WO1985003706A1 - Punaglandines et leur utilisation pharmaceutique - Google Patents

Punaglandines et leur utilisation pharmaceutique Download PDF

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Publication number
WO1985003706A1
WO1985003706A1 PCT/US1985/000226 US8500226W WO8503706A1 WO 1985003706 A1 WO1985003706 A1 WO 1985003706A1 US 8500226 W US8500226 W US 8500226W WO 8503706 A1 WO8503706 A1 WO 8503706A1
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WO
WIPO (PCT)
Prior art keywords
punaglandins
punaglandin
hydrogen atom
diacetoxy
chloro
Prior art date
Application number
PCT/US1985/000226
Other languages
English (en)
Inventor
Masanori Fukushima
Seizi Kurozumi
Paul J. Scheuer
Patrick T. K. Yu
Original Assignee
Hawaii University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hawaii University filed Critical Hawaii University
Publication of WO1985003706A1 publication Critical patent/WO1985003706A1/fr

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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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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.
PCT/US1985/000226 1984-02-14 1985-02-14 Punaglandines et leur utilisation pharmaceutique WO1985003706A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57993384A 1984-02-14 1984-02-14
US579,933 1984-02-14

Publications (1)

Publication Number Publication Date
WO1985003706A1 true WO1985003706A1 (fr) 1985-08-29

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ID=24318945

Family Applications (1)

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PCT/US1985/000226 WO1985003706A1 (fr) 1984-02-14 1985-02-14 Punaglandines et leur utilisation pharmaceutique

Country Status (3)

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EP (1) EP0172233A4 (fr)
JP (1) JPS61501703A (fr)
WO (1) WO1985003706A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4711895A (en) * 1984-10-22 1987-12-08 Teijin Limited 4-hydroxy-2-cyclopentenone, process for production thereof, pharmaceutical composition comprising it
US5116869A (en) * 1988-04-19 1992-05-26 Teijin Limited 2-substituted-2-cyclopentenones
US5216183A (en) * 1988-04-19 1993-06-01 Teijin Limited Cyclopentanone/cyclopentenone derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3755426A (en) * 1971-07-02 1973-08-28 American Home Prod 10-haloprostaglandin-a derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3755426A (en) * 1971-07-02 1973-08-28 American Home Prod 10-haloprostaglandin-a derivatives

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Chem. Pharm. Bull. Vol 31 (4), 1983 KOBAYASHI 'Absolute Stero-Structures of Claviridenone-A, B, -C and -D' pages 1440-43 *
GEKKAN YAKUJI, Vol. 24(6), (1982) Schever 'Bioactive Marine Metabolites see p.41 *
See also references of EP0172233A4 *
Tetrahedron Letters, Vol. 24(14), 1983 KIKUCHI 'Absolute Stereo-Chemistry of New Prostanoids Clavulone I, II and III pages 1549-1552 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4711895A (en) * 1984-10-22 1987-12-08 Teijin Limited 4-hydroxy-2-cyclopentenone, process for production thereof, pharmaceutical composition comprising it
US5116869A (en) * 1988-04-19 1992-05-26 Teijin Limited 2-substituted-2-cyclopentenones
US5216183A (en) * 1988-04-19 1993-06-01 Teijin Limited Cyclopentanone/cyclopentenone derivative

Also Published As

Publication number Publication date
EP0172233A4 (fr) 1986-07-29
JPS61501703A (ja) 1986-08-14
EP0172233A1 (fr) 1986-02-26

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