Aminomethylene substituted non-aromatic heterocycles and use as

Details Aminomethylene substituted non-aromatic heterocycles and use as Aminomethylene substituted non-aromatic heterocycles and use as

1995-05-25

1998-12-29

Gupta, Yogendra N.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514326, 514327, 546194, 546209, 546210, A61K 31445, C07D21136, C07D21156

Patent

active

058542620

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The present invention relates to novel aminomethylene substituted non-aromatic heterocycles, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P receptor antagonists. This invention also relates to novel intermediates used in the synthesis of such substance P receptor antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283.
The following references refer, collectively, to quinuclidine, piperidine, and azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists: U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992; U.S. patent application Ser. No. 724,268, filed Jul. 1, 1991; PCT Patent Application PCT/US 91/02853, filed Apr. 25, 1991; PCT Patent Application PCT/US 91/03369, filed May 14, 1991; PCT Patent Application PCT/US 91/05776, filed Aug. 20, 1991; PCT Patent Application PCT/US 92/00113, filed Jan. 17, 1992; PCT Patent Application PCT/US 92/03571, filed May 5, 1992; PCT Patent Application PCT/US 92/03317, filed Apr. 28, 1992; PCT Patent Application PCT/US 92/04697, filed Jun. 11, 1992; United States Patent Application 766,488, filed Sep. 26, 1991; U.S. patent application Ser. No. 790,934, filed Nov. 12, 1991; PCT Patent Application PCT/US 92/04002, filed May 19, 1992; Japanese Patent Application 065337/92, filed Mar. 23, 1992; and U.S. patent application Ser. No. 932,392, filed Aug. 19, 1992.


SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR3## wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the side chain containing NR.sup.2 R.sup.3 is attached to a carbon atom of ring system A;
W is hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted with from one to three fluorine atoms, --S(O).sub.v --(C.sub.1 -C.sub.6) alkyl wherein v is zero, one or two, halo, benzyloxy or (C.sub.1 -C.sub.6)alkoxy optionally substituted with from one to three fluorine atoms;
R.sup.1 is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl or thiophenyl), wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C.sub.1 -C.sub.6) alkyl optionally substituted with from one to three fluorine atoms and (C.sub.1 -C.sub.6) alkoxy optionally substituted with from one to three fluorine atoms;
the dotted lines in formula Ib indicate that one of the X'-Y' and Y'-Z' bonds may optionally be a double bond;
X' is selected from .dbd.CH--, --CH.sub.2 --, --O--, --S--, --SO--, H.sub.5)-- and .dbd.C(C.sub.6 H.sub.5)--;
Y' is selected from C.dbd.O, C.dbd.NR.sup.4, C.dbd.S, .dbd.CH--, --CH.sub.2 .dbd.C(C.sub.6 H.sub.5)--, --CH(C.sub.6 H.sub.5)--, .dbd.N--, --NH--, --N(R.sup.4)--, .dbd.C(halo)--, .dbd.C(OR.sup.4)--, .dbd.C(SR.sup.4)--, .dbd.C(NR.sup.4)--, --O--, .dbd.C(CF.sub.3)--, .dbd.C(CH.sub.2 C.sub.6 H.sub.5)--, --S-- and SO.sub.2, wherein the phenyl moieties of said .dbd.C(C.sub.6 H.sub.5)-- and --CH(C.sub.6 H.sub.5)-- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said optionally be substituted with fro

REFERENCES:
patent: 5162339 (1992-11-01), Lowe et al.
patent: 5232929 (1993-08-01), Desai et al.

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