N-heterocyclic derivatives as NOS inhibitors

Details N-heterocyclic derivatives as NOS inhibitors N-heterocyclic derivatives as NOS inhibitors

1999-08-26

2002-08-13

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S235800, C514S252010, C514S273000, C514S275000, C544S058600, C544S060000, C544S122000, C544S295000, C544S298000, C544S320000, C544S324000, C544S331000

Reexamination Certificate

active

06432947

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a series of N-heterocyclic compounds and derivatives useful as inhibitors of nitric oxide synthase (NOS) and to methods of therapy for various diseases employing those compounds.
BACKGROUND OF THE INVENTION
Nitrogen monoxide (NO) has been implicated in a number of diverse physiological processes, including smooth muscle relaxation, platelet inhibition, nerve transmission, immune regulation and penile erection. Nitric oxide is produced under various conditions by virtually all nucleated mammalian cells. A number of pathologies are ascribed to abnormalities in NO production including stroke, insulin dependent diabetes, septic shock-induced hypotension, rheumatoid arthritis and multiple sclerosis. Nitric oxide is synthesized in biological tissues by an enzyme called nitric oxide synthase (NOS) which uses NADPH and molecular oxygen to oxidize L-arginine to citrulline and nitric oxide.
Nitric oxide synthase (NOS) exists in at least three isoforms, which fall into two primary categories: constitutive and inducible. Two constitutive isoforms, which are calcium and calmodulin dependent, have been identified, and one inducible isoform has been identified. The constitutive isoforms are (1) a neuronal isoform, NOS-1 or nNOS, which is found in the brain and skeletal muscles and (2) an endothelial isoform, NOS-3 or eNOS, which is expressed in the endothelium of blood vessels, the epithelium of the bronchial tree and in the brain. These constitutive isoforms are not the target of the NOS inhibitors of the present invention.
The inducible isoform (NOS2 or iNOS) is expressed in virtually all nucleated mammalian cells following exposure to inflammatory cytokines or lipopolysaccharide. Its presence in macrophages and lung epithelial cells is particularly noteworthy. The inducible isoform is neither stimulated by calcium nor blocked by calmodulin antagonists. It contains several tightly bound co-factors, including FMN, FAD and tetrahydrobiopterin.
Nitric oxide generated by the inducible form of NOS has been implicated in the pathogenesis of inflammatory diseases. In experimental animals, hypotension induced by lipopolysaccharide or tumor necrosis factor &agr; can be reversed by NOS inhibitors. Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis and interleukin therapy in cancer patients. It is expected that an iNOS inhibitor would be effective in treating cytokine-induced hypotension. In addition, recent studies have suggested a role for NO in the pathogenesis of inflammation, and NOS inhibitors would therefore have beneficial effects on inflammatory bowel disease, cerebral ischemia and arthritis. Inhibitors of NOS may also be useful in treating adult respiratory distress syndrome (ARDS) and myocarditis, and they may be useful as adjuvants to short term immunosuppression in transplant therapy.
The diversity and ubiquity of NO function in physiology make the specific therapeutic targeting of NO-related phenomena an important consideration. Since endogenous NO production is the result of the actions of related but distinct isozymes, the differential inhibition of NOS isozymes allows more selective therapy with fewer side effects.
SUMMARY OF THE INVENTION
In one aspect, the invention is directed compounds of formula (I):
wherein:
A is —R
1
, —OR
1
, —C(O)N(R
1
)R
2
, —P(O)[N(R
1
)R
2
]
2
, —N(R
1
)C(O)R
2
, —N(R
16
)C(O)OR
2
, —N(R
1
)R
21
, —N(R
16
)C(O)N(R
1
)R
16
, —S(O)
t
R
1
, —SO
2
NHC(O)R
1
, —N(R
1
)SO
2
R
22
, —SO
2
N(R
1
)H, —C(O)NHSO
2
R
22
, or —CH═NOR
1
;
each X, Y and Z are independently N or C(R
19
);
each U is N or C(R
5
), provided that U is N only when X is N and Z and Y are CR
19
;
V is N(R
4
), S, O or C(R
4
)H;
each W is N or CH;
Q is chosen from the group consisting of a direct bond, —C(O)—, —O—, —C(═N—R
1
)—, —S(O)
t
, and —N(R
6
)—;
m is zero or an integer from 1 to 4;
n is zero or an integer from 1 to 3;
q is zero or one;
r is zero or one, provided that when Q and V are heteroatoms, m, q, and r cannot all be zero; when A is —OR
1
, —N(R
1
)C(O)R
2
, —N(R
16
)C(O)OR
2
, —N(R
1
)R
21
, —N(R
16
)C(O)N(R
1
)R
16
) , —S(O)
t
R
1
(where t is zero), or —N(R
1
)SO
2
R
22
, n, q, and r cannot all be zero; and when Q is a heteroatom and A is —OR
1
, —N(R
1
)C(O)R
2
, —N(R
16
)C(O)OR
2
, —N(R
1
)R
21
, —N(R
16
)C(O)N(R
1
)R
16
, —S(O)
t
R
1
(when t is zero) or —N(R
1
)SO
2
R
22
, m and n cannot both be zero;
t is zero, one or two;
each R
1
and R
2
are independently chosen from the group consisting of hydrogen, optionally substituted C
1
-C
20
alkyl, optionally substituted cycloalkyl, —[C
0
-C
8
alkyl]-R
9
, —[C
2
-C
8
alkenyl]-R
9
, —[C
2
-C
8
alkynyl]-R
9
, —[C
2
-C
8
alkyl]-R
10
(optionally substituted by hydroxy), —[C
1
-C
8
]—R
11
(optionally substituted by hydroxy), and optionally substituted heterocyclyl;
or R
1
and R
2
together with the nitrogen atom to which they are attached is an optionally substituted N-heterocyclyl;
R
3
is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, haloalkyl, —[C
1
-C
8
alkyl]-C(O)N(R
1
)R
2
, —[C
1
-C
8
alkyl]-N(R
1
)R
2
, —[C
1
-C
8
alkyl]-R
8
, —[C
2
-C
8
alkyl]-R
10
, —[C
1
-C
8
alkyl]-R
11
, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl);
or when Q is —N(R
6
)— or a direct bond to R
3
, R
3
may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl and —C(═NR
18
)—NH
2
;
or —Q—R
3
taken together represents —C(O)OH, —C(O)N(R
1
)R
2
, —C(═NH)—N(R
1
)R
2
or
R
4
is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyl, provided that when A is —R
1
or —OR
1
, R
4
cannot be hydrogen, and when V is CH, R
4
may additionally be hydroxy;
R
5
is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, —OR
16
, —S(O)
t
—R
16
, —N(R
16
)R
21
, —N(R
16
)C(O)N(R
1
)R
16
, —N(R
16
)C(O)OR
16
, —N(R
16
)C(O)R
16
, —[C
0
-C
8
alkyl]-C(O)OR
16
, —[C
0
-C
8
alkyl]-C(H)[C(O)OR
16
]
2
, and —[C
0
-C
8
alkyl]-C(O)N(R
1
)R
16
;
R
6
is chosen from the group consisting of hydrogen, alkyl, cycloalkyl, —[C
1
-C
8
alkyl]-R
8
, —[C
2
-C
8
alkyl]-R
10
, —[C
1
-C
8
alkyl]-R
11
, acyl, —C(O)R
8
, —C(O)—[C
1
-C
8
alkyl]-R
8
, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted arylaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, arylsulfonylaminocarbonyl, optionally substituted N-heterocyclyl, —C(═NH)—N(CN)R
1
, —C(O)—R
23
—N(R
1
)R
2
, —C(O)—R
23
—N(R
1
)C(O)—R
23
—N(R
1
)R
2
, and —C(O)—N(R
1
)—R
23
—C(O)OR
1
;
each R
8
and R
9
are independently chosen from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy);
each R
10
is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted —S(O)
t
—R
22
, acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, and alkylsulfonamido;
each R
11
is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl;
each R
12

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