Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-23
2002-05-14
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S181000, C548S312100
Reexamination Certificate
active
06387937
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
where W is
n is 0, 1, or 2; m is 0, 1, 2, or 3; Y and G are each independently oxygen or sulfur; Z is —O—, —S—, —NH, or —CH
2
; R
1
is hydrogen, C
1
to C
8
alkyl, substituted C
1
to C
8
alkyl substituted with one hydroxy, C
3
to C
8
alkenyl, C
3
to C
8
alkynyl, aryl, C
1
to C
3
alkylaryl, C
1
to C
3
alkylheteroaryl, or —Q—R
4
; R
2
and R
3
are each independently hydrogen, C
1
to C
8
alkyl, aryl, C
1
to C
3
alkylaryl, or C
1
to C
3
alkylheteroaryl; R
4
is cyano, trifluoromethyl, —COR
8
, —CO
2
R
9
, —CONR
9
R
10
, —OR
9
, —SO
2
NR
9
R
10
, or —S(O)
q
R
9
; R
9
and R
10
are each independently hydrogen, C
1
to C
9
alkyl, C
1
to C
3
alkylaryl, aryl, or R
9
and R
10
may together be taken to form three-to seven-membered alkyl ring or a three- to seven-membered heteroalkyl ring having 1 heteroatom of O; R
11
is hydrogen, —OR
12
, or —NHCOR
12
; R
12
is hydrogen, C
1
to C
8
alkyl, aryl, or C
1
to C
3
alkyl-aryl; q is 0, 1, or 2; Q is C
1
to C
3
alkyl; a first chiral carbon is designated by an asterisk; a second chiral carbon is designated by #; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C
1
to C
4
alkyl, halogen (e.g., fluorine, chlorine bromine or iodine), hydroxy, cyano, carboxamido, nitro, and C
1
to C
4
alkoxy, and the pharmaceutically acceptable salts thereof. These compounds are useful in treating migraine and other disorders.
The compounds of the invention include all optical isomers of formula I (e.g., R and S stereogenicity at any chiral site) and their racemic, diastereomeric, or epimeric mixtures. The epimers with the S absolute configuration at the chiral carbon site designated by # in formula I are preferred. When R
11
is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula I are preferred. When R
11
is —OR
12
or —NHCOR
12
and n is O or 1, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula I are preferred. When R
11
is —OR
12
or —NHCOR
12
and n is 2, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula I are preferred. When R
11
is —OR
12
or —NHCOR
12
and n is O
2
the
cis
epimers [(2S, 3S) absolute configuration in the azetidine ring] are particularly preferred. When R
11
is —OR
12
or —NHCOR
12
and n is 1, the
cis
epimers [(2S, 4R) absolute configuration in the pyrrolidine ring] are particularly preferred. When R
11
is —OR
12
or —NHCOR
12
and n is 2, the
cis
epimers [(2R, 5R) absolute configuration in the piperidine ring] are particularly preferred.
Unless otherwise indicated, the alkyl, alkenyl, and alkynyl groups referred to herein, as well as the alkyl and alkylene moieties of other groups referred to herein (e.g. alkoxy), may be linear or branched, and they may also be cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties.
Preferred compounds of the invention are compounds of the formula I wherein W is (i), (ii), or (iii); n is 1; m is 1; R
1
is hydrogen, C
1
to C
3
alkyl, or —CH
2
CH
2
OCH
3
; R
2
is hydrogen; and R
3
is hydrogen or —CH
2
Ph (Ph=phenyl). Of the foregoing preferred compounds, the epimers with the S optical configuration at the chiral carbon designated by # in formula I are more preferred. Of the foregoing preferred compounds, when R
11
is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula I are more preferred. Of the foregoing preferred compounds, when R
11
is —OR
12
or —NHCOR
12
, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula I are more preferred. Of the foregoing compounds, when R
11
is —OR
12
or —NHCOR
12
, the
cis
epimers [(2S, 4R) absolute configuration in the pyrrolidine ring] are particularly preferred.
The following compounds are particularly preferred:
3-[(N-2-Methoxyethyl)pyrrolidin-2R-ylmethyl]-4-(2-oxo-1,3-oxazolidin-4S-ylmethyl)-1H-indole;
5-(2-Oxo-1,3-oxazolidin-4S-ylmethyl)-3-(pyrrolidin-2R-ylmethyl)-1H-indole; and
3-(N-Methylpyrrolidin-2R-ylmethyl)-5-(2-oxo-1,3-oxazolidin-4R,S-ylmethyl)-1H-indole.
The present invention also relates to a pharmaceutical composition for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating a condition selected from hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a pharmaceutical composition for treating disorders arising from deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a method for treating disorders arising from deficient serotonergic neurotransmission (e.g., depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders) comprising administering to a mammal (e.g., a human) requiring such treatment an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such condition.
The present invention also relates to a compound of the formula
where W is
n is 0, 1, or 2; m is 0, 1, 2, or 3; Y and G are each independently oxygen or sulfur; Z is —O—, —S—, —NH, or —CH
2
; R
2
and R
3
are each independently hydrogen, C
1
to C
6
alkyl, aryl, C
1
to C
3
alkylaryl, and C
1
to C
3
alkylheteroaryl; R
5
is C
1
to C
O
alkyl, aryl, or C
1
to C
3
alkylaryl (preferably benzyl); R
11
is hydrogen, —OR
12
, or —NHCOR
12
; R
12
is hydrogen, C
1
to C
8
alkyl, aryl, or C
1
to C
3
alkyl-aryl; a first chiral carbon is designated by an asterisk; a second chiral carbon is designated by #; and the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently selected from phenyl and substituted phenyl, wherein said substituted phenyl may be substituted with one to three groups selected from C
1
to C
4
alkyl, halogen (e.g. fluorine, chlorine bromine or iodine), hydroxy, cyano, carboxamido, nitro, and C
1
to C
4
alkoxy. The epimers with the S absolute configuration at the chiral carbon site designated by # in formula II are preferred. When R
11
is hydrogen, the epimers with the R absolute configuration at the chiral carbon site designated by an asterisk in formula II are preferred. When R
11
is —OR
12
or —NHCOR
12
and n is O or 1, the epimers with the S absolute configuration at the chiral carbon site designated by an asterisk in formula II are preferred. When R
11
is —OR
12
or —NHCOR
12
and n is 2, the epimers with the R absolute configuration a
Macor John Eugene
Wythes Martin James
Gerstl Robert
Ginsburg Paul H.
Joran A. David
Pfizer Inc.
Richardson Peter C.
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