2-aminopyridines containing fused ring substituents

Details 2-aminopyridines containing fused ring substituents 2-aminopyridines containing fused ring substituents

2001-02-08

2002-04-16

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C435S184000, C514S318000, C514S255030, C514S252010, C546S311000, C546S268100, C546S194000, C544S360000

Reexamination Certificate

active

06372768

ABSTRACT:

The present invention relates to certain 2-aminopyridines containing fused ring substituents that exhibit activity as nitric oxide synthase (NOS) inhibitors, to pharmaceutical compositions containing them, and to their use in the treatment and prevention of central nervous system disorders, inflammatory disorders, septic shock, obesity and other diseases, disorders and conditions.
There are three known isoforms of NOS: an inducible form (I-NOS), and two constitutive forms referred to as, respectively, neuronal NOS (N-NOS) and endothelial NOS (E-NOS). Each of these enzymes carries out the conversion of arginine to citrulline, while producing a molecule of nitric oxide (NO) in response to various stimuli. It is believed that excess nitric oxide (NO) production by NOS plays a role in the pathology of a number of disorders and conditions in mammals. For example, NO produced by I-NOS is thought to play a role in diseases that involve systemic hypotension, such as toxic shock and therapy with certain cytokines. It has been shown that cancer patients treated with cytokines such as interleukin-1 (IL-1), interleukin-2 (IL-2) or tumor necrosis factor (TNF) suffer cytokine-induced shock and hypotension due to NO produced from macrophages, i.e., inducible NOS (I-NOS) (see
Chemical
&
Engineering News
, December 20, p. 33, (1993)). I-NOS inhibitors can reverse this. It is also believed that I-NOS plays a role in the pathology of diseases of the central nervous system such as ischemia. For example, inhibition of I-NOS has been shown to ameliorate cerebral ischemic damage in rats (see
Am. J. Physiol.,
268, p. R286 (1995)). Suppression of adjuvant-induced arthritis by selective inhibition of I-NOS is reported in
Eur. J. Pharmacol.,
273, p. 15-24 (1995).
NO produced by N-NOS is thought to play a role in diseases such as cerebral ischemia, pain, and opiate tolerance. For example, inhibition of N-NOS decreases infarct volume after proximal middle cerebral artery occlusion in the rat (see
J. Cerebr. Blood Flow Metab.,
14, p. 924-929 (1994)). N-NOS inhibition has also been shown to be effective in antinociception, as evidenced by activity in the late phase of the formalin-induced hindpaw licking and acetic acid-induced abdominal constriction assays (see
Br. J. Pharmacol.,
110, p. 219-224 (1993)). In addition, subcutaneous injection of Freund's adjuvant in the rat induces an increase in NOS-positive neurons in the spinal cord that is manifested in increased sensitivity to pain, which can be treated with NOS inhibitors (see
Japanese Journal of Pharmacology,
75, p. 327-335 (1997)). Finally, opioid withdrawal in rodents has been reported to be reduced by N-NOS inhibition (see
Neuropsychopharmacol.,
13, p. 269-293 (1995)).
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula I:
or pharmaceutically acceptable salts thereof, wherein
A and B are each independently H, or together, A and B form a ring fused to the phenyl ring, said ring being saturated or unsaturated and containing from 5 to 7 ring member atoms, where said ring member atoms may optionally comprise from 1 to 2 heteroatoms selected independently from the group consisting of N, O or S, provided that no two adjacent ring members are heteroatoms;
X is oxygen or a single bond;
Y is (C
1
-C
6
)alkyl;
R
1
is hydrogen, (C
1
-C
6
)alkyl or a (C
1
-C
6
alkyl) group substituted with —NR
2
R
3
wherein R
2
and R
3
are either selected independently from the group consisting of H, alkyl, aryl, aralkyl or tetrahydronaphthalene, wherein said aryl group or said aryl moiety of said aralkyl group is phenyl or naphthyl, said alkyl group or said alkyl moiety of said aralkyl group contains from one to six carbon atoms and is straight-chained or branched, and said aryl group, said tetrahydronaphthalene or said aryl moiety of said aralkyl group is optionally substituted with from one to three of halogen, nitro, cyano, amino, (C
1
-C
4
)alkoxy and (C
1
-C
4
)alkylamino moieties,
or R
2
and R
3
-form, together with the nitrogen to which they are attached, a heterocyclic ring, or a cyclic or bicyclic ring which is saturated or unsaturated.
Preferably, the heterocyclic ring formed from R
2
, R
3
and the nitrogen to which they are attached is a piperidine, azetidine, piperazine or pyrrolidine ring, optionally substituted with one or more substituents selected independently from the group consisting of (C
1
-C
6
)alkyl, amino, (C
1
-C
6
) alkylamino, [di-(C
1
-C
6
)alkyl]amino, phenyl-substituted 5- and 6-membered heterocyclic rings containing from 1 to 4 ring nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl. Preferably, the piperidine, azetidine, piperazine or pyrrolidine ring is substituted with from one to two substituents. Moreover, the phenyl moiety of any of the foregoing phenyl-containing substituents is itself optionally substituted with one or more substituents selected independently from halo, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy, nitro, amino, cyano, CF
3
and OCF
3
; preferably with from one to two substituents.
Preferably, the cyclic or bicyclic ring formed from R
2
1
R
3
and the nitrogen to which they are attached is a 6-amino-3-azabicyclo[3.1.0]hex-3-yl ring having the formula:
wherein R
4
and R
5
are each selected independently from the group consisting of H, (C
1
-C
6
)alkyl, phenyl, naphthyl, (C
1
-C
6
)alkyl-C(═O)—, HC(═O)—, (C
1
-C
6
)alkoxy-(C═O)—, phenyl-C(═O)—, naphthyl-C(═O)—, and R
6
R
7
NC(═O)—; R
6
and R
7
are each independently hydrogen or (C
1
-C
6
)alkyl.
The present invention also relates to preferred compounds of the formula I-a:
wherein the broken line represents an optional double bond;
Y is (C
1
-C
6
)alkyl; and
R
1
is hydrogen, (C
1
-C
6
)alkyl or a (C
1
-C
6
alkyl) group substituted with —NR
2
R
3
, wherein R
2
and R
3
are as defined above.
Some preferred compounds of formula I include:
1-[4-(6-Amino-pyridin-2-yl)-naphthalen-1-yloxymethyl]-cyclohexanol;
6-[4-(2-(2-Dimethylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;
6-[4-(2-Hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine; and
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-pyridin-2-ylamine.
Additional compounds of formula I include:
6-[4-(2-(2-Diethylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;
6-[4-(2-(2-Dipropylaminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;
6-[4-(2-(2-(N-methyl, N-benzyl)aminoethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine;
6-[4-(2-(2-(1-Piperidinyl)ethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine; and
6-[4-(2-(2-(N-methylpiperazin-4-yl)ethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine.
6-[4-(2-(2-(6-amino-3-azabicyclo[3.1.0] hex-2-yl)-ethoxy)-ethoxy)-naphthalen-1-yl]-pyridin-2-ylamine.
Also provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of a compound of this invention effective to treat various diseases, disorders and conditions in mammals, including humans. Further provided is a method of treating various diseases, disorders and conditions in mammals, including humans, said method comprising administering to the mammals an amount of a compound of this invention effective for such treatment.
Diseases, disorders and conditions to which the compositions and methods of this invention are directed include, without limitation: acute spinal cord injuries; anxiety disorders selected from the group consisting of panic attack, agoraphobia, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder and acute stress disorder; cancers, whether metastatic or not, selected from the group consisting of brain, breast, colon, lung, liver, ovarian, prostate, skin and stomach cancers, or cancers selected from the group consisting of

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