N-heterocyclic derivatives as NOS inhibitors

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

2001-03-22

2003-02-25

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252190, C514S269000, C514S274000, C514S341000, C544S123000, C544S310000, C544S319000, C546S272700

Reexamination Certificate

active

06525051

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
Nitric oxide (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 NO.
Nitric oxide synthase 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 (NOS-2 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 a 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
The compounds of the invention are inhibitors of iNOS and are therefore useful in conditions associated with the excessive production of NO. Accordingly, in one aspect, the invention is directed to compounds selected from the group consisting of the following formulae:
wherein:
each Z
1
is independently —(CH
2
)
m
—O— (where m is 0 to 2), —(CH
2
)
m
—S— (where m is 0 to 2), or —(CH
2
)
m
—N(R
7
)— (where m is 0 to 2);
each Z
2
is independently —O—(CH
2
)
m
— (where m is 0 to 2), —S—(CH
2
)
m
— (where m is 0 to 2), or —N(R
7
)—(CH
2
)
m
— (where m is 0 to 2);
Z
3
is —(CH
2
)
n
— (where n is 1 to 4), —O—(CH
2
)
m
— (where m is 0 to 2), —S—(CH
2
)
m
— (where m is 0 to 2), or —N(R
7
)—(CH
2
)
m
— (where m is 0 to 2);
each R
1
and R
3
are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, nitro, aralkoxy, —OR
8
, —R
11
—OR
8
, —N(R
8
)R
9
, —C(O)OR
8
, —R
11
—C(O)OR
8
, —C(O)N(R
8
)R
9
, —R
11
—C(O)N(R
8
)R
9
, —C(O)N(R
8
)CH
2
C(O)N(R
8
)R
9
, —N(R
8
)C(O)N(R
8
)R
9
, —N(R
8
)C(O)R
9
, —N(R
8
)S(O)
2
R
10
, and —N(R
8
)C(O)N(R
8
)—CH
2
C(O)N(R
8
)R
9
;
R
2
is hydrogen, alkyl, bromo, iodo, —N(R
7
)—(CH
2
)
p
—N(R
8
)R
9
(where p is 1 to 4), —(CH
2
)
q
—N(R
7
)—CH
2
—C(O)—OR
8
(where q is 0 to 3), 4-morpholinyl, 1-piperidinyl, 1-piperazinyl, or 1-pyrrolidinyl;
each R
4
is independently hydrogen or alkyl;
each R
5
is independently hydrogen, halo, haloalkyl, alkyl, nitro, —OR
8
, —C(O)OR
8
, —C(O)N(R
8
)R
9
, —N(R
8
)R
9
, —N(R
8
)C(O)R
8
, or —N(H)S(O)
2
R
10
;
each R
6
is independently hydrogen, alkyl, aryl, aralkyl, halo, —N(R
8
)R
9
, —N(R
7
)—(CH
2
)
p
—N(R
8
)R
9
(where p is 1 to 4), —(CH
2
)
q
—N(R
7
)—CH
2
—C(O)OR
8
(where q is 0 to 3), 4-morpholinyl, 1-piperidinyl, 1-piperazinyl, or 1-pyrrolidinyl;
each R
7
is hydrogen or alkyl;
each R
8
and R
9
is independently hydrogen, alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl);
each R
10
is alkyl, aryl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), or aralkyl (wherein the aryl is optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, aryl, aralkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl), and
each R
11
is independently an alkylene or alkylidene chain;
as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.
In another aspect, the invention is directed to pharmaceutical compositions useful in treating a condition in a mammal resulting from an abnormality in NO production, which compositions comprise a compound of the invention as described above and a pharmaceutically acceptable excipient.
In another aspect, the invention is directed to methods of treating a condition resulting from an abnormality in NO production which methods comprise administering to a mammal having a condition resulting from an abnormality in NO production a therapeutically effective amount of a compound of the invention as described above.
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
“Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
“Alkoxy” refers to a radical of the formula —OR
a
where R
a
is an alkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), and the like.
“Alkoxycarbonyl” refers to a radical of the formula —C(O)OR
a
where R
a
is an alkyl radical as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 1-methylethoxycarbonyl(iso-propoxycarbonyl), n-butoxycarbonyl, n-pentoxyc

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