Heterocyclic compounds, their production and use

Details Heterocyclic compounds, their production and use Heterocyclic compounds, their production and use

1993-04-23

2001-11-20

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S552000

Reexamination Certificate

active

06319916

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel heterocyclic compounds and salts thereof, and to pharmaceutical preparations. More particularly, the present invention relates to a cholinesterase inhibitor, especially to a therapeutic and/or prophylactic agent for senile dementia, Alzheimer and so on, novel heterocyclic compounds as active ingredients and salts thereof, to methods for preparing the same and to intermediate products thereof.
BACKGROUND OF THE INVENTION
With an increasing number of elderly people, there have been proposed various compounds having therapeutic and/or prophylactic actions on senile dementia. Among these compounds, there has been found a therapeutic/prophylactic action in physostigmine, a naturally-occurring cholinesterase inhibitor (International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 29, No.1, p.23-37(1991) etc.). Physostigmine has, however, such defects as a relatively short duration of the action and high toxicity.
On the other hand, various heterocyclic compounds have been suggested as synthetic medicines. For example, EP-A-0,378,207, U.S. Pat. No. 4,849,431 corresponding to JPA-62(1987)-234065, U.S. Pat. No. 4,895,841 corresponding to JPA-64(1989)-79151, JPA-2(1990)-169569 and EP-A-0,468,187 disclose cholinesterase inhibitors having nitrogen-containing heterocyclic ring (hereinafter referred to as N-containing heterocyclic ring). U.S. Pat. No. 4,064,255 corresponding to JPA-52(1977)-72829 and U.S. Pat. No. 4,208,417 corresponding to JPA-55(1980)-9070 respectively disclose heterocyclic compounds used as an antidepressant or antianxiety drugs.
More particularly, EP-A-0,378,207 discloses a cyclic amino compound of the following formula or salts thereof:
wherein B stands for an optionally substituted saturated or unsaturated 5- to 7-membered azaheterocylic group; A represents a bond, an alkylene group or an alkenylene group which may be substituted with a hydrocarbon residue, an oxo group or hydroxyl group;
represents a single bond or double bond (provided that A represents a bond,
represents a single bond); R
2
and R
3
independently represent a hydrogen atom or an optionally substituted hydrocarbon residue (provided that they are not H at the same time) or may form a cyclic amino group taken together with the adjacent nitrogen atom; n denotes 0, 1 or 2; and p notes 1 or 2, or salts thereof.
Practically it discloses a compound of the following formula among others:
In U.S. Pat. No. 4,849,431 corresponding to JPA-62(1987)-234065, there are disclosed piperidine derivatives of the following formula or pharmaceutically acceptable salts thereof:
wherein
R
1
represents a monovalent group derived from a member selected from optionally substituted benzene, pyridine, pyrazine, indole, anthraquinone, quinoline, optionally substituted phthalimide, homophtalimide, pyridine carboxylimide, pyridine-N-oxide, pyrazine carboxylimide, naphthalenedicarboxylimide, optionally substituted quinazolinedione, 1,8-naphthalimide, bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylimide and pyromellylimide;
X represents a group of the formula —(CH
2
)
m
— (wherein m denotes an integer of 0 to 7); a group of the formula —O(CH
2
)
n
—; a group of the formula —S(CH
2
)
n
—; a group of the formula —NH(CH
2
)
n
—; a group of the formula —SO
2
NH (CH
2
)
n
—; a group of the formula —NH—CO—(CH
2
)
n
—; a group of the formula —NH(CH
2
)
n
—CO—; a group of the formula —COO(CH
2
)
n
—; a group of the formula —CH
2
NH(CH
2
)
n
—; a group of the formula —CO—NR
3
—(CH
2
)
n
—(in the definition of X, in all formula, n each denotes an integer of 0 to 7; and R
3
represents a lower alkyl group or benzyl group); a group of the formula —O—CH
2
CH
2
CH(CH
3
)—; a group of the formula —O—CH(CH
3
)CH
2
CH
2
—; a group of the formula —O—CH
2
CH
2
CH═; or a group of the formula —O—CH
2
CH(OH)CH
2
—; Ring A represents a group of the formula
 a group of the formula
 a group of the formula
 a group of the formula
R
2
represents a hydrogen atom, a lower alkyl group, an optionally substituted benzyl group, optionally substituted benzoyl group, pyridyl group, 2-hydroxyethyl group, pyridylmethyl group or group of the formula:
(wherein Z represents a halogen atom).
Practically, there is disclosed a compounds of the following formula among them:
U.S. Pat. No. 4,895,841 corresponding to JPA-64(1989)-79151, and JPA-2(1990)-169569 disclose a cyclic amine derivative of the following general formula or pharmaceutically acceptable salts thereof:
wherein
J represents
(a) optionally substituted groups shown as follows; (1) a phenyl group, (2) a pyridyl group, (3) a pyrazyl group, (4) a quinolyl group, (5) a cyclohexyl group, (6) a quinoxalyl group or (7) a furyl group,
(b) a mono- or di-valent group selected from the following groups which may be substituted on the phenyl group; (1) an indanyl group, (2) an indanonyl group, (3) an indenyl group, (4) an indenonyl group, (5) an indandionyl group, (6) a tetranonyl group, (7) a benzsperonyl group, (8) an indanolyl group or (9) a group of the formula:
(c) a monovalent group derived from a cyclic amide compound,
(d) a lower alkyl group or
(e) a group of the formula R
1
—CH═CH— (wherein R
1
represents a hydrogen atom or a lower alkoxycarbonyl group);
B represents a group of the formula —(C(R
2
)H)
n
—; a group of the formula —CO—C(R
2
)H)
n
—; a group of the formula —NR
2
—(C(R
2
)H)
n
— (wherein R
2
represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or benzyl group); a group of the formula —CO—NR
4
—C(R
2
)H)
n
— (wherein R
4
represents a hydrogen atom, a lower alkyl group or a phenyl group), a group of the formula —CH═CH—(C(R
2
)H)
n
—; a group of the formula —O—COO—(C(R
2
)H)
n
—; a group of the formula —O—CO—NH—(C(R
2
)H)
n
—; a group of the formula —NH—CO—(C(R
2
)H)
n
—; a group of the formula —CH
2
—CO—NH—(C(R
2
)H)
n
—; a group of the formula —CO—NH—(C(R
2
)H)
n
—; a group of the formula —C(OH)H—(C(R
2
)H)
n
— (in the above formulae, n denotes 0 or an integer of 1 to 10, R
2
represents a hydrogen atom or a methyl group in the form of an alkylene group of the formula —(C(R
2
)H)
n
— which is unsubstituted or having one or more than one methyl group); a group of the formula═(CH—CH═CH)
b
— (wherein b denotes an integer of 1 to 3); a group of the formula═CH—(CH
2
)
c
— (wherein c denotes 0 or an integer of 1 to 9); a group of the formula═(CH—CH)
d
═ (wherein d denotes 0 or an integer of 1 to 5); a group of the formula═CO—CH═CH—CH
2
—; a group of the formula —CO—CH
2
—C(OH)H—CH
2
—; a group of the formula —C(CH
3
)H—CO—NH—CH
2
—; a group of the formula —CH═CH—CO—NH—(CH
2
)
2
—; a group of the formula —NH—; a group of the formula —O—; a group of the formula —S—; a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group;
T represents a nitrogen atom or a carbon atom;
Q represents a nitrogen atom, a carbon atom or a group of the formula >N→O;
K represents a hydrogen atom, an optionally substituted phenyl group, an arylalkyl group optionally substituted with a phenyl group, a cinnamyl group optionally substituted with phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl group, a cycloalkyl group, a lower alkoxycarbonyl group or an acyl group; q denotes an integer of 1 to 3 ═ and represents a single bond or a double bond, and a cholinesterase inhibitor containing the above mentioned compounds.
A practical embodiment thereof is the following compound.
EP-A-0,468,187 discloses a cyclic amide compound of the formula:
R
1
—(CH
2
)
n
—Z
wherein R
1
represents a group derived from an optionally substituted cyclic amide compound; n denotes an integer of 0 to 10; and Z represents a formula:
wherein R
2
represents an aryl group, a substituted aryl group, a cycloalkyl group or a heterocyclic group; m denotes an integer of 1 to 6; R
3
represents a hydrogen atom or a lower alkyl group; R
4
rep

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