Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
1999-11-18
2001-12-04
Padmanabhan, Sreeni (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C514S729000, C568S303000, C568S379000
Reexamination Certificate
active
06326405
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the pharmaceutical agents which use specific compound having an anticancer action and an apoptosis-inducing action as an effective component.
PRIOR ART
Pharmaceutical agents which have been used in clinical therapy include many agents such as anticancer agents, antibiotic substances, immunopotentiators, immunomodulators, etc. (such as alkylating agents, antimetabolites and plant alkaloids) but it can be hardly said that such a drug therapy has been completely established already.
Among those agents, prostaglandin A and J having a cyclopentenone ring among the prostaglandins derived from natural substances have been reported to have a possibility of being used as highly safe anticancer agents due to their inhibition of DNA synthesis and various derivatives of them have been synthesized (refer to the Japanese Laid-Open Patent Publication Sho-62/96438).
In recent years, a mode of apoptosis has been drawing the attention concerning the death of cell tissues.
Unlike necrosis which is a pathogenic death of cells, apoptosis is believed to be a death which is initially programmed in the gene of the cell itself. Thus, the gene which programs the apoptosis is activated by certain external or internal causes whereby programmed cell death gene protein is produced based upon said gene and then the cell itself is decomposed and dead by the resulting programmed death protein. If such apoptosis can be expressed in desired tissues or cells, it will be now possible to exclude the unnecessary or pathogenic cells from living body in their natural form and that will be significantly meaningful.
PROBLEMS TO BE SOLVED BY THE INVENTION
An object of the present invention is to offer an anticancer agent and an apoptosis-inducing agent in which a compound having an &agr;, &bgr;-unsaturated carbonyl group in its five-membered ring is an effective component.
MEANS TO SOLVE THE PROBLEMS
The present inventors have carried out an intensive investigation for achieving the above object and, as a result, they have found the compounds having an anticancer action, an apoptosis-inducing action, etc. whereupon they have accomplished the present invention.
The first feature of the present invention relates to an anticancer agent in which 4-cyclopentene-1,3-dione represented by the following formula [I] and/or 4-hydroxy-2-cyclopentenone represented by the following formula [III] are/is effective components(s).
The second feature of the present invention relates to an apoptosis-inducing agent in which 4-cyclopentene-1,3-dione represented by the above formula [I] and/or 4-hydroxy-2-cyclopentenone represented by the above formula [II] are/is effective component(s).
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention will now be specifically illustrated as hereunder.
Each of 4-cyclopentene-1,3-dione represented by the formula [I] and 4-hydroxy-2-cyclopentenone represented by the formula [II] is a known compound and can be manufactured by known methods or, alternatively, commercially available compounds may be used.
With regard to 4-cyclopentene-1,3-dione, it can be synthesized by a method by G. H. de Puy, et al. [
J. Am. Chem. Soc.,
82, 631 and 2909 (1960)], a method by V. A. Mirinov, et al. [
Chemical Abstracts,
18178e (1973)] or a method by Kirschke, et al. [
J. Prakt. Chem.,
317, 807 (1975)] or a commercially available substance such as a product by Aldrich (16, 168-3) may be used.
With regard to 4-hydroxy-2-cyclopentenone, it can be prepared by reduction of 4-cyclopentene-1,3-dione with cerium (III) chloride or with sodium borohydride. Known synthetic methods therefor are a method by T. Tanaka, et al. [
Tetrahedron,
32, 1713 (1976)], a method by M. Nara, et al. [
Tetrahedron,
36, 3161 (1980)] and a method by M. Gill, et al. [
Aust. J. Chem.,
34, 2587 (1981)]. Any of (R)-substance, (S)-substance and a mixture thereof may be used as the 4-hydroxy-2-cyclopentenone.
4-Cyclopentene-1, 3-dione and 4-hydroxy-2-cyclopentenone have an anticancer action and a cell growth inhibiting action to cancer cells such as human promyelocytic leukemia cells HL-60, human acute lymphoblastic leukemia cells MOLT-3, pulmonary cancer cells A-549, SV40-transformed pulmonary cancer cells WI-38VA13, hepatoma cells Hep G2, colon cancer cells HCT 116, human colon cancer cells SW 480, human colon cancer cells WiDr, stomach cancer cells AGS and myeloma cells. These compounds can be used in anticancer agent as an effective component and also have an apoptosis-inducing action to these cancer cells. Mechanism of the cell growth inhibiting action to cancer cells of these compounds used in the present invention does not limit the scope of the present invention at all and, for example, an apoptosis inducing action to cancer cells is covered by the present invention as well.
The anticancer agent of the present invention uses 4-cyclopentene-1,3-dione and/or 4-hydroxy-2-cyclopentenone having an anticancer action as an effective component and when these components are made into a pharmaceutical preparation by compounding with known pharmaceutical carriers, it is now possible to prepare an anticancer agent.
Generally, at least one of these is compounded with a pharmaceutically acceptable liquid or solid carrier and, if necessary, solvent, dispersing agent, emulsifier, buffer, stabilizer, filler, binder, disintegrating agent, lubricant, etc. are added thereto to give an anticancer agent which may be in solid such as tablets, granules, diluted powders, powders, capsules, etc. or in liquid such as solutions, suspensions, emulsions, etc. Further, this may be in a dry preparation which can be made into liquid by adding an appropriate carrier before use.
The pharmaceutical carrier may be selected depending upon the above-mentioned mode of the administration and form of the preparation. In the case of oral preparations, starch, lactose, sugar, mannitol, carboxymethyl cellulose, corn starch, inorganic salts, etc. may be used. In the manufacture of oral preparations, binders, disintegrating agents, surface-active agents, lubricants, fluidity promoters, taste-correctives, coloring agents, flavors, etc. may be further compounded therewith.
On the other hand, in the case of parenteral preparations, they may be prepared by common methods where 4-cyclopentene-1,3-dione and/or 4-hydroxy-2-cyclopentenone which is an effective component of the present invention is dissolved or suspended in a diluent such as distilled water for injection, physiological saline solution, aqueous solution of glucose, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. followed, if necessary, by adding bactericides, stabilizers, isotonic agents, analgesics, etc. thereto.
The anticancer agent of the present invention is administered by an appropriate route depending upon the form of the preparation. There is no particular limitation for the method of administration as well and it may be administered by means of oral use, external use and injection. Injection preparations are administered, for example, intravenously, intramuscularly, subcutaneously, intracutaneously, etc. while preparations for external use include suppositories, etc.
Dose as an anticancer agent is appropriately decided by its form of preparation, method of administration, purpose of use and age, body weight and symptom of the patient to be treated and it is not constant but, usually, the amount of 4-cyclopentene-1,3-dione and/or 4-hydroxy-2-cyclopentenone contained in the preparation is from 0.1 &mgr;g to 5 mg/kg per day (for adults). Of course, the dose may vary depending upon various conditions and, therefore, the dose less than above may be sufficient in some cases while, in other cases, the dose more than above may be necessary. The pharmaceutical agent of the present invention can be directly administered orally and, in addition, it can be added to any food and beverage so tha
Kato Ikunoshin
Kobayashi Eiji
Koyama Nobuto
Kolisch Hartwell Dickinson & McCormack & Heuser
Padmanabhan Sreeni
Takara Shuzo Co. Ltd.
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