Substituted benzylamino nitrogen containing non-aromatic heteroc

Details Substituted benzylamino nitrogen containing non-aromatic heteroc Substituted benzylamino nitrogen containing non-aromatic heteroc

1995-02-15

1998-02-24

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514212, 514278, 514314, 514426, 540543, 540597, 540602, 540605, 546 16, 546176, 546177, 546223, 548495, 548503, 548557, A61K 31445, A61K 3147, A61K 3140, C07D21156, C07D40112

Patent

active

057212554

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT/US 93/04063, filed May 5, 1993.


BACKGROUND OF THE INVENTION

The present invention relates to novel substituted benzylamino nitrogen containing 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 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 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, and 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 766,488, filed Sep. 26, 1991, U.S. patent application 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 ring A is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the side chain containing NR.sup.2 R.sup.3 is attached to a carbon atom of ring A; (C.sub.1 -C.sub.6)alkoxy optionally substituted with from one to three fluorine atoms; -C.sub.6)alkylamino, --S(O).sub.v --(C.sub.1 -C.sub.10)-alkyl wherein v is zero, one or two, --S(O).sub.v -aryl wherein v is zero, one or two, --O-aryl, --SO.sub.2 NR.sup.4 R.sup.5 wherein each of R.sup.4 and R.sup.5 is, independently, (C.sub.1 -C.sub.6)alkyl, or R.sup.4 and R.sup.5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons, ##STR3## wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, --N(SO.sub.2 --(C.sub.1 -C.sub.10)alkyl).sub.2 and ##STR4## and wherein the aryl moieties of said --S(O).sub.v -aryl, --O-aryl and ##STR5## are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy and halo; ##STR6## wherein a is 0, 1 or 2 and th

REFERENCES:
patent: 5026858 (1991-06-01), Vega-Noverola
patent: 5162339 (1992-11-01), Lowe, III
patent: 5232929 (1993-08-01), Desai et al.
patent: 5256671 (1993-10-01), Ladduwahetty
patent: 5373003 (1994-12-01), Lowe, III
Vaught JL. (1988) Life Sci. 43, 1419-1431.
Delgado JN, Remers WA. Textbook of Organic Medicinal and Pharmaceutical Chemistry, Ninth Edition, p. 30, 1991.
John A. Lowe, III et al., The Discovery of 2!-octan-3-amine as Novel, Nonpeptide Substance P Antagonist, J. Med. Chem., 1992, 35, 2591-2600.

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