6-AMINO-1,2-DIHYDRO-1-HYDROXY-2-IMINO-4-(4-HYDROXYPIPERIDIN-1-YL)-PYRIMIDINE HYDROXIMINOXIDIL HAVING ANTIFIBROBLASTIC ACTIVITY

Abstract: The 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-(4-hydroxypiperidin-1-yl)pyrim idine is endowed with antifibroblastic activity and may be used for the preparation of a drug useful for treating pathological conditions characterized by proliferation of the connective tissue.

Description: 6-amino-l,2-dihydro-l-hydroxy-2-imino-4-(4-hydroxypiperidin -1-yl-pyrimidine hydroxyminoxidil having antifibroblastic activity The present invention refers to the use of 6-a ino-l ,2-dihydro-hydroxy-2-imino-( -hydroxypiperidin-l -yDpyridine for the preparation of a medicament having antifibrotic activity useful for the treatment of proliferation conditions of the connective tissue and collagen accumulation. Is is known that pathological conditions such as keloids, hypertrophic scars and fibrotic conditions such as scleroderma, are characterized by an excessive proliferation of the connective tissue, whose main component is the finrous protein known as collagen. Said abnormal growth of the connective tissue, taking place also as a consequence of phlogistic processes of various kind (fractures, contusions, distortions, traumas etc.) hinders the physiological processes of tissue repair and healing. In the past, pharmacological agents potentially useful for limiting the collagen accumulation in fibrotic conditions have been proposed. Said agents, however, proved to be unsatisfactory because of toxicity problems or lack of specificity. More recently, the inhibiting activity of the fibroplast proliferation and of lysyl hydroxylase of two known anthypertensive drugs, hydralazine and inoxidil, has been described. Particularly minoxidil has been studied because of its additional capacity of stimulating hair growth. However, the main pharmacological activity of minoxidil, namely the antihypertensive and vasodilating activity, may limit the topical use of the drug, both in the known and widespread treatment of alopecias and in the proposed treatment of fibrotic conditions. It has now been found that a metabolite of minoxidil, the 6-amino-l,2-dihydro-l-hydroxy-2-imino-(4- -hydroxypiperidin-l)pyridine already described in the italian patent application n c 22518 A/84 as capable of stimulating the hair growth, shares the antifibroplastic action of minoxidil differing however from the parent molecule in the lack of antihypertensive and vasodilating activity. The use of the minoxidil metabolite according to the present invention for the preparation of a medicament having antifibrotic activity is therefore more advantageous in comparison with minoxidil because of possible side-effects that the latter may induce as a consequence • of its vasodilating and antihypertensive activity. The new pharmacological activity of the minoxidil metabolite of the invention, hereinafter referred to as SKM/101, was confirmed by inhibition tests of the enzymes prolylhydroxylase and lysylhydroxylase in human skin fibroplasts cultures, according to the method reported in Dermatologica 175(2), 12-18, 1987. A further confirmation was obtained from in vivo tests using guinea-pigs on whose back a silastic valve was implanted, SKM/101 may be formulated in topical phar¬ maceutical compositions, using conventional techniques and excipients. Examples of suited pharmaceutical compo- sitions are lotions, creams, ointments, sprays, gauzes, plasters, balsams and the like. A particularly convenient administration form consists of lyophilized bovine native collagen, impregnated with SKM/101 or its acceptable salts. The concentration of the active principle or of its salts in the above cited pharmaceutical compositions may range from 0.2 to 20% by weight. The compositions may also contain other active principles having complementary or anyhow useful activity such as vitamin A or its derivatives, vitamin E or its derivatives, ascorbic acid, glutathion, antioxidants. The pharmaceutical compositions of the invention may be administered one or more times a day, according to the pathology to be treated and of the kind of used formulations. For the treatment of keloids, hypertrophic scars, decubitus ulcers and generally facilitating the healing processes, plasters containing SKM/101 able to release slowly and gradually the active principle are particularly useful. SKM/101 may also be administered by local infiltration using known methods, in place of cortison. The following examples further illustrate the invention. EXAMPLE 1 Lotion Isopropylmyristate g 1.0 Polyethylenglycol g 2.0 Cetyl alcohol g 2.0 EDTA g 0.05 Ethanol g 15.00 SKM/101 g 10.00 Purified water to ml 100.00 EXAMPLE 2 Lotion Ethanol g 35.00 Propylen Glycol g 25.00 SKM/101 N-acetyl-cysteine salt g 15.00 Water q.s. • to 100 ml EXAMPLE 3 Cream Cetomacrogol g 1.00 Cetostearyl alcohol g 25.00 Glutathion g 0.20 Preserving agent q.s. Vitamine A acetate g 0.20 SKM/101 g 20.00 Purified water q.s. ml 100.00 EXAMPLE 4 Aerosol SKM/101 g 2.0 Ethanol g 5.0 Propellant gas g 6.5 EXAMPLE 5 Cream SKM/101 g 5.0 Polysorbate 80 g 1.0 Spermaceti g 10.0 Propylene glycol g 5.0 Vitamine E acetate g 0.20 Vitamine C acetate g 0.2 P-oxy benzoates g 0.1 Purified water q.s. ml 100 EXAMPLE 6 Gauze Each gauze 10 x 10 cm is soaked at saturation with 40 g of a mixture having the following composition: SKM/101 g 2.0 Collagen g 15.0 Glycerine g 10.0 Vitamine E acetate g 0.2 Purified water q.s, to g 40

Claims: CLAIMS 1. Use of 6-amino-l,2-dihydro-l-hydroxy-2-amino-(4-hy- droxypiperidin-l-yl)pyridine or of its pharmaceutically acceptable salts for the preparation of a medicament having antifibrotic activity. 2. Topical pharmaceutical compositions containing an effective amount of 6-amino-l,2-dihydro-l-hydroxy-2-ami- no-(4-hydroxypiperidin-l-yl)pyridine or of its pharmaceutically acceptable salts in admixture with an acceptable carrier. 3. Composition according to claim 2 in form of ointments, lotions, plasters, impregnated collagen sheets, gauzes, spray. 4. Compositions according to claim 2 or 3 containing also active principles having complementary or anyhow useful activity.

Inventors: GATTI FRANCESCO, GATTI, FRANCESCO
Applicants: KEMIOS S R L BIO MEDICAL RESEA, KEMIOS S.R.L. BIO MEDICAL RESEARCH
Application year: 1990
Main classification: A61K31
IPC codes: A61K31