JPH0325437B2 - - Google Patents
Info
- Publication number
- JPH0325437B2 JPH0325437B2 JP56172658A JP17265881A JPH0325437B2 JP H0325437 B2 JPH0325437 B2 JP H0325437B2 JP 56172658 A JP56172658 A JP 56172658A JP 17265881 A JP17265881 A JP 17265881A JP H0325437 B2 JPH0325437 B2 JP H0325437B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- reaction
- acid
- lys
- salts
- 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
- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 n-octanoyl Chemical group 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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 3
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 208000035473 Communicable disease Diseases 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 230000003449 preventive effect Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PPQNQXQZIWHJRB-UHFFFAOYSA-N Methylcholanthrene Chemical compound C1=CC=C2C3=CC4=CC=C(C)C(CC5)=C4C5=C3C=CC2=C1 PPQNQXQZIWHJRB-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-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
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 125000001288 lysyl group Chemical group 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000013077 target material Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000006150 trypticase soy agar Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Description
本発明は新規なペプチド化合物に関するもので
あり、詳細には薬理活性を有する新規ペプチド化
合物若しくはその医薬として許容される塩、該化
合物の製造法および該化合物を含有する医薬組成
物に関するものである。
本発明者等は、これ迄にも数多くのペプチド化
合物の合成に成功し、多くの国で特許出願を完了
している(例えば、特願昭55−106279号)。
その後、本発明者等は更に研究の結果、上記出
願明細書には具体的の開示のない新規な化合物を
合成することに成功し、それらの化合物がすぐれ
た実験的感染症の予防効果並びに抗癌作用を有す
ることを見出し、この発明を完成した。
本発明の新規ペプチド化合物は次式()で示
される。
(式中R1はn−オクタノイルまたはステアロ
イル、R2は水素またはベンジル、R3は1−カル
ボキシエチルアミノ、R4は水素、R5は水素また
はベンジルオキシカルボニルをそれぞれ意味す
る)
一般式()で示される新規ペプチド化合物に
おける医薬として許容される塩としては、例えば
アルカリ金属塩(例えば、ナトリウム塩、カリウ
ム塩等)、アルカリ土類金属塩(例えば、カルシ
ウム塩等)、アンモニウム塩、有機アミン塩、(例
えば、エタノールアミン塩、トリエチルアミン
塩、ジシクロヘキシルアミン塩等)等の様な無機
或いは有機塩基との塩、メタンスルホン酸塩、塩
酸塩、硫酸塩、硝酸塩、燐酸塩等の有機或いは無
機酸との酸付加塩等が挙げられる。
本発明の新規ペプチド化合物()は以下に詳
述する様々な方法で合成することができる。
() ペプチド結合形成反応:
() 保護基の脱離反応:
(式中R1はn−オクタノイルまたはステアロ
イル、R3は1−カルボキシエチルアミノをそれ
ぞれ意味する)
[] ペプチド結合形成反応[(1)〜(2)]:
この反応は下記の様に行うことができる。即
ち、まず各カルボキシ化合物若しくはその塩のカ
ルボキシ基を、常法により例えば酸ハロゲン化
物、酸アジド、酸無水物若しくは混合酸無水物、
活性エステル等の活性体にし、次いで、各アミノ
化合物と反応させることによつて目的化合物を合
成することができ、また各カルボキシ化合物若し
くはその塩と各アミノ化合物若しくはその塩を通
常使用される縮合剤例えばN,N−ジシクロヘキ
シルカルボジイミド等の存在下に直接反応させる
ことによつても目的化合物を合成することができ
る。
上記活性化方法のうち、好適な活性化方法及び
好適な縮合剤は、各カルボキシ化合物のカルボキ
シ保護基や各アミノ化合物の種類及び反応条件
(例えば反応溶媒、温度等)に応じて適宜選択さ
れる。
この反応は、塩化メチレン、クロロホルム、テ
トラヒドロフラン、ジオキサン、酢酸エチル、メ
タノール、エタノール、水等の溶媒中において、
−20℃から室温の範囲で円滑に進行する。又縮合
剤存在下の反応は通常無水条件下緩和な条件で行
なわれる。
[] 保護基の脱離反応:
この反応は、化合物(a)若しくはその塩を
アミノ及び/又はカルボキシ保護基の脱離反応に
付すことによつて、化合物(b)若しくはその
塩を合成する方法である。
[−1] アミノ保護基の脱離反応:
この反応は接触還元のような還元方法、液体ア
ンモニアアルカリ金属法、酸を用いる方法、酸亜
鉛法、塩基を用いる方法、ヒドラジン法等の通常
の方法によつて行なわれる。又反応温度は通常冷
却乃至室温程度で行われる。
[−2] カルボキシ保護基の脱離反応:
この反応は加水分解や還元等の通常の方法で行
なわれる。加水分解は通常溶媒中において、酸若
しくは塩基の存在下、冷却乃至加温の様な比較的
緩和な条件で円滑に進行する。還元は化学的還元
及び接触還元を含み、常法に従つて行なわれる。
反応は冷却乃至加温の様な比較的緩和な条件下で
通常溶媒中で行われる。
この発明で使用する出発化合物は既知化合物
(例えばヨーロツパ特許公開公報No.11283)や新規
化合物が含まれ、又該新規化合物は前述と同様の
方法で合成することができる。
この発明の目的化合物[]及び出発化合物は
分子内の不斉炭素原子による異性体を1又は2以
上含んでおり、この様な異性体も全て本発明の範
囲に含まれる。
本発明によつて提供される新規ペプチド化合物
()およびその医薬として許容される塩は、実
験的感染症に対する防ぎよ効果と抗癌作用を有す
ることが明らかになつた。
従つて新規ペプチド化合物()およびその医
薬として許容される塩は、病原微生物殊にグラム
陰性菌、グラム陽性菌およびかびによる感染症の
治療や人間及び各種動物の癌の治療に有用な物質
である。
新規ペプチド()の医薬としての有用性を示
す為に薬理データを以下の通り説明する。
マウスにおける実験的感染症に対する防ぎよ効
果:
マウスにおける実験的感染症の防ぎよ効果を知
る目的で、試験化合物を生理食塩水に溶解、希釈
し、夫々規定濃度の試験液を調製した。
雄のICR−系マウス(4周令)を10匹単位で1
群とした。トリプチケース・ソーイ寒天培地上で
大腸菌22を37℃で1夜培養し、生理食塩水に懸濁
させて2.6×109CFU/mlの微生物細胞濃度を有す
る懸濁液を得た。マウスに対して1匹当り8.7×
107CFUの菌体を腹腔内に投与した。尚、試験化
合物については、1群の10匹のマウスに対して、
予め4日間種々の量を腹腔内投与しておいた。菌
体投与後3日目の生存動物数から生存率を求め、
表に記載した。
The present invention relates to a novel peptide compound, and in particular to a novel peptide compound having pharmacological activity or a pharmaceutically acceptable salt thereof, a method for producing the compound, and a pharmaceutical composition containing the compound. The present inventors have so far succeeded in synthesizing many peptide compounds and have completed patent applications in many countries (for example, Japanese Patent Application No. 106279/1982). Subsequently, as a result of further research, the present inventors succeeded in synthesizing new compounds, which are not specifically disclosed in the above application specification, and found that these compounds had excellent preventive effects and anti-inflammatory effects on experimental infectious diseases. They discovered that it has a cancer effect and completed this invention. The novel peptide compound of the present invention is represented by the following formula (). (In the formula, R 1 means n-octanoyl or stearoyl, R 2 means hydrogen or benzyl, R 3 means 1-carboxyethylamino, R 4 means hydrogen, and R 5 means hydrogen or benzyloxycarbonyl.) General formula () Pharmaceutically acceptable salts of the novel peptide compound represented by include, for example, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, etc.), ammonium salts, and organic amine salts. (e.g., ethanolamine salt, triethylamine salt, dicyclohexylamine salt, etc.), with organic or inorganic acids such as methanesulfonate, hydrochloride, sulfate, nitrate, phosphate, etc. Examples include acid addition salts of. The novel peptide compounds () of the present invention can be synthesized by various methods detailed below. () Peptide bond formation reaction: () Protecting group elimination reaction: (In the formula, R 1 means n-octanoyl or stearoyl, and R 3 means 1-carboxyethylamino.) [] Peptide bond formation reaction [(1) to (2)]: This reaction is performed as follows. Can be done. That is, first, the carboxy group of each carboxy compound or its salt is converted into, for example, an acid halide, an acid azide, an acid anhydride, or a mixed acid anhydride, by a conventional method.
The target compound can be synthesized by converting it into an activated form such as an active ester and then reacting it with each amino compound, and also by combining each carboxy compound or its salt with each amino compound or its salt using a commonly used condensing agent. For example, the target compound can also be synthesized by direct reaction in the presence of N,N-dicyclohexylcarbodiimide or the like. Among the above activation methods, a suitable activation method and a suitable condensing agent are appropriately selected depending on the carboxy protecting group of each carboxy compound, the type of each amino compound, and reaction conditions (e.g. reaction solvent, temperature, etc.) . This reaction is carried out in a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane, ethyl acetate, methanol, ethanol, or water.
Proceeds smoothly at temperatures ranging from -20°C to room temperature. The reaction in the presence of a condensing agent is usually carried out under mild conditions under anhydrous conditions. [] Protecting group elimination reaction: This reaction is a method for synthesizing compound ( b ) or its salt by subjecting compound ( a ) or its salt to amino and/or carboxy protecting group elimination reaction. It is. [-1] Elimination reaction of amino protecting group: This reaction can be carried out by conventional methods such as reduction methods such as catalytic reduction, liquid ammonia alkali metal method, method using acid, zinc acid method, method using base, hydrazine method, etc. It is carried out by. The reaction temperature is usually about cooling to room temperature. [-2] Carboxy protecting group elimination reaction: This reaction is carried out by a conventional method such as hydrolysis or reduction. Hydrolysis normally proceeds smoothly in a solvent, in the presence of an acid or a base, and under relatively mild conditions such as cooling or heating. Reduction includes chemical reduction and catalytic reduction, and is carried out according to conventional methods.
The reaction is usually carried out in a solvent under relatively mild conditions such as cooling or heating. The starting compounds used in this invention include known compounds (for example, European Patent Publication No. 11283) and new compounds, and the new compounds can be synthesized by the same method as described above. The object compound [] and the starting compound of this invention contain one or more isomers due to asymmetric carbon atoms in the molecule, and all such isomers are also included in the scope of the invention. It has been revealed that the novel peptide compound () and its pharmaceutically acceptable salts provided by the present invention have preventive effects against experimental infectious diseases and anticancer effects. Therefore, the novel peptide compound () and its pharmaceutically acceptable salts are useful substances for the treatment of infectious diseases caused by pathogenic microorganisms, especially gram-negative bacteria, gram-positive bacteria, and fungi, and for the treatment of cancer in humans and various animals. . Pharmacological data will be explained below to demonstrate the usefulness of the novel peptide () as a medicine. Preventive effect against experimental infectious diseases in mice: For the purpose of determining the preventive effects against experimental infectious diseases in mice, test compounds were dissolved and diluted in physiological saline to prepare test solutions at specified concentrations. 10 male ICR mice (4 weeks old)
grouped. E. coli 22 was cultured on Trypticase Soy agar medium at 37° C. overnight and suspended in physiological saline to obtain a suspension having a microbial cell concentration of 2.6×10 9 CFU/ml. 8.7× per mouse
10 7 CFU of bacterial cells were administered intraperitoneally. In addition, regarding the test compound, for 10 mice in one group,
Various doses were previously administered intraperitoneally for 4 days. The survival rate was determined from the number of surviving animals on the 3rd day after the administration of the bacterial cells.
It is listed in the table.
【表】
抗癌作用:
(1) メチルコランスレン誘発による線維肉腫細胞
(Meth−A)を用いた。
BALB/Cマウスの胸腔内へMethA腫瘍細胞
を移植した。試験化合物はMethA移植の14日前、
移植1時間後および3日後の3回、胸腔内へ投与
した。試験化合物の抗癌作用はMethA移植マウ
スの延命を指標にして調べた。
結果は次表の通りである。[Table] Anticancer effect: (1) Methylcholanthrene-induced fibrosarcoma cells (Meth-A) were used. MethA tumor cells were transplanted into the thoracic cavity of BALB/C mice. Test compounds were administered 14 days before MethA implantation;
It was administered intrathoracically three times, 1 hour and 3 days after transplantation. The anticancer effect of the test compound was investigated using survival prolongation of MethA-implanted mice as an indicator. The results are shown in the table below.
【表】
本発明の医薬用組成物は、種々の医薬用製剤、
例えば、固形薬剤、半固形薬剤、液剤として提供
され、これらは外用、内服又は局所適用に好適な
有機若しくは無機の担体や賦形剤と本発明の活性
物質を含むものである。そして活性成分は、錠
剤、ペレツト、カプセル剤、坐剤、液剤、乳剤、
懸濁剤或いはその他適切な形態を形成する為の無
害で且つ医薬として受け入れ得る様な補助成分と
配合して利用される。この様な補助成分として
は、固形製剤、半固形製剤或いは液剤等の製造に
おいて効果的に使用される成分、例えば水、グル
コース、ラクトース、ゼラチン、マンニトール、
でんぷん糊、3珪酸マグネシウム、コーンスター
チ、ケラチン、コロイダルシリカ、ポテトスター
チ、尿素等が例示され、更に補助的に安定剤、増
量剤、着色剤、香料等を配合することもできる。
又本発明の医薬組成物には、活性成分の活性度を
保持する為に防腐剤や殺菌剤を配合することもで
きる。又該組成物中の活性成分配合量は、疾病の
進行度や状況に対して望ましい治療効果を発揮す
るに十分な量の活性成分を含ませるものとする。
本組成物を人体へ適用するに当つては、静脈内
投与、筋肉内投与或いは経口投与等が望まれる。
又本発明目的物質の有効投与量は対象患者の年令
が症状によつて変るが通常、人間或いは動物に対
し、体重1Kg当り0.1〜100mgを一日投与量とし、
製剤中の含有量は約50mg、100mg、250mg、500mg
とするのが一般的である。
以下本発明の実施例を説明する。以下の製造例
および実施例においては、出発物質および目的物
質は次の様な略号を用いて表わした。
Ala:アラニル
Glu:グルタミン
DAP:α,ε−ジアミノピメリル
Z:ベンジルオキシカルボニル
Boc:t−ブトキシカルボニル
Bzl:ベンジル
Su:N−ヒドロキシサクシンイミド
Lys:リジル
製造例
D−AlaOH(2)(1.78g)を水(40ml)、ジオキ
サン(40ml)、トリエチルアミン(4.04g)の混
合溶媒に溶解した。この溶液にBoc−L−Lys(ε
−Z)OSu(1)(9.26g)を添加し、得られた溶液
を室温で一晩反応させた後、濾過した。
濾液を蒸発させて得た油状物を溶解し、この溶
液に希塩酸を加え酸性化した後、酢酸エチルで抽
出した。有機溶媒層を水洗し、硫酸マグネシウム
で乾燥した後、溶媒を留去して白色泡状物を得
た。泡状物をトリフルオロ酢酸(30ml)に溶解
し、室温で30分間反応させた。過剰のトリフルオ
ロ酢酸を留去し、得られたペーストを水に溶解し
た。溶液をHP20カラムに通した後、カラムに水
及び水−メタノール(1:1)を+分に通し溶出
を行なつた。後者の溶出分を集め、溶媒を留去す
るとL−Lys(ε−Z)−D−AlaOH(3)(4.50g)
が得られた。
IR(Nujol):3350、3300、1685、1660、1640cm-1
NMR(CD3OD):δ1.30(3H,d,J=7Hz)、
1.20−1.70(6H,m)、2.86−3.50(2H,m)、
4.16(1H,q,J=7Hz)、5.00(2H,s)、
7.30(5H,s)
実施例 1
L−Lys(ε−Z)−D−AlaOH(2)(0.915g)
を塩化メチレン(40ml)、メタノール(40ml)及
びトリエチルアミン(0.53g)の混合液に溶解し
た。この溶液にn−オクタノイル−D−Glu(α
−OBZl)−γ−OSu(1)(1.20g)を添加し、室温
下に一夜放置した。反応混合物から溶媒を留去
し、ペースト状残留物に水(50ml)、エーテル
(50ml)、IN塩酸を加えた。得られた混合液を十
分撹拌し、エーテルを留去すると、残留水層から
結晶が析出した。この結晶を濾別し、水洗後、乾
燥すると、n−オクタノイル−γ−D−Glu(α
−OBZl)−L−Lys(ε−Z)−D−AlaOH(3)
(1.50g)が得られた。
IR(Nujol):3300、1725、1685、1650、1630cm-1
NMR(DMSO−d6,)δ:0.84(3H,t,J=7
Hz)、1.00−2.40(25H,m)、2.84−3.12(2H,
m),4.10−4.50
オクタノイル−γ−D−Glu(α−OBZl)−L
−Lys(ε−Z)−D−AlaOH(3)(1.20g)を酢酸
(50ml)に溶解し、パラジウム黒(150mg)を用い
て水素化した。触媒を濾去した濾液を蒸発させ、
残留ペーストを放置すると結晶が得られた。該結
晶をジエチルエーテルで十分に洗浄すると、オク
タノイル−γ−D−Glu(α−OH)−L−Lys−D
−AlaOH(4)(0.80g)が得られる。
[α]D=+41.7(C=0.2、酢酸)
IR(Nujol):3360、1710(sh)、1640cm-1
NMR(D2O)、δ:0.84(3H,obscure t,J=
7Hz)、1.00−2.50(25H,m)、2.80−3.10
(2H,m)、4.00−4.40(3H,m)
実施例 2
実施例1の工程(1)と同様にして、ステアロイル
−γ−D−Glu(α−OBzl)−L−Lys(ε−Z)−
D−AlaOH(3)を得た。
NMR(DMSO−d6),δ:0.84(3H,t,J=7
Hz)、1.00−2.40(45H,m)、2.80−3.10(2H,
m)、4.00−4.80(3H,m)、5.00(2H,s)、
5.08(2H,s)、7.32(10H,s)、7.80(1H,
d,J=8Hz)8.08(2H,t,J=8Hz)
実施例1の工程(2)と同様にして、ステアロイル
−γ−D−Glu(α−OH)−L−Lys−D−
AlaOH(4)を得た。
[α]D=−11.10(C=0.21、酢酸)
IR(Nujol):3350、1730、1640cm-1
NMR(NaOD−D2O),δ:0.68−2.80(50H,
m)、4.10−4.50(3H,m)[Table] The pharmaceutical composition of the present invention can be used in various pharmaceutical formulations,
For example, the active substance of the invention may be provided as a solid, semi-solid or liquid formulation, containing an organic or inorganic carrier or excipient suitable for external, internal or topical application. The active ingredient may be present in tablets, pellets, capsules, suppositories, solutions, emulsions,
It is used in combination with non-hazardous and pharmaceutically acceptable auxiliary ingredients to form a suspension or other suitable form. Such auxiliary ingredients include ingredients effectively used in the production of solid preparations, semi-solid preparations, liquid preparations, etc., such as water, glucose, lactose, gelatin, mannitol,
Examples include starch paste, magnesium trisilicate, corn starch, keratin, colloidal silica, potato starch, urea, etc., and stabilizers, fillers, colorants, fragrances, etc. may also be added as supplements.
Furthermore, the pharmaceutical composition of the present invention may contain a preservative or a bactericidal agent in order to maintain the activity of the active ingredient. The amount of the active ingredient in the composition is such that the amount of the active ingredient is sufficient to exert a desired therapeutic effect on the progress and condition of the disease. When applying this composition to the human body, intravenous administration, intramuscular administration, oral administration, etc. are desirable.
Although the effective dose of the substance of the present invention varies depending on the age of the target patient and the symptoms, the usual daily dose for humans or animals is 0.1 to 100 mg per 1 kg of body weight.
The content in the formulation is approximately 50mg, 100mg, 250mg, 500mg
It is common to do so. Examples of the present invention will be described below. In the following production examples and examples, starting materials and target materials are represented using the following abbreviations. Ala: Alanyl Glu: Glutamine DAP: α,ε-diaminopimelyl Z: Benzyloxycarbonyl Boc: t-butoxycarbonyl Bzl: Benzyl Su: N-hydroxysuccinimide Lys: Lysyl production example D-AlaOH (2) (1.78 g) was dissolved in a mixed solvent of water (40 ml), dioxane (40 ml), and triethylamine (4.04 g). Add Boc-L-Lys (ε
-Z)OSu(1) (9.26 g) was added and the resulting solution was reacted overnight at room temperature, then filtered. The oily substance obtained by evaporating the filtrate was dissolved, and the solution was acidified by adding dilute hydrochloric acid, and then extracted with ethyl acetate. After washing the organic solvent layer with water and drying with magnesium sulfate, the solvent was distilled off to obtain a white foam. The foam was dissolved in trifluoroacetic acid (30ml) and allowed to react for 30 minutes at room temperature. Excess trifluoroacetic acid was distilled off and the resulting paste was dissolved in water. After passing the solution through an HP20 column, elution was performed by passing water and water-methanol (1:1) through the column for + minutes. The latter eluate was collected and the solvent was distilled off to give L-Lys(ε-Z)-D-AlaOH(3) (4.50g)
was gotten. IR (Nujol): 3350, 3300, 1685, 1660, 1640cm -1 NMR (CD 3 OD): δ1.30 (3H, d, J = 7Hz),
1.20−1.70 (6H, m), 2.86−3.50 (2H, m),
4.16 (1H, q, J = 7Hz), 5.00 (2H, s),
7.30 (5H, s) Example 1 L-Lys(ε-Z)-D-AlaOH(2) (0.915g)
was dissolved in a mixture of methylene chloride (40 ml), methanol (40 ml) and triethylamine (0.53 g). Add n-octanoyl-D-Glu (α
-OBZl)-γ-OSu(1) (1.20 g) was added and left at room temperature overnight. The solvent was distilled off from the reaction mixture, and water (50 ml), ether (50 ml), and IN hydrochloric acid were added to the paste-like residue. The resulting mixed solution was sufficiently stirred and the ether was distilled off, and crystals were precipitated from the remaining aqueous layer. The crystals are filtered, washed with water, and dried, resulting in n-octanoyl-γ-D-Glu (α
−OBZl)−L−Lys(ε−Z)−D−AlaOH(3)
(1.50g) was obtained. IR (Nujol): 3300, 1725, 1685, 1650, 1630 cm -1 NMR (DMSO-d 6 ,) δ: 0.84 (3H, t, J = 7
Hz), 1.00-2.40 (25H, m), 2.84-3.12 (2H,
m), 4.10−4.50 Octanoyl-γ-D-Glu(α-OBZl)-L
-Lys(ε-Z)-D-AlaOH (3) (1.20 g) was dissolved in acetic acid (50 ml) and hydrogenated using palladium black (150 mg). The filtrate from which the catalyst has been filtered off is evaporated,
When the residual paste was allowed to stand, crystals were obtained. When the crystals were thoroughly washed with diethyl ether, octanoyl-γ-D-Glu(α-OH)-L-Lys-D
-AlaOH(4) (0.80 g) is obtained. [α] D = +41.7 (C = 0.2, acetic acid) IR (Nujol): 3360, 1710 (sh), 1640 cm -1 NMR (D 2 O), δ: 0.84 (3H, obscure t, J =
7Hz), 1.00-2.50 (25H, m), 2.80-3.10
(2H, m), 4.00−4.40 (3H, m) Example 2 In the same manner as step (1) of Example 1, stearoyl-γ-D-Glu(α-OBzl)-L-Lys(ε-Z)-
D-AlaOH (3) was obtained. NMR (DMSO- d6 ), δ: 0.84 (3H, t, J=7
Hz), 1.00-2.40 (45H, m), 2.80-3.10 (2H,
m), 4.00−4.80 (3H, m), 5.00 (2H, s),
5.08 (2H, s), 7.32 (10H, s), 7.80 (1H,
d, J = 8Hz) 8.08 (2H, t, J = 8Hz) Stearoyl-γ-D-Glu(α-OH)-L-Lys-D-
AlaOH (4) was obtained. [α] D = -11.10 (C = 0.21, acetic acid) IR (Nujol): 3350, 1730, 1640 cm -1 NMR (NaOD - D 2 O), δ: 0.68 - 2.80 (50H,
m), 4.10−4.50 (3H, m)
Claims (1)
イル、R2は水素またはベンジル、R3は1−カル
ボキシエチルアミノ、R4は水素、R5は水素また
はベンジルオキシカルボニルをそれぞれ意味す
る)で示されるペプチド化合物またはその医薬と
して許容される塩。[Claims] 1. General formula (In the formula, R 1 is n-octanoyl or stearoyl, R 2 is hydrogen or benzyl, R 3 is 1-carboxyethylamino, R 4 is hydrogen, and R 5 is hydrogen or benzyloxycarbonyl). A compound or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201241A US4322341A (en) | 1980-05-13 | 1980-10-27 | Peptide, process for preparation thereof and use thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57114556A JPS57114556A (en) | 1982-07-16 |
JPH0325437B2 true JPH0325437B2 (en) | 1991-04-05 |
Family
ID=22745059
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP56172658A Granted JPS57114556A (en) | 1980-10-27 | 1981-10-27 | Novel peptide compound and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS57114556A (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH068313B2 (en) * | 1983-02-08 | 1994-02-02 | 藤沢薬品工業株式会社 | Novel acylglutamyl lysine derivative |
JP4949557B2 (en) * | 1999-03-17 | 2012-06-13 | ノヴォ ノルディスク アー/エス | Peptide acylation method and novel acylating agent |
US7273921B2 (en) | 2002-09-25 | 2007-09-25 | Novo Nordisk A/S | Method for producing acylated peptides |
JP5217546B2 (en) * | 2007-07-03 | 2013-06-19 | Jsr株式会社 | Process for producing amino acid-N-carboxyanhydride |
JP5217547B2 (en) * | 2007-07-03 | 2013-06-19 | Jsr株式会社 | Process for producing amino acid-N-carboxyanhydride |
JP5217545B2 (en) * | 2008-03-19 | 2013-06-19 | Jsr株式会社 | Process for producing amino acid-N-carboxyanhydride |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5576850A (en) * | 1978-10-19 | 1980-06-10 | Anvar | Waterrsoluble compounds derived from extract of streptomyces stimulosus*their manufactures and immunologic adjuvant composition |
JPS5585552A (en) * | 1978-11-14 | 1980-06-27 | Fujisawa Pharmaceut Co Ltd | New lactyltetrapeptide |
JPS5636440A (en) * | 1979-06-29 | 1981-04-09 | Rhone Poulenc Ind | Tetrapeptide and pentapeptide* manufacture thereof and composition containing them |
JPS5645447A (en) * | 1979-06-29 | 1981-04-25 | Rhone Poulenc Ind | Tripeptides* their manufacture and composition containing them |
-
1981
- 1981-10-27 JP JP56172658A patent/JPS57114556A/en active Granted
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5576850A (en) * | 1978-10-19 | 1980-06-10 | Anvar | Waterrsoluble compounds derived from extract of streptomyces stimulosus*their manufactures and immunologic adjuvant composition |
JPS5585552A (en) * | 1978-11-14 | 1980-06-27 | Fujisawa Pharmaceut Co Ltd | New lactyltetrapeptide |
JPS5636440A (en) * | 1979-06-29 | 1981-04-09 | Rhone Poulenc Ind | Tetrapeptide and pentapeptide* manufacture thereof and composition containing them |
JPS5645447A (en) * | 1979-06-29 | 1981-04-25 | Rhone Poulenc Ind | Tripeptides* their manufacture and composition containing them |
Also Published As
Publication number | Publication date |
---|---|
JPS57114556A (en) | 1982-07-16 |
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