JPH0142936B2 - - Google Patents
Info
- Publication number
- JPH0142936B2 JPH0142936B2 JP55137007A JP13700780A JPH0142936B2 JP H0142936 B2 JPH0142936 B2 JP H0142936B2 JP 55137007 A JP55137007 A JP 55137007A JP 13700780 A JP13700780 A JP 13700780A JP H0142936 B2 JPH0142936 B2 JP H0142936B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- trans
- compound
- carbobenzoxy
- aminomethylcyclohexanecarboxylic
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical class NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 20
- 238000000034 method Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000862 absorption spectrum Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- -1 N-protected amino Chemical group 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- GYDJEQRTZSCIOI-UHFFFAOYSA-N Tranexamic acid Chemical compound NCC1CCC(C(O)=O)CC1 GYDJEQRTZSCIOI-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000002391 anti-complement effect Effects 0.000 description 3
- 108010008730 anticomplement Proteins 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229960003136 leucine Drugs 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 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 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 239000004395 L-leucine Substances 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- BQIVJVAZDJHDJF-LURJTMIESA-N ethyl (2s)-2-amino-3-methylbutanoate Chemical compound CCOC(=O)[C@@H](N)C(C)C BQIVJVAZDJHDJF-LURJTMIESA-N 0.000 description 1
- PQGVTLQEKCJXKF-RGMNGODLSA-N ethyl (2s)-2-amino-3-methylbutanoate;hydron;chloride Chemical compound Cl.CCOC(=O)[C@@H](N)C(C)C PQGVTLQEKCJXKF-RGMNGODLSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-O hydron;1,2-oxazole Chemical compound C=1C=[NH+]OC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-O 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [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
- 230000003287 optical effect Effects 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pyrrole Compounds (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は一般式（）
（式中、R1は水素原子又は低級アルキル基を、
R2は水素原子又は
The present invention is based on the general formula () (In the formula, R 1 is a hydrogen atom or a lower alkyl group,
R 2 is a hydrogen atom or
【式】を意
味する）で表わされる新規なトランス−４−アミ
ノメチルシクロヘキサンカルボン酸誘導体に関す
るものである。
前記一般式（）で表わされる本発明の化合物
は文献未載の新規化合物であり、抗補体作用、制
ガン作用、抗潰瘍作用、抗血栓作用等の薬理作用
を有し、医薬品として産業上有用な化合物であ
る。
前記一般式（）におけるR1の低級アルキル
基について更に具体的に説明すると、R1は炭素
数１〜４からなるメチル、エチル、ｎ−プロピ
ル、イソプロピル、ｎ−ブチル又はイソブチル等
の低級アルキル基を意味する。
本発明の化合物（）はトランス−４−アミノ
メチルシクロヘキサンカルボン酸とアミノ酸誘導
体（ロイシン、グリシン、アラニン、バリン等）
との反応において合成されるものであり、合成さ
れた化合物は光学異性体あるいはラセミ体である
事を問わない。又本発明の化合物（）はナトリ
ウム、カリウム、カルシウム等の無機塩及びモノ
エタノールアミン、ジエタノールアミン、トリエ
タノールアミン等の有機塩に導く事ができる。
アレルギー反応はCoombs and Gellによつて
４つの型に分類されているが、現在まで未だアレ
ルギー反応Type（アルツス型）に由来する全
身性ループスエリトマトーデス（SLE）、糸球体
腎炎、アレルギー性すい臓炎などの疾患を治療す
るすぐれた治療剤は見出されていない。
本発明者等は補体が上記アレルギー反応に関与
している事に着目し、抗補体作用を持つ化合物を
求めて鋭意研究した結果、一般式（）で表わさ
れる化合物がすぐれた抗補体作用を有することを
見出した。又、制ガン作用、抗血栓作用、抗潰瘍
作用等の薬理作用をも有することを見出し、本発
明を完成した。
次に本発明の製造法について説明するがこれは
一例にすぎず、当然他の化学的類似法によつても
製造できるものである。
本発明の目的化合物（）は当業者に一般的に
知られた公知のペプチドの化学合成法によつて容
易に合成することができる。例えば、(A)酸塩化物
法、(B)アジド法、(C)混合酸無水物法、(D)カルボジ
イミド法、(E)活性エステル法、(F)イソオキサゾリ
ウム法等によつて合成できる。
次に本発明の化合物の合成に特に有用な合成法
である(A)〜(C)について更に具体的に説明する。
(A) 酸塩化物法
Ｎ−保護アミノ酸を無溶媒又はベンゼン、エ
ーテル等の有機溶媒中塩化チオニル又は五塩化
リン等の塩化物と反応させＮ−保護アミノ酸塩
化物を合成し、当量の塩基の存在下に水溶液中
トランス−４−アミノメチルシクロヘキサンカ
ルボン酸のアルカリ塩又はテトラヒドロフラン
等の有機溶媒中、ｐ−アミノメチルシクロヘキ
サンカルボン酸エステルと縮合させて合成し、
所望により保護基を除去する。
(B) アジド法
Ｎ−保護アミノ酸エステルをヒドラジンによ
つてヒドラジドとし、これに亜硝酸を作用させ
てアジドとする。このアジドを水溶液中トラン
ス−４−アミノメチルシクロヘキサンカルボン
酸のアルカリ塩と、又は有機溶媒中、トランス
−４−アミノメチルシクロヘキサンカルボン酸
エステルと、反応させ所望により保護基を除去
する。
(C) 混合酸無水物法
Ｎ−保護アミノ酸とクロル炭酸アルキルから
得られる混合酸無水物に塩基の存在下にトラン
ス−４−アミノメチルシクロヘキサンカルボン
酸、又はエステルを０〜−５℃にて反応させ
る。所望によりＮ−保護基を除去する場合に
は、それぞれの保護基に応じた方法によつて除
去することができる。例えば、カルボベンゾキ
シ基及び置換カルボベンゾキシ基類の場合は接
触的水素化又は氷酢酸中の臭化水素によつて除
去できる。又、ｔ−ブチルオキシカルボニル基
は酢酸エチル中塩化水素を作用させて除去し、
トリフルオルアセチル基は温和なアルカリ性の
条件で除去できる。
以下に参考例及び実施例を示し本発明を更に具
体的に説明するが、勿論本発明はこれら実施例中
の化合物のみに限定されるものではない。
参考例 １
Ｌ−バリンエチルエステル塩酸塩14.0ｇをクロ
ロホルム50mlに溶解した溶液にトリエチルアミン
7.8ｇを加え、この溶液に氷冷下撹拌しながら塩
化カルボベンゾキシ13.1ｇとトリエチルアミン
7.8ｇを同時に滴下した。滴下終了後室温で２時
間撹拌し、反応液は酢酸エチルで抽出後水洗い
し、無水硫酸ナトリウムで乾燥した後、減圧下に
溶媒を留去して淡黄色液状のカルボベンゾキシ−
Ｌ−バリンエチルエステル17.3ｇを得た。
この化合物のマススペクトルの親イオン（ｍ／
ｅ）は279を示した。
参考例 ２
Ｌ−ロイシン6.5ｇを2Nの水酸化ナトリウム溶
液25mlに溶解し氷冷下に撹拌しながら塩化カルボ
ベンゾキシ8.5ｇと4N水酸化ナトリウム溶液12.5
ｇを同時に１時間で滴下した。更に室温で2.5時
間撹拌した後60mlのエーテルで抽出した。水層に
濃塩酸を加えてPH２とし分離してきた油状物を
100mlの酢酸エチルで３回抽出し、抽出液を水洗
い後、硫酸マグネシウムで乾燥した。減圧下に溶
媒を留去して無色針状晶のカルボベンゾキシ−Ｌ
−ロイシン12ｇを得た。
この化合物のマススペクトルの親イオン（ｍ／
ｅ）は265を示した。
実施例 １
カルボベンゾキシ−Ｌ−ロイシン2.6ｇをテト
ラヒドロフラン30mlに溶解し氷冷下にかきまぜな
がらトリエチルアミン１ｇを加え更に−10℃にて
クロル炭酸エチル１ｇを滴下した。更に10分間撹
拌後トランス−４−アミノメチルシクロヘキサン
カルボン酸1.6ｇを1Nの水酸化ナトリウム溶液10
mlに溶解した溶液を滴下した。滴下終了後反応液
は更に室温にて10時間撹拌した。反応終了後反応
液に希塩酸を加えてPH２とし酢酸エチルで３回抽
出し水洗い後硫酸マグネシウムで乾燥した。溶媒
を減圧下に留去して得られた化合物をエタノール
から再結晶して白色粉末状のカルボベンゾキシ−
Ｌ−ロイシル−トランス−４−アミノメチルシク
ロヘキサンカルボン酸3.1ｇを得た。
この化合物の融点、赤外吸収スペクトル及びマ
ススペクトルの親イオンｍ／ｅは次の通りであつ
た。
融 点；125〜128℃
赤外線吸収スペクトル；νc＝ｏ
1720〜1680、1650cm-1
マススペクトルの親イオンｍ／ｅ；404
実施例 ２
カルボベンゾキシ−Ｌ−ロイシル−トラスン−
４−アミノメチルシクロヘキサンカルボン酸3.0
ｇを水とメタノール（１：１）の混合溶液100ml
に溶解し、これらにパラジウムカーボン（10％）
を加え撹拌しながら水素ガスを４時間導入した。
更に15時間撹拌した後ろ過し、ろ液を濃縮して得
られた化合物を含水アルコールから再結晶してＬ
−ロイシル−トランス−４−アミノメチルシクロ
ヘキサンカルボン酸2.0ｇを得た。
この化合物の融点、赤外吸収スペクトル及びマ
ススペクトルの親イオンｍ／ｅは次の通りであつ
た。
融 点；190〜192℃
赤外吸収スペクトル；νc＝ｏ 1670、1630cm-1
マススペクトルの親イオンｍ／ｅ；270
実施例１〜２と同様な方法に準じて以下の化合
物を合成した。
Ｌ−グリシル−トランス−４−アミノメチルシク
ロヘキサンカルボン酸
融 点；209〜211℃
赤外吸収スペクトル；νc＝ｏ 1675、1650cm-1
Ｌ−アラニル−トランス−４−アミノメチルシク
ロヘキサンカルボン酸
融 点；226〜228℃
赤外吸収スペクトル；νc＝ｏ 1695、1650cm-1
Ｌ−バリル−トランス−４−アミノメチルシクロ
ヘキサンカリボン酸
融 点；216〜218℃
赤外吸収スペクトル；νc＝ｏ 1670〜1640cm-1
Ｎ−カルボベンゾキシ−Ｌ−アラニル−トランス
−４−アミノメチルシクロヘキサンカルボン酸
融 点；138〜139℃
赤外吸収スペクトル；νc＝ｏ
1710〜1685、1645cm-1
Ｎ−カルボベンゾキシ−Ｌ−バリル−トランス−
４−アミノメチルシクロヘキサンカルボン酸
融 点；160〜162℃
赤外吸収スペクトル；νc＝ｏ
1705〜1680、1645cm-1 The present invention relates to a novel trans-4-aminomethylcyclohexanecarboxylic acid derivative represented by the following formula: The compound of the present invention represented by the general formula () is a new compound that has not been described in any literature, and has pharmacological effects such as anti-complement, anti-cancer, anti-ulcer, and anti-thrombotic effects, and is industrially useful as a pharmaceutical. It is a useful compound. To explain more specifically the lower alkyl group of R 1 in the above general formula (), R 1 is a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. means. The compound () of the present invention is trans-4-aminomethylcyclohexanecarboxylic acid and amino acid derivatives (leucine, glycine, alanine, valine, etc.)
It is synthesized through a reaction with the compound, and the synthesized compound may be an optical isomer or a racemate. Moreover, the compound () of the present invention can be converted into inorganic salts such as sodium, potassium, and calcium, and organic salts such as monoethanolamine, diethanolamine, and triethanolamine. Allergic reactions have been classified into four types by Coombs and Gell, but to date, there are still three types: systemic lupus erythematosus (SLE), glomerulonephritis, and allergic pancreatitis derived from allergic reaction type (Arthus type). No excellent therapeutic agent has been found to treat such diseases. The present inventors focused on the fact that complement is involved in the above-mentioned allergic reactions, and as a result of intensive research in search of compounds with anti-complement action, the present inventors found that a compound represented by the general formula () has an excellent anti-complement action. It was found that it has an effect. They also discovered that it has pharmacological effects such as anticancer, antithrombotic, and antiulcer effects, and completed the present invention. Next, the manufacturing method of the present invention will be explained, but this is only an example, and it is naturally possible to manufacture by other chemically similar methods. The object compound () of the present invention can be easily synthesized by known chemical synthesis methods for peptides generally known to those skilled in the art. For example, by (A) acid chloride method, (B) azide method, (C) mixed acid anhydride method, (D) carbodiimide method, (E) active ester method, (F) isoxazolium method, etc. Can be synthesized. Next, synthetic methods (A) to (C) particularly useful for synthesizing the compounds of the present invention will be explained in more detail. (A) Acid chloride method An N-protected amino acid is reacted with a chloride such as thionyl chloride or phosphorus pentachloride without a solvent or in an organic solvent such as benzene or ether to synthesize an N-protected amino acid chloride. Synthesized by condensation with p-aminomethylcyclohexanecarboxylic acid ester in an aqueous solution in the presence of an alkali salt of trans-4-aminomethylcyclohexanecarboxylic acid or in an organic solvent such as tetrahydrofuran,
Protecting groups are removed if desired. (B) Azide method An N-protected amino acid ester is converted into a hydrazide using hydrazine, and then nitrous acid is reacted on the hydrazide to form an azide. This azide is reacted with an alkali salt of trans-4-aminomethylcyclohexanecarboxylic acid in an aqueous solution or with a trans-4-aminomethylcyclohexanecarboxylic acid ester in an organic solvent to remove the protecting group, if desired. (C) Mixed acid anhydride method A mixed acid anhydride obtained from an N-protected amino acid and an alkyl chlorocarbonate is reacted with trans-4-aminomethylcyclohexanecarboxylic acid or ester at 0 to -5°C in the presence of a base. let When the N-protecting group is removed as desired, it can be removed by a method appropriate for each protecting group. For example, carbobenzoxy groups and substituted carbobenzoxy groups can be removed by catalytic hydrogenation or hydrogen bromide in glacial acetic acid. In addition, the t-butyloxycarbonyl group was removed by the action of hydrogen chloride in ethyl acetate,
The trifluoroacetyl group can be removed under mild alkaline conditions. The present invention will be explained in more detail by referring to Reference Examples and Examples below, but of course the present invention is not limited only to the compounds in these Examples. Reference Example 1 Add triethylamine to a solution of 14.0 g of L-valine ethyl ester hydrochloride dissolved in 50 ml of chloroform.
Add 7.8g of carbobenzoxy chloride and triethylamine to this solution while stirring under ice cooling.
7.8g was added dropwise at the same time. After the addition was completed, the mixture was stirred at room temperature for 2 hours, and the reaction solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow liquid carbobenzoxy-
17.3 g of L-valine ethyl ester was obtained. The parent ion in the mass spectrum of this compound (m/
e) showed 279. Reference example 2 Dissolve 6.5 g of L-leucine in 25 ml of 2N sodium hydroxide solution, and while stirring under ice cooling, add 8.5 g of carbobenzoxy chloride and 12.5 g of 4N sodium hydroxide solution.
g was simultaneously added dropwise over 1 hour. After further stirring at room temperature for 2.5 hours, the mixture was extracted with 60 ml of ether. Add concentrated hydrochloric acid to the aqueous layer to adjust the pH to 2 and remove the separated oily substance.
Extraction was performed three times with 100 ml of ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain colorless needle-like crystals of carbobenzoxy-L.
- Obtained 12 g of leucine. The parent ion in the mass spectrum of this compound (m/
e) showed 265. Example 1 2.6 g of carbobenzoxy-L-leucine was dissolved in 30 ml of tetrahydrofuran, 1 g of triethylamine was added while stirring under ice cooling, and 1 g of ethyl chlorocarbonate was added dropwise at -10°C. After stirring for an additional 10 minutes, 1.6 g of trans-4-aminomethylcyclohexanecarboxylic acid was added to 1N sodium hydroxide solution.
ml solution was added dropwise. After completion of the dropwise addition, the reaction solution was further stirred at room temperature for 10 hours. After the reaction was completed, dilute hydrochloric acid was added to the reaction solution to adjust the pH to 2, followed by extraction three times with ethyl acetate, washing with water, and drying over magnesium sulfate. The compound obtained by distilling off the solvent under reduced pressure was recrystallized from ethanol to form a white powder of carbobenzoxy-
3.1 g of L-leucyl-trans-4-aminomethylcyclohexanecarboxylic acid was obtained. The melting point, infrared absorption spectrum, and mass spectrum parent ion m/e of this compound were as follows. Melting point: 125-128°C Infrared absorption spectrum: νc = o 1720-1680, 1650 cm -1 Parent ion m/e of mass spectrum: 404 Example 2 Carbobenzoxy-L-leucyl-trasne-
4-aminomethylcyclohexanecarboxylic acid 3.0
g to 100ml of a mixed solution of water and methanol (1:1)
Palladium on carbon (10%) dissolved in these
was added and hydrogen gas was introduced for 4 hours while stirring.
After stirring for an additional 15 hours, the compound was filtered, the filtrate was concentrated, and the resulting compound was recrystallized from hydroalcohol.
2.0 g of -leucyl-trans-4-aminomethylcyclohexanecarboxylic acid was obtained. The melting point, infrared absorption spectrum, and mass spectrum parent ion m/e of this compound were as follows. Melting point: 190-192°C Infrared absorption spectrum: νc=o 1670, 1630 cm -1 Parent ion m/e of mass spectrum: 270 The following compounds were synthesized according to the same method as in Examples 1 and 2. L-Glycyl-trans-4-aminomethylcyclohexanecarboxylic acid Melting point: 209-211°C Infrared absorption spectrum: νc=o 1675, 1650cm -1 L-Alanyl-trans-4-aminomethylcyclohexanecarboxylic acid Melting point: 226 ～228℃ Infrared absorption spectrum; νc=o 1695, 1650cm -1 L-valyl-trans-4-aminomethylcyclohexanecaribonic acid Melting point: 216～218℃ Infrared absorption spectrum; νc=o 1670～1640cm -1 N-carbobenzoxy-L-alanyl-trans-4-aminomethylcyclohexanecarboxylic acid Melting point: 138-139°C Infrared absorption spectrum: νc=o 1710-1685, 1645 cm -1 N-carbobenzoxy-L-valyl -Trans-
4-Aminomethylcyclohexanecarboxylic acid Melting point: 160-162℃ Infrared absorption spectrum: νc=o 1705-1680, 1645cm -1
Claims (1)
R2は水素原子又は【式】を意 味する）で表わされるトランス−４−アミノメチ
ルシクロヘキサンカルボン酸誘導体。[Claims] 1. General formula (In the formula, R 1 is a hydrogen atom or a lower alkyl group,
R 2 is a hydrogen atom or a trans-4-aminomethylcyclohexanecarboxylic acid derivative represented by [Formula].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55137007A JPS5759844A (en) | 1980-09-29 | 1980-09-29 | Trans-4-aminomethylcyclohexanecarboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP55137007A JPS5759844A (en) | 1980-09-29 | 1980-09-29 | Trans-4-aminomethylcyclohexanecarboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5759844A JPS5759844A (en) | 1982-04-10 |
| JPH0142936B2 true JPH0142936B2 (en) | 1989-09-18 |
Family
ID=15188621
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP55137007A Granted JPS5759844A (en) | 1980-09-29 | 1980-09-29 | Trans-4-aminomethylcyclohexanecarboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5759844A (en) |
-
1980
- 1980-09-29 JP JP55137007A patent/JPS5759844A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5759844A (en) | 1982-04-10 |
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