Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1994-01-13
2001-07-03
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...
C514S260100, C514S322000, C514S323000, C544S292000, C546S153000, C546S199000, C546S201000
Reexamination Certificate
active
06255322
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed to neuroprotective (antiischemic excitatory amino acid receptor blocking) 2-(4-hydroxypiperidino)-1-alkanol derivatives defined by formula (I) below; pharmaceutically acceptable salts thereof; a method of using these compounds in the treatment of stroke, traumatic injury to the brain and spinal cord, and neuronal degenerative diseases including (but not limited to) senile dementias such as Alzheimer's disease, Huntington's disease and Parkinson's disease in mammals, especially humans; and to certain intermediates therefor.
Ifenprodil (A) is a racemic, so-called dl-erythro compound having the relative stereochemical formula
which is marketed as a hypotensive agent, a utility shared by a number of close analogs. Carron et al., U.S. Pat. No. 3,509,164; Carron et al., Drug Res., v. 21, pp. 1992-1999 (1971). More recently, ifenprodil has been shown to possess antiischemic and excitatory amino acid receptor blocking activity. Gotti et al., J. Pharm. Exp. Therap., v. 247, pp. 1211-21 (1988); Carter et al., loc. cit., pp. 1222-32 (1988).
See also French Patent 2546166 and EPO publication EP-A1-351282, published Jan. 17, 1990. A goal, substantially met by the present invention, has been to find compounds possessing neuroprotective activity in good measure, while at the same time having lowered or no significant hypotensive effect.
Certain 1-phenyl-3-(4-aryl-4-acyloxy-piperidino)-1-propanols have also been reported to be useful as analgesics, U.S. Pat. No. 3,294,804; 1-[4-(amino- and hydroxy-alkyl)phenyl]-2-(4-hydroxy-4-tolylpiperazino)-1-alkanols and alkanones have been reported to possess analgesic, antihypertensive, psycho-tropic or antiinflamatory activity, Japanese Kokai 53-02,474 (CA 89:43498y; Derwent Abs. 14858A) and 53-59,675 (CA 89:146938w; Derwent Abs. 48671A); and 2-piperidino-1-alkanol derivatives have been reported to be active as antiischemics, EP 398,578-A and Der 90-350,327/47.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the formula
wherein R
1
, R
2
and R
3
are each selected from the group consisting of hydrogen, alkyl having 1 to 6 carbons,
phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, alkyl having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, amino, nitro and alkoxy having 1 to 4 carbons;
or R
1
and R
2
when taken together form a methylene, ethylene, propylene or butylene group;
m is 0 to 2;
n is 1 or 2;
X and Y are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, trifluoromethyl, alkoxy having 1 to 4 carbons, alkyl having 1 to 4 carbons, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent on said substituted phenoxy is selected from the group consisting of hydrogen, hydroxy, alkyl having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, nitro, amino and alkoxy having 1 to 4 carbons;
M and Q are each selected from the group consisting of hydrogen, hydroxy, amino, chloro, bromo, fluoro, trifluoromethyl, nitro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, N,N-dialkylamino having 1 to 4 carbons in each of said alkyls, N-alkylamino having 1 to 4 carbons, NHCOR
4
, NHCOOR
5
and NHSO
2
R
6
;
wherein R
4
is selected from the group consisting of hydrogen, alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, alkyl having 1 to 4 carbons and alkoxy having 1 to 4 carbons;
and wherein R
5
and R
6
are each selected from the group consisting of alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, alkyl having 1 to 4 carbons and alkoxy having 1 to 4 carbons;
or M and Q when taken together form a divalent radical Z, wherein Z is selected from the group consisting of
wherein R
7
and R
8
are each selected from the group consisting of hydrogen and methyl;
and the pharmaceutically acceptable acid addition salts of these compounds.
The expression “pharmaceutically acceptable acid addition salts” is intended to include but is not limited to such salts as the hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate, maleate, and succinate. Such salts are conventionally prepared by reacting the free base form of the compound (I) with an appropriate acid, usually one molar equivalent, and in a solvent. Those salts which do not precipitate directly are generally isolated by evaporation of the solvent and/or addition of a non-solvent followed by filtration.
A preferred group of compounds of the present invention are those in which N and Q form a radical Z, wherein Z is
R
1
and R
2
are hydrogen and R
3
is methyl and the compounds possess 1
r*
, 2
s*
or erythro relative stereochemistry at the 1- and 2-positions of the propanol chain, i.e.,
A second preferred group of compounds of this invention are those in which N and Q form a radical Z, wherein Z is
R
1
and R
2
are hydrogen and R
3
is methyl and the compounds possess 1
s*
, 2
s*
or threo relative stereochemistry at the 1- and 2- positions of the propanol chain, i.e.,
The present invention is also directed to pharmaceutical compositions containing a compound of the invention of formula I, and to methods of treating a mammal, particularly human subject, suffering from a central nervous disorder, which comprises administering to said mammal a neuroprotective effective amount of a compound of the formula (I). Said compositions and methods are particularly valuable in the treatment of traumatic injury to the brain and spinal cord, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease and related disorders of the central nervous system.
The present invention is further directed to intermediate compounds of the formula
wherein
R
2
and R
3
are each selected from the group consisting of hydrogen, alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, alkyl having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, amino, nitro and alkoxy having 1 to 4 carbons;
m is 0 to 2;
n is 1 or 2;
X and Y are each selected from the group consisting of hydrogen, chloro, bromo, fluoro, trifluoromethyl, alkoxy having 1 to 4 carbons, alkyl having 1 to 4 carbons, hydroxy, amino, nitro and substituted phenoxy, wherein the substituent on said substituted phenoxy is selected from the group consisting of hydrogen, hydroxy, alkyl having 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, nitro, amino and alkoxy having 1 to 4 carbons;
M and Q are each selected from the group consisting of hydrogen, hydroxy, amino, chloro, bromo, fluoro, trifluoromethyl, nitro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, N,N-dialkylamino having 1 to 4 carbons in each of said alkyls, N-alkylamino having 1 to 4 carbons, NHCOR
4
, NHCOOR
5
and NHSO
2
R
6
;
wherein R
4
is each selected from the group consisting of hydrogen, alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, chloro, brono, fluoro, trifluoromethyl, amino, nitro, alkyl having 1 to 4 carbons and alkoxy having 1 to 4 carbons;
and wherein R
5
and R
6
are each selected from the group consisting of alkyl having 1 to 6 carbons, phenyl and substituted phenyl, wherein the substituent on said substituted phenyl is selected from the group consisting of hydroxy, chloro, bromo, fluoro, trifluoromethyl, amino, nitro, alkyl having 1 to 4 carbons and alkoxy having 1 to 4 carbons;
or N and Q when taken together form a divalent radical Z, wherein Z is selected from the group consisting of
and wherein R
7
Benson Gregg C.
Chang Ceila
Crissey Todd M.
Pfizer Inc.
Richardson Peter C.
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