JPH0338265B2 - - Google Patents
Info
- Publication number
- JPH0338265B2 JPH0338265B2 JP56010832A JP1083281A JPH0338265B2 JP H0338265 B2 JPH0338265 B2 JP H0338265B2 JP 56010832 A JP56010832 A JP 56010832A JP 1083281 A JP1083281 A JP 1083281A JP H0338265 B2 JPH0338265 B2 JP H0338265B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- guanidinomethylcyclohexanecarboxylic
- general formula
- compound
- 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 - Lifetime
Links
- 239000002253 acid Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- JBRMEFWJFBHUKG-UHFFFAOYSA-N 4-[(diaminomethylideneamino)methyl]cyclohexane-1-carboxylic acid Chemical compound NC(N)=NCC1CCC(C(O)=O)CC1 JBRMEFWJFBHUKG-UHFFFAOYSA-N 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 11
- -1 4-guanidinomethylcyclohexanecarboxylic acid compound Chemical class 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 108091005804 Peptidases Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 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 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- KUFFULVDNCHOFZ-UHFFFAOYSA-N 2,4-xylenol Chemical compound CC1=CC=C(O)C(C)=C1 KUFFULVDNCHOFZ-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
- MNVMYTVDDOXZLS-UHFFFAOYSA-N 4-methoxyguaiacol Natural products COC1=CC=C(O)C(OC)=C1 MNVMYTVDDOXZLS-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-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
- 239000002841 Lewis acid Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 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
- 239000005844 Thymol Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- ZXPNHQOWDWPUEH-UHFFFAOYSA-N boric acid;sulfuric acid Chemical compound OB(O)O.OS(O)(=O)=O ZXPNHQOWDWPUEH-UHFFFAOYSA-N 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ANFZRGMDGDYNGA-UHFFFAOYSA-N ethyl acetate;propan-2-ol Chemical compound CC(C)O.CCOC(C)=O ANFZRGMDGDYNGA-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000007517 lewis acids Chemical class 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
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は新規なカルボン酸エステル類およびそ
の酸付加塩ならびにその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel carboxylic acid esters and acid addition salts thereof and processes for their production.
４−グアニジノメチルシクロヘキサンカルボン
酸はほとんど抗プラスミン作用を示さないことは
知られている〔Ａ、Okanoet al.、J.Med.
Chem.、Vol.15、No.3247（1972）〕。そして、その
エステル類に関しては全く文献に記載されていな
い。 It is known that 4-guanidinomethylcyclohexanecarboxylic acid shows almost no antiplasmin effect [A, Okano et al., J. Med.
Chem., Vol.15, No.3247 (1972)]. The esters are not described at all in the literature.
本発明者らは、４−グアニジノメチルシクロヘ
キサンカルボン酸系化合物を合成し、その薬理作
用を検討していたところ、意外にも次の一般式
（）
（式中、R1およびR2は、それぞれ独立に炭素数
１〜４個のアルキル基を示す）
で表わされる新規なカルボン酸エステル類および
その酸付加塩が優れた蛋白分解酵素阻害作用を有
することを身いだし本発明を完成した。 The present inventors synthesized a 4-guanidinomethylcyclohexanecarboxylic acid compound and investigated its pharmacological action, and unexpectedly found the following general formula () (In the formula, R 1 and R 2 each independently represent an alkyl group having 1 to 4 carbon atoms) Novel carboxylic acid esters and acid addition salts thereof have excellent protease inhibitory effects. After learning this, he completed the present invention.
従つて、本発明の目的は優れた蛋白分解酵素阻
害作用を有する上記一般式（）で表わされる新
規化合物を提供することにある。 Therefore, an object of the present invention is to provide a novel compound represented by the above general formula () having an excellent protease inhibitory effect.
他の目的は、一般式（）で表わされる化合物
を製造するための方法を提供することにある。 Another object is to provide a method for producing a compound represented by the general formula ().
一般式（）の本発明化合物中でいう炭素数１
〜４個のアルキル基としては、メチル基、エチル
基、プロピル基、イソプロピル基、ブチル基、ｔ
−ブチル基等があげられる。酸付加塩としては、
塩酸、硫酸、リン酸、臭化水素酸、酢酸、乳酸、
マレイン酸、フマル酸、酒石酸、クエン酸、メタ
ンスルホン酸、ｐ−トルエンスルホン酸などとの
酸付加塩があげられる。また、本発明化合物に
は、シスおよびトランス異性体が存在するが、ト
ランス体が特に好ましい。 The number of carbon atoms in the compound of the present invention of general formula () is 1
~4 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t
-butyl group, etc. As an acid addition salt,
Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid,
Examples include acid addition salts with maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. Furthermore, the compound of the present invention has cis and trans isomers, but the trans isomer is particularly preferred.
本発明の一般式（）の新規なカルボン酸エス
テル類およびその酸付加塩は、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
誘導体に次の式（）
（式中、R1およびR2は前記と同じ）
で表わされる化合物を反応させ、所望により生成
物を酸付加塩に変換せしめることにより製造され
る。 The novel carboxylic acid esters of the general formula () and acid addition salts thereof of the present invention can be obtained by adding 4-guanidinomethylcyclohexanecarboxylic acid or a reactive derivative thereof to the following formula (): (In the formula, R 1 and R 2 are the same as above.) It is produced by reacting a compound represented by the following and optionally converting the product into an acid addition salt.
４−グアニジノメチルシクロヘキサンカルボン
酸の反応性誘導体としては、酸クロライド、酸プ
ロマイド等の酸ハライド、クロル蟻酸エチルエス
テル、クロル蟻酸ブチルエステルなどとの混合酸
無水物などがあげられる。反応は温度〜還流温度
で１時間〜20日間撹拌することにより進められ
る。ここで用いられる溶媒としてはジメチルホル
ムアミド、ジメチルアセトアミド、ビリジン、ジ
クロルメタン、ジクロルエタン、クロロホルム、
アセトニトリルなどがあげられる。反応の進行に
つれて生成する酸を不活性にするためにトリエチ
ルアミン、ジメチルアニリンなどの三級アミンを
共存させると好都合である。 Examples of reactive derivatives of 4-guanidinomethylcyclohexanecarboxylic acid include acid halides such as acid chloride and acid bromide, and mixed acid anhydrides with ethyl chloroformate, butyl chloroformate, and the like. The reaction is carried out by stirring for 1 hour to 20 days at temperatures between reflux and reflux. The solvents used here include dimethylformamide, dimethylacetamide, pyridine, dichloromethane, dichloroethane, chloroform,
Examples include acetonitrile. It is advantageous to coexist a tertiary amine such as triethylamine or dimethylaniline in order to inactivate the acid generated as the reaction progresses.
次に４−グアニジノメチルシクロヘキサンカル
ボン酸をカルボキシル基遊離のままで反応させる
場合には、ジシクロヘキシルカルボジイミドなど
のカルボジイミド類、オキシ塩化燐、三弗化ホウ
素などのルイス酸あるいは硫酸−ホウ酸などを縮
合剤として用いると好適である。反応は室温〜還
流温度で行なわれ、用いられる溶媒としては上記
のもののほかにトルエン、キシレン、ジメチルス
ルホキシドまたはこれらの混合物があげられる。 Next, when reacting 4-guanidinomethylcyclohexanecarboxylic acid with the carboxyl group free, carbodiimides such as dicyclohexylcarbodiimide, Lewis acids such as phosphorous oxychloride, boron trifluoride, or sulfuric acid-boric acid are used as condensing agents. It is suitable to use it as The reaction is carried out at room temperature to reflux temperature, and solvents used include toluene, xylene, dimethyl sulfoxide, or mixtures thereof in addition to those mentioned above.
また、一般式（）の本発明化合物は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
の酸付加塩に、式（）の化合物に塩化チオニル
を反応させて得られるスルフアイト化合物を反応
させることによつても製造される。 The compound of the present invention of general formula () can also be produced by reacting 4-guanidinomethylcyclohexanecarboxylic acid or its acid addition salt with a sulfite compound obtained by reacting the compound of formula () with thionyl chloride. be done.
以上の如くして得られた一般式（）の化合物
は、所望により反応化合物より常法により前記し
た塩の形で単離できる。また、生成物の単離後に
塩の形に変換してもよい。 The compound of general formula () obtained as described above can be isolated in the form of the above-mentioned salt from the reaction compound by a conventional method, if desired. It is also possible to convert the product into a salt form after isolation.
一般式（）の本発明化合物は優れた蛋白分解
酵素阻害作用を有する。すなわち、蛋白分解酵素
阻害作用は種々の蛋白分解酵素の対応する合成基
質を水解する能力をいかに本発明化合物が阻害す
るかを測定することにより行つた。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2′−イソプロピル−5′−メチルフエニルエ
ステル塩酸塩はカリクレインに対して3.2×
10-4Mの濃度で50％阻害した。（基質：Ｎ−ペン
ゾイルアルギニンエチルエステル）
次に実施例を挙げて本発明を詳細に説明する。 The compound of the present invention represented by the general formula () has an excellent protease inhibitory effect. That is, the protease inhibitory effect was determined by measuring how well the compounds of the present invention inhibit the ability of various proteases to hydrolyze the corresponding synthetic substrates. For example, trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-isopropyl-5'-methylphenyl ester hydrochloride has a 3.2x
A concentration of 10 -4 M inhibited 50%. (Substrate: N-penzoylarginine ethyl ester) Next, the present invention will be explained in detail with reference to Examples.
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2′−イソプロピル−5′−メチルフ
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10.0ｇ、チモール6.4ｇおよ
びジシクロヘキシルカルボジイミド8.75ｇを無水
ピリジン100mlに懸濁させ、室温で36時間撹拌し
た。不要物を別後、液を減圧下に溶媒留去し
た。残渣に氷冷下に0.1N塩酸200mlを加え室温で
12時間撹拌した。析出した結晶を別後、液に
少量の水を加えて放置すると白色結晶が析出し
た。これを、メタノールに溶解し、不溶分を別
後、液より溶媒留去し、残渣に水を加えて白色
結晶を得た。これを水−メタノールより再結晶し
て融点158〜160℃の無色針状晶としてトランス−
４−グアニジノメチルシクロヘキサンカルボン酸
2′−イソプロピル−5′−メチルフエニルエステル
塩酸塩6.0ｇを得た。Example 1 Trans-4-guanidinomethylcyclohexanecarboxylic acid 2'-isopropyl-5'-methylphenyl ester hydrochloride: 10.0 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6.4 g of thymol and 8.75 g of dicyclohexylcarbodiimide. The suspension was suspended in 100 ml of anhydrous pyridine and stirred at room temperature for 36 hours. After removing unnecessary materials, the solvent was distilled off under reduced pressure. Add 200ml of 0.1N hydrochloric acid to the residue under ice-cooling and stir at room temperature.
Stirred for 12 hours. After separating the precipitated crystals, a small amount of water was added to the liquid and when it was left to stand, white crystals were precipitated. This was dissolved in methanol, and after separating the insoluble matter, the solvent was distilled off from the liquid, and water was added to the residue to obtain white crystals. This was recrystallized from water-methanol to form colorless needle crystals with a melting point of 158-160°C.
4-guanidinomethylcyclohexanecarboxylic acid
6.0 g of 2'-isopropyl-5'-methylphenyl ester hydrochloride was obtained.
TRνKBr naxcm-1：1730（Ｃ＝Ｏ）
NMR（CD3OD）δ：1.15（6H、ｄ、CH（ＣＨ 3）2）
0.91〜2.36（10H、ｍ、シクロヘキサン水素）
2.27（3H、ｓ、ＣＨ 3）
2.95（1H、ｍ、ＣＨ（CH3）2）
3.05（2H、ｄ、ＣＨ 2N）
6.67〜7.24（3H、ｍ、芳香族水素）
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2′，4′−ジメチルフエニルエステ
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5.9ｇ、ジシクロヘキシルカ
ルボジイミド6.18ｇおよび２，４−ジメチルフエ
ノール3.66ｇを無水ピリジン100mlに懸濁させ、
30℃にて４日間撹拌した。不溶物を別後、液
を減圧下に濃縮した。残渣をエーテルおよび酢酸
エチルにて洗浄後、ベンゼンを加えて撹拌して結
晶を析出させた。得られた結晶をイソプロパノー
ル−酢酸エチルより再結晶して融点151〜153℃の
無色結晶としてトランス−４−グアニジノメチル
シクロヘキサンカルボン酸2′，4′−ジメチルフエ
ニルエステル塩酸塩6.22ｇ（収率73％）を得た。TRν KBr nax cm -1 : 1730 (C=O) NMR (CD 3 OD) δ: 1.15 (6H, d, CH( CH 3 ) 2 ) 0.91-2.36 (10H, m, cyclohexane hydrogen) 2.27 (3H, s, CH 3 ) 2.95 (1H, m, CH (CH 3 ) 2 ) 3.05 (2H, d, CH 2 N) 6.67-7.24 (3H, m, aromatic hydrogen) Example 2 Trans-4- Guanidinomethylcyclohexanecarboxylic acid 2',4'-dimethylphenyl ester hydrochloride: 5.9 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 6.18 g of dicyclohexylcarbodiimide and 3.66 g of 2,4-dimethylphenol in 100 ml of anhydrous pyridine. suspend,
The mixture was stirred at 30°C for 4 days. After separating the insoluble matter, the liquid was concentrated under reduced pressure. After washing the residue with ether and ethyl acetate, benzene was added and stirred to precipitate crystals. The obtained crystals were recrystallized from isopropanol-ethyl acetate to give 6.22 g of trans-4-guanidinomethylcyclohexanecarboxylic acid 2',4'-dimethylphenyl ester hydrochloride (yield 73 %) was obtained.
IRνKBr naxcm-1：1745（Ｃ＝Ｏ）IRν KBr nax cm -1 : 1745 (C=O)
Claims (1)
１〜４個のアルキル基を示す） で表わされる新規なカルボン酸エステル類および
その酸付加塩。 ２ 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、R1およびR2は、それぞれ独立に炭素数
１〜４個のアルキル基を示す） で表わされる化合物を反応させ、所望により生成
物を酸付加塩に変換せしめることを特徴とする、 一般式 （式中、R1およびR2は、前記と同じ） で表わされる新規なカルボン酸エステル類および
その酸付加塩の製造法。[Claims] 1. General formula (In the formula, R 1 and R 2 each independently represent an alkyl group having 1 to 4 carbon atoms.) Novel carboxylic acid esters and acid addition salts thereof. 2 4-guanidinomethylcyclohexanecarboxylic acid or its reactive derivative with the formula (In the formula, R 1 and R 2 each independently represent an alkyl group having 1 to 4 carbon atoms) is reacted, and the product is optionally converted into an acid addition salt. , general formula (In the formula, R 1 and R 2 are the same as above.) A method for producing a novel carboxylic acid ester and an acid addition salt thereof.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1083281A JPS57126463A (en) | 1981-01-29 | 1981-01-29 | Novel carboxylic ester and its preparation |
| US06/336,707 US4465851A (en) | 1981-01-22 | 1982-01-04 | Guanidinocyclohexanecarboxylic acid derivatives |
| NL8200110A NL8200110A (en) | 1981-01-22 | 1982-01-13 | NEW COMPOUNDS WITH ANTI-ALLERGENIC EFFECTS, PROCESS FOR THEIR PREPARATION AND PREPARATIONS CONTAINING THEM. |
| BR8200212A BR8200212A (en) | 1981-01-22 | 1982-01-13 | PROCESS FOR THE PREPARATION OF GUANIDINOCICLOHEXANOCARBOXYLIC ACID AND ITS DERIVATIVES |
| BE0/207062A BE891790A (en) | 1981-01-22 | 1982-01-15 | NOVEL GUANIDINOCYCLOHEXANE-CARBOXYLIC ACID DERIVATIVES AND THEIR PRODUCTION METHOD |
| GB8201092A GB2093835B (en) | 1981-01-22 | 1982-01-15 | Novel guanidinocyclohexanecarboxylic acid derivatives and a process for producing the same |
| CA000394507A CA1180716A (en) | 1981-01-22 | 1982-01-20 | Guanidinocyclohexanecarboxylic acid derivatives and process for producing the same |
| SE8200309A SE455789B (en) | 1981-01-22 | 1982-01-20 | GUANIDINOCYCLOHEXANCHARBOXYLIC ACID DERIVATIVES IN TRANSFORM AND A PROCEDURE FOR PREPARING THEREOF |
| DE19823201817 DE3201817A1 (en) | 1981-01-22 | 1982-01-21 | NEW GUANIDINOCYCLOHEXANCARBONSAE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM |
| IT67060/82A IT1191163B (en) | 1981-01-22 | 1982-01-21 | DERIVATIVES OF GUANIDINO ACID CYCLEHEXARBOXYL AND PROCEDURE FOR THEIR PRODUCTION |
| CH380/82A CH652119A5 (en) | 1981-01-22 | 1982-01-21 | DERIVATIVES OF GUANIDINOCYCLOHEXANECARBOXYLIC ACID AND THEIR MANUFACTURING PROCESS. |
| FR8201032A FR2498183A1 (en) | 1981-01-22 | 1982-01-22 | NOVEL GUANIDINOCYCLOHEXANECARBOXYLIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC USE THEREOF |
| KR8200269A KR880001104B1 (en) | 1981-01-22 | 1982-01-22 | Process for the preparation of guanidino cyclohexane carboxic acid derivation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1083281A JPS57126463A (en) | 1981-01-29 | 1981-01-29 | Novel carboxylic ester and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS57126463A JPS57126463A (en) | 1982-08-06 |
| JPH0338265B2 true JPH0338265B2 (en) | 1991-06-10 |
Family
ID=11761323
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1083281A Granted JPS57126463A (en) | 1981-01-22 | 1981-01-29 | Novel carboxylic ester and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS57126463A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69535475T2 (en) | 1994-08-30 | 2008-01-03 | Nagase Chemtex Corp. | Guanidinomethylcyclohexanecarboxylic acid ester derivatives |
| AU1171697A (en) | 1995-12-22 | 1997-07-17 | Teikoku Chemical Industries Co., Ltd. | Anti helicobacter pylori agent |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5692261A (en) * | 1979-12-26 | 1981-07-25 | Nippon Chemiphar Co Ltd | Novel cyclohexanecarboxylic derivative and its preparation |
-
1981
- 1981-01-29 JP JP1083281A patent/JPS57126463A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5692261A (en) * | 1979-12-26 | 1981-07-25 | Nippon Chemiphar Co Ltd | Novel cyclohexanecarboxylic derivative and its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS57126463A (en) | 1982-08-06 |
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