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Therapeutic uses of di-aryl acid derivatives |
| RE40558 |
Therapeutic uses of di-aryl acid derivatives
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| Patent Drawings: | |
| Inventor: |
Jayyosi, et al. |
| Date Issued: |
October 28, 2008 |
| Application: |
11/254,215 |
| Filed: |
October 20, 2005 |
| Inventors: |
Jayyosi; Zaid (Flemington, NJ)
McGeehan; Gerard M. (Wilmington, DE)
Kelley; Michael F. (West Chester, PA)
Labaudiniere; Richard F. (Sherborn, MA)
Zhang; Litao (Churchville, PA)
Groneberg; Robert D. (Boulder, CO)
McGarry; Daniel G. (Branchburg, NJ)
Caulfield; Thomas J. (Lebanon, NJ)
Minnich; Anne (Flemington, NJ)
Bobko; Mark (Exton, PA)
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| Assignee: |
Sanofi-Aventis Deutschland GmbH (Frankfurt am Main, DE) |
| Primary Examiner: |
Balasubram; Venkataraman |
| Assistant Examiner: |
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| Attorney Or Agent: |
Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P. |
| U.S. Class: |
514/311; 514/247; 514/256; 514/266.1; 514/308; 514/362; 514/363; 514/364; 514/365; 514/367; 514/372; 514/373; 514/374; 514/375; 514/378; 514/383; 514/396; 514/406; 514/410; 514/438; 514/439; 544/224; 544/283; 544/335; 544/336; 546/139; 546/152; 546/266; 548/128; 548/131; 548/136; 548/146; 548/206; 548/215; 548/235; 548/240; 548/262.2; 548/304.4; 548/341.1; 548/452 |
| Field Of Search: |
546/152; 548/235; 514/311; 514/374 |
| International Class: |
C07D 215/14; A61K 31/421; A61K 31/47; A61P 3/04; A61P 3/10; A61P 9/02; C07D 263/32 |
| U.S Patent Documents: |
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| Foreign Patent Documents: |
248922; 0 520 723; 0 657 422; 0 845 451; WO 87/05510; WO 97/27847; WO 97/27857; WO 97/28137; WO 97/28149; WO 98/27974; WO 99/08501; WO 99/11255; WO 99/15520; WO 99/16758; WO 99/20275; WO 00/64876 |
| Other References: |
West, Anthony R., Solid State Chemistry and its Applications, Wiley, New York, 1988, pp. 358 & 365. cited by examiner.
Vippagunta et al., Advanced Drug Delivery Reviews 48: 3-26, 2001. cited by examiner.
Jones A.B., Medical Research RReviews, vol. 21, No. 6, 540552, 2001. cited by examiner.
Kozikowski et al, Tetrahedron Lett.28/43,5125-8(1987), also cited as Chem.Abstract 110:56678. cited by examiner.
Co-pending U.S. Application No. 09/724,496, filed on Nov. 28, 2000. cited by other.
Picard et al., PubMed Abstr.: 12055342: "PPAR gama and Glucose Homeostasis," Annu. Rev. Nutr., 22, 167-197 (2002). cited by other.
Molavi et al. PubMed Abstr.: 12000972: "PPAR Ligands as . . . another Pandoras Box," J. Cardiov. Pharm. Ther., Jan. 7, 7/1, 1-8 (2002). cited by other.
Kozikowski et al., Chem Abstr., 110:56678; also cited as Tetrahedroon Lett., 28/43, 5125-28 (1987). cited by other.
Kahovcova et al., Chem. Abstr., 111:115036; also cited as CS 248922 (1987). cited by other.
Bloomgarden, Z., "Insulin Resistance: Current Concepts," Clinical Therapeutics, vol. 20, No. 2, pp. 216-231 (1998). cited by other.
Torra, I.P. et al., "Peroxisome proliferator-activated receptor alpha in metabolic disease, Inflammation, atherosclerosis and aging," Current Opinion in Lipidology, vol. 10, pp. 151-159 (1999). cited by other. |
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| Abstract: |
The use of diaryl acid derivatives of formula (I) ##STR00001## or pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof, wherein the variables shown are defined in the disclosure, and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor. |
| Claim: |
What is claimed is:
1. A compound of formula (I) ##STR00198## wherein: ##STR00199## is oxazolyl or quinolinyl, which are optionally substituted by one or more ring system substituents; ##STR00200## is phenyl, which is optionally substituted by one or more ring system substituents, in addition to being substituted by group Z; A is ##STR00201## .[.B and E are a chemical bond;.]. a is 1; b is 0 or 1; .[.c is 0;.]. .[.d is 0;.]. g is1-5; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are, independently, hydrogen, halogen or alkyl, wherein alkyl is optionally substituted by one or more alkyl group substituents; Z is R.sub.21O.sub.2C--, R.sub.21OC--, --CN, R.sub.21O.sub.2SHNCO--,R.sub.21O.sub.2SHN--, (R.sub.21).sub.2NCO-- or R.sub.21O--; R.sub.21 is independently hydrogen, alkyl, which is optionally substituted by one or more alkyl group substituents, aryl, which is optionally substituted by one or more ring systemsubstituents, cycloalkyl, which is optionally substituted by one or more ring system substituents, or aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted byone or more alkyl group substituents; R.sub.15, R.sub.16 are independently hydrogen, alkyl, which is optionally substituted by one or more alkyl group substituents, aralkyl, wherein the aryl portion is optionally substituted by one or more ring systemsubstituents and the alkyl portion is optionally substituted by one or more alkyl group substituents, or alkoxycarbonyl, wherein the alkyl portion is optionally substituted by one or more alkyl group substituents; or a pharmaceutically acceptable saltthereof, .Iadd.or .Iaddend.an N-oxide thereof, .[.a hydrate thereof or a solvate thereof,.]. wherein alkyl is an aliphatic hydrocarbon group which is straight or branched having 1 to about 20 carbon atoms; aryl is an aromatic monocyclic or multicyclicring system of about 6 to about 14 carbon atoms; a ring system substituent is halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy, unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy; andan alkyl group substituent is unsubstituted acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl, unsubstituted pyridylmethyloxycarbonylmethyl or unsubstituted alkoxycarbonyl.
2. A compound according to claim 1 wherein .[.a=0;.]. R.sub.15 and R.sub.16 are hydrogen; g is 1, 2, 3 or 4; and b=0.
3. A compound according to claim 1 wherein Z is R.sub.21O.sub.2SHNCO--, and R.sub.21 is phenyl, wherein phenyl is optionally substituted by one or more ring system substituents.
4. A compound according to claim 1 wherein Z is --CO.sub.2H or --CN.
5. A compound according to claim 1 wherein ##STR00202## is unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl; or 2-substituted-oxazol4-yl or 2,5disubstituted-oxazol4-yl; 4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl; wherein an indicated substituent is a ring system substituent.
6. A compound as claimed in claim 1, wherein the compound is 2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoic acid.
7. A compound as claimed in claim 1, which is of formula ##STR00203## wherein b=0; R.sub.1, R.sub.2, R.sub.3, R.sub.4 are hydrogen R.sub.15, R.sub.16 are hydrogen; g=2, 3, 4 or 5; Z is R.sub.21O.sub.2C--, R.sub.21OC--, or R.sub.21O--; R' ishydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy or unsubstituted aralkyloxy; and R'' is hydrogen, halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy,unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy, or a pharmaceutically acceptable salt thereof, .Iadd.or .Iaddend.an N-oxide thereof.[., a hydrate thereof or a solvate thereof.]. .
8. A compound according to claim 7, wherein Z is --CO.sub.2H.
9. A compound according to claim 7, wherein R' is hydrogen; and R'' is lower alkyl of 1 to about 4 carbon atoms.
10. A compound according to claim 7, wherein ##STR00204## is 2-substituted-oxazol-4-yl, wherein the substituent is a ring system substituent.
11. A compound according to claim 1, wherein the compound is ##STR00205## ##STR00206##
12. A compound according to claim 1, wherein the compound is ##STR00207##
13. A compound .[.according to claim 1.]. , wherein the compound is ##STR00208##
14. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
.[.15. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound wherein the disorder is associated with a physiological detrimental blood level of insulin, glucose, free fatty acids, or triglycerides..].
.[.16. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the physiological disorder is hyperglycemia..].
.[.17. The method according to claim 16, wherein the hyperglycemia is diabetes..].
18. .[.The method according to claim 16, wherein the hyperglycemia is.]. .Iadd.A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand bindingactivity, comprising administering to the patient a pharmaceutically effective amount of the compound, wherein the disorder is .Iaddend.Type II diabetes.
.[.19. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the physiological disorder is hyperinsulinism..].
.[.20. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the physiological disorder is insulin resistance..].
.[.21. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the physiological disorder is a cardiovascular condition..].
.[.22. The method according to claim 21, wherein the cardiovascular condition is atherosclerosis..].
.[.23. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the physiological disorder is hyperlipidemia..].
24. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effectiveamount of the compound, wherein the physiological disorder is hypertension.
25. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 1 having PPAR ligand binding activity, comprising administering to the patient a pharmaceutically effectiveamount of the compound, wherein the physiological disorder is an eating disorder.
.Iadd.26. A compound of formula (I) ##STR00209## wherein: ##STR00210## is a oxazolyl or quinolinyl, which are optionally substituted by one or more substituents selected from phenyl optionally substituted by one or more ring systemsubstituents, thienyl optionally substituted by one or more ring system substituents, cycloalkyl optionally substituted by one or more ring system substituents, lower alkyl optionally substituted by one or more alkyl group substituents, branched alkyloptionally substituted by one or more alkyl group substituents, fluoro, chloro, alkoxy wherein the alkyl portion is optionally substituted by one or more alkyl group substituents, aralkyloxy wherein the aryl portion is optionally substituted with one ormore ring system substituents and the alkyl portion is optionally substituted with one or more alkyl group substituents, trifluoromethyl, and trifluoromethyloxy; ##STR00211## is phenyl, which is optionally substituted by one or more ring systemsubstituents, in addition to being substituted by group Z; ##STR00212## a is 1; b is 0 or 1; g is 1-5; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are, independently, hydrogen, halogen or alkyl, wherein alkyl is optionally substituted by one or more alkylgroup substituents; Z is R.sub.21O.sub.2C--, R.sub.21OC--, --CN, R.sub.21O.sub.2SHNCO--, R.sub.21O.sub.2SHN--, (R.sub.21).sub.2NCO-- or R.sub.21O--; R.sub.21 is independently hydrogen, alkyl, which is optionally substituted by one or more alkyl groupsubstituents, aryl, which is optionally substituted by one or more ring system substituents, cycloalkyl, which is optionally substituted by one or more ring system substituents, or aralkyl, wherein the aryl portion is optionally substituted by one ormore ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents; R.sub.15, R.sub.16 are independently hydrogen, alkyl, which is optionally substituted by one or more alkyl group substituents,aralkyl, wherein the aryl portion is optionally substituted by one or more ring system substituents and the alkyl portion is optionally substituted by one or more alkyl group substituents, or alkoxycarbonyl, wherein the alkyl portion is optionallysubstituted by one or more alkyl group substituents; or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, wherein alkyl is an aliphatic hydrocarbon group which is straight or branched having 1 to about 20 carbon atoms; aryl is anaromatic monocyclic or multicyclic ring system of about 6 to about 14 carbon atoms; a ring system substituent is halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy, unsubstituted aralkyloxy orunsubstituted cycloalkylalkyloxy; and an alkyl group substituent is unsubstituted acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl, unsubstituted pyridylmethyloxycarbonylmethyl orunsubstituted alkoxycarbonyl..Iaddend.
.Iadd.27. A compound according to claim 26 wherein R.sub.15 and R.sub.16 are hydrogen; and g is 1, 2, 3 or 4..Iaddend.
.Iadd.28. A compound according to claim 26 wherein Z is R.sub.21O.sub.2SHNCO--, and R.sub.21 is phenyl, wherein phenyl is optionally substituted by one or more ring system substituents..Iaddend.
.Iadd.29. A compound according to claim 26 wherein Z is --CO.sub.2H or --CN..Iaddend.
.Iadd.30. A compound according to claim 26 wherein ##STR00213## is unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl; or 2-substituted-oxazol-4-ylor 2,5 disubstituted-oxazol-4-yl; 4-substituted oxazol-2-yl or 4,5-disubstituted-oxazol-2-yl; wherein an indicated substituent is selected from phenyl optionally substituted by one or more ring system substituents, thienyl optionally substituted by oneor more ring system substituents, cycloalkyl optionally substituted by one or more ring system substituents, lower alkyl optionally substituted by one or more alkyl group substituents, branched alkyl optionally substituted by one or more alkyl groupsubstituents, fluoro, chloro, alkoxy wherein the alkyl portion is optionally substituted by one or more alkyl group substituents, aralkyloxy wherein the aryl portion is optionally substituted with one or more ring system substituents and the alkylportion is optionally substituted with one or more alkyl group substituents, trifluoromethyl and trifluoromethyloxy..Iaddend.
.Iadd.31. A compound as claimed in claim 26, which is of formula ##STR00214## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 are hydrogen R.sub.15, R.sub.16 are hydrogen; g=2, 3, 4 or 5; Z is R.sub.21O.sub.2C--, R.sub.21OC--, or R.sub.21O--; R'and R'' are independently hydrogen or ring system substituents or a pharmaceutically acceptable salt thereof, or an N-oxide thereof..Iaddend.
.Iadd.32. A compound according to claim 31, wherein Z is --CO.sub.2H..Iaddend.
.Iadd.33. A compound according to claim 31, wherein R' is hydrogen; and R'' is lower alkyl of 1 to about 4 carbon atoms..Iaddend.
.Iadd.34. A compound according to claim 31, wherein ##STR00215## is 2-substituted-oxazol-4-yl, wherein the substituent is unsubstituted phenyl..Iaddend.
.Iadd.35. A compound according to claim 26, wherein ##STR00216## is oxazolyl, which is substituted by unsubstituted phenyl..Iaddend.
.Iadd.36. A compound, wherein the compound is ##STR00217## ##STR00218## or a pharmaceutically acceptable salt thereof, or an N-oxide thereof..Iaddend.
.Iadd.37. A compound according to claim 26, wherein the compound is ##STR00219## or a pharmaceutically acceptable salt thereof, or an N-oxide thereof..Iaddend.
.Iadd.38. A compound, wherein the compound is ##STR00220## or a pharmaceutically acceptable salt thereof, or an N-oxide thereof..Iaddend.
.Iadd.39. A pharmaceutical composition comprising a pharmaceutically acceptable amount of the compound according to claim 26 and a pharmaceutically acceptable carrier..Iaddend.
.Iadd.40. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 26 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the disorder is Type II diabetes..Iaddend.
.Iadd.41. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 26 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the physiological disorder is hypertension..Iaddend.
.Iadd.42. A method of treating a patient suffering from a physiological disorder capable of being modulated by a compound according to claim 26 having PPAR ligand binding activity, comprising administering to the patient a pharmaceuticallyeffective amount of the compound, wherein the physiological disorder is an eating disorder..Iaddend. |
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