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1. (WO1985002540) ANALGESIC AND ANTI-INFLAMMATORY COMPOSITIONS COMPRISING XANTHINES AND METHODS OF USING SAME
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Claims
1. A pharmaceutical composition of matter adapted to elicit an onset hastened and enhanced analgesic and anti-inflammatory response in a mammalian organism in need of such treatment, said composition comprising an analgesically and anti-inflammatorily effective amount of an active drug component and an active drug potentiating adjuvant therefor, said active drug comprising ibuprofen, naproxen, fenoprofen, indoprofen, diflunisal or pharmaceutically acceptable salts thereof and said adjuvant comprising an active drug analgesic and anti-inflammatory onset hastening and enhancing amount of a xanthine derivative of the formula


or a pharmaceutically acceptable non-toxic salt thereof wherein
R1-R3, inclusive, independently represent
hydrogen, C1-C6alkyl, C1-C6alkoxy,
C1-C6haloalkyl, C3-C6cycloalkyl, hydroxy
(C1-C6) alkyl, halogen, hydroxy(C1-C4) - alkylamino(C1-C4) alkyl, C1-C4(dialkyl) amino- (C1-C4) alkyl, C1-C4alkylcarbonyl(C1-C4) alkyl,
C1-C6alkylamino, C1-C6 (dialkyl) amino, indolyl,
phenyl or allyl;

R4 is hydrogen, C1-C6alkyl, halo (C1-C6) alkyl,
C1-C6alkylamino, C1-C6alkylthio, nitro, carboxy
C1-C6 (dialkyl) amino, C3-C6Cycloalkyl,
phenyl, naphthyl, ar(C1-C4)alkyl, or a
group of the formula

where R5 is halo, C1-C6alkyl, C1-C6alkoxy,
C1-C6alkylthio, nitro or C1-C6alkylamino
and n is 1, 2 or 3, with the proviso that R1, R2 and R3 cannot all be methyl when R4 is hydrogen.

2. A composition according to Claim 1, wherein said active drug is ibuprofen or a pharmaceutically acceptable salt thereof.

3. A composition according to Claim 1, wherein said active drug is naproxen or a pharmaceutically acceptable salt thereof.

4. A composition according to Claim 1, wherein said active drug is fenoprofen or a pharmaceutically acceptable salt thereof.

5. A composition according to Claim 1, wherein said active drug is indoprofen or a pharmaceutically acceptable salt thereof.

6. A composition according to Claim 1, wherein said active drug is diflunisal or a pharmaceutically acceptable salt thereof.

7. The xanthine derivative of the composition according to Claim 1, wherein R1, R2 and R3 represent

C1-C6alkyl, halo (C1-C6) alkyl, C1-C4 (dialkyl) amino
(C1-C4) alkyl or hydroxy (C1-C6) alkyl and R4 represents C1-C6 (dialkyl) amino,C1-C6alkylthio, phenyl or the group of formula (II).

8. The xanthine derivative according to
Claims 1 or 7, wherein R1 and R2 are the same and represent C1-C6 alkyl, R3 represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halo (C1-C6) alkyl and R4 represents hydrogen, C1-C6 alkylthio, C1-C6 alkylamino or phenyl.

9. The xanthine derivative according to
Claims 1 or 7, wherein R1 represents hydrogen, R2 and R3 represent C1-C6 alkyl, and R4 represents hydrogen, C1-C6 alkyl, halo (C1-C6) alkyl, phenyl or the group of formula (II) .

10. The xanthine derivative according to
Claims 1 or 7, wherein R1 and R2 are the same and represent C1-C6 alkyl, R3 is hydrogen and R4 represents halo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylthio, nitro, C1-C6 alkylamino, C1-C6 (dialkyl) amino, ar(C1-C4) alkyl, phenyl or the group of formula (II) .

11. The xanthine derivative according to
Claims 1 or 7, wherein R1 and R2 represent hydrogen, methyl, ethyl, propyl, butyl, isobutyl, propenyl or isopropenyl, R3 represents hydrogen, methyl, ethyl, butyl, 2-haloethyl, or 2-hydroxyethyl and R4 represents hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, methylthio, ethylthio, nitro, methylamino, dimethylamino, phenyl, naphtfayl, halophenyl, methoxy, phenyl, nitrophenyl, dimethylaminophenyl, dichlorophenyl or hydroxy phenyl.

12. The xanthine derivative of the composition according to Claim 1, wherein said derivative is 8-phenyl-1,3-dimethyIxanthine.

13. The xanthine derivative of the composition according to Claim 1, wherein said derivative is 8-phenyl-1,3,-diethylxanthine.

14. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-methylthio-1,3-dimethyl xanthine.

15. The xanthine derivative of the composition according to Claim 12, wherein said derivative is
8-methylamino-1,3-dimethyl xanthine.

16. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-dimethylamino-1,3-dimethyl xanthine.

17. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-methyl-1,3-dimethyl xanthine.

18. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-ethyl-1,3-dimethyl xanthine.

19. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-propyl-1,3-dimethyl xanthine.

20. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-cyclopropyl-1,3-dimethyl xanthine.

21. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-cyclopentyl-1,3-dimethyl xanthine.

22. The xanthine derivative of the composition according to claim 1, wherein said derivative is
8-(chlorophenyl)-1,3-dimethyl xanthine.

23. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-(bromophenyl)-1,3-dimethyl xanthine.

24. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-(methoxyphenyl)-1,3-dimethyl xanthine.

25. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-(nitrophenyl)-1,3-dimethyl xanthine.

26. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-(dimethylaminophenyl)-1,3-dimethyl xanthine.

27. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-(2,6-dimethyl-4-hydroxyphenyl)-1,3-dimethyl xanthine.

28. The xanthine derivative of the composition according to Claim 1, wherein said derivative is xanthine.

29. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
3,7-dimethyl xanthine.

30. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-phenyl-1-methyl xanthine.

31. The xanthine derivative of the composition according to claim 1, wherein said derivative is
1,7-dimethyl xanthine.

32. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1-methyl xanthine.

33. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1,3-dimethyl xanthine.

34. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
8-ethyl-1,3,7-trimethyl xanthine.

35. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
7-methoxy-8-phenyl-1,3-dimethyl xanthine.

36. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1-methyl-3-isobutyl xanthine.

37. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1-ethyl-3,7-dimethyl xanthine.

38. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1,3-diethyl xanthine.

39. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1,3,7-triethyl xanthine.

40. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1,3-dipropyl xanthine.

41. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1,3-diallyl xanthine.

42. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1-butyl-3,7-dimethyl xanthine.

43. The xanthine derivative of the composition according to Claim 1, wherein said derivative is
1-hexyl-3,7-dimethyl xanthine.

44. A composition according to Claim 1, comprising from about 60 to 200 mg of said xanthine derivative.

45. A composition according to Claim 1, comprising from about 20 to 100 mg of said xanthine derivative.

46. A composition according to Claim 1, comprising from about 125 mg to 500 mg diflunisal and from about 65 to 150 mg of said xanthine derivative.

47. A composition according to Claim 1, comprising from about 50 to 400 mg ibuprofen.

48. A composition according to Claim 1, comprising from about 125 to about 500 mg naproxen and from about 65 to about 150 mg of said xanthine derivative in sustained release form.

49. A composition according to Claim 1, comprising from about 50 to about 200 mg fenoprofen.

50. A composition according to Claim 1, further comprising a nontoxie pharmaceutically acceptable inert carrier.

51. A composition according to claim 1, said composition being adapted for oral administration.

52. A composition according to Claim 1, said composition being adapted for rectal administration.

53. A composition according to Claim 1, said composition being formulated as a suppository.

54. A method of eliciting an onset hastened and enhanced analgesic and anti-inflammatory response in a mammalian organism in need of such treatment
comprising administering to such organisn an analgesically and anti-inflammatorily effective amount of a pharmaceutical composition of matter comprising an
analgesically and anti-inflammatorily effective amount of an active drug component and an active drug potentiating adjuvant therefor, said active drug comprising ibuprofen, naproxen, fenoprofen, indoprofen, diflunisal or pharmaceutically acceptable salts thereof and said adjuvant comprising an active drug analgesic and
anti-inflammatory onset hastening and enhancing amount of a xanthine derivative of the formula
or a pharmaceutically acceptable non-toxic salt thereof wherein
R1-R3, inclusive, independently represent
hydrogen, C1-C6alkyl, C1-C6alkoxy,
C1-C6haloalkyl, C3-C6Cycloalkyl, hydroxy
(C1-C6) alkyl, halogen, hydroxy(C1-C4) - alkylamino (C1-C4) alkyl, C1 -C4 (dialkyl) amino- (C1-C4) alkyl, C1-C4alkylcarbonyl (C1-C4) alkyl,
C1-C6alkylamino, C1-C6 (dialkyl) amino,
indolyl, phenyl or allyl;

R4 is hydrogen, C1-C6alkyl, halo (C1-C6) alkyl,
C1-C6alkylamino, C1-C6alkylthio, nitro, carboxy,
C1-C6 (dialkyl) amino, C3-C6cycloalkyl,
phenyl, naphthyl, ar(C1-C4) alkyl, or a
group of the formula



where R5 is halo, C1-C6alkyl, C1-C6alkoxy, C1-C6alkyl- this, nitro, or C1-C6alkylamino and n is 1, 2 or 3, with the proviso that R1, R2 and R3 cannot all be methyl when R4 is hydrogen.

55. A pharmaceutical composition of matter adapted to elicit an onset hastened and enhanced
analgesic and anti-inflammatory response in a mammalian organism in need of such treatment, said composition comprising:
(a) an analgesically effective amount of an
orally analgesically active narcotic analgesic drug or pharmaceutically acceptable
salt thereof;
(b) an analgesically and anti-inflammatorily
effective amount of a nonsteroidal anti- inflammatory active drug comprising
ibuprofen, naproxen, fenoprofen, indoprofen,
diflunisal or pharmaceutically acceptable
salts thereof; and
(c) an active drug potentiating adjuvant for
active drugs (a) and (b) , said adjuvant
comprising an active drug analgesic and
anti-inflammatory onset hastening and
enhancing amount of a xanthine derivative
of the formula

or a pharmaceutically acceptable non-toxic salt thereof wherein
R1-R3, inclusive, independently represent
hydrogen, C1-C6alkyl, C1-C6alkoxy,
C1-C6haloalkyl, C3-C6cycloalkyl, hydroxy
(C1-C6)alkyl, halogen, hydroxy(C1-C4)- alkylamino (C1-C4) alkyl, C1-C4 (dialkyl) amino- (C1-C4) alkyl, C1-C4alkylcarbonyl (C1-C4) alkyl,
C1-C6alkylamino, C1-C6 (dialkyl) amino, indolyl, pnenyl or allyl;

R4 is hydrogen, C1-C6alkyl, halo(C1-C6) alkyl,
C1-C6alkylamino, C1-C6alkylthio, nitro, carboxy,
C1-C6 (dialkyl) amino, C3-C6cycloalkyl,
phenyl, naphthyl, ar(C1-C4)alkyl, or a
group of the formula



where R5 is halo, C1-C6alkyl, C1-C6alkoxy, C1-C6alkyl-this, nitro, or C1-C6alkylamino and n is 1, 2 or 3,
with the proviso that R1, R2 and R3 cannot all be methyl when R4 is hydrogen.
56. The composition according to Claim 55, wherein said non steroidal anti-inflammatory active
drug (b) comprises ibuprofen, fenoprofen or diflunisal.

57. The composition according to Claim 55, wherein the narcotic analgesic is propiram fumarate.

58. The composition according to Claim 55, wherein the narcotic analgesic is buprenorphine
hydromorphone, oxycodone, nalbuphine, butorphanol or
meptazinol or an orally analgesically active pharmaceutically acceptable acid addition salt thereof.

59. The composition according to Claim 55, wherein the narcotic analgesic is propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, codeine sulfate or codeine phosphate.

60. The composition according to Claim 55, wherein the narcotic analgesic is pentazoeine hydrochloride, nalbuphine hydrochloride, butorphanol tartrate or
meptazinol hydrochloride.

61. The xanthine derivative of the composition according to Claim 55, wherein R1, R2 and R3 represent C1-C6alkyl, halo (C1-C6) alkyl, C1-C4(dialkyl) amino
(C1-C4) alkyl or hydroxy (C1-C6) alkyl and R4 represents C1-C6 (dialkyl) amino, C1-C6alkylthio, phenyl or the group of formual (II).

62. The xanthine derivative of the composition according to Claim 55, wherein R1 and R2 are the same and represent C1-C6 alkyl, R3 represents hydrogen,
C1-C6 alkyl, C1-C6 alkoxy or halo (C1-C6) alkyl and
R4 represents hydrogen, C1-C6 alkylthio, C1-C6 alkylamino or phenyl.

63. The xanthine derivative of the composition according to Claim 55, wherein R1 represents hydrogen, R2 and R3 represent C1-C6 alkyl, and R4 represents hydrogen, C1-C6 alkyl, halo (C1-C6) alkyl, phenyl or the group of formula (II) .

64. The xanthine derivative of the composition according to Claim 55, wherein R1 and R2 are the same and represent C1-C6 alkyl, R3 is hydrogen and R4 represents halo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkyl-thio, nitro, C1-C6 alkylamino, C1-C6 (dialkyl) amino, ar(C1-C4) alkyl, phenyl or the group of formula (II).

65. The xanthine derivative of the composition according to Claim 55, wherein R1 and R2 represent hydrogen, methyl, ethyl, propyl, butyl, isobutyl,
propenyl or isopropenyl, R3 represents hydrogen,
methyl, ethyl, butyl, 2-haloethyl, or 2-hydroxyethyl and R4 represents hydrogen, methyl, ethyl, propyl, cyelopropyl, cyclohexyl, methylthio, ethylthio, nitro, methylamino, dimethylamino, phenyl, naphthyl, halophenyl, methoxy, phenyl, nitrophenyl, dimethylaminophenyl, dichlorophenyl or hydroxy phenyl.

66. The xanthine derivative of the composition according to Claim 55, wherein said derivative is 8-phenyl-1,3-dimethyl xanthine.

67. The xanthine derivative of the composition according to Claim 55, wherein said derivative is

1,3-dimethyl xanthine.

68. The xanthine derivative of the composition according to Claim 55, wherein said derivative is 8-phenyl-1,3-diethyl xanthine.

69. The xanthine derivative of the composition according to Claim 55, wherein said derivative is 8-(p-bromophenyl)1,3-dimethyl xanthine.

70. A composition according to Claim 55, comprising from about 60 to 200 mg of said xanthine derivative.

71. A composition according to Claim 55, comprising from about 20 to about 100 mg of xanthine derivative.

72. A composition according to Claim 55, further comprising a nontoxic pharmaceutically acceptable inert carrier.

73. A composition according to Claim 55, said composition being adapted for oral administration.

74. A composition according to Claim 55, said composition being adapted for rectal administration.

75. A method of eliciting an onset hastened and enhanced analgesic and anti-inflammatory response in a mammalian organism in need of sueh treatment comprising administering the pharmaceutical composition of Claim 55 to such organism.