JP2641622B2 - Prostaglandin E lower 1 analog - Google Patents
Prostaglandin E lower 1 analogInfo
- Publication number
- JP2641622B2 JP2641622B2 JP4507785A JP50778592A JP2641622B2 JP 2641622 B2 JP2641622 B2 JP 2641622B2 JP 4507785 A JP4507785 A JP 4507785A JP 50778592 A JP50778592 A JP 50778592A JP 2641622 B2 JP2641622 B2 JP 2641622B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- group
- pge
- cdcl
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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- 125000000217 alkyl group Chemical group 0.000 claims description 13
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- 125000001931 aliphatic group Chemical group 0.000 claims description 5
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- 150000003839 salts Chemical class 0.000 claims description 5
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- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006622 cycloheptylmethyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- ZSYZSZTWBOHQQK-UHFFFAOYSA-L dilithium;dichloride Chemical compound [Li+].[Li+].[Cl-].[Cl-] ZSYZSZTWBOHQQK-UHFFFAOYSA-L 0.000 description 1
- JGHYBJVUQGTEEB-UHFFFAOYSA-M dimethylalumanylium;chloride Chemical compound C[Al](C)Cl JGHYBJVUQGTEEB-UHFFFAOYSA-M 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 239000003995 emulsifying agent Substances 0.000 description 1
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- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 108010021666 lipase II Proteins 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- HLVIVLQEPITJNH-UHFFFAOYSA-N tert-butyl-(4,4-dimethyloct-1-yn-3-yloxy)-dimethylsilane Chemical group CCCCC(C)(C)C(C#C)O[Si](C)(C)C(C)(C)C HLVIVLQEPITJNH-UHFFFAOYSA-N 0.000 description 1
- HQSDNUBPNJEFFQ-CQSZACIVSA-N tert-butyl-[(1s)-1-cyclohexylprop-2-ynoxy]-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[C@H](C#C)C1CCCCC1 HQSDNUBPNJEFFQ-CQSZACIVSA-N 0.000 description 1
- YYBRSFNTOQITLH-OAHLLOKOSA-N tert-butyl-[(2s)-1-cyclohexylbut-3-yn-2-yl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[C@H](C#C)CC1CCCCC1 YYBRSFNTOQITLH-OAHLLOKOSA-N 0.000 description 1
- YTEMCMDLNWBDAG-CQSZACIVSA-N tert-butyl-[(2s)-1-cyclopentylbut-3-yn-2-yl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[C@H](C#C)CC1CCCC1 YTEMCMDLNWBDAG-CQSZACIVSA-N 0.000 description 1
- PNDZMPNMXSAJCA-ZYMOGRSISA-N tert-butyl-[(3s)-5,9-dimethyldec-8-en-1-yn-3-yl]oxy-dimethylsilane Chemical compound CC(C)=CCCC(C)C[C@H](O[Si](C)(C)C(C)(C)C)C#C PNDZMPNMXSAJCA-ZYMOGRSISA-N 0.000 description 1
- NEDMJIVBACTDON-UHFFFAOYSA-N tert-butyl-[tert-butyl(methyl)silyl]oxy-methylsilane Chemical compound CC(C)(C)[SiH](C)O[SiH](C)C(C)(C)C NEDMJIVBACTDON-UHFFFAOYSA-N 0.000 description 1
- OEPUWDJPUOTBBQ-YSSOQSIOSA-N tert-butyl-dimethyl-[(3s)-4-methylnona-1,6-diyn-3-yl]oxysilane Chemical group CCC#CCC(C)[C@@H](C#C)O[Si](C)(C)C(C)(C)C OEPUWDJPUOTBBQ-YSSOQSIOSA-N 0.000 description 1
- KIGGNWHCOCQERD-ARLHGKGLSA-N tert-butyl-dimethyl-[(3s)-4-methyloct-1-yn-3-yl]oxysilane Chemical group CCCCC(C)[C@@H](C#C)O[Si](C)(C)C(C)(C)C KIGGNWHCOCQERD-ARLHGKGLSA-N 0.000 description 1
- CHDOHQCYVUDHBB-OEMAIJDKSA-N tert-butyl-dimethyl-[(3s)-5-methyldec-1-yn-3-yl]oxysilane Chemical compound CCCCCC(C)C[C@@H](C#C)O[Si](C)(C)C(C)(C)C CHDOHQCYVUDHBB-OEMAIJDKSA-N 0.000 description 1
- JLZODEVNYCZFMH-HUUCEWRRSA-N tert-butyl-dimethyl-[(3s,5r)-5-methylnon-1-yn-3-yl]oxysilane Chemical compound CCCC[C@@H](C)C[C@@H](C#C)O[Si](C)(C)C(C)(C)C JLZODEVNYCZFMH-HUUCEWRRSA-N 0.000 description 1
- JLZODEVNYCZFMH-LSDHHAIUSA-N tert-butyl-dimethyl-[(3s,5s)-5-methylnon-1-yn-3-yl]oxysilane Chemical group CCCC[C@H](C)C[C@@H](C#C)O[Si](C)(C)C(C)(C)C JLZODEVNYCZFMH-LSDHHAIUSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】 技術分野 本発明は新規なプロスタグランジン（以下PGと略称す
る）E1類縁体に関する。Description: TECHNICAL FIELD The present invention (hereinafter abbreviated as PG) novel prostaglandin related to E 1 analogues.
背景技術 PGは微量で種々の重要な生理作用を発揮することか
ら、医薬への応用を意図して天然PG及び夥しい数のその
誘導体の合成と生物活性の検討が行なわれてきた。BACKGROUND ART Since PG exerts various important physiological actions in a very small amount, synthesis and biological activity of natural PG and a large number of its derivatives have been studied for application to medicine.
その中でもPGE1は、血小板凝集抑制作用、血圧低下作
用などの特徴ある作用を有し末梢循環障害を改善する医
薬として実用化されており、このため多数のPGE1類縁体
も検討されてきた。しかしながら、従来のPGE1類縁体は
生体内での代謝が速く、従って効果が持続しないという
欠点があった。また、従来のPGE1類縁体は経口で投与し
た場合、副作用として下剤を誘発するため、高い用量で
投与できず、十分な効果を挙げることができなかった。PGE 1 Among them, the platelet aggregation inhibitory action, have been put into practical use as a pharmaceutical for improving the distinctive peripheral circulatory disorder has an action such as hypotensive effect, and therefore a large number of PGE 1 analogues have also been investigated. However, conventional PGE 1 analogs have the disadvantage that their metabolism in vivo is fast and therefore their effects are not sustained. In addition, the conventional PGE 1 analog, when administered orally, induces laxatives as a side effect, so that it could not be administered at a high dose and could not have a sufficient effect.
一方、PGE1の13,14位の二重結合を三重結合に変えた1
3,14−ジデヒドロPGE1類縁体として、13,14−ジデヒド
ロPGE1メチルエステル、６−ヒドロキシ−13,14−ジデ
ヒドロPGE1が知られている。On the other hand, the double bond at the 13,14 position of PGE 1 was changed to a triple bond.
As 3,14-didehydro PGE 1 analogs, 13,14-didehydro PGE 1 methyl ester and 6-hydroxy-13,14-didehydro PGE 1 are known.
本発明は従来のPGE1類縁体よりも薬効が優れ、持続性
がよく、かつ副作用が軽減された新規なPGE1類縁体を提
供することを目的とする。An object of the present invention is to provide a novel PGE 1 analog which has better efficacy than conventional PGE 1 analogs, has good durability, and has reduced side effects.
発明の開示 本発明者らは鋭意研究を進めた結果、PGE1類縁体にお
いて、13,14位に３重結合を有し、かつ16位または17位
に分岐を有し、さらに2,3位を２重結合または３重結合
にした化合物が前記課題を解決できることを見いだし、
本発明を完成した。We disclosed our invention is a result of our intensive studies, the PGE 1 analogues, has a triple bond in 13,14 position, and has a branch in the position 16 or position 17, further 2,3 A compound having a double bond or a triple bond can solve the above problem,
The present invention has been completed.
すなわち、本発明は、式 （式中、Ａはビニレン基またはエチニレン基を示し、R1
は水素原子、炭素原子数１〜６個のアルキル基またはア
リル基を示し、R2は炭素原子数５〜10個の分岐脂肪族炭
化水素基を示し、ｎは３〜６の整数を示す。）で表され
るPGE18類縁体及びその塩である。That is, the present invention uses the formula (Wherein A represents a vinylene group or an ethynylene group, and R 1
Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an allyl group, R 2 represents a branched aliphatic hydrocarbon group having 5 to 10 carbon atoms, and n represents an integer of 3 to 6. ) Is a PGE 1 8 analogs and salts thereof represented by.
本発明において、炭素原子数１〜６個のアルキル基と
は、直鎖状または分枝鎖状のものをいい、例えばメチル
基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−
ブチル基、イソブチル基、ｔ−ブチル基、ｎ−ペンチル
基、イソペンチル基などである。In the present invention, the alkyl group having 1 to 6 carbon atoms means a linear or branched one, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-alkyl group.
Butyl, isobutyl, t-butyl, n-pentyl, isopentyl and the like.
炭素原子数５〜10個の分岐脂肪族炭化水素基とは、そ
のα位またはβ位に分岐を有する脂肪族炭化水素基であ
り、具体的には分岐鎖状アルキル基（例えば１−メチル
ペンチル基、２−メチルペンチル基、１−メチルヘキシ
ル基、２−メチルヘキシル基、2,4−ジメチルペンチル
基、２−エチルペンチル基、２−メチルヘプチル基、２
−エチルヘキシル基、２−プロピルペンチル基、2,6−
ジメチルヘプチル基など）、シクロアルキル基（例えば
シクロペンチル基、シクロヘキシル基、シクロヘプチル
基など）、シクロアルキル基で置換された炭素原子数１
または２個のアルキル基（例えばシクロペンチルメチル
基、シクロヘキシルメチル基、シクロヘプチルメチル
基、シクロペンチルエチル基、シクロヘキシルエチル
基、シクロヘプチルエチル基など）、分枝鎖状アルケニ
ル基（例えば上記分枝鎖状アルキル基においてその任意
の位置の単結合の一つを二重結合に変えた基で、2,6−
ジメチルヘプタ−５−ニル基など）、分枝鎖状アルケニ
ル基（例えば上記分枝鎖状アルキル基においてその任意
の位置の単結合の一つを三重結合に変えた基で、１−メ
チルペント−３−イニル基、１−メチルヘキサ−３−イ
ニル基、２−メチルヘキサ−３−イニル基など）であ
る。The branched aliphatic hydrocarbon group having 5 to 10 carbon atoms is an aliphatic hydrocarbon group having a branch at the α-position or the β-position, and specifically, a branched alkyl group (eg, 1-methylpentyl) Group, 2-methylpentyl group, 1-methylhexyl group, 2-methylhexyl group, 2,4-dimethylpentyl group, 2-ethylpentyl group, 2-methylheptyl group, 2
-Ethylhexyl group, 2-propylpentyl group, 2,6-
A dimethylheptyl group, a cycloalkyl group (eg, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, etc.), and a carbon atom substituted with a cycloalkyl group having 1 carbon atom
Or two alkyl groups (eg, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclopentylethyl group, cyclohexylethyl group, cycloheptylethyl group, etc.), a branched alkenyl group (eg, the above-mentioned branched alkyl group) A group in which one of the single bonds at any position in the group has been changed to a double bond,
A dimethylhept-5-yl group or the like, a branched alkenyl group (for example, a group in which one of the single bonds at any position in the above-mentioned branched alkyl group is changed to a triple bond, 1-methylpent-3) -Inyl group, 1-methylhex-3-ynyl group, 2-methylhex-3-ynyl group, etc.).
式（Ｉ）の化合物の塩とは、式（Ｉ）においてR1が水
素原子の化合物の場合の、ナトリウム、カリウム、アル
ミニウムなどの金属との塩あるいはトリアルキルアミン
などの有機アミンとの塩である。The salt of the compound of the formula (I) is a salt with a metal such as sodium, potassium or aluminum or a salt with an organic amine such as a trialkylamine when R 1 is a compound in which R 1 is a hydrogen atom. is there.
式（Ｉ）の化合物は、例えば以下に挙げる方法により
容易に製造できる。The compound of the formula (I) can be easily produced, for example, by the methods described below.
（反応式中、R3およびR4は同一または異なって水酸基の
保護基を示し、R5およびR6は同一または異なって炭素原
子数１〜10個のアルキル基を示し、R7は水素原子を除く
R1であり、R2、Ａおよびｎは前記と同意義である。ここ
で、水酸基の保護基とはプロスタグランジンの分野で通
常用いられるものであり、例えばｔ−ブチルジメチルシ
リル基、トリエチルシリル基、フェニルジメチルシリル
基、テトラヒドロピロリル基、テトラヒドロフラニル
基、メトキシメチル基、エトキシエチル基、ベンジル基
などである。） すなわち、まず、佐藤らの方法［ジャーナル・オブ・
オーガニック・ケミストリー（J.Org.Chem.），第53
巻，第5590ページ（1988年）］により公知である式（I
I）の化合物に、式（III）で表される有機アルミニウム
化合物0.8〜2.0当量を−10〜30℃、好ましくは０〜10℃
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、ジエチルエーテル、塩化メチレン、ｎ−ヘキ
サンなど）中で反応させることにより立体特異的に式
（IV）の化合物が得られる。 (In the reaction formula, R 3 and R 4 are the same or different and each represents a hydroxyl-protecting group; R 5 and R 6 are the same or different and represent an alkyl group having 1 to 10 carbon atoms; R 7 is a hydrogen atom except for
R 1 , R 2 , A and n are as defined above. Here, the hydroxyl-protecting group is one commonly used in the field of prostaglandins, for example, t-butyldimethylsilyl, triethylsilyl, phenyldimethylsilyl, tetrahydropyrrolyl, tetrahydrofuranyl, methoxymethyl Group, ethoxyethyl group, benzyl group and the like. That is, first, the method of Sato et al. [Journal of
Organic Chemistry (J.Org.Chem.), No. 53
Vol., P. 5590 (1988)].
0.8 to 2.0 equivalents of the organoaluminum compound represented by the formula (III) is added to the compound of I) at -10 to 30C, preferably 0 to 10C.
In an inert solvent (eg, benzene, toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane, etc.) to give the compound of formula (IV) stereospecifically.
ここで、式（III）の有機アルミニウム化合物は、例
えば佐藤らの方法［テトラヘドロン レターズ（Tetrah
edron Lett.），第30巻，第7083ページ（1989年）］に
より製造される式 （式中、R2およびR4は前記と同意義である。）で表され
るアセチレン化合物にアルキルリチウル（例えばｎ−ブ
チルリチウム、ｔ−ブチルリチウムなど）0.8〜1.5当量
を−20〜30℃、好ましくは−10〜０℃にて加え、さらに
好ましくは10〜30℃にて完全に反応を完了させた後、−
20〜30℃にて式 R5R6−Al−Ｘ （式中、R5およびR6は前記と同意義であり、Ｘはハロゲ
ン原子を示す。）で表されるハロゲン化アルキルアルミ
ニウム（例えば塩化ジエチルアルミニウム、塩化ジメチ
ルアルミニウムなど）を0.8〜1.5当量加えて調製する。
この反応においては不活性有機溶媒（例えばベンゼン、
トルエン、テトラヒドロフラン、ジエチルエーテル、塩
化メチレン、ｎ−ヘキサンなど）を用いることが好まし
い。Here, the organoaluminum compound of the formula (III) can be prepared, for example, by the method of Sato et al. [Tetrahedron Letters (Tetrah
edron Lett.), Volume 30, Page 7083 (1989)] (Wherein R 2 and R 4 have the same meanings as described above). An alkylacetyl (e.g., n-butyllithium, t-butyllithium, etc.) is added to the acetylene compound represented by C., preferably at −10 to 0 ° C., more preferably at 10 to 30 ° C., after completing the reaction completely,
Wherein R 5 R 6 -Al-X at 20 to 30 ° C. (wherein, R 5 and R 6 are as defined above, X is a halogen atom.) Alkylaluminum halides represented by (e.g. 0.8-1.5 equivalents of diethylaluminum chloride, dimethylaluminum chloride).
In this reaction, an inert organic solvent (eg, benzene,
It is preferable to use toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane and the like.
次に、式（IV）の化合物を、式（Ｖ）で表される有機
銅化合物0.5〜４当量およびクロロトリメチルシラン0.5
〜４当量と不活性溶媒（例えばテトラヒドロフラン、ジ
エチルエーテル、塩化メチレン、トルエン、ｎ−ヘキサ
ンなど）中、−78〜40℃で反応させ、式（VI）の化合物
とする。Next, the compound of the formula (IV) is mixed with 0.5 to 4 equivalents of the organocopper compound represented by the formula (V) and 0.5 parts of chlorotrimethylsilane.
To 4 equivalents in an inert solvent (eg, tetrahydrofuran, diethyl ether, methylene chloride, toluene, n-hexane, etc.) at −78 to 40 ° C. to obtain a compound of the formula (VI).
ここで、式（Ｖ）の有機銅化合物は、式 Ｉ−（CH2）n-1−Ａ−COOR7 （VIII） （式中、R7、Ａおよびｎは前記と同意義である。）で表
されるヨウ素化合物から、公知の方法［P.Knochelら，
ジャーナル・オブ・オーガニック・ケミストリー，第53
巻，第2390ページ（1988年）］により調製できる。すな
わち、式（VIII）のヨウ素化合物を、例えば1,2−ジブ
ロモメタン、クロロトリメチル、ヨウ素などで活性化さ
れた亜鉛0.8〜５当量と、不活性溶媒（例えばテトラヒ
ドロフラン、ジエチルエーテル、ｎ−ヘキサン、ｎ−ペ
ンタン、ジオキサンなど）中で反応させることにより式 IZn−（CH2）n-1−Ａ−COOR7 （式中、R7、Ａおよびｎは前記と同意義である。）で表
される有機亜鉛化合物へと誘導する。この際、必要に応
じて加熱してもよい。加熱温度は溶媒の沸点にもよる
が、通常30〜150℃、好ましくは40〜80℃である。得ら
れた有機亜鉛化合物を、−50〜10℃にて、シアン化銅
（１〜2.5当量）、塩化リチウム（２〜５当量）を含む
前記不活性溶媒中で反応させることにより、式（Ｖ）の
有機銅化合物を得ることができる。Here, the organocopper compound of the formula (V) is represented by the formula I- (CH 2 ) n-1 -A-COOR 7 (VIII) (wherein R 7 , A and n are as defined above). From an iodine compound represented by the formula [P. Knochel et al.
Journal of Organic Chemistry, 53
Volume, page 2390 (1988)]. That is, an iodine compound of the formula (VIII) is prepared by, for example, 0.8 to 5 equivalents of zinc activated with 1,2-dibromomethane, chlorotrimethyl, iodine or the like, and an inert solvent (eg, tetrahydrofuran, diethyl ether, n-hexane, n- pentane, formula were reacted in dioxane) IZn- (CH 2) n- 1 -A-COOR 7 ( wherein, R 7, a and n are represented by the the same meaning.) To an organozinc compound. At this time, heating may be performed if necessary. The heating temperature depends on the boiling point of the solvent, but is usually 30 to 150 ° C, preferably 40 to 80 ° C. The obtained organozinc compound is reacted at −50 to 10 ° C. in the inert solvent containing copper cyanide (1 to 2.5 equivalents) and lithium chloride (2 to 5 equivalents) to obtain a compound of the formula (V) )) Can be obtained.
次いで、式（VI）の化合物を、無機酸（例えば塩酸の
水溶液）または有機酸もしくはそのアミン塩（例えばｐ
−トルエンスルホン酸、ｐ−トルエンスルホン酸ピリジ
ン塩など）を用い、有機溶媒（例えばアセトン、メタノ
ール、エタノール、イソプロパノール、ジエチルエーテ
ルあるいはこれらの混合溶媒など）中、０〜40℃にて加
水分解することにより、立体選択的に式（VII）の化合
物が得られる。The compound of formula (VI) is then converted to an inorganic acid (eg, an aqueous solution of hydrochloric acid) or an organic acid or an amine salt thereof (eg, p
-Hydrolysis at 0 to 40 ° C. in an organic solvent (for example, acetone, methanol, ethanol, isopropanol, diethyl ether or a mixture thereof) using toluene sulfonic acid, p-toluene sulfonic acid pyridine salt or the like. Yields the compound of formula (VII) in a stereoselective manner.
最後に、式（VII）の化合物の水酸基の保護基をプロ
スタグランジンの分野における通常の方法を用いて脱保
護し、式（Ｉ）においてR1が水素原子以外の基である本
発明の化合物［式（I a）の化合物）を得る。Finally, the hydroxyl protecting group of the compound of formula (VII) is deprotected using conventional methods in the field of prostaglandins, and the compound of the present invention wherein R 1 is a group other than a hydrogen atom in formula (I) [Compound of formula (Ia)] is obtained.
式（Ｉ）においてR1が水素原子である本発明の化合物
［式（I b）の化合物］は、式（I a）の化合物のうち、
R7が炭素原子数１〜６個のアルキル基である化合物［こ
れを式（I c）の化合物とする。］のエステル部分を加
水分解することにより得ることができる。In the formula (I), the compound of the present invention wherein R 1 is a hydrogen atom [compound of the formula (Ib)] is a compound of the formula (Ia)
A compound in which R 7 is an alkyl group having 1 to 6 carbon atoms [this is referred to as a compound of the formula (Ic). ] Can be obtained by hydrolyzing the ester moiety of
加水分解は、式（I c）の化合物を、リン酸緩衝液、
トリス−塩酸緩衝液などの緩衝液中、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ることにより行
う。Hydrolyzing the compound of formula (Ic) with a phosphate buffer,
The reaction is carried out by reacting with an enzyme in a buffer such as a Tris-HCl buffer, if necessary, using an organic solvent (miscible with water such as acetone, methanol and ethanol).
使用する酵素としては、微生物が生産する酵素（例え
ばキャンディダ属、シュードモナス属に属する微生物が
生産する酵素）、動物の臓器から調製される酵素（例え
ばブタ肝臓やブタ膵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挙げると、リパーゼVII（シ
グマ社製，キャンディダ属の微生物由来）、リパーゼAY
（天野製薬社製，キャンディダ属の微生物由来）、リパ
ーゼMF（天野製薬社製，シュードモナス属の微生物由
来）、PLE−Ａ（天野製薬社製，ブタ肝臓より調製）、
エステラーゼ（シグマ社製，ブタ肝臓より調製）、リパ
ーゼII（シグマ社製，ブタ膵臓より調製）、リポプロテ
インリパーゼ（東京化成工業社製，ブタ膵臓より調製）
などである。Enzymes used include enzymes produced by microorganisms (eg, enzymes produced by microorganisms belonging to the genus Candida and Pseudomonas), enzymes prepared from animal organs (eg, enzymes prepared from pig liver and pig pancreas), and the like. Specific examples of commercially available enzymes include Lipase VII (manufactured by Sigma, derived from a microorganism of the genus Candida), Lipase AY
(Manufactured by Amano Pharmaceutical Co., derived from a microorganism of the genus Candida), lipase MF (manufactured by Amano Pharmaceutical Co., derived from a microorganism of the genus Pseudomonas), PLE-A (manufactured by Amano Pharmaceutical Co., prepared from pig liver),
Esterase (Sigma, prepared from pig liver), Lipase II (Sigma, prepared from pig pancreas), Lipoprotein lipase (Tokyo Kasei Kogyo, prepared from pig pancreas)
And so on.
酵素の使用量は、酵素の力価及び基質［式（I c）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。The amount of the enzyme to be used may be appropriately selected according to the titer of the enzyme and the amount of the substrate [compound of the formula (Ic)], but is usually 0.1 to 20 parts by weight of the substrate.
反応温度は、25〜50℃、好ましくは30〜35℃である。 The reaction temperature is 25-50 ° C, preferably 30-35 ° C.
（２）式（Ｉ）においてR1が水素原子である本発明の化
合物は、前記（Ｉ）の式（VII）においてR7がアリル基
である化合物から以下の方法によっても製造することが
できる。(2) The compound of the present invention wherein R 1 is a hydrogen atom in the formula (I) can also be produced from the compound in which R 7 is an allyl group in the formula (VII) of the above (I) by the following method. .
（反応式中、R2、R3、R4、Ａおよびｎは前記と同意義で
ある。） すなわち、まず、前記（Ｉ）の式（VII）においてR7
がアリル基である化合物［式（VII′）の化合物］を、
パラジウム触媒の存在下１〜10当量の有機アミンまたは
アンモニアと反応させ、式（IX）の化合物とする。 (In the reaction formula, R 2 , R 3 , R 4 , A and n have the same meanings as described above.) That is, first, in the formula (VII) of the above (I), R 7
Is a compound of the formula (VII ′)
Reaction with 1 to 10 equivalents of an organic amine or ammonia in the presence of a palladium catalyst to give a compound of formula (IX).
ここで、パラジウム触媒としては、トリス（ジベンジ
リデンアセトン）二パラジウム（０）クロロホルム、ビ
ス（ジベンジリデンアセトン）パラジウム（０）、テト
ラキス（トリフェニルホスフィン）パラジウム（０）、
ビス（アセチルアセトナート）パラジウム（II）、ジク
ロロビス（ベンゾニトリル）パラジウム（II）などが挙
げられる。パラジウム触媒の使用量は、0.01〜0.5当量
である。Here, as the palladium catalyst, tris (dibenzylideneacetone) dipalladium (0) chloroform, bis (dibenzylideneacetone) palladium (0), tetrakis (triphenylphosphine) palladium (0),
Bis (acetylacetonato) palladium (II), dichlorobis (benzonitrile) palladium (II) and the like can be mentioned. The used amount of the palladium catalyst is 0.01 to 0.5 equivalent.
また、有機アミンとは第１級または第２級の有機アミ
ンであり、例えばエチルアミン、ジエチルアミン、モル
ホリン、ピペリジンなどが挙げられる。The organic amine is a primary or secondary organic amine, and examples thereof include ethylamine, diethylamine, morpholine, and piperidine.
本反応においては必要に応じて不活性有機溶媒（例え
ばジエチルエーテル、テトラヒドロフランなど）を加え
ることができる。また、パラジウム触媒にすでにホスフ
ィン類が配位している場合を除き、ホスフィン類（例え
ばトリエチルホスフィン、トリブチルノスフィン、トリ
フェニルホスフィンなど）を加えることが好ましい。In this reaction, an inert organic solvent (eg, diethyl ether, tetrahydrofuran, etc.) can be added as necessary. It is preferable to add phosphines (for example, triethylphosphine, tributylnosphine, triphenylphosphine, etc.) unless phosphines are already coordinated to the palladium catalyst.
次に、式（IX）の化合物の水酸基の保護基をプロスタ
グランジンの分野における通常の方法を用いて脱保護す
ることにより、式（Ｉ）においてR1が水素原子である本
発明の化合物［式（I d）の化合物］を得ることができ
る。Next, the hydroxyl-protecting group of the compound of the formula (IX) is deprotected by using a conventional method in the field of prostaglandins, whereby the compound of the present invention wherein R 1 is a hydrogen atom in the formula (I) [ Compound of Formula (Id)].
（３）式（Ｉ）においてＡがシスのビニレン基であり、
R1が水素原子または炭素原子数１〜６個のアルキル基で
ある化合物は、前記（Ｉ）の式（VII）においてＡがエ
チニレン基である化合物から以下の方法によっても製造
することができる。(3) In the formula (I), A is a cis vinylene group;
The compound in which R 1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms can also be produced from the compound in which A is an ethynylene group in the formula (VII) of the above (I) by the following method.
（反応式中、R2、R3、R4、R7およびｎは前記と同意義で
あり、R10は、R7が炭素原子数１〜６個のアルキル基を
示すときは同じものを示し、R7がアリル基を示すときは
水素原子を示す。） すなわち、まず、前記（Ｉ）の式（VII）においてＡ
がエチニレン基である化合物［式（VII″）の化合物］
を、パラジウム触媒の存在下、１〜10当量のギ酸と反応
させ、式（Ｘ）の化合物とする。 (In the reaction formula, R 2 , R 3 , R 4 , R 7 and n are as defined above, and R 10 is the same when R 7 represents an alkyl group having 1 to 6 carbon atoms. And when R 7 represents an allyl group, it represents a hydrogen atom.) That is, first, in formula (VII) of the above (I), A
Is a compound of the formula (VII ″)
Is reacted with 1 to 10 equivalents of formic acid in the presence of a palladium catalyst to give a compound of formula (X).
ここで、パラジウム触媒の種類および使用量は前記
（２）と同じである。Here, the type and amount of the palladium catalyst are the same as in the above (2).
本反応においては必要に応じて不活性有機溶媒（例え
ばジエチルエーテル、テトラヒドロフランなど）や第１
級または第２級の有機アミン（例えばエチルアミン、ジ
エチルアミン、モルホリン、ピペリジンなど）を加える
ことができる。また、パラジウム触媒にすでにホスフィ
ン類が配位している場合を除き、ホスフィン類（例えば
トリエチルホスフィン、トリブチルホスフィン、トリフ
ェニルホスフィンなど）を加えることが好ましい。In this reaction, if necessary, an inert organic solvent (eg, diethyl ether, tetrahydrofuran, etc.)
Grade or secondary organic amines (eg, ethylamine, diethylamine, morpholine, piperidine, etc.) can be added. It is preferable to add phosphines (for example, triethylphosphine, tributylphosphine, triphenylphosphine, etc.) unless phosphines are already coordinated to the palladium catalyst.
次に、式（Ｘ）の化合物の水酸基の保護基をプロスタ
グランジンの分野における通常の方法を用いて脱保護す
ることにより、式（Ｉ）においてＡがシスのビニレン基
であり、R1が水素原子数１〜６個のアルキル基である本
発明の化合物［式（I e）の化合物］を得ることができ
る。Next, by deprotecting the hydroxyl-protecting group of the compound of the formula (X) using a conventional method in the field of prostaglandins, A in the formula (I) is a cis vinylene group and R 1 is A compound of the present invention, which is an alkyl group having 1 to 6 hydrogen atoms [compound of formula (Ie)] can be obtained.
本発明の化合物は、経口的にまたは非経口的に（例え
ば静脈内、直腸内、膣内）、投与することができる。経
口投与の剤型としては、例えば錠剤、顆粒剤、カプセル
剤などの固形製剤、溶液剤、脂肪乳剤、リポソーム懸濁
剤などの液体製剤を用いることができる。この経口投与
製剤として用いる場合には、α，β，もしくはγ−シク
ロデキストリンまたはメチル化シクロデキストリン等と
包接化合物を形成させて製剤化することもできる。静脈
内投与の製剤としては、水性または非水性溶液剤、乳化
剤、懸濁剤、使用直前に注射用溶媒に溶解して使用する
固形製剤等を用いることができる。また、直腸内投与の
製剤としては坐剤、膣内投与の製剤としてはペッサリ等
の剤型を用いることができる。投与量は0.1〜100μｇで
あり、これを１日１〜３回に分けて投与する。The compounds of the present invention can be administered orally or parenterally (eg, intravenously, rectally, vaginally). As the dosage form for oral administration, for example, solid preparations such as tablets, granules and capsules, and liquid preparations such as solutions, fat emulsions and liposome suspensions can be used. When used as a preparation for oral administration, it can be prepared by forming an inclusion compound with α, β, or γ-cyclodextrin or methylated cyclodextrin. As preparations for intravenous administration, aqueous or non-aqueous solutions, emulsifiers, suspensions, solid preparations to be dissolved in a solvent for injection immediately before use, and the like can be used. As a preparation for rectal administration, a suppository, and as a preparation for vaginal administration, a dosage form such as pessary can be used. The dose is 0.1 to 100 µg, which is administered once to three times a day.
産業上の利用可能性 本発明の化合物は、後記試験例からも明らかなよう
に、強い血小板凝集抑制作用を有し、しかもその持続製
がよい。また、本発明化合物は、確実な薬理作用を示す
用量でPGで最も問題となっている下痢を殆ど誘発しない
ことから、末梢循環障害をはじめとする種々の疾患を治
療する医薬として有用である。INDUSTRIAL APPLICABILITY As is clear from the test examples described later, the compounds of the present invention have a strong platelet aggregation-inhibiting action, and their continuous production is good. Further, the compound of the present invention hardly induces diarrhea, which is the most problematic in PG, at a dose showing a certain pharmacological action, and is therefore useful as a medicament for treating various diseases including peripheral circulatory disorders.
以下、本発明の効果を試験例により具体的に説明す
る。Hereinafter, the effects of the present invention will be specifically described with reference to test examples.
試験例１ ［モルモット血小板凝集抑制試験］ 一晩絶食した雄性ハートレー系モルモット（体重300
〜500g）を１群５匹または６匹として使用した。被検薬
物はエタノールに溶解後、0.5％カルボジメチルセルロ
ース溶液に懸濁した。エタノールの最終濃度は１％以下
とした。被検物を1kgあたり50μｇ（溶液としては1kgあ
たり5cc）経口投与し、２または８時間後にペントバル
ビタール20mg/kgを腹腔内投与することによって麻酔し
た後に開腹し、腹部大動脈よりプラスチックシリンジを
用いて3.2％クエン酸ナトリウム１容に対して９容の血
液を採取した。血液を120×ｇで10分間遠心分離し、上
清をPRPとした。残りの血液を更に1100×ｇで10分間遠
心分離し、乏血小板血漿（PPP）を得た。PRPの血小板数
をPPPを用いて４〜６×105血小板/mm3に調製した。血小
板凝集の測定はBornの方法（Nature,第194巻，第92ペー
ジ,1962年）に準じて行なった。すなわちアグリゴメー
ターを用いて275μｌのPRPを37℃、1000rpm撹拌下、３
分間インキュベート後にADP（終濃度３μＭ）またはコ
ラーゲン（終濃度３μg/ml）をそれぞれ25μｌ添加する
ことにより血小板凝集を惹起し、その５分以内の光透過
度の最大凝集率とした。0.5％カルボキシメチルセルロ
ース溶液投与群をコトロール群としてその最大凝集率に
対する被検物投与群の凝集抑制率を下記の式により算出
した。Test Example 1 [Guinea Pig Platelet Aggregation Inhibition Test] Male Hartley guinea pig (body weight 300) fasted overnight
500500 g) were used as 5 or 6 animals per group. The test drug was dissolved in ethanol and then suspended in a 0.5% carbodimethylcellulose solution. The final concentration of ethanol was 1% or less. The test substance was orally administered at 50 μg / kg (5 cc / kg as a solution), anesthetized by intraperitoneal administration of pentobarbital 20 mg / kg 2 or 8 hours later, and the abdomen was opened. The abdominal aorta was opened using a plastic syringe. 9 volumes of blood were collected per 1 volume of 3.2% sodium citrate. The blood was centrifuged at 120 × g for 10 minutes, and the supernatant was used as PRP. The remaining blood was further centrifuged at 1100 × g for 10 minutes to obtain platelet poor plasma (PPP). The platelet count of PRP was adjusted to 4-6 × 10 5 platelets / mm 3 using PPP. The measurement of platelet aggregation was performed according to the method of Born (Nature, vol. 194, p. 92, 1962). That is, using an aggregometer, 275 μl of PRP was stirred at 37 ° C. and 1000 rpm for 3 hours.
After incubation for 25 minutes, platelet aggregation was induced by adding 25 μl of ADP (final concentration 3 μM) or collagen (final concentration 3 μg / ml), respectively, and the maximum aggregation rate of light transmittance within 5 minutes was determined. The 0.5% carboxymethylcellulose solution administration group was used as a control group, and the aggregation inhibition rate of the test substance administration group with respect to the maximum aggregation rate was calculated by the following formula.
結果を表１に示した。なお、比較化合物として、実施
例23で製造した化合物９の13,14位の三重結合の部分を
二重結合に変えた化合物（limaprost）［坪井ら,Arch.I
ntern.Pharmacodyn.Ther.,第247巻，第89ページ（1980
年）］のデーターをのせた。 The results are shown in Table 1. As a comparative compound, a compound (limaprost) in which the triple bond at the positions 13 and 14 of compound 9 prepared in Example 23 was changed to a double bond [Tsuboi et al., Arch.
ntern.Pharmacodyn.Ther., Volume 247, Page 89 (1980
Year)] data.
また、この試験では投与２時間後まで糞の状態を観察
した。limaprost投与群では著しい下痢が認められた
が、本発明化合物投与群では軽度の軟便のみであった。In this test, the state of feces was observed up to 2 hours after administration. Significant diarrhea was observed in the limaprost administration group, but only mild loose stool was observed in the compound of the present invention administration group.
試験例２ ［ウサギ血小板凝集抑制試験］ 体重2.5〜4.0kgのニュージーランド・ホワイト系ウサ
ギを１群４匹として試験に供した。エーテル麻酔下、こ
のウサギの総頚動脈により、3.2％クエン酸ナトリウム
溶液１容に対して９容の血液を採取した。採取した血液
は、1100rpmで15分間遠心分離し、その上層を多血小板
血漿（PRP）とした。 Test Example 2 [Rabbit Platelet Aggregation Inhibition Test] New Zealand white rabbits weighing 2.5 to 4.0 kg were subjected to the test as a group of four rabbits. Under ether anesthesia, 9 volumes of blood were collected per 1 volume of 3.2% sodium citrate solution via the common carotid artery of the rabbit. The collected blood was centrifuged at 1100 rpm for 15 minutes, and the upper layer thereof was used as platelet-rich plasma (PRP).
血小板凝集の測定はBornの方法（Nature,第194巻，第
927ページ,1962年）に準じて行なった。PRP275μｌにエ
タノールに溶解した各種濃度の被験薬１μｌを加え、37
℃、1000rpm撹拌下、３分後に凝集惹起剤［アデノシン
ジホスフェート（ADP）最終濃度５μＭ］25μｌを添加
し、血小板凝集計（アグリゴメーター）により最大凝集
率（血小板の凝集を惹起してから５分以内の光透過度の
最大変化）を測定した。Platelet aggregation is measured by the method of Born (Nature, vol. 194, vol.
927 pages, 1962). To 1 μl of various concentrations of the test drug dissolved in ethanol was added to 275 μl of PRP.
After 3 minutes under stirring at 1000 ° C. and 25 ° C., 25 μl of an aggregation-inducing agent [adenosine diphosphate (ADP) final concentration of 5 μM] was added, and the maximum agglutination rate (5 μg after inducing platelet aggregation) was measured using a platelet aggregometer (aggregometer). The maximum change in light transmittance within minutes) was measured.
凝集抑制活性は、凝集抑制率を被験薬溶液の代わりに
エタノールを用いた場合の凝集に対して算出し、その用
量反応曲線からIC50値を求めた。Aggregation inhibitory activity was determined by calculating the aggregation inhibition rate for the aggregation when ethanol was used instead of the test drug solution, and the IC 50 value was determined from the dose-response curve.
その結果を表２に示した。表中の化合物番号は後記強
実施例に示す化合物番号である。なお、IC50値は平均値
で示してある。The results are shown in Table 2. The compound numbers in the table are the compound numbers shown in the following strong examples. Incidentally, IC 50 values are shown by average value.
試験例３ ［ヒト血小板凝集抑制試験］ ヒトより採血し、直ちに1/10容の3.8％クエン酸ナト
リウム水溶液と混合した。室温下に、180×ｇで15分間
遠心分離し、上層よりPRPを得た。 Test Example 3 [Human Platelet Aggregation Inhibition Test] Blood was collected from a human and immediately mixed with 1/10 volume of a 3.8% aqueous sodium citrate solution. The mixture was centrifuged at 180 xg for 15 minutes at room temperature to obtain PRP from the upper layer.
血小板凝集の測定はBornの方法（Nature,第194巻，第
927ページ,1962年）に準じて行なった。アグリゴメータ
ーを用い、PRP100μｌおよび各種濃度の被検薬溶液５μ
ｌを加え、37℃、1000rpm撹拌下、１分間インキュベー
ト後に５μｌのADPを添加することにより血小板凝集を
惹起し、最大凝集率を求めた。Platelet aggregation is measured by the method of Born (Nature, vol. 194, vol.
927 pages, 1962). Using an aggregometer, 100 µl of PRP and 5 µl of the test drug solution of various concentrations
Then, platelet aggregation was induced by adding 5 μl of ADP after incubating at 37 ° C. and stirring at 1000 rpm for 1 minute, and the maximum aggregation rate was determined.
凝集抑制活性は、抑制率を被検薬物溶液のかわりに生
理食塩水を用いた場合の凝集に対して算出し、その用量
反応曲線からIC50を求め、同時に測定して得たPGE1のIC
50に対する相対活性として評価した。Aggregation inhibiting activity, the inhibition rate was calculated against aggregation when physiological saline was used in place of the test drug solution, calculated and IC 50 from the dose response curves, PGE 1 of IC obtained by measuring simultaneously
It was evaluated as relative activity to 50 .
結果を表３に示した。なお、化合物番号は後記実施例
に示す化合物番号である。The results are shown in Table 3. The compound numbers are the compound numbers shown in the examples described later.
試験例４ ［麻酔犬での血圧低下試験］ 体重13kgの雄性雑犬をペントバルビタールナトリウム
30mg/kg静脈内投与により麻酔後、左大腿動脈に挿入し
たカニューレを血圧トランスジューサーに接続し血圧を
測定した。被検物はエタノールに溶解後、必要に応じて
エタノールで希釈し各10μｌを左前肢静脈に挿入したカ
ニューレを介して静脈内に投与した。各被試物による血
圧低下率を下記の式により算出した。 Test Example 4 [blood pressure lowering test in anesthetized dog] Male pentobarbital weighing 13 kg was treated with sodium pentobarbital
After anesthesia with 30 mg / kg intravenous administration, the cannula inserted into the left femoral artery was connected to a blood pressure transducer to measure blood pressure. The test substance was dissolved in ethanol, diluted with ethanol as needed, and 10 μl each was intravenously administered through a cannula inserted into the left forelimb vein. The rate of decrease in blood pressure due to each specimen was calculated by the following equation.
後記実施例で製造した化合物1,化合物３及び化合物９
のそれぞれ0.03μg/kg投与による血圧低下率はそれぞれ
10.1％,11.5％，及び23.7％であった。これに対し、PGE
1及び３μg/kg投与による血圧低下率はそれぞれ13.9％
及び23.7％、またlimaprostの0.5及び１μg/kg投与によ
る血圧低下率はそれぞれ13.9％及び23.8％であった。 Compound 1, Compound 3 and Compound 9 prepared in Examples described later
Blood pressure reduction rate by 0.03μg / kg administration
10.1%, 11.5%, and 23.7%. In contrast, PGE
13.9% decrease in blood pressure by 1 and 3μg / kg
And 23.7%, and the blood pressure reduction rates by limaprost administration at 0.5 and 1 μg / kg were 13.9% and 23.8%, respectively.
発明を実施するための最良の形態 以下、実施例を挙げて本発明をさらに詳細に説明す
る。BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to examples.
注）化合物の命名中、例えば「17,18,19,20−テトラノ
ル」のように「ノル」とは、その位置の炭素鎖がないこ
とを意味し（例の場合だと17〜20位の酸素鎖がないこと
を意味する。）、例えば「2a,2b−ジホモ」のように
「ホモ」とは、その位置に炭素鎖が多くなることを意味
する（例の場合だと２位と３位の間に2a,2bの２つの炭
素鎖があることを意味する。）。Note) In the nomenclature of the compound, "nor" means that there is no carbon chain at that position, for example, "17,18,19,20-tetranor". For example, "homo" such as "2a, 2b-dihomo" means that there are more carbon chains at that position (in the case of the example, the positions 2 and 3 are not present). It means that there are two carbon chains 2a and 2b between the positions.)
なお、実施例で製造した化合物の一覧を表４に示し
た。Table 4 shows a list of the compounds produced in the examples.
実施例１ （2E,17S）−17,20−ジメチル−2,3,13,14−テトラデヒ
ドロ−PGE1メチルエステル（化合物１） （１）（3S,5S）−３−（ｔ−ブチルジメチルシロキサ
ン）−５−メチルノナ−１−イン（3.85g）をベンゼン2
8.8mlに溶解し,0℃でｎ−ブチルリチウム（1.95M,ヘキ
サン溶液,6.4ml）を加え，同温で30分間撹拌した。この
溶液に０℃でジエチルアルミニウムクロリド（0.97M,ヘ
キサン溶液,14.8ml）を加え，室温まで昇温後30分間撹
拌した。 Example 1 (2E, 17S) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 methyl ester (compound 1) (1) (3S, 5S) -3- (t-butyldimethyl) Siloxane) -5-methylnon-1-yne (3.85 g) in benzene 2
The mixture was dissolved in 8.8 ml, n-butyllithium (1.95 M, hexane solution, 6.4 ml) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. To this solution was added diethylaluminum chloride (0.97M, hexane solution, 14.8 ml) at 0 ° C, and the mixture was heated to room temperature and stirred for 30 minutes.
この溶液に室温で（4R）−２−（N,N−ジエチルアミ
ノ）メチル−４−（ｔ−ブチルジメチルシロキサン）シ
クロペント−２−エン−１−オン（0.25M,ベンゼン溶
液,38.4ml）を加え,15分間撹拌した。To this solution was added (4R) -2- (N, N-diethylamino) methyl-4- (t-butyldimethylsiloxane) cyclopent-2-en-1-one (0.25 M, benzene solution, 38.4 ml) at room temperature. , And stirred for 15 minutes.
反応液をヘキサン（100ml）−飽和塩化アンモニウム
水溶液（100ml）−塩酸水溶液（3M,30ml）の混合液に撹
拌しながら注いだ後，有機層を分離し，飽和重曹水溶液
（50ml）で洗浄した。得られた有機層の乾燥，濃縮を経
て得られた残渣をシリカゲルカラムクロマトグラフィー
（展開溶媒；ヘキサン：エーテル＝10:1）で精製して
（3R,4R）−２−メチレン−３−［（３′S,5′Ｓ）−
３′−（ｔ−ブチルジメチルシロキシ）−５′−メチル
ノナー１′−イニル］−４−（ｔ−ブチルジメチルシロ
キシ）シクロペンタン−１−オン3.72gを得た。1 H−NMR（CDCl3,200MHz）δppm: 0.09,0.10and0.12（3s,12H）,0.89（s,18H）,0.80〜0.9
9（m,6H）,1.00〜1.72（m,9H）,2.32（dd,J＝7.4Hz,18.
0Hz,1H）,2.71（dd,J＝6.6Hz,18.0Hz,1H）,3.47〜3.56
（m,1H）,4.15〜4.33（m,1H）,4.44（dt,J＝1.6Hz,7.0H
z,1H）,5.54（d,J＝2.6Hz,1H）,6.13（d,J＝3.0Hz,1H） IR（neat）： 2930,2850,1740,1640,1460,1360,1250,1120,1080,835,7
70cm-1 （２）−70℃において（4E）−５−カルボメトキシペン
ト−４−エニル亜鉛（II）ヨージド（0.64Mテトラヒド
ロフラン溶液,2.81ml）にシアン化銅（Ｉ）・２塩化リ
チウム（392mg）のテトラヒドロフラン溶液2.25mlを加
え同温度で15分間撹拌した。この溶液に−70℃で上記
（１）で得た化合物（434mg）とクロロトリメチルシラ
ン0.21mlのジエチルエーテル溶液3mlを加え、撹拌しな
がら約２時間かけて室温まで昇温した。The reaction solution was poured into a mixed solution of hexane (100 ml) -aqueous saturated ammonium chloride solution (100 ml) -aqueous hydrochloric acid solution (3 M, 30 ml) while stirring, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (50 ml). The residue obtained through drying and concentration of the obtained organic layer was purified by silica gel column chromatography (developing solvent; hexane: ether = 10: 1) to give (3R, 4R) -2-methylene-3-[( 3'S, 5'S)-
3.72 g of 3 '-(t-butyldimethylsiloxy) -5'-methylnoner 1'-ynyl] -4- (t-butyldimethylsiloxy) cyclopentan-1-one was obtained. 1 H-NMR (CDCl 3 , 200 MHz) δ ppm: 0.09, 0.10 and 0.12 (3s, 12H), 0.89 (s, 18H), 0.80 to 0.9
9 (m, 6H), 1.00 to 1.72 (m, 9H), 2.32 (dd, J = 7.4 Hz, 18.
0Hz, 1H), 2.71 (dd, J = 6.6Hz, 18.0Hz, 1H), 3.47 ~ 3.56
(M, 1H), 4.15 to 4.33 (m, 1H), 4.44 (dt, J = 1.6Hz, 7.0H
z, 1H), 5.54 (d, J = 2.6Hz, 1H), 6.13 (d, J = 3.0Hz, 1H) IR (neat): 2930,2850,1740,1640,1460,1360,1250,1120,1080 , 835,7
(4E) -5-Carbomethoxypent-4-enylzinc (II) iodide (0.64 M solution in tetrahydrofuran, 2.81 ml) at 70 cm -1 (2) -70 ° C., copper (I) cyanide.lithium dichloride (392 mg) ) Of 2.25 ml of a tetrahydrofuran solution was added, and the mixture was stirred at the same temperature for 15 minutes. The compound (434 mg) obtained in the above (1) and 3 ml of a diethyl ether solution of 0.21 ml of chlorotrimethylsilane were added to this solution at -70 ° C, and the temperature was raised to room temperature over about 2 hours with stirring.
反応液に飽和塩化アンモニウム水溶液15mlを加え、ヘ
キサンで抽出した。有機層を飽和食塩水で洗浄後、乾
燥、濃縮を経て得られた残渣エーテル−イソプロピルア
ルコール（1:4）3.5mlに溶解し、ｐ−トルエンスルホン
酸ピリジン塩（8.8mg,0.035mmol）を加えた後、室温で1
2時間撹拌した。15 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with hexane. The organic layer was washed with saturated saline, dried, concentrated and dissolved in 3.5 ml of ether-isopropyl alcohol (1: 4), and p-toluenesulfonic acid pyridine salt (8.8 mg, 0.035 mmol) was added. Then 1 at room temperature
Stir for 2 hours.
反応液にヘキサン20mlおよび飽和重炭酸ナトリウム水
溶液10mlを加え抽出後、有機層を乾燥、濃縮を経て得ら
れた残渣をシリカゲルカラムクロマトグラフィー（展開
溶媒；ヘキサン：エーテル＝4:1）にかけ（2E,17S）−1
7,20−ジメチル−2,3,13,14−テトラデヒドロ−PGE1メ
チルエステル11,15−ビス（ｔ−ブチルジメチルシリル
エーテル）532mgを得た。1 H−NMR（CDCl3,200MHz）δppm: 0.10（s,6H）,0.11（s,3H）,0.13（s,3H）,0.83〜0.98
（m,6H）,0.89（s,9H）,0.90（s,9H）,1.06〜1.82（m,1
5H）,2.11〜2.29（m,3H）,2.17（dd,J＝7.0Hz,18.0Hz,1
H）,2.59〜2.77（m,2H）,3.73（s,3H）,4.23〜4.35（m,
1H）,4.43（dt,J＝1.5Hz,7.0Hz,1H）,5.82（dt,J＝1.5H
z,15.7Hz,1H）,6.96（dt,J＝6.9Hz,15.7Hz,1H） IR（neat）： 2954,2930,2858,2234,1748,1728,1660,1463,1436,1362,
1326,1259,1198,1124,1092,1006,838,779,670cm-1 （３）上記（２）で得た化合物（532mg,0.857mmol）を
アセトニトリル（29ml）に溶解し、０℃で50％フッ化水
素酸水溶液（6.9ml）を加えた。０℃で90分間撹拌した
後、反応液を酢酸エチル（40ml）と飽和重炭酸ナトリウ
ム水溶液（230ml）中に注いだ。酢酸エチルで抽出し、
飽和重炭酸ナトリウム水溶液および飽和食塩水で洗浄
後、乾燥、濃縮を経て得られた残渣をシリカゲルカラム
クロマトグラフィー（展開溶媒；酢酸エチル：メタノー
ル＝40:1）で精製して標記化合物350mgを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.83〜0.97（m,6H）,1.08〜1.90（m,15H）,2.12〜2.30
（m,4H）,2.62（dd,J＝9.0Hz,10.5Hz,1H）,2.75（dd,J
＝7.3Hz,18.5Hz,1H）,2.92（dr.s,2H）,3.72（s,3H）,
4.27〜4.36（m,1H）,4.47（dt,J＝1.0Hz,6.7Hz,1H）,5.
68（d,J＝15.7Hz,1H）,6.96（dt,J＝7.4Hz,15.7Hz,1H） IR（neat）： 3380,2910,2230,1720,1700,1650,1435,1270,1040cm-1 実施例２ （2E,16RS）−16,20−ジメチル−2,3,13,14,18,18,19,1
9−オクタデヒドロ−PEG1メチルエステル（化合物２） （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S,4RS）−３−（ｔ−ブチルジメチルシ
ロキシ）−４−メチルノナ−1,6−ジインを用い、実質
的に実施例１（１）と同様にして（3R,4R）−２−メチ
レン−３−［（３′S,4′RS）−３′−（ｔ−ブチルジ
メチルシロキシ）−４′−メチルノナ−１′,6′−ジイ
ニル］−４−（ｔ−ブチルジメチルシロキシ）シクロペ
ンタン−１−オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.09,0.10and0.12（3s,12H）,0.88（s,18H）,1.02and1.
03（2d,J＝6.8Hz and6.8Hz,3H）,1.10（t,J＝7.3Hz,3
H）,1.73〜1.91（m,1H）,2.00〜2.39（m,4H）,2.32（d
d,J＝7.4Hz,17.9Hz,1H）,2.70（dd,J＝6.4Hz,17.9Hz,1
H）,3.53（d,J＝6.5Hz,1H）,4.21〜4.30（m,1H）,4.37a
nd4.47（2d,J＝4.1Hz,6.3Hz,1H）,5.54（d,J＝2.7Hz,1
H）,6.13（d,J＝3.0Hz,1H） IR（neat）： 2960,2934,2862,2364,1738,1649,1473,1363,1255,1123,
1079,837,777cm-1 （２）上記（１）で得た化合物を用い、実施例（２）お
よび（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.90〜1.16（m,6H）,1.30〜1.99（m,7H）,2.40〜2.37
（m,8H）,2.63（t,J＝10.0Hz,1H）,2.75（dd,J＝7.2Hz,
18.5Hz,1H）,3.72（s,3H）,4.27〜4.38（m,1H）,4.42an
d4.46（2d,J＝6.6Hz and J＝4.4Hz,1H）,5.82（d,J＝1
5.7Hz,1H）,6.95（dt,J＝7.4Hz,15.7Hz,1H） IR（neat）： 3390,2910,2230,1730,1690,1650,1430,1270,1010cm-1 実施例３ （2E）−16,17,18,19,20−ペンタノル−15−シクロヘキ
シル−2,3,13,14−テトラデヒドロ−PEG1メチルエステ
ル（化合物３） （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S）−３−（ｔ−ブチルジメチルシロキ
シ）−３−シクロヘキシルプロパ−１−インを用い、実
質的に実施例１（１）と同様にして（3R,4R）−２−メ
チレン−３−［（３′Ｓ）−３′−（ｔ−ブチルジメチ
ルシロキシ）−３′−シクロヘキシルプロパ−１′−イ
ニル］−４−（ｔ−ブチルジメチルシロキシ）シクロペ
ンタン−１−オンを得た。1 H−NMR（CDCl3,200MHz）δppm: 0.07,0.08and0.12（3s,12H）,0.88（s,18H）,0.92〜1.9
2（m,11H）,2.32（dd,J＝7.4Hz,17.8Hz,1H）,2.71（dd,
J＝6.5Hz,17.8Hz,1H）,3.48〜3.58（m,1H）,4.11（dd,J
＝1.4Hz,6.2Hz,1H）,4.20〜4.32（m,1H）,5.55（d,J＝
2.6Hz,1H）,6.13（d,J＝3.0Hz,1H） IR（neat）： 2930,2850,1735,1640,1470,1380,1255,1105,830,770cm
-1 （２）上記（１）で得た化合物を用い、実施例１（２）
および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.96〜1.95（m,17H）,2.12〜2.40（m,4H）,2.63（ddd,J
＝1.6Hz,8.4Hz,11.8Hz,1H）,2.76（dd,J＝7.4Hz,18.5H
z,1H）,2.83（br.s,2H）,3.73（s,3H）,4.18（dd,J＝1.
6Hz,6.2Hz,1H）,4.27〜4.38（m,1H）,5.83（d,J＝15.7H
z,1H）,6.96（dt,J＝15.7,7.0Hz,1H） IR（neat）： 3400,2920,2230,1720,1700,1650,1440,1270,1160cm-1 実施例４ （17S）−17,20−ジメチル−2,2,3,3,13,14−ヘキサデ
ヒドロ−PGE1メチルエステル（化合物４） 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに５
−カルボメトキシペント−４−イニル亜鉛（II）ヨージ
ドを用い、実質的に実施例１と同様にして、標記化合物
を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.90（t,J＝6.8Hz,3H）,0.92（d,J＝6.4Hz,3H）,1.10〜
1.89（m,15H）,2.18〜2.31（m,1H）,2.23（d,J＝5.7Hz,
1H）,2.24（dd,J＝8.9Hz,18.6Hz,1H）,2.36（t,J＝6.5H
z,2H）,2.66（ddd,J＝1.8Hz,8.1Hz,11.2Hz,1H）,2.71
（d,J＝3.4Hz,1H）,2.76（ddd,J＝1.3Hz,7.2Hz,18.6Hz,
1H）,3.76（s,3H）,4.28〜4.38（m,1H）,4.43〜4.51
（m,1H） IR（neat）： 3402,2930,2861,2237,1746,1718,1436,1259,1152,1078,
754cm-1 実施例５ （16RS）−16,20−ジメチル−2,2,3,3,13,14,18,18,19,
19−デカデヒドロ−PGE1メチルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに５
−カルボメトキシペント−４−イニル亜鉛（II）ヨージ
ドを用い、実施例１（１）で得た化合物の代わりに実施
例２（１）で得た化合物を用い、実質的に実施例１
（２）および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 1.05（d,J＝6.7Hz,3H）,1.11（t,J＝7.5Hz,3H）,1.79〜
1.90（m,1H）,2.01〜2.88（m,15H）,2.92（br.s,2H）,
3.10（q,J＝7.6Hz,1H）,3.71（s,3H）,4.24〜4.33（m,1
H）,4.32and4.38（2d,J＝4.1Hz and J＝2.9Hz,1H） 実施例６ （2E,17S）−17,20−ジメチル−2,3,13,14−テトラデヒ
ドロ−PGE1n−ブチルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに
（4E）−５−カルボブトキシペント−４−エニル亜鉛
（II）ヨージドを用い、実質的に実施例１と同様にし
て、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.78〜0.97（m,9H）,1.09〜1.86（m,19H）,2.12〜2.30
（m,4H）,2.55〜2.68（m,1H）,2.74（dd,J＝7.2Hz,18.6
Hz,1H）,4.12（t,J＝6.6Hz,2H）,4.26〜4.36（m,1H）,
4.46（t,J＝6.9Hz,1H）,5.82（d,J＝15.7Hz,1H）,6.94
（dt,J＝7.3Hz,15.7Hz,1H） IR（neat）： 3370,2920,2310,1720,1690,1640,1450,1260,1170,1060c
m-1 実施例７ （2E,17S）−17−メチル−20−エチル−2,3,13,14−テ
トラデヒドロ−PGE1メチルエステル （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S,5RS）−３−（ｔ−ブチルジメチルシ
ロキシ）−５−メチルデカ−１−インを用い、実質的に
実施例１（１）と同様にして（3R,4R）−２−メチレン
−３−［３′S,5′RS）−３′−（ｔ−ブチルジメチル
シロキシ）−５′−メチルデカ−１′−イニル］−４−
（ｔ−ブチルジメチルシロキシ）シクロペンタン−１−
オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.10and0.13（2s,12H）,0.80〜1.05（m,24H）,1.06〜1.
80（m,11H）,2.33（dd,J＝7.4Hz,18.1Hz,1H）,2.71（d
d,J＝6.3Hz,18.1Hz,1H）,3.43〜3.66（m,1H）,4.20〜4.
35（m,1H）,4.45（t,J＝6.5Hz,1H）,5.55（br.s,1H）,
6.14（br.s,1H） IR（neat）： 2920,2850,2330,1730,1630,1460,1360,1240,1110,1080,
830,770cm-1 （２）上記（１）で得た化合物を用い、実施例１（２）
および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.70〜0.92（m,6H）,0.92〜1.85（m,17H）,1.85〜2.33
（m,4H）,2.33〜2.79（m,1H）,2.73（dd,J＝7.1Hz,18.4
Hz,1H）,3.71（s,3H）,4.15〜4.49（m,2H）,5.81（d,J
＝15.6Hz,1H）,6.92（dt,J＝7.5Hz,15.6Hz,1H） IR（neat）： 3390,2930,2860,2220,1720,1710,1650,1440,1280,1040c
m-1 実施例８ （2E,17R）−17,20−ジメチル−2,3,13,14−テトラデヒ
ドロ−PGE1メチルエステル（化合物５） （１）実施例（１）において、（3S,5S）−３−（ｔ−
ブチルジメチルシロキシ）−５−メチルノナ−１−イン
の代わりに（3S,5R）−３−（ｔ−ブチルジメチルシロ
キシ）−５−メチルノナ−１−インを用い、実質的に実
施例１（１）と同様にして（3R,4R）−２−メチレン−
３−［（３′S,5′Ｒ）−３′−（ｔ−ブチルジメチル
シロキシ）−５′−メチルノナ−１′−イニル］−４−
（ｔ−ブチルジメチルシロキシ）シクロペンタン−１−
オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.03〜0.15（m,12H）,0.80〜0.93（m,24H）,1.06〜1.80
（m,9H）,2.33（dd,J＝7.4Hz,17.9Hz,1H）,2.71（dd,J
＝6.4Hz,17.9Hz,1H）,3.41〜3.56（m,1H）,4.20〜4.32
（m,1H）,4.44（t,J＝6.6Hz,1H）,5.55（br.s,1H）,6.1
4（br.s,1H） IR（neat）： 2920,2850,2210,1730,1630,1450,1360,1240,1100,1080,
820,760cm-1 （２）上記（１）式で得た化合物を用い、実施例１
（２）および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.70〜0.98（m,6H）,1.05〜1.90（m,15H）,2.02〜2.36
（m,4H）,2.55（br.s,2H）,2.43〜2.84（m,1H）,2.77
（dd,J＝7.3Hz,18.6Hz,1H）,3.74（s,3H）,4.28〜4.56
（m,2H）,5.84（d,J＝15.7Hz,1H）,6.99（dt,J＝7.5Hz,
15.7Hz,1H） IR（neat）： 3390,2930,2860,2220,1730,1660,1460,1440,1280,1040c
m-1 実施例９ （2E）−17,18,19,20−テトラノル−16−シクロヘキシ
ル−2,2,13,14−テトラデヒドロ−PGE1メチルエステル （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S）−３−（ｔ−ブチルジメチルシロキ
シ）−４−シクロヘキシルブト−１−インを用い、実質
的に実施例１（１）と同様にして（3R,4R）−２−メチ
レン−３−［（３′Ｓ）−３′−（ｔ−ブチルジメチル
シロキシ）−４′−シクロヘキシルブト−１′−イニ
ル］−４−（ｔ−ブチルジメチルシロキシ）シクロペン
タン−１−オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.07〜0.14（m,12H）,0.89（s,18H）,1.03〜1.80（m,13
H）,2.33（dd,J＝7.4Hz,17.9Hz,1H）,2.71（dd,J＝6.4H
z,17.9Hz,1H）,3.41〜3.54（m,1H）,4.22〜4.32（m,1
H）,4.47（t,J＝6.8Hz,1H）,5.55（d,J＝2.5Hz,1H）,6.
14（d,J＝2.7Hz,1H） IR（neat）： 2930,2850,1735,1640,1460,1360,1250,1220,1100,1000,
940,830,770cm-1 （２）上記（１）で得た化合物を用い、実施例１（２）
および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.81〜1.85（m,19H）,2.10〜2.42（m,4H）,2.55〜2.66
（m,1H）,2.73（dd,J＝7.2Hz,18.4Hz,1H）,3.73（s,3
H）,4.29（q,J＝8.5Hz,1H）,4.45（t,J＝6.3Hz,1H）,5.
80（d,J＝15.7Hz,1H）,6.96（dt,J＝7.0Hz,15.7Hz,1H） IR（neat）： 3400,2920,2850,2320,1720,1700,1650,1440,1270,1200,
1160,1035,980cm-1 実施例10 （2E）−17,18,19,20−テトラノル−16−シクロペンチ
ル−2,3,13,14−テトラデヒドロ−PGE1メチルエステル （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S）−３−（ｔ−ブチルジメチルシロキ
シ）−４−シクロペンチルブト−１−インを用い、実質
的に実施例１（１）と同様にして（3R,4R）−２−メチ
レン−３−［（３′Ｓ）−３′−（ｔ−ブチルジメチル
シロキシ）４′−シクロペンチルブト−１′−イニル］
−４−（ｔ−ブチルジメチルシロキシ）シクロペンタン
−１−オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.07〜0.17（m,12H）,0.89（s,18H）,1.03〜2.02（m,11
H）,2.33（dd,J＝7.6Hz,17.9Hz,1H）,2.71（dd,J＝6.4H
z,17.9Hz,1H）,3.41〜3.58（m,1H）,4.22〜4.31（m,1
H）,4.39（t,J＝6.7Hz,1H）,5.55（d,J＝2.4Hz,1H）,6.
14（d,J＝3.0Hz,1H） IR（neat）： 2930,2850,1735,1638,1460,1360,1245,1220,1100,1000,
935,825,770cm-1 （２）上記（１）で得た化合物を用い、実施例１（２）
および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 1.02〜2.05（m,17H）,2.13〜2.31（m,4H）,2.52〜2.66
（m,1H）,2.74（dd,J＝7.2Hz,18.7Hz,1H）,3.72（s,3
H）,4.25〜4.43（m,1H）,4.39（t,J＝7.1Hz,1H）,5.81
（d,J＝15.7Hz,1H）,6.94（dt,J＝6.9Hz,15.7Hz,1H） IR（neat）： 3380,2920,2855,2240,1715,1650,1440,1270,1160,1035,
725cm-1 実施例11 （2E,17RS）−20−ノニル−17−メチル−19−（２′−
メチルプロパ−１′−エニル）−2,3,13,14−テトラデ
ヒドロ−PGE1メチルエステル （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S,5RS）−３−（ｔ−ブチルジメチルシ
ロキシ）−5,9−ジメチルデカ−８−エン−１−インを
用い、実質的に実施例１（１）と同様にして（3R,4R）
−２−メチレン−３−［（３′S,5′RS）−３′−（ｔ
−ブチルジメチルシロキシ）−５′,9′−ジメチルデカ
−８′−エン−１′−イニル］−４−（ｔ−ブチルジメ
チルシロキシ）シクロペンタン−１−オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.10and0.13（2s,12H）,0.80〜1.02（m,21H）,1.05〜1.
82（m,5H）,1.60（s,3H）,1.67（s,3H）,1.90〜2.06
（m,2H）,2.33（dd,J＝7.4Hz,17.8Hz,1H）,2.71（dd,J
＝6.4Hz,17.8Hz,1H）,3.49〜3.57（m,1H）,4.22〜4.37
（m,1H）,4.45（t,J＝5.9Hz,1H）,5.08（t,J＝6.1Hz,1
H）,5.55（d,J＝1.8Hz,1H）,6.14（d,J＝2.5Hz,1H） （２）上記（１）式で得た化合物を用い、実施例１
（２）および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.82〜1.01（m,3H）,1.10〜2.35（m,16H）,1.59（s,3
H）,1.67（s,3H）,2.56〜2.65（m,2H）,2.74（dd,J＝7.
3Hz,18.5Hz,1H）,3.72（s,3H）,4.25〜4.36（m,1H）,4.
46（t,J＝6.6Hz,1H）,5.08（t,J＝5.7Hz,1H）,5.82（d,
J＝15.6Hz,1H）,6.95（dt,J＝6.8Hz,15.6Hz,1H） IR（neat）： 3400,2920,2860,2270,1725,1705,1650,1440,1280,1020c
m-1 実施例12 （17S）−17,20−ジメチル−2,2,3,3,13,14−ヘキサデ
ヒドロPGE1 n−ブチルエステル（化合物６） 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに５
−カルボブトキシペント−４−イニル亜鉛（II）ヨージ
ドを用い、実質的に実施例１と同様にして、標記化合物
を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.78〜0.98（m,9H）,1.05〜1.88（m,19H）,2.16〜2.42
（m,4H）,2.57〜2.66（m,1H）,2.74（dd,J＝7.1Hz,18.5
Hz,1H）,4.14（t,J＝6.6Hz,2H）,4,25〜4,37（m,1H）,
4,45（t,J＝6.9Hz,1H） IR（neat）： 3400,2940,2240,1740,1700,1460,1250,1070cm-1 実施例13 17,18,19,20−テトラノル−16−シクロヘキシル−2,2,
3,3,13,14−ヘキソデヒドロ−PGE1メチルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに５
−カルボブトキシペント−４−イニル亜鉛（II）ヨージ
ドを用い、実施例１（１）で得た化合物を代わりに実施
例９（１）で得た化合物を用い、実質的に実施例１
（２）および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.86〜1.86（m,19H）,2.19〜2.30（m,1H）,2.4（dd,J＝
8.9Hz,18.5Hz,1H）,2.33〜2.41（m,2H）,2.66（ddd,J＝
1.8Hz,8.2Hz,11.2Hz,1H）,2.76（ddd,J＝1.3Hz,7.3Hz,1
8.5Hz,1H）,3.76（s,3H）,4.29〜4.38（m,1H）,4.49（d
t,J＝1.8Hz,6.4Hz,1H） IR（neat）： 3408,2926,2853,2237,1746,1714,1436,1260,1152,1078,
1046,754cm-1 実施例14 （17RS）−20−ノル−17−メチル−19−（２′−メチル
プロパ−１′−エニル）−2,2,3,3,13,14−ヘキサデヒ
ドロ−PGE1メチルエステル（化合物７） 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに５
−カルボメトキシペント−４−イニル亜鉛（II）ヨージ
ドを用い、実施例１（１）で得た化合物を代わりに実施
例11（１）で得た化合物を用い、実質的に実施例１
（２）および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.95（d,J＝6.6Hz,3H）,1.14〜2.10（m,13H）,1.61（s,
3H）,1.68（s,3H）,2.19〜2.30（m,1H）,2.24（dd,J＝
8.9Hz,18.5Hz,1H）,2.32〜2.40（m,2H）,2.66（ddd,J＝
1.6Hz,8.2Hz,11.2Hz,1H）,2.76（ddd,J＝1.1Hz,7.3Hz,1
8.5Hz,1H）,3.76（s,3H）,4.28〜4.36（m,1H）,4.43〜
4.53（m,1H）,5.04〜5.13（m,1H） IR（neat）： 3401,2929,2864,2237,1746,1718,1436,1376,1259,1153,
1078,822,754cm-1 実施例15 （2E,16RS）−16−メチル−2,3,13,14−テトラヒドロ−
PGE1メチルエステル （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S,4RS）−３−（ｔ−ブチルジメチルシ
ロキシ）−４−メチルオクト−１−インを用い、実質的
に実施例１（１）と同様にして（3R,4R）−２−メチレ
ン−３−［（３′S,4′RS）−３′−（ｔ−ブチルジメ
チルシロキシ）−４′−メチルオクト−１′−イニル］
−４−（ｔ−ブチルジメチルシロキシ）シクロペンタン
−１−オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.03〜0.17（m,12H）,0.60〜1.75（m,31H）,2.33（dd,J
＝7.3Hz,17.9Hz,1H）,2.72（dd,J＝6.4Hz,17,9Hz,1H）,
3.48〜3.58（m,1H）,4.15〜4.56（m,1H）,5.56（d,J＝
3.0Hz,1H）,6.14（d,J＝3.5Hz,1H） IR（neat）： 2957,2931,2858,2231,1738,1644,1464,1362,1255,1083,
1006,940,838,778,671cm-1 （２）上記（１）で得た化合物を用い、実施例１（２）
および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.85〜0.96（m,3H）,0.99（d,J＝6.7Hz,3H）,1.10〜1.8
7（m,13H）,2.17〜2.30（m,3H）,2.24（dd,J＝9.1Hz,1
8.5Hz,1H）,2.64（ddd,J＝1.7Hz,8.2Hz,9.9Hz,1H）,2.7
6（dd,J＝7.3Hz,18.5Hz,1H）,3.73（s,3H）,4.25〜4.38
（m,2H）,5.38（d,J＝15.7Hz,1H）,6.96（dt,J＝7.0Hz,
15.7Hz,1H） IR（neat）： 3420,2931,2860,2236,1746,1728,1657,1438,1275,1203,
1158,1079,1036cm-1 実施例16 （2E,15RS）−16,16−ジメチル−2,3,13,14−テトラデ
ヒドロ−PGE1メチルエステル （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3RS）−３−（ｔ−ブチルジメチルシロ
キシ）−4,4−ジメチルオクト−１−インを用い、実質
的に実施例１（１）と同様にして（3R,4R）−２−メチ
レン−３−［（３′RS）−３′−（ｔ−ブチルジメチル
シロキシ）−４′,4′−ジメチルオクト−１′−イニ
ル］−４−（ｔ−ブチルジメチルシロキシ）シクロペン
タン−１−オンを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.02〜0.17（m,12H）,0.73〜1.64（m,33H）,2.33（dd,J
＝7.0Hz,17.8Hz,1H）,2.72（dd,J＝6.4Hz,17.8Hz,1H）,
3.49〜3.59（m,1H）,4.02〜4.07（m,1H）,4.22〜4.34
（m,1H）,5.53〜5.58（m,1H）,6.15（d,J＝3.0Hz,1H） IR（neat）： 2957,2931,2212,1738,1714,1621,1472,1387,1363,1256,
1083,1007,940,838,778,671cm-1 （２）上記（１）で得た化合物を用い、実施例１（２）
および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.91（t,J＝7.0Hz,3H）,0.94（s,3H）,0.96（s,3H）,1.
19〜1.87（m,12H）,2.15〜2.35（m,3H）,2.24（dd,J＝
9.2Hz,18.5Hz,1H）,2.65（ddd,J＝1.8Hz,8.3Hz,11.4Hz,
1H）,2.76（ddd,J＝1.3Hz,7.3Hz,18.5Hz,1H）,3.73（s,
3H）,4.07〜4.17（m,1H）,4.27〜4.40（m,1H）,5.82（d
t,J＝1.5Hz,15.6Hz,1H）,6.95（dt,J＝7.0Hz,15.6Hz,1
H） IR（neat）： 3435,2932,2861,2233,1746,1728,1657,1438,1385,1275,
1202,1159,1079,1034cm-1 実施例17 （2E,17S）−2a−ホモ−17,20−ジメチル−2,2a,13,14
−テトラデヒドロ−PGE1メチルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに
（5E）−６−カルボメトキシヘキシ−５−エニル亜鉛
（II）ヨージドを用い、実質的に実施例１と同様にし
て、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.86〜0.95（m,6H）,1.10〜1.83（m,17H）,2.16〜2.29
（m,3H）,2.23（dd,J＝9.0Hz,18.5Hz,1H）,2.64（ddd,J
＝1.7Hz,8.2Hz,11.3Hz,1H）,2.76（ddd,J＝1.3Hz,7.2H
z,18.5Hz,1H）,3.73（s,3H）,4.28〜4.38（m,1H）,4.48
（dt,J＝1.7Hz,7.1Hz,1H）,5.82（dt,J＝1.5Hz,15.7Hz,
1H）,6.96（dt,J＝7.0Hz,15.7Hz,1H） IR（neat）： 3419,2930,2858,2237,1747,1729,1658,1462,1438,1319,
1276,1201,1162,1078,1044,853,727cm-1 実施例18 （2E,17S）−2a,2b−ジホモ−17,20−ジメチル−2,2a,1
3,14−テトラデヒドロ−PGE1メチルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに
（6E）−７−カルボメトキシヘキシ−６−イニル亜鉛
（II）ヨージドを用い、実質的に実施例１と同様にし
て、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.85〜0.96（m,6H）,1.06〜1.86（m,19H）,2.15〜2.27
（m,3H）,2.23（dd,J＝9.2Hz,18.5Hz,1H）,2.65（ddd,J
＝1.7Hz,8.3Hz,11.5Hz,1H）,2.75（ddd,J＝1.2Hz,7.2H
z,18.5Hz,1H）,3.73（s,3H）,4.28〜4.38（m,1H）,4.47
（dt,J＝1.7Hz,7.1Hz,1H）,5.82（dt,J＝1.5Hz,15.6Hz,
1H）,6.96（dt,J＝7.0Hz,15.6Hz,1H） IR（neat）： 3413,2929,2858,2236,1746,1728,1657,1438,1273,1201,
1172,1044,984cm-1 実施例19 （17S）−２−ノル−17,20−ジメチル−3,3,4,4,13,14
−ヘキサデヒドロ−PGE1メチルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに４
−カルボメトキシブト−３−イニル亜鉛（II）ヨードジ
を用い、実質的に実施例１と同様にして、標記化合物を
得た。1 H−NMR（CDCl3,300MHz）δppm: 0.86〜0.95（m,6H）,1.10〜1.95（m,13H）,2.05（d,J＝
5.8Hz,1H）,2.22〜2.31（m,1H）,2.25（dd,J＝8.8Hz,1
8.6Hz,1H）,2.38（t,J＝6.9Hz,2H）,2.45（d,J＝3.4Hz,
1H）,2.66（ddd,J＝1.7Hz,8.1Hz,11.2Hz,1H）,2.77（dd
d,J＝1.3Hz,7.3Hz,18.6Hz,1H）,3.76（s,3H）,4.30〜4.
40（m,1H）,4.43〜4.52（m,1H） IR（neat）： 3402,2955,2929,2872,2238,1747,1717,1436,1379,1260,
1153,1077,754cm-1 実施例20 （17S）−2a−ホモ−17,20−ジメチル−2,2,2a,2a,13,1
4−ヘキサデヒドロ−PGE1メチルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに６
−カルボメトキシヘキシ−５−イニル亜鉛（II）ヨージ
ドを用い、実質的に実施例１と同様にして、標記化合物
を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.85〜0.96（m,6H）,1.12〜1.86（m,17H）,2.24（dd,J
＝9.7Hz,18.5Hz,1H）,2.20〜2.30（m,1H）,2.34（t,J＝
6.9Hz,2H）,2.65（ddd,J＝1.7Hz,8.3Hz,11.2Hz,1H）,2.
76（ddd,J＝1.3Hz,7.1Hz,18.5Hz,1H）,3.76（s,3H）,4.
27〜4.38（m,1H）,4.48（dt,J＝1.7Hz,7.1Hz,1H） IR（neat）： 3408,2931,2860,2238,1747,1717,1461,1436,1328,1259,
1157,1078,754cm-1 実施例21 （2E,17R）−17,20−ジメチル−2,3,13,14−テトラデヒ
ドロ−PGE1アリルエステル 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに
（4E）−５−カルボ［（プロパ−２′−エニル）オキ
シ］ペント−４−エニル亜鉛（II）ヨージドを用い、実
施例１（１）で得た化合物の代わりに実施例８（１）で
得た化合物を用い、実質的に実施例１（２）および
（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.89（t,J＝6.3Hz,3H）,0.93（d,J＝6.6Hz,3H）,1.12〜
1.86（m,15H）,2.15〜2.31（m,3H）,2.23（dd,J＝9.2H
z,18.4Hz,1H）,2.63（ddd,J＝1.8Hz,8.3Hz,11.3Hz,1
H）,2.76（ddd,J＝1.3Hz,7.3Hz,18.4Hz,1H）,4.27〜4.3
8（m,1H）,4.43〜4.51（m,1H）,4.64（ddd,J＝1.4Hz,1.
4Hz,5.7Hz,1H）,5.24（ddt,J＝1.4Hz,1.4Hz,10.4Hz,1
H）,5.33（ddt,J＝1.4Hz,1.4Hz,17.2Hz,1H）,5.86（dt,
J＝1.5Hz,15.6Hz,1H）,5.95（ddt,J＝5.7Hz,10.4Hz,17.
2Hz,1H）,6.99（dt,J＝7.0Hz,15.6Hz,1H） IR（neat）： 3412,2930,2859,2236,1747,1324,1652,1461,1383,1274,
1176,1030,991,935,729cm-1 実施例22 （17R）−17,20−ジメチル−2,2,3,3,13,14−ヘキサデ
ヒドロ−PGE1メチルエステル（化合物８） 実施例１（２）において、（4E）−５−カルボメトキ
シペント−４−エニル亜鉛（II）ヨージドの代わりに５
−カルボメトキシペント−４−イニル亜鉛（II）ヨージ
ドを用い、実施例１（１）で得た化合物の代わりに実施
例８（１）で得た化合物を用い、実質的に実施例１
（２）および（３）と同様にして、標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm: 0.90（t,J＝6.4Hz,3H）,0.93（d,J＝6.6Hz,3H）,1.12〜
1.86（m,15H）,2.08（d,J＝5.9Hz,1H）,2.18〜2.29（m,
1H）,2.24（dd,J＝8.9Hz,18.6Hz,1H）,2.32〜2.41（m,2
H）,2.51（d,J＝3.4Hz,1H）,2.66（ddd,J＝1.8Hz,8.1H
z,11.2Hz,1H）,2.77（ddd,J＝1.3Hz,7.2Hz,18.6Hz,1
H）,3.77（s,3H）,4.28〜4.39（m,1H）,4.43〜4.52（m,
1H） IR（neat）： 3412,2930,2861,2237,1747,1715,1436,1384,1260,1153,
1078,821,754cm-1 実施例23 （2E,17S）−17,20−ジメチル−2,3,13,14−テトラデヒ
ドロ−PGE1（化合物９） リパーゼVII500mgを22.5mlのリン酸緩衝液（10mM,pH
7.0）に溶解し、2.5mlの50％（v/v）アセトン一水に溶
解した（2E,17S）−17,20−ジメチル−2,3,13,14−テト
ラデヒドロ−PGE1メチルエステル（実施例１で得た化合
物）50mg（0.127mmol）を加え、30℃で５時間撹拌し
た。反応液を酢酸エチル30mlで３回抽出し、有機層を飽
和食塩水30mlで洗浄後、無水硫酸マグネシウムで乾燥、
濃縮した。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：メタノール＝4
0:1）で精製し、標記化合物41mgを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.86〜0.94（m,3H）,0.91（d,J＝6.3Hz,3H）,1.10〜1.8
8（m,15H）,2.18〜2.35（m,3H）,2.24（dd,J＝8.8Hz,1
8.6Hz,1H）,2.64（ddd,J＝1.7Hz,8.1Hz,11.2Hz,1H）,2.
76（ddd,J＝1.2Hz,7.3Hz,18.6Hz,1H）,4.28〜4.38（m,1
H）,4.47（dt,J＝1.7Hz,7.1Hz,1H）,5.84（dt,J＝1.5H
z,15.6Hz,1H）,7.06（dt,J＝7.1Hz,15.6Hz,1H） IR（neat）： 3391,2930,2859,2239,1741,1698,1654,1461,1381,1285,
1164,1076,984,757cm-1 実施例24〜39 以下の実施例24〜39で製造した化合物は、実施例１〜
22で得た化合物のうち、対応する原料を用いて、実施例
23と同様に加水分解して製造したものである。The reaction mixture was extracted with 20 ml of hexane and 10 ml of a saturated aqueous solution of sodium bicarbonate, and the organic layer was dried and concentrated. 17S) -1
532 mg of 7,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 methyl ester 11,15-bis (t-butyldimethylsilyl ether) were obtained. 1 H-NMR (CDCl 3 , 200 MHz) δ ppm: 0.10 (s, 6H), 0.11 (s, 3H), 0.13 (s, 3H), 0.83 to 0.98
(M, 6H), 0.89 (s, 9H), 0.90 (s, 9H), 1.06 to 1.82 (m, 1
5H), 2.11 to 2.29 (m, 3H), 2.17 (dd, J = 7.0Hz, 18.0Hz, 1
H), 2.59 ~ 2.77 (m, 2H), 3.73 (s, 3H), 4.23 ~ 4.35 (m,
1H), 4.43 (dt, J = 1.5Hz, 7.0Hz, 1H), 5.82 (dt, J = 1.5H
z, 15.7Hz, 1H), 6.96 (dt, J = 6.9Hz, 15.7Hz, 1H) IR (neat): 2954,2930,2858,2234,1748,1728,1660,1463,1436,1362,
1326,1259,1198,1124,1092,1006,838,779,670 cm -1 (3) The compound (532 mg, 0.857 mmol) obtained in the above (2) is dissolved in acetonitrile (29 ml) and 50% hydrogen fluoride at 0 ° C. An aqueous acid solution (6.9 ml) was added. After stirring at 0 ° C. for 90 minutes, the reaction was poured into ethyl acetate (40 ml) and saturated aqueous sodium bicarbonate (230 ml). Extract with ethyl acetate,
After washing with a saturated aqueous solution of sodium bicarbonate and brine, drying and concentration, the residue obtained was purified by silica gel column chromatography (developing solvent; ethyl acetate: methanol = 40: 1) to obtain 350 mg of the title compound. . 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.83 to 0.97 (m, 6H), 1.08 to 1.90 (m, 15H), 2.12 to 2.30
(M, 4H), 2.62 (dd, J = 9.0Hz, 10.5Hz, 1H), 2.75 (dd, J
= 7.3Hz, 18.5Hz, 1H), 2.92 (dr.s, 2H), 3.72 (s, 3H),
4.27 to 4.36 (m, 1H), 4.47 (dt, J = 1.0 Hz, 6.7 Hz, 1H), 5.
68 (d, J = 15.7Hz, 1H), 6.96 (dt, J = 7.4Hz, 15.7Hz, 1H) IR (neat): 3380,2910,2230,1720,1700,1650,1435,1270,1040cm -1 Example 2 (2E, 16RS) -16,20-dimethyl-2,3,13,14,18,18,19,1
9-Octadehydro-PEG 1 methyl ester (Compound 2) (1) In Example 1 (1), (3S, 5S) -3- (t
Example 1 was substantially replaced with (3S, 4RS) -3- (t-butyldimethylsiloxy) -4-methylnona-1,6-diyne instead of -butyldimethylsiloxy) -5-methylnon-1-yne. (3R, 4R) -2-methylene-3-[(3'S, 4'RS) -3 '-(t-butyldimethylsiloxy) -4'-methylnona-1', 6 in the same manner as (1). '-Diynyl] -4- (t-butyldimethylsiloxy) cyclopentan-1-one was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.09, 0.10 and 0.12 (3s, 12H), 0.88 (s, 18H), 1.02 and 1.
03 (2d, J = 6.8Hz and6.8Hz, 3H), 1.10 (t, J = 7.3Hz, 3
H), 1.73 ~ 1.91 (m, 1H), 2.00 ~ 2.39 (m, 4H), 2.32 (d
d, J = 7.4Hz, 17.9Hz, 1H), 2.70 (dd, J = 6.4Hz, 17.9Hz, 1
H), 3.53 (d, J = 6.5Hz, 1H), 4.21-4.30 (m, 1H), 4.37a
nd4.47 (2d, J = 4.1Hz, 6.3Hz, 1H), 5.54 (d, J = 2.7Hz, 1
H), 6.13 (d, J = 3.0Hz, 1H) IR (neat): 2960,2934,2862,2364,1738,1649,1473,1363,1255,1123,
1079,837,777cm -1 (2) Using the compound obtained in the above (1), the title compound was obtained in the same manner as in Examples (2) and (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.90 to 1.16 (m, 6H), 1.30 to 1.99 (m, 7H), 2.40 to 2.37
(M, 8H), 2.63 (t, J = 10.0Hz, 1H), 2.75 (dd, J = 7.2Hz,
18.5Hz, 1H), 3.72 (s, 3H), 4.27 to 4.38 (m, 1H), 4.42an
d4.46 (2d, J = 6.6Hz and J = 4.4Hz, 1H), 5.82 (d, J = 1
5.7Hz, 1H), 6.95 (dt, J = 7.4Hz, 15.7Hz, 1H) IR (neat): 3390,2910,2230,1730,1690,1650,1430,1270,1010cm- 1 Example 3 (2E) -16,17,18,19,20-pentanor-15-cyclohexyl-2,3,13,14-tetradehydro-PEG 1 methyl ester (compound 3) (1) In Example 1 (1), (3S, 5S) -3- (t
Example 1 (1) substantially using (3S) -3- (t-butyldimethylsiloxy) -3-cyclohexylprop-1-yne instead of -butyldimethylsiloxy) -5-methylnon-1-yne (3R, 4R) -2-methylene-3-[(3'S) -3 '-(t-butyldimethylsiloxy) -3'-cyclohexylprop-1'-ynyl] -4- (t -Butyldimethylsiloxy) cyclopentan-1-one was obtained. 1 H-NMR (CDCl 3 , 200 MHz) δ ppm: 0.07, 0.08 and 0.12 (3 s, 12 H), 0.88 (s, 18 H), 0.92 to 1.9
2 (m, 11H), 2.32 (dd, J = 7.4Hz, 17.8Hz, 1H), 2.71 (dd,
J = 6.5Hz, 17.8Hz, 1H), 3.48 ~ 3.58 (m, 1H), 4.11 (dd, J
= 1.4Hz, 6.2Hz, 1H), 4.20-4.32 (m, 1H), 5.55 (d, J =
2.6Hz, 1H), 6.13 (d, J = 3.0Hz, 1H) IR (neat): 2930,2850,1735,1640,1470,1380,1255,1105,830,770cm
-1 (2) Example 1 (2) using the compound obtained in the above (1)
The title compound was obtained in the same manner as in (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.96 to 1.95 (m, 17H), 2.12 to 2.40 (m, 4H), 2.63 (ddd, J
= 1.6Hz, 8.4Hz, 11.8Hz, 1H), 2.76 (dd, J = 7.4Hz, 18.5H
z, 1H), 2.83 (br.s, 2H), 3.73 (s, 3H), 4.18 (dd, J = 1.
6Hz, 6.2Hz, 1H), 4.27-4.38 (m, 1H), 5.83 (d, J = 15.7H
z, 1H), 6.96 (dt, J = 15.7, 7.0 Hz, 1H) IR (neat): 3400, 2920, 2230, 1720, 1700, 1650, 1440, 1270, 1160 cm -1 Example 4 (17S) -17 , 20-Dimethyl-2,2,3,3,13,14-hexadehydro-PGE 1 methyl ester (compound 4) In Example 1 (2), (4E) -5-carbomethoxypent-4-enylzinc (II) 5 instead of iodide
Using -carbomethoxypent-4-ynylzinc (II) iodide, the title compound was obtained in substantially the same manner as in Example 1. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.90 (t, J = 6.8 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H), 1.10-
1.89 (m, 15H), 2.18 ~ 2.31 (m, 1H), 2.23 (d, J = 5.7Hz,
1H), 2.24 (dd, J = 8.9Hz, 18.6Hz, 1H), 2.36 (t, J = 6.5H
z, 2H), 2.66 (ddd, J = 1.8Hz, 8.1Hz, 11.2Hz, 1H), 2.71
(D, J = 3.4Hz, 1H), 2.76 (ddd, J = 1.3Hz, 7.2Hz, 18.6Hz,
1H), 3.76 (s, 3H), 4.28 to 4.38 (m, 1H), 4.43 to 4.51
(M, 1H) IR (neat): 3402,2930,2861,2237,1746,1718,1436,1259,1152,1078,
754 cm -1 Example 5 (16RS) -16,20-dimethyl-2,2,3,3,13,14,18,18,19,
19-decadehydro-PGE 1 methyl ester In Example 1 (2), 5 (carboxy) pent-4-enylzinc (II) was replaced by 5 instead of (4E) -5-carbomethoxypent-4-enylzinc.
Using -carbomethoxypent-4-ynylzinc (II) iodide and substituting the compound obtained in Example 1 (1) for the compound obtained in Example 2 (1), substantially
The title compound was obtained in the same manner as in (2) and (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 1.05 (d, J = 6.7 Hz, 3H), 1.11 (t, J = 7.5 Hz, 3H), 1.79-
1.90 (m, 1H), 2.01 ~ 2.88 (m, 15H), 2.92 (br.s, 2H),
3.10 (q, J = 7.6Hz, 1H), 3.71 (s, 3H), 4.24 ~ 4.33 (m, 1
H), 4.32 and 4.38 (2d, J = 4.1 Hz and J = 2.9 Hz, 1 H) Example 6 (2E, 17S) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 n-butyl ester In Example 1 (2), (4E) -5-carbobutoxypent-4-enylzinc (II) was used instead of (4E) -5-carbomethoxypent-4-enylzinc (II) iodide. The title compound was obtained in substantially the same manner as in Example 1 using iodide. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.78 to 0.97 (m, 9H), 1.09 to 1.86 (m, 19H), 2.12 to 2.30
(M, 4H), 2.55-2.68 (m, 1H), 2.74 (dd, J = 7.2Hz, 18.6
Hz, 1H), 4.12 (t, J = 6.6Hz, 2H), 4.26-4.36 (m, 1H),
4.46 (t, J = 6.9 Hz, 1H), 5.82 (d, J = 15.7 Hz, 1H), 6.94
(Dt, J = 7.3Hz, 15.7Hz, 1H) IR (neat): 3370,2920,2310,1720,1690,1640,1450,1260,1170,1060c
m- 1 Example 7 (2E, 17S) -17-methyl-20-ethyl-2,3,13,14-tetradehydro-PGE 1 methyl ester (1) In Example 1 (1), (3S, 5S ) -3- (t
(3S, 5RS) -3- (t-butyldimethylsiloxy) -5-methyldec-1-yne was used in place of -butyldimethylsiloxy) -5-methylnon-1-yne, and substantially the same as in Example 1 (1 )), (3R, 4R) -2-methylene-3- [3'S, 5'RS) -3 '-(t-butyldimethylsiloxy) -5'-methyldec-1'-ynyl] -4 −
(T-butyldimethylsiloxy) cyclopentane-1-
Got on. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.10 and 0.13 (2s, 12H), 0.80 to 1.05 (m, 24H), 1.06 to 1.
80 (m, 11H), 2.33 (dd, J = 7.4Hz, 18.1Hz, 1H), 2.71 (d
d, J = 6.3Hz, 18.1Hz, 1H), 3.43 to 3.66 (m, 1H), 4.20 to 4.
35 (m, 1H), 4.45 (t, J = 6.5Hz, 1H), 5.55 (br.s, 1H),
6.14 (br.s, 1H) IR (neat): 2920,2850,2330,1730,1630,1460,1360,1240,1110,1080,
830,770 cm -1 (2) Using the compound obtained in the above (1), Example 1 (2)
The title compound was obtained in the same manner as in (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.70 to 0.92 (m, 6H), 0.92 to 1.85 (m, 17H), 1.85 to 2.33
(M, 4H), 2.33 ~ 2.79 (m, 1H), 2.73 (dd, J = 7.1Hz, 18.4
Hz, 1H), 3.71 (s, 3H), 4.15 to 4.49 (m, 2H), 5.81 (d, J
= 15.6Hz, 1H), 6.92 (dt, J = 7.5Hz, 15.6Hz, 1H) IR (neat): 3390,2930,2860,2220,1720,1710,1650,1440,1280,1040c
m- 1 Example 8 (2E, 17R) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 methyl ester (compound 5) (1) In Example (1), (3S, 5S) -3- (t-
Example 1 (1) was substantially carried out using (3S, 5R) -3- (t-butyldimethylsiloxy) -5-methylnon-1-yne instead of (butyldimethylsiloxy) -5-methylnon-1-yne. (3R, 4R) -2-methylene-
3-[(3'S, 5'R) -3 '-(t-butyldimethylsiloxy) -5'-methylnon-1'-ynyl] -4-
(T-butyldimethylsiloxy) cyclopentane-1-
Got on. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.03 to 0.15 (m, 12H), 0.80 to 0.93 (m, 24H), 1.06 to 1.80
(M, 9H), 2.33 (dd, J = 7.4Hz, 17.9Hz, 1H), 2.71 (dd, J
= 6.4Hz, 17.9Hz, 1H), 3.41 ~ 3.56 (m, 1H), 4.20 ~ 4.32
(M, 1H), 4.44 (t, J = 6.6Hz, 1H), 5.55 (br.s, 1H), 6.1
4 (br.s, 1H) IR (neat): 2920, 2850, 2210, 1730, 1630, 1450, 1360, 1240, 1100, 1080,
820,760 cm -1 (2) Using the compound obtained by the above formula (1), Example 1
The title compound was obtained in the same manner as in (2) and (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.70 to 0.98 (m, 6H), 1.05 to 1.90 (m, 15H), 2.02 to 2.36
(M, 4H), 2.55 (br.s, 2H), 2.43 to 2.84 (m, 1H), 2.77
(Dd, J = 7.3Hz, 18.6Hz, 1H), 3.74 (s, 3H), 4.28-4.56
(M, 2H), 5.84 (d, J = 15.7Hz, 1H), 6.99 (dt, J = 7.5Hz,
15.7Hz, 1H) IR (neat): 3390,2930,2860,2220,1730,1660,1460,1440,1280,1040c
m- 1 Example 9 (2E) -17,18,19,20-tetranor-16-cyclohexyl-2,2,13,14-tetradehydro-PGE 1 methyl ester (1) In Example 1 (1) (3S, 5S) -3- (t
Example 1 (1) was conducted using (3S) -3- (t-butyldimethylsiloxy) -4-cyclohexylbut-1-yne instead of (-butyldimethylsiloxy) -5-methylnon-1-yne. (3R, 4R) -2-methylene-3-[(3'S) -3 '-(t-butyldimethylsiloxy) -4'-cyclohexylbut-1'-ynyl] -4- (t -Butyldimethylsiloxy) cyclopentan-1-one was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.07 to 0.14 (m, 12H), 0.89 (s, 18H), 1.03 to 1.80 (m, 13
H), 2.33 (dd, J = 7.4Hz, 17.9Hz, 1H), 2.71 (dd, J = 6.4H
z, 17.9Hz, 1H), 3.41 ~ 3.54 (m, 1H), 4.22 ~ 4.32 (m, 1
H), 4.47 (t, J = 6.8 Hz, 1H), 5.55 (d, J = 2.5 Hz, 1H), 6.
14 (d, J = 2.7Hz, 1H) IR (neat): 2930,2850,1735,1640,1460,1360,1250,1220,1100,1000,
940,830,770 cm -1 (2) Using the compound obtained in the above (1), Example 1 (2)
The title compound was obtained in the same manner as in (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.81 to 1.85 (m, 19H), 2.10 to 2.42 (m, 4H), 2.55 to 2.66
(M, 1H), 2.73 (dd, J = 7.2Hz, 18.4Hz, 1H), 3.73 (s, 3
H), 4.29 (q, J = 8.5 Hz, 1H), 4.45 (t, J = 6.3 Hz, 1H), 5.
80 (d, J = 15.7Hz, 1H), 6.96 (dt, J = 7.0Hz, 15.7Hz, 1H) IR (neat): 3400,2920,2850,2320,1720,1700,1650,1440,1270,1200 ,
1160,1035,980cm- 1 Example 10 (2E) -17,18,19,20-Tetranor-16-cyclopentyl-2,3,13,14-tetradehydro-PGE 1 methyl ester (1) Example 1 ( In 1), (3S, 5S) -3- (t
Example 1 (1) substantially using (3S) -3- (t-butyldimethylsiloxy) -4-cyclopentylbut-1-yne instead of -butyldimethylsiloxy) -5-methylnon-1-yne (3R, 4R) -2-methylene-3-[(3'S) -3 '-(t-butyldimethylsiloxy) 4'-cyclopentylbut-1'-ynyl]
4- (t-Butyldimethylsiloxy) cyclopentan-1-one was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.07 to 0.17 (m, 12H), 0.89 (s, 18H), 1.03 to 2.02 (m, 11
H), 2.33 (dd, J = 7.6Hz, 17.9Hz, 1H), 2.71 (dd, J = 6.4H
z, 17.9Hz, 1H), 3.41 ~ 3.58 (m, 1H), 4.22 ~ 4.31 (m, 1
H), 4.39 (t, J = 6.7 Hz, 1H), 5.55 (d, J = 2.4 Hz, 1H), 6.
14 (d, J = 3.0Hz, 1H) IR (neat): 2930,2850,1735,1638,1460,1360,1245,1220,1100,1000,
935,825,770 cm -1 (2) Using the compound obtained in the above (1), Example 1 (2)
The title compound was obtained in the same manner as in (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 1.02 to 2.05 (m, 17H), 2.13 to 2.31 (m, 4H), 2.52 to 2.66
(M, 1H), 2.74 (dd, J = 7.2Hz, 18.7Hz, 1H), 3.72 (s, 3
H), 4.25-4.43 (m, 1H), 4.39 (t, J = 7.1 Hz, 1H), 5.81
(D, J = 15.7Hz, 1H), 6.94 (dt, J = 6.9Hz, 15.7Hz, 1H) IR (neat): 3380, 2920, 2855, 2240, 1715, 1650, 1440, 1270, 1160, 1035,
725 cm -1 Example 11 (2E, 17RS) -20-Nonyl-17-methyl-19- (2'-
Methylprop-1'-enyl) -2,3,13,14-tetradehydro-PGE 1 methyl ester (1) In Example 1 (1), (3S, 5S) -3- (t
-Butyldimethylsiloxy) -5-methylnon-1-yn was replaced by (3S, 5RS) -3- (t-butyldimethylsiloxy) -5,9-dimethyldec-8-en-1-yne, (3R, 4R) in the same manner as in Example 1 (1)
-2-methylene-3-[(3'S, 5'RS) -3 '-(t
-Butyldimethylsiloxy) -5 ', 9'-dimethyldec-8'-en-1'-ynyl] -4- (t-butyldimethylsiloxy) cyclopentan-1-one. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.10 and 0.13 (2s, 12H), 0.80 to 1.02 (m, 21H), 1.05 to 1.
82 (m, 5H), 1.60 (s, 3H), 1.67 (s, 3H), 1.90 to 2.06
(M, 2H), 2.33 (dd, J = 7.4Hz, 17.8Hz, 1H), 2.71 (dd, J
= 6.4Hz, 17.8Hz, 1H), 3.49 ~ 3.57 (m, 1H), 4.22 ~ 4.37
(M, 1H), 4.45 (t, J = 5.9Hz, 1H), 5.08 (t, J = 6.1Hz, 1
H), 5.55 (d, J = 1.8 Hz, 1H), 6.14 (d, J = 2.5 Hz, 1H) (2) Using the compound obtained by the above formula (1), Example 1
The title compound was obtained in the same manner as in (2) and (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.82 to 1.01 (m, 3H), 1.10 to 2.35 (m, 16H), 1.59 (s, 3
H), 1.67 (s, 3H), 2.56 to 2.65 (m, 2H), 2.74 (dd, J = 7.
3Hz, 18.5Hz, 1H), 3.72 (s, 3H), 4.25 to 4.36 (m, 1H), 4.
46 (t, J = 6.6Hz, 1H), 5.08 (t, J = 5.7Hz, 1H), 5.82 (d,
J = 15.6Hz, 1H), 6.95 (dt, J = 6.8Hz, 15.6Hz, 1H) IR (neat): 3400,2920,2860,2270,1725,1705,1650,1440,1280,1020c
m- 1 Example 12 (17S) -17,20-dimethyl-2,2,3,3,13,14-hexadehydro PGE 1 n-butyl ester (Compound 6) In Example 1 (2), (4E 5) instead of 5-carbomethoxypent-4-enylzinc (II) iodide
-The title compound was obtained in substantially the same manner as in Example 1 using -carbobutoxypent-4-ynylzinc (II) iodide. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.78 to 0.98 (m, 9H), 1.05 to 1.88 (m, 19H), 2.16 to 2.42
(M, 4H), 2.57-2.66 (m, 1H), 2.74 (dd, J = 7.1Hz, 18.5
Hz, 1H), 4.14 (t, J = 6.6 Hz, 2H), 4,25-4,37 (m, 1H),
4,45 (t, J = 6.9 Hz, 1H) IR (neat): 3400,2940,2240,1740,1700,1460,1250,1070 cm -1 Example 13 17,18,19,20-tetranor-16- Cyclohexyl-2,2,
3,3,13,14-hexodehydro-PGE 1 methyl ester In Example 1 (2), 5 (5) was used instead of (4E) -5-carbomethoxypent-4-enylzinc (II) iodide.
Using -carbobutoxypent-4-ynylzinc (II) iodide and substituting the compound obtained in Example 1 (1) with the compound obtained in Example 9 (1), substantially
The title compound was obtained in the same manner as in (2) and (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.86 to 1.86 (m, 19H), 2.19 to 2.30 (m, 1H), 2.4 (dd, J =
8.9Hz, 18.5Hz, 1H), 2.33-2.41 (m, 2H), 2.66 (ddd, J =
1.8Hz, 8.2Hz, 11.2Hz, 1H), 2.76 (ddd, J = 1.3Hz, 7.3Hz, 1
8.5Hz, 1H), 3.76 (s, 3H), 4.29 to 4.38 (m, 1H), 4.49 (d
t, J = 1.8Hz, 6.4Hz, 1H) IR (neat): 3408,2926,2853,2237,1746,1714,1436,1260,1152,1078,
1046,754 cm -1 Example 14 (17RS) -20-nor-17-methyl-19- (2'-methylprop-1'-enyl) -2,2,3,3,13,14-hexadehydro-PGE 1 Methyl ester (Compound 7) In Example 1 (2), instead of (4E) -5-carbomethoxypent-4-enylzinc (II) iodide, 5
-Carbomethoxypent-4-ynylzinc (II) iodide was used, and the compound obtained in Example 11 (1) was used instead of the compound obtained in Example 1 (1).
The title compound was obtained in the same manner as in (2) and (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.95 (d, J = 6.6 Hz, 3H), 1.14 to 2.10 (m, 13H), 1.61 (s,
3H), 1.68 (s, 3H), 2.19 to 2.30 (m, 1H), 2.24 (dd, J =
8.9Hz, 18.5Hz, 1H), 2.32 ~ 2.40 (m, 2H), 2.66 (ddd, J =
1.6Hz, 8.2Hz, 11.2Hz, 1H), 2.76 (ddd, J = 1.1Hz, 7.3Hz, 1
8.5Hz, 1H), 3.76 (s, 3H), 4.28 ~ 4.36 (m, 1H), 4.43 ~
4.53 (m, 1H), 5.04 to 5.13 (m, 1H) IR (neat): 3401,2929,2864,2237,1746,1718,1436,1376,1259,1153,
1078,822,754 cm -1 Example 15 (2E, 16RS) -16-methyl-2,3,13,14-tetrahydro-
PGE 1 methyl ester (1) In Example 1 (1), (3S, 5S) -3- (t
Example 1 (1) was obtained by substituting (3S, 4RS) -3- (t-butyldimethylsiloxy) -4-methyloct-1-yne for (-butyldimethylsiloxy) -5-methylnon-1-yne. )) And (3R, 4R) -2-methylene-3-[(3'S, 4'RS) -3 '-(t-butyldimethylsiloxy) -4'-methyloct-1'-ynyl]
4- (t-Butyldimethylsiloxy) cyclopentan-1-one was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.03 to 0.17 (m, 12H), 0.60 to 1.75 (m, 31H), 2.33 (dd, J
= 7.3Hz, 17.9Hz, 1H), 2.72 (dd, J = 6.4Hz, 17,9Hz, 1H),
3.48 to 3.58 (m, 1H), 4.15 to 4.56 (m, 1H), 5.56 (d, J =
3.0Hz, 1H), 6.14 (d, J = 3.5Hz, 1H) IR (neat): 2957,2931,2858,2231,1738,1644,1464,1362,1255,1083,
1006,940,838,778,671 cm -1 (2) Using the compound obtained in the above (1), Example 1 (2)
The title compound was obtained in the same manner as in (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.85 to 0.96 (m, 3H), 0.99 (d, J = 6.7 Hz, 3H), 1.10 to 1.8
7 (m, 13H), 2.17 to 2.30 (m, 3H), 2.24 (dd, J = 9.1 Hz, 1
8.5Hz, 1H), 2.64 (ddd, J = 1.7Hz, 8.2Hz, 9.9Hz, 1H), 2.7
6 (dd, J = 7.3Hz, 18.5Hz, 1H), 3.73 (s, 3H), 4.25-4.38
(M, 2H), 5.38 (d, J = 15.7Hz, 1H), 6.96 (dt, J = 7.0Hz,
15.7Hz, 1H) IR (neat): 3420,2931,2860,2236,1746,1728,1657,1438,1275,1203,
1158,1079,1036 cm -1 Example 16 (2E, 15RS) -16,16-dimethyl-2,3,13,14-tetradehydro-PGE 1 methyl ester (1) In Example 1 (1), (3S , 5S) -3- (t
Example 3 (substituted by (3RS) -3- (t-butyldimethylsiloxy) -4,4-dimethyloct-1-yne) instead of (-butyldimethylsiloxy) -5-methylnon-1-yne. (3R, 4R) -2-methylene-3-[(3'RS) -3 '-(t-butyldimethylsiloxy) -4', 4'-dimethyloct-1'-ynyl] in the same manner as in 1). 4- (t-Butyldimethylsiloxy) cyclopentan-1-one was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.02 to 0.17 (m, 12H), 0.73 to 1.64 (m, 33H), 2.33 (dd, J
= 7.0Hz, 17.8Hz, 1H), 2.72 (dd, J = 6.4Hz, 17.8Hz, 1H),
3.49 to 3.59 (m, 1H), 4.02 to 4.07 (m, 1H), 4.22 to 4.34
(M, 1H), 5.53 to 5.58 (m, 1H), 6.15 (d, J = 3.0 Hz, 1H) IR (neat): 2957,2931,2212,1738,1714,1621,1472,1387,1363,1256 ,
1083,1007,940,838,778,671cm -1 (2) Using the compound obtained in the above (1), Example 1 (2)
The title compound was obtained in the same manner as in (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.91 (t, J = 7.0 Hz, 3H), 0.94 (s, 3H), 0.96 (s, 3H), 1.
19-1.87 (m, 12H), 2.15-2.35 (m, 3H), 2.24 (dd, J =
9.2Hz, 18.5Hz, 1H), 2.65 (ddd, J = 1.8Hz, 8.3Hz, 11.4Hz,
1H), 2.76 (ddd, J = 1.3Hz, 7.3Hz, 18.5Hz, 1H), 3.73 (s,
3H), 4.07 to 4.17 (m, 1H), 4.27 to 4.40 (m, 1H), 5.82 (d
t, J = 1.5Hz, 15.6Hz, 1H), 6.95 (dt, J = 7.0Hz, 15.6Hz, 1
H) IR (neat): 3435,2932,2861,2233,1746,1728,1657,1438,1385,1275,
1202,1159,1079,1034cm- 1 Example 17 (2E, 17S) -2a-Homo-17,20-dimethyl-2,2a, 13,14
-Tetradehydro-PGE 1 methyl ester In Example 1 (2), (5E) -6-carbomethoxyhex-5-yl was used instead of (4E) -5-carbomethoxypent-4-enylzinc (II) iodide. The title compound was obtained in substantially the same manner as in Example 1 using enylzinc (II) iodide. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.86 to 0.95 (m, 6H), 1.10 to 1.83 (m, 17H), 2.16 to 2.29
(M, 3H), 2.23 (dd, J = 9.0Hz, 18.5Hz, 1H), 2.64 (ddd, J
= 1.7Hz, 8.2Hz, 11.3Hz, 1H), 2.76 (ddd, J = 1.3Hz, 7.2H
z, 18.5Hz, 1H), 3.73 (s, 3H), 4.28-4.38 (m, 1H), 4.48
(Dt, J = 1.7Hz, 7.1Hz, 1H), 5.82 (dt, J = 1.5Hz, 15.7Hz,
1H), 6.96 (dt, J = 7.0Hz, 15.7Hz, 1H) IR (neat): 3419,2930,2858,2237,1747,1729,1658,1462,1438,1319,
1276,1201,1162,1078,1044,853,727cm- 1 Example 18 (2E, 17S) -2a, 2b-Dihomo-17,20-dimethyl-2,2a, 1
3,14-tetradehydro-PGE 1 methyl ester In Example 1 (2), (6E) -7-carbomethoxyhexyl was used instead of (4E) -5-carbomethoxypent-4-enylzinc (II) iodide. The title compound was obtained in substantially the same manner as in Example 1 using -6-ynylzinc (II) iodide. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.85 to 0.96 (m, 6H), 1.06 to 1.86 (m, 19H), 2.15 to 2.27
(M, 3H), 2.23 (dd, J = 9.2Hz, 18.5Hz, 1H), 2.65 (ddd, J
= 1.7Hz, 8.3Hz, 11.5Hz, 1H), 2.75 (ddd, J = 1.2Hz, 7.2H
z, 18.5Hz, 1H), 3.73 (s, 3H), 4.28-4.38 (m, 1H), 4.47
(Dt, J = 1.7Hz, 7.1Hz, 1H), 5.82 (dt, J = 1.5Hz, 15.6Hz,
1H), 6.96 (dt, J = 7.0Hz, 15.6Hz, 1H) IR (neat): 3413,2929,2858,2236,1746,1728,1657,1438,1273,1201,
1172,1044,984 cm -1 Example 19 (17S) -2-nor-17,20-dimethyl-3,3,4,4,13,14
-Hexadehydro-PGE 1 methyl ester In Example 1 (2), 4 (E) -5-carbomethoxypent-4-enylzinc (II) was replaced by 4
Using -carbomethoxybut-3-ynylzinc (II) iodine, the title compound was obtained in substantially the same manner as in Example 1. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.86 to 0.95 (m, 6H), 1.10 to 1.95 (m, 13H), 2.05 (d, J =
5.8Hz, 1H), 2.22 ~ 2.31 (m, 1H), 2.25 (dd, J = 8.8Hz, 1
8.6Hz, 1H), 2.38 (t, J = 6.9Hz, 2H), 2.45 (d, J = 3.4Hz,
1H), 2.66 (ddd, J = 1.7Hz, 8.1Hz, 11.2Hz, 1H), 2.77 (dd
d, J = 1.3Hz, 7.3Hz, 18.6Hz, 1H), 3.76 (s, 3H), 4.30-4.
40 (m, 1H), 4.43 to 4.52 (m, 1H) IR (neat): 3402,2955,2929,2872,2238,1747,1717,1436,1379,1260,
1153,1077,754cm -1 Example 20 (17S) -2a-homo-17,20-dimethyl-2,2,2a, 2a, 13,1
4-Hexadehydro-PGE 1 methyl ester In Example 1 (2), instead of (4E) -5-carbomethoxypent-4-enylzinc (II) iodide, 6
Using -carbomethoxyhex-5-ynylzinc (II) iodide, the title compound was obtained in substantially the same manner as in Example 1. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.85 to 0.96 (m, 6H), 1.12 to 1.86 (m, 17H), 2.24 (dd, J
= 9.7Hz, 18.5Hz, 1H), 2.20-2.30 (m, 1H), 2.34 (t, J =
6.9Hz, 2H), 2.65 (ddd, J = 1.7Hz, 8.3Hz, 11.2Hz, 1H), 2.
76 (ddd, J = 1.3Hz, 7.1Hz, 18.5Hz, 1H), 3.76 (s, 3H), 4.
27 to 4.38 (m, 1H), 4.48 (dt, J = 1.7 Hz, 7.1 Hz, 1H) IR (neat): 3408,2931,2860,2238,1747,1717,1461,1436,1328,1259,
1157,1078,754 cm -1 Example 21 (2E, 17R) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 allyl ester In Example 1 (2), (4E) -5 Example 1 using (4E) -5-carbo [(prop-2'-enyl) oxy] pent-4-enylzinc (II) iodide instead of -carbomethoxypent-4-enylzinc (II) iodide The title compound was obtained in substantially the same manner as in Examples 1 (2) and (3) using the compound obtained in Example 8 (1) instead of the compound obtained in (1). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.89 (t, J = 6.3 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.12 to
1.86 (m, 15H), 2.15 to 2.31 (m, 3H), 2.23 (dd, J = 9.2H
z, 18.4Hz, 1H), 2.63 (ddd, J = 1.8Hz, 8.3Hz, 11.3Hz, 1
H), 2.76 (ddd, J = 1.3Hz, 7.3Hz, 18.4Hz, 1H), 4.27-4.3
8 (m, 1H), 4.43 to 4.51 (m, 1H), 4.64 (ddd, J = 1.4 Hz, 1.
4Hz, 5.7Hz, 1H), 5.24 (ddt, J = 1.4Hz, 1.4Hz, 10.4Hz, 1
H), 5.33 (ddt, J = 1.4Hz, 1.4Hz, 17.2Hz, 1H), 5.86 (dt,
J = 1.5Hz, 15.6Hz, 1H), 5.95 (ddt, J = 5.7Hz, 10.4Hz, 17.
2Hz, 1H), 6.99 (dt, J = 7.0Hz, 15.6Hz, 1H) IR (neat): 3412,2930,2859,2236,1747,1324,1652,1461,1383,1274,
1176,1030,991,935,729cm -1 Example 22 (17R) -17,20-dimethyl-2,2,3,3,13,14-hexadehydro-PGE 1 methyl ester (Compound 8) Example 1 (2) In place of (4E) -5-carbomethoxypent-4-enylzinc (II) iodide,
Using -carbomethoxypent-4-ynylzinc (II) iodide and substituting the compound obtained in Example 1 (1) with the compound obtained in Example 8 (1), substantially
The title compound was obtained in the same manner as in (2) and (3). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.90 (t, J = 6.4 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.12 to
1.86 (m, 15H), 2.08 (d, J = 5.9Hz, 1H), 2.18-2.29 (m,
1H), 2.24 (dd, J = 8.9Hz, 18.6Hz, 1H), 2.32 to 2.41 (m, 2
H), 2.51 (d, J = 3.4Hz, 1H), 2.66 (ddd, J = 1.8Hz, 8.1H
z, 11.2Hz, 1H), 2.77 (ddd, J = 1.3Hz, 7.2Hz, 18.6Hz, 1
H), 3.77 (s, 3H), 4.28-4.39 (m, 1H), 4.43-4.52 (m,
1H) IR (neat): 3412,2930,2861,2237,1747,1715,1436,1384,1260,1153,
1078,821,754 cm -1 Example 23 (2E, 17S) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 (compound 9) 500 mg of lipase VII was added to 22.5 ml of a phosphate buffer (10 mM , pH
7.0) and (2E, 17S) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 methyl ester (2E, 17S) dissolved in 2.5 ml of 50% (v / v) acetone / water. 50 mg (0.127 mmol) of the compound obtained in Example 1) was added, and the mixture was stirred at 30 ° C for 5 hours. The reaction solution was extracted three times with 30 ml of ethyl acetate, and the organic layer was washed with 30 ml of saturated saline and dried over anhydrous magnesium sulfate.
Concentrated. The obtained crude product is subjected to silica gel column chromatography (developing solvent; ethyl acetate: methanol = 4).
0: 1) to give 41 mg of the title compound. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.86 to 0.94 (m, 3H), 0.91 (d, J = 6.3 Hz, 3H), 1.10 to 1.8
8 (m, 15H), 2.18 ~ 2.35 (m, 3H), 2.24 (dd, J = 8.8Hz, 1
8.6Hz, 1H), 2.64 (ddd, J = 1.7Hz, 8.1Hz, 11.2Hz, 1H), 2.
76 (ddd, J = 1.2Hz, 7.3Hz, 18.6Hz, 1H), 4.28-4.38 (m, 1
H), 4.47 (dt, J = 1.7Hz, 7.1Hz, 1H), 5.84 (dt, J = 1.5H
z, 15.6Hz, 1H), 7.06 (dt, J = 7.1Hz, 15.6Hz, 1H) IR (neat): 3391,2930,2859,2239,1741,1698,1654,1461,1381,1285,
1164,1076,984,757 cm -1 Examples 24 to 39 The compounds prepared in Examples 24 to 39 below are compounds of Examples 1 to 39.
Using the corresponding raw materials among the compounds obtained in Example 22,
Manufactured by hydrolysis in the same manner as 23.
実施例24 （2E,16RS）−16,20−ジメチル−2,3,13,14,18,1,8,19,
19−オクタデヒドロ−PGE1（化合物10）1 H−NMR（CDCl3,300MHz）δppm: 0.90〜1.32（m,6H）,1.35〜2.01（m,7H）,2.04〜2.50
（m,8H）,2.63（t,J＝10.0Hz,1H）,2.75（dd,J＝7.2Hz,
18.5Hz,1H）,4.27〜4.37（m,1H）,4.41and4.45（2d,J＝
6.5Hz and J＝4.5Hz,1H）,5.82（d,J＝15.7Hz,1H）,7.0
4（dt,J＝15.7Hz,7.3Hz,1H） 実施例25 （2E）−16,17,18,19,20−ペンタノル−15−シクロヘキ
シル−2.3,13,14−テトラデヒドロ−PGE1（化合物11）1 H−NMR（CDCl3,300MHz）δppm: 0.83〜1.98（m,17H）,2.12〜2.42（m,4H）,2.63（t,J＝
9.3Hz,1H）,2.75（dd,J＝7,7Hz,18,7Hz,1H）,4.17（d,J
＝6.1Hz,1H）,4.27〜4.37（m,1H）,5.82（d,J＝15.6Hz,
1H）,7.04（dt,J＝15.6Hz,6.5Hz,1H） 実施例26 （16RS）−16,20−ジメチル−2,2,3,3,13,14,18,18,19,
19−デカデヒドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 1.05（d,J＝6.7Hz,3H）,1.11（t,J＝7.5Hz,3H）,1.79〜
1.90（m,1H）,2.01〜2.88（m,15H）,3.10（q,J＝7.6Hz,
1H）,3.71（s,3H）,4.24〜4.33（m,1H）,4.32and4.38
（2d,J＝4.1Hz and J＝2.9Hz,1H）,6.51（br,s,3H） 実施例27 （17S）−17,20−ジメチル−2,2,3,3,13,14−ヘキサデ
ヒドロ−PGE1（化合物12）1 H−NMR（CDCl3,300MHz）δppm: 0.80〜0.92（m,6H）,1.02〜1.88（m,15H）,2.20〜2.46
（m,2H）,2.37（t,J＝6.0Hz,2H）,2.59〜2.66（m,1H）,
2.75（dd,J＝7.4Hz,18.5Hz,1H）,4.28〜4.42（m,1H）,
4.46（t,J＝6.4Hz,1H） IR（neat）： 3370,2930,2240,1700,1370,1240,1040,730cm-1 実施例28 （2E,17RS）−17−メチル−20−エチル−2,3,13,14−テ
トラデヒドロ−PGE1（化合物13）1 H−NMR（CDCl3,300MHz）δppm: 0.73〜1.01（m,6H）,1.01〜1.89（m,17H）,2.11〜2.38
（m,4H）,2.52〜2.82（m,1H）,2.75（dd,J＝7.1Hz,18.4
Hz,1H）,4.22〜4.49（m,2H）,5.83（d,J＝15.5Hz,1H）,
7.04（dt,J＝7.4Hz,15.5Hz,1H） IR（neat）： 3350,2920,2860,2320,1700,1650,1380,1280,1160,980cm
-1 実施例29 （2E,17R）−17,20−ジメチル−2,3,13,14−テトラデヒ
ドロ−PGE1（化合物14）1 H−NMR（CDCl3,300MHz）δppm: 0.86〜0.95（m,3H）,0.93（d,J＝6.6Hz,3H）,1.09〜1.8
6（m,15H）,2.18〜2.31（m,3H）,2.24（dd,J＝9.1Hz,1
8.5Hz,1H）,2.64（ddd,J＝1.7Hz,8.3Hz,11.4Hz,1H）,2.
76（ddd,J＝1.3Hz,7.3Hz,18.5Hz,1H）,4.27〜4.37（m,1
H）,4.43〜4.51（m,1H）,5.84（dt,J＝1.4Hz,15.6Hz,1
H）,7.60（dt,J＝7.0Hz,15.6Hz,1H） IR（neat）： 3368,2930,2860,2238,1745,1697,1653,1462,1383,1285,
1158,1071,984,758,668cm-1 実施例30 （2E）−17,18,19,20−テトラノル−16−シクロヘキシ
ル−2,2,13,14−テトラデヒドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 0.82〜1.82（m,19H）,2.12〜2.37（m,4H）,2.54〜2.69
（m,1H）,2.77（dd,J＝7.4Hz,18.6Hz,1H）,4.25〜4.52
（m,2H）,5.84（d,J＝15.4Hz,1H）,7.05（dt,J＝7.0Hz,
15.4Hz,1H） IR（neat）： 3380,2900,2850,2315,1690,1400,1270,1160,1020,975cm
-1 実施例31 （2E）−17,18,19,20−テトラノル−16−シクロペンチ
ル−2,2,13,14−テトラデヒドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 1.01〜2.08（m,17H）,2.13〜2.31（m,4H）,2.52〜2.67
（m,1H）,2.76（dd,J＝7.2Hz,18.5Hz,1H）,4.27〜4.47
（m,1H）,4.41（t,J＝7.0Hz,1H）,5.84（d,J＝15.7Hz,1
H）,7.05（dt,J＝7.1Hz,15.7Hz,1H） IR（neat）： 3380,2920,2850,2320,1690,1645,1400,1280,1150,1075,
1035,980cm-1 実施例32 （2E,17RS）−20−ノル−17−メチル−19−（２′−メ
チルプロパ−１′−エニル）−2,3,13,14−テトラデヒ
ドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 0.82〜1.00（m,3H）,1.06〜2.35（m,16H）,1.59（s,3
H）,1.67（s,3H）,2.58〜2.67（m,2H）,2.75（dd,J＝7.
2Hz,18.6Hz,1H）,4.26〜4.49（m,2H）,5.00〜5.12（m,1
H）,5.83（d,J＝15.5Hz,1H）,7.04（dt,J＝7.1Hz,15.5H
z,1H） 実施例33 （2E,16RS）−16−メチル−2,3,13,14−テトラデヒドロ
−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 0.84〜0.96（m,3H）,0.99（d,J＝6.7Hz,3H）,1.10〜1.9
0（m,13H）,2.16〜2.36（m,3H）,2.24（dd,J＝9.0Hz,1
8.6Hz,1H）,2.65（ddd,J＝1.8Hz,8.3Hz,11.4Hz,1H）,2.
76（ddd,J＝1.3Hz,7.3Hz,18.6Hz,1H）,4.27〜4.39（m,2
H）,5.84（dt,J＝1.5Hz,15.6Hz,1H）,7.05（dt,J＝7.0H
z,15.6Hz,1H） IR（neat）： 3391,2931,2860,2237,1744,1698,1653,1462,1481,1378,
1284,1158,1078,1032,758cm-1 実施例34 （2E,15RS）−16,16−ジメチル−2,3,13,14−テトラデ
ヒドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 0.91（t,J＝6.9Hz,3H）,0.94（s,3H）,0.96（s,3H）,1.
15〜1.87（m,12H）,2.20〜2.32（m,3H）,2.23（dd,J＝
9.1Hz,18.5Hz,1H）,2.66（dd,J＝1.7Hz,8.2Hz,11.4Hz,1
H）,2.77（ddd,J＝1.2Hz,7.3HZ,18.5Hz,1HH）,4.08〜4.
17（m,1H）,4.29〜4.39（m,1H）,5.84（dt,J＝1.5Hz,1
5.6Hz,1H）,7.05（dt,J＝7.0Hz,15.6Hz,1H） IR（neat）： 3392,2932,2861,2235,1743,1697,1653,1385,1284,1159,
1077,1024cm-1 実施例35 （2E,17S）−2a−ホモ−17,20−ジメチル−2,2a,13,14
−テトラデヒドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 0.85〜0.97（m,6H）,1.10〜1.87（m,17H）,2.17〜2.30
（m,3H）,2.24（dd,J＝9.2Hz,18.5Hz,1H）,2.64（ddd,J
＝1.7Hz,8.3Hz,11.2Hz,1H）,2.76（ddd,J＝1.2Hz,7.2H
z,18.5Hz,1H）,4.28〜4.38（m,1H）,4.48（dt,J＝1.7H
z,7.4Hz,1H）,5.83（dt,J＝1.4Hz,15.6Hz,1H）,7.06（d
t,J＝7.0Hz,15.6Hz,1H） IR（neat）： 3369,2929,2858,2237,1744,1697,1654,1384,1284,1160,
1075,983cm-1 実施例36 （2E,17S）−2a,2b−ジホモ−17,20−ジメチル−2,2a,1
3,14−テトラデヒドロ−PGE1（化合物15）1 H−NMR（CDCl3,300MHz）δppm: 0.84〜0.95（m,6H）,1.12〜1.84（m,19H）,2.17〜2.30
（m,3H）,2.23（dd,J＝9.2Hz,18.4Hz,1H）,2.65（ddd,J
＝1.7Hz,8.3Hz,11.5Hz,1H）,2.76（ddd,J＝1.2Hz,7.2H
z,18.4Hz,1H）,4.28〜4.38（m,1H）,4.47（dt,J＝1.7H
z,7.1Hz,1H）,5.83（dt,J＝1.4Hz,15.6Hz,1H）,7.06（d
t,J＝7.0Hz,15.6Hz,1H） IR（neat）： 3382,2928,2858,2237,1746,1697,1653,1465,1418,1379,
1284,1162,1076,1046,984cm-1 実施例37 （17S）−２−ノル−17,20−ジメチル−3,3,4,4,13,14
−ヘキサデヒドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 0.86〜0.95（m,6H）,1.10〜1.96（m,13H）,2.21〜2.34
（m,1H）,2.26（dd,J＝8.8Hz,18.7Hz,1H）,2.40（t,J＝
6.4Hz,2H）,2.68（ddd,J＝1.5Hz,8.3Hz,11.3Hz,1H）,2.
78（ddd,J＝1.1Hz,7.3Hz,18.7Hz,1H）,4.30〜4.41（m,1
H）,4.42〜4.54（m,1H） IR（neat）： 3392,2956,2929,2872,2237,1739,1698,1458,1383,1266,
1154,1070,757cm-1 実施例38 （17S）−2a−ホモ−17,20−ジメチル−2,2,2a,2a,13,1
4−ヘキサデヒドロ−PGE1 1 H−NMR（CDCl3,300MHz）δppm: 0.85〜0.96（m,6H）,1.12〜1.88（m,17H）,2.19〜2.33
（m,1H）,2.25（dd,J＝8.9Hz,18.5Hz,1H）,2.37（t,J＝
6.9Hz,2H）,2.67（ddd,J＝1.7Hz,8.3Hz,11.2Hz,1H）,2.
77（ddd,J＝1.3Hz,7.1Hz,18.5Hz,1H）,4.29〜4.39（m,1
H）,4.50（dt,J＝1.7Hz,7.6Hz,1H） IR（neat）： 3392,2930,2860,2236,1707,1462,1384,1241,1073,757cm
-1 実施例39 （17R）−17,20−ジメチル−2,2,3,3,13,14−ヘキサデ
ヒドロ−PGE1（化合物16）1 H−NMR（CDCl3,300MHz）δppm: 0.82〜0.96（m,3H）,0.93（d,J＝6.6Hz,3H）,1.10〜1.8
8（m,15H）,2.22〜2.32（m,1H）,2.26（dd,J＝9.0Hz,1
8.6Hz,1H）,2.37〜2.44（m,2H）,2.68（ddd,J＝1.7Hz,
8.2Hz,11.3Hz,1H）,2.78（ddd,J＝1.2Hz,7.4Hz,18.6Hz,
1H）,4.29〜4.39（m,1H）,4.45〜4.52（m,1H） IR（neat）： 3391,2930,2861,2237,1740,1697,1462,1384,1259,1154,
1071,757cm-1 実施例40 （2E,17R）−17,20−ジメチル−2,3,13,14−テトラデヒ
ドロ−PGE1（化合物14） （１）−70℃において（4E）−５−カルボ［（プロパ−
２′−エニル）オキシ］ペント−４−エニル亜鉛（II）
ヨージド（0.81Mテトラヒドロフラン溶液,13.5ml,10.9m
mol）にシアン化銅（Ｉ）・２塩化リチウム（2.37g,13.
6mmol）のテトラヒドロフラン溶液（13.6ml）を加え、
同温度で15分間撹拌した。この溶液に−70℃で実施例８
（１）で得た（3R,4R）−２−メチレン−３−［（３′
S,5′SR）−３′−（ｔ−ブチルジメチルシロキシ）−
５′−メチルノナ−１′−イニル］−４−（ｔ−ブチル
ジメチルシロキシ）−シクロペンタン−１−オン（2.69
g,5.45mmol）およびトリメチルシリルクロリド（1.25m
l,9.81mmol）のジエチルエーテル溶液を加え、撹拌しな
がら約２時間かけて室温まで昇温した。反応液に飽和塩
化アンモニウム水溶液（80ml）を加え、ｎ−ヘキサンで
抽出した。有機層を飽和食塩水で洗浄後、乾燥、濃縮を
経て得られた残渣をエーテル−イソプロピルアルコール
（1:4,22ml）に溶解し、ｐ−トルエンスルホン酸ピリジ
ン塩（68mg,0.27mmol）を加えた後、室温で12時間撹拌
した。反応液にエーテル（50ml）、飽和重炭酸ナトリウ
ム水溶液（20ml）を加え抽出後、有機層を乾燥、濃縮を
経て得られた残渣をシリカゲルカラムクロマトグラフィ
ー（ｎ−ヘキサン：エーテル＝4:1）にかけ（2E,17R）
−17,20−ジメチル−2,3,13,14−テトラデヒドロ−PGE1
アリルエステル11,15−ビス（ｔ−ブチルジメチルシリ
ルエーテル）2.52gを得た。1 H−NMR（CDCl3,300MHz）δppm; 0.09,0.11and0.12（3s,12H）,0.71〜1.00（m,6H）,0.87
and0.98（2s,18H）,1.00〜1.80（m,15H）,2.08〜2.29
（m,4H）,2.60〜2.73（m,2H）,4.22〜4.32（m,1H）,4.3
4〜4.48（m,1H）,4.63（d,J＝5.7Hz,2H）,5.19〜5.37
（m,2H）,5.84（d,J＝15.5Hz,1H）,5.83〜6.01（m,1
H）,6.98（dt,J＝15.5Hz,7.0Hz,1H） IR（neat）： 2955,2930,2858,2235,1749,1726,1655,1463,1380,1362,
1256,1124,1089,991,838,778,669cm-1 （２）上記（１）製造した化合物（194mg,0.30mmol）の
テトラヒドロフラン（3.0ml）の溶液に、テトラキス
（トリフェニルホスフィン）パラジウム（０）（34.7m
g,0.030mmol）を加え、室温で10分間撹拌した。これに
モルホリン（0.130ml,1.50mmol）を加え、室温で20分間
撹拌した後、飽和食塩水（10ml）を加え、ｎ−ヘキサン
（15ml）で抽出した。有機層を乾燥、濃縮して得られた
残渣をシリカゲルカラムクマトグラフィー（ｎ−ヘキサ
ン：エーテル＝9:1）にかけ（2E,17R）−17,20−ジメチ
ル−2,3,13,14−テトラデヒドロ−PGE111,15−ビス（ｔ
−ブチルジメチルシリルエーテル）135mgを得た。1 H−NMR（CDCl3,300MHz）δppm: 0.10,0.11and0.13（3s,12H）,0.76〜1.00（m,6H）,0.87
and0.89（2s,18H）,1.00〜1.92（m,15H）,2.09〜2.31
（m,4H）,2.59〜2.72（m,2H）,4.21〜4.34（m,1H）,4.3
6〜4.46（m,1H）,5.82（d,J＝15.7Hz,1H）,7.06（dt,J
＝6.9Hz,15.7Hz,1H） IR（neat）： 2955,2930,2858,2236,1749,1698,1652,1464,1421,1382,
1362,1286,1253,1123,1089,985,940,838,778,670cm-1 （３）上記（２）の方法で製造した化合物（920mg,1.52
mmol）をアセトニトリル（51ml）に溶解し、０℃で50％
フッ化水素酸水溶液（12.2ml）を加えた。０℃で90分間
撹拌した後、反応液を酢酸エチル（100ml）と飽和重炭
酸ナトリウム水溶液（350ml）中に注いだ。酢酸エチル
で抽出し、飽和食塩水で洗浄後、乾燥、濃縮して得られ
た残渣をシリカゲルカラムクロマトグラフィー（エーテ
ル：酢酸エチル＝1:1）で精製して標記化合物568mgを得
た。（実施例29と同一物）。Example 24 (2E, 16RS) -16,20-dimethyl-2,3,13,14,18,1,8,19,
19-octadehydro-PGE 1 (compound 10) 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.90 to 1.32 (m, 6H), 1.35 to 2.01 (m, 7H), 2.04 to 2.50
(M, 8H), 2.63 (t, J = 10.0Hz, 1H), 2.75 (dd, J = 7.2Hz,
18.5Hz, 1H), 4.27-4.37 (m, 1H), 4.41and4.45 (2d, J =
6.5Hz and J = 4.5Hz, 1H), 5.82 (d, J = 15.7Hz, 1H), 7.0
4 (dt, J = 15.7 Hz, 7.3 Hz, 1 H) Example 25 (2E) -16,17,18,19,20-pentanor-15-cyclohexyl-2.3,13,14-tetradehydro-PGE 1 (Compound 11) 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.83 to 1.98 (m, 17H), 2.12 to 2.42 (m, 4H), 2.63 (t, J =
9.3Hz, 1H), 2.75 (dd, J = 7,7Hz, 18,7Hz, 1H), 4.17 (d, J
= 6.1Hz, 1H), 4.27 ~ 4.37 (m, 1H), 5.82 (d, J = 15.6Hz,
1H), 7.04 (dt, J = 15.6Hz, 6.5Hz, 1H) Example 26 (16RS) -16,20-dimethyl-2,2,3,3,13,14,18,18,19,
19- Dekadehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm: 1.05 (d, J = 6.7Hz, 3H), 1.11 (t, J = 7.5Hz, 3H), 1.79~
1.90 (m, 1H), 2.01 ~ 2.88 (m, 15H), 3.10 (q, J = 7.6Hz,
1H), 3.71 (s, 3H), 4.24 ~ 4.33 (m, 1H), 4.32and4.38
(2d, J = 4.1 Hz and J = 2.9 Hz, 1H), 6.51 (br, s, 3H) Example 27 (17S) -17,20-dimethyl-2,2,3,3,13,14-hexa Dehydro-PGE 1 (compound 12) 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.80 to 0.92 (m, 6H), 1.02 to 1.88 (m, 15H), 2.20 to 2.46
(M, 2H), 2.37 (t, J = 6.0Hz, 2H), 2.59 ~ 2.66 (m, 1H),
2.75 (dd, J = 7.4Hz, 18.5Hz, 1H), 4.28 ~ 4.42 (m, 1H),
4.46 (t, J = 6.4 Hz, 1H) IR (neat): 3370, 2930, 2240, 1700, 1370, 1240, 1040, 730 cm -1 Example 28 (2E, 17RS) -17-methyl-20-ethyl- 2,3,13,14-tetradehydro-PGE1 (compound 13) 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.73 to 1.01 (m, 6H), 1.01 to 1.89 (m, 17H), 2.11 to 2.38
(M, 4H), 2.52 ~ 2.82 (m, 1H), 2.75 (dd, J = 7.1Hz, 18.4
Hz, 1H), 4.22-4.49 (m, 2H), 5.83 (d, J = 15.5Hz, 1H),
7.04 (dt, J = 7.4Hz, 15.5Hz, 1H) IR (neat): 3350,2920,2860,2320,1700,1650,1380,1280,1160,980cm
-1 Example 29 (2E, 17R) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 (compound 14) 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.86 to 0.95 ( m, 3H), 0.93 (d, J = 6.6Hz, 3H), 1.09-1.8
6 (m, 15H), 2.18 ~ 2.31 (m, 3H), 2.24 (dd, J = 9.1Hz, 1
8.5Hz, 1H), 2.64 (ddd, J = 1.7Hz, 8.3Hz, 11.4Hz, 1H), 2.
76 (ddd, J = 1.3Hz, 7.3Hz, 18.5Hz, 1H), 4.27 ~ 4.37 (m, 1
H), 4.43 ~ 4.51 (m, 1H), 5.84 (dt, J = 1.4Hz, 15.6Hz, 1
H), 7.60 (dt, J = 7.0Hz, 15.6Hz, 1H) IR (neat): 3368,2930,2860,2238,1745,1697,1653,1462,1383,1285,
1158,1071,984,758,668Cm -1 Example 30 (2E) 17,18,19,20 tetranor-16-cyclohexyl -2,2,13,14- Tetoradehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm: 0.82 ~ 1.82 (m, 19H), 2.12 ~ 2.37 (m, 4H), 2.54 ~ 2.69
(M, 1H), 2.77 (dd, J = 7.4Hz, 18.6Hz, 1H), 4.25-4.52
(M, 2H), 5.84 (d, J = 15.4Hz, 1H), 7.05 (dt, J = 7.0Hz,
15.4Hz, 1H) IR (neat): 3380,2900,2850,2315,1690,1400,1270,1160,1020,975cm
-1 Example 31 (2E) 17,18,19,20 tetranor-16-cyclopentyl -2,2,13,14- Tetoradehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm: 1.01~ 2.08 (m, 17H), 2.13 to 2.31 (m, 4H), 2.52 to 2.67
(M, 1H), 2.76 (dd, J = 7.2Hz, 18.5Hz, 1H), 4.27-4.47
(M, 1H), 4.41 (t, J = 7.0Hz, 1H), 5.84 (d, J = 15.7Hz, 1
H), 7.05 (dt, J = 7.1Hz, 15.7Hz, 1H) IR (neat): 3380, 2920, 2850, 2320, 1690, 1645, 1400, 1280, 1150, 1075,
1035,980Cm -1 Example 32 (2E, 17RS) -20- nor-17-methyl-19 (2'-methylprop-1'-enyl) -2,3,13,14- Tetoradehidoro -PGE 1 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.82 to 1.00 (m, 3H), 1.06 to 2.35 (m, 16H), 1.59 (s, 3
H), 1.67 (s, 3H), 2.58 to 2.67 (m, 2H), 2.75 (dd, J = 7.
2Hz, 18.6Hz, 1H), 4.26 ~ 4.99 (m, 2H), 5.00 ~ 5.12 (m, 1
H), 5.83 (d, J = 15.5Hz, 1H), 7.04 (dt, J = 7.1Hz, 15.5H
z, IH) Example 33 (2E, 16RS) -16- methyl -2,3,13,14- Tetoradehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm: 0.84~0.96 (m, 3H) , 0.99 (d, J = 6.7Hz, 3H), 1.10 ~ 1.9
0 (m, 13H), 2.16 to 2.36 (m, 3H), 2.24 (dd, J = 9.0Hz, 1
8.6Hz, 1H), 2.65 (ddd, J = 1.8Hz, 8.3Hz, 11.4Hz, 1H), 2.
76 (ddd, J = 1.3Hz, 7.3Hz, 18.6Hz, 1H), 4.27 ~ 4.39 (m, 2
H), 5.84 (dt, J = 1.5Hz, 15.6Hz, 1H), 7.05 (dt, J = 7.0H
z, 15.6Hz, 1H) IR (neat): 3391,2931,2860,2237,1744,1698,1653,1462,1481,1378,
1284,1158,1078,1032,758Cm -1 Example 34 (2E, 15RS) -16,16- dimethyl -2,3,13,14- Tetoradehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm : 0.91 (t, J = 6.9Hz, 3H), 0.94 (s, 3H), 0.96 (s, 3H), 1.
15 ~ 1.87 (m, 12H), 2.20 ~ 2.32 (m, 3H), 2.23 (dd, J =
9.1Hz, 18.5Hz, 1H), 2.66 (dd, J = 1.7Hz, 8.2Hz, 11.4Hz, 1
H), 2.77 (ddd, J = 1.2Hz, 7.3HZ, 18.5Hz, 1HH), 4.08-4.
17 (m, 1H), 4.29 to 4.39 (m, 1H), 5.84 (dt, J = 1.5 Hz, 1
5.6Hz, 1H), 7.05 (dt, J = 7.0Hz, 15.6Hz, 1H) IR (neat): 3392,2932,2861,2235,1743,1697,1653,1385,1284,1159,
1077,1024 cm -1 Example 35 (2E, 17S) -2a-homo-17,20-dimethyl-2,2a, 13,14
- Tetoradehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm: 0.85~0.97 (m, 6H), 1.10~1.87 (m, 17H), 2.17~2.30
(M, 3H), 2.24 (dd, J = 9.2Hz, 18.5Hz, 1H), 2.64 (ddd, J
= 1.7Hz, 8.3Hz, 11.2Hz, 1H), 2.76 (ddd, J = 1.2Hz, 7.2H
z, 18.5Hz, 1H), 4.28-4.38 (m, 1H), 4.48 (dt, J = 1.7H
z, 7.4Hz, 1H), 5.83 (dt, J = 1.4Hz, 15.6Hz, 1H), 7.06 (d
t, J = 7.0Hz, 15.6Hz, 1H) IR (neat): 3369,2929,2858,2237,1744,1697,1654,1384,1284,1160,
1075,983 cm -1 Example 36 (2E, 17S) -2a, 2b-Dihomo-17,20-dimethyl-2,2a, 1
3,14-tetradehydro-PGE 1 (compound 15) 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.84 to 0.95 (m, 6H), 1.12 to 1.84 (m, 19H), 2.17 to 2.30
(M, 3H), 2.23 (dd, J = 9.2Hz, 18.4Hz, 1H), 2.65 (ddd, J
= 1.7Hz, 8.3Hz, 11.5Hz, 1H), 2.76 (ddd, J = 1.2Hz, 7.2H
z, 18.4Hz, 1H), 4.28-4.38 (m, 1H), 4.47 (dt, J = 1.7H
z, 7.1Hz, 1H), 5.83 (dt, J = 1.4Hz, 15.6Hz, 1H), 7.06 (d
t, J = 7.0Hz, 15.6Hz, 1H) IR (neat): 3382,2928,2858,2237,1746,1697,1653,1465,1418,1379,
1284,1162,1076,1046,984cm- 1 Example 37 (17S) -2-nor-17,20-dimethyl-3,3,4,4,13,14
- Hekisadehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm: 0.86~0.95 (m, 6H), 1.10~1.96 (m, 13H), 2.21~2.34
(M, 1H), 2.26 (dd, J = 8.8Hz, 18.7Hz, 1H), 2.40 (t, J =
6.4Hz, 2H), 2.68 (ddd, J = 1.5Hz, 8.3Hz, 11.3Hz, 1H), 2.
78 (ddd, J = 1.1 Hz, 7.3 Hz, 18.7 Hz, 1H), 4.30 to 4.41 (m, 1
H), 4.42 to 4.54 (m, 1H) IR (neat): 3392,2956,2929,2872,2237,1739,1698,1458,1383,1266,
1154,1070,757 cm -1 Example 38 (17S) -2a-homo-17,20-dimethyl-2,2,2a, 2a, 13,1
4 Hekisadehidoro -PGE 1 1 H-NMR (CDCl 3, 300MHz) δppm: 0.85~0.96 (m, 6H), 1.12~1.88 (m, 17H), 2.19~2.33
(M, 1H), 2.25 (dd, J = 8.9Hz, 18.5Hz, 1H), 2.37 (t, J =
6.9Hz, 2H), 2.67 (ddd, J = 1.7Hz, 8.3Hz, 11.2Hz, 1H), 2.
77 (ddd, J = 1.3Hz, 7.1Hz, 18.5Hz, 1H), 4.29-4.39 (m, 1
H), 4.50 (dt, J = 1.7Hz, 7.6Hz, 1H) IR (neat): 3392,2930,2860,2236,1707,1462,1384,1241,1073,757cm
-1 Example 39 (17R) -17,20-dimethyl-2,2,3,3,13,14-hexadehydro-PGE 1 (compound 16) 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.82 to 0.96 (m, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.10 to 1.8
8 (m, 15H), 2.22 ~ 2.32 (m, 1H), 2.26 (dd, J = 9.0Hz, 1
8.6Hz, 1H), 2.37 ~ 2.44 (m, 2H), 2.68 (ddd, J = 1.7Hz,
8.2Hz, 11.3Hz, 1H), 2.78 (ddd, J = 1.2Hz, 7.4Hz, 18.6Hz,
1H), 4.29 to 4.39 (m, 1H), 4.45 to 4.52 (m, 1H) IR (neat): 3391,2930,2861,2237,1740,1697,1462,1384,1259,1154,
1071,757 cm -1 Example 40 (2E, 17R) -17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1 (compound 14) (1) At -70 ° C (4E) -5 Carbo [(proper
2'-enyl) oxy] pent-4-enylzinc (II)
Iodide (0.81M tetrahydrofuran solution, 13.5ml, 10.9m
mol) to copper (I) cyanide · lithium dichloride (2.37 g, 13.
6 mmol) in tetrahydrofuran (13.6 ml)
The mixture was stirred at the same temperature for 15 minutes. Example 8 was added to this solution at -70 ° C.
(3R, 4R) -2-methylene-3-[(3 ′) obtained in (1)
S, 5'SR) -3 '-(t-butyldimethylsiloxy)-
5'-Methylnon-1'-ynyl] -4- (t-butyldimethylsiloxy) -cyclopentan-1-one (2.69
g, 5.45 mmol) and trimethylsilyl chloride (1.25 m
(9.81 mmol) in diethyl ether, and the mixture was heated to room temperature over about 2 hours with stirring. A saturated aqueous ammonium chloride solution (80 ml) was added to the reaction solution, and the mixture was extracted with n-hexane. The organic layer was washed with saturated saline, dried and concentrated. The residue obtained was dissolved in ether-isopropyl alcohol (1: 4, 22 ml), and p-toluenesulfonic acid pyridine salt (68 mg, 0.27 mmol) was added. Then, the mixture was stirred at room temperature for 12 hours. Ether (50 ml) and saturated aqueous sodium bicarbonate solution (20 ml) were added to the reaction solution, and the mixture was extracted. The organic layer was dried and concentrated. The residue obtained was subjected to silica gel column chromatography (n-hexane: ether = 4: 1). (2E, 17R)
-17,20-dimethyl-2,3,13,14-tetradehydro-PGE 1
2.52 g of allyl ester 11,15-bis (t-butyldimethylsilyl ether) was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm; 0.09, 0.11 and 0.12 (3 s, 12H), 0.71 to 1.00 (m, 6H), 0.87
and0.98 (2s, 18H), 1.00-1.80 (m, 15H), 2.08-2.29
(M, 4H), 2.60 to 2.73 (m, 2H), 4.22 to 4.32 (m, 1H), 4.3
4 to 4.48 (m, 1H), 4.63 (d, J = 5.7 Hz, 2H), 5.19 to 5.37
(M, 2H), 5.84 (d, J = 15.5Hz, 1H), 5.83-6.01 (m, 1
H), 6.98 (dt, J = 15.5Hz, 7.0Hz, 1H) IR (neat): 2955,2930,2858,2235,1749,1726,1655,1463,1380,1362,
1256,1124,1089,991,838,778,669cm -1 (2) Tetrakis (triphenylphosphine) palladium (0) (34.7m
g, 0.030 mmol) and stirred at room temperature for 10 minutes. To this, morpholine (0.130 ml, 1.50 mmol) was added, and after stirring at room temperature for 20 minutes, saturated saline (10 ml) was added, and the mixture was extracted with n-hexane (15 ml). The residue obtained by drying and concentrating the organic layer was subjected to silica gel column chromatography (n-hexane: ether = 9: 1) (2E, 17R) -17,20-dimethyl-2,3,13,14-tetrahedral. Dehydro-PGE 1 11,15-bis (t
-Butyldimethylsilyl ether) 135 mg were obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm: 0.10, 0.11 and 0.13 (3 s, 12H), 0.76 to 1.00 (m, 6H), 0.87
and0.89 (2s, 18H), 1.00-1.92 (m, 15H), 2.09-2.31
(M, 4H), 2.59 ~ 2.72 (m, 2H), 4.21 ~ 4.34 (m, 1H), 4.3
6 to 4.46 (m, 1H), 5.82 (d, J = 15.7 Hz, 1H), 7.06 (dt, J
= 6.9Hz, 15.7Hz, 1H) IR (neat): 2955,2930,2858,2236,1749,1698,1652,1464,1421,1382,
1362,1286,1253,1123,1089,985,940,838,778,670cm -1 (3) The compound (920 mg, 1.52
mmol) in acetonitrile (51 ml) and 50% at 0 ° C.
An aqueous solution of hydrofluoric acid (12.2 ml) was added. After stirring at 0 ° C. for 90 minutes, the reaction was poured into ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (350 ml). After extraction with ethyl acetate, washing with a saturated saline solution, drying and concentration, the resulting residue was purified by silica gel column chromatography (ether: ethyl acetate = 1: 1) to obtain 568 mg of the title compound. (Same thing as Example 29).
実施例41 （2Z,17S）−17,20−ジメチル−2,3,13,14−テトリデヒ
ドロ−PGE1メチルエステル （１）実施例１（２）において、（4E）−５−カルボメ
トキシペント−４−エニル亜鉛（II）ヨージドの代わり
に５−カルボメトキシペント−４−イニル亜鉛（II）ヨ
ージドを用い、実質的に実施例１（１）および（２）と
同様にして、（17S）−17,20−ジメチル−2,2,3,3,13,1
4−ヘキサデヒドロ−PGE1メチルエステル11,15−ビス
（ｔ−ブチルジメチルシリルエーテル）を得た。1 H−NMR（CDCl3,300MHz）δppm; 0.10（s,6H）,0.11（s,3H）,0.13（s,3H）,0.83〜1.00
（m,6H）,0,89（s,9H）,0.90（s,9H）,1.05〜1.85（m,1
5H）,2.13〜2.27（m,1H）,2.17（dd,J＝6.8Hz,18.3Hz,1
H）,2.34（t,J＝6.5Hz,2H）,2.58〜2.76（m,2H）,3.75
（s,3H）,4.23〜4.36（m,1H）,4.43（dt,J＝1.4Hz,6.9H
z,1H） IR（neat）： 2954,2930,2858,2239,1749,1719,1463,1435,1256,1079,
837,779cm-1 （２）ギ酸（0.29ml,6.65mmol）、トリエチルアミン
（0.79ml,5.69mmol），トリス（ジペンジリデンアセト
ン）二パラジウム（０）・クロロホルム複合体（51.8m
g,0.05mmol）およびトリブチルホスフィン（47ml,0.19m
mol）を混合し、室温で10分間撹拌した。これにテトラ
ヒドロフラン（9.7ml）を加え、室温で15分間撹拌した
後、（１）で製造した化合物（1.18g,1.90mmol）のテト
ラヒドロフラン溶液（9.7ml）を加え、50℃で30分間撹
拌した。室温に冷却した後、飽和食塩水（20ml）を加
え、ｎ−ヘキサン（20ml）で抽出した。有機層を乾燥、
濃縮して得られた残渣をシリカゲルカラムクマトグラフ
ィー（ｎ−ヘキサン：エーテル＝2:1）にかけ標記化合
物405mgを得た。1 H−NMR（CDCl3,300MHz）δppm; 0.83〜0.98（m,6H）,1.09〜1.90（m,15H）,2.10〜2.36
（m,4H）,2.56〜2.68（m,1H）,2.75（dd,J＝7.3Hz,18.4
Hz,1H）,3.72（s,3H）,4.20〜4.38（m,1H）,4.47（t,J
＝5.7Hz,1H）,5.79（d,J＝11.5Hz,1H）,6.31（dt,J＝7.
5Hz,11.5Hz,1H） IR（neat）： 3413,2930,2859,2235,1749,1728,1649,1462,1438,1319,
1276,1162,1042cm-1 実施例42 （2Z）−17,18,19,20−テトラノル−16−シクロペンチ
ル−2,3,13,14−テトラデヒドロ−PGE1 （１）実施例１（１）において、（3S,5S）−３−（ｔ
−ブチルジメチルシロキシ）−５−メチルノナ−１−イ
ンの代わりに（3S）−３−（ｔ−ブチルィメチルシロキ
シ）−３−シクロペンチルプロパ−１−インを用い、実
施例１（２）において、（4E）−５−カルボメトキシペ
ント−４−エニル亜鉛（II）ヨージドの代わりに（4E）
−５−カルボ［（プロパ−２′−エニル）オキシ］ペン
ト−４−エニル亜鉛（II）ヨージドを用い、実質的に実
施例１（１）および（２）と同様にして17,18,19,20−
テトラノル−16−シクロペンチル−2,3,13,14−ヘキサ
デヒドロ−PGE1アリルエステル11,15−ビス（ｔ−ブチ
ルメチルシリルエーテル）を得た。1 H−NMR（CDCl3,300MHz）δppm; 0.09,0.11and0.12（3s,12H）,0.89（s,18H）,1.01〜1.8
5（m,17H）,1.86〜2.11（m,1H）,2.17（dd,J＝7.1Hz,1
8.3Hz,1H）,2.34（t,J＝6.6Hz,2H）,2.61〜2.67（m,2
H）,4.25〜4.41（m,2H）,4.64（d,J＝5.8Hz,2H）,5.22
〜5.45（m,2H）,5.93（ddt,J＝5.8Hz,10.4Hz,17.0Hz,1
H） （２）（１）で得た化合物を用い、実施例41（２）と実
質的に同様にして標記化合物を得た。1 H−NMR（CDCl3,300MHz）δppm; 1.00〜2.03（m,17H）,2.07〜2.30（m,2H）,2.52〜2.74
（m,4H）,4.22〜4.41（m,2H）,5.78（dt,J＝11.4Hz,1
H）,6.30（dt,J＝7.5Hz,11.4Hz,1H）Example 41 (2Z, 17S) -17,20-dimethyl-2,3,13,14-tetridehydro-PGE 1 methyl ester (1) In Example 1 (2), (4E) -5-carbomethoxypent- Substituting 5-carbomethoxypent-4-ynylzinc (II) iodide for 4-enylzinc (II) iodide, (17S)-was performed in substantially the same manner as in Examples 1 (1) and (2). 17,20-dimethyl-2,2,3,3,13,1
4-Hexadehydro-PGE 1 methyl ester 11,15-bis (t-butyldimethylsilyl ether) was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm; 0.10 (s, 6H), 0.11 (s, 3H), 0.13 (s, 3H), 0.83 to 1.00
(M, 6H), 0,89 (s, 9H), 0.90 (s, 9H), 1.05-1.85 (m, 1
5H), 2.13 to 2.27 (m, 1H), 2.17 (dd, J = 6.8 Hz, 18.3 Hz, 1
H), 2.34 (t, J = 6.5Hz, 2H), 2.58-2.76 (m, 2H), 3.75
(S, 3H), 4.23-4.36 (m, 1H), 4.43 (dt, J = 1.4Hz, 6.9H
z, 1H) IR (neat): 2954,2930,2858,2239,1749,1719,1463,1435,1256,1079,
837,779cm -1 (2) Formic acid (0.29 ml, 6.65 mmol), triethylamine (0.79 ml, 5.69 mmol), tris (dipendylideneacetone) dipalladium (0) / chloroform complex (51.8 m
g, 0.05 mmol) and tributylphosphine (47 ml, 0.19 m
mol) were mixed and stirred at room temperature for 10 minutes. Tetrahydrofuran (9.7 ml) was added thereto, and the mixture was stirred at room temperature for 15 minutes. Then, a tetrahydrofuran solution (9.7 ml) of the compound (1.18 g, 1.90 mmol) produced in (1) was added, and the mixture was stirred at 50 ° C. for 30 minutes. After cooling to room temperature, saturated saline (20 ml) was added, and the mixture was extracted with n-hexane (20 ml). Dry the organic layer,
The residue obtained by concentration was subjected to silica gel column chromatography (n-hexane: ether = 2: 1) to obtain 405 mg of the title compound. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm; 0.83 to 0.98 (m, 6H), 1.09 to 1.90 (m, 15H), 2.10 to 2.36
(M, 4H), 2.56-2.68 (m, 1H), 2.75 (dd, J = 7.3Hz, 18.4
Hz, 1H), 3.72 (s, 3H), 4.20-4.38 (m, 1H), 4.47 (t, J
= 5.7Hz, 1H), 5.79 (d, J = 11.5Hz, 1H), 6.31 (dt, J = 7.
5Hz, 11.5Hz, 1H) IR (neat): 3413,2930,2859,2235,1749,1728,1649,1462,1438,1319,
1276,1162,1042 cm -1 Example 42 (2Z) -17,18,19,20-tetranor-16-cyclopentyl-2,3,13,14-tetradehydro-PGE 1 (1) Example 1 (1) In (3S, 5S) -3- (t
In Example 1 (2), (3S) -3- (t-butylmethylsiloxy) -3-cyclopentylprop-1-yne was used in place of -butyldimethylsiloxy) -5-methylnon-1-yne. (4E) -5-carbomethoxypent-4-enylzinc (II) Instead of iodide, (4E)
17,18,19 using substantially 5-carbo [(prop-2'-enyl) oxy] pent-4-enylzinc (II) iodide in substantially the same manner as in Examples 1 (1) and (2). , 20−
Tetranor-16-cyclopentyl-2,3,13,14-hexadehydro-PGE 1 allyl ester 11,15-bis (t-butylmethylsilyl ether) was obtained. 1 H-NMR (CDCl 3 , 300 MHz) δ ppm; 0.09, 0.11 and 0.12 (3 s, 12 H), 0.89 (s, 18 H), 1.01 to 1.8
5 (m, 17H), 1.86 ~ 2.11 (m, 1H), 2.17 (dd, J = 7.1Hz, 1
8.3Hz, 1H), 2.34 (t, J = 6.6Hz, 2H), 2.61 ~ 2.77 (m, 2
H), 4.25-4.41 (m, 2H), 4.64 (d, J = 5.8Hz, 2H), 5.22
~ 5.45 (m, 2H), 5.93 (ddt, J = 5.8Hz, 10.4Hz, 17.0Hz, 1
H) (2) Using the compound obtained in (1), the title compound was obtained in substantially the same manner as in Example 41 (2). 1 H-NMR (CDCl 3 , 300 MHz) δ ppm; 1.00 to 2.03 (m, 17H), 2.07 to 2.30 (m, 2H), 2.52 to 2.74
(M, 4H), 4.22 ~ 4.41 (m, 2H), 5.78 (dt, J = 11.4Hz, 1
H), 6.30 (dt, J = 7.5Hz, 11.4Hz, 1H)
フロントページの続き (72)発明者 武藤 賢 埼玉県大宮市上小町1440−２ 藤屋アパ ート107号 (72)発明者 小野 直哉 東京都豊島区高田３丁目６番６号 大正 セントラルマンションＣ棟327 (72)発明者 五藤 准 埼玉県大宮市奈良町30番16号Continuation of the front page (72) Inventor Ken Muto 1440-2 Kamikomachi, Omiya City, Saitama Prefecture No. 107 Fujiya Apart 107 (72) Inventor Naoya Ono 3-6-6 Takada, Toshima-ku, Tokyo Taisho Central Mansion C 327 (72) Inventor Jun Goto 30-16 Nara-cho, Omiya-shi, Saitama
Claims (2)
は水素原子、炭素原子数１〜６個のアルキル基またはア
リル基を示し、R2は炭素原子数５〜10個の分岐脂肪族炭
化水素基を示し、ｎは３〜６の整数を示す。）で表され
るプロスタグランジンPGE1類縁体及びその塩。1. Expression (after correction) (Wherein A represents a vinylene group or an ethynylene group, and R 1
Represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an allyl group, R 2 represents a branched aliphatic hydrocarbon group having 5 to 10 carbon atoms, and n represents an integer of 3 to 6. Prostaglandin PGE 1 analogs and salts thereof represented by).
は炭素原子数１〜６個のアルキル基またはアリル基を示
し、R2は炭素原子数５〜10個の分岐脂肪族炭化水素基を
示し、R3およびR4は同一または異なって水酸基の保護基
を示し、ｎは３〜６の整数を示す。）で表される化合
物。2. The (addition) expression (In the formula, A represents a vinylene group or an ethynylene group, R 7
Represents an alkyl group or an allyl group having 1 to 6 carbon atoms, R 2 represents a branched aliphatic hydrocarbon group having 5 to 10 carbon atoms, and R 3 and R 4 are the same or different and protect a hydroxyl group. And n represents an integer of 3 to 6. ).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4507785A JP2641622B2 (en) | 1991-04-22 | 1992-04-21 | Prostaglandin E lower 1 analog |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3-182112 | 1991-04-22 | ||
| JP18211291 | 1991-04-22 | ||
| JP3-296739 | 1991-08-27 | ||
| JP29673991 | 1991-08-27 | ||
| JP4507785A JP2641622B2 (en) | 1991-04-22 | 1992-04-21 | Prostaglandin E lower 1 analog |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2641622B2 true JP2641622B2 (en) | 1997-08-20 |
Family
ID=27325116
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4507785A Expired - Fee Related JP2641622B2 (en) | 1991-04-22 | 1992-04-21 | Prostaglandin E lower 1 analog |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2641622B2 (en) |
-
1992
- 1992-04-21 JP JP4507785A patent/JP2641622B2/en not_active Expired - Fee Related
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