4-indole derivatives as serotonin agonists and antagonists

Details 4-indole derivatives as serotonin agonists and antagonists 4-indole derivatives as serotonin agonists and antagonists

1998-08-11

2001-07-03

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S253030, C514S254030, C514S254090, C514S320000, C514S323000, C514S217030, C514S217080, C514S210010, C514S414000, C514S422000, C544S361000, C544S364000, C544S367000, C544S368000, C544S373000, C544S376000, C540S596000, C540S602000, C546S201000, C546S269100, C548S466000, C548S525000, C548S950000

Reexamination Certificate

active

06255306

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to 4-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 or preventing disorders the treatment or prevention of which is facilitated by enhanced serotonergic neurotransmission.
U.S. Pat. No. 4,839,377, issued Jun. 13, 1989, and U.S. Pat. No. 4,855,314, issued Aug. 8, 1989, refer to 5-substituted 3-aminoalkyl indoles. The compounds are said to be useful for the treatment of migraine.
British Patent 2,035,310, published Jun. 18, 1980, 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 Publication 303,506, published Jan. 15, 1989, 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 Publication 354,777, published Feb. 14, 1990, refers to N-piperidinyl:indolyl:ethyl-alkane sulfonamide derivatives. The compounds are said to have 5HT
1
receptor agonist and vasoconstrictor activity and to be useful in treating cephalic pain.
European Patent Publication 438,230, published Jul. 24, 1991, 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.
European Patent Publication 313,397, published Apr. 26, 1989, refers to 5-heterocyclic indole derivatives. The compounds are said to have exceptional properties for the treatment and prophylaxis of migraine, cluster headache, and headache associated with vascular disorders. These compounds are also said to have exceptional “5-HT
1
-like” receptor agonism.
International Patent Publication WO 91/18897, published Dec. 12, 1991, refers to 5-heterocyclic indole derivatives. The compounds are said to have exceptional properties for the treatment and prophylaxis of migraine, cluster headache, and headache associated with vascular disorders. These compound are also said to have exceptional “5-HT
1
-like” receptor agonism.
European Patent Publication 457,701 published Nov. 21, 1991, refers to aryloxy amine derivatives as having high affinity for 5-HT
1D
serotonin receptors. These compounds are said to be useful for treating diseases related to serotonin receptor dysfunction, for example, migraine.
European Patent Publication 497,512 A2, published Aug. 5, 1992, refers to a class of imidazole, triazole, and tetrazole derivatives which are selective agonists for 5-HT
1
like receptors. These compounds are said to be useful for treating migraine and associated disorders.
International Patent Publication WO 93/00086, published Jan. 7, 1993, describes a series of tetrahydrocarbazone derivatives as 5-HT
1
receptor agonists useful for the treatment of migraine and related conditions.
International Patent Publications WO 93/23396, published Nov. 25, 1993, refers to fused imidazole and triazole derivatives as 5-HT
1
receptor agonists for the treatment of migraine and other disorders.
P. Schoeffter et al. refer to methyl 4-{4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2-yl)butyl]-1-piperazinyl}1H-indole-3-carboxylate as a selective antagonist for the 5-HT
1A
receptor in their paper “SDZ216-525, a selective and potent 5-Ht
1A
receptor antagonist” European Journal of Pharmacology, 244, 251-257 (1993).
International Patent Publication WO 94/06769, published Mar. 3, 1994, refers to 2-substituted-4-piperazine-benzothiophene derivatives that are serotonin 5-HT
1A
and 5-HT
1D
receptor agents useful in the treatment of anxiety, depression, migraine, stroke, angina and hypertension.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
wherein X is oxygen or
R
1
is a group of the formula
R
2
and R
3
are independently selected from hydrogen, (C
1
to C
6
)alkyl; (C
1
to C
3
)alkylaryl; (C
1
to C
3
)alkylheteroaryl, —NH(C═O)R
6
, —(C═O)NHR
6
, —O(C═O)R
6
, —(C═O)OR
6
, —(C═O)R
6
, OR
6
, —SO
n
R
6
, —NHSO
n
R
6
, —SO
n
NHR
6
, aryl, and heteroaryl, with the proviso that R
2
and R
3
are not both hydrogen; or
R
2
and R
3
may optionally be taken together to form a group of the formula —(C═O)NH—(CHR
6
)—CH
2
—;
R
4
is hydrogen, (C
1
to C
3
)alkyl, —CHO, —(C═O)CH
3
, and (C
1
to C
3
)alkylaryl;
R
5
is hydrogen, (C
1
to C
3
)alkyl, or (C
1
to C
3
)alkylaryl;
R
6
is hydrogen, (C
1
to C
6
)alkyl, (C
1
to C
3
)alkylaryl, (C
1
to C
3
)alkylheteroaryl, aryl, heteroaryl, and —(CH
2
)—Y—R
7
;
R
7
is hydrogen, (C
1
to C
6
)alkyl, (C
1
to C
3
)alkylaryl, (C
1
to C
3
)alkylheteroaryl, —(C═O)NHR
8
, —(C═O)OR
8
, —(C═O)R
8
, —OR
8
, —SO
n
R
8
, —SO
n
NHR
8
, aryl, and heteroaryl;
R
8
is hydrogen, (C
1
to C
3
)alkyl, aryl, heteroaryl, (C
1
to C
3
)alkylaryl and (C
1
to C
3
)alkylheteroaryl;
Y is oxygen, —SO
n
—, or NH;
a and n are independently 0, 1, or 2;
and said heteroaryl groups and the heteroaryl moieties of said alkylheteroaryl groups are selected from pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4triazinyl, 1,2,3-triazinyl, 1,3,5triazinyl, 1,2,5-thiadiazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, chromenyl, isoindolyl, indolyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl and benzoxazinyl;
and said heteroaryl groups and the heteroaryl moieties of said alkylheteroaryl groups may optionally be substituted with from one to three substituents independently selected from (C
1
to C
4
)alkyl, halogen (e.g., fluorine, chlorine bromine or iodine), hydroxy, cyano, carboxamido, nitro, (C
1
to C
4
)alkoxy, (C
1
to C
3
)alkylaryl, (C
1
to C
3
)alkylheteroaryl, aryl, heteroaryl, and —(CH
2
)—Y—R
7
;
said aryl groups and the aryl moieties of said alkylaryl groups may optionally be substituted with one to three substituents independently 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
pharmaceutically acceptable salts thereof.
The compounds of formula I may have chiral centers and therefore may exist in different enantiomeric forms. This invention relates to all optical isomers and all stereoisomers of compounds of the formula I, and mixtures thereof. When R
1
is a group of the formula III, IV or V
the R enantiomers (e.g., IIIa′, IVa′ and Va′ as depicted above) at the chiral carbon designated by an asterisk in the ring in which “R
1
” occurs are preferred. When R
1
is IIIa and “a” is one there is no chiral center.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The present invention also relates to the pharmaceutically acceptable base salts of compounds of

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