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WO1994008960A1 - Analogue de prostaglandine e¿1? - Google Patents

Analogue de prostaglandine e¿1? Download PDF

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Publication number
WO1994008960A1
WO1994008960A1 PCT/JP1993/001506 JP9301506W WO9408960A1 WO 1994008960 A1 WO1994008960 A1 WO 1994008960A1 JP 9301506 W JP9301506 W JP 9301506W WO 9408960 A1 WO9408960 A1 WO 9408960A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
phenoxy
pge
group
Prior art date
Application number
PCT/JP1993/001506
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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.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU52854/93A priority Critical patent/AU5285493A/en
Publication of WO1994008960A1 publication Critical patent/WO1994008960A1/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

Definitions

  • the present invention relates to novel prostaglandin analogs
  • Prostaglandin (hereinafter abbreviated as PG) exerts various important physiological actions in a very small amount.
  • An object of the present invention is to provide a novel PGE, analog having a more selective and potent anti-ulcer effect than conventionally known PGE, analog, and excellent in durability.
  • the present inventors have a triple bond at positions 13 and 14, a fuoxy group at the terminal position of the ⁇ chain, and a double bond or a triple bond at positions 2 and 3.
  • the present inventors have found that a specific PGE! Analog having a heavy bond has excellent bioactivity, in particular, a selective and long-lasting potent anti-ulcer effect, and completed the present invention.
  • ⁇ represents a vinylene group or an ethylene group
  • PGE analog and a salt thereof.
  • the “alkyl group” is a linear or branched saturated aliphatic hydrocarbon group
  • examples of the Ci Cs alkyl group include methyl, ethyl, n-propyl, isopropyl, and n-butyl.
  • Isobutyl, se Examples thereof include c-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-octyl, and 2-ethylhexyl groups.
  • a methyl group or a tert-butyl group is preferable.
  • the ⁇ cycloalkyl group '' is an alicyclic hydrocarbon group
  • the C 3 -C 8 cycloalkyl group includes, for example, cyclopropinole, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, Particularly, a cyclohexyl group is preferable.
  • Isopentyl Esters (2E) —16-phenoxy 17, 18, 19, 20—tetranolue 2,3,13,14—tetradehydro PGE, n-hexylester; (2E) —16—phenoxy-17 , 18, 19, 20—Deranolu 2,3,13,14—Tetradehydro PGE! N—Tayloctylester; (2 E) —16—Phenoxy-1, 17, 18, 19, 20—Te Tolanol 1 , 3,13,14—Tetradehydro PGE!
  • N-octyl ester 16-Phenoxy-1 17,18,19,20-Tetranolozole 2,2,3,3,13 , 14- Hexadehydro PGE! 2-Ethylhexyl ester; 16-Phenoxy-1, 17, 18, 19, 20-Tetranolane 2,2,3,3,13,14-Hexadecide mouth PGE i Cyclobutyl ester: 16-Phenoxy-1 17,18 , 19, 20-tetranol-1,2,3,3,13,14-hexadehydro PGE, cyclopentyl ester; 16-phenoxy-1,17,18,19,20-tetranolone 2,2,3,3 1,13,14-Hexadehydro PGE t Cyclohexyl ester; 16-Phenoxy 17, 18, 19, 20-Tetra nonore 2,2,3,3,13,14-Hexadehydro PGE!
  • the compound of the above formula (I) can be present in the form of a free acid or in the form of a salt.
  • salts include: alkali metal salts such as sodium salt and potassium salt c ; alkaline earth metal salts such as calcium salt and magnesium salt: other metal salts such as aluminum salt: ammonium salt; triethylamid And salts with organic amines such as trialkylamines-pyridines, and the like.
  • Particularly, pharmaceutically acceptable salts are suitable.
  • the compounds of formula (I) of the present invention can be prepared, for example, by the method summarized in Reaction Scheme A below. Reaction formula A
  • R 11 represents a C! Cs alkyl group or a C 3 -C 8 cycloalkyl group
  • R 2 and R 3 are the same or different and each represents a hydroxyl-protecting group, and A has the same meaning as described above.
  • the protecting group for the hydroxyl group can be a protecting group usually used in the field of prostaglandin chemistry which can be removed by a usual deprotecting group reaction, for example, hydrolysis, hydrogenolysis and the like.
  • a protecting group usually used in the field of prostaglandin chemistry which can be removed by a usual deprotecting group reaction, for example, hydrolysis, hydrogenolysis and the like.
  • a compound of formula ( ⁇ ) is added to a compound of formula ( ⁇ ).
  • m) in an inert solvent e.g., benzene, toluene, tetrahydrofuran, etc.
  • an inert solvent e.g., benzene, toluene, tetrahydrofuran, etc.
  • a temperature of about 110 to about 30 ° C, preferably about 0 to about 10 ° C in an amount of about 0.8 to about 2 equivalents of the organic aluminum compound represented by Reaction in dimethyl ether, methylene chloride, n-hexane, etc.
  • the organoaluminum compound of the above formula (m) used as a raw material can be prepared, for example, by the method shown in the following reaction formula B.
  • R 3 has the same meaning as described above.
  • the alcohol compound represented by the formula (VI) is reacted with oxalyl chloride in dimethyl sulfoxide (DMS0) to give an aldehyde,
  • the oxidation is, for example, L (+) - tartaric acid 0 Jiisopuropiru about at using t- Puchiruhai Doropaokishido and dichloroethane port methane in - 2 0 by reacting at a temperature of ° C stereoselectively performed.
  • the resulting epoxy compound is further methanesulfonylated and subjected to a substitution reaction with lithium chloride to obtain a compound of the formula (X).
  • the compound of the formula (IV) obtained in the first step is combined with about 0.5 to about 4 equivalents of the organocopper compound represented by the formula (V) and about 0.5 to about 4 equivalents of trimethylsilane, and an inert solvent.
  • an inert solvent E.g., tetrahydrofuran, getyl ether, methylene chloride, toluene, n-hexane, etc.
  • the organocopper compound of the formula (V) is represented by the formula
  • iodine compound represented by the following formula [for example, the method described in P. Knochel et al., Journal of Organic Chemistry, Vol. 53, pp. 2390 (1988)].
  • an organic zinc compound represented by the formula represented by the formula: At this time, heating may be performed if necessary.
  • the heating temperature depends on the boiling point of the solvent, but it can be usually about 30 to about 150 ° (preferably, about 40 to about 80 ° C.)
  • the obtained organic zinc compound is heated to about _50 to about 10 °.
  • the organocopper compound of formula (V) Can get.
  • the compound of formula (VI) obtained in the second step is treated with an inorganic acid (for example, an aqueous solution of hydrochloric acid) or an organic acid or an amine salt thereof (for example, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, etc.)
  • Organic solvents eg acetone, methanol, ethanol, isopropanol, Hydrolysis at a temperature of about 0 to about 40 ° C. in one ter or a mixed solvent thereof gives a compound of formula ( ⁇ ) in a stereoselective manner.
  • R 1 is a C, -C 8 alkyl. group or C 3 -C 8 cycloalkyl group, to give a compound of the present invention that are ie R 11 [the compound of formula (I a)].
  • the compound of the present invention wherein R 1 is a hydrogen atom in the formula (I) [the compound of the formula (lb)] can be obtained by hydrolyzing the ester moiety (R 11 ) of the compound of the formula (Ia). .
  • Hydrolysis is performed, for example, by mixing the compound of (la) in a buffer such as a phosphate buffer or a tris-hydrochloride buffer with an organic solvent (water, such as acetone, methanol or ethanol) as necessary.
  • a buffer such as a phosphate buffer or a tris-hydrochloride buffer
  • an organic solvent water, such as acetone, methanol or ethanol
  • enzymes examples include hydrolases produced by microorganisms (eg, enzymes produced by microorganisms belonging to the genera Candida and Pseudomonas), hydrolases prepared from animal organs (eg, pig liver) Lipase W (manufactured by Sigma, derived from a microorganism of the genus Candida), lipase AY (manufactured by Amano Pharmaceutical Co., Ltd., Japan).
  • microorganisms eg, enzymes produced by microorganisms belonging to the genera Candida and Pseudomonas
  • hydrolases prepared from animal organs eg, pig liver
  • Lipase W manufactured by Sigma, derived from a microorganism of the genus Candida
  • lipase AY manufactured by Amano Pharmaceutical Co., Ltd., Japan.
  • Lipase MF (manufactured by Amano Pharmaceutical Co., derived from Pseudomonas sp.), PLE-A (manufactured by Amano Pharmaceutical Co., prepared from pig liver), esterase (manufactured by Sigma Co., prepared from pig liver), Lipase ⁇ (manufactured by Sigma, prepared from pig knee), lipoprotein lipase (Tokyo Chemical Industry Co., Ltd.) Manufactured by Pig Teng).
  • the amount of the enzyme to be used may be appropriately selected according to the titer of the enzyme and the amount of the substrate [compound (la)], but is usually about 0.1 to about 20 times the weight of the substrate.
  • the reaction temperature can be about 25 to about 50 ° C, preferably about 30 to about 35 ° C.
  • the product of each of the above steps can be separated and purified from the reaction mixture, if necessary, by a method known per se, for example, by a method such as column chromatography.
  • the compound of the formula (I) of the present invention has a strong gastric mucosal protective action and a gastric acid secretion inhibitory action, as well as excellent sustainability, as is clear from the following test examples. Further, the compound of the present invention, as apparent from the following test results,
  • mice Male Wistar rats (body weight 250-300) were used as 2 animals per group (5 animals only in the control group). Under a urethane anesthesia, a cannula for intragastric perfusion was mounted in the stomach, and 0.9% physiological saline was perfused in the stomach with a perfusion pump. Drugs dissolved in a small amount of ethanol and diluted with physiological saline (dosages are shown in Table 1) were administered into the femoral vein, and 5 minutes later, histamine was administered in the same manner. Gastric acid secreted by histamine is automatically titrated
  • ID rats were used as male rats (body weight: 180-200 g) as 7-8 animals per group. After fasting the rat for 18 hours, the drug was dissolved in a small amount of ethanol and diluted with physiological saline (dose is shown in Table 1). Oral administration of the drug was performed. Oral administration. Sixty minutes after administration of hydrochloric acid, the stomach was removed under ether anesthesia, and the length of gastric mucosal lesion was measured. Table 5 shows the results.
  • Hartley male guinea pigs were used.
  • the ileum longitudinal muscle was excised, suspended in a Magnus tube (Kreps solution, 37 ° C, 30 ml), loaded with a tension of about 1 g under aeration of mixed gas, and subjected to isometric contraction of the ileal smooth muscle by the test drug. Recorded in.
  • control drug in Table 3 below is a compound having the following structure. The same applies to Tables 4 and 5.
  • P 815 cells Biochemical Pharmacology, Vol. 30, from the literature of the 1325-1332 page (1981) described, it is known to have a EP 2 receptor. This test was performed according to this document. P 815 cells using P 81 5 cells obtained from the pre-dose mice ascites (10 7 Bruno 1111) intraperitoneally, [3 H] PGE 2 and (2 nM) as ligand, receptor binding experiments was done. Experimental results show a rate of inhibiting the binding of a ligand of the test drug (10- 9 M). Table 4 shows the results. Table 4
  • the compounds of the present invention act via the EP 2 receptor is found to be extremely weak.
  • test method was performed according to Acta Physiol. Scand. Vol. 96, pp. 150-159 (1976). 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.
  • the compounds of the present invention is seen to act selectively against E [rho 3 receptor. Therefore, the compounds of the present invention are expected to be used as anti-ulcer agents having high potency and few side effects for the treatment of peptic ulcers in mammals, especially humans.
  • the compound of the present invention is formulated together with a pharmaceutically acceptable adjuvant into a dosage form suitable for administration, and is orally or parenterally (for example, it can be administered intravenously, rectally, or vaginally.
  • a pharmaceutically acceptable adjuvant for example, it can be administered intravenously, rectally, or vaginally.
  • preparations for oral administration for example, solid preparations such as tablets, granules and capsules, and liquid preparations such as solutions, fat emulsions and ribosome suspensions can be used.
  • the compound of the present invention is used in an oral administration preparation, the compound may be formed into an inclusion compound with 1, 1-, or arcyclodextrin or methylated cyclodextrin. Can be formulated.
  • aqueous or non-aqueous solutions emulsifiers, suspensions, solid preparations to be dissolved in a solvent for injection immediately before use, and the like can be used.
  • formulations for rectal administration can be in the form of suppositories, and those for vaginal administration can be in the form of besari.
  • Additives that can be used to prepare such formulations include, for example, excipients such as crystalline cellulose, lactose, corn starch, mannitol; lubricants such as magnesium stearate, talc; Binders such as polyvinylpyrrolidone: disintegrants such as calcium carboxymethylcellulose; fluidity improvers such as light water and geic acid; solubilizers such as distilled water for injection, physiological saline, Ringer's solution; methyl paraoxybenzoate, Preservatives such as propyl paraoxybenzoate; emulsifiers such as arabia gum and lecithin; surfactants such as tween and span.
  • excipients such as crystalline cellulose, lactose, corn starch, mannitol
  • lubricants such as magnesium stearate, talc
  • Binders such as polyvinylpyrrolidone: disintegrants such as calcium carboxymethylcellulose; fluidity improvers such
  • the dose of the compound of the present invention can be varied over a wide range depending on the age, sex, weight, severity of symptoms, judgment of a physician, etc. of a patient, but the standard daily dose per adult is It is 0.1 to 100 g and can be administered once to three times a day as needed.
  • Disobutylaluminum hydride (1.5 M, toluene solution, 473 ml, 0.708 mol) was added to a 350 ml solution of the compound (61.8 g, 0.322 mol) obtained in (3) above with argon. After dripping at 40 ° C under an air stream, the mixture was stirred for 15 minutes. Acidify with hydrochloric acid under ice-cooling, filter off insolubles, and wash the filtrate with hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine. did. The organic layer was dried and concentrated, and the obtained crude product was distilled under reduced pressure to obtain 44.0 g of (2E) -4-pentoxy-1-butene-1-ol.
  • Example 6 In the same manner as in Example (1), 16-f X-nonoxy-1,18,1 9,20-tetranor-1,2,3,3.13,14-hexadecyl draw PG E 1 t-butyl ester 11,15_bis (t-butyldimethylsilyl ether) 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 analogue de prostaglandine E1 répondant à la formule générale (I) dans laquelle A représente vinylène ou éthinylène, et R1 représente hydrogène, alkyle C¿1?-C8 ou bien cycloalkyle C3-C8. Ce composé a un effet antiulcéreux sélectif, persistant et puissant, il est donc utile dans le traitement de l'ulcère gastro-duodénal.
PCT/JP1993/001506 1992-10-20 1993-10-20 Analogue de prostaglandine e¿1? WO1994008960A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52854/93A AU5285493A (en) 1992-10-20 1993-10-20 Prostaglandin e1 analog

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP28192392 1992-10-20
JP4/281923 1992-10-20
JP7948793 1993-04-06
JP5/79487 1993-04-06

Publications (1)

Publication Number Publication Date
WO1994008960A1 true WO1994008960A1 (fr) 1994-04-28

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Application Number Title Priority Date Filing Date
PCT/JP1993/001506 WO1994008960A1 (fr) 1992-10-20 1993-10-20 Analogue de prostaglandine e¿1?

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AU (1) AU5285493A (fr)
WO (1) WO1994008960A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9364404B2 (en) 2012-08-17 2016-06-14 L'oreal Dye composition comprising a cationic O-alkyl-substituted meta-phenylenediamine derivative

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU657953B2 (en) * 1991-04-22 1995-03-30 Fumie Sato Prostaglandin E1 analogue

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5392744A (en) * 1977-01-24 1978-08-15 Searle & Co Derivative of omegaaaryloxyy133 prostin acid
JPS5416453A (en) * 1977-07-05 1979-02-07 Upjohn Co Composition and method
JPH05117230A (ja) * 1991-04-22 1993-05-14 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5392744A (en) * 1977-01-24 1978-08-15 Searle & Co Derivative of omegaaaryloxyy133 prostin acid
JPS5416453A (en) * 1977-07-05 1979-02-07 Upjohn Co Composition and method
JPH05117230A (ja) * 1991-04-22 1993-05-14 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9364404B2 (en) 2012-08-17 2016-06-14 L'oreal Dye composition comprising a cationic O-alkyl-substituted meta-phenylenediamine derivative

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AU5285493A (en) 1994-05-09

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