J.M., Eur. J. Biochem. 1982, 122, 87- 93).
  • Hepatocytes (75 mg wet weight/mL) were incubated in 1 mL Krebs- bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1 mg/mL BSA, and test compound concentrations from 1 to 500 ⁇ M. Incubations were carried out in a 95 % oxygen, 5 % carbon dioxide atmosphere in closed, 50- mL Falcon tubes submerged in a rapidly shaking water bath (37 0 C). After 1 hour, an aliquot (0.25 mL) was removed, transferred to an Eppendorf tube and centrifuged. 50 ⁇ L of supernatant was then assayed for glucose content using a Sigma Glucose Oxidase kit as per the manufacturer's instructions. Three compounds were tested for their ability to inhibit gluconeogenesis in rat hepatocytes. Two of three compounds tested demonstrated inhibition of gluconeogenesis.
  • Example F Blood Glucose Lowering in Fasted Rats
  • Example G Effect of FBPase Inhibitors on Gluconeogenesis from Lactate/pyruvate in Rat Hepatocytes: Glucose Production Inhibition and Fructose 1,6-bisphosphate Accumulation
  • Isolated rat hepatocytes are prepared as described in Example E and incubated under the identical conditions described. Reactions are terminated by removing an aliquot (250 ⁇ L) of cell suspension and spinning it through a layer of oil (0.8 mL silicone/mineral oil, 4/1) into a 10 % perchloric acid layer (100 ⁇ L). After removal of the oil layer, the acidic cell extract layer is neutralized by addition of l/3rd volume of 3 M KOH/3 M KH2CO3. After thorough mixing and centrifugation, the supernatant is analyzed for glucose content as described in Example E, and also for fructose 1,6-bisphosphate.
  • Fructose 1 ,6-bisphosphate is assayed spectrophotometrically by coupling its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH, which is monitored at 340 nm.
  • Reaction mixtures (1 mL) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/mL glycerol 3-phosphate dehydrogenase, 2 units/mL triosephosphate isomerase, and 50-100 ⁇ L cell extract. After a 30 minute preincubation at 37 0 C, 1 unit/mL of aldolase is added and the change in absorbance measured until a stable value is obtained. Two moles of NADH are oxidized in this reaction per mole of fructose 1 ,6- bisphosphate present in the cell extract.
  • the vehicle used for drug administration is 10 mM bicarbonate.
  • One hour post injection rats are anesthetized with halothane and a liver biopsy (approx. 1 g) is taken as well as a blood sample (2 mL) from the posterior vena cava. A heparin flushed syringe and needle is used for blood collection.
  • the liver sample is immediately homogenized in ice-cold 10 % perchloric acid (3 mL), centrifuged, and the supernatant neutralized with l/3rd volume of 3 M KOH/3 M KH2CO3. Following centrifugation and filtration,
  • Example G Blood glucose is measured in the blood sample as described in Example E. Plasma is then quickly prepared by centrifugation and extracted by addition of methanol to 60 % (v/v). The methanolic extract is clarified by centrifugation and filtration and then analyzed by HPLC as described above.
  • Elevation of fructose- 1 ,6-bisphosphate levels in the livers from the drug-treated group is consistent with the inhibition of glucose production at the level of FBPase in the gluconeogenic pathway.
  • Zucker Diabetic Fatty rats purchased at 7 weeks of age are used at age 16 weeks in the 24-hour fasted state.
  • the rats are purchased from Genetics Models Inc. and fed the recommended Purina 5008 diet (6.5 % fat).
  • Their fasting hyperglycemia at 24 hours generally ranges from 150 mg/dLto 310 mg/dLblood glucose.
  • the stock solution is made up at 25 mg/mL in deionized water and adjusted to neutratility by dropwise addition of 5 N NaOH.
  • 5 control animals are dosed with saline. Blood glucose is measured at the time of dosing and 2 hours post dose as described in Example E.
  • Diabetes is induced in male Sprague-Dawley rats (250-300g) by intraperitoneal injection of 55 mg/kg streptozotocin (Sigma Chemical Co.).
  • 24 animals are selected with fed blood glucose values (8 am) between 350 and 600 mg/dL and divided into two statistically equivalent groups.
  • Blood glucose is measured in blood obtained from a tail vein nick by means of a HemoCue Inc. (Mission Viejo, CA) glucose analyzer.
  • One group of 12 subsequently receives inhibitor (100 mg/kg intraperitoneally) and the other 12 (“controls”) an equivalent volume of saline. Food is removed from the animals.
  • Blood glucose is measured in each animal four hours after dosing, and a second dose of drug or saline is then administered. Four hours later, a final blood glucose measurement is made.
  • Prodrugs are dissolved in 10 % ethanol/90 % polyethylene glycol (mw 400) and administered by oral gavage at doses of approximately 20 or 40 mg/kg parent compound equivalents to 6-hour fasted, Sprague Dawley rats (220-240 g). The rats are subsequently placed in metabolic cages and urine is collected for 24 hours. The quantity of parent compound excreted into urine is determined by HPLC analysis. An ODS column eluted with a gradient from potassium phosphate buffer, pH 5.5 to acetonitrile is employed for these measurements. Detection is at 310-325 nm.
  • the percentage oral bioavailability is estimated by comparison of the recovery in urine of the parent compound generated from the prodrug, to that recovered in urine 24 hours after intravenous administration of unsubstitutcd parent compound at approximately 10 mg/kg.
  • Parent compounds are typically dissolved in dimethyl sulfoxide, and administered via the tail vein in animals that are briefly anesthetized with halothane.
  • the compound is prepared in deionized water, adjusted to neutrality with sodium hydroxide, and brought into solution by sonication prior to administration.
  • Blood glucose is measured immediately prior to dosing, and at 1 hour intervals thereafter.
  • Blood samples are obtained from the tail vein, and measurments made by means of a Hemocue glucose analyzer (Hemocue Inc, Mission Viejo, California) used according to the manufacturer's instructions. A lowering of blood glucose levels is consistent with inhibition of FBPase activity.

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Abstract

The invention relates to compounds of Formula I-III and IX-XIII, their prodrugs and salts and co-crystals thereof. The invention further relates to process and methods of making and using the same.

Description

NOVEL INHIBITORS OF FRUCTOSE 1,6-BISPHOSPHATASE
Background of the Invention
Field Of The Invention
The present invention is directed towards novel nucleoside analogs, including deazapurine nucleoside analogs that are potent inhibitors of fructose 1,6-bisphosphatase (FBPase). In one aspect, the invention is directed toward phosphonic acids and prodrugs thereof. In another aspect, the present invention is directed to the preparation and the clinical use of these FBPase inhibitors as a method of treatment or prevention of diseases responsive to inhibition of gluconeogenesis and in diseases responsive to lower blood glucose levels.
The compounds are also useful in treating or preventing excess glycogen storage diseases and diseases such as metabolic disordersincluding hypercholesterolemia, hyperlipidemia which are exacerbated by hyperinsulinema and hyperglycemia.
Description of Related Art
The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All cited publications are incorporated by reference in their entirety.
Diabetes mellitus (or diabetes) is one of the most prevalent diseases in the world today. Diabetic patients have been divided into two classes, namely type 1 and type 2 diabetes. Type 2 accounts for approximately 90% of all diabetics and is estimated to affect 12-14 million adults in the U. S. alone (6.6% of the population). Type 2 diabetes is characterized by both fasting hyperglycemia and exaggerated postprandial increases in plasma glucose levels. Type 2 diabetes is associated with a variety of long-term complications, including microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease. Numerous studies in animal models demonstrate a causal relationship between long term hyperglycemia and complications. Results from the Diabetes Control and Complications Trial (DCCT) and the Stockholm Prospective Study demonstrate this relationship for the first time in man by showing that insulin-dependent (Type 1) diabetics with tighter glycemic control are at substantially lower risk for the development and progression of these complications. Tighter control is also expected to benefit Type 2 diabetes patients.
Gluconeogenesis from pyruvate and other 3-carbon precursors is a highly regulated biosynthetic pathway requiring eleven enzymes. Seven enzymes catalyze reversible reactions and are common to both gluconeogenesis and glycolysis. Four enzymes catalyze reactions unique to gluconeogenesis, namely pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose- 1,6-bisphosphatase and glucose-6-phosphatase. Overall flux through the pathway is controlled by the specific activities of these enzymes, the enzymes that catalyzed the corresponding steps in the glycolytic direction, and by substrate availability. Dietary factors (glucose, fat) and hormones (insulin, glucagon, glucocorticoids, epinephrine) coordinatively regulate enzyme activities in the gluconeogenesis and glycolysis pathways through gene expression and post-translational mechanisms.
Synthetic inhibitors of FBPase have also been reported. McNiel reported that fructose-2,6-bisphosphate analogs inhibit FBPase by binding to the substrate site. J. Am. Chem. Soc, 106:7851-7853 (1984); U.S. Patent No. 4,968,790 (1984). These compounds, however, were relatively weak and did not inhibit glucose production in hepatocytes presumably due to poor cell penetration.
Gruber reported that some nucleosides can lower blood glucose in the whole animal through inhibition of FBPase. These compounds exert their activity by first undergoing phosphorylation to the corresponding monophosphate (EP 0427 799 Bl).
Gruber et al., U.S. Patent No. 5,658,889, described the use of inhibitors of the AMP site of FBPase to treat diabetes. WO 98/39344, WO/39343, WO 98/39342, U.S. Patent No. 6,489,476, and U.S. 2002/0173490 describe specific inhibitors of FBPase to treat diabetes. More recently, Dang et al., U.S. Patent No. 6,489,476, described novel heteroaromatic compounds containing a phosphonate group that are inhibitors of FBPase. Reddy et al., U.S. Patent 6,054,587, described novel indole and azaindole compounds containing a phosphonate group that are inhibitors of FBPase. Dang et al., U.S. Patent 6,284,748, described novel purine compounds containing a phosphonate group that are inhibitors of FBPase. Bookser et al., U.S. Patent 6,919,322, described novel aryl phosphonate compounds that are inhibitors of FBPase. Kasibhatla, et al., U.S. Patnent No. 6,399,782, described benzimidazole compounds containing a phosphonate group that are inhibitors of FBPase. Further, Dang et al., WO 2006/023515, described novel 5-ketothiazole compounds containing a phosphonate group that are inhibitors of FBPase. The above disclosures also further describe the use of the FBPase inhibitors for the treatment of diabetes and other related diseases and disorders. Erion et al., U.S. Patent Application 2004/0167178, and van Poelje et al., U.S. Patent Application 2003/0073728, described a combination of an FBPase inhibitor and antidibetic agents for the treatment of diabetes.
Brief Summary of the Invention
The present invention relates to compounds and pharmaceutical compositions of Formula I-III and IX-XIII, including pharmaceutically acceptable salts, co-crystals and prodrugs thereof.
Also provided are methods for treating a disease or condition, the methods comprising the step of administering to an animal a therapeutically effective amount of a pharmaceutical composition comprising a compound of invention.
Also provided are methods of making or manufacturing compounds of invention, including pharmaceutically acceptable salts, co-crystals or prodrugs thereof. Detailed Description of the Invention
Definitions
As used herein, the following terms are defined with the following meanings:
"Acyl" refers to -C(O)RS where Rs is alkyl, heterocycloalkyl, or aryl.
"Acylalkyl" refers to an alkyl-C(O)-alk-, wherein "alk" is alkylene.
"Acylamino" refers to and RWC(O)-NRW-, wherein Rw is -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
"Acyloxy" refers to the ester group -0-C(O)R1, where R1 is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.
"Alicyclic" refers to a cyclic group or compound which combines the properties of aliphatic and cyclic compounds and include cycloalkyl and bridged cycloalkyl compounds. The cyclic compound includes heterocycles. Cyclohexenylethyl, cyclohexanylethyl, and norbornyl are suitable alicyclic groups. Such groups may be optionally substituted.
"Alkanoyl" refers to the group alkyl-C(O)-.
"Alkenyl" refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups included alkenylene and alkynylene. Alkenyl groups may be optionally substituted. Suitable alkenyl groups include allyl. "1-alkenyl" refers to alkenyl groups where the double bond is between the first and second carbon atom. If the 1-alkenyl group is attached to another group, it is attached at the first carbon.
"Alkylaminoalkyl-"refers to the group -alk-NRu-alk- wherein "alk" is alkylene, and Ru is H or lower alkyl. "Lower alkylaminoalkyl-"refers to groups where the alkyl and the alkylene group are lower alkyl and alkylene, respectively.
"Alkylaminoalkylcarboxy" refers to the group alkyl-NRu-alk-C(O)-O- where "alk" is an alkylene group, and Ru is a H or lower alkyl. "Alkylaminoaryl-"refers to the group alkyl-NRvl-aryl- wherein "aryl" is a divalent group and Rv! is -H, alkyl, aralkyl, or heterocycloalkyl. In "lower alkylaminoaryl-", the alkyl group is lower alkyl.
"Alkylaminocarbonyl" refers to the group alk-NR-C(O)- where R is a H or lower alkyl, and "alk" is an alkyl group. "-Alkylaminocarbonyl-" refers to same group, except when "alk" is alkylene. When X is - alkylaminocarbonyl- the alkyl portion is attached to M and the carbonyl portion to Gg.
"-Alkylcarbonylamino-" refers to the group -alk-C(O)-NR- where "alk" is an alkylene group, and R is a H or lower alkyl. When X is - alkylcarbonylamino-, the alkyl group is attached to M and the amino group is attached to G8
"Alkoxy-" or "alkyloxy-" refers to the group alkyl-O. "-Alkoxy-" or "-alkyloxy-" refers to the group -alkylene-O-. When X is -alkoxy- or - alkyloxy-, the alkyl portion is attached to M.
"Alkoxyalkyl-" or "alkyloxyalkyl-" refers to the group alkyl-O-alk- wherein "alk" is an alkylene group. When X is -alkoxyalkyl-" or "-alkyloxyalkyl-" then the terms refer to -alk-O-alk- wherein "alk" is an alkylene group. In "lower alkoxyalkyl-", each alkyl and alkylene is lower alkyl and alkylene, respectively.
"Alkoxyaryl-" refers to an aryl group substituted with an alkyloxy group. In "lower alkyloxyaryl-", the alkyl group is lower alkyl.
"Alkoxycarbonyloxy-" refers to alky 1-0-C(O)-O-.
"Alkyl" refers to a straight or branched chain or cyclic chain hydrocarbon radical with only single carbon-carbon bonds. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be optionally substituted. Alkyl groups are Ci-C12.
"Alkylaryl-" refers to alkyl-arylene-. "-Alkylaryl-" refers to -alkylene- arylene-. When X is alkylaryl, the alkylene is attached to M and the arylene is attached to G8. monovalent aryl group or divalent arylene (e.g., when X is -alkylaryl-) group substituted with an alkyl group. "Lower alkylaryl-" refers to such groups where alkyl is lower alkyl.
"Alkylene-aryl-" refers to a divalent aklylene substituted aryl group, with one valency on the aryl group and one valency on the alkylene group. "Lower alkylaryl-" refers to such groups where alkyl is lower alkyl.
"Alkylene" refers to a divalent straight chain, branched chain or cyclic saturated aliphatic group. In one aspect the alkylene group contains up to and including 10 atoms. In another aspect the alkylene chain contains up to and including 6 atoms. In a further aspect the alkylene groups contains up to and including 4 atoms. The alkylene group can be either straight, branched chain or cyclic.
"Alkylthio-" refers to the group alkyl-S- and -alkylthio- refers to - alkylene-S-. When X is -alkylthio-, the alkyl group is attached to M.
"Alkylthioalkyl-" refers to the group alkyl-S-alk- wherein "alk" is an alkylene group. "-Alkylthioalkyl- refers to -alkylene-S-alkylene-. In "lower alkylthioalkyl-" each alkyl and alkylene is lower alkyl and alkylene, respectively.
"Alkylthiocarbonyloxy-" refers to alkyl-S-C(O)-O-.
"Alkynyl" refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups. Alkynyl groups may be optionally substituted. Suitable alkynyl groups include ethynyl. "1 -alkynyl" refers to alkynyl groups where the triple bond is between the first and second carbon atom. If the 1-alkynyl group is attached to another group, e.g., it is a W substituent attached to the cyclic phosphonate, it is attached at the first carbon.
"Amido" refers to the NRW 2 group next to an acyl or sulfonyl group as in NRW 2-C(O)-, RWC(O)-NRW-, NRW 2-S(=O)2- and RWS(=O)2-NRW-, wherein each Rw independently includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
"Amino" refers to -NRxlRxl wherein each Rxl is independently selected from hydrogen, alkyl, aryl, aralkyl and heterocycloalkyl, all except H aarree ooppttiionally substituted, or wherein both Rxl together form a cyclic ring system. "Aminocarbonylamino" refers to - NR^C(O)-NR'-, where R' is selected from a bond, -H, alkyl, aryl, aralkyl, and heterocycloalkyl
"Aminoalkyl" refers to the group NRVaIk- wherein "alk" is an alkylene group and R* is selected from a bond, -H, alkyl, aryl, aralkyl, and heterocycloalkyl .
"Aminocarboxamidoalkyl" refers to the group
NRy 2-C(O)-N(Ry)-alk- wherein each Ry is independently an alkyl group or H and "alk" is an alkylene group. "Lower aminocarboxamidoalkyl-" refers to such groups wherein "alk" is lower alkylene.
"Animal" includes birds and mammals, in one embodiment a mammal, including a dog, cat, cow, horse, goat, sheep, pig or human. In one embodiment the animal is a human. In another embodiment the animal is a male. In another embodiment the animal is a female.
"Aralkyl" refers to aryl -alkylene-. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted. "-Aralkyl-" refers to -arylene-alkylene-. When X is aralkyl, the arylene is attached to M and the alkylene is attached to G8.
"Aralkyloxyalkyl-" refers to the group aryl-alk-O-alk- wherein "alk" is an alkylene group. "Lower aralkyloxyalkyl-" refers to such groups where the alkylene groups are lower alkylene.
"Aroyl" refers to the group aryl-C(O)-.
"Aryl" refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl, bicylic aryl (e.g., naphthyl) and biaryl groups (e.g., biphenyl), all of which may be optionally substituted.
"Arylamino" refers to the group aryl-NH-.
"Alkylamino" refers to the group -NR-alk- wherein "alk" is alkylene and R is a H or lower alkyl. When X is alkylamino, the alkylene group is attached to M and the amino group to G8.
"Aralkylamino" refers to the group -NR-alk-aryl wherein "alk" is alkylene.
"Arylene" refers to divalent aromatic ring systems which have 5-14 atoms and at least one ring having a conjugated pi electron system and includes carbocyclic arylene, heterocyclic arylene and biarylene groups, all of which may be optionally substituted.
"Arylaminoalkyl-"refers to the group aryl-N(Rw)-alk- wherein "alk" is an alkylene group and Rw is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. In "lower arylaminoalkyl-", the alkylene group is lower alkylene.
"Aryloxy" refers to aryl-O-.
"Aryloxyalkyl-"refers to an alkyl group substituted with an aryloxy group.
"Aryloxycarbonyl" refers to the group aryl-O-C(O)-.
"Aryloxycarbonyloxy-"refers to ary 1-0-C(O)-O-.
"Atherosclerosis" refers to a condition characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries wherein such deposits provoke fibrosis and calcification. Atherosclerosis raises the risk of angina, stroke, heart attack, or other cardiac or cardiovascular conditions.
"Biaryl" represents aryl groups which have 5-14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.
"Binding" means the specific association of the compound of interest to the target of interest, .e.g., a receptor.
"C2-6-perfluoroalkyl" refers to a 2 to 6 carbon alkyl group where all of the carbon atoms are exhaustively substituted with fluorine. Non limiting examples include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, pentafluorocyclopropyl, and the like.
"C4_8-cycloalkenyl" refers to a non-aromatic, carbocyclic group having 4 to 8 carbon atoms and containing at least one double bond.
"C3_8-cycloalkyloxy" refers to -O-C^g-cycloalkyl where Cv8- cycloalkyl is an aliphatic carbocyclic group having 3 to 8 carbon atoms
"C3-8-cycloalkylthio" refers to -S-C3-g-cycloalkyl where Cv8- cycloalkyl is a 3 to 8 aliphatic carbocyclic group having 3 to 8 carbon atoms
"-Carboxylamido" or "carboxamido" refer to NRW 2-C(0)-, wherein each Rw include -H, alkyl, aryl, aralkyl, and heterocycloalkyl. "Carboxamidoalkylaryl" refers to NRw 2-C(O)-alk-aryl- where "alk" is alkyl and Rw includes H, alkyl, aryl, aralkyl, and heterocycloalkyl.
"Carboxamidoaryl" refers to NRw-C(O)-aryl- wherein "alk" is alkylene and Rw include H, alkyl, aryl, aralkyl, and heterocycloalkyl.
"Carbocyclic aryl" groups are groups which have 6-14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
"Carbonylalkyl" refers to -C(O)-alk-, where "alk" is alkylene. When X is carbonylalkyl, the carbonyl is attached to M and the alkylene is attached to G8.
"Carboxy esters" refers to -C(O)ORZ where Rz is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, each optionally substituted.
"Carboxyl" refers to -C(O)OH.
"Cyano" refers to — C≡N.
"Cyclic alkyl" or "cycloalkyl" refers to alkyl groups that are cyclic of 3 to 10 carbon atoms, and, in one aspect, are 3 to 6 carbon atoms. The cycloalkyl groups include fused cyclic, bridged cyclic and spirocyclic groups. Examples of cyclic alkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalin, bicycle[3.1.1]heptane, bycyclo[2.2.1]heptane, bycyclo[2.2.2]octane, bicycle[3.2.2]nonane, spiro[2.5]octane, spiro[3.5]nonane, adamantyl and the like. Such groups may be substituted.
"Cycloalkyloxy" refers to the group cycloalkyl-O-.
"Cycloalkylalkoxy" refers to the group cycloalkyl-alkyl-O-.
"Co-crystal" as used herein means a crystalline material comprised of two or more unique solids at room temperature that are H-bonded.
"Coronary heart disease" or "coronary disease" refers to an imbalance between myocardial functional requirements and the capacity of the coronary vessels to supply sufficient blood flow. It is a form of myocardial ischemia (insufficient blood supply to the heart muscle) caused by a decreased capacity of the coronary vessels. "Diabetes" refers to a heterogeneous group of disorders that share glucose intolerance in common. It refers to disorders in which carbohydrate utilization is reduced and that of lipid and protein enhanced; and may be characterized by hyperglycemia, glycosuria, ketoacidosis, neuropathy or nephropathy, increased hepatic glucose production, insulin resistance in various tissues, insufficient insulin secretion and enhanced or poorly controlled glucagon secretion from the pancreas.
Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient.
Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. The vast majority of cases of diabetes fall into two broad etiopathogenetic categories. In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. In the other, much more prevalent category, type 2 diabetes, the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. In the latter category, a degree of hyperglycemia sufficient to cause pathologic and functional changes in various target tissues, but without clinical symptoms, may be present for a long period of time before diabetes is detected. During this asymptomatic period, it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load.
Criteria for the diagnosis of diabetes include: 1. Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl (11.1 mmol/1). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss; or
2. FPG 126 mg/dl (7.0 mmol/1). Fasting is defined as no caloric intake for at least 8 h; or
3. 2-h postload glucose 200 mg/dl (11.1 mmol/1) during an OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
Etiologic classification of diabetes mellitus, as embodiments, are as follows:
I. Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)
A. Immune mediated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) III. Other specific types
A. Genetic defects of β-cell function
1. Chromosome 12, HNF-U (M0DY3)
2. Chromosome 7, glucokinase (MODY2)
3. Chromosome 20, HNF-Aa (MODY 1 )
4. Chromosome 13, insulin promoter factor- 1 (IPF-I; M0DY4)
5. Chromosome 17, HNF-lβ (M0DY5)
6. Chromosome 2, NeuroDl (MODY6)
7. Mitochondrial DNA
8. Others
B. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome 4. Lipoatrophic diabetes
5. Others
C. Diseases of the exocrine pancreas
1. Pancreatitis
2. Trauma/pancreatectomy
3. Neoplasia
4. Cystic fibrosis
5. Hemochromatosis
6. Fibrocalculous pancreatopathy
7. Others
D. Endocrinopathies
1. Acromegaly
2. Cushing's syndrome
3. Glucagonoma
4. Pheochromocytoma
5. Hyperthyroidism
6. Somatostatinoma
7. Aldosteronoma
8. Others
E. Drug- - or chemical-induced
1. Vacor
2. Pentamidine
3. Nicotinic acid
4. Glucocorticoids
5. Thyroid hormone
6. Diazoxide
7. β-adrenergic agonists
8. Thiazides
9. Dilantin
10. α-Interferon
11. Others
F. Infections
1. Congenital rubella 2. Cytomegalovirus
3. Others
G. Uncommon forms of immune-mediated diabetes
1. "Stiff-man" syndrome
2. Anti-insulin receptor antibodies
3. Others
H. Other genetic syndromes sometimes associated with diabetes
1. Down ' s syndrome
2. Klinefelter' s syndrome
3. Turner's syndrome
4. Wolfram's syndrome
5. Friedreich's ataxia
6. Huntington's chorea
7. Laurence-Moon-Biedl syndrome
8. Myotonic dystrophy
9. Porphyria
10. Prader-Willi syndrome
11. Others
IV. Gestational diabetes mellitus (GDM)
"Energy expenditure" means basal or resting metabolic rate as defined by Schoeller et al, J Appl Physiol. ;53(4):955-9 (1982). Increases in the resting metabolic rate can be also be measured using increases in O2 consumption and/or CO2 efflux and/or increases in organ or body temperature.
"Enhanced oral bioavailability" refers to an increase of at least 50% of the absorption of the dose of the parent drug, unless otherwise specified. In an additional aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100% (at least a doubling of the absorption). Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drag metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following systemic administration of the compound administered orally.
"Enhancing" refers to increasing or improving a specific property. "Guanidine" refers to both -NR-C(NR)-NR2 as well as -N=C(NR2)2 where each R group is independently selected from the group of - H, alkyl, alkenyl, alkynyl, aryl, and alicyclic, all optionally substituted. The term "perhalo" refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Suitable perhaloalkyl groups include -CF3 and -CFCI2.
"Haloalkyl" refers to an alkyl group substituted with one halo (halogen group).
"Halogen" or "halo" refers to -F, -Cl, -Br and -I.
"Heteroalicyclic" refers to an alicyclic group or compound having 1 to 4 heteroatoms selected from nitrogen, sulfur, phosphorus and oxygen.
"Heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.
"Heteroarylene" refers to a divalent, aromatic, heterocyclic ring containing 5-14 ring atoms wherein 1 to 4 heteroatoms in the aromatic ring are ring atoms and the remainder of the ring atoms being carbon atoms.
Alternative: "Heteroarylene" refers to a divalent heterocyclic aryl or heteroaryl group.
"Heterocyclic" or "heterocyclyl" refer to cyclic groups of 3 to 10 atoms or cyclic groups of 3 to 6 atoms. These groups contain at least one heteroatom, and in some aspects contain 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups may be attached through a nitrogen or carbon atom in the ring. Heterocyclic and heterocyclyl cyclic groups include, e.g., heterocyclic alkyl or heterocycloalkyl groups. The heterocyclic alkyl groups include unsaturated cyclic, fused cyclic and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.
"Heterocyclic aryl" or "heteroaryl groups" are groups which have 5-14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, and the like, all optionally substituted.
"Hydroxyalkyl" refers to an alkyl group substituted with one -OH.
"Hypercholesterolemia" refers to presence of an abnormally large amount of cholesterol in the cells and plasma of the circulating blood.
"Hyperinsulinemia" refers to a patient with a fasting serum insulin concentration of at least 12 uU/mL.
"Hyperlipidemia" or "lipemia" refers to the presence of an abnormally large amount of lipids in the circulating blood.
"Insulin resistance" is defined clinically as the impaired ability of a known quantity of exogenous or endogenous insulin to increase whole body glucose uptake and utilization.
"Impaired glucose tolerance (IGT)" refers to a condition known to precede the development of overt Type 2 diabetes. It is characterized by abnormal blood glucose excursions following a meal. The current criteria for the diagnosis of IGT are based on 2-h plasma glucose levels post a 75g oral glucose test (144-199 mg/dL). Although variable from population to population studied, IGT progresses to full-blown NIDDM at a rate of 1.5 to 7.3% per year, with a mean of 3-4% per year. Individuals with IGT are believed to have a 6 to 10-fold increased risk in developing Type 2 diabetes. IGT is an independent risk factor for the development of cardiovascular disease.
"Increased or enhanced liver specificity" refers to an increase in the liver specificity ratio in animals treated with a compound of the present invention and a control compound.
"Lower" referred to herein in connection with organic radicals or compounds respectively defines such radicals or compounds as containing up to and including 10 carbon atoms. One aspect of this invention provides organic radicals or compounds as containing up to and including 6 carbon atoms. Yet another aspect of the invention provides organic radicals or compounds that contain one to four carbon atoms. Such groups may be straight chain, branched, or cyclic.
"Liver" refers to the liver organ. "Liver specificity" refers to the ratio:
[drug or a drug metabolite in liver tissue 1
[drug or a drug metabolite in blood or another tissue]
as measured in animals treated with the drug or a prodrug. The ratio can be determined by measuring tissue levels at a specific time or may represent an AUC based on values measured at three or more time points.
"Metabolic disease" includes diseases and conditions such as obesity, diabetes and lipid disorders such as hypercholesterolemia, hyperlipidemia, hypertriglyceridemia as well as disorders that are associated with abnormal levels of lipoproteins, lipids, carbohydrates and insulin such as metabolic syndrome X, diabetes, impaired glucose tolerance, atherosclerosis, coronary heart disease, cardiovascular disease.
"Metabolic Syndrome" or "Metabolic Syndrome X" to a condition identified by the presence of three or more of these components:
• Central obesity as measured by waist circumference:
Men: Greater than 40 inches Women: Greater than 35 inches
• Fasting blood triglycerides greater than or equal to 150 mg/dL
• Blood HDL cholesterol:
Men: Less than 40 mg/dL Women: Less than 50 mg/dL
• Blood pressure greater than or equal to 130/85 mmHg
• Fasting blood glucose greater than or equal to 110 mg/dL "Nitro" refers to -NO2.
"Obesity" refers to the condition of being obese. Being obese is defined as a BMI of 30.0 or greater; and extreme obesity is defined at a BMI of 40 or greater. "Overweight" is defined as a body mass index of 25.0 to 29.9.
"Oxo" refers to =0 in an alkyl or heterocycloalkyl group.
"Perhalo" refers to groups wherein every C-H bond has been replaced with a C-halo bond on an aliphatic or aryl group. Non-linking examples of perhaloalkyl groups include -CF3 and -CFCl2. "Pharmaceutically acceptable salt" includes salts of compounds of the invention derived from the combination of a compound of this invention and an organic or inorganic acid or base. Suitable acids include acetic acid, adipic acid, benzenesulfonic acid,
(+)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonic acid, citric acid, 1 ,2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid, oleic acid, 4,4'-methylenebis [3-hydroxy-2-naphthalenecarboxylic acid], phosphoric acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, sulfosalicylic acid, tannic acid, tartaric acid, terphthalic acid, and p-toluenesulfonic acid.
"Patient" means an animal. In one embodiement a patient is a mammal. In one embodiment a patient is a human.
"Preventing" includes a slowing of the progress or development of a disease before onset or precluding onset of a disease.
"Prodrug" as used herein refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s), or a combination of each. Standard prodrugs are formed using groups attached to functionality, e.g., HO-, HS-, HOOC-, .NHR, associated with the drug, that cleave in vivo. Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. The groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of the invention, fall within this scope. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound. In some cases, the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound. Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems" pp.352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed. by E. B. Roche, American Pharmaceutical Association, Washington, 1977; and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press, Oxford, 1980.
"Significant" or "statistically significant" means a result (i.e. experimental assay result) where the p-value is <0.05 (i.e. the chance of a type I error is less than 5%) as determined by an art-accepted measure of statistical significance appropriate to the experimental design.
"Substituted" or "optionally substituted" includes groups substituted by one to six substituents, independently selected from lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxy esters, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylaminoaryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower -carboxamidoalkylaryl, lower -carboxamidoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy-, lower aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and lower arylalkyloxy alkyl.
"Substituted aryl" and "substituted heteroaryl" refers to aryl and heteroaryl groups substituted with 1-3 substituents. These substituents are selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.
"Sulphon(yl)amido" or "sulfon(yl)amido" refer to NRW 2-S(=O)2- and RWS(=O)2-NRW-, wherein each Rw independely include alkyl, aryl, aralkyl, and heterocycloalkyl.
"Sulfonamidoalkylaryl" and "sulfonamidoaryl" refers to an aryl-alk-NRw-S(=O)2-, and ar-NRw-S(=O)2-, respectively where "ar" is aryl, "alk" is alkylene, Rw includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl.
"Sulphonate" or "sulfonate" refers to -SO2OR", where Rw is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.
"Sulphonyl" or "sulfonyl" refers to -SO2RW, where Rw is alkyl, aryl, aralkyl, or heterocycloalkyl.
"Therapeutically effective amount" means an amount of a compound or a combination of compounds that ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition.
"Treating" or "treatment" of a disease includes a slowing of the progress or development of a disease after onset or actually reversing some or all of the disease affects. Treatment also includes palliative treatment.
"Type 1 diabetes" (formerly known as "childhood," "juvenile," "insulin-dependent" diabetes) is a form of diabetes characterized by an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers. Type 1 diabetes may be caused by immune mediated beta-cell destruction, usually leading to absolute insulin deficiency or may be idiopathic, having no known etiologies.
"Type 2 diabetes" refers to a heterogeneous disorder characterized by impaired insulin secretion by the pancreas and insulin resistance in tissues such as the liver, muscle and adipose tissue. The manifestations of the disease include one or more of the following: impaired glucose tolerance, fasting hyperglycemia, glycosuria, decreased levels of insulin, increased levels of glucagon, increased hepatic glucose output, reduced hepatic glucose uptake and glycogen storage, reduced whole body glucose uptake and utilization, dyslipidemia, fatty liver, ketoacidosis, microvascular diseases such as retinopathy, nephropathy and neuropathy, and macrovascular diseases such as coronary heart disease.
"Phosphonate, phosphonic acid monoester and phosphinate prodrug" refers to compounds that break down chemically or enzymatically to a phosphonic acid or phosphinc acid group in vivo. As employed herein the term includes, but is not limited to, the following groups and combinations of these groups:
Acyloxyalkyl esters which are well described in the literature (Farquhar et al., J. Pharm. Sci., 72: 324-325 (1983)).
Other acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).
Another class of these double esters known as alkyloxycarbonyloxymethyl esters, as shown in formula A, where Ra is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino; each Rc is independently -H, alkyl, aryl, alkylaryl, or heterocycloalkyl have been studied in the area of β-lactam antibiotics (Nishimura et al., J. Antibiotics, 40(1): 81-90 (1987); for a review see Ferres, H., Drugs of Today, 19: 499 (1983)). More recently Cathy, M. S., et al. (Abstract from AAPS Western Regional Meeting, April, 1997) showed that these alkyloxycarbonyloxymethyl ester prodrugs on (9-[(R)-2-phosphonomethoxy)propyl]adenine (PMPA) are bioavailable up to 30% in dogs.
Figure imgf000021_0001
Formula Al Formula A2 wherein Ra and Rc are independently H, alkyl, aryl, alkylaryl, and alicyclic; (see WO 90/08155; WO 90/10636) and Rb, for e.g., is selected from -OH, -CH3, -H, -0-CH3 or monoester prodrug moiety.
Other acyloxyalkyl esters are possible in which a cyclic alkyl ring is formed such as shown in formula B. These esters have been shown to generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions (e.g., Freed et al., Biochem. Pharm., 38: 3193-3198 (1989)).
Figure imgf000022_0001
Formula B 1 Formula B2
wherein Rd is -H, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl.
Aryl esters have also been used as phosphonate prodrugs (e.g., DeLambert et al., J. Med. Chem. 37(7): 498-511 (1994); Serafinowska et al., J. Med. Chem. 38(8): 1372-9 (1995). Phenyl as well as mono and poly- substituted phenyl proesters have generated the parent phosphonic acid in studies conducted in animals and in man (Formula C). Another approach has been described where Re is a carboxylic ester ortho to the phosphate (Khamnei et al., J. Med. Chem. 39: 4109-15 (1996)).
Figure imgf000022_0002
Formula Cl Formula C2 wherein Re is -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, or heterocycloalkyl and Rb is selected, for e.g., from -OH, -CH3, -H, -O-CH3 or monoester prodrug moiety.
Benzyl esters have also been reported to generate the parent phosphonic acid. In some cases, using substituents at the para-position can accelerate the hydrolysis. Benzyl analogs with 4-acyloxy or 4-alkyloxy group [Formula D, X = -H, OR or 0(CO)R or 0(CO)OR] can generate the 4- hydroxy compound more readily through the action of enzymes, e.g., oxidases, esterases, etc. Examples of this class of prodrugs are described in Mitchell et al., J. Chem. Soc. Perkin Trans. 1 2345 (1992); WO 91/19721.
Figure imgf000023_0001
Formula Dl Formula D2
wherein R and R8 are independently -H, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; R is selected, for e.g., from -OH, -CH3, -H, -O-CH3 or monoester prodrug moiety, as described therein.
Rh and R1 are independently -H, alkyl, aryl, alkylaryl, halogen, or cyclic alkyl.
Thio-containing phosphonate proesters may also be useful in the delivery of drugs to hepatocytes. These proesters contain a protected thioethyl moiety as shown in formula E. One or more of the oxygens of the phosphonate can be esterified. Since the mechanism that results in de- esterification requires the generation of a free thiolate, a variety of thiol protecting groups are possible. For example, the disulfide is reduced by a reductase-mediated process (Puech et al., Antiviral Res. 22: 155-174 (1993)). Thioesters will also generate free thiolates after esterase-mediated hydrolysis Benzaria, et al., J. Med. Chem., 39(25): 4958-65 (1996)). Cyclic analogs are also possible and were shown to liberate phosphonate in isolated rat hepatocytes. The cyclic disulfide shown below has not been previously described and is novel.
Figure imgf000024_0001
Formula El Formula El Formula E3
wherein RJ is alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio and Rb is selected, for e.g., from -OH, -CH3, -H, -O-CH3 or monoester prodrug moiety.
Other examples of suitable prodrugs include proester classes exemplified by Biller and Magnin (U.S. 5,157,027); Serafinowska et al., J. Med. Chem,. 38(8): 1372-9 (1995); Starrett et al., J. Med. Chem, 37: 1857 (1994); Martin et al. J. Pharm. Sci. 76: 180 (1987); Alexander et al., Collect. Czech. Chem. Commun, 59: 1853 (1994); and EP 0 632048 Al. Some of the structural classes described are optionally substituted, including fused lactones attached at the omega position (formulae E4 and E5) and optionally substituted 2-oxo-l,3-dioxolenes attached through a methylene to the phosphorus oxygen (formula E6) such as:
Figure imgf000024_0002
Formula E4a Formula E4b
Figure imgf000025_0001
Formula E5a Formula E5b
Figure imgf000025_0002
Formula E6a Formula E6b
wherein Rm is -H, alkyl, cycloalkyl, or heterocycloalkyl; Rb is selected, for e.g., from -OH, -CH3, -H, -O-CH3 or monoester prodrug moiety and Rk is - H, alkyl, aryl, alkylaryl, cyano, alkoxy, acyloxy, halogen, amino, heterocycloalkyl, or alkoxy carbonyl.
The prodrugs of Formula E6 are an example of "optionally substituted heterocycloalkyl where the cyclic moiety contains a carbonate or thiocarbonate."
Propyl phosphonate proesters can also be used to deliver drugs into hepatocytes. These proesters may contain a hydroxyl and hydroxyl group derivatives at the 3-position of the propyl group as shown in formula F2. The Rn and Rp groups can form a cyclic ring system as shown in formula F2. One or more of the oxygens of the phosphonate can be esterified.
Figure imgf000026_0001
Figure imgf000026_0002
Formula F2a Formula F2b
wherein Rn is alkyl, aryl, or heteroaryl;
Rp is alkylcarbonyloxy, or alkyloxycarbonyloxy;
Rb is selected, for e.g., from -OH, -CH3, -H, -O-CH3 or monoester prodrug moiety ;and
Rq is alkyl, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, halogen, hydrogen, hydroxy, acyloxy, or amino.
Phosphoramidate derivatives have been explored as phosphate prodrugs (e.g., McGuigan et al., J. Med. Chem., 42: 393 (1999) and references cited therein) as shown in Formula G and H, wherein Rr, for example.is lower alkyl, lower aryl, lower aralkyl, and as described therein..
Figure imgf000026_0003
Formula Gl Formula G2
Figure imgf000027_0001
Figure imgf000027_0002
Formula H2
Cyclic phosphoramidates have also been studied as phosphonate prodrugs because of their speculated higher stability compared to non-cyclic phosphoramidates (e.g., Starrett et al., J. Med. Chem., 37: 1857 (1994)).
Another type of phosphoramidate prodrug was reported as the combination of S-acyl-2-thioethyl ester and phosphoramidate (Egron et al., Nucleosides & Nucleotides, 18, 981 (1999)) as shown in Formula J wherein Rc is alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino and Ra is -H, alkyl, aryl, alkylaryl, or heterocycloalkyl:
Figure imgf000027_0003
Formula J
Other prodrugs are possible based on literature reports such as substituted ethyls for example, bis(trichloroethyl)esters as disclosed by McGuigan, et al., Bioorg Med. Chem. Lett., 3:1207-1210 (1993), and the phenyl and benzyl combined nucleotide esters reported by Meier, C. et al., Bioorg. Med. Chem. Lett. 7:99-104 (1997).
The structure of formula L has a plane of symmetry running through the phosphorus-oxygen double bond when both R60S are the same, V=W, and V and W (defined herein) are either both pointing up or both pointing down. The same is true of structures where both -NR60S are replaced with -O-.
Figure imgf000028_0001
Formula L
The term "cyclic phosphonate ester of 1,3-propane diol", "cyclic phosphonate diester of 1,3-propane diol", "2 oxo 2λ5 [1,3,2] dioxaphosphonane", "2 oxo [1,3,2] dioxaphosphonane", "dioxaphosphonane" refers to the following:
Figure imgf000028_0002
Formula M
The phrase "together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally containing 1 heteroatom, substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus" includes the following:
Figure imgf000028_0003
The structure shown above (left) has an additional 3 carbon atoms that forms a five member cyclic group. Such cyclic groups must possess the listed substitution to be oxidized.
The phrase "together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, that is fused to an aryl group attached at the beta and gamma position to the G attached to the phosphorus" includes the following:
Figure imgf000029_0001
Formula O
The phrase "together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus" includes the following:
Figure imgf000029_0002
Formula P
The structure above has an acyloxy substituent that is three carbon atoms from a Y, and an optional substituent, -CH3, on the new 6-membered ring. There has to be at least one hydrogen at each of the following positions: the carbon attached to Z; both carbons alpha to the carbon labeled "3"; and the carbon attached to "OC(O)CH3" above. The phrase "together W and W are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl" includes the following:
Figure imgf000030_0001
Formula Q
The structure above has V=aryl, and a spiro-fused cyclopropyl group for W and W.
The term "cyclic phosphon(amid)ate" refers to:
Figure imgf000030_0002
Formula R, wherein Y is independently - -OO-- oorr --NNRR660-. The carbon attached to V must have a C-H bond. The carbon attached to Z must also have a C-H bond. For cylic 1,3-propanyl phonsponate prodrugs of compounds of the present invention the term "cis" stereochemistry refers to the spatial relationship of the V group and the carbon attached to the phosphorus atom on the six-membered ring. The formula below shows a cis stereochemistry.
Figure imgf000031_0001
Formula S
The term "trans" stereochemistry for the same moiety refers to the spatial relationship of the V group and the carbon, attached to the phosphorus atom, on the six-membered ring. The formula below shows a trans- stereochemistry.
Figure imgf000031_0002
Formula T
The formula below shows another trans-stereochemistry of the same moiety.
Figure imgf000031_0003
Formula U The terms "S-configuration", "S-isomer" and "S-prodrug" of the same refers to the absolute configuration S of carbon C. The formula below shows the S-stereochemistry.
Figure imgf000032_0001
Formula W
The terms "R-configuration", "R-isomer" and "R-prodrug" of the same refers to the absolute configuration R of carbon C . The formula below shows the R-stereochemistry.
Figure imgf000032_0002
Formula Y
The term "percent enantiomeric excess (% ee)" refers to optical purity. It is obtained by using the following formula:
ΓRI - rsi x 100 = %R - %s
[R] + [S] where [R] is the amount of the R isomer and [S] is the amount of the S isomer. This formula provides the % ee when R is the dominant isomer.
The term "enantioenriched" or "enantiomerically enriched" refers to a sample of a chiral compound that consists of more of one enantiomer than the other. The extent to which a sample is enantiomerically enriched is quantitated by the enantiomeric ratio or the enantiomeric excess.
Compounds:
The present invention relates to compounds of general Formulas I- III and IX-XIII and pharmaceutically acceptable salts, co-crystals and prodrugs thereof, and methods of making and using the same.
One aspect of the present invention provides for compounds of general Formulas I-III:
Figure imgf000033_0001
Formula I Formula I Formula III
wherein:
Gi, G2, G3, G6, G7 and G9 are each independently selected from the group consisting of C and N;
G8 is C;
A is selected from the group consisting of absent, -H, -NR8 2, -NO2, - OR7, -SR7, -C(O)NR5 2, halo, -C(O)R11, -SO2R9, guanidine, -C(NH)NR5 2, - NHSO2R20, -SO2NR5 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Q-Csalkyl, C^Csalkenyl, C2-C5alkynyl, and lower alicyclic;
L is selected from the group consisting of absent, -H, -NR 2, -NO2, - OR7, -SR7, -C(O)NR5 2, halo, -C(O)R11, -SO2R9, guanidine, -C(NH)NR5 2, - NHSO2R20, -SO2NR5 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-Csalkyl, C2-C5alkenyl, C2-C5alkynyl, and lower alicyclic; or together A and L form a cyclic group;
E is selected from the group consisting of absent, -H, -NR8 2, -NO2, - OR7, -SR7, -C(O)NR5 2, halo, -C(O)R11, -SO2R9, guanidine, -C(NH)NR5 2, - NHSO2R20, -SO2NR5 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-Csalkyl, C2-Csalkenyl, C2-Csalkynyl, and lower alicyclic; or together E and J form a cyclic group; or
J is selected from the group consisting of absent, -H, -NR 2, -NO2, - OR7, -SR7, -C(O)NR5 2, halo, -C(O)R11 , -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl; or together J and D form a cyclic group;
D is selected from the group consisting of absent, -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R9, -S(O)2R9, -C(O)R11 ,-C(O)-OR9, -CONHR9, -NR2 2, and -OR9, each, except H, optionally substituted; or together D and X form a cyclic group;
X is selected from the group consisting of -alkylamino-, - alkylene(hydroxy)-, -alkylene(carboxyl)-, -alkylene(phosphonate)-, -alkylene-, -alkenylene-, -alkynylene-, -alkylene(sulfonate)-, -arylene-, -carbonylalkyl-, - (l,l-dihalo)alkylene-, -aminocarbonylamino-, -alkylaminoalkyl-, - alkoxyalkyl-, -alkylthioalkyl-, -alkylthio-, - alkylaminocarbonyl -, - alkylcarbonylamino-, -alicyclic-, -aralkyl-, and -alkylaryl-, each optionally substituted; or together X and D form a cyclic group; M is -P(O)(YR21)Y'R21;
Y and Y' are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y' are both -0-, R21 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R52)2OC(O)NR52 2, -NR52-C(O)-R53, -C(R52)2-OC(O)R5\ -C(R52)2-O-C(O)OR53, -C(R52)2OC(O)S R53, -alkyl-S-C(O)R53, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y' are both -NRV-, then R21 attached to -NRV- is independently selected from the group consisting of -H, -[C(R52)2]P-COOR53, -C(If)2COOR53, -[C(R52)2]P-C(O)SR53, and -cycloalkylene-COOR53; when Y is -O- and Y' is NRV, then R21 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2- heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R52)2OC(O)NR52 2, -NR52-C(O)-R53, -C(R5V-OC(O)R53, -C(R52)2-O-C(O)OR53, -C(R52)2OC(O)S R53,
-alkyl-S-C(O)R53, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R21 attached to -NRV- is independently selected from the group consisting of -H, -[C(R52)2]P-COOR53, -C(RX)2COOR53, -[C(R52)2]P-C(O)SR53, and -cycloalkylene-COOR53; wherein if both R21 are alkyl, at least one is higher alkyl; or when Y and Y' are independently selected from -O- and -NRV-, then R21 and R21 together form a cyclic group comprising -alkyl-S-S-alkyl-, or R21 and R21 together are the group:
Figure imgf000035_0001
wherein:
V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; and
Z is selected from the group consisting of - CHR52OH, -CHR52OC(O)R53,
CHR52OC(S)R53, -CHR52OC(S)OR53, -CHR52OC(O)SR53, -CHR52OCO2R53, - OR52,
-SR52, -CHR52N3, -CH2aryl, -CH(aryl)OH, -CH(CH=CR52 2)OH, -CH(C≡CR52)OH, -R52, -NR52 2,-OCOR5\ -OCO2R53, -SCOR53, -SCO2R53, -NHCOR52, -NHCO2R53, -CH2NHaTyI, -(CH2)P-OR52, and -(CH2)p-SR52;or
W and W are as defined above and together V and Z are connected via (a) an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon, optionally substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus, or (b) an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, wherein said cyclic group is fused to an aryl group at the beta and gamma position to a Y or Y that is attached to the phosphorus; or
W and Z are as defined above and together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon ring atoms optionally substituted with one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy, said substituent attached to one of said carbon ring atoms that is three atoms from a Y or Y' that is attached to the phosphorus; or
W is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon; or
Z is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together W and W are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining ring atoms are carbon;
R52 is selected from the group consisting of R53 and -H;
R53 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Rx is independently selected from the group consisting of -H, and alkyl, or together Rx and Rx form a cycloalkyl group;
Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; p is an integer 2 or 3;
9 Q
R is selected from the group consisting of R and -H;
R is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl;
R is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and -C(O)R10;
R8 is selected from the group consisting of -H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R10, or together they form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R is selected from the group consisting of -H, lower alkyl, -NH2, lower aryl, and lower perhaloalkyl;
R is selected from the group consisting of alkyl, aryl, -OH, -NH2 and
-OR9;
R2 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; wherein, a) V, Z, W, W are not all -H, b) when Z is -R52, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl, and, c) said compound of Formula I-III is not a compound of Formulas IV-VIII as represented by
Figure imgf000037_0001
Formula IV,
Figure imgf000038_0001
Formula V,
Figure imgf000039_0001
Formula VI,
Figure imgf000039_0002
Formula VII, and
Figure imgf000039_0003
Formula VIII; or a pharmaceutically acceptable salt, co-crystal or prodrug thereof.
In one aspect the present invention provides for compounds of Formulas IX or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula IX, wherein the substituents (Gi-G^, G7-G9, L, E, J, D, X and M) are as defined above; B is C1-C5 alkyl, C2-C5 alkenyl, C2- C5 alkynyl, lower alicyclic or aralkyl; and, X" is Cl" or Br":
Figure imgf000040_0001
Formula IX.
In one aspect the present invention provides for compounds of Formula X or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula X, wherein the substituents (G7-G9, L, E, J, D, X and M) are as defined above:
Figure imgf000040_0002
Formula X.
In one aspect the present invention provides for compounds of Formula XI or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XI, wherein the substituents (Gi, G2, Ge5G7-Gg, A, L, E, D, X and M) are as defined above; B is CrC5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, lower alicyclic or aralkyl; and, X" is Cl" or Br"
Figure imgf000041_0001
Formula XI.
In one aspect the present invention provides for compounds of Formula XII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XII, wherein the substituents (Gi, G2, G6, G7-G9, A, L, E, D, X and M) are as defined above.
Figure imgf000041_0002
In one aspect the present invention provides for compounds of Formula XIII or a pharmaceutically acceptable salt, co-crystal or prodrug thereof as represented by Formula XIII, wherein the substituents (G7-G9, A, L, E,D, X and M) are as defined above:
Figure imgf000041_0003
Formula XIII.
In one aspect A, L, and E are independently selected from the group consisting of absent-H, -NR 2, -NO2, hydroxy, alkylaminocarbonyl, halogen, - OR7, -SR7, lower perhaloalkyl, and C)-C5 alkyl.
In another aspect A, L and E are independently selected from the group consisting of absent -NR8 2, -H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower alkyl.
In another aspect A is selected from the group consisting of absent - NR8 2, -H, halogen, lower perhaloalkyl, and lower alkyl.
In another aspect L and E are independently selected from the group consisting of absent -H, lower alkoxy, lower alkyl, and halogen.
In another aspect J is selected from the group consisting of absent -H, halogen, lower alkyl, lower hydroxylalkyl, -NR8 2, lower R8 2N-alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic.
In another aspect J is selected from the group consisting of absent -H, halogen, and lower alkyl-, lower hydroxyalkyl-, -NR8 2, lower R8 2N-alkyl-, lower haloalkyl, lower alkenyl, alicyclic, and aryl.
In another aspect J is selected from the group consisting of alicyclic and lower alkyl.
In another aspect A and L together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
In another aspect L and E together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
In another aspect E and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
In another aspect D and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
In another aspect D and X together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl. In another aspect X is selected from the group consisting of -alkylene-, -alkynylene-, -arylene-, -alkoxyalkyl-, -alkylthio-, -alkylaminocarbonyl-, - alkylcarbonylamino-, -(l,l-dihalo)alkylene, -carbonylalkyl-, -alkylene(OH)-, and -alkylene(sulfonate)-.
In another aspect X is selected from the group consisting of - heteroarylene-, -alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, - alkylene(sulfonate)-, and -alkoxyalkyl-.
In another aspect X is selected from the group consisting of - heteroarylene-, -alkylaminocarbonyl-, and -alkoxyalkyl-.
In another aspect X is selected from the group consisting of - methylaminocarbonyl-, - methoxymethyl-, and furan-2,5-diyl.
In another aspect X is not substituted with a phosphonic acid or ester.
In another aspect, when X is substituted with a phosphonic acid or ester, then A is -NR8 2 and D is not -H.
In another aspect, when X is -arylene- or -alkylaryl-, X does not link Gs and M through position 1 and 4 a 6-membered aromatic ring.
In another aspect X is Furan-2,5-diyl, Pyridin-2,6-diyl, Oxazol-2,5- diyl, -C(O)-OCH2-, -C(O)-NHCH2-, -C(O)-SOE-, -C(0)-N(Me)CH2-, - NHC(0)-CH2-, -CH2θ CH2-, wherein the direction of X is from G8 to M.
In another aspect R20 and R7 are independently selected from the group consisting of -H, and lower alkyl.
In another aspect A, L, and E are independently selected from the group consisting of absent -H, lower alkyl, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and -NR8 2; X is selected from the group consisting of - arylene-, -alkoxyalkyl-, -alkylene-, -alkylthio-, -(l,l-dihalo)alkylene-, - carbonyl-, -alkylene-, -alkylene(hydroxy)-, -alkylene(sulfonate)-, - alkylaminocarbonyl-, and -alkylcarbonylamino-; and each R5 and R7 is independently -H, or lower alkyl.
In another aspect A, L, and E are independently selected from the group consisting of absent -H, lower alkyl, halogen, and -NR8 2; J is selected from the group consisting of -H, halogen, haloalkyl, hydroxyalkyl, R 2N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic, or together with D forms a cyclic group; and X is selected from the group consisting of -heteroarylene-, - alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, and -alkoxyalkyl-.
In another aspect A is selected from the group consisting of -H, -NH2, - F, and -CH3; L is selected from the group consisting of -H, -F, -OCH3, -Cl, and -CH3; E is selected from the group consisting of -H and -Cl; J is selected from the group consisting of -H, halo, C1-C5 hydroxyalkyl, C1-C5 haloalkyl, R8 2N- Ci-Csalkyl, Q-Csalicyclic, and Q-Csalkyl; X is selected from the group consisting Of -CH2OCHi- and furan-2,5-diyl; and, D is lower alkyl.
In one aspect M is selected from the group consisting of -P(O)[-OCR52 2OC(O)R53]2, -P(O)[-OCR52 2OC(O)OR"]2, -P(O)[-N(H)CR52 2C(O)OR53]2, -P(O)[-N(H)CR52 2C(O)OR53][-ORπ], -P(O) [-OCH(V)CH2CH2O-], -P(O)(OH)(OR11), -P(O)(ORe)(ORe), -P(O)[-OCR52 2OC(O)R53](ORe), -P(O)[-OCR52 2OC(O)OR53](ORe), and -P(O)[-N(H)CR52 2C(O)OR53](ORe); wherein:
V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl;
Re is selected from the group consisting of optionally substituted -C1-C12 alkyl, optionally substituted -C2-Ci2 alkenyl, optionally substituted -C2-Ci2 alkynyl, optionally substituted -(CR57 2)naryl, optionally substituted -(CR57 2)ncycloalkyl, and optionally substituted -(CR57 2)nheterocycloalky 1 ; n is an integer from 1 to 3; each R57 is independently selected from the group consisting of hydrogen, optionally substituted -Q-C4 alkyl, halogen, optionally substituted -0-Ci-C4 alkyl, -OCF3, optionally substituted -S-Ci-C4 alkyl, -NR58R59, optionally substituted -C2-C4 alkenyl, and optionally substituted -C2-C4 alkynyl; with the proviso that when one R57 is attached to C through an O, S, or N atom, then the other R57 attached to the same C is a hydrogen, or attached via a carbon atom;
R58 is selected from hydrogen and optionally substituted -Ci-C4 alkyl; and, R59 is selected from the group consisting of hydrogen and optionally substituted -Q-C4 alkyl, optionally substituted -C(O)-Ci-C4 alkyl and -C(O)H.
In the above compounds the asymmetric carbon of alpha-amino esters is of the L-configuration.
In another aspect M is selected from the group consisting of -PO3H2, -P(O)[-OCR52 2OC(O)R53]2, -P(O)[-OCR52 2OC(O)OR53]2, -P(O)[-N(H)CR522C(O)OR"]2, -P(O)[-N(H)CR52 2C(O)OR53][-ORπ], -P(O) [-OCH(V)CH2CH2O-], , -P(O)(OReXORe), -P(O)[-OCR52 2OC(O)R53](ORe), -P(O)[-OCR52 2OC(O)OR 53](ORe), -P(O)[-N(H)CR52 2C(O)OR53](ORe), and -P(O)(OH)(NH2); wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
In another aspect M is selected from the group consisting of -PO3H2, -P(O)[-OCH2OC(O)-r-butyl]2, -P(O)[-OCH2OC(O)O-i-propyl]2, -P(O)[-N(H)CH(CH3)C(O)O CH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(0)[-N(H)CH (CH3)C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-N(H)C (CH3)2C(O)OCH2CH3] [3,4-methylenedioxyphenyl] , -P(0)[-0CH (3-chlorophenyl)CH2CH2O-], -P(O)[-OCH(pyrid-4-yl)CH2CH2O-], -P(O)[-OCH2OC(O)- f-butyl](OCH3), -P(O)[-OCH2OC(O)O-/-propyl](OCH3), -P(0)[-0CH (CH3)OC(OH-butyl] (OCH3), -P(O)[-OCH(CH3)OC(O)O-/-propyl] (OCH3), -P(O)[-N(H)CH(CH3)C(O)OCH2CH3](OCH3), -P(O)[-N(H)C(CH3)2C(O)OCH2CH3](OCH3), and -P(O)(OH)(NH2).
In another aspect M is selected from wherein Y and Y' are each independently selected from -O- and -NRV-; together R2' and R21 are the group:
Figure imgf000046_0001
wherein V is substituted aryl or substituted heteroaryl.
In another aspect Z is selected from hydrogen, W is hydrogen, and W is hydrogen.
In another aspect V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl and 3,5-dichlorophenyl.
Another aspect provides for the use of a compound of the invention for the manufacture of a medicament for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which an FBPase inhibitor(s) is indicated.
Another aspect provides for the use of a compound of the invention for the manufacture of a medicament for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels, the method comprising the step of administering to a patient a therapeutically effective amount a compound of the invention, or a pharmaceutically acceptable salt or prodrugs thereof.
Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type I diabetes, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type II diabetes, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of impaired glucose tolerance, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of insulin resistance, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
Another aspect provides for methods for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of hyperglycemia, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
Another aspect provides for methods for treating, preventing, delaying the time to onset of or reducing the risk for the development or progression accelerated gluconeogenesis, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
Another aspect provides for methods for treating, preventing, delaying the time to onset of or reducing the risk for the development or progression increased or excessive (greater than normal levels) hepatic glucose output, the method comprising the step of administering to a patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.
Another aspect provides for a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically exceptable excipient.
Another aspect provides for a pharmaceutical composition comprising a salt or co-crystal of a compound of Formula I-III or IX-XIII and a pharmaceutically exceptable excipient. Formulations:
In one aspect, compounds of the invention are administered in a total daily dose of 0.01 to 2500 mg. In one aspect the range is about 1 mg to about 1000 mg. In one aspect the range is about 1 mg to about 500 mg. In one aspect the range is about 10 mg to about 500 mg. The dose may be administered in as many divided doses as is convenient or necessary.
In another aspect, compounds of the invention are administered in a unit dose of a range between 0.01 to 1000 mg. In one aspect the range is about 0.1 mg to about 500 mg. In one aspect the range is about 0.1 mg to about 100 mg. In one aspect the range is about 1 mg to about 1000 mg. In one aspect the range is about 1 mg to about 500 mg. In one aspect the range is about 1 mg to about 100 mg. In one aspect the range is about 1 mg to about 10 mg. In one aspect the range is about 10 mg to about 1000 mg. In one aspect the range is about 10 mg to about 500 mg. In one aspect the range is about 10 mg to about 100 mg. In one aspect, the unit dose is 10 mg. In one aspect, the unit dose is 25 mg. In one aspect, the unit dose is 50 mg. In one aspect, the unit dose is 75 mg. In one aspect, the unit dose is 100 mg. In one aspect, the unit dose is 150 mg. In one aspect, the unit dose is 200 mg. In one aspect, the unit dose is 250 mg. In one aspect, the unit dose is 300 mg. In one aspect, the unit dose is 400 mg. In one aspect, the unit dose is 500 mg. In one aspect, the unit dose is 600 mg. In one aspect, the unit dose is 700 mg. In one aspect, the unit dose is 800 mg. In one aspect, the unit dose is 900 mg. In one aspect, the unit dose is 1000 mg.
In one aspect the compound is administered QD (once a day). In another aspect the compound is administered BID (twice a day). In another aspect the compound is administered TID (three times a day). In another aspect the compound is administered QID (four times a day). In one aspect the compound is administered before a meal. In one aspect the compound is administered after a meal. In one aspect the compound is administered in the morning hours. In one aspect the compound is administered upon awaking in the morning. In one aspect the compound is administered in the evening hours. In one aspect the compound is administered at bedtime in the evening. Compounds of this invention may be used in combination with other pharmaceutical agents. The compounds may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). Administration of the compound may occur at or near the time in which the other pharmaceutical agent is administered or at a different time. The compounds of this invention may be used in a multidrug regimen, also known as combination or 'cocktail' therapy, wherein, multiple agents may be administered together, may be administered separately at the same time or at different intervals, or administered sequentially. The compounds of this invention may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy by another agent in a treatment program. For the purposes of this invention, the compounds may be administered by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters. Intravenous administration is generally preferred.
Pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucoranate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, subsalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.
Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. One aspect relates to the administration of a pharmaceutically acceptable composition of the present invention by controlled- or delayed-release means. Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts.
A variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the crystalline forms of the invention. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598, 123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5, 639,476; 5,354,556; 5,733,566; and 6,365,185; each of which is incorporated herein by reference. These dosage forms can be used to provide delayed or controlled- release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS, Alza Corporation, Mountain View, Calif. USA), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions. Additionally, ion exchange materials can be used to prepare immobilized, adsorbed co-crystals and thus effect controlled delivery of the drug. Examples of specific anion exchangers include, but are not limited to, Duolite A568 and Duolite AP143 (Rohm & Haas, Spring House, PA, USA). One aspect of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable composition comprising a crystalline form of a compound of the present invention and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition, medicament or dosage forms is formulated for controlled-release. In another aspect, the dosage form utilizes an osmotic drug delivery system.
A particular and well-known osmotic drug delivery system is referred to as OROS (Alza Corporation, Mountain View, Calif. USA). This technology can readily be adapted for the delivery of compounds and compositions of the invention. Various aspects of the technology are disclosed in U.S. Pat. Nos. 6, 375, 978; 6,368,626 ; 6,342,249; 6,333,050; 6,287,295; 6, 283,953; 6,270,787; 6,245,357; and 6,132,420; each of which is incorporated herein by reference. Specific adaptations of OROS that can be used to administer compounds and compositions of the invention include, but are not limited to, the OROS; Push- PuIl, Delayed Push-Pull, Multi-Layer Push- Pull, and Push-Stick Systems, all of which are well known. See, e.g., http://www. alza.com. Additional OROS systems that can be used for the controlled oral delivery of compounds and compositions ofthe invention include OROS- CT and L-OROS (Id.; see also, Delivery Times, vol. II, issue II (Alza Corporation).
Conventional OROS oral dosage forms are made by compressing a drug powder (e.g. a crystalline form selected from Forms A-D) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser). Kim, Cherug-ju, Controlled Release Dosage Form Design, 231-238 (Technomic Publishing, Lancaster, PA: 2000). The advantage of such dosage forms is that the delivery rate of the drug is not influenced by physiological or experimental conditions. Even a drug with a pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium. But because these advantages are provided by a build-up of osmotic pressure within the dosage form after administration, conventional OROS drug delivery systems cannot be used to effectively deliver drugs with low water solubility. Id. at 234.
A specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drug layer located within the cavity adjacent to the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer interposed between the inner surface of the wall and at least the external surface of the drag layer located within the cavity, wherein the drug layer comprises a crystalline form of a compound of the present invention. See U.S. Pat. No. 6,368,626, the entirety of which is incorporated herein by reference.
Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drug layer, wherein the active agent formulation comprises a crystalline form of a compound of the present invention. See U. S. Pat. No. 6,342,249, the entirety of which is incorporated herein by reference.
In another aspect, a pharmaceutical composition or medicament comprising a crystalline form of a compound of the present invention is administered transdermally. Such a transdermal (TD) delivery can avoid first- pass metabolism. Additionally, a "pill-and-patch" strategy can be taken, where only a fraction of the daily dose is delivered through the skin to generate basal systemic levels, onto which oral therapy is added. Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachid oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. This is particularly advantageous with the compounds of the invention when such compounds are susceptible to acid hydrolysis.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Formulations suitable for parenteral administration may be administered in a continuous infusion manner via an indwelling pump or via a hospital bag. Continuous infusion includes the infusion by an external pump. The infusions may be done through a Hickman or PICC or any other suitable means of administering a formulation either parenterally or i.v.
Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug.
It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
Examples: Synthesis of the Compounds of the Invention:
Synthesis of Compounds of Formula 1 :
Synthesis of the compounds encompassed by the present invention typically includes some or all of the following general steps: (1) synthesis of the prodrug ; (2) phosphonate deprotection; (3) substitution of the heterocycle; (4) substitution or modification of 2-substituent; (5) cyclization to generate bicyclic base ring system; (6) synthesis of the linker-PO^; and (7) synthesis of the monocyclic base precursor. A detailed discussion of each step is given below.
Figure imgf000057_0001
1
(wherein G4 and G5 are each independently selected from C or N)
1) Preparation of a Phosphonate Prodrug
Prodrugs can be introduced at different stages of the synthesis. Most often these prodrugs are made from the phosphonic acids of compounds of the invention because of their lability.
Phosphonic acids of compounds of the invention can be alkylated with electrophiles such as alkyl halides and alkyl sulfonates under nucleophilic substitution conditions to give phosphonate esters. For example, compounds of invention wherein YR21 is an acyloxyalkyl group can be prepared by direct alkylation of compounds of invention with an appropriate acyloxyalkyl halide (e.g., Cl, Br, I; Phosphorus Sulfur 54:143 (1990); Synthesis 62 (1988)) in the presence of a suitable base (e.g., pyridine, TEA, diisopropylethylamine) in suitable solvents such as DMF (J. Med. Chem. 37:1875 (1994)). The carboxylate component of these acyloxyalkyl halides includes but is not limited to acetate, propionate, isobutyrate, pivalate, benzoate, carbonate and other carboxylates.
Dimethylformamide dialkyl acetals can also be used for the alkylation of phosphonic acids (Collect. Czech Chem. Comma. 59:1853 (1994)). Compounds of invention wherein YR21 is a cyclic carbonate, a lactone or a phthalidyl group can also be synthesized by direct alkylation of the free phosphonic acids with appropriate halides in the presence of a suitable base such as NaH or diisopropylethylamine (/. Med. Chem. 38:1372 (1995); J. Med. Chem. 57:1857 (1994); J. Pharm. ScL 76:180 (1987)).
Alternatively, these phosphonate prodrugs can be synthesized by the reactions of the corresponding dichlorophosphonates and an alcohol (Collect Czech Chem. Commun. 59:1853 (1994)). For example, a dichlorophosphonate is reacted with substituted phenols and arylalkyl alcohols in the presence of a base such as pyridine or TEA to give the compounds of of the invention wherein YR21 is an aryl group (J. Med. Chem. 39:4109 (1996); J. Med. Chem. 38:1372 (1995); J. Med. Chem. 37:498 (1994)) or an arylalkyl group (J. Chem. Soc. Perkin Trans. 1 38:2345 (1992)). The disulfide-containing prodrugs (Antiviral Res. 22:155 (1993)) can be prepared from a dichlorophosphonate and 2-hydroxyethyldisulfide under standard conditions. Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs. For example, treatment of a dichlorophosphonate with ammonia gives both a monophosphonamide and a diphosphonamide; treatment of a dichlorophosphonate with l-amino-3- propanol gives a cyclic 1 ,3-propylphosphonamide; treatment of a chlorophosphonate monophenyl ester with an amino acid ester in the presence of a suitable base gives a substituted monophenyl monophosphonamidate.
Such reactive dichlorophosphonates can be generated from the corresponding phosphonic acids with a chlorinating agent (e.g., thionyl chloride, J. Med. Chem. 1857 (1994); oxalyl chloride, Tetrahedron Lett. 37:3261 (1990); phosphorous pentachloride, Synthesis 490 (1974)). Alternatively, a dichlorophosphonate can be generated from its corresponding disilyl phosphonate esters (Synth. Comma. 17:107 '1 (1987)) or dialkyl phosphonate esters (Tetrahedron Lett. 24:4405 (1983); Bull. Soc. CMm. 750:485 (1993)).
It is envisioned that compounds of the invention can be mixed phosphonate ester (e.g., phenyl and benzyl esters, or phenyl and acyloxyalkyl esters) including the chemically combined mixed esters such as phenyl and benzyl combined prodrugs reported in Bioorg. Med. Chem. Lett. 7:99 (1997).
Dichlorophosphonates are also useful for the preparation of various phosphonamides as prodrugs. For example, treatment of a dichlorophosphonate with an amine (e.g. an amino acid alkyl ester such as L- alanine ethyl ester) in the presence of a suitable base (e.g. triethylamine, pyridine, etc.) gives the corresponding bisphosphonamide; treatment of a dichlorophosphonate with l-amino-3-propanol gives a cyclic 1,3- propylphosphonamide; treatment of a chlorophosphonate monophenyl ester with an amino acid ester in the presence of a suitable base gives a substituted monophenyl monophosphonamidate. Direct couplings of a phosphonic acid with an amine (e.g. an amino acid alkyl ester such as L-alanine ethyl ester) are also reported to give the corresponding bisamidates under Mukaiyama conditions (J. Am. Chem. Soc, 94:8528 (1972)).
The SATE (5-acetyl thioethyl) prodrugs can be synthesized by the coupling reaction of the phosphonic acids of compounds of the invention and S-acyl-2-thioethanol in the presence of DCC, EDCI or PyBOP (J. Med. Chem. 59:1981 (1996)).
Cyclic phosphonate esters of substituted 1 ,3-propane diols can be synthesized by either reactions of the corresponding dichlorophosphonate with a substituted 1,3-propanediol or coupling reactions using suitable coupling reagents (e.g., DCC, EDCI, PyBOP; Synthesis 62 (1988)). The reactive dichlorophosphonate intermediates can be prepared from the corresponding acids and chlorinating agents such as thionyl chloride (J. Med. Chem. 1857 (1994)), oxalyl chloride (Tetrahedron Lett. 57:3261 (1990)) and phosphorus pentachloride (Synthesis 490 (1974)). Alternatively, these dichlorophosphonates can also be generated from disilyl esters (Synth. Commun. 77:1071 (1987)) and dialkyl esters (Tetrahedron Lett. 24:4405 (1983); Bull. Soc. Chim. Fr., 750:485 (1993)). Alternatively, these cyclic phosphonate esters of substituted 1,3- propane diols are prepared from phosphonic acids by coupling with diols under Mitsunobu reaction conditions (Synthesis 1 (1981); J.Org. Chem. 52:6331 (1992)), and other acid coupling reagents including, but not limited to, carbodiimides (Collect. Czech. Chem. Commun. 59: 1853 (1994); Bioorg. Med. Chem. Lett. 2:145 (1992); Tetrahedron Lett. 29:1189 (1988)), and benzotriazolyloxytris-(dimethylamino) phosphonium salts (Tetrahedron Lett. 34:6743 (1993)).
Phosphonic acids also undergo cyclic prodrug formation with cyclic acetals or cyclic ortho esters of substituted propane-l,3-diols to provide prodrugs as in the case of carboxylic acid esters (HeIv. Chim. Acta. 48:1746 (1965)). Alternatively, more reactive cyclic sulfites or sulfates are also suitable coupling precursors to react with phosphonic acid salts. These precursors can be made from the corresponding diols as described in the literature.
Alternatively, cyclic phosphonate esters of substituted 1,3-propane diols can be synthesized by trans esterification reaction with substituted 1,3- propane diol under suitable conditions. Mixed anhydrides of parent phosphonic acids generated in situ under appropriate conditions react with diols to give prodrugs as in the case of carboxylic acid esters (Bull. Chem. Soc. Jpn. 52:1989 (1979)). Aryl esters of phosphonates are also known to undergo transesterification with alkoxy intermediates (Tetrahedron Lett. 38:2597 (1997); Synthesis 968 (1993)).
One aspect of the present invention provides methods to synthesize and isolate single isomers of prodrugs of phosphonic acids of compounds of the invention. Because phosphorus is a stereogenic atom, formation of a prodrug with a substituted- 1,3-propane-diol will produce a mixture of isomers. For example, formation of a prodrug with a racemic l-(V)-substituted- 1,3-propane diol gives a racemic mixture of cis-prodrugs and a racemic mixture of trans- prodrags. In an other aspect, the use of the enantioenriched substituted- 1,3- propane diol with the R-configuration gives enantioenriched R-cis-and R- trans-prodrugs. These compounds can be separated by a combination of column chromatography and/or fractional crystallization. YR21 can also be introduced at an early stage of the synthesis. For example, compounds of the invention where R21 is phenyl can be prepared by phosphorylation of 2-furanyl bicyclic base subjected to a strong base (e.g. LDA) and chlorodiphenyl phosphonate. Alternatively, such compounds can be prepared by alkylation of lithiated furfuraldehyde followed by ring closure to the bicyclic base.
Figure imgf000061_0001
It is envisioned that compounds of the invention can be mixed phosphonate esters (e.g. phenyl benzyl phosphonate esters, phenyl acyloxyalkyl phosphonate esters, phenyl aminoacid esters etc). For example, the chemically combined phenyl-benzyl prodrugs are reported by Meier, et al. Bioorg. Med. Chem. Lett, 1997, 7: 99.
The substituted cyclic propyl phosphonate esters of compounds of the invention, can be synthesized by reaction of the corresponding dichlorophosphonate and the substituted 1,3-propane diol. The following are some methods to prepare the substituted 1,3-propane diols.
Synthesis of the 1,3-Propane Diols Used in the Preparation of Certain Prodrugs
The discussion of this step includes various synthetic methods for the preparation of the following types of propane- 1,3-diols: i) 1 -substituted; ii) 2- substituted; and iii) 1,2- or 1 ,3-annulated. Different groups on the prodrug part of the molecule i.e., on the propane diol moiety can be introduced or modified either during the synthesis of the diols or after the synthesis of the prodrugs. i) 1 -Substituted 1 ,3-propanediols
1 ,3-Propanediols useful in the synthesis of compounds in the present invention can be prepared using various synthetic methods. As described in Scheme A, additions of an aryl Grignard to a l-hydroxy-propan-3-al give 1-aryl-substituted 1 ,3-propanediols (path a). This method is suitable for the conversion of various aryl halides to l-arylsubstituted-l,3-propanediols (J. Org. Chem. 1988, 55, 911). Conversions of aryl halides to 1-substituted 1,3-propanediols can also be achieved using Heck reactions (e.g., couplings with a 1 ,3-diox-4-ene) followed by reductions and subsequent hydrolysis reactions (Tetrahedron Lett. 1992, 33, 6845). Various aromatic aldehydes can also be converted to 1-substituted- 1,3-propanediols using alkenyl Grignard addition reactions followed by hydroboration-oxidation reactions (path b).
Scheme A
Figure imgf000062_0001
A = OR, NR(R)1 wherein each R is independently selected from groups including alkyl and aralkly(e.g., Bn);
M = Metal;
R' = is a protecting group such as Bn, Si(R")(R")-, wherein each R" is independently alkyl or aryl, or -C-O-Me. Aldol reactions between an enolate (e.g., lithium, boron, tin enolates) of a carboxylic acid derivative (e.g., tert-butyl acetate) and an aldehyde (e.g., the Evans's aldol reactions) are especially useful for the asymmetric synthesis of enantioenriched 1 ,3-propanediols. For example, reaction of a metal enolate of f-butyl acetate with an aromatic aldehyde followed by reduction of the ester (path e) gives a 1,3-propanediol (J. Org. Chem. 1990, 55 4744). Alternatively, epoxidation of cinnamyl alcohols using known methods (e.g., Sharpless epoxidations and other asymmetric epoxidation reactions) followed by reduction reactions (e.g., using Red- Al) give various 1,3-propanedioIs (path c). Enantioenriched 1 ,3-propanediols can be obtained via asymmetric reduction reactions (e.g., enantioselective borane reductions) of 3-hydroxy-ketones (Tetrahedron Lett. 1997, 38761). Alternatively, resolution of racemic 1,3-propanediols using various methods (e.g., enzymatic or chemical methods) can also give enantioenriched 1,3-propanediol. Propan-3-ols with a 1-heteroaryl substituent (e.g., a pyridyl, a quinolinyl or an isoquinolinyl) can be oxygenated to give 1 -substituted 1 ,3-propanediols using N-oxide formation reactions followed by a rearrangement reaction in acetic anhydride conditions (path d) (Tetrahedron 1981, 37, 1871).
ii) 2-Substituted 1,3-propanediols
A variety of 2-substituted 1 ,3-propanediols useful for the synthesis of compounds of Formula I can be prepared from various other 1 ,3-propanediols (e.g., 2-(hydroxymethy I)- 1,3-propanediols) using conventional chemistry (Comprehensive Organic Transformations, VCH, New York, 1989). For example, as described in Scheme B, reductions of a trialkoxycarbonylmethane under known conditions give a triol via complete reduction (path a) or a bis(hydroxymethyl)acetic acid via selective hydrolysis of one of the ester groups followed by reduction of the remaining two other ester groups. Nitrotriols are also known to give triols via reductive elimination (path b) (Synthesis 1987, 8, 742). Furthermore, a 2-(hydroxy methyl)- 1,3-propanediol can be converted to a mono acylated derivative (e.g., acetyl, methoxycarbonyl) using an acyl chloride or an alkyl chloroformate (e.g., acetyl chloride or methyl chloroformate) (path d) using known chemistry (Protective Groups In Organic Synthesis ; Wiley, New York, 1990). Other functional group manipulations can also be used to prepare 1 ,3-propanediols such as oxidation of one the hydroxymethyl groups in a 2-(hydroxymethyl)- 1 ,3-propanediol to an aldehyde followed by addition reactions with an aryl Grignard (path c). Aldehydes can also be converted to alkyl amines via reductive amination reactions (path e).
Scheme B
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
K = COR or OCOR, wherein R is alkyl or aryl; R1 = is a protecting group such as Bn, Si(R")(R")- wherein each R" is independently alkyl or aryl, or -C-O-Me; R" = H if final compound or standard protecting group if intermediate.
iii) Annulated 1,3-propane diols
Prodrugs of formula I where V - Z or V - W are fused by three carbons are made from cyclohexane diol derivatives. Commercially available cis, cis- 1,3,5-cyclohexane triol can be used for prodrug formation. This cyclohexanetriol can also be modified as described in the case of 2-substituted propan-l,3-diols to give various analogues. These modifications can either be made before or after formation of prodrugs. Various 1 ,3-cyclohexane diols can be made by Diels- Alder methodology using pyrone as the diene (Posner, et. al., Tetrahedron Lett., 1991, 32, 5295). Cyclohexyl diol derivatives are also made by nitrile oxide olefin-additions (Curran, et. al., J. Am. Chem. Soc, 1985, 107, 6023). Alternatively, cyclohexyl precursors can be made from quinic acid (Rao, et. al., Tetrahedron Lett., 1991, 32, 547.)
2) Phosphonate Deprotection
Compounds of formula 6, may be prepared from phosphonate esters of formula 5, using known phosphate and phosphonate ester cleavage conditions. In general, silyl halides have been used to cleave the various phosphonate esters, followed by mild hydrolysis of the resulting silyl phosphonate esters to give the desired phosphonic acids. Depending on the stability of the products, these reactions are usually accomplished in the presence of acid scavengers such as 1,1,1,3,3,3-hexamethyldisilazane, 2,6-lutidine, etc. Such silyl halides include, chlorotrimethylsilane (Rabinowitz, J. Org. Chem., 1963, 28: 2975), bromotrimethylsilane (McKenna, et al, Tetrahedron Lett., 1977, 155), iodotrimethylsilane (Blackburn, et al, J. Chem. Soc, Chem. Commun., 1978, 870). Alternately, phosphonate esters can be cleaved under strong acid conditions, (e.g HBr, HCl, etc.) in polar solvents, preferably acetic acid (Moffatt, et al, U.S. Patent 3,524,846, 1970) or water. These esters can also be cleaved via dichlorophosphonates, prepared by treating the esters with halogenating agents e.g. phosphorus pentachloride, thionyl chloride, BBr3, etc.(Pelchowicz, et al, J. Chem. Soc, 1961, 238) followed by aqueous hydrolysis to give phosphonic acids. Aryl and benzyl phosphonate esters can be cleaved under hydrogenolysis conditions (Lejczak, et al, Synthesis, 1982, 412; Elliott, et al, J. Med. Chem., 1985, 28: 1208; Baddiley, et al, Nature, 1953, 171: 16 ) or dissolving metal reduction conditions(Shafer, et al, J. Am. Chem. Soc, 1977, 99: 5118). Electrochemical (Shono, et al, J. Org. Chem., 1979, 44: 4508) and pyrolysis (Gupta, et al, Synth. Commun., 1980, 10: 299) conditions have also been used to cleave various phosphonate esters.
3) Substitution of the Heterocycle
The bicyclic base ring system of formula 4, may require further elaboration to provide desired compounds of formula 5. i) Substitution of the 6-membered Ring Electrophilic and nucleophilic substitution reactions enable incoφoration of the desired substitutions encompassed by the formula 5. (March, Advanced Organic Chemistry by, Wiley-Interscience, 1992, 501-521; 641-654). For example, treatment of the compounds of formula 4 , where G6 is C, A is NH2, L and J are hydrogens with NBS, NCS or NIS in halogenated solvents such as carbon tetrachloride or chloroform gives halo-substituted compounds of formula 5 (L and/or J are halogens). Compounds of formula 5, where A is NO2, L and/or J are alkenyl, alkynyl, alkyl, or aryl groups, and Y is H or alkyl, may be prepared from compounds of formula 4, where A is NO2, R is H or alkyl, and L and/or J are halogens, preferably bromide or iodide, through Stille coupling (Stille, Angew. Chem. Int. Ed. Engl. 1986, 25: 508- 524). Treatment of the compounds of formula 4, where A is NO2, and L and/or J are bromides, with a coupling reagent (e.g. tributyl(vinyl)tin, phenylboronic acid, propargyl alcohol, N,yV-propargyl amine etc.) in presence of palladium catalyst [e.g. bis(triphenylphosphine)palladium (IΙ)chloride, tetrakis(triphenylphosphine) palladium(O), etc.] in solvent, such as DMF, toluene, etc. provides the coupling products. The compounds thus obtained can be modified as needed. For example vinyl or propargyl alcohol derivatives can be hydrogenated to give the ethyl or propyl alcohol derivatives respectively. These alcohols can be further modified as required via alkyl halides (ref. Wagner et al. Tetrahedron Lett. 1989, 30, 557.) or alkyl sulfonates etc. to a number of substituted alky Is such as amino alkyl compounds by subjecting them to nucleophilic substitution reactions (March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 293- 500). Alternatively, these substitutions can also be done by metal exchange followed by quenching with an appropriate nucleophile (Jerry March, Advanced Organic Chemistry , Wiley-Interscience, 1992, 606-609). Nucleophilic addition reactions can also be useful in preparing compounds of formula 5. For example, when A is NO2, L and/or J are halogens, nucleophiles such as alkoxides, thiols, amines, etc. provide the halogen displacement products. (March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 649-676). Another example is addition reactions, for example cyclopropanation (Vorbruggen et dX,Tetrahedron Lett. 1975, 629), on the olefins(e.g. styryl type) synthesized through Stille coupling.
If required, these substituted compounds can be further modified to the desired products. For example, reduction of the NO2 to NH2 may be done in many different ways, e.g. Pd/C, H2, aq. Na2S2O4, etc. (Larock, Comprehensive Organic Transformations , VCH, 412-415). These primary aromatic amines can also be modified as needed. For example, N-acetyl derivatives can be prepared by treatment with acetyl chloride or acetic anhydride in the presence of a base such as pyridine. The mono- or di- alkylamines can be synthesized by direct alkylation, using a base such as NaH in polar solvents such as DMF or by reductive alkylation methods (ref. Abdel- Magid et al. Tetrahedron Lett. 1990, 31, 5595; also see ref. March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 898-900 for more methods).
The functionalization of deaza-purine analogs can be prepared from corresponding diaminoprecursors. Diaminoprecursors of variety of nitrogen heterocycles, such as pyridyl, pyrazinyl and pyridazinyl bases can be further transformed into bicyclic systems as shown in the following synthesis of 1- deaza analogs. These compounds may be functionalized as shown below by activation to N-oxide. The resulting phosphonate substituted bicyclic systems may be further transformed to alpha-haloamines via nitration (Wanner, et al, Nucleosides, Nucleotides & Nucleic Acids 2004, 23: 1313, Cristalli, et al., J. Med. Chem., 1987, 30: 1686)
Figure imgf000067_0001
1. PCI,
2. [H]
3. Halogenation
Figure imgf000067_0002
ii) Alkylation of the Imidazole Ring
Alkylation of the heterocycle of formula 4, (where R and J are both H) is obtained through two distinct methods that are amenable to a large number of electrophiles: a) Mitsunobu alkylation, and b) base alkylation. a) Mitsunobu Alkylation
Alkylation of the bicyclic base ring system of formula 4, is achieved by treatment of an alcohol, triphenylphosphine and dialkylazodicarboxylate with heterocycle and a non-nucleophilic base such as Hunigs base in polar solvents such as CH3CN (Zwierzak et al, Liebigs Ann. Chem. 1986, 402). b) Base Alkylation
Alternately, the bicyclic base ring system of formula 4 can be deprotonated with a suitable base, preferably cesium carbonate in a polar aprotic solvent such as DMF, and the resulting anion is alkylated with an appropriate electrophilic component Y-L' , where L' is a leaving group preferably bromide or iodide.
4) Substitution or Modification of a 2-substituent
Another key intermediate envisioned in the synthesis of compounds of formula 4 are substituted 2-methylbicyclic bases. These compounds are readily prepared by condensing Ac2O with the appropriate 1,2-diamine (Phillips, J. Chem. Soc, 1928, 29: 1305). These compounds are useful in the synthesis of formula 1, wherein X is CH2ZCH2(Z=O5S5NH). For example, compounds where Z=O are readily prepared by treatment of the 2- methylbicyclic base with a halogenating agent such as NBS followed by reaction with the α-hydroxy phosphonate ester (also see section 6, Synthesis of the Linker-PO3R2). Alternately, a heterosubstituted methyl phosphonates can also be prepared by displacement reactions on phosphonomethyl halides or sulfonates (Phillion et al, Tetrahedron Lett., 1986, 27: 1477.) with an appropriate nucleophile e.g. 2-hydroxylmethylbicyclic base compound which can be prepared using a variety of methods, including oxidation of the substituted 2-methylbicyclic bases.
Similarly, compounds of formula 1, where X is carboxypropyl or sulfonopropyl can be prepared from the reaction of 2-(2-iodoethyl) bicyclic base and corresponding phosphonomethylcarboxylate or phosphonomethylsulfonate (Carretero et al., Tetrahedron, 1987, 43, 5125) in the presence of base such as NaH in polar aprotic solvents such as DMF. The substituted 2-(2-iodoethyl) bicyclic base can be prepared from condensation of the corresponding substituted diamine and 3-halopropanaldehyde. Also see ref. Magnin, D. R. et al. J. Med. Chem. 1996, 39, 657 for the preparation of α- phosphosulfonic acids.
The componds of formula 4 where X is all carbon e.g. -(CH2)3- can be prepared by Stille coupling (Stille Angew. Chem. Int. Ed. Engl. 1986, 25: 508- 524) of the dialkylphosphopropenyl tributylstanne (J. Org. Chem. 1993, 58: 6531.) and appropriate 2-bromobicyclic base (Misery, et al, Tetrahedron Lett., 1986, 27: 1051).
The componds of formula 4 where X is an amide linker e.g. -CONHCH2- can be synthesized using the following two steps. Treatment of the appropriate 1,2-1,2-diamine with trihalomethylacetamidate preferably trichloromethylacetamidate in polar solvent such as acetic acid followed by hydrolysis of the trihalomethyl group with strong aqueous base (e.g. KOH) gives the bicyclic base-2-carboxylic acid (Eur. J. Med. Chem., 1993, 28: 71). Condensation of the acid with an amino phosphonate e.g. diethyl(aminomethyl)phosphonate in presence of a coupling agent (e.g. pyBOP) in a polar solvent such as methylene chloride provides the amide linked phosphonate.
The componds of formula 4 where X is an amide linker e.g. -NHCOCH2- can be synthesized using the following two steps. Treatment of the appropriate 1 ,2-diamine with cyanogenbromide (Johnson, et al, J. Med. Chem., 1993, 36: 3361) in polar solvent such as MeOH gives the 2-amino bicyclic base. Condensation of the 2-aminobicyclic base with a carboxylic acid e.g. diethyl(carboxymethyl)phosphonate using standard coupling conditions (Klausner, et al, Synthesis, 1972, 453) provides the amide linked phosphonate. The 2-aminobicyclic bases can also be prepared from the 2- bromobicyclic base via the 2-azidobicyclic base using known methods (Chem. Rev. 1988, SS: 297).
5) Cyclization to Generate Bicvclic base Ring System
The bicyclic base ring systems of formula 4 is preferably assembled by condensation of substituted 1,2-diamines with an aldehyde (RCHO, where R is e.g. aliphatic, heteroaliphatic, aromatic or heteroaromatic etc.) using known methods; (a) in presence of Fe3+ salts, preferably FeCl3, in polar solvents such as DMF, EtOH etc., (b) reflux in non-polar solvents such as toluene followed by oxidation, preferably with iodine (Bistocchi et al, Collect. Czech. Chem. C, 1985, 50(9): 1959.)-, (c) in cases of protected aldehydes, the first condensation can be achieved in the presence of a dilute inorganic acid, preferably 10 % H2SO4, in polar solvents such as THF, followed by oxidation with I2. Alternatively, this coupling can be achieved with an anhydride (RCOOCOR), a carboxylic acid (RCOOH), with a nitrile (RCN) by methods reported by Hein, et al, J. Am. Chem. Soc. 1957, 79, 427.; and Applegate, et al, US 5,310,923; or imidates (R-C(=NH)-OEt) ref. Maryanoff, et al. J. Med. Chem. 1995, 38: 16.
Figure imgf000070_0001
Advantageously, these bicyclic base ring systems can be constructed using solid phase synthesis (ref: Phillips et al. Jet. Lett., 1996, 37: 4887; Lee et al, Tet. Lett, 1998: 35: 201.
Synthesis of substituted bicyclic base precursors towards compounds of formula 1 where G4 or G5 is a -N< or where G7 is a =CH- may be attained by the procedures described in WO9839342 Al.
6) Synthesis of the Linker-POjR?
Coupling of aromatic or aliphatic aldehydes, ketals or acetals of aldehydes, and acid derivatives with attached phophonate esters are particularly well suited for the synthesis of compounds of formula 1. i) Preparation of Aryl and Heteroaryl Phosphonate Esters
Aryl functionalized phosphonate linkers can be prepared by lithiation of an aromatic ring using methods well described in literature (Gschwend, Org. React. 1979, 26, 1; Durst, Comprehensive Carbanion Chemistry, Vol. 5, Elsevier, New York, 1984) followed by addition of phosphorylating agents (e.g. ClPO3R2). Phosphonate esters are also introduced by Arbuzov-Michaelis reaction of primary halides (Brill, T. B., Chem Rev., 1984, 84: 577). Aryl halides undergo Ni2+ catalysed reaction with trialkylphosphites to give aryl phosphonate containing compounds (Balthazar, et al, J. Org. Chem., 1980, 45: 5425). Aromatic triflates are known to result in phosphonates with ClPO3R2 in the presence of a palladium catalyst (Petrakis, et al, J. Am. Chem. Soc, 1987, 109: 2831; Lu, et al, Synthesis, 1987, 726). In another method, aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin, Tetrahedron Lett., 1981, 22: 3375; Casteel, et al, Synthesis, 1991, 691). Using the same method described above, arylphosphate esters, where X is aryloxy, can also be made. N-Alkoxy aryl salts with alkali metal derivatives of dialkyl phosphonate provide general synthesis for heteroaryl-2-phosphonate linkers (Redmore, J. Org. Chem., 1970, 55: 4114).
In the linker phosphonate synthesis, aldehyde, ketone, or carboxylic acid functionalities can also be introduced after the phosphonate ester is formed. A lithiation reaction can be used to incorporate the aldehyde or ketone functionalities, although other methods known to generate aromatic aldehydes or ketones can be envisioned as well (e.g. Vilsmeier-Hack reaction, Reimar-Teimann reaction etc.; Pizey, Synthetic reagents, 1974, 7: 1; Wynberg, H., et al, Org. React. 1982, 28: 1; palladium catalyzed coupling reaction of acid halides and organotin compounds). For example, for the lithiation reaction, the lithiated aromatic ring can be treated with reagents that directly generate the aldehyde (e.g. DMF, HCOOR, efc.)(Einchorn, J., et al, Tetrahedron Lett., 1986, 27: 1791), or the ketone (e.g. Weinreb's amide, RCOOR'). The lithiated aromatic ring can also be treated with reagents that lead to a group that is subsequently transformed into the aldehyde or ketone group using known chemistry (synthesis of aldehyde and ketone from alcohol, ester, cyano, alkene, etc.). It is also envisioned that the sequence of these reactions can be reversed, i.e. the aldehyde and ketone moieties can be incorporated first, followed by the phosphorylation reaction. The order of the reaction will depend on reaction conditions and protecting groups. Prior to the phosphorylation it is also envisioned that it may be advantageous to protect the aldehyde or ketone using well-known methods (acetal, aminal, hydrazone, ketal, etc.), and then the aldehyde or ketone is unmasked after phosphorylation. (Protective groups in Organic Synthesis, Greene, T. W., 1991, Wiley, New York).
The above mentioned methods and analogous can also be extended to the heteroaryl linkers e.g. pyridine, furan, thiophene etc.
ii) Preparation of Aliphatic and Heteroaliphatic Phosphonate Esters Compounds of formula 3, where M is CO2R and X is alkyl can be synthesized using reactions well known in the art. Trialkyl phosphites attack lactones at the β-carbon atom, causing the alkyl-oxygen cleavage of the lactone ring, to yield alkyl(dialkylphosphono)esters. This reaction can be applied to many types of lactones such as β-lactones, γ-lactones etc. as reported by McConnell et al, J. Am. Chem. Soc, 1956, 78, 4453. Alternatively, these type of compounds can be synthesized using the Arbuzov reaction (Chem. Rev. 1984, 84: 577). The linkers Ar(Z)alkyl phosphonates (Ar=aryl; Z=O5S etc.) can be prepared from the reaction of substituted aryls e.g. salicylaldehyde with an appropriate phosphonate electrophile [L(CfO)nPO3R2, L is a leaving group, preferably iodine; Walsh et al, J. Am. Chem. Soc, 1956, 78, 4455.] in the presence of a base, preferably K2CO3 or NaH, in a polar aprotic solvent, such as DMF or DMSO. For the preparation of α- phosphosulfonic acids see ref. Magnin, D. R. et al. J. Med. Chem. 1996, 39, 657; and ref. cited therein.
Compounds of formula 3, where M is CO2R or CHO and X is carbonylalkyl can be synthesized from the acid chlorides (for example H(O)C- CH2C(O)Cl) and P(OEt)3 (Chem. Rev. 1984, 84: 577). These α- ketophosphonates can be converted to the α-hydroxyphoshonates and α,α- dihalophosphonates (ref. Smyth, et al. Tett. Lett, 1992, 33, 4137). For another method of synthesizing these α,α-dihalophosphonates see the ref. Martin et al. Tett. Lett. 1992, 33, 1839.
Compounds of formula 3, where X is a heteroalkyl linker e.g. - CH2ZCH2- where Z=O1S etc. and M is aldehyde or its protected form such as dialkyl acetal (Protective groups in Organic Synthesis, Greene, T. W., 1991, Wiley, New York) can be prepared by nucleophilic substitution reactions (March, Advanced Organic Chemistry , Wiley-Interscience, Fourth Edition, 1992, 293-500) to give unsymmetrical ethers. For example linkers of formula 3, where X is alkyloxymethyl can be synthesized through direct alkylation of the hydroxymethyl phosphonate ester, with the desired alkyl halide [L(CH2)nCH(OMe)2, L is a leaving group, preferably bromine or iodine] in the presence of a base, preferably NaH, in a polar aprotic solvent, such as DMF or DMSO. These methods and analogous methods can be extended to the heteroalkyl linkers e.g. -CH2ZCH2- where Z=S, NH etc.
7) Synthesis of the monocyclic base precursors Monocyclic base precursors utilized in the preparation of compounds of formula 1 , can be synthesized using methods well known in the art.
(a) Compounds of formula 2, where R is H, can be synthesized from monocyclic 6-membered heterocycles compounds. Most heterocycles may be nitrated given the wide variety of nitrating agents available(March, Advanced Organic Chemistry , Wiley-Interscience, 1992, 522-525). Primary aromatic amines are often N-acetylated before nitration by treatment with acetyl chloride or acetic anhydride. Nitration of the these amino substituted 6- membered heterocycle derivatives using 60 % HNO3 and H2SO4 (Monge et al, J. Med. Chem., 1995, 38: 1786; Ridd Chem. Soc. Rev. 1991, 20: 149-165), followed by deprotection by strong acid (e.g. H2SO4, HCl, etc.), and hydrogenation (e.g. H2, Pd/C; Na2S2O4; etc.) of the resulting 3-nitro-2-amino heterocycles provides the desired substituted 1,2-diamines. Similarly, substituted heteroarylhalides (F,Cl,Br,I) can also be nitrated to provide α- halonitro compounds followed by nucleophilic addition (e.g. NH3, NH2OH, etc) and reduction to generate the diamines.
(b) Diamines of formula 2, R is alkyl, can be produced using alkylamine displacement of alpha-haloheterocycles. Such resulting alpha- alkylamino heterocycles can then be transformed to nitro-amines via nitration. The nitro group can be reduced with number of reagents preferably sodium dithionite to provide the corresponding diamine. This diamine is then subjected to cyclization.
(c) The compounds of formula 2, where R is alkyl or aryl, can be synthesized using the method of Ohmori et al, J. Med. Chem. 1996, 39: 3971. Nucleophilic substitution of the o-halonitropyridine, pyrimidine or pyrazines by treatment with various alkylamines followed by reduction (e.g. Na2S2O4 ) of the nitro group provides the desired compounds. Alternately, the compounds of formula 2, where R is H, can be synthesized from these o- halonitrobenzenes via o-azidonitrobenzenes followed by reduction of the nitro group to provide the desired compound.
(d) Alternately, diamines of formula 2 where R is not H are prepared by reductive alkylation of the amino substituted pyridine, pyrimidine or pyrazines with various aldehydes(e.g. akyl, aryl etc.) in the presence of a reducing agent preferably NaB(OAc)3 followed by reduction (e.g. Na2S2O4 ; Pd/C, H2 etc.) of the nitro group (Magid et al Tetrahedron Lett. 1990, 31: 5595). Synthesis of substituted monocyclic base precursors towards compounds of formula 1 where G4 or G5 is a -N< or where G7 is a =CH- may be attained from the appropriate starting materials by the procedures described in WO9839342 Al.
EXAMPLES
Example 1: 2-(2-Phosphono-5-furanyl)-4-azabenzimidazole
Step A:
Preparation of 2-Furaldehyde-5-diethylphosphonate Method A:
To a solution of 25 mL (147.5 mmol) 2-furaldehyde diethyl acetal in 25 ml of THF at -78 °C, was added 96 mL (147.2 mmol) of a 1.6 M BuLi hexane solution. The solution was allowed to stir for 1 h at -78 C and 24 mL (166.1 mmol) chlorodiethylphosphonate was added and stirred for 0.5 h. The mixture was quenched at -78 C with a saturated NH4Cl solution. The precipitates formed were filtered and the filtrate concentrated. The mixture was partitioned between water and CH2Cl2 and separated. The organic layer was dried with sodium sulfate, filtered and the solvent removed under reduced pressure. The resulting brown oil was treated with 80% acetic acid and heated at 90 C for 4 h. Chromatography on silica using 75% ethyl acetate/hexanes yielded 9.1 g (39.2 mmol, 26.6%) of clear oil. Method B:
To a solution of 2.8 mL (13.75 mmol) TMEDA and 1.0 mL (13.75 mmol) furan in 9 mL of diethyl ether at -78 C, was added 8.6 mL (13.75 mmol) of a 1.6 M BuLi hexane solution. The solution was allowed to stir for 0.5 hour at -78 C and 2.19 mL (15.25 mmol) chlorodiethylphosphonate was added and stirred for 2 h. The mixture was quenched at -78 C with a saturated sodium bicarbonate solution. The mixture was partitioned between water and CH2Cl2 and separated. The organic layer was dried with sodium sulfate, filtered and the solvent removed under reduced pressure. The resulting brown oil was purified through Kugelrohr distillation yielding 1.978 g (9.696 mmol, 70.5%) of a clear oil.
To a solution of 16.01 g (78.41 mmol) 2-diethylphosphonfuran in 400 mL of tetrahydrofuran at -78 °C, was added 58.81 mL (117.62 mmol) of a 2M LDA solution. The solution was allowed to stir for 0.3 h at -78 C and 9.67 mL (156.82 mmol) methylchloroformate was added and stirred for 0.5 h. The mixture was quenched at -78 C with a saturated sodium bicarbonate solution. The mixture was partitioned between water and CH2CI2 and separated. The organic layer was dried with sodium sulfate, filtered and the solvent removed under reduced pressure. The resulting oil was purified by silica gel chromatography yielding 5.6 g (18.2 mmol, 31%) of a clear yellow oil.
Method C:
To a solution of 168 g (1.75 mol) 2-furaldehyde in 500 mL toluene was added 215 mL (1.75 mol) of N,N' -dimethyl ethylene diamine. The solution was refluxed using a Dean Stark trap to remove H2O. After 2 hours of reflux, the solvent was removed under reduced pressure. The resulting dark mixture was vacuum distilled (3 mm Hg) and the fraction at 59-61 0C was collected yielding 247.8 g (85%) of clear, colorless oil.
A solution of 33.25 g (0.2 mol) furan-2-(N,N'-dimethylimidazolidine) and 30.2 mL (0.2 mol) tetramethylethylenediamine in 125 mL THF was cooled in a dry ice/IPA bath. A solution of 112 mL n-BuLi in hexane(0.28 mol,2.5M) was added dropwise, maintaining temperature between -50 and -40 0C during addition. The reaction was allowed to warm to 0 0C over 30 minutes and was maintained at 0 0C for 45 minutes. The reaction was then cooled in a dry ice/IPA bath to -55 0C. This cooled solution was transferred to a solution of 34.7 mL (0.24 mol) diethylchlorophosphate in 125 mL THF and cooled in a dry ice/IPA bath over 45 minutes maintaining the reaction temperature between -50 0C and -38 0C. The reaction was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. Ethyl acetate and H2O were added to the residue and the layers separated. The H2O layer was washed with ethyl acetate. The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure yielding 59.6 g (98%) of a brown oil.
To a solution of 59.6 g 5-diethylphosphonofuran-2-(N,N'- dimethylimidazolidine) in 30 mL H2O was added 11.5 mL of cone. H2SO4 dropwise until pH = 1 was obtained. The aqueous reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to a brown oil. The brown oil was added to a silica column and was eluted with hexane/ethyl acetate. Product fractions were pooled and evaporated under reduced pressure yielding a dark yellow oil, 28.2 g (62%).
Step B:
General Procedure for coupling-Cyclization of aldehyde and diamine precursors:
A solution of 1.0 mmol of substituted 1 ,2-diamine and 1.0 mmol of 2- furaldehyde-5-diethylphosphonate in 2 mL of MeOH and AcOH mixture (3:1) was stirred at room temperature for 16 h. Extraction and chromatography provided the condensation product as a solid. Step C: General procedure for TMSBr hydrolysis of phosphonate diesters:
To a solution of 1.0 mmol of substituted phosphonate diester in 5 mL of anhydrous CH2Cl2 was added 10.0 mmol TMSBr at 0°C. After 16 h stirring at room temperature the solvent and excess TMSBr were removed under reduced pressure. The residue was taken into 15 mL of a 1/5 mixture of acetone/water and was stirred for 16 h at room temperature. The resulting solid was filtered, washed with water, EtOAc, and MeOH and was dried under vacuum at 500C.
Figure imgf000076_0001
Anal Calcd for C10H8N3O4P. 1.25 HBr. 0.75 H2O: C, 31.62; H, 2.85; N, 1 1.06. Found: C, 31.64; H, 2.91 ; N, 10.92. Example 2:
Step A and B:
Alkylation precursor was made as described in steps A and B of example 1.
Step C:
General Procedure for cesium carbonate mediated N-alkylation:
A suspension of 1.5 mmol cesium carbonate, 1.0 mmol of substituted annulated imidazole and 1.0 mmol of electrophile in 5 mL of dry DMF was heated at 80° C for 1-16 h. Extraction and chromatography provided the alkylation product(s). Step D: Diethylphosphonate was hydrolysed as described in step C of example 1.
Figure imgf000077_0001
2.1: l-Isobutyl-2-(2-phosphono-5-furanyl)-4-azabenzimidazole
Anal Calcd for Ci4H16N3O4P: C, 52.34; H, 5.02; N, 13.08. Found: C, 51.96; H,
5.02; N, 12.96.
Figure imgf000077_0002
2.2: 3-Isobutyl-2-(2-phosphono-5-furanyl)-4-azabenzimidazole Anal Calcd for Ci4Hi6N3O4P. 1.75 H2O: C, 47.66; H, 5.57; N, 11.91. Found: C, 47.73; H, 5.50; N, 11.90.
Example 3: Compounds of example 3 were made starting from commercially available 3,4-diamino-pyridine following steps A-D of example 2.
Figure imgf000078_0001
3.1: l-lsobutyl-2-(2-phosphono-5-furanyl)-5-azabenzimidazole Anal Calcd for Ci4H16N3O4P. 1.25 H2O: C, 48.91 ; H, 5.42; N, 12.22. Found: C, 48.85; H, 5.34; N, 12.06.
Figure imgf000078_0002
3.2: 3-Isobutyl-2-(2-phosphono-5-furanyl)-5-azabenzimidazole. Anal Calcd for Ci4Hi6N3O4P. 1.0 HBr. 1.15 H2O: C, 39.76; H, 4.60; N, 9.94; Br, 18.89. Found: C, 39.44; H, 4.53; N, 9.69; Br, 19.27.
Example 4: 5-Methoxy-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine
Step A: General procedure of alkylamine substitution of alpha-halopyridine:
To a solution of 20 mmol of substituted alpha-halopyridine in 70 mL of DMF was added 35 mmol of alkyl or arylamine at 0 0C. After 0.5 h TLC indicated the completion of reaction. The reaction mixture was then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried, and evaporated to yield the displacement products.
Step B: Preparation of 1,2-diamines via dithionite reduction:
To a solution of 1.0 mmol of substituted nitroamine in 15 mL of MeOH was added 15mL of saturated aqueous solution of sodium dithionite at 0 C. Reaction mixture was warmed to room temperature and allowed to stir for 2-3 hours. Filtration followed by removal of solvent and extraction with EtOAc provided the pure diamine.
Steps C and D were carried-out as described in example steps B and C of example 1.
Figure imgf000079_0001
Anal Calcd for C15Hi8N3O5P.: C, 51.29; H, 5.16; N, 11.96. Found: C, 51.04; H, 5.10; N, 11.87.
Example 5: l-Isobutyl-7-N-oxo-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine, hydrogen bromide salt
Example 2.1 was made as described in steps A-C.
Step D:
To a solution of example 2.1 (420 mg, 1.1 mmol) in acetic acid (1 mL) was added 30% hydrogen peroxide (0.25 mL) and the mixture was heated overnight at 85 C. The reaction mixture was then evaporated to dryness and azeotroped with toluene (2 X 10 mL). The crude product was chromatographed with 5% MeOH-CH2Cl2 to give 150 mg of N-oxide.
Step E:
Diethylphosphonate was hydrolysed as described in step C of example 1.
Figure imgf000079_0002
Anal Calcd for C14H16N3O5P. 1.5 H2O. 1.0 HBr.: C, 37.77; H, 4.53; N, 9.44. Found: C, 37.98; H, 4.57; N, 9.28. MH+ Calcd for Q4H16]ShO5P: 338. Found: 338.
Example 6: 4-Amino-5-chloro-l-isobutyl-2-[2-(5- phosphono)furanyl]imidazo[4,5-b]pyridine
Step A:
To a solution of 2-chloro-3-nitro-pyridine (4.7 g, 29.6 mmol) in ethanol (60 mL) was added isobutylamine (5.89 mL, 59.2 mmol) and the reaction was stirred at room temperature for 48 hours. Upon completion of the reaction, 10%Pd-C (1 g) was added and stirred overnight under hydrogen. The catalyst was then filtered-off and the reaction mixture was concentrated and used in the next step without further purification.
Step B:
Diamine obtained in step A was coupled and cyclized with 2-Furaldehyde-5- diethylphosphonate utilizing the procedure described in step B of example 1.
Step C:
N-oxide was made as described in step E of example 5.
Step D:
To a solution of N-oxide (200 mg, 0.50 mmol) in trifluoroacetic acid (0.2 mL, 2.5 mmol) at 0 C was added fuming nitric acid (0.1 mL). The reaction was heated to 75 C overnight, quenched with ice followed by 30% aq ammonium hydroxide. The mixture was then extracted with dichloromethane (2 X 50 mL) and the organic layer was washed and dried. The extract was evaporated and the crude was chromatographed utilizing 5% methanol-dichloromethane to give 100 mg of pure product. Phosphorus trichloride (0.52, 6 mmol) was added to a solution of N-oxide (230 mg, 0.60 mmol) in acetonitrile (2 mL) and the resulting mixture was stirred for Ih at 80 C. The reaction mixture was then concentrated under vacuum and quenched with ice followed by 30% aq ammonium hydroxide. Extraction of the aqueous layer with dichloromethane (2 X 50 mL) followed by washing, drying and evaporation gave crude reduction product. Chromatography with 70% EtOAc -dichloromethane gave 165 mg of the pure product.
A mixture of nitro compound (165 mg, 0.45 mmol) and 80 mg of 10 % Pd/C in 5 mL of EtOAc (5 mL) was hydrogenated using H2 from a balloon for 1 h. The reaction mixture was then filtered through Celite and chromatographed with 5% MeOH-dichlorome thane to provide the reduction product as an yellow oil (70 mg).
Step G: To a solution of amino compound (30 mg, 0.076 mmol) in methanol (2 mL) was added N-chlorosuccinimide. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated upon completion of the reaction and the crude product was chromatographed using 2% to 5% MeOH-dichloromethane to provide the pure chlorinated product (23 mg).
Step H:
Diethylphosphonate product from step G was hydrolyzed utilizing TMSBr following the procedure described in Step C of example 1.
Figure imgf000081_0001
MH+ Calcd for Ci4Hi6ClN4O4P: 371. Found: 371. Example 7: 7-Methyl-6-chloro-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine
Step A:
Chlorination of 2-amino-3-nitro-4-methyl-pyridine was attained utilizing the procedure as described in step G of example 6.
Step B:
Dithionite reduction of 2-amino-3-nitro-4-methyl-5-chloro-pyridine was done following the procedure described in step B of example 4.
Step C:
Diamine obtained in step B was coupled and cyclized with 2-Furaldehyde-5- diethylphosphonate utilizing the procedure described in step B of example 1.
Step D:
Diethylphosphonate product from step C was hydrolyzed utilizing TMSBr following the procedure described in Step C of example 1.
Figure imgf000082_0001
Anal Calcd for CnH9ClN3O4P. 0.5 H2O : C, 40.95; H, 3.12; N, 13.02. Found: C, 40.78; H, 3.13; N, 12.82.
Example 8: 7-Methyl-6-chloro-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine-N4-ethyl bromide.
The cyclization product prepared as in steps A-C of example 7 was utilized for quaternization of pyridine.
Step D:
To a solution of cyclized product (92 mg, 0.25 mmol) in acetone (5 mL) was added iodomethane (0.1 mL). The reaction mixture was stirred overnight at reflux temperature and concentrated under reduced pressure to yield the crude product. Chromatography of the crude with 5% to 10% MeOH- dichloromethane gave 35 mg of pure product.
Step E:
Diethylphosphonate product from step D was hydrolyzed utilizing TMSBr following the procedure described in Step C of example 1.
Figure imgf000083_0001
Anal Calcd for Ci3H14ClBrN3O4P: C, 36.95; H, 3.34; N, 9.94. Found: C, 37.32; H, 3.69; N, 9.58.
Example 9: 7-Methyl-6-chloro-2-[2-(5-phosphono)furanyl] imidazo[4,5-b]pyridine
The cyclization product prepared as in steps A-C of example 7 was utilized for alkylation.
Step D:
Alkylation with isobutyl bromide was attained as described in step C of example 2.
Step E:
Diethylphosphonate product from step D was hydrolyzed utilizing TMSBr following the procedure described in Step C of example 1.
Figure imgf000084_0001
Anal Calcd for Ci5Hi7ClN3O4P: C, 48.73; H, 4.63; N, 1 1.36. Found: C, 48.63; H, 4.68; N, 11.02.
Biological Examples
Examples of use of the method of the invention includes the following. Examples A and E were actually performed. The remaining examples are prophetic. It will be understood that these examples are exemplary and that the method of the invention is not limited solely to these examples. Besides the following Examples, assays that may be useful for identifying compounds which inhibit gluconeogenesis include the following animal models of diabetes: i. Animals with pancreatic beta-cells destroyed by specific chemical cytotoxins such as Alloxan or Streptozotocin (e.g. the Streptozotocin-treated mouse, rat, dog, and monkey). Kodama, H., Fujita, M., Yamaguchi, L, Japanese Journal of Pharmacology 66:331-336 (1994) (mouse); Youn, J.H., Kim, J.K., Buchanan, T.A., Diabetes 43:564-511 (1994) (rat); Le Marchand, Y., Loten, E.G., Assimacopoulos-Jannet, F., et al., Diabetes 27:1182-88 (1978) (dog); and Pitkin, R.M., Reynolds, W.A., Diabetes 79:70-85 (1970) (monkey). ii. Mutant mice such as the C57BL/Ks db/db, C57BL/Ks ob/ob, and C57BL/6J ob/ob strains from Jackson Laboratory, Bar Harbor, and others such as Yellow Obese, T-KK, and New Zealand Obese. Coleman, D.L., Hummel, K.P., Diabetologia 3:238-248 (1967) (C57BL/Ks db/db); Coleman, D.L., Diabetologia 74:141-148 (1978) (C57BL/6J ob/ob); Wolff, G.L., Pitot, H.C., Genetics 75:109-123 (1973) (Yellow Obese); Dulin, W.E., Wyse, B.M., Diabetologia 6:317-323 (1970) (T-KK); and Bielschowsky, M., Bielschowsky, F. Proceedings of the University ofOtago Medical School 31:29-31 (1953) (New Zealand Obese). iii. Mutant rats such as the Zucker fa/fa Rat rendered diabetic with Streptozotocin or Dexamethasone, the Zucker Diabetic Fatty Rat, and the Wistar Kyoto Fatty Rat. Stolz, KJ. , Martin, RJ. Journal of Nutrition 772:997-1002 (1982) (Streptozotocin); Ogawa, A., Johnson, J.H., Ohnbeda, M., McAllister, C.T., Inman, L., Alam, T., Unger, R.H., The Journal of Clinical Investigation 90:497-504 (1992) (Dexamethasone); Clark, J.B., Palmer, CJ., Shaw, W.N., Proceedings of the Society for Experimental Biology and Medicine /73:68-75 (1983) (Zucker Diabetic Fatty Rat); and Idida, H., Shino, A., Matsuo, T., et al, Diabetes 50:1045-1050 (1981) (Wistar Kyoto Fatty Rat). iv. Animals with spontaneous diabetes such as the Chinese Hamster, the Guinea Pig, the New Zealand White Rabbit, and non-human primates such as the Rhesus monkey and Squirrel monkey. Gerritsen, G.C., Connel, M.A., Blanks, M.C., Proceedings of the Nutrition Society 40:231 245 (1981) (Chinese Hamster); Lang, CM., Munger, B.L., Diabetes 25:434-443 (1976) (Guinea Pig); Conaway, H.H., Brown, CJ., Sanders, L.L. et al., Journal of Heredity 77:179-186 (1980) (New Zealand White Rabbit); Hansen, B.C., Bodkin, M.L., Diabetologia 29:713-719 (1986) (Rhesus monkey); and Davidson, I.W., Lang, CM., Blackwell, W.L., Diabetes 76:395-401 (1967) (Squirrel monkey). v. Animals with nutritionally induced diabetes such as the Sand Rat, the Spiny Mouse, the Mongolian Gerbil, and the Cohen Sucrose-Induced Diabetic Rat. Schmidt-Nielsen, K., Hainess, H.B., Hackel, D.B., Science /45:689-690 (1964) (Sand Rat); Gonet, A.E., Stauffacher, W., Pictet, R., et al, Diabetologia 7:162-171 (1965) (Spiny Mouse); Boquist, L., Diabetologia 8:274-282 (1972) (Mongolian Gerbil); and Cohen, A.M., Teitebaum, A., Saliternik, R., Metabolism 27:235-240 (1972) (Cohen Sucrose-Induced Diabetic Rat). vi. Any other animal with one of the following or a combination of the following characteristics resulting from a genetic predisposition, genetic engineering, selective breeding, or chemical or nutritional induction: impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, accelerated gluconeogenesis, increased hepatic glucose output.
Example A: Inhibition of Human Liver FBPase.
E. coli strain BL21 transformed with a human liver FBPase-encoding plasmid was obtained from Dr. M. R. El-Maghrabi at the State University of New York at Stony Brook. hlFBPase was typically purified from 10 liters of E. coli culture as described (M. Gidh-Jain et al., The Journal of Biological Chemistry 1994, 269, 27732-27738). Enzymatic activity was measured spectrophotometrically in reactions that coupled the formation of product (fructose 6-phosphate) to the reduction of dimethylthiazoldiphenyltetrazolium bromide (MTT) via NADP and phenazine methosulfate (PMS) , using phosphoglucose isomerase and glucose 6-phosphate dehydrogenase as the coupling enzymes. Reaction mixtures (200 μL) were made up in 96-well microtitre plates, and consisted of 50 mM Tris-HCl, pH 7.4, 100 mM KCl, 5 mM EGTA, 2 mM MgCl2, 0.2 mM NADP, 1 mg/mL BSA, 1 mM MTT, 0.6 mM PMS, 1 unit/mL phosphoglucose isomerase, 2 units/mL glucose 6- phosphate dehydrogenase, and 0.150 mM substrate (fructose 1 ,6- bisphosphate). Inhibitor concentrations were varied from 0.01 μM to 10 μM. Reactions were started by the addition of 0.002 units of pure hlFBPase and were monitored for 7 minutes at 590 nm in a Molecular Devices Plate Reader (37 0C). Results demonstrated inhibition of hlFBPase activity by comounds of the present invention. The compound of Example 3.2 had the lowest activity with an IC50 >100μM. Representative compounds of the invention were further shown to inhibit hlFBPase activity in a dose-dependent manner.
Example B: In vitro Inhibition of Rat Liver and Mouse Liver FBPase.
Inhibitors of FBPase may also be identified by assaying rat and mouse liver FBPase. E. coli strain BL21 transformed with a rat liver FBPase-encoding plasmid is purified as described in El-Maghrabi, M.R., and Pilkis, SJ. Biochem. Biophys. Res. Commun. 1991, 776, 137-144. Mouse liver FBPase is obtained by homogenizing freshly isolated mouse liver in 100 mM Tris-HCl buffer, pH 7.4, containing 1 mM EGTA, and 10 % glycerol. The homogenate is clarified by centrifugation, and the 45-75 % ammonium sulfate fraction prepared. This fraction is redissolved in the homogenization buffer and desalted on a PD-10 gel filtration column (Biorad) eluted with same. This partially purified fraction is used for enzyme assays. Both rat liver and mouse liver FBPase are assayed as described for human liver FBPase. Generally, as reflected by the higher IC50 values, the rat and mouse liver enzymes are less sensitive to inhibition by the compounds tested than the human liver enzyme.
Example C: AMP Site Binding
To determine whether compounds bind to the allosteric AMP binding site of hlFBPase, the enzyme is incubated with radiolabeled AMP in the presence of a range of test compound concentrations. The reaction mixtures
3 consist of 25 mM H-AMP (54 mCi/mmol) and 0 -1000 mM test compound in
25 mM Tris-HCl, pH 7.4, 100 mM KCl and 1 mM MgCl2. 1.45 mg of homogeneous FBPase (±1 nmole) is added last. After a 1 minute incubation, AMP bound to FBPase is separated from unbound AMP by means of a centrifugal ultrafiltration unit ("Ultrafree-MC", Millipore) used according to the instructions of the manufacturer. The radioactivity in aliquots (100 μL) of the upper compartment of the unit (the retentate, which contains enzyme and label) and the lower compartment (the filtrate, which contains unbound label) are quantified using a Beckman liquid scintillation counter. The amount of AMP bound to the enzyme is estimated by comparing the counts in the filtrate (the unbound label) to the total counts in the retentate.
Example D: AMP Site/Enzyme Selectivity
To determine the selectivity of compounds towards FBPase, effects of FBPase inhibitors on 5 key AMP binding enzymes are measured using the assays described below:
Adenosine Kinase: Human adenosine kinase is purified from an E. coli expression system as described by Spychala et al. (Spychala, J., Datta, N.S., Takabayashi, K., Datta, M., Fox, I.H., Gribbin, T., and Mitchell, B.S. Proc. Natl. Acad. Sci. USA 1996, 93, 1232-1237). Activity is measured essentially as described by Yamada et al. (Yamada, Y., Goto, H., Ogasawara, N. Biochim. Biophys. Acta 1988, 660, 36-43.) with a few minor modifications. Assay mixtures contain 50 mM TRIS-maleate buffer, pH 7.0, 0.1 % BSA, 1 mM ATP 1 mM MgCl2, 1.0 μM [U-14C] adenosine (400-600 mCi/mmol) and varying duplicate concentrations of inhibitor. C-AMP is separated from unreacted C-adenosine by absorption to anion exchange paper (Whatman) and quantified by scintillation counting.
Adenosine Monophosphate Deaminase: Porcine heart AMPDA is purified essentially as described by Smiley et al. (Smiley, K.L., Jr, Berry, AJ., and Suelter, CH. J. Biol. Chem. 1967, 242, 2502-2506) through the phosphocellulose step. Inhibition of AMPDA activity is determined at 37 0C in a 0.1 mL assay mixture containing inhibitor, -0.005U AMPDA, 0.1 % bovine serum albumin, 10 mM ATP, 250 mM KCl, and 50 mM MOPS at pH 6.5. The concentration of the substrate AMP is varied from 0.125 - 10.0 mM. Catalysis is initiated by the addition of enzyme to the otherwise complete reaction mixture, and terminated after 5 minutes by injection into an HPLC system. Activities are determined from the amount of IMP formed during 5 minutes. IMP is separated from AMP by HPLC using a Beckman Ultrasil- SAX anion exchange column (4.6 mm x 25 cm) with an isocratic buffer system (12.5 mM potassium phosphate, 30 mM KCl, pH 3.5) and detected spectrophotometrically by absorbance at 254 nm.
Phosphofructokinase: Enzyme (rabbit liver) is purchased from Sigma. Activity is measured at 30 0C in reactions in which the formation of fructose 1 ,6-bisphosphate is coupled to the oxidation of NADH via the action of aldolase, triosephosphate isomerase, and α-glycerophosphate dehydrogenase. Reaction mixtures (200 μL) are made up in 96-well microtitre plates and are read at 340 nm in a Molecular Devices Microplate Reader. The mixtures consist of 200 mM Tris-HCl pH 7.0, 2 mM DTT, 2 mM MgC12, 0.2 mM NADH, 0.2 mM ATP, 0.5 mM Fructose 6-phosphate, 1 unit aldolase/mL, 3 units/mL triosephosphate isomerase, and 4 units/mL α -glycerophosphate dehydrogenase. Test compound concentrations range from 1 to 500 μM. Reactions are started by the addition of 0.0025 units of phosphofructokinase and are monitored for 15 minutes.
Glycogen Phosphorylase: Enzyme (rabbit muscle) is purchased from Sigma. Activity is measured at 37 0C in reactions in which the formation of glucose 1 -phosphate is coupled to the reduction of NADP via phosphoglucomutase and glucose 6-phosphate dehydrogenase. Assays are performed on 96-well microtitre plates and are read at 340 nm on a Molecular Devices Microplate Reader. Reaction mixtures consist of 20 mM imidazole, pH 7.4, 20 mM MgCl2, 150 mM potassium acetate, 5 mM potassium phosphate, 1 mM DTT, 1 mg/mL BSA, 0.1 mM NADP, 1 unit/mL phosphoglucomutase, 1 unit/mL glucose 6-phosphate dehydrogenase, 0.5 % glycogen. Test compound concentrations range from 1 to 500 μM. Reactions are started by the addition of 17 μg enzyme and are monitored for 20 minutes. Adenylate Kinase: Enzyme (rabbit muscle) is purchased from Sigma. Activity is measured at 37 0C in reaction mixtures (100 μL) containing 100 mM Hepes, pH 7.4, 45 mM MgCl2, 1 mM EGTA, 100 mM KCl, 2 mg/mL BSA, 1 mM AMP and 2 mM ATP. Reactions are started by addition of 4.4 ng enzyme and terminated after 5 minutes by addition of 17 μL perchloric acid. Precipitated protein is removed by centrifugation and the supernatant neutralized by addition of 33 μL 3 M KOH/3 M KH2CO3. The neutralized solution is clarified by centrifugation and filtration and analyzed for ADP content (enzyme activity) by HPLC using a YMC ODS AQ column (25 X 4.6 cm). A gradient is run from 0.1 M KH2PO4, pH 6, 8 mM tetrabutyl ammonium hydrogen sulfate to 75 % acetonitrile. Absorbance is monitored at 254 nM.
Example E: Inhibition of GIuconeogenesis in Rat Hepatocytes
Hepatocytes were prepared from overnight fasted Sprague-Dawley rats (250-300 g) according to the procedure of Berry and Friend (Berry, M.N., Friend, D.S., J. Cell. Biol. 1969, 43, 506-520) as modified by Groen (Groen, A.K., Sips, H.J., Vervoorn, R.C., Tager, J.M., Eur. J. Biochem. 1982, 122, 87- 93). Hepatocytes (75 mg wet weight/mL) were incubated in 1 mL Krebs- bicarbonate buffer containing 10 mM Lactate, 1 mM pyruvate, 1 mg/mL BSA, and test compound concentrations from 1 to 500 μM. Incubations were carried out in a 95 % oxygen, 5 % carbon dioxide atmosphere in closed, 50- mL Falcon tubes submerged in a rapidly shaking water bath (37 0C). After 1 hour, an aliquot (0.25 mL) was removed, transferred to an Eppendorf tube and centrifuged. 50 μL of supernatant was then assayed for glucose content using a Sigma Glucose Oxidase kit as per the manufacturer's instructions. Three compounds were tested for their ability to inhibit gluconeogenesis in rat hepatocytes. Two of three compounds tested demonstrated inhibition of gluconeogenesis.
Example F: Blood Glucose Lowering in Fasted Rats
Sprague Dawley rats (250-300 g) are fasted for 18 hours and then dosed intraperitoneally with 20 mg/kg of test compound. The vehicle used for drag administration is 50 mM sodium bicarbonate. Blood samples are obtained from the tail vein of conscious animals just prior to injection and one hour post injection. Blood glucose is measured using a HemoCue Inc. glucose analyzer according to the instructions of the manufacturer. Example G: Effect of FBPase Inhibitors on Gluconeogenesis from Lactate/pyruvate in Rat Hepatocytes: Glucose Production Inhibition and Fructose 1,6-bisphosphate Accumulation
Isolated rat hepatocytes are prepared as described in Example E and incubated under the identical conditions described. Reactions are terminated by removing an aliquot (250 μL) of cell suspension and spinning it through a layer of oil (0.8 mL silicone/mineral oil, 4/1) into a 10 % perchloric acid layer (100 μL). After removal of the oil layer, the acidic cell extract layer is neutralized by addition of l/3rd volume of 3 M KOH/3 M KH2CO3. After thorough mixing and centrifugation, the supernatant is analyzed for glucose content as described in Example E, and also for fructose 1,6-bisphosphate. Fructose 1 ,6-bisphosphate is assayed spectrophotometrically by coupling its enzymatic conversion to glycerol 3-phosphate to the oxidation of NADH, which is monitored at 340 nm. Reaction mixtures (1 mL) consist of 200 mM Tris-HCl, pH 7.4, 0.3 mM NADH, 2 units/mL glycerol 3-phosphate dehydrogenase, 2 units/mL triosephosphate isomerase, and 50-100 μL cell extract. After a 30 minute preincubation at 37 0C, 1 unit/mL of aldolase is added and the change in absorbance measured until a stable value is obtained. Two moles of NADH are oxidized in this reaction per mole of fructose 1 ,6- bisphosphate present in the cell extract.
Inhibition of glucose production from lactate/pyruvate in rat hepatocytes and the accumulation of fructose 1,6 bisphosphate (the substrate of FBPase) is consistent with the inhibition of FBPase.
Example H: Analysis of Drug Levels and Liver Fructose-1,6- bisphosphate Accumulation in Rats
Sprague-Dawley rats (250-300 g) are fasted for 18 hours and then dosed intraperitoneally either with saline (n = 3) or 20 mgs/kg of FBPase inhibitor (n = 4). The vehicle used for drug administration is 10 mM bicarbonate. One hour post injection rats are anesthetized with halothane and a liver biopsy (approx. 1 g) is taken as well as a blood sample (2 mL) from the posterior vena cava. A heparin flushed syringe and needle is used for blood collection. The liver sample is immediately homogenized in ice-cold 10 % perchloric acid (3 mL), centrifuged, and the supernatant neutralized with l/3rd volume of 3 M KOH/3 M KH2CO3. Following centrifugation and filtration,
50 μL of the neutralized extract is analyzed for FBPase inhibitor content by HPLC. A reverse phase YMC ODS AQ column (250 X 4.6 cm) is used and eluted with a gradient from 10 mM sodium phosphate pH 5.5 to 75 % acetonitrile. Absorbance is monitored at 310 nm. The concentration of fructose- 1 ,6-bisphosphate in liver is also quantified using the method described in Example G. Blood glucose is measured in the blood sample as described in Example E. Plasma is then quickly prepared by centrifugation and extracted by addition of methanol to 60 % (v/v). The methanolic extract is clarified by centrifugation and filtration and then analyzed by HPLC as described above.
Elevation of fructose- 1 ,6-bisphosphate levels in the livers from the drug-treated group is consistent with the inhibition of glucose production at the level of FBPase in the gluconeogenic pathway.
Example I: Blood Glucose Lowering in Zucker Diabetic Fatty Rats
Zucker Diabetic Fatty rats purchased at 7 weeks of age are used at age 16 weeks in the 24-hour fasted state. The rats are purchased from Genetics Models Inc. and fed the recommended Purina 5008 diet (6.5 % fat). Their fasting hyperglycemia at 24 hours generally ranges from 150 mg/dLto 310 mg/dLblood glucose.
FBPase inhibitor is administered at a dose of 50 mg/kg by intraperitoneal injection (n = 6). The stock solution is made up at 25 mg/mL in deionized water and adjusted to neutratility by dropwise addition of 5 N NaOH. 5 control animals are dosed with saline. Blood glucose is measured at the time of dosing and 2 hours post dose as described in Example E.
Example J: Inhibition of Gluconeogenesis in Zucker Diabetic Fatty Rats
Three 20-week old Zucker Diabetic Fatty rats are dosed with FBPase inhibitor and three with saline as described in Example I. Fifteen minutes post-injection, the animals are anesthetized with sodium pentobarbitol (30 mgs, i.p.) and 14 C-bicarbonate ( 20 μCi /100 g of body weight) is administered via the tail vein. Blood samples (0.6 mL) are obtained by cardiac puncture 10 and 20 minutes post tracer injection. Blood (0.5 mL) is diluted into 6 mL deionized water and protein precipitated by addition of 1 mL zinc sulfate (0.3 N ) and 1 mL barium hydroxide (0.3 N ). The mixture is centrifuged (20 minutes, IOOOX g) and 5 mL of the resulting supernatant is then combined with 1 g of a mixed bed ion exchange resin (1 part AG 50W-
X8, 100-200 mesh, hydrogen form and 2 parts of AG 1-X8, 100-200 mesh, acetate form) to separate 14 C-bicarbonate from 14 C-glucose. The slurry is shaken at room temperature for four hours and then allowed to settle. An aliquot of the supernatant (0.5 mL) was then counted in 5 mL scintillation cocktail. A reduction in the incorporation of 14 C-bicarbonate into glucose inidcates gluconeogenesis is inhibited by the drug.
Example K: Blood Glucose Lowering in Streptozotocin-treated Rats
Diabetes is induced in male Sprague-Dawley rats (250-300g) by intraperitoneal injection of 55 mg/kg streptozotocin (Sigma Chemical Co.). Six days later, 24 animals are selected with fed blood glucose values (8 am) between 350 and 600 mg/dL and divided into two statistically equivalent groups. Blood glucose is measured in blood obtained from a tail vein nick by means of a HemoCue Inc. (Mission Viejo, CA) glucose analyzer. One group of 12 subsequently receives inhibitor (100 mg/kg intraperitoneally) and the other 12 ("controls") an equivalent volume of saline. Food is removed from the animals. Blood glucose is measured in each animal four hours after dosing, and a second dose of drug or saline is then administered. Four hours later, a final blood glucose measurement is made.
Example L: Estimation of the Oral Bioavailability of Prodrugs of Phosphonic Acids:
Prodrugs are dissolved in 10 % ethanol/90 % polyethylene glycol (mw 400) and administered by oral gavage at doses of approximately 20 or 40 mg/kg parent compound equivalents to 6-hour fasted, Sprague Dawley rats (220-240 g). The rats are subsequently placed in metabolic cages and urine is collected for 24 hours. The quantity of parent compound excreted into urine is determined by HPLC analysis. An ODS column eluted with a gradient from potassium phosphate buffer, pH 5.5 to acetonitrile is employed for these measurements. Detection is at 310-325 nm. The percentage oral bioavailability is estimated by comparison of the recovery in urine of the parent compound generated from the prodrug, to that recovered in urine 24 hours after intravenous administration of unsubstitutcd parent compound at approximately 10 mg/kg. Parent compounds are typically dissolved in dimethyl sulfoxide, and administered via the tail vein in animals that are briefly anesthetized with halothane. Example M. Glucose Lowering Following Oral Administration of FBPase Inhibitors:
FBPase inhibitor is administered by oral gavage at doses of 30, 100 and 250 mg/kg to 18-hour fasted, Sprague Dawley rats (250-300g; n= 4- 5/group). The compound is prepared in deionized water, adjusted to neutrality with sodium hydroxide, and brought into solution by sonication prior to administration. Blood glucose is measured immediately prior to dosing, and at 1 hour intervals thereafter. Blood samples are obtained from the tail vein, and measurments made by means of a Hemocue glucose analyzer (Hemocue Inc, Mission Viejo, California) used according to the manufacturer's instructions. A lowering of blood glucose levels is consistent with inhibition of FBPase activity.

Claims

What is Claimed Is:
1. A compound of a general formula selected from Formulas I-III:
Figure imgf000094_0001
Formula I Formula I Il Formula I
wherein:
Gi, G2, G3, G6, G7 and G9 are each independently selected from the group consisting of C and N;
G8 is C;
A is selected from the group consisting of absent, -H, -NR8 2, -NO2, - OR7, -SR7, -C(O)NR5 J, halo, -C(O)R11, -SO2R9, guanidine, -C(NH)NR5 2, - NHSO2R20, -SO2NR5 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, d-Csalkyl, C2-Csalkenyl, C2-Csalkynyl, and lower alicyclic;
L is selected from the group consisting of absent, -H, -NR8 2, -NO2, - OR7, -SR7, -C(O)NR5 2, halo, -C(O)R1 ', -SO2R9, guanidine, -C(NH)NR5 2, - NHSO2R20, -SO2NR5 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-C5alkyl, CrCsalkenyl, CrCsalkynyl, and lower alicyclic; or together A and L form a cyclic group;
E is selected from the group consisting of absent, -H, -NR 2, -NO2, - OR7, -SR7, -C(O)NR5 2, halo, -C(O)R1 ', -SO2R9, guanidine, -C(NH)NR5 2, - NHSO2R20, -SO2NR5 2, -CN, sulfoxide, perhaloacyl, perhaloalkyl, perhaloalkoxy, Ci-C5alkyl, C2-C5alkenyl, C2-C5alkynyl, and lower alicyclic; or together E and J form a cyclic group; or
J is selected from the group consisting of absent, -H, -NR 2, -NO2, - OR7, -SR7, -C(O)NR5 2, halo, -C(O)R11 , -CN, sulfonyl, sulfoxide, perhaloalkyl, hydroxyalkyl, perhaloalkoxy, alkyl, haloalkyl, aminoalkyl, alkenyl, alkynyl, alicyclic, aryl, and aralkyl; or together J and D form a cyclic group;
D is selected from the group consisting of absent, -H, alkyl, alkenyl, alkynyl, aryl, alicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, -C(O)R9, -S(O)2R9, -C(O)R11 ,-C(O)-OR9, -CONHR9, -NR2 2, and -OR9, each, except H, optionally substituted; or together D and X form a cyclic group;
X is selected from the group consisting of -alkylamino-, - alkylene(hydroxy)-, -alkylene(carboxyl)-, -alkylene(phosphonate)-, -alkylene-, -alkenylene-, -alkynylene-, -alkylene(sulfonate)-, -arylene-, -carbonyl alkyl-, - (l,l-dihalo)alkylene-, -aminocarbonylamino-, -alkylaminoalkyl-, - alkoxyalkyl-, -alkylthioalkyl-, -alkylthio-, - alkylaminocarbonyl -, - alkylcarbonylamino-, -alicyclic-, -aralkyl-, and -alkylaryl-, each optionally substituted; or together X and D form a cyclic group; M is -P(O)(YR21)Y'R21;
Y and Y' are each independently selected from the group consisting of -0-, and -NRV-; when Y and Y' are both -0-, R21 attached to -O- is independently selected from the group consisting of -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R52)2OC(O)NR52 2, -NR52-C(O)-R53, -C(R52)2-OC(O)R53, -C(R52)2-O-C(O)OR53, -C(R52)2OC(O)S R53, -alkyl-S-C(O)R5\ -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; when Y and Y' are both -NR\ then R21 attached to -NRV- is independently selected from the group consisting of -H, -[C(R52)2]P-COOR53, -C(RX)2COOR53, -[C(R52)2]P-C(O)SR5\ and -cycloalkylene-COOR53; when Y is -O- and Y' is NR\ then R21 attached to -O- is independently selected from the group consisting of -H. alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2- heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, -C(R52)2OC(O)NR52 2, -NR52-C(O)-R53, -C(R52)2-OC(O)R53, -C(R52)2-O-C(O)OR5\ -C(R52)2OC(O)S
R53,
-alkyl-S-C(O)R53, -alkyl-S-S-alkylhydroxy, and -alkyl-S-S-S-alkylhydroxy; and R21 attached to -NRV- is independently selected from the group consisting of -H, -[C(R52)2]P-COOR53, -C(R1^2COOR53, -[C(R52)2]P-C(O)SR53, and
-cycloalkylene-COOR53; wherein if both R21 are alkyl, at least one is higher alkyl; or when Y and Y' are independently selected from -O- and -NRV-, then R21 and R ' together form a cyclic group comprising -alkyl-S-S-alkyl-, or R21 and R21 together are the group:
Figure imgf000096_0001
wherein:
V, W, and W are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; and
Z is selected from the group consisting of - CHR52OH, -CHR52OC(O)R53,
CHR52OC(S)R53, -CHR52OC(S)OR53, -CHR52OC(O)SR53, -CHR52OCO2R53, - OR52,
-SR52, -CHR52N3, -CH2aiyl, -CH(aryl)OH, -CH(CH=CR52 2)OH, -CH(C≡CR52)OH, -R52, -NR5VOCOR53, -OCO2R53, -SCOR53, -SCO2R53, -NHCOR52, -NHCO2R53, -CH2NHaTyI, -(CH2)P-OR52, and -(CH2)p-SR52;or
W and W are as defined above and together V and Z are connected via (a) an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon, optionally substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus, or (b) an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, wherein said cyclic group is fused to an aryl group at the beta and gamma position to a Y or Y that is attached to the phosphorus; or
W and Z are as defined above and together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon ring atoms optionally substituted with one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy or aryloxycarbonyloxy, said substituent attached to one of said carbon ring atoms that is three atoms from a Y or Y' that is attached to the phosphorus; or
W is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining ring atoms are carbon; or
Z is as defined above, V is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and together W and W are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining ring atoms are carbon;
R52 is selected from the group consisting of R53 and -H;
R53 is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl;
Rx is independently selected from the group consisting of -H, and alkyl, or together Rx and Rx form a cycloalkyl group;
Rv is selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl; p is an integer 2 or 3;
R2 is selected from the group consisting of R9 and -H;
R5 is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, and lower aryl; R7 is selected from the group consisting of -H, lower alkyl, lower alicyclic, lower aralkyl, lower aryl, and -C(O)R1 ;
R8 is selected from the group consisting of -H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, -C(O)R10, or together they form a bidentate alkyl;
R9 is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R1 is selected from the group consisting of -H, lower alkyl, -NH2, lower aryl, and lower perhaloalkyl;
R11 is selected from the group consisting of alkyl, aryl, -OH, -NH2 and
-OR9;
R20 is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, and lower alicyclic; wherein, a) V, Z, W, W are not all -H, b) when Z is -R52, then at least one of V, W, and W is not -H, alkyl, aralkyl, or heterocycloalkyl, and, c) said compound of Formula I-III is not a compound of a formula selected from Formulas IV-VIII:
Figure imgf000098_0001
Formula IV,
Figure imgf000099_0001
Formula V,
Figure imgf000100_0001
Formula VI,
Figure imgf000100_0002
Formula VII, and
Figure imgf000100_0003
Formula VIII; or a pharmaceutically acceptable salt, co-crystal or prodrug thereof.
2. The compound of claim 1, wherein said compound is a compound of Formula IX:
Figure imgf000101_0001
Formula IX, wherein B is Ci-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, lower alicyclic or aralkyl; and, X" is Cl" or Br".
3. The compound of claim 1, wherein said compound is a compound of Formula X:
Figure imgf000101_0002
Formula X.
4. The compound of claim 1 , wherein said compound is a compound of Formula XI:
Figure imgf000101_0003
Formula XI, wherein B is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, lower alicyclic or aralkyl; and, X" is Cl" or Br"
5. The compound of claim 1 , wherein said compound is a compound of Formula XII:
Figure imgf000102_0001
Formula XII.
6. The compound of claim 1 , wherein said compound is a compound of Formula XIII:
Figure imgf000102_0002
Formula XIII.
7. The compound of claim 1, wherein A, L, and E are independently selected from the group consisting of absent -H, -NR8 2, -NO2, hydroxy, alkylaminocarbonyl, halogen, -OR7, -SR7, lower perhaloalkyl, and C1-C5 alkyl.
8. The compound of claim 1, wherein A, L and E are independently selected from the group consisting of absent, -NR 2, -H, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and lower alkyl.
9. The compound of claim 1, wherein A is selected from the group consisting absent of -NR8 2, -H, halogen, lower perhaloalkyl, and lower alkyl.
10. The compound of claim 1, wherein L and E are independently selected from the group consisting of absent-H, lower alkoxy, lower alkyl, and halogen.
11. The compound of claim 1 , wherein J is selected from the group consisting of absent-H, halogen, lower alkyl, lower hydroxylalkyl, -NR8 2, lower R82N- alkyl, lower haloalkyl, lower perhaloalkyl, lower alkenyl, lower alkynyl, lower aryl, heterocyclic, and alicyclic.
12. The compound of claim 1, wherein J is selected from the group consisting of absent-H, halogen, and lower alkyl-, lower hydroxyalkyl-, -NR8 2, lower R8 2N-alkyl-, lower haloalkyl, lower alkenyl, alicyclic, and aryl.
13. The compound of claim 1, wherein J is selected from the group consisting of alicyclic and lower alkyl.
14. The compound of claim 1, wherein A and L together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
15. The compound of claim 1, wherein L and E together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
16. The compound of claim 1, wherein E and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
17. The compound of claim 1, wherein D and J together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
18. The compound of claim 1, wherein D and X together form a cyclic group selected from cycloalklyl, heterocycloalkyl, aryl or heteroaryl.
19. The compound of claim 1, wherein X is selected from the group consisting of -alkylene-, -alkynylene-, -arylene-, -alkoxyalkyl-, -alkylthio-, - alkylaminocarbonyl-, -alkylcarbonylamino-, -(l,l-dihalo)alkylene, - carbonylalkyl-, -alkylene(OH)-, and -alkylene(sulfonate)-.
20. The compound of claim 1, wherein X is selected from the group consisting of -heteroarylene-, -alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, - alkylene( sulfonate)-, and -alkoxyalkyl-.
21. The compound of claim 1, wherein X is selected from the group consisting of -heteroarylene-, -alkylaminocarbonyl-, and -alkoxyalkyl-.
22. The compound of claim 1, wherem X is selected from the group consisting of -methylaminocarbonyl-, - methoxymethyl-, and furan-2,5-diyl.
23. The compound of claim 1, wherein X is not substituted with a phosphonic acid or ester.
24. The compound of claim 1, wherein when X is substituted with a phosphonic acid or ester, then A is -NR 2 and D is not -H.
25. The compound of claim 1 , wherein X is -arylene- or -alkylaryk
26. The compound of claim 1, wherein R20 and R7 are independently selected from the group consisting of -H, and lower alkyl.
27. The compound of claim 1, wherein: A, L, and E are independently selected from the group consisting of -H, lower alkyl, hydroxy, halogen, lower alkoxy, lower perhaloalkyl, and -NR 2; X is selected from the group consisting of - arylene-, -alkoxyalkyl-, -alkylene-, -alkylthio-, -(l,l-dihalo)alkylene-, - carbonyl-, -alkylene-, -alkylene(hydroxy)-, -alkylene( sulfonate)-, - alkylaminocarbonyl-, and -alkylcarbonylamino-; and each R5 and R7 is independently -H, or lower alkyl.
28. The compound of claim 1, wherein: A, L, and E are independently selected from the group consisting of -H, lower alkyl, halogen, and -NR 2; J is selected from the group consisting of -H, halogen, haloalkyl, hydroxyalkyl, R8 2N-alkyl, lower alkyl, lower aryl, heterocyclic, and alicyclic, or together with D forms a cyclic group; and X is selected from the group consisting of -heteroarylene-, - alkylaminocarbonyl-, -(l,l-dihalo)alkylene-, and -alkoxyalkyl-.
29. The compound of claim 1, wherein: A is selected from the group consisting of -H, -NH2, -F, and -CH3; L is selected from the group consisting of -H, -F, -OCH3, -Cl, and -CH3; E is selected from the group consisting of -H and -Cl; J is selected from the group consisting of -H, halo, Cj-C5 hydroxyalkyl, CpC5 haloalkyl, R8 2N- CrC5alkyl, CrC5alicyclic, and Q- C5alkyl; X is selected from the group consisting of -CH2OCH2- and furan-2,5- diyl; and, D is lower alkyl.
30. The compound of claim 1, wherein M is selected from the group consisting of -P(O)[-OCR52 2OC(O)R53]2, -P(O)[-OCR52 2OC(O)OR53]2, -P(O)[-N(H)CR52 2C(O)OR53]2, -P(O)[-N(H)CR52 2C(O)OR53][-ORπ], -P(O)[-OCH(V)CH2CH2O-], -P(O)(OH)(OR11), -P(O)(ORe)(ORe), -P(O)[-OCR52 2OC(O)R53](ORe), -P(O)[-OCR52 2OC(O)OR53](ORe), and -P(O)[-N(H)CR52 2C(O)OR53](ORe); wherein:
V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl; Re is selected from the group consisting of optionally substituted -Ci-Cn alkyl, optionally substituted -C2-Cn alkenyl, optionally substituted -C2-Cn alkynyl, optionally substituted -(CR57 2)naryl, optionally substituted -(CR572)ncycloalkyl, and optionally substituted -(CR57 2)nheterocycloalkyl; n is an integer from 1 to 3; each R57 is independently selected from the group consisting of hydrogen, optionally substituted -Ci-C4 alkyl, halogen, optionally substituted -0-Ci-C4 alkyl, -OCF3, optionally substituted -S-Ci-C4 alkyl, -NR58R59, optionally substituted -C2-C4 alkenyl, and optionally substituted -C2-C4 alkynyl; with the proviso that when one R57 is attached to C through an O, S, or N atom, then the other R57 attached to the same C is a hydrogen, or attached via a carbon atom;
R58 is selected from hydrogen and optionally substituted -C1-C4 alkyl; and,
R59 is selected from the group consisting of hydrogen and optionally substituted -Ci-C4 alkyl, optionally substituted -C(O)-Ci-C4 alkyl and -C(O)H.
31. The compound of claim 1 , wherein M is selected from the group consisting Of -PO3H2, -P(O)[-OCR52 2OC(O)R53]2,
-P(0)[-0CR52 2OC(O)0R53]2, -P(O)[-N(H)CR52 2C(O)0R53]2, -P(O)[-N(H)CR522C(O)OR53][-ORn], -P(O)[-OCH(V)CH2CH2O-], , -P(0)(0Re)(0Re), -P(O)[-OCR52 2OC(O)R53](ORe), -P(O)[-OCR52 2OC(O)OR 53](ORe), -P(O)[-N(H)CR52 2C(O)OR53](ORe), and -P(O)(OH)(NH2); wherein V is selected from the group consisting of optionally substituted aryl, aryl, heteroaryl, and optionally substituted heteroaryl.
32. The compound of claim 1, wherein M is selected from the group consisting Of -PO3H2, -P(O)[-OCH2OC(O)-f-butyl]2, -P(O)[-OCH2OC(O)O-j-propyl]2, -P(O)[-N(H)CH(CH3)C(O)O CH2CH3]2, -P(O)[-N(H)C(CH3)2C(O)OCH2CH3]2, -P(0)[-N(H)CH (CH3)C(O)OCH2CH3] [3,4-methylenedioxyρhenyl], -P(O)[-N(H)C
(CH3)2C(O)OCH2CH3][3,4-methylenedioxyphenyl], -P(O)[-OCH
(3-chlorophenyl)CH2CH2O-], -P(O)[-OCH(pyrid-4-yl)CH2CH2O-],
-P(O)[-OCH2OC(O)- f-buty I](OCH3), -P(O)[-OCH2OC(O)O-/-propyl](OCH3), -P(O)[-OCH
(CH3)OC(O)-f-butyl](OCH3), -P(O)[-OCH(CH3)OC(O)O-i-ρropyl]
(OCH3), -P(O)[-N(H)CH(CH3)C(O)OCH2CH3](OCH3),
-P(O)[-N(H)C(CH3)2C(O)OCH2CH3](OCH3), and -P(O)(OH)(NH2).
33. The compound of claim 1, wherein M is selected from wherein Y and Y' aarree eeaacchh iinndependently selected from -O- and -NRV-; together R21 and R21 are the group:
Figure imgf000107_0001
wherein V is substituted aryl or substituted heteroaryl.
34. The compound of claim 33, wherein Z is selected from hydrogen, W is hydrogen, and W is hydrogen.
35. The compound of claim 33, wherein V is selected from the group consisting of 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3-fluorophenyl, pyrid-4-yl, pyrid-3-yl and 3,5-dichlorophenyl.
36. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
37. A unit dose of the pharmaceutical composition of claim 7.
38. A method of using the compound of claim 1 in the manufacture of a medicament for treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which an FBPase inhibitor(s) is indicated.
39. A method of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition responsive to inhibition of gluconeogenesis or responsive to lowered blood glucose levels, the method comprising the step of administering to a patient a therapeutically effective amount a compound of claim 1.
40. A method of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type I diabetes, the method comprising the step of administering to a patient a therapeutically effective amount the composition of claim 36.
41. A method of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of Type II diabetes, the method comprising the step of administering to a patient a therapeutically effective amount the composition of claim 36.
42. A method of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of impaired glucose tolerance, the method comprising the step of administering to a patient a therapeutically effective amount the composition of claim 36.
43. A method of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of insulin resistance, the method comprising the step of administering to a patient a therapeutically effective amount the composition of claim 36.
44. A method of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of hyperglycemia, the method comprising the step of administering to a patient a therapeutically effective amount the composition of claim 36.
45. A method of treating, preventing, delaying the time to onset of or reducing the risk for the development or progression accelerated gluconeogenesis, the method comprising the step of administering to a patient a therapeutically effective amount the composition of claim 36.
46. A method of treating, preventing, delaying the time to onset of or reducing the risk for the development or progression increased or excessive hepatic glucose output, the method comprising the step of administering to a patient a therapeutically effective amount the composition of claim 36.
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