Vasoconstrictive substituted 2,3-dihydro-1,4-dioxinopyridines

Details Vasoconstrictive substituted 2,3-dihydro-1,4-dioxinopyridines Vasoconstrictive substituted 2,3-dihydro-1,4-dioxinopyridines

1997-08-06

1999-11-23

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546115, C07D49104, A61K 31435

Patent

active

059901233

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel substituted 2,3-dihydro-1,4-dioxinopyridines, processes for their preparations, pharmaceutical compositions containing them and their use as a medicine, in particular for the prevention or treatment of disorders characterized by excessive vasodilatation, especially migraine.
Migraine is a non-lethal disease suffered by one in ten individuals. The main symptom is headache; other symptoms include vomiting and photophobia. For many years the most widely used treatment for migraine involved the administration of ergotalkaloids, which show however several adverse side effects. Recently a tryptamine derivative, i.e. sumatriptan, was introduced as a novel antimigraine drug. We have now surprisingly found that the present novel substituted 2,3-dihydro-1,4-dioxinopyridines show 5-HT.sub.1 -like agonistic activity and can thus be used in the treatment of disorders characterized by excessive vasodilatation, especially migraine.
EP-A-0,559,285, published on Sep. 8, 1993, discloses 1,4-dioxino[2,3-b]pyridine derivatives as strong serotonine ligands with preference for the 5-HT.sub.1A receptor useful as antidepressants or as anti-anxiety agents.
The present invention is concerned with compounds of formula ##STR2## the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein .dbd.a.sub.1 --a.sub.2 .dbd.a.sub.3 --a.sub.4 .dbd. is a bivalent radical of formula: C.sub.1-6 alkyl or C.sub.1-6 alkyloxy;
R.sup.1, R.sup.2 and R.sup.3 each independently are hydrogen or C.sub.1-6 alkyl;
Alk.sup.1 is C.sub.1-5 alkanediyl;
Alk.sup.2 is C.sub.2-15 alkanediyl;
Q is a radical of formula ##STR3## wherein
R.sup.4 is hydrogen, cyano, aminocarbonyl or C.sub.1-6 alkyl;
R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 alkenyl or C.sub.3-6 alkynyl;
R.sup.6 is hydrogen or C.sub.1-6 alkyl; or
R.sup.5 and R.sup.6 taken together may form a bivalent radical of formula --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5 --;
R.sup.7 and R.sup.8 each independently are hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.9 is hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, amino-carbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.10 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, or aryl C.sub.1-6 alkyl;
R.sup.11 and R.sup.12 are hydrogen or taken together with the carbon atom to which they are connected form C(O);
q is 1 or 2;
R.sup.13 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl, or aryl C.sub.1-6 alkyl;
R.sup.14 is hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.15 and R.sup.16 each independently are hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkyl-aminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.17 and R.sup.18 each independently are hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino, mono- or di(C.sub.1-6 alkyl)amino, mono- or di(C.sub.3-6 cycloalkyl)amino, aminocarbonyl, C.sub.1-6 alkyloxycarbonylamino, C.sub.1-6 alkyl-aminocarbonylamino, piperidinyl, pyrrolidinyl;
R.sup.19 and R.sup.20 each independently are hydrogen, hydroxy, halo, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy, C.sub.1-6 alkylthio, cyano, amino,

REFERENCES:
International Search Report Application No. PCT/EP96/00396, May 1996.
International Preliminary Examination Report Application No. , Nov. 1996 PCT/EP96/00396.

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