Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-26
2000-01-04
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514211, 5142305, 540552, 544 50, 544 90, A61K 3154, A61K 31535, C07D27916, C07D26512
Patent
active
060110325
DESCRIPTION:
BRIEF SUMMARY
The present application is a U.S. National Application filed under 35 USC 371 of PCT/FR96/01176, filed Jul. 25, 1996, based upon French application Serial No. 95.09079 filed July 26, 1995.
Coronary diseases constitute the prime cause of death in the western world. Myocardial ischemia has a highly complex etiology and is treated only with drugs that act indirectly. The derivatives currently used in myocardial infarction and angina are beta-blockers, nitro derivatives and calcium inhibitors which all act indirectly by a hemodynamic phenomenon.
However, it is accepted that the metabolites produced very early in ischemia (phospholipid catabolism and glycolysis) interfere with the inactivation of the sodium current. This inactivation generates, via the sodium/calcium exchanger in myocytes, an excess calcium charge (Kohlhardt M. et al. (1989) FASEB J. 3 pp. 1963-7 and Undrovinas A.I. et al. (1991) Circulation Research 71 pp. 1231-41). This final excess calcium charge induces contraction of the myocyte.
Recently, novel compounds with no appreciable hemodynamic effect and which act on the excess sodium charge have been claimed (Massingham R., John G. W. and Van Zwieten, Drugs of Today (1991) 27 (8), pp. 459-77) by the Janssen laboratories (E. Boddeke et al., TIPS (1987) 10 pp. 397-400; Ver Donck L., Borgers M., Verdonk F., Cardiovascular Research (1993) 27 pp. 349-357, patent EP 0,184,257) and Syntex (Patmore L. et al. Br J Pharmacol (1991) 104 suppl. 175 P; Alps B. J., Br J Clin Pharmacol (1992) 34 199-206 and U.S. Pat. No. 4,829,065.
In patent EP 0,184,257 representing the closest prior art, the products claimed consist partly of N-(2-benzothiazolyl-1-(phenoxyalkyl)-4-piperidinamine derivatives in which the leader products are R 56865 and Sabeluzole of formula: ##STR2##
MOLECULES CLAIMED
The molecules of the present invention belong to the class of N-substituted 1-(phenoxyalkyl)-4-piperidinamines of formula I: ##STR3## in which R.sub.1 to R.sub.4, which may be identical or different, represent: can be substituted on the aromatic with one or two radicals defined as R.sub.1,
The invention also relates--when they exist--both to the pure R or S isomers and to mixtures thereof.
The present invention includes the therapeutically acceptable inorganic or organic salts of the compounds of general formula I and the possible hydrates thereof.
The invention also relates to the process for the preparation of the compounds claimed, as well as to their application as drugs.
The molecules of the present invention have potentially considerable cytoprotective properties on the heart or neurons, these properties generally being superior to those of the controls R 56865 and sabeluzole mentioned above.
SYNTHESIS OF THE COMPOUNDS OF FORMULA I
Depending on the size of the rings, one or more approaches may be envisaged for the synthesis of the compounds I.
Two routes of access are used to prepare the benzo(xa or thia)zines: indeed, it is possible to start with substituted 2-(halomethyl)phenyliso(thio)cyanates or 4-piperidyliso(thio)cyanates--substituted in position 1. methyl)-phenyliso(thio)cyanates:
(cf. Synthetic Scheme I)
These compounds (II) are prepared by substitutive radical halogenation of suitably substituted o-tolyliso(thio)-cyanates (cf. J. Gonda and P. Kristian Collect Czech Chem Commun (1986) 51 pp. 2802-9; J. Gonda and M. Barnikol Collect Czech Chem Commun (1990) 55 pp. 752-60 and E. Klauke and L. Oehlmann, Synthesis (1978) pp. 376-7). The 4-piperidinamines (III) used can be substituted in position 1 either with the radical (R.sub.3, R.sub.4 --C.sub.6 H.sub.3 --W--Y--) of the present invention (cf. A. M. Ismaiel et al. J Med Chem (1993) 36 pp. 2519-25) or protected in the form of the benzyl derivative (G. C. Cain Bioorg Med Chem Letters (1994), 4, pp. 329-34) or in the form of the ethyl carbamate. The condensation between the 2 molecules (II, III) is carried out according to Gonda and P. Kristian; Gonda and Barnikol already mentioned or W. Gauss and H. J. Kabbe, Synthesis (1978) pp. 377-9, and leads: to Bingwei V. Y
John Gareth W.
Legrand Bruno
Patoiseau Jean-Fran.cedilla.ois
Rieu Jean-Pierre
Valentin Jean-Pierre
Coleman Brenda
Pierre Fabre Medicament
Raymond Richard L.
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