Amidino compounds useful as nitric oxide synthase inhibitors

Details Amidino compounds useful as nitric oxide synthase inhibitors Amidino compounds useful as nitric oxide synthase inhibitors

2001-03-23

2003-07-01

Richter, Johann (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C560S153000, C562S557000

Reexamination Certificate

active

06586474

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to amidino compounds and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
2. Related Art
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.
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.
There are at least three types of NO synthase as follows:
(i) a constitutive, Ca
++
/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca
++
/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca
++
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.
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.
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.
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 including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA 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).
The following individual publications disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase:
PCT Patent Application No. WO 96/35677.
PCT Patent Application No. WO 96/33175.
PCT Patent Application No. WO 96/15120.
PCT Patent Application No. WO 95/11014.
PCT Patent Application No. WO 95/11231.
PCT Patent Application No. WO 99/46240.
PCT Patent Application No. WO 95/24382.
PCT Patent Application No. WO 94/12165.
PCT Patent Application No. WO 94/14780.
PCT Patent Application No. WO 93/13055.
PCT Patent Application No. WO 99/62875.
European Patent No. EP0446699A1.
U.S. Pat. No. 5,132,453.
U.S. Pat. No. 5,684,008.
U.S. Pat. No. 5,830,917.
U.S. Pat. No. 5,854,251.
U.S. Pat. No. 5,863,931.
U.S. Pat. No. 5,919,787.
U.S. Pat. No. 5,945,408.
U.S. Pat. No. 5,981,511.
PCT Patent Application No. WO 95/25717 discloses certain amidino derivatives as being useful in inhibiting inducible nitric oxide synthase.
PCT Patent Application No. WO 99/62875 discloses further amidino compounds as being useful in inhibiting inducible nitric oxide synthase.
SUMMARY OF THE INVENTION
Compounds have now been found which 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 unable to penetrate certain non-target organs in test systems, especially in comparison to the compounds of WO 95/25717. 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.
In a broad aspect, the present invention is directed to novel compounds, 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.
In one embodiment, the present invention provides a compound or a salt thereof, the compound having a structure corresponding to Formula 1:
wherein:
X is selected from the group consisting of —S—, —S(O)—, and —S(O)
2
—;
R
2
is selected from the group consisting of C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, C
1
-C
5
alkoxy-C
1
alkyl, and C
1
-C
5
alkylthio-C
1
alkyl;
with respect to R
3
and R
8
:
R
8
is selected from the group consisting of —OR
14
and —N(R
15
)(R
16
); and R
3
is selected from the group consisting of —H, —OH, —C(O)—R
17
, —C(O)—O—R
18
, and —C(O)—S—R
19
; or
R
8
is —N(R
20
)—, and R
3
is —C(O)—, wherein R
8
and R
3
together with the atoms to which they are attached form a ring; or
R
8
is —O—, and R
3
is —C(R
21
)(R
22
)—, wherein R
8
and R
3
together with the atoms to which they are attached form a ring;
if R
3
is —C(R
21
)(R
22
)—, then R
4
is —C(O)—O—R
23
; otherwise R
4
is —H;
R
1
, R
5
, R
6
, and R
7
independently are selected from the group consisting of —H, halogen, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, and C
1
-C
5
alkoxy-C
1
alkyl;
R
9
and R
10
independently are selected from the group consisting of —H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, and C
1
-C
5
alkoxy-C
1
alkyl;
with respect to R
11
and R
12
:
R
11
is selected from the group consisting of —H, —OH, —C(O)—O—R
24
, and —C(O)—S—R
25
; and R
12
is selected from the group consisting of —H, —OH, —C(O)—O—R
26
, and —C(O)—S—R
27
; or
R
11
is —O—, and R
12
is —C(O)—, wherein R
11
and R
12
together with the atoms to which they are attached form a ring; or
R
11
is —C(O)—, and R
12
is —O—, wherein R
11
and R
12
together with the atoms to which they are attached form a ring; and
R
13
is C
1
alkyl;
R
14
is selected from the group consisting of —H and C
1
-C
6
alkyl; wherein when R
14
is C
1
-C
6
alkyl, R
14
is optionally substituted by one or more moieties selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
with respect to R
15
and R
16
:
R
15
is selected from the

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