Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-03-09
1996-11-12
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514322, 514323, 514324, 546196, 546197, 546198, 546199, 546201, 546202, A61K 31445, C07D27762, C07D41706
Patent
active
055740464
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US92/07230 filed Aug. 31, 1992 and published as WO93/07140 Apr. 15, 1993 which is a continuation of U.S. Ser. No. 07/771,283 filed Oct. 3, 1991 now abandoned.
BACKGROUND OF THE INVENTION
The present invention relates to heteroaryl amines of the formula I below, and pharmaceutically acceptable salts of such compounds. The compounds of formula I are acetylcholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.
Alzheimer's disease is associated with degeneration of cholinergic neurons in the basal forebrain that play a fundamental role in cognitive functions, including memory. Becker et al., Drug Development Research, 12, 163-195 (1988). As a result of such degeneration, patients suffering from the disease exhibit a marked reduction in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity and choline uptake.
It is known that acetylcholinesterase inhibitors are effective in enhancing cholinergic activity and useful in improving the memory of Alzheimer's patients. By inhibiting acetylcholinesterase enzyme, these compounds increase the level of the neurotransmitter acetylcholine, in the brain and thus enhance memory. Becker et al., supra, report that behavioral changes following cholinesterase inhibition appear to coincide with predicted peak levels of acetylcholine in the brain. They also discuss the efficacy of the three known acetylcholinesterase inhibitors physostigmine, metrifonate, and tetrahydroaminoacridine.
U.S. patent application Ser. No. 07/639,614, filed Jan. 10, 1991, and U.S. patent application Ser. No. 07/676,918, filed Mar. 28, 1991, both of which are assigned in common with the present application, also refer to heteroaryl amine acetylcholinesterase inhibitors.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein one of R.sup.2, R.sup.3 and the side chain containing ##STR3## may optionally be attached to the carbon atom designated by an asterisk in ring B rather than to a member of ring A;
ring A is benzo, thieno, pyrido, pyrazino, pyrimido, furano, seleno, pyrrolo, thiazolo, or imidazolo;
R.sup.1 is phenyl, phenyl-(C.sub.1 -C.sub.6)alkyl, cinnamyl or heteroarylmethyl, wherein the heteroaryl moiety of said heteroarylmethyl is selected from imidazolo, thiazolo, thieno, pyrido and isoxazolo, and wherein said phenyl and said heteroaryl moiety may optionally be substituted with one or two substituents independently selected from (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy and halo;
R.sup.2 and R.sup.3 are independently selected from hydrogen, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkyl optionally substituted with from one to three fluorine atoms, benzyloxy, hydroxy, phenyl, benzyl, halo, nitro, cyano, COOR.sup.4, CONHR.sup.4, NR.sup.4 R.sup.5, NR.sup.4 COR.sup.5, or SO.sub.p CH.sub.2 -phenyl wherein p is 0, 1 or 2;
or R.sup.2 and R.sup.3 are attached to adjacent carbon atoms and form, together with the carbons to which they are attached, a five or six membered ring wherein each atom of the ring is carbon, nitrogen or oxygen (e.g., a methylenedioxy, ethylenedioxy or lactam ring);
R.sup.4 and R.sup.5 are independently selected from hydrogen and (C.sub.1 -C.sub.6 )alkyl, or R.sup.4 and R.sup.5, when part of said NR.sup.4 R.sup.5, optionally form, together with the nitrogen to which they are attached, a ring containing four to eight members wherein one atom of the ring is nitrogen and the others are carbon, oxygen or nitrogen, or R.sup.4 and R.sup.5, when part of said NR.sup.4 COR.sup.5, optionally form, together with the nitrogen and carbon to which they are attached, a four to eight membered lactam ring;
X is nitrogen or CH;
Y is oxygen, sulfur or NR.sup.6 ;
R.sup.6 is hydrogen, (C.sub.1 -C.sub.6)alkyl, CO(C.sub.1 -C.sub.6)alkyl or SO.sub.2 --, phenyl, wherein the phenyl moiety of said SO.sub.2 -phenyl may optionally be substituted with from one to five substituents independently selected from (C.sub.1 -
REFERENCES:
patent: 2814625 (1957-11-01), Speeter et al.
patent: 4167632 (1979-09-01), Jaunin
patent: 4791104 (1988-12-01), Picciola et al.
patent: 4839377 (1989-06-01), Bays et al.
patent: 4908372 (1990-03-01), Carr
patent: 4971980 (1990-11-01), Giani et al.
patent: 5064840 (1991-11-01), Carr
patent: 5371093 (1994-12-01), Carr
Djuric et al., "Chemoselective Reductions of 2-Acyl-1H-indole-3-carboxaldehydes", J. Heterocyclic Chem., 22, 1425 (1985).
Appel "Current Neurology" Yearbook Med. Publish. pp. 313-317 (1987).
Wilbraham et al "Organic and Biochemistry" S. Ill. Univ. pp. 268-270 Cummings Publish. (1985).
Carr et al "Preparation of piperidinyl benzimidazoles" CA117: 212496a (1992).
Jassens et al "Preparation of piperidinyl benzimidazole ketones" CA117: 111638f (1992).
Maynard et al "Convergent synthesis" CA121: 35406y (1994).
Schubert et al "Synthesis and properties of alycyclic imidazoles" CA58: 4542d (1963).
Chen Yuhpyng L.
Nagel Arthur A.
Chang Ceila
De Benedictis Karen
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
LandOfFree
Heteroaryl amines as novel acetylcholinesterase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heteroaryl amines as novel acetylcholinesterase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heteroaryl amines as novel acetylcholinesterase inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-562861