Claims
- 1. A 5-alkylidene-4-substituted-2-cyclopentenone represented by the following formula (I)-2 ##STR15##wherein R.sup.2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 9 carbon atoms which may have a substituent, or a cycloalkyl group having 3 to 8 carbon atoms which may have a substituent;
- R.sup.3 represents a hydrogen atom, a hydroxyl group, or a hydroxyl group protected by a tri(C.sub.1-7 hydrocarbon) silyl group or an acetal linkage together with the oxygen atom of the hydroxyl group;
- R.sup.4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or one equivalent of a cation;
- the symbol represents a single, double or triple bond;
- the symbol represents a single or double bond; and
- the substitutents are selected from the group consisting of a group of the formula --COOR.sup.4 in which R.sup.4 is defined as above; a group of the formula --OR.sup.5 in which R.sup.5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted by a halogen atom, a carboacyl group having 1 to 7 carbon atoms, or a phenyl group, the phenyl group being optionally substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; a phenyl group which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; and a cycloalkyl group having 3 to 8 carbon atoms which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms.
- 2. A method for inhibiting proliferation of leukemia cells in which the leukemia cells are present in an animal in which the cancer cells are present which comprises administering to said animal an inbibitory dose of 4,5-disubstituted-2-cyclopentenone represented by the following formula (I)-2: ##STR16## wherein R.sup.2, R.sup.3, R.sup.4 and the symbol are the same as defined below, and the symbol represents a single or double bond;
- R.sup.2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 9 carbon atoms which may have a substituent, or a cycloalkyl group having 3 to 8 carbon atoms which may have a substituent;
- R.sup.3 represents a hydrogen atom, a hydroxyl group, or a hydroxyl group protected by a tri(C.sub.1-7 hydrocarbon) silyl group or an acetyl linkage together with the oxygen atom of the hydroxy group;
- R.sup.4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or 1 equivalent of a cation; and said substituents are selected from the group consisting of a group of the formula --COOR.sup.4 in which R.sup.4 is as defined above, a group of the formula --OR.sup.5 in which R.sup.5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted by a halogen atom, a carboacyl group having 1 to 7 carbon atoms or a phenyl group, the phenyl group being optionally substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; a phenyl group which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; and a cycloalkyl group having 3 to 8 carbon atoms which may be substituted by halogen atom, an acid group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; and the symbol represents a single, double or triple bond.
- 3. The method of claim 2 wherein the inhibitory dose is in an amount of from about 1 microgram to 100 milligram/kilogram body weight per day.
- 4. A pharmaceutical composition for treatment of tumors comprising a therapeutically effective amount of a 5-alkylidene-4-substituted-2-cyclopentenone as an antitumor agent represented by the following formula (I)-2 ##STR17## wherein R.sup.2 represents a hydrogen atom, a linear or branched alkyl group having 1 to 9 carbon atoms which may have a substituent, or a cycloalkyl group having 3 to 8 carbon atoms which may have a substituent;
- R.sup.3 represents a hydrogen atom, a hydroxyl group, or a hydroxyl group protected by a tri(C.sub.1-7 hydrocarbon) silyl group or an acetal linkage together with the oxygen atom of the hydroxyl group;
- R.sup.4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or one equivalent of a cation;
- the symbol represents a single, double or triple bond;
- the symbol represents a single or double bond; and
- the substitutents are selected from the group consisting of a group of the formula --COOR.sup.4 in which R.sup.4 is defined as above; a group of the formula --OR.sup.5 in which R.sup.5 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted by a halogen atom, a carboacyl group having 1 to 7 carbon atoms, or a phenyl group, the phenyl group being optionally substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; a phenyl group which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms,
- and a pharmaceutically acceptable carrier.
- 5. A medicament in unit dosage form comprising the pharmaceutical composition of claim 4.
Priority Claims (4)
| Number |
Date |
Country |
Kind |
| 57-175267 |
Oct 1982 |
JPX |
|
| 57-175268 |
Oct 1982 |
JPX |
|
| 58-21617 |
Feb 1983 |
JPX |
|
| 58-38190 |
Mar 1983 |
JPX |
|
(i) Compounds of formula (I)
This application is a continuation of application Ser. No. 534,256, filed Sept. 21, 1983.
This invention relates to novel 5-membered cyclic compounds, a process for production thereof, and a pharmaceutical use thereof.
Prostaglandin (PG) is a living body regulating substance which is involved in various biological reactions such as contraction of smooth muscles, lowering of blood pressures and inhibition of platelet aggregation. It has been anticipated that prostaglandin as a living body regulating substance affects proliferation of cells. Santoro et al. reported in Cancer. Res. 37, 3774 (1977) that PGE series inhibit growth of tumors of B16 melanoma cell in vivo. W. A. Turner et al. reported that PGA series inhibit tumor cell proliferation and induce differentiation as a result of experiments in vitro using B16 melanoma cell and mouse neuroblastoma [Prostaglandins and Cancer: First International Conference, pages 365-368 (1982)].
Honn et al. reported a possibility of using PGA series as antitumor agents in view of the fact that PGA series strongly inhibit synthesis of DNA [Biochem. Biophys. Res. Commun. 87, 795 (1979)].
M. Fukushima et al. examined the effect of PGD.sub.2 to inhibit proliferation of mouse leukemia cell L1210 and human leukemia cell lines, and reported that IC.sub.50 of PGD.sub.2 on L1210 cell is 2.4 micrograms/ml [Biochem. Biophys. Res. Commn., 105, 956 (1982)].
It is an object of this invention to provide novel 5-membered cyclic compounds.
Another object of this invention is to provide novel 5-membered cyclic compounds which have a 5-membered cyclic ring like certain kinds of prostaglandin.
Still another object of this invention is to provide a pharmaceutical use of the 5-membered cyclic compounds of the invention, especially their use as an antitumor agent.
Still another object of this invention is to provide novel 5-membered cyclic compounds which have better antitumor activity than hitherto known PG series.
Still another object of this invention is to provide novel 5-membered cyclic compounds as highly safe substances with antitumor activity which have no effect on normal cells and do not exhibit any significant toxicity.
Still another object of this invention is to provide novel 5-membered cyclic compounds which show nearly selective antitumor activity as a biological activity and do not substantially show hypotensive activity or platelet aggregation inhibiting activity exhibited by known PGA.sub.2 , and which are therefore very suitable for use as an antitumor agent.
Still another object of this invention is to provide a very simple process for producing the 5-membered cyclic compounds of the invention.
Further objects and advantages of this invention will become apparent from the following description.
As the novel cyclic 5-membered compounds of the invention, the present invention provides a 4,5-disubstituted-2-cyclopentenone selected from the group consisting of 5-alkylidene-4-substituted-2-cyclopentenones represented by the following formula (I) ##STR1##
wherein W represents an aliphatic hydrocarbon group having 1 to 12 carbon atoms which may have a substituent, and Y represents an aliphatic hydrocarbon group having 1 to 12 carbon atoms which may have a substituent, and 5-(1-hydroxy aliphatic hydrocarbon)-4-substituted-2-cyclopentenones represented by the following formula (II) ##STR2## wherein W' and Y' are the same as W and Y above respectively. According to this invention, the 5-alkylidene-4-substituted-2-cyclopentenones of formula (I) can be produced by subjecting 5-alkylidene-3-hydroxy-4-substituted -cyclopentanones represented by the following formula (III) ##STR3## wherein W' and Y' are the same as W and Y above respectively, to dehydration reaction, and as required, subjecting the resulting product to a deprotecting, hydrolyzing or salt-forming reaction.
Some of the compounds of formula (III) are disclosed in European Laid-Open Patent Publication No. 0079733 and U.S. patent application Ser. No. 438,379, and are known. The compounds of formula (III) can be produced by converting a 3-hydroxy-5-(1-hydroxy-aliphatic hydrocarbon)-4-substituted-cyclopentanone represented by the following formula (IV) ##STR4## wherein W" and Y" are the same as W and Y above, respectively, to a corresponding 3-(t-butyldimethylsilyloxy)-5(1-methanesulfonyloxy-aliphatic hydrocarbon)-4-substituted-cyclopentanone, thereafter removing the methanesulfonyloxy group as methanesulfonic acid from the resulting cyclopentanone and further removing the t-butyldimethylsilyl group from it. Some of the compounds of formula (IV) are disclosed in European Laid-Open Patent Publications Nos. 0019475 and 0079733, U.S. Pat. No. 4,315,032 and U.S. Pat. Application Ser. No. 438379. The above process for producing the compound of formula (III) from the compound of formula (IV) is substantially the same as the methods described in European Laid-Open Patent Publication No. 0079733 and U.S. patent application Ser. No. 438,378. Accordingly, the disclosures of the above-cited European Laid-Open Patent Publications and U.S. Patent and U.S. patent application are incorporated herein as reference.
According to the present invention, the 5(1-hydroxy-aliphatic hydrocarbon)-4-substituted-2cyclopentenones of formula (II) can be produced by subjecting a 5-(1-hydroxy-aliphatic hydrocarbon)3-hydroxy-4-substituted-cyclopentanone represented by the following formula (IV) ##STR5## wherein W" and Y" are the same as W and Y above respectively, to dehydration reaction, and as required, subjecting the resulting product to a deprotecting, hydrolyzing or salt-forming reaction.
Now, the first process of this invention starting from the 5-alkylidene-3-hydroxy-4-substituted-cyclopentanone of formula (III) and the second process of the invention starting from the 5-(alpha-hydroxyaliphatic hydrocarbon)-3-hydroxy-4-substituted cyclopentanone of formula (IV) will be described in detail.
In the first process, W' in formula (III) defining the starting material is an aliphatic hydrocarbon group having 1 to 12 carbon atoms, and Y' is likewise an aliphatic hydrocarbon group having 1 to 12 carbon atoms. These aliphatic hydrocarbon groups may be substituted.
The aliphatic hydrocarbon groups for W' and Y' may be linear, branched or cyclic or may contain a carbon-carbon double or triple bond.
Preferably, the aliphatic hydrocarbon groups include, for example, linear or branched C.sub.1-12 alkyl, alkenyl or alkynyl groups, and cycloalkyl groups having 3 to 8 carbon atoms.
Specific examples of alkyl groups having 1 to 12 carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.
Specific examples of the alkenyl groups having 1 to 12 carbon atoms are ethenyl, 1-propen-1-yl, 2-propen-1-yl, 1-buten-1-yl, 1,3-butadien-1-yl, 2-buten-1-yl, 1-penten-1-yl, 2-penten-1-yl, 1-hexen-1-yl, 2-hexen-1-yl, 1,5-hexadien-1-yl, 3-hexen-1-yl, 1-hepten-1-yl, 1-octen-1-yl, 1,7-octadien-1-yl, 1-nonen-1-yl, 1-decen-1-yl, 1-undecen-1-yl and 1- dodecen-1-yl.
Specific examples of the alkynyl groups having 1 to 12 carbon atoms are ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-buten-1-yne-1-yl, 2-butyn-1-yl, 1-pentyn-1-yl, 2-pentyn-1-yl, 1-hexyn-1-yl, 2-hexyn-1-yl, 5-hexen-1-yne-1-yl, 3-hexyn-1-yl, 1-heptyn-1-yl, 1-octyn-1-yl, 7-octen-1-yne-1-yl, 1-nonyn-1-yl, 1-decyn-1-yl, 1-undecyn-1-yl and 1-dodecyn-1-yl.
Examples of the cycloalkyl groups having 3 to 8 carbon atoms are cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl and cyclohexenyl.
These aliphatic hydrocarbon groups may have substituents.
Examples of the substituents include groups of the formula-13 COOR.sup.4 (wherein R.sup.4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or one equivalent of a cation); groups of the formula --OR.sup.5 (wherein R.sup.5 represents a hydrogen atom, a C.sub.1-6 alkyl which may be substituted by a halogen atom, a C.sub.1-7 carboacyl group, or a phenyl group which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms); a phenyl group which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms; and cycloalkyl groups having 3 to 8 carbon atoms which may be substituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms.
Specific examples of the groups of the formula --COOR.sup.4 are those in which R.sup.4 is the same alkyl group as above having 1 to 10 carbon atoms, or one equivalent of a cation, for example an ammonium cation such as NH.sub.4.sup.+, tetramethyl ammonium, monomethyl ammonium, dimethyl ammonium, trimethyl ammonium, benzyl ammonium, phenethyl ammonium, morpholinium cation, monoethanol ammonium or piperidinium cation, an alkali metal cation such as Na.sup.30 or K.sup.30 , or a divalent or trivalent metal cation such as 1/2Ca.sup.2 +, 1/2Mg.sup.2+ 1/2Zn.sup.2+ or 1/3Al.sup.3+.
Specific examples of the groups of the formula --OR.sup.5 include a hydroxyl group; alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-pentoxy and n-hexoxy; carboacyloxy groups having 1 to 7 carbon atoms such as acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy, n-valeryloxy, isovaleryloxy, caproyloxy, enanthyloxy and benzoyloxy; and a phenoxy group. The C.sub.1-6 alkoxy groups for --OR.sup.5 may be substituted by halogen atoms, thus providing chloromethoxy, dichloromethoxy, trifluoromethoxy, etc. The phenyl moiety of the phenoxy group for --OR.sup.5 may be substituted by a halogen atom such as chloro, bromo or fluoro, an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl or butyl, or an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy or butoxy.
A phenyl group or a cycloalkyl group having 3 to 8 carbon atoms may also be substituents for the aforesaid aliphatic hydrocarbon groups. The phenyl group and the C.sub.3-8 cycloalkyl group may be substituted by the same substituents as described above, i.e. a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms. According to this invention, the aforesaid first process which comprises subjecting the 5-alkylidene-3-hydroxy-4-substituted cyclopentenone of formula (III) to dehydration reaction and as required subjecting the resulting product to a deprotecting, hydrolyzing or salt-forming reaction is preferably performed by producing a 5-alkylidene-4-substituted-2-cyclopentenone represented by the following formula (I)-1 ##STR6## wherein R.sup.1 represents a hydrogen atom or an aliphatic hydrocarbon group having 1 to 10 carbon atoms which may have a substituent, R.sup.2 represents a hydrogen atom, or an aliphatic hydrocarbon group having 1 to 9 carbon atoms which may have a substituent, R.sup.3 represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, and the symbol represents a single, double or triple bond, from a 5-alkylidene-3-hydroxy-4-substituted cyclopentenone represented by the following formula (III)-1 ##STR7## wherein R.sup.1, R.sup.2, R.sup.3, and the symbol are the same as given for formula (I)-1. The dehydration reaction of the 5-alkylidene-3-hydroxy- 4-substituted cyclopentenone of formula (III) or (III)-1 is preferably carried out in the presence of a dehydrating agent. Examples of the dehydrating agent include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid and phosphoric acid, organic carboxylic acids such as propionic acid, oxalic acid, citric acid and maleic acid, and organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p toluenesulfonic acid. Of these, the inorganic acids and organic carboxylic acids are preferred. The amount of the dehydrating agent used is preferably 0.5 to 100 moles, especially preferably 1 to 50 moles per mole of the 5-alkylidene-3-hydroxy-4-substituted cyclopentanone. As a reaction solvent, there may be used an ether such as tetrahydrofuran, dioxane, dimethoxyethane or diethyl ether, an alcohol such as methanol or ethanol, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, and water, either singly or in combination with each other.
The reaction temperature is preferably 0.degree. to 80.degree. C., especially preferably 10.degree. to 50 .degree. C.
The reaction time varies depending upon the starting compound, the dehydrating agent and the reaction solvent used in the reaction. Usually, it is 10 minutes to 10 days, preferably 20 minutes to 5 days.
The 5-alkylidene-3-hydroxy-4-substituted cyclopentenone of formula (III) [including formula (III)-1]can be produced, for example, in accordance with the following reaction formula. ##STR8##
Specifically, it can be produced by reacting the corresponding 3-hydroxy-5-(1-hydroxy-aliphatic hydrocarbon)-4-substituted cyclopentanone derivative of formula (IV)' with methanesulfonyl chloride in the presence of a basic compound and then eliminating the protective group.
As can be understood from the above reaction formula, it is possible to subject the 5-alkylidene-3-hydroxy-4-substituted cyclopentanone of formula (III)' in which the 3-position hydroxyl group is protected by a t-butyldimethylsilyl group to a deprotection reaction using a deprotecting aid such as acetic acid thereby removing the protective group at the 3-position and forming the 5-alkylidene-3-hydroxy-4 -substituted cyclopentanone in situ, and subsequently to subject this reaction mixture to the dehydration reaction in accordance with this invention.
According to the dehydration reaction of this invention, a corresponding compound (final desired compound) having a double bond formed between the 2-and 3-positions in formula (II) as a result of removal of the 3-position hydroxyl group is formed. When the resulting final compound has in the group W' and/or Y' a group removable by hydrolysis or deprotection or a group capable of forming a salt by salt-forming forming reaction and it is desired to obtain a final product by hydrolysis, deprotection or salt-forming reaction, the above dehydration reaction in the process of this invention can be followed by such a reaction.
Groups capable of being removed by hydrolysis are, for example, carboacyl groups or ester groups. The carboacyl groups can be hydrolyzed, for example, in an aqueous solution of sodium hydroxide, potassium hydroxide or calcium hydroxide, a water-alcohol mixture, a methanol or ethanol solution containing sodium methoxide, potassium methoxide or sodium ethoxide. The ester groups can be hydrolyzed, for example, in water or a solvent containing water at a temperature of -10.degree. C. to +60.degree. C. for a period of about 10 minutes to about 24 hours using an enzyme such as lipase.
Groups capable of being removed by deprotection are, for example, groups forming an acetal linkage with the oxygen atom of the hydroxyl group, or tri(C.sub.1-7 hydrocarbon)silyl groups. The removal of the protective group can be performed suitably, for example by using acetic acid, a pyridinium salt of p-toluenesulfonic acid, a cation exchange resin, etc. as a catalyst and water, tetrahydrofuran, diethyl ether, dioxane, acetone, acetonitrile, etc. as a reaction solvent when the protective group is a group forming an acetal linkage together with the oxygen atom of the hydroxyl group. The reaction is carried out usually at a temperature of -78.degree. C. to +30.degree. C. for about 10 minutes to about 3 days. When the protective group is a tri(C.sub.1-7 hydrocarbon)silyl group, the deprotecting reaction may be carried out in the presence of acetic acid, tetrabutyl ammonium fluoride, cesium fluoride, etc. in the same reaction solvent as cited above at the same temperature and for the same period of time as mentioned above.
When the final compound has a carboxyl group in the molecule, it can then optionally be subjected to a salt-forming reaction to obtain the final compound as a carboxylate salt. The salt-forming reaction is known per se, and is carried out by neutralizing the carboxylic acid with a nearly equivalent of a basic compound such as sodium hydroxide, potassium hydroxide or sodium carbonate, or ammonia, trimethylamine, monoethanolamine or morpholine in a customary manner. The final desired compound can be isolated and purified, for example, by silica gel column chromatography, silica gel thin-layer chromatography, high-performance liquid chromatography, Florisil column chromatography, etc.
The 5-alkylidene-4-substituted-2-cyclopentenones of formula (I) in accordance with this invention can also be produced by treating the 5-(1-hydroxy-aliphatic hydrocarbon)-4-substituted-2-cyclopentenones of formula (II) with methanesulfonyl chloride in the presence of basic compounds. The basic compounds may be amines such as dimethylaminopyridine, triethylamine, isopropylcyclohexylamine, isopropyldimethylamine and diisopropylamine. A reaction solvent may be used, and examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, ethers such as diethyl ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene. Methanesulfonyl chloride is used generally in an amount of 1 to 10 moles per mole of the 5-(1-hydroxy-aliphatic hydrocarbon)-4-substituted-2-cyclopentenone of formula (II), and the reaction temperature may be from 0.degree. to 50.degree. C., preferably 15.degree. to 25.degree. C. The method disclosed in European Laid-Open Patent Publication No. 0079733 may be referred to in performing the above process.
In the second process of this invention, W" in formula (IV) defining the starting material is an aliphatic hydrocarbon group having 1 to 12, and Y" is likewise an aliphatic hydrocarbon group having 1 to carbon atoms. These aliphatic hydrocarbon groups may be substituted. Specific examples of W" and Y" may be the same as those given hereinabove for W' and Y'.
According to this invention, the second process is preferably carried out by producing a 4-substituted-5-(1-hydroxy-aliphatic hydrocarbon)-2-cyclopentenone represented by the following formula (II)-1 ##STR9## wherein R.sup.1, R.sup.2, R.sup.3 and the symbol are the same as defined for formula (III)-1 above, from a 5-(1-hydroxy-aliphatic hydrocarbon)-3-hydroxy-4-substituted cyclopentanone represented by the following formula (IV)-1 ##STR10## wherein R.sup.1, R.sup.2, R.sup.3, and the symbol are the same for formula (II)-1. The dehydration reaction of the compound of formula (IV) or (IV)-1 can be carried out under quite same reaction conditions as in the aforesaid first process. In this reaction, the reaction temperature is preferably 0 .degree. to 130.degree. C., especially preferably 30.degree. to 110.degree. C.
Deprotection, hydrolysis and salt-forming reaction can all be carried out in quite the same ways as described in regard to the first process
Thus, according to this invention, there are provided 5-alkylidene-4-substituted-2-cyclopentenones represented by the following formula (I) ##STR11## wherein W and Y are as defined above, and 5-(1-hydroxy-aliphatic hydrocarbon)-4-substituted- 2 -cyclopentenones represented by the following formula (II) ##STR12## wherein W' and Y' are as defined above, as novel 5-membered cyclic compounds.
Among the compounds of formula (I), those of the following compounds (I)-1 ##STR13## wherein R.sup.1 represents a hydrogen atom, or an aliphatic hydrocarbon group having 1 to 10 carbon atoms which may be substituted, R.sup.2 represents a hydrogen atom, or an aliphatic hydrocarbon group having 1 to 9 carbon atoms which may be substituted, R.sup.3 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group, and the symbol represents a single, double or triple bond, are preferred, and those of the following formula (I)-2 ##STR14##wherein R.sup.2, R.sup.3, R.sup.4 and the symbol are as defined above, and the symbol represents a single or double bond, (A-type prostaglandins) are especially preferred.
R.sup.1 in formulae (I)-1 and (II)-1 represents a hydrogen atom or an aliphatic hydrocarbon group having 1 to 10 carbon atoms. The aliphatic hydrocarbon group may be substituted.
The aliphatic hydrocarbon group having 1 to 10 carbon atoms may be linear, branched or cyclic, and may have a carbon-carbon double bond.
Examples of preferred aliphatic hydrocarbon groups having 1 to 10 carbon atoms include linear or branched alkyl or alkenyl groups and cycloalkyl groups having 3 to 8 carbon atoms.
Specific examples of the alkyl groups having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
Specific examples of the alkenyl groups having 1 to 10 carbon atoms include ethenyl, 1-propen-1-yl, 2-propen-1-yl, 3-buten-1-yl, 1-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, 6-penten-1-yl, 7-octen-1-yl, 8-nonen-1-yl and 9-decen-1-yl. Of these, 1-propen-1-yl, 2-propen-1-yl, 3-buten-1-yl, 4-penten-1-yl and 5-hexen-1-yl are preferred.
Examples of the cycloalkyl groups having 3 to 8 carbon atoms are the same as those given for W' and Y' in formula (III).
R.sup.2 in formulae (I)-1, (I)-2, (II)-1 and (II)-2 represents a hydrogen atom or an aliphatic hydrocarbon group having 1 to 9 carbon atoms. The aliphatic hydrocarbon group may be substituted.
Examples of the aliphatic hydrocarbon groups having 1 to 9 carbon atoms include linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl, n-heptyl and n-octyl, and the same C.sub.3-8 cycloalkyl groups as exemplified above. R.sup.3 in formulae (I)-1, (I)-2, (II)-1 and (II)-2 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. Examples of the protective group for the hydroxyl group are tri(C.sub.1-7 hydrocarbon)silyl groups and groups forming an acetal linkage with the oxygen atom of the hydroxyl group.
Specific examples of preferred tri(C.sub.1-7 hydrocarbon)silyl groups include tri(C.sub.1-4 alkyl)silyl groups such as trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, diphenyl(C.sub.1-4 alkyl)silkyl groups such as t-butyldiphenylsilyl, and a tribenzylsilyl group.
Examples of the groups forming an acetal linkage together with the oxygen atom of the hydroxyl group include methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl and 6,6-dimethyl-3-oxa-2-oxo-bicyclo[3.1.0]- hex-4-yl groups. Of these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2propyl, (2-methoxyethoxy)methyl and 6,6-dimethyl-3-oxa-2-oxo-bicyclo[3.1.0]hex-4-yl groups are particularly preferred.
The following examples are given for the novel cyclic 5-membered compounds of the above formulae (I) [including formulae (I)-1 and (I)-2] and (II) [including formulae (II)-1 and (II)-2].
Investigations of the present inventors have shown that the novel cyclic 5-membered compounds of this invention, i.e. the 5-alkylidene-4-substituted 2-cyclopentenones of formula (I) and the 5-(alpha-hydroxy-aliphatic hydrocarbon)-4-substituted-2-cyclopentenones of formula (II), and the 5-alkylidene-3-hydroxy-4-substituted cyclopentanones of formula (III) used as starting materials for the production of the compounds of formula (I) in the first process of this invention have excellent pharmacological activities.
Accordingly, the present invention also provides a pharmaceutical composition comprising as an active ingredient a 5-membered cyclic compound selected from the group consisting of the 5-alkylidene-4-substituted-2-cyclopentenones of formula (I), the 5-(1-hydroxy-hydrocarbon)-4-substituted-2-cyclopentenones of formula (II), and the 5-alkylidene-3-hydroxy-4-substituted cyclopentanones of formula (III), and a pharmaceutically acceptable carrier.
The 5-membered cyclic compounds of formulae (I), (II) and (III) in accordance with this invention exhibit strong anticancer activity in low concentrations against L1210 leukemia cells and are very useful as antitumor agents. They are also useful as compounds having antiviral activity.
According to this invention, the 5-membered cyclic compounds can be administered orally, or parenterally through intrarectal, subcutaneous, intramuscular and intravenous routes, for example. For oral administration, the compounds of this invention may be formulated into solid or liquid preparations. Examples of the solid preparations are tablets, pills, powders and granules. In these solid preparations, at least one of the 5-membered cyclic compounds is mixed with sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethyl cellulose, etc. These preaprations can be formed in accordance with customary operations. The solid preparations may also include a lubricant, a sweetener, a stabilizer, an antiseptic, etc. such as calcium stearate, magnesium stearate or glycerol.
Examples of the liquid preparations for oral administration are emulsions, solutions, suspensions, syrups, and elixirs. The liquid preparations may further include a wetting agent, a suspending aid, a sweetener, a flavor, an aroma, a stabilizer, etc. The liquid preparations may be filled in capsules made of an absorbable material such as gelatin.
For intrarectal administration, ordinary suppositories such as soft gelatin capsules are used.
Examples of preparations for parenteral administration through other routes are preparations for subcutaneous, intramuscular or intravenous injection in the form of aseptic aqueous or non-aqueous solutions, suspensions and emulsions. The nonaqueous solutions and suspensions may include propylene glycol, polyethylene glycol, olive oil or injectable organic esters such as ethyl oleate. Such preparations may also contain an antiseptic, an emulsifier, a dispersant, a stabilizer, etc. These injectable preparations can be made aseptic by filtration through a bacteria-holding filter, blending of a germicide, or irradiation.
The dose of the 5-membered cyclic compound of this invention differs depending upon the condition, age, sex and body weight of a subject to which it is to be administered, the route of administration, etc. Usually, it can be administered in a dose of about l.mu.g to 100 mg/kg-body weight/day. The dose may be a single dose, or may be divided into several portions, for example 2 to 6 portions.
The pharmaceutical composition of this invention is preferably used as a medicament in unit dosage form.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
| 4099014 |
Peterson |
Jul 1978 |
|
| 4560703 |
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|
Foreign Referenced Citations (1)
| Number |
Date |
Country |
| 79733 |
May 1983 |
EPX |
Non-Patent Literature Citations (1)
| Entry |
| Bohlmann, Phytochemistry, 21, 125 (1982) abstract only. |
Continuations (1)
|
Number |
Date |
Country |
| Parent |
534256 |
Sep 1983 |
|
Patent Grant
4766147
