WO1994027962A1 - Analogue de la prostaglandine e¿1? - Google Patents

Analogue de la prostaglandine e¿1? Download PDF

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Publication number
WO1994027962A1
WO1994027962A1 PCT/JP1994/000635 JP9400635W WO9427962A1 WO 1994027962 A1 WO1994027962 A1 WO 1994027962A1 JP 9400635 W JP9400635 W JP 9400635W WO 9427962 A1 WO9427962 A1 WO 9427962A1
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WIPO (PCT)
Prior art keywords
compound
group
solution
formula
added
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Application number
PCT/JP1994/000635
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English (en)
Japanese (ja)
Inventor
Fumie Sato
Takehiro Amano
Kazuya Kameo
Tohru Tanami
Masaru Mutoh
Naoya Ono
Jun Goto
Original Assignee
Taisho Pharmaceutical Co., Ltd.
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.)
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Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU65132/94A priority Critical patent/AU6513294A/en
Publication of WO1994027962A1 publication Critical patent/WO1994027962A1/fr

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    • 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
    • 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
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen

Definitions

  • the present invention relates to a novel prostaglandin (hereinafter abbreviated as PG) E1 analog having an antiulcer activity.
  • PG prostaglandin
  • PGE! Is known to have characteristic actions such as cytoprotective action and acid secretion inhibitory action.Therefore, many PGE t analogs have been studied as therapeutic agents for peptic ulcer. Have been. Among them, as a 1 3, 1 4-position of the double bond was changed to a triple bond 1 3, 1 4 Jidehi mud PGE t analogues of PGE t, 1 3, 1 4 - Jidehi de port PGE t Methyl ester (Japanese Patent Application Laid-Open No. Sho 52-2004 / 46), 6-hydroxyl 13, 14-didehydro PGE! (U.S. Pat. No. 4,131,738) is known, and Japanese Unexamined Patent Publication No.
  • the conventionally known PG ⁇ 1 analog has the disadvantage that it is rapidly metabolized in vivo, and therefore its effect is not sustained.
  • conventional PG, and its analogs induce side effects such as diarrhea, so that they cannot be administered at a high dose and have a drawback that they cannot provide sufficient effects.
  • An object of the present invention is to provide a PG, analog having a more selective and potent anti-ulcer activity than conventionally known PG analogs and having excellent drug efficacy. Disclosure of the invention
  • the present inventors have found that they have a triple bond at positions 13 and 14 and have a funoushi group at the terminal position of the ⁇ chain, and 3 at positions 4 and 5.
  • the present inventors have found that a specific compound having a heavy bond can solve the above problem, and have completed the present invention. That is, the present invention provides a formula
  • R represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, and A represents an oxygen atom or a mono-NH— group.
  • a in the formula (I) is an oxygen atom.
  • A is a —NH— group.
  • the alkyl group means a linear or branched one, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-alkyl group.
  • the salt of the compound of the formula (I) is a compound of the formula (I) wherein A is an oxygen atom and R is a hydrogen atom, which is sodium, potassium or aluminum. It is a salt with a metal such as aluminum or a salt with an organic amine such as trialkylamine.
  • R is a methyl group, a t-butyl group, or a cyclohexyl group.
  • the compound of the formula (I) can be easily produced, for example, by the following method.
  • R 1 and R 2 are the same or different and each represents a hydroxyl-protecting group, A has the same meaning as described above, and R 3 is R excluding a hydrogen atom when A represents an oxygen atom.
  • A represents a —NH— group, it has the same meaning as R.
  • the protecting group for a hydroxyl group is one commonly used in the field of prostaglandin, for example, t-butyldimethylene Ryl group, Trietinolesilyl group, Phenyldimethylsilyl group, Tetrahydropropylanil group, Tetrahydrofuranyl group, Methoxymethyl group Ethoxy group, benzyl group, etc.
  • organic aluminum compound of the formula (III) can be prepared, for example, by the following method.
  • the alcohol compound represented by the formula (VII) is reacted with oxalyl chloride in DS0 to form an aldehyde, and then condensed with malonic acid in pyridine, followed by decarboxylation.
  • the product is esterified with sulfuric acid in methanol to give the compound of formula (VIII).
  • the methyl ester moiety of the compound of the formula (VI 11) is reduced with diisobutyl aluminum hydroxide to alcohol, and the double bond moiety is formed with L (+)-disopropyl tartrate and titanate.
  • the compound is stereoselectively converted to an epoxy compound.
  • the obtained epoxy compound is further subjected to methanesulfonylide and substitution reaction with lithium chloride to obtain a compound of the formula (IX).
  • the compound of the formula (X) is reacted with n-butyllithium and then reacted with getylaluminum euromide chloride to prepare the compound of the formula (III).
  • the compound of the formula (IV) is combined with 0.5 to 4 equivalents of the compound of the formula (V) and a radical generator (eg, azobisisobutyronitrile, azobiscyclohexane, benzoyl peroxide).
  • a radical generator eg, azobisisobutyronitrile, azobiscyclohexane, benzoyl peroxide.
  • a radical reducing agent for example, tributyltin hydride, triunyltin hydride, dibutyltin hydride, dibutyltin hydride, etc.
  • an inert solvent eg, benzene, toluene, xylene, n-hexane, n-pentane, etc.
  • the compound of the present invention wherein A is an oxygen atom and R is a hydrogen atom is a compound of the formula (Ia) wherein A is an oxygen atom Atomic -This compound is referred to as a compound of (Ic). ] Can be obtained by hydrolyzing the ester moiety of
  • the compound of (Ic) is added to a buffer solution such as a phosphate buffer or a tris-HCl buffer, and if necessary, an organic solvent (e.g., acetate, methanol, ethanol, etc.). By mixing with an enzyme.
  • a buffer solution such as a phosphate buffer or a tris-HCl buffer
  • an organic solvent e.g., acetate, methanol, ethanol, etc.
  • Enzymes used include enzymes produced by microorganisms (for example, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas) and enzymes prepared from animal organs (for example, pig liver and pig liver).
  • examples of commercially available enzymes include lipase VII (manufactured by Sigma and derived from Candida microorganism) and lipase AY (manufactured by Amano Pharmaceutical Co. and derived from Candida microorganism).
  • Lipase MF (manufactured by Amano Pharmaceutical Co., derived from microorganisms of the genus Pseudomonas), PLE—A (manufactured by Amano Pharmaceutical Co., prepared from pig liver), Esterase (manufactured by Sigma Co., prepared from pig liver), Lipase H ( And lipoprotein lipase (manufactured by Tokyo Kasei Kogyo Co., Ltd., prepared from pig kidney).
  • the amount of the enzyme to be used may be appropriately selected depending on the titer of the enzyme and the amount of the substrate [compound of (Ic)], but is usually 0.1 to 20 parts by weight of the substrate.
  • the reaction temperature is from 25 to 50 ° C, preferably from 30 to 35 ° C.
  • the compounds of the present invention can be administered orally or parenterally (eg, intravenously, rectally, vaginally).
  • the dosage form for oral administration for example, solid preparations such as tablets, granules, capsules and the like, and liquid preparations such as solutions, fat emulsions and liposome suspensions can be used.
  • it can be formulated by forming an inclusion compound with ⁇ , 7-cyclodextrin or methylated cyclodextrin.
  • preparations for intravenous administration aqueous or non-aqueous solutions, emulsifiers, suspensions, solid preparations to be used by dissolving in an injection solvent immediately before use, and the like can be used.
  • formulations for rectal administration include suppositories
  • formulations for vaginal administration include dosage forms such as pessaries.
  • the dosage is 0.1 to 100 g, which is to be administered once to three times a day.
  • the compound of the present invention has a strong protective effect on gastric mucosa and a suppressive effect on gastric acid secretion.
  • the persistence is excellent.
  • the compound of the present invention since the compound of the present invention has a strong selectivity of the drug efficacy, as is clear from the test examples described below, it has few side effects and hardly induces diarrhea which is the most problematic in PG at a dose showing a certain pharmacological action Therefore, it is useful as a drug for treating peptic ulcer.
  • test method was performed according to the British Journal of Pharmacology, Vol. 11, 379, 395 (1956).
  • ileum longitudinal muscle was excised, suspended in a Magnus tube (creps solution, 37 ° C, 30 ml), and about 1 g of tension was applied under mixed gas aeration to induce contraction of the ileal smooth muscle by the test drug. Recorded isometrically.
  • P815 P815 cells Cells obtained from Ma c scan of ascites prior intraperitoneally (1 0 7 / ml) using, as a re-cancer de the [3 H] PGE 2 (2 n M), receptor An experiment was performed. 1 0 of the test drug - results expressed in 6 percent inhibition inhibitory effect of the binding of Li cancer de in M (%), suppressed in the compound prepared in Example 1 below was not recognized, as the comparison drug The suppression rate of PGE 2 used was 49.5%. c. EP 3 rather effect study of the receptor [14 C] A Mi Roh bi Li down accumulation inhibition test> The test method, Acta Physiol. Scand., Vol. 96, to the 150 159 pages (1976) --I went accordingly.
  • Japanese white male male heron was used. After the stomach of the egret was removed under anesthesia, the gastric mucosal wall cells were isolated by enzyme treatment. Was added to parietal cells (3 X 10 5 cells) [1 C] A Mi Roh bi Li down (AP), test drug (1CT 5 M) and human is te Mi emissions (10- 5 M), I 20 min An incubation (37 ° C) was performed, and the amount of [ 14 C] AP taken into the cells was measured using a scintillation counter.
  • the inhibitory effect of the test drug on the amount of [ 14 C] AP accumulated by histamine stimulation was expressed as the inhibitory rate.
  • the inhibitory rate of the compound produced in Example 1 described later was 49.4%.
  • the present invention compound was divide to act selectively to EP 3 receptors. Therefore, the compound of the present invention is potent and can be an antiulcer agent with few side effects.
  • the mixture was heated and stirred at 140 ° C. for 1 hour and then cooled to room temperature.
  • the reaction mixture was acidified with hydrochloric acid and extracted with ether.
  • the ether layer was extracted with an aqueous sodium hydroxide solution. After washing, the aqueous layer was acidified with hydrochloric acid and extracted with ether, and the organic layer was washed with saturated saline.
  • the organic layer was dried and concentrated to obtain 28.2 g of (2E) —4-butanoic acid 2-butenoic acid.
  • n-Butyl lithium (32.4 g, 0.163 mol) obtained in the above (7) was added to a solution of tetrahydrofuran at 160 ml of n-butyllithium.
  • reaction solution was passed through a short column filled with silica gel, concentrated under reduced pressure, purified again by silica gel column chromatography, and then subjected to 16-phenol.
  • Example 2 16—Phenoxy 17 19,20—Tetrananole 4,4,5,5_5_13 3_14—Hexadehydrose PGE, isopropyl ester production (1) Obtained in Example 1 (1) 16-phenoxine 17, 18, 19, 20-tetranolane 4,4,5,5,1 in the same manner as in Example 1 (2) 3,14-Hexadehydro-PGE t isoprovir ester 11, 15-bis (t'butyldimethylsilyl ether) was obtained.
  • Example 1 (1) Using the compound obtained in Example 1 (1), in the same manner as in Example 1 (2), 16-phenoxy-17, 18, 17, 19, 20 — tetra 1,4-, 5,5,13,14-hexadehydro PGE] n-butyl ester 11,15-bis (t-butyldimethylsilyl ether) was obtained.
  • Example 4 16 1,7,1,8,19,20—Tetrano no 1,4,4.55 2 1 3j1 4 Oxadehydro PGE Production of cyclohexylester (1)
  • Example 1 Using the compound obtained in (1), in the same manner as in Example 1 (2), 16 — FUNKOSHI 17, 18, 18, 19, 20 — TETRANO4, 4 , 5, 5, 13 and 14 Hexadehydro draw PGE and cyclohexyl ester 11 and 15-bis (t-butyldimethylsilyl ether) were obtained.
  • Example 1 (1) Using the compound obtained in Example 1 (1), and treating it in the same manner as in Example 1 (2), No Norre 4, 4, 5, 5, 13
  • Example 1 (1) Using the compound obtained in Example 1 (1), and in the same manner as in Example 1 (2), 16 — phenoxy 17, 18, 19, 20, 20 — tetra No. 4, 4, 5, 5, 13, 13 14 Hexadehydro PGE! Cyclohexylamide 11, 15-bis (t-butyldimethylsilyl olenoether) was obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un nouvel analogue de la prostaglandine E1(PGE1) ayant un effet cytoprotecteur et un effet inhibiteur des sécrétions gastriques supérieurs à ceux des analogues classiques de la PGE1, dont la durée de l'effet thérapeutique est longue et dont les effets secondaires sont réduits. Ce nouvel analogue de la prostaglandine E1 est représenté par la formule générale (I), dans laquelle R représente hydrogène, alkyle C1-C8 ou cycloalkyle C3-C8, et A représente oxygène ou -NH-.
PCT/JP1994/000635 1993-05-26 1994-04-18 Analogue de la prostaglandine e¿1? WO1994027962A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65132/94A AU6513294A (en) 1993-05-26 1994-04-18 Prostaglandin e1 analog

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/122995 1993-05-26
JP12299593 1993-05-26

Publications (1)

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WO1994027962A1 true WO1994027962A1 (fr) 1994-12-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018220888A1 (fr) * 2017-05-31 2018-12-06 国立大学法人東北大学 Dérivé de bloc de noyau pge1, et procédé de fabrication de celui-ci

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52100446A (en) * 1976-02-13 1977-08-23 Upjohn Co Compositions and process
JPS53135957A (en) * 1977-04-11 1978-11-28 Upjohn Co Composition and its preparation
JPS5416453A (en) * 1977-07-05 1979-02-07 Upjohn Co Composition and method

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52100446A (en) * 1976-02-13 1977-08-23 Upjohn Co Compositions and process
JPS53135957A (en) * 1977-04-11 1978-11-28 Upjohn Co Composition and its preparation
JPS5416453A (en) * 1977-07-05 1979-02-07 Upjohn Co Composition and method

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018220888A1 (fr) * 2017-05-31 2018-12-06 国立大学法人東北大学 Dérivé de bloc de noyau pge1, et procédé de fabrication de celui-ci
JPWO2018220888A1 (ja) * 2017-05-31 2020-05-07 国立大学法人東北大学 Ｐｇｅ１コアブロック誘導体およびその製造方法

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Publication number Publication date
AU6513294A (en) 1994-12-20

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