Indole derivatives as 5-HT1 agonists

Details Indole derivatives as 5-HT1 agonists Indole derivatives as 5-HT1 agonists

2000-10-23

2002-06-25

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S312100

Reexamination Certificate

active

06410739

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to indole derivatives, to processes and intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The active compounds of the present invention are useful in treating migraine and other disorders.
U.S. Pat. Nos. 4,839,377 and 4,855,314 and European Patent Application Publication Number 313397 refer to 5-substituted 3-aminoalkyl indoles. The compounds are said to be useful for the treatment of migraine.
British Patent Application 040279 refers to 3-aminoalkyl-1H-indole-5-thioamides and carboxamides. The compounds are said to be useful in treating hypertension, Raymond's disease and migraine.
European Patent Application Publication Number 303506 refers to 3-poly:hydro-pyridyl-5-substituted-1H-indoles. The compounds are said to have 5-HT
1
receptor agonist and vasoconstrictor activity and to be useful in treating migraine.
European Patent Application Publication Number 354777 refers to N-piperidinyl:indoyl:ethyl-alkane sulfonamide derivatives. The compounds are said to have 5-HT
1
receptor agonist and vasoconstrictor activity and to be useful in treating cephalic pain.
European Patent Applications Publication Numbers 438230, 494774, and 49752 refers to indole-substituted five-membered heteroaromatic compounds. The compounds are said to have 5-HT
1
-like receptor agonist activity and to be useful in the treatment of migraine and other disorders for which a selective agonist of these receptors is indicated.
International Patent Application PCT/GB91/00908 and European Patent Application No. 313397A refers to 5-heterocyclic indole derivatives. The compounds are said to exhibit properties useful in the treatment and prophylaxis of migraine, cluster headache, and headache associated with vascular disorders. These compounds are also said to the “5-HT
1
-like” receptor agonism.
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
alkyheteroaryl, 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
alkyheteroaryl; R
4
is cyano, trifluoromethyl, —COR
9
, —CO
2
R
9
, —CONR
9
R
10
, —OR
9
, —SO
2
NR
8
R
10
, or —S(O)
4
R
9
; R
9
and R
10
are each independently hydrogen, C
1
to C
8
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
alkyoxy, 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 sterogenicity 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 0 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 0, the
cis
epimers [(2S, 3S) absolute configuration in the axetidine 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)pyrrolldin-2R-ylmethyl]-5-(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

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