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Amidino compounds useful as nitric oxide synthase inhibitors

Imported: 25 Feb '17 | Published: 01 Jul '03

Ronald Keith Webber, Richard C. Durley, Alok K. Awasthi, Arija A. Bergmanis, Kam F. Fok, Scott S. Ganser, Timothy J. Hagen, E. Ann Hallinan, Donald W. Hansen, Jr., Brian S. Hickory, Pamela T. Manning, Michael Mao, Alan E. Moormann, Barnett S. Pitzele, Michelle A. Promo, et al.

USPTO - Utility Patents

Abstract

The present invention relates to amidino compounds and salts and prodrugs thereof. In another embodiment the present invention also provides a use of the present compounds in therapy, particular as nitric oxide synthase inhibitors. In a further embodiment, the present invention provides methods of making the amidino compounds.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, the compound having a structure corresponding to Formula 1:

wherein:

2. The compound of claim 1 wherein R

8 is —OH.

3. The compound of claim 2 wherein X is S.

4. The compound of claim 3 wherein R

3, R

4, R

11 and R

12 each is —H.

5. The compound of claim 4 wherein R

1, R

5, R

6, R

7, R

9, and R

10 independently are selected from the group consisting of —H and C

1-C

3 alkyl.

6. The compound of claim 5 wherein R

5, R

6, R

7, R

9, and R

10 each is —H.

7. The compound of claim 6 wherein R

13 is fluoromethyl.

8. The compound of claim 6 wherein R

13 is methyl.

9. The compound of claim 8 wherein R

2 is C

1-C

6 alkyl optionally substituted with a substituent selected from the group consisting of —OH, alkoxy, and halogen.

10. The compound of claim 9 wherein R

2 is C

1 alkyl optionally substituted with halogen.

11. The compound of claim 10 wherein R

2 is fluoromethyl.

12. The compound of claim 9 wherein R

2 is hydroxymethyl.

13. The compound of claim 9 wherein R

2 is methoxymethyl.

14. The compound of claim 8 wherein R

1 is selected from the group consisting of —H and C

1-C

6 alkyl optionally substituted with a substituent selected from the group consisting of —OH, alkoxy, and halogen.

15. The compound of claim 14 wherein R

1 is —H.

16. The compound of claim 14 wherein R

1 is C

1-C

6 alkyl optionally substituted with a substituent selected from the group consisting of alkoxy and halogen.

17. The compound of 16 wherein R

1 is ethyl.

18. The compound of claim 14 wherein R

1 is C

1 alkyl optionally substituted with a substituent selected from the group consisting of —OH, alkoxy, and halogen.

19. The compound of claim 18 wherein R

1 is methyl.

20. The compound of claim 18 wherein R

1 is fluoromethyl.

21. The compound of claim 18 wherein R

1 is hydroxymethyl.

22. The compound of claim 18 wherein R

1 is C

1-C

6 alkoxymethyl.

23. The compound of claim 18 wherein R

1 is C

1-C

6 methoxymethyl.

24. The compound of claim 1 wherein R

8 is —OR

14.

25. The compound of claim 24 wherein R

14 is C

1-C

6 alkyl optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl.

26. The compound of claim 25 wherein R

14 is C

1-C

3 alkyl.

27. The compound of claim 26 wherein R

14 is methyl.

28. The compound of claim 1 wherein R

8 is —N(R

15)(R

16).

29. The compound of claim 1 wherein R

8 is —N(R

20)—, and R

3 is —C(O)—, wherein R

8 and R

3 together with the atoms to which they are attached form a ring.

30. The compound of claim 1 wherein R

8 is —O—, and R

3 is —C(R

21)(R

22)—, wherein R

8 and R

3 together with the atoms to which they are attached form a ring.

31. The compound of claim 1 wherein R

11 is selected from the group consisting of —OH, —C(O)—O—R

24, and —C(O)—S—R

25.

32. The compound of claim 31 wherein R

11 is —OH.

33. The compound of claim 32 wherein R

12 is —H.

34. The compound of claim 1 wherein R

11 is —O—, and R

12 is —C(O)—, wherein R

11 and R

12 together with the atoms to which they are attached form a ring.

35. The compound of claim 1 wherein R

11 is —C(O)—, and R

12 is —O—, wherein R

11 and R

12 together with the atoms to which they are attached form a ring.

36. The compound of claim 1 wherein R

12 is selected from the group consisting of —OH, —C(O)—O—R

26, and —C(O)—S—R

27.

37. The compound of claim 36 wherein R

11 is —H.

38. The compound of claim 1 wherein the compound is in the form of a pharmaceutically-acceptable salt.

39. The pharmaceutically-acceptable salt of claim 38 having at least one anionic counterion.

40. The pharmaceutically-acceptable salt of claim 39 wherein the anionic counterion is selected from the group consisting of a halide, a carboxylate, a sulfonate, a sulfate, a phosphate, a phosphonate, a resin-bound anion, and a nitrate.

41. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is a halide.

42. The pharmaceutically-acceptable salt of claim 41 wherein the halide is chloride.

43. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is a carboxylate.

44. The pharmaceutically-acceptable salt of claim 43 wherein the carboxylate is selected from the group consisting of formate, acetate, propionate, trifluoroacetate, succinate, salicylate, DL-aspartate, D-aspartate, L-aspartate, DL-glutamate, D-glutamate, L-glutamate, glycerate, succinate, steric, DL-tartarate, D-tartarate, L-tartarate, (±)-mandelate, (R)-(−)-mandelate, (S)-(+)-mandelate, citrate, mucate, maleate, malonate, benzoate, DL-malate, D-malate, L-malate, hemi-malate, 1-adamantaneacetate, 1-adamantanecarboxylate, flavianate, sulfonoacetate, (+)-lactate, L-(+)-lactate, D-(−)-lactate, pamoate, D-alpha-galacturonate, glycerate, DL-cystate, D-cystate, L-cystate, DL-homocystate, D-homocystate, L-homocystate, DL-cysteate, D-cysteate, L-cysteate, (4S)-hydroxy-L-proline, cyclopropane-1,1-dicarboxylate, 2,2-dimethylmalonate, squarate, tyrosine anion, proline anion, fumarate, 1-hydroxy-2-naphthoate, phosphonoacetate, carbonate, bicarbonate, 3-phosphonopropionate, DL-pyroglutamate, D-pyroglutamate, and L-pyroglutamate.

45. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is a sulfonate.

46. The pharmaceutically-acceptable salt of claim 45 wherein the sulfonate is selected from the group consisting of methanesulfonate, toluenesulfonate, benzenesulfonate, trifluoromethylsulfonate, ethanesulfonate, (±)-camphorsulfonate, naphthalenesulfonate, 1R-(−)-camphorsulfonate, 1S-(+)-camphorsulfonate, 2-mesitylenesulfonate, 1,5-naphthalenedisulfonate, 1,2-ethanedisulfonate, 1,3-propanedisulfonate, 3-N-morpholino)propane sulfonate, biphenylsulfonate, isethionate, and 1-hydroxy-2-naphthalenesulfonate.

47. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is a sulfate.

48. The pharmaceutically-acceptable salt of claim 47 wherein the sulfate is selected from the group consisting of sulfate, monopotassium sulfate, monosodium sulfate, and hydrogen sulfate.

49. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is a phosphate.

50. The pharmaceutically-acceptable salt of claim 49 wherein the phosphate is selected from the group consisting of phosphate, dihydrogen phosphate, potassium hydrogen phosphate, dipotassium phosphate, potassium phosphate, sodium hydrogen phosphate, disodium phosphate, sodium phosphate, calcium phosphate, and hexafluorophosphate.

51. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is a phosphonate.

52. The pharmaceutically-acceptable salt of claim 51 wherein the phosphonate is selected from the group consisting of vinylphosphonate, 2-carboxyethylphosphonate and phenylphosphonate.

53. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is a resin-bound anion.

54. The pharmaceutically-acceptable salt of claim 53 wherein the resin-bound anion is selected from the group consisting of a resin comprising polyacrylate and a resin comprising sulfonated poly(styrene divinylbenzene).

55. The pharmaceutically-acceptable salt of claim 40 wherein the anionic counterion is nitrate.

56. The pharmaceutically-acceptable salt of claim 39 wherein the anion is selected from the group consisting of DL-ascorbate, D-ascorbate, and L-ascorbate.

57. The pharmaceutically-acceptable salt of claim 38 having at least one cationic counterion.

58. The pharmaceutically-acceptable salt of claim 57 wherein the cationic counterion is selected from the group consisting of an ammonium cation, a alkali metal cation, an alkaline earth metal cation, a transition metal cation, and a resin-bound cation.

59. The pharmaceutically-acceptable salt of claim 58 wherein the cationic counterion is an ammonium cation.

60. The pharmaceutically-acceptable salt of claim 59 wherein the ammonium cation is selected from the group consisting of ammonium, methyl ammonium, dimethylammonium, trimethylammonium, tetramethylammonium, ethanolammonium, dicyclohexylammonium, guanidinium, and ethylenediammonium cation.

61. The pharmaceutically-acceptable salt of claim 58 wherein the cationic counterion is an alkali metal cation.

62. The pharmaceutically-acceptable salt of claim 61 wherein the alkali metal cation is selected from the group consisting of lithium cation, sodium cation, potassium cation, and cesium cation.

63. The pharmaceutically-acceptable salt of claim 58 wherein the cationic counterion is an alkaline earth metal cation.

64. The pharmaceutically-acceptable salt of claim 63 wherein the alkaline earth metal cation is selected from the group consisting of beryllium cation, magnesium cation, and calcium cation.

65. The pharmaceutically-acceptable salt of claim 58 wherein the cationic counterion is a transition metal cation.

66. The pharmaceutically-acceptable salt of claim 65 wherein the transition metal cation is a zinc cation.

67. The pharmaceutically-acceptable salt of claim 58 wherein the cationic counterion is a resin-bound cation.

68. The pharmaceutically-acceptable salt of claim 67 wherein the resin-bound cation is a cationically functionalized poly(styrene divinylbenzene) resin.

69. The pharmaceutically-acceptable salt of claim 68 wherein the resin-bound cation is an aminated poly(styrene divinylbenzene) resin.

70. The pharmaceutically-acceptable salt of claim 67 wherein the resin-bound cation is a canonically functionalized polyacrylic resin.

71. The pharmaceutically-acceptable salt of claim 67 wherein the resin-bound cation is an aminated polyacrylic resin.

72. S-[(1S)-2-[(1-Iminoethyl)amino]-1-methylethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

73. S-[(1R/S)-2-[(1-Iminoethyl)amino]-1-ethylethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

74. S-[(1S)-2-[(1-iminoethyl)amino]-1-(fluoromethyl)ethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

75. S-[2-[(1-Iminoethyl)amino]ethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

76. S-[(1R)-2-[(1Iminoethyl)amino]-1-methylethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

77. S-[(1R)-2-[(1-Iminoethyl)amino]-1-methylethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

78. S-[(1R/S)-2-[(1-Iminoethyl)amino]-1-ethylethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

79. S-[(1S)-2-[(1-Iminoethyl)amino]-1-fluoromethylethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

80. 2-[[[2-(1-Iminoethyl)amino]ethyl]thio]methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

81. 2-[[[(1R)-2-[(1-Iminoethyl)amino]-1-methylethyl]thio]-methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

82. 2-[[[(1R/S)-2-(1-Iminoethyl)amino)-1-ethylethyl]-thio]methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

83. 2-[[[(1S)-2-[(1-Iminoethyl)amino]-1-fluoromethylethyl]-thio]methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

84. S-[(R/S)-2-[(1-Iminoethyl)amino]-1-(trifluoromethyl)ethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

85. S-[2-(1-Iminoethylamino)ethyl]-2-methyl-(D/L)-cysteine, or a pharmaceutically acceptable salt thereof.

86. S-[2-[(1-Iminoethyl)amino]ethyl]-2-fluoromethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

87. (2R)-2-Amino-3-[[2-[(1-iminoethyl)amino]ethylsulfinyl]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.

88. (2R)-2-Amino-3-[[2-[(1-iminoethyl)amino]ethyl]sulfonyl]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.

89. N-{4-Chlorophenyl)methylene]—S—[2-[[(4-chlorophenyl)methylene]amino]ethyl]-L-cysteine, methyl ester.

90. N-[4-Chlorophenyl)methylene]—S—[2-[[(4-chlorophenyl)methylene]amino]ethyl]-2-methyl-D/L-cysteine, methyl ester.

91. A method for the treatment or prevention of an inflammation-related disorder wherein the method comprises treating a subject in need thereof with an inflammation-related disorder-treating or preventing amount of a compound or a pharmaceutically acceptable salt thereof, the compound having a structure corresponding to Formula 1:

wherein:

92. The method of claim 91 wherein the compound is 2-[[[2-[(1-iminoethyl) amino]ethyl]thio]methyl]—O—methyl-D-serine, or a pharmaceutically acceptable salt thereof.

93. The method of claim 91 wherein the compound is S-[(1S)-2-[(1-iminoethyl)amino]-1-methylethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

94. The method of claim 91 wherein the compound is S-[(1R/S)-2-[(1-iminoethyl) amino]-1-ethylethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

95. The method of claim 91 wherein the compound is S-[(1S)-2-[(1-iminoethyl)amino]-1-(fluoromethyl) ethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

96. The method of claim 91 wherein the compound is S-[2-[(1-iminoethyl)amino]ethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

97. The method of claim 91 wherein the compound is S-[(1R)-2-[(1-iminoethyl)amino]-1-methylethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

98. The method of claim 91 wherein the compound is S-[(1R)-2-[(1-iminoethyl)amino]-1-methylethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

99. The method of claim 91 wherein the compound is S-[(1R/S)-2-[(1-iminoethyl)amino]-1-ethylethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

100. The method of claim 91 wherein the compound is S-[(1S)-2-[(1-iminoethyl)amino]-1-fluoromethylethyl]-2-ethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

101. The method of claim 91 wherein the compound is 2-[[[2-(1-iminoethyl)amino]ethyl]thio]methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

102. The method of claim 91 wherein the compound is 2-[[[(1R)-2-[(1-iminoethyl) amino]-1-methylethyl]thio]-methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

103. The method of claim 91 wherein the compound is 2-[[[(1R/S)-2-(1-iminoethyl)amino)-1-ethylethyl]-thio]methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

104. The method of claim 91 wherein the compound is 2-[[[(1S)-2-[(1-iminoethyl) amino]-1-fluoromethylethyl]-thio]methyl]-D-valine, or a pharmaceutically acceptable salt thereof.

105. The method of claim 91 wherein the compound is S-[(R/S)-2-[(1-iminoethyl)amino]-1-(trifluoromethyl) ethyl]-2-methyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

106. The method of claim 91 wherein the compound is S-[2-[(1-iminoethyl)amino]ethyl]-2-fluoromethyl-L-cysteine, or a pharmaceutically acceptable salt thereof.

107. The method of claim 91 wherein the compound is (2R)-2-amino-3-[[2-[(1-iminoethyl) amino]ethyl]sulfinyl]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.

108. The method of claim 91 wherein the compound is (2R)-2-amino-3-[[2-[(1-iminoethyl) amino]ethyl]sulfonyl]-2-methylpropanoic acid, or a pharmaceutically acceptable salt thereof.