Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-09-17
1998-08-25
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544284, 544291, 514259, A61K 31505, C07D40304
Patent
active
057983623
DESCRIPTION:
BRIEF SUMMARY
This is a 35 USC .sctn.371 national stage application based on PCT/EP94/01001, filed Mar. 17, 1995.
The present invention refers to new derivatives of 4-amino-6,7-dimethoxyquinazoline having .alpha.-antagonist activity, their isomeric mixtures, the enantiomers, their addition salts with pharmaceutically acceptable acids or the pharmaceutical compositions containing them. Among the quinazoline derivatives already known, in particular those comprising in their structure the piperazine-group, many present an antihypertensive or hypotensive activity both systemic and intraocular, and also a regulating activity on the biosynthesis of cholesterole. For example U.S. Pat. No. 3,511,836 describes quinazoline-derivatives having anti-hypertensive action. In particular among the described compounds the 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine (Prasozine) is actually used for this kind of therapy.
In U.S. Pat. No. 4,026,894 other compounds structurally related to the above said are described, among them the )!piperazine (Terazosine) is used as hypotensive agent and in the therapy of prostate benign hyperplasia (BPH).
However, in the therapeutical treatment with the above said compounds, some undesired side effects where observed, such as: cephalea, somnolence, asthenia, nausea, palpitation. In some cases also postural effects were observed in conjunction with the usual symptoms associated with the decreasing of pressure, i.e. vertigo and light-headed. It is therefore still desired to develop substances which, although therapeutically active against the above said disorders, show less marked side effects.
U.S. Pat. No. 5,110,927 describes prazosin analogues substituted at position 4 of the piperazinyl ring with a wide-variety of substituents, such as phenylaminothiocarbonyl, cinnamoyl or bicyclooctadienecarbonyl residues, as well as with the 2-phenylethylcarbonyl, the phenoxymethylcarbonyl, the 2-naphtylcarbonyl or the phenylaminocarbonyl group.
GB-A-2,068,961 and EP-A-28031 disclose antihypertensive 4-amino-6,7-dimethoxy-quinazolines substituted at position 2 with a substituted piperazinyl or homopiperazinyl ring, and disclose in particular the 2-piperazinyl-quinazolines substituted at position 4 of the piperazinyl ring with a phenylalkylcarbonyl or a phenooxyalkylcarbonyl residue (GB-A-2.068.961), or with an optionally substituted phenylaminocarbonyl residue (EP-A-28031).
U.S. Pat. No. 4,062.844 reports antihypertensive 4-amino-2-(1-piperazinyl)-6,7-dimethoxy-quinazolines substituted at position 4 of the piperazinyl ring with a wide range of groups, such as a phenylcarbonyl, an alkyloxycarbonyl, an (unsubstituted-phenoxy)carbonyl group or a dialkylaminocarbonyl group.
Other known antihypertensive compounds are the 4-amino-6,7-dimethoxy-quinazolines substituted at position 2 of the quinazoline ring with a variety of N-methylaminoalkyl residues, among which the N-methyl-diphenyl-4,4-n-butylamino group (FR-A-2,389,614), or with hydroxyacyl groups, such as the 4-(2hydroxy-2-phenylacetyl)piperazin-1-yl group (EP-A-225,866).
It was now founded, and it is an object of the present invention, that modifying the substituents of the piperazine-ring new derivatives are obtained showing a good affinity for the .alpha..sub.1 -adrenoreceptors and lower toxicity when compared with the known compounds.
The compounds according to the present invention have general formula (I) ##STR1## wherein B represent one of the following groups: ##STR2## wherein:
A is chosen in the group of: a chemical bond, --CO--, --CONH--, each of them being represented in order to show that the left side is the part linked to the heterocyclic ring and the right side is linked to the alkyl-chain;
R.sub.1 and R.sub.2, same or different, represent independently from each other an hydrogen atom, linear or branched alkyl- group having from 1 to 4 carbon atoms;
n is 0 or 1;
m is comprised between 0 and 4 and
R represents a group: aryl, diarylmethyl, aroyl, aryl(hydroxy)methyl, alkyloxycarbonyl, aryloxy unsubstituted or possibly substit
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Boi Carlo
Leonardi Amedeo
Motta Gianni
Testa Rodolfo
Grumbling Matthew V.
Recordati S.A. Chemical and Pharmaceutical Company
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