Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-12-28
1995-01-31
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514456, 514465, 514469, 514555, 514562, 514530, 514538, 549 51, 549 57, 549409, 549405, 549436, 549467, 560 10, 560 12, 560 13, 560 16, 562430, A61K 3134, A61K 3138, C07D30781, C07D33360
Patent
active
053859316
DESCRIPTION:
BRIEF SUMMARY
The present invention, made at the Centre de Recherche PIERRE FABRE (Pierre Fabre Research Center) relates to new sulphonamides, their preparation and their application as a medicament.
Platelet anti-aggregants--the essential activity of which is to combat thrombosis--are increasingly being used either for preventive purposes or as therapeutic adjuvants in this indication as well as in angina, myocardial infarction, atheroma and cardiac ischemia. Thromboxane A.sub.2 (TxA.sub.2) is the mediator most frequently involved in platelet aggregation and is the most powerful proaggregant agent which forms in the course of a metabolization path from arachidonic acid at the platelet level (F. Numano, Atherosclerose and antiplatelet therapy, Drugs of Today, 21, 41, 1985). In physiological disorders, the action of TxA.sub.2 can be stopped during various stages of its formation and, in particular, by inhibiting either its synthesis or its action, by blocking the TxA.sub.2 receptors causing aggregation.
The research on molecules antagonizing the TxA.sub.2 receptors is a recent and promising approach for combating the damage caused by this. (Antithrombotic Agents, M. KUCHAR and V. REJMOLEC, Drug of the Future 11, 689, 1986; Comparison of the action of TxA.sub.2 receptor antagonists, A. M. LEFER, Drugs of Today 21, 283, 1985).
The compounds of the present invention have the general formula I ##STR4## in which: R represents a straight-chain or branched lower alkyl radical containing from 1 to 9 C and, by way of non-limiting example: Me, Et, Pr, Bu, iBu . . . ; groups: lower alkyl (1 to 4 C) or halogen or alkoxy, trifluoromethyl, nitro, amino, lower dialkylamino (1 to 4 C) and, by way of non-limiting example: Me, Et, i-Pr, F, Cl, Br, MeO, EtO, NO.sub.2, NH.sub.2, NMe.sub.2, CF.sub.3 ; thiophenyl radical; lower alkyl, a benzyl and, by way of non-limiting example: Me, Et, i-Pr; group having 1 to 6 C and, by way of non-limiting example: Me, Et, i-Pr, i-Bu; methoxy; C) alkyl and, by way of non-limiting example: Me, Et, i-Pr, i-Bu; --CH.sub.2 --; --CH--OR.sub.4 ; --C=O; --C=N--OR.sub.4 ; ##STR5## where R.sub.4 =H or Me. A represents a benzo-carbocyclic or benzo-heterocyclic bivalent radical chosen from the following (a) to (j): ##STR6## n=1 to 4 inclusive.
The present invention also includes the therapeutically acceptable inorganic or organic salts of compounds of the general formula I in which R.sub.3 =H and, by way of non-limiting example, the sodium, calcium, zinc, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium and tris(2-hydroxyethyl)ammonium salts and also their hydrates where appropriate and the hydrates of the precursor acids.
When the compounds of general formula I contain at least one asymmetric carbon, the present invention also relates to the racemic mixtures and the various enantiomers or diasteroisomers or their mixtures.
The present invention also relates to the use of the compounds of general formula I as a medicament and to the pharmaceutical compositions containing this medicament. The pharmaceutical compositions according to the present invention can use one or more compounds of formula I, if appropriate in combination with one or more other active principles.
Finally, the processes for synthesis of the compounds of general formula I also form part of the present invention.
SYNTHESIS OF THE COMPOUNDS OF GENERAL STRUCTURE I
The base starting material for all of the syntheses is the ester of the acid in the 2- or 3-position of the indane derivative or benzo-heterocycle envisaged (compound II), where A has the same meaning as in I, with the exception of the radicals b, e, h, and j, and where R.sub.5 has the same value as R.sub.3 defined in I, with the exception of hydrogen.
In a first period, the compound II is subjected to a Friedel-Crafts reaction with the aid of a suitably substituted acid chloride of general formula III, where n and R.sub.2 have the same meaning as in the formula I and where Y represents a halogen (bromine or chlorine) or an alkoxycarbonylamino of formula R.sub.8 OCONR.sub.1 (where R.su
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patent: 4866196 (1989-09-01), Iwakuma et al.
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D. F. McClure, et al., J. Org. Chem., "Chiral .alpha.-Amino Ketones from the Friedel-Crafts Reaction of Protected Amino Acids," 46(11), pp. 2431-2433, (1981).
J. March (I), "Advanced Organic Chemistry," 2nd ed., pp. 353-356, 363-365, and 369-370, McGraw Hill Cook Co., New York (1977).
J. March (II), "Advanced Organic Chemistry" 3rd ed. pp. 353-354, Joh Wiley & Sons, New York (1985).
J. March, "Advanced Organic Chemistry" 3rd ed., pp. 392-393, and 804-806 John Wiley & Sons, New York (1985).
W. Foye, "Principles of Medicinal Chemistry" 2nd ed. pp. 80-81, Lea & Febiger, Philadelphia (1981).
Bigg Dennis
Duflos Alain
Rieu Jean-Pierre
Pierre Fabre Medicament
Raymond Richard L.
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