JPS6338023B2 - - Google Patents
Info
- Publication number
- JPS6338023B2 JPS6338023B2 JP55096666A JP9666680A JPS6338023B2 JP S6338023 B2 JPS6338023 B2 JP S6338023B2 JP 55096666 A JP55096666 A JP 55096666A JP 9666680 A JP9666680 A JP 9666680A JP S6338023 B2 JPS6338023 B2 JP S6338023B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- trans
- guanidinomethylcyclohexanecarboxylic
- formula
- ester hydrochloride
- 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
Links
- -1 4-guanidinomethylcyclohexanecarboxylic acid aryl ester compound Chemical class 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- JBRMEFWJFBHUKG-LJGSYFOKSA-N NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 Chemical compound NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 JBRMEFWJFBHUKG-LJGSYFOKSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 238000000921 elemental analysis Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- JBRMEFWJFBHUKG-UHFFFAOYSA-N 4-[(diaminomethylideneamino)methyl]cyclohexane-1-carboxylic acid Chemical compound NC(N)=NCC1CCC(C(O)=O)CC1 JBRMEFWJFBHUKG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- QCVUPSYRZFNUBN-UHFFFAOYSA-N 4-[(diaminomethylideneamino)methyl]cyclohexane-1-carboxylic acid;hydrochloride Chemical compound Cl.NC(N)=NCC1CCC(C(O)=O)CC1 QCVUPSYRZFNUBN-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 2
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229960005356 urokinase Drugs 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 101710081722 Antitrypsin Proteins 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- MOZDKDIOPSPTBH-UHFFFAOYSA-N Benzyl parahydroxybenzoate Chemical compound C1=CC(O)=CC=C1C(=O)OCC1=CC=CC=C1 MOZDKDIOPSPTBH-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OJUUJWNTVBJDAO-FNIRFVFUSA-N Cl.Cl.NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 Chemical compound Cl.Cl.NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 OJUUJWNTVBJDAO-FNIRFVFUSA-N 0.000 description 1
- QCVUPSYRZFNUBN-MEZFUOHNSA-N Cl.NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 Chemical compound Cl.NC(=N)NC[C@H]1CC[C@H](C(O)=O)CC1 QCVUPSYRZFNUBN-MEZFUOHNSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000288 anti-kallikrein effect Effects 0.000 description 1
- 230000001475 anti-trypsic effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003541 chymotrypsin inhibitor Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- RFNODQARGNZURK-UHFFFAOYSA-N methyl 2-acetamidoacetate Chemical compound COC(=O)CNC(C)=O RFNODQARGNZURK-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 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
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- GJLNWLVPAHNBQN-UHFFFAOYSA-N phenyl 4-hydroxybenzoate Chemical compound C1=CC(O)=CC=C1C(=O)OC1=CC=CC=C1 GJLNWLVPAHNBQN-UHFFFAOYSA-N 0.000 description 1
- 229960000969 phenyl salicylate Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
Landscapes
- Enzymes And Modification Thereof (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
この発明は新規な4―グアニジノメチルシクロ
ヘキサンカルボン酸アリールエステル化合物及び
その製造方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 4-guanidinomethylcyclohexanecarboxylic acid aryl ester compound and a method for producing the same.
本発明者らは、4―グアニジノメチルシクロヘ
キサンカルボン酸アリールエステルが優れたタン
パタ質分解酵素阻害作用を有することを見い出し
或る種化合物については既に特許出願に及んでい
るものである(特願昭54−168272号)が、本願発
明において更に、新規な4―グアニジノメチルシ
クロヘキサンカルボン酸アリールエステル化合物
とその製造方法を提供するものである。 The present inventors have discovered that 4-guanidinomethylcyclohexanecarboxylic acid aryl ester has an excellent protease inhibitory effect, and have already filed a patent application for certain compounds (Patent application filed in 1973). -168272) further provides a novel 4-guanidinomethylcyclohexanecarboxylic acid aryl ester compound and a method for producing the same.
本願発明によつて提供される新規化合物は、す
ぐれたタンパタ質分解酵素阻害作用を有し、従つ
て有用な薬理活性を有するものである。 The novel compounds provided by the present invention have excellent proteolytic enzyme inhibitory effects and therefore have useful pharmacological activities.
本願発明によつて提供される新規化合物は式
〔〕
[式中Rは水素原子、低級アルキル基、ベンジ
ル基、フエニル基を示し、―COORはメタ位又は
パラ位に置換している。]で示される。 The novel compound provided by the present invention has the formula [] [In the formula, R represents a hydrogen atom, a lower alkyl group, a benzyl group, or a phenyl group, and --COOR is substituted at the meta or para position. ].
ここにおいてRとしては、H,―CH3,―
C2H5,―C3H7,―C4H9,―C6H5,―CH2―
C6H5などが挙げられ、―COORはメタ位又はパ
ラ位に置換していることを示す。 Here, R is H, -CH 3 , -
C 2 H 5 , ―C 3 H 7 , ―C 4 H 9 , ―C 6 H 5 , ―CH 2 ―
Examples include C 6 H 5 , and -COOR indicates substitution at the meta or para position.
本発明化合物は窒素原子を有しているので各種
酸との塩体を構成するが、これら各種塩体も本発
明に含まれる。ここにおいて用いられる各種酸と
しては、塩酸、硫酸、リン酸、臭化水素酸などの
無機酸や、酢酸、乳酸、マレイン酸、フマル酸、
酒石酸、クエン酸、グルコン酸、メタンスルホン
酸などの有機酸が挙げられる。 Since the compound of the present invention has a nitrogen atom, it forms salts with various acids, and these various salts are also included in the present invention. Various acids used here include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, acetic acid, lactic acid, maleic acid, fumaric acid,
Examples include organic acids such as tartaric acid, citric acid, gluconic acid, and methanesulfonic acid.
式〔〕で示される化合物には幾何異性体が存
在するが、これら異性体も本発明に含まれる。 Geometric isomers exist in the compound represented by formula [], and these isomers are also included in the present invention.
次に、本発明によつて提供される新規4―グア
ニジノメチルシクロヘキサンカルボン酸アリール
エステルは次のようにして造られる。即ち、式
〔〕
で示される4―グアニジノメチルシクロヘキサン
カルボン酸またはその反応性誘導体に式〔〕
[式中R′は低級アルキル基、ベンジン基、フ
エニル基を示し、―COOR′はメタ位又はパラ位
に置換していることを示す]
で示される化合物を反応させることによつて式
〔〕
[式中Rは水素原子、低級アルキル基、ベンジ
ル基、フエニル基を示し、―COORはメタ位又は
パラ位に置換していることを示す]
で示される化合物が造られる。 Next, the novel 4-guanidinomethylcyclohexanecarboxylic acid aryl ester provided by the present invention is prepared as follows. That is, the formula [] 4-guanidinomethylcyclohexanecarboxylic acid or its reactive derivative represented by the formula [] [In the formula, R' represents a lower alkyl group, benzine group, or phenyl group, and -COOR' represents substitution at the meta or para position] By reacting a compound represented by the formula [] [In the formula, R represents a hydrogen atom, a lower alkyl group, a benzyl group, or a phenyl group, and --COOR represents substitution at the meta or para position.] A compound represented by the following formula is produced.
ここにおいて式〔〕における反応性誘導体と
しては酸クロライド、酸ブロマイドなどの酸ハラ
イド、酸無水物、各種活性エステルなどが挙げら
れる。反応に際し用いられる溶媒としては、ジメ
チルホルムアミド、ジメチルアセタミド、ピリジ
ン、アセトニトリル、ジクロルエタンなどが挙げ
られる。 Here, examples of the reactive derivative in formula [] include acid halides such as acid chloride and acid bromide, acid anhydrides, and various active esters. Examples of the solvent used in the reaction include dimethylformamide, dimethylacetamide, pyridine, acetonitrile, and dichloroethane.
式〔〕で示される化合物のカルボキシル基遊
離の状態で、反応に供するときは、縮合剤とし
て、ジシクロヘキシルカルボジイミド、N―アル
キル―2―ハロピリジニウム塩などを用いるとよ
い。 When the compound represented by the formula [] is subjected to the reaction in a state in which the carboxyl group is free, dicyclohexylcarbodiimide, N-alkyl-2-halopyridinium salt, etc. may be used as the condensing agent.
式〔〕で示される化合物における置換基Rが
水素原子を示す場合は、場合により原料の一つと
して用いられる式〔〕で示される化合物は、置
換基R′が水素原子を示すものをあらかじめ反応
に関与しないように保護された型にして反応に供
され、反応終了後、反応生成物から適宜方法で保
護基を除去することによつて好適に造られる。 When the substituent R in the compound represented by the formula [] represents a hydrogen atom, the compound represented by the formula [], which may be used as one of the raw materials, may be prepared by reacting the substituent R′ representing a hydrogen atom in advance. It is suitably produced by subjecting it to the reaction in a protected form so as not to participate in the reaction, and removing the protecting group from the reaction product by an appropriate method after the reaction is completed.
かくして得られる式〔〕で示される化合物は
次に示すようにすぐれた活性を有することがわか
つた。即ち、抗トリプシン作用、抗キモトリプシ
ン作用、抗トロンピン作用、抗カリクレイン作用
及び抗ウロキナーゼ作用について、合成あるいは
天然基質をこれらの蛋白分解酵素が加水分解する
のを本発明化合物がいかに阻害するかを測定する
ことにより検討した。 The thus obtained compound represented by the formula [] was found to have excellent activity as shown below. That is, with respect to antitrypsin, antichymotrypsin, antithrompin, antikallikrein, and antiurokinase effects, it is determined how well the compound of the present invention inhibits the hydrolysis of synthetic or natural substrates by these proteases. This was considered.
実験はザ・ジヤーナル・オブ・バイオケミスト
リー(The Journal of Biochemistry)、58、
214(1964)に記載の方法を参考にして行つた。そ
の結果、本発明化合物は上記の蛋白分解酵素を強
力に阻害した。例えば、トランス―4―グアニジ
ノメチルシクロヘキサンカルボン酸―4′―エトキ
シカルボニルフエニルエステル塩酸塩は、ウロキ
ナーゼをN―アセチルグリジンメチルエステルを
基質とした実験で0.1mM濃度で50%阻害した。 The experiment was published in The Journal of Biochemistry, 58 .
214 (1964). As a result, the compound of the present invention strongly inhibited the above proteolytic enzymes. For example, trans-4-guanidinomethylcyclohexanecarboxylic acid-4'-ethoxycarbonylphenyl ester hydrochloride inhibited urokinase by 50% at a concentration of 0.1 mM in an experiment using N-acetylglycine methyl ester as a substrate.
以下本発明を詳述するために実施例を記述す
る。 Examples will be described below to explain the present invention in detail.
参考例 1
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―2′―フエノキシカルボニルフエ
ニルエステル塩酸塩
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸塩酸塩27.5g、サリチル酸フエニル
25g、N、N′―ジシクロヘキシルカルボジイミ
ド26.5gをN、N′―ジメチルホルムアミド100ml
に懸濁し、室温で21時間反応する。水150ml、塩
酸120mlを加え析出する結晶を取し、水洗のの
ちメタノールで抽出する不溶物を別後、濃縮
し、残渣にエーテルを加えて結晶物を得る。この
ものはトランス―4―グアニジノメチルシクロヘ
キサンカルボン酸―2′―フエノキシカルボニルフ
エニルエステル塩酸塩で、得量34.1g(67.5%)
融点157〜162℃である。Reference example 1 Trans-4-guanidinomethylcyclohexanecarboxylic acid-2'-phenoxycarbonyl phenyl ester hydrochloride Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride 27.5g, phenyl salicylate
25g, N,N'-dicyclohexylcarbodiimide 26.5g, N,N'-dimethylformamide 100ml
and react at room temperature for 21 hours. Add 150 ml of water and 120 ml of hydrochloric acid to collect the precipitated crystals, wash with water and extract with methanol. After separating the insoluble matter, concentrate and add ether to the residue to obtain the crystals. This product was trans-4-guanidinomethylcyclohexanecarboxylic acid-2'-phenoxycarbonyl phenyl ester hydrochloride, yield 34.1g (67.5%), melting point 157-162°C.
IR νmax(cm-1) 1740、1750(C=O)
NMR δ:CD3OD
0.7〜3.1(m、12H)
6.8〜8.1(m、9H)
元素分析
C22H25N3O4・HClとして
C H N
計算値(%) 61.18 6.07 9.73
測定値(%) 61.01 5.95 9.79
実施例 1
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―3′―ベンジルオキシカルボニル
フエニルエステル塩酸塩
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸塩酸塩109.8g、m―オキシ安息香
酸ベンジル106.3gをピリジン450mlに懸濁し、室
温で22時間反応する。ピリジンを留去したのち水
100mlを加え、塩酸で酸性とし不溶物を遠心分離
法によつて単離し、このものをメタノールで抽出
する。メタノールを留去し、残渣をイソプロピル
アルコールから再結晶し、169.5g(81.6%)の
トランス―4―グアニジノメチルシクロヘキサン
カルボン酸―3′―ベンジルオキシカルボニルフエ
ニルエステル塩酸塩を得る。 融点75〜80℃
IR νmax(cm-1) 1725、1755(C=O)
NMR δ:CD3OD
0.8〜3.2(m、12H)
5.3(s、2H)
6.9〜8.0(m、9H)
元素分析
C23H27N3O4・HClとして
C H N
計算値(%) 61.95 6.33 9.42
測定値(%) 61.37 6.18 9.58
実施例2
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―3′―ヒドロキシカルボニルフエ
ニルエステル塩酸塩
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―3′―ベンジルオキシカルボニルフ
エニルエステル塩酸塩80gをメタノール、酢酸の
混合溶媒中、パラジウム一炭素を触媒として加水
素分解する。所定量の水素を吸収したのち、触媒
を別し、液を濃縮し、結晶を得る。このもの
をメタノールから再結晶し、56.8g(89.0%)の
トランス―4―グアニジノメチルシクロヘキサン
カルボン酸―3′―ヒドロキシカルボニルフエニル
エステル塩酸塩を得る。 IR νmax (cm -1 ) 1740, 1750 (C=O) NMR δ: CD 3 OD 0.7-3.1 (m, 12H) 6.8-8.1 (m, 9H) Elemental analysis C 22 H 25 N 3 O 4・HCl C H N Calculated value (%) 61.18 6.07 9.73 Measured value (%) 61.01 5.95 9.79 Example 1 Trans-4-guanidinomethylcyclohexanecarboxylic acid-3'-benzyloxycarbonylphenyl ester hydrochloride Trans-4-guanidinomethylcyclohexane 109.8 g of carboxylic hydrochloride and 106.3 g of benzyl m-oxybenzoate were suspended in 450 ml of pyridine and reacted at room temperature for 22 hours. After distilling off the pyridine, water
Add 100 ml, acidify with hydrochloric acid, isolate insoluble matter by centrifugation, and extract this with methanol. Methanol was distilled off, and the residue was recrystallized from isopropyl alcohol to obtain 169.5 g (81.6%) of trans-4-guanidinomethylcyclohexanecarboxylic acid-3'-benzyloxycarbonylphenyl ester hydrochloride. Melting point 75-80℃ IR νmax (cm -1 ) 1725, 1755 (C=O) NMR δ: CD 3 OD 0.8-3.2 (m, 12H) 5.3 (s, 2H) 6.9-8.0 (m, 9H) Elemental analysis C 23 H 27 N 3 O 4・HCl C H N Calculated value (%) 61.95 6.33 9.42 Measured value (%) 61.37 6.18 9.58 Example 2 Trans-4-guanidinomethylcyclohexanecarboxylic acid-3'-hydroxycarbonylphenyl Ester hydrochloride 80 g of trans-4-guanidinomethylcyclohexanecarboxylic acid-3'-benzyloxycarbonylphenyl ester hydrochloride is hydrolyzed in a mixed solvent of methanol and acetic acid using palladium on carbon as a catalyst. After absorbing a predetermined amount of hydrogen, the catalyst is separated and the liquid is concentrated to obtain crystals. This product was recrystallized from methanol to obtain 56.8 g (89.0%) of trans-4-guanidinomethylcyclohexanecarboxylic acid-3'-hydroxycarbonylphenyl ester hydrochloride.
融 点 197〜200℃
IR νmax(cm-1) 1700、1740(C=O)
NMR δ:CD3OD
0.8〜3.2(m、12H)
7.0〜8.0(m、4H)
元素分析
C16H21N3O4・HClとして
C H N
計算値(%) 54.01 6.23 11.81
測定値(%) 53.96 6.21 11.89
実施例 3
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―4′―エトキシカルボニルフエニ
ルエステル塩酸塩
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸塩酸塩35.4g、p―オキシ安息香酸
エチル25g、N、N′―ジシクロヘキシルカルボ
ジイミド34.0gをピリジン350mlに懸濁し、室温
で17時間反応する。ピリジンを留去したのち水を
300ml加え塩酸で酸性とする。析出する結晶を
取し、このものをメタノール500mlで抽出する。
メタノールを濃縮し残渣をエタノールから再結晶
し、33.7g(58.5%)のトランス―4―グアニジ
ノメチルシクロヘキサンカルボン酸―4′―エトキ
シカルボニルフエニルエステル塩酸塩を得た。 Melting point 197-200℃ IR νmax (cm -1 ) 1700, 1740 (C=O) NMR δ: CD 3 OD 0.8-3.2 (m, 12H) 7.0-8.0 (m, 4H) Elemental analysis C 16 H 21 N As 3 O 4・HCl C H N Calculated value (%) 54.01 6.23 11.81 Measured value (%) 53.96 6.21 11.89 Example 3 Trans-4-guanidinomethylcyclohexanecarboxylic acid-4'-ethoxycarbonylphenyl ester hydrochloride Trans- 35.4 g of 4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 25 g of ethyl p-oxybenzoate, and 34.0 g of N,N'-dicyclohexylcarbodiimide were suspended in 350 ml of pyridine and reacted at room temperature for 17 hours. After distilling off the pyridine, add water.
Add 300ml and make acidic with hydrochloric acid. Collect the precipitated crystals and extract them with 500 ml of methanol.
The methanol was concentrated and the residue was recrystallized from ethanol to obtain 33.7 g (58.5%) of trans-4-guanidinomethylcyclohexanecarboxylic acid-4'-ethoxycarbonylphenyl ester hydrochloride.
融 点 181〜184℃
このものは、ウロキナーゼをN―アセチルグリ
シルリジンメチルエステルを基質とした実験で
0.1mMで50%阻害した。 Melting point: 181-184℃ This product was tested using urokinase as a substrate using N-acetylglycyrrhizine methyl ester.
50% inhibition was achieved at 0.1mM.
IR νmax(cm-1) 1715、1755(C=O)
NMR δ:CD3OD
0.6〜3.1(m、t、15H)
4.3(q、2H)
7.1,8.0(d、d、4H)
元素分析
C18H25N3O4・HClとして
C H N
計算値(%) 56.32 6.83 10.95
測定値(%) 56.21 6.79 11.03
実施例 4
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―4′―ヒドロキシカルボニルフエ
ニルエステル塩酸塩
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―4′―ベンジルオキシカルボニルフ
エニルエステル塩酸塩65gをメタノール300ml、
酢酸300mlの溶媒に溶かし、パラジウム一炭素を
触媒として、加水素分解する。所定量の水素を吸
収させたのち、触媒を別し、液を濃縮し、結
晶を得る。このものをメタノールから再結晶し
45.8g(88.3%)のトランス―4―グアニジノメ
チルシクロヘキサンカルボン酸―4′―ヒドロキシ
カルボニルフエニルエステル塩酸塩を得る。 IR νmax (cm -1 ) 1715, 1755 (C=O) NMR δ: CD 3 OD 0.6-3.1 (m, t, 15H) 4.3 (q, 2H) 7.1, 8.0 (d, d, 4H) Elemental analysis C 18 H 25 N 3 O 4・HCl C H N Calculated value (%) 56.32 6.83 10.95 Measured value (%) 56.21 6.79 11.03 Example 4 Trans-4-guanidinomethylcyclohexanecarboxylic acid-4'-hydroxycarbonylphenyl ester Hydrochloride Trans-4-guanidinomethylcyclohexanecarboxylic acid-4'-benzyloxycarbonylphenyl ester hydrochloride 65g, methanol 300ml,
Dissolve in 300 ml of acetic acid and hydrogenolyze using palladium on carbon as a catalyst. After absorbing a predetermined amount of hydrogen, the catalyst is separated and the liquid is concentrated to obtain crystals. Recrystallize this from methanol
45.8 g (88.3%) of trans-4-guanidinomethylcyclohexanecarboxylic acid-4'-hydroxycarbonylphenyl ester hydrochloride is obtained.
融 点 225.5〜228℃
IR νmax(cm-1) 1750(C=O)
NMR δ:DMSO―d6
0.8〜3.2(m、12H)
7.2,8.0(d、d、4H)
元素分析
C16H21N3O4・HClとして
C H N
計算値(%) 54.01 6.23 11.81
測定値(%) 53.89 6.21 11.97
実施例 5
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸―3′―メトキシカルボニルフエニ
ルエステル塩酸塩
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸塩酸塩35.4g、3―ハライドキシ安
息香酸メチル22.8g、N、N′―ジシクロヘキシル
カルボジイミド34.0gをピリジン300mlに懸濁し、
室温で24時間反応する。不溶物を別後、液を
濃縮し残渣を塩酸で酸性とし、クロロホルムで抽
出する。クロロホルムを留去後残渣をアセトンで
再結晶し、20.9g(37.7%)のトランス―4―グ
アニジノメチルシクロヘキサンカルボン酸―3′―
メトキシカルボニルフエニルエステル塩酸塩を得
る。 Melting point 225.5-228℃ IR νmax (cm -1 ) 1750 (C=O) NMR δ:DMSO-d 6 0.8-3.2 (m, 12H) 7.2, 8.0 (d, d, 4H) Elemental analysis C 16 H 21 As N 3 O 4・HCl C H N Calculated value (%) 54.01 6.23 11.81 Measured value (%) 53.89 6.21 11.97 Example 5 Trans-4-guanidinomethylcyclohexanecarboxylic acid-3'-methoxycarbonylphenyl ester hydrochloride Trans 35.4 g of -4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 22.8 g of methyl 3-halidoxybenzoate, and 34.0 g of N,N'-dicyclohexylcarbodiimide were suspended in 300 ml of pyridine,
Incubate for 24 hours at room temperature. After separating the insoluble matter, the liquid is concentrated, the residue is made acidic with hydrochloric acid, and extracted with chloroform. After chloroform was distilled off, the residue was recrystallized from acetone to obtain 20.9g (37.7%) of trans-4-guanidinomethylcyclohexanecarboxylic acid-3'-
Methoxycarbonyl phenyl ester hydrochloride is obtained.
融 点 138〜147℃
IR νmax(cm-1) 1705、1745(C=O)
NMR δ:CD3OD
0.8〜3.2(m、12H)
3.9(s、3H)
7.0〜8.1(m、4H)
元素分析
C17H35N3O4・HClとして
C H N
計算値(%) 55.21 6.54 11.36
測定値(%) 54.93 6.48 11.43
実施例 6
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸4′―フエノキシカルボニルフエニ
ルエステル塩酸塩:
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸塩酸塩22.0g、4―ヒドロキシ安息
香酸フエニルエステル20.0gおよびジシクロヘキ
シルカルボジイミド22.9gをピリジン100ml中に
懸濁させ、室温にて30時間撹拌した。反応混合物
よりピリジンを留去した後、残渣に水を加え、塩
酸酸性として析出した結晶をメタノール500mlで
抽出した。メタノールを留去し、エーテルで処理
して白色結晶を得た。得られた結晶をエタノール
から再結晶してトランス―4―グアニジノメチル
シクロヘキサンカルボン酸4′―フエノキシカルボ
ニルフエニルエステル塩酸塩21.5g(収率53.5
%)を得た。 Melting point 138-147℃ IR νmax (cm -1 ) 1705, 1745 (C=O) NMR δ: CD 3 OD 0.8-3.2 (m, 12H) 3.9 (s, 3H) 7.0-8.1 (m, 4H) Element Analysis C 17 H 35 N 3 O 4・HCl C H N Calculated value (%) 55.21 6.54 11.36 Measured value (%) 54.93 6.48 11.43 Example 6 4'-Phenoxycarbonyl trans-4-guanidinomethylcyclohexanecarboxylate Phenyl ester hydrochloride: 22.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 20.0 g of 4-hydroxybenzoic acid phenyl ester, and 22.9 g of dicyclohexylcarbodiimide were suspended in 100 ml of pyridine and stirred at room temperature for 30 hours. did. After pyridine was distilled off from the reaction mixture, water was added to the residue, acidified with hydrochloric acid, and the precipitated crystals were extracted with 500 ml of methanol. Methanol was distilled off, and white crystals were obtained by treatment with ether. The obtained crystals were recrystallized from ethanol to obtain 21.5 g of trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-phenoxycarbonyl phenyl ester hydrochloride (yield: 53.5
%) was obtained.
融 点 166〜170℃
IR:νmax(cm-1) 1740,1745(C=O)
NMR:δ:CD3OD
0.7〜3.1(m、12H)
7.0〜8.3(m、9H)
元素分析 C22H25N3O4・HClとして
計算値(%)C:61.18 H:6.07 N:9.73
測定値(%)C:61.09 H:6.12 N:9.78
実施例 7
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸4′―ベンジルオキシカルボニルフ
エニルエステル塩酸塩:
トランス―4―グアニジノメチルシクロヘキサ
ンカルボン酸塩酸塩119.4g、4―ヒドロキシ安
息香酸ベンジルエステル115.6gおよびジシクロ
ヘキシルカルボジイミド114.9gをジメチルホル
ムアミド430mlに懸濁させ、室温にて20時間撹拌
した。反応混合物に水1500mlを加え、塩酸500ml
にて酸性とした。得られた結晶をメタノールにて
抽出し、不溶物を別した後、溶媒を留去した。
残渣をメタノール―水から再結晶して、トランス
―4―グアニジノメチルシクロヘキサンカルボン
酸4′―ベンジルオキシカルボニルフエニルエステ
ル塩酸塩148.5g(収率65.8%)を得た。 Melting point 166-170℃ IR: νmax (cm -1 ) 1740, 1745 (C=O) NMR: δ: CD 3 OD 0.7-3.1 (m, 12H) 7.0-8.3 (m, 9H) Elemental analysis C 22 H As 25 N 3 O 4・HCl Calculated value (%) C: 61.18 H: 6.07 N: 9.73 Measured value (%) C: 61.09 H: 6.12 N: 9.78 Example 7 Trans-4-guanidinomethylcyclohexanecarboxylic acid 4' -Benzyloxycarbonyl phenyl ester hydrochloride: 119.4 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 115.6 g of 4-hydroxybenzoic acid benzyl ester and 114.9 g of dicyclohexylcarbodiimide were suspended in 430 ml of dimethylformamide, and the suspension was suspended at room temperature. Stirred for 20 hours. Add 1500ml of water to the reaction mixture and add 500ml of hydrochloric acid.
The mixture was made acidic. The obtained crystals were extracted with methanol, insoluble materials were separated, and then the solvent was distilled off.
The residue was recrystallized from methanol-water to obtain 148.5 g (yield: 65.8%) of trans-4-guanidinomethylcyclohexanecarboxylic acid 4'-benzyloxycarbonylphenyl ester hydrochloride.
融 点 134〜138℃ IR:νmax(cm-1) 1710,1750(C=O) NMR:δCD3OD 0.8〜3.2(m、12H) 5.35(s、2H) 7.2,8.1(d,d,4H) 7.4(s,5H) 元素分析 C23H27N3O4・HClとしての 計算値(%)C:61.95 H:6.33 N:9.42 測定値(%)C:61.47 H:6.18 N:9.53 Melting point 134-138℃ IR: νmax (cm -1 ) 1710, 1750 (C=O) NMR: δCD 3 OD 0.8-3.2 (m, 12H) 5.35 (s, 2H) 7.2, 8.1 (d, d, 4H ) 7.4 (s, 5H) Elemental analysis C 23 H 27 N 3 O 4・HCl Calculated value (%) C: 61.95 H: 6.33 N: 9.42 Measured value (%) C: 61.47 H: 6.18 N: 9.53
Claims (1)
ル基、フエニル基を示し、―COORはメタ位又は
パラ位に置換している] で示される4―グアニジノメチルシクロヘキサン
カルボン酸アリールエステル化合物又はその酸付
加塩。[Claims] 1 formula [In the formula, R represents a hydrogen atom, a lower alkyl group, a benzyl group, or a phenyl group, and -COOR is substituted at the meta or para position] 4-guanidinomethylcyclohexanecarboxylic acid aryl ester compound or its acid Added salt.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9666680A JPS5721360A (en) | 1980-07-14 | 1980-07-14 | Allyl 4-guanidinomethylcyclohexanecarboxylate and its preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9666680A JPS5721360A (en) | 1980-07-14 | 1980-07-14 | Allyl 4-guanidinomethylcyclohexanecarboxylate and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5721360A JPS5721360A (en) | 1982-02-04 |
JPS6338023B2 true JPS6338023B2 (en) | 1988-07-28 |
Family
ID=14171130
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP9666680A Granted JPS5721360A (en) | 1980-07-14 | 1980-07-14 | Allyl 4-guanidinomethylcyclohexanecarboxylate and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5721360A (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69316681T2 (en) * | 1992-08-27 | 1998-05-14 | Shiseido Co Ltd | External composition containing depigmenting agents to be applied to the skin |
WO1996006825A1 (en) | 1994-08-30 | 1996-03-07 | Teikoku Chemical Industries Co., Ltd. | Guanidinomethyl cyclohexane carboxylic ester derivative |
WO1997023207A1 (en) | 1995-12-22 | 1997-07-03 | Teikoku Chemical Industries Co., Ltd. | Anti-helicobacter pylori agent |
-
1980
- 1980-07-14 JP JP9666680A patent/JPS5721360A/en active Granted
Non-Patent Citations (1)
Title |
---|
JOURNAL.OF MEDICINAL.CHEMISTRY=1972 * |
Also Published As
Publication number | Publication date |
---|---|
JPS5721360A (en) | 1982-02-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4278680A (en) | Hypoglycaemically and hypolipidaemically active derivatives of phenylacetic acid | |
USRE29650E (en) | Phthalide penicillin ester intermediates | |
SU865125A3 (en) | Method of preparing imidazole derivatives or thir salts | |
CA1106838A (en) | 6-(2,3-dihydro-5-benzofuranyl) acetamido penicillin derivatives | |
US3468939A (en) | 4- and 5-aryl-1-naphthaleneacetic acid compounds | |
JPS6338023B2 (en) | ||
US4724102A (en) | Optical resolution of racemic mixtures of alpha-naphthylpropionic acids and derivatives of said acids | |
CA1238342A (en) | Omega-/2,4-dihalobiphenylyl/oxo alkanoic acids and a process for their preparation | |
JPS6150941B2 (en) | ||
JPH032134B2 (en) | ||
JPS6332073B2 (en) | ||
JPS6332065B2 (en) | ||
JPS631940B2 (en) | ||
JPH02343B2 (en) | ||
US4568690A (en) | 1-Methyl-5-p-methylbenzoylpyrrole-2-acetamidoacetanilides with antiinflammatory, analgesic, antipyretic and anti-platelet aggregant activity | |
JP2977237B2 (en) | Optical resolution method of dropropidine | |
JPH024588B2 (en) | ||
JPS60152485A (en) | Manufacture of benzothiazine compound | |
JPS6338022B2 (en) | ||
JPS632255B2 (en) | ||
JPH0520425B2 (en) | ||
JPS6324988B2 (en) | ||
JPS6324994B2 (en) | ||
JPS6346743B2 (en) | ||
KR810001695B1 (en) | Process for the preparation of terephthalamide derivatives |