Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-02-05
1997-10-14
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514272, 514275, 544323, 544325, 544326, 544327, 544329, 544332, 544105, C07D23942, C07D31918, C07D40512, A61K 31505
Patent
active
056773102
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT Application Ser. No. PCT/EP 94/02702, filed Aug. 12, 1994, which claims priority from European Patent Application Ser. No. 93.202.445.8, filed on Aug. 19, 1993; and European Patent Application Ser. No. 93.202.444.1, filed on Aug. 19, 1993.
The present invention relates to novel substituted aryloxyalkyldiamine derivatives, processes for their preparations, pharmaceutical compositions containing them and their use as a medicine, in particular for the prevention and/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 aryloxyalkyl diamine derivatives show 5-HT.sub.1 -like agonistic activity and can thus be used in the treatment of disorders characterized by excessive vasodilatation, especially migraine.
In Arzneimittel-Forschung, 25, 1404 (1975) some guanidine and amidinc derivatives, among which having noradrenaline depleting activity.
In EP-0,511,072 derivatives of 2-aminopyrimidine-4-carboxamide having the general formula (A) are disclosed as antagonists of .alpha..sub.1 -adrenergic receptors. ##STR3## The present invention is concerned with compounds having the formula ##STR4## the pharmaceutically acceptable acid addition salts thereof, and the stereochemically isomeric forms thereof, wherein
R.sup.1 and R.sup.2 each independently are hydrogen or C.sub.1-6 alkyl;
R.sup.3 is C.sub.1-6 alkyl, hydroxy, cyano, halo, C.sub.1-6 alkyloxy, aryloxy, arylmethoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkyl-S-, C.sub.1-6 alkyl(S.dbd.O)--, C.sub.1-6 alkylcarbonyl;
R.sup.4 is hydrogen, halo, hydroxy, C.sub.1-6 alkyl, or C.sub.1-6 alkyloxy; or R.sup.3 and R.sup.4 taken together form a bivalent radical of formula ##STR5## in these bivalent radicals one or two hydrogen atoms may be substituted with C.sub.1-6 alkyl, C.sub.1-6 alkylcarbonyl or C.sub.1-6 alkyl-S(O)--; --NR.sup.8 --; --NR.sup.8 --; --O--S(O).sub.2 --; alkyl-S(O)--; C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, aryloxy or arylmethoxy; ##STR6## wherein R.sup.9 is hydrogen, cyano, aminocarbonyl or C.sub.1-6 alkyl; alkynyl, C.sub.3-6 cycloalkyl or arylC.sub.1-6 alkyl; --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5 --, or a piperazine which is optionally substituted with C.sub.1-6 alkyl; R.sup.23, R.sup.24, R.sup.25, R.sup.26, R.sup.27, R.sup.28, R.sup.29, R.sup.36, R.sup.37 and R.sup.38 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; alkyl, C.sub.1-6 alkylcarbonyl, or arylC.sub.1-6 alkyl; atom to which they are connected form C(O); atom to which they are connected form C(O); taken together may form a bivalent radical of formula (CH.sub.2).sub.3 or (CH.sub.2).sub.4 which is optionally substituted with C.sub.1-6 alkyl; and C.sub.1-6 alkyloxy.
All the compounds of formula (I) are deemed novel except for isopropyl; R.sup.4 is hydrogen; R.sup.5 is hydrogen; R.sup.6 is chloro, fluoro or methyl; R.sup.7 is hydrogen; R.sup.2 is hydrogen or methyl; R.sup.1 is hydrogen; Alk.sup.1 is 1,2-ethanediyl or 1,3-propanediyl; Alk.sup.2 is 1,2-ethanediyl or 1,3-propanediyl; Q is a radical of formula (bb), wherein R.sup.12 is hydrogen and R.sup.13 is 4-aminocarbonyl.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope
REFERENCES:
patent: 4438128 (1984-03-01), Wiedemann et al.
patent: 4593039 (1986-06-01), Baldwin et al.
patent: 5229392 (1993-07-01), George et al.
Benkert et al., Arzneimittel Forschung. Drug Research, vol. 25, No. 9, 1975, pp. 1404-1408.
De Bruyn Marcel Frans Leopold
Van Lommen Guy Rosalia Eugene
Wigerinck Piet Tom Bert Paul
Janssen Pharmaceutica N.V.
Metz Charles J.
Rao Deepak R.
Shah Mukund J.
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