U.S. patent application number 10/978817 was filed with the patent office on 2005-05-26 for 2-amino-2-alkyl-5 heptenoic and heptynoic acid derivatives useful as nitric oxide synthase inhibitors.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Bergmanis, Arija A., Grapperhaus, Margaret, Hagen, Timothy J., Hallinan, E. Ann, Hansen, Donald W. JR., Kramer, Steven W., Massa, Mark A., Pitzele, Barnett S., Sikorski, James, Wang, Lijuan Jane, Webber, Ronald Keith.
Application Number | 20050113451 10/978817 |
Document ID | / |
Family ID | 22874118 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050113451 |
Kind Code |
A1 |
Hansen, Donald W. JR. ; et
al. |
May 26, 2005 |
2-amino-2-alkyl-5 heptenoic and heptynoic acid derivatives useful
as nitric oxide synthase inhibitors
Abstract
The present invention relates to 2-amino-2-alkyl-5 heptenoic and
heptynoic acid derivatives and their use in therapy, in particular
their use as nitric oxide synthase inhibitors.
Inventors: |
Hansen, Donald W. JR.;
(Skokie, IL) ; Webber, Ronald Keith; (St. Charles,
MO) ; Pitzele, Barnett S.; (Skokie, IL) ;
Sikorski, James; (Atlanta, GA) ; Massa, Mark A.;
(Ballwin, MO) ; Hagen, Timothy J.; (Gurnee,
IL) ; Grapperhaus, Margaret; (Troy, IL) ;
Wang, Lijuan Jane; (Wildwood, MO) ; Bergmanis, Arija
A.; (Des Plaines, IL) ; Kramer, Steven W.;
(Des Plaines, IL) ; Hallinan, E. Ann; (Evanston,
IL) |
Correspondence
Address: |
PHARMACIA CORPORATION of PFIZER INC.
Corporate Patent Department
P.O. Box 1027
Chesterfield
MO
63006
US
|
Assignee: |
Pharmacia Corporation
St. Louis
MO
|
Family ID: |
22874118 |
Appl. No.: |
10/978817 |
Filed: |
November 1, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10978817 |
Nov 1, 2004 |
|
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09953049 |
Sep 15, 2001 |
|
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60232683 |
Sep 15, 2000 |
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Current U.S.
Class: |
514/565 ;
562/439 |
Current CPC
Class: |
A61P 19/02 20180101;
C07F 7/1804 20130101; A61P 43/00 20180101; C07C 271/22 20130101;
C07C 259/14 20130101; A61P 1/04 20180101; A61P 25/28 20180101; C07C
229/30 20130101; A61P 9/00 20180101; A61P 9/10 20180101; A61P 37/00
20180101; A61P 27/06 20180101; A61P 17/02 20180101; C07C 257/14
20130101; C07D 413/06 20130101; A61P 21/04 20180101; A61P 19/00
20180101; A61P 11/06 20180101; C07D 271/07 20130101; A61P 1/16
20180101; C07B 2200/09 20130101; A61P 17/06 20180101; A61P 3/10
20180101; A61P 1/02 20180101; A61P 19/08 20180101; A61P 25/06
20180101; C07B 2200/07 20130101; A61P 27/02 20180101; A61P 11/00
20180101; A61P 35/00 20180101; A61P 25/04 20180101; A61P 29/00
20180101 |
Class at
Publication: |
514/565 ;
562/439 |
International
Class: |
A61K 031/198; C07C
291/00 |
Claims
What is claimed:
1. A compound of Formula I: 157or a pharmaceutically acceptable
salt thereof, wherein: R.sup.1 is selected from the group
consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo.
2. The compound of claim 1 wherein the compound is the Z
isomer.
3. The compound of claim 2 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy.
4. The compound of claim 3 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by fluorine or
alkoxy.
5. The compound of claim 3 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl; said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy.
6. The compound of claim 3 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl
optionally substituted by fluorine.
7. The compound of claim 3 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
8. The compound of claim 3 wherein: R.sup.1 is hydrogen; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
9. The compound of claim 8 wherein: R.sup.1 is hydrogen; R.sup.2 is
selected from the group consisting of hydrogen and halo; and
R.sup.3 is C.sub.1-C.sub.3 alkyl.
10. The compound of claim 9 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and fluorine; and
R.sup.3 is C.sub.1-C.sub.3 alkyl.
11. The compound of claim 10 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and fluorine; and
R.sup.3 is methyl.
12. The compound of claim 11 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is methyl.
13. The compound of claim 11 wherein: R.sup.1 is hydrogen; R.sup.2
is fluorine; and R.sup.3 is methyl.
14. The compound of claim 3 wherein: R.sup.1 is halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
15. The compound of claim 14 wherein: R.sup.1 is halo; R.sup.2 is
halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
16. The compound of claim 15 wherein: R.sup.1 is fluorine; R.sup.2
is fluorine; and R.sup.3 is methyl.
17. The compound of claim 14 wherein: R.sup.1 is fluorine; R.sup.2
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
18. The compound of claim 17 wherein: R.sup.1 is fluorine; R.sup.2
is hydrogen; and R.sup.3 is methyl.
19. The compound of claim 3 wherein: R.sup.1 is methyl; R.sup.2 is
hydrogen; and R.sup.3 is methyl.
20. The compound of claim 3 wherein: R.sup.1 is hydrogen; R.sup.2
is methyl; and R.sup.3 is methyl.
21. The compound of claim 3 wherein: R.sup.1 is methyl; R.sup.2 is
methyl; and R.sup.3 is methyl.
22. The compound of claim 2 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy or one or
more fluorine; R.sup.2 is selected from the group consisting of
hydrogen, halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by one or more alkoxy or
halo.
23. The compound of claim 22 wherein: R.sup.1 is selected from the
group consisting of hydrogen and fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
24. The compound of claim 23 wherein: R.sup.1 is hydrogen; R.sup.2
is CH.sub.2F; and R.sup.3 is methyl.
25. The compound of claim 22 wherein: R.sup.1 is CH.sub.2F; R.sup.2
is hydrogen; and R.sup.3 is methyl.
26. The compound of claim 22 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is CH.sub.2F.
27. The compound of claim 22 wherein: R.sup.1 is hydrogen; R.sup.2
is methoxymethyl; and R.sup.3 is methyl.
28. The compound of claim 22 wherein: R.sup.1 is methoxymethyl;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
29. The compound of claim 22 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is methoxymethyl.
30. The compound of claim 1 wherein the compound is the E
isomer.
31. The compound of claim 30 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by one or more halo or
alkoxy.
32. The compound of claim 31 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl; said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy.
33. The compound of claim 31 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl
optionally substituted by fluorine.
34. The compound of claim 31 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by fluorine or
alkoxy.
35. The compound of claim 31 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
36. The compound of claim 31 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
37. The compound of claim 36 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and halo; and
R.sup.3 is C.sub.1-C.sub.3 alkyl.
38. The compound of claim 37 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and fluorine; and
R.sup.3 is C.sub.1-C.sub.3 alkyl.
39. The compound of claim 38 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and fluorine; and
R.sup.3 is methyl.
40. The compound of claim 39 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is methyl.
41. The compound of claim 39 wherein: R.sup.1 is hydrogen; R.sup.2
is fluorine; and R.sup.3 is methyl.
42. The compound of claim 31 wherein: R.sup.1 is halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
43. The compound of claim 42 wherein: R.sup.1 is halo; R.sup.2 is
halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
44. The compound of claim 39 wherein: R.sup.1 is fluorine; R.sup.2
is fluorine; and R.sup.3 is methyl.
45. The compound of claim 42 wherein: R.sup.1 is fluorine; R.sup.2
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
46. The compound of claim 45 wherein: R.sup.1 is fluorine; R.sup.2
is hydrogen; and R.sup.3 is methyl.
47. The compound of claim 31 wherein: R.sup.1 is methyl; R.sup.2 is
hydrogen; and R.sup.3 is methyl.
48. The compound of claim 31 wherein: R.sup.1 is hydrogen; R.sup.2
is methyl; and R.sup.3 is methyl.
49. The compound of claim 31 wherein: R.sup.1 is methyl; R.sup.2 is
methyl; and R.sup.3 is methyl.
50. The compound of claim 30 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy or one or
more fluorine; R.sup.2 is selected from the group consisting of
hydrogen, halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by alkoxy or one or more
halo.
51. The compound of claim 50 wherein: R.sup.1 is selected from the
group consisting of hydrogen and fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
52. The compound of claim 51 wherein: R.sup.1 is hydrogen; R.sup.2
is CH.sub.2F; and R.sup.3 is methyl.
53. The compound of claim 50 wherein: R.sup.1 is CH.sub.2F; R.sup.2
is hydrogen; and R.sup.3 is methyl.
54. The compound of claim 50 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is CH.sub.2F.
55. The compound of claim 50 wherein: R.sup.1 is hydrogen; R.sup.2
is methoxymethyl; and R.sup.3 is methyl.
56. The compound of claim 50 wherein: R.sup.1 is methoxymethyl;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
57. The compound of claim 50 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is methoxymethyl.
58. A compound of Formula II 158or a pharmaceutically acceptable
salt thereof, wherein: R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo.
59. The compound of claim 58 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl substituted by one or more halo.
60. The compound of claim 59 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl substituted by one or more fluorine.
61. The compound of claim 59 wherein: R.sup.3 is methyl substituted
by one or more halo.
62. The compound of claim 61 wherein: R.sup.3 is methyl substituted
by one or more fluorine.
63. The compound of claim 61 wherein: R.sup.3 is CH.sub.2F.
64. The compound recited in claim 59 wherein: R.sup.3 is
C.sub.1-C.sub.5 alkyl substituted by alkoxy.
65. The compound of claim 64 wherein: R.sup.3 is methoxy
methyl.
66. The compound of claim 59 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl.
67. The compound of claim 65 wherein: R.sup.3 is methyl.
68. A compound of Formula III 159or a pharmaceutically acceptable
salt thereof, wherein: R.sup.1 is selected from the group
consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo.
69. The compound of claim 68 wherein the compound is the Z
isomer.
70. The compound of claim 69 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by one or more halo or
alkoxy.
71. The compound of claim 69 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl; said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy
72. The compound of claim 69 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl
optionally substituted by fluorine.
73. The compound of claim 70 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by fluorine or
alkoxy.
74. The compound of claim 70 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
75. The compound of claim 70 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
76. The compound of claim 75 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and halo; and
R.sup.3 is C.sub.1-C.sub.3 alkyl.
77. The compound of claim 76 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and fluorine; and
R.sup.3 is C.sub.1-C.sub.3 alkyl.
78. The compound of claim 77 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen and fluorine; and
R.sup.3 is methyl.
79. The compound of claim 78 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is methyl.
80. The compound of claim 78 wherein: R.sup.1 is hydrogen; R.sup.2
is fluorine; and R.sup.3 is methyl.
81. The compound of claim 70 wherein: R.sup.1 is halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
82. The compound of claim 81 wherein: R.sup.1 is halo; R.sup.2 is
halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
83. The compound of claim 82 wherein: R.sup.1 is fluorine; R.sup.2
is fluorine; and R.sup.3 is methyl.
84. The compound of claim 81 wherein: R.sup.1 is fluorine; R.sup.2
is selected from the group consisting of hydrogen and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
85. The compound of claim 84 wherein: R.sup.1 is fluorine; R.sup.2
is hydrogen; and R.sup.3 is methyl.
86. The compound of claim 70 wherein: R.sup.1 is methyl; R.sup.2 is
hydrogen; and R.sup.3 is methyl.
87. The compound of claim 70 wherein: R.sup.1 is hydrogen; R.sup.2
is methyl; and R.sup.3 is methyl.
88. The compound of claim 70 wherein: R.sup.1 is methyl; R.sup.2 is
methyl; and R.sup.3 is methyl.
89. The compound of claim 69 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy or one or
more fluorine; R.sup.2 is selected from the group consisting of
hydrogen, halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by one or more alkoxy or
halo.
90. The compound of claim 89 wherein: R.sup.1 is selected from the
group consisting of hydrogen and fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
91. The compound of claim 90 wherein: R.sup.1 is hydrogen; R.sup.2
is CH.sub.2F; and R.sup.3 is methyl.
92. The compound of claim 89 wherein: R.sup.1 is CH.sub.2F; R.sup.2
is hydrogen; and R.sup.3 is methyl.
93. The compound of claim 89 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is CH.sub.2F.
94. The compound of claim 89 wherein: R.sup.1 is hydrogen; R.sup.2
is methoxymethyl; and R.sup.3 is methyl.
95. The compound of claim 89 wherein: R.sup.1 is methoxymethyl;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
96. The compound of claim 89 wherein: R.sup.1 is hydrogen; R.sup.2
is hydrogen; and R.sup.3 is methoxymethyl.
97. The compound of claim 68 wherein the compound is the E
isomer.
98. The compound of claim 97 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by one or more halo or
alkoxy.
99. The compound of claim 98 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl; said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy
100. The compound of claim 98 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl
optionally substituted by fluorine.
101. The compound of claim 98 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by one or more
fluorine or alkoxy.
102. The compound of claim 98 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
103. The compound of claim 98 wherein: R.sup.1 is hydrogen; R.sup.2
is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
104. The compound of claim 103 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and halo;
and R.sup.3 is C.sub.1-C.sub.3 alkyl.
105. The compound of claim 104 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and
fluorine; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
106. The compound of claim 105 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and
fluorine; and R.sup.3 is methyl.
107. The compound of claim 106 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
108. The compound of claim 106 wherein: R.sup.1 is hydrogen;
R.sup.2 is fluorine; and R.sup.3 is methyl.
109. The compound of claim 98 wherein: R.sup.1 is halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
110. The compound of claim 109 wherein: R.sup.1 is halo; R.sup.2 is
halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
111. The compound of claim 110 wherein: R.sup.1 is fluorine;
R.sup.2 is fluorine; and R.sup.3 is methyl.
112. The compound of claim 109 wherein: R.sup.1 is fluorine;
R.sup.2 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
113. The compound of claim 112 wherein: R.sup.1 is fluorine;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
114. The compound of claim 98 wherein: R.sup.1 is methyl; R.sup.2
is hydrogen; and R.sup.3 is methyl.
115. The compound of claim 98 wherein: R.sup.1 is hydrogen; R.sup.2
is methyl; and R.sup.3 is methyl.
116. The compound of claim 98 wherein: R.sup.1 is methyl; R.sup.2
is methyl; and R.sup.3 is methyl.
117. The compound of claim 97 wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy or one or
more fluorine; R.sup.2 is selected from the group consisting of
hydrogen, halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by one or more alkoxy or
halo.
118. The compound of claim 117 wherein: R.sup.1 is selected from
the group consisting of hydrogen and fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
119. The compound of claim 118 wherein: R.sup.1 is hydrogen;
R.sup.2 is CH.sub.2F; and R.sup.3 is methyl.
120. The compound of claim 117 wherein: R.sup.1 is CH.sub.2F;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
121. The compound of claim 117 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is CH.sub.2F.
122. The compound of claim 117 wherein: R.sup.1 is hydrogen;
R.sup.2 is methoxymethyl; and R.sup.3 is methyl.
123. The compound of claim 117 wherein: R.sup.1 is methoxymethyl;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
124. The compound of claim 117 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is methoxymethyl.
125. A compound of Formula IV 160or a pharmaceutically acceptable
salt thereof, wherein: R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo.
126. The compound of claim 125 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl substituted by one or more halo.
127. The compound of claim 126 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl substituted by one or more fluorine.
128. The compound of claim 126 wherein: R.sup.3 is methyl
substituted by one or more halo.
129. The compound of claim 128 wherein: R.sup.3 is methyl
substituted by one or more fluorine.
130. The compound of claim 128 wherein: R.sup.3 is CH.sub.2F.
131. The compound recited in claim 126 wherein: R.sup.3 is
C.sub.1-C.sub.5 alkyl substituted by alkoxy.
132. The compound of claim 131 wherein: R.sup.3 is methoxy
methyl.
133. The compound of claim 126 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl.
134. The compound of claim 132 wherein: R.sup.3 is methyl.
135. A compound of Formula V 161or a pharmaceutically acceptable
salt thereof, wherein: R.sup.1 is selected from the group
consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo.
136. The compound of claim 135 wherein the compound is the Z
isomer.
137. The compound of claim 136 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy.
138. The compound of claim 137 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy
139. The compound of claim 137 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl
optionally substituted by fluorine.
140. The compound of claim 136 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by fluorine or
alkoxy.
141. The compound of claim 137 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
142. The compound of claim 137 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
143. The compound of claim 142 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and halo;
and R.sup.3 is C.sub.1-C.sub.3 alkyl.
144. The compound of claim 143 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and
fluorine; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
145. The compound of claim 144 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and
fluorine; and R.sup.3 is methyl.
146. The compound of claim 145 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
147. The compound of claim 145 wherein: R.sup.1 is hydrogen;
R.sup.2 is fluorine; and R.sup.3 is methyl.
148. The compound of claim 137 wherein: R.sup.1 is halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
149. The compound of claim 148 wherein: R.sup.1 is halo; R.sup.2 is
halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
150. The compound of claim 149 wherein: R.sup.1 is fluorine;
R.sup.2 is fluorine; and R.sup.3 is methyl.
151. The compound of claim 148 wherein: R.sup.1 is fluorine;
R.sup.2 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
152. The compound of claim 151 wherein: R.sup.1 is fluorine;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
153. The compound of claim 137 wherein: R.sup.1 is methyl; R.sup.2
is hydrogen; and R.sup.3 is methyl.
154. The compound of claim 137 wherein: R.sup.1 is hydrogen;
R.sup.2 is methyl; and R.sup.3 is methyl.
155. The compound of claim 137 wherein: R.sup.1 is methyl; R.sup.2
is methyl; and R.sup.3 is methyl.
156. The compound of claim 136 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy or one
or more fluorine; R.sup.2 is selected from the group consisting of
hydrogen, halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy
or one or more halo.
157. The compound of claim 156 wherein: R.sup.1 is selected from
the group consisting of hydrogen and fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
158. The compound of claim 157 wherein: R.sup.1 is hydrogen;
R.sup.2 is CH.sub.2F; and R.sup.3 is methyl.
159. The compound of claim 156 wherein: R.sup.1 is CH.sub.2F;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
160. The compound of claim 159 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is CH.sub.2F.
161. The compound of claim 159 wherein: R.sup.1 is hydrogen;
R.sup.2 is methoxymethyl; and R.sup.3 is methyl.
162. The compound of claim 156 wherein: R.sup.1 is methoxymethyl;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
163. The compound of claim 156 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is methoxymethyl.
164. The compound of claim 135 wherein the compound is the E
isomer.
165. The compound of claim 164 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by one or more halo or
alkoxy.
166. The compound of claim 165 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy
167. The compound of claim 165 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl
optionally substituted by fluorine.
168. The compound of claim 165 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by fluorine or
alkoxy.
169. The compound of claim 165 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.3 alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
170. The compound of claim 165 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
171. The compound of claim 170 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and halo;
and R.sup.3 is C.sub.1-C.sub.3 alkyl.
172. The compound of claim 171 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and
fluorine; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
173. The compound of claim 172 wherein: R.sup.1 is hydrogen;
R.sup.2 is selected from the group consisting of hydrogen and
fluorine; and R.sup.3 is methyl.
174. The compound of claim 172 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
175. The compound of claim 173 wherein: R.sup.1 is hydrogen;
R.sup.2 is fluorine; and R.sup.3 is methyl.
176. The compound of claim 165 wherein: R.sup.1 is halo; R.sup.2 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
177. The compound of claim 176 wherein: R.sup.1 is halo; R.sup.2 is
halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
178. The compound of claim 177 wherein: R.sup.1 is fluorine;
R.sup.2 is fluorine; and R.sup.3 is methyl.
179. The compound of claim 176 wherein: R.sup.1 is fluorine;
R.sup.2 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
180. The compound of claim 179 wherein: R.sup.1 is fluorine;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
181. The compound of claim 165 wherein: R.sup.1 is methyl; R.sup.2
is hydrogen; and R.sup.3 is methyl.
182. The compound of claim 165 wherein: R.sup.1 is hydrogen;
R.sup.2 is methyl; and R.sup.3 is methyl.
183. The compound of claim 165 wherein: R.sup.1 is methyl; R.sup.2
is methyl; and R.sup.3 is methyl.
184. The compound of claim 164 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy or one
or more fluorine; R.sup.2 is selected from the group consisting of
hydrogen, halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by one or more alkoxy or
halo.
185. The compound of claim 184 wherein: R.sup.1 is selected from
the group consisting of hydrogen and fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
186. The compound of claim 185 wherein: R.sup.1 is hydrogen;
R.sup.2 is CH.sub.2F; and R.sup.3 is methyl.
187. The compound of claim 185 wherein: R.sup.1 is CH.sub.2F;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
188. The compound of claim 184 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is CH.sub.2F.
189. The compound of claim 184 wherein: R.sup.1 is hydrogen;
R.sup.2 is methoxymethyl; and R.sup.3 is methyl.
190. The compound of claim 184 wherein: R.sup.1 is methoxymethyl;
R.sup.2 is hydrogen; and R.sup.3 is methyl.
191. The compound of claim 184 wherein: R.sup.1 is hydrogen;
R.sup.2 is hydrogen; and R.sup.3 is methoxymethyl.
192. A compound of Formula VI 162or a pharmaceutically acceptable
salt thereof, wherein: R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo.
193. The compound of claim 192 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl substituted by one or more halo.
194. The compound of claim 193 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl substituted by one or more fluorine.
195. The compound of claim 193 wherein: R.sup.3 is methyl
substituted by one or more halo.
196. The compound of claim 195 wherein: R.sup.3 is methyl
substituted by one or more fluorine.
197. The compound of claim 195 wherein: R.sup.3 is CH.sub.2F.
198. The compound recited in claim 193 wherein: R.sup.3 is
C.sub.1-C.sub.5 alkyl substituted by alkoxy.
199. The compound of claim 198 wherein: R.sup.3 is methoxy
methyl.
200. The compound of claim 193 wherein: R.sup.3 is C.sub.1-C.sub.5
alkyl.
201. The compound of claim 199 wherein: R.sup.3 is methyl.
202. A novel intermediate compound selected from:
163164165166167
203. A compound selected from the group consisting of:
(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid;
(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-hepteno-
ic acid;
(2R/S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-hep-
tenoic acid;
(2R/S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-
-heptenoic acid;
(2R/S,5Z)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amin-
o]-5-heptenoic acid;
(2R,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)am-
ino]-5-heptenoic acid;
(2S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)-
amino]-5-heptenoic acid;
(2S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-imino-
ethyl)amino]-5-heptenoic acid;
(2R,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-
-iminoethyl)amino]-5-heptenoic acid;
(2R/S,5Z)-2-amino-2-methyl-5,6-difluo-
ro-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2S,5Z)-2-amino-2-methyl-6-fl-
uoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2S,5Z)-2-amino-2-methyl-7-- [(1-iminoethyl)amino]-5-heptenoic
acid; (2S,5Z)-2-amino-2-methyl-7-[(1-imi-
noethyl)amino]-5-heptenoic acid;
(2R,5Z)-2-amino-2-methyl-7-[(1-iminoethyl- )amino]-5-heptenoic
acid; (2R/S,5E)-2-amino-2-methyl-7-[(1-iminoethyl)amin-
o]-5-heptenoic acid;
(2R/S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-hep- tynoic acid;
(2S,5E)-2-amino-2-ethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-he-
ptenoic acid;
(2S,5E)-2-amino-2-methoxymethyl-6-fluoro-7-[(1-iminoethyl)am-
ino]-5-heptenoic acid;
(2S,5E)-2-amino-2-fluoromethyl-6-fluoro-7-[(1-imino-
ethyl)amino]-5-heptenoic acid;
(2S,5E)-2-amino-2,5-dimethyl-6-fluoro-7-[(1-
-iminoethyl)amino]-5-heptenoic acid;
(2S,5Z)-2-amino-5-fluoromethyl-2-meth-
yl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2S,5E)-2-amino-2,6-dimethyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid;
(2S,5Z)-2-amino-6-fluoromethyl-2-methyl-5-fluoro-7-[(1-iminoethyl)a-
mino]-5-heptenoic acid;
(2S,5Z)-2-amino-2-ethyl-7-[(1-iminoethyl)amino]-5-- heptenoic acid;
(2S,5Z)-2-amino-2-methoxymethyl-7-[(1-iminoethyl)amino]-5--
heptenoic acid;
(2S,5Z)-2-amino-2-fluoromethyl-7-[(1-iminoethyl)amino]-5-h-
eptenoic acid;
(2S,5Z)-2-amino-2,5-dimethyl-7-[(1-iminoethyl)amino]-5-hept- enoic
acid;
(2S,5E)-2-amino-5-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino-
]-5-heptenoic acid;
(2S,5Z)-2-amino-2,6-dimethyl-7-[(1-iminoethyl)amino]-5- -heptenoic
acid; (2S,5E)-2-amino-6-fluoromethyl-2-methyl-7-[(1-iminoethyl)-
amino]-5-heptenoic acid;
(2S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-h- eptynoic acid;
(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-
-heptenoic acid, dihydrochloride;
(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1--
iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2R/S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2R/S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoeth-
yl)amino]-5-heptenoic acid, dihydrochloride;
(2R/S,5Z)-2-amino-2-methyl-5--
fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2R,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl-
)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-methyl-5,6-di-
fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2R,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2R/S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-imin-
oethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-methyl--
6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride;
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-hepte- noic
acid, dihydrochloride;
(2R,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amin- o]-5-heptenoic
acid, dihydrochloride; (2R/S,5E)-2-amino-2-methyl-7-[(1-imi-
noethyl)amino]-5-heptenoic acid, dihydrochloride;
(2R/S)-2-amino-2-methyl-- 7-[(1-iminoethyl)amino]-5-heptynoic acid,
dihydrochloride;
(2S,5E)-2-amino-2-ethyl-6-fluoro-7-[(-1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5E)-2-amino-2-methoxymethyl-6-fluoro-7-[(1-imi-
noethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5E)-2-amino-2-fluoro-
methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride;
(2S,5E)-2-amino-2,5-dimethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5Z)-2-amino-5-fluoromethyl-2-methyl-6-fluoro-7-
-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5E)-2-amino-2,6-dimethyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5Z)-2-amino-6-fluoromethyl-2-methyl-5-fluoro-7-
-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-ethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride;
(2S,5Z)-2-amino-2-methoxymethyl-7-[(1-iminoethyl)amino]--
5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-fluoromethyl-7-[(1-im-
inoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2,5-dim- ethyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5E)-2-amino-5-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-hepteno-
ic acid, dihydrochloride;
(2S,5Z)-2-amino-2,6-dimethyl-7-[(1-iminoethyl)am- ino]-5-heptenoic
acid, dihydrochloride; (2S,5E)-2-amino-6-fluoromethyl-2-m-
ethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
and (2S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptynoic acid,
dihydrochloride.
204. A novel intermediate compound selected from:
4-[(2E)-5-[[(1,1-dimethy-
lethyl)dimethylsilyl]oxy]-2-fluoro-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(-
4H)-one;
4-[(2E)-2-fluoro-5-hydroxy-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5-
(4H)-one;
4-[(2E)-2-fluoro-5-iodo-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4-
H)-one;
(3S,6R)-3-[(3E)-4-fluoro-5-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-y-
l)-3-pentenyl]-3,6-dihydro-3-methyl-6-(1-methylethyl)-5-phenyl-2H-1,4-oxaz-
in-2-one;
N-[(2E)-5-[(3S,6R)-3,6-dihydro-3-methyl-6-(1-methylethyl)-2-oxo--
5-phenyl-2H-1,4-oxazin-3-yl]-2-fluoro-2-pentenyl]ethanimidamide;
(5E)-2-amino-6-fluoro-2-methyl-7-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl-
)-5-heptenoic acid, methyl ester;
(2S,5E)-2-amino-6-fluoro-2-methyl-7-(3-m-
ethyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-heptenoic acid, methyl
ester;
(2S,5E)-2-amino-6-fluoro-7-[[(1E)-1-(hydroxyimino)ethyl]amino]-2-methyl-5-
-heptenoic acid;
(2S,5E)-2-amino-6-fluoro-7-[(1-iminoethyl)amino]-2-methyl-
-5-heptenoic acid, methyl ester;
(2R,5E)-2-amino-6-fluoro-2-methyl-7-(3-me-
thyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-heptenoic acid, methyl
ester;
(2R,5E)-2-amino-6-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-heptenoic
acid, ethyl ester;
(5E)-2-amino-6-fluoro-7-(3-methyl-5-oxo-1,2,4-oxadiazo-
l-4(5H)-yl)-5-heptenoic acid, methyl ester;
(5E)-2-[[(1Z)-(4-chlorophenyl)-
methylidene]amino]-6-fluoro-7-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5--
heptenoic acid, methyl ester;
(5E)-2-amino-6-fluoro-2-methyl-7-(3-methyl-5-
-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-heptenoic acid, methyl ester;
(5E)-2-amino-6-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-heptenoic
acid, methyl ester; Methyl
(5E)-7-[(tert-butoxycarbonyl)amino]-2-{[(1Z)-(2,4-di-
chlorophenyl)methylidene]amino}-5-fluoro-2-methylhept-5-enoate;
(5E)-2,7-diamino-5-fluoro-2-methyl-5-heptenoic acid, methyl ester,
dihydrochloride;
(5E)-2-amino-5-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-
-heptenoic acid, methyl ester, monohydrochloride;
(5Z)-2-[[(1E)-(2,4-dichl-
orophenyl)methylidene]amino]-7-[[(1,1-dimethylethoxy)carbonyl]amino]-5-flu-
oro-2-methyl-5-heptenoic acid, methyl ester;
(5Z)-2,7-diamino-5-fluoro-2-m- ethyl-5-heptenoic acid, methyl
ester, dihydrochloride;
(5Z)-2-amino-5-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-heptenoic
acid, methyl ester, dihydrochloride;
4-[(2Z)-5-hydroxy-2-pentenyl]-3-methyl-1,2- ,4-oxadiazol-5(4H)-one;
(3Z)-5-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-3- -pentenyl
ester, acetic acid, trifluoro-; 4-[(2Z)-5-[(2R,4S)-3-benzoyl-2-(-
1,1-dimethylethyl)-4-methyl-5-oxo-4-oxazolidinyl]-2-pentenyl]-3-methyl-1,2-
,4-oxadiazol-5(4H)-one;
3-Methyl-4-[5-(tetrahydro-pyran-2-yloxy)-pent-2-en-
yl]-4H-[1,2,4]oxadiazol-5-one;
4-(5-Hydroxy-pent-2-enyl)-3-methyl-4H-[1,2,- 4]oxadiazol-5-one;
Methanesulfonic acid 5-(3-methyl-5-oxo-[1,2,4]oxadiazol-
-4-yl)-pent-3-enyl ester;
4-(5-Iodo-pent-2-enyl)-3-methyl-4H-[1,2,4]oxadia- zol-5-one;
Rac-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-h-
ept-5-enoic acid methyl ester;
Rac-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2-
,4]oxadiazol-4-yl)-hept-5-enoic acid;
(2S,5Z)-2-Amino-2-methyl-7-(3-methyl-
-5-oxo-[1,2,4]oxadiazol-4-yl)-hept-5-enoic acid methyl ester;
(2S,5Z)-7-Acetimidoylamino-2-amino-2-methyl-hept-5-enoic acid
methyl ester, dihydrochloride hydrate;
(2S,5Z)-2-amino-7-[[(1E)-1-(hydroxyimino)-
ethyl]amino]-2-methyl-5-heptenoic acid;
4-[(2E)-5-[[(1,1-dimethylethyl)dim-
ethylsilyl]oxy]-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4H)-one;
4-[(2E)-5-hydroxy-2-pentenyl]-3-methyl-2,4-oxadiazol-5(4H)-one;
(5E)-2-[[(1E)-(3,4-dichlorophenyl)methylidene]amino]-2-methyl-7-(3-methyl-
-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-heptenoic acid, methyl ester;
(5E)-2-amino-2-methyl-7-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-hepte-
noic acid, methyl ester; and Methyl
(5E)-2-amino-7-(ethanimidoylamino)-2-m- ethylhept-5-enoate.
205. A pharmaceutical composition comprising at least one compound
selected from the group consisting of:
(2S,5E)-2-amino-2-methyl-6-fluoro--
7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2R,5E)-2-amino-2-methyl-6-fluor-
o-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2R/S,5E)-2-amino-2-methyl-6-f-
luoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2R/S,5E)-2-amino-2-methyl-
-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2R/S,5Z)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid;
(2R,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-hepteno-
ic acid;
(2S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-hepte-
noic acid;
(2S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-
-heptenoic acid;
(2R,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)am-
ino]-5-heptenoic acid;
(2R/S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-imino-
ethyl)amino]-5-heptenoic acid;
(2S,5Z)-2-amino-2-methyl-6-fluoro-7-[(1-imi-
noethyl)amino]-5-heptenoic acid;
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl- )amino]-5-heptenoic
acid; (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-
-5-heptenoic acid;
(2R,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-hept- enoic
acid;
(2R/S,5E)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid; (2R/S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptynoic
acid;
(2S,5E)-2-amino-2-ethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid;
(2S,5E)-2-amino-2-methoxymethyl-6-fluoro-7-[(1-iminoethyl)amino]-5--
heptenoic acid;
(2S,5E)-2-amino-2-fluoromethyl-6-fluoro-7-[(1-iminoethyl)a-
mino]-5-heptenoic acid;
(2S,5E)-2-amino-2,5-dimethyl-6-fluoro-7-[(1-iminoe-
thyl)amino]-5-heptenoic acid;
(2S,5Z)-2-amino-5-fluoromethyl-2-methyl-6-fl-
uoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2S,5E)-2-amino-2,6-dimethy-
l-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid;
(2S,5Z)-2-amino-6-fluoromethyl-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]--
5-heptenoic acid;
(2S,5Z)-2-amino-2-ethyl-7-[(1-iminoethyl)amino]-5-hepten- oic acid;
(2S,5Z)-2-amino-2-methoxymethyl-7-[(1-iminoethyl)amino]-5-hepten-
oic acid;
(2S,5Z)-2-amino-2-fluoromethyl-7-[(1-iminoethyl)amino]-5-hepteno-
ic acid;
(2S,5Z)-2-amino-2,5-dimethyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid;
(2S,5E)-2-amino-5-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-h-
eptenoic acid;
(2S,5Z)-2-amino-2,6-dimethyl-7-[(1-iminoethyl)amino]-5-hept- enoic
acid;
(2S,5E)-2-amino-6-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino-
]-5-heptenoic acid;
(2S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptyn- oic acid;
(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-hept-
enoic acid, dihydrochloride;
(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-imino-
ethyl)amino]-5-heptenoic acid, dihydrochloride;
(2R/S,5E)-2-amino-2-methyl-
-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride;
(2R/S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2R/S,5Z)-2-amino-2-methyl-5-fluoro-7-[(1-iminoeth-
yl)amino]-5-heptenoic acid, dihydrochloride;
(2R,5E)-2-amino-2-methyl-5-fl-
uoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoe-
thyl)amino]-5-heptenoic acid, dihydrochloride;
(2R,5Z)-2-amino-2-methyl-5,-
6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride;
(2R/S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-hepteno-
ic acid, dihydrochloride;
(2S,5Z)-2-amino-2-methyl-6-fluoro-7-[(1-iminoeth-
yl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-methyl-7-[(- 1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride;
(2R,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-hepte- noic
acid, dihydrochloride;
(2R/S,5E)-2-amino-2-methyl-7-[(1-iminoethyl)am- ino]-5-heptenoic
acid, dihydrochloride; (2R/S)-2-amino-2-methyl-7-[(1-imin-
oethyl)amino]-5-heptynoic acid, dihydrochloride;
(2S,5E)-2-amino-2-ethyl-6-
-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5E)-2-amino-2-methoxymethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-hepten-
oic acid, dihydrochloride;
(2S,5E)-2-amino-2-fluoromethyl-6-fluoro-7-[(1-i-
minoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5E)-2-amino-2,5-dimethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5Z)-2-amino-5-fluoromethyl-2-methyl-6-fluoro-7-
-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5E)-2-amino-2,6-dimethyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5Z)-2-amino-6-fluoromethyl-2-methyl-5-fluoro-7-
-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-ethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride;
(2S,5Z)-2-amino-2-methoxymethyl-7-[(1-iminoethyl)amino]--
5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2-fluoromethyl-7-[(1-im-
inoethyl)amino]-5-heptenoic acid, dihydrochloride;
(2S,5Z)-2-amino-2,5-dim- ethyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride;
(2S,5E)-2-amino-5-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-hepteno-
ic acid, dihydrochloride;
(2S,5Z)-2-amino-2,6-dimethyl-7-[(1-iminoethyl)am- ino]-5-heptenoic
acid, dihydrochloride; (2S,5E)-2-amino-6-fluoromethyl-2-m-
ethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, dihydrochloride;
and (2S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptynoic acid,
dihydrochloride.
206. A compound of Formula VII: 168or a pharmaceutically acceptable
salt thereof, wherein: R.sup.1 is selected from the group
consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is selected from the group
consisting of halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by halo or alkoxy, said alkoxy
optionally substituted by one or more halo.
207. The compound of claim 206 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is selected from the
group consisting of halo and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy.
208. The compound of claim 206 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen and halo; and
R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
209. The compound of claim 207 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo.
210. The compound of claim 209 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; `R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by one or
more halo
211. The compound of claim 208 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is halo.
212. The compound of claim 211 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is fluorine.
213. The compound of claim 210 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy, said alkoxy
optionally substituted by one or more halo; R.sup.4 is selected
from the group consisting of hydrogen, halo and C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy; and R.sup.5 is C.sub.1-C.sub.5 alkyl substituted by
halo.
214. The compound of claim 213 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy, said alkoxy
optionally substituted by one or more halo; R.sup.4 is selected
from the group consisting of hydrogen, halo and C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy; and R.sup.5 is CH.sub.2F.
215. The compound of claim 214 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is CH.sub.2F.
216. The compound of claim 208 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
halo; and R.sup.5 is halo.
217. The compound of claim 208 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is halo.
218. The compound of claim 217 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
fluorine, and R.sup.5 is fluorine.
219. The compound of claim 210 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is methyl.
220. A compound of Formula VIII: 169or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is selected from the
group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is selected from the group
consisting of halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by halo or alkoxy, said alkoxy
optionally substituted by one or more halo.
221. The compound of claim 220 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo, R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is selected from the
group consisting of halo and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy.
222. The compound of claim 220 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen and halo; and
R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
223. The compound of claim 221 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo.
224. The compound of claim 223 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by one or
more halo
225. The compound of claim 222 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is halo.
226. The compound of claim 225 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo;. R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is fluorine.
227. The compound of claim 224 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy, said alkoxy
optionally substituted by one or more halo; R.sup.4 is selected
from the group consisting of hydrogen, halo and C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy; and R.sup.5 is C.sub.1-C.sub.5 alkyl substituted by
halo.
228. The compound of claim 227 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy, said alkoxy
optionally substituted by one or more halo; R.sup.4 is selected
from the group consisting of hydrogen, halo and C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy; and R.sup.5 is CH.sub.2F.
229. The compound of claim 228 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is CH.sub.2F.
230. The compound of claim 222 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by a halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
halo; and R.sup.5 is halo.
231. The compound of claim 221 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is halo.
232. The compound of claim 231 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
fluorine; and R.sup.5 is fluorine.
233. The compound of claim 224 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is methyl.
234. A compound of Formula IX: 170or a pharmaceutically acceptable
salt thereof, wherein: R.sup.1 is selected from the group
consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.2 is
selected from the group consisting of hydrogen halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo, and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is selected from the group
consisting of halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5
alkyl optionally substituted by halo or alkoxy, said alkoxy
optionally substituted by one or more halo.
235. The compound of claim 234 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is selected from the
group consisting of halo and C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy.
236. The compound of claim 234 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy said alkoxy optionally substituted by
one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen and halo; and
R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
237. The compound of claim 235 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo.
238. The compound of claim 237 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
selected from the group consisting of hydrogen, halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy; and R.sup.5 is C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by one or
more halo
239. The compound of claim 234 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is halo.
240. The compound of claim 239 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; and R.sup.5 is fluorine.
241. The compound of claim 238 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy, said alkoxy
optionally substituted by one or more halo; R.sup.4 is selected
from the group consisting of hydrogen, halo and C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy; and R.sup.5 is C.sub.1-C.sub.5 alkyl substituted by
halo.
242. The compound of claim 241 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by alkoxy, said alkoxy
optionally substituted by one or more halo; R.sup.4 is selected
from the group consisting of hydrogen, halo and C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy; and R.sup.5 is CH.sub.2F.
243. The compound of claim 242 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is CH.sub.2F.
244. The compound of claim 236 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
halo; and R.sup.5 is halo.
245. The compound of claim 234 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is halo.
246. The compound of claim 245 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
fluorine; and R.sup.5 is fluorine.
247. The compound of claim 238 wherein: R.sup.1 is selected from
the group consisting of hydrogen, halo, and C.sub.1-C.sub.5 alkyl,
said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo;
R.sup.2 is selected from the group consisting of hydrogen, halo,
and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.3 is C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by halo or alkoxy,
said alkoxy optionally substituted by one or more halo; R.sup.4 is
hydrogen; and R.sup.5 is methyl.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/232,683, filed Sep. 15, 2000.
FIELD OF THE INVENTION
[0002] The present invention relates to 2-amino-2-alkyl-5 heptenoic
and heptynoic acid derivatives and their use in therapy, in
particular their use as nitric oxide synthase inhibitors.
RELATED ART
[0003] It has been known since the early 1980's that the vascular
relaxation caused by acetylcholine is dependent on the vascular
endothelium. The endothelium-derived relaxing factor (EDRF), now
known to be nitric oxide (NO) is generated in the vascular
endothelium by nitric oxide synthase (NOS). The activity of NO as a
vasodilator has been known for well over 100 years. In addition, NO
is the active species deriving from amylnitrite, glyceryltrinitrate
and other nitrovasodilators. The identification of EDRF as NO has
coincided with the discovery of a biochemical pathway by which NO
is synthesized from the amino acid L-arginine by the enzyme NO
synthase.
[0004] Nitric oxide is an endogenous stimulator of the soluble
guanylate cyclase. In addition to endothelium-dependent relaxation,
NO is involved in a number of biological actions including
cytotoxicity of phagocytic cells and cell-to-cell communication in
the central nervous system.
[0005] There are at least three types of NO synthase as
follows:
[0006] (i) a constitutive, Ca.sup.++/calmodulin dependent enzyme,
located in the endothelium, that releases NO in response to
receptor or physical stimulation.
[0007] (ii) a constitutive, Ca.sup.++/calmodulin dependent enzyme,
located in the brain, that releases NO in response to receptor or
physical stimulation.
[0008] (iii) a Ca.sup.++ independent enzyme which is induced after
activation of vascular smooth muscle, macrophages, endothelial
cells, and a number of other cells by endotoxin and cytokines. Once
expressed, this inducible nitric oxide synthase (hereinafter
"iNOS") generates NO continuously for long periods.
[0009] The NO released by each of the two constitutive enzymes acts
as a transduction mechanism underlying several physiological
responses. The NO produced by the inducible enzyme is a cytotoxic
molecule for tumor cells and invading microorganisms. It also
appears that adverse effects of excess NO production, in particular
pathological vasodilation and tissue damage, may result largely
from the NO synthesized by iNOS.
[0010] There is a growing body of evidence that NO may be involved
in the degeneration of cartilage which takes place as a result of
certain conditions such as arthritis and it is also known that NO
synthesis is increased in rheumatoid arthritis and in
osteoarthritis.
[0011] Some of the NO synthase inhibitors proposed for therapeutic
use are non-selective; they inhibit both the constitutive and the
inducible NO synthases. Use of such a non-selective NO synthase
inhibitor requires that great care be taken in order to avoid the
potentially serious consequences of over-inhibition of the
constitutive NO-synthase, such consequences including hypertension
and possible thrombosis and tissue damage. In particular, in the
case of the therapeutic use of L-NMMA (a non-selective NO synthase
inhibitor) for the treatment of toxic shock it has been recommended
that the patient must be subject to continuous blood pressure
monitoring throughout the treatment. Thus, while non-selective NO
synthase inhibitors have therapeutic utility provided that
appropriate precautions are taken, NO synthase inhibitors which are
selective in the sense that they inhibit the inducible NO synthase
to a considerably greater extent than the constitutive isoforms of
NO synthase would be of even greater therapeutic benefit and easier
to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
[0012] PCT International Publication No. WO 93/13055 and U.S. Pat.
No. 5,132,453, the disclosure of which are hereby incorporated by
reference in their entirety as if written herein, disclose
compounds that inhibit nitric oxide synthesis and preferentially
inhibit the inducible isoform of nitric oxide synthase.
[0013] PCT International Publication No. WO 95/25717 discloses
certain amidino derivatives as being useful in inhibiting inducible
nitric oxide synthase.
[0014] Various attempts have been made to improve the potency and
selectivity of NOS inhibitors by adding one or more rigidifying
elements to the inhibitor's structure. Publications by Y. Lee et al
(Bioorg. Med. Chem. 7, 1097 (1999)) and R. J. Young et al (Bioorg.
Med. Chem. Lett. 10, 597 (2000)) teach that imposing conformational
rigidity with one or more carbon-carbon double bonds is not a
favorable approach to impart selectivity for NOS inhibitors.
SUMMARY OF THE INVENTION
[0015] Compounds have now been found which have the advantage of
being very efficacious in the human cartilage explant assay, a
model for osteoarthritis.
[0016] The present invention demonstrates that a carbon-carbon
double bond can be used as a rigidifying element, and the resulting
compounds have unexpected potency and selectivity for inhibition of
inducible NOS.
[0017] Moreover, the publication by Y. Lee et al (Bioorg. Med.
Chem. 7, 1097 (1999)) teaches that when a carbon-carbon double bond
is used to constrain the arginine backbone, the geometric isomer
placing the carbon framework in a cis or Z orientation produces a
less favorable interaction with NOS. In contrast, olefinic
derivatives of arginine placing the carbon framework in the trans
or E configuration are better substrates. The present invention
demonstrates that a carbon-carbon double bond imparts a favorable
interaction with inducible NOS, such that the resulting compounds
have unexpected potency and selectivity for inhibition of inducible
NOS over the constitutive isoforms.
[0018] Further, compounds of the present invention have the
advantage of being very efficacious as iNOS inhibitors in the human
cartilage explant assay, a model for osteoarthritis. At the same
time the compounds of the present invention are surprisingly less
able to penetrate certain non-target organs in test systems,
especially in comparison to the compounds of WO 93/13055. This
surprising differentiation in expected access between the target
organ (cartilage) and other organs is an unexpected advantage for
the compounds of the present invention.
[0019] In a broad aspect, compounds of the present invention are
represented by: 1
[0020] or a pharmaceutically acceptable salt thereof, wherein:
[0021] R.sup.1 is, halo, C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5
alkyl substituted by alkoxy or one or more halo;
[0022] R.sup.2 is hydrogen, halo, C.sub.1-C.sub.5 alkyl or
C.sub.1-C.sub.5 alkyl substituted by alkoxy or one or more halo;
and R.sup.3 is C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkyl be
substituted by alkoxy or one or more halo.
[0023] In an embodiment represented by Formula I, the invention is
represented to a compound of formula I: 2
[0024] or a pharmaceutically acceptable salt thereof, wherein:
[0025] R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0026] halo or alkoxy, said alkoxy optionally substituted by one or
more halo;
[0027] R.sup.2 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0028] halo or alkoxy, said alkoxy optionally substituted by one or
more halo; and
[0029] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo
[0030] In an embodiment represented by Formula II, the invention
relates to: 3
[0031] or a pharmaceutically acceptable salt thereof, wherein:
[0032] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0033] In an embodiment represented by Formula III, the invention
relates to: 4
[0034] or a pharmaceutically acceptable salt thereof, wherein:
[0035] R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0036] halo or alkoxy, said alkoxy optionally substituted by one or
more halo;
[0037] R.sup.2 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0038] halo or alkoxy, said alkoxy optionally substituted by one or
more halo; and
[0039] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0040] In an embodiment represented by Formula IV, the invention
relates to: 5
[0041] or a pharmaceutically acceptable salt thereof, wherein:
[0042] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0043] In an embodiment represented by Formula V, the invention
relates to: 6
[0044] or a pharmaceutically acceptable salt thereof, wherein:
[0045] R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0046] halo or alkoxy, said alkoxy optionally substituted by one or
more halo;
[0047] R.sup.2 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0048] halo or alkoxy, said alkoxy optionally substituted by one or
more halo; and
[0049] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo
[0050] In an embodiment represented by Formula VI, the invention
relates to: 7
[0051] or a pharmaceutically acceptable salt thereof, wherein:
[0052] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0053] In a broad aspect, the present invention is directed to
novel compounds, pharmaceutical compositions, process for preparing
novel compounds, process for preparing pharmaceutical compositions,
and methods of using said compounds and compositions for inhibiting
or modulating nitric oxide synthesis in a subject in need of such
inhibition or modulation by administering a compound which
preferentially inhibits or modulates the inducible isoform of
nitric oxide synthase over the constitutive isoforms of nitric
oxide synthase. It is also another object of the present invention
to lower nitric oxide levels in a subject in need of such lowering.
The present compounds possess useful nitric oxide synthase
inhibiting activity, and are expected to be useful in the treatment
or prophylaxis of a disease or condition in which the synthesis or
over-synthesis of nitric oxide forms a contributory part.
[0054] Compounds of the present invention will be useful for
treating, among other things, inflammation in a subject, or for
treating other nitric oxide synthase-mediated disorders, such as,
as an analgesic in the treatment of pain and headaches. The
compounds of the present invention will be useful in the treatment
of pain including somatogenic (either nociceptive or neuropathic),
both acute and chronic, and could be used in a situation including
neuropathic pain for which a common NSAID, opioid analgesic or
certain anti-convulsants would traditionally be administered.
[0055] Conditions in which the compounds of the present invention
will provide an advantage in inhibiting NO production from
L-arginine include arthritic conditions. For example, compounds of
the present invention will be useful to treat arthritis, including
but not limited to rheumatoid arthritis, spondyloarthropathies,
gouty arthritis, osteoarthritis, systemic lupus erythematosus,
juvenile arthritis, acute rheumatic arthritis, enteropathic
arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic
arthritis.
[0056] Compounds of the invention will be further useful in the
treatment of asthma, bronchitis, menstrual cramps (e.g.,
dysmenorrhea), premature labor, tendinitis, bursitis, skin-related
conditions such as psoriasis, eczema, burns, sunburn, dermatitis,
pancreatitis, hepatitis, and post-operative inflammation including
inflammation from ophthalmic surgery such as cataract surgery and
refractive surgery. Compounds of the invention also would be useful
to treat gastrointestinal conditions such as inflammatory bowel
disease, Crohn's disease, gastritis, irritable bowel syndrome and
ulcerative colitis.
[0057] Compounds of the invention would be useful in treating
inflammation and tissue damage in such diseases as vascular
diseases, migraine headaches, periarteritis nodosa, thyroiditis,
aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever,
type I diabetes, neuromuscular junction disease including
myasthenia gravis, white matter disease including multiple
sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,
polymyositis, gingivitis, nephritis, hypersensitivity, swelling
occurring after injury, myocardial ischemia, and the like. The
compounds would also be useful in the treatment of ophthalmic
diseases, such as glaucoma, retinitis, retinopathies, uveitis,
ocular photophobia, and of inflammation and pain associated with
acute injury to the eye tissue. Of particular interest among the
uses of the present inventive compounds is the treatment of
glaucoma, especially where symptoms of glaucoma are caused by the
production of nitric oxide, such as in nitric oxide-mediated nerve
damage. The compounds would also be useful in the treatment of
pulmonary inflammation, such as that associated with viral
infections and cystic fibrosis. The compounds would also be useful
for the treatment of certain central nervous system disorders, such
as cortical dementias including Alzheimer's disease, and central
nervous system damage resulting from stroke, ischemia and trauma.
These compounds would also be useful in the treatment of allergic
rhinitis, respiratory distress syndrome, endotoxin shock syndrome,
and atherosclerosis. The compounds would also be useful in the
treatment of pain, including but not limited to postoperative pain,
dental pain, muscular pain, pain caused by temperoramandibular
joint syndrome, and pain resulting from cancer. The compounds would
be useful for the prevention of dementias, such as Alzheimer's
disease.
[0058] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals and other
vertebrates. More preferred animals include horses, dogs, and
cats.
[0059] The present compounds may also be used in co-therapies,
partially or completely, in place of other conventional
antiinflammatory therapies, such as together with steroids, NSAIDs,
COX-2 selective inhibitors, matrix metalloproteinase inhibitors,
5-lipoxygenase inhibitors, LTB.sub.4 antagonists and LTA.sub.4
hydrolase inhibitors.
[0060] Other conditions in which the compounds of the present
invention will provide an advantage in inhibiting NO inhibition
include cardiovascular ischemia, diabetes (type I or type II),
congestive heart failure, myocarditis, atherosclerosis, migraine,
glaucoma, aortic aneurysm, reflux esophagitis, diarrhea, irritable
bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis,
hyperalgesia (allodynia), cerebral ischemia (both focal ischemia,
thrombotic stroke and global ischemia (for example, secondary to
cardiac arrest), multiple sclerosis and other central nervous
system disorders mediated by NO, for example Parkinson's disease.
Further neurodegenerative disorders in which NO inhibition may be
useful include nerve degeneration or nerve necrosis in disorders
such as hypoxia, hypoglycemia, epilepsy, and in cases of central
nervous system (CNS) trauma (such as spinal cord and head injury),
hyperbaric oxygen convulsions and toxicity, dementia, such as, for
example pre-senile dementia, and AIDS-related dementia, cachexia,
Sydenham's chorea, Huntington's disease, Amyotrophic Lateral
Sclerosis, Korsakoff's disease, imbecility relating to a cerebral
vessel disorder, sleeping disorders, schizophrenia, depression,
depression or other symptoms associated with Premenstrual Syndrome
(PMS), anxiety and septic shock.
[0061] Still other disorders or conditions which will be
advantageously treated by the compounds of the present invention
include treatment of prevention of opiate tolerance in patients
needing protracted opiate analgesics, and benzodiazepine tolerance
in patients taking benzodiazepines, and other addictive behavior,
for example, nicotine addiction, alcoholism, and eating disorders.
The compounds and methods of the present invention will also be
useful in the treatment or prevention of drug withdrawal symptoms,
for example treatment or prevention of symptoms of withdrawal from
opiate, alcohol, or tobacco addiction. The present inventive
compounds may also be useful to prevent tissue damage when
therapeutically combined with antibacterial or antiviral
agents.
[0062] The compounds of the present invention will also be useful
in inhibiting NO production from L-arginine including systemic
hypotension associated with septic and/or toxic hemorrhagic shock
induced by a wide variety of agents; therapy with cytokines such as
TNF, IL-1 and IL-2; and as an adjuvant to short term
immunosuppression in transplant therapy.
[0063] Compounds of the invention are useful for the prevention or
treatment of cancer, such as colorectal cancer, and cancer of the
breast, lung, prostate, bladder, cervix and skin. The present
invention is further directed to the use of the compounds of the
present invention for the treatment and prevention of neoplasias.
The neoplasias that will be treatable or preventable by the
compounds and methods of the present invention include brain
cancer, bone cancer, a leukemia, such as, for example chronic
lymphocytic leukemia, a lymphoma, epithelial cell-derived neoplasia
(epithelial carcinoma) such as basal cell carcinoma,
adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth
cancer, esophogeal cancer, small bowel cancer and stomach cancer,
colon cancer, liver cancer, bladder cancer, pancreas cancer,
urogenital cancers, such as ovary cancer, cervical cancer, vulvar
cancer, and lung cancer, breast cancer and skin cancer, such as
squamous cell, melanoma, and basal cell cancers, prostate cancer,
renal cell carcinoma, and other known cancers that effect
epithelial cells throughout the body. Compounds of the present
invention will be effective as well for treatment of mesenchymal
derived neoplasias. Preferably, the neoplasia to be treated is
selected from gastrointestinal cancer, liver cancer, bladder
cancer, pancreas cancer, ovary cancer, prostate cancer, cervical
cancer, vulvar cancer, lung cancer, breast cancer and skin cancer,
such as squamous cell and basal cell cancers. The present compounds
and methods can also be used to treat the fibrosis which occurs
with radiation therapy. The present compounds and methods can be
used to treat subjects having adenomatous polyps, including those
with familial adenomatous polyposis (FAP). Additionally, the
present compounds and methods can be used to prevent polyps from
forming in patients at risk of FAP.
[0064] Conjunctive treatment of a compound of the present invention
with another antineoplastic agent will produce a synergistic effect
or alternatively reduce the toxic side effects associated with
chemotherapy by reducing the therapeutic dose of the side
effect-causing agent needed for therapeutic efficacy or by directly
reducing symptoms of toxic side effects caused by the side
effect-causing agent. A compound of the present invention will
further be useful as an adjunct to radiation therapy to reduce side
effects or enhance efficacy. In the present invention, another
agent which can be combined therapeutically with a compound of the
present invention includes any therapeutic agent which is capable
of inhibiting the enzyme cyclooxygenase-2 ("COX-2"). Preferably
such COX-2 inhibiting agents inhibit COX-2 selectively relative to
the enzyme cyclooxygenase-1 ("COX-1"). Such a COX-2 inhibitor is
known as a "COX-2 selective inhibitor". More preferably, a compound
of the present invention can be therapeutically combined with a
COX-2 selective inhibitor wherein the COX-2 selective inhibitor
selectively inhibits COX-2 at a ratio of at least 10:1 relative to
inhibition of COX-1, more preferably at least 30:1, and still more
preferably at least 50:1 in an in vitro test. COX-2 selective
inhibitors useful in therapeutic combination with the compounds of
the present invention include celecoxib, valdecoxib, deracoxib,
etoricoxib, rofecoxib, ABT-963
(2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfo-
nyl)phenyl-3(2H)-pyridazinone; described in PCT Patent Application
No. WO 00/24719), or meloxicam. A compound of the present invention
can also be advantageously used in therapeutic combination with a
prodrug of a COX-2 selective inhibitor, for example parecoxib.
[0065] Another chemotherapeutic agent which will be useful in
combination with a compound of the present invention can be
selected, for example, from the following non-comprehensive and
non-limiting list:
[0066] Alpha-difluoromethylornithine (DFMO), 5-FU-fibrinogen,
acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,
Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate
stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,
dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi
DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015,
fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil,
N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl
pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,
methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI
NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,
pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda
TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate,
tyrosine kinase inhibitors, tyrosine protein kinase inhibitors,
Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamide analogues,
altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil,
budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139,
Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American
Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384,
Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic,
Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine,
Erbamont FCE-24517, estramustine phosphate sodium, fotemustine,
Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,
iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku
NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU,
prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline
SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku
TA-077, tauromustine, temozolomide, teroxirone, tetraplatin,
trimelamol, Taiho 4181-A, aclarubicin, actinomycin D,
actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto
AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline,
azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers
BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605,
Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin
sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,
dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79,
Kyowa Hakko DC-88A, Kyowa Hakko DC89A1, Kyowa Hakko DC92B,
ditrisarubicin B, Shionogi DOB-41, doxorubicin,
doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,
esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954,
Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,
gregatin-A, grincamycin, herbimycin, idarubicin, illudins,
kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery
KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko
KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303,
menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin,
Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International
NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,
pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I,
rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo
SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,
sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical
SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2,
talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A,
Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi
Y-25024 zorubicin, alpha-carotene, alpha-difluoromethyl-arginine,
acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide,
amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston
A10, antineoplaston A2, antineoplaston A3, antineoplaston A5,
antineoplaston AS2-1, Henkel APD, aphidicolin glycinate,
asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript,
Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481,
Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773,
caracemide, carmethizole hydrochloride, Ajinomoto CDAF,
chlorsulfaquinoxalone, Chemex CHX-2053, Chemex CHX-100,
Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert
CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN
compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11,
crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz
D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B,
dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin,
Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693,
elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine,
etoposide, etretinate, fenretinide, Fujisawa FR-57704; gallium
nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan
NMF-5N, hexadecylphosphocholine, Green Cross HO-221,
homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine,
isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak
K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American
Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly
LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco
MEDR-340, merbarone, merocyanine derivatives,
methylanilinoacridine, Molecular Genetics MGI-136, minactivin,
mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo
MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,
N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole
derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI
NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine,
Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert
PD-11707, Warner-Lambert PD-115934, Warner-Lambert PD-131141,
Pierre Fabre PE-1001, ICRT peptide D, piroxantrone,
polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane,
procarbazine, proglumide, Invitron protease nexin I, Tobishi
RA-700, razoxane, Sapporo Breweries RBS, restrictin-P,
retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc
RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray
SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,
spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,
Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide
dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303,
teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol,
Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028,
ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine,
vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, with
anolides, Yamanouchi YM-534, uroguanylin, combretastatin,
dolastatin, idarubicin, epirubicin, estramustine, cyclophosphamide,
9-amino-2-(S)-camptothecin, topotecan, irinotecan (Camptosar),
exemestane, decapeptyl (tryptorelin), or an omega-3 fatty acid.
[0067] Examples of radioprotective agents which may be used in a
combination therapy with the compounds of this invention include
AD-5, adchnon, amifostine analogues, detox, dimesna, 1-102, MM-159,
N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine,
WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide
dismutase (Chiron) and superoxide dismutase Enzon.
[0068] The compounds of the present invention will also be useful
in treatment or prevention of angiogenesis-related disorders or
conditions, for example, tumor growth, metastasis, macular
degeneration, and atherosclerosis.
[0069] In a further embodiment, the present invention also provides
therapeutic combinations for the treatment or prevention of
ophthalmic disorders or conditions such as glaucoma. For example
the present inventive compounds advantageously will be used in
therapeutic combination with a drug which reduces the intraocular
pressure of patients afflicted with glaucoma. Such intraocular
pressure-reducing drugs include without limitation; latanoprost,
travoprost, bimatoprost, or unoprostol. The therapeutic combination
of a compound of the present invention plus an intraocular
pressure-reducing drug will be useful because each is believed to
achieve its effects by affecting a different mechanism.
[0070] In another combination of the present invention, the present
inventive compounds can be used in therapeutic combination with an
antihyperlipidemic or cholesterol-lowering drug such as a
benzothiepine or a benzothiazepine antihyperlipidemic drug.
Examples of benzothiepine antihyperlipidemic drugs useful in the
present inventive therapeutic combination can be found in U.S. Pat.
No. 5,994,391, herein incorporated by reference. Some
benzothiazepine antihyperlipidemic drugs are described in WO
93/16055. Alternatively, the antihyperlipidemic or
cholesterol-lowering drug useful in combination with a compound of
the present invention can be an HMG Co-A reductase inhibitor.
Examples of HMG Co-A reductase inhibitors useful in the present
therapeutic combination include, individually, benfluorex,
fluvastatin, lovastatin, provastatin, simvastatin, atorvastatin,
cerivastatin, bervastatin, ZD-9720 (described in PCT Patent
Application No. WO 97/06802), ZD-4522 (CAS No. 147098-20-2 for the
calcium salt; CAS No. 147098-18-8 for the sodium salt; described in
European Patent No. EP 521471), BMS 180431 (CAS No. 129829-03-4),
or NK-104 (CAS No. 141750-63-2). The therapeutic combination of a
compound of the present invention plus an antihyperlipidemic or
cholesterol-lowering drug will be useful, for example, in reducing
the risk of formation of atherosclerotic lesions in blood vessels.
For example, atherosclerotic lesions often initiate at inflamed
sites in blood vessels. It is established that antihyperlipidemic
or cholesterol-lowering drug reduce risk of formation of
atherosclerotic lesions by lowering lipid levels in blood. Without
limiting the invention to a single mechanism of action, it is
believed that one way the compounds of the present combination will
work in concert to provide improved control of atherosclerotic
lesions by, for example, reducing inflammation of the blood vessels
in concert with lowering blood lipid levels.
[0071] In another embodiment of the invention, the present
compounds can be used in combination with other compounds or
therapies for the treatment of central nervous conditions or
disorders such as migraine. For example, the present compounds can
be used in therapeutic combination with caffeine, a 5-HT-1B/1D
agonist (for example, a triptan such as sumatriptan, naratriptan,
zolmitriptan, rizatriptan, almotriptan, or frovatriptan), a
dopamine D4 antagonist (e.g., sonepiprazole), aspirin,
acetaminophen, ibuprofen, indomethacin, naproxen sodium,
isometheptene, dichloralphenazone, butalbital, an ergot alkaloid
(e.g., ergotamine, dihydroergotamine, bromocriptine, ergonovine, or
methyl ergonovine), a tricyclic antidepressant (e.g., amitriptyline
or nortriptyline), a serotonergic antagonist (e.g., methysergide or
cyproheptadine), a beta-andrenergic antagonist (e.g., propranolol,
timolol, atenolol, nadolol, or metprolol), or a monoamine oxidase
inhbitor (e.g., phenelzine or isocarboxazid).
[0072] A further embodiment provides a therapeutic combination of a
compound of the present invention with an opioid compound. Opioid
compounds useful in this combination include without limitation
morphine, methadone, hydromorphone, oxymorphone, levorphanol,
levallorphan, codeine, dihydrocodeine, dihydrohydroxycodeinone,
pentazocine, hydrocodone, oxycodone, nalmefene, etorphine,
levorphanol, fentanyl, sufentanil, DAMGO, butorphanol,
buprenorphine, naloxone, naltrexone, CTOP, diprenorphine,
beta-funaltrexamine, naloxonazine, nalorphine, pentazocine,
nalbuphine, naloxone benzoylhydrazone, bremazocine,
ethylketocyclazocine, U50,488, U69,593, spiradoline,
nor-binaltorphimine, naltrindole, DPDPE, [D-1a.sup.2,
glu.sup.4]deltorphin, DSLET, met-enkephalin, leu-enkaphalin,
beta-endorphin, dynorphin A, dynorphin B, and alpha-neoendorphin.
An advantage to the combination of the present invention with an
opioid compound is that the present inventive compounds will allow
a reduction in the dose of the opioid compound, thereby reducing
the risk or severity of opioid side effects, such as opioid
addiction.
DETAILED DESCRIPTION OF THE INVENTION
[0073] In a broad aspect, compounds of the present invention are
represented by: 8
[0074] or a pharmaceutically acceptable salt thereof, wherein:
[0075] R.sup.1 is hydrogen, halo, C.sub.1-C.sub.5 alkyl or
C.sub.1-C.sub.5 alkyl substituted by alkoxy or one or
more-halo;
[0076] R.sup.2 is hydrogen, halo, C.sub.1-C.sub.5 alkyl or
C.sub.1-C.sub.5 alkyl substituted by alkoxy or one or more halo;
and R.sup.3 is C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkyl
substituted by alkoxy or one or more halo.
[0077] In an embodiment represented by Formula I, the invention is
represented to a compound of formula I: 9
[0078] or a pharmaceutically acceptable salt thereof, wherein:
[0079] R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0080] halo or alkoxy, said alkoxy optionally substituted by one or
more halo;
[0081] R.sup.2 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0082] halo or alkoxy, said alkoxy optionally substituted by one or
more halo; and
[0083] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo
[0084] In one embodiment of the present invention represented by
Formula I, the compound is the Z isomer.
[0085] In another embodiment of the present invention represented
by Formula I, the compound is the E isomer.
[0086] In yet another embodiment of the present invention
represented by Formula I, R.sup.1 is hydrogen, halo, or
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.2 is hydrogen, halo or C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo; and
R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy.
[0087] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.3 alkyl;
R.sup.2 is hydrogen, halo or C.sub.1-C.sub.3 alkyl; and R.sup.3 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by fluorine or alkoxy.
[0088] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.3 alkyl;
R.sup.2 is hydrogen, halo or C.sub.1-C.sub.3 alkyl; and R.sup.3 is
C.sub.1-C.sub.3 alkyl.
[0089] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is hydrogen, halo or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0090] In a still further embodiment of the present invention
represented by Formula I, R.sup.1 is hydrogen; R.sup.2 is hydrogen
or halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0091] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is hydrogen or fluorine;
and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0092] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is hydrogen or fluorine;
and R.sup.3 is methyl.
[0093] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3
is methyl.
[0094] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is fluorine; and R.sup.3
is methyl.
[0095] In another embodiment of the present invention represented
by Formula I, R.sup.1 is halo; R.sup.2 is hydrogen, halo or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0096] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is halo; R.sup.2 is halo; and R.sup.3 is
C.sub.1-C.sub.3 alkyl.
[0097] In another embodiment of the present invention represented
by Formula I, R.sup.1 is fluorine; R.sup.2 is fluorine; and R.sup.3
is methyl.
[0098] In another embodiment of the present invention represented
by Formula I, R.sup.1 is fluorine; R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
[0099] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is fluorine; R.sup.2 is hydrogen; and R.sup.3
is methyl.
[0100] In another embodiment of the present invention represented
by Formula I, R.sup.1 is methyl; R.sup.2 is hydrogen; and R.sup.3
is methyl.
[0101] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is methyl; and R.sup.3
is methyl.
[0102] In another embodiment of the present invention represented
by Formula I, R.sup.1 is methyl; R.sup.2 is methyl; and R.sup.3 is
methyl.
[0103] In yet another embodiment of the present invention
represented by Formula I,: R.sup.1 is hydrogen, halo or
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by alkoxy or one or more fluorine; R.sup.2 is hydrogen,
halo or C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by one or more alkoxy or
halo.
[0104] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen or fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
[0105] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is CH.sub.2F; and
R.sup.3 is methyl.
[0106] In still another embodiment of the present invention
represented by Formula I, R.sup.1 is CH.sub.2F; R.sup.2 is
hydrogen; and R.sup.3 is methyl.
[0107] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3
is CH.sub.2F.
[0108] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is methoxymethyl; and
R.sup.3 is methyl.
[0109] In a further embodiment of the present invention represented
by Formula I, R.sup.1 is methoxymethyl; R.sup.2 is hydrogen; and
R.sup.3 is methyl.
[0110] In another embodiment of the present invention represented
by Formula I, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3
is methoxymethyl.
[0111] In an embodiment represented by Formula II, the invention
relates to: 10
[0112] or a pharmaceutically acceptable salt thereof, wherein:
[0113] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0114] In another embodiment of the present invention represented
by Formula II, R.sup.3 is C.sub.1-C.sub.5 alkyl substituted by one
or more halo.
[0115] In a further embodiment of the present invention represented
by Formula II, R.sup.3 is C.sub.1-C.sub.5 alkyl substituted by one
or more fluorine.
[0116] In still another embodiment of the present invention
represented by Formula II, R.sup.3 is methyl substituted by one or
more halo.
[0117] In yet another embodiment of the present invention
represented by Formula II, R.sup.3 is methyl substituted by one or
more fluorine.
[0118] In another embodiment of the present invention represented
by Formula II, R.sup.3 is CH.sub.2F.
[0119] In still another embodiment of the present invention
represented by Formula II, R.sup.3 is C.sub.1-C.sub.5 alkyl
substituted by alkoxy.
[0120] In a further embodiment of the present invention represented
by Formula II, R.sup.3 is methoxy methyl.
[0121] In yet another embodiment of the present invention
represented by Formula II, R.sup.3 is C.sub.1-C.sub.5 alkyl.
[0122] In another embodiment of the present invention represented
by Formula II, R.sup.3 is methyl.
[0123] In an embodiment represented by Formula III, the invention
relates to: 11
[0124] or a pharmaceutically acceptable salt thereof, wherein:
[0125] R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0126] halo or alkoxy, said alkoxy optionally substituted by one or
more halo;
[0127] R.sup.2 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0128] halo or alkoxy, said alkoxy optionally substituted by one or
more halo; and
[0129] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0130] In one embodiment of the present invention represented by
Formula III, the compound is the Z isomer.
[0131] In another embodiment of the present invention represented
by Formula III, the compound is the E isomer.
[0132] In yet another embodiment of the present invention
represented by Formula III, R.sup.1 is hydrogen, halo, or
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.2 is hydrogen, halo or C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo; and
R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy.
[0133] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.3
alkyl; R.sup.2 is hydrogen, halo or C.sub.1-C.sub.3 alkyl; and
R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by fluorine or alkoxy.
[0134] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.3
alkyl; R.sup.2 is hydrogen, halo or C.sub.1-C.sub.3 alkyl; and
R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0135] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is hydrogen, halo or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0136] In a still further embodiment of the present invention
represented by Formula III, R.sup.1 is hydrogen; R.sup.2 is
hydrogen or halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0137] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is hydrogen or
fluorine; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0138] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is hydrogen or
fluorine; and R.sup.3 is methyl.
[0139] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and
R.sup.3 is methyl.
[0140] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is fluorine; and
R.sup.3 is methyl.
[0141] In another embodiment of the present invention represented
by Formula III, R.sup.1 is halo; R.sup.2 is hydrogen, halo or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0142] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is halo; R.sup.2 is halo; and R.sup.3 is
C.sub.1-C.sub.3 alkyl.
[0143] In another embodiment of the present invention represented
by Formula III, R.sup.1 is fluorine; R.sup.2 is fluorine; and
R.sup.3 is methyl.
[0144] In another embodiment of the present invention represented
by Formula III, R.sup.1 is fluorine; R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
[0145] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is fluorine; R.sup.2 is hydrogen; and
R.sup.3 is methyl.
[0146] In another embodiment of the present invention represented
by Formula III, R.sup.1 is methyl; R.sup.2 is hydrogen; and R.sup.3
is methyl.
[0147] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is methyl; and R.sup.3
is methyl.
[0148] In another embodiment of the present invention represented
by Formula III, R.sup.1 is methyl; R.sup.2 is methyl; and R.sup.3
is methyl.
[0149] In yet another embodiment of the present invention
represented by Formula III,: R.sup.1 is hydrogen, halo or
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by alkoxy or one or more fluorine; R.sup.2 is hydrogen,
halo or C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by one or more alkoxy or
halo.
[0150] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen or fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
[0151] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is CH.sub.2F; and
R.sup.3 is methyl.
[0152] In still another embodiment of the present invention
represented by Formula III, R.sup.1 is CH.sub.2F; R.sup.2 is
hydrogen; and R.sup.3 is methyl.
[0153] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R is
CH.sub.2F.
[0154] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is methoxymethyl; and
R.sup.3 is methyl.
[0155] In a further embodiment of the present invention represented
by Formula III, R.sup.1 is methoxymethyl; R.sup.2 is hydrogen; and
R.sup.3 is methyl.
[0156] In another embodiment of the present invention represented
by Formula III, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and
R.sup.3 is methoxymethyl.
[0157] In an embodiment represented by Formula IV, the invention
relates to: 12
[0158] or a pharmaceutically acceptable salt thereof, wherein:
[0159] R.sup.3 is C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkyl
substituted by alkoxy or one or more halo.
[0160] In another embodiment of the present invention represented
by Formula IV, R.sup.3 is C.sub.1-C.sub.5 alkyl substituted by one
or more halo.
[0161] In a further embodiment of the present invention represented
by Formula IV, R.sup.3 is C.sub.1-C.sub.5 alkyl substituted by one
or more fluorine.
[0162] In still another embodiment of the present invention
represented by Formula IV, R.sup.3 is methyl substituted by one or
more halo.
[0163] In yet another embodiment of the present invention
represented by Formula IV, R.sup.3 is methyl substituted by one or
more fluorine. In another embodiment of the present invention
represented by Formula IV, R.sup.3 is CH.sub.2F.
[0164] In still another embodiment of the present invention
represented by Formula IV, R.sup.3 is C.sub.1-C.sub.5 alkyl
substituted by alkoxy.
[0165] In a further embodiment of the present invention represented
by Formula IV, R.sup.3 is methoxy methyl.
[0166] In yet another embodiment of the present invention
represented by Formula IV, R.sup.3 is C.sub.1-C.sub.5 alkyl.
[0167] In another embodiment of the present invention represented
by Formula IV, R.sup.3 is methyl.
[0168] In an embodiment represented by Formula V, the invention
relates to: 13
[0169] or a pharmaceutically acceptable salt thereof, wherein:
[0170] R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0171] halo or alkoxy, said alkoxy optionally substituted by one or
more halo;
[0172] R.sup.2 is hydrogen, halo, or C.sub.1-C.sub.5 alkyl, said
C.sub.1-C.sub.5 alkyl optionally substituted by
[0173] halo or alkoxy, said alkoxy optionally substituted by one or
more halo; and
[0174] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0175] In one embodiment of the present invention represented by
Formula V, the compound is the Z isomer.
[0176] In another embodiment of the present invention represented
by Formula V, the compound is the E isomer.
[0177] In yet another embodiment of the present invention
represented by Formula V, R.sup.1 is hydrogen, halo, or
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo; R.sup.2 is hydrogen, halo or C.sub.1-C.sub.5
alkyl, said C.sub.1-C.sub.5 alkyl optionally substituted by halo or
alkoxy, said alkoxy optionally substituted by one or more halo; and
R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy.
[0178] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.3 alkyl;
R.sup.2 is hydrogen, halo or C.sub.1-C.sub.3 alkyl; and R.sup.3 is
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by fluorine or alkoxy.
[0179] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen, halo, or C.sub.1-C.sub.3 alkyl;
R.sup.2 is hydrogen, halo or C.sub.1-C.sub.3 alkyl; and R.sup.3 is
C.sub.1-C.sub.3 alkyl.
[0180] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is hydrogen, halo or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0181] In a still further embodiment of the present invention
represented by Formula V, R.sup.1 is hydrogen; R.sup.2 is hydrogen
or halo; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0182] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is hydrogen or fluorine;
and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0183] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is hydrogen or fluorine;
and R.sup.3 is methyl.
[0184] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3
is methyl.
[0185] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is fluorine; and R.sup.3
is methyl.
[0186] In another embodiment of the present invention represented
by Formula V, R.sup.1 is halo; R.sup.2 is hydrogen, halo or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is C.sub.1-C.sub.3 alkyl.
[0187] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is halo; R.sup.2 is halo; and R.sup.3 is
C.sub.1-C.sub.3 alkyl.
[0188] In another embodiment of the present invention represented
by Formula V, R.sup.1 is fluorine; R.sup.2 is fluorine; and R.sup.3
is methyl.
[0189] In another embodiment of the present invention represented
by Formula V, R.sup.1 is fluorine; R.sup.2 is hydrogen or
C.sub.1-C.sub.3 alkyl; and R.sup.3 is methyl.
[0190] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is fluorine; R.sup.2 is hydrogen; and R.sup.3
is methyl.
[0191] In another embodiment of the present invention represented
by Formula V, R.sup.1 is methyl; R.sup.2 is hydrogen; and R.sup.3
is methyl.
[0192] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is methyl; and R.sup.3
is methyl.
[0193] In another embodiment of the present invention represented
by Formula V, R.sup.1 is methyl; R.sup.2 is methyl; and R.sup.3 is
methyl.
[0194] In yet another embodiment of the present invention
represented by Formula V,: R.sup.1 is hydrogen, halo or
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by alkoxy or one or more fluorine; R.sup.2 is hydrogen,
halo or C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy or one or more fluorine; and
R.sup.3 is methyl optionally substituted by one or more alkoxy or
halo.
[0195] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen or fluorine; R.sup.2 is
C.sub.1-C.sub.3 alkyl substituted by one or more halo; and R.sup.3
is methyl.
[0196] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is CH.sub.2F; and
R.sup.3 is methyl.
[0197] In still another embodiment of the present invention
represented by Formula V, R.sup.1 is CH.sub.2F; R.sup.2 is
hydrogen; and R.sup.3 is methyl.
[0198] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3
is CH.sub.2F.
[0199] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is methoxymethyl; and
R.sup.3 is methyl.
[0200] In a further embodiment of the present invention represented
by Formula V, R.sup.1 is methoxymethyl; R.sup.2 is hydrogen; and
R.sup.3 is methyl.
[0201] In another embodiment of the present invention represented
by Formula V, R.sup.1 is hydrogen; R.sup.2 is hydrogen; and R.sup.3
is methoxymethyl.
[0202] In an embodiment represented by Formula VI, the invention
relates to: 14
[0203] or a pharmaceutically acceptable salt thereof, wherein:
[0204] R.sup.3 is C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkyl
substituted by alkoxy or one or more halo.
[0205] In another embodiment of the present invention represented
by Formula VI, R.sup.3 is C.sub.1-C.sub.5 alkyl substituted by one
or more halo.
[0206] In a further embodiment of the present invention represented
by Formula VI, R.sup.3 is C.sub.1-C.sub.5 alkyl substituted by one
or more fluorine.
[0207] In still another embodiment of the present invention
represented by Formula VI, R.sup.3 is methyl substituted by one or
more halo.
[0208] In yet another embodiment of the present invention
represented by Formula VI, R.sup.3 is methyl substituted by one or
more fluorine. In another embodiment of the present invention
represented by Formula VI, R.sup.3 is CH.sub.2F.
[0209] In still another embodiment of the present invention
represented by Formula VI, R.sup.3 is C.sub.1-C.sub.5 alkyl
substituted by alkoxy.
[0210] In a further embodiment of the present invention represented
by Formula VI, R.sup.3 is methoxy methyl.
[0211] In yet another embodiment of the present invention
represented by Formula VI, R.sup.3 is C.sub.1-C.sub.5 alkyl.
[0212] In another embodiment of the present invention represented
by Formula VI, R.sup.3 is methyl.
[0213] Another embodiment of the present invention resides in a
compound of Formula VII: 15
[0214] or a pharmaceutically acceptable salt thereof, wherein:
[0215] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0216] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0217] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0218] R.sup.4 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0219] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo.
[0220] In a further embodiment of the present invention represented
by Formula VII:
[0221] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0222] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0223] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0224] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0225] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
[0226] In yet another embodiment of the present invention
represented by Formula VII:
[0227] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0228] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0229] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0230] R.sup.4 is selected from the group consisting of hydrogen
and halo; and
[0231] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
[0232] In another embodiment of the present invention represented
by Formula VII:
[0233] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0234] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0235] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0236] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0237] R.sup.5 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0238] In a further embodiment of the present invention represented
by Formula VII:
[0239] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0240] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0241] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0242] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0243] R.sup.5 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by one or more halo
[0244] In yet another embodiment of the present invention
represented by Formula VII:
[0245] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0246] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0247] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0248] R.sup.4 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0249] R.sup.5 is halo.
[0250] In a further embodiment of the present invention represented
by Formula VII:
[0251] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0252] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0253] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0254] R.sup.4 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0255] R.sup.5 is fluorine.
[0256] In another embodiment of the present invention represented
by Formula VII:
[0257] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0258] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0259] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy, said alkoxy optionally
substituted by one or more halo;
[0260] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0261] R.sup.5 is C.sub.1-C.sub.5 alkyl substituted by halo.
[0262] In a further embodiment of the present invention represented
by Formula VII:
[0263] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0264] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0265] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy, said alkoxy optionally
substituted by one or more halo;
[0266] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0267] R.sup.5 is CH.sub.2F.
[0268] In another embodiment of the present invention represented
by Formula VII:
[0269] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0270] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0271] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0272] R.sup.4 is hydrogen; and
[0273] R.sup.5 is CH.sub.2F.
[0274] In another embodiment of the present invention represented
by Formula VII:
[0275] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0276] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0277] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0278] R.sup.4 is halo; and
[0279] R.sup.5 is halo.
[0280] In a further embodiment of the present invention represented
by Formula VII:
[0281] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0282] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0283] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0284] R.sup.4 is fluorine; and
[0285] R.sup.5 is halo.
[0286] In another embodiment of the present invention represented
by Formula VII:
[0287] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0288] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0289] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0290] R.sup.4 is fluorine; and
[0291] R.sup.5 is fluorine.
[0292] In another embodiment of the present invention represented
by Formula VII:
[0293] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0294] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0295] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0296] R.sup.4 is hydrogen; and
[0297] R.sup.5 is methyl.
[0298] Another embodiment of the present invention resides in a
compound of Formula VIII: 16
[0299] or a pharmaceutically acceptable salt thereof, wherein:
[0300] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0301] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0302] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0303] R.sup.4 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0304] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo.
[0305] In another embodiment of the present invention represented
by Formula VIII:
[0306] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0307] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0308] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0309] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0310] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
[0311] In another embodiment of the present invention represented
by Formula VIII:
[0312] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0313] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0314] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0315] R.sup.4 is selected from the group consisting of hydrogen
and halo; and
[0316] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
[0317] In another embodiment of the present invention represented
by Formula VIII:
[0318] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0319] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0320] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0321] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0322] R.sup.5 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0323] In another embodiment of the present invention represented
by Formula VIII:
[0324] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0325] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0326] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0327] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0328] R.sup.5 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by one or more halo
[0329] In another embodiment of the present invention represented
by Formula VIII:
[0330] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0331] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0332] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0333] R.sup.4 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0334] R.sup.5 is halo.
[0335] In another embodiment of the present invention represented
by Formula VIII:
[0336] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0337] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0338] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0339] R.sup.4 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0340] R.sup.5 is fluorine.
[0341] In another embodiment of the present invention represented
by Formula VIII:
[0342] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0343] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0344] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy, said alkoxy optionally
substituted by one or more halo;
[0345] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0346] R.sup.5 is C.sub.1-C.sub.5 alkyl substituted by halo.
[0347] In another embodiment of the present invention represented
by Formula VIII:
[0348] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0349] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0350] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy, said alkoxy optionally
substituted by one or more halo;
[0351] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0352] R.sup.5 is CH.sub.2F.
[0353] In another embodiment of the present invention represented
by Formula VIII:
[0354] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0355] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0356] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0357] R.sup.4 is hydrogen; and
[0358] R.sup.5 is CH.sub.2F.
[0359] In another embodiment of the present invention represented
by Formula VIII:
[0360] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0361] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0362] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0363] R.sup.4 is halo; and
[0364] R.sup.5 is halo.
[0365] In another embodiment of the present invention represented
by Formula VIII:
[0366] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0367] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0368] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0369] R.sup.4 is fluorine; and
[0370] R.sup.5 is halo.
[0371] In another embodiment of the present invention represented
by Formula VIII:
[0372] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0373] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0374] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0375] R.sup.4 is fluorine; and
[0376] R.sup.5 is fluorine.
[0377] In another embodiment of the present invention represented
by Formula VIII:
[0378] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0379] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0380] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0381] R.sup.4 is hydrogen; and
[0382] R.sup.5 is methyl.
[0383] Another embodiment of the present invention resides in a
compound of Formula IX: 17
[0384] or a pharmaceutically acceptable salt thereof, wherein:
[0385] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0386] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0387] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0388] R.sup.4 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0389] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy, said alkoxy optionally substituted
by one or more halo.
[0390] In another embodiment of the present invention represented
by Formula IX:
[0391] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0392] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0393] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0394] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0395] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
[0396] In another embodiment of the present invention represented
by Formula IX:
[0397] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0398] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0399] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0400] R.sup.4 is selected from the group consisting of hydrogen
and halo; and
[0401] R.sup.5 is selected from the group consisting of halo and
C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl optionally
substituted by halo or alkoxy.
[0402] In another embodiment of the present invention represented
by Formula IX:
[0403] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0404] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0405] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0406] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0407] R.sup.5 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo.
[0408] In another embodiment of the present invention represented
by Formula IX:
[0409] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0410] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0411] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0412] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0413] R.sup.5 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by one or more halo
[0414] In another embodiment of the present invention represented
by Formula IX:
[0415] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0416] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0417] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0418] R.sup.4 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0419] R.sup.5 is halo.
[0420] In another embodiment of the present invention represented
by Formula IX:
[0421] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0422] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0423] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0424] R.sup.4 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo; and
[0425] R.sup.5 is fluorine.
[0426] In another embodiment of the present invention represented
by Formula IX:
[0427] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0428] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0429] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy, said alkoxy optionally
substituted by one or more halo;
[0430] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0431] R.sup.5 is C.sub.1-C.sub.5 alkyl substituted by halo.
[0432] In another embodiment of the present invention represented
by Formula IX:
[0433] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0434] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0435] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by alkoxy, said alkoxy optionally
substituted by one or more halo;
[0436] R.sup.4 is selected from the group consisting of hydrogen,
halo and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy; and
[0437] R.sup.5 is CH.sub.2F.
[0438] In another embodiment of the present invention represented
by Formula IX:
[0439] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0440] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0441] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0442] R.sup.4 is hydrogen; and
[0443] R.sup.5 is CH.sub.2F.
[0444] In another embodiment of the present invention represented
by Formula IX:
[0445] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0446] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0447] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0448] R.sup.4 is halo; and
[0449] R.sup.5 is halo.
[0450] In another embodiment of the present invention represented
by Formula IX:
[0451] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0452] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0453] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0454] R.sup.4 is fluorine; and
[0455] R.sup.5 is halo.
[0456] In another embodiment of the present invention represented
by Formula IX:
[0457] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0458] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0459] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0460] R.sup.4 is fluorine; and
[0461] R.sup.5 is fluorine.
[0462] In another embodiment of the present invention represented
by Formula IX:
[0463] R.sup.1 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0464] R.sup.2 is selected from the group consisting of hydrogen,
halo, and C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0465] R.sup.3 is C.sub.1-C.sub.5 alkyl, said C.sub.1-C.sub.5 alkyl
optionally substituted by halo or alkoxy, said alkoxy optionally
substituted by one or more halo;
[0466] R.sup.4 is hydrogen; and
[0467] R.sup.5 is methyl.
[0468] The present invention also includes pharmaceutical
compositions that comprise a compound of Formula I, II, III, IV, V,
VI, VII, VIII or IX.
[0469] Methods of using the compounds of Formula I, II, III, IV, V,
VI, VII, VIII or IX include the use of inhibiting nitric oxide
synthesis in a subject in need of such inhibition by administering
a therapeutically effective amount of the present compound,
selectively inhibiting nitric oxide synthesis produced by inducible
nitric oxide synthase over nitric oxide produced by the
constitutive forms of nitric oxide synthase in a subject in need of
such inhibition by administering a therapeutically effective amount
of a compound of Formula I, II, III, IV, V, or VI, lowering nitric
oxide levels in a subject in need of such by administering a
therapeutically effective amount of a compound of Formula I, II,
III, IV, V, VI, VII, VIII or IX, lowering nitric oxide levels in a
subject in need of such by administering a therapeutically
effective amount of a pharmaceutical composition comprising a
compound of Formula Formula I, I, III, IV, V, VI, VII, VIII or
IX
[0470] Compounds of the present invention will be useful for
treating, among other things, inflammation in a subject, or for
treating other nitric oxide synthase-mediated disorders, such as,
as an analgesic in the treatment of pain and headaches, or as an
antipyretic for the treatment of fever. For example, compounds of
the present invention will be useful to treat arthritis, including
but not limited to rheumatoid arthritis, spondyloarthropathies,
gouty arthritis, osteoarthritis, systemic lupus erythematosus,
juvenile arthritis, acute rheumatic arthritis, enteropathic
arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic
arthritis. Conditions in which the compounds of the present
invention will provide an advantage in inhibiting NO production
from L-arginine include arthritic conditions.
[0471] Compounds of the invention will be further useful in the
treatment of asthma, bronchitis, menstrual cramps (e.g.,
dysmenorrhea), premature labor, tendinitis, bursitis, skin-related
conditions such as psoriasis, eczema, bums, sunburn, dermatitis,
pancreatitis, hepatitis, and from post-operative inflammation
including from ophthalmic surgery such as cataract surgery and
refractive surgery. Compounds of the invention also would be useful
to treat gastrointestinal conditions such as inflammatory bowel
disease, Crohn's disease, gastritis, irritable bowel syndrome and
ulcerative colitis. Compounds of the invention would be useful for
the prevention or treatment of cancer, such as colorectal cancer,
and cancer of the breast, lung, prostate, bladder, cervix and skin.
Compounds of the invention would be useful in treating inflammation
and tissue damage in such diseases as vascular diseases, migraine
headaches, periarteritis nodosa, thyroiditis, aplastic anemia,
Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes,
neuromuscular junction disease including myasthenia gravis, white
matter disease including multiple sclerosis, sarcoidosis, nephrotic
syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis,
hypersensitivity, swelling occurring after injury, myocardial
ischemia, and the like. The compounds would also be useful in the
treatment of ophthalmic diseases, such as glaucoma, retinitis,
retinopathies, uveitis, ocular photophobia, and of inflammation and
pain associated with acute injury to the eye tissue. Of particular
interest among the uses of the present inventive compounds is the
treatment of glaucoma, especially where symptoms of glaucoma are
caused by the production of nitric oxide, such as in nitric
oxide-mediated nerve damage. The compounds would also be useful in
the treatment of pulmonary inflammation, such as that associated
with viral infections and cystic fibrosis. The compounds would also
be useful for the treatment of certain central nervous system
disorders, such as cortical dementias including Alzheimer's
disease, and central nervous system damage resulting from stroke,
ischemia and trauma. The compounds of the invention are useful as
anti-inflammatory agents, such as for the treatment of arthritis,
with the additional benefit of having significantly less harmful
side effects. These compounds would also be useful in the treatment
of allergic rhinitis, respiratory distress syndrome, endotoxin
shock syndrome, and atherosclerosis. The compounds would also be
useful in the treatment of pain, but not limited to postoperative
pain, dental pain, muscular pain, and pain resulting from cancer.
The compounds would be useful for the prevention of dementias, such
as Alzheimer's disease.
[0472] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals, rodents, and
the like. More preferred animals include horses, dogs, and
cats.
[0473] The present compounds may also be used in co-therapies,
partially or completely, in place of other conventional
antiinflammatory therapies, such as together with steroids, NSAIDs,
COX-2 selective inhibitors, 5-lipoxygenase inhibitors, LTB.sub.4
antagonists and LTA.sub.4 hydrolase inhibitors.
[0474] Other conditions in which the compounds of the present
invention will provide an advantage in inhibiting NO inhibition
include cardiovascular ischemia, diabetes (type I or type A),
congestive heart failure, myocarditis, atherosclerosis, migraine,
glaucoma, aortic aneurysm, reflux esophagitis, diarrhea, irritable
bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis,
hyperalgesia (allodynia), cerebral ischemia (both focal ischemia,
thrombotic stroke and global ischemia (for example, secondary to
cardiac arrest), multiple sclerosis and other central nervous
system disorders mediated by NO, for example Parkinson's disease.
Further neurodegenerative disorders in which NO inhibition may be
useful include nerve degeneration or nerve necrosis in disorders
such as hypoxia, hypoglycemia, epilepsy, and in cases of central
nervous system (CNS) trauma (such as spinal cord and head injury),
hyperbaric oxygen convulsions and toxicity, dementia e.g.
pre-senile dementia, and AIDS-related dementia, cachexia,
Sydenham's chorea, Huntington's disease, Amyotrophic Lateral
Sclerosis, Korsakoff's disease, imbecility relating to a cerebral
vessel disorder, sleeping disorders, schizophrenia, depression,
depression or other symptoms associated with Premenstrual Syndrome
(PMS), anxiety and septic shock.
[0475] The compounds of the present invention will also be useful
in the treatment of pain including somatogenic (either nociceptive
or neuropathic), both acute and chronic. A nitric oxide inhibitor
could be used in any situation including neuropathic pain that a
common NSAID or opioid analgesic would traditionally be
administered.
[0476] Still other disorders or conditions which will be
advantageously treated by the compounds of the present invention
include treatment of prevention of opiate tolerance in patients
needing protracted opiate analgesics, and benzodiazepine tolerance
in patients taking benzodiazepines, and other addictive behavior,
for example, nicotine addiction, alcoholism, and eating disorders.
The compounds and methods of the present invention will also be
useful in the treatment or prevention of drug withdrawal symptoms,
for example treatment or prevention of symptoms of withdrawal from
opiate, alcohol, or tobacco addiction. The present inventive
compounds may also be useful to prevent tissue damage when
therapeutically combined with antibacterial or antiviral
agents.
[0477] The compounds of the present invention will also be useful
in inhibiting NO production from L-arginine including systemic
hypotension associated with septic and/or toxic hemorrhagic shock
induced by a wide variety of agents; therapy with cytokines such as
TNF, IL-1 and IL-2; and as an adjuvant to short term
immunosuppression in transplant therapy.
[0478] The present invention is further directed to the use of the
compounds of the present invention for the treatment and prevention
of neoplasias. The neoplasias that will be treatable or preventable
by the compounds and methods of the present invention include brain
cancer, bone cancer, a leukemia, a lymphoma, epithelial
cell-derived neoplasia (epithelial carcinoma) such as basal cell
carcinoma, adenocarcinoma, gastrointestinal cancer such as lip
cancer, mouth cancer, esophogeal cancer, small bowel cancer and
stomach cancer, colon cancer, liver cancer, bladder cancer,
pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast
cancer and skin cancer, such as squamous cell and basal cell
cancers, prostate cancer, renal cell carcinoma, and other known
cancers that effect epithelial cells throughout the body.
Preferably, the neoplasia is selected from gastrointestinal cancer,
liver cancer, bladder cancer, pancreas cancer, ovary cancer,
prostate cancer, cervical cancer, lung cancer, breast cancer and
skin cancer, such as squamous cell and basal cell cancers. The
present compounds and methods can also be used to treat the
fibrosis which occurs with radiation therapy. The present compounds
and methods can be used to treat subjects having adenomatous
polyps, including those with familial adenomatous polyposis (FAP).
Additionally, the present compounds and methods can be used to
prevent polyps from forming in patients at risk of FAP.
[0479] Conjunctive treatment of a compound of the present invention
with another antineoplastic agent will produce a synergistic effect
or alternatively reduce the toxic side effects associated with
chemotherapy by reducing the therapeutic dose of the side
effect-causing agent needed for therapeutic efficacy or by directly
reducing symptoms of toxic side effects caused by the side
effect-causing agent. A compound of the present invention will
further be useful as an adjunct to radiation therapy to reduce side
effects or enhance efficacy. In the present invention, another
agent which can be combined therapeutically with a compound of the
present invention includes any therapeutic agent which is capable
of inhibiting the enzyme cyclooxygenase-2 ("COX-2"). Preferably
such COX-2 inhibiting agents inhibit COX-2 selectively relative to
the enzyme cyclooxygenase-1 ("COX-1"). Such a COX-2 inhibitor is
known as a "COX-2 selective inhibitor". More preferably, a compound
of the present invention can be therapeutically combined with a
COX-2 selective inhibitor wherein the COX-2 selective inhibitor
selectively inhibits COX-2 at a ratio of at least 10:1 relative to
inhibition of COX-1, more preferably at least 30:1, and still more
preferably at least 50:1 in an in vitro test. COX-2 selective
inhibitors useful in therapeutic combination with the compounds of
the present invention include celecoxib, valdecoxib, deracoxib,
etoricoxib, rofecoxib, ABT-963
(2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfo-
nyl)phenyl-3(2H)-pyridazinone; described in PCT Patent Application
No. WO 00/24719), or meloxicam. A compound of the present invention
can also be advantageously used in therapeutic combination with a
prodrug of a COX-2 selective inhibitor, for example parecoxib.
[0480] Another chemotherapeutic agent which will be useful in
combination with a compound of the present invention can be
selected, for example, from the following non-comprehensive and
non-limiting list:
[0481] Alpha-difluoromethylornithine (DFMO), 5-FU-fibrinogen,
acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,
Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate
stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,
dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi
DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015,
fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil,
N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropyl
pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,
methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI
NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,
pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda
TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate,
tyrosine kinase inhibitors, tyrosine protein kinase inhibitors,
Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamide analogues,
altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil,
budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139,
Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American
Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384,
Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum cytostatic,
Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine,
Erbamont FCE-24517, estramustine phosphate sodium, fotemustine,
Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,
iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku
NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU,
prednimistine, Proter PTT-119; ranimustine, semustine, SmithKline
SK&F-101772, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku
TA-077, tauromustine, temozolomide, teroxirone, tetraplatin,
trimelamol, Taiho 4181-A, aclarubicin, actinomycin D,
actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto
AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline,
azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers
BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605,
Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin
sulfate, bryostatin-1, Taiho C-1027 calichemycin, chromoximycin,
dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79,
Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B,
ditrisarubicin B, Shionogi DOB-41, doxorubicin,
doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,
esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont. FCE-21954,
Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,
gregatin-A, grincamycin, herbimycin, idarubicin, illudins,
kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery
KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko
KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303,
menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin,
Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International
NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,
pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I,
rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo
SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,
sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical
SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2,
talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A,
Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi
Y-25024 zorubicin, alpha-carotene, alpha-difluoromethyl-arginine,
acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide,
amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston
A10, antineoplaston A2, antineoplaston A3, antineoplaston A5,
antineoplaston AS2-1, Henkel APD, aphidicolin glycinate,
asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript,
Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481,
Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773,
caracemide, carmethizole hydrochloride, Ajinomoto CDAF,
chlorsulfaquinoxalone, Chemex CHX-2053, Chemex CHX-100,
Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert
CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN
compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11,
crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz
D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B,
dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin,
Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693,
elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine,
etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium
nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan
NMF-5N, hexadecylphosphocholine, Green Cross HO-221,
homoharringtonine, hydroxyurea BTG ICRF-187, ilmofosine,
isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak
K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American
Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly
LY-186641, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco
MEDR-340, merbarone, merocyanine derivatives,
methylanilinoacridine, Molecular Genetics MGI-136, minactivin,
mitonafide, mitoquidone, mopidamol, motretinide, Zenyaku Kogyo
MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,
N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole
derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI
NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocine,
Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert
PD-111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141,
Pierre Fabre PE-1001, ICRT peptide D, piroxantrone,
polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane,
procarbazine, proglumide, Invitron protease nexin I, Tobishi
RA-700, razoxane, Sapporo Breweries RBS, restrictin-P,
retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc
RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray
SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,
spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,
Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide
dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303,
teniposide, thaliblastine, Eastman Kodak TJB=29, tocotrienol,
Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028,
ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine,
vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, with
anolides, Yamanouchi YM-534, uroguanylin, combretastatin,
dolastatin, idarubicin, epirubicin, estramustine, cyclophosphamide,
9-amino-2-(S)-camptothecin, topotecan, irinotecan (Camptosar),
exemestane, decapeptyl (tryptorelin), or an omega-3 fatty acid.
[0482] Examples of radioprotective agents which may be used in a
combination therapy with the compounds of this invention include
AD-5, adchnon, amifostine analogues, detox, dimesna, 1-102, MM-159,
N-acylated-dehydroalanines, TGF-Genentech, tiprotimod, amifostine,
WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide
dismutase (Chiron) and superoxide dismutase Enzon.
[0483] The compounds of the present invention will also be useful
in treatment or prevention of angiogenesis-related disorders or
conditions, for example, tumor growth, metastasis, macular
degeneration, and atherosclerosis.
[0484] In a further embodiment, the present invention also provides
therapeutic combinations for the treatment or prevention of
ophthalmic disorders or conditions such as glaucoma. For example
the present inventive compounds advantageously will be used in
therapeutic combination with a drug which reduces the intraocular
pressure of patients afflicted with glaucoma. Such intraocular
pressure-reducing drugs include without limitation latanoprost,
travoprost, bimatoprost, or unoprostol. The therapeutic combination
of a compound of the present invention plus an intraocular
pressure-reducing drug will be useful because each is believed to
achieve its effects by affecting a different mechanism.
[0485] In another combination of the present invention, the present
inventive compounds can be used in therapeutic combination with an
antihyperlipidemic or cholesterol-lowering drug such as a
benzothiepine or a benzothiazepine antihyperlipidemic drug.
Examples of benzothiepine antihyperlipidemic drugs useful in the
present inventive therapeutic combination can be found in U.S. Pat.
No. 5,994,391, herein incorporated by reference. Some
benzothiazepine antihyperlipidemic drugs are described in WO
93/16055. Alternatively, the antihyperlipidemic or
cholesterol-lowering drug useful in combination with a compound of
the present invention can be an HMG Co-A reductase inhibitor.
Examples of HMG Co-A reductase inhibitors useful in the present
therapeutic combination include, individually, benfluorex,
fluvastatin, lovastatin, provastatin, simvastatin, atorvastatin,
cerivastatin, bervastatin, ZD-9720 (described in PCT Patent
Application No. WO 97/06802), ZD-4522 (CAS No. 147098-20-2 for the
calcium salt; CAS No. 147098-18-8 for the sodium salt; described in
European Patent No. EP 521471), BMS 180431 (CAS No. 129829-03-4),
or NK-104 (CAS No. 141750-63-2). The therapeutic combination of a
compound of the present invention plus an antihyperlipidemic or
cholesterol-lowering drug will be useful, for example, in reducing
the risk of formation of atherosclerotic lesions in blood vessels.
For example, atherosclerotic lesions often initiate at inflamed
sites in blood vessels. It is established that antihyperlipidemic
or cholesterol-lowering drug reduce risk of formation of
atherosclerotic lesions by lowering lipid levels in blood. Without
limiting the invention to a single mechanism of action, it is
believed that one way the compounds of the present combination will
work in concert to provide improved control of atherosclerotic
lesions by, for example, reducing inflammation of the blood vessels
in concert with lowering blood lipid levels.
[0486] In another embodiment of the invention, the present
compounds can be used in combination with other compounds or
therapies for the treatment of central nervous conditions or
disorders such as migraine. For example, the present compounds can
be used in therapeutic combination with caffeine, a 5-HT-1B/1D
agonist (for example, a triptan such as sumatriptan, naratriptan,
zolmitriptan, rizatriptan, almotriptan, or frovatriptan), a
dopamine D4 antagonist (e.g., sonepiprazole), aspirin,
acetaminophen, ibuprofen, indomethacin, naproxen sodium,
isometheptene, dichloralphenazone, butalbital, an ergot alkaloid
(e.g., ergotamine, dihydroergotamine, bromocriptine, ergonovine, or
methyl ergonovine), a tricyclic antidepressant (e.g., amitriptyline
or nortriptyline), a serotonergic antagonist (e.g., methysergide or
cyproheptadine), a beta-andrenergic antagonist (e.g., propranolol,
timolol, atenolol, nadolol, or metprolol), or a monoamine oxidase
inhbitor (e.g., phenelzine or isocarboxazid).
[0487] A further embodiment provides a therapeutic combination of a
compound of the present invention with an opioid compound. Opioid
compounds useful in this combination include without limitation
morphine, methadone, hydromorphone, oxymorphone, levorphanol,
levallorphan, codeine, dihydrocodeine, dihydrohydroxycodeinone,
pentazocine, hydrocodone, oxycodone, nalmefene, etorphine,
levorphanol, fentanyl, sufentanil, DAMGO, butorphanol,
buprenorphine, naloxone, naltrexone, CTOP, diprenorphine,
beta-funaltrexamine, naloxonazine, nalorphine, pentazocine,
nalbuphine, naloxone benzoylhydrazone, bremazocine,
ethylketocyclazocine, U50,488, U69,593, spiradoline,
nor-binaltorphimine, naltrindole, DPDPE, [D-1a.sup.2,
glu.sup.4]deltorphin, DSLET, met-enkephalin, leu-enkaphalin,
beta-endorphin, dynorphin A, dynorphin B, and alpha-neoendorphin.
An advantage to the combination of the present invention with an
opioid compound is that the present inventive compounds will allow
a reduction in the dose of the opioid compound, thereby reducing
the risk or severity of opioid side effects, such as opioid
addiction.
[0488] Definitions
[0489] The term "alkyl", alone or in combination, means an acyclic
aliphatic radical, linear or branched, preferably containing from 1
to about 10 carbon atoms and more preferably containing from 1 to
about 6 carbon atoms. Alkyl radicals can be optionally substituted
with groups as defined below. Examples of such radicals include
methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, isopropyl,
n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,
aminopentyl, iso-amyl, hexyl, octyl and the like.
[0490] The term "alkenyl" refers to an unsaturated, acyclic
hydrocarbon radical, linear or branched, in so much as it contains
at least one double bond. Such radicals containing from 2 to about
6 carbon atoms, preferably from 2 to about 4 carbon atoms, more
preferably from 2 to about 3 carbon atoms. Alkenyl radicals may be
optionally substituted with groups as defined below. Examples of
suitable alkenyl radicals include propenyl, 2-chloropropylenyl,
buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl,
3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl,
and octen-1-yl, and the like.
[0491] The term "alkynyl" refers to an unsaturated, acyclic
hydrocarbon radical, linear or branched, in so much as it contains
one or more triple bonds, such radicals containing 2 to about 6
carbon atoms, preferably from 2 to about 4 carbon atoms, more
preferably from 2 to about 3 carbon atoms. Alkynyl radicals may be
optionally substituted with groups as defined below. Examples of
suitable alkynyl radicals include ethynyl, propynyl,
hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl,
4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl,
hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
[0492] The term "oxo" means a doubly bonded oxygen.
[0493] The term"alkoxy" means a radical comprising an alkyl radical
that is bonded to an oxygen atom, such as a methoxy radical. More
preferred alkoxy radicals are "lower alkoxy" radicals having one to
about ten carbon atoms. Still more preferred alkoxy radicals have
one to about six carbon atoms. Non-limiting xamples of such
radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and
tert-butoxy.
[0494] The phrase "optionally substituted" means that the indicated
radical may, but need not be substituted for hydrogen. Thus, the
phrase "optionally substituted by one or more" means that if a
substitution is made at the indicated moiety, more than one
substitution is contemplated as well. In this regard, if more than
one optional substituent exists, either substituent may be
selected, or a combination of substituents may be selected, or more
than one of the same substituent may be selected. By way of
example, and not limitation, the phrase "C.sub.1-C.sub.5 alkyl
optionally substituted by one or more halo or alkoxy" should be
taken to mean, for example, that methyl, ethyl, propyl, butyl, or
pentyl may have at all substitutable positions: hydrogen, fluorine,
chlorine or other halogen, methoxy, ethoxy, propoxy, iso butoxy,
tert-butoxy, pentoxy or other alkoxy radicals, and combinations
thereof. Non-limiting examples include: propyl, iso-propyl,
methoxypropyl, fluoromethyl, fluoropropyl, 1-fluoro-methoxymethyl
and the like.
[0495] Although nitrogen protecting groups are illustratively shown
as, t-butoxycarbonyl, or t-BOC, any suitable nitrogen protecting
group could be substituted in the synthesis of the compounds of the
present invention. Numerous protected amino groups useful in the
present invention for are described by Theodora W. Greene and Peter
G. M. Wuts (Protective Groups in Organic Synthesis, 3rd ed., John
Wiley & Sons, New York, 1999, pp. 494-653). For example NZ can
be a 4-chlorobenzylimino group. In one embodiment of the present
invention, the protected amino group is any such group resulting
from the reaction of an aldehyde with the corresponding amino group
to form a Schiff base. A large variety of deprotecting reagents can
be advantageously used in the present invention to effect the
conversion of the intermediate to the desired compound. Many such
deprotecting reagents are described by Greene and Wuts, supra. For
example, when the protected amino group is a 4-chlorobenzylimino
group or a t-butoxycarbonylamino group, preferably the deprotecting
reagent is an acid. Some useful acid deprotecting agents include,
without limitation, hydrochloric acid, hydrobromic acid, sulfuric
acid, trifluoroacetic acid, phosphoric acid, phosphorus acid, and
acetic acid.
[0496] When a compound is described by both a structure and a name,
the name is intended to correspond to the indicated structure, and
similarly the structure is intended to correspond with the
indicated name.
[0497] The term "Combination therapy" means the administration of
two or more therapeutic agents to treat a therapeutic condition or
disorder described in the present disclosure, for example
atherosclerosis, pain, inflammation, migraine, neoplasia,
angiogenisis-related conditions or disorder, or other indicated
conditions. Such administration encompasses co-administration of
two or more therapeutic agents in a substantially simultaneous
manner, such as in a single capsule (or other delivery means)
having a fixed ratio of active ingredients or in multiple, separate
capsules ( or other delivery means) for each active ingredient. In
addition, such administration also encompasses use of each type of
therapeutic agent in a sequential manner. In either case, the
treatment regimen will provide beneficial effects of the drug
combination in treating the conditions or disorders described
herein.
[0498] The phrase "therapeutically effective" in the context of
combination therapy is intended to qualify the combined amount of
active ingredients in the combination therapy. This combined amount
will achieve the goal of reducing or eliminating the indicated
condition, or alleviating the symptoms of the indicated
condition.
ILLUSTRATIVE EXAMPLES
[0499] The following synthesis schemes and examples are shown for
illustrative purposes and in no way intended to limit the scope of
the invention. Where isomers are not defined, utilization of
appropriate chromatography methods will afford single isomers. 18
19
EXAMPLE 1
[0500] 20
(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0501] 21
[0502] Example-1A) To a cold (-78.degree. C.) solution of triethyl
2-fluorophosphonoacetate (25.4 g, 105 mmol) in 100 mL of THF was
added n-butyl lithium (63 mL of 1.6 M in hexane, 101 mmol). This
mixture was stirred at -78.degree. C. for 20 min producing a bright
yellow solution. A solution of crude
3-[(tert-butyldimethylsilyl)oxy]propanal (J. Org. Chem., 1994, 59,
1139-1148) (20.0 g, 105 mmol) in 120 mL of THF was then added
dropwise over ten minutes, and the resulting mixture was stirred
for 1.5 h at -78.degree. C., at which time analysis by thin layer
chromatography (5% ethyl acetate in hexane) showed that no starting
material remained. The reaction was quenched at -78.degree. C. with
sat. aqueous NH.sub.4Cl (150 mL). The organic layer was collected,
and the aqueous layer was extracted with diethyl ether (300 mL).
The combined organics were washed with brine (200 mL), dried over
MgSO.sub.4, filtered and concentrated. The crude material was
filtered through a plug of silica gel (150 g) eluting with hexane
(2 L) to give 14.38 g (52%) of the desired
(2E)-5-[[(1,1-dimethylethyl)di-methylsilyl]oxy]-2-fluoro-2-penten-
oic acid ethyl ester product as a clear oil. .sup.1H NMR and
.sup.19F NMR indicated that the isolated product had an approximate
E:Z ratio of 95:5.
[0503] HRMS calcd. for C.sub.13H.sub.26FO.sub.3Si: m/z=277.1635
[M+H].sup.+, found: 277.1645.
[0504] .sup.1H NMR (CDCl.sub.3) .delta. 0.06 (s, 6H), 0.94 (s, 9H),
1.38 (t, 3H), 2.74 (m, 2H), 3.70 (m, 2H), 4.31 (q, 2H), 6.0 (dt,
vinyl, 1H).
[0505] .sup.19F NMR (CDCl.sub.3) .delta. -129.78 (d, 0.05 F, J=35
Hz, 5% Z-isomer), -121.65 (d, 0.95 F, J=23 Hz, 95% E-isomer).
22
[0506] Example-1B) To a solution of Example-1A (6.76 g, 24.5 mmol)
in 100 mL of methanol at room temperature was added solid
NaBH.sub.4 (4.2 g, 220 mmol) in 1.4 g portions over three hours.
After 3.5 hours water was added (10 mL). Additional solid
NaBH.sub.4 (4.2 g, 220 mmol) was added in 1.4 g portions over three
hours. The reaction was quenched with 150 mL of sat. aqueous
NH.sub.4Cl and extracted with diethyl ether (2.times.250 mL). The
organic layers were combined, dried over MgSO.sub.4, filtered and
concentrated. The crude material, 4.81 g of clear oil, was purified
by flash column chromatography on silica gel eluting with 10% ethyl
acetate in hexane to give 2.39 g (42%) of the desired
(2E)-5-[[(1,1-dimethylethyl-
)dimethylsilyl]oxy]-2-fluoro-2-penten-1-ol product as a clear oil,
that contained an approximate E:Z ratio of 93:7 by .sup.19F
NMR.
[0507] HRMS calcd. for C.sub.11H.sub.24FO.sub.2Si: m/z=235.1530
[M+H].sup.+, found: 235.1536.
[0508] .sup.1H NMR (CDCl.sub.3) .delta. 0.06 (s, 6H), 0.88 (s, 9H),
2.35 (m, 2H), 3.62 (t, 2H), 4.19 (dd, 2H), 5.2 (dt, vinyl, 1H).
[0509] .sup.19F NMR (CDCl.sub.3) .delta. -120.0 (dt, 0.07F, 7%
Z-isomer), -109.82 (q, 0.93 F, J=21 Hz, 93% E-isomer). 23
[0510] Example-1C) To a mixture of Example-1B (2.25 g, 9.58 mmol),
polymer-supported triphenylphosphine (3 mmol/g, 1.86 g, 15 mmol)
and 3-methyl-1,2,4-oxadiazolin-5-one (1.25 g, 12.5 mmol) in 60 mL
of THF was added dropwise diethylazodicarboxylate (2.35 mL, 14.7
mmol). The reaction mixture was stirred for 1 h at room
temperature, and additional 3-methyl-1,2,4-oxadiazolin-5-one (0.30
g, 3.0 mmol) was added. After 30 minutes, the mixture was filtered
through celite, and the filtrate was concentrated. The resulting
yellow oil was triturated with diethyl ether (30 mL) and the solid
removed by filtration. The filtrate was concentrated, triturated
with hexane (30 mL) and filtered. The filtrates was concentrated to
an oil which was purified by flash column chromatography on silica
gel eluting with 15% ethyl acetate in hexane-to give 1.83 g (60%)
of the desired 4-[(2E)-5-[[(1,1-dimethylethyl)dimethyls-
ilyl]oxy]-2-fluoro-2-pentenyl]-3-methyl-1,2,4-oxadi-azol-5(4H)-one
product as a clear oil, that contained only the desired E-isomer by
.sup.19F NMR.
[0511] HRMS calcd. for C.sub.14H.sub.26FN.sub.2O.sub.3Si:
m/z=317.1697 [M+H].sup.+, found: 317.1699.
[0512] .sup.1H NMR (CDCl.sub.3) .delta. 0.04 (s, 6H), 0.85 (s, 9H),
2.28 (s, 3H), 2.37 (m, 2H), 3.64 (t, 2H), 4.32 (d, 2H), 5.4 (dt,
vinyl, 1H).
[0513] .sup.19F NMR (CDCl.sub.3) .delta. -10.20 (q, 1 F, J=21 Hz).
24
[0514] Example-1D) A solution of Example-1C (1.83 g, 5.78 mmol) in
a mixture of acetic acid (6 mL), THF (2 mL) and water (2 mL) was
stirred at room temperature for 2.5 hours. The resulting solution
was concentrated in vacuo to an oil which was dissolved in diethyl
ether (50 mL). The organic layer was washed with saturated
NaHCO.sub.3, and the aqueous layer was extracted with diethyl ether
(2.times.50 mL) and ethyl acetate (2.times.50 mL). The combined
organic layers were dried (MgSO.sub.4), filtered and evaporated to
give 1.15 g (98%) of the desired
4-[(2E)-2-fluoro-5-hydroxy-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4H)-one
product as a clear colorless oil.
[0515] HRMS calcd. for C.sub.8H.sub.12FN.sub.2O.sub.3: m/z=203.0832
[M+H].sup.+, found: 203.0822.
[0516] .sup.1H NMR (CDCl.sub.3) .delta. 2.31 (3H), 2.4 (m, 2H),
3.66 (t, 2H), 4.37 (d, 2H), 5.42 (dt, vinyl, 1H). .sup.19F NMR
(CDCl.sub.3) .delta. -110.20 (q, 1 F, J=21 Hz). 25
[0517] Example-1E) To a CH.sub.2Cl.sub.2 (2 mL) solution of
triphenylphosphine (238 mg, 0.91 mmol) and imidazole (92 mg) at
0.degree. C. was added solid iodine (230 mg, 0.91 mmol), and the
mixture was stirred for 5 minutes. To the resulting yellow slurry
was added a CH.sub.2Cl.sub.2 (1.5 mL) solution of Example-1D (0.15
g, 0.74 mmol). The slurry was allowed to warm to room temperature
and stirred 30 minutes. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (10 mL), washed with saturated
Na.sub.2S.sub.2O.sub.3 (5 mL) and brine (5 mL), dried (MgSO.sub.4),
filtered and evaporated to an oil. Addition of diethyl ether (10
mL) to the oil gave a white precipitate that was removed by
filtration and the filtrate was concentrated to an oil. The crude
material was purified by flash column chromatography on silica gel
eluting with 30% ethyl acetate in hexane to give 0.18 g (78%) of
the desired
4-[(2E)-2-fluoro-5-iodo-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4H-
)-one product as a clear oil, which solidified upon standing,
mp=58.1-58.6.degree. C.
[0518] Anal. calcd. for C.sub.8H.sub.10FN.sub.2O.sub.2: C, 30.79;
H, 3.23; N, 8.98. Found: C, 30.83; H, 3.11; N, 8.85. HRMS calcd.
for C.sub.8H.sub.11FIN.sub.2O.sub.2: m/z=330.0115 [M+H].sup.+,
found: 330.0104.
[0519] .sup.1H NMR (CDCl.sub.3) .delta. 2.31 (s, 3H), 2.75 (q, 2H),
3.21 (t, 2H), 4.31 (d, 2H), 5.39 (dt, vinyl, 1H). .sup.19F NMR
(CDCl.sub.3) .delta. -108.21 (q, 1F, J=21 Hz). 26
[0520] Example-1F) To a 1-methyl-2-pyrrolidinone (12 mL) solution
of (3S,
6R)-6-isopropyl-3-methyl-5-phenyl-3,6-dihydro-2H-1,4-oxazin-2-one
(Synthesis, 1999, 4, 704-717) (1.10 g, 4.76 mmol), LiI (0.63 g,
4.76 mmol) and Example-1E (0.85 g, 2.72 mmol) in an ice bath was
added
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphor-
ine (1.38 mL, 4.76 mmol). The yellow solution became orange upon
addition of the base, and the resulting solution was allowed to
stir at room temperature for 1 hour. The reaction mixture was
diluted with ethyl acetate (100 mL), washed with water (2.times.30
mL), dried (MgSO.sub.4), filtered and evaporated to a yellow oil.
The crude material was purified by flash column chromatography on
silica gel eluting with 30% ethyl acetate in hexane to give 0.64 g
(57%) of the desired alkylated product as a clear oil.
[0521] .sup.1H NMR (C.sub.6D.sub.6) .delta. 0.57 (d, 3H), 0.89 (d,
3H), 1.30 (s, 3H), 1.65 (s, 3H), 1.8 (m, 2H), 2.0 (m, 2H), 2.1 (m,
1H), 3.22 (m, 2H), 4.88 (dt, vinyl, 1H), 5.49 (d, 1H), 7.1 (m, 3H),
7.6 (m, 2H). .sup.19F NMR (CDCl.sub.3) .delta. -110.37 (q, 1 F,
J=21 Hz). 27
[0522] Example-1G) To a methanol (20 mL) solution of Example-1F
(0.13 g, 0.31 mmol) was added Lindlar catalyst (1.0 g). The stirred
slurry was heated to 60.degree. C. for 1 hour, and additional
Lindlar catalyst (0.30 g) was added. The slurry was stirred an
additional 1 hour at 60.degree. C., then cooled to room
temperature. The catalyst was removed by filtration through celite,
and the filtrate was stripped to give 0.58 g (100%) of the desired
deprotected amidine product as a pale yellow oil.
[0523] MS: m/z=374.2 [M+H].sup.+
[0524] .sup.1H NMR (CD.sub.3OD) .delta. 0.77 (d, 3H), 1.07 (d, 3H),
1.58 (s, 3H), 2.02 (s, 3H), 1.8-2.2 (m, 5H), 3.83 (d, 2H), 5.20
(dt, vinyl, 1H), 5.69 (d, 1H), 7.4 (m, 3H), 7.7 m, 2H)
[0525] .sup.19F NMR (CDCl.sub.3) .delta. -109.4 (m, 1F, J=21
Hz)
[0526] Example-1) A solution of the product from Example-1G (0.58
g, 1.54 mmol) in 1.5 N HCl (25 mL) was washed with diethyl ether
(2.times.20 mL) and refluxed for 1 hour. The solvent was stripped
and the crude amino acid ester was dissolved in 6 N HCl (15 mL) and
heated to reflux. After six hours, the solvent was removed in
vacuo, and the resulting foam was purified by reverse-phase HPLC
eluting with a 30 minute gradient of 0-40% CH.sub.3CN/H.sub.2O
0.25% acetic acid). Fractions containing product were combined and
concentrated to a foam. The product was dissolved in 1 N HCl and
the solvent removed in vacuo (2.times.) to give 0.15 g (29%) of the
desired
(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-hepte-
noic acid, dihydrochloride product.
[0527] HRMS calcd. for C.sub.10H.sub.19FN.sub.3O.sub.2:
m/z=232.1461 [M+H].sup.+, found: 232.1485.
[0528] .sup.1H NMR (D.sub.2O) .delta. 1.43 (s, 3H), 2.10 (s, 3H),
1.8-2.1 (m, 4H), 3.98 (d, 2H) 5.29 (dt, vinyl, 1H). .sup.19F NMR
(CDCl.sub.3) .delta. -109.97 (q, 1 F, J=21 Hz). 28
EXAMPLE 2
[0529] 29
(2S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0530] 30
[0531] Example-2A) To a 1-methyl-2-pyrrolidinone (7500 mL) solution
of methyl N-[(3,4-dichlorophenyl)-methylene]-alaninate (748.5 g,
2.88 mol) under nitrogen was added LiI (385.5 g, 2.88 mol) and the
resulting slurry stirred approximately 20 minutes to give a clear
solution. The solid from Example-1E (750 g, 2.40 mol) was then
added and the resulting solution cooled in an ice bath to
.about.0.degree. C. Neat BTPP (900 g, 2.88 mol) was added dropwise
over 25 minutes maintaining the internal temperature below
5.degree. C. After stirring for an additional 1.5 hour at 5.degree.
C., the reaction was determined to be complete by HPLC. At this
time, 7500 mL of methyl t-butyl ether (MTBE) was added followed by
addition of 9750 mL of a water/crushed ice mixture. The temperature
rose to 20.degree. C. during this operation. After stirring
vigorously for 5-10 minutes, the layers were separated and the
aqueous layer washed with twice with 6000 mL of MTBE. The MTBE
layers were combined and washed two times with 7500 mL of water.
The resulting MTBE solution was then concentrated to .about.5000
mL, treated with 11625 mL of 1.0 N HCl, and stirred vigorously at
room temperature for one hour. The layers were separated and the
aqueous layer washed with 7500 ml of MTBE. About 1 kg of sodium
chloride was added to the aqueous layer and the resulting mixture
stirred until all the salt had dissolved. At this point, 7500 mL of
ethyl acetate was added, the resulting mixture cooled to 10.degree.
C., and 2025 mL of 6.0 N sodium hydroxide added with good
agitation. The resulting pH should be about 9. The layers were
separated and the aqueous layer was saturated with sodium chloride
and extracted again with 7500 mL of ethyl acetate. The combined
ethyl acetate extracts were dried (MgSO.sub.4) and concentrated to
a light oil. It should be noted that the ethyl acetate was not
complete removed. With agitation, 3000 ml of hexane then is added
to generate a slurry that was cooled to 10.degree. C. The granular
solid was collected by filtration and washed with 1500 mL of
hexane. About 564 g (82% yield) of the desired pure aminoester
(>95% pure by HPLC) was obtained as a white solid, m.p.
82.9-83.0.degree. C. LCMS: m/z=288.2 [M+H].sup.+. Chiral HPLC
(Chiralpak-AD normal phase column, 100% acetonitrile, 210 nm, 1
mL/min): Two major peaks at 4.71 and 5.36 min (1:1).
[0532] .sup.1H NMR (CDCl.sub.3): .delta. 1.40 (s, 3H), 1.7-1.8 (m,
2H), 2.0 (br s, 2H), 2.2 (m, 2H), 2.29 (s, 3H), 3.73 (s, 3H), 4.34
(dd, 2H), 5.33 (dt, 1H). 31
[0533] Example-2B) Separation of the individual enantiomers of the
product from Example-2A was accomplished on preparative scale using
chiral HPLC chromatography (ChiralPak-AD, normal phase column, 100%
acetonitrile) to give the desired pure (2S)-2-methyl amino ester
product title product. ChiralPak-AD, normal phase column, 100%
acetonitrile, 210 nm, 1 mL/min): 5.14 min (99%). 32
[0534] Example-2C) A slurry of the product of Example-2B (2.30 g,
8.01 mmol) in 0.993 M NaOH (30.0 ml, 29.79 mmol) was stirred 2
hours at room temperature. To the resulting clear colorless
solution was added 1.023 M HCl (29.10 mL, 29.76 mmol). The
resulting clear solution was concentrated until a precipitate began
to form (approx. 30 mL). The slurry was warmed to give a clear
solution that was allowed to stand at room temperature overnight.
The precipitate was isolated by filtration. The solid was washed
with cold water (2.times.10 mL), cold methanol (2.times.10 mL) and
Et.sub.2O (2.times.20 mL). The white solid was dried in vacuo at
40.degree. C. 4 hours to give 1.04 g (53%) of the desired N-hydroxy
illustrated product. mp=247.2.degree. C.
[0535] Anal. calcd. for C.sub.10H.sub.18FN3O.sub.3: C, 48.57; H,
7.34; N, 16.99; Cl, 0.0. Found: C, 48.49; H, 7.37; N, 16.91; Cl,
0.0.
[0536] HRMS calcd. for C.sub.10H.sub.19FN.sub.3O.sub.3:
m/z=248.1410 [M+H].sup.+, found: 248.1390.
[0537] .sup.1H NMR (D.sub.2O) .delta. 1.35 (s, 3H), 1.81 (s, 3H),
1.7-2.0 (m, 4H), 3.87 (d, 2H) 5.29 (dt, vinyl, 1H). .sup.19F NMR
(CDCl.sub.3) .delta. -112.51 (q, 1 F, J=21 Hz).
[0538] Example-2) To a solution of Example-2C in methanol is added
Lindlar catalyst. The stirred slurry is refluxed for 2 hours, then
cooled to room temperature. The catalyst is removed by filtration
through celite, and the filtrate is stripped. The resulting solid
is dissolved in water and concentrated repeatedly from 1.0 N HCl to
give the desired
(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride product. 33
[0539] Example-2D) A solution of 73.5 g (0.3 mol) of the product
from Example-2B was dissolved in 300 mL of methanol and added
dropwise to a preformed mixture of 13.7 g of Lindlar catalyst and
73.5 g of formic acid (1.53 mol) in 312 mL of methanol while
maintaining the reaction temperature between 22.degree. C. and
26.degree. C. After stirring at room temperature for an additional
15 hrs, the reaction was determined to be complete by F.sup.19 NMR.
The resulting reaction mixture was filtered through celite and the
celite washed 3 times with 125 mL of methanol. The methanol
filtrates were combined and concentrated to generate 115 g of the
desired amidine title product as a viscous oil.
[0540] MS: m/z=246 (M+H).sup.+.
[0541] .sup.1H NMR (CD.sub.3OD) .delta.1.6 (s, 3H) 2.0-2.2 (m, 4H)
2.3 (s, 3H), 3.9 (s, 3H), 4.2 (d, 2H), 5.4 (dt,vinyl), 8.4 (s,
3H).
[0542] F.sup.19 NMR (CD.sub.3OD) .delta. -110.4 (q, J=21 Hz) -111.7
(q, J=21 Hz).
[0543] In order to remove trace levels of lead, the crude product
was dissolved in 750 mL of methanol and 150 g of a thiol-based
resin (Deloxan THP 11) was added. After stirring 3 hrs at room
temperature, the resin was filtered off and washed 2 times with 500
mL methanol. The filtrates were collected and concentrated to 99 g
of the desired amidine title product as a viscous oil.
[0544] Alternatively:
[0545] A total of 5.0 g of the product from Example-2B (0.0174
mole, 1.0 equiv) was mixed with 5.0 g of zinc dust (0.0765 moles,
4.39 equiv) in 40 mL of 1-butanol and 10 mL of acetic acid. After
stirring for 5 hrs at 50.degree. C., LC analyses indicated the
reaction to be complete. The solids were readily filtered off. The
filtrate, after cooling in ice water to 7.degree. C., was treated
with 30 mL of 6 N NaOH (0.180 moles) in one portion with vigorous
stirring. After cooling the reaction mixture from 33.degree. C. to
20.degree. C., the clear butanol layer was separated off and the
aqueous layer extracted again with 40 mL of 1-butanol. The butanol
extracts were combined, washed with 30 mL of brine followed by
approx 10 mL of 6N HCl. After concentration at 70.degree. C., a
clear glass resulted which was identified as the desired amidine
title product.
[0546] Example-2) A solution of 99 g of the product from Example-2D
in 6 N HCl was refluxed for 1 hr at which time LC analyses
indicated the reaction to be complete. The solvent was removed in
vacuo to yield 89.2 g of a glassy oil which was dissolved in a
mixture of 1466 mL ethanol and 7.5 ml of deionized water. THF was
added to this agitated solution at ambient temperature until the
cloud point was reached (5.5 liters). An additional 30 ml of
deionized water was added and the solution agitated overnight at
room temperature. The resulting slurry was filtered and washed with
200 mL of THF to yield 65 g of a white solid identified as the
desired title product.
[0547] [.alpha.].sub.D.sup.25=+7.2 (c=0.9, H.sub.2O)
[0548] mp=126-130.degree. C.
[0549] MS: m/z=232 (M+H).sup.+.
[0550] Anal. Calcd for
C.sub.10H.sub.22N.sub.3F.sub.1O.sub.3Cl.sub.2: C, 37.28; H, 6.88;
N, 13.04; Cl, 22.01. Found: C, 37.52, H, 6.84, N, 13.21, Cl,
21.81.
[0551] .sup.1H NMR (D.sub.2O) .delta. 1.4 (s, 3H), 1.8-2.1 (m, 4H),
1.9 (s,3H), 4.0(d, 2H), 5.3(dt, vinyl, 1H).
[0552] F.sup.19 NMR (D.sub.2O) .delta. -109.6 (q, J=21 Hz) -112.1
(q, J=21 Hz). 34
EXAMPLE 3
[0553] 35
(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0554] 36
[0555] Example-3A) Separation of the individual enantiomers of the
product from Example-2A was accomplished on preparative scale using
chiral HPLC chromatography to give the desired pure (2R)-2-methyl
amino ester product. 37
[0556] Example-3B) The product from Example-3A is dissolved in
water and acetic acid. Zinc dust is added, and the mixture is
heated at 60.degree. C. until HPLC analysis shows that little of
the starting material remains. The Zn is filtered through celite
from the reaction mixture, and the filtrate is concentrated. The
crude material is purified by reverse-phase HPLC column
chromatography. Fractions containing product are combined and
concentrated affording the desired (2R)-2-methyl acetamidine
product.
[0557] Example-3) A solution of Example-3B in 2.0 N HCl is refluxed
for 2 h. The solvent is removed in vacuo. The resulting solid is
dissolved in water and concentrated repeatedly from 1.0 N HCl to
give the desired
(2R,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride product. 38
EXAMPLE 4
[0558] 39
(2R/S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0559] 40
[0560] Example-4A) To an 1-methyl-2-pyrrolidinone (5 mL) solution
of methyl N-[(4-chlorophenyl)methylene]-glycinate (0.33 g, 1.6
mmol), LiI (0.20 g, 1.0 mmol) and a sample of the product of
Example-1E (0.30 g, 0.96 mmol) in an ice bath was added
2-tert-butylimino-2-diethylamino-1,3--
dimethylperhydro-1,3,2-diazaphosphorine (0.433 mL, 1.5 mmol). The
solution was allowed to stir at room temperature for 1.5 hours. The
reaction mixture was diluted with ethyl acetate (30 mL), washed
with water (2.times.20 mL), dried (MgSO.sub.4), filtered, and
evaporated to give the crude desired racemic alkylated imine as a
yellow oil.
[0561] The crude material was dissolved in ethyl acetate (10 mL)
and 1N HCl (10 mL) was added. The mixture was stirred for 2 hours
at room temperature, and the organic layer was separated. The
aqueous layer was neutralized with solid NaHCO.sub.3 and extracted
with ethyl acetate (2.times.30 mL). The organic layer was dried
(MgSO.sub.4), filtered and evaporated to give 0.13 g of the desired
title racemic amino ester product as a yellow oil. This product was
used in the next step without further purification. LCMS: m/z=288.2
[M+H].sup.+. 41
[0562] Example-4B) To a CH.sub.2Cl.sub.2 (15 mL) solution of
Example-4A (1.36 g, 4.98 mmol) was added 4-chlorobenzaldehyde (0.70
g, 5.0 mmol) and MgSO.sub.4 (.about.5 g). The slurry was stirred at
room temperature for 18 hours. The slurry was filtered, and the
filtrate stripped to give 1.98 g (100%) of the desired title imine
product as a pale yellow oil. This product was used in the next
step without further purification.
[0563] .sup.1H NMR (C.sub.6D.sub.6) .delta. 1.34 (s, 3H), 2.0 (br
m, 4H), 3.32 (s, 3H), 3.42 (m, 2H), 3.83 (t, 1H), 4.98 (dt, vinyl,
1H). 42
[0564] Example-4C) To a CH.sub.2Cl.sub.2 (2 mL) solution of the
product of Example-4B (0.25 g, 0.63 mmol) was added methyl iodide
(0.200 mL, 3.23 mmol) and
O(9)-allyl-N-(9-anthracenylmethyl)-cinchonidinium bromide (40 mg,
0.066 mmol). The solution was cooled to -78.degree. C. and neat
BTPP (0.289 mL, 0.95 mmol) was added. The resulting orange solution
was stirred at -78.degree. C. for 2 hours and allowed to reach
-50.degree. C. After 2 hours at -50.degree. C., the solution was
diluted with CH.sub.2Cl.sub.2 (10 mL), washed with water (10 mL),
dried (MgSO.sub.4), filtered, and evaporated to give the crude
desired racemic alkylated imine as a yellow oil.
[0565] The crude material was dissolved in ethyl acetate (10 mL)
and 1N HCl (10 mL) was added. The mixture was stirred for 1 hour at
room temperature, and the organic layer was separated. The aqueous
layer was neutralized with solid NaHCO.sub.3 and extracted with
ethyl acetate (2.times.30 mL). The organic layer was dried
(MgSO.sub.4), filtered and evaporated to give 0.16 g of the desired
racemic 2-methylamino ester product as a yellow oil. The product
was used in the next step without further purification. LCMS:
m/z=288.2 [M+H].sup.+. 43
[0566] Example-4D) The racemic product from Example-4C is dissolved
in water and acetic acid. Zinc dust is added, and the mixture is
heated at 60.degree. C. until HPLC analysis shows that little of
the starting material remains. The Zn dust is filtered through
celite from the reaction mixture, and the filtrate is concentrated.
The crude material is purified by reverse-phase HPLC column
chromatography. Fractions containing product are combined and
concentrated affording the desired acetamidine product.
[0567] Example-4) A solution of racemic Example-4D in 2.0 N HCl is
refluxed for 1 h. The solvent is removed in-vacuo. The resulting
solid is dissolved in water and concentrated repeatedly from 1.0 N
HCl to give the desired title
(2R/S,5E)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-
-5-heptenoic acid, dihydrochloride product. 44 45
EXAMPLE 5
[0568] 46
(2R/S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0569] 47
[0570] Example-5A) Phosphono fluoroacetate (10.75 mL, 53 mmol) was
dissolved in 90 mL methylene chloride and cooled to 0.degree. C.
under Argon. DBU (8 mL, 53 mmol) was added. An exotherm was
observed raising the temperature to 5.degree. C. The reaction was
stirred between 5-10.degree. C. for 10 min. It was then cooled back
down to -5.degree. C. N-tertiary butyloxycarbonyl glycinal (7 g, 44
mmol) dissolved in 90 mL of methylene chloride was added drop-wise
to the aforementioned anionic solution. The temperature was
maintained between 0-5.degree. C. during the addition. The reaction
mixture slowly raised to room temperature and was stirred for 12
hours. The resulting mixture was extracted with 175 mL of 0.5 N
aqueous potassium bisulfate solution. The organic layer was washed
with 50% sodium chloride solution, dried (sodium sulfate), filtered
and stripped in vacuo to yield a dark oil which was the title
material (10 g, 92% crude yield).
[0571] .sup.1H NMR (CDCl.sub.3) .delta.: 1.3-1.4 (m, 3H), 1.45 (s,
9H), 3.95-4.0 (m, 2H), 4.2-4.4 (m, 2H), 6.0-6.2 (m, 1H) 48
[0572] Example-5B) The title material from Example 5A (8.1 g, 33
mmol) dissolved in tetrahydrofuran under Argon was cooled down to
0.degree. C. Lithium borohydride in tetrahydrofuran (20 mL, 39.6
mmol) was then added to this solution dropwise maintaining the
temperature between 0-5.degree. C. The reaction mixture slowly rose
to room temperature and was stirred for 12 hours. The solvent was
removed in vacuo. The residue was then dissolved in 150 mL of
methylene chloride and this solution was extracted with 100 mL of
0.5N aqueous potassium bisulfate solution. The organic layer was
dried (sodium sulfate), filtered and stripped in vacuo to yield 13
g of a dark oil which was purified on silica gel to give both the Z
and E isomer of the title material in a 60/40 ratio and an overall
yield (including overlap) of 97%.
[0573] Z-isomer:
[0574] .sup.1H NMR (CDCl.sub.3) .delta.: 1.4-1.5 (s, 9H), 3.75-3.85
(m, 2H), 4.24-4.32 (m, 2H), 5.15-5.25 (m, 1H)
[0575] E-isomer:
[0576] .sup.1H NMR (CDCl.sub.3) .delta.: 1.4-1.5 (s, 9H), 3.75-3.78
(m, 2H), 4.1-4.15 (m, 2H), 4.95-5.1 (m, 1H) 49
[0577] Example-5C) The E-isomer from Example-5B was dissolved in
acetonitrile and cooled to 0.degree. C. Pyridine (1.5 eqv) was then
added followed by solid dibromotriphenylphosphorane (1.3 eqv) added
portion-wise over 10 min. The reaction mixture was stirred under
Argon for 24 hours at room temperature. The precipitate formed was
filtered off. The filtrate was concentrated in vacuo to give an oil
that was purified on silica gel to give the title material. 50
[0578] Example-5D) The compound from Example-5B is dissolved in dry
Tetrahydrofuran. Magnesium turnings are then added (2 eqv) to the
reaction vessel. The reaction mixture is then heated to a reflux
and maintained for 1 hour. N,N-Dimethylformamide (2 eqv) is added.
The reaction mixture is refluxed for an additional two hours before
it is cooled to room temperature. The mixture is filtered and the
filtrate is stripped in vacuo to give the title material. 51
[0579] Example-5E) The product from Example-5D is dissolved in
Tetrahydrofuran and cooled to 0.degree. C. under nitrogen. Lithium
borohydride in THF (1.05 eqv) is then added slowly keeping the
temperature between 0-5.degree. C. The temperature of the reaction
mixture is then raised to room temperature and the mix is stirred
overnight. The solvent is removed in vacuo. The residue is
dissolved in methylene chloride and extracted with a 0.5 N aqueous
potassium bisulfate solution. The organic layer is washed with 50%
sodium chloride solution, dried (sodium sulfate) and stripped to
give the title material. 52
[0580] Example-5F) The product of Example-5E is dissolved in
acetonitrile. This solution is cooled to 0.degree. C. before
pyridine (1.5 eqv) is added. Solid dibromotriphenylphosphorane (1.3
eqv) is then added portion-wise over 10 min. The reaction mixture
is stirred under Argon for 24 hours at room temperature. The
precipitate formed is filtered off and the filtrate concentrated in
vacuo to give an oil that is purified on silica gel to give the
desired bromo derivative. 53
[0581] Example-5G) N-p-chloro phenylimine alanine methyl ester is
dissolved in tetrahydrofuran and this solution is purged with
Argon. NaH (1.2 eqv) is then added whereupon the solution turns
bright orange and subsequently a deep red. A solution of the title
material from Example-5F in tetrahydrofuran is added to the above
anionic solution. An exotherm is expected raising the temperature
to near 40.degree. C. The reaction mixture is maintained between
48-52.degree. C. for 2 hours before it is cooled to room
temperature and filtered. The filtrate is stripped in vacuo to
yield the title material. 54
[0582] Example-5H) The product of Example-5G is treated with 1N
hydrochloric acid and the solution is stirred for an hour at room
temperature. This solution is extracted with ethylacetate and the
aqueous layer is stripped in vacuo at 56.degree. C. to yield the
title material. 55
[0583] Example-5I) The product of Example-5H is dissolved in
distilled water and copper carbonate (0.5 eqv) is then added after
the pH is adjusted to 7 with 1N NaOH. The reaction mixture is
refluxed for 2 hours and then cooled to room temperature and
filtered. Ethyl acetamidate hydrochloride (1.1 eqv) is then added
portion-wise to this filtrate with stirring and adjusting the pH to
8.5 after each portion is added. The reaction mixture is then
stirred for an hour before it is applied to a cation exchange resin
column and eluted with 0.8 N aqueous ammonia. The ammonia is
removed from eluant in vacuo. The eluant is subsequently acidified
with 2N Hydrochloric acid to pH 2 and concentrated to dryness. The
residue is then purified on reverse phase HPLC to yield the title
material.
[0584] Example-5) The product of Example-5I is dissolved in 2N
hydrochloric acid. This reaction mixture is heated to a reflux and
stirred for 6 hours before it is cooled to room temperature. The
solvent is then removed in vacuo. The residue is dissolved in water
and subsequently stripped on the rotary evaporator to remove excess
hydrochloric acid. The residue is again dissolved in water and
lyophilized to give the title E-isomer product.
EXAMPLE 6
[0585] 56
(2R/S,5Z)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0586] 57
[0587] Example 6A) The Z-isomer from Example 5B is dissolved in
acetonitrile and this solution was cooled to 0.degree. C. Pyridine
(1.5 eqv) is then added followed by the addition of solid
dibromotriphenylphosphorane (1.3 eqv) added portion-wise over 10
min. The reaction mixture is stirred under Argon for 24 hours at
room temperature. A precipitate formed is filtered off. The
filtrate is then concentrated in vacuo to give an oil that is
purified on silica gel to give the title material. 58
[0588] Example 6B) The product of Example 6A is dissolved in dry
tetrahydrofuran. Magnesium turnings are then added (2 eqv) to the
solution. The reaction mixture heated to a reflux and maintained
for 1 hour. N,N-Dimethylformamide (2 eqv) is then added. The
reaction mixture is refluxed for an additional two hours, cooled to
room temperature and filtered. The filtrate is stripped in vacuo to
give the title material. 59
[0589] Example 6C) The product of Example-6B is dissolved in
tetrahydrofuran and this solution cooled to 0.degree. C. under
nitrogen. Lithium borohydride in THF (1.05 eqv) is added slowly
keeping the temperature between 0-5.degree. C. The temperature of
the reaction mixture is raised to room temperature and the mix is
stirred overnight. The solvent is removed in vacuo. The residue is
dissolved in methylene chloride and extracted with 0.5 N aqueous
potassium bisulfate solution. The organic layer is washed with 50%
sodium chloride solution, dried (sodium sulfate) and stripped to
give the title material. 60
[0590] Example 6D) The product of Example 6C is dissolved in
acetonitrile and the solution cooled to 0.degree. C. Pyridine (1.5
eqv) is then added followed by solid dibromotriphenylphosphorane
(1.3 eqv) added portion-wise. The reaction mixture is stirred under
Argon for 24 hours at room temperature. A precipitate formed is
filtered off. The filtrate is concentrated in vacuo to give an oil
that is purified on silica gel to give the desired title bromo
derivative. 61
[0591] Example 6E) N-p-chloro phenylimine alanine methyl ester is
dissolved in tetrahydrofuran and this solution is purged with
Argon. NaH (1.2 eqv) is added whereupon the solution turns bright
orange and subsequently a deep red. A solution of the product of
Example 6D dissolved in tetrahydrofuran is added to the above
anionic solution. An exotherm is observed and the reaction mixture
is maintained between 48-52.degree. C. for 2 hours. The reaction is
cooled to room temperature and filtered. The filtrate is stripped
in vacuo to yield the title material. 62
[0592] Example 6F) The product of Example 6E is treated with 1N
hydrochloric acid and the solution is stirred for an hour at room
temperature before it is extracted with ethylacetate. The aqueous
layer is stripped in vacuo at 56.degree. C. to yield the title
material. 63
[0593] Example 6G) The product of Example 6F is dissolved in
distilled water. Copper carbonate (0.5 eqv) is added after the pH
was adjusted to 7 with 1N NaOH. The reaction mixture is refluxed
for 2 hours and then cooled to room temperature and filtered. Ethyl
acetamidate hydrochloride (1.1 eqv) is added portion-wise to this
filtrate with stirring and adjusting the pH to 8.5 after every
portion added. The reaction mixture is stirred for an hour before
it is applied to a cation exchange resin column, eluting with 0.8 N
aqueous ammonia. The ammonia is removed from eluant in vacuo. The
eluant is subsequently acidified with 2N Hydrochloric acid to pH 2
and concentrated to dryness. The residue is purified on reverse
phase HPLC to yield the title material.
[0594] Example 6) A solution the product of Example 6G dissolved in
15 mL of 2N hydrochloric acid is heated to a reflux and stirred for
6 hours. After cooling this solution to room temperature, solvent
is removed in vacuo. The residue is dissolved in 25 mL of water and
stripped on the rotary evaporator to remove excess hydrochloric
acid. The residue is dissolved in water and lyophilized to give the
title Z-isomer.
EXAMPLE 7
[0595] 64
(2R,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 8
[0596] 65
(2S,5E)-2-amino-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0597] 66
EXAMPLE 9
[0598] 67
(2S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 10
[0599] 68
(2R,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 11
[0600] 69
(2R/S,5Z)-2-amino-2-methyl-5,6-difluoro-7-[(1-iminoethyl)amino]-5-heptenoi-
c acid, dihydrochloride
[0601] 70
EXAMPLE 12
[0602] 71
(2S,5Z)-2-amino-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0603] 72
EXAMPLE 13
[0604] 73
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride
[0605] 74
[0606] Example-13A) The title compound,
(Z)-5-t-butyldimethylsilyloxy-2-pe- nten-1-ol, was prepared from
5,5-dihydro-2-pyrone (Aldrich) by the method of Harold, Mohr and
Tamm Helvetica Chimica Acta 66,2, 1983 744-754. 75
[0607] Example-13B) To a solution of Example-13A (720 mg, 3.3 mmol)
in CH.sub.2Cl.sub.2 (25 mL) was added Et.sub.3N (525 mg, 5.3 mmol)
and methanesulfonyl chloride (561 mg, 4.90 mmol). The reaction
mixture was stirred for 15 min at 0.degree. C. then at room
temperature for 16 h. Additional CH.sub.2Cl.sub.2 was added. The
solution was extracted with NaHCO.sub.3 and brine before it was
dried to yield 790 mg of a yellow oil. The oil was dissolved in DMF
(20 mL) and Na salt of 3-methyl-1,2,4-oxadiazolin-5-one (513 mg,
3.7 mmol) was added to the reaction mix. The resulting solution was
stirred at 50.degree. C. for 16 h. The solvent was removed in vacuo
and the residue partitioned between EtOAc and brine. The organic
layer was dried (Na.sub.2SO.sub.4) and concentrated to yield an oil
which was purified by flash column chromatography on silica gel
eluting with ether:hexane (1:1) to give 780 mg (79%) of the desired
protected Z-allylic cyclic amidine product as a clear oil that
contained only the desired Z-isomer by .sup.1HNMR. 76
[0608] Example-13C) A solution of Example-13B (100 mg, 0.34 mmol)
in a mixture of acetic acid (1 mL), THF (3 mL) and water (1 mL) was
stirred at room temperature for 16 hours. The resulting solution
was concentrated in vacuo to an oil which was dissolved in EtOAc.
The organic layer was washed with saturated NaHCO.sub.3, dried
(Na.sub.2SO.sub.4), filtered and evaporated to give 80 mg (quant.)
of the desired alcohol title product as a clear colorless oil.
77
[0609] Example-13D) To a CH.sub.2Cl.sub.2 (3 mL) solution of
Example-13C (80 mg, 0.43 mmol) was added Et.sub.3N (44 mg) and
triflic anhydride (146 mg, 0.52 mmol) at 0.degree. C., the mixture
was stirred for 1.5 h. The solution was concentrated in vacuo. The
crude material was purified by flash column chromatography on
silica gel eluting with EtOAc:hexane (1:1) to give 62 mg (44%) of
the desired triflate product as a clear oil. 78
[0610] Example-13E) To a THF (10 mL) solution of
(2S,4S)-3-benzoyl-2-t-but- yl-4-methyl-1,3-oxazolidin-5-one (Ref.)
(532 mg, 2.04 mmol) at -78.degree. C. was added KHMDS (4.48 mL, 2.2
mmol, 0.5 M in THF). The resulting orange colored solution was
stirred for 15 min. followed by the addition of the product of
Example 13D (580 mg, 1.8 mmol). The resulting solution was allowed
to warm to room temperature followed by the addition of KHSO.sub.4
(10%, 1.5 mL) brine and EtOAc. The organic layer was separated,
dried and concentrated in vacuo to yield 960 mg of a yellow oil.
The crude material was purified by flash column chromatography on
silica gel eluting with EtOAc:hexane (1:1) to give 138 mg (18%) of
the desired alkylated title product as a clear oil.
[0611] Example-13) To a methanol (10 mL) solution of the product of
Example-13E (138 mg, 0.32 mmol) was added Lindlar catalyst (260
mg). The stirred slurry was refluxed for 2 hours and then cooled to
room temperature. The catalyst was removed by filtration through
celite, and the filtrate was stripped to give the desired
deprotected amidine product as a pale yellow oil. A solution of the
yellow oil in HCl (6N, 10 mL) was refluxed for 1.75 hours. The
solvent was removed in vacuo, and the resulting foam was purified
by reverse-phase HPLC eluting with a 30 minute gradient of 0-40%
CH.sub.3CN/H.sub.2O (0.25% acetic acid). Fractions containing
product were combined and concentrated to a foam. To give 34 mg
(20%) of the title product.
[0612] MS calcd. for C.sub.10H.sub.19N.sub.3O.sub.2: m/z=214
[M+H]+, found: 214. (100%)
[0613] The monhydrochloride product was dissolved in 1 N HCl and
the solvent removed in vacuo (2.times.) to give the desired
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride product.
[0614] MS calcd. for C.sub.10H.sub.19N.sub.3O.sub.2: m/z=214
[M+H]+, found: 214 (100%)
[0615] .sup.1H NMR (D.sub.2O) .delta. 1.40 (s, 3H), 1.5-2.0 (m, 4H)
1.90 (s, 3H), 3.55 (m, 2H) 5.15-5.25 (m, vinyl, 1H), 5.30-5.45 (m,
vinyl, 1H). 7980
EXAMPLE 14
[0616] 81
(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride
[0617] 82
4-[(Tetrahydropyranyl)oxy]butyne
[0618] Example 14A) A mixture of 4-dihydro-2H-pyridine (293.2 g 3.5
mol) and concentrated HCl (1.1 mL) was cooled to 5.degree. C. While
continuing to cool externally, 3-butyn-1-ol (231.5 g, 3.3 mol) was
added over a period of 30 minutes allowing the temperature to reach
50.degree. C. Reaction was held with mixing at room temperature for
2.5 hours before it was diluted with MTBE (1.0 L). The resulting
mixture was washed with saturated sodium bicarbonate (2.times.150
mL). The organic phase was dried over sodium sulfate and
concentrated under reduced pressure to afford 500 g (98% crude
yield) of product; GC area % of 96%. 83
5-(Tetrahydro-pyran-2-yloxy)-pent-2-yn-1-ol
[0619] Example 14B) To a solution of the
4-[(tetrahydropyranyl)oxy]butyne product of Example 14A (50.0 g,
0.33 mol) in THF (125 mL) was added a solution of 2N EtMgCl in THF
(242 mL, 0.48 mol) under a nitrogen atmosphere over a 30 minute
period, allowing the temperature to rise to 48.degree. C. Mixture
was further heated to 66.degree. C. and was held at this
temperature for 2 hours before cooling to ambient temperature.
Paraformaldehyde (14.5 g, 0.48 mol) was added (small exotherm was
observed) and the resulting mixture was heated to 45.degree. C.
After 1 hour of controlling the temperature between 45-55.degree.
C., the mixture turned clear. At this point, the mixture was heated
up to 66.degree. C. and stirred for 2.5 hours. Mixture was cooled
to room temperature and saturated ammonium chloride (125 mL) was
added slowly over 30 minutes (strong exotherm was observed) keeping
the temperature below 40.degree. C. The liquid phase was separated
by decantation; ethyl acetate (250 mL) and brine (50 mL) were
added. The organic phase was separated and washed with brine
(2.times.50 mL) and water (1.times.50 mL). The organic layer was
dried over sodium sulfate and concentrated under reduced pressure
to afford 51 g of a lightly yellow colored oil (85% crude yield);
GC area %=88% title product, 6% starting material. 84
5-(Tetrahydro-pyran-2-yloxy)-pent-2-en-1-ol
[0620] Example 14C) To a 500 mL Parr bottle, under a nitrogen
atmosphere, was charged the
5-(tetrahydro-pyran-2-yloxy)-pent-2-yn-1-ol product of Example 14B
(40.2 g, 0.22 mol), Lindlar catalyst (2.0 g), ethanol (120 mL),
hexane (120 mL), and 2,6-lutidine (457 mg). Reaction mixture was
purged five times each with nitrogen and hydrogen gas. Parr bottle
was pressurized with hydrogen to 5 psi and shaken until 98% of the
theoretical hydrogen was consumed. Hydrogen was released from the
vessel and the reaction was purged with nitrogen five times.
Mixture was filtered through a pad of Solka Floc and the catalyst
was rinsed with ethanol (2.times.50 mL). The filtrate and rinses
were combined and concentrated under reduced pressure to afford
40.3 g (99% yield) of the title material as a yellow colored oil
(GC area %=96%). 85
3-Methyl-4-[5-(tetrahydro-pyran-2-yloxy)-pent-2-enyl]-4H-[1,2,4]oxadiazol--
5-one
[0621] Example 14D) To a solution of the
5-(tetrahydro-pyran-2-yloxy)-pent- -2-en-1-ol product of Example
14C (11.8 g, 0.063 mol) in toluene (42 mL) was added) triethylamine
(6.4 g, 0.063 mol). The mixture was cooled to -5.degree. C. and
methanesulfonyl chloride (7.3 g, 0.63 mol) was added via syringe at
such rate as to keep the pot temperature below 10.degree. C. The
mixture was allowed to warm to room temperature and stirred for two
hours. The mixture was filtered by suction and rinsed on the filter
with toluene (2.times.20 mL). The filtrate and washes were added to
a mixture of the sodium salt of 3-methyl-1,2,4-oxadiazolin-5-one
(8.6 g, 0.063 mol) in DMF (10 mL). The mixture was stirred with a
mechanical stirrer and heated at 45.degree. C. for 5 hours. Water
(40 mL) was added and the mixture was stirred for 5 minutes and
then the layers were separated. The toluene layer was washed with
water (3.times.20 mL), dried over MgSO.sub.4, and concentrated to
afford 16.5 g (97.3%) of an orange colored crude product (area % GC
consisted of 71% title product, 18% toluene, and 4% of an
impurity). 86
4-(5-Hydroxy-pent-2-enyl)-3-methyl-4H-[1,2,4]oxadiazol-S-one
[0622] Example 14E) To a solution the
3-methyl-4-[5-(tetrahydro-pyran-2-yl-
oxy)-pent-2-enyl]-4H-[1,2,4]oxadi-az-ol-5-one product of Example
14D (16 g, 0.06 mol) in methanol (48 mL) was added
p-toluenesulfonic acid (0.34 g, 2.0 mmol). The mixture was stirred
at room temperature for four hours. Sodium bicarbonate (0.27 g, 3.0
mmol) was added and the mixture was concentrated on a rotary
evaporator. The residue was diluted with saturated NaHCO.sub.3 (20
mL) and the resulting mixture was extracted with ethyl acetate
(2.times.60 mL). Extracts were combined and washed with water
(2.times.25 mL), dried over MgSO.sub.4, and concentrated to afford
8.4 g of the crude, orange colored oil title product (area %
GC=80%). 87
Methanesulfonic acid
5-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-pent-3-enyl ester
[0623] Example 14F) To a solution of the
4-(5-Hydroxy-pent-2-enyl)-3-methy- l-4H-[1,2,4]oxadiazol-5-one
product of Example 14E (8.27 g, 0.045 mol) in methylene chloride
(33 mL) was added triethylamine (5.0 g, 0.49 mol). The mixture was
cooled to -5.degree. C. and methanesulfonyl chloride (5.5 g, 0.048
mol) was added at such rate as to keep the temperature below
8.degree. C. The cooling bath was removed and the mixture was
stirred for 3 hours as it warmed up to room temperature. Water (15
mL) was added and the mixture was stirred for 5 minutes and then
the layers were separated. The organic phase was washed with water
(10 mL), dried over MgSO.sub.4, and concentrated to give a light
amber colored residue. The residue was dissolved in ethyl acetate
(8 mL) and kept at 5.degree. C. overnight. Precipitated solids were
filtered off by suction and rinsed on the filter with minimum
volume of ethyl acetate and then air-dried on the filter to afford
6.8 g (58% yield) of the title product.
[0624] .sup.1H NMR (CDCl.sub.3) .delta. 5.76 (dtt, J=10.9, 7.5, 1.5
Hz, 1H), .delta. 5.59 (dtt, J=10.9, 7.0, 1.5 Hz, 1H), .delta. 4.31
(t, J=6.3 Hz, 2H), .delta. 4.27 (dd, J=7.0, 1.5 Hz, 2H), .delta.
3.04 (s, 3H), .delta. 2.67 (q, J=6.7 Hz, 2H), .delta. 2.28 (s,
3H)
[0625] .sup.13C (CDCl.sub.3) .delta. 159.0, 156.3, 129.9, 125.1,
68.4, 38.9, 37.2, 27.5, 10.2.
[0626] IR (cm.sup.-1) 1758, 1605, 1342,1320,1170.
[0627] Anal. Calcd. for C.sub.9H.sub.14N.sub.2O.sub.5S: C, 41.21;
H, 5.38; N, 10.68. Found: C, 41.15; H, 5.41; N, 10.51. 88
4-(5-Iodo-pent-2-enyl)-3-methyl-4H-[1,2,4]oxadiazol-5-one
[0628] Example 14G) To a solution of the methanesulfonic acid
5-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-pent-3-enyl ester product
of Example 14F (20.0 g, 0.076 mol) in acetone (160 ml) was added
sodium iodide (17.15 g, 0.114 mol). The mixture was heated to
reflux and was stirred for 3 hours. External heating, was stopped
and the mixture was held at room temperature overnight. Solids were
removed by filtration and rinsed on the filter. The filtrate and
washes were combined and concentrated and the heterogeneous residue
was extracted with ethyl acetate (120 mL). The organic layer was
washed with water (60 mL), 15% aqueous solution of sodium
thiosulfate (60 mL) and water (60 mL); dried over MgSO.sub.4 and
concentrated under reduced pressure to afford 22.1 g (98% yield) of
the title oil product. 89
2-[(3,4-Dichloro-benzylidene)-amino]-propionic acid methyl
ester
[0629] Example 14H) To a mechanically stirred slurry of L-alanine
methyl ester hydrochloride (200.0 g, 1.43 mol) in methylene
chloride (2.1 L) under a nitrogen atmosphere was added
triethylamine (199.7 mL, 1.43 mol) over 12 min (during the addition
solids partially dissolved and then reprecipitated). After 10 min,
3,4-dichlorobenzaldehyde (227.5 g, 1.30 mol) and magnesium sulfate
(173.0 g, 1.43 mol) were added (temperature increased 6.degree. C.
over 30 min). After 2.5 h, the mixture was filtered. The filtrate
was washed with water (1.times.1 L) and brine (1.times.500 mL),
dried over sodium sulfate, filtered and concentrated to give 313.3
g, 92.4% yield of oil product.
[0630] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.25 (s, 1H), 7.91
(d, 1H), 7.58 (dd, 1H), 7.49 (d, 1H), 4.17 (t, 1H), 3.76 (s, 3H),
1.53 (d, 3H). Anal. Calcd for C.sub.11H.sub.11C.sub.12NO.sub.2: C,
50.79; H, 4.26; Cl, 27.26; N, 5.38. Found: C, 50.37; H, 4.10; Cl,
26.87; N, 5.38. 90
Rac-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-hept-5-enoic
acid methyl ester
[0631] Example 141) Method A. A solution of the product of Example
14G (114.2 g, 0.39 mol) and the product of Example 14H (151.5 g,
0.58 mol) in dimethylformamide (1.4 L) under nitrogen atmosphere
was cooled to -8.degree. C. Lithium iodide (78.1 g, 0.58 mol) was
then added in 3 equal portions over 19 min. The mixture was stirred
for 20 min at -7.degree. C. and then
(tert-butylimino)-tris(pyrrolidino)phosphorane (194.0 mL, 0.62) was
added over 36 min (maximum temperature=-2.6.degree. C.). After 10
min, the cooling bath was removed and the solution was stirred at
ambient temperature for 1 h. The mixture was then poured into cold
water (1.4 L) and extracted with ethyl acetate (2.times.1.0 L). The
combined organic layers were washed with water (2.times.400 mL) and
brine. The ethyl acetate layer was treated with 1 N HCl (780 mL)
and stirred for 1 h. The aqueous layer was separated and extracted
with ethyl acetate (2.times.400 mL) and then neutralized with
sodium bicarbonate (110 g). The mixture was extracted with ethyl
acetate (1.times.500 mL). The organic layer was dried over sodium
sulfate, filtered, concentrated and then treated with methyl
t-butyl ether to give a crystalline product: first crop 14.4 g;
second crop 6.6 g (GC purity=96.2 and 91.9%, respectively). The
aqueous phase was saturated with sodium chloride and extracted with
ethyl acetate (4.times.500 mL). The combined organic layers were
dried over sodium sulfate, filtered, concentrated and then treated
with methyl t-butyl ether to give a crystalline product: first crop
33.4 g; second crop 10.8 g (GC purity=89.6 and 88.8%, respectively.
Total crude yield 65.2 g, 62.4%.
[0632] Method B. To a solution of the product of Example 14G (20.7
g, 0.070 mol) and the product of Example 14H (22.9 g, 0.088 mol) in
dimethylformamide (207 mL) under a nitrogen atmosphere was added
cesium carbonate (29.8 g, 0.092). The mixture was stirred at rt for
16 h and then diluted with water (300 mL) and extracted with ethyl
acetate (2.times.200 mL). The combined ethyl acetate layers were
washed with water (3.times.100 mL) and brine and then treated with
1 N HCl (184 mL). After 1 h, the layers were separated and the
aqueous layer was extracted with ethyl acetate (3.times.100 mL) and
then neutralized with sodium bicarbonate (15.5 g). The mixture was
extracted with ethyl acetate (1.times.150 mL). The aqueous layer
was saturated with sodium chloride and extracted with ethyl acetate
(3.times.100 mL). The combined organic layers were dried over
sodium sulfate, filtered and concentrated to give a yellow solid,
11.9 g, 62.9%; GC purity=96.6%. The crude product was
recrystallized from warm methyl t-butyl ether or ethyl acetate.
[0633] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.68 (m, 1H), 5.36
(m, 1H), 4.23 (d, 2H), 3.73 (s, 3H), 2.43 (s, 3H), 2.18 (m, 2H),
1.81 (m, 1H), 1.69 (s, br, 2H), 1.66 (m, 1H), (1.36, 3H)
[0634] .sup.13C NMR (400 MHz, CDCl.sub.3) .delta. 177.60, 159.01,
156.10, 135.12, 121.82, 57.48, 52.29, 40.12, 39.00, 26.62, 22.56,
10.41 91
Rac-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-hept-5-enoic
acid
[0635] Example 14J) The product of Example 14J (0.269 g, 1 mmol)
was dissolved in 5 mL 2 N HCl and heated to reflux under argon.
After refluxing for 6 hrs followed by stirring at room temperature
for 72 hours, an aliquot was removed and checked by .sup.1H NMR.
Approximately 6% of unreacted starting ester remained along with
the desired product (verified by LC-MS). The aqueous portion was
removed in vacuo, leaving 0.38 g of a thick, amber oil. After
purification via reverse phase chromatography, followed by
lyophilization, one obtained 0.23 g, 90.2% of the title compound as
white, non-deliquescent solids.
[0636] Anal. Calcd. for
C.sub.11H.sub.17N.sub.3O.sub.4.0.77H.sub.2O: C, 49.09; H, 6.94; N,
15.61. Found: C, 48.71; H, 6.94; N, 15.98
[0637] Mass spec: M+1=256. 92
(2S,5Z)-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-hept-5-e-
noic acid methyl ester
[0638] Example 14K) The title compound (827.3 g) was separated from
its R enantiomer by preparative chiral chromatography using
Novaprep 200 instrument with steady state recycling option. The
material was dissolved in absolute ethanol at a concentration of 40
mg/ml and loaded on a 50.times.500 mm prepacked Chiral Technologies
stainless steel column. The adsorbent was 20.mu. ChiralPak AD. The
mobile phase was ethanol/triethylamine 100/0.1; the flow rate
equaled 125 ml per min. The crude solution (25 mL) was loaded on
the column every 12 mins. A steady state recycling technique was
used. Solvent was removed using a rotovap. The final product was
isolated as gold oil which solidified on standing; 399.0 g (96.4%
recovery).
[0639] .sup.1H (400 MHz, CD.sub.3OD) .delta. 5.68 (dtt, 1H,
J.sub.olefinic=10.7 Hz), 5.43 (dtt, 1H, J.sub.olefinic=10.7 Hz),
4.82 (s, br, 2H), 4.28 (d, 2H, J=5.5 Hz), 3.73 (s, 3H), 2.27 (s,
3H), 2.26 (m, 1H), 2.14 (m,1H), 1.82 (ddd, 1H, J=13.6,11.3, 5.4
Hz), 1.67 (ddd, 1H, J=13.6, 11.2, 5.5 Hz), 1.34 (s, 3H)
[0640] .sup.13C NMR (400 MHz, CD.sub.3OD) .delta. 178.49, 161.13,
158.70, 135.92, 123.47, 58.55, 52.77, 41.38, 39.96, 26.23, 23.47,
10.23
[0641] Anal. Calcd for C.sub.12H.sub.19N.sub.3O.sub.4: C, 53.52; H,
7.11; N, 15.60. Found: C 52.35; H, 7.20; N, 15.60. 93
(2S,5Z)-7-Acetimidoylamino-2-amino-2-methyl-hept-5-enoic acid
methyl ester, dihydrochloride hydrate
[0642] Example 14L) To a solution of the product of Example 14K
(114.5 g, 0.425 mol) in methanol (2.4 L) was added the solid
dibenzoyl-L-tartaric acid (152.5 g, 0.425 mol) and 88% formic acid
(147 mL, 3.428 mol) at ambient temperature. A slurry of Lindlar
catalyst, 5 wt % palladium on calcium carbonate poisoned with lead
acetate (37.9 g), in methanol (200 mL) was prepared under nitrogen.
The solution of starting material was then added at ambient
temperature to the light grey catalyst slurry followed by a
methanol rinse (200 mL). The heterogeneous reaction mixture was
heated at 45.degree. C, for 11/2 hours. Steady gas evolution was
observed starting at about 40.degree. C. which indicated the
ongoing reaction. The mixture was cooled in an ice/water bath and
then filtered through a plug of Supercell HyFlo. The yellow
solution was concentrated in vacuo to give a viscous oil, which was
dissolved and partitioned between 2 N aqueous HCl (2 L) and ethyl
acetate (0.8 L). Layers were separated and the aqueous layer was
washed once with ethyl acetate (0.8 L). Solvent and volatiles were
removed in vacuo at elevated temperatures (=70.degree. C.). The
intermediate product was used in next the step without further
purification or characterization. LC-MS [M+H].sup.+=228.
[0643] Example 14) The crude product of Example 14L (170 g) was
dissolved in 2 N aqueous HCl (1 L). The resulting orange solution
was refluxed overnight before it was allowed to cool back to
ambient temperature. The reaction mixture was concentrated to about
1/3 of its volume, and the acidic solution was passed through a
solid phase extraction cartridge (25 g of C18 silica) to remove
color and other impurities. Solvent was removed in vacuo
(=70.degree. C.) to give 208 g of crude product as yellowish gum.
The crude gum (31.3 g) was taken up in water (250 mL) and the
material was loaded onto a pretreated ion exchange column packed
with the acidic resin Dowex 50WX4-400 (about 600 g). The resin was
first washed with water (1 L), then with dilute aqueous HCl (1 L of
10/90 v/v conc. HCl/water). The product was eluted off the resin
with higher ion strength aqueous HCl (1.5 L of 20/90 v/v to 25/75
v/v conc. HCl/water). The aqueous solvent was removed in vacuo
(=70.degree. C.), and the gummy residue was taken up in 4 vol %
aqueous trifluoroacetic acid (100 mL). The aqueous solvent was
removed in vacuo (=70.degree. C.), and the procedure was repeated
once more. The residue was then dried under high vacuum to give
32.2 g of gum as the trifluoroacetic acid salt.
[0644] Crude
(2S,5Z)-7-acetimidoylamino-2-amino-2-methyl-hept-5-enoic acid,
ditrifluoroace-tic acid salt hydrate (32.2 g) was purified by
reverse-phase preparative chromatography. The crude was dissolved
in 0.1% aqueous TFA (50 ml) and loaded onto a 2-inch ID.times.1
meter stainless steel column packed with adsorbent (BHK polar W/S,
50.mu., 1.16 kg). The product was eluted at a flow rate of 120
mL/min with a step gradient from 0.1% aqueous TFA to 25/75/0.1
acetonitrile/water/TFA. The loading ratio was 36:1 w/w silica to
sample. Solvent was removed in vacuo, and the material was
converted into the HCl salt by repeated rinses with dilute aqueous
HCl and solvent removals in vacuo. Drying under high vacuum gave
27.4 g of the title dihydrochloride hydrate as yellowish gum.
[0645] LC-MS [M+H].sup.+=214.16 Da
[0646] .sup.1H NMR (D.sub.2O, .delta.): 1.48 (s, 3H), 1.8-1.9 (AB,
2H), 2.10 (s, 3H), 2.01/2.12 (AB, 2H), 3.78 (d, 2H), rotamere 3.87
(d, 2H), 5.6/5.5 (dt, 2H, 11 Hz)
[0647] .sup.13C NMR (D.sub.2O) .delta.: 18.7, 21.5, 21.6, 36.4,
39.1, 59.8, 122.6, 134.3, 164.5, 173.7
[0648] Elemental Anal. Calcd. for
C.sub.10H.sub.19N.sub.3O.sub.2.2.2HCl.2 H.sub.2O: C, 36.21; H,
8.33; N, 12.67; Cl 23.51. Found: C, 36.03; H, 7.72; N, 12.67; Cl,
23.60.
EXAMPLE 15
[0649] 94
(2R,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride
[0650] The R-enantiomer isolated during the separation described in
Example 14K (1.13 g, 4.2 mmol) was dissolved in 11 mL 25% aqueous
acetic acid and heated to 60.degree. C. Zinc dust (1.10 g) was then
added in 4 equal portions at 30-minute intervals. After heating for
a total of 3 hours, an aliquot was removed and checked by LC-MS,
which indicated only a trace of unreacted starting material
remaining, along with desired product. The mixture was cooled to
room temperature, filtered and stripped in vacuo, leaving 2.31 g of
a slushy white solid. The methyl ester was hydrolysed with dilute
hot HCl to the title compound. After purification by reverse phase
chromatography followed by lyophilization, 0.31 g of the title
compound as a glassy solid was obtained.
[0651] Anal. Calcd. for C.sub.10H.sub.19N.sub.3O.sub.2.1.22
HCl.1.15 H.sub.2O: C, 46.13; H, 8.15; N, 15.09; Cl, 15.53.
[0652] Found: C, 46.38; H, 8.51, N, 15.13, Cl, 15.80
[0653] Mass spec: M+1=214
EXAMPLE 16
[0654] 95
(2R/S,5E)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
[0655] 96
[0656] Example 16A) A sample of
(E/Z)-5-t-butyldimethylsilyloxy-2-penten-1- -ol was prepared from
5,5-dihydro-2-pyrone (Aldrich) by the method of Harold, Mohr and
Tamm Helvetica Chimica Acta 66,2, 1983 744-754. 97
[0657] Example 16B) To a solution of the product of Example 16A
(17.7 gm, 81.8 mmol) in THF (230 mL), at 0.degree. C. was added
Et.sub.3N (12.4 gm, 122.7 mmol), followed by methanesulfonyl
chloride (11.25 gm, 98.2 mmol), so that .DELTA.T<+10.degree. C.
(.about.30 minutes). The reaction mixture was stirred for an
additional 1 hour at 0.degree. C. A 25 mL aliquot of saturated
KHCO.sub.3 was then added followed by 25 mL DI H.sub.2O. The layers
were separated, and the organic was washed with 25 mL 5% citric
acid solution followed by 25 mL brine. The organic layer was then
dried over MgSO.sub.4, filtered and then concentrated in vacuo to
yield 23.3 gm (79.1 mmol) of a yellow oil. .sup.1HNMR indicated the
mesylated alcohol in a 2:1 ratio (E:Z). This oil was dissolved in
DMF (225 mL) and to this solution was added the sodium salt of
3-methyl-1,2,4-oxadiazolin-5-one (17.7 gm, 118.6 mmol) and the
mixture was stirred for 48 hr. The mixture was then concentrated
and partitioned between EA and water. The organic layer was
separated and then washed with brine, and dried over MgSO.sub.4.
The suspension was filtered and concentrated in vacuo to yield 23
gm of desired alkylated product (2:1, E:Z, by .sup.1HNMR). This
material was purified by column chromatography (5% IPA:Heptane) to
yield 3 gram pure desired title E isomer by .sup.1HNMR. 98
[0658] Example 16C) To a solution of the product of Example 16B (3
gm) in THF (6 mL), was added glacial acetic acid (6 mL) and 5 mL
H.sub.2O. The reaction was stirred at room temperature for 5 hr
before being concentrated in vacuo to yield 2.25 g of the desired
material as indicated by .sup.1HNMR. The crude mixture was then
carried on without purification. 99
[0659] Example 16D) To a -10.degree. C. solution of imidazole (1.49
gm, 21.96 mmol) and triphenyl phosphine (3.84 g, 14.65 mmol), in
CH.sub.2Cl.sub.2 (25 mL) was added Iodine (3.71 g, 14.65 mmol). To
this mixture was added, dropwise, a solution of Example 16C (2.25
g, 12.2 mmol) in CH.sub.2Cl.sub.2. This mixture was then stirred at
room temperature for 5 hr. The crude mixture was poured onto a
5.times.10 cm bed of silica, and the product was eluted with 20%
EA:Hexanes. The organics were then concentrated to yield 3.6 gm
oily iodo derivative. Lithium Iodide (2.46 gm, 18.36 mmol) was then
dissolved in DMF (30 mL) and cooled to -10.degree. C. To this
solution was added the product of Example 14H (4.8 g, 18.36 mmol),
followed by the iodo compound (3.6 gm, 12.2 mmol). The BTTP (6.1
gm, 19.5 mmol) was then added dropwise. After stirring for 18 hr
from -10.degree. C. to room temperature, the reaction mixture was
transferred to a separatory funnel and diluted with 120 mL of EA.
The organic layer was washed with 80 ml of H.sub.2O, dried over
MgSO.sub.4, filtered and CIV to yield 4.1 g of product. .sup.1HNMR
indicated that this was the desired compound that was used in the
subsequent reaction. 100
[0660] Example 16E) The product of Example 16D (4.1 g) was
dissolved in 15 mL of EA. To this was added 50 mL of 1N HCl and the
mixture was stirred at room temperature for 4.5 hrs. The reaction
was transferred to seperatory funnel and the acidic layer was
separated. The organic layer was washed with 15 mL 1N HCl and the
combined aqueous layers were adjusted pH to .about.7.5 with
KHCO.sub.3. The free base was isolated by washing aqueous layer 3
times with 50 mL of methylene chloride. This was dried over
MgSO.sub.4, filtered, and CIV to yield 3.2 g. The residue was
purified via reverse phase HPLC to obtained 1 g of pure desired E
title compound.
[0661] .sup.1HNMR (CDCl.sub.3) .delta. 1.33 (s, 3H), 1.6-1.7 (m,
1H), 1.75-1.85 (m, 1H), 1.95-2.2 (m, 2H), 2.25 (s, 3H), 3.7 (s,
3H), 4.12 (d, 2H, J=6 Hz), 5.45-5.55 (m, 1H), 5.65-5.75 (m, 1H)
101
[0662] Example 16F) To a reaction tube was added 180 mg of the
product of Example 16E in 10 mL methanol. To this solution was
charged 360 mg of Lindlar catalyst (200 mol %) and 300 .mu.L of
formic acid. The tube was sealed and heated to 60.degree. C. for 18
hrs. The reaction was allowed to cool and filtered through celite.
To the filtrate was added 2 mL of 1N HCl and CIV to yield 150 mg of
the title product. .sup.1HNMR indicates desired conversion to
amidine. This material was carried into the next reaction without
purification.
[0663] .sup.1HNMR (D.sub.2O) .delta. 1.5 (s, 3H), 1.85-2.05 (m,
3H), 2.1-2.2 (m, 1H), 2.15 (s, 3H), 3.7 (s, 3H), 3.9(d, 2H, J=6
Hz), 5.55-5.65 (m, 1H), 5.70-5.80 (m, 1H).
[0664] Example 16) The product of Example 16F (100 mg) was
dissolved in 10 mL 2N HCl and reluxed for 24 hrs. .sup.1HNMR of
aliquot indicated complete hydrolysis. Therefore, CIV to yield 90
mg of crude amino acid. This material was purified on reversed
phase HPLC to give 78 mg pure desired title E isomer.
[0665] .sup.1HNMR (D.sub.2O) .delta. 1.5 (s, 3H), 1.90-2.15 (m,
3H), 2.18-2.29 (m, 1H), 2.22 (s, 3H), 3.95(d, 2H, J=6 Hz),
5.55-5.65 (m, 1H), 5.70-5.80 (m, 1H)
[0666] Elemental analysis (for desired containing 2.3 mol HCl and
0.5 mol H20); C %(calc.) 39.23, (found) 39.21, H %(calc.) 7.34
(found) 7.51, N %(calc.) 13.73 (found) 13.48. 102
EXAMPLE 17
[0667] 103
(2R/S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptynoic acid,
dihydrochloride
EXAMPLE 18
[0668] 104
(2S,5E)-2-amino-2-ethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 19
[0669] 105
(2S,5E)-2-amino-2-methoxymethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-hepteno-
ic acid, dihydrochloride
EXAMPLE 20
[0670] 106
(2S,5E)-2-amino-2-fluoromethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoi-
c acid, dihydrochloride
EXAMPLE 21
[0671] 107
(2S,5E)-2-amino-2,5-dimethyl-6-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 22
[0672] 108
(2S,5Z)-2-amino-5-fluoromethyl-2-methyl-6-fluoro-7-[(1-iminoethyl)amino]-5-
-heptenoic acid, dihydrochloride
EXAMPLE 23
[0673] 109
(2S,5E)-2-amino-2,6-dimethyl-5-fluoro-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 24
[0674] 110
(2S,5Z)-2-amino-6-fluoromethyl-2-methyl-5-fluoro-7-[(1-iminoethyl)amino]-5-
-heptenoic acid, dihydrochloride
EXAMPLE 25
[0675] 111
(2S,5Z)-2-amino-2-ethyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,
dihydrochloride
EXAMPLE 26
[0676] 112
(2S,5Z)-2-amino-2-methoxymethyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 27
[0677] 113
(2S,5Z)-2-amino-2-fluoromethyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 28
[0678] 114
(2S,5Z)-2-amino-2,5-dimethyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 29
[0679] 115
(2S,5E)-2-amino-5-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoi-
c acid, dihydrochloride
EXAMPLE 30
[0680] 116
(2S,5Z)-2-amino-2,6-dimethyl-7-[(1-iminoethyl)amino]-5-heptenoic
acid, dihydrochloride
EXAMPLE 31
[0681] 117
(2S,5E)-2-amino-6-fluoromethyl-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoi-
c acid, dihydrochloride
EXAMPLE 32
[0682] 118
(2S)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptynoic acid,
dihydrochloride
[0683] Novel Intermediates
[0684] Novel intermediates useful in synthesizing compounds of the
present invention include:
[0685]
4-[(2E)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-fluoro-2-penten-
yl]-3-methyl-1,2,4-oxadiazol-5(4H)-one; 119
[0686]
4-[(2E)-2-fluoro-5-hydroxy-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4-
H)-one; 120
[0687]
4-[(2E)-2-fluoro-5-iodo-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4H)--
one; 121
[0688]
(3S,6R)-3-[(3E)-4-fluoro-5-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl-
)-3-pentenyl]-3,6-dihydro-3-methyl-6-(1-methylethyl)-5-phenyl-2H-1,4-oxazi-
n-2-one; 122
[0689]
N-[(2E)-5-[(3S,6R)-3,6-dihydro-3-methyl-6-(1-methylethyl)-2-oxo-5-p-
henyl-2H-1,4-oxazin-3-yl]-2-fluoro-2-pentenyl]ethanimidamide;
123
[0690]
(5E)-2-amino-6-fluoro-2-methyl-7-(3-methyl-5-oxo-1,2,4-oxadiazol-4(-
5H)-yl)-5-heptenoic acid, methyl ester; 124
[0691]
(2S,5E)-2-amino-6-fluoro-2-methyl-7-(3-methyl-5-oxo-1,2,4-oxadiazol-
-4(5H)-yl-5-heptenoic acid, methyl ester; 125
[0692]
(2S,5E)-2-amino-6-fluoro-7-[[(1E)-1-(hydroxyimino)ethyl]amino]-2-me-
thyl-5-heptenoic acid; 126
[0693]
(2S,5E)-2-amino-6-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-hepteno-
ic acid, methyl ester; 127
[0694]
(2R,5E)-2-amino-6-fluoro-2-methyl-7-(3-methyl-5-oxo-1,2,4-oxadiazol-
-4(5H)-yl-5-heptenoic acid, methyl ester; 128
[0695]
(2R,5E)-2-amino-6-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-hepteno-
ic acid, ethyl ester; 129
[0696]
(5E)-2-amino-6-fluoro-7-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-
-heptenoic acid, methyl ester; 130
[0697]
(5E)-2-[[(1Z)-(4-chlorophenyl)methylidene]amino]-6-fluoro-7-(3-meth-
yl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-heptenoic acid, methyl ester;
131
[0698]
(5E)-2-amino-6-fluoro-2-methyl-7-(3-methyl-5-oxo-1,2,4-oxadiazol-4(-
5H)-yl)-5-heptenoic acid, methyl ester; 132
[0699]
(5E)-2-amino-6-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-heptenoic
acid, methyl ester; 133
[0700] Methyl
(5E)-7-[(tert-butoxycarbonyl)amino]-2-{[(1Z)-(2,4-dichloroph-
enyl)methylidene]amino}-5-fluoro-2-methylhept-5-enoate; 134
[0701] (5E)-2,7-diamino-5-fluoro-2-methyl-5-heptenoic acid, methyl
ester, dihydrochloride; 135
[0702]
(5E)-2-amino-5-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-heptenoic
acid, methyl ester, monohydrochloride; 136
[0703]
(5Z)-2-[[(1E)-(2,4-dichlorophenyl)methylidene]amino]-7-[[(1,1-dimet-
hylethoxy)carbonyl]amino]-5-fluoro-2-methyl-5-heptenoic acid,
methyl ester; 137
[0704] (5Z)-2,7-diamino-5-fluoro-2-methyl-5-heptenoic acid, methyl
ester, dihydrochloride; 138
[0705]
(5Z)-2-amino-5-fluoro-7-[(1-iminoethyl)amino]-2-methyl-5-heptenoic
acid, methyl ester, dihydrochloride; 139
[0706]
4-[(2Z)-5-hydroxy-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4H)-one;
140
[0707] (3Z)-5-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-3-pentenyl
ester, acetic acid, trifluoro-; 141
[0708]
4-[(2Z)-5-[(2R,4S)-3-benzoyl-2-(1,1-dimethylethyl)-4-methyl-5-oxo-4-
-oxazolidinyl]-2-pentenyl]-3-methyl-1,2,4-oxadiazol-5(4H)-one;
142
[0709]
3-Methyl-4-[5-(tetrahydro-pyran-2-yloxy)-pent-2-enyl]4H-[1,2,4]oxad-
iazol-5-one; 143
[0710]
4-(5-Hydroxy-pent-2-enyl)-3-methyl-4H-[1,2,4]oxadiazol-5-one;
144
[0711] Methanesulfonic acid
5-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-pent-- 3-enyl ester;
145
[0712] 4-(5-Iodo-pent-2-enyl)-3-methyl-4H-[1,2,4]oxadiazol-5-one;
146
[0713]
Rac-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-hept--
5-enoic acid methyl ester; 147
[0714]
Rac-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-hept--
5-enoic acid; 148
[0715]
(2S,5Z)-2-Amino-2-methyl-7-(3-methyl-5-oxo-[1,2,4]oxadiazol-4-yl)-h-
ept-5-enoic acid methyl ester; 149
[0716] (2S,5Z)-7-Acetimidoylamino-2-amino-2-methyl-hept-5-enoic
acid methyl ester, dihydrochloride hydrate; 150
[0717]
(2S,5Z)-2-amino-7-[[(1E)-1-(hydroxyimino)ethyl]amino]-2-methyl-5-he-
ptenoic acid; 151
[0718]
4-[(2E)-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pentenyl]-3-met-
hyl-1,2,4-oxadiazol-5(4H)-one; 152
[0719]
4-[(2E)-5-hydroxy-2-pentenyl]-3-methyl-2,4-oxadiazol-5(4H)-one;
153
[0720]
(5E)-2-[[(1E)-(3,4-dichlorophenyl)methylidene]amino]-2-methyl-7-(3--
methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-heptenoic acid, methyl
ester; 154
[0721]
(5E)-2-amino-2-methyl-7-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)-5-
-heptenoic acid, methyl ester; and 155
[0722] Methyl
(5E)-2-amino-7-(ethanimidoylamino)-2-methylhept-5-enoate. 156
[0723] Biological Data
[0724] Some or all of the following assays are used to demonstrate
the nitric oxide synthase inhibitory activity of the invention's
compounds as well as demonstrate the useful pharmacological
properties.
[0725] Citrulline Assay for Nitric Oxide Synthase
[0726] Nitric oxide synthase (NOS) activity can be measured by
monitoring the conversion of L-[2,3-.sup.3H]-arginine to
L-[2,3-.sup.3H]-citrulline (Bredt and Snyder, Proc. Natl. Acad.
Sci. U.S.A., 87, 682-685, 1990 and Moore et al, J. Med. Chem., 39
669-672, 1996). Human inducible NOS (hiNOS), human endothelial
constitutive NOS (hecNOS) and human neuronal constitutive NOS
(hncNOS) are each cloned from RNA extracted from human tissue. The
cDNA for human inducible NOS (hiNOS) is isolated from a
.lambda.cDNA library made from RNA extracted from a colon sample
from a patient with ulcerative colitis. The cDNA for human
endothelial constitutive NOS (hecNOS) is isolated from a
.lambda.cDNA library made from RNA extracted from human umbilical
vein endothelial cells (HUVEC) and the cDNA for human neuronal
constitutive NOS (hncNOS) is isolated from a .lambda.cDNA library
made from RNA extracted from human cerebellum obtained from a
cadaver. The recombinant enzymes are expressed in Sf9 insect cells
using a baculovirus vector (Rodi et al, in The Biology of Nitric
Oxide, Pt. 4: Enzymology, Biochemistry and Immunology, Moncada, S.,
Feelisch, M., Busse, R., Higgs, E., Eds.; Portland Press Ltd.:
London, 1995; pp 447-450). Enzyme activity is isolated from soluble
cell extracts and partially purified by DEAE-Sepharose
chromatography. To measure NOS activity, 10 .mu.L of enzyme is
added to 40 .mu.L of 50 mM Tris (pH 7.6) in the presence or absence
of test compounds and the reaction initiated by the addition of 50
.mu.L of a reaction mixture containing 50 mM Tris (pH 7.6), 2.0
mg/mL bovine serum albumin, 2.0 mM DTT, 4.0 mM CaCl.sub.2, 20 .mu.M
FAD, 100 .mu.M tetrahydrobiopterin, 0.4 mM NADPH and 60 .mu.M
L-arginine containing 0.9 .mu.Ci of L-[2,3-.sup.3H]-arginine. The
final concentration of L-arginine in the assay is 30 .mu.M. For
hecNOS or hncNOS, calmodulin is included at a final concentration
of 40-100 nM. Following incubation at 37.degree. C. for 15 minutes,
the reaction is terminated by addition of 400 .mu.L of a suspension
(1 part resin, 3 parts buffer) of Dowex 50W X-8 cation exchange
resin (sodium form) in a stop buffer containing 10 mM EGTA, 100 mM
HEPES, pH 5.5 and 1 mM L-citrulline. After mixing the resin is
allowed to settle and L-[2,3-.sup.3H]-Citrulline formation is
determined by counting aliquots of the supernatant with a liquid
scintillation counter. IC.sub.50 values can be determined by
testing each compound at several concentrations. Results are
reported in Table I as the IC.sub.50 values of compounds for hiNOS,
hecNOS and hncNOS.
1 TABLE I Example IC.sub.50 [.mu.M] Number hiNOS hecNOS hncNOS 1
0.4 37 7.6 3 56 352 584 4 0.57 52 13 14 0.7 31 12 15 121 1930
1480
[0727] In vivo Assay
[0728] Rats can be treated with an intraperitoneal injection of
1-12.5 mg/kg of endotoxin (LPS) to induce systemic expression of
inducible nitric oxide synthase, resulting in markedly elevated
plasma nitrite/nitrate levels. Compounds are administered orally
0.5-1 hours prior to LPS administration and plasma nitrite/nitrate
levels are determined 5 hours following LPS administration. The
results can be used to show that the administration of the nitric
oxide synthase inhibitors decreases the rise in plasma
nitrite/nitrate levels, a reliable indicator of the production of
nitric oxide induced by endotoxin. ED.sub.50 values (mg/kg) for
inhibition of the LPS-induced increase in plasma nitrite/nitrate
levels are shown in Table II.
2TABLE II ED.sub.50's for Examples determined in endotoxin-treated
rats All compounds administered orally unless otherwise noted. 1
0.4 4 0.3 14 0.3
[0729] Raw Cell Nitrite Assay
[0730] RAW 264.7 cells can be plated to confluency on a 96-well
tissue culture plate grown overnight (17 h) in the presence of LPS
to induce NOS. A row of 3-6 wells can be left untreated and serve
as controls for subtraction of nonspecific background. The media
can be removed from each well and the cells washed twice with
Kreb-Ringers-Hepes (25 mM, pH 7.4) with 2 mg/ml glucose. The cells
are then placed on ice and incubated with 50 .mu.L of buffer
containing L-arginine (30 .mu.M) .+-.inhibitors for 1 h. The assay
can be initiated by warming the plate to 37.degree. C. in a water
bath for 1 h. Production of nitrite by intracellular iNOS will be
linear with time. To terminate the cellular assay, the plate of
cells can be placed on ice and the nitrite-containing buffer
removed and analyzed for nitrite using a previously published
fluorescent determination for nitrite (T. P. Misko et al,
Analytical Biochemistry, 214, 11-16, 1993).
[0731] Human Cartilage Explant Assay
[0732] Bone pieces are-rinsed twice-with Dulbecco's Phosphate
Buffered Saline (GibcoBRL) and once with Dulbecco's Modified Eagles
Medium (GibcoBRL) and placed into a petri dish with phenol red free
Minimum Essential Medium (MEM) (GibcoBRL). Cartilage was cut into
small explants of approximately 1545 mg in weight and one or two
explants per well are placed into either 96 or 48 well culture
plates with 200-500 .mu.L of culture media per well. The culture
media was either a custom modification of Minimum Essential
Medium(Eagle) with Earle's salts (GibcoBRL) prepared without
L-Arginine, without L-Glutamine and without phenol red or a custom
modification of serumless Neuman and Tytell (GibcoBRL) medium
prepared without L-arginine, without insulin, without ascorbic
acid, without L-glutamine and without phenol red. Both are
supplemented before use with 100 .mu.M L-Arginine (Sigma), 2 mM
L-glutamine, 1.times.HL-1 supplement (BioWhittaker), 50 mg/ml
ascorbic acid (Sigma) and 150 pg/ml recombinant human IL-1.beta.
(RD Systems) to induce nitric oxide synthase. Compounds are then
added in 10 .mu.L aliquots and the explants incubated at 37.degree.
C. with 5% CO.sub.2 for 18-24 hours.
[0733] The day old supernatant is then discarded and replaced with
fresh culture media containing recombinant human IL-1.beta. and
compound and incubated for another 20-24 hours. This supernatant is
analyzed for nitrite with a fluorometric assay (Misko et al, Anal.
Biochem., 214, 11-16, 1993). All samples are done in quadruplicate.
Unstimulated controls are cultured in media in the absence of
recombinant human IL-1.beta.. IC.sub.50 values (Table III) are
determined from plotting the percent inhibition of nitrite
production at six different concentrations of inhibitor.
3 TABLE III Example No. IC.sub.50 [.mu.M] 1 0.4 14 0.8
[0734] Assay for Time Dependent Inhibition
[0735] Compounds are evaluated for time dependent inhibition of
human NOS isoforms by preincubation of the compound with the enzyme
at 37.degree. C. in the presence of the citrulline enzyme assay
components, minus L-arginine, for times ranging from 0-60 minutes.
Aliquots (10 .mu.L) are removed at 0, 10, 21 and 60 minutes and
immediately added to a citrulline assay enzyme reaction mixture
containing L-[2,3-.sup.3H]-arginine and a final L-arginine
concentration of 30 .mu.M in a final volume of 100 .mu.L. The
reaction is allowed to proceed for 15 minutes at 37.degree. C. and
terminated by addition of a suspension of Dowex 50W X-8 cation
exchange resin as described above for the citrulline NOS assay. The
% inhibition of NOS activity by an inhibitor is taken as the per
cent inhibition in activity compared to control enzyme preincubated
for the same time in the absence of inhibitor. Time-dependent
inhibition can be demonstrated as an increase in inhibition with
increasing preincubation time.
* * * * *