Indole derivatives

Details Indole derivatives Indole derivatives

1994-05-20

1997-06-17

Grumbling, Matthew V.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514272, 514323, 514333, 514339, 514414, 514266, 514361, 514417, 514370, 514375, 514381, 544277, 544212, 544333, 546256, 5462774, 5462687, 548466, 548468, 548465, 548128, 548455, 548181, 548207, 548254, A61K 3140, A61K 31395, A61K 31495, A61K 31505

Patent

active

056397526

DESCRIPTION:

BRIEF SUMMARY
This is the national stage under 35 U.S.C. .sctn.371 of application no. PCT/US92/08306 filed Oct. 6, 1992.


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, Raynaud's disease and migraine.
European Patent Application Publication Number 303506 refers to 3-poly:hydropyridyl-5-substituted-1H-indoles. The compound are said to have 5HT.sub.1 -receptor agonist and vasoconstrictor activity and to be useful in treating migraine.
European Patent Application Publication Number 354777 refers to N-piperidinyl:indolyl:ethyl-alkane sulfonamide derivatives. The compound are said to have 5HT.sub.1 -receptor agonist and vasoconstrictor activity and to be useful in treating cephalic pain.


SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR4## wherein Z is ##STR5## R.sub.1 is equal to ##STR6## X is O, NH, or S; A, B, D, E, and F are each independently C, N, O, or S; R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are each independently hydrogen, C.sub.1 to C.sub.6 alkyl, aryl, C.sub.1 to C.sub.3 alkyl-aryl, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, nitro, --NR.sub.7 R.sub.8, --(CH.sub.2).sub.m OR.sub.9, --SR.sub.9, --SO.sub.2 R.sub.9,--SO.sub.2 NR.sub.7 R.sub.8, --NR.sub.7 SO.sub.2 R.sub.8, --NR.sub.7 CO.sub.2 R.sub.9, --NR.sub.7 COR.sub.9, --CONR.sub.7 R.sub.8, or --CO.sub.2 R.sub.9 ; one of R.sub.2 and R.sub.3, R.sub.3 and R.sub.4, R.sub.4 and R.sub.5, or R.sub.5 and R.sub.6 may be taken together to form a five- to seven-membered alkyl ring, a six-membered aryl ring, a five- to seven-membered heteroalkyl ring having 1 heteroatom of N, O, or S, or a five- to six-membered heteroaryl ring having 1 or 2 heteroatoms of N, O, or S; R.sub.7 and R.sub.8 are each independently hydrogen, C.sub.1 to C.sub.6 alkyl, --(CH.sub.2).sub.q R.sub.10, C.sub.1 to C.sub.3 alkyl-aryl, aryl, or R.sup.7 and R.sup.8 may be taken together to form a four- to six-membered ring; R.sub.9 is hydrogen, C.sub.1 to C.sub.6 a alkyl, C.sub.1 to C.sub.3 alkyl-aryl, aryl, or --(CH.sub.2).sub.w R.sub.11 ; R.sub.10 and R.sub.11 are each independently --OH, --OR.sub.12, --CO.sub.2 R.sub.12, --CONHR.sub.12, or cyano; R.sub.12 is hydrogen, C.sub.1 to C.sub.6 alkyl, aryl, or C.sub.1 to C.sub.6 alkyl-aryl; R.sub.13 is hydrogen, --OR.sub.14, or --NHCOR.sub.14 ; R.sub.14 is to C.sub.1 alkyl or C.sub.6 to C.sub.3 alkyl-aryl; n is 0, 1, or 2; m is 1, 2, or 3; q is 2, 3, or 4; w is 2, 3, or 4; the above aryl groups and the aryl moieties of the above alkyl-aryl groups are independently phenyl or substituted phenyl, wherein said substituted phenyl may be substituted with one to three of C.sub.1 to C.sub.4 alkyl, halogen, hydroxy, cyano, carboxamido, nitro, and C.sub.1 to C.sub.4 alkoxy; and a broken line represents an optional double bond, and the pharmaceutically acceptable salts thereof. These compounds are useful in treating migraine and other conditions discussed below.
The compounds of the invention include all optical isomers of formula I (e.g. R and S enantiomers) and their racemic and diastereomeric mixtures. When R.sub.1 is equal to ##STR7## the R diastereomer with the chiral carbon designated by * are preferred. When R.sub.13 is --OR.sub.14 or --NHCOR.sub.14, the cis epimers [(2R,4R) absolute configuration] are particularly preferred.
Unless otherwise indicated, the alkyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g. alkoxy), may be line

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Green et al., "Correlation of electronic structures of indole derivatives with their biological activities," Chemical Abstracts, vol. 74, No. 40779v, 1971.
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Elliott Shaw et al.--J. Am. Chem. Soc., 1877 (1953).
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