Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1994-07-20
1996-05-28
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514647, 514648, 514659, 564306, 564317, 564367, 564370, 564372, 564452, A61K 3113, C07C21127
Patent
active
055212204
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to novel acyclic ethylenediamine derivatives, 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 (having originally been isolated from gut) 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 wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has recently been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrositis, and in gastrointestinal disorders and diseases of the GI tract such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache," edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)).
Quinuclidine, piperidine, azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists are referred to in U.S. patent application Ser. No. 566,338 filed Nov. 20, 1989, 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, U.S. patent application Ser. No. 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, and Japanese Patent Application No. 065337/92, filed Mar. 23, 1992.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein R.sup.1 is hydrogen, (C.sub.1 -C.sub.8) alkyl, a saturated (C.sub.6 -C.sub.10) carbocyclic ring system containing two fused rings, a saturated (C.sub.6 -C.sub.10) carbocyclic bridged ring system containing two rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C.sub.1 -C.sub.6) alkyl optionally substituted with from one to three fluorine atoms and (C.sub.1 -C.sub.8) alkoxy optionally substituted with from one to three fluorine atoms;
R.sup.2 is hydrogen, benzyl or a group of the formula ##STR3## wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH.sub.2).sub.m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH.sub.2).sub.m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH.sub.2).sub.m may optionally be substituted with R.sup.9 ;
R.sup.8 and R.sup.9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkoxy, ##STR4## (C.sub.1 -C.sub.6)
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Bekelnitzky Seymour G.
Dentz Bernard
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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