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WO2003013526A1 - Composes anticoagulants - Google Patents

Composes anticoagulants Download PDF

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Publication number
WO2003013526A1
WO2003013526A1 PCT/US2002/024664 US0224664W WO03013526A1 WO 2003013526 A1 WO2003013526 A1 WO 2003013526A1 US 0224664 W US0224664 W US 0224664W WO 03013526 A1 WO03013526 A1 WO 03013526A1
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WO
WIPO (PCT)
Prior art keywords
imidazol
aminopyridin
propanoic acid
alkyl
group
Prior art date
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PCT/US2002/024664
Other languages
English (en)
Inventor
James C. Barrow
Harold G. Selnick
Philippe G. Nantermet
Kenneth E. Rittle
Daniel R. Mcmasters
Shaun R. Stauffer
Stacey Bolinger
Original Assignee
Merck & Co. Inc.
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Publication of WO2003013526A1 publication Critical patent/WO2003013526A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds, and pharmaceutically acceptable salts thereof, which inhibit basic carboxypeptidases, more specifically carboxypeptidase U, and thus can be used in the prevention and treatment of diseases wherein inhibition of carboxypeptidase U is beneficial.
  • the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a pharmaceutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.
  • Fibrinolysis is the result of a series of enzymatic reactions resulting in the degradation of fibrin by plasmin.
  • the activation of plasminogen is the central process in fibrinolysis.
  • the cleavage of plasminogen to produce plasmin is accomplished by the plasminogen activators, tissue-type plasminogen activator or urokinase-type plasminogen activator.
  • Initial plasmin degradation of fibrin generates carboxy-terminal lysine residues that serves as high affinity binding sites for plasminogen. Since plasminogen bound to fibrin is much more readily activated to plasmin than free plasminogen this mechanism provides a positive feedback regulation of fibrinolysis.
  • One of the endogenous inhibitors to fibrinolysis is carboxypeptidase U
  • CPU is also known as plasma carboxypeptidase B, active thrombin activatable fibrinolysis inhibitor (TAFIa), carboxypeptidase R and inducable carboxypeptidase activity.
  • TAFIa active thrombin activatable fibrinolysis inhibitor
  • CPU is formed during coagulation and fibrinolysis from its precursor proCPU by the action of proteolytic enzymes e.g. thrombin, thrombin- thrombomodulin complex or plasmin.
  • proteolytic enzymes e.g. thrombin, thrombin- thrombomodulin complex or plasmin.
  • CPU cleaves basic amino acids at the carboxy- terminal of fibrin fragments. The loss of carboxy-terminal lysines and thereby of lysine binding sites for plasminogen then serves to inhibit fibrinolysis.
  • Inhibitors of carboxypeptidase U are described in WO 00/66557, WO 00/66550, WO 00/66152, and WO 02/14285.
  • Guanidinoethylmercaptosuccinic acid is reported as carboxypeptidase N inhibitor. More recently, this compound has been shown to inhibit CPU, Eaton, D.L., et al, The Journal of Biological Chemistry, 266 (1991) 21833-21838.
  • the invention includes compounds for inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • the compounds can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.
  • the invention also includes a compound for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, atherosclerosis, adhesions, dermal scarring, cancer, fibrotic conditions, inflammatory diseases and those conditions which benefit from maintaining or enhancing bradykinin levels in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier.
  • the invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.
  • Compounds of the invention are useful as carboxypeptidase U inhibitors and have therapeutic value in for example, preventing coronary artery disease. They are useful in preventing thrombosis and in thrombolytic therapy.
  • the invention includes compounds having the following structure:
  • A is a) COOR5, b) tetrazole, or c) a carboxylic acid isostere, wherein R5 is 1) hydrogen,
  • Ci_8 alkyl wherein the alkyl substituent is selected from the group consisting of i) aryl, ii) heterocycle, iii) -NR6R7, iv) -OR6, and v) -CHR6OC(O)R7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, Ci-6 alkyl, and aryl;
  • X is a) C _6 alkyl, substituted with one or more basic groups, or b) Y-W, wherein Y is 1) (CR8R9),
  • R8, RlO, and R 12 are independently selected from the group consisting of hydrogen, C ⁇ _4 alkyl, OR14, F, and NR14R15, wherein Rl4 and Rl5 are independently selected from the group consisting of hydrogen and Ci-4 alkyl, and wherein R9, Rl 1, and Rl3 are independently selected from the group consisting of hydrogen, F and Ci-4 alkyl, and wherein W is 1) a C3-7 cycloalkyl ring wherein at least one ring carbon atom is substituted with a basic group,
  • each ring carbon atom is independently unsubstituted or mono- or bi-substituted with a basic group, halogen, or Ci-4 alkyl, or
  • Rl is selected from the group consisting of a) hydrogen, b) C ⁇ _4 alkyl, c) OR16, d) F, and e) NR16R17,
  • Rl6 and Rl are independently selected from the group consisting of hydrogen and C1.4 alkyl
  • R2 is selected from the group consisting of a) hydrogen, b) methyl, c) phenyl, unsubstituted or independently mono- or di-substituted with a substitutent selected from the group consisting of halogen, phenyl, Ci-4 alkyl, CF3, CN, OCH3, NH2, NO2, pyridine and pyrimidine, d) Ci-4 alkenyl, and e) A1-(A2)O-1-(A )O-1-(A )O_I-A5, wherein
  • Al is C ⁇ _7 alkylene, wherein each carbon atom is independently unsubstituted or mono- or di-substituted with a substitutent selected from the group consisting of F, CF3 and Ci_4 alkyl,
  • A2 is selected from the group consisting of C(O), C(O)NH, NHC(O), and -
  • A is a bond or C 1.3 alkylene, where each carbon atom is independently unsubstituted or mono- or di-substituted with Ci-4 alkyl, A4 is a bond, O, or OCH2, and
  • phenyl unsubstituted or independently mono- or di-substituted with a substitutent selected from the group consisting of halogen, phenyl, Ci-4 alkyl, CF3, CN, OCH3 and NH2, 2) pyridinyl,
  • Rl8 and Rl are independently selected from the group of consisting of hydrogen and C1.4 alkyl
  • Z2 is a bond or Ci-4 alkylene
  • R20 and R21 are independently selected from the group consisting of hydrogen, phenyl, CN or difluorophenyl
  • R2' is selected from the group consisting of a) hydrogen, b) methyl, c) phenyl, unsubstituted or independently mono- or di-substituted with a substitutent selected from the group consisting of halogen, phenyl, C _4 alkyl, CF3, CN, OCH3, NH2, NO2, pyridine and pyrimidine, d) Ci-4 alkenyl, and e) Al '-(A2 O-1-(A3')0-1-(A4')O-1-A5', wherein
  • A2' is selected from the group consisting of C(O), C(O)NH, NHC(O), and -
  • A3' is a bond or Ci-3 alkylene, where each carbon atom is independently unsubstituted or mono- or di-substituted with Ci_4 alkyl, A ' is a bond, O, or OCH2, and
  • phenyl unsubstituted or independently mono- or di-substituted with a substitutent selected from the group consisting of halogen, phenyl, Ci_ 4 alkyl, CF3, CN, OCH3 and NH2, 2) pyridinyl,
  • Rl8' and Rl ' are independently selected from the group of consisting of hydrogen and Ci_4 alkyl
  • Z2 ' is a bond or C 1 -.4 alkylene
  • R20 ' and R21 ' are independently selected from the group consisting of hydrogen, phenyl, CN or difluorophenyl;
  • R2" is selected from the group consisting of a) hydrogen, b) methyl, c) phenyl, unsubstituted or independently mono- or di-substituted with a substitutent selected from the group consisting of halogen, phenyl, Ci-4 alkyl, CF3, CN, OCH3, NH2, NO2, pyridine and pyrimidine, d) C ⁇ _4 alkenyl, and e) A1"-(A2")O-1-(A3")O-1-(A4")O-1-A5", wherein
  • Al is Ci-7 alkylene, wherein each carbon atom is independently unsubstituted or mono- or di-substituted with a substitutent selected from the group consisting of F, CF3 and Ci-4 alkyl, A2" is selected from the group consisting of C(O), C(O)NH, NHC(O), and -
  • NHSO2 is a bond or Ci-3 alkylene, where each carbon atom is independently unsubstituted or mono- or di-substituted with C1.4 alkyl, A4" is a bond, O, or OCH2, and A5"is
  • phenyl unsubstituted or independently mono- or di-substituted with a substitutent selected from the group consisting of halogen, phenyl, C ⁇ _ 4 alkyl, CF3, CN, OCH3 and NH2, 2) pyridinyl,
  • Z2" is a bond or C _4 alkylene
  • R20" and R 1" are independently selected from the group consisting of hydrogen, phenyl, CN or difluorophenyl
  • R3 is a) hydrogen, b) unsubstituted or substituted C ⁇ _6 alkyl, c) unsubstituted or substituted phenyl, d) unsubstituted or substituted naphthyl, or e) unsubstituted or substituted heterocycle, wherein one or more substituents in substituted alkyl is independently selected from the group consisting of F, Ci_6 alkyl, phenyl, naphthyl, and heterocyle, and one or more substituents in substituted phenyl, substituted naphthyl and substituted heterocycle is independently selected from the group consisting of phenyl, naphthyl, heterocyle, -CF3, -CN, Ci-6 alkyl, hydroxy, C1.4 alkoxy; halogen, -NO2, -NR23R24, -SO2R23, SO2NR 3R24 -CONR23R24 or C0R23 ?
  • R23 and R24 are independently selected hydrogen and C L4 alkyl; and R4 is a) hydrogen, b) unsubstituted or substituted Ci-6 alkyl, c) unsubstituted or substituted phenyl, d) unsubstituted or substituted naphthyl, e) unsubstituted or substituted heterocycle, or f) unsubstituted or substituted Ci-4 alkylenearyl, wherein one or more substituents in substituted alkyl is independently selected from the group consisting of F, Ci-6 alkyl, phenyl, naphthyl, and heterocyle, and one or more substituents in substituted phenyl, substituted naphthyl and substituted heterocycle is independently selected from the group consisting of phenyl, naphthyl, heterocyle, -CF3, -CN, Ci_6 alkyl, hydroxy, C ⁇ _4 alkoxy; halogen, -NO2, -NR25
  • A is COOH
  • Rl is hydrogen
  • R is hydrogen
  • R4 is hydrogen
  • R2' is hydrogen and
  • R2" is a) phenyl, unsubstituted or substituted with C ⁇ _4 alkyl, or b) A1 "-A5", wherein
  • Ci-2 alkylene wherein each carbon atom is independently unsubstituted or mono- or di-substituted with a substitutent selected from the group consisting of F, CF3 and Ci-4 alkyl , and
  • phenyl unsubstituted or independently mono- or di-substituted with a substitutent selected from the group consisting of halogen, phenyl, Cl-4 alkyl, CF3, CN, OCH3 and NH2, or
  • X is a) C ⁇ _4 alkyl, substituted with NH2, or b) Y-W, wherein Y is (CH2)l-2 and wherein W is
  • each ring carbon atom is independently unsubstituted, mono- or bi-substituted with NH2, CH3 or CI.
  • X is selected from the group consisting of
  • R2 is selected from the group consisting of hydrogen, methyl, phenyl, unsubstituted or substituted with Ci-4 alkyl, NH2, CN, NO2, pyridine or pyrimidine,
  • a 1 -(A2)O_ 1-(A3)O- 1 -(A4)O_ 1 - A5 wherein Al is (CH2)l-7 or CH(CH 3 ),
  • A2 is selected from the group consisting of C(O), C(O)NH, NHC(O), and -NHSO2,
  • A3 is a bond, (CH2)l-3 or C(CH3)2CH2,
  • A4 is a bond, O, or OCH2,
  • A5 is selected from the group consisting of CF 3 , CH 3) CH(CH 3 ) 2 , C(CH 3 ) 3 , CH(CH 2 CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 3 ) 2 , NH 2 , OH, COOH,
  • the inhibiting effect of the compounds of the invention was estimated using assays described in and based on Hendriks et al., Biochemica et Biophysica Acta, 1034 (1990) pp. 86-92, and Wang et al. The Journal of Biological Chemistry, 269, pp. 15937-15944 (1994).
  • Carboxypeptidase U was isolated from human serum with rabbit thrombomodulin modified from reports by Hendriks et al 1990 and Wang et al 1994.
  • ⁇ -Aminocaproic acid (EACA) was added for stabilizing carboxypeptidase U during the isolation.
  • Activity of carboxypeptidase U was measured using a synthetic peptide. Assay solutions were stopped by potato carboxypeptidase inhibitor.
  • the activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.
  • the compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.
  • the compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention.
  • the compounds of the invention also include tautomeric forms, with all tautomeric forms being included in the present invention.
  • IPr2Net diisopropyl ethyl amine
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, “C ⁇ _6 alkyl”, denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl).
  • alkyl groups refer to groups having one or more defined substituents.
  • alkenyl is intended to include both branched- and straight-chain unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms (e.g. ethenyl, propenyl, 1-butenyl, 2-butenyl); "substituted” alkenyl groups refer to groups having one or more defined substituents.
  • alkoxy represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • halogen as used herein, means fluoro, chloro, bromo and iodo.
  • counterion is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.
  • carboxylic isostere includes an acidic group having a pKa of from about -5 to about 7, e.g.
  • -S(O)2NHR a (where R a can be Ci-4 alkyl), -S(O)2OH, -P(O)(OH)NH2, - P(O)(OH)OCH2CH3, -C(O)NH(CN),
  • basic group includes groups where the conjugate acid of said group has a pKa of from about 5 to about 15, such as an amino, amidino, guanidino, or pyridinyl.
  • cycloalkyl and “cycloC3_7alky ⁇ ” mean nonaromatic cyclic hydrocarbon groups having the specified number of carbon atoms and are intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.
  • aryl as used herein except where noted, represents a stable 6- to 10-membered mono- or bicyclic ring system such as phenyl, or naphthyl, wherein at least one ring is aromatic.
  • the aryl ring can be unsubstituted or substituted with one or more of -CF3, -CN, C ⁇ -4 alkyl; hydroxy; Ci_ 4 alkoxy; halogen, e.g. F, CI, Br, or I; -NO2; -NRaRb; -SO2R a ; SO2NRaRb ; _
  • R a and Rb are independently selected hydrogen and C 1-4 alkyl.
  • alkylenearyl such as "Ci-4 alkylenearyl” refers to a substituent which is an aryl group attached to the substituted atom with an alkylene linker, e.g. -CH2CH2C6H5.
  • heterocycle represents a stable 5- to 7-membered monocyclic- or stable 8- to 11-membered fused bicyclic or stable 11- to 15-membered tricyclic ring system, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • Bicyclic unsaturated ring systems include bicyclic ring systems which may be partially unsaturated or fully unsaturated.
  • Partially unsaturated bicyclic ring systems include, for example, cyclopentenopyridinyl, benzodioxan, methylenedioxyphenyl groups.
  • Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimid
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Amino substituents may be represented by 1 NH 2 or ? N
  • Amino substituents may be represented by 1 NH 2 or ? N
  • Hydroxy substituents may be represented by % OH or %— O p or example, the structures
  • the pharmaceutically-acceptable salts of the compounds of Formula I include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfamic, phosphoric, nitric and the like, or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tart
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl
  • diamyl sulfates long chain halides
  • Carboxypeptidase U Inhibitors - Therapeutic Uses- Method of Using Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy.
  • the term "patient” used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.
  • Carboxypeptidase U inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • carboxypeptidase U inhibitors can be added to or contacted with any medium containing or suspected of containing carboxypeptidase U and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.
  • Compounds of the invention are useful for treating or preventing venous thromboembolism (e.g. obstruction or occlusion of a vein by a detached thrombus; obstruction or occlusion of a lung artery by a detached thrombus), cardiogenic thromboembolism (e.g. obstruction or occlusion of the heart by a detached thrombus), arterial thrombosis (e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery), atherosclerosis (e.g. arteriosclerosis characterized by irregularly distributed lipid deposits) in mammals, and for lowering the propensity of devices that come into contact with blood to clot blood.
  • venous thromboembolism e.g. obstruction or occlusion of a vein by a detached thrombus
  • cardiogenic thromboembolism e.g. obstruction or occlusion of the heart by a detached thrombus
  • Examples of venous thromboembolism which may be treated or prevented with compounds of the invention include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin III deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds of the invention are useful for maintaining patency of indwelling catheters.
  • cardiogenic thromboembolism examples include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.
  • arterial thrombosis examples include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local anemia due to obstruction (such as by arterial narrowing) of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease. Also with regard to arterial thrombosis, compounds of the invention are useful for maintaining patency in arteriovenous cannulas.
  • Atherosclerosis examples include arteriosclerosis.
  • devices that come into contact with blood include vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems
  • the carboxypeptidase U inhibitors of the invention are also useful for angiogenesis and for treating cancer diseases by inhibiting coagulation and moderating blood vessel formation.
  • diseases include the proliferation of tumor cells and the pathologic neovascularization (or angiogenesis) that supports solid tumor growth.
  • the instant compounds inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580, 1995).
  • the instant compounds are also useful in combination with known anti-cancer agents.
  • Such known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transf erase inhibitors, HMG-CoA reductase inhibitors, HJV protease inhibitors, reverse transcriptase inhibitors, kinase insert domain receptor (KDR) kinase inhibitors (such as those disclosed in patent publications WO 0129025, WO 0117995 and U.S. Patent 6306874), and other angiogenesis inhibitors.
  • KDR kinase insert domain receptor
  • Carboxypeptidase U inhibitors are also useful for treating pain and inflammation, particularly arthritis and related arthritic conditions.
  • Carboxypeptidase U inhibitors are also useful in thrombolytic therapy, especially when combined with thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies.
  • Carboxypeptidase U inhibitors are also useful in the treatment of atherosclerosis.
  • Atherosclerosis is a common condition in subjects suffering from peripheral vascular disease, insulin resistance and the group of conditions commonly referred to as 'Syndrome X.
  • Syndrome X is a term often used to group together a number of interrelated diseases.
  • the first stage of syndrome X consists of insulin resistance, abnormal cholesterol and triglyceride levels, obesity and hypertension. Any one of these conditions may be used to diagnose the start of Syndrome X.
  • the disease may then progress with one condition leading to the development of another in the group. For example insulin resistance is associated with high lipid levels, hypertension and obesity.
  • the disease then cascades, with the development of each additional condition increasing the risk of developing more serious diseases. This can progress to the development of diabetes, kidney disease and heart disease. These diseases may lead to stroke, myocardial infarction and organ failure.
  • Carboxypeptidase U inhibitors are also effective in inhibiting tumor maturation and progression. Metastasis is a complex and multifactorial process which is not yet fully understood. Accordingly, whilst not wishing to be bound by any theory, it is believed that the haemostatic system is involved at several levels of cancer pathology, including neovascularization, shedding of cells from the primary tumor, invasion of the blood supply, adherence to the vessel wall and growth at the metastatic site. It is thought that the efficacy of carboxypeptidase U inhibitors stems from an ability to reduce fibrin deposition around solid tumors and thereby inhibit the above processes.
  • the carboxypeptidase U inhibitors can also be co-administered with suitable anticoagulants (e.g.
  • suitable antiplatelet agents including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), aspirin, platelet inhibitors (e.g. dipyridamole), inhibitors of ADP-induced platelet aggregation (e.g. clopidogrel) or platelet aggregation inhibitors such as ticlopidine, to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g.
  • HMG CoA reductase inhibitors such as lovastatin and simvastatin, HMG CoA synthase inhibitors, etc.
  • HMG CoA reductase inhibitors such as lovastatin and simvastatin, HMG CoA synthase inhibitors, etc.
  • atherosclerosis For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and carboxypeptidase U inhibitors.
  • carboxypeptidase U inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.
  • Carboxypeptidase U inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.
  • Typical doses of carboxypeptidase U inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of carboxypeptidase U inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of carboxypeptidase U inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.
  • the carboxypeptidase U inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti- aggregation agent. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
  • the carboxypeptidase U inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation.
  • the carboxypeptidase U inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the carboxypeptidase U inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the carboxypeptidase U inhibitors may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • carboxypeptidase U inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • the dosage regimen utilizing the carboxypeptidase U inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of the carboxypeptidase U inhibitors when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, for example 0.025-7.5 mg/kg/day, more specifically 0.1-2.5 mg/kg/day, and even more specifically 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis).
  • An 80 kg patient for example, would receive between about 0.8 mg/day and 2.4 g/day, for example 2-600 mg/day, specifically 8-200 mg/day, more specifically 8-40 mg/kg/day.
  • a suitably prepared medicament for once a day administration would thus contain between about 0.8 mg and 2.4 g, for example 2 mg and 600 mg, specifically 8 mg and 200 mg, and more specifically 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg.
  • the carboxypeptidase U inhibitors may also be administered in divided doses of two, three, or four times daily.
  • a suitably prepared medicament would contain between about 0.4 mg and 4 g, for example 1 mg and 300 mg, specifically 4 mg and 100 mg, and more specifically 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.
  • the patient would receive the active ingredient in quantities sufficient to deliver between about 0.025-7.5 mg/kg/day, for example 0.1- 2.5 mg/kg/day, specifically 0.1-0.5 mg/kg/day.
  • Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day.
  • a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g.
  • 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml and administered in amounts per day of between about 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg.
  • an 80 kg patient receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day.
  • Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers.
  • the choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.
  • the compounds can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.
  • the carboxypeptidase U inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
  • tert-butyl 5-( " bromomethyl)pyridin-2-ylcarbamate (1-4) To a solution of 9.92 g (44.2 mmol) of tert-butyl 5-(hydroxymethyl) ⁇ yridin-2-ylcarbamate (1-3) in 220 mL THF cooled to 0 °C was added 10.3 mL (88.4 mmol) lutidine, 7.68 g (88.4 mmol) lithium bromide and 15.41 g (88.4 mmol) methanesulfonic anhydride. Continued stirring in ice bath for 5 min, then warmed to 55 °C for 3.5 h.
  • tert-butyl 4-methylpyridin-2-ylcarbamate (3-1) (20 g, 96 mmol) (obtained from 2-amino-4-methyl-pyridine and di-tertbutyl-dicarbonate) in 175 mL THF cooled to -78 °C was added nBuLi (84 mL, 201.7 mmol, 2.4 M in hexane) dropwise.
  • nBuLi 84 mL, 201.7 mmol, 2.4 M in hexane
  • the reaction mixture was cannulated to a -78 °C cooled addition funnel mounted on the side arm of a 2L flask containing cyanogen bromide (81.4 g, 768.3 mmol) in 500 mL THF cooled to -100 °C.
  • the cannulated cooled slurry was added dropwise to the cyanogen bromide/THF mixture while keeping the internal temperature below or at -100 °C and while maintaining vigorous stirring.
  • the reaction mixture was stirred at -100 °C for an extra 30 min. Water (500 mL) was added and the reaction mixture is extracted with EtOAc. The organic layer was washed with 10% KHSO 4 , brine and dried over sodium sulfate.
  • reaction mixture was diluted with 600 mL CH 2 C1 2 and washed first with a mixture of 300 mL water and 50 mL of 10% aqueous KHSO 4 , then 300 mL water and finally 300 mL brine.
  • the CH 2 C1 2 layer was dried over Na 2 SO 4 , filtered, and concentrated.
  • 2-(lH-imidazol-4-yl)-4-piperidin-3-ylbutanoic acid (5-23) was prepared from tert-butyl 3-(2-iodoethyl)piperidine-l-carboxylate (derived from the corresponding amino-acid similarly as described in scheme 4) and dimethyl 2-( ⁇ l-[(4- methylphenyl)sulfonyl]-lH-imidazol-4-yl ⁇ methyl)malonate (5-3) using a similar procedure as described for the preparation of (5-5).
  • 2-(lH-imidazol-4-yl)-5-(lH-imidazol-5-yl)pentanoic acid was prepared from 4-(3-iodopropyl)-N,N-dimethyl-lH-imidazole-l-sulfonamide (derived from methyl 3- ⁇ l-[(dimethylamino)sulfonyl]-lH-imidazol-4-yl ⁇ propanoate similarly as described in scheme 4) and dimethyl 2-( ⁇ l-[(4-methylphenyl)sulfonyl]-lH- imidazol-4-yl ⁇ methyl)malonate (5-3) using a similar procedure as described for the preparation of (5-5).
  • reaction mixture is stirred at room temperature for 3 h 30, filtered on a silica gel pad eluting with 25% EtOAc in hexane, concentrated in vacuo and purified by flash chromatography (silica gel, 0% to 30% EtOAc in hexane) to give tert-butyl 3-(2-iodoethyl)azetidine-l-carboxylate (6-3) (138 mg).
  • Electrospray mass spectrum M+H 312.5. 4-azetidin-3-yl-2-l l-r(4-methylphenyl)sulfonyl1-lH-imidazol-4-yl)butanoic acid (6- 4 ⁇
  • reaction mixture is diluted with EtOAc, washed with aqueous N ⁇ 4 CI, water and brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 30% to 70% EtOAc in hexane) to give tert-butyl 3-(4-methoxy-3- ⁇ l-[(4-methylphenyl)sulfonyl]-lH-imidazol-4-yl ⁇ -4- oxobutyl)azetidine-l-carboxylate containing ca. 20% dialkylated product.
  • reaction mixture was concentrated in vacuo and purified by preparative reverse phase HPLC (20x150 mm C18 column, 0-95% AcN/H 2 O (0.1%TFA) over 25 minutes) to give 4-azetidin-3-yl-2- ⁇ l-[(4- methylphenyl)sulfonyl]-lH-imidazol-4-yl ⁇ butanoic acid bis-TFA salt (6-4).
  • T ⁇ F was added 0.45 mL (1.12 mmol, 2.5M solution in hexane) butyllithium and the reaction mixture was allowed to stir 5 minutes at 0 °C before transferring this mixture via cannula to a 0°C solution of 0.3g (1.0 mmol) methyl ⁇ l-[(4- methylphenyl)sulfonyl]-lH-imidazol-4-yl ⁇ acetate (5-2) in 3 mL T ⁇ F.
  • 6-amino-2-(lH-imidazol-4-yl)hexanoic acid (7-3) To a solution of 0.009g (0.018 mmol) methyl 6-(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)-2- ⁇ l-[(4-methylphenyl)sulfonyl]-lH-imidazol-4- yl ⁇ hexanoate (7-2) in 1 mL methanol was added 3 uL (0.1 mmol) hydrazine and the reaction mixture was stirred at room temperature for 3 days, then 0.18 mL (0.18mmol, IM solution in water) NaO ⁇ was added and the reaction mixture stirred an additional 2 days then reduced to 0.3 mL.
  • 6-methylamino-2-(lH-imidazol-4-yl)hexanoic acid (7-9) was prepared from tert-butyl 4-iodobutyl(methyl)carbamate and dimethyl 2-( ⁇ 1 - [(4- methylphenyl)sulfonyl]-l ⁇ -imidazol-4-yl ⁇ methyl)malonate (5-3) using a similar procedure as described for the preparation of (5-5).
  • Electrospray Mass Spectrum M+H 212.6
  • 6-dimethylamino-2-(lH-imidazol-4-yl)hexanoic acid (7-10) was prepared from dimethyl 2-(4-aminobutyl)-2- ⁇ l-[(4-methylphenyl)sulfonyl]-l ⁇ - imidazol-4-yl ⁇ malonate (prepared from l-iodo-4-pthalimidobutane and dimethyl 2- ( ⁇ l-[(4-methylphenyl)sulfonyl]-lH-imidazol-4-yl ⁇ methyl)malonate (5-3), followed by phthalimide removal with hydrazine) by dimethylation with formaldehyde and sodium triacetoxyborohydride and final deprotection as described in the conversion of (5-4) to
  • reaction mixture was allowed to stir 16 hours, then another 0.02g (0.08 mmol) 2-cyclohexylethyl trifluoromethanesulfonate was added.
  • the reaction mixture was then stirred 2 more hours, diluted with 75 mL CH 2 C1 2 , washed with 50 mL saturated aqueous sodium bicarbonate solution, 50 mL brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • reaction mixture was concentrated in vacuo, and purified by flash chromatography (silica gel, 300 g, 4% to 10% MeOH containing 10%) NH 4 OH in dichloromethane) to give methyl 3- ⁇ 6-[(tert- butoxycarbonyl)amino]pyridin-3-yl ⁇ -2-(lH-imidazol-4-yl)propanoate (10-2) (4.43 g) as a white solid.
  • the THF was removed under a stream of nitogen and the residual aqueous solution purified by reverse phase preparative HPLC (20x150 mm YMC C18 PRO, 5% to 95% aqueous CH 3 CN containing 0.1% TFA) to provide methyl 3- ⁇ 6-[(tert-butoxycarbonyl)amino]pyridin-3-yl ⁇ -2-[l-(2-oxo-2- pyrrolidin-l-ylethyl)-lH-imidazol-4-yl]propanoic acid which was treated with 1 mL TFA at room temperature for lhl5 to give 3-(6-aminopyridin-3-yl)-2-[l-(2-oxo-2- pyrrolidin-l-ylethyl)-lH-imidazol-4-yl]propanoic acid bis TFA salt (10-4) (95 mg) as a white solid after concentration in vacuo and subsequent liophilization.
  • the residual aqueous solution was purified by reverse phase preparative HPLC (20x150 mm YMC C18 PRO, 5% to 95% aqueous CH 3 CN containing 0.1% TFA, multiple injections) to provide (2R)-3- ⁇ 6-[(tert-butoxycarbonyl)amino]pyridin-3-yl ⁇ -2- ⁇ l-[2-(4,4- diphenylpiperidin-l-yl)-2-oxoethyl]-lH-imidazol-4-yl ⁇ propanoic acid which was treated with 5 mL TFA at room temperature for 1 h to give (2R)-3-(6-aminopyridin-3- yl)-2- ⁇ 1 -[2-(4,4-diphenylpiperidin- 1 -yl)-2-oxoethyl]- lH-imidazol-4-yl ⁇ propanoic acid bis TFA salt after concentration in vacuo.
  • reaction mixture was filtered and purified by preparative reverse phase HPLC (20x150 mm C18 column, 0-95% CH 3 CN/H 2 O (0.1%TFA) over 25 minutes) to give 16.3mg of ethyl 3-(6-aminopyridin-3-yl)-2-(l- methyl-lH-imidazol-2-yl)propanoate (13-4) as its di-trifluoroacetate salt.
  • reaction was concentrated to dryness, redissolved in 250 uL water and purified by preparative reverse phase HPLC (20x150 mm C18 column, 0-95% CH 3 CN/H 2 O (0.1%TFA) over 25 minutes) to give 6.9mg of 3-(6-aminopyridin-3-yl)-2-(l-methyl- lH-imidazol-2-yl)propanoic acid (13-5) as its di-trifluoroacetate salt.
  • reaction was stirred overnight at room temperature, then 0.5 mL methylene chloride and 130 uL (1.72 mmol) trifluoroacetic acid were added and the reaction stirred at reflux for 3 hours.
  • the reaction was concentrated to dryness, treated with 3.0 mL water and extracted with diethyl ether (2x).
  • the acidic water phase was then loaded onto a Varian Bond Elut SCX ion exchange (sulfonic acid) column (pretreated with 1:1 CH3CN:H 2 O). Washed column with 5 mL CH 3 CN followed by MeOH containing 5% NH 3 .
  • reaction mixture was cooled, dissolved by adding 1.2 mL aqueous 0.5N HCI and purifying by preparative reverse phase HPLC (20x150 mm C18 column, 0-95% CH 3 CN/H 2 O (0.1%TFA) over 25 minutes) to give 13.3mg of 5- [2-(lH-imidazol-4-yl)-2-(2H-tetraazol-5-yl)ethyl]pyridin-2-amine (15-3) as its ditrifluoroacetate salt.
  • the organic layer was washed with 300 mL saturated aqueous sodium bicarbonate solution, 300 mL brine, dried over Na 2 SO 4 , filtered and concentrated.
  • the reaction was allowed to warm to room temperature and poured into a solution of saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (3X50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure . The residue was purified by reverse phase HPLC eluting with 5-95% acetonitrile / water buffered with 0.025% TFA.
  • 4-Cyanomethylimidazole (6.0 g, 56 mmol) was suspended in a 200 mL CH2CI2 solution containing triethylamine (7.8 mL, 56 mmol). The reaction mixture was cooled in an ice bath and p-toluenesulfonylchloride (10.7 g, 56 mmol) added as a solid. After 15 min. the ice bath was removed and after 15 additional min. the reaction mixture was diluted with 50 mL CH2CI2 and washed first with a mixture of 50 mL water and 15 mL of sat. NH4CI, followed by 100 mL water and finally 40 mL of brine.
  • the enolate solution was cannula transferred to a 0 °C pre- cooled THF/Mel solution (1 mL THF, 1.04 mL Mel, 17 mmol). Upon complete addition of the enolate solution the ice-bath was removed and the mixture allowed to warm to room temperature. After 3.5 h the mixture was quenched with sat. aq. NH4CI, diluted with 10 mL of H2O and then repeatedly extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness.
  • reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 0% EtOAc in hexane to 30%) to give 338 mg 2-(4-iodo-2-methylbutyl)-lH-isoindole-l,3(2H)-dione (25-2).
  • 6-amino-2-(lH-imidazol-4-yl)-5-methylhexanoic acid 25-3 was prepared from alkylation of 5-3 with 2-(4-iodo-2-methylbutyl)-lH-isoindole-l,3(2H)- dione (25-2) using a similar procedure as described for the preparation of 5-4 from 5- 3 (Scheme 5), followed by ester hydrolysis/phthalimide removal with 6N HCl/hydrazine using a similar procedure as described for the preparation of 7-6 from 7-5 (Scheme 7). 6-amino-2-(lH-imidazol-4-yl)-5-methylhexanoic acid dihydrochloride, 1:1 mixture of diastereoisomers.
  • 6-amino-2-(lH-imidazol-4-yl)-5,5-dimethylhexanoic acid (26-3) Prepared from 2-(4-iodo-2,2-dimethylbutyl)-lH-isoindole-l,3(2H)- dione (26-2) and 5-3 using as similar procedure (alkylation, hydrolysis and phthalimide removal) as described for the preparation of 6-amino-2-(lH-imidazol-4- yl)-5-methylhexanoic acid (25-3).
  • HRMS ES calculated for C ⁇ H 19 N 3 O 2 : 226.1550, found: 226.1561.
  • Typical tablet cores suitable for administration of carboxypeptidase U inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:
  • Mannitol, microcrystalline cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.
  • compositions A-C Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the following active compounds are prepared as illustrated below (compositions A-C).
  • Active I is compound 3-(6-amino-5-methylpyridin-3-yl)-2-(lH-imidazol-4- yl)propanoic acid.
  • All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.
  • compositions of compound 3 ⁇ (6-an ⁇ no-5-methylpyridin-3- yl)-2-(lH-imidazol-4-yl)propanoic acid (Active I) tablets are shown below:
  • Active I, mannitol and microcrystalline cellulose were sieved through mesh screens of specified size (generally 250 to 750 ⁇ m) and combined in a suitable blender. The mixture was subsequently blended (typically 15 to 30 min) until the drug was uniformly distributed in the resulting dry powder blend. Magnesium stearate was screened and added to the blender, after which a precompression tablet blend was achieved upon additional mixing (typically 2 to 10 min). The precompression tablet blend was then compacted under an applied force, typically ranging from 0.5 to 2.5 metric tons, sufficient to yield tablets of suitable physical strength with acceptable disintegration times (specifications will vary with the size and potency of the compressed tablet). In the case of the 2, 10 and 50 mg potencies, the tablets were dedusted and film-coated with an aqueous dispersion of water-soluble polymers and pigment.
  • Tablet preparation via dry granulation Alternatively, a dry powder blend is compacted under modest forces and remilled to afford granules of specified particle size. The granules are then mixed with magnesium stearate and tabletted as stated above.
  • Intravenous formulations of compound 3-(6-amino-5-methylpyridm-3- yl)-2-(lH-imidazol-4-yl)propanoic acid (Active I) were prepared according to general intravenous formulation procedures.
  • compositions A-C are as follows:
  • buffer acids such as L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be substituted for glucuronic acid.

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Abstract

L'invention concerne des composés utiles pour l'inhibition de la carboxypeptidase U et d'occlusions thrombotiques associées de structure (I) et des sels acceptables sur le plan pharmaceutique de ceux-ci. Dans cette structure, t désigne N ou N(R2'), u représente C(R3) ou N(R2') et v désigne C(R2), N ou N(R2), pour autant que : 1) quand t représente N et u désigne C(R3), v représente N(R2); 2) quand t désigne N et u représente N(R2'), v désigne C(R2) et 3) quand t désigne N(R2') et u représente C(R3), v représente N ou N(R2).
PCT/US2002/024664 2001-08-08 2002-08-02 Composes anticoagulants WO2003013526A1 (fr)

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WO2005105781A1 (fr) * 2004-04-22 2005-11-10 Sanofi-Aventis Deutschland Gmbh Derives d'imidazole servant d'inhibiteurs de tafia
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
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WO2007045339A1 (fr) * 2005-10-15 2007-04-26 Sanofi-Aventis Derives imidazole servant d'inhibiteurs de tafi-a
US7230002B2 (en) 2004-02-03 2007-06-12 Glenmark Pharmaceuticals Ltd. Dipeptidyl peptidase IV inhibitors; processes for their preparation and compositions thereof
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
WO2007044885A3 (fr) * 2005-10-11 2007-11-22 Chemocentryx Inc Derives de piperidine et leurs procedes d'utilisation
JP2008515768A (ja) * 2004-06-17 2008-05-15 エム ユー エス シー ファンデーション フォー リサーチ ディベロップメント 非天然アミノ酸
WO2008106692A1 (fr) 2007-03-01 2008-09-04 Novartis Vaccines And Diagnostics, Inc. Inhibiteurs de pim kinase et procédés de leur utilisation
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WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
US7482367B2 (en) 2005-08-30 2009-01-27 Novartis Vaccines And Diagnostics, Inc. Substituted benzimidazoles and methods of their use
US7553854B2 (en) 2006-04-19 2009-06-30 Novartis Vaccines And Diagnostics, Inc. 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
WO2010050525A1 (fr) 2008-10-29 2010-05-06 大正製薬株式会社 Composé ayant une activité inhibitrice des tafia
US7776909B2 (en) 2003-02-06 2010-08-17 Dompe Pha.R.Ma S.P.A. 2-aryl-acetic acids, their derivatives and pharmaceutical compositions containing them
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WO2011115064A1 (fr) 2010-03-18 2011-09-22 第一三共株式会社 Dérivé d'imidazole substitué par cycloalkyle
WO2012018754A2 (fr) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
WO2012024170A2 (fr) 2010-08-17 2012-02-23 Merck Sharp & Dohme Corp. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)
WO2012027236A1 (fr) 2010-08-23 2012-03-01 Schering Corporation Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
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JP2012510472A (ja) * 2008-12-01 2012-05-10 ターガセプト，インコーポレイテッド （Ｒ）−３−ビニルピロリジン−１−カルボン酸ｔｅｒｔ−ブチルおよびそのための中間体の製造方法
WO2012062730A1 (fr) 2010-11-11 2012-05-18 Sanofi Procédé de fabrication de dérivés d'acide 3-(6-amino-pyridin-3yl)-2-acrylique
WO2012145471A1 (fr) 2011-04-21 2012-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline
WO2013076178A1 (fr) 2011-11-25 2013-05-30 Sanofi Sels cristallins d'acide (r)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1h-imidazol-4-yl)-propionique
WO2013076179A1 (fr) 2011-11-25 2013-05-30 Sanofi Sels de sodium de l'acide (r)-3-[6-amino-pyridin-3-yl]-2-(1-cyclohexyl-1h-imidazol-4-yl)-propionique
WO2013165816A2 (fr) 2012-05-02 2013-11-07 Merck Sharp & Dohme Corp. Compositions de petit acide nucléique interférent (sina)
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US8710232B2 (en) 2004-04-22 2014-04-29 Sanofi-Aventis Deutschland Gmbh Imidazole derivatives used as TAFIa inhibitors
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RU2533819C2 (ru) * 2008-12-01 2014-11-20 Таргасепт, Инк. Синтез и новые солевые формы (r)-5-((e)-2-(пирролидин-3-илвинил)пиримидина
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WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
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WO2017170460A1 (fr) 2016-03-29 2017-10-05 第一三共株式会社 Agent thérapeutique contre les maladies inflammatoires de l'intestin
US9834527B2 (en) 2013-06-10 2017-12-05 Sanofi Macrocyclic urea derivatives as inhibitors of TAFIa, their preparation and their use as pharmaceuticals
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US8648110B2 (en) 2003-02-06 2014-02-11 Dompe Pha.R.Ma S.P.A. 2-aryl-acetic acids, their derivatives and pharmaceutical compositions containing them
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US8710232B2 (en) 2004-04-22 2014-04-29 Sanofi-Aventis Deutschland Gmbh Imidazole derivatives used as TAFIa inhibitors
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WO2005105781A1 (fr) * 2004-04-22 2005-11-10 Sanofi-Aventis Deutschland Gmbh Derives d'imidazole servant d'inhibiteurs de tafia
EP1864979A1 (fr) 2004-04-22 2007-12-12 Sanofi-Aventis Deutschland GmbH Dérivés d'imidazole comme inhibiteurs de TAFALA
RU2375356C2 (ru) * 2004-04-22 2009-12-10 Санофи-Авентис Дойчланд Гмбх ПРОИЗВОДНЫЕ ИМИДАЗОЛА В КАЧЕСТВЕ ИНГИБИТОРОВ TAFIa
JP2008515768A (ja) * 2004-06-17 2008-05-15 エム ユー エス シー ファンデーション フォー リサーチ ディベロップメント 非天然アミノ酸
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EP2805945A1 (fr) 2007-01-10 2014-11-26 MSD Italia S.r.l. Indazoles substitués d'amide en tant qu'inhibiteurs PARP de poly(ADP-ribose)polymérase
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JP2012510472A (ja) * 2008-12-01 2012-05-10 ターガセプト，インコーポレイテッド （Ｒ）−３−ビニルピロリジン−１−カルボン酸ｔｅｒｔ−ブチルおよびそのための中間体の製造方法
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US9834527B2 (en) 2013-06-10 2017-12-05 Sanofi Macrocyclic urea derivatives as inhibitors of TAFIa, their preparation and their use as pharmaceuticals
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