Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-24
2001-09-04
Oswecki, Jane C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S343000, C514S428000, C514S429000, C514S444000, C514S461000, C544S141000, C546S278400, C548S517000, C548S518000, C548S527000, C548S542000, C549S059000, C549S472000
Reexamination Certificate
active
06284785
ABSTRACT:
BACKGROUND OF THE INVENTION
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
SUMMARY OF THE INVENTION
The present invention is concerned with 1-arenesulfonyl-2-aryl-pyrrolidine and piperidine derivatives of formula
wherein
R
1
signifies hydrogen, lower alkyl or hydroxy-lower alkyl;
R
2
signifies furyl, thienyl, pyridyl or phenyl, which is optionally substituted by 1 to 3 substituents, selected from lower alkyl, lower alkoxy, halogen, cyano, CF
3
or —N(R
4
)
2
;
R
3
signifies naphthyl or phenyl, which is optionally substituted by 1 to 3 substituents, selected from lower alkyl, lower alkoxy, halogen, acetyl, cyano, hydroxy-lower alkyl, —CH
2
-morpholin-4-yl, lower alkyl-oxy-lower alkyl, lower alkyl-N(R
4
)
2
or CF
3
;
R
4
signifies, independently from each other, hydrogen or lower alkyl,
as well as their pharmaceutically acceptable salts.
Compounds of formula I are novel with the exception of (RS)-2-phenyl-1-(toluene-4-sulfonyl)-pyrrolidine and (RS)-1-(toluene-4-sulfonyl)-2-p-tolyl-pyrrolidine. The manufacture of these compounds is described in J. Org. Chem., 51, (1986) 4089-4090. Furthermore, the preparation of (RS)-2-phenyl-1-(toluene-4-sulfonyl)-pyrrolidine is described in Liebigs Ann. Chem., 762, (1972) 93-105.
It has surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor modulators, acting as antagonists or agonists. Compounds of formula I are distinguished by valuable therapeutic properties.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of formula I,
in the scope of the present invention are those, in which
R
1
signifies hydrogen or methyl;
R
2
signifies phenyl, optionally substituted by halogen, lower alkyl, CF
3
or —N(CH
3
)
2
;
with the exception of (RS)-2-phenyl-1-(toluene-4-sulfonyl)-pyrrolidine and (RS)-1-(toluene-4-sulfonyl)-2-p-tolyl-pyrrolidine and their salts.
The following are examples of such compounds:
(RS)-2-(3-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-1-(4-chloro-benzenesulfonyl)-2-(3-fluoro-phenyl)-pyrrolidine,
(RS)-1-(4-chloro-benzenesulfonyl)-2-phenyl-pyrrolidine,
(RS)-2-(4-chloro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-1-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine,
(RS)-2-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-1-benzenesulfonyl-2-(4-chloro-phenyl)-pyrrolidine,
(RS)-1-(4-fluoro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine,
(RS)-2-(4-fluoro-phenyl)-1-(toluene-2-sulfonyl)-pyrrolidine,
(RS)-1-(4-chloro-benzenesulfonyl)-2-p-tolyl-pyrrolidine,
(RS)-1-(4-ethyl-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine,
(RS)-1-(toluene-4-sulfonyl)-2-m-tolyl-pyrrolidine,
(RS)-2-(3-chloro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(3,4-difluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(3-chloro-4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-1-(4-fluoro-benzenesulfonyl)-2-(4-dimethylamino-3-chloro-phenyl)-pyrrolidine,
(RS)-1-(toluene-4-sulfonyl)-2-(4-trifluoromethyl-phenyl)-pyrrolidine,
(RS)-2-(4-chloro-3-methyl-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(4-fluoro-phenyl)-1-(4-trifluoromethyl-benzenesulfonyl)-pyrrolidine,
(RS)-2-(N,N-dimethylamino-phenyl)-1-(4-fluoro-benzenesulfonyl)-pyrrolidine,
(R)-1-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine,
(S)-1-(4-chloro-benzenesulfonyl)-2-(4-fluoro-phenyl)-pyrrolidine,
(RS)-2-(4-ethyl-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(4-ethyl-phenyl)-1-(4-fluoro-benzenesulfonyl)-pyrrolidine,
(S)-2-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(R)-2-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-(4-fluoro-phenyl)-1-(4-methoxymethyl-benzenesulfonyl)-pyrrolidine and
(2RS,3RS)-2-(4-fluoro-phenyl)-3-methyl-1-(toluene-4-sulfonyl)-pyrrolidine
Compounds of formula I, in which
R
1
signifies hydrogen; and
R
2
signifies furyl, thienyl or pyridyl;
are also preferred.
The following are examples of such compounds:
(RS)-1-(4-chloro-benzenesulfonyl)-2-thien-2-yl-pyrrolidine,
(RS)-2-thien-2-yl-1-(toluene-4-sulfonyl)-pyrrolidine,
(RS)-2-thien-3-yl-1-(toluene-4-sulfonyl)-pyrrolidine and
(RS)-2-furan-2-yl-1-(toluene-4-sulfonyl)-pyrrolidine.
The invention embraces all stereoisomeric forms in addition to the racemates.
Unless otherwise indicated, the following definitions are set forth to illustrate and defined the meaning and scope of the various terms used to describe the invention herein.
The term “lower alkyl” denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term “lower alkoxy” denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term “halogen” embraces fluorine, chlorine, bromine and iodine.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by:
reacting a compound of the formula
with a compound of formula
and, if desired,
converting a functional group in a compound of formula I into another functional group and, if desired,
converting a compound of formula I into a pharmaceutically acceptable salt.
In accordance with the invention an appropriately substituted compound of formula II, for example (RS)-2-(3-fluoro-phenyl)-pyrrolidine, is reacted with a suitable compound of formula III, for example toluene-4-sulfonyl chloride. The reaction according to known methods takes place at room temperature within 16 hours in an inert solvent, for example in dichloromethane. After evaporating the solvent, the mixture is dissolved in water and extracted with a suitable solvent, for example ethyl acetate and p
Mutel Vincent
Vieira Eric
Wichmann Jurgen
Dawson Arthur D.
Epstein William H.
Hoffmann La Roche Inc.
Johnston George W.
Oswecki Jane C.
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