JP4985400B2 - Prostaglandin derivatives - Google Patents

Description

  The present invention relates to novel prostaglandin derivatives, pharmaceutically acceptable salts and hydrates thereof.

Prostaglandin E ₂ (hereinafter referred to as “PGE ₂ ”) is known as a metabolite of the arachidonic acid cascade and is known to have various physiological actions.

In recent studies, the PGE ₂ receptors are roughly four subtypes exist and are reported (EP1, EP2, EP3, EP4 ), in which, EP4 receptor the PGE ₂ as a ligand, It has been reported that it exhibits anti-inflammatory action in vivo (Non-patent Document 1), and EP4 agonists are used for autoimmune diseases, rheumatoid arthritis, psoriasis, asthma, hepatitis, nephritis, atherosclerosis, myocarditis It is considered useful for treatment of sepsis, myocardial infarction, and the like. It is also considered useful for alleviating rejection at the time of organ transplantation and intimal thickening after percutaneous transvascular coronary angioplasty. However, since conventional EP4 agonists activate a signal transduction mechanism through an increase in intracellular cAMP, when EP4 agonists are administered systemically, they have vasodilatory effects and side effects such as blood pressure lowering Is concerned.

  Recently, the anti-inflammatory mechanism of EP4 receptor has been reported to be via a pathway different from cAMP-dependent cell signaling, which has been reported so far, and there is a possibility of a drug with few side effects such as blood pressure reduction. It has been suggested (Non-Patent Document 2).

  On the other hand, PG derivatives having a phenyl group at the 16-position of PG have been disclosed (Patent Document 1), but these compounds are three-dimensional structures in which the hydroxyl group at the 11-position, which is very important for the activity expression of PGs, is non-natural. It is an isomer and no pharmacological activity is described.

  In addition, a PG derivative having a phenyl group at the 16-position is disclosed as an EP4 agonist (Non-patent Document 3), but a compound having a triple bond at positions 13 and 14 of the ω side chain is not disclosed.

  Furthermore, there is no specific disclosure of a compound that has separated anti-inflammatory action and cAMP production.

U.S. Patent Publication No. 4328355 Takayama, K., J Biol Chem 277 (2002), 44147-44154 Takayama, K., J Biol Chem 277 (2002), 44147-44154., Takayama, K., Atherosclerosis Supplements, 4-2 (2002), 313 Bioorg. Med. Chem., 10, 1743 (2002), Bioorg. Med. Chem., 10, 989 (2002)

  The object of the present invention is to provide a compound having a weak cAMP production enhancing action while having a sufficient anti-inflammatory action in order to reduce the side effects which are concerned with EP4 agonists.

  As a result of researches to find a compound having an anti-inflammatory action and an activity of enhancing cAMP production, the present inventors have found that the novel prostaglandin derivative represented by the formula (I) has an excellent anti-inflammatory effect. The present invention was completed by finding that the cAMP production enhancing action was separated while having the action.

  That is, the present invention provides a compound of formula (I)

[式中、Ｒ¹は水素原子、炭素原子数１〜４個のアルキル基または炭素原子数２〜４個のアルケニル基を示し、
Xはエチレン基、トリメチレン基、ビニレン基、エチニレン基または ―ＳＣＨ₂− で示される基を示し、
Ｒ²、Ｒ³はそれぞれ水素原子、ハロゲン原子、炭素原子数１〜６個のアルキル基、炭素原子数１〜６個のハロアルキル基、炭素原子数１〜６個のアルコキシ基、炭素原子数1〜６個のアルコキシ基で置換された炭素原子数1〜６個のアルキル基、フェニル基、置換フェニル基、フリル基またはチエニル基を示す。]で表されるプロスタグランジン誘導体、その製薬学的に許容される塩またはその水和物である。

[Wherein R ¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms,
X represents an ethylene group, a trimethylene group, a vinylene group, an ethynylene group or a group represented by —SCH ₂ —;
R ² and R ³ are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or 1 carbon atom. An alkyl group having 1 to 6 carbon atoms, a phenyl group, a substituted phenyl group, a furyl group, or a thienyl group substituted with 6 alkoxy groups; Or a pharmaceutically acceptable salt or hydrate thereof.

  It has been found that the compound of the present invention does not promote cAMP production while having excellent anti-inflammatory action.

  In the present invention, the alkyl group having 1 to 4 carbon atoms means a linear or branched alkyl group, and includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert- A butyl group etc. are mentioned.

  The alkenyl group having 2 to 4 carbon atoms represents a straight chain or branched alkenyl group, and examples thereof include a 2-propenyl group, a 2-methyl-2-propenyl group, and a 2-methyl-2-butenyl group. It is done.

  A vinylene group is a trans vinylene group or a cis vinylene group.

  The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  An alkyl group having 1 to 6 carbon atoms means a linear or branched alkyl group having 1 to 6 carbon atoms, and includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and n-butyl. Group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, n-hexyl group and the like.

  The haloalkyl group having 1 to 6 carbon atoms refers to a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms, a fluoromethyl group, Examples thereof include a chloromethyl group, a bromomethyl group, a difluoromethyl group, a trifluoromethyl group, and a pentafluoroethyl group.

  An alkoxy group having 1 to 6 carbon atoms means a linear, branched or cyclic saturated or unsaturated alkoxy group having 1 to 6 carbon atoms, and includes a methoxy group, an ethoxy group, a propoxy group, an iso group. Examples thereof include a propoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, an allyloxy group, and a cyclohexyloxy group.

  An alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms is substituted with a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms is shown, and examples thereof include a methoxymethyl group, an ethoxymethyl group, an isopropoxymethyl group, a cyclohexyloxymethyl group, and a 2-methoxyethyl group.

  The substituted phenyl group is 1 selected from the group consisting of (halogen atom, alkyl group having 1 to 6 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, and alkoxy group having 1 to 6 carbon atoms). Indicates a phenyl group substituted with ~ 5.

  The furyl group is a 2-furyl group or a 3-furyl group.

  The thienyl group is a 2-thienyl group or a 3-thienyl group.

  Examples of pharmaceutically acceptable salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, and benzylamine. And salts with piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, tris (hydroxymethyl) aminomethane, and tetraalkylammonium salts.

  Compounds of formula (I) can be prepared by the method summarized in Reaction Scheme 1 below.

（反応式１中、Ｒ¹¹は水素原子を除くＲ¹と同意義であり、Ｘ，Ｒ²，Ｒ³は前記と同意義であり、ＴＢＳはｔｅｒｔ−ブチルジメチルシリル基を示す。）
以下、反応式１を説明する。

(In Reaction Scheme 1, R ¹¹ has the same meaning as R ¹ excluding a hydrogen atom, X, R ² and R ³ have the same meaning as described above, and TBS represents a tert-butyldimethylsilyl group.)
Hereinafter, Reaction Formula 1 will be described.

Each reaction of the above reaction formula 1 is carried out by a method known by Sato et al. [J. Org. Chem., 53, 5590 (1988)]. Further, the compound represented by the general formula (III) used as a starting material is known per se or can be easily produced by a known method. For example, among the compounds represented by the formula (III), a compound in which R ² is a 3-methoxymethyl group and R ³ is a hydrogen atom is described in JP-A No. 2001-89444.

(1-1) The compound of formula (III) is reacted with 0.5 to 1.2 molar equivalents of n-BuLi and then 0.5 to 2.0 molar equivalents of Et ₂ AlCl to prepare an alkynylaluminum reagent. II) The compound represented by 0.8 to 2.0 molar equivalent is reacted at −78 to 30 ° C. in an inert solvent (for example, benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.). To obtain the compound of formula (IV).

(1-2) 0.5 to 4 molar equivalents of an organocopper compound represented by the formula (V) and 0.5 to 4.0 molar equivalents of trimethylchlorosilane are added to an inert solvent (for example, benzene) , Toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, n-pentane, etc.) at −78 to 40 ° C., and further an inorganic acid (eg hydrochloric acid, sulfuric acid, nitric acid etc.) or an organic acid (eg acetic acid, p-toluenesulfonic acid or the like) or an amine salt thereof (for example, p-toluenesulfonic acid pyridine salt or the like) in an organic solvent (for example, acetone, methanol, ethanol, isopropanol, diethyl ether or a mixed solvent thereof) Hydrolysis at 40 ° C. gives the compound of formula (VI).

(1-3) The compound of formula (VI) is mixed with methanol, ethanol, acetonitrile, a mixed solvent thereof, or these under conditions usually used with hydrofluoric acid, pyridinium poly (hydrogen fluoride), hydrochloric acid, etc. In a mixed solvent with water, the tert-butyldimethylsilyl group, which is a protecting group for a hydroxyl group, is removed to obtain a PG derivative of the formula (Ia) according to the present invention in which R ¹ is other than a hydrogen atom in the formula (I).

(1-4) Using a compound of formula (Ia) in a buffer solution such as phosphate buffer or Tris-HCl buffer, if necessary, an organic solvent (miscible with water such as acetone, methanol, ethanol). By reacting with an enzyme and hydrolyzing, a PG derivative of the formula (Ib) according to the present invention in which R ¹ is a hydrogen atom in the formula (I) is obtained.

  Examples of the enzyme include enzymes produced by microorganisms (for example, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas), enzymes prepared from animal organs (for example, enzymes prepared from porcine liver and porcine pancreas), etc. Specific examples of commercially available enzymes include lipase VII (manufactured by Sigma, Candida microorganisms), lipase AY (Amano Pharmaceutical, Candida microorganisms), lipase PS (Amano Pharmaceutical, Pseudomonas microorganisms), lipase MF (Amano Pharmaceutical, Pseudomonas microorganisms), PLE (Sigma, prepared from pig liver), Lipase II (Sigma, prepared from pig pancreas), lipoprotein lipase ( Tokyo Chemical Industry Co., Ltd., prepared from porcine pancreas).

  The amount of the enzyme used may be appropriately selected according to the titer of the enzyme and the amount of the substrate [compound of formula (Ia)], but is usually 0.1 to 20 parts by weight of the substrate. The reaction temperature is 25-50 ° C, preferably 30-40 ° C.

  The compounds of the present invention can also be produced by the method summarized in Reaction Scheme 2 below.

（反応式２中、Ｒ¹¹,Ｘ，Ｒ²，Ｒ³は前記と同意義であり、MetはLi,Na,Mg等の金属を示し、TBSはtert-ブチルジメチルシリル基、TMSはトリメチルシリル基を示す。）
以下、反応式２を説明する。

(In Reaction Formula 2, R ¹¹ , X, R ² and R ³ are as defined above, Met represents a metal such as Li, Na, Mg, etc., TBS represents a tert-butyldimethylsilyl group, and TMS represents a trimethylsilyl group. Is shown.)
Hereinafter, Reaction Formula 2 will be described.

  The first step of Reaction Scheme 2 is carried out by a known method according to WO 2004/087724. Moreover, the halide which is a precursor of the compound represented by the formula (XI) is known per se or can be easily produced by a known method.

(2-1) An organometallic reagent prepared by reacting a compound of the formula (VIII) with 0.5 to 1.2 equivalents of n-BuLi and then 0.5 to 2.0 equivalents of Me ₃ AlC and TBSOTf (tert-butyl Existence of 0.5 to 5.0 equivalents of dimethylsilyl triflate, compounds 0.8 to 2.0 represented by the general formula (VII) known from literature (Tetrahedron Lett., 1990, 31,4481 or WO 2004/087724) The trimethylsilyl group is selectively removed by reacting with an equivalent amount at −78 to 30 ° C. in an inert solvent (eg, benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.) and then treating with dilute hydrochloric acid. By protection, a compound of general formula (IX) is obtained.

(2-2) The compound of the general formula (IX) is added with _{2 to} 10 equivalents of an oxidizing agent such as MnO ₂ and Dess-Martin reagent as an inert solvent (for example, benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane). Etc.) to obtain a compound of the general formula (X).

(2-3) 0.5-10 equivalents of a compound represented by the general formula (XI) prepared from a metal such as Li, Na, Mg and the corresponding halide, and a compound of the general formula (X) In the formula (I), the reaction is carried out in the presence of 0.5 to 10 equivalents of a Lewis acid such as TiCl ₄ or SnCl ₄ and then the same reaction as in the third step (1-3) of the reaction formula 1 is performed. A PG derivative of the formula (Ia) according to the invention in which R ¹ is other than a hydrogen atom can be obtained.

(2-4) A PG derivative of the formula (Ib) according to the present invention in which R ¹ is a hydrogen atom in the formula (I) is obtained by carrying out a reaction similar to the fourth step (1-4) of the reaction formula 1. be able to.

  The compounds of the present invention can be administered systemically or locally orally, parenterally, such as intravenously, nasally. These can be orally administered, for example, in the form of tablets, powders, granules, powders, capsules, liquids, emulsions, suspensions and the like that can be produced by conventional methods.

  As a preparation for intravenous administration, an aqueous or non-aqueous solution, an emulsion, a suspension, a solid preparation dissolved in an injection solvent immediately before use, or the like can be used. For nasal administration, a drug-containing solution and powder (hard capsule) are generally sprayed quantitatively into the nasal cavity using a dedicated nasal or spray device. In addition, the compound of the present invention can be formulated by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like. Furthermore, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like. Although the dosage varies depending on age, weight, etc., it is 1 ng to 1000 mg / day for an adult, and this is administered once or divided into several times a day.

  As typical compounds of the formula (I) according to the present invention, the following may be mentioned.

実施例
以下、実施例および試験例により本発明を具体的に説明する。
参考例１
3-ブロモフェニル酢酸 エチル エステル

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples and test examples.
Reference example 1
3-Bromophenylacetic acid ethyl ester

3-ブロモフェニル酢酸（50.0g）のEtOH（232ml）溶液に濃硫酸（3.0ml）を加え、5時間加熱還流後、室温で14.5時間攪拌した。反応液を約１/２の体積まで濃縮し、ヘキサン−酢酸エチルの混合溶液（4:1,200ml×3）で抽出し、有機層を飽和重曹水（30ml）、飽和食塩水(30ml)で洗浄し、無水硫酸マグネシウムで乾燥、ろ過後減圧濃縮し得られた残渣を減圧蒸留（沸点；83℃/0.46mmHg）し、表記化合物（無色油状物、54.93g）を得た。
¹H-NMR(CDCl₃, 300MHz) δppm; 1.26(t, J=7.2Hz, 3H), 3.58(s, 2H), 4.16(q, J=7.2Hz, 2H), 7.15-7.28(m, 2H), 7.36-7.48(m, 2H),
IR(neat):2982,1736,1596,1570,1475,1430,1368,1334,1250,1219,1157,1091,1073,1031,998,944,891,841,781,682,432 cm^-1

Concentrated sulfuric acid (3.0 ml) was added to a solution of 3-bromophenylacetic acid (50.0 g) in EtOH (232 ml), heated under reflux for 5 hours, and stirred at room temperature for 14.5 hours. The reaction solution is concentrated to about 1/2 volume, extracted with a mixed solution of hexane-ethyl acetate (4: 1, 200 ml × 3), and the organic layer is washed with saturated aqueous sodium hydrogen carbonate (30 ml) and saturated brine (30 ml). The residue obtained after drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was distilled under reduced pressure (boiling point; 83 ° C./0.46 mmHg) to obtain the title compound (colorless oil, 54.93 g).
¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.26 (t, J = 7.2Hz, 3H), 3.58 (s, 2H), 4.16 (q, J = 7.2Hz, 2H), 7.15-7.28 (m, 2H ), 7.36-7.48 (m, 2H),
IR (neat): 2982,1736,1596,1570,1475,1430,1368,1334,1250,1219,1157,1091,1073,1031,998,944,891,841,781,682,432 cm ^-1

Reference example 2
3-biphenylacetic acid ethyl ester

参考例１で得られた化合物（45.04g）、フェニルホウ酸（33.89g）、K₂CO₃(51.21g)のトルエン（370ml）懸濁液にPd(PPh₃)₄（5.0g）を加え、100℃で23時間攪拌した。反応液を室温まで冷却し、飽和重曹水（600ml）を加え、ヘキサン−酢酸エチルの混合溶液（3:1,500ml）で抽出し、有機層を飽和食塩水(600ml)で洗浄し、無水硫酸マグネシウムで乾燥、ろ過後減圧濃縮し得られた残渣をシリカカラムクロマトグラフィー（展開溶媒；酢酸エチル/ヘキサン＝0〜5％）で精製して表記化合物（無色油状物、41.43g）を得た。
¹H-NMR(CDCl₃, 300MHz) δppm; 1.27(t, J=7.1Hz, 3H), 3.68(s, 2H), 4.17(q, J=7.1Hz, 2H), 7.24-7.64(m, 9H)
IR(neat):3033,2982,1733,1600,1576,1480,1455,1423,1368,1294,1252,1206,1155,1096,1032,899,846,754,699,616,409cm^-1

Pd (PPh ₃ ) ₄ (5.0 g) was added to a suspension of the compound (45.04 g) obtained in Reference Example 1, phenylboric acid (33.89 g) and K ₂ CO ₃ (51.21 g) in toluene (370 ml), The mixture was stirred at 100 ° C. for 23 hours. The reaction mixture is cooled to room temperature, saturated aqueous sodium hydrogen carbonate (600 ml) is added, and the mixture is extracted with a mixed solution of hexane-ethyl acetate (3: 1,500 ml). The organic layer is washed with saturated brine (600 ml), and anhydrous magnesium sulfate. The residue obtained after drying, filtration and concentration under reduced pressure was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 0 to 5%) to obtain the title compound (colorless oil, 41.43 g).
¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.27 (t, J = 7.1Hz, 3H), 3.68 (s, 2H), 4.17 (q, J = 7.1Hz, 2H), 7.24-7.64 (m, 9H )
IR (neat): 3033,2982,1733,1600,1576,1480,1455,1423,1368,1294,1252,1206,1155,1096,1032,899,846,754,699,616,409cm ^-1

Reference example 3
1- (3-biphenyl) -3-butyn-2-ol

参考例２で得られた化合物（41.43g）のトルエン（575ml）溶液に、アルゴン雰囲気下、-70℃でジイソブチルアルミニウムヒドリド（0.93M,ヘキサン溶液、195ml）を1時間かけて滴下し、同温で1時間攪拌後、-70℃でエチニルマグネシウムクロリド(0.5M, THF溶液, 690ml)を3時間かけて滴下した。

Diisobutylaluminum hydride (0.93M, hexane solution, 195 ml) was added dropwise to a toluene (575 ml) solution of the compound obtained in Reference Example 2 (41.43 g) at −70 ° C. in an argon atmosphere over 1 hour. After stirring for 1 hour, ethynyl magnesium chloride (0.5 M, THF solution, 690 ml) was added dropwise at −70 ° C. over 3 hours.

The reaction mixture was warmed to room temperature over 3 hours, added to aqueous hydrochloric acid (3.0 M, 1000 ml), extracted with ethyl acetate (500 ml × 2), and the organic layer was washed with saturated brine (1000 ml). The residue obtained after drying with magnesium, filtration and concentration under reduced pressure was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5 to 15%) to obtain the title compound (pale yellow oil, 32.58 g). .
¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.91 (d, J = 5.9Hz, 1H), 2.52 (d, J = 2.2Hz, 1H), 3.07 (dd, J = 13.5,6.5Hz, 1H), 3.12 (dd, J = 13.5,6.1Hz, 1H), 4.59-4.70 (m, 1H), 7.24-7.63 (m, 9H),
IR (neat): 3544,3378,3289,3033,2926,2117,1600,1575,1480,1455,1421,1386,1291,1093,1036,973,899,850,797,757,729,701,646,584,550cm ^-1

Reference example 4
(S) -1- (3-Biphenyl) -3-butyn-2-ol

参考例３で得られた化合物（32.14g）のトルエン（722ml）溶液に、リパーゼPS（天野製薬社製，72.3g）とイソプロペニル酢酸(72.2ml)を加え、37℃で7.5日間激しく撹拌した。反応液をろ過後、濃縮して得られた残渣をシリカカラムクロマトグラフィー（展開溶媒；酢酸エチル/ヘキサン＝5〜15％）で精製して（S）-2-アセチルオキシ-1-（3-ビフェニル）-3-ブチン（淡黄色油状物、20.46g）と（R）-1-（3-ビフェニル）-3-ブチン-2-オール（淡黄色油状物、13.87g）を得た。得られた（R）-1-（3-ビフェニル）-3-ブチン-2-オール（13.87g）のTHF（124ml）溶液に、0℃でPPh₃（19.64g）、酢酸（4.29ml）、およびジエチルアゾジカルボキシレート（40％トルエン溶液、32.9ml）を加え、室温に昇温し1時間攪拌した。

Lipase PS (Amano Pharmaceutical Co., Ltd., 72.3 g) and isopropenyl acetic acid (72.2 ml) were added to a toluene (722 ml) solution of the compound (32.14 g) obtained in Reference Example 3 and stirred vigorously at 37 ° C. for 7.5 days. . The reaction solution is filtered and concentrated, and the residue obtained is purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5 to 15%) and purified by (S) -2-acetyloxy-1- (3- Biphenyl) -3-butyne (light yellow oil, 20.46 g) and (R) -1- (3-biphenyl) -3-butyn-2-ol (light yellow oil, 13.87 g) were obtained. In a THF (124 ml) solution of the obtained (R) -1- (3-biphenyl) -3-butyn-2-ol (13.87 g), PPh ₃ (19.64 g), acetic acid (4.29 ml), And diethyl azodicarboxylate (40% toluene solution, 32.9 ml) was added, and the mixture was warmed to room temperature and stirred for 1 hour.

After cooling to 0 ° C., PPh ₃ (13.09 g), acetic acid (2.86 ml), and diethyl azodicarboxylate (40% toluene solution, 21.9 ml) were added, and the mixture was warmed to room temperature and stirred for 30 minutes.

The reaction mixture was concentrated, and the resulting residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5%) and obtained (S) -2-acetyloxy-1- (3-biphenyl) -3-Butyne (light yellow oil) was dissolved in MeOH (208 ml), K ₂ CO ₃ (862 mg) was added, and the mixture was stirred for 1.5 hours at room temperature.

The reaction mixture was concentrated to about 1/3 volume, aqueous hydrochloric acid (1.0 M, 400 ml) was added, and the mixture was extracted with a mixed solution of hexane-ethyl acetate (1: 1, 300 ml × 2). 400 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 0-5%) to give the title compound (colorless oil) 12.65 g,> 98% ee [analyzed by ¹ H-NMR by MTPA Steal method]).

^{The 1} H-NMR spectrum was consistent with the compound obtained in Reference Example 3.

Reference Example 5
(S) -1- (3-Biphenyl) -2- (t-butyldimethylsilyloxy) -3-butyne

参考例４で得られた化合物（12.64g）のDMF（113ml）溶液に、0℃でイミダゾール(7.739g)とt-ブチルジメチルシリルクロリド（10.28g）を加え、室温で14時間拌した。

To a DMF (113 ml) solution of the compound obtained in Reference Example 4 (12.64 g), imidazole (7.739 g) and t-butyldimethylsilyl chloride (10.28 g) were added at 0 ° C., and the mixture was stirred at room temperature for 14 hours.

Saturated aqueous sodium hydrogen carbonate (500 ml) was added to the reaction mixture, and the mixture was extracted with hexane (500 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (500 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (developing solvent; ethyl acetate / hexane = 0-4%) gave the title compound (colorless oil, 18.98 g).
¹ H-NMR (CDCl ₃ , 300MHz) δppm; 0.06 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 2.51 (d, J = 2.0Hz, 1H), 3.03-3.18 (m , 12H), 4.56-4.64 (m, 1H), 7.26-7.69 (m, 9H),
[α] _D ²⁶ 27.8 ° (C.1.38 CHCl ₃ )

Reference Example 6
(3R, 4R) -3-((S) -4-biphenyl-3-yl- (3-tert-butyldimethylsilyloxy) -1-butyn-1-yl)-(4-tert-butyldimethylsilyloxy) ) -2-Methylenecyclopentanone

  To a toluene (169 ml) solution of the compound (18.84 g) obtained in Reference Example 5 was added n-butyllithium (2.64 M, hexane solution, 20.8 ml) at 0 ° C. under an argon atmosphere, and the mixture was stirred at room temperature for 20 minutes. Diethylaluminum chloride (10.93M, hexane solution, 63.6 ml) was added to this solution at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. To this solution was added (4R) -2- (N, N-diethylamino) methyl-4- (t-butyldimethylsiloxy) cyclopent-2-en-1-one (0.25M, toluene solution, 169 ml) at room temperature, Stir for 50 minutes. The reaction solution was added to a mixed solution of hexane (100 ml) -saturated aqueous ammonium chloride solution (80 ml) -aqueous hydrochloric acid solution (2M, 60 ml) with stirring, and then the organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (60 ml). The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the resulting residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 0-5%) to give the title compound (pale yellow oil) 21.45 g) was obtained.

Reference Example 7
(2E) -17,18,19,20-Tetranor-16- (3-biphenyl) -2,3,13,14-tetradehydro-PGE ₁ methyl ester 11,15-bis (t-butyldimethylsilyl ether)

（4E）-5-カルボメトキシペント-4-エニル亜鉛(II)ヨージド（0.75M,THF溶液，6.0ml）に、-70℃でシアン化銅（I）・２塩化リチウム（1.0M，THF溶液，3.0ml）を加え同温度で２０分間撹拌した。この溶液に-70℃において、参考例６で得られた化合物（0.3M，THF溶液，5.0ml）とクロロトリメチルシラン（0.34ml）を加え、撹拌しながら約2時間かけて室温まで昇温した。

(4E) -5-Carbomethoxypent-4-enylzinc (II) iodide (0.75M, THF solution, 6.0ml) at -70 ° C with copper (I) cyanide / lithium dichloride (1.0M, THF solution) , 3.0 ml) and stirred at the same temperature for 20 minutes. To this solution, the compound obtained in Reference Example 6 (0.3 M, THF solution, 5.0 ml) and chlorotrimethylsilane (0.34 ml) were added at −70 ° C., and the temperature was raised to room temperature over about 2 hours with stirring. .

A saturated aqueous ammonium chloride solution (23 ml) was added to the reaction mixture, and the mixture was extracted with hexane (10 ml). The organic layer was washed with saturated brine, dried and concentrated. The residue obtained was dissolved in diethyl ether (1.5 ml) -isopropyl alcohol (6.0 ml), pyridinium p-toluenesulfonate (8 mg) was added, and Stir for 16 hours. Hexane (100 ml) was added to the reaction mixture, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried and concentrated. The residue obtained was purified by silica gel column chromatography (developing solvent; ethyl acetate / hexane = 6%). To give the title compound (pale yellow oil, 497 mg).
¹ H-NMR (CDCl ₃ , 300 MHz) δppm; -0.09 (s, 3H), -0.05 (s, 3H), 0.06 (s, 3H), 0.09 (s, 3H), 0.82 (s, 9H), 0.88 (s, 9H), 1.10-1.80 (m, 6H), 2.05-2.25 (m, 3H), 2.13 (dd, J = 17.7, 6.5Hz, 1H), 2.51-2.71 (m, 2H), 2.91-3.07 (m, 2H), 3.72 (s, 3H), 4.16-4.27 (m, 1H), 4.49-4.60 (m, 1H), 5.81 (dt, J = 15.6, 1.5Hz, 1H), 6.94 (dt, J = 15.6, 6.9Hz, 1H), 7.16-7.61 (m, 9H)
IR (neat): 2952, 2930, 2858, 2234, 1747, 1727, 1659, 1600, 1472, 1463, 1436, 1361, 1258, 1196, 1123, 1082, 1006, 940, 883, 838, 779, 757, 702 , 669 cm ^-1
MS (ES +) m / z: 711 (M + Na) ⁺

(2E) -17,18,19,20-Tetranor-16- (3-biphenyl) -2,3,13,14-tetradehydro-PGE ₁ (Compound 33)

参考例７で得られた化合物（483mg）をCH₃CN(23ml)に溶解し、0℃で46％フッ化水素酸水溶液（5.3ml）を加え、同温度で3時間撹拌した。反応液を酢酸エチル（100ml）−飽和重曹水（150ml）中に撹拌しながら注いだ後、有機層を分離し水層を酢酸エチル（100ml）抽出した。有機層を合わせて飽和重曹水（100ml×2）で洗浄後、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧濃縮して得られた粗精製物をシリカゲルカラムクロマトグラフィー（展開溶媒；酢酸エチル/ヘキサン＝50〜67％）で精製し、表記化合物（無色油状物、287mg）を得た。
¹H-NMR(CDCl₃, 300MHz) δppm; 1.12-1.78(m, 6H), 2.06-2.23(m, 3H), 2.14(dd, J=18.5, 9.2Hz, 1H), 2.32(d, J=3.4Hz, 1H), 2.46(d, J=5.9Hz, 1H), 2.39-2.70(m, 1H), 2.63(ddd, J=18.5, 7.3, 1.4Hz, 1H), 2.99-3.16(m, 2H), 3.71(s, 3H), 4.07-4.21(m, 1H), 4.63-4.74(m, 1H), 5.80(dt, J=15.6, 1.5Hz, 1H), 6.94(dt, J=15.6, 7.1Hz, 1H), 7.21-7.62(m, 9H)
IR(neat): 3406, 3232, 2930, 2859, 2235, 1743, 1722, 1655, 1600, 1575, 1480, 1437, 1320, 1277, 1203, 1157, 1077, 1038, 988, 858, 800, 758, 728, 702, 616, 415 cm^-1
MS(ES+) m/z: 483(M+Na)⁺

The compound (483 mg) obtained in Reference Example 7 was dissolved in CH ₃ CN (23 ml), 46% aqueous hydrofluoric acid solution (5.3 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was poured into ethyl acetate (100 ml) -saturated aqueous sodium hydrogen carbonate (150 ml) with stirring, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 ml). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate (100 ml × 2), dried over anhydrous magnesium sulfate, and filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (developing solvent; ethyl acetate / hexane = 50 to 67%) to obtain the title compound (colorless oil, 287 mg).
¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.12-1.78 (m, 6H), 2.06-2.23 (m, 3H), 2.14 (dd, J = 18.5, 9.2 Hz, 1H), 2.32 (d, J = 3.4Hz, 1H), 2.46 (d, J = 5.9Hz, 1H), 2.39-2.70 (m, 1H), 2.63 (ddd, J = 18.5, 7.3, 1.4Hz, 1H), 2.99-3.16 (m, 2H ), 3.71 (s, 3H), 4.07-4.21 (m, 1H), 4.63-4.74 (m, 1H), 5.80 (dt, J = 15.6, 1.5Hz, 1H), 6.94 (dt, J = 15.6, 7.1 Hz, 1H), 7.21-7.62 (m, 9H)
IR (neat): 3406, 3232, 2930, 2859, 2235, 1743, 1722, 1655, 1600, 1575, 1480, 1437, 1320, 1277, 1203, 1157, 1077, 1038, 988, 858, 800, 758, 728 , 702, 616, 415 cm ^-1
MS (ES +) m / z: 483 (M + Na) ⁺

(2E) -17,18,19,20-Tetranor-16- (3-biphenyl) -2,3,13,14-tetradehydro-PGE ₁ (compound 34)

実施例１で得られた化合物（190mg）のアセトン（8.5ml）溶液に水（85ml）、リン酸緩衝液（ｐＨ＝7.0，0.2M，5.3ml）を加え、さらにリパーゼPS（天野製薬社製，5.32g）を加え、室温で12時間激しく撹拌した。反応混合物をセライトろ過し、ろ液を3規定塩酸を加えｐＨ＝6とした後、反応混合液を約１/4の体積まで濃縮し、硫酸アンモニウムで塩析し、酢酸エチル(100ml×2)で抽出し、有機層を飽和食塩水(30ml)で洗浄、無水硫酸マグネシウムで乾燥、濾過した。濾液を減圧下濃縮し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；酢酸エチル/ヘキサン＝50〜67％）により精製し、標記化合物（94 mg）を得た。
¹H-NMR(CDCl₃, 300MHz) δppm; 1.10-3.40(m, 14H), 2.14(dd, J=18.7, 9.0Hz, 1H), 3.05(dd, J=13.5, 6.4Hz, 1H), 3.10(dd, J=13.5, 6.6Hz, 1H), 4.07-4.22(m, 1H), 4.63-4.75(m, 1H), 5.80(d, J=15.7Hz, 1H), 7.02(dt, J=15.7, 7.2Hz, 1H), 7.21-7.63(m, 9H)
IR(neat): 3384, 2930, 2859, 2238, 1740, 1694, 1652, 1606, 1480, 1422, 1285, 1236, 1156, 1076, 1036, 988, 799, 757, 728, 702, 616 cm^-1
MS(ES+) m/z: 469(M+Na)⁺ ; MS(ES-) m/z: 445(M-H)^-

Water (85 ml) and phosphate buffer (pH = 7.0, 0.2 M, 5.3 ml) were added to a solution of the compound (190 mg) obtained in Example 1 in acetone (8.5 ml), and lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.) was added. , 5.32 g) was added and stirred vigorously at room temperature for 12 hours. The reaction mixture was filtered through Celite, and the filtrate was adjusted to pH = 6 by adding 3N hydrochloric acid. The reaction mixture was concentrated to about 1/4 volume, salted out with ammonium sulfate, and ethyl acetate (100 ml × 2). The organic layer was washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate and filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (developing solvent; ethyl acetate / hexane = 50 to 67%) to obtain the title compound (94 mg).
¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.10-3.40 (m, 14H), 2.14 (dd, J = 18.7, 9.0Hz, 1H), 3.05 (dd, J = 13.5, 6.4Hz, 1H), 3.10 (dd, J = 13.5, 6.6Hz, 1H), 4.07-4.22 (m, 1H), 4.63-4.75 (m, 1H), 5.80 (d, J = 15.7Hz, 1H), 7.02 (dt, J = 15.7 , 7.2Hz, 1H), 7.21-7.63 (m, 9H)
IR (neat): 3384, 2930, 2859, 2238, 1740, 1694, 1652, 1606, 1480, 1422, 1285, 1236, 1156, 1076, 1036, 988, 799, 757, 728, 702, 616 cm ^-1
MS (ES +) m / z: 469 (M + Na) ⁺ ; MS (ES-) m / z: 445 (MH) ^-

  Using terminal acetylene compounds obtained by performing the same operations as those described in Reference Examples 1-5 or JP-A-2001-89444, the same operations as in Reference Examples 6, 7, Example 1 and Example 2 were performed. By performing this, the following compounds of the present invention were obtained.

17,18,19,20-Tetranor-2,3,13,14-tetradehydro-16- (3'-methylbiphenyl-3-yl) -PGE ₁ (Compound 56)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.22-1.77(m, 9H), 2.06-2.25(m, 3H), 2.14(dd, J=18.6,9.2Hz, 1H), 2.41(s, 3H), 2.49-2.63(m, 2H), 2.96-3.13(m, 2H), 4.04-4.20(m, 1H), 4.60-4.71(m, 1H), 5.79(d, J=15.5Hz, 1H), 6.94-7.07(m, 1H), 7.12-7.52(m, 8H)
MS(ES+) m/z: 483(M+Na)⁺; MS(ES-) m/z: 459(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.22-1.77 (m, 9H), 2.06-2.25 (m, 3H), 2.14 (dd, J = 18.6, 9.2 Hz, 1H), 2.41 (s, 3H) , 2.49-2.63 (m, 2H), 2.96-3.13 (m, 2H), 4.04-4.20 (m, 1H), 4.60-4.71 (m, 1H), 5.79 (d, J = 15.5Hz, 1H), 6.94 -7.07 (m, 1H), 7.12-7.52 (m, 8H)
MS (ES +) m / z: 483 (M + Na) ⁺ ; MS (ES-) m / z: 459 (MH) ⁺

(2E) -17,18,19,20-Tetranor-16- (3-methoxymethylphenyl) -2,3,13,14-tetradehydro-PGE ₁ (Compound 18)

¹H-NMR(CDCl₃, 300MHz) δppm: 1.37-1.86(m, 9H), 2.12-2.31(m, 3H), 2.19(dd, J=18.6, 9.4Hz, 1H), 2.50-2.61(m, 1H), 2.64-2.75(m, 1H), 2.93-3.09(m, 2H), 3.45(s, 3H), 4.13-4.24(m, 1H), 4.47(s, 2H), 4.62-4.69(m, 1H), 5.83(d, J=15.7Hz, 1H), 7.03(dt, J=15.7, 7.2Hz, 1H), 7.16-7.38(m, 4H)
IR(neat): 3400, 2930, 2860, 2236, 1744, 1697, 1652, 1448, 1384, 1284, 1194, 1159, 1085, 1039, 886, 793, 758, 703, 667, 552 cm^-1
MS(ES+): 437(M+Na)⁺; MS(ES-): 413(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.37-1.86 (m, 9H), 2.12-2.31 (m, 3H), 2.19 (dd, J = 18.6, 9.4Hz, 1H), 2.50-2.61 (m, 1H), 2.64-2.75 (m, 1H), 2.93-3.09 (m, 2H), 3.45 (s, 3H), 4.13-4.24 (m, 1H), 4.47 (s, 2H), 4.62-4.69 (m, 1H), 5.83 (d, J = 15.7Hz, 1H), 7.03 (dt, J = 15.7, 7.2Hz, 1H), 7.16-7.38 (m, 4H)
IR (neat): 3400, 2930, 2860, 2236, 1744, 1697, 1652, 1448, 1384, 1284, 1194, 1159, 1085, 1039, 886, 793, 758, 703, 667, 552 cm ^-1
MS (ES +): 437 (M + Na) ⁺ ; MS (ES-): 413 (MH) ^-

Examples 5 to 19
Using the terminal acetylene compound obtained by performing the same operation as in Reference Examples 1 to 5 or JP-A-2001-89444, the same operation as in Reference Example 6 was performed, and in Reference Example 7 (4E)- The following compounds of the present invention were obtained by carrying out the same operations as in Example 1 and Example 2 using the corresponding organozinc reagent instead of 5-carbomethoxypent-4-enylzinc (II) iodide.

17,18,19,20-tetranor-16- (3-biphenyl) -2,2,3,3,13,14-hexadehydro-PGE ₁ (compound 36)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.39-1.78(m, 6H), 2.08-2.22(m, 1H), 2.15(dd, J=18.7, 9.0Hz, 1H), 2.25-2.38(m, 2H), 2.54-2.69(m, 2H), 3.05(dd, J=13.4, 6.5Hz, 1H), 3.10(dd, J=13.4, 6.4Hz, 1H), 3.18-3.72(m, 3H), 4.10-4.21(m, 1H), 4.63-4.72(m, 1H), 7.21-7.61(m, 9H)
IR(neat); 3386, 3031, 2932, 2864, 2622, 2235, 1738, 1699, 1600, 1588, 1480, 1455, 1421, 1328, 1259, 1157, 1074, 1036, 900, 797, 757, 728, 702, 616, 594 cm^-1
MS(ES-) m/z: 443 (M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.39-1.78 (m, 6H), 2.08-2.22 (m, 1H), 2.15 (dd, J = 18.7, 9.0 Hz, 1H), 2.25-2.38 (m, 2H), 2.54-2.69 (m, 2H), 3.05 (dd, J = 13.4, 6.5Hz, 1H), 3.10 (dd, J = 13.4, 6.4Hz, 1H), 3.18-3.72 (m, 3H), 4.10 -4.21 (m, 1H), 4.63-4.72 (m, 1H), 7.21-7.61 (m, 9H)
IR (neat); 3386, 3031, 2932, 2864, 2622, 2235, 1738, 1699, 1600, 1588, 1480, 1455, 1421, 1328, 1259, 1157, 1074, 1036, 900, 797, 757, 728, 702 , 616, 594 cm ^-1
MS (ES-) m / z: 443 (MH) ^-

17,18,19,20-tetranor-16- (3-methoxyphenyl) -2,2,3,3,13,14-hexadehydro-PGE ₁ (compound 16)

¹H-NMR(CDCl₃, 300MHz) δppm: 1.22-1.84(m, 6H), 2.14-2.42(m, 4H), 2.57-2.75(m, 2H), 2.93-3.70(m, 5H), 3.42(s, 3H), 4.12-4.24(m, 1H), 4.44(s, 2H), 4.58-4.70(m, 1H), 7.12-7.37(m, 4H)
IR(neat): 3400, 2930, 2235, 1740, 1712, 1436, 1384, 1261, 1193, 1159, 1079, 755, 703, 593 cm^-1
MS(ES-): 411(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.22-1.84 (m, 6H), 2.14-2.42 (m, 4H), 2.57-2.75 (m, 2H), 2.93-3.70 (m, 5H), 3.42 ( s, 3H), 4.12-4.24 (m, 1H), 4.44 (s, 2H), 4.58-4.70 (m, 1H), 7.12-7.37 (m, 4H)
IR (neat): 3400, 2930, 2235, 1740, 1712, 1436, 1384, 1261, 1193, 1159, 1079, 755, 703, 593 cm ^-1
MS (ES-): 411 (MH) ^-

17,18,19,20-tetranor-16-phenyl-2,2,3,3,13,14-hexadehydro-PGE ₁ (compound 2)

¹H-NMR(CDCl₃, 300MHz) δppm: 1.40-1.83(m, 6H), 2.15-2.26(m, 1H), 2.21(dd, J=18.6, 9.1Hz, 1H), 2.33-2.42(m, 2H), 2.61(ddd, J=11.3, 8.2, 1.8Hz, 1H), 2.72(ddd, J=18.6, 7.3, 1.3Hz, 1H), 2.99(dd, J=13.2, 6.5Hz, 1H), 3.04(dd, J=13.2, 6.5Hz, 1H), 4.18-4.29(m, 1H), 4.66(dt, J=1.8Hz, 6.5Hz, 1H), 7.18-7.37(m, 5H)
IR(neat): 3392, 3208, 2931, 2864, 2236, 1736, 1698, 1496, 1455, 1385, 1244, 1157, 1077, 1032, 755, 702 cm^-1
MS(FAB)(+KI)m/z: 407(M+K)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.40-1.83 (m, 6H), 2.15-2.26 (m, 1H), 2.21 (dd, J = 18.6, 9.1Hz, 1H), 2.33-2.42 (m, 2H), 2.61 (ddd, J = 11.3, 8.2, 1.8Hz, 1H), 2.72 (ddd, J = 18.6, 7.3, 1.3Hz, 1H), 2.99 (dd, J = 13.2, 6.5Hz, 1H), 3.04 (dd, J = 13.2, 6.5Hz, 1H), 4.18-4.29 (m, 1H), 4.66 (dt, J = 1.8Hz, 6.5Hz, 1H), 7.18-7.37 (m, 5H)
IR (neat): 3392, 3208, 2931, 2864, 2236, 1736, 1698, 1496, 1455, 1385, 1244, 1157, 1077, 1032, 755, 702 cm ^-1
MS (FAB) (+ KI) m / z: 407 (M + K) ⁺

3-thia-17,18,19,20-tetranor-16-phenyl-13,14-didehydro-PGE ₁ (compound 8)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.46-1.82(m, 6H), 2.15-2.29(m, 1H), 2.21(dd, J=18.6, 9.1Hz, 1H), 2.56-2.77(m, 4H), 2.94-3.10(m, 2H), 3.10-4.30(m, 3H), 3.22(s, 2H), 4.17-4.27(m, 1H), 4.67(dt, J=6.7, 1.8Hz, 1H), 7.16-7.37(m, 5H)
IR(neat): 3400, 3029, 2930, 2860, 2236, 1734, 1496, 1455, 1385, 1288, 1157, 1078, 1034, 894, 746, 702, 540 cm^-1
MS(ES+) m/z: 413(M+Na) ⁺; MS(ES-) m/z: 389(M-H) ^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.46-1.82 (m, 6H), 2.15-2.29 (m, 1H), 2.21 (dd, J = 18.6, 9.1Hz, 1H), 2.56-2.77 (m, 4H), 2.94-3.10 (m, 2H), 3.10-4.30 (m, 3H), 3.22 (s, 2H), 4.17-4.27 (m, 1H), 4.67 (dt, J = 6.7, 1.8Hz, 1H) , 7.16-7.37 (m, 5H)
IR (neat): 3400, 3029, 2930, 2860, 2236, 1734, 1496, 1455, 1385, 1288, 1157, 1078, 1034, 894, 746, 702, 540 cm ^-1
MS (ES +) m / z: 413 (M + Na) ⁺ ; MS (ES-) m / z: 389 (MH) ^-

3-thia-17,18,19,20-tetranor-16- (3-biphenyl) -13,14-didehydro-PGE ₁ (compound 10)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.37-1.78(m, 6H), 2.09-2.21(m, 1H), 2.15(dd, J=18.6, 6.9Hz, 1H), 2.52-2.69(m, 4H), 3.02-3.15(m, 2H), 2.80-4.30(m, 3H), 3.19(s, 2H), 4.07-4.19(m, 1H), 4.66-4.75(m, 1H), 7.22-7.28(m, 1H), 7.30-7.53(m, 6H), 7.55-7.62(m, 2H)
IR(neat):3400, 3032, 2930, 2860, 2236, 1734, 1600, 1480, 1456, 1421, 1288, 1157, 1090, 1038, 901, 799, 758, 729, 703, 668, 616, 579, 503 cm^-1
MS(ES+) m/z: 489(M+Na) ⁺; MS(ES-) m/z: 465(M-H) ^-

¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.37-1.78 (m, 6H), 2.09-2.21 (m, 1H), 2.15 (dd, J = 18.6, 6.9 Hz, 1H), 2.52-2.69 (m, 4H), 3.02-3.15 (m, 2H), 2.80-4.30 (m, 3H), 3.19 (s, 2H), 4.07-4.19 (m, 1H), 4.66-4.75 (m, 1H), 7.22-7.28 ( m, 1H), 7.30-7.53 (m, 6H), 7.55-7.62 (m, 2H)
IR (neat): 3400, 3032, 2930, 2860, 2236, 1734, 1600, 1480, 1456, 1421, 1288, 1157, 1090, 1038, 901, 799, 758, 729, 703, 668, 616, 579, 503 cm ^-1
MS (ES +) m / z: 489 (M + Na) ⁺ ; MS (ES-) m / z: 465 (MH) ^-

3-thia-17,18,19,20-tetranor-16- (3-methoxymethylphenyl) -13,14-didehydro-PGE ₁ (compound 12)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.40-1.85(m, 6H), 2.08-3.60(m, 12H), 2.21(dd, J=18.5, 9.5Hz, 1H), 3.45(s, 3H), 4.12-4.26(m, 1H), 4.48(s, 2H), 4.65-4.75(m, 1H), 7.17-7.39(m, 4H)
IR(neat): 3400, 2930, 2860, 2236, 1740, 1733, 1488, 1448, 1385, 1287, 1159, 1087, 1039, 891, 791, 757, 704, 667, 555 cm^-1
MS(ES-) m/z: 433(M-H) ^-

¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.40-1.85 (m, 6H), 2.08-3.60 (m, 12H), 2.21 (dd, J = 18.5, 9.5Hz, 1H), 3.45 (s, 3H) , 4.12-4.26 (m, 1H), 4.48 (s, 2H), 4.65-4.75 (m, 1H), 7.17-7.39 (m, 4H)
IR (neat): 3400, 2930, 2860, 2236, 1740, 1733, 1488, 1448, 1385, 1287, 1159, 1087, 1039, 891, 791, 757, 704, 667, 555 cm ^-1
MS (ES-) m / z: 433 (MH) ^-

3-thia-17,18,19,20-tetranor-16- (3-cyclohexyloxymethylphenyl) -13,14-didehydro-PGE ₁ (compound 14)

¹H-NMR(CDCl₃, 300MHz) δppm: 1.12-1.88(m, 14H), 1.96-2.06(m, 2H), 2.14-2.26(m, 1H), 2.20(dd, J=18.7, 9.5Hz, 1H), 2.50-3.60(m, 10H), 3.20(s, 2H), 4.09-4.23(m, 1H), 4.56(s, 2H), 4.67-4.73(m, 1H), 7.16-7.38(m, 4H)
IR(neat): 3400, 2931, 2857, 2236, 1740, 1715, 1610, 1488, 1450, 1385, 1363, 1346, 1287, 1157, 1073, 955, 891, 790, 757, 703, 666 cm^-1
MS(ES+): 525(M+Na)⁺; MS(ES-): 501(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.12-1.88 (m, 14H), 1.96-2.06 (m, 2H), 2.14-2.26 (m, 1H), 2.20 (dd, J = 18.7, 9.5Hz, 1H), 2.50-3.60 (m, 10H), 3.20 (s, 2H), 4.09-4.23 (m, 1H), 4.56 (s, 2H), 4.67-4.73 (m, 1H), 7.16-7.38 (m, 4H)
IR (neat): 3400, 2931, 2857, 2236, 1740, 1715, 1610, 1488, 1450, 1385, 1363, 1346, 1287, 1157, 1073, 955, 891, 790, 757, 703, 666 cm ^-1
MS (ES +): 525 (M + Na) ⁺ ; MS (ES-): 501 (MH) ^-

3-thia-17,18,19,20-tetranor-16- (3-ethoxymethylphenyl) -13,14-didehydro-PGE ₁ (compound 20)

¹H-NMR(CDCl₃, 300MHz) δppm: 1.27(t, J=7.0Hz, 3H), 1.41-1.88(m, 6H), 2.14-2.29(m, 1H), 2.20(dd, J=18.7, 9.2Hz, 1H), 2.52-2.75(m, 4H), 2.94-3.10(m, 2H), 3.21(s, 2H), 3.36-4.40(m, 4H), 3.63(q, J=7.0Hz, 2H), 4.52(s, 2H), 4.65-4.73(m, 1H), 7.08-7.40(m, 4H)
IR(neat): 3418, 3027, 2934, 2861, 2235, 1739, 1603, 1496, 1455, 1436, 1286, 1152, 1065, 1011, 919, 749, 702, 589 cm^-1
MS(ES+) m/z: 471(M+Na)⁺ ; MS(ES-) m/z: 447(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.27 (t, J = 7.0 Hz, 3H), 1.41-1.88 (m, 6H), 2.14-2.29 (m, 1H), 2.20 (dd, J = 18.7, 9.2Hz, 1H), 2.52-2.75 (m, 4H), 2.94-3.10 (m, 2H), 3.21 (s, 2H), 3.36-4.40 (m, 4H), 3.63 (q, J = 7.0Hz, 2H ), 4.52 (s, 2H), 4.65-4.73 (m, 1H), 7.08-7.40 (m, 4H)
IR (neat): 3418, 3027, 2934, 2861, 2235, 1739, 1603, 1496, 1455, 1436, 1286, 1152, 1065, 1011, 919, 749, 702, 589 cm ^-1
MS (ES +) m / z: 471 (M + Na) ⁺ ; MS (ES-) m / z: 447 (MH) ^-

3-thia-17,18,19,20-tetranor-16- (3-isopropyloxymethylphenyl) -13,14-didehydro-PGE ₁ (compound 22)

¹H-NMR(CDCl₃, 300MHz) δppm: 1.25(d, J=6.4Hz, 6H), 1.41-1.86(m, 6H), 2.13-2.29(m, 1H), 2.20(dd, J=18.5, 9.3Hz, 1H), 2.49-2.74(m, 4H), 2.93-3.10(m, 2H), 3.20(s, 2H), 3.40-4.25(m,5H), 4.52(s, 2H), 4.65-4.73(m, 1H), 7.06-7.36(m, 4H)
IR(neat): 3385, 2971, 2928, 2863, 2236, 1738, 1488, 1446, 1384, 1334, 1286, 1140, 1041, 908, 787, 702, 554 cm^-1
MS(ES+) m/z: 485(M+Na)⁺；MS(ES-) m/z: 461(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 1.25 (d, J = 6.4 Hz, 6H), 1.41-1.86 (m, 6H), 2.13-2.29 (m, 1H), 2.20 (dd, J = 18.5, 9.3Hz, 1H), 2.49-2.74 (m, 4H), 2.93-3.10 (m, 2H), 3.20 (s, 2H), 3.40-4.25 (m, 5H), 4.52 (s, 2H), 4.65-4.73 (m, 1H), 7.06-7.36 (m, 4H)
IR (neat): 3385, 2971, 2928, 2863, 2236, 1738, 1488, 1446, 1384, 1334, 1286, 1140, 1041, 908, 787, 702, 554 cm ^-1
MS (ES +) m / z: 485 (M + Na) ⁺ ; MS (ES-) m / z: 461 (MH) ⁻

3-thia-17,18,19,20-tetranor-16- [3- (2-methoxy) ethylphenyl] -13,14-didehydro-PGE ₁ (compound 24)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.49-1.84(m, 6H), 2.15-2.31(m, 1H), 2.21(dd, J=18.6, 9.6Hz, 1H), 2.55-3.80(m, 9H), 2.89(t, J=6.5Hz, 2H), 3.22(s, 2H), 3.36(s, 3H), 3.68(t, J=6.5Hz, 2H), 4.17-4.28(m, 1H), 4.65-4.73(m, 1H), 7.02-7.20(m, 3H), 7.22-7.29(m, 1H)
IR(neat):3418, 2932, 2862, 2654, 2237, 1732, 1609, 1488, 1446, 1417, 1385, 1286, 1157, 1103, 1043, 902, 786, 757, 705, 666, 568 cm^-1
MS(ES+) m/z: 471(M+Na) ⁺; MS(ES-) m/z: 447(M-H) ^-

¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.49-1.84 (m, 6H), 2.15-2.31 (m, 1H), 2.21 (dd, J = 18.6, 9.6 Hz, 1H), 2.55-3.80 (m, 9H), 2.89 (t, J = 6.5Hz, 2H), 3.22 (s, 2H), 3.36 (s, 3H), 3.68 (t, J = 6.5Hz, 2H), 4.17-4.28 (m, 1H), 4.65-4.73 (m, 1H), 7.02-7.20 (m, 3H), 7.22-7.29 (m, 1H)
IR (neat): 3418, 2932, 2862, 2654, 2237, 1732, 1609, 1488, 1446, 1417, 1385, 1286, 1157, 1103, 1043, 902, 786, 757, 705, 666, 568 cm ^-1
MS (ES +) m / z: 471 (M + Na) ⁺ ; MS (ES-) m / z: 447 (MH) ^-

3-thia-17,18,19,20-tetranor-16- (3-ethylphenyl) -13,14-didehydro-PGE ₁ (compound 26)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.24(t, J=7.5Hz, 3H), 1.45-1.85(m, 6H), 1.88-3.40(m, 12H), 2.21(dd, J=18.6, 9.2Hz, 1H), 3.22(s, 2H), 4.17-4.30(m, 1H), 4.58-4.75(m, 1H), 6.97-7.16(m, 3H), 7.20-7.30(m, 1H)
IR(neat):3385, 2929, 2234, 1731, 1607, 1446, 1384, 1288, 1157, 1033, 798, 736, 703 cm^-1
MS(ES+) m/z: 441(M+Na) ⁺; MS(ES-) m/z: 417(M-H) ^-

¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.24 (t, J = 7.5Hz, 3H), 1.45-1.85 (m, 6H), 1.88-3.40 (m, 12H), 2.21 (dd, J = 18.6, 9.2Hz, 1H), 3.22 (s, 2H), 4.17-4.30 (m, 1H), 4.58-4.75 (m, 1H), 6.97-7.16 (m, 3H), 7.20-7.30 (m, 1H)
IR (neat): 3385, 2929, 2234, 1731, 1607, 1446, 1384, 1288, 1157, 1033, 798, 736, 703 cm ^-1
MS (ES +) m / z: 441 (M + Na) ⁺ ; MS (ES-) m / z: 417 (MH) ^-

3-thia-17,18,19,20-tetranor-16- (3-isopropylphenyl) -13,14-didehydro-PGE ₁ (compound 28)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.10-3.30(m, 17H), 1.25(d, J=7.0Hz, 6H), 2.21(dd, J=18.6, 9.1Hz, 1H), 3.22(s, 2H), 4.19-4.29(m, 1H), 4.59-4.71(m, 1H), 6.98-7.17(m, 3H), 7.20-7.29(m, 1H)
IR(neat):3418, 2959, 2926, 2865, 2238, 1738, 1732, 1715, 1606, 1488, 1463, 1445, 1384, 1286, 1152, 1088, 1035, 792, 727, 706 cm^-1
MS(ES+) m/z: 455(M+Na) ⁺; MS(ES-) m/z: 431(M-H) ^-

¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.10-3.30 (m, 17H), 1.25 (d, J = 7.0Hz, 6H), 2.21 (dd, J = 18.6, 9.1Hz, 1H), 3.22 (s , 2H), 4.19-4.29 (m, 1H), 4.59-4.71 (m, 1H), 6.98-7.17 (m, 3H), 7.20-7.29 (m, 1H)
IR (neat): 3418, 2959, 2926, 2865, 2238, 1738, 1732, 1715, 1606, 1488, 1463, 1445, 1384, 1286, 1152, 1088, 1035, 792, 727, 706 cm ^-1
MS (ES +) m / z: 455 (M + Na) ⁺ ; MS (ES-) m / z: 431 (MH) ^-

17,18,19,20-Tetranor-16- (3-methoxymethylphenyl) -13,14-didehydro-PGE ₁ (compound 6)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.20-1.82 (m, 13H), 2.12-2.29 (m, 1H), 2.19 (dd, J=18.6, 9.3Hz, 1H), 2.34 (t, J=7.2Hz, 2H), 2.57 (ddd, J=11.7, 8.6, 1.9Hz, 2H), 2.69 (ddd, J=18.6, 7.4, 1.2Hz, 1H), 2.99 (dd, J=13.4, 6.5Hz, 1H), 3.04 (dd, J=13.4, 6.1Hz, 1H), 3.44 (s, 3H), 4.12-4.25 (m, 1H), 4.47 (s, 2H), 4.63-4.70 (m, 1H), 7.10-7.38 (m, 4H)
IR(neat): 3400, 2930, 2859, 2236, 1740, 1448, 1385, 1239, 1193, 1160, 1085, 1039, 793, 758, 703, 618 cm^-1
MS(ES+)m/z: 439(M+Na)⁺ ; MS(ES-)m/z: 415(M-H)-

¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.20-1.82 (m, 13H), 2.12-2.29 (m, 1H), 2.19 (dd, J = 18.6, 9.3Hz, 1H), 2.34 (t, J = 7.2Hz, 2H), 2.57 (ddd, J = 11.7, 8.6, 1.9Hz, 2H), 2.69 (ddd, J = 18.6, 7.4, 1.2Hz, 1H), 2.99 (dd, J = 13.4, 6.5Hz, 1H ), 3.04 (dd, J = 13.4, 6.1Hz, 1H), 3.44 (s, 3H), 4.12-4.25 (m, 1H), 4.47 (s, 2H), 4.63-4.70 (m, 1H), 7.10- 7.38 (m, 4H)
IR (neat): 3400, 2930, 2859, 2236, 1740, 1448, 1385, 1239, 1193, 1160, 1085, 1039, 793, 758, 703, 618 cm ^-1
MS (ES +) m / z: 439 (M + Na) ⁺ ; MS (ES-) m / z: 415 (MH)-

17,18,19,20-Tetranor-16- (3-biphenyl) -13,14-didehydro-PGE ₁ (compound 32)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.18-2.70(m, 18H), 2.14(dd, J=18.7, 9.2Hz, 1H), 3.00-3.14(m, 2H), 4.07-4.21(m, 1H), 4.64-4.73(m, 1H), 7.21-7.63(m, 9H)
IR(neat): 3386, 2932, 2858, 2236, 1736, 1708, 1600, 1576, 1480, 1455, 1420, 1324, 1236, 1158, 1102, 1077, 1037, 1001, 901, 800, 757, 728, 702, 616 cm^-1
MS(ES+) m/z: 471(M+Na) ⁺; MS(ES-) m/z: 447(M-H) ^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.18-2.70 (m, 18H), 2.14 (dd, J = 18.7, 9.2 Hz, 1H), 3.00-3.14 (m, 2H), 4.07-4.21 (m, 1H), 4.64-4.73 (m, 1H), 7.21-7.63 (m, 9H)
IR (neat): 3386, 2932, 2858, 2236, 1736, 1708, 1600, 1576, 1480, 1455, 1420, 1324, 1236, 1158, 1102, 1077, 1037, 1001, 901, 800, 757, 728, 702 , 616 cm ^-1
MS (ES +) m / z: 471 (M + Na) ⁺ ; MS (ES-) m / z: 447 (MH) ^-

1a-Homo-17,18,19,20-tetranor-16- (3-biphenyl) -13,14-didehydro-PGE ₁ (compound 30)

¹NMR(CDCl₃, 300MHz) δppm; 1.22-1.82(m, 15H), 2.09-2.21(m, 1H), 2.15(dd, J=18.3, 9.2Hz, 1H), 2.34(t, J=7.2Hz, 2H), 2.53-2.69(m, 2H), 3.01-3.15(m, 2H), 4.07-4.21(m, 1H), 4.65-4.73(m, 1H), 7.22-7.61(m, 9H)
IR(neat): 3388, 3034, 2930, 2857, 2237, 1738, 1713, 1600, 1576, 1480, 1455, 1421, 1324, 1285, 1236, 1159, 1077, 1037, 1001, 900, 799, 757, 728, 702, 616 cm^-1
MS(ES+) m/z: 485 (M+Na)⁺; MS(ES-) m/z: 461 (M-H)^-

¹ NMR (CDCl ₃ , 300MHz) δppm; 1.22-1.82 (m, 15H), 2.09-2.21 (m, 1H), 2.15 (dd, J = 18.3, 9.2Hz, 1H), 2.34 (t, J = 7.2Hz , 2H), 2.53-2.69 (m, 2H), 3.01-3.15 (m, 2H), 4.07-4.21 (m, 1H), 4.65-4.73 (m, 1H), 7.22-7.61 (m, 9H)
IR (neat): 3388, 3034, 2930, 2857, 2237, 1738, 1713, 1600, 1576, 1480, 1455, 1421, 1324, 1285, 1236, 1159, 1077, 1037, 1001, 900, 799, 757, 728 , 702, 616 cm ^-1
MS (ES +) m / z: 485 (M + Na) ⁺ ; MS (ES-) m / z: 461 (MH) ^-

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-chlorophenyl) -PGE ₁ (compound 44)
(1) (E)-[(4R, 5R) -2,4-bis (t-butyldimethylsiloxy) -5- (3-hydroxyprop-1-yl) cyclopent-1-enyl] hept-2-ene Acid methyl ester

トリメチルシリルオキシ-2-プロピン（246μl）のEt₂O（6.4ml）溶液に、アルゴン雰囲気下、-78℃でｎ-ブチルリチウム（2.64M，ヘキサン溶液, 568μl）を加え、40分間撹拌した。同温度でAlMe₃（1.01M，ヘキサン溶液, 1.49ml）を加え30分間攪拌後、(E)-7-[(R)-3-(tert-ブチルジメチルシロキシ)-5-オキソ-シクロペント-1-エニル]-ヘプト-2-エン酸 メチルエステル（353mg）のEt₂O（3.33ml）溶液とtert-ブチルジメチルシリルトリフラート（276μl）を加え、同温度で1時間攪拌した。

To a solution of trimethylsilyloxy-2-propyne (246 μl) in Et ₂ O (6.4 ml) was added n-butyllithium (2.64 M, hexane solution, 568 μl) at −78 ° C. in an argon atmosphere, and the mixture was stirred for 40 minutes. After adding AlMe ₃ (1.01M, hexane solution, 1.49 ml) at the same temperature and stirring for 30 minutes, (E) -7-[(R) -3- (tert-butyldimethylsiloxy) -5-oxo-cyclopent-1 -Ethyl] -hept-2-enoic acid methyl ester (353 mg) in Et ₂ O (3.33 ml) and tert-butyldimethylsilyl triflate (276 μl) were added and stirred at the same temperature for 1 hour.

The reaction solution was added to saturated aqueous ammonium chloride solution (50 ml) and extracted with Et ₂ O (50 ml). To the organic layer was added THF (10 ml), and the mixture was washed with aqueous hydrochloric acid (1M, 50 ml) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 10-15%) to obtain the desired product (colorless oil, 262 mg).
¹ H-NMR (CDCl ₃ , 300 MHz) δppm: 0.09 (s, 3H), 0.11 (s, 3H), 0.12 (2s, 6H), 0.90 (s, 9H), 0.93 (s, 9H), 1.22-1.63 (m, 4H), 1.74 (t, J = 6.1Hz, 1H), 1.90-2.30 (m, 5H), 2.49-2.62 (m, 1H), 3.18-3.27 (m, 1H), 3.73 (s, 3H ), 4.23-4.35 (m, 1H), 4.27 (dd, J = 6.1,1.6Hz, 2H), 5.83 (dt, J = 15.6,1.5Hz, 1H)
IR (neat): 3445,2953,2931,2898,2858,2221,1728,1683,1657,1472,1463,1437,1408,1390,1362,1316,1228,1217,1178,1151,1103,1026,1007 , 979,939,912,876,839,812,780,672cm ^-1
MS (ES +): 545 (M + Na) ⁺ ; MS (ES-): 521 (MH) ^-

(2) (E)-[(4R, 5R) -2,4-bis (t-butyldimethylsiloxy) -5- (3-oxoprop-1-yl) cyclopent-1-enyl] hept-2-enoic acid Methyl ester

実施例２０（１）で得られた化合物（92mg）のCHCl₃（3.5ml）溶液に、Dess-Martin 試薬（149mg）を室温で加え、30分攪拌した。反応溶液に飽和塩化アンモニウム水溶液（20ml）を加えEt₂O（20ml×2）で抽出し、有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた残渣をシリカカラムクロマトグラフィー（展開溶媒；酢酸エチル/ヘキサン＝5％）で精製して表記化合物（無色油状物、79mg）を得た。
¹H-NMR(CDCl₃,300MHz)δppm: 0.09(s,3H), 0.11(s,3H), 0.13(s,3H), 0.14(s,3H), 0.89(s,9H), 0.93(s,9H), 1.30-1.58(m,4H), 1.90-2.06(m,1H), 2.12-2.34(m,4H), 2.51-2.70(m,1H), 3.34-3.41(m,1H), 3.72(s,3H), 4.39(dt,J=7.3,4.6Hz,1H), 5.81(dt,J=15.6,1.6Hz,1H), 6.96(dt,J=15.6,7.0Hz,1H), 9.21(d,J=0.8Hz,1H)
MS(ES+):543(M+Na)⁺

To a solution of the compound (92 mg) obtained in Example 20 (1) in CHCl ₃ (3.5 ml), Dess-Martin reagent (149 mg) was added at room temperature and stirred for 30 minutes. A saturated aqueous ammonium chloride solution (20 ml) was added to the reaction solution, and the mixture was extracted with Et ₂ O (20 ml × 2). The obtained residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5%) to obtain the title compound (colorless oil, 79 mg).
¹ H-NMR (CDCl ₃ , 300MHz) δppm: 0.09 (s, 3H), 0.11 (s, 3H), 0.13 (s, 3H), 0.14 (s, 3H), 0.89 (s, 9H), 0.93 (s , 9H), 1.30-1.58 (m, 4H), 1.90-2.06 (m, 1H), 2.12-2.34 (m, 4H), 2.51-2.70 (m, 1H), 3.34-3.41 (m, 1H), 3.72 (s, 3H), 4.39 (dt, J = 7.3,4.6Hz, 1H), 5.81 (dt, J = 15.6,1.6Hz, 1H), 6.96 (dt, J = 15.6,7.0Hz, 1H), 9.21 ( d, J = 0.8Hz, 1H)
MS (ES +): 543 (M + Na) ⁺

(3) 15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-chlorophenyl) -PGE ₁ methyl ester

亜鉛粉末（301mg）のTHF（5.0ml）懸濁液に、アルゴン雰囲気下、室温でクロロトリメチルシラン（50μl）を加え10分間攪拌後、0℃で3-クロロベンジルブロミド(302μl)を加え同温度で1時間攪拌した。0℃でクロロトリメチルシラン（50μl）を加え30分攪拌して得られた有機亜鉛試薬の上澄み（2.5ml）とTiCl₄（100μl）を-78℃で実施例３（２）で得られた化合物（146mg）のTHF(5.0ml)溶液に加え、2時間かけて室温まで昇温した。

Chlorotrimethylsilane (50 μl) was added to a suspension of zinc powder (301 mg) in THF (5.0 ml) at room temperature under an argon atmosphere, stirred for 10 minutes, and 3-chlorobenzyl bromide (302 μl) was added at 0 ° C. at the same temperature. For 1 hour. Compound obtained from Example 3 (2) at -78 ° C with the supernatant of organic zinc reagent (2.5 ml) and TiCl ₄ (100 µl) obtained by adding chlorotrimethylsilane (50 µl) at 0 ° C and stirring for 30 minutes (146 mg) in THF (5.0 ml) was added and the temperature was raised to room temperature over 2 hours.

The reaction solution was added to a mixture of Et ₂ O (50 ml) -saturated aqueous ammonium chloride solution (45 ml) -hydrochloric acid solution (3.0 M, 5.0 nl) with stirring, and then the organic layer was separated, water (50 ml), saturated Washed with brine (50 ml). The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue obtained was subjected to silica column chromatography (developing solvent; ethyl acetate / hexane = 5 to 20%) to remove the low polar compound. (116 mg) was dissolved in CH ₃ CN (6.3 ml), 46% aqueous hydrofluoric acid solution (1.4 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 2.5 hr. The reaction mixture was poured into ethyl acetate (50 ml) -saturated aqueous sodium hydrogen carbonate (40 ml) with stirring, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate (40 ml), dried over anhydrous magnesium sulfate, and filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (developing solvent; ethyl acetate / hexane = 50 to 67%) to obtain the title compound (colorless oil, 44 mg).
¹ H-NMR (CDCl ₃ , 300MHz) δppm; 1.18-2.85 (m, 14H), 2.89-3.06 (m, 2H), 3.73 (s, 3H), 4.20-4.34 (m, 1H), 4.57-4.72 ( m, 1H), 5.73-5.90 (m, 1H), 6.85-7.37 (m, 5H)
IR (neat): 3419,2932,2860,2236,1744,1723,1657,1599,1574,1478,1436,1316,1279,1206,1158,1080,1038,870,781,703,685,556,442 cm ^-1
MS (ES +) m / z: 441 (M + Na) ⁺ ; MS (ES-) m / z: 417 (MH) ⁺

(4) 15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-chlorophenyl) -PGE ₁

実施例２０（３）で得た化合物を用い、実施例２と同様の操作を行うことにより標記化合物を得た。
¹H-NMR(CDCl₃, 300MHz) δppm; 1.14-1.84(m, 9H), 2.09-2.39(m, 3H), 2.321(d, J=18.5,9.2Hz, 1H), 2.52-2.80(m, 2H), 2.86-3.11(m, 2H), 4.19-4.32(m, 1H), 4.58-4.68(m, 1H), 5.76-5.88(m, 1H), 6.96-7.36(m, 1H)
IR(neat):3383,2932,2860,2237,1740,1694,1652,1599,1574,1477,1430,1311,1283,1235,1207,1158,1079,1035,985,870,780,703,685,554 cm^-1
MS(ES+) m/z: 427(M+Na)⁺; MS(ES-) m/z: 403(M-H)⁺

The title compound was obtained by the same procedures as in Example 2 using the compound obtained in Example 20 (3).
¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.14-1.84 (m, 9H), 2.09-2.39 (m, 3H), 2.321 (d, J = 18.5, 9.2 Hz, 1H), 2.52-2.80 (m, 2H), 2.86-3.11 (m, 2H), 4.19-4.32 (m, 1H), 4.58-4.68 (m, 1H), 5.76-5.88 (m, 1H), 6.96-7.36 (m, 1H)
IR (neat): 3383,2932,2860,2237,1740,1694,1652,1599,1574,1477,1430,1311,1283,1235,1207,1158,1079,1035,985,870,780,703,685,554 cm ^-1
MS (ES +) m / z: 427 (M + Na) ⁺ ; MS (ES-) m / z: 403 (MH) ⁺

Examples 21-38
The following compounds of the present invention were obtained by the same procedure as in Example 20 using benzyl halide corresponding to the change of 3-chlorobenzyl bromide in Example 20 (3).

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (2-methylphenyl) -PGE ₁ (compound 37)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.00-2.42(m, 13H), 2.38(s, 3H), 2.52-2.84(m, 2H), 2.92-3.16(m, 2H), 4.15-4.30(m, 1H), 4.58-4.71(m, 1H), 5.77-5.90(m, 1H), 6.92-7.30(m, 5H)
IR(neat):3384,3064,3020,2929,2859,2236,1731,1695,1652,1494,1456,1384,1286,1158,1108,1075,1030,986,870,800,746,667,559,451,418 cm^-1
MS(ES+) m/z: 407(M+Na)⁺; MS(ES-) m/z: 383(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.00-2.42 (m, 13H), 2.38 (s, 3H), 2.52-2.84 (m, 2H), 2.92-3.16 (m, 2H), 4.15-4.30 ( m, 1H), 4.58-4.71 (m, 1H), 5.77-5.90 (m, 1H), 6.92-7.30 (m, 5H)
IR (neat): 3384,3064,3020,2929,2859,2236,1731,1695,1652,1494,1456,1384,1286,1158,1108,1075,1030,986,870,800,746,667,559,451,418 cm ^-1
MS (ES +) m / z: 407 (M + Na) ⁺ ; MS (ES-) m / z: 383 (MH) ^-

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-methylphenyl) -PGE ₁ (compound 38)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.20-1.84(m, 9H), 2.08-2.40(m, 3H), 2.20(dd, J=18.6,9.2Hz, 1H), 2.34(s, 3H), 2.52-2.63(m, 1H), 2.65-2.78(m, 1H), 2.78-3.05(m, 2H), 4.15-4.30(m, 1H), 4.55-4.68(m, 1H), 5.83(d, J=15.2Hz, 1H), 6.93-7.30(m, 5H),
IR(neat):3384,3024,2929,2860,2237,1741,1697,1652,1610,1590,1488,1417,1310,1285,1236,1158,1095,1078,1037,985,882,777cm^-1
MS(ES+) m/z: 407(M+Na)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.20-1.84 (m, 9H), 2.08-2.40 (m, 3H), 2.20 (dd, J = 18.6, 9.2 Hz, 1H), 2.34 (s, 3H) , 2.52-2.63 (m, 1H), 2.65-2.78 (m, 1H), 2.78-3.05 (m, 2H), 4.15-4.30 (m, 1H), 4.55-4.68 (m, 1H), 5.83 (d, J = 15.2Hz, 1H), 6.93-7.30 (m, 5H),
IR (neat): 3384,3024,2929,2860,2237,1741,1697,1652,1610,1590,1488,1417,1310,1285,1236,1158,1095,1078,1037,985,882,777cm ^-1
MS (ES +) m / z: 407 (M + Na) ⁺

15 (αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (4-methylphenyl) -PGE ₁ (compound 39)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.13-1.83(m, 9H), 2.08-2.40(m, 3H), 2.20(dd, J=18.4,9.2Hz, 1H), 2.33(s, 3H), 2.52-2.63(m, 1H), 2.65-2.78(m, 1H), 2.86-3.04(m, 2H), 4.18-4.29(m, 1H), 4.56-4.66(m, 1H), 5.76-5.88(m, 1H), 6.92-7.24(m, 5H),
IR(neat):3386,3022,2927,2860,2236,1741,1697,1652,1516,1417,1285,1235,1158,1108,1077,1036,984,883,863,846,805,760,666,554,491cm^-1
MS(ES+) m/z: 407(M+Na)⁺; MS(ES-) m/z: 383(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.13-1.83 (m, 9H), 2.08-2.40 (m, 3H), 2.20 (dd, J = 18.4,9.2Hz, 1H), 2.33 (s, 3H) , 2.52-2.63 (m, 1H), 2.65-2.78 (m, 1H), 2.86-3.04 (m, 2H), 4.18-4.29 (m, 1H), 4.56-4.66 (m, 1H), 5.76-5.88 ( m, 1H), 6.92-7.24 (m, 5H),
IR (neat): 3386,3022,2927,2860,2236,1741,1697,1652,1516,1417,1285,1235,1158,1108,1077,1036,984,883,863,846,805,760,666,554,491cm ^-1
MS (ES +) m / z: 407 (M + Na) ⁺ ; MS (ES-) m / z: 383 (MH) ^-

15 (αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (2-biphenyl) -PGE ₁ (compound 40)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.10-1.83(m, 8H), 2.08-2.29(m, 4H), 2.17(dd, J=18.5,9.2Hz, 1H), 2.47-2.57(m, 1H), 2.69(dd, J=18.5,7.4Hz,1H), 2.99(dd, J=13.8,6.9Hz, 1H), 3.04-3.32(m, 1H), 4.12-4.22(m, 1/2H), 4.32-4.48(m, 1H), 4.62-4.70(m, 1/2H), 5.72-5.87(m,1H), 6.94-7.10(m, 1H), 7.19-7.46(m,9H)
IR(neat): 3386, 3059, 2932, 2860, 2233, 1738, 1694, 1652, 1480, 1436, 1313, 1282, 1235, 1159, 1038, 1010, 986, 876, 753, 704, 665, 617, 541, 469 cm^-1
MS(ES+) m/z: 469(M+Na)⁺; MS(ES-) m/z: 445(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.10-1.83 (m, 8H), 2.08-2.29 (m, 4H), 2.17 (dd, J = 18.5, 9.2 Hz, 1H), 2.47-2.57 (m, 1H), 2.69 (dd, J = 18.5, 7.4Hz, 1H), 2.99 (dd, J = 13.8, 6.9Hz, 1H), 3.04-3.32 (m, 1H), 4.12-4.22 (m, 1 / 2H) , 4.32-4.48 (m, 1H), 4.62-4.70 (m, 1 / 2H), 5.72-5.87 (m, 1H), 6.94-7.10 (m, 1H), 7.19-7.46 (m, 9H)
IR (neat): 3386, 3059, 2932, 2860, 2233, 1738, 1694, 1652, 1480, 1436, 1313, 1282, 1235, 1159, 1038, 1010, 986, 876, 753, 704, 665, 617, 541 , 469 cm ^-1
MS (ES +) m / z: 469 (M + Na) ⁺ ; MS (ES-) m / z: 445 (MH) ^-

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-biphenyl) -PGE ₁ (compound 41)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.00-2.80(m, 15H), 2.95-3.23(m, 2H), 4.07-4.21(m, 1H), 4.62-4.75(m, 1H), 5.80(d, J=15.7Hz, 1H), 6.92-7.63(m,10H)
IR(neat):3385,3060,3033,2929,2859,2235,1741,1695,1652,1606,1576,1480,1455,1420,1310,1285,1235,1156,1076,1036,985,892,799,757,728,702,668,616 cm^-1
MS(ES+) m/z: 469(M+Na)⁺; MS(ES-) m/z: 445(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.00-2.80 (m, 15H), 2.95-3.23 (m, 2H), 4.07-4.21 (m, 1H), 4.62-4.75 (m, 1H), 5.80 ( d, J = 15.7Hz, 1H), 6.92-7.63 (m, 10H)
IR (neat): 3385,3060,3033,2929,2859,2235,1741,1695,1652,1606,1576,1480,1455,1420,1310,1285,1235,1156,1076,1036,985,892,799,757,728,702,668,616 cm ^-1
MS (ES +) m / z: 469 (M + Na) ⁺ ; MS (ES-) m / z: 445 (MH) ^-

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (4-biphenyl) -PGE ₁ (compound 42)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.18-1.84(m, 6H), 2.13-2.32(m, 4H), 2.20(dd, J=18.5,9.1Hz, 1H), 2.52-2.65(m, 1H), 2.72(dd, J=18.5,7.2Hz, 1H), 2.95-3.24(m, 2H), 3.05(d, J=6.8Hz, 2H), 4.20-4.31(m, 1H), 4.60-4.79(m, 1H), 5.80(brd, J=15.5Hz, 1H), 6.93-7.08(m, 1H), 7.30-7.62(m,9H)
IR(neat): 3388, 3029, 2931, 2860, 2236, 1732, 1694, 1652, 1520, 1488, 1412, 1312, 1286, 1236, 1157, 1038, 1008, 847, 823, 761, 699, 560 cm^-1
MS(ES+) m/z: 469(M+Na)⁺; MS(ES-) m/z: 445(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.18-1.84 (m, 6H), 2.13-2.32 (m, 4H), 2.20 (dd, J = 18.5, 9.1 Hz, 1H), 2.52-2.65 (m, 1H), 2.72 (dd, J = 18.5, 7.2Hz, 1H), 2.95-3.24 (m, 2H), 3.05 (d, J = 6.8Hz, 2H), 4.20-4.31 (m, 1H), 4.60-4.79 (m, 1H), 5.80 (brd, J = 15.5Hz, 1H), 6.93-7.08 (m, 1H), 7.30-7.62 (m, 9H)
IR (neat): 3388, 3029 , 2931, 2860, 2236, 1732, 1694, 1652, 1520, 1488, 1412, 1312, 1286, 1236, 1157, 1038, 1008, 847, 823, 761, 699, 560 cm - ¹
MS (ES +) m / z: 469 (M + Na) ⁺ ; MS (ES-) m / z: 445 (MH) ^-

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (2-chlorophenyl) -PGE ₁ (compound 43)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.22-1.84(m, 6H), 2.13-2.33(m, 5H), 2.21(dd, J=18.4,9.1Hz, 1H), 2.53-2.80(m, 2H), 3.08-3.29(m, 1H), 3.14(dd, J=13.4,6.9Hz, 1H), 3.24(dd, J=13.4,6.9Hz, 1H), 4.20-4.32(m, 1H), 4.69-4.82(m, 1H), 5.79-5.90(m, 1H), 6.98-7.12(m, 1H), 7.18-7.43(m, 4H)
IR(neat): 3382, 2934, 2861, 2237, 1732, 1694, 1652, 1573, 1475, 1444, 1312, 1283, 1159, 1053, 1041, 985, 874, 754, 684, 548 cm^-1
MS(ES+) m/z: 427(M+Na)⁺; MS(ES-) m/z: 403(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.22-1.84 (m, 6H), 2.13-2.33 (m, 5H), 2.21 (dd, J = 18.4, 9.1Hz, 1H), 2.53-2.80 (m, 2H), 3.08-3.29 (m, 1H), 3.14 (dd, J = 13.4, 6.9Hz, 1H), 3.24 (dd, J = 13.4, 6.9Hz, 1H), 4.20-4.32 (m, 1H), 4.69 -4.82 (m, 1H), 5.79-5.90 (m, 1H), 6.98-7.12 (m, 1H), 7.18-7.43 (m, 4H)
IR (neat): 3382, 2934, 2861, 2237, 1732, 1694, 1652, 1573, 1475, 1444, 1312, 1283, 1159, 1053, 1041, 985, 874, 754, 684, 548 cm ^-1
MS (ES +) m / z: 427 (M + Na) ⁺ ; MS (ES-) m / z: 403 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (4-chlorophenyl) -PGE ₁ (compound 45)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.15-1.90(m, 7H), 2.13-2.32(m, 6H), 2.55-2.65(m, 1H), 2.74(dd, J=18.9,7.4Hz, 1H), 2.97(d, J=6.4Hz, 2H), 4.20-4.35(m, 1H), 4.55-4.65(m, 1H), 5.82(d, J=13.9Hz, 1H), 6.97-7.10(m, 1H), 7.18-7.33(m, 4H)
IR(neat): 3382, 2933, 2861, 2236, 1739, 1694, 1652, 1493, 1408, 1282, 1158, 1090, 1036, 1016, 985, 841, 808, 671, 548 cm^-1
MS(ES+) m/z: 427(M+Na)⁺; MS(ES-) m/z: 403(M-H)^-

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.15-1.90 (m, 7H), 2.13-2.32 (m, 6H), 2.55-2.65 (m, 1H), 2.74 (dd, J = 18.9, 7.4Hz, 1H), 2.97 (d, J = 6.4Hz, 2H), 4.20-4.35 (m, 1H), 4.55-4.65 (m, 1H), 5.82 (d, J = 13.9Hz, 1H), 6.97-7.10 (m , 1H), 7.18-7.33 (m, 4H)
IR (neat): 3382, 2933, 2861, 2236, 1739, 1694, 1652, 1493, 1408, 1282, 1158, 1090, 1036, 1016, 985, 841, 808, 671, 548 cm ^-1
MS (ES +) m / z: 427 (M + Na) ⁺ ; MS (ES-) m / z: 403 (MH) ^-

15 (αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-methoxyphenyl) -PGE ₁ (compound 46)

¹H-NMR(CDCl₃, 300MHz) δppm; 0.96-3.10(m, 16H), 2.21(dd, J=18.7,9.2Hz, 1H), 3.81(s, 3H), 4.17-4.30(m, 1H), 4.56-4.68(m, 1H), 5.77-5.88(m, 1H), 6.73-7.30(m, 5H)
IR(neat):3387,2934,2860,2236,1741,1695,1651,1603,1585,1490,1454,1437,1313,1258,1154,1080,1042,994,876,779,746,696,555 cm^-1
MS(ES+) m/z: 423(M+Na)⁺
MS(ES-) m/z: 399(M-H)⁺

¹ H-NMR (CDCl ₃ , 300MHz) δppm; 0.96-3.10 (m, 16H), 2.21 (dd, J = 18.7,9.2Hz, 1H), 3.81 (s, 3H), 4.17-4.30 (m, 1H) , 4.56-4.68 (m, 1H), 5.77-5.88 (m, 1H), 6.73-7.30 (m, 5H)
IR (neat): 3387,2934,2860,2236,1741,1695,1651,1603,1585,1490,1454,1437,1313,1258,1154,1080,1042,994,876,779,746,696,555 cm ^-1
MS (ES +) m / z: 423 (M + Na) ⁺
MS (ES-) m / z: 399 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16-phenyl-PGE ₁ (compound 47)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.12-1.83(m, 8H), 2.12-2.30(m, 5H), 2.52-2.63(m, 1H), 2.66-2.77(m, 1H), 2.94-3.10(m, 2H), 4.13-4.28(m, 1H), 4.62-4.69(m, 1H), 5.83(d, J=15.7Hz, 1H), 6.97-7.11(m, 1H), 7.20-7.37(m, 5H)
IR(neat): 3413, 3030, 2933, 2860, 2238, 1740, 1694, 1652, 1496, 1455, 1402, 1385, 1309, 1275, 1232, 1205, 1158, 1100, 1078, 1032, 989, 744, 701, 668, 547 cm^-1
MS(ES+) m/z: 393(M+Na)⁺; MS(ES-) m/z: 369(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.12-1.83 (m, 8H), 2.12-2.30 (m, 5H), 2.52-2.63 (m, 1H), 2.66-2.77 (m, 1H), 2.94- 3.10 (m, 2H), 4.13-4.28 (m, 1H), 4.62-4.69 (m, 1H), 5.83 (d, J = 15.7Hz, 1H), 6.97-7.11 (m, 1H), 7.20-7.37 ( m, 5H)
IR (neat): 3413, 3030, 2933, 2860, 2238, 1740, 1694, 1652, 1496, 1455, 1402, 1385, 1309, 1275, 1232, 1205, 1158, 1100, 1078, 1032, 989, 744, 701 , 668, 547 cm ^-1
MS (ES +) m / z: 393 (M + Na) ⁺ ; MS (ES-) m / z: 369 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-fluorophenyl) -PGE ₁ (compound 48)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.15-1.84(m, 9H), 2.12-2.32(m, 3H), 2.21(dd, J=18.6,9.2Hz, 1H), 2.55-2.65(m, 6H), 2.73(dd, J=18.66,7.8Hz, 1H), 3.00(d, J=6.4Hz, 2H), 4.19-4.31(m, 1H), 4.59-4.69(m, 1H), 5.82(d, J=15.5Hz, 1H), 6.90-7.33(m, 5H)
IR(neat): 3412, 2933, 2861, 2236, 1739, 1694, 1652, 1618, 1589, 1488, 1448, 1403, 1310, 1274, 1249, 1142, 1099, 1077, 1037, 984, 868, 840, 783, 754, 520, 462, 425 cm^-1
MS(ES+) m/z: 411(M+Na)⁺; MS(ES-) m/z: 387(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.15-1.84 (m, 9H), 2.12-2.32 (m, 3H), 2.21 (dd, J = 18.6, 9.2 Hz, 1H), 2.55-2.65 (m, 6H), 2.73 (dd, J = 18.66,7.8Hz, 1H), 3.00 (d, J = 6.4Hz, 2H), 4.19-4.31 (m, 1H), 4.59-4.69 (m, 1H), 5.82 (d , J = 15.5Hz, 1H), 6.90-7.33 (m, 5H)
IR (neat): 3412, 2933, 2861, 2236, 1739, 1694, 1652, 1618, 1589, 1488, 1448, 1403, 1310, 1274, 1249, 1142, 1099, 1077, 1037, 984, 868, 840, 783 , 754, 520, 462, 425 cm ^-1
MS (ES +) m / z: 411 (M + Na) ⁺ ; MS (ES-) m / z: 387 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-trifluorophenyl) -PGE ₁ (compound 49)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.18-1.84(m, 9H), 2.09-2.30(m, 4H), 2.54-2.79(m, 2H), 2.95-3.22(m, 2H), 4.18-4.30(m, 1H), 4.59-4.71(m, 1H), 5.74-5.87(m, 1H), 5.93-7.10(m, H), 7.35-7.60(m,4H)
IR(neat):3383,2935,2863,2236,1739,1694,1652,1493,1451,1418,1329,1287,1236,1201,1163,1124,1096,1075,1037,985,920,884,800,754,704,666,544 cm^-1
MS(ES+) m/z: 461(M+Na)⁺; MS(ES-) m/z: 437(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.18-1.84 (m, 9H), 2.09-2.30 (m, 4H), 2.54-2.79 (m, 2H), 2.95-3.22 (m, 2H), 4.18- 4.30 (m, 1H), 4.59-4.71 (m, 1H), 5.74-5.87 (m, 1H), 5.93-7.10 (m, H), 7.35-7.60 (m, 4H)
IR (neat): 3383,2935,2863,2236,1739,1694,1652,1493,1451,1418,1329,1287,1236,1201,1163,1124,1096,1075,1037,985,920,884,800,754,704,666,544 cm ^-1
MS (ES +) m / z: 461 (M + Na) ⁺ ; MS (ES-) m / z: 437 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (2,5-dichlorophenyl) -PGE ₁ (compound 50)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.16-1.86(m, 9H), 2.13-2.34(m, 4H), 2.55-2.80(m, 2H), 3.02-3.25(m, 2H), 4.22-4.33(m, 1H), 4.68-4.77(m, 1H), 5.78-5.89(m, 1H), 6.96-7.12(m, 1H), 7.16-7.42(m, 3H)
IR(neat):3412,2934,2860,2237,1739,1694,1652,1588,1562,1467,1395,1310,1282,1233,1202,1157,1098,1048,985,878,813,728,667,551,466 cm^-1
MS(ES+) m/z: 461(M+Na)⁺; MS(ES-) m/z: 437(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.16-1.86 (m, 9H), 2.13-2.34 (m, 4H), 2.55-2.80 (m, 2H), 3.02-3.25 (m, 2H), 4.22- 4.33 (m, 1H), 4.68-4.77 (m, 1H), 5.78-5.89 (m, 1H), 6.96-7.12 (m, 1H), 7.16-7.42 (m, 3H)
IR (neat): 3412,2934,2860,2237,1739,1694,1652,1588,1562,1467,1395,1310,1282,1233,1202,1157,1098,1048,985,878,813,728,667,551,466 cm ^-1
MS (ES +) m / z: 461 (M + Na) ⁺ ; MS (ES-) m / z: 437 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3,4-dichlorophenyl) -PGE ₁ (compound 51)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.05-2.41(m, 13H), 2.54-3.10(m, 4H), 4.14-4.33(m, 1H), 4.54-4.66(m, 1H), 5.74-5.87(m, 1H), 6.87-7.46(m, 4H)
MS(ES+) m/z: 461(M+Na)⁺; MS(ES-) m/z: 437(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.05-2.41 (m, 13H), 2.54-3.10 (m, 4H), 4.14-4.33 (m, 1H), 4.54-4.66 (m, 1H), 5.74- 5.87 (m, 1H), 6.87-7.46 (m, 4H)
MS (ES +) m / z: 461 (M + Na) ⁺ ; MS (ES-) m / z: 437 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-furanylphenyl) -PGE ₁ (compound 52)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.20-1.80(m, 8H), 2.09-2.26(m, 3H), 2.17(dd, J=18.4,9.2Hz, 1H), 2.51-2.75(m, 1H), 2.68(dd, J=18.4,7.2Hz, 1H), 2.95-3.12(m, 2H), 4.15-4.27(m, 1H), 4.58-4.77(m, 1H), 5.80(d, J=15.4Hz, 1H), 6.47(dd, J=3.3,1.9Hz, 1H), 6.66(d, J=3.3Hz, 1H), 6.93-7.10(m, 1H), 7.16(d, J=7.7Hz, 1H), 7.33(t, J=7.7Hz, 1H), 7.44-7.48(m,1H), 7.56(d, J=7.7Hz, 1H), 7.61(s, 1H)
IR(neat): 3384, 2932, 2860, 2237, 1739, 1694, 1652, 1503, 1486, 1446, 1418, 1371, 1313, 1285, 1220, 1193, 1156, 1078, 1035, 1014, 985, 926, 886, 791, 738, 699, 667, 595 cm^-1
MS(ES+) m/z: 459(M+Na)⁺; MS(ES-) m/z: 435(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.20-1.80 (m, 8H), 2.09-2.26 (m, 3H), 2.17 (dd, J = 18.4, 9.2 Hz, 1H), 2.51-2.75 (m, 1H), 2.68 (dd, J = 18.4, 7.2Hz, 1H), 2.95-3.12 (m, 2H), 4.15-4.27 (m, 1H), 4.58-4.77 (m, 1H), 5.80 (d, J = 15.4Hz, 1H), 6.47 (dd, J = 3.3,1.9Hz, 1H), 6.66 (d, J = 3.3Hz, 1H), 6.93-7.10 (m, 1H), 7.16 (d, J = 7.7Hz, 1H), 7.33 (t, J = 7.7Hz, 1H), 7.44-7.48 (m, 1H), 7.56 (d, J = 7.7Hz, 1H), 7.61 (s, 1H)
IR (neat): 3384, 2932, 2860, 2237, 1739, 1694, 1652, 1503, 1486, 1446, 1418, 1371, 1313, 1285, 1220, 1193, 1156, 1078, 1035, 1014, 985, 926, 886 , 791, 738, 699, 667, 595 cm ^-1
MS (ES +) m / z: 459 (M + Na) ⁺ ; MS (ES-) m / z: 435 (MH) ⁺

15αβ-17,18,19,20-Tetranor-2,3,13,14-tetradehydro-16- (2'-methylbiphenyl-3-yl) -PGE ₁ (Compound 53)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.17-1.80(m, 8H), 2.08-2.35(m, 5H), 2.27(s, 3H), 2.50-2.71(m, 2H), 2.99-3.13(m, 2H), 4.08-4.22(m, 1H), 4.61-4.73(m, 1H), 5.82(d, J=15.5Hz, 1H), 6.95-7.10(m, 1H), 7.15-7.43(m, 8H)
IR(neat): 3412, 3020, 2932, 2860, 2234, 1742, 1695, 1651, 1477, 1421, 1402, 1385, 1311, 1284, 1232, 1158, 1076, 1031, 987, 799, 758, 728, 715, 666, 624, 464 cm^-1
MS(ES+) m/z: 483(M+Na)⁺; MS(ES-) m/z: 459(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.17-1.80 (m, 8H), 2.08-2.35 (m, 5H), 2.27 (s, 3H), 2.50-2.71 (m, 2H), 2.99-3.13 ( m, 2H), 4.08-4.22 (m, 1H), 4.61-4.73 (m, 1H), 5.82 (d, J = 15.5Hz, 1H), 6.95-7.10 (m, 1H), 7.15-7.43 (m, 8H)
IR (neat): 3412, 3020, 2932, 2860, 2234, 1742, 1695, 1651, 1477, 1421, 1402, 1385, 1311, 1284, 1232, 1158, 1076, 1031, 987, 799, 758, 728, 715 , 666, 624, 464 cm ^-1
MS (ES +) m / z: 483 (M + Na) ⁺ ; MS (ES-) m / z: 459 (MH) ⁺

15αβ-17,18,19,20-Tetranor-2,3,13,14-tetradehydro-16- (3'-methylbiphenyl-3-yl) -PGE ₁ (Compound 54)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.19-1.80(m, 8H), 2.03-2.28(m, 5H), 2.41(s, 3H), 2.49-2.73(m, 2H), 2.98-3.22(m, 2H), 4.08-4.21(m, 1H), 4.60-4.73(m, 1H), 5.80(d, J=15.7Hz, 1H), 6.88-7.56(m, 9H)
IR(neat): 3385, 3030, 2928, 2859, 2235, 1742, 1694, 1652, 1604, 1581, 1475, 1461, 1417, 1311, 1284, 1234, 1158, 1091, 1036, 984, 882, 778, 700, 667, 552 cm^-1
MS(ES+) m/z: 483(M+Na)⁺; MS(ES-) m/z: 459(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δ ppm; 1.19-1.80 (m, 8H), 2.03-2.28 (m, 5H), 2.41 (s, 3H), 2.49-2.73 (m, 2H), 2.98-3.22 ( m, 2H), 4.08-4.21 (m, 1H), 4.60-4.73 (m, 1H), 5.80 (d, J = 15.7Hz, 1H), 6.88-7.56 (m, 9H)
IR (neat): 3385, 3030, 2928, 2859, 2235, 1742, 1694, 1652, 1604, 1581, 1475, 1461, 1417, 1311, 1284, 1234, 1158, 1091, 1036, 984, 882, 778, 700 , 667, 552 cm ^-1
MS (ES +) m / z: 483 (M + Na) ⁺ ; MS (ES-) m / z: 459 (MH) ⁺

15αβ-17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (4'-methylbiphenyl-3-yl) -PGE ₁ (compound 55)

¹H-NMR(CDCl₃, 300MHz) δppm; 1.15-1.80(m, 9H), 2.03-2.35(m, 4H), 2.39(s, 3H), 2.49-2.70(m, 2H), 2.98-3.22(m, 2H), 4.08-4.23(m, 1H), 4.69(t, J=6.2Hz, 1H), 5.80(d, J=16.2Hz, 1H), 6.94-7.08(m, 1H), 7.17-7.57(m, 8H)
IR(neat): 3385, 3026, 2931, 2861, 2238, 1743, 1694, 1652, 1606, 1528, 1484, 1434, 1418, 1402, 1312, 1285, 1234, 1188, 1157, 1095, 1078, 1035, 985, 824, 787, 759, 708, 667, 558 cm^-1
MS(ES+) m/z: 483(M+Na)⁺; MS(ES-) m/z: 459(M-H)⁺

¹ H-NMR (CDCl ₃ , 300 MHz) δppm; 1.15-1.80 (m, 9H), 2.03-2.35 (m, 4H), 2.39 (s, 3H), 2.49-2.70 (m, 2H), 2.98-3.22 ( m, 2H), 4.08-4.23 (m, 1H), 4.69 (t, J = 6.2Hz, 1H), 5.80 (d, J = 16.2Hz, 1H), 6.94-7.08 (m, 1H), 7.17-7.57 (m, 8H)
IR (neat): 3385, 3026, 2931, 2861, 2238, 1743, 1694, 1652, 1606, 1528, 1484, 1434, 1418, 1402, 1312, 1285, 1234, 1188, 1157, 1095, 1078, 1035, 985 , 824, 787, 759, 708, 667, 558 cm ^-1
MS (ES +) m / z: 483 (M + Na) ⁺ ; MS (ES-) m / z: 459 (MH) ⁺

Test Example 1 [anti-inflammatory activity]
Anti-inflammatory activity was determined according to the method described in the literature (Takayama, K., et al. (2002). Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem 277, 44147-44154.). Specifically, human peripheral blood monocytes were purified and cultured for 1 week to differentiate into macrophages. The evaluation compound was added to the differentiated macrophages to a final concentration of 10 nM and incubated for 30 minutes. After the culture, E. coli-derived lipopolysaccharide (LPS) was added to a final concentration of 5 ng / ml, and further cultured for 18 hours. After the culture, the cell supernatant was collected, and the amount of chemokine (MIP-1β) produced was measured by ELISA. A medium solution was used as a negative control for anti-inflammatory activity, and PGE ₂ was used as a positive control. The amount of MIP-1β produced when a negative control was added was defined as 100%, and the amount of MIP-1β remaining (% of control) when 10 nM of each compound was added and cultured. The results are shown in Table 2 together with Test Example 2.

Test Example 2 [Measurement of cAMP Production]
Evaluation compounds were added to differentiated macrophages to a final concentration of 1-1000 nM and incubated for 45 minutes. After culturing, the cells were disrupted, and intracellular cAMP was quantified by the EIA method. When the amount of cAMP when 1000 nMPGE ₂ was treated under the same conditions was taken as 100%, the ED50 value of each compound was calculated. The results are shown in Table 2 together with Test Example 1.

  As is apparent from the table, the compound of the present invention has a strong anti-inflammatory activity, while the cAMP production is very low.

Test Example 3 [Production inhibitory effect of compounds on various cytokine / chemokine production]
This was performed according to the method described in the literature (Takayama, K., et al. (2002). Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem 277, 44147-44154.). Specifically, purified human peripheral blood monocytes were cultured for 1 week and differentiated into macrophages. The evaluation compound was added to the differentiated macrophages to a final concentration of 0.1 to 100 nM and incubated for 30 minutes. After the culture, E. coli-derived lipopolysaccharide (LPS) was added to a final concentration of 5 ng / ml, and further cultured for 18 hours. After culturing, the cell supernatant was collected, and cytokine (TNFα) and chemokine (MCP-1, MIP-1β) production amounts were measured by ELISA. A medium solution was used as a negative control for anti-inflammatory activity, and PGE ₂ was used as a positive control. The production inhibition concentration (IC50 value) of each compound was calculated with the amount of cytokine production when a negative control was added as 100%. The results are shown in Table 3.

  As is clear from the table, the compound of the present invention strongly suppressed the production of various cytokines.

Test Example 4 [Inhibition of serum cytokine production in sepsis]
BALB / c mice were administered D-Galactosamine 450 mg / kg intraperitoneally and simultaneously with Indomethacine 3 mg / kg and orally administered for 65 min, followed by intraperitoneal LPS 500 μg / kg to develop sepsis. The test compound was dissolved in phosphate buffer and administered subcutaneously 1 min before intraperitoneal administration of LPS.

  The amount of TNFα in the serum after 1.5 hours was measured. Statistical processing was performed using Dunnett's method.

  The results are shown in FIG.

  As is clear from FIG. 1, the compound of the present invention was found to strongly suppress the production of serum cytokines in sepsis.

Test Example 5 [Effects on expression of MCP-1 in myocardial infarction]
After connecting a ventilator to the anesthetized rat, thoracotomy was performed to expose the heart. The reperfusion injury after myocardial infarction was induced by tying the distal part of the coronary artery 3-4 mm from the origin of the coronary artery by the snare method, making the myocardium ischemic for 30 minutes, and then reperfusion. 24 hours after reperfusion, the infarct region was excised, the tissue was crushed in a Tris buffer containing a protease inhibitor and a surfactant, and a soluble fraction was obtained by centrifugation. The total protein amount of the soluble fraction was measured by the BCA method. The amount of MCP-1 in the soluble fraction was measured by ELISA. The test compound (Compound 34) was dissolved subcutaneously in phosphate buffer 3 times 5 minutes before, 6 hours, and 12 hours after reperfusion. The results are shown in FIG.

  As is clear from FIG. 2, the compound of the present invention remarkably suppressed the expression level of MCP-1 in the myocardial infarction lesion.

  Since the compound of the present invention has excellent anti-inflammatory activity, autoimmune disease, rheumatoid arthritis, psoriasis, asthma, hepatitis, nephritis, atherosclerosis, myocarditis, sepsis, myocardial infarction, rejection during organ transplantation, It is useful for diseases such as intimal thickening after percutaneous transvascular coronary angioplasty, and is useful as a drug with few side effects such as lowering blood pressure.

It is the figure which showed the serum cytokine production inhibitory effect in sepsis, and the vertical axis | shaft showed the TNF (alpha) amount (ng / ml) in serum, and the horizontal axis | shaft showed the compound name and dosage (mg / Kg). In the figure, “***” indicates P <0.005. It is the figure which showed the effect with respect to MCP-1 expression in a rat myocardial infarction, and the vertical axis | shaft showed the amount of MCP-1 protein (ng / protein mg), and the horizontal axis | shaft showed the drug dosage.

Claims (1)

Formula (I)

[Wherein, R ¹ represents a hydrogen atom,
X is bi ylene group, ethynylene group, or -SCH ₂ - represents a group represented by,
R ² is a hydrogen atom,
R ³ represents a hydrogen atom, a phenyl group, a phenyl group or a furyl group substituted with one alkyl group having 1 to 6 carbon atoms . ]
Or a pharmaceutically acceptable salt or hydrate thereof.

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