Intermediates useful for the preparation of antihistaminic...

Details Intermediates useful for the preparation of antihistaminic... Intermediates useful for the preparation of antihistaminic...

2003-02-12

2004-08-17

Chang, Celia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S239000, C514S317000

Reexamination Certificate

active

06777555

ABSTRACT:

BACKGROUND OF THE INVENTION
These antihistaminic piperidine derivatives can be described by the following formula:
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen;
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
3
is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof,
with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0.
SUMMARY OF THE INVENTION
The present invention provides novel intermediates useful for the preparation of certain antihistaminic piperidine derivatives of formula (I)
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen; or
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
3
is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof,
with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0.
These novel intermediates are described by the following formulas:
wherein
A is a hydrogen or hydroxy; and
R
5
is H, —CH
2
OD wherein D is hydrogen, acetate or benzoate, —CHO, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
A is a hydrogen or hydroxy; and
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
A is a hydrogen or hydroxy; and
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R
5
is H, CH
2
OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, —COOH or —CONR
6
R
7
wherein R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy;
R
5
is H, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5; and
A is a hydrogen or hydroxy.
wherein A is a hydrogen or hydroxy.
wherein
Hal is Cl, Br or I;
n is an integer of from 1 to 5;
A is a hydrogen or hydroxy; and
R
5
is H, CH
2
OD wherein D is hydrogen, acetate or benzoate, CHO, Br, Cl, I, CN, —COOH, —COOalkyl or —CONR
6
R
7
wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched and R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy; and
individual optical isomers thereof.
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen; or
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
5
is H, Br, Cl, I, CN or —CONR
6
R
7
wherein R
6
and R
7
are each independently H, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or R
6
and R
7
taken together with the nitrogen atom form a pyrrolidine, piperidine or morpholine, with the proviso that R
6
and R
7
cannot both be represented by C
1
-C
6
alkoxy;
A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0.
In addition, the present invention provides novel processes for preparing the antihistaminic piperidine derivatives of formula
wherein
W represents —C(═O)— or —CH(OH)—;
R
1
represents hydrogen or hydroxy;
R
2
represents hydrogen; or
R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
;
n is an integer of from 1 to 5;
m is an integer 0 or 1;
R
3
is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
each of A is hydrogen or hydroxy; and
pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R
1
and R
2
are taken together to form a second bond between the carbon atoms bearing R
1
and R
2
or where R
1
represented hydroxy, m is an integer 0, comprising the steps of:
(a) reacting a cumene compound of the formula
wherein A is as defined above with a &ohgr;-halo compound of the formula
wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce a &ohgr;-halo cumylketone compound;
(b) reacting the &ohgr;-halo cumylketone compound with a suitable halogenating agent to give a &ohgr;-halo-halocumylketone compound;
(c) reacting the &ohgr;-halo-halocumylketone compound compound with a suitable cyanating agent to give a &ohgr;-halo-cyanocumylketone compound;
(d) reacting the &ohgr;-halo-cyanocumylketone compound with an appropriate straight or branched C
1
-C
6
alcohol in the presence of a suitable anhydrous acid to give a &ohgr;′-halo-&agr;′-keto-&agr;,&agr;-dimethylphenylacetic acid imidate compound;
(e) reacting the &ohgr;′-halo-&agr;′-keto-&agr;,&agr;-dimethylphenylacetic acid imidate compound with water to give a &ohgr;′-halo-&agr;′-keto-&agr;,&agr;-dimethylphenylacetic acid ester compound;
(f) reacting the &ohgr;′-halo-&agr;′-keto-&agr;,&agr;-dimethylphenylacetic acid ester compound with a piperidine compound of the formula
wh

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