Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1995-09-18
2002-08-20
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S872000, C514S318000, C514S319000, C514S323000, C514S324000, C514S326000, C546S002000, C546S010000, C546S013000
Reexamination Certificate
active
06436961
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for preparing and resolving 3-amino-2-phenylpiperidine and for synthesizing from the enantiomers of such compound certain pharmaceutically active substituted 2-phenyl-3-benzylaminopiperidines. The substituted 2-phenyl3-benzylaminopiperidines that can be prepared by the processes of this invention are substance P receptor antagonists and are useful in the treatment and prevention of inflammatory, gastrointestinal and central nervous system disorders, as well as several other disorders.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and possesses the characteristic amino acid sequence illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al.,
Journal of Medicinal Chemistry,
25, 1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrositis, and in gastrointestinal disorders and diseases of the GI tract such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in “Trends in Cluster Headache,” edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)).
The substituted 2-phenyl-3-benzylaminopiperidines that can be prepared by the processes of this invention, as well as methods for preparing such compounds, are referred to in U.S. patent application Ser. No. 07/724,268, which was filed on Jul. 1, 1990 and World Patent Application PCT/US92/03571, which was published on Jan. 7, 1993 (WO 93/00331). Methods for preparing such compounds are also referred to in U.S. patent application Ser. No. 07/800,667, which was filed on Nov. 27,1991 and World Patent Application PCT/US92/00065 which was published on Oct. 15, 1992 (WO 92,17449).
SUMMARY OF THE INVENTION
The present invention relates to a process for resolving racemic or optically enriched 3-amino-2-phenylpiperidine, comprising reacting a starting material which is racemic 2-phenyl-3-aminopiperidine or an optically active mixture of (2R,3R)-3-amino-2-phenylpiperidine and (2S,3S)-3-amino-2-phenylpiperidine with L-(+)-mandelic acid or D-(−)-mandelic acid.
This invention also relates to a process for preparing a compound of the formula
comprising reacting L-(+)-mandelic acid with either racemic 3-amino-2-phenylpiperidine or an optically active mixture of (2R,3R)-3-amino-2-phenylpiperidine and (2S,3S)-3-amino-2-phenylpiperidine to form a compound of the formula IA, or reacting D-(−)-mandelic acid with either racemic 3-amino-2-phenylpiperidine or an optically active mixture of (2R,3R)-3-amino-2-phenylpiperidine and (2S,3S)-3-amino-2-phenylpiperidine to form a compound of the formula IB.
This invention also relates to the above process, wherein the compound of formula IA or IB formed is neutralized to form, respectively, (2S,3S)-3-amino-2-phenylpiperidine or (2R,3R)-3-amino-2-phenylpiperidine.
This invention also relates to the above process wherein the (2S,3S)-3-amino-2-piperidine or (2R,3R)-3-amino-2-piperidine formed is reacted with either (a) a compound of the formula
wherein X is a leaving group (e.g., chloro, bromo, iodo or imidazole) and R
1
is aryl selected from indanyl, phenyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C
3
-C
7
) cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from chloro, fluoro, bromo, iodo, nitro, (C
1
-C
10
) alkyl optionally substituted from one to three fluoro groups, (C
1
-C
10
) alkoxy optionally substituted with from one to three fluoro groups, amino,
(C
1
-C
10
)alkyl-S—, (C
1
-C
10
)alkyl-SO
2
—, phenyl, phenoxy, (C
1
-C
10
)alkyl-SO
2
NH—, (C
1
-C
10
)alkyl-SO
2
NH—(C
1
-C
10
)alkyl-, (C
1
-C
10
)alkylamino-di(C
1
-C
10
)alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, (C
1
-C
6
)alkylamino, (C
1
-C
6
)dialkylamino,
and
wherein the nitrogen atoms of said amino and (C
1
-C
6
) alkylamino groups may optionally be protected with an appropriate protecting group; and R
2
is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, (C
1
-C
10
)alkyl optionally substituted with from one to three fluoro groups and (C
1
-C
10
) alkoxy optionally substituted with from one to three fluoro groups, followed by treatment of the resulting amide with a reducing agent, (b) a compound of the formula R
1
CHO, wherein R
1
is defined as above, in the presence of a reducing agent, or (c) a compound of the formula R
1
CH
2
X, wherein R
1
is defined as above and X is a leaving group (e.g., chloro, bromo, iodo, mesylate or tosylate), to form respectively, a compound of the formula
wherein R
1
is defined as above.
This invention also relates to the novel optically active salts of formulae IA and IB.
The term “halo”, as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
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 “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined as above.
The term “one or more substituents,” as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.
Preferred embodiments of this invention are the resolution processes referred to above wherein the resolving agent is L-(+)-mandelic acid and the solvent is acetonitrile.
Other preferred embodiments of this invention are compounds of the formula VA or VB wherein R
1
is phenyl or substituted phenyl. More preferred are compounds of the formula VA wherein R
1
is phenyl substituted with from 1 to 3 substituents independently selected from one to three fluorine atoms and (C
1
-C
16
)alkoxy optionally substituted with from one to three fluorine atoms.
DETAILED DESCRIPTION OF THE INVENTION
The processes of this invention are depicted in the following reaction scheme. Unless otherwise indicated, in the reaction scheme and discussion that follow, R
1
is defined as above.
Referring to scheme 1, the pyridine of formula II is reduced to form the corresponding piperidine of formula III. This reduction is generally accomplished using either sodium in alcohol, lithium aluminum hydride/aluminum trichloride, electrolytic reduction or hydrogen in the presence of a metal catalyst. The reduction with sodium is generally conducted in a boiling alcohol, preferably butanol, at a temperature from about 20° C. to about the reflux temperature of the solvent, preferably at about 120° C. The reduction with lithium aluminum hydride/aluminum trichloride is usually carried out in ether, tetrahydrofuran (THF) or dimethoxyethane, preferably ether, at a temperature from about 25° C. to about 100° C., preferably at about room temperature. The electrolytic reduction is conducted, preferably, at room temperature, but temperatures from about 10° C. to about 60° C. are also suitable.
Hydrogenation in the presence of a metal catalyst is the preferred method of reduction. Suitable hydrogenation cataly
Snyder William M.
Watson, Jr. Harry A.
Wilcox Glenn E.
DeBenedictis Karen
Ginsburg Paul H.
Pfizer INC
Richardson Peter C.
Travers Russell
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