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EP1363913A2 - Sels de derives de pyrimidine pour utilisation contre les maladies coronaires vasculaires et l'atherosclerose - Google Patents

Sels de derives de pyrimidine pour utilisation contre les maladies coronaires vasculaires et l'atherosclerose

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Publication number
EP1363913A2
EP1363913A2 EP02711124A EP02711124A EP1363913A2 EP 1363913 A2 EP1363913 A2 EP 1363913A2 EP 02711124 A EP02711124 A EP 02711124A EP 02711124 A EP02711124 A EP 02711124A EP 1363913 A2 EP1363913 A2 EP 1363913A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
ethoxy
oxo
salt
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02711124A
Other languages
German (de)
English (en)
Inventor
Om Reddy c/o Dr. Reddy's Res. Foundation GADDAM
C. C/O Dr. Reddy's Research Foundation BATCHU
R. K. Dr. Reddy's Res. Foundation POTLAPALLY
R.S. c/o Dr. Reddy's Res.Foundation MAMILLAPALLI
B. R. c/o Dept. of Chemistry BCC PARASELLI
N. V. S. R. Dr. Reddy's Res. Foundation MAMIDI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Laboratories Ltd
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Filing date
Publication date
Application filed by Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Publication of EP1363913A2 publication Critical patent/EP1363913A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
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    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates, to pharmaceutically acceptable salts of compound of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the present invention also relates to a process for the preparation of the above said pharmaceutically acceptable salts, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, pharmaceutically acceptable solvates, and pharmaceutical compositions containing them.
  • the compounds of the present invention lower plasma glucose, triglycerides, lower total cholesterol (TC) and increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL), which have a beneficial effect on coronary heart disease and atherosclerosis.
  • TC total cholesterol
  • HDL high density lipoprotein
  • LDL low density lipoprotein
  • the compounds of general formula (I) are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of hyperglycemia, hyperlipidemia, hypercholesterolemia, lowering of atlierogenic lipoproteins, NLDL (very low density lipoprotein) and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy.
  • the compounds of general formula (I) are also useful for the treatment and/or prophylaxis of type 2 diabetes, leptin resistance, atherosclerosis, impaired glucose tolerance, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myo tonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, eating disorders, inflammation and for the treatment of cancer.
  • PCOS polycystic ovarian syndrome
  • the compounds of the present invention are also useful in the treatment and/or prophylaxis of the above said diseases in combination/concomittant with one or more HMG CoA reductase inhibitors, hypolipidemic/hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol and probucol.
  • Atherosclerosis and other peripheral vascular diseases effect the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and development of effective therapeutic strategies.
  • Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called “normal” level. Recently, it has been accepted that "ideal" plasma levels of cholesterol are much below the "normal” level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the "optimum” (or “ideal”) value. There is clearly a definite cause and effect- relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterified forms with various lipoproteins such as Low density lipoprotein (LDL), Intermediate density lipoprotein (IDL), High density lipoprotein (HDL) and partially as Very low density lipoprotein (NLDL).
  • LDL Low density lipoprotein
  • IDL Intermediate density lipoprotein
  • HDL High density lipoprotein
  • NLDL Very low density lipoprotein
  • Obesity is a disease highly prevalent in affluent societies and in the developing world and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression have been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems.
  • Diabetes and insulin resistance is yet another disease which severely effects the quality of large population in the world. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes.
  • diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., 75 (1985) 809 - 817; N. Engl. J. Med 317 (1987) 350-357; J. Clin. Endocrinol. Metab., 66 (1988) 580 - 583; J. Clin.
  • Peroxisome proliferator activated receptors are members of the nuclear receptor super family.
  • the gamma ( ⁇ ) isoform of PPAR (PPAR ⁇ ) has been implicated in regulating differentiation of adipocytes (Endocrinology, 135 (1994) 798-800) and energy homeostasis (Cell, 83 (1995) 803-812), whereas the alpha ( ⁇ ) isoform of PPAR (PPAR ⁇ ) mediates fatty acid oxidation (Trend. Endocrin. Metab., 4 (1993) 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. 5 (1995) 618 — 621).
  • PPAR ⁇ agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that compounds which are agonists for both PPAR ⁇ and PPAR ⁇ are suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar effect between the insulin sensitizer (PPAR ⁇ agonist) and HMG Co A reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma (EP 0 753 298).
  • PPAR ⁇ plays an important role in adipocyte differentiation (Cell, 87 (1996) 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, 79 (1994) 1147- 1156) including cell cycle withdrawal. PPAR ⁇ is consistently expressed in certain cells and activation of this nuclear receptor with PPAR ⁇ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci, 94 (1997) 237-241) and inhibition of expression of prostate cancer tissue (Cancer Research 58 (1998) 3344-3352).
  • Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardiovascular diseases and such other interrelated complications.
  • Kallen et al Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to the PPAR agonist expression lower plasma leptin concentrations.
  • compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO 98/02159).
  • X represents O or S ;
  • the groups Rl, R ⁇ and group R ⁇ when attached to the carbon atom may be same or different and represent hydrogen, halogen, hydroxy, nitro, cyano, formyl or optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, hydroxyalkyl, amino, acylamino, alkylamino, arylamino, aralkylamino, aminoalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aryloxycarbon
  • the pharmaceutically acceptable salts of the general formula (I) have significant formulation and bulk handling advantages in view of the their stability. Objective of the Invention
  • the present invention provides pharmaceutically acceptable salts of ⁇ - aryl- ⁇ -oxysubstituted alkylcarboxylic acids of the formula (I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having good stability and solubility, which can be used for the treatment and / or prophylaxis of diseases related to increased levels of lipids, especially to treat hyperlipidemia, and for the treatment of type II diabetes, impaired glucose intolerance, leptin resistance, atherosclerosis, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, coronary artery disease and other cardiovascular disorders, renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy; retinopathy, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome
  • the present invention provides pharmaceutically acceptable salts of ⁇ - aryl- ⁇ -oxysubstituted alkylcarboxylic acids of the formula (I) and their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPAR ⁇ and / or PPAR ⁇ , and optionally inhibit HMG CoA reductase, in addition to agonist activity against PPAR ⁇ and / or PPAR ⁇ .
  • the present invention provides pharmaceutically acceptable salts of ⁇ - aryl- ⁇ -oxysubstituted alkylcarboxylic acids of the formula (I) and then- derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
  • the present invention provides a process for the preparation of pharmaceutically salts of ⁇ -aryl- ⁇ -oxysubstituted alkylcarboxylic acids and their derivatives of the formula (I) as defined above, their analogs, their tautomeric forms, their stereoisomers, their polymorphs and their pharmaceutically acceptable solvates.
  • the present invention provides pharmaceutical compositions containing compounds of the general formula (I), their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • the present invention relates to pharmaceutically acceptable salts having the general formula (I)
  • R 1 represents hydrogen, alkyl or. aryl group
  • M represents, a counter ion or a moiety which forms a pharmaceutically acceptable salt
  • p is an integer ranging from 1 to 2
  • A represents a cyclic structure given below :
  • R and R may be same or different and independently represent hydrogen, halogen, hydroxy, nitro, cyano, alkyl or alkoxy group; R represents hydrogen, halogen, hydroxy, nitro, cyano, azido, formyl or unsubstituted or substituted groups selected from alkyl, cycloalkyl, alkoxy, aryl, heterocyclyl, heteroaryl, amino, monoalkylamino, dialkylamino or alkoxyalkyl groups.
  • Suitable groups represented by R 1 may be selected from hydrogen, linear or branched ( -C 6 )alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; aryl group such as phenyl or naphthyl.
  • Suitable groups represented by R 2 and R 3 may be selected from hydrogen, halogen atom such as fluorine, chlorine, bromine or iodine; hydroxy, nitro, cyano, linear or branched ( -C 6 )alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl, heptyl and the like; linear or branched ( -C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like.
  • Suitable groups represented by R may be selected from hydrogen, halogen, hydroxy, nitro, cyano, azido ? formyl or unsubstituted or substituted, linear or branched ( -C 6 )alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, hexyl and the like; unsubstituted or substituted, linear or branched (C]-C 6 )alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy and the like; cyclo(C 3 -C 6 )alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, the cycloalkyl group may be substituted; aryl group such as pheny
  • the substituents may be selected from halogen atom such as fluorine, chlorine, bromine or iodine; alkyl group such as methyl, ethyl, isopropyl, n-propyl, n- butyl and the like.
  • Suitable groups represented by M may be selected from sodium, Mg, calcium, potassium, Li, glucamine, N-methyl glucamine, N-octyl glucamine, dicyclohexylamine, t-butyl amine, methyl benzylamine, tris(hydroxymethyl)amino methane (tromethamine), phenyl glycinol, lysine, arginine, metformin, aminoguanidine, aminoguanidine hydrogen carbonate, imidazole, piperazine, dimethyl piperazine, pyrrolidine, benzylamine, phenyl glycine methyl ester, phenylalanine benzyl ester or morpholine.
  • Particularly useful compounds according to the present invention include : ( ⁇ ) 3-[4-[2-(2-Ethyl-4-oxo-3,4-dihydroquinazolin-3-yl)ethoxy]phenyl]-2- ethoxypropanoic acid phenyl glycinol salt;
  • the compound of the formula (III) used may be either optically pure form or a racemic form.
  • the base employed in the reaction may be selected from sodium hydroxide, sodium methoxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, magnesium hydroxide, glucamine, N- methylglucamine, N-octylglucamine, dicyclohexylamine, t-butylamine, methyl benzylamine, tris(hydroxymethyl)aminomethane, phenyl glycinol, lysine, arginine, metformin, aminoguanidine, aminoguanidine hydrogen carbonate, imidazole, piperazine, dimethyl piperazine, pyrrolidine, benzylamine, phenyl glycine methyl ester, phenylalanine benzyl ester or morpholine.
  • the solvent employed may be selected from alcohols such as ethanol, methanol, isopropanol, butanol and the like; ketones such as acetone, diethyl ketone, methyl ethyl ketone or their mixtures; ethers such as diethyl ether, ether, tetrahydrofuran, dioxane, dibutyl ether and the like or DMF, DMSO, xylene, toluene, ethyl acetate and the like or mixture thereof.
  • alcohols such as ethanol, methanol, isopropanol, butanol and the like
  • ketones such as acetone, diethyl ketone, methyl ethyl ketone or their mixtures
  • ethers such as diethyl ether, ether, tetrahydrofuran, dioxane, dibutyl ether and the like or DMF, DMSO, xylene, toluen
  • the pharmaceutically acceptable salts of the general formula (I) have significant formulation and bulk handling advantages in view of the their physicochemical properties and their stability.
  • polymorphs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the stereoisomers of the compounds forming part of this invention may be prepared .by using compound of formula (I) in its single enantiomeric form in the process by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with optically pure bases such as brucine, cinchona alkaloids and their derivatives, optically pure 2-alkyl phenethyl amine, phenyl glycinol and the like. The diastereomeric salts may be obtained in pure form by fractional crystallization. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981).
  • solvates of the compounds of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol and the like, preferably water and recrystallizing by using different crystallization techniques.
  • the present invention provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, lowering of atlierogenic lipoproteins, NLDL and LDL.
  • the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, nephropathy.
  • the compounds of general formula (I) are also useful for the treatment/prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, and other cardiovascular disorders.
  • These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, as inflammatory agents, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, retinopathy, arteriosclerosis, xanthoma and for the treatment of cancer.
  • PCOS polycystic ovarian syndrome
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of the above said diseases in combination concomittant with one or more HMG CoA reductase inhibitors, hypolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol or their combination.
  • HMG CoA reductase inhibitors, hypolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol or their combination.
  • the compounds of the present invention in combination with HMG CoA reductase inhibitors, hypolipidemic hypolipoproteinemic agents can be administered together or within such a period to act synergistically.
  • the HMG CoA reductase inhibitors may be selected from those used for the treatment or prevention of hyperlipidemia such as lovastatin, provastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin and their analogs thereof.
  • Suitable fibric acid derivative may be gemf ⁇ brozil, clofibrate, fenofibrate, ciprofibrate, benzaf ⁇ brate and their analogs thereof.
  • the present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, then- derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable solvates and one or more HMG CoA reductase inhibitors, hypolipidemic / hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • suitable solid or liquid carriers or diluents or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 1 to 20 %, preferably 1 to 10 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the active ingredient can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
  • the active ingredient can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds.
  • Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions.
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the preparation may contain the active ingredient of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes. Tablets, dragees or capsules having talc and / or a carbohydrate carried binder arid the like are particularly suitable for any oral application.
  • carriers for tablets, dragees or capsules include lactose, com starch and / or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • Tablet Production Example a) 1) Active ingredient 30 g
  • ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure.
  • Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
  • the compound of the formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
  • Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
  • the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose.
  • the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
  • reaction mixture was maintained by gentle reflux of reaction mixture at 75-85 °C for 10 h.
  • the reaction mixture was cooled to room temperature and stirred for 12 h at room temperature.
  • the reaction mixture was cooled to -5 °C and maintained at that temperature for 2 h under stirring.
  • reaction mixture was maintained by gentle reflux of reaction mixture at 75-85 °C for 10 h.
  • the reaction mixture was cooled to room temperature and stirred for 12 h at room temperature. Distill off the isopropanol on rotavapor water bath at 45-55 °C under stirring.
  • the product could not be isolated as fine solid, because of hygroscopic nature and obtained as sticky gummy mass (weighs about 2 g, yield 75 %, purity 99 % by HPLC).
  • reaction mixture After addition of the arginine solution, the reaction mixture becomes clear and precipitation appeared immediately in the reaction mixture. Maintained the gentle reflux of reaction mixture at 75-85 °C for 4-8 h and monitored the progress of the reaction. The reaction mixture was cooled to room temperature and stirred for 2 h at room temperature.
  • IR as KBr shows the following absorption bands (cm "1 ) 3400-3300 (N-H stretch), 3120 (-C-H aromatic), 2930 (-C-H aliphatic), 1660 (-COO stretch), 1587 (-CONH stretch), 1400 (-COO stretch).
  • Example-17 3-[4-[2-(l,5-Dimethyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3- d]pyrimidin-6-yl)ethoxy]phenyl]-2-ethoxypropionic acid potassium salt
  • Example-22 (.) 3-[4-[2-(l,5-Dimethyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo[4,3- d]pyrimidin-6-yl)ethoxy]phenyl]-2-ethoxypropionie acid R-(+) methyl benzylamine salt
  • reaction mixture (0.81 g) was added to the reaction mixture at 60 °C in about 10 minutes under stirring. Maintained gentle reflux of the reaction mixture for 12-14 hr and monitored the progress of the reaction. The reaction mixture was cooled to RT and stirred for 2-3 h at room temperature.
  • reaction mixture 50 ml were added to 250 ml four necked round bottom flask, fitted with a mechanical stirrer and reflux condenser. The reaction mixture was slowly heated to 55-60 °C for complete dissolution of the mass. Metformin (1.41 g) as free base was added to the reaction mixture at 60 °C in about 10 minutes under stirring. Maintained gentle reflux of the reaction mixture for 12-14 hr and monitored the progress of the reaction. The reaction mixture was cooled to RT and stirred for 2-3 h at room temperature.
  • reaction mass cooled to 15 °C, continued stirring for overnight.
  • the compounds of the present invention lowered random blood sugar level, triglyceride, total cholesterol, LDL, NLDL and increased HDL. This was demonstrated by in vitro as well as in vivo animal experiments.
  • Ligand binding domain of hPPAR ⁇ was fused to D ⁇ A binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector. Using superfect (Qiagen, Germany) as transfecting reagent HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound was added at different concentrations after 42 hrs of transfection and incubated overnight. Luciferase activity as. a function of compound binding/activation capacity of PPAR ⁇ was measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan).
  • Ligand binding domain of hPPAR ⁇ l was fused to D ⁇ A binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector.
  • lipofectamine Gibco BRL, USA
  • HEK-293 cells were transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter.
  • Compound was added at 1 ⁇ M concentration after 48 hrs of transfection and incubated overnight.
  • Luciferase activity as a function of drug binding/activation capacity of PPAR ⁇ 1 was measured using Packard Luclite kit (Packard, USA) in Packard Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn HoUis. Gene. 1992. 118 .: 137 -141; Guide to Eukaryotic Transfections with Cationic Lipid Reagents. Life Technologies, GIBCO BRL, USA).
  • Liver microsome bound reductase is prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometric assays are carried out in 100 mM KH 2 PO 4 , 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 ⁇ g of liver microsomal enzyme. Total reaction mixture volume is kept as 1 ml. Reaction is started by addition of HMG CoA. Reaction mixture is incubated at 37°C for 30 min and decrease in absorbance at 340 nm is recorded. Reaction mixture without substrate is used as blank (Goldstein, J. L and Brown, M. S. Progress in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol. J. Lipid Res. 1984, 25: 1450 - 1461). The test compounds will inhibit the HMG CoA reductase enzyme.
  • mice C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic.
  • db/db model mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled.
  • the state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities.
  • mice Male C57BL KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment.
  • the mice were provided with standard feed (National Institute of Nutrition (NIN), India) and acidified water, ad libitum.
  • the animals having more than 350 mg / dl blood sugar were used for testing.
  • the number of animals in each group was 4. Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 0.1 mg to 30 mg / kg through oral gavage daily for 6 days.
  • the control group received vehicle (dose 10 ml / kg).
  • the random blood sugar and triglyceride levels were measured by collecting blood (100 ⁇ l) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma.
  • the plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-PO 4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India) methods respectively.
  • the blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula.
  • the ob/ob mice are obtained at 5 weeks of age from Bomholtgard, Denmark and are used at 8 weeks of age.
  • Zucker fa/fa fatty rats are obtained from IffaCredo, France at 10 weeks of age and are used at 13 weeks of age.
  • the animals are maintained under 12 hour light and dark cycle at 25 + 1°C. Animals are given standard laboratory chow (NIN, India) and water, ad libitum (Fujiwara, T., Yoshioka, S. 5 Yoshioka, T., Ushiyama, I and Horikoshi, H. Characterization of new oral antidiabetic agent CS-045. Studies in KK and ob/ob mice and Zucker fatty rats. Diabetes. 1988. 37 : 1549 - 1558).
  • the test compounds will be administered at 0.1 to 30 mg/kg/day dose for 9 days.
  • the control animals receives the vehicle (0.25% carboxymethylcellulose, dose 10 ml/kg) through oral gavage.
  • the blood samples can be collected in fed state 1 hour after drug administration on 0 and 9 day of treatment.
  • the blood can be collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes.
  • plasma sample will be separated for triglyceride, glucose, free fatty acid, total cholesterol and insulin estimations.
  • Measurement of plasma triglyceride, glucose, total cholesterol can be done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India).
  • the plasma free fatty acid will be measured using a commercial kit from Boehringer Mannheim, Germany.
  • the plasma insulin can be measured using a RIA kit (BARC, India). The reduction of various parameters examined will be calculated according to the formula given below.
  • mice Male Sprague Dawley rats (NIN stock) are bred in DRF animal house. Animals are maintained under 12 hour light and dark cycle at 25 ⁇ 1°C. Rats of 180 - 200 gram body weight range were used for the experiment. Animals are made hypercholesterolemic by feeding 2% cholesterol and 1% sodium cholate mixed with standard laboratory chow [National Iristitute of Nutrition (NIN), India] for 6 days. Throughout the experimental period .the animals are maintained on the same diet (Petit, D., Bonnefis, M. T., Rey, C and Infante, R. Effects of ciprofibrate on liver lipids and lipoprotein synthesis in normo- and hyperlipidemic rats. Atherosclerosis. 1988. 74 : 215 - 225). The test compounds can be administered orally at a dose 0.1 to 30 mg/kg/day for 3 days. Control group is treated with vehicle alone (0.25 % Carboxymethylcellulose; dose 10 ml/kg).
  • the blood samples can be collected in fed state 1 hour after drug administration on 0 and 3 day of compound treatment.
  • the blood can be collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample will be separated for total cholesterol, HDL and triglyceride estimations. Measurement of plasma triglyceride, total cholesterol and HDL are done using commercial kits (Dr. Reddy's Laboratory, Diagnostic Division, India). LDL and NLDL cholesterol can be calculated from the data obtained for total cholesterol, HDL and triglyceride. The reduction of various parameters examined are calculated according to the fonnula given below.
  • SAM Male Swiss albino mice
  • Male Guinea pigs were obtained from ⁇ I ⁇ and housed in DRF animal house. All these animals were maintained under 12 hour light and dark cycle at 25 ⁇ 1 °C. Animals were given standard laboratory chow ( ⁇ I ⁇ , India) and water, ad libitum. SAM of 20 - 25 g body weight range and Guinea pigs of 500 - 700 g body weight range were used (Oliver, P., Plancke, M. O., Marzin, D., Clavey, N., Sauzieres, J and Fruchart, J. C.
  • mice were treated with vehicle (0.25% Carboxymethylcellulose; dose 10 ml/kg).
  • the test compounds were administered orally to Guinea pigs at 0.3 to 30 mg/kg/day dose for 6 days.
  • Control animals were treated with vehicle (0.25% Carboxymethylcellulose; dose 5 ml/kg).
  • the blood samples were collected in fed state 1 hour after drug administration on 0 and 6 day of freatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride and total cholesterol (Wieland, O. Methods of Enzymatic analysis. Bergermeyer, H. O., Ed., 1963. 211 - 214; Trinder, P. Ann. Clin. Biochem. 1969. 6 : 24 - 27).
  • Measurement of plasma triglyceride, total cholesterol and HDL were done using commercial kits (Dr. Reddy's Diagnostic Division, India).
  • test compounds can be administered orally at 1 to 30 mg/kg/day dose for 15 days.
  • Control group animals are treated with vehicle (Mill Q water, dose 10 ml/kg/day). Body weights are measured on every 3 r day.
  • Formulae for calculation :
  • LDL and NLDL cholesterol levels were calculated according to the formula :
  • Triglyceride LDL cholesterol in mg/dl [ Total cholesterol - HDL cholesterol - ] mg/dl
  • NLDL cholesterol in mg/dl [Total cholesterol - HDL cholesterol - LDL cholesterol] mg/dl.
  • mice Male Wistar rats (220 - 250 gm) were used in the experiments. The animals were maintained under standard laboratory conditions and had free access to feed and water ad libitum. Before experimentation animals were fasted overnight ( ⁇ 15 h) during which they had free access to water ad libitum.
  • AUC ( o- t) The area under the plasma concentration versus time curve up to the last quantifiable time point, AUC ( o- t) was obtained by the linear and log-linear trapezoidal summation.
  • K ⁇ was calculated by the linear regression of the log-transformed concentrations of the drug in the terminal phase.

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Abstract

L'invention concerne des sels des composés pharmaceutiquement acceptables représentés par la formule (I), leurs dérivés, leurs analogues, leurs formes tautomères, leur stéréoisomères, leurs polymorphes, leurs solvants pharmaceutiquement acceptables et des compositions pharmaceutiquement acceptables contenant lesdits composés.
EP02711124A 2001-02-05 2002-02-05 Sels de derives de pyrimidine pour utilisation contre les maladies coronaires vasculaires et l'atherosclerose Withdrawn EP1363913A2 (fr)

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US20030171399A1 (en) 2000-06-28 2003-09-11 Tularik Inc. Quinolinyl and benzothiazolyl modulators
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US7223761B2 (en) 2003-10-03 2007-05-29 Amgen Inc. Salts and polymorphs of a potent antidiabetic compound
CN104202977A (zh) * 2012-03-22 2014-12-10 转化技术制药有限责任公司 小分子glp1r激动剂的三(羟甲基)氨基甲烷盐及其药物组合物和用途

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