EP0172233A1 - Punaglandins and pharmaceutical use thereof - Google Patents

Punaglandins and pharmaceutical use thereof

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Publication number
EP0172233A1
EP0172233A1 EP85901218A EP85901218A EP0172233A1 EP 0172233 A1 EP0172233 A1 EP 0172233A1 EP 85901218 A EP85901218 A EP 85901218A EP 85901218 A EP85901218 A EP 85901218A EP 0172233 A1 EP0172233 A1 EP 0172233A1
Authority
EP
European Patent Office
Prior art keywords
punaglandins
punaglandin
hydrogen atom
diacetoxy
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP85901218A
Other languages
German (de)
French (fr)
Other versions
EP0172233A4 (en
Inventor
Masanori 1-22 Shinpo-Cho Fukushima
Seizi Kurozumi
Paul J. Scheuer
Patrick T. K. Yu
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University of Hawaii
Original Assignee
University of Hawaii
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Publication date
Application filed by University of Hawaii filed Critical University of Hawaii
Publication of EP0172233A1 publication Critical patent/EP0172233A1/en
Publication of EP0172233A4 publication Critical patent/EP0172233A4/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P31/00—Preparation of compounds containing a five-membered ring having two side-chains in ortho position to each other, and having at least one oxygen atom directly bound to the ring in ortho position to one of the side-chains, one side-chain containing, not directly bound to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having at least one oxygen atom bound in gamma-position to the ring, e.g. prostaglandins
    • C12P31/005—Preparation of compounds containing a five-membered ring having two side-chains in ortho position to each other, and having at least one oxygen atom directly bound to the ring in ortho position to one of the side-chains, one side-chain containing, not directly bound to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having at least one oxygen atom bound in gamma-position to the ring, e.g. prostaglandins by fermentation or enzyme-using processes from marine organisms, e.g. Plexaura Homomalla
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof

Definitions

  • the present invention relates to punaglandins and the pharmaceutical use thereof, and more specifically relates to the novel compounds of punaglandins which are physiologically active substances derived from marine fauna and are useful as antitumor activity, and relates to the pharmaceutical use thereof.
  • Prostaglandins are natural substances which have a wide variety of pharmacological activities such as blood platelet aggregation inhibitory action, blood pressure lowering action, etc. and accordingly are valuable compounds to be used as an effective remedy for peripheral circulatory failure in recent medical treatment.
  • prostaglandins A are known for having a double bond in the cyclopentane ring in their molecules.
  • prostaglandin A 2 is known as a compound having a function to lower the blood pressure (Amer. J. Med. Sci., 263, 335 (1972)).
  • prostaglandins A are expected to possibly have a function as antitumor drugs because of an admitted fact that prostaglandins A strongly suppress the formation of DNA (Biochem. Biophys. Res. Commun., vol. 87, p. 795 (1979)).
  • punaglandin 1 and punaglandin 2 which have a structure similar to the above-mentioned prostaglandins A, are extracted and isolated from Telesto riisei, a marine animal which grows attached to a solid surface. They are expected to be physiologically active substances of marine origin, and have their structure already established and identified (Gekkan Yakuji, or Monthly Drugs and Medical Instruments, vol. 24, No. 6, p. 37-43 (1982)). However, nothing has yet been disclosed concretely as to what pharmacological activities these punaglandins have.
  • a primary object of the present invention is to provide novel punaglandins different, from punaglandin 1 or 2.
  • Another object of this invention is to provide the pharmaceutical use of the punaglandins, especially their use as an antitumor drug.
  • a further object of this invention is to provide novel punaglandins which are superior in antitumor activity to the hitherto known prostaglandins A.
  • R 1 represents a hydrogen atom, a C 1 -C 10 alkyl group, or one equivalent, of cation
  • R 2 , R 3 , and R 4 are identical or different and each represents a hydrogen atom or a C 2 -C 10 acyl group
  • the symbol ........ indicates a single bond or a double bond.
  • R 1 in the formula (I) represents a hydrogen atom, a C 1 -C 10 alkyl group, or one equivalent of cation.
  • the C 1 -C 10 alkyl groups are linear or branched alkyl groups having 1 to 10 carbon atoms such as 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.
  • ammonlum cations such as NH 4+ , tetramethylammonium, monomethylammonium, dimethylammonium, trimethyl-ammonium, benzylammonium, phenethylammonium, morpholium cation, monoethanolammonium, and piperidium cation, alkali metal cations such as Na + and K + ; and divalent or t ⁇ valent metallic cations such as 1/2 Ca 2+ , 1/2 Mg 2+ ,
  • R 2 , R 3 , and R 4 are identical or different and each represents a hydrogen atom or a C 2 -C 10 acyl group.
  • C 2 -C 10 acyl groups are acetyl, propionyl, n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, caproyl, enanthoyl and benzoyl.
  • R 2 and R 3 are preferably an acetyl group, and R 4 is preferably a hydrogen atom.
  • the punaglandins of the present invention are punaglandins 3
  • the punaglandins of the present invention are punaglandins 4.
  • the punaglandins of the present invention can be prepared according to the process mentioned below.
  • this extraction about 5.7 g of an extract is obtained from about 360 g of freeze-dried Telesto riisei.
  • About 2.4 g of aqueous methanolic residue is obtained from partition of this extract between the extraction conducted by use of hexane and the succeeding extraction conducted by use of a mixture of methanol and water (9 : 1).
  • the punaglandins of the aforementioned formula (I), where R 1 is a hydrogen atom, a C 1 -C 10 alkyl group other than methyl group, or one equivalent of cation; R 2 and R 3 are respectively a hydrogen atom or a C 2 -C 10 acyl group other than acetyl groups; and R 4 is a C 2 -C 10 acyl group, can be obtained by subjecting the above-mentioned punaglandin compounds (punaglandin 3 and punaglandin 4 ) obtained by extraction and isolation to the generally known hydrolysis reaction, esterification reaction, or salt-forming reaction, or a combination thereof.
  • hydrolysis reaction the hydrolysis reaction to be carried out in methanol or ethanol in the presence of sodium methoxide, potassium methoxide, sodium methoxide, or the like and the hydrolysis reaction to be conducted in an aqueous solution of sodium hydroxide, potassium hydroxide, or the like may be mentioned.
  • enzymatic hydrolysis can also be applied to this case.
  • the neutralization reaction conducted by use of such a basic compound as sodium hydroxide, potassium hydroxide, ammonia, etc. may be mentioned.
  • the punaglandins provided by the present invention especially display a strong effect of suppressing the proliferation of cells even at low concentration when used against L1210 leukemia cells, thus amply proving that they are very useful as the antitumor drugs.
  • the punaglandins of this invention can be administered to a patient orally, or parenterally through percutaneous, subcutaneous, intramuscular, intravenous, intrarectal, for example.
  • Preparations for oral administration may be prepared, for instance, in the form of tablets, pills, granules, powders, solutions, suspensions, and capsules.
  • tablets can be made according in the usual manner by use of such excipients as lactose, starch, calcium carbonate, crystalline cellulose, and silicic acid; such binders as carboxymethyl cellulose, methyl cellulose, potassium phosphate, and polyvinyl pyrrolidone; such disintegrators as sodium alginate, sodium hydrogencarbonate, sodium lauryl sulfate, and monoglyceride stearate; such moisturizers as glycerin, etc. ; such absorbents as kaolin, and colloidal silica; and such lubricants as refined talc and powdered boric acid.
  • Preparations in the form of pills, powders and granules can also be prepared respectively according to the ordinary methods by use of the excipients, etc. mentioned above.
  • Preparations in the form of solutions and suspensions can be prepared according to the ordinary method by use of, for instance, such glycerol esters as tricaprylin, triacetin, etc., purified water; and such alcohols as ethanol, etc.
  • Preparations in the form of capsules can be prepared by filling gelatin capsules, etc. with granules, powders, or solutions prepared in the above.
  • Preparations for percutaneous administration may be prepared, for instance, in the form of ointments and creams.
  • Ointments can be prepared by use of such fatty oils as castor oil, olive oil, and vaseline, and creams by use of fatty oils and such emulsifying agents as diethylene glycol, sorbitan monofatty acid ester, etc. according to the ordinary methods, respectively.
  • injections formulated into solutions and suspensions there are injections formulated into solutions and suspensions.
  • propylene glycol, polyethylene glycol, olive oil, and ethyl oleate, for instance, are usually used and some antiseptics, stabilizers, etc. are added thereto, if necessary.
  • Injections can be sterilized by filtration through the bacterial filter and by addition of a bactericide thereto.
  • ordinary suppositories formulated into soft gelatin capsules is used for rectal administration.
  • the punaglandins which are the active ingredients of the present invention can also be contained in the preparations as their inclusion compounds formed with any of ⁇ -, ⁇ -, ⁇ -cyclic dextrins or their methylated cyclic dextrins.
  • the effective dose of the punaglandins provided with this invention varies with the age, sex, and conditions of a patient; however, it is ordinarily in the range of 10 2 -2x10 5 ⁇ g/kg/day, preferably in the range of 5x10 2 -10 4 ⁇ g/kg/day.
  • the present invention provides the novel compounds of punaglandins which are useful as antitumor drugs by themselves, and antitumor preparations which contain punaglandins as an active ingredient.
  • the fraction which was eluted earlier was further subjected to C-18 reversed-phase high-pressure liquid chromatography by use of a mixture of water and methanol (3 : 7) to obtain punaglandin 3 from the first eluate and punaglandin 4 from the succeeding eluate.
  • L1210 carcinoma cells were grown in the RPM11640 medium containing 10% fetal calf serum, and the concentration of the cells was adjusted to 1x10 5 cells/ml.
  • Punaglandin 3 and punaglandin 4 were respectively dissolved in 99.5% ethanol.
  • the final concentration of the ethanol solutions was adjusted to less than 0.1%, and it was then added to the respective culture medium.
  • the culture medium was maintained at 37°C in a stationary condition for 4 days. As a control, 0.1% ethanol was used. After the cultivation, the number of surviving cells were measured after dyeing with Trypan Blue.
  • the concentration (IC 50 ) of punaglandin 3 to inhibit the proliferation of L1210 carcinoma cells was 0.10 ⁇ g/ml, and IC 50 of punaglandin 4 was 0.030 ⁇ g/ml.
  • Punaglandin 3 was dissolved in fractionated coconut oil in concentration of 100 mg/ml.
  • Soft capsules were prepared in the usual manner with a soft capsule-making machine in accordance with the below-mentioned recipe, each capsule being made to contain 10 mg of punaglandin 3 as active ingredient.

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  • Wood Science & Technology (AREA)
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Abstract

De nouvelles punaglandines AD5-(2,3-diacétoxy-6-méthoxycarbonyle hexylidène)-2-chloro-4-)2,5-octadiényle)-4-hydroxy-2-cyclopenténone, ou 5-(2,3-diacétoxy-6-méthoxycarbonyle hexylidène)-2-chloro-4-(2-octényle)-4-hydroxy-2-cyclopenténone BD sont isolées d'un animal marin, Telesto riisei. Ces nouvelles punaglandines ont une activité pharmaceutique pour traiter des tumeurs.New AD5- (2,3-diacetoxy-6-methoxycarbonyl hexylidene) -2-chloro-4-) 2,5-octadienyl) -4-hydroxy-2-cyclopentenone, or 5- (2,3-diacetoxy-) punaglandins 6-methoxycarbonyl hexylidene) -2-chloro-4- (2-octenyl) -4-hydroxy-2-cyclopentenone BD are isolated from a marine animal, Telesto riisei. These new punaglandins have pharmaceutical activity to treat tumors.

Description

PUNAGLANDINS AND PHARMACEUTICAL USE THEREOF
BACKGROUND OF THE INVENTION
The present invention relates to punaglandins and the pharmaceutical use thereof, and more specifically relates to the novel compounds of punaglandins which are physiologically active substances derived from marine fauna and are useful as antitumor activity, and relates to the pharmaceutical use thereof. DESCRIPTION OF THE PRIOR ART Prostaglandins are natural substances which have a wide variety of pharmacological activities such as blood platelet aggregation inhibitory action, blood pressure lowering action, etc. and accordingly are valuable compounds to be used as an effective remedy for peripheral circulatory failure in recent medical treatment. Of the prostaglandins, prostaglandins A are known for having a double bond in the cyclopentane ring in their molecules. For instance, prostaglandin A2 is known as a compound having a function to lower the blood pressure (Amer. J. Med. Sci., 263, 335 (1972)).
In recent years, prostaglandins A are expected to possibly have a function as antitumor drugs because of an admitted fact that prostaglandins A strongly suppress the formation of DNA (Biochem. Biophys. Res. Commun., vol. 87, p. 795 (1979)).
Apart from the aforementioned prostaglandins, punaglandin 1 and punaglandin 2, which have a structure similar to the above-mentioned prostaglandins A, are extracted and isolated from Telesto riisei, a marine animal which grows attached to a solid surface. They are expected to be physiologically active substances of marine origin, and have their structure already established and identified (Gekkan Yakuji, or Monthly Drugs and Medical Instruments, vol. 24, No. 6, p. 37-43 (1982)). However, nothing has yet been disclosed concretely as to what pharmacological activities these punaglandins have.
SUMMARY OF THE INVENTION
A primary object of the present invention is to provide novel punaglandins different, from punaglandin 1 or 2.
Another object of this invention is to provide the pharmaceutical use of the punaglandins, especially their use as an antitumor drug.
A further object of this invention is to provide novel punaglandins which are superior in antitumor activity to the hitherto known prostaglandins A.
Other objects and advantages of this invention will become apparent from the following detailed description.
These objects and advantages of this invention are achieved by the punaglandins which are expressed by the following formula (I):
wherein R1 represents a hydrogen atom, a C1-C10 alkyl group, or one equivalent, of cation; R2, R3, and R4 are identical or different and each represents a hydrogen atom or a C2-C10 acyl group; and the symbol ........ indicates a single bond or a double bond.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS R1 in the formula (I) represents a hydrogen atom, a C1-C10 alkyl group, or one equivalent of cation.
The C1-C10 alkyl groups are linear or branched alkyl groups having 1 to 10 carbon atoms such as 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.
Examples of one equivalent of cations are ammonlum cations such as NH4+, tetramethylammonium, monomethylammonium, dimethylammonium, trimethyl-ammonium, benzylammonium, phenethylammonium, morpholium cation, monoethanolammonium, and piperidium cation, alkali metal cations such as Na+ and K+; and divalent or tπvalent metallic cations such as 1/2 Ca 2+, 1/2 Mg2+,
1/2 Zn2+, and 1/3 Al3+.
R2, R3, and R4 are identical or different and each represents a hydrogen atom or a C2-C10 acyl group.
Examples of the C2-C10 acyl groups are acetyl, propionyl, n-butyryl, iso-butyryl, n-valeryl, iso-valeryl, caproyl, enanthoyl and benzoyl. R2 and R3 are preferably an acetyl group, and R4 is preferably a hydrogen atom.
The symbol in the formula (I) represents a single or a double bond.
In the aforementioned formula (I), if the symbol ........ is a double bond, the punaglandins of the present invention are punaglandins 3, and if the symbol ........ is a single bond, the punaglandins of the present invention are punaglandins 4.
Specific examples of the compounds of formula (I) are given below.
(100) punaglandin 3 [5-(2,3-diacetoxy-6- methoxycarbonylhexylidene)-2-chloro-4-(2,5- octadienyl)-4-hydroxy-2-cyclopentenone] (102) punaglandin 4 [5-(2,3-diacetoxy-6- methoxycarbonylhexylidene)-2-chloro-4- (2-octenyl)-4-hydroxy-2-cyclopentenone] (104) 5- (2 , 3-diacetoxy-6-carboxy- hexylidene)-2-chloro-4- (2, 5-octadienyl)-
4-hydroxy-2-cyclopentenone
(106 ) 5- (2 , 3-diacetoxy-6-carboxyhexylidene)-2-chloro-4-(2-octenyl)-4- hydroxy-2-cyclopentenone
(108) 5-(2,3-diacetoxy-6-ethoxycarbonylhexylidene)-2-chloro-4-(2,5-octadienyl)- 4-hydroxy-2-cyclopentenone
(110) 5-(2,3-diacetoxy-6-ethoxycarbonylhexylidene)-2-chloro-4-(2-octenyl)-4- hydroxy-2-cyclopentenone
(112) 5-(2,3-diacetoxy-6-propoxycarbonylhexylidene)-2-chloro-4-(2,5-octadienyl)- 4-hydroxy-2-cyclopentene
(114) 5-(2,3-diacetoxy-6-propoxycarbonylhexylidene)-2-chloro-4-(2-octenyl)-4- hydroxy-2-cyclopentenone
(116) sodium salt of (104)
(118) sodium salt of (106)
(120) aluminum salt of (104)
(122) aluminum salt of (106)
The punaglandins of the present invention can be prepared according to the process mentioned below.
The punaglandins expressed by the formula (I), wherein R1 is a methyl group, R2 and R3 are both acetyl groups, R4 is a hydrogen atom, and the symbol ........ represents a single or double bond
(the compound is punaglandin 3 when the symbol is a double bond and the compound is punaglandin 4 when the symbol ........ is a single bond) , are extracted and isolated from a marine animal called Telesto riisei as follows.
The marine animal, Telesto riisei, is subjected to an extraction in a Soxhlet extractor first by use of hexane and then a mixture of methanol and water (methanol : water = 9 : 1) as the extracting reagents. In this extraction, about 5.7 g of an extract is obtained from about 360 g of freeze-dried Telesto riisei. About 2.4 g of aqueous methanolic residue is obtained from partition of this extract between the extraction conducted by use of hexane and the succeeding extraction conducted by use of a mixture of methanol and water (9 : 1).
About 2.4 g of this extract is subjected to column chromatography on silica gel using ethyl acetate - hexane (4 : 6) as an eluent to yield two fractions which exhibit the ultraviolet absorption. Of these two fractions, the fraction which is eluted earlier is further subjected to high pressure liquid chromatography by use of a mixture of water and methanol (3 : 7) as a developer to obtain firstly an eluate of punaglandin 3 and then an eluate of punaglandin 4. The respective eluates are concentrated to give desired punaglandin 3 and punaglandin 4.
The punaglandins of the aforementioned formula (I), where R1 is a hydrogen atom, a C1-C10 alkyl group other than methyl group, or one equivalent of cation; R2 and R3 are respectively a hydrogen atom or a C2-C10 acyl group other than acetyl groups; and R4 is a C2-C10 acyl group, can be obtained by subjecting the above-mentioned punaglandin compounds (punaglandin 3 and punaglandin 4 ) obtained by extraction and isolation to the generally known hydrolysis reaction, esterification reaction, or salt-forming reaction, or a combination thereof.
As the hydrolysis reaction, the hydrolysis reaction to be carried out in methanol or ethanol in the presence of sodium methoxide, potassium methoxide, sodium methoxide, or the like and the hydrolysis reaction to be conducted in an aqueous solution of sodium hydroxide, potassium hydroxide, or the like may be mentioned. Alternatively, enzymatic hydrolysis can also be applied to this case.
As the esterification reaction generally adopted, there is a method in which punaglandins are allowed to react with such an alcohol compound as methanol, ethanol, propanol, butanol, etc., in the presence of such an acidic compound as sulfuric acid, hydrochloric acid, p-toluene sulfonic acid, pyridine-p-toluene sulfonic acid salt (PPTS), etc., or another method, in which punaglandins are made to react with such an acyl halide compound as acetyl chloride, propionyl chloride, etc.
As the salt-forming reaction, for instance, the neutralization reaction conducted by use of such a basic compound as sodium hydroxide, potassium hydroxide, ammonia, etc. may be mentioned.
The punaglandins provided by the present invention especially display a strong effect of suppressing the proliferation of cells even at low concentration when used against L1210 leukemia cells, thus amply proving that they are very useful as the antitumor drugs.
The punaglandins of this invention can be administered to a patient orally, or parenterally through percutaneous, subcutaneous, intramuscular, intravenous, intrarectal, for example.
Preparations for oral administration may be prepared, for instance, in the form of tablets, pills, granules, powders, solutions, suspensions, and capsules.
In preparing the preparations in the form of tablets, tablets can be made according in the usual manner by use of such excipients as lactose, starch, calcium carbonate, crystalline cellulose, and silicic acid; such binders as carboxymethyl cellulose, methyl cellulose, potassium phosphate, and polyvinyl pyrrolidone; such disintegrators as sodium alginate, sodium hydrogencarbonate, sodium lauryl sulfate, and monoglyceride stearate; such moisturizers as glycerin, etc. ; such absorbents as kaolin, and colloidal silica; and such lubricants as refined talc and powdered boric acid. Preparations in the form of pills, powders and granules can also be prepared respectively according to the ordinary methods by use of the excipients, etc. mentioned above.
Preparations in the form of solutions and suspensions can be prepared according to the ordinary method by use of, for instance, such glycerol esters as tricaprylin, triacetin, etc., purified water; and such alcohols as ethanol, etc. Preparations in the form of capsules can be prepared by filling gelatin capsules, etc. with granules, powders, or solutions prepared in the above.
Preparations for percutaneous administration may be prepared, for instance, in the form of ointments and creams. Ointments can be prepared by use of such fatty oils as castor oil, olive oil, and vaseline, and creams by use of fatty oils and such emulsifying agents as diethylene glycol, sorbitan monofatty acid ester, etc. according to the ordinary methods, respectively.
As preparations for subcutaneous, intramascular, or intravenous administration, there are injections formulated into solutions and suspensions. In the preparation of solutions and suspensions, propylene glycol, polyethylene glycol, olive oil, and ethyl oleate, for instance, are usually used and some antiseptics, stabilizers, etc. are added thereto, if necessary. Injections can be sterilized by filtration through the bacterial filter and by addition of a bactericide thereto. For rectal administration, ordinary suppositories formulated into soft gelatin capsules is used.
The punaglandins which are the active ingredients of the present invention can also be contained in the preparations as their inclusion compounds formed with any of α-, β-, ɣ-cyclic dextrins or their methylated cyclic dextrins.
The effective dose of the punaglandins provided with this invention varies with the age, sex, and conditions of a patient; however, it is ordinarily in the range of 10 2-2x105 μg/kg/day, preferably in the range of 5x10 2-104 μg/kg/day.
As described in detail in the above, the present invention provides the novel compounds of punaglandins which are useful as antitumor drugs by themselves, and antitumor preparations which contain punaglandins as an active ingredient.
The following examples are given to illustrate the present invention in more detail.
Example 1
360 g of a freeze-dried marine animal Telesto riisei was subjected to an extraction in a Sexhlet extractor first by use of hexane and then a mixture of methanol and water (methanol : water = 9 : 1) as the extracting reagents and 5.7 g of an extract was obtained.
In the course of this extraction, 2.4 g of aqueous methanolic residue was obtained from partition of this extract between hexane and a mixture of methanol and water. This extract thus obtained was chromatographed on a column of silica gel using a mixture of ethyl acetate and hexane (4 : 6) as an eluent. Of the eluates eluted from the column, two fractions which exhibited the ultraviolet absorption were collected. Of these two fractions, the fraction which was eluted earlier was further subjected to C-18 reversed-phase high-pressure liquid chromatography by use of a mixture of water and methanol (3 : 7) to obtain punaglandin 3 from the first eluate and punaglandin 4 from the succeeding eluate.
Physical properties of punaglandin 3: MW: 496
C25H33ClO8 (αD=+66.8°, C0.54, MeOH)
UV: λmax=238 nm (ε=8600, MeOH)
IR(CHCl3, cm-1): 3100-3600(broad), 2960,
2940, 1725, 1680 (shoulder), 1378, 1235 (broad),
990-1110(broad)
'HNMR(360MH2, in CDCl3, δppm): 7.27(1H, H11, s),
6.35(1H, H4, d, J=9.1, 4.3), 5.53(1H, H15),
5.41(1H, H18), 5.35-5.20 (3H, H14, H17, H5),
3.65(3H, OMe), 3.01(1H, H13a, dd, J=8.1, 14.3),
2.74(2H, H16, dd, J=7.1, 7.1), 2.68(1H, H13b, dd, J=7.0, 14.3), 2.31(2H, H2, n), 2.09(3H,
OAc , s ), 2.05(5H, OAc, H19), 1.6-1.75(4H, H3 , H4), 0.94(3H, H20, t, J=7.5)
Physical properties of punaglandin 4: MW: 498
C25H35ClO8
UV: λmax=240 nm (ε=6900, MeOH)
IR(CHCl3, cm-1): 3150-3600(broad), 2930, 2860(shoulder), 1725, 1675(shoulder), 1375, 1150-1300(broad), 1000-1100(broad) 'HNMR(300MH2, in CDCl3, αppm) : 7.25(1H, H11, s), 6.33(1H, H7, d, J=9.1), 6.01(1H, H6, dd, J=9.1, 4.3), 5.52(1H, H15, dt, J=10.9, 6.7), 5.20-5.30 (2H, H14, H5), 3.63(3H, OMe, s), 2.95(1H, H13a, dd, J-9.5, 13.5), 2.62(1H, H13b, dd, J=7.2,
13.5),2.30(2H, H2, m) , 2.10(3H, OAc, s), 1.95- 2.05(5H,OAc, H16), 1.60-1.70(4H, H3, H4), 1.20- 1.40(6H,H17-H19), 0.86(3H, H20, t, J=7.1)
Mass(70eV, m/2): 420(M+-AcOH-H2O), 387(M+-C8H5) ,
378(M+-2ACOH), 360(M+-2AcOH-H2O), 347(M+-2ACOH- OMe), 327(M+-C8H15-AcOH), 285, 267(M+-C8H15- 2AcOH),253, 235.
Example 2
(i) Determination of antitumor activity in vitro
L1210 carcinoma cells were grown in the RPM11640 medium containing 10% fetal calf serum, and the concentration of the cells was adjusted to 1x105 cells/ml. Punaglandin 3 and punaglandin 4 were respectively dissolved in 99.5% ethanol. Prior to use, the final concentration of the ethanol solutions was adjusted to less than 0.1%, and it was then added to the respective culture medium. The culture medium was maintained at 37°C in a stationary condition for 4 days. As a control, 0.1% ethanol was used. After the cultivation, the number of surviving cells were measured after dyeing with Trypan Blue.
The concentration (IC50) of punaglandin 3 to inhibit the proliferation of L1210 carcinoma cells was 0.10 μg/ml, and IC50 of punaglandin 4 was 0.030 μg/ml.
(ii) Determination of antitumor activity in vivo 1x105 Ehrlich ascites carcinoma cells were intraperitoneally administered to ICR mice, and
24 hours thereafter, 5 mg/kg/day of punaglandin 3 and punaglandin 4 were respectively intraperitoneally administered to the mice for 9 days. The period of survival of these animals was observed. The average survival period of the mice treated with punaglandin 3 was 28.6±4.5 days and the increased life span (ILS%) was higher than that of the control by 50.5% and the number of the mice living more than 45 days was 1/6 the treated group. The average survival period of punaglandin 4 was 34.0±4.5 days, the ILS% was higher by 78.9%, and the number of the mice living more than 45 days was 1/6 the treated group.
Example 3
Punaglandin 3 was dissolved in fractionated coconut oil in concentration of 100 mg/ml. Soft capsules were prepared in the usual manner with a soft capsule-making machine in accordance with the below-mentioned recipe, each capsule being made to contain 10 mg of punaglandin 3 as active ingredient.
Gelatin 10 parts by weight
Glycerin 5 parts by weight
Sorbic acid 0.08 parts by weight
Purified water 14 parts by weight

Claims

1. Punaglandins expressed by the following formula ( I ) :
wherein R1 represents a hydrogen atom, a C1-C10 alkyl group, or one equivalent of cation; R2, R3, and R4 are identical or different and each represents a hydrogen atom or a C2-C10 acyl group; and the symbol indicates a single bond or double bond.
2. The punaglandin according to claim 1, wherein in the above-mentioned formula ( I ) R2 and R3 are respectively an acetyl group and R4 is a hydrogen atom.
3. A pharmaceutical composition for treatment of malignant tumors comprising punaglandins expressed by the following formula (I) and a pharmaceutically acceptable carrier
wherein R1 represents a hydrogen atom, a C1-C10 alkyl group, or one equivalent of cation; R2, R3, and R4 are identical or different and each represents a hydrogen atom or a C2-C10 acyl group; and the symbol indicates a single bond or a double bond.
4. A medicament in unit dosage form comprising the pharmaceutical composition of claim 3.
5. A method for treatment of malignant tumors comprising the administration of punaglandins in pharmaceutically effective amount.
6. The method of claim 5 wherein said pharmaceutically effective amount is in the range of 10 2 to 2x105 μg/kg/day.
EP19850901218 1984-02-14 1985-02-14 Punaglandins and pharmaceutical use thereof. Pending EP0172233A4 (en)

Applications Claiming Priority (2)

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US579933 1984-02-14

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US4711895A (en) * 1984-10-22 1987-12-08 Teijin Limited 4-hydroxy-2-cyclopentenone, process for production thereof, pharmaceutical composition comprising it
US5216183A (en) * 1988-04-19 1993-06-01 Teijin Limited Cyclopentanone/cyclopentenone derivative
AU615534B2 (en) * 1988-04-19 1991-10-03 Teijin Limited 2-substituted-2-cyclopentenones

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US3755426A (en) * 1971-07-02 1973-08-28 American Home Prod 10-haloprostaglandin-a derivatives

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WO1985003706A1 (en) 1985-08-29
JPS61501703A (en) 1986-08-14
EP0172233A4 (en) 1986-07-29

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