Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-27
2001-10-16
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06303635
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a thrombolytic drug which can be orally administered. In particular, the present invention relates to a thrombolytic drug having a function of accelerating the release of a tissue plasminogen activator (t-PA) in vascular endothelial cells, while exerting substantially no effect on the release of type-1 plasminogen activator inhibitor (PAI-1) which deactivates t-PA or reducing the release thereof.
A thrombosis caused by the blood coagulation in the bodies causes serious diseases such as hypertension, stroke and myocardial infarction. Usually drugs affecting the blood such as antiplatelet drugs, anticoagulant drugs and thrombolytic drugs are used for these diseases. Although the antiplatelet drugs and anticoagulant drugs are effective in preventing the formation of thrombi, the effects of them on the patients having the thrombi already formed are only slight and an early fibrinolytic therapy with a thrombolytic drug is necessitated. In the fibrinolytic therapy, a factor capable of developing a fibrinolytic reaction is given in order to dissolve and thereby to remove the thrombi. As the thrombolytic agents, those obtained from fibrinolytic substances per se such as tissue plasminogen activators, urokinase, streptokinase and prourokinase by a gene recombination technique have been used hitherto. However, such a thrombolytic agent must be directly applied to a location of the thrombus formation or the blood vessel. Under these circumstances, the development of a thrombolytic drug which can be orally administered has been demanded.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide an oral thrombolytic drug having a function of accelerating the release of a tissue plasminogen activator (t-PA) in vascular endothelial cells, while exerting substantially no effect on the release of type-1 plasminogen activator inhibitor (PAI-1) which deactivates t-PA or reducing the release thereof.
This and other objects of the invention will be apparent from the following description and Examples.
After intensive investigations, the inventors have found that cyproheptadine known as an antihistaminic agent or antiserotonergic agent and specified piperidine derivatives known as serotonin antagonists or antiplatelet agents [Japanese Patent Unexamined Published Application (hereinafter referred to as “J. P. KOKAI”) No. Hei 8-3135] have functions of accelerating the release of t-PA from the vascular endothelial cells and reducing the release of PAI-1 which deactivates t-PA and inhibits the fibrinolytic reaction. The present invention has been completed on the basis of this finding.
Namely, the present invention relates a thrombolytic drug containing a compound of the following formula (I) or (II) or a salt thereof as the active ingredient:
wherein n represents an integer of 2 or 3, Y represents a hydrogen atom or halogen atom, and X represents a formyl group, acetyl group or hydrogen atom.
BEST MODE FOR CARRYING OUT THE INVENTION
Cyproheptadine of above formula (I) is a known compound having antiserotonergic effect, antihistaminic effect, atropine-like effect, etc., and mentioned in Japanese pharmacopoeia C-587. This compound is easily available on the market as, for example, Periactin (registered trade name of an antihistaminic agent of Banyu Pharmaceutical Co., Ltd.) or cyproheptadine hydrochloride (a compound of Sigma Co.).
The piperidine derivatives of above formula (II) are well-known compounds. They can be easily produced by a well-known process such as that described in J. P. KOKAI No. Hei 8-3135. Reaction scheme I shows an example of the production processes. Di-t-butyl dicarbonate (2) is reacted with 2-aminoethyl bromide hydrobromide (3) in the presence of sodium hydrogencarbonate to obtain N-t-butoxycarbonyl-2-bromoethylamine (4). This compound (4) is condensed with 4-(5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine (5) in the presence of a base such as triethylamine to obtain 4-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine (6). This compound (6) is condensed with a compound (7), from which t-butoxycarbonyl group has been removed with 4 M hydrochloric acid/dioxane, and 1-formylisonipecotic acid (8) in the presence of a condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to obtain 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cycloheptene-5-ylidene)-1-piperidinyl))ethylisonipecotic acid amide (9).
Among the compounds of formula (II), a compound wherein n is 2, Y is hydrogen atom and X is formyl group is preferred.
The reaction product thus obtained by the above-described process is isolated in the form of the free compound or it can be treated by an ordinary salt-forming process, and isolated in the form of a salt. The isolation can be conducted by an ordinary technique such as extraction, concentration, evaporation, crystallization or any of various chromatographic methods.
The salts of the compounds of the above formulae (I) and (II) include acid-addition salts thereof with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and carbonic acid and also organic acids such as formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid and benzenesulfonic acid.
The compound of formula (I) or its salt has a function of accelerating the release of t-PA, while exerting substantially no influence on the release of PAI-1 which deactivates t-PA or reducing the release thereof and, therefore, it is useful as a thrombolytic agent in the fibrinolytic therapy.
The compound of formula (II) or its salt has a function of specifically accelerating the release of t-PA, while exerting substantially no influence on the release of PAI-1 which deactivates t-PA and, therefore, it is useful as a thrombolytic agent in the fibrinolytic therapy.
The dosage forms of the thrombolytic drug containing the compound of formula (I) or (II) or its salt as the active ingredient are ordinary ones such as tablets, powder, pills, granules, sugar-coated tablets, emulsion, capsules, solution, parenteral solution and suppositories. Those products can be prepared by using a carrier, filler and other preparation adjuvants in an ordinary manner.
When the compound of formula (I) or (II) or salt thereof is used as the thrombolytic agent, it can be administered either orally or parenterally. The dose, which varies depending on the age, body weight, conditions and administration method, is about 0.1 to 500 mg/day, preferably 1 to 50 mg/day, for adults in the oral administration and 0.01 to 100 mg/day, preferably 0.1 to 10 mg/day, in the parenteral administration.
The compound of formula (I) or (II) or salt thereof directly acts on the vascular endothelial cells to specifically accelerate the release of the t-PA having the thrombolytic function. Thus, such a compound is useful in the thrombolytic therapy against the thrombosis.
REFERENCES:
patent: 5932593 (1999-08-01), Makino et al.
patent: 52-87177 (1977-07-01), None
patent: 8-3135 (1996-01-01), None
Minsker, D. et al, “Inhibition of Platelet Aggregation by Cyproheptadine” Platelets Thromb. Proc. Symp. Meeting Date 1972, 1974 pp. 161-176, X000973564.
Nowak, G. et al, Influence of Cyproheptadine on Endotoxin-Induced Disseminated Intravascular Coagulation (DIC) in Weaned Pigs), Thrombosis and Haemostasis, 1985, pp. 252-254, XP000973507.
Larry R. Bush, “Effects of the Serotonin Antagonists, Cyproheptadine, Ketanserin and Mianserin, on Cyclic Flow Reductions in Stenosed Canine Coronary Arteries”, The Journal of Pharmacology and Experimental Therapeutics, vol. 240, No. 2, pp. 674-682, 1987.
Minsker,David et al. Inhibition of platelet aggreation by cyproheptadine. Chemical Abstracts vol. 82, 1975, (38511y).
Kawai Yohko
Kihara Hideaki
Watanabe Kiyoaki
Yamamoto Hiroshi
Yoshimoto Ryota
Ajinomoto Co. Inc.
Criares Theodore J.
Kim Jennifer
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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