WO2006137472A1 - Prostaglandin derivative - Google Patents

Abstract

A prostaglandin derivative represented by the formula: (I) wherein R1 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 the formula: -SCH2-; R2 and R3 independently represent 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, an alkyl group having 1 to 6 carbon atoms which is substituted by an alkoxy group having 1 to 6 carbon atoms, a phenyl group, a substituted phenyl group, a furyl group or a thienyl group, or a pharmaceutically acceptable salt thereof or a hydrate of the derivative or salt. These compounds show a satisfactory level of anti-inflammatory effect while minimizing the cAMP production-enhancing effect and is provided for reducing the adverse side effects that may be caused by an EP4 agonist.

Description

明 細 書 Specification

プロスタグランジン誘導体 Prostaglandin derivatives

技術分野 Technical field

[0001] 本発明は、新規なプロスタグランジン誘導体、その薬学的に許容される塩および水 和物に関する。 [0001] The present invention relates to a novel prostaglandin derivative, a pharmaceutically acceptable salt and a hydrate thereof.

背景技術 Background art

[0002] プロスタグランジン E (以下「PGE」と!、う）はァラキドン酸カスケードの代謝産物とし [0002] Prostaglandin E (hereinafter “PGE”!) Is a metabolite of the arachidonic acid cascade.

2 2 twenty two

て知られており、多彩な生理作用を有することが知られている。 It is known that it has various physiological actions.

[0003] 近年の研究の中で、 PGE受容体には大別して 4つのサブタイプ（EP1,EP2,EP3,EP [0003] In recent studies, PGE receptors are roughly divided into four subtypes (EP1, EP2, EP3, EP

2 2

4)の存在が報告されており、その中で、 EP4受容体は PGEをリガンドとして、生体内 4) has been reported, in which the EP4 receptor uses PGE as a ligand in vivo.

2 2

の抗炎症作用を発現することが報告されており（非特許文献 1)、 EP4作動薬は自己 免疫疾患、慢性関節リウマチ、乾癬、喘息、肝炎、腎炎、粥状動脈硬化症、心筋炎、 敗血症、心筋梗塞等の治療に有用であると考えられている。また臓器移植時の拒絶 緩和、経皮的経血管的冠動脈形成術後の血管内膜肥厚の緩和に有用であると考え られる。し力しながら、従来の EP4作動薬は細胞内の cAMP量上昇を介した情報伝達 機構を活性化することから、全身性に EP4作動薬を投与した場合、血管拡張作用を 有し、血圧降下等の副作用が懸念される。 EP4 agonists have been reported to exhibit anti-inflammatory effects of autoimmune diseases, rheumatoid arthritis, psoriasis, asthma, hepatitis, nephritis, atherosclerosis, myocarditis, sepsis It is considered useful for the treatment of 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 lower blood pressure. Such side effects are concerned.

[0004] 最近、 EP4受容体の抗炎症作用機序は、これまで報告されて 、る、 cAMP依存的な 細胞情報伝達とは異なる経路を介することが報告され、血圧低下等の副作用の少な Vヽ薬剤の可能性が示唆されて!ヽる (非特許文献 2)。 [0004] Recently, the mechanism of anti-inflammatory action of EP4 receptor has been reported so far, and it has been reported to be via a pathway different from cAMP-dependent cell signal transduction. The possibility of a drug is suggested! (Non-patent document 2).

[0005] 一方、 PGの 16位にフエ-ル基を有する PG誘導体は開示されている（特許文献 1) 力、これらの化合物は PG類の活性発現に非常に重要である 11位水酸基が非天然型 である立体異性体であり、また薬理活性にっ 、ては記載されて 、な!/、。 [0005] On the other hand, PG derivatives having a phenol group at the 16-position of PG have been disclosed (Patent Document 1). These compounds are very important for the expression of the activity of PGs. It is a stereoisomer that is a natural type, and it has been described for pharmacological activity.

[0006] また、 16位にフエ-ル基を有する PG誘導体力 ¾P4作動薬として開示されて 、る（非 特許文献 3)力 ω側鎖の 13,14位力 ¾重結合である化合物は開示されていない。 [0006] Further, a PG derivative having a phenyl group at position 16 is disclosed as a P4 agonist (Non-patent Document 3) A compound having a force at the 13,14 position of a ω side chain and a double bond is disclosed. It has not been.

[0007] さらに、抗炎症作用と cAMP産生とを分離されたィ匕合物について具体的に開示して いるものはない。 [0008] 特許文献 1：米国特許公報第 4328355号[0007] Furthermore, there is no specific disclosure of a compound in which anti-inflammatory action and cAMP production are separated. [0008] Patent Document 1: US Patent Publication No. 4328355

非特許文献 l : Takayama, K., J Biol Chem 277(2002), 44147-44154 Non-patent literature l: Takayama, K., J Biol Chem 277 (2002), 44147-44154

非特許文献 2 : Takayama, K., J Biol Chem 277(2002), 44147-44154., Takayama, K., Atherosclerosis Supplements, 4-2 (2002), 313 Non-Patent Document 2: Takayama, K., J Biol Chem 277 (2002), 44147-44154., Takayama, K., Atherosclerosis Supplements, 4-2 (2002), 313

非特許文献 3 : Bioorg. Med.Chem., 10,1743(2002), Bioorg. Med. Chem., 10,989(2002 ) Non-Patent Document 3: Bioorg. Med. Chem., 10, 1743 (2002), Bioorg. Med. Chem., 10, 989 (2002)

発明の開示 Disclosure of the invention

発明が解決しょうとする課題 Problems to be solved by the invention

[0009] 本発明は、 EP4作動薬で懸念される副作用を低減させるために、十分な抗炎症作 用を有しながら、 cAMP産生増強作用が弱い化合物を提供することを目的とする。 課題を解決するための手段[0009] An 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 a side effect which is concerned with an EP4 agonist. Means for solving the problem

[0010] 本発明者らは、抗炎症作用を有し、 cAMP産生増強活性の分離された化合物を見 出すべく研究を行った結果、式 (I)で表される新規プロスタグランジン誘導体が、優れ た抗炎症作用を有しながら、 cAMP産生増強作用が分離されていることを見出し、本 発明を完成した。[0010] As a result of researches to find a compound having an anti-inflammatory action and a cAMP production enhancing activity, the present inventors have found that a novel prostaglandin derivative represented by the formula (I) is It was found that cAMP production enhancing action was separated while having excellent anti-inflammatory action, and the present invention was completed.

[0011] すなわち、本発明は、式 (I)[0011] That is, the present invention provides a compound of formula (I)

[0012] [化 1][0012] [Chemical 1]

[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、[Wherein R¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms,

Xはエチレン基、トリメチレン基、ビニレン基、ェチ-レン基または一 SCH -で示さ X represents an ethylene group, a trimethylene group, a vinylene group, an ethylene group or a single SCH-

2 れる を示し、 2

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、フエニル 基、置換フエ-ル基、フリル基またはチェ二ル基を示す。 ]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。R² and R³ are each a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, carbon A haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms, a phenyl group, A substituted phenol group, a furyl group or a cheryl group is shown. Or a pharmaceutically acceptable salt or hydrate thereof.

発明の効果 The invention's effect

[0013] 本発明の化合物は優れた抗炎症作用を有しながら cAMP産生を促進しな 、ことが わかった。 [0013] It has been found that the compound of the present invention does not promote cAMP production while having an excellent anti-inflammatory action.

発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION

[0014] 本発明において、炭素原子数 1〜4個のアルキル基とは、直鎖または分枝鎖状のァ ルキル基を示し、メチル基、ェチル基、プロピル基、イソプロピル基、ブチル基、イソ ブチル基、 tert-ブチル基などが挙げられる。[0014] In the present invention, the alkyl group having 1 to 4 carbon atoms means a linear or branched alkyl group, and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an iso- group. Examples thereof include a butyl group and a tert-butyl group.

[0015] 炭素原子数 2〜4個のアルケニル基とは、直鎖または分枝鎖状のァルケ-ル基を 示し、 2—プロぺ-ル基、 2—メチル 2—プロぺ-ル基、 2—メチルー 2—ブテュル基 などが挙げられる。[0015] An alkenyl group having 2 to 4 carbon atoms is a linear or branched alkenyl group, which is a 2-propellyl group, a 2-methyl-2-propellyl group, Examples include 2-methyl-2-butul group.

[0016] ビ-レン基とは、トランスビ-レン基またはシスビ-レン基である。 [0016] The beylene group is a trans-butylene group or a cis-butylene group.

[0017] ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子である。[0017] The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0018] 炭素原子数 1〜6個のアルキル基とは炭素原子 1〜6個を有する直鎖又は分岐鎖 状のアルキル基を意味し、メチル基、ェチル基、 n—プロピル基、イソプロピル基、 n ブチル基、イソブチル基、 tert ブチル基、 sec ブチル基、 n ペンチル基、イソ ペンチル基，ネオペンチル基、 tert ペンチル基、 n—へキシル基などが挙げられる[0018] The 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, n butyl, isobutyl, tert butyl, sec butyl, n pentyl, isopentyl, neopentyl, tert pentyl, n-hexyl, etc.

[0019] 炭素原子数 1〜6個のハロアルキル基とは、 1〜5個のハロゲン原子で置換された 炭素原子数 1〜6個の直鎖状又は分枝鎖状のアルキル基を示し、フルォロメチル基 、クロロメチル基、ブロモメチル基、ジフルォロメチル基、トリフルォロメチル基、ペンタ フルオルェチル基などが挙げられる。[0019] 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, Group, chloromethyl group, bromomethyl group, difluoromethyl group, trifluoromethyl group, pentafluoroethyl group and the like.

[0020] 炭素原子数 1〜6個のアルコキシ基とは炭素原子 1〜6個を有する直鎖、分岐鎖状 または環状の飽和または不飽和のアルコキシ基を意味し、メトキシ基、エトキシ基、プ 口ポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、 sec-ブトキシ基、 tert-ブト キシ基、ペンチルォキシ基、へキシルォキシ基、ァリルォキシ基、シクロへキシルォキ シ基などを挙げることができる。[0020] 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, and a Oral poxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-buto Examples thereof include a xy group, a pentyloxy group, a hexyloxy group, a allyloxy group, and a cyclohexyloxy group.

[0021] 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 とは、炭素原子 1〜6個を有する直鎖、分岐鎖状または環状のアルコキシ基で置換さ れた炭素原子数 1〜6個のアルキル基を示し、メトキシメチル基、エトキシメチル基、ィ ソプロポキシメチル基、シクロへキシルォキシメチル基、 2—メトキシェチル基などが挙 げられる。 [0021] An alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 1 to 6 carbon atoms is a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms. A substituted alkyl group having 1 to 6 carbon atoms is exemplified, and examples thereof include a methoxymethyl group, an ethoxymethyl group, an isopropoxymethyl group, a cyclohexyloxymethyl group, and a 2-methoxyethyl group.

[0022] 置換フ -ル基とは、（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及び炭素原子数 1〜6個のアルコキシ基）からなる群より 選ばれる 1〜5個で置換されたフエ-ル基を示す。 [0022] The substituted full group consists 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). It represents a phenyl group substituted with 1 to 5 groups selected from the group.

[0023] フリル基とは 2—フリル基または 3—フリル基である。[0023] The furyl group is a 2-furyl group or a 3-furyl group.

[0024] チェ-ル基とは 2—チェ-ル基または 3—チェ-ル基である。[0024] The chael group is a 2-chael group or a 3-chael group.

[0025] 製薬学的に許容される塩の例としては、ナトリウム、カリウムなどのアルカリ金属との 塩、カルシウム、マグネシウムなどのアルカリ土類金属との塩、アンモニア、メチルアミ ン、ジメチルァミン、シクロペンチルァミン、ベンジルァミン、ピぺリジン、モノエタノー ルァミン、ジエタノールァミン、モノメチルモノエタノールァミン、トロメタミン、リジン、トリ ス（ヒドロキシメチル）ァミノメタンなどとの塩およびテトラアルキルアンモ-ゥム塩が挙 げられる。[0025] 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, and cyclopentylamine. And salts with benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine, tris (hydroxymethyl) aminomethane, and tetraalkylammonium salts.

[0026] 式 (I)の化合物は、以下の反応式 1に要約する方法により製造できる。 [0026] The compound of the formula (I) can be produced by the method summarized in the following Reaction Scheme 1.

[0027] [化 2][0027] [Chemical 2]

反応式 1Reaction formula 1

(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。）(In Reaction Scheme 1, R¹¹ has the same meaning as R¹ excluding a hydrogen atom, X, R² and R³ have the same meaning as described above, and TBS represents a tert butyldimethylsilyl group.)

以下、反応式 1を説明する。 Hereinafter, Reaction Formula 1 will be described.

[0028] 上記反応式 1の各反応は佐藤らにより公知の方法 [J.Org.Chem.,53,5590(1988)]に より行われる。また、出発物質として用いる一般式 (III)で示される化合物はそれ自体 公知であるか、あるいは公知の方法により容易に製造することができる。例えば、式 (II I)で示される化合物中、 R²が 3—メトキシメチル基であり R³が水素原子である化合物 は、特開 2001-89444号に記載されている。[0028] 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)]. 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 compounds represented by the formula (II I), a compound in which R² is a 3-methoxymethyl group and R³ is a hydrogen atom is described in JP-A-2001-89444.

[0029] (1-1) 式 (III)の化合物に、 n- BuLi0.5〜1.2モル当量と、次いで Et Α :ΐ0.5〜2.0モ (1-1) 0.5-1.2 molar equivalent of n-BuLi in the compound of formula (III), followed by Et Α: ΐ0.5-2.0 mol

2 2

ル当量を反応させアルキニルアルミニウム試薬を調整し、式 (Π)で示される化合物 0. 8〜2. 0モル当量を 78〜30°Cで不活性溶媒（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、式 (IV)の化合物を得る。The alkynylaluminum reagent is prepared by reacting the alkynyl aluminum reagent, and 0.8 to 2.0 molar equivalents of the compound represented by the formula (Π) are added at 78 to 30 ° C. with an inert solvent (for example, benzene, toluene, tetrahydrofuran, Thiol ether, methylene chloride, n-hexane, etc.) To obtain a compound of formula (IV).

[0030] (1-2)式 (IV)の化合物に式 (V)で表される有機銅化合物 0. 5〜4モル当量とトリメチ ルクロロシラン 0. 5〜4. 0モル当量とを不活性溶媒（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、 n—ペンタンなど）中 、— 78〜40°Cで反応させ、さらに無機酸 (例えば塩酸、硫酸、硝酸など)または有機 酸（例えば酢酸、 p—トルエンスルホン酸など）もしくはそのアミン塩（例えば p—トルェ 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、ジェチルエーテルあるいはこれらの混合溶媒など）中、 0〜40 °Cにて加水分解することにより式 (VI)の化合物を得る。 [0030] (1-2) The compound of formula (IV) is inerted with 0.5 to 4 mole equivalent of the organocopper compound represented by formula (V) and 0.5 to 4.0 mole equivalent of trimethylchlorosilane. In a solvent (for example, benzene, toluene, tetrahydrofuran, jetyl ether, methylene chloride, n-hexane, n-pentane, etc.), the reaction is performed at −78 to 40 ° C., and further an inorganic acid (for example, hydrochloric acid, sulfuric acid, nitric acid, etc.) ) Or an organic acid (eg acetic acid, p-toluenesulfonic acid, etc.) or an amine salt thereof (eg p-toluenesulfonic acid pyridine salt, etc.), and an organic solvent (eg acetone, methanol, ethanol, isopropanol, jetyl ether or The compound of formula (VI) is obtained by hydrolysis at 0 to 40 ° C. in a mixed solvent thereof).

[0031] (1-3)式 (VI)の化合物をフッ化水素酸、ピリジ-ゥム ポリ（ハイドロゲンフロリド）、塩 酸などを用い通常行われる条件にて、メタノール、エタノール、ァセトニトリルあるいは これらの混合溶媒または、これらと水との混合溶媒中、水酸基の保護基である tert— プチルジメチルシリル基をはずし、式 (I)において R¹が水素原子以外である本発明に 係わる式 (la)の PG誘導体を得る。[0031] (1-3) Methanol, ethanol, acetonitrile, or the like under the conditions usually used with hydrofluoric acid, pyridinium poly (hydrogen fluoride), hydrochloric acid, etc., as the compound of formula (VI) In the mixed solvent of or a mixed solvent of these and water, the tert-butyldimethylsilyl group which is a protecting group for the hydroxyl group is removed, and in the formula (I), R¹ is other than a hydrogen atom. To obtain a PG derivative.

[0032] (1-4)式 (la)の化合物をリン酸緩衝液、トリス一塩酸緩衝液などの緩衝液中、必要に 応じて有機溶媒 (アセトン、メタノール、エタノールなどの水と混和するもの）を用いて 酵素と反応させ加水分解することにより、式 (I)において R¹が水素原子である本発明 に係わる式 (lb)の PG誘導体を得る。[0032] (1-4) A compound of formula (la) is mixed with an organic solvent (acetone, methanol, ethanol, or other water as necessary) in a buffer solution such as a phosphate buffer solution or a tris monohydrochloride buffer solution. To obtain a PG derivative of the formula (lb) according to the present invention in which R¹ is a hydrogen atom in the formula (I).

[0033] 酵素としては、微生物が生産する酵素 (例えば、キャンディダ属、シユードモナス属 に属する微生物が生産する酵素）、動物の臓器力も調製される酵素 (例えば、ブタ肝 臓ゃブタ脾臓より調製される酵素)などであり、市販の酵素で具体例をあげると、リバ ーゼ VII (シグマ社製、キャンディダ属の微生物由来）、リパーゼ AY (天野製薬製、キ ヤンディダ属の微生物由来）、リパーゼ PS (天野製薬製、シユードモナス属の微生物 由来）、リパーゼ MF (天野製薬製、シユードモナス属の微生物由来）、 PLE (シグマ 社製、ブタ肝臓より調製)、リパーゼ II (シグマ社製、ブタ脾臓より調製)、リポプロティ ンリパーゼ (東京化成工業社製、ブタ脾臓より調製)などである。 [0033] Examples of the enzyme include enzymes produced by microorganisms (for example, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas), enzymes that can also adjust animal organ strength (for example, porcine liver and porcine spleen). Specific examples of commercially available enzymes include Ribase VII (manufactured by Sigma, Candida spp.), Lipase AY (Amano, manufactured by Candida spp.), Lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.), lipase MF (manufactured by Amano Pharmaceutical Co., Ltd.), PLE (manufactured by Sigma, prepared from pig liver), lipase II (manufactured by Sigma, prepared from porcine spleen) ), Lipoprotein lipase (manufactured by Tokyo Chemical Industry Co., Ltd., prepared from porcine spleen).

[0034] 酵素の使用量は、酵素の力価および基質 [式 (la)の化合物]の量に応じて適宜選 択すればよいが、通常は基質の 0. 1〜20倍重量部である。反応温度は、 25〜50°C 、好ましくは 30〜40°Cである。[0034] 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 (la)], but is usually 0.1 to 20 times by weight of the substrate. . Reaction temperature is 25-50 ° C The temperature is preferably 30 to 40 ° C.

[0035] また、本発明の化合物は、以下の反応式 2に要約する方法によっても製造できる。[0035] The compounds of the present invention can also be produced by the method summarized in Reaction Scheme 2 below.

[0036] [化 3][0036] [Chemical 3]

反応式 2 Reaction formula 2

.OTW1S

.OTW1S

(IX) (IX)

酸化

Oxidation

(反応式 2中、 R^U,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、(In Reaction Formula 2, R^U , X, R² , R³ are as defined above, Met represents a metal such as Li, Na, Mg, etc.

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。）TBS represents a tert-butyldimethylsilyl group, and TMS represents a trimethylsilyl group. )

以下、反応式 2を説明する。 Hereinafter, Reaction Formula 2 will be described.

[0037] 反応式 2の第 1工程は WO2004/087724により公知の方法で行われる。また、式（[0037] The first step of Reaction Scheme 2 is carried out by a known method according to WO2004 / 087724. Also, the formula (

XI)で示される化合物の前駆体であるハロゲン化物はそれ自体公知であるか、または 公知の方法により容易に製造することができる。The halide which is a precursor of the compound represented by XI) is known per se or can be easily produced by a known method.

[0038] (2- 1)式 (VIII)の化合物を n- BuLi0.5〜1.2当量と、次いで Me A1C 0.5〜2.0当量を(2-1) A compound of formula (VIII) is added with 0.5 to 1.2 equivalents of n-BuLi, and then 0.5 to 2.0 equivalents of Me A1C.

3 Three

反応させ調整した有機金属試薬と TBSOT tert -プチルジメチルシリルトリフラート 0.5 〜5.0当量の存在化、文献（Tetrahedron Lett., 1990,31,4481または WO2004/087 724)により公知の一般式 (VII)で示される化合物 0. 8〜2. 0当量と 78〜30°Cで不 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、次いで希塩酸で処理することによりトリメチ ルシリル基を選択的に脱保護することにより、一般式 (IX)の化合物を得る。Presence of reaction-adjusted organometallic reagent and TBSOT tert-butyldimethylsilyl triflate 0.5-5.0 equivalents, represented by the general formula (VII) known from literature (Tetrahedron Lett., 1990,31,4481 or WO2004 / 087 724) Compound with 0.8 to 2.0 equivalent and 78 to 30 ° C By selectively deprotecting the trimethylsilyl group by reacting in an active solvent (for example, benzene, toluene, tetrahydrofuran, jetyl ether, methylene chloride, n-hexane, etc.) and then treating with dilute hydrochloric acid. A compound of general formula (IX) is obtained.

[0039] (2-2)一般式 (IX)の化合物を MnO、 Dess-Martin試薬等の酸化剤 2〜 10当量を不[0039] (2-2) A compound of the general formula (IX) is added with 2 to 10 equivalents of an oxidizing agent such as MnO or Dess-Martin reagent.

2 2

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）中で反応させ一般式 (X)の化合物を得る。 The reaction is carried out in an active solvent (for example, benzene, toluene, tetrahydrofuran, jetyl ether, methylene chloride, n-hexane, etc.) to obtain a compound of the general formula (X).

[0040] (2-3) Li,Na,Mg等の金属と対応するハロゲン化物より調整される一般式 (XI)で示さ れる化合物 0.5〜10当量を、一般式 (X)の化合物と、必要に応じて TiCl ,SnCl等のル[0040] (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) are necessary. TiCl, SnCl, etc.

4 4 イス酸 0.5〜10当量の存在下反応させ、次いで反応式 1の第 3工程（1-3)と同様の 反応を行うことにより、式 (I)において R¹が水素原子以外である本発明に係わる式 (la4 4 This reaction is carried out in the presence of 0.5 to 10 equivalents of isotic acid, and then the same reaction as in the third step (1-3) of Reaction Scheme 1 is performed, whereby R¹ is other than a hydrogen atom in Formula (I). Inventive formula (la

)の PG誘導体を得ることができる。) PG derivatives can be obtained.

[0041] (2-4)反応式 1の第 4工程（1-4)と同様の反応を行うことにより式 (I)において R¹が水 素原子である本発明に係わる式 (lb)の PG誘導体を得ることができる。[0041] (2-4) By performing the same reaction as in the fourth step (1-4) of Reaction Formula 1, in Formula (I), R¹ is a hydrogen atom. PG derivatives can be obtained.

[0042] 本発明の化合物は、全身的または局所的に経口または静脈内、経鼻投与などの非 経口的に投与することができる。これらは、例えば、通常の方法により製造することが できる錠剤、粉剤、顆粒剤、散剤、カプセル剤、液剤、乳剤、懸濁剤等の形で経口投 与することができる。[0042] The compound of the present invention can be administered systemically or locally orally, parenterally, such as intravenously or nasally. These can be administered orally, for example, in the form of tablets, powders, granules, powders, capsules, liquids, emulsions, suspensions and the like that can be produced by conventional methods.

[0043] 静脈内投与の製剤としては、水性または非水性溶液剤、乳剤、懸濁剤、使用直前 に注射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。経鼻投与としては 、一般に薬物を含有した溶液および粉末 (硬カプセル)で、専用の点鼻器あるいは噴 霧器を用い鼻腔内に定量的にスプレー (噴霧)投与される。また、本発明の化合物は 、 a、 j8もしくは γ —シクロデキストリンまたはメチルイ匕シクロデキストリン等と包接ィ匕合 物を形成させて製剤化することもできる。更に、その水性または非水性溶液剤、乳剤 、懸濁剤等を注射等により投与することができる。投与量は年齢、体重等により異な る力 成人に対し lng〜： LOOOmgZ日であり、これを 1日 1回または数回に分けて投 与する。 [0043] 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 atomizer. The compound of the present invention can also be formulated by forming an inclusion complex with a, j8, γ-cyclodextrin, methyl thiocyclodextrin, or the like. Furthermore, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like. Dosage varies depending on age, body weight, etc. For adults, it is lng to: LOOOmgZ days, which are given once or divided into several times a day.

[0044] 本発明に係る代表的な式 (I)の化合物としては下記をあげることができる。 [0044] Typical examples of the compound of the formula (I) according to the present invention include the following.

[0045] [表 1-1] 化合物 No. 構造 化合物 No. 構造[0045] [Table 1-1] Compound No. Structure Compound No. Structure

化合物 1Compound 1

化合物 2Compound 2

化合物 3

Compound 3

化合物 4 化合物 11 一 。^0 化合物 5 化合物 12Compound 4 Compound 11 ^ 0 Compound 5 Compound 12

ー 化合物 6 化合物 13-Compound 6 Compound 13

^H。^≥ X^H.≥ X

化合物フ 化合物 14

Compound F Compound 14

表 1-2]

表 1-3]Table 1-2]

Table 1-3]

表 1-4]

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。

Table 1-4]

Example Hereinafter, the present invention will be specifically described with reference to Examples and Test Examples.

参考例 1 Reference example 1

3-ブロモフエ二ノレ酢酸 ェチノレエステノレ 3-Bromophenol Acetic Acid Ethenore

[化 4]

[Chemical 4]

3-ブロモフヱ-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、へキ サン—酢酸ェチルの混合溶液 (4: 1 ,200ml X 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°C/0.46mmHg)し、表記化合物（無色油状物、 54.93 g)を得た。Concentrated sulfuric acid (3.0 ml) was added to a solution of 3-bromophenol-acetic 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 mixture was concentrated to about 1/2 volume, extracted with a mixed solution of hexane-ethyl acetate (4: 1, 200 ml X 3), and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 ml) and saturated brine (30 ml). ), Dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (boiling point; 83 ° C / 0.46 mmHg) to obtain the title compound (colorless oil, 54.93 g).

^-NMRCCDCl , 300MHz) δ ppm; 1.26(t, J=7.2Hz, 3H), 3.58(s, 2H), 4.16(q, J=7.2 ^ -NMRCCDCl, 300MHz) δ ppm; 1.26 (t, J = 7.2Hz, 3H), 3.58 (s, 2H), 4.16 (q, J = 7.2

3 Three

Hz, 2H), 7.15-7.28(m, 2H), 7.36- 7.48(m, 2H), Hz, 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, 10 IR (neat): 2982, 1736, 1596, 1570, 1475, 1430, 1368, 1334, 1250, 1219, 1157, 1091, 1073, 10

31,998,944,891,841,781,682,432 cm—¹31,998,944,891,841,781,682,432 cm—¹

[0050] 参考例 2[0050] Reference Example 2

3-ビフエ-ル酢酸 ェチルエステル 3-biphenylacetic acid ethyl ester

[0051] [化 5][0051] [Chemical 5]

参考例 1で得られた化合物（45.04g)、フエ-ルホウ酸（33.89g)、 K CO (51.21g)のト The compound obtained in Reference Example 1 (45.04g), phenol boric acid (33.89g), KCO (51.21g)

2 3 twenty three

ルェン (370ml)懸濁液に Pd(PPh ) (5.0g)を加え、 100°Cで 23時間攪拌した。反応液を Pd (PPh 3) (5.0 g) was added to a suspension of Luen (370 ml), and the mixture was stirred at 100 ° C. for 23 hours. Reaction liquid

3 4 3 4

室温まで冷却し、飽和重曹水（600ml)を加え、へキサン 酢酸ェチルの混合溶液 (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 酸ェチル /へキサン =0〜5%)で精製して表記化合物（無色油状物、 41.43g)を得たCool to room temperature, add saturated aqueous sodium hydrogen carbonate (600 ml), extract with hexane ethyl acetate mixed solution (3: 1,500 ml), wash the organic layer with saturated brine (600 ml), dry over anhydrous magnesium sulfate, After filtration, the residue obtained by concentration under reduced pressure was subjected to silica column chromatography (developing solvent; vinegar The title compound (colorless oily product, 41.43 g) was obtained by purification with ethyl acetate / hexane = 0-5%.

H-NMR(CDC1 , 300MHz) δ ppm; 1.27(t, J=7.1Hz, 3H), 3.68(s, 2H), 4.17(q, J=7.1H-NMR (CDC1, 300MHz) δ ppm; 1.27 (t, J = 7.1Hz, 3H), 3.68 (s, 2H), 4.17 (q, J = 7.1

3 Three

Hz, 2H), 7.24-7.64(m, 9H) Hz, 2H), 7.24-7.64 (m, 9H)

IR(neat):3033,2982, 1733, 1600,1576,1480,1455, 1423, 1368,1294,1252, 1206,1155, 10 IR (neat): 3033,2982, 1733, 1600,1576,1480,1455, 1423, 1368,1294,1252, 1206,1155, 10

96,1032,899,846,754,699,616,409cm"¹96,1032,899,846,754,699,616,409cm "¹

[0052] 参考例 3 [0052] Reference Example 3

1- (3-ビフエ-ル） -3-ブチン- 2-オール 1- (3-biphenyl) -3-butyne-2-ol

[0053] [化 6][0053] [Chemical 6]

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°Cでジイソブチルアルミニウムヒドリド（0.93M,へキサン溶液、 195ml)を 1時間力 けて滴下し、同温で 1時間攪拌後、 - 70°Cでェチュ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。 To a solution of the compound obtained in Reference Example 2 (41.43g) in toluene (575ml), diisobutylaluminum hydride (0.93M, hexane solution, 195ml) was added dropwise at -70 ° C in an argon atmosphere for 1 hour. After stirring at the same temperature for 1 hour, etulmagnesium chloride (0.5M, THF solution, 690 ml) was added dropwise at -70 ° C over 3 hours.

[0054] 反応液を 3時間かけて室温まで昇温し、塩酸水溶液 (3.0M, 1000ml)に加え、酢酸ェ チル (500ml X 2)で抽出し、有機層を飽和食塩水 (1000ml)で洗浄し、無水硫酸マグネ シゥムで乾燥、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;酢酸ェチル /へキサン =5〜15%)で精製して表記化合物 (淡黄色油状物、 32. 58g)を得た。 [0054] The reaction mixture was warmed to room temperature over 3 hours, added to aqueous hydrochloric acid (3.0M, 1000ml), extracted with ethyl acetate (500ml x 2), and the organic layer was washed with saturated brine (1000ml). The residue obtained after drying over anhydrous magnesium sulfate, filtration, and concentration under reduced pressure was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5-15%) to purify the title compound (pale yellow oil, 32. 58 g) was obtained.

^-NMRCCDCl , 300MHz) δ ppm; 1.91(d, J=5.9Hz, IH), 2.52(d, J=2.2Hz, IH), 3.07 ^ -NMRCCDCl, 300MHz) δ ppm; 1.91 (d, J = 5.9Hz, IH), 2.52 (d, J = 2.2Hz, IH), 3.07

3 Three

(dd, J=13.5,6.5Hz, IH), 3.12(dd,J=13.5,6.1Hz, IH), 4.59— 4.70(m, IH), 7.24-7.63(m , 9H), (dd, J = 13.5,6.5Hz, IH), 3.12 (dd, J = 13.5,6.1Hz, IH), 4.59-4.70 (m, IH), 7.24-7.63 (m, 9H),

IR(neat):3544,3378,3289,3033,2926,2117,1600,1575, 1480,1455, 1421, 1386,1291, 10 IR (neat): 3544,3378,3289,3033,2926,2117,1600,1575, 1480,1455, 1421, 1386,1291, 10

93,1036,973,899,850,797,757,729,701,646,584,550cm"¹93,1036,973,899,850,797,757,729,701,646,584,550cm "¹

[0055] 参考例 4 [0055] Reference Example 4

(S) -1- (3-ビフヱ-ル） -3-ブチン- 2-オール [0056] [ィ匕 7](S) -1- (3-Bifyl) -3-butyn-2-ol [0056] [7]

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)とイソプロべ-ル酢酸 (72.2ml)を加え、 37°C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;酢酸ェチル /へキサン =5〜15%)で精製して（S) -2-ァセチルォキシ -1- (3-ビフ ェニル） -3-ブチン（淡黄色油状物、 20.46g)と（R) -1- (3-ビフエ-ル） -3-ブチン- 2-ォ ール (淡黄色油状物、 13.87g)を得た。得られた (R) -l- (3-ビフエニル) -3-ブチン- 2- オール（13.87g)の THF (124ml)溶液に、 0°Cで PPh (19.64g)、酢酸（4.29ml)、および

To a solution of the compound (32.14 g) obtained in Reference Example 3 in toluene (722 ml), add lipase PS (Amano Pharmaceutical Co., Ltd., 72.3 g) and isopropyl acetate (72.2 ml) at 37 ° C for 7.5 days. Stir vigorously. After filtering the reaction solution, the residue obtained by concentrating was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5-15%) and purified by (S) -2-acetylyl-1- (3 -Biphenyl) -3-butyne (pale yellow oil, 20.46g) and (R) -1- (3-biphenyl) -3-butyne-2-ol (pale yellow oil, 13.87g) Got. The obtained (R) -l- (3-biphenyl) -3-butyn-2-ol (13.87 g) in THF (124 ml) was added at 0 ° C with PPh (19.64 g), acetic acid (4.29 ml), and

3 Three

ジェチルァ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。 Jetylazodicarboxylate (40% toluene solution, 32.9 ml) was added, and the mixture was warmed to room temperature and stirred for 1 hour.

[0057] 0°Cに冷却後、 PPh (13.09g)、酢酸（2.86ml)、およびジェチルァゾジカルボキシレ [0057] After cooling to 0 ° C, PPh (13.09 g), acetic acid (2.86 ml), and jetylazodicarboxylate

3 Three

ート (40%トルエン溶液、 21.9ml)をカ卩え、室温に昇温し、 30分間攪拌した。 (40% toluene solution, 21.9 ml) was added, and the mixture was warmed to room temperature and stirred for 30 minutes.

[0058] 反応液を濃縮し、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；酢酸ェ チル /へキサン =5%)で精製して得られた (S) -2-ァセチルォキシ -1- (3-ビフエ-ル） - 3-ブチン (淡黄色油状物）を MeOH(208ml)に溶解し、 K CO (862mg)をカ卩ぇ 1.5時間[0058] The reaction solution was concentrated, and the resulting residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5%) to obtain (S) -2-acetylyl-1- ( 3-biphenyl)-3-butyne (pale yellow oil) was dissolved in MeOH (208 ml) and K CO (862 mg) was added for 1.5 hours.

2 3 twenty three

室温で攪拌した。 Stir at room temperature.

[0059] 反応混合物を約 1/3の体積まで濃縮し、塩酸水溶液（1.0M,400ml)を加え、へキサ ン―酢酸ェチルの混合溶液 ( 1： 1,300ml X 2)で抽出し、有機層を飽和重曹水 (400ml) 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力 ラムクロマトグラフィー（展開溶媒;酢酸ェチル /へキサン = 0〜5%)で精製して表記 化合物（無色油状物、 12.65g,〉98%ee[MTPA^テル法による¹ H- NMRより解析])を得 た。[0059] Concentrate the reaction mixture to about 1/3 volume, add aqueous hydrochloric acid (1.0 M, 400 ml), extract with hexane-ethyl acetate mixed solution (1: 1,300 ml X 2), and extract the organic layer. Was washed with saturated aqueous sodium hydrogen carbonate (400 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent; ethyl acetate / hexane = 0-5%). To give the title compound (colorless oil, 12.65 g,> 98% ee [analyzed by¹ H-NMR by MTPA ^ ter method]).

[0060] ^-NMR ^ベクトルは参考例 3で得られたィ匕合物と一致した。 [0060] The ^ -NMR ^ vector was consistent with the compound obtained in Reference Example 3.

[0061] 参考例 5[0061] Reference Example 5

(S) -1- (3-ビフエ-ル） -2- (t-ブチルジメチルシリルォキシ） -3-ブチン [0062] [ィ匕 8]

(S) -1- (3-biphenyl) -2- (t-butyldimethylsilyloxy) -3-butyne [0062] [8]

参考例 4で得られた化合物（12.64g)の DMF (113ml)溶液に、 0°Cでイミダゾール (7.7 39g)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 (12.64 g) obtained in Reference Example 4, imidazole (7.7 39 g) and t-butyldimethylsilyl chloride (10.28 g) were added at 0 ° C., and the mixture was stirred at room temperature for 14 hours.

[0063] 反応液に飽和重曹水（500ml)を加え、へキサン (500ml)で抽出し、有機層を飽和重 曹水（500ml)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;酢酸ェチル /へキサン = 0〜4%)で 精製して表記化合物 (無色油状物、 18.98g)を得た。[0063] Saturated aqueous sodium bicarbonate (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 bicarbonate (500 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 0-4%) to obtain the title compound (colorless oil, 18.98 g).

1H-NMR(CDC1 , 300MHz) δ ppm; 0.06(s, 3H), 0.07(s, 3H), 0.89(s, 9H), 2.51(d, J=2 1H-NMR (CDC1, 300MHz) δ ppm; 0.06 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 2.51 (d, J = 2

3 Three

•0Hz, 1H), 3.03-3.18(m, 12H), 4.56— 4.64(m, 1H), 7.26— 7.69(m, 9H), • 0Hz, 1H), 3.03-3.18 (m, 12H), 4.56— 4.64 (m, 1H), 7.26— 7.69 (m, 9H),

[ a ]²⁶ 27.8。 (C.1.38 CHC1 )[a]²⁶ 27.8. (C.1.38 CHC1)

D 3 D 3

[0064] 参考例 6 [0064] Reference Example 6

(3R,4R) - 3-((S)-4-ビフエ-ル -3-ィル-（3- t-ブチルジメチルシリルォキシ） -1-ブチ ン -1-ィル) - (4- t-ブチルジメチルシリルォキシ） -2-メチレンシクロペンタノン (3R, 4R)-3-((S) -4-biphenyl-3-yl- (3-t-butyldimethylsilyloxy) -1-butyn-1-yl)-(4- t-butyldimethylsilyloxy) -2-methylenecyclopentanone

[0065] [化 9][0065] [Chemical 9]

参考例 5で得られた化合物 (18.84g)のトルエン（169ml)溶液に、アルゴン雰囲気下 0 °Cで n-ブチルリチウム（2.64M,へキサン溶液、 20.8ml)をカ卩え、室温で 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（10.93M,へキサン溶液、 63.6ml)を 加え、室温で 30分間撹拌した。この溶液に室温で (4R)- 2-(N, N-ジェチルァミノ)メチ ル -4- (t-ブチルジメチルシロキシ）シクロペンタ- 2-ェン- 1-オン（0.25M, トルエン溶 液、 169ml)を加え、 50分間撹拌した。反応液をへキサン（100ml)—飽和塩ィ匕アンモ -ゥム水溶液 (80ml)—塩酸水溶液 (2M, 60ml)の混合液に撹拌しながら加えた後、 有機層を分離し、飽和重曹水溶液 (60ml)で洗浄した。得られた有機層を無水硫酸 マグネシウムで乾燥、濾過後濃縮して得た残渣をシリカカラムクロマトグラフィー（展開 溶媒;酢酸ェチル /へキサン =0〜5%)で精製して表記化合物 (淡黄色油状物、 21.4 5g)を得た。To a solution of the compound obtained in Reference Example 5 (18.84g) in toluene (169ml) was added n-butyllithium (2.64M, hexane solution, 20.8ml) at 0 ° C under an argon atmosphere. Stir for minutes. To this solution was added jetyl aluminum chloride (10.93M, hexane solution, 63.6 ml) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. (4R) -2- (N, N-Jetylamino) methyl-4- (t-butyldimethylsiloxy) cyclopent-2-en-1-one (0.25M, toluene solution, 169ml) at room temperature And stirred for 50 minutes. The reaction solution was added to a mixed solution of hexane (100 ml) -saturated aqueous solution of ammonium chloride (80 ml) -hydrochloric acid solution (2M, 60 ml) with stirring. 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 Product, 21.4 5 g).

[0067] 参考例 7 [0067] Reference Example 7

(2E)- 17,18,19,20-テトラノル- 16- (3-ビフエ-ル)- 2,3,13,14-テトラデヒドロ- PGE メチ (2E)-17,18,19,20-Tetranor-16- (3-biphenyl) -2,3,13,14-tetradehydro-PGE methyl

1 ルエステル 11,15-ビス (t-ブチルジメチルシリル エーテル） 1 Luster 11,15-bis (t-butyldimethylsilyl ether)

[0068] [化 10] [0068] [Chemical 10]

(4E) -5-カルボメトキシベント- 4-ェ-ル亜鉛 (II)ョージド（0.75M,THF溶液， 6.0ml) に、- 70°Cでシアン化銅（Ι) · 2塩化リチウム（1.0M, THF溶液， 3.0ml)を力卩ぇ同温度で 20分間撹拌した。この溶液に- 70°Cにおいて、参考例 6で得られたィ匕合物（0.3M, T HF溶液， 5.0ml)とクロロトリメチルシラン（0.34ml)をカ卩え、撹拌しながら約 2時間かけて 室温まで昇温した。 (4E) -5-Carbomethoxybento-4-ethylzinc (II) iodide (0.75M, THF solution, 6.0ml) at -70 ° C with copper cyanide (シ ア ン) · lithium dichloride (1.0M , THF solution, 3.0 ml) was stirred at the same temperature for 20 minutes. In this solution, at −70 ° C., the mixture (0.3 M, THF solution, 5.0 ml) obtained in Reference Example 6 and chlorotrimethylsilane (0.34 ml) were added and stirred for about 2 hours. The temperature was raised to room temperature.

[0069] 反応液に飽和塩化アンモ-ゥム水溶液 (23ml)を加え、へキサン抽出 (10ml)した。有 機層を飽和食塩水で洗浄後、乾燥、濃縮して得られた残渣をジェチルエーテル（1.5 ml)—イソプロピルアルコール（6.0ml)に溶解し、ピリジ-ゥム p—トルエンスルホネー ト（8mg)を加え、室温で 16時間撹拌した。反応液にへキサン（100ml)をカ卩え、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 口マトグラフィー (展開溶媒;酢酸ェチル /へキサン =6%)で精製して表記化合物 (淡 黄色油状、 497mg)を得た。 [0069] A saturated aqueous ammonium chloride solution (23 ml) was added to the reaction solution, followed by extraction with hexane (10 ml). The organic layer was washed with saturated brine, dried and concentrated. The residue obtained was dissolved in jetyl ether (1.5 ml) -isopropyl alcohol (6.0 ml), and pyridinium p-toluenesulfonate ( 8 mg) was added and stirred at room temperature for 16 hours. Hexane (100 ml) is added to the reaction solution, washed with saturated aqueous sodium bicarbonate and saturated brine, dried and concentrated, and the residue obtained is purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane). = 6%) to give the title compound (pale yellow oil, 497 mg).

^-NMRCCDCl , 300MHz) δ ppm;— 0.09(s, 3H),— 0.05(s, 3H), 0.06(s, 3H), 0.09(s, 3 ^ -NMRCCDCl, 300MHz) δ ppm; — 0.09 (s, 3H), — 0.05 (s, 3H), 0.06 (s, 3H), 0.09 (s, 3

3 Three

H), 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, IH), 2.51-2.71(m, 2H), 2.91— 3.07(m, 2H), 3.72(s, 3H), 4.16— 4.27(m, IH), 4. 49-4.60(m, IH), 5.81(dt, J=15.6, 1.5Hz, IH), 6.94(dt, J=15.6, 6.9Hz, IH), 7.16-7.6 +(ΒΝ+ )ε8 ：^ζ/ω (+S3)S ト ui。 qif '919 'ZOL 'SZL '8SZ '008 '838 '886 '8S0T 'ΖΖΟΐ 'Ζ3Π 'ΖΟΖΙ ' LLZl 'ΟΖΖΙ ' LZ \ '08 ΐ 'SZST Ό09ΐ 'SS9I 'ΖΖΙΧ 'ZfLl ' ΖΖΖ '6 SZ ΌΖ6Ζ 'ΖΖΖΖ '90 ε： Bsu) IH), 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, IH), 2.51 -2.71 (m, 2H), 2.91- 3.07 (m, 2H), 3.72 (s, 3H), 4.16- 4.27 (m, IH), 4. 49-4.60 (m, IH), 5.81 (dt, J = 15.6, 1.5Hz, IH), 6.94 (dt, J = 15.6, 6.9Hz, IH), 7.16-7.6 + (ΒΝ +) ε8:^ζ / ω (+ S3) S to ui. qif '919' ZOL 'SZL' 8SZ '008' 838 '886' 8S0T 'ΖΖΟΐ' Ζ3Π 'ΖΟΖΙ' LLZl 'ΟΖΖΙ' LZ \ '08 ΐ 'SZST Ό09ΐ' SS9I 'ΖΖΙΧ' ZfLl 'ΖΖΖ' 6 SZ ΌΖ6Ζ 'ΖΖΖΖ '90 ε: Bsu) I

(Η6 ' 9· (Η6 '9

1-\τΐ '(Ηΐ 'ΖΗΓΖ '9"ST=f »6·9 '(Ηΐ 'ZHS'I '9"ST=f P)08'S '(Ηΐ 'ω) - ε9·1- \ τΐ '(Ηΐ' ΖΗΓΖ '9 "ST = f» 6 · 9' (Ηΐ 'ZHS'I' 9 "ST = f P) 08'S '(Ηΐ' ω)-ε9

'(Ηΐ ^)\Z- - '(HS '{ΗΖ 'ω)9ΐ·ε— 66 '(Ηΐ 'ζΗ 'ΐ 'ε· 'S'8I=f 'PPP)S9 '(Ηΐ ^) \ Z--' (HS '{ΗΖ' ω) 9ΐε- 66 '(Ηΐ' ζΗ 'ΐ' ε · 'S'8I = f' PPP) S9

•Ζ '(Ηΐ 'ω)ΟΖ — 6S '(Ηΐ

'Ρ)Ζζ'Ζ '(Ηΐ ·6 'S'8I• Ζ '(Ηΐ' ω) ΟΖ — 6S '(Ηΐ

'Ρ) Ζζ'Ζ' (Ηΐ 6 'S'8I

=f 'W)fVZ '(HS 'ω)εζ — 90 '(Η9 'ω)8Ζ·ΐ— Sri -raddg (ZH OOS^,SlDaD)H N-H_T= f 'W) fVZ' (HS 'ω) εζ — 90' (Η9 'ω) 8Ζ · ΐ— Sri -raddg (ZH OOS^{, S} lDaD) H NH_T

。 (^Si¾8s " ^ w ) ^^m. (^Si ¾8s "^ w) ^^ m

、つ攝慰、 （％Z9〜os=ベ ^^/ ^エ邈 瀚缀 翘）一 ^ Mム マ ^ 、 ¾^(sx )(n)氺最軍 a 靱ェ: 簠斜单 m (Μκπ), 攝 consolation, (% Z9〜os = Be ^^ / ^ 邈 瀚 缀 翘) One ^ M Mumah ^, ¾ ^ (sx) (n) )

^mm^ ^m^ ^、 ? (^OSI)氺最軍 a 靱ー ^ mm ^ ^ m ^ ^,? (^ OSI)

(\ oi) ^^ ^m^ ^ W^ ^n I O^'S) 缀氺邈峯 氺; ^ ％9 つ。 0 a¾^Kl^UIS2)ND Hつ ¾ (^ZSf) <¾?^ ^¾ ^ P}%(\ oi) ^^ ^ m ^ ^ W ^ ^ n IO ^ 'S) 缀 氺 邈 峯 氺; ^% 9. 0 a¾ ^ Kl^UI S2) ND H ¾ (^ ZSf) <¾? ^ ^ ¾ ^ P}%

[Π^] [ 00] [Π ^] [00]

) ΰ、 ¾^ 4^— 'εΐ'ε — ( / ェ ε)— 9ΐ— //^ l^— 0^6Γ8ΓΖΐ— (3 [OZOO]) ΰ, ¾ ^ 4 ^ — 'εΐ'ε — (/ ｅ ε) — 9ΐ— // ^ l ^ — 0 ^ 6Γ8ΓΖΐ— (3 [OZOO]

₊( )iiL： z/ui (+S3)S₊ () iiL: z / ui (+ S3) S

ト ra。 699 'ZOL 'L L '6ZZ '8S8 'S88 '0f6 '9001 '2801 'ZZW '96Π 'S ZI ' ΐθεΐ '9 'Z9fl 'ZL l '009ΐ '6S9I 'LZLl 'L Ll ' ZZZ '8S82 ： BSU) I To ra. 699 'ZOL' LL '6ZZ' 8S8 'S88' 0f6 '9001' 2801 'ZZW '96 Π' S ZI 'ΐθεΐ' 9 'Z9fl' ZL l '009 ΐ' 6S9I 'LZLl' L Ll 'ZZZ' 8S82: BSU) I

(H6 'ω)ΐ (H6 'ω) ΐ

81· 実施例 281 · Example 2

[0072] (2E)- 17,18,19,20-テトラノル- 16- (3-ビフエ-ル)- 2,3,13,14-テトラデヒドロ- PGE ( 化合物 34) [0072] (2E) -17,18,19,20-tetranor-16- (3-biphenyl) -2,3,13,14-tetradehydro-PGE (compound 34)

[0073] [化 12][0073] [Chemical 12]

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)をカロ 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-ゥムで塩 祈し、酢酸ェチル (100ml X 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;酢酸ェチル /へキサン =50〜67%)により精製 し、標記化合物 (94 mg)を得た。 Water (85 ml) and phosphate buffer (pH = 7.0, 0.2M, 5.3 ml) were added to a solution of the compound obtained in Example 1 (190 mg) in acetone (8.5 ml) and lipase PS (manufactured by Amano Pharmaceutical Co., Ltd.) , 5.32 g) 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 with ammonium sulfate, and ethyl acetate (100 ml). The mixture was extracted with X2), and 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).

^-NMRCCDCl , 300MHz) δ ppm; 1.10— 3.40(m, 14H), 2.14(dd, J=18.7, 9.0Hz, 1H), ^ -NMRCCDCl, 300MHz) δ ppm; 1.10- 3.40 (m, 14H), 2.14 (dd, J = 18.7, 9.0Hz, 1H),

3 Three

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) 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—¹IR (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)MS (ES +) m / z: 469 (M + Na)⁺ ; MS (ES-) m / z: 445 (M— H)

[0074] 参考例 1〜5または特開 2001-89444に記載の方法と同様の操作を行うことにより 得られた末端アセチレン化合物を用い、参考例 6、 7、実施例 1および実施例 2と同様 の操作を行うことにより以下の本発明化合物を得た。[0074] Using terminal acetylene compounds obtained by performing the same operations as in Reference Examples 1 to 5 or JP-A-2001-89444, the same as Reference Examples 6, 7, Example 1 and Example 2 The following compounds of the present invention were obtained by carrying out the above operations.

実施例 3 Example 3

17.18.19.20-テトラノル- 2.3.13.14-テトラデヒドロ- 16-(3'-メチルビフエニル -3-ィル) -PGE (化合物 56) [0076] [化 13]17.18.19.20-Tetranor-2.3.13.14-Tetradedehydro-16- (3'-methylbiphenyl-3-yl) -PGE (Compound 56) [0076] [Chemical 13]

H-NMR(CDC1 , 300MHz) δ ppm; 1.22-1.77(m, 9H), 2.06-2.25(m, 3H), 2.14(dd, J= H-NMR (CDC1, 300 MHz) δ ppm; 1.22-1.77 (m, 9H), 2.06-2.25 (m, 3H), 2.14 (dd, J =

3 Three

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, 1 H), 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) 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, 1 H), 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)+MS (ES +) m / z: 483 (M + Na)⁺ ; MS (ES-) m / z: 459 (M— H) +

実施例 4 Example 4

[0077] (2E)- 17,18,19,20-テトラノル- 16- (3-メトキシメチルフエ-ル)- 2,3,13,14-テトラデヒド [0077] (2E) -17,18,19,20-tetranor-16- (3-methoxymethylphenol) -2,3,13,14-tetradehydride

Π- PGE (化合物 18)Π-PGE (Compound 18)

[0078] [化 14][0078] [Chemical 14]

H-NMR(CDC1 , 300MHz) δ ppm: 1.37— 1.86(m, 9H), 2.12- 2.31(m, 3H), 2.19(dd, J=H-NMR (CDC1, 300MHz) δ ppm: 1.37— 1.86 (m, 9H), 2.12- 2.31 (m, 3H), 2.19 (dd, J =

3 Three

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, 3 H), 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) 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—¹IR (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)—MS (ES +): 437 (M + Na)⁺ ; MS (ES-): 413 (M— H) —

[0079] 実施例 5〜実施例 19[0079] Example 5 to Example 19

参考例 1〜5または特開 2001-89444に記載の方法と同様の操作を行うことにより 得られた末端アセチレン化合物を用い、参考例 6と同様の操作を行い、参考例 7にお V、て（4E) -5-カルボメトキシベント- 4-ェ-ル亜鉛 (II)ョージドのかわりに、対応する有 機亜鉛試薬を用い、実施例 1および実施例 2と同様の操作を行うことにより以下の本 発明化合物を得た。Using the terminal acetylene compound obtained by the same procedure as described in Reference Examples 1 to 5 or JP-A-2001-89444, the same procedure as in Reference Example 6 was performed. (4E) -5-Carbomethoxy bent 4-ethyl zinc (II) The following compounds of the present invention were obtained by carrying out the same operations as in Example 1 and Example 2 using a mechanical zinc reagent.

実施例 5 Example 5

[0080] 17.18.19.20-テトラノル- 16- (3-ビフエ二ル)- 2.2.3.3.13.14-へキサデヒドロ- PGE ( 化合物 36) [0080] 17.18.19.20-Tetranor-16- (3-biphenyl)-2.2.3.3.13.14-hexadehydro-PGE (compound 36)

[0081] [化 15][0081] [Chemical 15]

H-NMR(CDC1 , 300MHz) δ ppm; 1.39-1.78(m, 6H), 2.08-2.22(m, IH), 2.15(dd, J= H-NMR (CDC1, 300MHz) δ ppm; 1.39-1.78 (m, 6H), 2.08-2.22 (m, IH), 2.15 (dd, J =

3 Three

18.7, 9.0Hz, IH), 2.25— 2.38(m, 2H), 2.54— 2.69(m, 2H), 3.05(dd, J=13.4, 6.5Hz, IH ), 3.10(dd, J=13.4, 6.4Hz, IH), 3.18— 3.72(m, 3H), 4.10— 4.21(m, IH), 4.63— 4.72(m, IH), 7.21-7.61(m, 9H) 18.7, 9.0Hz, IH), 2.25- 2.38 (m, 2H), 2.54-2.69 (m, 2H), 3.05 (dd, J = 13.4, 6.5Hz, IH), 3.10 (dd, J = 13.4, 6.4Hz , IH), 3.18—3.72 (m, 3H), 4.10—4.21 (m, IH), 4.63—4.72 (m, IH), 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)—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) —

実施例 6 Example 6

[0082] 17,18,19,20-テトラノル- 16- (3-メトキシフエ二ル)- 2,2,3,3,13,14-へキサデヒドロ- PG [0082] 17,18,19,20-Tetranor-16- (3-methoxyphenyl) -2,2,3,3,13,14-hexadehydro-PG

Ε_ι (化合物 16)Ε_ι (Compound 16)

[0083] [化 16][0083] [Chemical 16]

H-NMR(CDC1 , 300MHz) δ ppm: 1.22— 1.84(m, 6H), 2.14-2.42(m, 4H), 2.57-2.75(H-NMR (CDC1, 300MHz) δ ppm: 1.22— 1.84 (m, 6H), 2.14-2.42 (m, 4H), 2.57-2.75 (

3 Three

m, 2H), 2.93-3.70(m, 5H), 3.42(s, 3H), 4.12-4.24(m, IH), 4.44(s, 2H), 4.58— 4.70(m =f 'VV)IZ'Z '(Ηΐ 'ω)62·2-3Γ2 '(Η9 'ω)^'ΐ- 9 'ΐ： d ρ (ΖΗ兩 OS ' ϋα )Η顺— Ηm, 2H), 2.93-3.70 (m, 5H), 3.42 (s, 3H), 4.12-4.24 (m, IH), 4.44 (s, 2H), 4.58— 4.70 (m = f 'VV) IZ'Z' (Ηΐ 'ω) 62 · 2-3Γ2' (Η9 'ω) ^' ΐ-9 'ΐ: d ρ (ΖΗ 兩 OS' ϋα) Η 顺 — Η

[8ΐ^ ] 800]

[9800][8ΐ ^] 800]

[9800]

τ_ωο zoL 'eez 'z£0i ' zoi ' Sn ' Zl 'S8ST 'SS I '96 ΐ '8691 '9SZT '9S22 ' 98S 'TS62 '26SS： BSU) Iτ_ωο zoL 'eez' z £ 0i 'zoi' Sn 'Zl' S8ST 'SS I '96 ΐ' 8691 '9SZT' 9S22 '98S' TS62 '26SS: BSU) I

(HS 'ω) ε· -8Γ '(Ηΐ 'ZHS'9 'ζΗ8·ΐ=ί" '1Ρ)99· '(Ηΐ )6 ト81 (HS 'ω) ε · -8Γ' (Ηΐ 'ZHS'9' ζΗ8 · ΐ = ί "'1Ρ) 99 ·' (Ηΐ) 6 to 81

'(Ηΐ 'ZHS'9 'Ζτΐ=ί 'ΡΡ) 0·ε '(HI 'ZHS'9 'Ζτΐ=ί 'ΡΡ)66 '(Ηΐ 'ZHS'I 'S" '9·8ΐ= f 'VVV)ZL-Z '(Ηΐ 'ζΗ8·ΐ '2"8 'ε·ΐΐ=ί" 'ΡΡΡ)ΐ9 '{ΗΖ '^)ΖνΖ-ΖΖ '(Ηΐ 'ΖΗΓ6 '9·8ΐ '(Ηΐ' ZHS'9 'Ζτΐ = ί' ΡΡ) 0 · ε '(HI' ZHS'9 'Ζτΐ = ί' ΡΡ) 66 '(Ηΐ' ZHS'I 'S' '9 · 8ΐ = f' VVV ) ZL-Z '(Ηΐ' ζΗ8 · ΐ '2 "8' ε · ΐΐ = ί" 'ΡΡΡ) ΐ9' {ΗΖ '^) ΖνΖ-ΖΖ' (Ηΐ 'ΖΗΓ6' 9 · 8ΐ

=Γ 'ΡΡ)ΐ2'2 '(Ηΐ 'ω)92·2-3Γ2 '(Η9 'ω)ε8·ΐ— 0 ·ΐ： ^dd 9 (ZH OOS ^ Ιつ) WN— Η_τ= Γ 'ΡΡ) ΐ2'2' (Ηΐ 'ω) 92 · 2-3Γ2' (Η9 'ω) ε8 · ΐ— 0 · ΐ: ^ dd 9 (ZH OOS ^ Ι つ) WN— Η_τ

[ ΐ^ ] [S800]

[ΐ ^] [S800]

_(H-n)llf :(-S3)S_ (H-n) llf: (-S3) S

ト ura 26s 'εοζ Ura 26s' εοζ

'eez '6ζοΐ '6en 'εβπ H ' 8ει '9ε ΐ 'ST T Ofn '^zzz OS6S 'οο ε :(^⁹")ΗΙ'eez' 6ζοΐ '6en' εβπ H '8ει' 9ε ΐ 'ST T Ofn' ^ zzz OS6S 'οο ε: (^⁹ ") ΗΙ

{ '^)LZ-L-ZVL '(HI ' zz 18.6, 9.1Hz, IH), 2.56-2.77(m, 4H), 2.94-3.10(m, 2H), 3.10- 4.30(m, 3H), 3.22(s, 2 H), 4.17-4.27(m, IH), 4.67(dt, J=6.7, 1.8Hz, IH), 7.16-7.37(m, 5H){'^) LZ-L-ZVL' (HI 'zz 18.6, 9.1Hz, IH), 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, IH ), 4.67 (dt, J = 6.7, 1.8Hz, IH), 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—¹IR (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)― MS (ES +) m / z: 413 (M + Na) +; MS (ES-) m / z: 389 (M— H)

実施例 9 Example 9

[0088] 3-チア- 17.18.19.20-テトラノル- 16- (3-ビフエ-ル） -13.14-ジデヒドロ- PGE (化合 物 10) [0088] 3-thia-17.18.19.20-tetranor-16- (3-biphenyl) -13.14-didehydro-PGE (compound 10)

[0089] [化 19] [0089] [Chemical 19]

H-NMR(CDC1 , 300MHz) δ ppm; 1.37-1.78(m, 6H), 2.09-2.21(m, IH), 2.15(dd, J=H-NMR (CDC1, 300MHz) δ ppm; 1.37-1.78 (m, 6H), 2.09-2.21 (m, IH), 2.15 (dd, J =

3 Three

18.6, 6.9Hz, IH), 2.52— 2.69(m, 4H), 3.02-3.15(m, 2H), 2.80— 4.30(m, 3H), 3.19(s, 2 H), 4.07-4.19(m, IH), 4.66— 4.75(m, IH), 7.22-7.28(m, IH), 7.30— 7.53(m, 6H), 7.55 -7.62(m, 2H) 18.6, 6.9Hz, IH), 2.52— 2.69 (m, 4H), 3.02-3.15 (m, 2H), 2.80— 4.30 (m, 3H), 3.19 (s, 2 H), 4.07-4.19 (m, IH ), 4.66-4.75 (m, IH), 7.22-7.28 (m, IH), 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—¹IR (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)― MS (ES +) m / z: 489 (M + Na) +; MS (ES-) m / z: 465 (M— H)

実施例 10 Example 10

[0090] 3-チア- 17,18,19,20-テトラノル- 16- (3-メトキシメチルフエ-ル） -13, 14-ジデヒドロ- PGE (化合物 12) [0090] 3-thia-17,18,19,20-tetranor-16- (3-methoxymethylphenol) -13,14-didehydro-PGE (compound 12)

[0091] [化 20] - w'si- /-ェ ^ ^ Hェ- ε)- 9ΐ - / / 4 - os'6r8r - ^- ε [湖0][0091] [Chemical 20] -w'si- / -e ^ ^ H e- ε)-9ΐ-/ / 4-os'6r8r-^-ε [Lake 0]

_(Η- )ΐ03 :(-S3)S ·₊(¾Ν+ )323 :(+S3)S_ (Η-) ΐ03: (-S3) S ·₊ (¾Ν +) 323: (+ S3) S

ト ui。 999 'SOZ 'ZSZ Ό6Ζ '168 'SS6 'SZOT 'Ζ3Π 'Ζ82ΐ ' To ui. 999 'SOZ' ZSZ Ό6Ζ '168' SS6 'SZOT' Ζ3Π 'Ζ82ΐ'

9 ει 'εθετ 'essi 'osw '88 ΐ 'ΟΪΘΪ 'STZT

9 ει 'εθετ' essi 'osw '88 ΐ' ΟΪΘΪ 'STZT

(Η 'ω)8ε· -9Γ '(Ηΐ )εζ·ト Ζ9· '(Η2 's)9S' '(Ηΐ ' ω)εΖ· —60· '{HZ 'WZ '(Η0ΐ 'ω)09'ε— OS'S '(Ηΐ 'ZHS'6 ' ·8ΐ=ί" 'VWZ '(Ηΐ 'ω) 92"2-^rS '(Η2 )90 - 96·ΐ '(HW 'ω)88·ΐ- ΖΓΐ： ^dd 9 (ZH OOS ' DaD)H N-H_T(Η 'ω) 8ε · -9Γ' (Ηΐ) εζ · G Ζ9 · '(Η2' s) 9S '' (Ηΐ 'ω) εΖ · —60 ·' {HZ 'WZ' (Η0ΐ 'ω) 09' ε— OS'S '(Ηΐ'ZHS'6'· 8ΐ = ί "' VWZ '(Ηΐ' ω) 92" 2- ^ rS '(Η2) 90-96 · ΐ' (HW 'ω) 88 · ΐ- ΖΓΐ : ^ Dd 9 (ZH OOS 'DaD) H NH_T

[ΙΖ^ [S600]

[ΙΖ ^ [S600]

Γει- ( ェ ^ ^ ^ /^^ /^- ε)- 9ΐ - //^ d^- os'6r8rzi- ^- ε [ζβοο Γει- (é ^ ^ ^ / ^^ / ^-ε)-9ΐ-// ^ d ^-os'6r8rzi- ^-ε [ζβοο

_ (H-n)ZZf ： z/ui (-S3)S_ (H-n) ZZf: z / ui (-S3) S

τ_ωο SSS 'Z99 'W 'ZSZ 'T6Z '168 '6S0T ' Ζ80Ϊ '63Π 'S8ST '8 '88 ΐ 'SSZT Ό^ ΐ '9ZZZ '0982 'ΟΟ ε :(^⁹")ΗΙτ_ωο SSS 'Z99' W 'ZSZ' T6Z '168' 6S0T 'Ζ80Ϊ '63 Π' S8ST '8 '88 ΐ' SSZT Ό ^ ΐ '9ZZZ' 0982 'ΟΟ ε: (^⁹ ") ΗΙ

Ζ '(Ηΐ )S ' - S9' '{HZ '^s)8 ' '(Ηΐ '^)9Z-f-ZVf '(HS ^) VZ '(Ηΐ 'ZHS'6 'S'8I= f 'W)IZ'Z HZl 'ω)09·ε— 80 '(Η9 ¾)S8'I— '^dd 9 (ZH OOS ^ Ιつ) WN— Η_τΖ '(Ηΐ) S'-S9 '' (HZ '^s ) 8''(Ηΐ' ^) 9Z-f-ZVf '(HS ^) VZ' (Ηΐ 'ZHS'6'S'8I = f 'W ) IZ'Z HZl 'ω) 09 · ε— 80' (Η9 ¾) S8'I— '^ dd 9 (ZH OOS ^ Ι) WN— Η_τ

OAV _(H-Vi)l9f ：^ζ/ω (-83)8^'₊(^+^)38^：^ζ/ω (+S3)S

OAV _ (H-Vi) l9f:^ζ / ω (-83) 8 ^ '₊ (^ + ^) 38 ^:^ζ / ω (+ S3) S

τ_ωο f 'ZOL 'Z8Z '806 'ΐΜΠ ' ( ΐ '982ΐ 'mi 'fSZl '9 '88 ΐ '8SZT '9ΖΖΖ 'Z9SZ '8262 'TZ62 'S8SS： BSU) I τ_ωο f 'ZOL' Z8Z '806' ΐΜΠ '(ΐ' 982ΐ 'mi' fSZl '9 '88 ΐ' 8SZT '9ΖΖΖ' Z9SZ '8262' TZ62 'S8SS: BSU) I

(Hf 'ω)9ε· -90" '(Ηΐ ト S9' HZ 's)zq- Η9'^)9Ζ' -0Υ£ HZ '^s(Hf 'ω) 9ε · -90 "' (Ηΐ S9 'HZ' s) zq- Η9 '^) 9Ζ' -0Υ £ HZ '^s

)οζτ '{ΗΖ 'ω)οι·ε— ε6 '{ '^fL'z-evz '(HI 'we 's'8i=f 'PP)OS '(HI '^)βζ τ-£ΥΖ '(Η9 'ω)98·ΐ— '(Η9 ^ΗΥ9=ί '?) ΖΊ： ^dd ρ (ZH OOS ^ Ιつ) WN— Η_τ) οζτ '{ΗΖ' ω) οι · ε— ε6 '{' ^ fL'z-evz '(HI' we 's'8i = f' PP) OS '(HI' ^) βζ τ- £ ΥΖ '( Η9 'ω) 98 · ΐ—' (Η9 ^ ΗΥ9 = ί '?) ΖΊ: ^ dd ρ (ZH OOS ^ Ι つ) WN— Η_τ

[ 600]

[600]

- ΐ'ει- ( ェ ^ ^ ^ / ! i - ε)- 9ΐ - / / 4 - os'6r8r - ^- ε [96θο] -ΐ'ει- (é ^ ^ ^ /! i-ε)-9ΐ-/ / 4-os'6r8r-^-ε [96θο]

_(H-Vi)Lff ： z/ui (-S3)S ·^:z/^m (+S3)S_ (H-Vi) Lff: z / ui (-S3) S ·^{: z} /^m (+ S3) S

τ_ωο 683 'ZOL '6fL '6ΐ6 'ΐΐθΐ '390ΐ ' sen '9 '9ε ΐ 'ssw '9βη 'εοθΐ 'e ' ζζζ 'ηβζ Ίζοζ 'sin τ_ωο 683 'ZOL' 6fL '6ΐ6' ΐΐθΐ '390ΐ' sen '9' 9ε ΐ 'ssw' 9βη 'εοθΐ' e 'ζζζ' ηβζ Ίζοζ 'sin

0Ί '(HI 'ω)εζ·— S9' HZ 's)zg- HZ 'zH0" =f '&)s9's H 'ω)ο · -9ε·ε HZ 's )ιζτ '{Hz 'ω)οι·ε- 6 '{ '^ Z-Z^Z '(HI ·6 ' ·8ΐ=ί" 'vwz '(HI '^)βζ τ-fVZ '(Η9 'ω)88·ΐ— '(HS0Ί '(HI' ω) εζ · — S9 'HZ' s) zg- HZ 'zH0 "= f' &) s9's H 'ω) ο · -9ε · ε HZ' s) ιζτ '{Hz' ω) οι · Ε- 6 '{' ^ ZZ ^ Z '(HI · 6' · 8ΐ = ί "'vwz' (HI '^) βζ τ-fVZ' (Η9 'ω) 88 · ΐ—' (HS

\_ZZ \ [S600] \ _ZZ \ [S600]

93 [0098] 3-チア- 17,18,19,20-テトラノル- 16-「3-(2-メトキシ)ェチルフエ-ル 1-13, 14-ジデヒド 口- PGE (化合物 24)93 [0098] 3-thia-17,18,19,20-tetranor-16- "3- (2-methoxy) ethylphenyl 1-13, 14-dide mouth-PGE (compound 24)

[0099] [化 24] [0099] [Chemical 24]

H-NMR(CDC1 , 300MHz) δ ppm; 1.49— 1.84(m, 6H), 2.15- 2.31(m, IH), 2.21(dd, J=H-NMR (CDC1, 300MHz) δ ppm; 1.49— 1.84 (m, 6H), 2.15- 2.31 (m, IH), 2.21 (dd, J =

3 Three

18.6, 9.6Hz, IH), 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, IH), 4.65- 4.73(m, IH), 7.02-7.20(m, 3H), 7.22 -7.29(m, IH) 18.6, 9.6Hz, IH), 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 = 6.5 Hz, 2H), 4.17-4.28 (m, IH), 4.65- 4.73 (m, IH), 7.02-7.20 (m, 3H), 7.22 -7.29 (m, IH)

IR(neat):3418, 2932, 2862, 2654, 2237, 1732, 1609, 1488, 1446, 1417, 1385, 1286, 1157, 1103, 1043, 902, 786, 757, 705, 666, 568 cm—¹IR (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)― MS (ES +) m / z: 471 (M + Na) +; MS (ES-) m / z: 447 (M-H)

実施例 15 Example 15

[0100] 3-チア- 17.18.19.20-テトラノル- 16- (3-ェチルフエ-ル)- 13.14-ジデヒドロ- PGE ( 化合物 26) [0100] 3-thia-17.18.19.20-tetranor-16- (3-ethylphenyl) -13.14-didehydro-PGE (compound 26)

[0101] [化 25][0101] [Chemical 25]

H-NMR(CDC1 , 300MHz) δ ppm; 1.24(t, J=7.5Hz, 3H), 1.45— 1.85(m, 6H), 1.88—3.H-NMR (CDC1, 300MHz) δ ppm; 1.24 (t, J = 7.5Hz, 3H), 1.45— 1.85 (m, 6H), 1.88—3.

3 Three

40(m, 12H), 2.21(dd, J=18.6, 9.2Hz, IH), 3.22(s, 2H), 4.17- 4.30(m, IH), 4.58-4.75 (m, IH), 6.97-7.16(m, 3H), 7.20- 7.30(m, IH) 40 (m, 12H), 2.21 (dd, J = 18.6, 9.2Hz, IH), 3.22 (s, 2H), 4.17-4.30 (m, IH), 4.58-4.75 (m, IH), 6.97-7.16 ( m, 3H), 7.20-7.30 (m, IH)

IR(neat):3385, 2929, 2234, 1731, 1607, 1446, 1384, 1288, 1157, 1033, 798, 736, 7 9 '(Η2 'ζΗ6·ΐ '9·8 'Γΐΐ=ί" 'ΡΡΡ) Ι^Ζ '{ΗΖ '^ΗΖ' L=[ ' ) WZ '(Ηΐ 'W6 '9·8ΐ=ί"IR (neat): 3385, 2929, 2234, 1731, 1607, 1446, 1384, 1288, 1157, 1033, 798, 736, 7 9 '(Η2' ζΗ6 · ΐ '9 · 8' Γΐΐ = ί "'ΡΡΡ) Ι ^ Ζ' {ΗΖ '^ ΗΖ' L = [') WZ' (Ηΐ 'W6' 9 · 8ΐ = ί"

PP) 6VZ '(Ηΐ 'ω) 62"2-2rS '(HST 'ω) 28"T-02"T '^dd 9 (ZH OOS ^ Ιつ) WN— ΗPP) 6VZ '(Ηΐ' ω) 62 "2-2rS '(HST' ω) 28" T-02 "T '^ dd 9 (ZH OOS ^ Ι) WN— Η

\IZ \ [SOTO] \ IZ \ [SOTO]

(9呦^(9 呦 ^

^Od- ΰ、 ¾^ - ΐ·εΐ- ( / ェ ^ ^ EH - ε)- 9ΐ - //^ d^- 0^6ΐ·8ΐ·Ζΐ [雨。] ^ Od- ΰ, ¾ ^-ΐ · εΐ- (/ é ^ ^ EH-ε)-9ΐ-// ^ d ^-0 ^ 6ΐ · 8ΐ · Ζΐ [Rain. ]

Li m Li m

_ (H-Vi)l£f ： z/ui (-S3)S ·₊ (BN+ )SS ： z/m (+S3)S_ (H-Vi) l £ f: z / ui (-S3) S · + (BN +) SS: z / m (+ S3) S

ト ui。 90 'LZL 'Z6L 'SCOT '8801 'Z 11 '9821 'fSZl To ui. 90 'LZL' Z6L 'SCOT' 8801 'Z 11' 9821 'fSZl

' ffl 'Z9fl '88 1 '9091 'STZT 'ZZLl '8SZT 'SZZZ ' 9SZ '9262 '6 6Ζ '8ΐ ε„ Ι'ffl' Z9fl '88 1 '9091' STZT 'ZZLl' 8SZT 'SZZZ' 9SZ '9262' 6 6Ζ '8ΐ ε „Ι

(HI 'ra)62" -02" '(HS (HI 'ra) 62 "-02"' (HS

ΖΓΖ-86"9 '(HI - 6S' '(HI )6 - 6ΐ· '(Η2 ' ·ε '(Ηΐ 'ΖΗΓ6 '9·8ΐ=ί" 'ΡΖΓΖ-86 "9 '(HI-6S' '(HI) 6-6ΐ' (Η2 '· ε' (Ηΐ 'ΖΗΓ6' 9 · 8ΐ = ί" 'Ρ

V)IZ'Z '(Η9 '?) ΖΊ '(ΗΖΐ 'ω)οε·ε— ΟΓΐ -raddg (ZH OOS ' Iつ αつ) WN— Η_τV) IZ'Z '(Η9'?) ΖΊ '(ΗΖΐ' ω) οε · ε— ΟΓΐ -raddg (ZH OOS 'α one) WN— Η_τ

Od- ΰ、 ¾^ - ΐ·εΐ- ( / ェ / ci l C - ε)- 9ΐ - //^ d^- 0 61'81 1- ^- ε Od- ΰ, ¾ ^-ΐ · εΐ- (/ é / ci l C-ε)-9ΐ-// ^ d ^-0 61'81 1- ^-ε

_ (H-Vi)Llf ： z/ui (-S3)S ·₊ ( )l ： ζ/ω (+S3)S_ (H-Vi) Llf: z / ui (-S3) S ·₊ () l: ζ / ω (+ S3) S

τ_ωο εο

LZ

τ_ωο εο

LZ

[62^ ] [6010] [62 ^] [6010]

(οε呦(οε 呦

^Od- ΰ、 ¾^ - 'εΐ- / ェ - ε)- 9ΐ - / / 4 - 0 6Γ8ΓΖΐ- ¾ -^Βΐ [8010]^ Od- ΰ, ¾ ^-'εΐ- / d-ε)-9ΐ-/ / 4-0 6Γ8ΓΖΐ- ¾-^Β ΐ [8010]

_ (H-Vi)Lff ： z/ui (-S3)S ·₊ ( )lL ： ζ/ω (+S3)S_ (H-Vi) Lff: z / ui (-S3) S ·₊ () lL: ζ / ω (+ S3) S

ト ω。 9Ϊ9 'ZOL 'SZL 'L L '008 '106 'ΐθθΐ 'ZSOT 'ΖΖΟΐ 'ΖΟΠ '83Π '9ΖΖΙ ' fZZl 'OZfl ' fl '08 ΐ '9ZST '0091 '80Ζΐ '9SZT '9ΖΖΖ 'S SZ 'ZZ6Z '98SS :(^⁹")ΗΙG ω. 9Ϊ9 'ZOL' SZL 'LL' 008 '106' ΐθθΐ 'ZSOT' ΖΖΟΐ 'ΖΟΠ' 83 '' 9 '' fZZl 'OZfl' fl '08 ΐ '9ZST' 0091 '80''9SZT' 9ΖΖΖ 'S SZ' ZZ6Z '98SS: (^⁹ ") ΗΙ

(Η6 'ω)ε9· -ΐζ· '(Ηΐ '^)ZL- -W '(Ηΐ ' - 0' '{ΗΖ 'ω) ΐ·ε— οο·ε (Η6 'ω) ε9 · -ΐζ ·' (Ηΐ '^) ZL- -W' (Ηΐ '-0' '{ΗΖ' ω) ΐε- οο · ε

'(Ηΐ 'Z"8T=f 'W)WZ '(Η8ΐ 'ω)0Ζ — 8ΐ·ΐ '^dd ρ (ZH OOS ^ Ιつ) WN— Η_τ'(Ηΐ' Z "8T = f 'W) WZ' (Η8ΐ 'ω) 0Ζ — 8ΐ · ΐ' ^ dd ρ (ZH OOS ^ Ι つ) WN— Η_τ

[SZ^ [ ΟΐΟ] [SZ ^ [ΟΐΟ]

(^ ^ ) ^Od— ΰ、¾^ — WSI— ( / ェ ε)— 9ΐ— //^ d^— 0^6ΐ·8ΐ·Ζΐ [9010](^ ^) ^ Od— ΰ 、 ¾ ^ — WSI— (/ ε ε) — 9ΐ— // ^ d ^ — 0 ^ 6ΐ · 8ΐ · Ζΐ [9010]

-(H-Vi) lf ： z/ui(— S3)SW · +(BN+ )6£ :^z/^(+S3)S-(H-Vi) lf: z / ui (— S3) SW · + (BN +) 6 £:^z / ^ (+ S3) S

τ_ωο 8Ϊ9 'SOZ '8SZ 'S6Z ' τ_ωο 8Ϊ9 'SOZ' 8SZ 'S6Z'

6S0T '380ΐ '09Π 'εβΐΐ '6S2T 'S8ST '8 'Of LI '9ΖΖΖ '6 SZ ΌΖ6Ζ 'OOfZ： Bsu) I6S0T '380' '09' 'εβ' '6S2T' S8ST '8' Of LI '9' '6 SZ ΌΖ6' 'OOfZ: Bsu) I

"Ζ-ΟΓΖ '(Ηΐ 'ω) Ο ^-εθ^ '(Η2 's) Ζ · '(Ηΐ 'ω) SS^-S '(HS 's) '(Ηΐ '^Η'Ζ-ΟΓΖ' (Ηΐ 'ω) Ο ^ -εθ ^' (Η2 's) Ζ ·' (Ηΐ 'ω) SS ^ -S' (HS 's)' (Ηΐ '^ Η

Γ9 'VZ\=[ 'ΡΡ) Μ)·ε '(Ηΐ 'ZHS'9 'VZ\=[ 'ΡΡ) 66 '(Ηΐ '^ΗΖ'Ι ί '9·8ΐ=ί" 'ΡΡΡ) 6Γ9 'VZ \ = [' ΡΡ) Μ) · ε '(Ηΐ' ZHS'9 'VZ \ = [' ΡΡ) 66 '(Ηΐ' ^ ΗΖ'Ι ί '9 ・ 8ΐ = ί "' ΡΡΡ) 6

83 NMR(CDC1 , 300MHz) δ ppm; 1.22— 1.82(m, 15H), 2.09— 2.21(m, 1H), 2.15(dd, J=l83 NMR (CDC1, 300MHz) δ ppm; 1.22—1.82 (m, 15H), 2.09—2.21 (m, 1H), 2.15 (dd, J = l

3Three

8.3, 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) 8.3, 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)—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) —

実施例 20 Example 20

[0110] 15 α 5 -17.18.19.20-テトラノル- 2.3.13.14-テトラデヒドロ- 16- (3-クロ口フエ二ル)- P GE_i (化合物 44)[0110] 15 α 5 -17.18.19.20-Tetranor- 2.3.13.14-Tetradehydro-16- (3-clophenyl) -P GE_i (Compound 44)

( 1) (E)— [(4R,5R)- 2,4-ビス (t-ブチルジメチルシロキシ) -5- (3-ヒドロキシプロパ- 1-ィ ル）シクロペント- 1-ェ -ル]ヘプト- 2-ェン酸 メチル エステル (1) (E) — [(4R, 5R) -2,4-Bis (t-butyldimethylsiloxy) -5- (3-hydroxyprop-1-yl) cyclopent-1-yl] hept- 2-Enoic acid methyl ester

[0111] [化 30][0111] [Chemical 30]

トリメチルシリルォキシ -2-プロピン（246 μ 1)の Et 0 (6.4ml)溶液に、アルゴン雰囲気 Trimethylsilyloxy-2-propyne (246 μ 1) in Et 0 (6.4 ml) solution in argon atmosphere

2 2

下、 - 78°Cで n-ブチルリチウム（2.64M,へキサン溶液， 568 μ 1)を加え、 40分間撹拌 した。同温度で AlMe (1.01M,へキサン溶液， 1.49ml)をカ卩ぇ 30分間攪拌後、（E)- 7- [ Then, n-butyllithium (2.64 M, hexane solution, 568 μ 1) was added at −78 ° C., and the mixture was stirred for 40 minutes. After stirring AlMe (1.01M, hexane solution, 1.49 ml) at the same temperature for 30 minutes, (E) -7- [

3 Three

(R)- 3- (tert-ブチルジメチルシロキシ) -5-ォキソ -シクロベント- 1-ェニル] -ヘプト- 2-ェ ン酸 メチルエステル（353mg)の Et 0 (3.33ml)溶液と tert-ブチルジメチルシリルトリフ (R) -3- (tert-Butyldimethylsiloxy) -5-oxo-cyclobento-1-enyl] -hept-2-enoic acid methyl ester (353 mg) in Et 0 (3.33 ml) and tert-butyldimethyl Cyril Triff

2 2

ラート (276 1)を加え、同温度で 1時間攪拌した。 Lat (276 1) was added and stirred at the same temperature for 1 hour.

[0112] 反応溶液を飽和塩ィ匕アンモ-ゥム水溶液 (50ml)に加えて Et 0 (50ml)で抽出し、有[0112] The reaction solution was added to saturated aqueous solution of ammonium chloride (50 ml) and extracted with Et 0 (50 ml).

2 2

機層に THF(lOml)をカ卩え、塩酸水溶液（1M, 50ml)、飽和食塩水（50ml)で洗浄し、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;酢酸ェチル /へキサン = 10〜15%)で精製して目的物（ 無色油状物、 262mg)を得た。 THF (lOml) was added to the organic layer, washed with aqueous hydrochloric acid (1M, 50ml) and saturated brine (50ml), and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (eluent: ethyl acetate / hexane = 10-15%) to obtain the desired product (colorless oil, 262 mg).

^-NMRCCDCl ,300ΜΗζ) δ ppm: 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,lH), 1.90-2.30(m,5H), 2.49-2.62(m,l H), 3.18-3.27(m,lH), 3.73(s,3H), 4.23- 4.35(m,lH), 4.27(dd,J=6.1,1.6Hz,2H), 5.83( dt,J=15.6,1.5Hz,lH)^ -NMRCCDCl, 300ΜΗζ) δ ppm: 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, lH), 1.90-2.30 (m, 5H), 2.49-2.62 (m, l H), 3.18-3.27 (m, lH), 3.73 (s, 3H), 4.23- 4.35 (m, lH), 4.27 (dd, J = 6.1,1.6Hz, 2H), 5.83 (dt, J = 15.6,1.5Hz, lH)

IR(neat):3445,2953,2931,2898,2858,2221, 1728,1683, 1657,1472, 1463, 1437,1408,13 90,1362,1316,1228,1217,1178,1151,1103,1026,1007,979,939,912,876,839,812,780, IR (neat): 3445,2953,2931,2898,2858,2221, 1728,1683, 1657,1472, 1463, 1437,1408,13 90,1362,1316,1228,1217,1178,1151,1103,1026, 1007,979,939,912,876,839,812,780,

672cm"¹672cm "¹

MS(ES+):545(M+Na)⁺； MS(ES— ):521(M— H)—MS (ES +): 545 (M + Na)⁺ ; MS (ES—): 521 (M—H) —

[0113] (2) (E) [(4R,5R)- 2,4-ビス (t-ブチルジメチルシロキシ) -5- (3-ォキソプロパ -1-ィル[0113] (2) (E) [(4R, 5R) -2,4-Bis (t-butyldimethylsiloxy) -5- (3-oxoprop-1-yl

)シクロペント- 1-ェニル]ヘプト- 2-ェン酸メチルエステル) Cyclopent-1-enyl] hept-2-enoic acid methyl ester

[0114] [化 31][0114] [Chemical 31]

実施例 20 (1)で得られた化合物（92mg)の CHC1 (3.5ml)溶液に、 Dess-Martin試 Example 20 A solution of the compound (92 mg) obtained in (1) (92 mg) in CHC1 (3.5 ml) was added to a Dess-Martin test.

3 Three

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-ゥム水溶液 (20ml)を加え Et 0 (20ml X 2)で抽出し、有機層を無水硫酸マグネシウムで乾燥後、 The drug (149 mg) was added at room temperature and stirred for 30 minutes. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction solution, extracted with Et 0 (20 ml X 2), the organic layer was dried over anhydrous magnesium sulfate,

2 2

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;酢酸ェチル /へキサン = 5%)で精製して表記化合物 (無色油状物、 79mg)を得た。 Concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (developing solvent; ethyl acetate / hexane = 5%) to obtain the title compound (colorless oil, 79 mg).

^-NMRCCDCl ,300ΜΗζ) δ ppm: 0.09(s,3H), 0.11(s,3H), 0.13(s,3H), 0.14(s,3H), 0. ^ -NMRCCDCl, 300ΜΗζ) δ ppm: 0.09 (s, 3H), 0.11 (s, 3H), 0.13 (s, 3H), 0.14 (s, 3H), 0.

3 Three

89(s,9H), 0.93(s,9H), 1.30— 1.58(m,4H), 1.90— 2.06(m,lH), 2.12-2.34(m,4H), 2.51—2. 70(m,lH), 3.34-3.41(m,lH), 3.72(s,3H), 4.39(dt,J=7.3,4.6Hz,lH), 5.81(dt,J=15.6,l. 6Hz,lH), 6.96(dt,J=15.6,7.0Hz,lH), 9.21(d,J=0.8Hz,lH) 89 (s, 9H), 0.93 (s, 9H), 1.30- 1.58 (m, 4H), 1.90- 2.06 (m, lH), 2.12-2.34 (m, 4H), 2.51-2.70 (m, lH ), 3.34-3.41 (m, lH), 3.72 (s, 3H), 4.39 (dt, J = 7.3,4.6Hz, lH), 5.81 (dt, J = 15.6, l.6Hz, lH), 6.96 (dt , J = 15.6,7.0Hz, lH), 9.21 (d, J = 0.8Hz, lH)

MS(ES+):543(M+Na)⁺MS (ES +): 543 (M + Na)⁺

[0115] (3) 15 a j8 -17,18,19,20-テトラノル- 2,3,13,14-テトラデヒドロ- 16- (3-クロ口フエ-ル) - PGE メチルエステル [0115] (3) 15 a j8 -17,18,19,20-Tetranor-2,3,13,14-Tetradedehydro-16- (3-clonal phenyl)-PGE methyl ester

1 1

[0116] [化 32]

[0116] [Chemical 32]

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 (50 μ 1)をカ卩ぇ 10分間攪拌後、 0°Cで 3-クロ口ベンジルブロミド (302 μ 1)をカロ え同温度で 1時間攪拌した。 0°Cでクロロトリメチルシラン (50 1)をカ卩ぇ 30分攪拌して 得られた有機亜鉛試薬の上澄み (2.5ml)と TiCl (100 μ 1)を- 78°Cで実施例 3 (2)で得 To a suspension of zinc powder (301 mg) in THF (5.0 ml), stir chlorotrimethylsilane (50 μ 1) at room temperature in an argon atmosphere for 10 minutes, and then at 0 ° C, 3-chlorodiethyl bromide (302 μ 1) was stirred and stirred at the same temperature for 1 hour. Chlorotrimethylsilane (50 1) was stirred at 0 ° C for 30 minutes. The supernatant of the organozinc reagent (2.5 ml) and TiCl (100 μ 1) obtained at -78 ° C were used in Example 3 (2 )

4 Four

られた化合物（146mg)の THF(5.0ml)溶液にカ卩え、 2時間かけて室温まで昇温した。 The resulting compound (146 mg) was poured into a THF (5.0 ml) solution, and the temperature was raised to room temperature over 2 hours.

[0117] 反応液を Et 0 (50ml) 飽和塩化アンモニゥム水溶液 (45ml)—塩酸水溶液（3.0M,[0117] The reaction solution was mixed with Et 0 (50 ml) saturated aqueous ammonium chloride solution (45 ml) -hydrochloric acid solution (3.0 M,

2 2

5.0nl)の混合液に撹拌しながら加えた後、有機層を分離し、水 (50ml)、飽和食塩水（ 50ml)で洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥、濾過後濃縮して 得た残渣をシリカカラムクロマトグラフィー（展開溶媒;酢酸ェチル /へキサン = 5〜20 %)に付して低極性ィ匕合物を取り除いた残渣（116mg)を CH CN(6.3ml)に溶解し、 0°C After adding to a mixed solution of 5.0 nl) with stirring, the organic layer was separated and washed with water (50 ml) and saturated brine (50 ml). The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was subjected to silica column chromatography (developing solvent; ethyl acetate / hexane = 5 to 20%) to give a low-polarity compound. The residue (116 mg) was removed and dissolved in CH CN (6.3 ml) at 0 ° C

3 Three

で 46%フッ化水素酸水溶液（1.4ml)をカ卩え、同温度で 2.5時間撹拌した。反応液を酢 酸ェチル (50ml)—飽和重曹水 (40ml)中に撹拌しながら注いだ後、有機層を分離し 、水層を酢酸ェチル (50ml)抽出した。有機層を合わせて飽和重曹水 (40ml)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;酢酸ェチル /へキサン = 50〜67% )で精製し、表記化合物 (無色油状物、 44mg)を得た。 Then, 46% aqueous hydrofluoric acid solution (1.4 ml) was added and stirred at the same temperature for 2.5 hours. The reaction mixture was poured into ethyl acetate (50 ml) —saturated aqueous sodium bicarbonate (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).

^-NMRCCDCl , 300MHz) δ ppm; 1.18— 2.85(m, 14H), 2.89-3.06(m, 2H), 3.73(s, 3 ^ -NMRCCDCl, 300MHz) δ ppm; 1.18— 2.85 (m, 14H), 2.89-3.06 (m, 2H), 3.73 (s, 3

3 Three

H), 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, 1657,1599,1574,1478,1436,1316,1279,12 06,1158,1080,1038,870,781,703,685,556,442 cm—¹H), 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, 1657,1599,1574,1478,1436,1316,1279,12 06,1158,1080,1038,870,781,703,685,556,442 cm—¹

MS(ES+) m/z: 441(M+Na)⁺; MS(ES-) m/z: 417(M— H)+MS (ES +) m / z: 441 (M + Na)⁺ ; MS (ES-) m / z: 417 (M— H) +

[0118] (4) 15 a j8 -17,18,19,20-テトラノル- 2,3,13,14-テトラデヒドロ- 16- (3-クロ口フエ-ル) - PGE[0118] (4) 15 a j8 -17,18,19,20-Tetranor-2,3,13,14-Tetradedehydro-16- (3-clomental-fell)-PGE

1 1

[0119] [化 33]

[0119] [Chemical 33]

実施例 20 (3)で得たィ匕合物を用い、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。 Example 20 Using the compound obtained in (3), the title compound was obtained in the same manner as in Example 2.

1H-NMR(CDC1 , 300MHz) δ ppm; 1.14— 1.84(m, 9H), 2.09-2.39(m, 3H), 2.321(d, J= 1H-NMR (CDC1, 300MHz) δ ppm; 1.14— 1.84 (m, 9H), 2.09-2.39 (m, 3H), 2.321 (d, J =

3 Three

18.5,9.2Hz, IH), 2.52-2.80(m, 2H), 2.86— 3.1 l(m, 2H), 4.19— 4.32(m, IH), 4.58—4.6 8(m, IH), 5.76-5.88(m, IH), 6.96— 7.36(m, IH) 18.5, 9.2Hz, IH), 2.52-2.80 (m, 2H), 2.86—3.1 l (m, 2H), 4.19—4.32 (m, IH), 4.58—4.6 8 (m, IH), 5.76-5.88 ( m, IH), 6.96—7.36 (m, IH)

IR(neat):3383,2932,2860,2237,1740,1694,1652, 1599,1574,1477,1430,1311, 1283, 12 35,1207,1158,1079,1035,985,870,780,703,685,554 cm—¹IR (neat): 3383,2932,2860,2237,1740,1694,1652, 1599,1574,1477,1430,1311, 1283, 12 35,1207,1158,1079,1035,985,870,780,703,685,554 cm—¹

MS(ES+) m/z: 427(M+Na)⁺; MS(ES-) m/z: 403(M— H)+MS (ES +) m / z: 427 (M + Na)⁺ ; MS (ES-) m / z: 403 (M- H) +

[0120] 実施例 21〜実施例 38[0120] Example 21 to Example 38

実施例 20 (3)において、 3-クロ口ベンジルブ口ミドの変わりに対応するべンジルハラ イドを用い、実施例 20と同様の操作を行うことにより、以下の本発明化合物を得た。 実施例 21 In Example 20 (3), the following compounds of the present invention were obtained by carrying out the same operations as in Example 20 using benzyl halide corresponding to the change of 3-chloroguchi benzylbutamide. Example 21

[0121] 15 α -17,18,19,20-テトラノル- 2,3,13,14-テトラデヒドロ- 16- (2-メチルフエ二ル)- Ρ [0121] 15 α -17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (2-methylphenyl)-Ρ

GE (化合物 37)GE (Compound 37)

[0122] [化 34][0122] [Chemical 34]

H-NMR(CDC1 , 300MHz) δ ppm; 1.00— 2.42(m, 13H), 2.38(s, 3H), 2.52— 2.84(m, 2 H-NMR (CDC1, 300MHz) δ ppm; 1.00— 2.42 (m, 13H), 2.38 (s, 3H), 2.52— 2.84 (m, 2

3 Three

H), 2.92-3.16(m, 2H), 4.15- 4.30(m, IH), 4.58- 4.71(m, IH), 5.77— 5.90(m, IH), 6.92 -7.30(m, 5H) H), 2.92-3.16 (m, 2H), 4.15- 4.30 (m, IH), 4.58- 4.71 (m, IH), 5.77— 5.90 (m, IH), 6.92 -7.30 (m, 5H)

IR(neat):3384,3064,3020,2929,2859,2236,1731, 1695, 1652, 1494,1456,1384,1286,11 58,1108,1075,1030,986,870,800,746,667,559,451,418 cmIR (neat): 3384,3064,3020,2929,2859,2236,1731, 1695, 1652, 1494,1456,1384,1286,11 58,1108,1075,1030,986,870,800,746,667,559,451,418 cm

MS(ES+) m/z: 407(M+Na)⁺; MS(ES-) m/z: 383(M— H)—MS (ES +) m / z: 407 (M + Na)⁺ ; MS (ES-) m / z: 383 (M— H) —

実施例 22 Example 22

[0123] 15 α 5 -17.18.19.20-テトラノル- 2.3.13.14-テトラデヒドロ- 16- (3-メチルフエ二ル)- P [0123] 15 α 5 -17.18.19.20-tetranor-2.3.13.14-tetradehydro-16- (3-methylphenyl)-P

GE_i (化合物 38)GE_i (Compound 38)

[0124] [化 35][0124] [Chemical 35]

H-NMR(CDC1 , 300MHz) δ ppm; 1.20— 1.84(m, 9H), 2.08— 2.40(m, 3H), 2.20(dd, J= H-NMR (CDC1, 300MHz) δ ppm; 1.20— 1.84 (m, 9H), 2.08— 2.40 (m, 3H), 2.20 (dd, J =

3 Three

18.6,9.2Hz, IH), 2.34(s, 3H), 2.52— 2.63(m, IH), 2.65-2.78(m, IH), 2.78— 3.05(m, 2 H), 4.15-4.30(m, IH), 4.55— 4.68(m, IH), 5.83(d, J=15.2Hz, IH), 6.93— 7.30(m, 5H), 18.6,9.2Hz, IH), 2.34 (s, 3H), 2.52— 2.63 (m, IH), 2.65-2.78 (m, IH), 2.78— 3.05 (m, 2 H), 4.15-4.30 (m, IH ), 4.55— 4.68 (m, IH), 5.83 (d, J = 15.2Hz, IH), 6.93— 7.30 (m, 5H),

IR(neat):3384,3024,2929,2860,2237,1741, 1697,1652, 1610,1590,1488,1417,1310,12IR (neat): 3384,3024,2929,2860,2237,1741, 1697,1652, 1610,1590,1488,1417,1310,12

85,1236,1158,1095,1078,1037,985,882,777cm"¹85,1236,1158,1095,1078,1037,985,882,777cm "¹

MS(ES+) m/z: 407(M+Na)⁺MS (ES +) m / z: 407 (M + Na)⁺

実施例 23 Example 23

[0125] 15( α -17,18,19,20-テトラノル- 2,3,13,14-テトラデヒドロ- 16- (4-メチルフエ-ル)- P [0125] 15 (α -17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (4-methylphenol)-P

GE_i (化合物 39)GE_i (Compound 39)

[0126] [化 36][0126] [Chemical 36]

H-NMR(CDC1 , 300MHz) δ ppm; 1.13— 1.83(m, 9H), 2.08— 2.40(m, 3H), 2.20(dd, J= H-NMR (CDC1, 300MHz) δ ppm; 1.13— 1.83 (m, 9H), 2.08— 2.40 (m, 3H), 2.20 (dd, J =

3 Three

18.4,9.2Hz, IH), 2.33(s, 3H), 2.52— 2.63(m, IH), 2.65-2.78(m, IH), 2.86— 3.04(m, 2 H), 4.18-4.29(m, IH), 4.56- 4.66(m, IH), 5.76- 5.88(m, IH), 6.92-7.24(m, 5H), (ΗΟΐ' 9Ή6·9 '(Ηΐ 'P)08"S '(Ηΐ )SZ 'ト S9' '(Ηΐ 'ω) ΐζ^- Ο^ ΗΖ '^)£Ζ - 6'Ζ '(Η3ΐ ',8 - 00·ΐ： d ρ (ΖΗ兩 OS ' ϋα )Η顺 - Η_Τ18.4,9.2Hz, IH), 2.33 (s, 3H), 2.52— 2.63 (m, IH), 2.65-2.78 (m, IH), 2.86— 3.04 (m, 2 H), 4.18-4.29 (m, IH ), 4.56- 4.66 (m, IH), 5.76-5.88 (m, IH), 6.92-7.24 (m, 5H), (ΗΟΐ '9Ή6 · 9' (Ηΐ 'P) 08 "S' (Ηΐ) SZ 'G S9''(Ηΐ' ω) ΐζ ^-Ο ^ ΗΖ '^) £ Ζ-6'Ζ' (Η3ΐ ', 8-00 · ΐ: d ρ (ΖΗ 兩 OS 'ϋα) Η 顺-Η_Τ

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OAV

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〔 s〔〕9寸90

[S [] 9 inch 90

H-NMR(CDC1 , 300MHz) δ ppm; 1.16— 1.86(m, 9H), 2.13— 2.34(m, 4H), 2.55- 2.80( H-NMR (CDC1, 300MHz) δ ppm; 1.16— 1.86 (m, 9H), 2.13— 2.34 (m, 4H), 2.55- 2.80 (

3 Three

m, 2H), 3.02-3.25(m, 2H), 4.22- 4.33(m, IH), 4.68-4.77(m, IH), 5.78— 5.89(m, IH), 6.96-7.12(m, IH), 7.16-7.42(m, 3H) m, 2H), 3.02-3.25 (m, 2H), 4.22- 4.33 (m, IH), 4.68-4.77 (m, IH), 5.78— 5.89 (m, IH), 6.96-7.12 (m, IH), 7.16-7.42 (m, 3H)

IR(neat):3412,2934,2860,2237,1739,1694,1652, 1588,1562, 1467,1395, 1310,1282, 12 33,1202,1157,1098,1048,985,878,813,728,667,551,466 cm—¹IR (neat): 3412,2934,2860,2237,1739,1694,1652, 1588,1562, 1467,1395, 1310,1282, 12 33,1202,1157,1098,1048,985,878,813,728,667,551,466 cm—¹

MS(ES+) m/z: 461(M+Na)⁺; MS(ES-) m/z: 437(M— H)+MS (ES +) m / z: 461 (M + Na)⁺ ; MS (ES-) m / z: 437 (M— H) +

実施例 34 Example 34

[0147] 15 α -17,18,19,20-テトラノル- 2,3,13,14-テトラデヒドロ- 16- (3,4-ジクロロフエ-ル )- PGE (化合物 51) [0147] 15 α-17,18,19,20-Tetranor-2,3,13,14-tetradehydro-16- (3,4-dichlorophenol) -PGE (Compound 51)

[0148] [化 47] [0148] [Chemical 47]

H-NMR(CDC1 , 300MHz) δ ppm; 1.05— 2.41(m, 13H), 2.54-3.10(m, 4H), 4.14—4.33 H-NMR (CDC1, 300MHz) δ ppm; 1.05—2.41 (m, 13H), 2.54-3.10 (m, 4H), 4.14—4.33

3 Three

(m, IH), 4.54-4.66(m, IH), 5.74-5.87(m, IH), 6.87— 7.46(m, 4H) (m, IH), 4.54-4.66 (m, IH), 5.74-5.87 (m, IH), 6.87—7.46 (m, 4H)

MS(ES+) m/z: 461(M+Na)⁺; MS(ES-) m/z: 437(M— H)+MS (ES +) m / z: 461 (M + Na)⁺ ; MS (ES-) m / z: 437 (M— H) +

実施例 35 Example 35

[0149] 15 α -17,18,19,20-テトラノル- 2,3,13,14-テトラデヒドロ- 16- (3-フラニルフエニル) [0149] 15 α -17,18,19,20-tetranor-2,3,13,14-tetradehydro-16- (3-furanylphenyl)

-PGE_i (化合物 52)-PGE_i (Compound 52)

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[TS^ ] [9ST0] [TS ^] [9ST0]

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[oe^ ] [ ιο]

ZL LiWmi OAV 文献 (Takayama, K.,ら (2002). Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Chem 277, 44147-44154.) 記載の方法にしたがい抗炎症活性を求めた。具体的には、ヒト末梢血単球を精製し 1 週間培養しマクロファージに分ィ匕させた。分化マクロファージに評価化合物を ΙΟηΜ 最終濃度になるように添加し 30分間培養した。培養後、大腸菌由来リポポリサッカライ ド (LPS)を最終濃度 5ng/mlになるように添加し、さらに 18時間培養した。培養後、細 胞上清を回収し、ケモカイン (MIP-1 j8 )産生量を ELISA法にて測定した。抗炎症活 性の陰性対照としては媒体溶液を、陽性対照としては PGEを用いた。陰性対照を添[oe ^] [ιο]

ZL LiWmi OAV 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, cultured for 1 week, and separated into macrophages. The compound to be evaluated was added to differentiated macrophages to a final concentration of ΙΟηΜ and incubated for 30 minutes. After culturing, 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 the amount of chemokine (MIP-1 j8) produced was measured by ELISA. The medium solution was used as a negative control for anti-inflammatory activity, and PGE was used as a positive control. With negative control

2 2

加した際の MIP-1 β産生量を 100%として、それぞれの化合物 10ηΜを加えて培養し た時の残存 MIP-1 18量（％of control)とした。結果を試験例 2と合わせて表 2に示した The amount of MIP-1 β produced at the time of addition was defined as 100%, and the amount of MIP-1 18 remaining (% of control) when each compound 10η て was added and cultured. The results are shown in Table 2 together with Test Example 2.

[0158] 試験例 2 [cAMP産生量の測定][0158] Test Example 2 [Measurement of cAMP Production]

分ィ匕マクロファージに評価化合物を 1〜： LOOOnM最終濃度になるように添加し 45分 間培養した。培養後、細胞を破砕し、細胞内の cAMPを EIA法にて定量した。 ΙΟΟΟηΜ PGEを同一条件下で処理した時の cAMP量を 100%とした際、それぞれの化合物の E The compound to be evaluated was added to the macrophage macrophages 1 to: LOOOnM at a final concentration and cultured for 45 minutes. After culturing, the cells were disrupted, and intracellular cAMP was quantified by the EIA method. When the amount of cAMP when ΙΟΟΟηΜ PGE was treated under the same conditions was taken as 100%, the E of each compound

22

D50値を算出した。結果を、試験例 1と合わせて表 2に示した。 D50 value was calculated. The results are shown in Table 2 together with Test Example 1.

[0159] [表 2][0159] [Table 2]

[0160] 表から明らかなように、本発明の化合物は強力な抗炎症活性を有する一方、 cAMP 産生は非常に低い化合物であることがわ力つた。[0160] As is apparent from the table, the compounds of the present invention have potent anti-inflammatory activity, while cAMP It was proved that the production was a very low compound.

[0161] 試験例 3 [各種サイト力イン/ケモカイン産生に対する化合物の産生抑制効果] [0161] Test Example 3 [Production inhibitory effect of compounds on various site power in / chemokine production]

文献 (Takayama, K.,ら (2002). Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biol Cnem 277, 4414/-44154.) 記載の方法に従って行った。具体的には、精製したヒト末梢血単球を 1週間培養しマ クロファージに分化させた。分化マクロファージに評価化合物を 0. 1〜100ηΜ最終濃 度になるように添加し 30分間培養した。培養後、大腸菌由来リポポリサッカライド (LPS )を最終濃度 5ng/mlになるように添加し、さらに 18時間培養した。培養後、細胞上清 を回収し、サイト力イン（TNF a )、ケモカイン（MCP- 1、 MIP- 1 j8 )産生量を ELISA法に て測定した。抗炎症活性の陰性対照としては媒体溶液を、陽性対照としては PGEを It was carried out 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 Cnem 277, 4414 / -44154.). Specifically, purified human peripheral blood monocytes were cultured for 1 week and differentiated into macrophages. The compound to be evaluated was added to differentiated macrophages to a final concentration of 0.1-100 ηΜ 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 the amount of cytoforce-in (TNFa) and chemokine (MCP-1, MIP-1 j8) production was measured by ELISA. Medium control as a negative control for anti-inflammatory activity and PGE as a positive control

2 用いた。陰性対照を添加した際のサイト力イン産生量を 100%として、それぞれの化 合物の産生阻害濃度 (IC50値)を算出した。結果を表 3に示した。 2 Used. The production inhibition concentration (IC50 value) of each compound was calculated with the amount of production of cyto force-in when a negative control was added as 100%. The results are shown in Table 3.

[0162] [表 3][0162] [Table 3]

[0163] 表から明らかなように、本発明の化合物は各種サイト力インの産生を強力に抑制し た。[0163] As is apparent from the table, the compounds of the present invention strongly suppressed the production of various cyto force ins.

[0164] 試験例 4 [敗血症における血清サイト力イン産生抑制効果] [0164] Test Example 4 [Inhibition of serum site force in production in sepsis]

BALB/cマウスに D- Galactosamine 450mg/kg腹腔内投与と同時に Indomethacine 3mg/kg経口投与を行い 65min放置したのち LPS 500 /z g/kg腹腔内投与し、敗血症 を発症させた。被験化合物は LPS腹腔内投与の lmin前にリン酸緩衝液に溶解し皮 下投与した。 BALB / c mice were administered D-galactosamine 450 mg / kg intraperitoneally and simultaneously with Indomethacine 3 mg / kg and left for 65 min, followed by LPS 500 / z g / kg intraperitoneally to develop sepsis. The test compound was dissolved in phosphate buffer and administered subcutaneously 1 min before LPS intraperitoneal administration.

[0165] 1. 5時間後の血清中の TNF a量を測定した。統計処理は Dunnett法を用いて行つ た。 [0165] 1. The amount of TNFa in the serum after 5 hours was measured. Statistical processing was performed using the Dunnett method.

[0166] 結果を図 1に示した。 [0167] 図 1から明らかなように、本発明の化合物は敗血症における血清サイト力イン産生を 強力に抑制することがわ力つた。The results are shown in FIG. [0167] As is apparent from Fig. 1, the compound of the present invention was found to potently inhibit the production of serum cytodynamic force in sepsis.

[0168] 試験例 5 [心筋梗塞巣中の MCP-1発現に対する効果] [0168] Test Example 5 [Effects on MCP-1 expression in myocardial infarction lesions]

麻酔したラットに人工呼吸器を接続後、開胸手術を行い、心臓を露出させた。スネ ァ一法にて冠動脈の起始部から 3-4 mm遠位部を結さくし、心筋を 30分虚血状態と したのち、再灌流することにより、心筋梗塞後の再灌流障害を誘発させた。再灌流 24 時間後、梗塞領域を切除し、蛋白分解酵素阻害剤、界面活性剤含有の Tris緩衝液 中で組織を破砕し、遠心分離により可溶性分画を得た。可溶性分画の総蛋白質量は BCA法で測定した。可溶性分画の MCP— 1量は ELISA法にて測定した。被験化 合物 (化合物 34)は再灌流 5分前、 6時間後、 12時間後の 3回リン酸緩衝液に溶解し 皮下投与した。結果を図 2に示した。 After connecting a ventilator to the anesthetized rat, thoracotomy was performed to expose the heart. Using a snare method, connect the 3-4 mm distal part from the origin of the coronary artery, leave the myocardium in the ischemic state for 30 minutes, and then reperfuse to induce reperfusion injury after myocardial infarction. It was. 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 content 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.

[0169] 図 2から明らかなように、本発明の化合物は心筋梗塞巣中の MCP-1発現量を顕著 に抑制した。 [0169] As is apparent from Fig. 2, the compound of the present invention remarkably suppressed the expression level of MCP-1 in myocardial infarction.

産業上の利用可能性 Industrial applicability

[0170] 本発明の化合物は優れた抗炎症活性を有するため、自己免疫疾患、慢性関節リュ 一マチ、乾癬、喘息、肝炎、腎炎、粥状動脈硬化症、心筋炎、敗血症、心筋梗塞、臓 器移植時の拒絶、経皮的経血管的冠動脈形成術後の血管内膜肥厚などの疾患に 対して有用であり、血圧降下等の副作用の少ない薬剤として有用である。[0170] Since the compound of the present invention has excellent anti-inflammatory activity, autoimmune disease, chronic arthritis, psoriasis, asthma, hepatitis, nephritis, atherosclerosis, myocarditis, sepsis, myocardial infarction, viscera It is useful for diseases such as rejection at the time of organ transplantation, and intimal thickening after percutaneous transvascular coronary angioplasty, and it is useful as a drug with few side effects such as lowering blood pressure.

図面の簡単な説明 Brief Description of Drawings

[0171] [図 1]敗血症における血清サイト力イン産生抑制効果を示した図であり縦軸に血清中 の TNF a量 (ng/ml)、横軸に化合物名および投与量 (mg/Kg)を示した。なお、図中「* **」は P〈0. 005を示す。 [0171] [Fig. 1] A graph showing the effect of suppressing the production of serum site force in sepsis in sepsis, where the vertical axis represents the amount of TNFa in the serum (ng / ml) and the horizontal axis represents the compound name and dose (mg / Kg) showed that. In the figure, “* **” indicates P <0.005.

[図 2]ラット心筋梗塞巣中の MCP-1発現に対する効果を示した図であり、縦軸に MCP -1蛋白量 (ng/protein mg)、横軸に薬物投与量を示した。 FIG. 2 is a graph showing the effect on the expression of MCP-1 in rat myocardial infarction, where the vertical axis indicates the amount of MCP-1 protein (ng / protein mg) and the horizontal axis indicates the drug dose.

Claims

請求の範囲 式 (I) Claim Formula (I)

[化 1] [Chemical 1]

[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、[Wherein R¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms,

Xはエチレン基、トリメチレン基、ビニレン基、ェチ-レン基または一 SCH -で示さ X represents an ethylene group, a trimethylene group, a vinylene group, an ethylene group or a single SCH-

2 れる を示し、 2

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、フエニル 基、置換フエ-ル基、フリル基またはチェ二ル基を示す。 ]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。R² and R³ 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, and the number of carbon atoms. An alkyl group having 1 to 6 carbon atoms substituted with 1 to 6 alkoxy groups, a phenyl group, a substituted phenyl group, a furyl group, or a phenyl group. Or a pharmaceutically acceptable salt or hydrate thereof.