JPH032133A - Cyclopentane derivative and antipode thereof - Google Patents
Cyclopentane derivative and antipode thereofInfo
- Publication number
- JPH032133A JPH032133A JP13583089A JP13583089A JPH032133A JP H032133 A JPH032133 A JP H032133A JP 13583089 A JP13583089 A JP 13583089A JP 13583089 A JP13583089 A JP 13583089A JP H032133 A JPH032133 A JP H032133A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- antipode
- enantiomer
- cyclopentane derivative
- cyclopentane
- 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.)
- Pending
Links
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 title claims 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- -1 (1S, 3R, 5R)-3-hydroxy-5-isopropenyl-2-methylcyclopentane-1-carboxylic acid Chemical compound 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 150000001940 cyclopentanes Chemical class 0.000 abstract description 8
- 229940127218 antiplatelet drug Drugs 0.000 abstract 1
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 210000004623 platelet-rich plasma Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- MNIBBVOEXUQHFF-UHFFFAOYSA-N 1-methylcyclopentanecarboxylic acid Chemical compound OC(=O)C1(C)CCCC1 MNIBBVOEXUQHFF-UHFFFAOYSA-N 0.000 description 1
- ZTVIKZXZYLEVOL-DGKWVBSXSA-N 2-hydroxy-2-phenylacetic acid [(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] ester Chemical group C([C@H]1CC[C@@H](C2)N1C)C2OC(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-DGKWVBSXSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000208202 Linaceae Species 0.000 description 1
- 235000004431 Linum usitatissimum Nutrition 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical class CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 101100472152 Trypanosoma brucei brucei (strain 927/4 GUTat10.1) REL1 gene Proteins 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 230000002467 anti-pepsin effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- JCAZSWWHFJVFPP-UHFFFAOYSA-N methyl 5-chloro-5-oxopentanoate Chemical compound COC(=O)CCCC(Cl)=O JCAZSWWHFJVFPP-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、新規なシクロペンタン誘導体及びその対掌体
、及びその製法に係る。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel cyclopentane derivative, its enantiomer, and a method for producing the same.
従来の技術
発明者らは、先の特許出願（特願昭８２−１８６７１４
号）において、４−イソプロペニル−１−メチル−６オ
キソノクロヘキサンー１．２−エボキンド（１）を、塩
基
０ＣＨｓ
（式中、Ｍ−アルカリ金属）と反応させた後、加水分解
して３−ヒドロキン−５−イソプロペニル−２−メチル
シクロベンタン−１−カルボン酸（２）を生成し、該カ
ルボン酸を酸化した後、加熱することからなる２−イソ
プロペニル−５−メチル−４オキソシクロヘキサン−１
−カルボン酸（３）の製法を開示した。The inventors of the conventional technology filed an earlier patent application (Japanese Patent Application No. 82-186714).
No. 3), 4-isopropenyl-1-methyl-6oxonochlorohexane-1,2-evoquinde (1) was reacted with a base 0CHs (in the formula, M-alkali metal) and then hydrolyzed to give 3 - 2-isopropenyl-5-methyl-4oxocyclohexane consisting of producing hydroquine-5-isopropenyl-2-methylcyclobentane-1-carboxylic acid (2), oxidizing the carboxylic acid, and then heating. -1
-A method for producing carboxylic acid (3) was disclosed.
この製法の過程は次式で示される。The process of this manufacturing method is shown by the following equation.
さらに、発明者らは、該特許出願において、これらシク
ロペンタンカルホン酸（２）及び（３）が薬理活性とし
て抗消化性潰瘍作用を有することを証明した。Furthermore, the inventors demonstrated in the patent application that these cyclopentanecarphonic acids (2) and (3) have anti-peptic ulcer activity as a pharmacological activity.
発明が解決しようとする課題
ところで、近年、成人病の１つとして血栓症の発生が増
大し、これによる後遺症が重大な問題となっており、こ
れらの治療及び予防は今後の高齢化社会においては不可
欠となっている。Problems to be Solved by the Invention In recent years, the incidence of thrombosis has increased as one of the adult diseases, and the sequelae caused by this have become a serious problem, and the treatment and prevention of these diseases will be important in the future aging society. It has become essential.
課題を解決するための手段
発明者らは、血栓症の予防、治療に有用な化合物を得る
ことを目的として、鋭意研究、検討を重ねた結果、後述
の一般式（Ｉ）で表されるシクロペンタン誘導体及びそ
の対掌体が血栓症の原因となる血小板の凝集を効果的に
抑制することを見出し、本発明に至った。Means for Solving the Problems The inventors have conducted intensive research and studies with the aim of obtaining compounds useful for the prevention and treatment of thrombosis. The inventors have discovered that pentane derivatives and their enantiomers effectively inhibit platelet aggregation, which causes thrombosis, leading to the present invention.
従って、本発明の目的は、一般式（１）（式中、Ｒ１及
びＲ２は水素又はアシル基であり、は立体化学が不明か
、立体異性体の混合を意味する）で表されるシクロペン
タン誘導体及びその対掌体を提供することである。Therefore, the object of the present invention is to provide a cyclopentane compound represented by the general formula (1) (wherein R1 and R2 are hydrogen or an acyl group, and means that the stereochemistry is unknown or a mixture of stereoisomers). The object of the present invention is to provide derivatives and their enantiomers.
本発明の他の目的は、（ＩＳ、３Ｒ，５Ｒ）−３−ヒド
ロキン−５−イソプロペニル−２−メチルシクロペンタ
ン−１−カルボン酸又はその対掌体を還元して、式
で表される化合物またはその対掌体とし、ついで単一工
程又は２段階でアノル化することを特徴とする前記一般
式（Ｉ）で表されるシクロペンタン誘導体及びその対掌
体の製法を提供することにある。Another object of the present invention is to reduce (IS,3R,5R)-3-hydroquine-5-isopropenyl-2-methylcyclopentane-1-carboxylic acid or its enantiomer to An object of the present invention is to provide a method for producing a cyclopentane derivative represented by the general formula (I) and its enantiomer, which comprises preparing a compound or its enantiomer and then anorizing it in a single step or two steps. .
作用
本発明によるシクロペンタン誘導体におけるアシル基と
しては炭素数２ないし１０のものが挙げられ、これらの
アシル基は置換されていてもよい。Function The acyl group in the cyclopentane derivative according to the present invention includes those having 2 to 10 carbon atoms, and these acyl groups may be substituted.
また、同時に２つのアシル基が存在する場合、これらの
アシル基は互いに同一のもの、又は相違するいずれであ
ってもよい。Furthermore, when two acyl groups are present at the same time, these acyl groups may be the same or different.
本発明によるシクロペンタン誘導体の製造過程は次のと
おりである（式中、ｘ、ｘ’はいずれもアシル基であり
、同−又は相違するしのである）。The process for producing the cyclopentane derivative according to the present invention is as follows (in the formula, x and x' are both acyl groups, and are the same or different).
各反応について説明する。Each reaction will be explained.
反応（１）
この工程は還元の工程であり、還元剤としては水素化ア
ルミニウムリチウム、水素化ホウ素リチウム、水素化ホ
ウ素ナトリウムなどを用いることができる。Reaction (1) This step is a reduction step, and lithium aluminum hydride, lithium borohydride, sodium borohydride, etc. can be used as the reducing agent.
反応（２）
この工程は、前記反応（１）によって得られたアルコー
ルをアシル化する工程であり、ピリジン、トリエチルア
ミンなどの塩基の存在下に、対応する酸無水物、酸ハロ
ゲン化物、及び活性エステル等のアシル化剤を用いるの
が望ましい。Reaction (2) This step is a step of acylating the alcohol obtained in the above reaction (1), and in the presence of a base such as pyridine or triethylamine, the corresponding acid anhydride, acid halide, and active ester are acylated. It is desirable to use an acylating agent such as
反応（３）
この工程もアシル化の工程であり、前記反応（２）にお
ける生成物のうち、モノアシル化生成物についてざらに
アシル化を行うものであり、すでに導入されているアシ
ル基と同−又は異種のアシル基を導入できる。反応条件
及び使用できるアシル化剤に関しては前記反応（２）と
同様である。Reaction (3) This step is also an acylation step, and among the products in reaction (2), the monoacylated product is roughly acylated, and the acyl group is the same as the acyl group already introduced. Alternatively, a different type of acyl group can be introduced. The reaction conditions and the acylating agent that can be used are the same as those for reaction (2) above.
このようにして生成される本発明のシクロペンタン誘導
体は、原料の３−ヒドロキシ−５−イソプロペニル−２
−メチルシクロペンタン−１−カルボン酸と異なり、薬
理活性として血小板凝集抑制作用を育しており、原料化
合物にはない特異な特性を育するものである。The cyclopentane derivative of the present invention produced in this way can be obtained from the raw material 3-hydroxy-5-isopropenyl-2.
-Different from methylcyclopentane-1-carboxylic acid, it exhibits platelet aggregation inhibiting action as a pharmacological activity, and has unique properties not found in raw material compounds.
本発明をさらに詳述するため、以下にいくつかの好適な
具体例を例示するが、本発明はこれらに限定されない。In order to further explain the present invention in detail, some preferred specific examples are illustrated below, but the present invention is not limited thereto.
実施例１
Ｐ−１９
水素化リチウムアルミニウム２．８５９（７５ｉｕｏｌ
）を無水テトラヒドロフランに＠濁し、窒素雰囲気下、
０℃で攪拌しながら、（ＩＳ、２Ｒ１５Ｒ）−３−ヒド
ロキシ−２−メチル−５−（１−メチルエチニル）シク
ロペンクンカルボン酸９．２０９（５０ｘｘｏｌ）の無
水テトラヒドロフラン溶液を滴下し、室温で１時間攪拌
した。反応液にエーテルを加え、次いで過剰の還元剤を
２０％水酸化ナトリウムで処理し、反応液を濾過した。Example 1 P-19 Lithium aluminum hydride 2.859 (75 iuol
) in anhydrous tetrahydrofuran, and under nitrogen atmosphere,
While stirring at 0°C, a solution of (IS, 2R15R)-3-hydroxy-2-methyl-5-(1-methylethynyl)cyclopencunecarboxylic acid 9.209 (50xxol) in anhydrous tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature. Stirred for 1 hour. Ether was added to the reaction solution, then excess reducing agent was treated with 20% sodium hydroxide, and the reaction solution was filtered.
Ｐ液の溶媒を留去し、得られた結晶をベンゼン、ヘキサ
ン、シクロヘキサンから再結晶し、化合物針−１９をｍ
ｐ５５−５６℃の無色結晶として定量的に得た（８．５
１ｊ；収率−１００％）。The solvent of the P solution was distilled off, the obtained crystals were recrystallized from benzene, hexane, and cyclohexane, and compound needle-19 was
Obtained quantitatively as colorless crystals with p55-56°C (8.5
1j; yield -100%).
［α］２５： −９，８” （Ｃ＝ １．００． Ｃ
ＨＣｌ２ｊ）ｉＲνＣＨ”’（ｃｍ−リ： ３４００（
ｂｒ）、 １６４０（ｂｒ）ｆｌａｘ
’Ｈ−ＮＭＲ（４００ＭＨｚ、ＣＤＣＱＪδ１．０５（
３Ｈ，ｄｊ＝ ７Ｈ２，ＣＨ３）： １．７２（３Ｈ，
５ＣＨ１）： ３．ｓｇ ３．６７（２Ｈ，ｍ、ＣＨ
ｔＯＨ）；４．７１及び４．７８（各々ＩＨ，各々ｂｒ
ｓ、Ｃ＝ＣＨｔ）ＭＳ（ＣＩｏＨＩｌｌＯｌ）、理論
値ｍ／ｚ １５２．１２０１（Ｍ” ＨｔＯ）測定値
ｒａ／ｚ １５２．１２１６（Ｍ” −Ｈ，０）実施例
２
０Ｈ
Ｐ−１９
ＭＰ−３３八 ＭＰ−２２１１Ｐ−３
３Ｃ実施例１で得られた化合物（ＭＰ−１９）０．３６
９（２ｘｚｏｌ）及びピリノン０．３２９（４ｘｘｏｌ
）を酢酸エチルに溶解し、窒素雰囲気下、０℃で攪拌し
ながら、メチル４−（クロロフォルミル）ブヂレート０
．５５ｘＱ（４ｘｉｏｌ）を滴下した。反応液を酢酸エ
チルで抽出し、抽出液を炭酸水素ナトリウム水溶液、飽
和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後
、溶媒を留去し、残留物をシリカゲル力ラムクロマトフ
ラフィー（石油エーテル−酢酸エチル−２：１）により
精製し、化合物ＭＰ−３３Ａ（０，１２９；収率１３％
）、ＭＰ−２２Ｃ０，０６９，収率１０％）、ＭＰ−３
３Ｃ（０，２２９；収率３５％）をそれぞれ無色油状物
として得た。[α]25: -9,8" (C= 1.00.C
HCl2j)iRνCH"'(cm-ri: 3400(
br), 1640(br)flax'H-NMR(400MHz, CDCQJδ1.05(
3H, dj = 7H2, CH3): 1.72 (3H,
5CH1): 3. sg 3.67 (2H, m, CH
tOH); 4.71 and 4.78 (each IH, each br
s, C=CHt) MS (CIoHIllOl), theoretical value m/z 152.1201 (M" HtO) measured value ra/z 152.1216 (M" -H,0) Example 2 0H P-19 MP-33 8 MP-2211P-3
3C Compound obtained in Example 1 (MP-19) 0.36
9 (2xzol) and pyrinone 0.329 (4xxol
) was dissolved in ethyl acetate, and while stirring at 0°C under a nitrogen atmosphere, methyl 4-(chloroformyl) butyrate 0.
．． 55xQ (4xiol) was added dropwise. The reaction solution was extracted with ethyl acetate, the extract was washed successively with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (petroleum ether). Purification with ethyl acetate (2:1) yielded compound MP-33A (0,129; yield 13%).
), MP-22C0,069, yield 10%), MP-3
3C (0.229; yield 35%) was obtained as a colorless oil.
ＭＰ−３３Ａ
ＩＲν”’ （ｃｍ−’） ： １７２０ａＸ
Ｈ−ＮＭＲ（６０ＭＨ２，ＣＣｌ２４）δ １．０４（
３１１ｂｒ ｄ Ｊ＝５ＨｚＣＨ３）、１．７３（３Ｈ
，ｓ、ＣＨ３）３．６０（６Ｈ，ｓ、２ＸＯｃＨ３）
４．６５（２Ｈｓ、ＣＨａ）、４．６５（２Ｈ，ｓ、ｃ
ｍ ＣＨｔ）
ＭＳ（ＣＩＱＨ１４） ： ｍ／ｚ １３４（
Ｍ”−Ｃ＋ｔｌｌｚｏＯａ）（Ｃ＋５ｌ（ｔ４０ａ）
’、 ｍａ７２８０（Ｍ”−Ｃｅ！ＬｏＯｔ）Ｐ−
２２
ＩＲｖ ＣＨＣＱ’（ｃｍ−’） ： １７３０（ｂｒ
）ａＸ
Ｈ−ＮＭＲ（６０Ｍ）ｌｚ、ＣＣＣ４）δ： １０５（
３１１，ｄ、Ｊ＝６１１ｚ、Ｃｌｌ３）１．６８（３ｔ
１．ｓ、ｃＩｌａ）Ｊ、４８（２Ｈ，ｄ、Ｊ＝４Ｈｚ、
ＣＨｚＯ）Ｉ）３．５８（３Ｈ，Ｓ、０ＣＨ３）、４．
６８（２Ｈ，ｓ、Ｃ＝ＣＨ，）
ＭＳ（Ｃ，、Ｈ，，０，） ： ｍ／ｚ ２８０
（ｋｌ” −ＨｔＯ）ＭＰ−３３Ｃ
’Ｈ−ＮＭＲ（６０ＭＨｚ、ＣＣｌ４）δ： １．０
５（３Ｈ，ｄ、Ｊ＝６Ｈｚ、ＣＨｓ）１．７３（３Ｈ，
ｓ、Ｃ１，）、３．６０（３Ｈ，ｓ、０ｃＨａ）、４．
６５（２Ｈ，ｓ。MP-33A IRν"'(cm-'): 1720aX H-NMR (60MH2, CCl24) δ 1.04 (
311br d J=5HzCH3), 1.73(3H
, s, CH3) 3.60 (6H, s, 2XOcH3) 4.65 (2Hs, CHa), 4.65 (2H, s, c
m CHt) MS (CIQH14): m/z 134 (
M”-C+tllzoOa)(C+5l(t40a)
', ma7280(M"-Ce!LoOt)P-
22 IRv CHCQ'(cm-'): 1730 (br
) aX H-NMR (60M) lz, CCC4) δ: 105 (
311, d, J=611z, Cll3) 1.68 (3t
1. s, cIla) J, 48 (2H, d, J=4Hz,
CHzO)I) 3.58 (3H,S,0CH3), 4.
68(2H,s,C=CH,) MS(C,,H,,0,): m/z 280
(kl''-HtO)MP-33C'H-NMR (60MHz, CCl4) δ: 1.0
5 (3H, d, J=6Hz, CHs) 1.73 (3H,
s, C1,), 3.60 (3H, s, 0cHa), 4.
65 (2H, s.
Ｃ＝ＣＨｔ）
ＭＳ（Ｃ＋ｏＨ＋ａＯ） ： ＩＩｌ／Ｚ １
５２（ｂ！＋ＣａＨ＋ｏＯａ）（Ｃ＋ＪｔａＯｔ）
： ｍ／ｚ ２８０（Ｍ”−ＨｔＯ）実施例３
ＭＰ−２２ＭＰ−２３
実施例２で得られた化合物（ＭＰ−２２）１．４０１ｉ
＋（４，７１１０１）、ピリジン０．４８９（６，１ｉ
＋ａ＋ｏｌ）及び無水ｎ−カプロン酸５．０１９（２３
ｍｘｏｌ）を無水塩化メチレンに溶解し、窒素雰囲気下
、室温で２４時間攪拌した。反応液の溶媒を留去し、残
留物を酢酸エチルで抽出し、抽出液を硫酸水素ケリラム
水溶液、炭酸水素ナトリウム水溶液、飽和食塩水で順次
洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去し
、残留物をソリ力ゲル力ラムクロマトグラフィー（ヘン
ゼン酢酸エチル−２０＋１）により精製し、化合物（Ｍ
Ｐ２３）１．１８９（収率６３％）を無色油状物として
得た。C=CHt) MS(C+oH+aO): IIl/Z 1
52(b!+CaH+oOa)(C+JtaOt)
: m/z 280 (M”-HtO) Example 3 MP-22MP-23 Compound obtained in Example 2 (MP-22) 1.401i
+ (4,71101), pyridine 0.489 (6,1i
+a+ol) and n-caproic anhydride 5.019 (23
mxol) was dissolved in anhydrous methylene chloride and stirred at room temperature under nitrogen atmosphere for 24 hours. The solvent of the reaction solution was distilled off, the residue was extracted with ethyl acetate, the extract was washed successively with an aqueous solution of Keryram hydrogen sulfate, an aqueous solution of sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by gel column chromatography (Hensen's ethyl acetate-20+1) to obtain the compound (M
P23) 1.189 (63% yield) was obtained as a colorless oil.
ＩＲνＣ””（ｃｎ＋−’） ： １７２０（ｂｒ）、
１６４０ａｘ
Ｈ−ＮＩＩＲ（４００ＭＨｚ、 ＣＤＣ１３）δ０．９
０５（３Ｈ，ｔ、Ｊ＝ ７Ｈｚ、ＣＨ５）、１．１１（
３Ｈ，ｄ、Ｊ・７Ｈｚ、Ｃｔ１３）、１．７０（３Ｈ９
ｓ、ｃＨ３）、２．２８（２Ｈ，ｔ、Ｊ＝８Ｈｚ、ＣＨ
ｓ）、２．２３（４８，ｑ、Ｊ＝ ７１１ｚ、２ＸＣＨ
ｔ）２．５７（ＩＨ，ｍ、ＣＨ）Ｊ、６７（３Ｈ，ｓ、
０ＣＨ３）、３．９７及び４．１５（各々ＩＨ，各々ｄ
ｄｊ−１１Ｈｚ、６ｔｌｚ及びＪ＝ １１）ｉｚ、５Ｈ
ｚ、０Ｃ１１，）、４．７４（ＩＨｌｍ、ｃｌＩ）。IRνC""(cn+-'): 1720 (br),
1640ax H-NIIR (400MHz, CDC13) δ0.9
05 (3H, t, J = 7Hz, CH5), 1.11 (
3H, d, J・7Hz, Ct13), 1.70 (3H9
s, cH3), 2.28 (2H, t, J=8Hz, CH
s), 2.23 (48, q, J = 711z, 2XCH
t) 2.57 (IH, m, CH) J, 67 (3H, s,
0CH3), 3.97 and 4.15 (each IH, each d
dj-11Hz, 6tlz and J=11)iz, 5H
z, 0C11,), 4.74 (IHlm, cll).
４．７６（２Ｈ，ｓ、Ｃ−ＣＨｚ）
ＭＳ（Ｃ＋ａＨｔｓＯｔ） ： ｍ／ｚ ２５
０（Ｍ＋Ｃ６ＨＩ００４）（ＣＩ８１１２４０４）
： ｍ／ｚ ２８０（Ｍ＋Ｃ６Ｈ１２０り実施例
４
実施例５
Ｐ−５１
（ＩＲ，２Ｓ、３Ｓ、５Ｓ）−３−ヒドロキシ−２−メ
チル−５（ｌ−メチルエチニル）シクロベンタンヵルボ
ン酸９−２０１７（５０３１肋ｌ）を用いて実施例！と
同様の反応、操作を行い、化合物ＭＰ−５１（７，９４
ｇ、 ９３．４％）をｍｐ５Ｌ−５９℃（ノイソプロビ
ルエーテルーヘキサンより再結晶）の鱗片状品として得
た。各種スペクトルデータは実施例１で得られたＭＰ−
１９のデータと一致した。4.76 (2H, s, C-CHz) MS (C+aHtsOt): m/z 25
0 (M+C6HI004) (CI8112404)
: m/z 280 (M+C6H120 Example 4 Example 5 P-51 (IR, 2S, 3S, 5S)-3-hydroxy-2-methyl-5(l-methylethynyl)cyclobentanecarboxylic acid 9-2017 (5031 liters), the same reaction and operation as in Example! were carried out, and the compound MP-51 (7,94
g, 93.4%) was obtained as a scaly product at mp5L-59°C (recrystallized from noisopropylether-hexane). Various spectral data are MP- obtained in Example 1.
The data were consistent with 19 data.
ｐ−ｓｔ
ＭＰ−５２ＭＰ−５３ＭＰ−５４
実施例４で得られたＭＰ−５１２，３０１＋（１３，５
３ｚｘｏｌ）を用いて、実施例２と同様の反応操作を行
い、ＭＰ５２（９０（１＋ｙ９．１５．６％）、ＭＰ−
５３（２８８ｘＬ ７．１％）及びＭＰ−５４（１，２
５９，３ｔ、０％）を得た。p-st MP-52MP-53MP-54 MP-512,301+(13,5
The same reaction operation as in Example 2 was carried out using MP52 (90 (1+y9.15.6%), MP-
53 (288xL 7.1%) and MP-54 (1,2
59.3t, 0%) was obtained.
ＭＰ−５２、ＭＰ−５３、ＭＰ−５４の各種スペクトル
データは、実施例２で得られたＭｌ”−３３ＡＳＭＰ−
２２、ＭＰ３３Ｃのデータとそれぞれ一致した。Various spectral data of MP-52, MP-53, and MP-54 are based on Ml''-33ASMP- obtained in Example 2.
22 and MP33C data, respectively.
実施例６
上記実施例で得られたシクロペンタン誘導体について、
下記試験方法に従って、血小板凝集抑制効果を評価した
。Example 6 Regarding the cyclopentane derivative obtained in the above example,
The platelet aggregation inhibitory effect was evaluated according to the following test method.
［試験方法］
体重２．５ｋｇ〜３２に９の雄性ウサギを使用し、３．
８％クエン酸存在下（血液１０容に対しクエン酸１容）
にて頚動脈採血を行った。採取した血液を直ちに遠心分
離し、多血小板血漿（ＰＲＰ）及び乏血小板血漿（ＰＰ
Ｐ）に分離した。遠心分離の条件は、ＰＲＰニア６０ｒ
ｐｍ、１５分間、ＰＰＰ＋２６０Ｏｒｐｍ、 １０分間
とした。血小板凝集の測定を、ＰＲＰの透過度をＯとし
、ＰＰＰの透過度を１００とした比濁法にて実施した（
二光バイオサイエンス社製、ヘマトレーサーＶ）。[Test Method] Using 9 male rabbits weighing 2.5 kg to 32 kg, 3.
In the presence of 8% citric acid (1 volume of citric acid per 10 volumes of blood)
Carotid artery blood was collected. The collected blood was immediately centrifuged to separate platelet-rich plasma (PRP) and platelet-poor plasma (PP).
P) was separated. The conditions for centrifugation are PRP Nia 60r.
pm for 15 minutes, PPP+260Orpm for 10 minutes. Measurement of platelet aggregation was carried out by turbidimetry, with the permeability of PRP set to 0 and the permeability of PPP set to 100 (
Hematotracer V) manufactured by Niko Bioscience.
被験物質の血小板凝集に対する抑制作用を以下の手順に
て測定した。すなわち、２００μｅのＰＲＰを１分間予
備加温（３７℃、 １０１０００ｒｐ シ、被験物質溶
液１０ｄ（初蟲度：水又は１０〜５０％エタノール溶液
）を２μｇ加え（終濃度・１００μＭ）、３分後に凝集
剤としてコラーゲン（Ｈｏｒｍ社：終濃度１０μ９／
ｚＱ）を添加した。The inhibitory effect of the test substance on platelet aggregation was measured according to the following procedure. That is, 200 μe of PRP was prewarmed for 1 minute (37°C, 101,000 rp), 2 μg of test substance solution (10d: water or 10-50% ethanol solution) was added (final concentration: 100 μM), and aggregation occurred after 3 minutes. Collagen (Horm: final concentration 10μ9/
zQ) was added.
［評価］
各被験物質の効果を、次式によって抑制率を算出して評
価した。[Evaluation] The effect of each test substance was evaluated by calculating the inhibition rate using the following formula.
抑制率（％）−
（（溶媒添加の最大凝集率−被験物質添加の最大凝集率
）／溶媒添加の最大凝集率）ｘ１００得られた結果を次
表に示す。Inhibition rate (%) - ((maximum aggregation rate of solvent addition - maximum aggregation rate of test substance addition)/maximum aggregation rate of solvent addition) x 100 The obtained results are shown in the following table.
同様にして、３−ヒドロキシ−５−イソプロペニル−２
−メチルシクロベンクン−１−カルボン酸の血小板凝集
抑制効果を評価したところ、抑制率は０％であった。Similarly, 3-hydroxy-5-isopropenyl-2
- When the platelet aggregation inhibiting effect of methylcyclobencune-1-carboxylic acid was evaluated, the inhibition rate was 0%.
発明の効果
本発明によるシクロペンタン誘導体は、原料の３−ヒド
ロキン−５−イソプロペニル−２−メチルシクロベンタ
ン−ｌ−カルボン酸と比べて類似した構造を有するもの
ではあるが、その薬理活性として、該化合物と異なり血
小板凝集作用を有しており、血栓症の予防、治療におい
て有用な物質である。Effects of the Invention Although the cyclopentane derivative according to the present invention has a similar structure compared to the raw material 3-hydroquine-5-isopropenyl-2-methylcyclobentane-l-carboxylic acid, its pharmacological activity is Unlike the above compounds, it has a platelet aggregation effect and is a useful substance in the prevention and treatment of thrombosis.
Claims (1)
■は立体化学が不明か、立体異性体の混合を意味する）
で表されるシクロペンタン誘導体及びその対掌体。 ２ （１Ｓ、３Ｒ、５Ｒ）−３−ヒドロキシ−５−イソ
プロペニル−２−メチルシクロペンタン−１−カルボン
酸又はその対掌体を還元することを特徴とする、特許請
求の範囲第１項記載のシクロペンタン誘導体及びその対
掌体の製法。 ３ 一般式（II） ▲数式、化学式、表等があります▼ （式中、Ｒ＾３及びＲ＾４は水素又はアシル基であるが
、同時に水素であることはなく、■は立体化学が不明か
、立体異性体の混合を意味する）で表されるシクロペン
タン誘導体又はその対掌体の製法において、 ▲数式、化学式、表等があります▼ で表される化合物又はその対掌体を単一工程又は２段階
でアシル化することを特徴とする、シクロペンタン誘導
体及びその対掌体の製法。[Claims] 1 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 are hydrogen or an acyl group,
■ means the stereochemistry is unknown or a mixture of stereoisomers)
A cyclopentane derivative represented by and its enantiomer. 2 (1S, 3R, 5R)-3-hydroxy-5-isopropenyl-2-methylcyclopentane-1-carboxylic acid or its enantiomer is reduced, according to claim 1. A method for producing a cyclopentane derivative and its enantiomer. 3 General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 and R^4 are hydrogen or acyl groups, but they are not hydrogen at the same time, and ■ indicates that the stereochemistry is unknown. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the method for producing cyclopentane derivatives or their enantiomers represented by A method for producing a cyclopentane derivative and its enantiomer, characterized by acylation in one step or two steps.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13583089A JPH032133A (en) | 1989-05-31 | 1989-05-31 | Cyclopentane derivative and antipode thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13583089A JPH032133A (en) | 1989-05-31 | 1989-05-31 | Cyclopentane derivative and antipode thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH032133A true JPH032133A (en) | 1991-01-08 |
Family
ID=15160780
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13583089A Pending JPH032133A (en) | 1989-05-31 | 1989-05-31 | Cyclopentane derivative and antipode thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH032133A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19803705B4 (en) * | 1997-01-30 | 2006-02-16 | Mazda Motor Corp. | Airbag system for a vehicle |
-
1989
- 1989-05-31 JP JP13583089A patent/JPH032133A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19803705B4 (en) * | 1997-01-30 | 2006-02-16 | Mazda Motor Corp. | Airbag system for a vehicle |
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