Branched alkoxy-substituted 2-aminopyridines as NOS inhibitors

Details Branched alkoxy-substituted 2-aminopyridines as NOS inhibitors Branched alkoxy-substituted 2-aminopyridines as NOS inhibitors

2000-03-28

2002-03-26

Fan, Jane (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S255030, C514S339000, C514S304000, C514S278000, C514S318000, C514S343000, C544S360000, C546S148000, C546S276700, C546S125000, C546S019000, C546S194000, C546S276400

Reexamination Certificate

active

06362195

ABSTRACT:

The present invention relates to certain branched alkoxy-subsituted 2-aminopyridines 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
, Dec. 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 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
wherein X is CHOH; CH
2
; or CHR
10
, wherein R
10
(ethylene or n-propylene), together with the CH of CHR
10
, the adjacent CH
2
group, and the nitrogen of NR
1
R
2
, forms a five or six membered saturated ring, in which case R
2
is a single bond;
R
1
, R
2
(when X is not CHR
10
), R
3
and R
4
are selected, independently, from (C
1
-C
6
) alkyl, tetrahydronaphthalene, aryl and aralkyl, wherein said aryl and the aryl moiety of said aralkyl is phenyl or naphthyl and the alkyl moiety is 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
(when X is not CHR
10
), together with the nitrogen to which they are attached, form a piperazine, piperidine or pyrolidine ring or a 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
5
and R
6
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
8
R
9
NC(═O)— wherein R
8
and R
9
are selected, independently, from hydrogen and (C
1
-C
6
)alkyl;
R
7
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
;
and wherein R
3
and R
4
, together with the carbon to which they are attached, form an optionally substituted carbocyclic ring of from 3 to 8 members;
and the pharmaceutically acceptable salts of such compounds.
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, succinatate, 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 terms “halo” and “halogen”, as used herein, unless otherwise indicated, include chloro, fluoro, bromo and iodo.
More specific embodiments of the present invention include:
(a) compounds of the formula I wherein R
1
, R
2
, R
3
and R
4
are selected, independently, from (C
1
-C
6
)alkyl;
(b) compounds of the formula I wherein R
3
and R
4
are selected, independently, from (C
1
-C
6
)alkyl, and R
1
and R
2
, together with the nitrogen to which they are attached, form a ring;
(c) compounds of the formula I wherein one of R
1
and R
2
is selected from (C
1
-C
6
)alkyl, and the other is selected from phenyl or phenyl-(C
1
-C
6
)alkyl;
(d) compounds of the formula I wherein R
1
and R
2
, together with the nitrogen to which they are attached, form a piperazine, piperidine or pyrrolidine ring; and
(e) compounds of the formula I wherein R
1
and R
2
are selected, independently from (C
1
-C
6
)alkyl, and R
3
and R
4
, together with the carbon to which they are attached, form a ring.
Examples of specific preferred embodiments of this invention are:
6-[2-Isopropoxy-4-((4-phenethylpiperazin-1-yl)-ethyl)-phenyl]-pyridin-2-ylamine;
6-[2-Isobutoxy-4-((4-phenethylpiperazin-1-yl)-ethyl)-phenyl]-pyridin-2-ylamine;
6-[2-Isobutoxy-4-((4-dimethylaminoethyl)-phenyl]-pyridin-2-ylamine;
6-[2-Isopropoxy-(N-(2-methyl)propyl)-4-(pyrrolidin-3-yl)-phenyl]-pyridin-2-ylamine;
1-[4-(6-Amino-pyridin-2-y)-3-isopropoxy-phenyl]-2-(4-phenethyl-piperazin-1-yl)-ethanol;
6-[2-Cyclopentyloxy-4-((4-dimethylaminoethyl)-phenyl]-pyridin-2-ylamine;
6-[2-Cyclopentyloxy-4-((4-phenethylpiperazin-1-yl)-ethyl)-phenyl]-pyridin-2-ylamine; and the pharamaceutically acceptable salts of the foregoing compounds.
Other examples of sp

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