Heterocyclic-cyclic amine derivatives as cholinesterase...

Details Heterocyclic-cyclic amine derivatives as cholinesterase... Heterocyclic-cyclic amine derivatives as cholinesterase...

2001-09-19

2002-12-24

Stockton, Laura L. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06498255

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to heterocyclic-cyclic amine derivatives of the formula I below, and pharmaceutically acceptable salts of such compounds. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.
Alzheimer's disease is associated with degeneration of a 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.
European Patent Application EP A 0 229 391 relates to piperidine derivatives of the formula: R
1
—X—A—R
2
. European Patent Application EP A 296 560 relates to a cyclic amine compound of the formula
All documents cited herein, including the foregoing, are incorporated herein in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein R
1
and R
2
are independently selected from hydrogen, (C
1
-C
6
)alkoxy, benzyloxy, phenoxy, hydroxy, phenyl, benzyl, halo, nitro, cyano, COR
5
, —COOR
5
, —CONHR
5
, —NR
5
R
6
, —NR
5
COR
6
, —OCONR
5
R
6
, —NHCOOR
5
, (C
1
-C
6
)alkyl optionally substituted with from 1 to 3 fluorine atoms; SO
p
CH
2
-phenyl or SO
p
(C
1
-C
6
)alkyl, wherein p is 0, 1 or 2; pyridylmethyloxy or thienylmethyloxy; 2-oxazolyl, 2-thiazolyl and benzenesulfonamide; wherein the phenyl moieties of said phenoxy, benzyloxy, phenyl, benzyl and benzenesulfonamide groups, the pyridyl and thienyl moieties of said pyridylmethyloxy or thienylmethyloxy and the oxazolyl and thiazolyl moieties of said 2-oxaxolyl and 2-thiazolyl may optionally be substituted with 1 or 2 substituents independently selected from halo, (C
1
-C
4
)alkyl, trifluoromethyl, (C
1
-C
4
)alkoxy, cyano, nitro and hydroxy.
or R
1
and R
2
, when attached to adjacent carbon atoms and when X is oxygen, sulfur or NR
4
wherein R
4
is hydrogen or (C
1
-C
4
alkyl) may form, together with the carbon atoms to which they are attached, a group of the formula
 wherein J is oxygen, sulfur or NR
4
, “a” is 1 or 2, R
3
is hydrogen or (C
1
-C
6
)alkyl and Q is oxygen, sulfur, NH, CHCH
3
, C(CH
3
)
2
, —CH═CH—, or (CH
2
)
l
wherein l is an integer from 1 to 3;
X is oxygen, sulfur, —CH═CH—, —CH═N—, —N═CH—, —N═N—, or NR
4
wherein R
4
is hydrogen or (C
1
-C
4
)alkyl;
Y is —(CH
2
)
m
—, —CH═CH(CH
2
)
n
—, —NR
4
(CH
2
)
m
—, or —O(CH
2
)
m
— wherein R
4
is defined as above, n is an integer from 0 to 3 and m is an integer from 1 to 3;
R
5
and R
6
are each independently selected from hydrogen, (C
1
-C
6
)alkyl, phenyl or benzyl, wherein the phenyl moieties of said phenyl and benzyl may optionally be substituted with 1 or 2 substituents independently selected from fluoro, chloro, bromo, iodo, (C
1
-C
4
)alkyl, trifluoromethyl, (C
1
-C
4
)alkoxy, cyano, nitro and hydroxy, or NR
5
R
6
together form a 4 to 8 membered ring wherein one atom of the ring is nitrogen and the others are carbon, oxygen or nitrogen (e.g. pyrrolidinyl, piperidinyl, morpholino, piperazinyl or N-methylpiperazinyl), or NR
5
COR
6
together form a 4 to 8 membered cyclic lactam ring;
M is —CH— or nitrogen;
L is phenyl, phenyl-(C
1
-C
6
)alkyl, cinnamyl or pyridylmethyl, wherein the phenyl moieties of said phenyl and phenyl-(C
1
-C
6
)alkyl may optionally be substituted with 1 to 3 substituents independently selected from (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
6
)alkylcarbonyl, —OCONR
5
R
6
, —NHCOOR
5
or halo; or L is a group of the formula
 wherein b is an integer from 1 to 4, R
13
and R
14
are independently selected from hydrogen, (C
1
-C
4
)alkyl, halo and phenyl, E and F are independently selected from —CH— and nitrogen, and G is oxygen, sulfur or NR
4
wherein R
4
is defined as above, with the proviso that when E and F are both nitrogen, one of R
13
and R
14
is absent; and
R
7
and R
8
are independently selected from hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylcarbonyl and (C
1
-C
6
)alkoxy, with the proviso that said (C
1
-C
6
)alkoxy is not attached to a carbon that is adjacent to a nitrogen.
This invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. Examples of such pharmaceutically acceptable acid addition salts are the salts of hydrochloric acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-toluoyl tartaric acid, and mandelic acid.
This invention also relates to a pharmaceutical composition for inhibiting cholinesterase comprising a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method for inhibiting cholinesterase in a mammal comprising administering to a mammal an amount of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof effective in inhibiting cholinesterase.
This invention also relates to a method for enhancing memory or treating or preventing Alzheimer's disease in a mammal comprising administering to a mammal an amount of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof effective in enhancing memory or treating or preventing Alzheimer's disease.
This invention also relates to compounds of the formula
wherein W is a leaving group; j is an integer from 0 to 2; R
10
is a nitrogen protecting group; and R
7
and R
8
are independently selected from hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylcarbonyl and (C
1
-C
6
)alkoxy, with the proviso that said (C
1
-C
6
)alkoxy is not attached to a carbon that is adjacent to a carbon that is adjacent to a nitrogen. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
This invention also relates to compounds of the formula
wherein
R
1
, R
2
,
R
7
, R
8
,
X, Y and M are as defined above and R
11
is hydrogen or a nitrogen protecting group. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
This invention also relates to compounds of the formula:
wherein R
1
, R
2
, R
7
, R
8
and L are as defined above and Y′ is —CH═CH—(CH
2
)
n
— or —(CH
2
)
m
—. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
The term “mammal”, as used herein, includes humans.
The term “halo”, as used herein, includes chloro, bromo, iodo or fluoro.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties or combinations thereof.
The term “(C
1
-C
4
)alkylcarbonyl”, as used herein, refers to a substituent of the formula
wherein R
15
is alkyl.
The term “(C
1
-C
4
)alkoxycarbonyl”, as used herein, refers to a substituent of the formula V above, wherein R
15
is (C
1
-C
4
)alkoxy.
The term “(C
1
-C
6
)alkoxycarbonyl”, as used herein, refers to a substituent of the formula V above, wherein R
15
is (C
1
-C
6
)alkoxy.
The term “(C
1
-C
6
)alkylcar

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