Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-01
2001-12-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S192000, C546S223000
Reexamination Certificate
active
06329396
ABSTRACT:
TECHNICAL FILED
This invention relates to substituted benzylaminopiperidine compounds of interest to those in the field of medical chemistry and chemotherapy. More particularly, it is concerned with a series of substituted piperidine compounds, including their pharmaceutically acceptable salts, which are of special value in view of their ability to antagonize substance P. These compounds are of use in treating a gastrointestinal disorder, a central nervous system (CNS) disorder, an inflammatory disease, emesis, urinary incontinence, pain, migraine, sunburn, angiogenesis, diseases, disorders and adverse conditions caused by
Helicobacter pylori,
or the like, especially CNS disorders in a mammalian subject, especially humans.
BACKGROUND ART
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having originally been isolated from the gut) and possesses a characteristic amino acid sequence that is 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 recently been shown to be involved in the transmission of pain or migraine, 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, and in gastrointestinal disorders and diseases of GI tract, like ulcerative colitis and Crohn's diseases, etc. It is also reported that the tachykinin antagonists are useful for the treatment of allergic conditions, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera and senile dementia of the Alzheimer type, emesis, sunburn and
Helicobacter pylori
infection.
International Publication No. WO 93/01170, WO 93/00331 and WO 93/11110 disclose a wide variety of piperidine derivatives, as tachykinin antagonists such as substance P antagonists.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides substituted piperidine compounds of the following chemical formula (I):
and its pharmaceutically acceptable salts, wherein
R is halo C
1
-C
8
alkyl, halo C
2
-C
8
alkenyl, halo C
2
-C
1
alkynyl or halo C
1
-C
8
alkyl substituted by hydroxy or C
1
-C
8
alkoxy; R
1
is hydrogen, halo or C
1
-C
6
alkoxy; or
R and R
1
, together with the two carbon atoms shared between the benzene ring and the R and R
1
, complete a fused C
4
-C
6
cycloalkyl wherein one carbon atom is optionally replaced by oxygen and wherein one or two of the carbon atoms are optionally substituted by up to five substituents selected from halo, C
1
-C
6
alkyl and halo C
1
-C
6
alkyl;
X is C
1
-C
6
alkoxy, halo C
1
-C
6
alkoxy, phenoxy or halo; and
Ar is phenyl optionally substituted by halo.
The piperidine compounds of the present invention of formula (I) exhibit good antagonist activity toward Substance P, particularly good activity against CNS disorders, and are thus useful for treatment of a gastrointestinal disorder, a central nervous system disorder, an inflammatory disease, emesis, urinary incontinence, pain, migraine, sunburn, angiogenesis, diseases, or disorders and adverse conditions caused by
Helicobacter pylori
in a mammalian subject, especially humans.
Accordingly, the present invention provides a pharmaceutical composition for the treatment of a gastrointestinal disorder, a central nervous system disorder, an inflammatory disease, emesis, urinary incontinence, pain, migraine, sunburn, angiogenesis, diseases disorders and adverse conditions caused by
Helicobacter pylori,
or the like, especially CNS disorders in a mammalian subject, especially humans, which comprises a therapeutically effective amount of a compound of the formula (I) together with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
In this specification,
the term “halo C
1
-C
8
alkyl” is used herein to mean a straight, branched or cyclic C
1
-C
8
alkyl radical substituted with one or more halogens (i.e., Cl, F, I or Br) including, but not limited to, trifluoromethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, trifluoroisopropyl, tetrafluoroisopropyl, pentafluoroisopropyl, hexafluoroisopropyl or heptafluoroisopropyl and the like;
the term “halo C
2
-C
8
alkenyl” is used herein to mean a straight, branched or cyclic C
2
-C
8
alkenyl radical substituted with one or more halogens (i.e., Cl, F, I or Br) including, but not limited to, 3,3,3-trifluoropropenyl, 1,1-dimethyl-4,4,4-trifluorobutenyl and the like;
the term “halo C
2
-C
8
alkynyl” is used herein to mean a straight, branched or cyclic C
2
-C
8
alkynyl radical substituted with one or more halogens (i.e., Cl, F, I or Br) including, but not limited to, 3,3,3-trifluoropropynyl, 1,1-dimethyl-4,4,4-trifluorobutynyl and the like; and
the term “halo C
1
-C
8
alkoxy” is used herein to mean a straight, branched or cyclic C
1
-C
8
alkoxy radical substituted with one or more halogens (i.e., Cl, F, I or Br) including, but not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and the like.
In the chemical formula (I):
R is preferably C
1
-C
6
alkyl, hydroxy C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl, wherein the alkyl, alkenyl and alkynyl moieties are substituted by two to seven halogen atoms.
In preferable embodiment of the present invention, R is C
1
-C
6
alkyl, hydroxy C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl, preferably C
1
-C
6
alkyl, these groups being substituted by two to three fluorine atoms. Examples of R are trifluoromethyl, difluoroethyl, trifluoroethyl, trifluoroisopropyl, trifluoro-tert-butyl, trifluoro-1,1-dimethylmethyl-3-butynyl, and 2-chlorotrifluoroisopropyl.
In another preferable embodiment of the present invention, R is C
1
-C
6
alkyl, hydroxy C
1
-C
6
alkyl, C
2
-C
6
alkenyl or C
2
-C
6
alkynyl, these groups being substituted by four to seven fluorine atoms. Examples of R are pentafluoroethyl, pentafluoropropyl, pentafluoroisopropenyl, hexafluoroisopropyl, heptafluoroisopropyl, hexafluoro-2-hydroxyisopropyl and hexafluoro-tert-butyl.
R
1
is preferably hydrogen or methoxy, more preferably hydrogen.
In another preferable embodiment of the present invention, R and R
1
may be taken together with the two carbon atoms shared between the benzene ring and the R and R
1
, to complete fused C
4
-C
6
cycloalkyl wherein one carbon atom is optionally replaced by oxygen. The one or two of the carbon atoms of the C
4
-C
6
cycloalkyl may be optionally substituted by up to four, more preferably one to two, substituents selected from a fluorine atom and trifluoromethyl. More preferably, R and R
1
, may be taken together with the two carbon atoms shared between the benzene ring and the R and R
1
, complete trifluoromethylcyclopentyl, trifluoromethylcyclohexyl, difluorocyclohexyl or difluorodimethylcyclohexyl.
X is preferably halo, methoxy, difluoromethoxy, trifluoromethoxy or phenoxy, more preferably methoxy, difluoromethoxy or trifluoromethoxy, most preferably methoxy. X is preferably at 2-position on the phenyl ring.
Ar is preferably phenyl.
Another preferred group of compounds of this invention includes the compounds of formula (Ia):
wherein R
1
is hydrogen, halo or methoxy; and R
2
and R
3
is independently selected from halo, C
1
-C
6
alkyl, C
2
-C
6
alkenyl and C
2
-C
6
alkynyl, or R
2
and R
3
together complete C
2
-C
6
alkylidene, wherein the alkyl, alkenyl, alkynyl and alkylidene moiety are optionally substituted by up to seven halogen atoms;
or R
1
and R
2
are taken together to complete a fused C
4
-C
6
cycloalkyl wherein one carbon atom is optionally replaced by oxygen, the C
4
-C
6
cycloalkyl being optionally substituted by up to four substituents selected from halo, C
1
-C
4
alkyl, and halo C
1
-C
4
alkyl.
In
Satake Kunio
Shishido Yuji
Wakabayashi Hiroaki
Ginsburg Paul H.
Pfizer Inc.
Rao Deepak R.
Richardson Peter C.
Shah Mukund J.
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