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WO1999031098A1 - Nouveaux derives de pyridine et de pyrimidine - Google Patents

Nouveaux derives de pyridine et de pyrimidine Download PDF

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Publication number
WO1999031098A1
WO1999031098A1 PCT/DK1998/000549 DK9800549W WO9931098A1 WO 1999031098 A1 WO1999031098 A1 WO 1999031098A1 DK 9800549 W DK9800549 W DK 9800549W WO 9931098 A1 WO9931098 A1 WO 9931098A1
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WO
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Prior art keywords
halogen
mercapto
optionally substituted
amino
hydroxy
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PCT/DK1998/000549
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English (en)
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WO1999031098A8 (fr
Inventor
Lars Jacob Stray Knutsen
Anker G. Lundemose
Claus Bekker Jeppesen
Anders Robert SØRENSEN
Gillian Mary Danielsen
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Novo Nordisk A/S
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Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU15562/99A priority Critical patent/AU1556299A/en
Publication of WO1999031098A1 publication Critical patent/WO1999031098A1/fr
Publication of WO1999031098A8 publication Critical patent/WO1999031098A8/fr

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    • 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 relates to novel pyridine and pyrimidine derivatives, to the use of these compounds as medicaments, to pharmaceutical compositions comprising the compounds, and to a method of treatment employing these compounds and compositions. More particularly, the present compounds reduce the blood glucose and are accordingly useful for the treatment of ailments and disorders where a re- duction of the blood glucose is beneficial.
  • Non-insulin dependent diabetes mellitus also known as maturity-onset diabetes or Type II diabetes
  • NIDDM maturity-onset diabetes
  • Type II diabetes is a condition that poses a major threat to the health of the citizens of the western world.
  • NIDDM accounts for over 85% of diabetes incidents world-wide and about 160 million people are suffering from NIDDM. The number of incidents is expected to increase considerably within the next decades especially in the developing countries.
  • NIDDM is associated with a very high frequency of morbid- ity and premature mortality resulting from a number of serious complications, eg cardiovascular disease (Weir, G.C., Leahy, J.L., (1994) Pathogenesis of non-insulin- dependent (Type II) diabetes mellitus. Joslin's Diabetes Mellitus 13th Ed.
  • NIDDM is characterised by both fasting and postprandial hyperglycaemia resulting from abnormali- ties in insulin secretion and insulin action.
  • a key feature which is almost always found in NIDDM is insulin resistance (Weir, G.C. et al. supra). In the insulin resistant state, the peripheral tissues and the liver exhibit a reduced sensitivity to insulin whereby the stimulation of glucose uptake into muscle and fat cells by insulin is blunted and the suppression of hepatic glucose output by insulin is incomplete.
  • the hyperglycaemia in patients suffering from NIDDM can usually be initially treated by diet, but eventually most NIDDM patients have to take oral antidiabetic agents and/or insulin injections to normalise their blood glucose levels.
  • oral antidiabetic agents are the suiphonylureas which act by increasing the secretion of insulin from the pancreas (Lebovitz, H.E., (1994) Oral antidiabetic agents. Joslin's Diabetes Mellitus 13th Ed. (Kahn, C.R., Weir G.C., Eds.), Lea & Fe- biger, Malvern, PA, pp.
  • references feature different pyrrolopyridinedione compounds which are stated to be useful as aldose reductase inhibitors, as compounds with an activity on the nervous system, in photolysis of eg butylmercury halides, as herbicides or as compounds with an effect against cataract, respectively.
  • the references neither disclose nor suggest that the pyrrolopyridinedione compounds may be effective to reduce the blood glucose.
  • compounds having a pyrimidopyridazinedione structure have been disclosed for use as chemiluminescent compounds, see Tominaga, Y. et al., Heterocy- cies (1996), 43, pp. 1597-1600; EP 491477; and Van Bergen, T.J. et al., J. Am. Chem. Soc. (1972), 94, pp. 8451-8471. None of these references give any mention of a blood glucose reduction.
  • WO 97/16432 discloses 1-(2-[2-isoxazol-3-ylbenzofuran-5-yloxy]ethylamino)-3- phenoxy-2(S)-ol which is stated to be useful to lower blood glucose levels when administered orally to mammals with hyperglycaemia or diabetes owing to a claimed selective ⁇ 3 -adrenoceptor agonistic activity.
  • the activation of ⁇ 3 -receptors is stated to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids).
  • WO 97/10825 discloses a group of compounds comprising a fused heterocycle such as indole which are stated to be selective ⁇ 3 -adrenergic agonists useful in the treatment of Type II diabetes and obesity.
  • the compounds are stated to exhibit a marked effect on lipolysis and to effectively increase insulin sensitivity.
  • the structure of these compounds is quite different from that of the present compounds.
  • thiazolidinediones have emerged as effective orally active antidiabetic agents that enhance the actions of insulin without promoting insulin secretion, see for example Saltiel, A.R. et al., Thiazolidinediones in the Treatment of Insulin Resistance and Type II Diabetes, Diabetes, Vol. 45, December 1996, pp. 1661-1669; EP 801 063; US Nos. 5,089,514; 4,342,771 ; 4,367,234; 4,340,605; and 5,306,726. These compounds reduce insulin resistance by increasing insulin-dependent glucose disposal and reducing the hepatic glucose output. However, the thiazolidinediones only exert their effect upon administration for a longer period and are accordingly not suitable for acute administration.
  • PPARs peroxisome prolif- erator-activated receptors
  • RXR retinoic acid X receptor
  • WO 97/31907 discloses substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to PPAR-gamma which are stated to be useful in the treatment and/or prophylaxis of hyperglycaemia, dyslipidemia and especially in the treatment of Type II diabetes.
  • the present invention provides a class of pyrimidine and pyridine derivatives which are effective in reducing the blood glucose without affecting the circulating insulin concentrations. Except for the above structures disclosed in the Available Chemicals Directory database and Johnson, R. S. et al., J. Chem. Soc, C (1970), pp. 796-800, respectively, the present compounds are novel per se thereby constituting a further aspect of the invention. The present compounds are very advantageous in exerting their effect after a single administration and are accordingly suitable for both acute and chronic therapy.
  • C ⁇ -alkyl as used herein represent a branched or straight hydrocarbon group having from 1 to 6 carbon atoms.
  • Typical C ⁇ -alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, etf-butyl, pen- tyl, isopentyl, hexyl, isohexyl and the like.
  • C 2 . 6 -alkenyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond.
  • groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, iso- propenyl, 1 ,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2- hexenyl and the like.
  • C 2 . 6 -alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
  • Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-methyl-1-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and the like.
  • C ⁇ -alkoxy refers to the group -O-C ⁇ -alkyl where C ⁇ -alky! is as defined above.
  • Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tetf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C ⁇ -alkanoyl refers to the group -CO-V where V is hydrogen or C ⁇ -alkyl as defined above.
  • Representative examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hexanoyl and the like.
  • C ⁇ -alkylthio refers to the group -S-C ⁇ -alkyl where C ⁇ -alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, propylthio, butylthio, pentylthio, hexylthio and the like.
  • C ⁇ -alkylamino refers to the group is as defined above. Representative examples are methylamino, ethylamino, isopropylamino, propylamino, butylamino, pentylamino, hexylamino and the like.
  • di-C ⁇ -alkylamino refers to the group -N-(C 1 ⁇ -alkyl) 2 where C.,. 6 -alkyl is as defined above.
  • Representative examples are dimethylamino, methylethylamino, diethylamino, methyl-n-propylamino, methyl- sec-butylamino, ethyl-n-butylamino, methyl-n-pentylamino, methyl-n-hexylamino and the like.
  • C ⁇ -alkanoylamino refers to the group -NH-CO-V where V is hydrogen or C ⁇ -alkyl as defined above. Representative examples are formylamino, acetylamino, propionylamino, isobutyrylamino, butyrylamino, valerylamino, hexanoylamino and the like.
  • C ⁇ -alkoxy is as defined above.
  • Representative examples are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, te/f-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, hexoxycarbonyl, isohexoxycarbonyl and the like
  • C 3 . 8 -cycloalkyl represents a carbocyclic group having from 3 to 8 carbon atoms eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, naphthyl (1-naphthyl or 2-naphthyl), anthracenyl (1- anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, indenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1-(1 ,2,3,4-tetrahydronaphthyl) and 2-(1 ,2,3,4- tetrahydronaphthyl).
  • heteroaryl as used herein is intended to include heterocyclic aromatic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, thiadiazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl and
  • Heteroaryl is also intended to include the partially or fully hydrogenated derivatives of the heterocyclic systems enumerated above.
  • Non-limiting examples of such partially or fully hydrogenated derivatives are pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxazolinyl, oxazepinyl, aziridinyl and tetrahydrofuranyl.
  • C L g-aralkyloxycarbonyl refers to the group -CO-O-C ⁇ - alkylaryl where C.,. 6 -alkyl and aryl are as defined above.
  • halogen means fluorine, chlorine, bromine or iodine.
  • the present invention relates to novel pyrimidine and pyridine derivatives of the general formula I
  • R 4 represents hydrogen or C ⁇ -alkyl which is optionally substituted with halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio,
  • Y represents N or CR 5 wherein R 5 is
  • C,. 6 -alkyl, C 2 . 6 -alkenyl or C 2 . 6 -alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio, C ⁇ -alkylamino or di- C ⁇ -alkylamino, or
  • R 1 represents
  • C ⁇ -alkyl C ⁇ -alkenyl or C ⁇ -alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio, C ⁇ -alkylamino or di- C ⁇ -alkylamino, or
  • Z represents O, S, SO or SO 2 ;
  • R 2 represents C ⁇ -alkyl, C 2 . 6 -alkenyl or C 2 ⁇ -alkynyl which are optionally substituted with halogen, hydroxy, C ⁇ -alkoxy, amino, nitro, carboxy, C ⁇ -alkylamino, di-C ⁇ - alkylamino, C ⁇ -alkanoylamino, C ⁇ -alkanoyl, C ⁇ -alkoxycarbonyl, C ⁇ - aralkyloxycarbonyl, mercapto, C ⁇ -alkylthio, C ⁇ -cycloalkyl, aryl or heteroaryl, where
  • the C 3 ⁇ -cycloalkyl, aryl and heteroaryl groups optionally are substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio, C L g-alkylamino or di-C ⁇ g - alkylamino, or
  • the group optionally is substituted with halogen, hydroxy, amino, mercapto, C L g-alkylamino or or
  • Z and R 2 taken together may represent C ⁇ -cycloalkyl, aryl or heteroaryl which are optionally substituted with C ⁇ -alkyl, halogen, hydroxy, C ⁇ -alkoxy, amino, nitro, carboxy, alkanoyl, C ⁇ -alkoxycarbonyl, C ⁇ -aralkyloxycarbonyl, mercapto or C ⁇ -alkylthio;
  • a preferred embodiment of the invention are the compounds of the formula I wherein X represents NR 4 wherein R 4 is as defined above; Y represents CR 5 wherein R 5 is as defined above; R 1 represents C ⁇ -alkyl optionally substituted as defined above; Z represents S or O; and R 2 represents C ⁇ -alkyl, C 2 _g-alkenyl or C 2 _g-alkynyl which are optionally substituted as defined above or C ⁇ -cycloalkyl, aryl or heteroaryl which are optionally substituted as defined above.
  • a further preferred embodiment of the invention are the compounds of the formula I wherein X represents NH; Y represents CH; R 1 represents C ⁇ -alkyl, preferably methyl; and R 2 represents C ⁇ -alkyl, C 2 _g-alkenyl or C ⁇ -alkynyl which are optionally substituted as defined above or phenyl, cyclohexyl, furyl, thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl or pyrrolyl which are optionally substituted as defined above.
  • Still a further preferred embodiment of the invention are the compounds of the formula I wherein R 2 represents C ⁇ -alkyl optionally substituted with halogen, C ⁇ - alkoxy or amino; cyclohexyl optionally substituted with halogen, C ⁇ -alkoxy, amino or C ⁇ -alkyl; or phenyl optionally substituted as defined above.
  • a further preferred embodiment of the invention are the compounds of the formula I as defined above wherein R 2 represents C ⁇ -alkyl optionally substituted with halogen, C ⁇ -alkoxy or amino; cyclohexyl optionally substituted with halogen, C ⁇ -alkoxy, amino or amino or C ⁇ -alkyl.
  • the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
  • a carbon to carbon double bond may be present in the molecule which may bring about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.
  • the compounds of the present invention may exist in different tautomeric forms. It is intended that any tautomeric forms which the compounds are able to form are included in the scope of the present invention.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulphuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulphonic, ethanesulphonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulphonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulphonic, p-toluenesulphonic acids and the like and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • Also intended as pharmaceutically acceptable acid addition salts are the hydrates which the present compounds are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low molecular weight solvents using methods known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
  • the compounds according to the present invention reduce the blood glucose and are accordingly useful for the treatment of disorders and ailments in which such a reduction is beneficial.
  • the invention relates to a compound of the general formula I'
  • R 4 represents hydrogen or which is optionally substituted with halogen, hydroxy, amino, mercapto,
  • Y represents N or CR 5 wherein R 5 is
  • R 1 represents
  • C,. 6 -aikyl, C 2 . 6 -alkenyl or C 2 . 6 -alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, or di- C 3 .g-cycloalkyl, aryl or heteroaryl which are optionally substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio, C L g-alkylamino or di-C ⁇ -alkylamino;
  • Z represents O, S, SO or SO 2 ;
  • R 2 represents
  • the aryl moiety of the aryl and heteroaryl groups optionally are substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, or
  • the aryl moiety of the C ⁇ -aralkyloxycarbonyl group optionally is substituted with C ⁇ -alkylamino or di-C ⁇ -alkylamino and
  • the C ⁇ -alkyl group optionally is substituted with halogen, hydroxy, amino, mercapto, or
  • Z and R 2 taken together may represent C ⁇ -cycloalkyl, aryl or heteroaryl which are optionally substituted with C ⁇ -alkyl, halogen, hydroxy, C ⁇ -alkoxy, amino, nitro, carboxy, alkanoyl, C ⁇ -alkoxycarbonyl, C ⁇ -aralkyloxycarbonyl, mercapto or C ⁇ -alkylthio;
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the formula I' as defined above or a pharma- ceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these together with one or more pharmaceutically acceptable carriers or diluents.
  • the invention relates to a compound of the formula I' as de- fined above
  • X, Y and R 1 are as defined for formula I';
  • Z represents O
  • R 2 represents
  • C 2 .g-alkenyl or C 2 . 6 -alkynyl which are optionally substituted with halogen, hydroxy, C ⁇ -alkanoylamino, C ⁇ -alkanoyl, C ⁇ -alkoxycarbonyl, C ⁇ -aralkyloxycarbonyl, mercapto, C 3 . 8 -cycloalkyl, aryl or heteroaryl, where - the aryl moiety of the C L g-aralkyloxycarbonyl group, the C ⁇ -cycloalkyl, aryl and heteroaryl groups optionally are substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, or di- C ⁇ -alkylamino, or
  • the invention relates to a compound of the formula I' as defined above
  • R 2 represents
  • C ⁇ -alkyl, C 2 . 6 -alkenyl or C 2 . 6 -alkynyl which are optionally substituted with halogen, hydroxy, C 3 . 8 -cycloalkyl, aryl or heteroaryl, where - the aryl moiety of the C ⁇ -aralkyloxycarbonyl group, the C 3 . 8 -cycloalkyl, aryl and heteroaryl groups optionally are substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, or di- C L g-alkylamino, or
  • C ⁇ -cycloalkyl or heteroaryl which are optionally substituted with C ⁇ -alkyl, halogen, hydroxy, C ⁇ -aralkyloxycarbonyl, mercapto or C ⁇ -al ylthio, where - the aryl moiety of the C ⁇ -aralkyloxycarbonyl group optionally is substituted with
  • the group optionally is substituted with halogen, hydroxy, amino, mercapto, or
  • aryl which is optionally substituted with C ⁇ -alkyl, iodo, bromo, fluoro, meta- chloro, ortho-chloro, di-chloro, tri-chloro, hydroxy, C ⁇ -alkoxy, amino, nitro, carboxy, C ⁇ -alkylamino, di-C ⁇ -alkylamino, C ⁇ -alkanoylamino, C ⁇ g-aralkyloxycarbonyl, mercapto or C L g-alkylthio, where
  • the aryl moiety of the C ⁇ -aralkyloxycarbonyl group optionally is substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C,.g-alkylthio, C ⁇ -alkylamino or di-C ⁇ -alkylamino and
  • the C ⁇ -alkyl group optionally is substituted with halogen, hydroxy, amino, mercapto,
  • the invention relates to a compound of the formula I' as defined above wherein X represents
  • R 4 represents hydrogen or C ⁇ -alkyl which is optionally substituted with halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio,
  • Y represents N or CR 5 wherein R 5 is
  • R 1 represents
  • C ⁇ -alkyl C 2 . 6 -alkenyl or C 2 . 6 -alkynyl which are optionally substituted with halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio, C ⁇ -alkylamino or di- C ⁇ -alkylamino, or C 3 . 8 -cycloalkyl, aryl or heteroaryl which are optionally substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, C ⁇ -alkoxy, C ⁇ -alkylthio, C ⁇ g -alkylamino or
  • Z represents SO or SO 2 ;
  • R 2 represents
  • the C 3 _ 8 -cycloalkyl, aryl and heteroaryl groups optionally are substituted with C ⁇ -alkyl, halogen, hydroxy, amino, mercapto, C L g-alkoxy, C ⁇ -alkylthio, C ⁇ -alkylamino or di- C ⁇ -alkylamino, or
  • C ⁇ -cycloalkyl aryl or heteroaryl which are optionally substituted with C ⁇ -alkyl, halogen, hydroxy, di-C ⁇ -alkylamino, C ⁇ -alkanoylamino, C ⁇ -alkanoyl, C ⁇ -alkoxycarbonyl, C ⁇ -aralkyloxycarbonyl, mercapto or where
  • the group optionally is substituted with halogen, hydroxy, amino, mercapto, or
  • Z and R 2 taken together may represent C ⁇ -cycloalkyl, aryl or heteroaryl which are optionally substituted with amino, nitro, carboxy, C ⁇ -alkylamino, di-C ⁇ -alkylamino, C L g-alkanoyiamino, C ⁇ - alkanoyl, C ⁇ -alkoxycarbonyl, C ⁇ -aralkyloxycarbonyl, mercapto or C ⁇ g -alkylthio;
  • the invention relates to the use of the compound of the general formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for the preparation of a medicament for the treatment and/or prevention of disorders where a reduction of the blood glucose is beneficial.
  • the invention relates to the use of the compound of the general formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for the preparation of a medicament for the treatment and/or prevention of disorders where a stimulation of the blood glucose uptake into muscle and fat cells is beneficial.
  • the invention relates to the use of the compound of the general formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these for the preparation of a medicament for the treatment and/or prevention of disorders involving elevated plasma blood glucose.
  • the present invention also relates to a method for the treatment of disorders in which a reduction of the blood glucose is beneficial the method comprising administering to a subject in need thereof an effective amount of a compound of the formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutical composition comprising the same as defined above.
  • a compound of the formula I' as defined above or a pharmaceutically acceptable salt thereof or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutical composition comprising the same as defined above.
  • dyslipidemia Type I diabetes, NIDDM, hy- pertriglyceridemia, syndrome X, insulin resistance, impaired glucose tolerance (IGT), obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, hyperlipidemia, cardiovascular diseases and hypertension.
  • ITT impaired glucose tolerance
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or preven- tion of NIDDM.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to NIDDM.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from NIDDM to insulin requiring Type II diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type I diabetes.
  • Such treatment and/or prevention is normally accompanied by insulin therapy.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adju- vants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy,19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intra- dermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well-known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar ad- ministration
  • typically doses are in the order of about half the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of formula I or I' contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I or I' with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above.
  • Physiologically acceptable salts of a com- pound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • solutions of the compounds of formula I or I' in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of admini- stration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • the pharmaceutical composition of the invention may comprise the compound of the formula I' in combination with further pharmacologically active substances eg an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.
  • pharmacologically active substances eg an antidiabetic or other pharmacologically active material, including other compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.
  • Suitable antidiabet- ics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise suiphonylureas (eg tolbutamide, glibenclamide, glipizide and glicazide), biguanides (eg metformin), oxadiazolidinediones, thiazolidinediones (eg troglitazone, ciglitazone, pioglitazone, rosiglitazone and the compounds disclosed in WO No 97/41097 to Dr.
  • suiphonylureas eg tolbutamide, glibenclamide, glipizide and glicazide
  • biguanides eg metformin
  • oxadiazolidinediones eg troglitazone, ciglitazone, pioglitazone, rosiglitazone and the compounds disclosed in WO No 97/41097 to Dr.
  • the compounds according to the invention may be administered in combination with antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART agonists, NPY antagonists, MC4 agonists, orexin antagonists, H3 antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, ⁇ 3 agonists, MSH agonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, glucagon, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR ⁇ agonists.
  • leptin is leptin, amphetamine, dexfenfluramine, sibutramine and oriistat.
  • the preparation of the compounds according to the present invention can be realised in many ways.
  • the starting materials are either known compounds or compounds which may be prepared in analogy with the preparation of similar known compounds.
  • the preparation of the compounds of this invention is illustrated in the scheme below.
  • HA 1 R 2 III is first deprotonated by a base such as sodium hydride (NaH), the resulting reactive species then displaces the leaving group LG on structure II to form com- pounds of structure la according to the invention.
  • the oxidation step can be carried out for example using potassium peroxymonosulphate to provide compounds of structure lb according to the invention. In some cases, appropriate protection methodology may need to be employed to avoid unwanted oxidations.
  • the structures of the compounds are confirmed by assignment of NMR spectra (from which representative peaks are quoted) and by mass spectroscopy MS and/or micro- analysis where appropriate.
  • the compounds used as starting materials are either known compounds or compounds which can be prepared by methods known per se.
  • NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments.
  • Mass Spectra were run on a Finnigan MAT TSQ70B as SP-MS. Flash chromatography was carried out on Merck silica gel 60 (Art 9385).
  • HPLC High performance liquid chromatography
  • 4-hydroxy-6-methylpyrrolo[3,4-c]pyridine-1 ,3-dione was prepared using the published route (Dickinson, CL. J. Amer. Chem. Soc. (1960), 82, 4367-4369). This compound (1.78 g, 10 mmol) was converted into 4-chloro-6-methylpyrrolo[3,4-c]pyridine-1 ,3- dione using phosphorus oxychloride (5.51 mL, 60 mmol), tetraethylammonium chloride (3.31 g, 20 mmol) and N,N-dimethylaniline (1.26 mL, 10 mmol) in acetonitrile (50 mL).
  • Pentanethiol (0.189 g, 1.8 mmol) was reacted with sodium hydride 80% in oil (0.054 g, 1.8 mmol) and 6-methyl-4-(methylsulphonyl)-1 H-pyrrolo[3,4-c]pyridine-1 ,3-(2H)- dione (0.36 g, 1.5 mmol) following the same procedure as outlined in method B.
  • the mixture was filtered and the filtrate treated with iodobenzene (0.41 g, 2 mmol) and tetrakis(triphenylphosphine) palladium(O) (10 mg, 0.5%).
  • the solution was stirred at ambient temperature for 72 h.
  • the reaction mixture was quenched with a saturated NH 4 CI solution (50 mL) and then extracted with dichloromethane (3 x 50 mL).
  • the ability of the present compounds to stimulate glucose incorporation into lipid was determined by the method of Moody et al. (Moody et al. (1974) Horm. Metab. Res. 6, 12-16), with slight modifications.
  • Primary mouse adipocytes were prepared by collagenase treatment of epididymal fatpads for 1.5 h at 36 °C (25 mM Hepes, 4% human serum albumin, 1 mM glucose, 800 U/mL collagenase Type 1 in Krebs buffer, pH 7.4), followed by filtration through gauze and two washes by gentle centrifugation.
  • the adipocytes were incubated with or without test compound at a submaximal con- centration of insulin for 2 h at 36 °C in the presence of D-(3- 3 H)-glucose, and the radioactivity incorporated into the lipid was determined by subsequent addition of an organic scintillation cocktail and counting. An increase in radioactivity incorporated in the presence of test compound reflects an increase in insulin sensitivity.

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Abstract

Nouvelle catégorie de dérivés substitués de pyridine et de pyrimidine, procédés servant à les préparer, compositions pharmaceutiques les contenant et leur utilisation pour le traitement et/ou la prévention de maladies nécessitant une diminution du glucose sanguin en tant que facteur de guérison. Ces dérivés sont particulièrement utiles pour le traitement et/ou la prévention du diabète sucré non insulino-dépendant (NIDDM).
PCT/DK1998/000549 1997-12-17 1998-12-11 Nouveaux derives de pyridine et de pyrimidine WO1999031098A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15562/99A AU1556299A (en) 1997-12-17 1998-12-11 Novel pyridine and pyrimidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1479/97 1997-12-17
DK147997 1997-12-17

Publications (2)

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WO1999031098A1 true WO1999031098A1 (fr) 1999-06-24
WO1999031098A8 WO1999031098A8 (fr) 1999-08-26

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AU (1) AU1556299A (fr)
WO (1) WO1999031098A1 (fr)
ZA (1) ZA9811565B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021532A1 (fr) * 2003-08-25 2005-03-10 Amgen Inc Derives 2,3-dihydro-1h-isoindol-1-one substitues et techniques d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EUR. J. MED. CHEM., Volume 31, 1996, A. DA SETTIMO et al., "Synthesis of Pyrrolo(3,4-c)Pyridine Derivatives Possessing an Acid Group and Their In Vitro and In Vivo Evaluation as Aldose Reductase Inhibitors", pages 49-58. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021532A1 (fr) * 2003-08-25 2005-03-10 Amgen Inc Derives 2,3-dihydro-1h-isoindol-1-one substitues et techniques d'utilisation
US7320992B2 (en) 2003-08-25 2008-01-22 Amgen Inc. Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use

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WO1999031098A8 (fr) 1999-08-26
AU1556299A (en) 1999-07-05

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