Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-19
1998-12-29
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514247, 514252, 514256, 514332, 514340, 514341, 514357, 514359, 514378, 514383, 514386, 514406, 514430, 514461, 540356, 544224, 544242, 546255, 5462727, 5462764, 546336, C07D40106, C07D23926, A61K 3144, A61K 31415
Patent
active
058542329
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/IB95/00189 filed Mar. 20, 1995.
This invention relates to novel substituted heterocyclic compounds, their pharmaceutically acceptable salts, pharmaceutical compositions containing them and methods of using them to treat Alzheimer's disease, age associated memory impairment, Parkinson's disease and other central nervous system disorders such as mental retardation, developmental disorders, disruptive behavioral disorders, organic mental disorders (including dementia and psychoactive substance induced organic mental disorders), psychoactive substance abuse disorders, mood disorders, anxiety disorders, somatoform disorders, dissociative disorders, attention deficit disorder, schizophrenia and personality disorders. The claimed compounds have the ability to enhance the release of neurotransmitters such as acetylcholine, dopamine and serotonin.
World Patent Application WO 93/14085, which was published on Jul. 22, 1993, refers to certain indole derivatives as having the ability to enhance the release of acetylcholine. The ability of similar compounds to enhance the release of acetylcholine is referred to by Wilkerson et al., J. Med. Chem., 36, 2899-2907 (1993), Smith et al., Drug Development Research, 29, 262-270 (1993), and Zaczek et al., Curr. Opin. Invest. Drugs, 2 (10), 1097-1104 (1993).
Substituted polycyclic compounds that enhance acetylcholine release are referred to in U.S. Pat. No. 5,278,162, which issued on Jan. 11, 1994 and World Patent Application WO 93/14092, which was published on Jul. 22, 1993.
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula ##STR2##
wherein both dotted lines represent optional double bonds;
m is an integer from zero to four;
Z is oxygen or sulfur when it is double bonded to ring A and Z is hydroxy, (C.sub.1 -C.sub.10) alkyl--S--, adamant--2--yl--S--, benzyl--S--, phenyl--C(=O)CH.sub.2 --S--, (C.sub.1 -C.sub.6)alkyl--O--C(=O)--CH.sub.2 --S-- or (H,H) (L, Z represents two hydrogen atoms, each of which is single bonded to the same carbon of ring A) when Z is single bonded to ring A;
X is CH.sub.2 CH.sub.2, NR.sup.1, CHR.sup.1 or a direct link between the carbon to which Z is attached and the carbon to which R.sup.3 and R.sup.4 are attached;
R.sup.1 is hydrogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylphenyl when ring A is saturated (i.e., when ring A contains no double bonds) and R.sup.1 is absent when ring A contains a double bond;
R.sup.2 and R.sup.6 are independently selected from naphthyl, phenyl, (C.sub.1 -C.sub.6)alkylphenyl, 1-adamantyl, 2-adamantyl, (C.sub.1 -C.sub.8) straight or branched alkyl, (C.sub.3 -C.sub.10) cycloalkyl and (C.sub.8 -C.sub.30)bicyclic or tricyclic alkyl; wherein said (C.sub.3 -C.sub.10)cycloalkyl and said (C.sub.8 -C.sub.30) bicyclic or tricyclic alkyl may optionally be substituted with a hydroxy group; and 5 wherein said adamantyl groups may optionally be substituted with from one to three substituents independently selected from (C.sub.1 -C.sub.6)alkyl, halo and hydroxy;
R.sup.3 and R.sup.4 are independently selected from benzyl, wherein the phenyl moiety of said benzyl may optionally be substituted with an amino or nitro group; hydrogen, phenyl, (N.tbd.C)-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl--O--C(=O)--(C.sub.1 -C.sub.6)alkyl and Het-CH.sub.2, wherein Het is selected from 2-, 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazolyl, thiophenyl and triazolyl;
R.sup.5 is hydrogen, phenyl-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.10)alkyl or (C.sub.1 -C.sub.6)alkyl--C(=O)--;
W is hydrogen, OR.sup.7, hydroxy, R.sup.11 or NR.sup.12 R.sup.13 ;
each of R.sup.7 and R.sup.11 is independently selected from (C.sub.1 -C.sub.6)alkyl;
each of R.sup.12 and R.sup.13 is independently selected from (C.sub.1 -C.sub.3)alkyl; and
R.sup.14 is hydrogen, (C.sub.1 -C.sub.4)alkyl, benzyl or phenyl;
with the proviso that (a) no more than one of the two dotted lines in formula IA can represent a double bond in any one compound, (b) when Z is (H, H), X is CH.sub.2 o
REFERENCES:
patent: 4216318 (1980-08-01), Brown et al.
Bright Gene M
Jasys Vytautas J
Seymour Patricia A
Villalobos Anabella
Volkmann Robert A.
Creagan B. Timothy
Davis Zinna Northington
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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