Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-11
2001-10-16
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S324000, C546S201000, C546S202000
Reexamination Certificate
active
06303633
ABSTRACT:
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
wherein one of R
2
, R
3
and the side chain containing
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
1
is phenyl, phenyl-(C
1
-C
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
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy and halo;
R
2
and R
3
are independently selected from hydrogen, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkyl optionally substituted with from one to three fluorine atoms, benzyloxy, hydroxy, phenyl, benzyl, halo, nitro, cyano, COOR
4
, CONHR
4
, NR
4
R
5
, NR
4
COR
5
, or SO
p
CH
2
-phenyl wherein p is 0, 1 or 2;
or R
2
and R
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
4
and R
5
are independently selected from hydrogen and (C
1
-C
6
)alkyl, or R
4
and R
5
, when part of said NR
4
R
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
4
and R
5
, when part of said NR
4
COR
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
6
;
R
6
is hydrogen, (C
1
-C
6
)alkyl, CO(C
1
-C
6
)alkyl or SO
2
—, phenyl, wherein the phenyl moiety of said SO
2
-phenyl may optionally be substituted with from one to five substituents independently selected from (C
1
-C
4
)alkyl;
n is an integer from 1 to 4;
each q is independently 1 or 2; and
Z is oxygen or sulfur;
with the proviso that any CH
q
group wherein q is 1 must be attached to one and only one other CH
q
group wherein q is 1.
The present 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, fumaric acid, maleic 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 further relates to a pharmaceutically composition for inhibiting acetylcholinesterase comprising a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
The invention further relates to a method for inhibiting acetylcholinesterase 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 acetylcholinesterase.
The invention further 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 or salt thereof effective in enhancing memory or treating or preventing Alzheimer's disease.
The term “mammal”, as used herein, includes humans.
The term “halo”, as used herein, includes chloro, bromo or fluoro.
Preferred compounds of this invention are compounds of the formula
wherein X is CH, CCH
3
, CCH
2
CH
3
or N; Y is NH, NCH
3
, NCH
2
CH
3
, S, O or NSO
2
C
6
H
5
; R
2
and R
3
are independently selected from the group consisting of (C
1
-C
4
)alkyl, chloro, fluoro, methoxy, amino and
or R
2
and R
3
, together with the carbons to which they are attached, form a &ggr;-lactam ring; and R
1
is benzyl, methoxybenzyl, fluorobenzyl or a group of the formula
wherein W is hydrogen, (C
1
-C
6
)alkyl, phenyl or benzyl.
Specific preferred compounds of the invention are:
1-(2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(2-phenyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl)-1-propanone;
1-(2-methyl-6-benzothiazolyl)-3-(1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(2-methyl-6-benzothiazolyl)-3-[1-[(2-methyl-4-thiazolyl)methyl]-4-piperidinyl]-1-propanone;
1-(5-methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(6-methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(3,5-dimethyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(benzo[b]thien-2-yl)-3-(1-(phenylmethyl)-4-piperidinyl)-1-propanone;
1-(benzofuran-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(1-phenylsulfonyl-6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(1-phenylsulfonyl-5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl)-1-propanone;
1-(5-amino-indol-2-yl)-3-(1-(phenylmethyl)-4-piperidinyl)-1-propanone; and
1-(5-acetylamino-indol-2-yl)-3-(1-(phenylmethyl)-4-piperidinyl)-1-propanone.
Examples of other compounds of the invention are:
1-(6-quinolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(5-indolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(5-benzthienyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(6-guinazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(6-benzoxazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(5-benzofuranyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(5-methyl-benzimidazol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(6-methyl-benzimidazol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(5-chloro-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;
1-(5-azaindol-2-yl)-3-[1-(p
Chen Yuhpyng L.
Nagel Arthur A.
Chang Ceila
Ginsburg Paul H.
Jacobs Seth H.
Pfizer Inc
Richardson Peter C.
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