Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1985-03-12
1987-05-12
Trousof, Natalie
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514632, 548351, 564228, A61K 31155, A61K 31415, C07D23352, C07C13310
Patent
active
046650857
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new amidines having an anti-hypertensive activity, and which are typically useful for the treatment of ocular hypertensions such as glaucoma.
The ocular hypertension phenomena are principally related to an imbalance between the rate of formation and the rate of flow of the aqueous humor.
The aqueous humor is produced by the ciliary body; it enters the posterior chamber, flows through the pupil and into the anterior chamber at the periphery of which it reaches the iraidocorneal angle. The apex of this angle is filled with a large mesh connective tissue: the trabeculum. At this level, the aqueous humor percolates the trabecular mesh, is collected in Schlemm's canal and then, via the aqueous veins, reaches the episcleral venous circulation and, finally, the systemic circulation.
In the subjects suffering from glaucoma, the rate of elimination of the aqueous humor is reduced, which results in an accumulation of aqueous humor and an ocular hypertension.
In the absence of treatment, this high pressure may interfere with the circulation of blood at the level of the nerve fibers of the retina and of the optic nerve, leading to the destruction of the optic nerve and blindness.
Examples of products commonly used in the treatment of glaucoma include: agonist, and timolol, a non selective .beta. sympathicolytic agent.
Different sudies have shown that the topical administration of products that stimulate the .alpha..sub.2 adrenergic receptors, such as clonidine and .alpha.-methyl epinephrine, produces a decrease of the intraocular pressure (ALLEN R. C., Invest. Ophthalmol., 15, (10), 815, 1976; KRIEGLSTEIN G. K., Invest. Ophthamlol. Vis. Sci. 17 (2), 149, 1978; HODAPP E., Arch. Ophthalmol., 99, 1208; 1981; LANGHAM M. E., Invest. Opthalmol. Vis. Sci. ARVO suppl., 22,230, 1982).
Due to its action on the central nervous system, clonidine exhibits detrimental side effects, in addition to its action on the intraocular pressure.
Also, in BSM 8175 and 7689 are described amidines of benzylidene amino guanidine type, for the systemic treatment of arterial hypertension. Such compounds include a sedative component, in view of their action on the central nervous system.
This invention is based on the discovery of new amidines which possess a stimulating .alpha..sub.2 adrenergic activity and which are practically free from any action on the central nervous system, and which are useful as antihypertensive agents, particularly in the ocular domain.
Thus, this invention relates to compounds of the formula ##STR2## in which: R.sub.1 and R.sub.2, independently from one another, represent a hydrogen atom, a C.sub.1-6 alkyl group or a hydroxy group; or R.sub.1 and R.sub.2 form together a divalent ethylene or trimethylene radical; alkoxy group, a mono- or polyhydroxy(C.sub.1-4 alkyl) group, an amino group, a (mono- or di-C.sub.1-4 alkyl)amino group, an acetamido group, or a sulfonamido group; alkyl)group, an amino group, a (mono- or di-C.sub.1-4 alkyl)amino group, an acetamido group or a sulfonamido group, R.sub.4 being at 3, 4 or 5 position; and formula ##STR3## --NH--, --N.dbd., --O-- and --S--, in which R.sub.5 represents a hydrogen atom, a C.sub.1-4 alkyl group, a hydroxy group, or a C.sub.1-4 alkoxy group,
This invention includes also within its scope therapeutic compositions comprising, as active ingredient, a compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof.
In the above definition, by the term "pharmaceutically acceptable acid addition salts" are meant the salts which possess the biological properties of the free bases, without having an undesirable effect. Such salts may typically by those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acidic metal salts such as disodium orthophosphate and monopotassium sulfate, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, fumaric acid, citric acid, malic acid, methanesulfonic acid, lactic acid, succinic acid, tar
REFERENCES:
patent: 3174978 (1965-03-01), Marxer
patent: 3211746 (1965-10-01), Marxer
Boehringer, Ingelheim GMBH Chemical Abstracts (1968) #47,453k (S. A. 6,706,503).
Battais Elisabeth
Bonne Claude
Coquelet Claude
Sincholle Daniel
Hendriksen L.
Laboratoires Chauvin-Blache
Trousof Natalie
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