Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-11-26
2000-09-19
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546306, C07D21375, A61K 3144
Patent
active
061212970
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of international application PCT/DK98 /00195 filed May 15, 1998.
This invention relates to a hitherto unknown class of compounds which shows strong activity in inhibiting undesirable cell proliferation in e.g. skin cells and cancer cells, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and Prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and cancer.
The compounds of the present invention are represented by the general formula I ##STR2## or their tautomeric forms, the attachment to the pyridine ring being in the 3- or 4-position, in which formula R.sub.1 stands for one or more substituents which can be the same or different and are selected from the group consisting of: hydrogen, halogen, trifluoromethyl, carboxy, C.sub.1 -C.sub.4 alkyl, alkoxy or alkoxycarbonyl, nitro, amino or cyano and Q stands for C.sub.9 -C.sub.20 divalent hydrocarbon radical which can be saturated, straight or branched or Q stands for C.sub.4 -C.sub.20 divalent hydrocarbon radical which can be cyclic or unsaturated and X stands for oxygen, sulfur or nitrogen the latter optionally being substituted by hydrogen or C.sub.1 -C.sub.4 alkyl and R.sub.2 stands for one or more substituents which can be the same or different and are selected from the group consisting of: hydrogen, C.sub.1 -.sub.4 alkyl or alkoxy, hydroxy, halogen, triflouromethyl, cyano, carboxamido, sulfamoyl or nitro.
If the present compounds contain one or more asymmetric carbon atoms, these compounds may form optical isomers or diastereoisomers. The present invention also comprises such isomers, and mixtures of same.
The present salts of the compounds of formula I may be formed with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, 4-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, succinic acid, benzoic acid and maleic acid.
Even if the present compounds are well absorbed after enteral administration, in some cases it can be advantageous to prepare suitable bioreversible derivatives of compounds of the invention, i.e. to prepare so-called prodrugs, preferably derivatives, the physicochemical properties of which leads to improved solubility at physiological pH and/or absorption and/or bioavailability of the compound in question.
Such derivatives are for instance pyridyl N-oxide derivatives of compounds of the invention, such compounds being prepared by oxidation of the pyridyl N by a suitable oxidising agent, e.g. with 3-chloroperbenzoic acid in an inert solvent, e.g. dichloromethane.
Other suitable methods to improve the physicochemical properties and/or solubility of the compounds concerned can be used as well.
N-Alkyl-N'-cyano-N"-pyridylguanidines, described in United Kingdom Patent No. 1,489,879, are potent potassium channel activators with a pronounced effect as pre-capillary vasodilators, reducing the total peripheral resistance in animals and in man, and are thus useful as antihypertensives. As stated in International Patent No. PCT/DK93/00291, filing date Sep. 13, 1993, Publication No. WO 94/06770 the introduction of aryloxy-containing radicals into the aliphatic groups from the above-cited U.K. Patent has led to structures showing more specific pharmacological effects on isolated tissues and cells and with no or a negligible effect on .sup.86 Rb-efflux from potassium channels, as compared with the established effect of compounds covered by the above-mentioned U.K. Patent.
The compounds of the present invention inhibit the proliferation of various tumour cell lines in cultures at lower concentrations than the known compounds, confer table 1 below, thus making them potentially useful in antineoplastic chemotherapy.
The inhibition of tumour cell proliferation was studied using different types of human cance
REFERENCES:
Schou et al: "Novel cyanoguanidines with potent oral antitumour activity", Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, vol. 7 No. 24, 1997 pp. 3095-3100, XP002079955.
Davis Zinna Northington
Leo Pharmaceutical Products Ltd. A/S
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