WO1994008960A1 - Prostaglandin e1 analog - Google Patents
Prostaglandin e1 analog Download PDFInfo
- 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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- WIPO (PCT)
- Prior art keywords
- compound
- formula
- phenoxy
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- 229910052782 aluminium Inorganic materials 0.000 description 1
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- 229960000212 aminophenazone Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- YFNONBGXNFCTMM-UHFFFAOYSA-N butoxybenzene Chemical compound CCCCOC1=CC=CC=C1 YFNONBGXNFCTMM-UHFFFAOYSA-N 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- QABCGOSYZHCPGN-UHFFFAOYSA-N chloro(dimethyl)silicon Chemical compound C[Si](C)Cl QABCGOSYZHCPGN-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- XEBCWEDRGPSHQH-UHFFFAOYSA-N diisopropyl tartrate Chemical compound CC(C)OC(=O)C(O)C(O)C(=O)OC(C)C XEBCWEDRGPSHQH-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
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- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- 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)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A prostaglandin E1 analog represented by formula (I), wherein A represents vinylene or ethinylene; and R1 represents hydrogen, C¿1?-C8 alkyl or C3-C8 cycloalkyl. This compound has a selective, persistent and potent antiulcerative effect and hence is useful for treating peptic ulcer.
Description
明 細 書 Specification
プロスタグランジン 類縁体 Prostaglandin analog
技術分野 Technical field
本発明は新規なプロスタグランジン 類縁体に関する, The present invention relates to novel prostaglandin analogs,
背景技術 Background art
プロスタグランジン （以下、 PGと略称する。 ） は微量で種々の重要 な生理作用を発揮することから、 従来より医薬への応用を意図して天然 Prostaglandin (hereinafter abbreviated as PG) exerts various important physiological actions in a very small amount.
P G及び夥しい数のその誘導体の合成と生物活性の検討が行なわれていThe synthesis and biological activity of PG and numerous derivatives have been studied.
^> o ^> o
その中でも PGE, は、 細胞保護作用、 酸分泌抑制作用などの特徴あ る作用を有していることが知られており、 このため多数の PGE! 類縁 体が消化性潰瘍治療薬として検討されてきた。 このうち、 PGE, の 13, 14位の二重結合を三重結合に変えた 13, 14-ジデヒ ドロ PG 類縁体としては、 13, 14—ジデヒ ドロ PGE, メチルエステル (特開昭 52 - 100446号公報） 、 6—ヒ ドロキシー 13, 14— ジデヒ ドロ PGEi (米国特許第 4, 131， 738号） が知られており、 また、 特開昭 52 - 100446·号公報、 米国特許第 4， 160, 101 号及び米国特許第 4， 249, 016号に記載の一般式で示される化合物 に ω鎖の末端にフエノキシ基を有する 13, 14—ジデヒ ドロ PGE, 類縁体が包含されている。 Among them, PGE is known to have characteristic actions such as cytoprotective action and acid secretion inhibitory action. For this reason, many PGE! Analogs have been studied as peptic ulcer therapeutics. Was. Among these, 13,14-didehydro PGE, methyl ester (13,14-didehydro PGE, methyl ester) wherein the double bond at the 13,14 position of PGE is changed to a triple bond Gazette) and 6-hydroxyl 13,14-didehydro PGEi (U.S. Pat. No. 4,131,738), and Japanese Patent Application Laid-Open No. 52-100446 · and U.S. Pat. The compounds represented by the general formulas described in US Pat. No. 101 and US Pat. No. 4,249,016 include 13,14-didehydro PGE, analogs having a phenoxy group at the end of the ω chain.
しかしながら、 従来知られている PGE! 類縁体は生体内での代謝が 速く、 従って効果が持続しないという欠点がある。 また、 従来の PGEi 類縁体は下痢を初めとした副作用を誘発するため、 高い用量で投与でき ず、 十分な効果を挙げることができないという欠点があった。
本発明の目的は、 従来知られている PGE, 類縁体よりも選択的で強 力な抗潰瘍作用を有し、 かつ持続性に優れた新規な P G E , 類縁体を提 供することにある。 However, the conventionally known PGE! Analog has the disadvantage that it is rapidly metabolized in vivo and therefore does not last long. In addition, conventional PGEi analogs have the drawback that they cannot be administered at high doses because they induce side effects such as diarrhea, and they cannot produce sufficient effects. 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.
発明の開示 Disclosure of the invention
本発明者らは鋭意研究を進めた結果、 13， 14位に 3重結合を有し、 かつ ω鎖の末端位にフユノキシ基を有し、 さらに 2, 3位に 2重結合ま たは 3重結合を有するある特定の PGE! 類縁体が、 優れた生理活性、 殊に選択的でかつ持続性に優れた強力な抗潰瘍作用を有することを見い だし、 本発明を完成した。 As a result of intensive studies, the present inventors have a triple bond at positions 13 and 14, a fuoxy group at the terminal position of the ω 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.
かく して、 本発明は式 Thus, the present invention provides the formula
式中、 Where:
Αはビニレン基またはェチ レン基を表わし、 Α represents a vinylene group or an ethylene group,
Rリま水素原子、 〇1〜(：8ァルキル基または（：3〜（ 8シクロァルキ ル基を表わす、 R Lima hydrogen atom, 〇 1 - (: 8 Arukiru group or a (: represents a 3 - (8 Shikuroaruki group,
で示されるプロスタグラジン (PGE 類縁体及びその塩を提供す るものである。 And a prostaglandin (PGE analog and a salt thereof).
本明細書において、 「アルキル基」 は直鎖状または分枝鎖状の飽和脂 肪族炭化水素基であり、 Ci Csアルキル基としては、 例えばメチル、 ェチル、 n—プロピル、 イソプロピル、 n—ブチル、 イソブチル、 s e
c—ブチル、 t e r t—ブチル、 n—ペンチル、 イソペンチル、 n—へ キシル、 n—ォクチル、 2—ェチルへキシル基などが挙げられ、 中でも メチル基または t e r t—ブチル基が好適である。 また、 「シクロアル キル基」 は脂環式炭化水素基であり、 C3〜C8シクロアルキル基には、 例えばシクロプロピノレ、 シクロブチル、 シクロペンチル、 シクロへキシ ル、 シクロへプチル、 シクロォクチル基が包含され、 特にシクロへキシ ル基が好ましい。 In the present specification, the “alkyl group” is a linear or branched saturated aliphatic hydrocarbon group, and 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. Among them, a methyl group or a tert-butyl group is preferable. The `` cycloalkyl group '' is an alicyclic hydrocarbon group, and the C 3 -C 8 cycloalkyl group includes, for example, cyclopropinole, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, Particularly, a cyclohexyl group is preferable.
本発明により提供される上記式 （ I ) の化合物の異体例を示せば次の とおりである。 . Illustrative examples of the compounds of the above formula (I) provided by the present invention are as follows. .
(2 E) — 16—フエノキシ一 17， 18, 19, 20—テトラノル一 2, 3, 13, 14—テトラデヒ ドロ PGEi メチルエステル； （2 E) 一 16—フエノキシ一 17, 18， 19, 20—テトラノル一 2， 3， 1 '3, 14—テトラデヒ ドロ PGE! ェチルエステル； （2 E) — 16—フエ ノキシ一 17, 18, 19， 20—テトラノル一 2, 3, 13, 14—テトラ デヒ ドロ PGE, プロピルエステル； （2 E) — 16—フエノキシ一 1 7, 18， 19, 20—テトラノル一 2, 3, 13, 14—テトラデヒ ドロ P G Ei n—ブチルエステル： （2 E) — 16—フヱノキシー 17, 18， 19, 20—テトラノル一 2, 3, 13, 14—テトラデヒ ドロ？0£! ィ ソブチルエステル： （2 E) — 16—フヱノキシー 17, 18, 19, 2 0—テトラノル一 2, 3, 13, 14—テトラデヒ ドロ PGEt t e r t —プチルエステル； （2 E) — 16—フヱノキシー 17, 18, 19, 2 0—テトラノル一 2, 3， 13, 14—テトラデヒ ドロ PGE! n—ペン チルエステル； （2 E) — 16—フエノキシ一 17, 18, 19， 20— テトラノル一 2, 3， 13， 14—テトラデヒ ドロ PGE! イソペンチル
エステル ： （2E) —16—フエノキシ一 17, 18, 19, 20—テ ト ラノルー 2， 3, 13, 14—テ トラデヒ ドロ PGE, n—へキシルエス テル； （2 E) —16—フエノキシ一 17, 18, 19, 20—テ ドラノ ルー 2, 3, 13, 14—テ トラデヒ ドロ PGE! n—才クチルエステル ； (2 E) — 16—フヱノキシ一 17, 18, 19, 20—テ トラノル一 2, 3, 13, 14—テ トラデヒ ドロ PGE! 2—ェチルへキシルエステ ノレ ； （2E) — 16—フエノキシ一 17, 18, 19, 20—テ トラノル — 2, 3， 13, 14—テ トラデヒ ドロ PGE, シクロブチルエステル ； (2 E) — 16—フエノキシ一 17, 18, 19, 20—テ トラノル一 2, 3， 13, 14—テ トラデヒ ドロ PGE, シクロペンチルエステル ； （2(2 E) — 16-phenoxy-1,17,18,19,20-tetranor-1,2,13,14-tetradehydro PGEi methyl ester; (2E) -16-phenoxy-1,17,18,19,20— Tetranor-1,2,3,1'3,14-tetradehydro PGE! Ethyl ester; (2E) —16-phenoxy-17,18,19,20-tetranor-1,2,13,14-tetradehydro PGE, Propyl ester; (2 E) — 16-phenoxy-1 7,18,19,20-tetranor-1,2,3,13,14-tetradehydro PG Ein-butyl ester: (2E) — 16-Phenoxy 17, 18, 19, 20—tetranor-1,2,3,13,14—tetradehydro? 0 £! Isobutyl ester: (2 E) — 16-Phenoxy 17, 18, 19, 20-tetranor-1,2,13,14-tetradehydro PGEt tert —butyl ester; (2 E) — 16— Phenoxy 17, 18, 19, 20-tetranor-1,2,3,13,14-tetradehydro PGE! N-pentyl ester; (2 E) — 16-phenoxy-1,17,19,20-tetranor-1,2 3, 13, 14—tetradehydro PGE! 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! 2-Ethylhexylester; (2E) — 16-phenoxy 17,18,19,20—Tetranol — 2,3,13,14—Tradedehydro PGE , Cyclobutyl ester; (2 E) —16-phenoxy-1,18,19,20—te tolanol 1,3,13,14—te toradehydro PGE, cyclopentyl ester; (2
E) — 16—フエノキシ一 17， 18, 19, 20—テ トラノル一 2, 3, 13, 14—テ トラデヒ ドロ PGE! シクロへキシルエステル ； （2E)E) — 16-phenoxy-1, 17, 18, 19, 20—te Tolanol 2,3,13,14—te Toradehydro PGE! Cyclohexyl ester; (2E)
—16—フエノキシ一17, 18, 19, 20—テトラノル一 2, 3， 13, 14—テ トラデヒ ドロ P G E , シクロへプチルエステル； （2E) — 1—16—phenoxy-1,17,18,19,20—tetranor-1,2,3,13,14—tetrahydro PGE, cycloheptyl ester; (2E) — 1
6—フエノキシ一 17, 18, 19, 20—テトラノル一 2, 3, 13， 14 —テ トラデヒ ドロ PGE! シクロォクチルエステル； （2E) — 16— フエノキシ一17, 18， 19, 20—テ トラノル一 2, 3, 13, 14—テ トラデヒ ドロ PGE, ； 16—フエノキシ一 1,7, 18, 19, 20—テ トラノノレ一 2, 2, 3, 3, 13, 14—へキサデヒ ドロ PGE! メチルェ ステル； 16—フエノキシ一 17, 18, 19, 20—テ トラノル一 2, 2， 3, 3, 13, 14—へキサデヒ ドロ PGE! ェチルエステル ； i 6—フヱ ノキシ一 17, 18, 19, 20—テ トラノル一 2, 2, 3, 3, 13.14— へキサデヒ ドロ PGEi プロピルエステル； 16—フヱノキシ一 17, 18, 19, 20—テ トラノノレ一 2, 2, 3, 3， 13, 14—へキサデヒ ド
口 P G E ! n—ブチルエステル ； 16—フヱノキシー 17, 18, 19, 20—テ トラノル一 2, 2, 3, 3, 13, 14—へキサデヒ ドロ PGE, ィソブチルエステル ； 16—フヱノキシ一 17, 18, 19, 20—テ ト ラノノレ一 2， 2, 3, 3, 13, 14—へキサデヒ ドロ PGE! t e r t— ブチルエステル ； 16—フエノキシ一 17, 18, 19, 20—テ トラノ ルー 2, 2, 3， 3, 13, 14—へキサデヒ ドロ PGE, n—ペンチルェ ステル ； 16—フエノキシ一 17, 18.19, 20—テ トラノル一 2, 2， 3.3, 13.14—へキサデヒ ドロ P G ィソペンチルエステル ； 1 6—フエノキシ一 17， 18， 19, 20—テ トラノル一 2, 2, 3, 3.1 3, 14一へキサデヒ ドロ P G E, n—へキシルエステル： 16—フエ ノキシ一 17, 18, 19, 20—テ トラノル一 2, 2, 3, 3, 13, 14— へキサデヒ ドロ PGE! n—ォクチルエステル； 16—フエノキシ一 1 7, 18, 19, 20—テ トラノゾレー 2， 2, 3, 3, 13, 14—へキサデヒ ドロ P G E！ 2—ェチルへキシルエステル； 16—フエノキシ一 17， 18, 19, 20—テ トラノノレー 2, 2, 3, 3, 13, 14—へキサデヒ ド 口 P G E i シクロブチルエステル： 16—フエノキシ一 17， 18, 19, 20—テ トラノル一 2, 2, 3, 3， 13, 14—へキサデヒ ドロ PGE, シクロペンチルエステル； 16—フヱノキシ一 17, 18， 19， 20— テ トラノノレ一 2, 2, 3, 3, 13, 14—へキサデヒ ドロ PGEt シクロ へキシルエステル； 16—フエノキシ一 17, 18, 19, 20—テ トラ ノノレー 2, 2, 3, 3, 13, 14—へキサデヒ ドロ PGE! シクロへプチ ルエステル； 16—フヱノキシー 17, 18, 19, 20—テ トラノル一 2, 2, 3, 3, 13, 14—へキサデヒ ドロ PGEi シクロォクチルエス テル； 16—フヱノキシ一 17， 18, 19， 20—テトラノル一 2, 2,
3， 3, 1.3, 14ーテトラデヒ ドロ PGE, 6-phenoxy-1,18,19,20-tetranor 1,2,13,14—tetradehydro PGE! Cyclooctyl ester; (2E) —16—phenoxy-1 17,18,19,20—te tolanol 1,2,13,13—Tetrahydro PGE ,; 16—Phenoxy 1,7,18,19,20—Te Tranore 1,2,3,3,13,14—Hexadehydro PGE! Stele; 16-phenoxy-1, 17, 18, 19, 20-te tranor-1,2,3,3,13,14-hexadehydro PGE! Ethyl ester; i6-phenoxy-1 17,18,19,20 —Te tranol 1,2,3,3,13—14—Hexadehydro PGEi propyl ester; 16—Phenoxy 17,18,19,20—Te tranorone 1,2,3,3,13,14—Hexadehy Do Mouth PGE! N-Butyl ester; 16-Phenoxy 17, 18, 19, 20-Tetranol 2,2,3,3,13,14-Hexadehydro PGE, Isobutyl ester; 16-Phenoxy-17 18, 19, 20—Tetranolone 2, 2, 3, 3, 13, 14—Hexadehydro PGE! Tert—butyl ester; 16—Phenoxy 17, 18, 19, 20—Tetranolulu 2, 2 1,3-, 3,13,14-Hexadehydro PGE, n-pentylester; 16-Phenoxy 17, 18.19, 20-Tetranol 1,2, 3.3, 13.14-Hexadehydro PG isopentyl ester; 1 6-Phenoxy-17,18,19,20-Tetranol 1,2,3,3.1 3,14-Hexadehydro PGE, n-Hexyl ester: 16-Phenoxy 17,18,19,20- Tetranol-I 2,2,3,3,13,14-Hexadehydro 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! Cyclohepti Ester; 16-phenoxy 17, 18, 19, 20-tetranol 1,2,3,3,13,14-hexadehydro PGEi cyclooctyl ester; 16-phenoxy-1,17,18,19,20- Tetranor 1 2, 2, 3, 3, 1.3, 14-tetradehydro PGE,
R1が水素原子を表わす場合の前記式 （I) の化合物は、 遊離酸の形 で存在することができ、 或いは塩の形で存在することもできる。 そのよ うな塩の例としては、 ナトリウム塩、 カリウム塩などのアルカリ金属塩 c ； カルシウム塩、 マグネシウム塩などのアルカリ土類金属塩： アルミ二 ゥム塩などのその他の金属塩： アンモニゥム塩； トリェチルァミ ンのよ うなトリアルキルァミ ンゃピリジンなどの有機ァミ ンとの塩が挙げられ、 特に製薬学的に許容しうる塩が好適である。 本発明の式 （ I) の化合物は、 例えば、 以下の反応式 Aに要約する方 o 法によって製造することができる。 反 応 式 A When R 1 represents a hydrogen atom, the compound of the above formula (I) can be present in the form of a free acid or in the form of a salt. Examples of such 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
Ru00C-A-(CH2)3Cu(CN)ZnI · 2LiCl 第 2工程 R u 00C-A- (CH 2 ) 3 Cu (CN) ZnI2LiCl 2nd step
クロロトリメチルシラン ゝ )
1 Chlorotrimethylsilane ゝ) 1
(VI) (VI)
第 3工程3rd step
R R
第 4工程4th step
第 5工程 Step 5
OH
上記反応式において、 OH In the above reaction formula,
R11は C! Csアルキル基または C3〜C8シクロアルキル基を表わ し、 R 11 represents a C! Cs alkyl group or a C 3 -C 8 cycloalkyl group,
R 2および R 3は同一もしぐは相異なり各々水酸基の保護基を表わし、 Aは前記と同義である。 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.
ここで水酸基の保護基は、 通常の脱保護基反応、 例えば加水分解、 水 素添加分解等により除去しうるプロスタグランジン化学の分野で通常用 いられる保護基であることができ、 例えば、 t e r t一プチルジメチル シリル、 トリェチルシリル、 フヱニルジメチルシリル、 テトラヒ ドロピ ラニル、 テトラヒ ドロフラニル、 メ 卜キシメチル、 ェ卜キシェチル、 ベ ンジル基などが挙げられる。 Here, 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. Monobutyldimethylsilyl, triethylsilyl, phenyldimethylsilyl, tetrahydroxypyranyl, tetrahydrofuranyl, methoxymethyl, ethoxyxetyl, benzyl group and the like.
以下、 上記 1〜5の各工程についてさらに説明する。 Hereinafter, each of the above steps 1 to 5 will be further described.
(第 1工程） (First step)
まず、 佐藤らの方法 [ジャーナル 'ォブ ·オーガニック ' ケミストリ — ( J. Org. Chem. ) , 第 53巻， 第 5590ページ （1988年） ] により公知の式 （Π) の化合物に、 式 （m) で示される有機アルミニゥ ム化合物約 0.8〜約 2当量を約一 10〜約 30 °C、 好ましくは約 0〜 約 10°Cの温度において不活性溶媒 （例えばベンゼン、 トルエン、 テト ラヒ ドロフラン、 ジェチルエーテル、 塩化メチレン、 n—へキサンなど） 中で反応させることにより、 立体特異的に式 （IV) の化合物が得られる。 原料として使用される上記式 （m) の有機アルミニウム化合物は、 例 えば以下の反応式 Bに示す方法にて調製することができる。
反 応 式 B
First, according to the method of Sato et al. [Journal 'Ob Organic' Chemistry — (J. Org. Chem.), Vol. 53, p. 5590 (1988)], a compound of formula (Π) is added to a compound of formula (Π). m) in an inert solvent (e.g., benzene, toluene, tetrahydrofuran, etc.) at 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.) gives the compound of formula (IV) stereospecifically. 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. Reaction formula B
1) ォキザリルクロリ ド ZDMS0 1) Oxalyl chloride ZDMS0
2) マロン酸 Zピリジン 2) Malonic acid Z pyridine
3) 硫酸ノメタノール
3) Nomethanol sulfate
1) ジイソブチルアルミニウムハイ ドライ ド1) Diisobutyl aluminum hydride
2) 酸化 2) oxidation
3) メタンスルホン酸クロリ ド 3) Methanesulfonic acid chloride
4) リチウムクロリ ド 4) Lithium chloride
(X)(X)
1) n—ブチルリチウム 1) n-butyl lithium
2) 保護 2) Protection
1) Π—ブチルリチウム 1) Π-butyl lithium
2) ジェチルアルミニウムクロリ ド 2) Jetyl aluminum chloride
0R;
上記反応式中、 0R ; In the above reaction formula,
R 3は前記と同義である。 R 3 has the same meaning as described above.
式 （VI) で示されるアルコー 化合物をォキザリルクロリ ドを用いジ メチルスルホキシド （D M S 0 ) 中にて反応しアルデヒ ドとした後、 ピ The alcohol compound represented by the formula (VI) is reacted with oxalyl chloride in dimethyl sulfoxide (DMS0) to give an aldehyde,
R リ ジン中にてマロン酸と縮合、 脱炭酸反応を行い、 次いで生成物をメタ ノール中で硫酸にてエステル化反応を行ない式 （K) の化合物を得る。 次に、 式 （IX) の化合物のメチルエステル部をジイソブチルアルミ二 ゥムハイ ドライ ドにて還元しアルコールとした後、 2重結合部を酸化し てエポキシ化合物とする。 ここで、 該酸化は例えば、 L ( + ) —酒石酸0 ジィソプロピルを用い t—プチルハイ ドロパーォキシドとジクロ口メタ ン中で約— 2 0 °Cの温度にて反応させることにより立体選択的に行なう。 得られるエポキシ化合物は、 更にメタンスルホニル化し、 塩化リチウム と置換反応を行い式 （X ) .の化合物を得る。 Condensation with malonic acid and decarboxylation reaction in R resin, and then esterification of the product with sulfuric acid in methanol to obtain the compound of formula (K). Next, the methyl ester portion of the compound of the formula (IX) is reduced with diisobutylaluminum hydride to form an alcohol, and the double bond portion is oxidized to obtain an epoxy compound. Here, 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).
式 （X ) の化合物はテトラヒ ドロフラン中で約一 7 0 °Cの温度にて n5 一ブチルリチウムと反応させ、 生成するアセチレン誘導体の水酸基を保 護することにより式 （XI) の化合物に導くことができる。 Compounds of formula (X) is reacted with n 5 one-butyllithium at a temperature of about a 7 0 ° C in as tetrahydrofuran, leads to hydroxyl groups of the resulting acetylene derivative to a compound of formula (XI) by protection be able to.
式 （XI) の化合物は、 n—ブチルリチウムと反応させた後にジェチル アルミニウムクロリ ドと反応させると式 （ tt) の化合物が生成する。 (第 2工程） The compound of formula (XI) reacts with n-butyllithium and then with getyl aluminum chloride to form the compound of formula (tt). (2nd step)
n 第 1工程で得られる式 （IV) の化合物を、 式 （V ) で示される有機銅 化合物約 0 . 5〜約 4当量およびクロ口 トリメチルシラン約 0 . 5〜約 4 当量と不活性溶媒 （例えばテトラヒ ドロフラン、 ジェチルエーテル、 塩 化メチレン、 トルエン、 n—へキサンなど） 中で約一 7 8〜約 4 0 °Cの 温度にて反応させ、 式 （VI) の化合物とする。
ここで、 式 （V) の有機銅化合物は、 式 n 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. (E.g., tetrahydrofuran, getyl ether, methylene chloride, toluene, n-hexane, etc.) at a temperature of about 178 to about 40 ° C to obtain a compound of the formula (VI). Here, the organocopper compound of the formula (V) is represented by the formula
I-(CH2)3-A-C00R (XE) I- (CH 2 ) 3 -A-C00R (XE)
式中、 A及び R11は前記と同義である、 Wherein A and R 11 are as defined above,
で示されるヨウ素化合物から、 公知の方法 [例えば P. Knochel ら、 ジャ ーナル ·ォブ ·オーガニック · ケミストリ一， 第 53卷， 第 2390ぺ ージ （1988年） に記載の方法] により調製することができる。 すな わち、 式 （ ） のヨウ素化合物を、 例えば 1, 2—ジブロモメタン、 ク 口ロ トリメチルシラン、 ヨウ素などで活性化された亜鉛約 0.8〜約 5 当量と、 不活性溶媒 （例えばテトラヒ ドロフラン、 ジェチルエーテル、 n—へキサン、 n—ペンタン、 ジォキサンなど） 中で反応させることに より式 From an 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)]. Can be. That is, about 0.8 to about 5 equivalents of zinc activated with, for example, 1,2-dibromomethane, octatrimethylsilane, iodine, and the like, and an inert solvent (eg, tetrahydrofuran) , Dimethyl ether, n-hexane, n-pentane, dioxane, etc.)
IZn—(CH2)3— A— C00R11 IZn— (CH 2 ) 3 — A— C00R 11
式中、 A及び R11は前記と同義である、 Wherein A and R 11 are as defined above,
で示される有機亜鉛化合物に誘導する。 この際、 必要に応じて加熱して もよい。 加熱温度は溶媒の沸点にもよるが、 通常約 30〜約 150° ( 、 好ましくは約 40〜約 80°Cとすることができる。 得られる有機亜鉛化 合物を、 約 _50〜約 10°Cの温度にて、 シアン化銅 （約 1〜約 2.5 当量） および塩化リチウム （約 2〜約 5当量） を含む前記不活性溶媒中 で反応させることにより、 式 （V) の有機銅化合物を得ることができる。 、第。丄 fe To an organic zinc compound 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 °. By reacting at a temperature of C in the inert solvent containing copper cyanide (about 1 to about 2.5 equivalents) and lithium chloride (about 2 to about 5 equivalents), the organocopper compound of formula (V) Can get.
第 2工程で得られる式 （VI) の化合物を、 無機酸 （例えば塩酸の水溶 液） または有機酸もしくはそのアミン塩 （例えば p—トルエンスルホン 酸、 p—トルエンスルホン酸ピリジン塩など） を用い、 有機溶媒 （例え ばアセトン、 メタノール、 エタノール、 イソプロパノール、 ジェチルェ
一テルあるいはこれらの混合溶媒など） 中で、 約 0〜約 40°Cの温度に て加水分解することにより、 立体選択的に式 （ π) の化合物が得られる。 (第 4工程） 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 (π) in a stereoselective manner. (4th step)
第 3工程で得られる式 （W) の化合物の水酸基の保護基をプロスタグ ランジン化学の分野における通常の方法を用いて脱保護し、 式 （I) に おいて R1が C ,〜C8アルキル基または C3〜C8シクロアルキル基、 す なわち R11である本発明の化合物 [式 （I a) の化合物] を得る。 The protecting group for the hydroxyl group of the compound of the formula (W) obtained in the third step is deprotected using a usual method in the field of prostaglandin chemistry, and in the formula (I), 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)].
(第 5工程） (Fifth step)
式 （I) において R1が水素原子である本発明の化合物 [式 （l b) の化合物] は、 式 （I a) の化合物のエステル部分 （R11) を加水分解 することにより得ることができる。 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). .
加水分解は、 例えば、 （l a) の化合物を、 リン酸緩衝液、 トリス— 塩酸緩衝液などの緩衝液中において、 必要に応じて有機溶媒 （ァセトン、 メタノール、 エタノールなどの水と混和するもの） を併用して酵素と反 応させることにより行うことができる。 ここで使用しうる酵素としては、 例えば、 微生物が生産する加水分解酵素 （例えばキャンディダ属、 シュ ードモナス属に属する微生物が生産する酵素） 、 動物の臓器から調製さ れる加水分解酵素 （例えばブタ肝臓やブタ脖臓より調製される酵素） な どが挙げられ、 市販の酵素で具体例を挙げると、 リパーゼ W (シグマ社 製、 キャンディダ属の微生物由来） 、 リパーゼ AY (天野製薬社製、 キヤ ンデイダ属の微生物由来） 、 リパーゼ MF (天野製薬社製、 シユードモ ナス属の微生物由来）、 PLE-A (天野製薬社製、 ブタ肝臓より調製）、 エステラーゼ （シグマ社製、 ブタ肝臓より調製） 、 リパーゼ Π (シグマ 社製、 ブタ膝臓より調製） 、 リポプロテインリパーゼ （東京化成工業社
製、 ブタ滕臓より調製） などである。 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. The reaction can be carried out by reacting the enzyme with the enzyme. Examples of enzymes that can be used here 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). 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 Π (manufactured by Sigma, prepared from pig knee), lipoprotein lipase (Tokyo Chemical Industry Co., Ltd.) Manufactured by Pig Teng).
酵素の使用量は、 酵素の力価及び基質 [ ( l a ) の化合物] の量に応 じて適宜選択すればよいが、 通常「ま基質の約 0 . 1〜約 2 0倍重量部で あり、 また反応温度は約 2 5〜約 5 0 °C、 好ましくは約 3 0〜約 3 5 °C とすることができる。 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.
上記各工程の生成物は、 必要に応じて、 それ自体既知の方法により、 例えば、 カラムクロマ卜グラフィ一などの方法により反応混合物から分 離、 精製することができる。 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.
本発明の式 （ I ) の化合物は、 下記の試験例から明らかなように、 強 い胃粘膜保護作用、 胃酸分泌抑制作用を有し、 しかもその持続性に優れ ている。 また、 本発明の化合物は、 下記の試験結果から明らかなように、 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,
E P 3受容体への選択性が高いので、 副作用が少なく、 確実な薬理作用 を示す用量で P Gで最も問題となっている下痢も殆ど誘発しないことか ら、 消化性潰瘍を治療するための薬剤として有用である。 なお、 各試験 例中の化合物番号は、 後記実施例に示す化合物番号に相当する。 Because of the high selectivity to the EP 3 receptor, fewer side effects, reliable most problematic and going on diarrhea at a dose showing pharmacological action in PG almost do not induce et al, agents for treating peptic ulcer Useful as In addition, the compound number in each test example corresponds to the compound number shown in Examples described later.
試験例 1 [胃酸分泌抑制作用試験] Test Example 1 [Stomach acid secretion inhibitory effect test]
ウィスター系雄性ラッ ト （体重2 5 0〜3 0 0 ） を 1群 2匹 （対照 群だけは 5匹） として使用した。 ウレタン麻酔下に胃内灌流用のカニュ 一レを胃内に装着し、 0 . 9 %生理食塩水を灌流用ポンプで胃内を灌流 した。 少量のエタノールに溶解して生理食塩水で希釈した薬物 （投与量 は表 1に示した） を大腿静脈内に投与し、 その 5分後にヒスタミ ンを同 様にして投与した。 ヒスタミンによって分泌された胃酸は自動滴定装置 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
( p H s t a t ) により 0 . 0 2規定の水酸化ナトリウムで中和滴定さ れ、 その消費量を胃酸分泌量とした。 その結果を表 1に示す。
Neutralization titration was performed with 0.02N sodium hydroxide according to (pH stat), and the consumed amount was defined as the amount of gastric acid secretion. The results are shown in Table 1.
*： ρ<0.05、 ： ρぐ 0.01 *: Ρ <0.05,: ρ is 0.01
試験例 2 [胃粘膜保護作用試験] Test Example 2 [Stomach mucosa protective effect test]
I D ゥイ ス夕一系雄性ラッ ト （体重 180〜200g) を 1群 7〜8匹と して使用した。 ラッ トを 18時間絶食絶水後、 少量のエタノールに溶解 して生理食塩水で希釈した薬物 （投与量は表 1に示した） を経口投与し, その 30分後に 0.6規定の塩酸 lm 1を経口投与した。 塩酸投与 60 分後、 エーテル麻酔下に胃を摘出し、 胃粘膜病変の長さを測定した。 そ 5 の結果を表 2に示す。 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.
表 2 Table 2
0 0
**： p<0.01
試験例 3 [E P受容体に対する選択性の検討試験] **: p <0.01 Test Example 3 [Selectivity test for EP receptor]
E P受容体に対する選択性の検討試験は British Journal of Pharma cology, 第 105巻， 第 271〜 78ページ （1992年） に記載の 文献に従って行った （E P 2受容体は下痢に関係することが報告されて おり、 また、 E P3受容体は胃酸分泌作用に関係していることも報告さ れている） 。 A study of selectivity for EP receptors was performed according to the literature described in the British Journal of Pharmacology, Vol. 105, pp. 271 to 78 (1992). (It has been reported that EP 2 receptors are associated with diarrhea.) and, also, EP 3 receptors have also been reported to be related to gastric acid secretion action).
(a) £ ?,受容体への作用検討 （モルモッ ト摘出回腸収縮作用試験） 試験方法は、 British Journal of Pharmacology, 第 1 1巻， 第 37 9〜 395ページ （1956年） に従って行った。 (a) Examination of the effect on £?, receptors (guinea pig isolated ileal contraction test) The test method was performed according to the British Journal of Pharmacology, Vol. 11, pp. 379-395 (1956).
ハートレー系雄性モルモッ トを使用した。 回腸縦走筋を摘出し、 マグ ヌス管 （クレプス溶液， 37°C, 30m l ) に懸垂し、 混合ガス通気下 約 1 gの張力を負荷し、 被験薬物による回腸平滑筋の収縮を等長的に記 録した。 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.
実験結果は、 被験薬物を 10-6Mとなるようにマグヌス管内に加えた 時の回腸の収縮をアセチルコリン （ACh) を 10-6Mとなるようにマ グヌス管内に加えた時の回腸の収縮高を 100%として収縮率で表す。 この結果を表 3に示す。 Experimental results, contraction of ileum when the contraction of the ileum when added to the Magnus tube to the test drug a 10- 6 M was added to the Ma Gunusu tube so that acetylcholine (ACh) and 10- 6 M The height is expressed as the shrinkage as 100%. Table 3 shows the results.
なお、 下記表 3における対照薬物は次の構造を有する化合物である。 表 4及び表 5においても同じである。
対照 AThe control drug in Table 3 below is a compound having the following structure. The same applies to Tables 4 and 5. Control A
OH 対照 B OH control B
OH OH
COOCH, 対照 C ：
対照 D
表 3 COOCH, control C: Control D Table 3
注） - は未測定 Note)-is not measured
この結果より、 PGE2は £ ！受容体に作用するが、 本発明の化合物 は作用しないことがわかる。 From this result, PGE 2 is £! It turns out that it acts on the receptor, but the compound of the present invention does not.
、 ,
(b) EP 2受容体への作用検討 （癌化肥満細胞由来 P 815細胞に おける受容体結合試験） (b) the action considered to EP 2 receptor (receptor definitive canceration mast cell-derived P 815 cell binding test)
P 815細胞は、 Biochemical Pharmacology, 第 30巻， 第 1325 〜1332ページ （1981年） 記載の文献により、 EP 2受容体を有 することが知られている。 本試験はこの文献に従って行った。 P 815細胞を腹腔内に前投与したマウスの腹水から得られた P 81 5細胞 （107個ノ1111 ) を用い、 [3H] PGE2 (2 nM) をリガン ドとして、 受容体結合実験を行った。 実験結果は、 被験薬物 （10— 9M) のリガンドの結合を阻害する割合で示す。 この結果を表 4に示す。
表 4 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
被験薬物 抑制率 (%) Study drug suppression rate (%)
化合物 1 一 24.6 Compound 1 1 24.6
化合物 2 -8.3 Compound 2 -8.3
化合物 3 16.8 Compound 3 16.8
化合物 4 2.4 Compound 4 2.4
化合物 5 19.8 Compound 5 19.8
対照 A 50.6 Control A 50.6
対照 B 22.1 Control B 22.1
i o 対照 C i o Control C
対照 D Control D
注） - は未測定 Note)-is not measured
この結果より、 本発明の化合物は EP 2受容体を介する作用は極めて 弱いことがわかる。 From this result, the compounds of the present invention act via the EP 2 receptor is found to be extremely weak.
15 (c) EP3受容体への作用検討 （ [14C] アミノピリン蓄積抑制作 用 験ノ 15 (c) acts considered to EP 3 receptors ([14 C] Ken'no for aminopyrine accumulation inhibiting operation
試験方法は、 Acta Physiol. Scand. 第 96巻， 第 150〜 159ぺ ージ （1976年） に従って行った。 日本白色系雄性ゥサギを使用した。 麻酔下にゥサギの胃を摘出後、 酵素処理により胃粘膜壁細胞を単離した。 The 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.
0 壁細胞 （3X 105個） に [14C] アミノビリ ン （AP) 、 被験薬物 （1 0— 5M) 及びヒスタ ミ ン （10—5M) を添加し、 20分間ィンキュベー シヨ ン （37°C) を行い、 細胞内に取り込まれた [14C] A P量をシン チレーションカウンターを用い測定した。 0 parietal cells (3X 10 5 cells) in [14 C] Aminobiri emissions (AP), test drug (1 0- 5 M) and Hisuta Mi down the (10- 5 M) was added, 20 minutes Inkyube to down (37 ° C), and the amount of [ 14 C] AP incorporated into the cells was measured using a scintillation counter.
実験結果は、 ヒスタミン刺激による [14C] AP蓄積量に対する被験
薬物の抑制作用を抑制率で表す。..この結果を表 5に示す ( The experimental results were based on a test for histamine-stimulated [ 14 C] AP accumulation. The inhibitory action of a drug is expressed as an inhibitory rate. .. The results are shown in Table 5 (
表 5 Table 5
以上の結果、 本発明の化合物は Ε Ρ 3受容体に対し選択的に作用する ことがわかる。 従って、 本発明の化合物は効力が強く、 副作用の少ない 抗潰瘍剤として、 哺乳動物、 殊にヒ卜の消化性潰瘍の処置のために使用 することが期待される。 As a result, 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.
本発明の化合物を薬剤として使用する場合、 本発明の化合物は、 製薬 学的に許容しうる添加剤 （adjuvant) と共に投与に適した剤型に製剤化 して、 経口的にまたは非経口的 （例えば静脈内、 直腸内、 膣内） に投与 することができる。 経口投与のための製剤としては、 例えば錠剤、 顆粒 剤、 カプセル剤などの固形製剤、 溶液剤、 脂肪乳剤、 リボソーム懸濁剤 などの液体製剤を用いることができる。 本発明の化合物を経口投与製剤 において用いる場合には、 該化合物を 一、 ^一もしくはアーシクロデ キストリンまたはメチル化シクロデキストリン等と包接化合物を形成さ
せて製剤化することもできる。 静脈内投与のための製剤としては、 水性 または非水性溶液剤、 乳化剤、 懸濁剤、 使用直前に注射用溶媒に溶解し て使用する固形製剤等を用いることができる。 また、 直腸内投与のため の製剤としては坐剤、 膣内投与のための製剤としてはべッサリ等の剤型 を用いることができる。 When the compound of the present invention is used as a drug, 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. As 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. When 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. As preparations for intravenous administration, 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. In addition, formulations for rectal administration can be in the form of suppositories, and those for vaginal administration can be in the form of besari.
このような製剤を調製するために用いうる添加剤としては、 例えば、 結晶セルロース、 乳糖、 トウモロコシデンプン、 マンニトールなどの賦 形剤； ステアリン酸マグネシウム、 タルクなどの滑沢剤； ヒ ドロキシプ 口ピルセルロース、 ポリビニルピロリ ドンなどの結合剤： カルボキシメ チルセルロースカルシウムなどの崩壊剤；軽質 水ゲイ酸などの流動性 向上剤；注射用蒸留水、 生理食塩水、 リンゲル液などの溶解剤；パラオ キシ安息香酸メチル、 パラォキシ安息香酸プロピルなどの保存剤 ； ァラ ビアゴム、 レシチンなどの乳化剤 ； ツイーン、 スパンなどの界面活性剤 などを挙げることができる。 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.
本発明の化合物の投与量は、 患者の年齢、 性別、 体重、 症状の軽重、 医師の判断等に応じて広い範囲にわたって変えることができるが、 標準 的な成人 1人あたりの 1日投与量は 0 . 1〜1 0 0 gであり、 必要に 応じてこれを 1日 1〜3回に分けて投与することができる。 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.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下、 実施例を挙げて本発明をさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples.
なお、 化合物の命名中、 例えば 「1 7 , 1 8 , 1 9 , 2 0—テトラノル」 なる表現における 「ノル」 とは、 その位潭の炭素鎖がないことを意味す る （上記例の場合、 1 7〜2 0位の炭素鎖がないことを意味する） 。 '製造例 1
(3 R) - 3 - ( t—プチルジメチルシ口キシ） 一 4—フエノキシ一 1ーブチン [式 （XO の化合物] の製造 In the compound naming, for example, “nor” in the expression “17,18,19,20-tetranor” means that there is no carbon chain at that position (in the case of the above example) , Meaning that there is no carbon chain at the 17-20 position). '' Production example 1 Production of (3R) -3- (t-butyldimethyloxy) -1-4-phenoxy-1-butyne [compound of formula (XO)]
(1) ォキザリルクロリ ド （48.0m 1， 0.55mo l ) の塩化メ チレン 30 Om 1溶液にアルゴン気流下、 一 30°Cでジメチルスルホキ (1) To a solution of oxalyl chloride (48.0 ml, 0.55 mol) in 30 Om1 of methylene chloride at 130 ° C in an argon stream at 130 ° C
5 シ ド （39.0ml, 0.55mo 1 ) の塩化メチレン 6 Om 1溶液を加 え 5分間同条件下で撹拌した。 ついで、 2—フヱノキシエタノール （6 9.1 g, 0.5 Omo 1 ) の塩化メチレン溶液 350m lを同条件下で 加え 15分間同条件下で撹拌した後、 トリェチルァミ ン （ 245 m 1， 1.75mo 1 ) を同条件下で加え 0°Cまで 2時間かけて昇温した。 こ0 れに水 750m lを加え有機層を分離した後、 水層を塩化メチレンで抽 出し、 有機層を合わせて塩酸水溶液、 飽和重曹水および飽和食塩水で洗 浄した。 有機層を乾燥、 濃縮して粗生成物のフエノキシァセトアルデヒ ド 67.5 gを得た。 A solution of 5 side (39.0 ml, 0.55 mol) in methylene chloride 6 Om1 was added, and the mixture was stirred for 5 minutes under the same conditions. Then, 350 ml of a methylene chloride solution of 2-phenoxyethanol (69.1 g, 0.5 Omo 1) was added under the same conditions, and the mixture was stirred for 15 minutes under the same conditions. Then, triethylamine (245 m 1, 1.75 mo 1) was added. ) Was added under the same conditions and the temperature was raised to 0 ° C over 2 hours. After separating the organic layer was added to this 0 Renimizu 750 meters l, the aqueous layer out extracted with methylene chloride, aqueous hydrochloric acid and the combined organic layers were wash with a saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried and concentrated to obtain 67.5 g of a crude product, phenoxyacetaldehyde.
(2) 上記 （1) で得た化合物 67.5 g、 ピリジン （40.4ml,5 0.5 Omo 1 ) およびマロン酸 （52.0 g， 0.50mo l) の混合 物を 100°Cで 1時間、 140°Cで 1時間加熱撹拌した後室温に冷却し た。 反応液を塩酸で酸性にしエーテル抽出し、 エーテル層を水酸化ナト リウム水溶液で抽出し、 エーテル洗浄し、 水層を塩酸で酸性とした後ェ 一テル抽出し、 有機層を飽和食塩水で洗浄した。 有機層を乾燥、 濃縮し 。 て （2E) — 4一フヱノキシー 2—ブテン酸を 28.2 g得た。 (2) above (1) compound obtained in 67.5 g, pyridine (40.4 mL, 5 0.5 Omo 1) and 1 hour at 100 ° C a mixture of malonic acid (52.0 g, 0.50mo l), at 140 ° C After heating and stirring for 1 hour, the mixture was 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 and washed with ether.The aqueous layer was acidified with hydrochloric acid and extracted with ether, and the organic layer was washed with saturated saline. did. The organic layer was dried and concentrated. This gave 28.2 g of (2E) —4-phenoxy-2-butenoic acid.
^-NMR (DMSO - d6, 200 MHz) <5 p p m； 4.77 (d d. J = 2.0 H z, 4.2Hz， 2H) , 6.03 (d t, J = 2. OH z, 15.8Hz, 1H) , 6.90-7.04 (m, 3H) , 6.95 (d t, J =4.2Hz, 15.8Hz, 1 H) , 7.24-7.40 (m， 2
H) , 12.41 (s， 1 H) ^ -NMR (DMSO-d 6 , 200 MHz) <5 ppm; 4.77 (d d. J = 2.0 Hz, 4.2 Hz, 2H), 6.03 (dt, J = 2. OH z, 15.8 Hz, 1H), 6.90-7.04 (m, 3H), 6.95 (dt, J = 4.2Hz, 15.8Hz, 1H), 7.24-7.40 (m, 2 H), 12.41 (s, 1 H)
I R (KB r ) ： 3435, 2894, 2685, 2593, 170 1, 1660, 1598, 1588, 1500, 1445, 1425, 1387, 1316， 1286, 1250, 1208, 1180, 10 95, 1073, 1027. 941, 927, 757 cm-1 IR (KBr): 3435, 2894, 2685, 2593, 1701, 1660, 1598, 1588, 1500, 1445, 1425, 1387, 1316, 1286, 1250, 1208, 1180, 10 95, 1073, 1027. 941, 927, 757 cm- 1
(3) 上記 （2) で得た化合物 （28.2g) のメタノール 150m (3) Methanol of the compound (28.2g) obtained in (2) above, 150m
1溶液に濃硫酸を触媒量加え室温で 7時間撹拌した後、 濃縮し飽和重曹 水を加え酢酸ェチル抽出し、 有機層を水および飽和食塩水で洗浄した。 有機層を乾燥、 濃縮して （2E) — 4一フエノキシー2—ブテン酸 メ チルエステル 27.9 gを得た。 A concentrated amount of concentrated sulfuric acid was added to one solution, the mixture was stirred at room temperature for 7 hours, concentrated, added with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline. The organic layer was dried and concentrated to obtain 27.9 g of (2E) -4-1-phenoxy-2-butenoic acid methyl ester.
•H-NMR (CDC 1 a. 200MHz) 5 p p m； 3.76 (s, 3H) ， 4.70 (d d, J = 2.1Hz, 4.1Hz, 2H) , 6.21 (d t, J = 2.1 H z, 15.8Hz, 1H) , 6.85〜7.03 (m, 3H) , 7.09 (d t, J = 4.1Hz, 15.8Hz, 1 H) , 7.2 3-7.40 (m, 2H) • H-NMR (CDC 1 a. 200MHz) 5 ppm; 3.76 (s, 3H), 4.70 (dd, J = 2.1Hz, 4.1Hz, 2H), 6.21 (dt, J = 2.1Hz, 15.8Hz, 1H) ), 6.85 to 7.03 (m, 3H), 7.09 (dt, J = 4.1 Hz, 15.8 Hz, 1 H), 7.2 3-7.40 (m, 2H)
I R (n e a t) : 2952, 1728, 1666, 1600, 15 89， 1496, 1437, 1384, 1310, 1279, 1244, 1196, 1174, 1093, 1030, 968, 840, 756. 692 cm"1 IR (neat): 2952, 1728, 1666, 1600, 1589, 1496, 1437, 1384, 1310, 1279, 1244, 1196, 1174, 1093, 1030, 968, 840, 756. 692 cm " 1
(4) 上記 （3) で得た化合物 （61.8 g, 0.322mo l ) のェ 一テル 350m l溶液にジィソブチルアルミニウムハイ ドライ ド （1. 5M, トルエン溶液， 473ml, 0.708 m o 1 ) をアルゴン気流 下一 40°Cで滴下した後、 15分間撹拌した。 氷冷下、 塩酸で酸性とし 不溶物を濾去し、 濾液を塩酸、 水、 飽和重曹水および飽和食塩水で洗浄
した。 有機層を乾燥、 濃縮して得られた粗生成物を減圧蒸留して （2E) — 4—フヱノキシ一 2—ブテン一 1一オール 44.0 gを得た。 (4) 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.
b p 107〜109°CZ0.69〜0.85mmH g b p 107 ~ 109 ° CZ 0.69 ~ 0.85mmH g
•H-NMR (C D C 1 a. 200 MHz) 5 p p m ; 1.49 (s， 5 1 H) , 4.15-4.24 (m, 2H) , 4.48-4.61 (m， 2H) , 5.88~6.12 (m, 2H) , 6.86-7.01 (m, 3H) ， 7. 22~7.35 (m， 2H) • H-NMR (CDC 1 a. 200 MHz) 5 ppm; 1.49 (s, 51H), 4.15-4.24 (m, 2H), 4.48-4.61 (m, 2H), 5.88 to 6.12 (m, 2H) , 6.86-7.01 (m, 3H), 7.22-7.35 (m, 2H)
I R (n e a t) : 3351, 2866, 1599, 1587, 14 95. 1461, 1384. 1303, 1243, 1174, 1089, I R (neat): 3351, 2866, 1599, 1587, 14 95. 1461, 1384. 1303, 1243, 1174, 1089,
10 1030, 1009， 990, 755, 692 cm"1 10 1030, 1009, 990, 755, 692 cm " 1
(5) 粉末のモレキュラシ一ブス 4 A (25.7 g) およびチタンテ トライソプロボキシド （16.0m 1 , 53.6mmo 1 ) の塩化メチレ ン 39 Om 1の混合物にアルゴン気流下、 一 20°Cで L一 （ + ) —酒石 酸ジイソプロピルエステル （13.8mし 64.3 mm o l ) を滴下し、 (5) A mixture of powdered molecular bus 4A (25.7 g) and titanium tetraisopropoxide (16.0 m 1, 53.6 mmo 1) in methylene chloride 39 Om 1 under an argon stream at 120 ° C. was added to a mixture of +) —Drip of diisopropyl tartrate (13.8m and 64.3mmol)
15 同条件下で 30分間撹拌した。 次いで、 この混合物に上記 （4) で得た 化合物 （44. O g, 268mmo 1 ) の塩化メチレン 214 m 1溶液 を加え、 一 20°Cで 1時間撹拌した。 この混合物を一 30°Cに冷却し、 t一ブチルハイ ド口パーォキシド （2.8 M, 塩化メチレン溶液， 17 2ml, 482 mm o l) を 55分間かけて滴下し、 滴下終了後一 20 0 °Cで 18時間撹拌しジメチルスルフイ ド （43. lm 1 , 587mmo 1) を加えて、 さらに同温度で 3時間撹拌した。 次いで酒石酸水溶液 （1 0%) 29.2m 1を加え室温で 1時間、 フッ化ナトリウム 188 gを 加えて 1時間、 セライ ト 107 gおよびエーテル 300mlを加えて 1 時間それぞれ撹拌した。 濾過、 濃縮して得られた油状物 112 gをさら
にエーテル 342mlに溶解し水酸化ナトリゥム水溶液 （IN, 167 m l ) を加え室温で 1.5時間撹拌した後、 有機層を分離し、 水層をェ 一テル抽出した。 有機層を合わせて飽和食塩水で洗浄、 乾燥、 濃縮して 得られた残渣をシリカゲルカラムクロマトグラフィー （展開溶媒； へキ サン：酢酸ェチル = 7 : 3) で精製して （2 S, 3 S) -2, 3一ェポキ シー 4一フヱノキシ一 1—ブタノール 40.6 gを得た。 15 The mixture was stirred for 30 minutes under the same conditions. Then, to this mixture was added a solution of the compound (44. Og, 268 mmo 1) obtained in (4) above in 214 ml of methylene chloride, and the mixture was stirred at 120 ° C. for 1 hour. The mixture was cooled to 130 ° C, and t-butylhydroxide peroxide (2.8 M, methylene chloride solution, 172 ml, 482 mmol) was added dropwise over 55 minutes. After stirring for an hour, dimethyl sulfide (43.lm1, 587mmo1) was added, and the mixture was further stirred at the same temperature for 3 hours. Then, 29.2 ml of an aqueous tartaric acid solution (10%) was added, and the mixture was added at room temperature for 1 hour, 188 g of sodium fluoride was added for 1 hour, 107 g of celite and 300 ml of ether were added, and the mixture was stirred for 1 hour. Filtration and concentration of 112 g of the obtained oil Was dissolved in 342 ml of ether, and an aqueous solution of sodium hydroxide (IN, 167 ml) was added. After stirring at room temperature for 1.5 hours, the organic layer was separated and the aqueous layer was extracted with ether. The organic layers were combined, washed with brine, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 7: 3) to give (2S, 3S ) -2,3 1-epoxy 4- 4-hydroxy-1-butanol 40.6 g was obtained.
'H-NMR (CD C 13, 200 MHz) 5p pm ; 1.54〜1.8 4 (m, 1 H) . 3.20〜3.27 (m， 1 H) . 3.38-3.46 (m ， 1 H) , 3.65〜 3.81 (m, 1H) ， 3.73〜 4.10 (m, 1 H) , 4.04 (d d， J =5.3 H z, 11.2H z, 1 H) , 4.26 (d d, J = 3.1 H z, 11.2Hz, 1 H) , 6.86〜7.03 (m, 3H) , 7.23〜7.36 (m, 2H) 'H-NMR (CD C 13, 200 MHz) 5p pm; 1.54 to 1.84 (m, 1 H). 3.20 to 3.27 (m, 1 H). 3.38 to 3.46 (m, 1 H), 3.65 to 3.81 ( m, 1H), 3.73 to 4.10 (m, 1H), 4.04 (dd, J = 5.3Hz, 11.2Hz, 1H), 4.26 (dd, J = 3.1Hz, 11.2Hz, 1H), 6.86 to 7.03 (m, 3H), 7.23 to 7.36 (m, 2H)
I R (n e a t) ： 3401, 2926. 2872, 1733, 16 00， 1588, 1495. 1245, 1084, 1038, 757， 693 cm-1 IR (neat): 3401, 2926. 2872, 1733, 1600, 1588, 1495. 1245, 1084, 1038, 757, 693 cm- 1
(6) 上記 （5) で得た化合物 （40.6 g, 0.225mo l ) およ びメシルクロリ ド （19.2ml, 0.248mo 1 ) の塩化メチレン 2 80m l溶液にトリェチルァミン （37.6m l， 0.270mo l) を 氷冷下で滴下した。 滴下後、 室温で 30分間撹拌し水、 飽和重曹水およ び飽和食塩水で洗浄した。 有機層を乾燥、 濃縮して （2S， 3 S) -2, 3一エポキシ一 1一メシロキシー 4ーフヱノキシブタン 56.7 gを得 た。 (6) To a solution of the compound obtained in (5) (40.6 g, 0.225 mol) and mesyl chloride (19.2 ml, 0.248 mol) in methylene chloride (280 ml) was added triethylamine (37.6 ml, 0.270 mol). The mixture was added dropwise under ice cooling. After the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried and concentrated to obtain 56.7 g of (2S, 3S) -2,3-epoxy-11-mesyloxy-4-phenoxybutane.
^-NMR (CDC ", 200 MHz) <5 p p m； 3.09 (s, 3H) , 3.33〜3.44 (m， 2H), 4.00〜4.6 l(m， 4H) ,
6.86〜7.04 (m， 3H) , 7.23〜7.39 (m， 2H) ^ -NMR (CDC ", 200 MHz) <5 ppm; 3.09 (s, 3H), 3.33 to 3.44 (m, 2H), 4.00 to 4.6 l (m, 4H), 6.86 to 7.04 (m, 3H), 7.23 to 7.39 (m, 2H)
(7) 上記 （6) で得た化合物 （56.1 g, 0.217mo l ) およ び塩化リチウム （18.4 g, 0.434mo 1 ) の N，N—ジメチルホ ルムアミ ド 217m 1溶液をアルゴン気流下、 55 °Cで 2.5時間加熱 撹拌した。 冷却後、 水 100m 1および飽和食塩水 300m lを加え酢 酸ェチル：へキサン （1 : 1) で抽出し、 有機層を飽和食塩水で洗浄し た。 有機層を乾燥、 濃縮して （2S.3 S) — 1一クロロー 2, 3—ェポ キシー 4ーフヱノキシブタン 38.7 gを得た。 (7) A solution of the compound obtained in (6) (56.1 g, 0.217 mol) and lithium chloride (18.4 g, 0.434 mol) in N, N-dimethylformamide (217 ml) in an argon stream at 55 ° C. The mixture was heated and stirred with C for 2.5 hours. After cooling, 100 ml of water and 300 ml of saturated saline were added, and extracted with ethyl acetate: hexane (1: 1), and the organic layer was washed with saturated saline. The organic layer was dried and concentrated to give (2S.3S) -1-chloro-2,3-epoxy 4-phenyloxybutane 38.7 g.
JH-NMR (C D C 13, 200MHz) <5p pm ; 3.27〜3.3 7 (m, 2H) , 3.63 (d, J = 5.1Hz, 2H) , 4.05 (d d, J = 4.8Hz, 11.3Hz, 1 H) , 4.23 (d d, J = 2.9 Hz, 11.3Hz, 1H) , 6.86〜7.02 (m, 3H) , 7.23 〜7.34 (m， 2H) J H-NMR (CDC 13, 200MHz) <5p pm; 3.27 to 3.37 (m, 2H), 3.63 (d, J = 5.1Hz, 2H), 4.05 (dd, J = 4.8Hz, 11.3Hz, 1H ), 4.23 (dd, J = 2.9 Hz, 11.3 Hz, 1H), 6.86 to 7.02 (m, 3H), 7.23 to 7.34 (m, 2H)
I R (n e a t) ： 2924, 1588, 1489, 1451， 14 26, 1389， 1334， 1308, 1295, 1244, 1233, I R (neat): 2924, 1588, 1489, 1451, 14 26, 1389, 1334, 1308, 1295, 1244, 1233,
1180, 1156, 1140, 1084, 1032, 1013， 92 2, 868, 815, 761, 738 cm-1 1180, 1156, 1140, 1084, 1032, 1013, 92 2, 868, 815, 761, 738 cm- 1
(8) 上記 （7) で得た化合物 （32.4 g， 0.163mo l) のテ トラヒ ドロフラン 160m l溶液に n—ブチルリチウム （ 2.5 M, へ キサン溶液， 196m l， 0.489mo 1 ) をアルゴン気流下、 一 7 (8) In a 160 ml solution of the compound obtained in (7) (32.4 g, 0.163 mol) in tetrahydrofuran, n-butyllithium (2.5 M, hexane solution, 196 ml, 0.489 mol) was added under an argon stream. 1 1
0°Cで滴下した。 滴下後、 同条件下で 30分間撹拌し飽和塩化アンモニ ゥム水溶液 200mlを加え酢酸ェチルで抽出し、 有機層を飽和食塩水 で洗浄した。 有機層を乾燥、 濃縮して得られた粗 ί成物をシリカゲル力 ラムクロマトグラフィー （展開溶媒；へキサン：酢酸ェチル == 17 : 3)
で精製して （3R) —3—ヒ ドロキシ一 4ーフヱノキシ一 1ーブチン 2 3.1 gを得た。 It was added dropwise at 0 ° C. After the dropwise addition, the mixture was stirred for 30 minutes under the same conditions, 200 ml of a saturated aqueous solution of ammonium chloride was added, extracted with ethyl acetate, and the organic layer was washed with saturated saline. The crude product obtained by drying and concentrating the organic layer is subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate == 17: 3). Then, (3R) -3-hydroxy-4-hydroxy-1-butyne (23.1 g) was obtained.
!H— NMR (CDC 13, 200 MHz) 5 p p m； 2.53 (d, J = 2.3H z, 1H) ， 2.56 (d, J = 5.4H z, 1 H) , 4.0 3〜4.21 (m， 2H) , 4.70〜4.83 (m, 1 H) , 6.88- 7.04 (m, 3H) , 7.23-7.36 (m, 2H) ! H—NMR (CDC 13, 200 MHz) 5 ppm; 2.53 (d, J = 2.3 Hz, 1H), 2.56 (d, J = 5.4 Hz, 1 H), 4.0 3 to 4.21 (m, 2H) , 4.70〜4.83 (m, 1H), 6.88- 7.04 (m, 3H), 7.23-7.36 (m, 2H)
I R (n e a t) : 3412, 3282. 2940, 2865. 21 26, 1602. 1589, 1499, 1456, 1327, 1309， 1295, 1254, 1173, 1082, 1049,. 969, 895, 752, 693, 674 cm-1 IR (neat): 3412, 3282. 2940, 2865.21 26, 1602. 1589, 1499, 1456, 1327, 1309, 1295, 1254, 1173, 1082, 1049, .969, 895, 752, 693, 674 cm- 1
(9) 上記 （8) で得た化合物 （23.1 g, 0.142mo l) およ びィミダゾール （19.3 g, 0.284mo 1 ) の N, N—ジメチルホ ルムァミ ド 140m 1溶液に氷冷下、 t—ブチルジメチルクロロシラン (25.6 g, 0.17 Omo 1 ) を加えた。 室温で一夜撹拌した後、 飽 和重曹水 650mlにあけ室温で 15分間撹拌し、 へキサン ：酢酸ェチ ル =4 ： 1で抽出し、 有機層を飽和重曹水および飽和食塩水で洗浄した。 有機層を乾燥、 濃縮して得られた粗生成物をシリカゲルカラムクロマト グラフィー （展開溶媒；へキサン：エーテル = 49 : 1) で精製し、 さ らに減圧蒸留して標記化合物 35.9 gを得た。 (9) A solution of the compound (23.1 g, 0.142 mol) and imidazole (19.3 g, 0.284 mol) obtained in (8) above in 140 ml of N, N-dimethylformamide was added under ice cooling to t-butyl. Dimethylchlorosilane (25.6 g, 0.17 Omo 1) was added. After stirring overnight at room temperature, the mixture was poured into 650 ml of saturated sodium bicarbonate solution, stirred at room temperature for 15 minutes, extracted with hexane: ethyl acetate = 4: 1, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline. The crude product obtained by drying and concentrating the organic layer was purified by silica gel column chromatography (developing solvent; hexane: ether = 49: 1), and further distilled under reduced pressure to obtain 35.9 g of the title compound. .
bp 108〜： L 10°CZ0.97mmH g bp 108 ~: L 10 ° CZ0.97mmH g
^-NMR (CDC 1 a. 200 MHz) <5 p p m ; 0.13 (s, 3H) , 0.17 (s, 3H) , 0.92 (s, 9H) , 2.45 (d, J = 2.2H z, 1 H) , 3.99〜 4.13 (m, 2H) , 4.68~4. 79 (m, 1H) , 6.86〜 7.00 (m, 3H) , 7.21〜 7.34
(m, 2 H) ^ -NMR (CDC 1 a. 200 MHz) <5 ppm; 0.13 (s, 3H), 0.17 (s, 3H), 0.92 (s, 9H), 2.45 (d, J = 2.2 Hz, 1 H), 3.99 to 4.13 (m, 2H), 4.68 to 4.79 (m, 1H), 6.86 to 7.00 (m, 3H), 7.21 to 7.34 (m, 2 H)
I R (n e a t) : 3308， 2955, 2930, 2885， 28 58, 2120, 1601, 1589, 1497, 1473, 1389, I R (neat): 3308, 2955, 2930, 2885, 2858, 2120, 1601, 1589, 1497, 1473, 1389,
1362， 1302, 1250, 1173， 1120， 1051， 96 5 5, 838, 781, 754, 691 cm-1 1362, 1302, 1250, 1173, 1120, 1051, 9655, 838, 781, 754, 691 cm- 1
実施例 1 Example 1
(2 E) 一 16—フヱノキシ一 2, 3, 13, 14—テトラデヒ ドロ一 17.18, 19, 20—テトラノル一 PGE, メチルエステル （化合物 (2 E) 1-16-Phenoxy-1,2,3,13,14-tetradehydro-17.18,19,20-Tetranor-1 PGE, methyl ester (compound
1) の製造 1) manufacture
10 (1) 製造例 1で得た化合物 （1.55 g, 5.60mmo l) をトル . ェン 17.2m 1に溶解し、 アルゴン気流下、 0°Cで n—プチルリチウ ム （2.5M. へキサン溶液， 2.1m l, 5.16 mmo 1 ) を加え、 同温度で 20分間撹拌した。 この溶液に 0°Cでジェチルアルミニウムク ロリ ド （ 0.94 M, へキサン溶液， 6.4ml, 6.02mmo l) を i s 加え、 室温まで昇温後 20分間撹拌した。 この溶液に室温で （4R) — 10 (1) The compound obtained in Production Example 1 (1.55 g, 5.60 mmol) was dissolved in 17.2 ml of toluene, and n-butyllithium (2.5 M. , 2.1 ml, 5.16 mmo 1) and stirred at the same temperature for 20 minutes. Getyl aluminum chloride (0.94 M, hexane solution, 6.4 ml, 6.02 mmol) was added to the solution at 0 ° C for i s, and the mixture was heated to room temperature and stirred for 20 minutes. Add this solution at room temperature (4R) —
2 - (N, N—ジェチルァミノ） メチルー 4— (tーブチルジメチルシ 口キシ） シクロペントー 2—ェン一 1—オン （0.25M, トルェン溶 液， 17.2m l, 4.30 mmo 1 ) を加え、 20分間撹拌した。 反応 液をへキサン （42m l) —飽和塩化アンモニゥム水溶液 （42ml) 2-(N, N-Jethylamino) methyl-4- (tert-butyldimethyloxy) cyclopent-2-ene-1-one (0.25M, toluene solution, 17.2ml, 4.30mmo1) and add for 20 minutes Stirred. Hexane (42ml) —Saturated aqueous ammonium chloride solution (42ml)
0 一塩酸水溶液 （3N, 12m 1 ) の混合液に撹拌しながら注いだ後、 有 機層を分離し、 水層をへキサン抽出し、 有機層を合わせて飽和重曹水お よび飽和食塩水で洗浄した。 有機層を乾燥、 濃縮して得られた残渣をシ リカゲルカラムクロマトグラフィー （展開溶媒；へキサン：酢酸ェチル = 50 : 1) で精製して （3R, 4R) — 2—メチレン一 3— [ (3'R)
一 3'— （ t—ブチルジメチルシロキシ） 一4' —フエノキシブター 1' ーィニル] 一 4— ( t—ブチルジメチルシロキシ） シクロペンタン一 1 一オン 1.07 gを得た。 0 After pouring into a mixed solution of aqueous monohydrochloric acid (3N, 12m1) with stirring, the organic layer was separated, the aqueous layer was extracted with hexane, and the organic layer was combined with saturated aqueous sodium hydrogen carbonate and saturated saline. Washed. The residue obtained by drying and concentrating the organic layer is purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 50: 1) to give (3R, 4R) —2-methylene-1-(— 3'R) 1.03 g of 1 3 '-(t-butyldimethylsiloxy) 1 4'-phenoxy butter 1'-ynyl] 14- (t-butyldimethylsiloxy) cyclopentane 111-one was obtained.
Ή-NMR (CDC 13, 200MHz) 5 p pm； 0.11 (s, 5 3H) ， 0.12 (s, 3H) , 0.15 (s， 6H) , 0.90 (s, 9H) , 0.91 (s, 9 H) , 2.33 (d d, J = 7.7 H z, 18. 0Hz, 1H) ， 2.72 (d d, J = 6.5 H z, 18.0Hz, 1 H) . 3.50〜 3.60 (m, 1 H) , 3.97〜 4.09 (m, 2H) , 4. 23〜 4.35 (m, 1H) , 4.73〜 4.83 (m, 1 H) , 5.56 ,。 （d d, J = 0.6Hz, 2.7 H z, 1 H) , 6.15 (d, J = 3.1 Hz, 1 H) , 6.85〜 7.00 (m, 3H) , 7.21-7.34 (m, 2H) Ή-NMR (CDC 13, 200MHz) 5 p pm; 0.11 (s, 53H), 0.12 (s, 3H), 0.15 (s, 6H), 0.90 (s, 9H), 0.91 (s, 9H), 2.33 (dd, J = 7.7 Hz, 18.0 Hz, 1H), 2.72 (dd, J = 6.5 Hz, 18.0 Hz, 1 H) .3.50 to 3.60 (m, 1 H), 3.97 to 4.09 (m, 2H), 4.23 to 4.35 (m, 1H), 4.73 to 4.83 (m, 1H), 5.56 ,. (Dd, J = 0.6 Hz, 2.7 Hz, 1 H), 6.15 (d, J = 3.1 Hz, 1 H), 6.85 to 7.00 (m, 3H), 7.21-7.34 (m, 2H)
I R (n e a t) : 2955, 2930, 2886, 2858, 22 41， 1737, 1643, 1601, 1589. 1497, 1472, 5 1389, 1362, 1288, 1251, 1114, 1050, 10 07. 975, 838, 780, 754 cm"1 IR (neat): 2955, 2930, 2886, 2858, 22 41, 1737, 1643, 1601, 1589. 1497, 1472, 5 1389, 1362, 1288, 1251, 1114, 1050, 10 07. 975, 838, 780, 754 cm " 1
(2) アルゴン気流下、 一 60°Cにおいて （E) — 5—カルボメ トキ シー 4一ペンテニル亜鉛 （Π) ョージド （0.69M, テトラヒ ドロフ ラン溶液， 4.6ml， 3.17mmo 1 ) にシアン化銅 （ I ) · 2塩化0 リチウム （1.0 M, テトラヒ ドロフラン溶液. 3.98m 1， 3.98 mmo 1 ) を加え同温度で 15分間撹拌した。 この溶液に一 60°Cで上 記 （1) で得た化合物 （796mg, 1.59mmo l) のジェチルェ 一テル 5.6 m 1の溶液とクロ口 トリメチルシラン （0.36m 1 , 2. 86 mmo 1 ) を加え、 撹拌しながら約 1.5時間かけて 0 °Cまで昇温
した。 反応液に飽和塩化アンモニゥム水溶液 36m 1を加え、 へキサン 抽出した。 有機層を飽和重曹水および飽和食塩水で洗浄後、 乾燥、 濃縮 して得られた残渣を 2—プロパノール （6.4m l ) —ジェチルエーテ ル （1.6m l ) に溶解し、 p—トルエンスルホン酸ピリジン塩 （20 mg, 0.08 Ommo 1 ) を加え室温で一夜撹拌した。 反応液にへキ サン 1 Om 1を加え、 飽和重曹水および飽和食塩水で洗浄後、 乾燥、 濃 縮して得られた残渣をシリカゲルカラムクロマ卜グラフィ一（展開溶媒； へキサン ：酢酸ェチル = 19 ： 1) で精製して （2 E) — 16—フエノ キシ一 2.3, 13, 14—テトラデヒ ドロー 17, 18， 19, 20—テト ラノル一PGE! メチルエステル 11 , 15—ビス （ tーブチルジメ チルシリルエーテル） 522mgを得た。 (2) At 60 ° C under a stream of argon, (E) -5-carboxy-4-pentenylzinc (Π) roside (0.69M, tetrahydrofuran solution, 4.6ml, 3.17mmo1) was added to copper cyanide ( I) · 2 chloride 0 lithium (1.0 M, as tetrahydrofuran solution. 3.98m 1, was stirred for 15 minutes at the same temperature was added a 3.98 mmo 1). To this solution was added a solution of the compound (796 mg, 1.59 mmol) obtained in the above (1) (5.6 ml) and trimethylsilane (0.36 ml, 2.86 mmol) at a temperature of 60 ° C. In addition, raise the temperature to 0 ° C over about 1.5 hours with stirring did. 36 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by hexane extraction. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried and concentrated, and the resulting residue was dissolved in 2-propanol (6.4 ml) -getyl ether (1.6 ml), and p-toluenesulfonic acid pyridine salt ( 20 mg, 0.08 Ommo 1) was added and the mixture was stirred at room temperature overnight. Hexane 1 Om 1 was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried and concentrated, and the residue obtained was subjected to silica gel column chromatography (developing solvent; hexane: ethyl acetate = 19: 1 Purification by 1) (2E)-16-phenoxy-I 2.3,13,14-tetradehydro 17,18,19,20-tetralanol-PGE! Methyl ester 11,15-bis (t-butyldimethyl) 522 mg of silyl ether) were obtained.
!H-NMR (CDC 13( 200MH z) 5 p pm ; 0. 10 (s, 3H) , 0. 1 1 (s, 3H) , 0. 13 (s, 3H) , 0.14 (s, 3H) , 0.89 (s, 9H) , 0.91 (s, 9H) , 1. 18-1.8 6 (m, 6 H) , 2.08〜 2.30 (m, 3H) , 2.17 (d d, J = 1.3 H z, 18.4H z, 1H) ， 2.58〜2.76 (m， 1 H) , 2.67 (d d, J = 6.9 H z, 18.4Hz, 1 H) , 3.72 (s, 3H) , 3.94〜 4.10 (m， 2H) , 4.30 (d d, J = 6.8 H z, 13.6H z, 1 H) , 4.68〜4.79 (m， 1 H) , 5.81 (d t, J = 1.5 H z, 15.7H z, 1 H) , 6.83〜7.04 (m, 4 H) ' 7.22-7.36 (m, 2H) ! H-NMR (CDC 13 ( 200MHz) 5 p pm; 0.10 (s, 3H), 0.11 (s, 3H), 0.13 (s, 3H), 0.14 (s, 3H) , 0.89 (s, 9H), 0.91 (s, 9H), 1.18-1.8 6 (m, 6H), 2.08-2.30 (m, 3H), 2.17 (dd, J = 1.3 Hz, 18.4 Hz) , 1H), 2.58 to 2.76 (m, 1H), 2.67 (dd, J = 6.9 Hz, 18.4 Hz, 1 H), 3.72 (s, 3H), 3.94 to 4.10 (m, 2H), 4.30 (dd , J = 6.8 Hz, 13.6 Hz, 1 H), 4.68 to 4.79 (m, 1 H), 5.81 (dt, J = 1.5 Hz, 15.7 Hz, 1 H), 6.83 to 7.04 (m, 4 H) '7.22-7.36 (m, 2H)
I R (n e a t) : 2952, 2931， 2887, 2858, 22 38, 1748, 1727, 1658, 1601, 1589， 1497， 1463, 1362, 1251, 1173, 1116, 1048, 10
07, 977. 940. 838, 780, 755, 692, 670cm-1 IR (neat): 2952, 2931, 2887, 2858, 22 38, 1748, 1727, 1658, 1601, 1589, 1497, 1463, 1362, 1251, 1173, 1116, 1048, 10 07, 977.940.838,780,755,692,670cm- 1
(3) 上記 （2) で得られた化合物 （52 Omg, 0.827mmol) のァセトニ卜リル 27.6m l溶液にフッ化水素酸水溶液 （46%) 6. 2m lを氷冷下で加え、 同温度で 2時間撹拌した。 反応液を飽和重曹水 20 Om 1にあけ酢酸ェチル抽出し、 有機層を飽和重曹水および飽和食 塩水で洗浄し、 乾燥、 濃縮して得られた残渣をシリカゲルカラムクロマ トグラフィー （展開溶媒；へキサン：酢酸ェチル = 1 : 1) で精製して 標記化合物 27 Omgを得た。 (3) To a solution of the compound obtained in the above (2) (52 Omg, 0.827 mmol) in acetonitrile (27.6 ml) was added 6.2 ml of an aqueous solution of hydrofluoric acid (46%) under ice-cooling. Stir for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (20 Om1) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried and concentrated, and the resulting residue was subjected to silica gel column chromatography (developing solvent; eluent). Purification by xane: ethyl acetate = 1: 1) gave 27 Omg of the title compound.
'H-NMR (CD C 1 a, 300MHz) 5 p pm； 1.38-1.8 6 (m, 6H) , 2.13〜2.31 (m, 3H) , 2.23 (d d， J =9. lHz. 18.5Hz, 1 H) , 2.65 (d d d, J = 1.8 H z, 8.3Hz, 11.4Hz, 1 H) , 2.76 (d d d, J = 1.3 H z, 7.6Hz, 18.5Hz, 1 H) , 2.85(d, J = 3.5Hz, 1 H), 3.06 (d, J = 5.2Hz, 1 H) , 3.71 (s, 3H) , 4.08 (d d, J =6.9Hz, 9.6Hz, 1 H) , 4.14 (d d, J =4. OHz, 9.6Hz, 1 H) , 4.28〜 4.40 (m, 1H) , 4.75 〜4.84 (m， 1 H) , 5.82 (d t, J = l.4Hz, 15.7Hz, 1H) , .6.88〜7.04 (m, 4H) , 7.24〜 ， 35 (m, 2H) I R (n e a t) : 3412, 2933. 2861, 2241. 17 44, 1723, 1656， 1600, 1588, 1496， 1456， 'H-NMR (CD C 1 a, 300 MHz) 5 ppm; 1.38-1.86 (m, 6H), 2.13 to 2.31 (m, 3H), 2.23 (dd, J = 9. lHz. 18.5 Hz, 1 H ), 2.65 (ddd, J = 1.8 Hz, 8.3 Hz, 11.4 Hz, 1 H), 2.76 (ddd, J = 1.3 Hz, 7.6 Hz, 18.5 Hz, 1 H), 2.85 (d, J = 3.5 Hz , 1 H), 3.06 (d, J = 5.2 Hz, 1 H), 3.71 (s, 3H), 4.08 (dd, J = 6.9 Hz, 9.6 Hz, 1 H), 4.14 (dd, J = 4.OHz , 9.6Hz, 1H), 4.28 to 4.40 (m, 1H), 4.75 to 4.84 (m, 1H), 5.82 (dt, J = l.4Hz, 15.7Hz, 1H), .6.88 to 7.04 (m, 1H) 4H), 7.24 ~, 35 (m, 2H) IR (neat): 3412, 2933. 2861, 2241. 17 44, 1723, 1656, 1600, 1588, 1496, 1456,
1438, 1385， 1291, 1246, 1174, 1080， 10 44, 988, 910, 756， 693 cm-1 1438, 1385, 1291, 1246, 1174, 1080, 1044, 988, 910, 756, 693 cm- 1
実施例 2 Example 2
(2 E) — 16—フエノキシ一 2, 3, 13, 14—テトラデヒ ドロー
17, 18, 19, 20—テトラノル一 PGE! の製造 (2 E) — 16-phenoxy-1,2,3,13,14-tetradehydro draw 17, 18, 19, 20—Manufacture of tetranor-one PGE!
実施例 1で得た化合物 （205mg, 0.512mmo 1 ) のァセ卜 ン 5.13m 1および水 5.13m 1の溶液をリン酸緩衝液 （1 OmM, p H= 7) 92.3m lに溶解し、 リパーゼ νπ (2.05 g) を加え、 3 0°Cで一夜撹拌した。 室温で食塩を加え塩折し酢酸ェチル抽出し、 乾燥、 濃縮して得られた残渣をシリカゲルカラムクロマトグラフィ一 （展開溶 媒；酢酸ェチル） で精製して標記化合物 153m gを得た。 A solution of the compound (205 mg, 0.512 mmol) obtained in Example 1 in 5.13 ml of acetone and 5.13 ml of water was dissolved in 92.3 ml of a phosphate buffer (1 OmM, pH = 7), and lipase was dissolved. νπ (2.05 g) was added, and the mixture was stirred at 30 ° C overnight. Salt was added at room temperature, and the mixture was salted, extracted with ethyl acetate, dried and concentrated, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to obtain 153 mg of the title compound.
'H-NMR (CDC 13, 300 MHz) 5 p pm； 1.32-1.8 'H-NMR (CDC 13, 300 MHz) 5 ppm; 1.32-1.8
5 (m, 6H) , 2.17〜 2.32 (m, 3H) , 2.23 (d d, J =9.2Hz, 18.6Hz, 1 H) , 2.64 (dd d, J =1.8Hz,5 (m, 6H), 2.17 to 2.32 (m, 3H), 2.23 (dd, J = 9.2 Hz, 18.6 Hz, 1 H), 2.64 (dd d, J = 1.8 Hz,
8.3 H z, 11.4Hz, 1 H) , 2.75 ( d d d . J = 1.3 H z ,8.3 Hz, 11.4 Hz, 1 H), 2.75 (d d d .J = 1.3 Hz,
7.3Hz, 18.6Hz, 1 H) , 2.80〜 4.40 ( b r , 3H) ,7.3Hz, 18.6Hz, 1H), 2.80 to 4.40 (br, 3H),
4.08 (d d, J =6.8Hz, 9.6Hz, 1 H) , 4.14 (d d.4.08 (d d, J = 6.8Hz, 9.6Hz, 1H), 4.14 (d d.
J = 3.9Hz, 9.6Hz, 1 H) ， 4.29-4.39 (m. 1 H) ， 4.80 (dd d, J = 1.8 H z, 3.9 H z, 6.8 H z, 1 H) , 5.J = 3.9Hz, 9.6Hz, 1H), 4.29-4.39 (m.1H), 4.80 (dd d, J = 1.8Hz, 3.9Hz, 6.8Hz, 1H), 5.
82 (d t, J = 1.4H z, 15.6Hz, 1H) . 6.90-7.1082 (d t, J = 1.4Hz, 15.6Hz, 1H) .6.90-7.10
(m, 4H) , 7.25-7.34 (m, 2H) (m, 4H), 7.25-7.34 (m, 2H)
I R (n e a t) : 3392, 2931, 2861, 2242, 17 I R (n e a t): 3392, 2931, 2861, 2242, 17
40， 1696, 1652, 1600, 1588. 1496, 1456, 1417, 1291, 1245, 1173, 1080, 1045， 9840, 1696, 1652, 1600, 1588. 1496, 1456, 1417, 1291, 1245, 1173, 1080, 1045, 98
4, 885, 756, 693 cm"1 4, 885, 756, 693 cm " 1
実施例 3 Example 3
_(2 E) 一 16-フヱノキシー 2, 3, 13, 14—テトラデヒ ドロ一 17.18, 19, 20—テトラノル一 PGE! n—ブチルエステルの製
(1) 実施例 1 (1) 及び （2) と同様にして （2E) —16—フエ ノキシ一 2, 3, 13, 14—テトラデヒ ドロ一 17, 18, 19, 20—テ トラノル一 PGE, n—ブチルエステル 11 , 15—ビス （ t—ブチ ルジメチルシリルエーテル） を得た。 _ (2 E) 16-Phenoxy 2,3,13,14-tetradehydro 17.18,19,20-tetranor PGE! N-Butyl ester (1) In the same manner as in Example 1 (1) and (2), (2E) —16-phenoxy-1,2,3,13,14—tetradehydro-17,18,19,20—tetranol—PGE, n-Butyl ester 11,15-bis (t-butyldimethylsilyl ether) was obtained.
•H-NMR (C D C 13, 200MHz) 5 p p m； 0.10 ( s , 3 H) , 0.11 (s, 3H) , 0.13 (s, 3H) ， 0.14 (s， 3H) , 0.88〜0.98 (m, 3H) , 0.89 (s, 9H) , 0.9 1 (s, 9H) , 1.24-1.83 (m, 1 OH) , 2.08-2.32 (m， 3H) , 2.17 (d d, J = 7.2 H z , 18.3H z, 1 H) , 2.58〜 2.75 (m, 1 H) , 2.67 (d d d, J = 1.1 H z, 6. 5Hz, 18.3Hz, 1 H) , 3.94~4.07 (m, 2H) , 4.1 2 ( t, J = 6.6Hz, 2H) , 4.24〜4.36 (m, 1 H) ' 4. 68〜4.80 (m, 1H) , 5.81 (d t, J = 1.5H z, 15.7 Hz, 1 H) , 6.84〜 7.02 (m, 4H) , 7.22-7.33 (m, 2H) • H-NMR (CDC 13, 200MHz) 5 ppm; 0.10 (s, 3H), 0.11 (s, 3H), 0.13 (s, 3H), 0.14 (s, 3H), 0.88 to 0.98 (m, 3H) , 0.89 (s, 9H), 0.9 1 (s, 9H), 1.24-1.83 (m, 1 OH), 2.08-2.32 (m, 3H), 2.17 (dd, J = 7.2 Hz, 18.3 Hz, 1 H), 2.58 to 2.75 (m, 1 H), 2.67 (ddd, J = 1.1 Hz, 6.5 Hz, 18.3 Hz, 1 H), 3.94 to 4.07 (m, 2H), 4.1 2 (t, J = 6.6Hz, 2H), 4.24 to 4.36 (m, 1H) '4.68 to 4.80 (m, 1H), 5.81 (dt, J = 1.5Hz, 15.7 Hz, 1H), 6.84 to 7.02 (m, 1H) 4H), 7.22-7.33 (m, 2H)
I R (n e a t ) ： 2956, 2931, 2858, 2240, 17 48， 1723, 1656, 1601, 1589, 1497, 1464, 1385. 1362, 1251, 1174， 1117, 1049, 10 07, 978, 838, 780, 755 cm-1 IR (neat): 2956, 2931, 2858, 2240, 1748, 1723, 1656, 1601, 1589, 1497, 1464, 1385. 1362, 1251, 1174, 1117, 1049, 1007, 978, 838, 780, 755 cm- 1
(2) 実施例 1 (3) と同様にして標記化合物を得た。 (2) The title compound was obtained in the same manner as in Example 1 (3).
— NMR (CD C 13, 300 MHz) <5 p p m； 0.94 ( t , J = 7.4H z, 3H) , 1.31-1.86 (m, 10H) , 2.05- 3.10 (b r , 2H) . 2.23 (d d, J = 9.2Hz, 18.5Hz,
1H) ， 2.58~2.82 (m, 3 H) , 2.64 (d d d, J = 1.7 Hz, 8.2Hz, 11.4Hz, 1H) , 2.75 (d d, J = 7.3H z, 18.5Hz, 1H) ， 4.08 ( d d, J = 7.0Hz, 9.7H z, 1 H) , 4.12 ( t, J =6.7Hz, 2H) , 4.13 (d d, J = 4.1Hz, 9.7Hz, 1 H) , 4.28〜4.39 (m, 1 H) , 4. 76〜4.83 (m, 1 H) , 5.81 (d t , J = 1.4 H z, 15.7 Hz, 1 H) , 6.90-7.03 (m, 3H) , 6.94 (d t , J = 6.9 H z , 15.7Hz, 1 H) . 7.25〜7.35 (m, 2H) — NMR (CD C 13, 300 MHz) <5 ppm; 0.94 (t, J = 7.4 Hz, 3H), 1.31-1.86 (m, 10H), 2.05- 3.10 (br, 2H). 2.23 (dd, J = 9.2Hz, 18.5Hz, 1H), 2.58 to 2.82 (m, 3 H), 2.64 (ddd, J = 1.7 Hz, 8.2 Hz, 11.4 Hz, 1H), 2.75 (dd, J = 7.3 Hz, 18.5 Hz, 1H), 4.08 (dd , J = 7.0Hz, 9.7Hz, 1H), 4.12 (t, J = 6.7Hz, 2H), 4.13 (dd, J = 4.1Hz, 9.7Hz, 1H), 4.28-4.39 (m, 1H ), 4.76 to 4.83 (m, 1 H), 5.81 (dt, J = 1.4 Hz, 15.7 Hz, 1 H), 6.90-7.03 (m, 3H), 6.94 (dt, J = 6.9 Hz, 15.7Hz, 1H) 7.25 to 7.35 (m, 2H)
I R (n e a t) ： 3419. 2934, 2872, 2242, 17 46， 1717, 1653， 1600, 1588, 1496， 1456, 1386, 1246, 1175, 1080， 1045, 985, 885, 756, 693 cm"1 IR (neat): 3419. 2934, 2872, 2242, 17 46, 1717, 1653, 1600, 1588, 1496, 1456, 1386, 1246, 1175, 1080, 1045, 985, 885, 756, 693 cm " 1
実施例, 4 Example, 4
(2E) — 16—フエノキシ一 2， 3, 13, 14—テトラデヒ ドロー (2E) — 16-phenoxy-1,2,3,13,14-tetradehydro draw
17, 18 , 1 9， 20—テトラノル一 PGE! t—ブチルエステル （化 合物 2) の製造 Production of 17, 18, 19, 20-tetranor-PGE! T-butyl ester (Compound 2)
(1) 実施例 1 (1) 及び （2) と同様にして （2E) —16—フエ ノキシ一 2, 3, 13, 14—テトラデヒ ドロ一 17, 18, 19, 20—テ トラノル一 PGE, t—ブチルエステル 11, 15—ビス （ tーブチ ルジメチルシリルエーテル） を得た。 (1) In the same manner as in Example 1 (1) and (2), (2E) —16-phenoxy-1,2,3,13,14—tetradehydro-17,18,19,20—tetranol—PGE, Thus, t-butyl ester 11,15-bis (t-butyldimethylsilyl ether) was obtained.
!H-NMR (CDC 13, 200 MHz) 5 p pm； 0.10 (s, 3H) , 0.11 (s, 3H) , 0.13 (s, 3 H) , 0.14 (s, 3H) , 0.89 (s, 9H) ， 0.91 (s, 9H) ， 1.23-1.8 4 (m， 6H) , 1.48 (s, 9H)， 2.05-2.33 (m， 3H),
2. 17 (d d, J = 7.3 H z. 18.3 H z , 1 H) , 2.58-2. 75 (m, 1 H) , 2.67 (d d d, J = 1.3 H z, 6.9 H z , 1 8.3H z, 1 H) , 3.94〜 4.07 (m, 2H) , 4.24-4.3 7 (m, I H) , 4. 70〜4.79 (m， I H) , 5. 73 (d t, J 5 = 1.5H z, 15.6H z, 1 H) , 6.84 (d t, J = 6.9H z, 15.6H z, 1 H) , 6.85〜7.00 (m. 3H) , 7.23-7. ! H-NMR (CDC 13, 200 MHz) 5 p pm; 0.10 (s, 3H), 0.11 (s, 3H), 0.13 (s, 3H), 0.14 (s, 3H), 0.89 (s, 9H) , 0.91 (s, 9H), 1.23-1.84 (m, 6H), 1.48 (s, 9H), 2.05-2.33 (m, 3H), 2.17 (dd, J = 7.3 Hz, 18.3 Hz, 1 H), 2.58-2.75 (m, 1 H), 2.67 (ddd, J = 1.3 Hz, 6.9 Hz, 18.3 Hz) , 1 H), 3.94 to 4.07 (m, 2H), 4.24-4.3 7 (m, IH), 4.70 to 4.79 (m, IH), 5.73 (dt, J 5 = 1.5 Hz, 15.6 H z, 1H), 6.84 (dt, J = 6.9Hz, 15.6Hz, 1H), 6.85-7.00 (m.3H), 7.23-7.
35 (m, 2H) 35 (m, 2H)
I R (n e a t ) ： 2931, 2858, 2241, 1748, 17 14， 1654, 1601. 1589， 1497, 1472, 1463, 10 1391, 1368, 1289, 1251， 1 157, 1 1 18， 10IR (neat): 2931, 2858, 2241, 1748, 17 14, 1654, 1601. 1589, 1497, 1472, 1463, 10 1391, 1368, 1289, 1251, 1 157, 1 118, 10
49, 1007. 979, 838， 780, 755 cm- 1 49, 1007. 979, 838, 780, 755 cm- 1
(2) 実施例 1 (3) と同様にして標記化合物を得た。 (2) The title compound was obtained in the same manner as in Example 1 (3).
—雇 R (CDC 13, 30 OMH z) 5 p pm ; 1.40-1.8 6 (m, 6H) , 1. 、48 (s, 9Η) , 2.11-2.31 (m， 3Η), —Hire R (CDC 13, 30 OMH z) 5 p pm; 1.40-1.8 6 (m, 6H), 1., 48 (s, 9Η), 2.11-2.31 (m, 3Η),
15 2.23 (d d, J = 9.2 H z, 18.6 H z, 1 H) , 2.65 (d d d, J = 1.8 H z, 8.2H z, 11.3 H z, 1 H) , 2. 76 (d d d， J = l.3 H z, 7.3H z, 18.6H z, 1 H) , 4.09 (d d, J = 6.8 H z, 9.6H z, IH) , 4.14 (d d, J = 4. 1 H z, 9.6 H z, 1 H) , 4.28〜 4.39 (m, IH) , 4.76〜 4.8 0 3 (m, 1 H) , 5.74 (d t, J = l.5Hz, 15.6H z, 1 H), 6.84 (d t， J = 7.0 H z , 15.6H z, IH) , 6.90〜7. 03 (m, 3H) , 7.24〜7.35 (m, 2H) 15 2.23 (dd, J = 9.2 Hz, 18.6 Hz, 1 H), 2.65 (ddd, J = 1.8 Hz, 8.2 Hz, 11.3 Hz, 1 H), 2.76 (ddd, J = l .3 Hz, 7.3 Hz, 18.6 Hz, 1 H), 4.09 (dd, J = 6.8 Hz, 9.6 Hz, IH), 4.14 (dd, J = 4.1 Hz, 9.6 Hz, 1H), 4.28 to 4.39 (m, IH), 4.76 to 4.803 (m, 1H), 5.74 (dt, J = l.5Hz, 15.6Hz, 1H), 6.84 (dt, J = 7.0 H z, 15.6H z, IH), 6.90 ~ 7.03 (m, 3H), 7.24 ~ 7.35 (m, 2H)
I R (n e a t) : 3413， 2978, 2933, 2862, 22 42. 1746， 1713. 1651, 1600， 1589, 1497,
1456, 1393， 1369. 1318, 1246, 1 158. 10 81, 1046, 986, 851, 756, 693 cm"1 IR (neat): 3413, 2978, 2933, 2862, 22 42. 1746, 1713. 1651, 1600, 1589, 1497, 1456, 1393, 1369. 1318, 1246, 1 158. 10 81, 1046, 986, 851, 756, 693 cm " 1
実施例 5 Example 5
(2 E) — 16—フエノキシ一 2, 3, 13， 14—テトラデヒ ドロー 17, 1 8, 19, 20—テトラノル一 PGEi シクロへキシルエステル (化合物 3) の製造 (2 E) — Production of 16-phenoxy-1,2,3,13,14-tetradehydro 17,1 8,19,20-tetranor-1-PGEi cyclohexyl ester (Compound 3)
(1) 実施例 1 (1) 及び （2) と同様にして （2 E) — 16—フエ ノキシ一 2, 3, 13, 14—テトラデヒ ドロー 17, 18, 19, 20—テ トラノル一 PGE! シクロへキシルエステル 11. 15—ビス （ t— プチルジメチルシリルエーテル） を得た。 (1) Example 1 (2E) —16-phenoxy-1,2,3,13,14—tetradehydro 17,18,19,20—te tolanol PGE! Cyclohexyl ester 11.15-bis (t-butyldimethylsilyl ether) was obtained.
JH-NMR (CD C 13. 200 MH z) ά p pm； 0. 10 ( s , 3H) , 0.1 1 (s, 3Η) , 0.13 (s, 3H) , 0. 14 (s, 3H) ,, 0.89 (s, 9H) , 0.91 (s, 9 H) , 1.20-1.9 6 (m， 16H) , 2.12〜2.26 (m， 3H) , 2. 17 (d d, J = 7.3H z, 18.3H z, 1 H) , 2.60-2.74 (m, 2H) , 3.95-4.08 (m, 2H) , 4.25〜 4.35 (m, 1 H) , 4. 71〜4.78 (m, 1H) , 4.80 (q u i n t, J =4.8H z, 1 H) , 5.79 (d t, J = 1.5H z, 15.6H z, 1 H) , 6.8 5〜7.00 (m, 4H) , 7.23〜了.33 (m, 2 H) J H-NMR (CD C 13.200 MHz) ά p pm; 0.10 (s, 3H), 0.11 (s, 3Η), 0.13 (s, 3H), 0.14 (s, 3H), , 0.89 (s, 9H), 0.91 (s, 9H), 1.20-1.96 (m, 16H), 2.12-2.26 (m, 3H), 2.17 (dd, J = 7.3 Hz, 18.3 Hz) , 1H), 2.60-2.74 (m, 2H), 3.95-4.08 (m, 2H), 4.25-4.35 (m, 1H), 4.71-4.78 (m, 1H), 4.80 (quint, J = 4.8 Hz, 1 H), 5.79 (dt, J = 1.5 Hz, 15.6 Hz, 1 H), 6.8 5 to 7.00 (m, 4 H), 7.23 to 33.m (2 H)
I R (n e a t) : 2932， 2858, 2240， 1748, 17 18, 1655， 1601， 1589， 1497， 1472, 1464, 1251, 1175, 1119, 1045, 1021, 978, 940, 838, 780， 754, 691. 670 cm'1 IR (neat): 2932, 2858, 2240, 1748, 17 18, 1655, 1601, 1589, 1497, 1472, 1464, 1251, 1175, 1119, 1045, 1021, 978, 940, 838, 780, 754, 691. 670 cm ' 1
(2) 実施例 1 (3) と同様にして標記化合物を得た。
!H-NMR (CDC ", 300MHz) <5 p pm ; 1. 18〜丄 .9 1 (m, 16H) , 2. 13-2.30 (m. 3H) , 2.23 (d d, J = 9. 1 H z, 18.5H z, 1 H), 2.30-3.06 (b r, 2H),(2) The title compound was obtained in the same manner as in Example 1 (3). ! H-NMR (CDC ", 300MHz) <5 p pm; 1.18 to 丄 0.91 (m, 16H), 2.13-2.30 (m.3H), 2.23 (dd, J = 9.1 H z, 18.5H z, 1 H), 2.30-3.06 (br, 2H),
2.65 (d d d, J = l 1.4H z. 8.3H z, 1.8H z, 1 H) , 2.75 (d d d, J = l.2H z, 7.3H z, 18.5H z, 1 H) ,2.65 (d d d, J = l 1.4H z.8.3H z, 1.8H z, 1H), 2.75 (d d d, J = l.2H z, 7.3H z, 18.5H z, 1 H),
4.08 (d d, J = 6.9 H z, 9.6H z, 1 H) ， 4. 14 (d d, J = 4.0 H z, 9.6H z, 1 H) , 4.30〜4.38 (m, 1 H) ,4.08 (d d, J = 6.9 Hz, 9.6 Hz, 1 H), 4.14 (dd, J = 4.0 Hz, 9.6 Hz, 1 H), 4.30 to 4.38 (m, 1 H),
4.74-4.84 (m, 2H) , 5.80 (d t, J = 1.5H z， 15. 6H z, 1 H) , 6.88-7.02 (m, 4H) , 7.27-7.33 (m, 2 H) 4.74-4.84 (m, 2H), 5.80 (d t, J = 1.5 Hz, 15.6 Hz, 1 H), 6.88-7.02 (m, 4H), 7.27-7.33 (m, 2 H)
I R (n e a t) ： 3419, 2937, 2860, 2241, 17 44, 1714, 1653, 1600, 1588, 1497, 1455, 1374, 1246, 1175, 1080, 1044, 1020, 98 9, 912; 756, 693, 510 cm-1 IR (neat): 3419, 2937, 2860, 2241, 17 44, 1714, 1653, 1600, 1588, 1497, 1455, 1374, 1246, 1175, 1080, 1044, 1020, 98 9, 912; 756, 693, 510 cm- 1
実施例 6 Example 6
16—フエノキシ一 17, 18, 19, 20—テトラノル一 2, 2 , 3, 3, 13, 1 4—へキサデヒ ドロー P G E , メチルエステル (化合物 4) の 製造 Production of 16-phenoxy-1,17,19,20-tetranor-1,2,3,3,13,14-hexadehydro PGE, methyl ester (compound 4)
(1) アルゴン気流下、 一 60。Cにおいて 5—カルボメ トキシ一 4— ペンテニル亜鉛 (Π) ョージド （0.64 M, テトラヒ ドロフラン溶液， 5.0m l , 3.2 Ommo 1 ) にシアン化銅 （ I ) · 2塩ィ匕リチウム (1.0M, テトラヒ ドロフラン溶液， 4.00m l , 4.0 Ommo 1 ) を加え同温度で 15分間撹拌した。 この溶液に一 60°Cで実施例 1 (1) で得た化合物 （801 mg, 1.6 Ommo 1 ) のジェチルエーテル 5.
6 m 1の溶液とクロ口 トリメチルシラン （0.37m l, 2.88關 ol) を加え、 撹拌しながら約 1.5時間かけて 0°Cまで昇温した。 反応液に 飽和塩化アンモニゥム水溶液 24m 1を加え、 へキサン抽出した。 有機 層を飽和重曹水および飽和食塩水で洗浄後、 乾燥、 濃縮して得られた残 5 渣を 2—プロパノール （6.4m l ) —ジェチルエーテル （1.6ml) に溶解し、 p—トルエンスルホン酸ピリジン塩 （2 Omg, 0.080 mmo 1 ) を加え室温で一夜撹拌した。 反応液にへキサン 10m 1を加 え、 飽和重曹水および飽和食塩水で洗浄後、 乾燥、 濃縮して得られた残 渣をシリカゲルカラムクロマトグラフィ一 （展開溶媒；へキサン ：酢酸 ,。 ェチル =19 : 1) で精製して 16—フヱノキシー 17, 18, 19, 2 0—テトラノノレ一 2, 2, 3, 3, 13, 14—へキサデヒ ドロ一 PGE, チルエステル 11， 15—ビス （ t—ブチルジメチルシリルエーテル） 493mgを得た。 (1) Under a stream of argon, one 60. In C, 5-carbomethoxy-1-4-pentenylzinc (II) chloride (0.64 M, tetrahydrofuran solution, 5.0 ml, 3.2 Ommo 1) was added to copper (I) cyanide · dichlorolithium (1.0 M, tetrahydrofuran solution) , 4.00 ml, 4.0 Ommo 1) and stirred at the same temperature for 15 minutes. To this solution was added getyl ether of the compound (801 mg, 1.6 Ommo 1) obtained in Example 1 (1) at 160 ° C. 5. A 6 ml solution and trimethylsilane (0.37 ml, 2.88 ol) were added, and the temperature was raised to 0 ° C over about 1.5 hours with stirring. To the reaction mixture was added 24 ml of a saturated aqueous solution of ammonium chloride, and the mixture was extracted with hexane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline, dried and concentrated, and the remaining 5 residues were dissolved in 2-propanol (6.4 ml) -getyl ether (1.6 ml), and p-toluenesulfonic acid was dissolved. A pyridine salt (2 Omg, 0.080 mmo 1) was added, and the mixture was stirred at room temperature overnight. Hexane (10 ml) was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, dried and concentrated. The residue obtained was subjected to silica gel column chromatography (developing solvent; hexane: acetic acid, ethyl acetate = 19). : 1) to purify 16-phenoxy 17, 18, 19, 20-tetranorenol 2,2,3,3,13,14-hexadehydro PGE, tyl ester 11,15-bis (t-butyldimethyl 493 mg of silyl ether) were obtained.
^-NMR (CDC 13, 200 MHz) 5 p p m； 0.10 (s. 5 3H) , 0.12 (s, 3H) , 0.14 (s, 3H) , 0.15 (s, 3H) , 0.89 (s， 9H) , 0.91 (s, 9H) , 1.20-1.8 6 (m, 6 H) , 2.13〜 2.39 (m, 3H) , 2.18 (d d, J = 18.2 H z, 7.2Hz, 1H) , 2.58〜2.76 (m, 2H) , 3.74 (s, 3H) , 3.95〜 4.08 (m, 2H) , 4.23-4. 。 37 (m， 1H) , 4.70〜4.80 (m, 1 H) , 6.85-7.02 (m, 3H) , 7.22〜7.35 (m, 2H) ^ -NMR (CDC 13, 200 MHz) 5 ppm; 0.10 (s. 53H), 0.12 (s, 3H), 0.14 (s, 3H), 0.15 (s, 3H), 0.89 (s, 9H), 0.91 (s, 9H), 1.20-1.8 6 (m, 6H), 2.13-2.39 (m, 3H), 2.18 (dd, J = 18.2 Hz, 7.2Hz, 1H), 2.58-2.76 (m, 2H) , 3.74 (s, 3H), 3.95 to 4.08 (m, 2H), 4.23-4. 37 (m, 1H), 4.70 to 4.80 (m, 1H), 6.85-7.02 (m, 3H), 7.22 to 7.35 (m, 2H)
I R (n e a t) : 2953， 2931, 2886, 2858, 22 38, 1748, 1718, 1601， 1497, 1463, 1435, 1362, 1255, 1116, 1079, 1050， 1007, 97
5, 838, 780, 754. 692. 670 cm-1 IR (neat): 2953, 2931, 2886, 2858, 22 38, 1748, 1718, 1601, 1497, 1463, 1435, 1362, 1255, 1116, 1079, 1050, 1007, 97 5, 838, 780, 754. 692.670 cm- 1
(2) 上記 （1) で得られた化合物 （465mg、 0.742 mm o 1 ) のァセトニトリル 24. 7m l溶液にフッ化水素酸水溶液 （46%) 5.6m 1を氷冷下で加え、 同温度で 2時間撹拌した。 反応液を飽和重 曹水 17 Om 1にあけ酢酸ェチル抽出し、 有機層を飽和重曹水および飽 和食塩水で洗浄し、 乾燥、 濃縮して得られた残渣をシリカゲルカラムク 口マトグラフィー （展開溶媒；へキサン ：酢酸ェチル = 1 : 1) で精製 して標記化合物 247mgを得た。 (2) To a solution of the compound obtained in (1) above (465 mg, 0.742 mmo 1) in acetonitrile (24.7 ml) was added 5.6 ml of an aqueous hydrofluoric acid solution (46%) under ice-cooling, and the mixture was added at the same temperature. Stir for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (17 Om1), extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried and concentrated, and the residue obtained was subjected to silica gel column chromatography (developing solvent). Hexane: ethyl acetate = 1: 1) to give 247 mg of the title compound.
- NMR (CDC 1 a, 300MH z) 5 p p m； 1.48-1.8 8 (m, 6H) ， 2.18~2.37 (m, 1 H) , 2.24 (d d, J = 18.6 H z, 9.0H z, 1 H) , 2.33 ( t, J = 6.5 H z, 2 H) , 2.67 (d d d, J = 11.3H z， 8.1H z, 1.8 H z , 1 H) , 2.76 (d d d, J = 18.6 H z , 7.3H z, 1.3H z, 1 H) , 2.82 (d， J = 3.6Hz, 1 H) , 2.96 (d, J =5.2 H z, 1H) , 3.74 (s, 3H) , 4.09 (d d, J =9.6H z, 6.9Hz, 1 H), 4.14 (d d, J = 9.6 H z , 4.0 H z. 1 H), 4.30〜 4.41 (m, 1 H) , 4.76〜 4.84 (m, 1 H) , 6. 91〜7.06 (m, 3H) , 7.25-7.35 (m, 2H) -NMR (CDC 1 a, 300 MHz) 5 ppm; 1.48-1.88 (m, 6H), 2.18 to 2.37 (m, 1 H), 2.24 (dd, J = 18.6 Hz, 9.0 Hz, 1 H) , 2.33 (t, J = 6.5Hz, 2H), 2.67 (ddd, J = 11.3Hz, 8.1Hz, 1.8Hz, 1H), 2.76 (ddd, J = 18.6Hz, 7.3Hz) , 1.3Hz, 1H), 2.82 (d, J = 3.6Hz, 1H), 2.96 (d, J = 5.2Hz, 1H), 3.74 (s, 3H), 4.09 (dd, J = 9.6H z, 6.9Hz, 1H), 4.14 (dd, J = 9.6Hz, 4.0Hz.1H), 4.30-4.41 (m, 1H), 4.76-4.84 (m, 1H), 6.91 ~ 7.06 (m, 3H), 7.25-7.35 (m, 2H)
I R (n e a t) : 3412, 3016, 2944, 2866, 22 37. 1745, 1714, 1600, 1588, 1496, 1456, 1436, 1385, 1260, 1154, 1079, 1046, 90 9, 755， 693, 667 cm-1 IR (neat): 3412, 3016, 2944, 2866, 22 37. 1745, 1714, 1600, 1588, 1496, 1456, 1436, 1385, 1260, 1154, 1079, 1046, 90 9, 755, 693, 667 cm- 1
実施例 7 Example 7
16—フエノキシ一 17， 18, 19, 20—テトラノル一 2, 2, 3, 3,
1 3, 14一へキサデヒ ドロー PGE, シク口へキシルエステルの製造16-phenoxy-1, 17, 18, 19, 20-tetranor 1,2,3,3 1 3, 14 Production of hexadehydrose PGE, hexyl hexyl ester
(1) 実施例 6 (1) と同様にして 16—フエノキシー17， 18, 1 9, 20—テトラノノレー 2, 2， 3, 3, 13, 14—へキサデヒ ドロー PG E！ シクロへキシルエステル 11, 15—ビス （ tーブチルジメチル シリルエーテル） を得た。(1) In the same manner as in Example 6 (1), 16-phenoxy 17, 18, 19, 20-tetranole 2,2,3,3,13,14-hexadehyd PG E! Cyclohexyl ester 11,15-bis (t-butyldimethylsilyl ether) was obtained.
— NMR (CD C 13, 200MHz) 5 p pm； 0.10 ( s , 3H) , 0.12 (s, 3 Η) , 0.14 (s, 3Η) , 0.15 (s, 3Η) , 0.90 (s, 9Η) , 0.91 (s, 9Η) , 1.18-1.9 7 (m, 16Η) , 2.13〜2.38 (m, 3Η) , 2.18 (d d, J =l 8.2Hz, 7.2Hz, 1 Η) , 2.58-2.76 (m, 2 Η) , 3.95〜 4.08 (m. 2H) , 4.23〜4.37 (m, 1Η) , 4. 67〜4.90 (m， 2Η) , 6.83〜7.00 (m, 3Η) , 7.21 〜7.35 (m, 2Η) — NMR (CD C 13, 200MHz) 5 ppm; 0.10 (s, 3H), 0.12 (s, 3Η), 0.14 (s, 3Η), 0.15 (s, 3Η), 0.90 (s, 9Η), 0.91 (s, 9Η), 1.18-1.9 7 (m, 16Η), 2.13-2.38 (m, 3Η), 2.18 (dd, J = l 8.2Hz, 7.2Hz, 1Η), 2.58-2.76 (m, 2Η ), 3.95 to 4.08 (m.2H), 4.23 to 4.37 (m, 1Η), 4.67 to 4.90 (m, 2Η), 6.83 to 7.00 (m, 3Η), 7.21 to 7.35 (m, 2Η)
I R (n e a t) : 2931, 2859, 2236, 1748, 17 07, 1642, 1601, 1497, 1463, 1385， 1252, 1114, 1077, 1012, 977, 838, 780, 754, 6 92 cm"1 IR (neat): 2931, 2859, 2236, 1748, 17 07, 1642, 1601, 1497, 1463, 1385, 1252, 1114, 1077, 1012, 977, 838, 780, 754, 6 92 cm " 1
(2) 実施例 6 (2) と同様にして標記化合物を得た。 (2) The title compound was obtained in the same manner as in Example 6 (2).
!H-NMR (CDC 1 a, 300MHz) (5p pm ; 1.15〜1.9 4 (m, 16 H) , 2.15-2.82 (b r, 2H) , 2.22〜 2.3 5 (m, 1 H) , 2.24(d d, J =l 8.5Hz, 8.9Hz, 1 H), 2.32 (t， J=6.5Hz, 2H) ， 2.67 (d d d, J = 10.1 Hz, 8.1Hz, 1.8Hz, 1 H) , 2.76 (d d d, J = 18.7 Hz, 7.4Hz, 1.3H z, 1 H) , 4.09 (d d, J = 9.6
H z, 7.0 H z. 1H) , 4.15 (d d. J = 9.6 H z, 4.1 H z, 1H) , 4.30〜4.40 (m, 1 H), 4.75〜4.88 (m, 2H), 6.90〜7.03 (m, 3H) , 7.25〜7.35 (m, 2H) ! H-NMR (CDC 1a, 300MHz) (5p pm; 1.15 to 1.94 (m, 16H), 2.15-2.82 (br, 2H), 2.22 to 2.35 (m, 1H), 2.24 (dd, J = l 8.5Hz, 8.9Hz, 1H), 2.32 (t, J = 6.5Hz, 2H), 2.67 (ddd, J = 10.1Hz, 8.1Hz, 1.8Hz, 1H), 2.76 (ddd, J = 18.7 Hz, 7.4Hz, 1.3Hz, 1H), 4.09 (dd, J = 9.6 Hz, 7.0 Hz.1H), 4.15 (d d.J = 9.6 Hz, 4.1 Hz, 1H), 4.30 to 4.40 (m, 1H), 4.75 to 4.88 (m, 2H), 6.90 to 7.03 (m, 3H), 7.25 to 7.35 (m, 2H)
I R (n e a t) : 3401, 2938, 2861, 2235, 17 45， 1703. 1600, 1496, 1455, 1385, 1253. 1174, 1077, 1045, 1012, 909, 754, 692 cm"1 IR (neat): 3401, 2938, 2861, 2235, 1745, 1703.1600, 1496, 1455, 1385, 1253. 1174, 1077, 1045, 1012, 909, 754, 692 cm " 1
実施例 8 Example 8
16—フ ノキシ一 17, 18, 19, 20—テトラノル— 2, 2, 3, 3. 16-Funoxy 17, 18, 19, 20-Tetranor 2, 2, 3, 3.
13, 14一へキサデヒ ドロー PGEi t—ブチルエステル （化合物 5) の製造 . Preparation of 13,14-hexadehydro-PGEit-butyl ester (Compound 5).
(1) 実施例 6 (1) と同様にして 16—フ Xノキシ一 17, 18, 1 9, 20—テトラノル一 2, 2, 3, 3.13, 14—へキサデヒ ドロー PG E 1 t一ブチルエステル 11 , 15 _ビス （ t一ブチルジメチルシリ ルエーテル） を得た。 (1) 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.
^- MR (CDC 13, 200 MH z) 5 p pm； 0. 10 (s, 3H) , 0. 12 (s, 3H) , 0.13 (s, 3H) , 0. 15 (s, 3H) , 0.89 (s, 9H) , 0.91 (s, 9H) , 1.20-1.8 6 (m, 6H) , 1.49 (s, 9 H) , 2.13〜 2.37 (m, 3H), 2.18 (d d, J = 18.2H z, 7.2Hz, 1 H) , 2.58-2. 76 (m， 2H) , 3.95〜 4.10 (m, 2H) , 4.24〜 4.37 (m, 1H) , 4.70〜4.80 (m， 1 H) , 6.84-7.00 (m, 3H) , 7.22-7.34 (m, 2H) ' ^-MR (CDC 13, 200 MHz) 5 p pm; 0.10 (s, 3H), 0.12 (s, 3H), 0.13 (s, 3H), 0.15 (s, 3H), 0.89 (s, 9H), 0.91 (s, 9H), 1.20-1.8 6 (m, 6H), 1.49 (s, 9 H), 2.13 to 2.37 (m, 3H), 2.18 (dd, J = 18.2H z, 7.2Hz, 1H), 2.58-2.76 (m, 2H), 3.95-4.10 (m, 2H), 4.24-4.37 (m, 1H), 4.70-4.80 (m, 1H), 6.84-7.00 ( m, 3H), 7.22-7.34 (m, 2H) ''
I R (n e a t) : 2953, 2931， 2858, 2237, 17
48， 1708, 1601, 1589. 1497, 1472, 1463, 1385, 1370, 1277, 1256, 1162, 1116, 10 78, 1050, 976, 838， 809. 780, 754, 692, 670 cm"1 IR (neat): 2953, 2931, 2858, 2237, 17 48, 1708, 1601, 1589. 1497, 1472, 1463, 1385, 1370, 1277, 1256, 1162, 1116, 10 78, 1050, 976, 838, 809.780, 754, 692, 670 cm " 1
(2) 実施例 6 (2) と同様にして標記化合物を得た。 (2) The title compound was obtained in the same manner as in Example 6 (2).
'H-NMR (CDC 13- 300 MHz) <5 p p m； 1.48 (s, 9H), 1.50〜1.86 (m, 6H) , 2.20〜2.34 (m, 1 Η). 2.25 (dd, J = 18.6Η ζ, 9.0Hz, 1 Η) , 2.30 (t， J =6.5Η ζ, 2Η) , 2.35〜3.10 (b r, 2Η) , 2.68 (d dd, J = 9.9Hz, 8.0Hz, 1.8 H z, 1 H) , 2.76 (d d d， J =l 8.6Hz, 7.3Hz, 1.3Hz, 1 H) , 4.09 (d d, J = 9.6 H z , 6.5Hz, 1 H) , 4.15 (d d, J = 9.6H z, 4.1Hz, 1 H) , 4.30〜4.40 (m, 1 H) , 4.80 ( d d d , J =6.7Hz, 4.1 H zf 1.8Hz, 1 H), 6.90-7.02 (m, 3H) , 7.25〜7.35 (m, 2 H) 'H-NMR (CDC 13-300 MHz) <5 ppm; 1.48 (s, 9H), 1.50-1.86 (m, 6H), 2.20-2.34 (m, 1Η). 2.25 (dd, J = 18.6Η ζ , 9.0Hz, 1Η), 2.30 (t, J = 6.5Η ζ, 2Η), 2.35 to 3.10 (br, 2Η), 2.68 (d dd, J = 9.9Hz, 8.0Hz, 1.8Hz, 1H) , 2.76 (ddd, J = l 8.6 Hz, 7.3 Hz, 1.3 Hz, 1 H), 4.09 (dd, J = 9.6 Hz, 6.5 Hz, 1 H), 4.15 (dd, J = 9.6 Hz, 4.1 Hz) , 1 H), 4.30 to 4.40 (m, 1 H), 4.80 (ddd, J = 6.7 Hz, 4.1 H z f 1.8 Hz, 1 H), 6.90-7.02 (m, 3H), 7.25 to 7.35 (m, 2 H)
I R (n e a t) : 3400, 2980, 2933, 2866, 22 36, 1746, 1704, 1600， 1589, 1496, 1456, 1429, 1395, 1385, 1370, 1279, 1248, 11 60， 1127, 1079, 1045, 844, 802, 756. 69 3, 512 cm— 1
IR (neat): 3400, 2980, 2933, 2866, 22 36, 1746, 1704, 1600, 1589, 1496, 1456, 1429, 1395, 1385, 1370, 1279, 1248, 11 60, 1127, 1079, 1045, 844 , 802, 756. 69 3, 512 cm— 1
Claims
請 求 の 範 囲 The scope of the claims
式中、 Where:
Aはビニレン基またはェチニレン基を表わし、 A represents a vinylene group or an ethynylene group,
R1は水素原子、 C! Ceアルキル基または C3〜（： 8シクロアルキ o ル基を表わす、 R 1 represents a hydrogen atom, a C! Ce alkyl group or a C 3- (: 8 cycloalkylo group,
で示されるプロスタグランジン 類縁体及びその塩。 A prostaglandin analog represented by the formula:
2. R1がメチル基、 t一ブチル基またはシクロへキシル基を表わす 請求の範囲第 1項記載の化合物。 2. The compound according to claim 1, wherein R 1 represents a methyl group, a t-butyl group, or a cyclohexyl group.
3. 請求の範囲第 1項記載の式 （Ί) の化合物または製薬学的に許容 しうるその塩を含有する薬剤。 3. A drug containing the compound of the formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof.
4. 請求の範囲第 1項記載の式 （I) の化合物または製薬学的に許容 しうるその塩を含有する抗潰瘍剤。 4. An anti-ulcer agent comprising the compound of the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
5. 請求の範囲第 1項記載の式 （I) の化合物または製薬学的に許容 しうるその塩及び製薬学的に許容しうる添加剤からなる薬学的組成物。 5. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
6. 請求の範囲第 1項記載の式 （I) の化合物または製薬学的に許容 しうるその塩の有効量を哺乳動物に投与することからなる哺乳動物にお ける消化性潰瘍の処置方法。 6. A method for treating peptic ulcer in a mammal, comprising administering to the mammal an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1.
7. 請求の範囲第 1項記載の式 （I) の化合物または製薬学的に許容 しうるその塩の病気の処置のための使用。
7. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 for the treatment of a disease.
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 |
|---|---|---|---|
| JP4/281923 | 1992-10-20 | ||
| JP28192392 | 1992-10-20 | ||
| JP5/79487 | 1993-04-06 | ||
| JP7948793 | 1993-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994008960A1 true WO1994008960A1 (en) | 1994-04-28 |
Family
ID=26420506
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1993/001506 WO1994008960A1 (en) | 1992-10-20 | 1993-10-20 | Prostaglandin e1 analog |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU5285493A (en) |
| WO (1) | WO1994008960A1 (en) |
Cited By (1)
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0591532A4 (en) * | 1991-04-22 | 1994-11-09 | Taisho Pharmaceutical Co Ltd | Prostaglandin e 1? analogue. |
Citations (3)
| 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 (en) * | 1991-04-22 | 1993-05-14 | Taisho Pharmaceut Co Ltd | Prostaglandin derivative |
-
1993
- 1993-10-20 WO PCT/JP1993/001506 patent/WO1994008960A1/en active Application Filing
- 1993-10-20 AU AU52854/93A patent/AU5285493A/en not_active Abandoned
Patent Citations (3)
| 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 (en) * | 1991-04-22 | 1993-05-14 | Taisho Pharmaceut Co Ltd | Prostaglandin derivative |
Cited By (1)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5285493A (en) | 1994-05-09 |
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