6-phenyl-pyridin-2-ylamine derivatives

Details 6-phenyl-pyridin-2-ylamine derivatives 6-phenyl-pyridin-2-ylamine derivatives

1997-03-13

2001-05-22

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S230500, C514S183000, C514S216000, C514S249000, C514S278000, C514S299000, C514S339000, C514S304000, C540S349000, C540S477000, C540S582000, C544S105000, C546S016000, C546S020000, C546S112000, C546S125000, C546S276700

Reexamination Certificate

active

06235747

ABSTRACT:

The present invention relates to certain 6-phenylpyridyl-2-amine derivatives 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 and other disorders.
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). Finally, opioid withdrawal in rodents has beer 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
and the pharmaceutically acceptable salts thereof, wherein
R
1
and R
2
are selected, independently, from (C
1
-C
6
) alkyl, tetrahydronaphthalene and aralkyl, wherein the aryl moiety of said aralkyl is phenyl or naphthyl and the alkyl moiety i:s straight or branched and contains from 1 to 6 carbon atoms, and wherein said (C
1
-C
6
) alkyl and said tetrahydronaphthalene and the aryl moiety of said aralkyl may optionally be substituted with from one to three substituents, preferably from zero to two substituents, that are selected, independently, from halo (e.g., chloro, fluoro, bromo, iodo), nitro, hydroxy, cyano, amino, (C
1
-C
4
) alkoxy, and (C
1
-C
4
) alkylamino;
or R
1
and R
2
form, together with the nitrogen to which they are attached, a piperazine, piperidine or pyrrolidine ring or an azabicyclic ring containing from 6 to 14 ring members, from 1 to 3 of which are nitrogen and the rest of which are carbon, wherein examples of said azabicyclic rings are the following
 wherein R
3
and R
4
are selected from hydrogen, (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
7
)
2
NC(═O)— wherein each R
7
is selected, independently, from hydrogen and (C
1
-C
6
)alkyl;
R
5
is selected from hydrogen, (C
1
-C
6
)alkyl, phenyl, naphthyl, phenyl-(C
1
-C
6
)alkyl- and naphthyl(C
1
-C
6
)alkyl-;
and wherein said piperazine, piperidine and pyrrolidine rings may optionally be substituted with one or more substituents, preferably with from zero to two substituents that are selected, independently, from (C
1
-C
6
)alkyl, amino, (C
1
-C
6
) alkylamino, [di-(C
1
-C
6
)alkyl]amino, phenyl substituted 5 to 6 membered heterocyclic rings containing from 1 to 4 rings nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of any of the foregoing substituents may optionally be substituted with one or more substituents, preferably with from zero to two substituents, that are selected, independently, from halo, (C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy, nitro, amino, cyano, CF
3
and OCF
3
;
n is 0,1 or 2; and each carbon of said (CH
2
)
n
can optionally be substituted with a substituent R
8
;
m is 0,1, or 2; and each carbon of said (CH
2
)
m
can optionally be substituted with a substituent R
9
;
each R
8
and each R
9
is selected, independently, from (C
1
-C
4
)alkyl, aryl-(C
1
-C
4
)alkyl wherein said aryl is selected from phenyl and naphthyl; allyl and phenallyl;
X and Y are selected, independently, from methyl, methoxy, hydroxy and hydrogen; and
R
10
is H(C
1
-C
6
) alkyl;
with the proviso that R
8
is absent when n is zero and R
9
is absent when m is zero.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term “one or more substituents”, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites.
The term “halo”, as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
Examples of preferred compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein NR
1
R
2
is:
4-phenoxycarbonylpiperazin-1-yl;
4-(4-fluorophenylacetyl)piperazin-1-yl;
4-phenylethylpiperazin-1-yl;
4-phenoxymethylcarbonylpiperazin-1-yl;
4-phenylaminocarbonylpiperazin-1-yl;
4-benzoylmethylpiperazin-1-yl; or
4-benzylcarbonylpiperazin-1-yl.
Other preferred compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein NR
1
R
2
is a group of the formula
wherein NR
3
R
4
is NH
2
.
Other preferred compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein NR
1
R
2
is a group of the formula
wherein R
5
is aralkyl, e.g., benzyl, and R
6
is (4-fluoro)phenylacetyl.
Specific preferred compounds of the present invention include the following:
1-4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-methoxy-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenoxy-ethanone;
(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-cyclopentyl-methanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl&r

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