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Paramétrages

1. WO2005066116 - OXIMES DE CHALCONE DISUBSTITUES UTILISES COMME AGONISTES SELECTIFS DES RECEPTEURS DES RETINOIDES RAR$G(G)

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique
WHAT IS CLAIMED IS:

1. A compound of the formula


wherein

R is selected from the groups consisting of the radicals defined by formulas (a) through (g)







where the dashed line in a ring represents a bond, or absence of a bond with the proviso that only one of the two dashed lines in the ring can represent a bond;

a * denotes a ring carbon to which the chalcone oxime group is attached;

X1 is O or S attached to the adjacent carbon with a double bond, or

X1 represents two R1 groups attached to the adjacent carbon;

X2 is O or S;

Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substitated with one or two R4 groups;

m is an integer having the values 0 to 6;

n is an integer having the values 0 to 2;

o is an integer having the values 0 or 1;

p is an integer having the values 1 or 2;

R1 is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;

R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH2, C1-6alkylamino or di(C1-6alkyl)amino;

R3 is H or alkyl of 1 to 10 carbons;

R4 is independently halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of

1 to 10 carbons;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or

2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl group of 1 to 6 carbons, cycloalkyl of 3 to 5 carbons, or alkenyl group containing 2 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or

trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCH3 or CH2OCH2OOC1-6alkyl, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C1-6alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or

C1-6alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

2. A compound in accordance with Claim 1 wherein Y is selected from the groups consisting of pheny, pyridyl, thienyl and furyl.

3. A compound in accordance with Claim 2 where Y is phenyl.

4. A compound in accordance with Claim 3 where the Y group is substituted by the chalcone-oxime and the A-B group in 1,4 (para) positions.

5. A compound in accordance with Claim 1 where the R group is represented by formula (a).

6. compound in accordance with Claim 5 where o is one (1).

7. A compound in accordance with Claim 6 where the dashed lines represent absence of a bond.

8. A compound in accordance with Claim 6 where one dashed line represents a bond.

9. A compound in accordance with Claim 5 where o is zero (0).

10. A compound in accordance with Claim 9 where the dashed lines represents a bond.

11. A compound in accordance with Claim 9 where the dashed lines represent absence of a bond.

12. A compound in accordance with Claim 1 where the R group is represented by formula (f).

13. A compound in accordance with Claim 12 where the dashed line represents absence of a bond.

14. A compound in accordance with Claim 13 where X2 is S.

15. A compound in accordance with Claim 13 where X2 is O.

16. A compound in accordance with Claim 1 where the R group is represented by formula (e).

17. A compound in accordance with Claim 16 where the dashed line represents absence of a bond.

18. A compound in accordance with Claim 1 where the R group is represented by formula (g).

19. A compound in accordance with Claim 18 where the dashed line represents absence of a bond.

20. A compound in accordance with Claim 1 where the A-B group represents (CH2)q-COOH or (CH2)q-COOR8 or a pharmaceutically acceptable salt of said compound.

21. A compound in accordance with Claim 20 where q is zero (0).

22. A compound of the formula


wherein

R1 is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;

R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH2, C1- 6alkylamino or di(C1-6alkyl)amino;

R3 is H or alkyl of 1 to 10 carbons;

R4 is halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons;

m is an integer having the values 0 to 8;

n is an integer having the values 0 to 2;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl group of 1 to 6 carbons, cycloalkyl of 3 to 5 carbons, or alkenyl group containing 2 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCH3 or CH2OCH2OOC1-6alkyl, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C1-6alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or

C1-6alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

23. A compound in accordance with Claim 22 that has the formula


wherein

R11, R12, R13 and R14 independently are hydrogen or methyl;

R4 is hydrogen or F, and

B is COOH or COOR8 or a pharmaceutically acceptable salt of said compound.

24. A compound in accordance with Claim 23 that has the formula


25. A compound in accordance with Claim 24 where R4 is H.

26. A compound in accordance with Claim 24 where R4 is F.

27. A compound in accordance with Claim 23 that has the formula


28. A compound in accordance with Claim 27 where R4 is H.

29. A compound in accordance with Claim 27 where R4 is F.

30. A compound in accordance with Claim 23 that has the formula


31. A compound in accordance with Claim 30 where R4 is H.

32. A compound of the formula


wherein

X2 is O or S;

R1 is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;

R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH2,

C1-6alkylamino or di(C1-6alkyl)amino;

R3 is H or alkyl of 1 to 10 carbons;

R4 is independently halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of

1 to 10 carbons;

m is an integer having the values 0 to 6;

n is an integer having the values 0 to 2;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or

2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl group of 1 to 6 carbons, cycloalkyl of 3 to 5 carbons, or alkenyl group containing 2 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCH3 or CH2OCH2OOC1-6alkyl, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C1-6alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or

C1-6alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

33. A compound in accordance with Claim 32 that has the formula


wherein

R11, R12, R13 and R14 independently are hydrogen or methyl;

R4 is hydrogen or F, and

B is COOH or COOR8 or a pharmaceutically acceptable salt of said compound.

34. A compound in accordance with Claim 33 where X2 is S.

35. A compound in accordance with Claim 34 where R13 and R14 are H.

36. A compound in accordance with Claim 35 where R4 is H.

37. A compound in accordance with Claim 35 where R4 is F.

38. A compound in accordance with Claim 33 where X2 is O.

39. A compound in accordance with Claim 38 where R11, R12, R13 and R14 are methyl.

40. A compound in accordance with Claim 39 where R4 is H.

41. A compound of the formula


wherein

X1 is O or S attached to the adjacent carbon with a double bond, or

X1 represents two R1 groups attached to the adjacent carbon;

R1 is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;

R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH2, C 1-6alkylamino or di(C1-6alkyl)amino;

R3 is H or alkyl of 1 to 10 carbons;

R4 is halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons;

m is an integer having the values 0 to 4;

n is an integer having the values 0 to 2;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl group of 1 to 6 carbons, cycloalkyl of 3 to 5 carbons, or alkenyl group containing 2 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCH3 or CH2OCH2OOC1-6alkyl, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C1-6alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or

C1-6alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

42. A compound in accordance with Claim 41 that has the formula


wherein

R4 is hydrogen or F, and

B is COOH or COOR8 or a pharmaceutically acceptable salt of said compound.

43. A compound in accordance with Claim 42 where R4 is H.

44. A compound of the formula


wherein

R1 is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;

R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH2,

C1-6alkylamino or di(C1-6alkyl)amino;

R3 is H or alkyl of 1 to 10 carbons;

R4 is halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons;

m is an integer having the values 0 to 6;

n is an integer having the values 0 to 2;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl group of 1 to 6 carbons, cycloalkyl of 3 to 5 carbons, or alkenyl group containing 2 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCH3 or CH2OCH2OOC1-6alkyl, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C 1-6alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or

C1-6alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

45. A compound in accordance with Claim 44 that has the formula


wherein

R4 is hydrogen or F, and

B is COOH or COOR8 or a pharmaceutically acceptable salt of said compound.

46. A compound in accordance with Claim 45 where R4 is H.

47. A compound in accordance with Claim 45 where R4 is F.

48. A compound of the formula


wherein

R1 is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;

R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH2, C1-

6alkylamino or di(C1-6alkyl)amino;

R3 is H or alkyl of 1 to 10 carbons;

R4 is independently halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of

1 to 10 carbons;

m is an integer having the values 0 to 6;

n is an integer having the values 0 to 2;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or

2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl group of 1 to 6 carbons, cycloalkyl of 3 to 5 carbons, or alkenyl group containing 2 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCH3 or CH2OCH2OOC1-6alkyl, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C1-6alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or

C 1-6alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

49. A compound in accordance with Claim 48 that has the formula


wherein

R4 is hydrogen or F, and

B is COOH or COOR8 or a pharmaceutically acceptable salt of said compound.

50. A compound in accordance with Claim 49 where R4 is H.

51. A compound in accordance with Claim 49 where R4 is F.

52. A compound of the formula


wherein

R1 is independently alkyl of 1 to 6 carbons, COOR3, F, Cl, Br or I;

R2 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, OH, SH, alkoxy having 1 to 6 carbons, alkylthio having 1 to 6 carbons, NH2, C1-6alkylamino or di(C1-6alkyl)amino;

R3 is H or alkyl of 1 to 10 carbons;

R4 is halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10 carbons;

m is an integer having the values 0 to 8;

A is (CH2)q where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is COOH or a pharmaceutically acceptable salt thereof, COOR8, CONR9R10, -CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, -COR7, CR7(OR12)2, CR7OR13O, or tri-lower alkylsilyl, where R7 is an alkyl group of 1 to 6 carbons, cycloalkyl of 3 to 5 carbons, or alkenyl group containing 2 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, CH2OCH3 or CH2OCH2OOC 1-6alkyl, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C1-6alkylphenyl, R11 is alkyl of 1 to 6 carbons, phenyl or

C1-6alkylphenyl, R12 is alkyl of 1 to 6 carbons, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.

53. A compound in accordance with Claim 52 that has the formula


wherein

R4 is hydrogen or F, and

B is COOH or COOR8 or a pharmaceutically acceptable salt of said compound.

54. A compound in accordance with Claim 53 where R4 is H.

55. A method of preventing or treating a pulmonary insufficiency condition or disease in a mammal in need thereof comprising administering a effective amount of one or more compounds of Claim 1.

56. The method of Claim 55, wherein the condition or disease is emphysema.

57. A method of preventing or treating a pulmonary insufficiency condition or disease in a mammal in need thereof comprising administering a therapeutically effective amount of one or more compounds of Claim 22.

58. The method of Claim 57, wherein the condition or disease is emphysema.

59. A method of preventing or treating a pulmonary insufficiency condition or disease in a mammal in need thereof comprising administering a therapeutically effective amount of one or more compounds of Claim 32.

60. The method of Claim 59, wherein the condition or disease is emphysema.

61. A method of preventing or treating a pulmonary insufficiency condition or disease in a mammal in need thereof comprising administering a therapeutically effective amount of one or more compounds of Claim 41.

62. The method of Claim 61, wherein the condition or disease is emphysema.

63. A method of preventing or treating a pulmonary insufficiency condition or disease in a mammal in need thereof comprising administering a

therapeutically effective amount of one or more compounds of Claim 44.

64. The method of Claim 63, wherein the condition or disease is emphysema.

65. A method of preventing or treating a pulmonary insufficiency condition or disease in a mammal in need thereof comprising administering a

therapeutically effective amount of one or more compounds of Claim 48.

66. The method of Claim 65, wherein the condition or disease is emphysema.

67. A method of preventing or treating a pulmonary insufficiency condition or disease in a mammal in need thereof comprising administering a

therapeutically effective amount of one or more compounds of Claim 52.

68. The method of Claim 67, wherein the condition or disease is emphysema.

69. A method of preventing or treating a disease or condition that is responsive to treatment with an RARγ agonist in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of one or more compounds in accordance with Claim 1.

70. The method of Claim 69, wherein the disease or condition is a skin disease or condition.

71. The method of Claim 70 wherein the diseases or condition is acne or

psoriasis.