Peroxisome proliferator activated receptor modulators

{
  "publication_number": "US2007082907A1",
  "country": "US",
  "kind": "A1",
  "title": "Peroxisome proliferator activated receptor modulators",
  "abstract": "The present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt, solvate hydrate or stereoisomer thereof, which is useful in treating or preventing disorders mediated by a peroxisome proliferator activated receptor (PPAR) such as syndrome X, type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, arteriosclerosis, and other disorders related to syndrome X and cardiovascular diseases.",
  "claims": [
    "1. A compound having a formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: is: a) aryl, b) a 5- to 10-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) C 3 -C 8 cycloalkyl, d) aliphatic group, or e) heterocyclyl, wherein aryl, heteroaryl, cycloalkyl, heterocyclyl and aliphatic group being optionally substituted with one or more groups independently selected from R 8; D a and D b are each independently: a bond or - [C(R c)(R d) n, wherein R c and R d are each independently hydrogen, C 1 -C 6 alkyl or aryl; Q is: - C(O)OR 5 or R 5A; X is: NR 6 C[O] p, NR 6 S(O) 2, C[O] p,NR 6, S(O) 2 NR 6 or NR 7; Y is: a bond, CH 2, S or O; is: n and r are each independently: 1, 2, 3 or 4; q is: 1, 2, 3, 4 or 5; p is: 1 or 2; R 1 and R 2 are each independently: hydrogen, C 1 -C 6 alkyl, halo or haloalkyl; R 3 and R 4 are each independently: hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or aryloxy; R 3 and R 4 are together a 3- to 6-membered carbocyclyl or heterocyclyl; R 5 is: hydrogen, C 1 -C 6 alkyl or aminoalkyl; R 5A is: carboxamide, sulfonamide, acylsulfonamide, tetrazole, R 6 is each independently: hydrogen, C 1 -C 12 alkyl, arylalkyl, C 3 -C 8 cycloalkyl, or (CH 2) n C(O)aryl, wherein alkyl, arylalkyl and cycloalkyl group being optionally substituted with one or more groups independently selected from R 8; R 7 is: hydrogen, acyl, or sulfonyl; R 8 and R 8a are each independently: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro, cyano, halo, haloalkyl, haloalkyloxy, aryl, heteroaryl, benzyl, aryloxy, SR 9, S[O] p R 9 or C[O] p R 9; and R 9 is: hydrogen, C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.",
    "2. The compound of claim 1, wherein aryl or heteroaryl are selected from the group consisting of phenyl, naphthyl, indolyl, isoindolyl, benzoimidazolyl, quinolinyl, isoquinolinyl, pyridyl, benzothiophenyl and benzofuranyl.",
    "3. The compound of claim 2, wherein the compound is structural formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: q is 1, 2, 3, 4, or 5.",
    "4. The compound of claim 3, wherein R 8 is disubstituted in 2 and 4 positions, or trisubstituted in 2, 4, and 6 positions of phenyl ring relative to -D b -.",
    "5. The compound of claim 3, wherein the compound is structural formula III, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y is: O or CH 2; R 1 is: hydrogen, halo or C 1 -C 4 alkyl; R 2, R 3 and R 4, R 6, R c and R d are each independently: hydrogen or C 1 -C 4 alkyl; (R 8) 1 and (R 8) 2 are each independently: hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or SR 9; R 6 is: hydrogen or C 1 -C 4 alkyl; and R 9 is: hydrogen or C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl",
    "6. The compound of claim 5, wherein the compound is structural formula IV, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 and R 2 are each independently: hydrogen, halo or C 1 -C 4 alkyl; R c, R d and R 6 are each independently: hydrogen or methyl; and (R 8) 1 and (R 8) 2 are each independently: hydrogen, F, Cl, Br, OMe, CF 3, OCF 3, SCH 3, NO 2, cyano, methyl, ethyl, isobutyl, isopropyl or tert-butyl.",
    "7. The compound of claim 6, wherein the compound is structural formula V, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 and R 2 are each independently: hydrogen, methyl, ethyl or fluoro; and (R 8) 1 and (R 8) 2 are each independently: hydrogen, F, Cl, Br, OMe, CF 3, OCF 3, SCH 3, NO 2, cyano, methyl, ethyl, isobutyl, isopropyl or tert-butyl.",
    "8. The compound of claim 7, wherein the compound having a structural formula VI, or a pharmaceutically acceptable salt or stereoisomer thereof.",
    "9. The compound of claim 3, wherein the compound is structural formula VII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 1 and R 2 are each independently: hydrogen, halo or C 1 -C 4 alkyl; R 6 is: hydrogen or C 1 -C 4 alkyl; R 8 is: hydrogen, halo, haloalky or haloalkyloxy, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or SR 9; and R 9 is: hydrogen or C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl.",
    "10. The compound of claim 9, wherein R 1, R 2 and R 6 are each independently hydrogen or methyl; and R 8 is hydrogen, F, Cl, Br, OMe, CF 3, OCF 3, SCH 3, NO 2, methyl, ethyl, isobutyl, isopropyl or tert-butyl.",
    "11. The compound of claim 1, wherein the compound is structural formula VIII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: q is 1, 2, 3 or 4; and E is S, O or NR 10 wherein R 10 is hydrogen or C 1 -C 4 alkyl.",
    "12. The compound of claim 11, wherein the compound is structural formula IX, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y is: O or CH 2; E is: S, O, NH or NCH 3, NCH 2 CH 3; R 1 is: hydrogen, C 1 -C 4 alkyl, halo or haloalkyl; R 2, R 3 and R 4, R 6, R c and R d are each independently: hydrogen or C 1 -C 4 alkyl; (R 8) 1 and (R 8) 2 are each independently: hydrogen, halo, haloalkyl, haloalkyloxy, cyano, nitro, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; and R 8 is: hydrogen or C 1 -C 4 alkyl.",
    "13. The compound of claim 12, wherein the compound having a structural formula X, R 1 and R 2 are each independently: hydrogen, halo or C 1 -C 4 alkyl; (R 8) 1 is: hydrogen, F, Cl, Br, OMe, CF 3, OCF 3, SCH 3, NO 2, cyano, nitro, methyl, ethyl, isobutyl, isopropyl or tert-butyl; R 8 is: hydrogen, methyl, ethyl or propyl; and R 10 is: hydrogen, methyl or ethyl.",
    "14. The compound of claim 12, wherein the compound having a structural formula XI, R 1 and R 2 are each independently: hydrogen, halo or C 1 -C 4 alkyl; (R 8) 1 is: hydrogen, F, Cl, Br, OMe, CF 3, OCF 3, SCH 3, NO 2, cyano, nitro, methyl, ethyl, isobutyl, isopropyl or tert-butyl; R 8 is: hydrogen, methyl, ethyl or propyl; and R 10 is: hydrogen, methyl or ethyl.",
    "15. The compound of claim 12, wherein the compound having a structural formula XII, or a pharmaceutically acceptable salt.",
    "16. The compound of claim 12, wherein the compound is structural formula XIII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y is: O or CH 2; R 1 is: hydrogen, C 1 -C 4 alkyl, halo or haloalkyl; R 2, R 3, R 4, R 6, R c and R d are each independently: hydrogen or C 1 -C 4 alkyl; R 8 are each independently: hydrogen or C 1 -C 4 alkyl; and (R 8) 1 is: hydrogen, halo, haloalkyl or haloalkyloxy, cyano, nitroC 1 -C 6 alkyl or C 1 -C 6 alkoxy.",
    "17. The compound of claim 16, wherein Y is O or CH 2; R 1 is hydrogen, methyl, F, Br or Cl; R 2 is hydrogen, methyl or ethyl; R 3, R 4, R 6, R 8, R c and R d are each independently hydrogen or methyl; and (R 8) 1 is hydrogen, F, Cl, Br, OMe, CF 3, OCF 3, SCH 3, NO 2, cyano, nitro, methyl, ethyl, isobutyl, isopropyl or tert-butyl.",
    "18. The compound of claim 15, wherein the compound having a structural formula XIV, or a pharmaceutically acceptable salt.",
    "19. The compound of claim 15, wherein the compound having a structural formula XV, or a pharmaceutically acceptable salt.",
    "20. The compound of claim 1, wherein the compound is structural formula XVI, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is 1, 2, 3, or 4.",
    "21. The compound of claim 20, wherein Y is O or CH 2; R 1, R 2, R 3, R 4 R c and R d are each independently hydrogen or C 1 -C 4 alkyl; n is 1 or 2; R 6 is hydrogen, C 1 -C 6 alkyl or arylalkyl; and R 8 is hydrogen, C 1 -C 6 alkoxy, halo or haloalkyl.",
    "22. The compound of claim 1, wherein the compound is structural formula XVII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 8a is hydrogen, C 1 -C 4 alkyl or aryl; and s is 1, 2, 3, 4, 5 or 6.",
    "23. The compound of claim 22, wherein the compound having a structural formula XVIII, R 2 is: hydrogen or C 1 -C 4 alkyl, R 8 is: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, haloalkyl or haloalkyloxy; R 8a is: hydrogen, methyl, or phenyl; and q is: 1 or 2.",
    "24. The compound of claim 1, wherein the compound having a structural formula XIX, or a pharmaceutically acceptable salt or stereoisomer thereof.",
    "25. The compound of claim 24, wherein Q is COOH; R 7 is hydrogen, mathanesulfonyl or acetyl; and R c and R d are each hydrogen.",
    "26. A compound of claim 1 selected from the group consisting of: No Structure Name 1 2-(4-{3-[(2-Chloro-4-tri- fluoromethyl-benzoylamino)-meth- yl]-5-fluoro-phenoxy}-2-meth- yl-phenoxy)-2-methyl- propionic acid 2 3-[4-(3-{[(5-Chloro-1H-indole-2-car- bonyl)-amino]-methyl}-5-fluoro- phenoxy)-2-methyl- phenyl]-propionic acid 3 2-(4-{3-Fluoro-5-[1-(2-methyl-4-tri- fluoromethyl- benzoylamino)-ethyl]-phenoxy}-2-methyl- phenoxy)-2-methyl- propionic acid (isomer 1) 4 2-[4-(3-{[(5-Chloro-3-methyl- benzo[b]thiophene-2-carbonyl)-ami- no]-methyl}-5-methyl- phenoxy)-2-methyl-phenoxy]-2-meth- yl-propionic acid 5 (R)-3-[4-(3-{1-[(5-Chloro-1,3-di- methyl-1H-indole-2-carbonyl)-ami- no]-ethyl}-5-fluoro- phenoxy)-2-methyl-phenyl]-pro- pionic acid 6 3-(2-Ethyl-4-{3-fluoro-5-[(2-meth- yl-4-trifluoromethyl- benzoylamino)-methyl]-phe- noxy}-phenyl)-propionic acid 7 2-(4-{3-[(2-Fluoro-4-tri- fluoromethyl-benzoylamino)-meth- yl]-5-methyl-phenoxy}-2-meth- yl-phenoxy)-2-methyl- propionic acid 8 (R)-2-[4-(3-{[(5-Chloro-1,3-di- methyl-1H-indole-2-carbonyl)-ami- no]-methyl}-5-methyl- phenoxy)-2-methyl-phenoxy]-2-meth- yl-propionic acid 9 3-[4-(3-Fluoro-5-{[(5-fluoro-3-meth- yl-1H-indole-2-carbonyl)-ami- no]-methyl}-phenoxy)-2-meth- yl-phenyl]-propionic acid 10 2-[4-(3-Fluoro-5-{[(5-fluoro-1,3-di- methyl-1H-indole-2-carbonyl)-ami- no]-methyl}-phe- noxy)-2-methyl- phenoxy]-2-methyl- propionic acid 11 (R)-3-[4-(3-{1-[(5-Fluoro-1,3-di- methyl-1H-indole-2-carbonyl)-ami- no]-ethyl}-5-methyl- phenoxy)-2-methyl-phenyl]-pro- pionic acid 12 2-Methyl-2-(2-methyl-4-{3-[(2-meth- yl-4-trifluoromethyl- benzoylamino)-methyl]-phe- noxy}-phenoxy)-propionic acid 13 2-(4-{3-Fluoro-5-[(2-methyl-4-tri- fluoromethyl-benzoylamino)-meth- yl]-phenoxy}-2-methyl- phenoxy)-2-methyl-propionic acid 14 (R)-3-[4-(3-Fluoro-5-{1-[(5-fluoro-1,3-di- methyl-1H-indole-2-car- bonyl)-amino]-ethyl}-phe- noxy)-2-methyl-phenyl]-pro- pionic acid 15 3-[4-(3-{[(5-Chloro-1,3-di- methyl-1H-indole-2-carbonyl)-ami- no]-methyl}-5-fluoro-phe- noxy)-2-methyl-phenyl]-pro- pionic acid 16 3-[4-(3-{[(5-Chloro-1,3-di- methyl-1H-indole-2-carbonyl)-ami- no]-methyl}-phenoxy)-2-methyl- phenyl]-propionic acid 17 3-[2-Ethyl-4-(3-fluoro-5-{[(5-fluoro-1,3-di- methyl-1H-indole-2-car- bonyl)-amino]-methyl}-phe- noxy)-phenyl]-propionic acid 18 3-(4-{3-[(2-Chloro-4-tri- fluoromethyl-benzoylamino)-meth- yl]-5-methyl-phenoxy}-2-ethyl- phenyl)-propionic acid",
    "27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt.",
    "28. A pharmaceutical composition comprising: (1) a compound of claims 1 - 26, or a pharmaceutically acceptable salt; (2) a second therapeutic agent selected from the group consisting of: insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, statins, acryl CoA:cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin; and (3) optionally a pharmaceutically acceptable carrier.",
    "29. A method of modulating a peroxisome proliferator activated receptor (PPAR) comprising the step of contacting the receptor with a compound of claims 1 - 26, or a pharmaceutically acceptable salt.",
    "30. The method of claim 29, wherein the PPAR is an alpha (α)-receptor.",
    "31. The method of claim 29, wherein the PPAR is a gamma (γ)-receptor.",
    "32. The method of claim 29, wherein the PPAR is a delta (δ)-receptor.",
    "33. The method of claim 29, wherein the PPAR is a gamma/delta (γ/δ)-receptor.",
    "34. The method of claim 29, wherein the PPAR is an alpha/gamma/delta (α/γ/δ)-receptor.",
    "35. A method for treating a PPAR-γ mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of claims 1 - 26.",
    "36. A method for treating a PPAR-δ mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of claims 1 - 26.",
    "37. A method for treating a PPAR-γ/δ mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of claims 1 - 26.",
    "38. A method for treating a PPAR-α/γ/δ mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of claims 1 - 26.",
    "39. A method for lowering blood-glucose in a mammal comprising the step of administering an effective amount of a compound of claim 1.",
    "40. A method of treating disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of claim 1.",
    "41. A method of treating diabetes mellitus in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of of claim 1.",
    "42. A method of treating cardiovascular disease in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt.",
    "43. A method of treating syndrome X in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of claims 1 - 26, or a pharmaceutically acceptable salt.",
    "44. A method of treating disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of claims 1 - 26 and an effective amount of second therapeutic agent selected from the group consisting of: insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, statins, acryl CoA:cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin.",
    "45. (canceled)"
  ],
  "cpc": [
    "C07D 213/81",
    "A61P 1/04",
    "A61P 1/14",
    "A61P 17/06",
    "A61P 19/02",
    "A61P 25/28",
    "A61P 29/00",
    "A61P 3/04",
    "A61P 3/06",
    "A61P 3/10",
    "A61P 43/00",
    "A61P 5/50",
    "A61P 7/02",
    "A61P 9/00",
    "A61P 9/04",
    "A61P 9/10",
    "A61P 9/12",
    "C07C 211/29",
    "C07C 233/73",
    "C07C 235/46",
    "C07C 235/48",
    "C07C 235/54",
    "C07C 235/84",
    "C07C 271/16",
    "C07C 311/04",
    "C07C 311/17",
    "C07C 317/44",
    "C07C 323/62",
    "C07D 209/30",
    "C07D 209/42",
    "C07D 213/56",
    "C07D 333/70"
  ],
  "assignees": [
    "LILLY CO ELI"
  ],
  "filing_date": "2004-11-16",
  "publication_date": "2007-04-12",
  "priority_date": "2003-11-25",
  "application_number": "US-57902804-A",
  "family_id": "34652292",
  "citations": [
    "US2002156311A1"
  ]
}