JPH0253797A - Peptide derivative and antidement agent containing same derivative - Google Patents
Peptide derivative and antidement agent containing same derivativeInfo
- Publication number
- JPH0253797A JPH0253797A JP63201356A JP20135688A JPH0253797A JP H0253797 A JPH0253797 A JP H0253797A JP 63201356 A JP63201356 A JP 63201356A JP 20135688 A JP20135688 A JP 20135688A JP H0253797 A JPH0253797 A JP H0253797A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- peptide
- carbon atoms
- cys
- 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.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000000524 functional group Chemical group 0.000 claims abstract description 9
- 150000001413 amino acids Chemical class 0.000 claims abstract description 7
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 229940125682 antidementia agent Drugs 0.000 claims description 3
- 239000002664 nootropic agent Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 22
- -1 p-methoxybenzyl Chemical group 0.000 abstract description 13
- 125000006239 protecting group Chemical group 0.000 abstract description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract description 4
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 125000001433 C-terminal amino-acid group Chemical group 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 210000003127 knee Anatomy 0.000 description 11
- 230000008018 melting Effects 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 230000004044 response Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 230000001777 nootropic effect Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 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 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 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
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 201000009570 retrograde amnesia Diseases 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 239000002253 acid Substances 0.000 description 2
- 238000010306 acid treatment Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 208000013677 cerebrovascular dementia Diseases 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-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
- XXYNZSATHOXXBJ-UHFFFAOYSA-N 4-hydroxyisoindole-1,3-dione Chemical compound OC1=CC=CC2=C1C(=O)NC2=O XXYNZSATHOXXBJ-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 244000186140 Asperula odorata Species 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical class OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-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
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 235000008526 Galium odoratum Nutrition 0.000 description 1
- 208000023105 Huntington disease Diseases 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
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 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
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- NJUISRMVIKYYCN-UHFFFAOYSA-N acetic acid;chloroform;methanol;hydrate Chemical compound O.OC.CC(O)=O.ClC(Cl)Cl NJUISRMVIKYYCN-UHFFFAOYSA-N 0.000 description 1
- XVUDRSZQKGTCPH-UHFFFAOYSA-N acetic acid;n,n-dimethylformamide Chemical compound CC(O)=O.CN(C)C=O XVUDRSZQKGTCPH-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 150000001944 cysteine derivatives Chemical class 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- DANUORFCFTYTSZ-UHFFFAOYSA-N epinigericin Natural products O1C2(C(CC(C)(O2)C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)C)C(C)C(OC)CC1CC1CCC(C)C(C(C)C(O)=O)O1 DANUORFCFTYTSZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 239000003721 gunpowder Substances 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000005056 memory consolidation Effects 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
- 210000005012 myelin Anatomy 0.000 description 1
- ZUSSTQCWRDLYJA-UHFFFAOYSA-N n-hydroxy-5-norbornene-2,3-dicarboximide Chemical compound C1=CC2CC1C1C2C(=O)N(O)C1=O ZUSSTQCWRDLYJA-UHFFFAOYSA-N 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- DANUORFCFTYTSZ-BIBFWWMMSA-N nigericin Chemical compound C([C@@H]1C[C@H]([C@H]([C@]2([C@@H](C[C@](C)(O2)C2O[C@@](C)(CC2)C2[C@H](CC(O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C)O1)C)OC)[C@H]1CC[C@H](C)C([C@@H](C)C(O)=O)O1 DANUORFCFTYTSZ-BIBFWWMMSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 238000011302 passive avoidance test Methods 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 150000003012 phosphoric acid amides Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 description 1
- 239000006228 supernatant 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 125000001990 thiamine group Chemical group 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 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
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
［産業上の利用分野］
本発明は、向知能作用をイ（−シ、従って医薬、特に抗
痴呆剤として有用なペプチド誘導体に関する。
［従来の技術］
パップレシンに向知能作用のあることは古くから知られ
ているか、最近パップレシンの断片とみなし得るペプチ
ド、例えば、
ｐＧＩｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−１、−Ａｒｇ−Ｇ
ｌｙ−ＮＩＩ２Ｃｙｓ−０１１、
また、
１１−八５ｎ−Ｃｙｓ−Ｐｒｏ−＾ｒｇ−Ｏ１１１ｔ
−（： ｙ ｓ −Ｏｆ＋
で表わされるペプチドにもパップレシンと同様に向知能
作用があることが報告された［サイエンス（Ｓｃｉｅｎ
ｃｅ ） ２２１．１３１０−＋３１２（１９８３）
］ ［プレインリサーチ（Ｂｒａｉｎ Ｒｅ５ｅａｒ
ｃｈ）３７１．１７（１９８６）］。
［発明が解決しようとする問題点］
本発明は、このようなパップレシン及びパップレシン断
片ペプチドよりも、さらに優れた向知能作用を・有する
新規なペプチド誘導体を提供することを目的とするもの
である。
［問題を解決するための手段］
本発明は、下記一般式（Ｉ）：
Ｑ’ −Ａｓｎ−Ｃｙｓ−Ｐｒｏ−Ａｍ０２
（Ｉ ）［式中、Ａは什ｇ又はＬ ｙ ｓを示
し、Ｑｌは、ｐＧｌｕ又はＨを示し、Ｑ２は、ｃｒｙ−
ｏ＋＋又はＯＨを示し、Ｗは下記一般式（■）：
Ｙ’−Ｇｙｓ−Ｙｌ（Ｈ）
（式中、ＹｌはＨ又はＣｏ−Ｔであり、ＹｌはＯＨ又は
Ｔであり、
（但し、Ｔは下記一般式（ＩＩＩ）二
Ｒ’Ｓ Ｃ１１０
（式中、Ｒ１は、炭素原子数２〜７のアルキルカルボニ
ル基、炭素原子数７〜１０のアリールカルボニル基及び
炭素原子数１〜６のアルキルチオ基からなる群から選ば
れた基である）、
又は、下記一般式（■）ニ
−Ｓ ［１１０
（式中、Ｒ２は、水素原子、炭素原子数２〜７のアルキ
ルカルボニル基、炭素原子数７〜１０のアリールカルボ
ニル基からなる群がら選ばれた基である）、
で表わされる基である）
Ｙｌ及びＹ２の少なくとも一方はＴを含む）で表わされ
る基であり、ペプチド構成アミノ酸はＬ型であるが、Ｐ
ｒｏ及び八ｒｇはＤ型であってもよい］
で表わされるペプチド誘導体、若しくはその官能基にお
ける誘導体、又はそれらの薬理学的に許容され得る塩に
関する。
また、本発明は、上記一般式（Ｉ）で表わされるペプチ
ド誘導体、若しくはその官能基における誘導体、又はそ
れらの薬理学的に許容され得る塩の有効量、及び薬理学
的に許容され得る担体若しくは希釈剤を含有してなる抗
痴呆剤に関する。
−］］二記一般式Ｉ）で表わされるペプチド誘導体の官
能基における誘導体は、下記のものを意味する。
ａ）１〜６個の炭素原子を有する脂肪族カルボン酸、好
ましくは酢酸から誘導されるＮ−アシル誘導体、
ｂ）アミド又は１〜６個の炭素原子のアルキル基を有す
るモノ−アルキル又はジ−アルキル置換アミド、及び、
ｃ）１〜１８個の炭素原子を有するアルコール、好まし
くは１〜６個の炭素原子を有する脂肪族アルコールから
誘導されるエステル。
上記ペプチド誘導体若しくはその官能基における誘導体
の薬理学的に許容され得る塩としては、酸付加塩及び塩
基性塩を挙げることができる。このような酸付加塩とし
ては、無機酸（例、塩酸、硫酸、燐酸）又は有機酸く例
、酢酸、プロピオン酸、クエン酸、酒石酸、リンゴ酸、
シュウ酸、メタンスルホン酸〉等の塩が挙げられる。ま
た、塩基性塩としては、ナトリウム塩、カリウム塩、ト
リエチルアミン塩等が挙げられる。
本明細占において、アミノ酸、ペプチド、保護基、溶媒
等は当該技術分野で慣用されている略号、或いは、ＩＵ
ＰＡＣ−ＩＵＢの命名委員会で採用された略号を使用し
ている。例えば下記の略号が使用される。また、光学配
置を示さない場合アミノ酸はＬ型を意味するものとする
。
Ａｓｎ ：アスパラギン
へｒｇ：アルギニン
にｙｓ ＋システィン
Ｇｌ、ｙ ニゲリシン
１１ＧＩＩＪ：ピログルタミン酸
Ｌｙｓ ：リジン
Ｐｒｏ ニブロリン
Ｂｏｃ ： ｔ−ブトキシカルボニル
Ｚ：ベンシルオキシカルボニル
Ｍｂｓ ・ρ−メトキシベンゼンスルホニルＭＢｚｌ
：Ｐ−メトキシベンジル
ＡＣ［Ｉｌ ：アセトアミドメチル
５ｃｒｎ ：カルボメトキシスルフェニルＯ５ｕ：Ｎ
−ヒドロキシコハク酸イミドエステルＤ（：Ｃ： Ｎ、
Ｎ’−ジシクロヘキシルカルボジイミドＤＧＩＪｒｅａ
： Ｎ、Ｎ’−ジシクロへキシルウレア１１０１］ｔ
： １−ヒドロキシヘンシトリアゾールＮＭＭ ： Ｎ
−メチルモルホリン
ＴＦＡ ： トリフルオロ酢酸
ＭＳΔ ：メタンスルホン酸
八ｃＯＥｔ、 ：酢酸エチル
Ａｃ０１１：酢酸
ＤＭＦ ： Ｎ、Ｎ−ジメチルホルムアミドＭｅＯＨ
：メタノール
本発明のペプチド誘導体は、先ずペプチド化学において
通常用いられる方法、例えば、５ｃｈｒ６ｄｅｒａｎｄ
Ｌｕｂｋｅ著「ザ ペプチド（Ｔｈｅ Ｐｅｐｔｉｄ
ｅｓ）」第巻、 Ａｃａｄｅｎ＋ｉｃ Ｐｒｅｓｓ、
Ｎｅｗ Ｙｏｒｋ、Ｕ、Ｓ、Ａ、（＋９６５年）、泉
屋信夫ら著「ペプチド合成の基礎と実験」丸善＠）（１
９８５年）などに記載されている方法（液相法及び固相
法）によってペプチド骨格を製造し、次いで、ペプチド
骨格のシスティン側鎖のメルカプト基にチアミン基を含
むシスティンの誘導体を反応させて、ジスルフィド結合
を形成させることによって製造することができる。また
、ペプチド骨格を構成するアミノ酸として、チアミンを
有するシスチン誘導体を使用して縮合反応によりペプチ
ド結合を形成させてもよい。
ペプチド結合を形成するための縮合方法として、アジド
法、酸クロライド法、酸無水物法、混合酸無水物法、Ｎ
、Ｎ’ −ジシクロへキシルカルボジイミド法、Ｎ、Ｎ
’ −ジシクロヘキシルカルボジイミド−アディティブ
法、活性エステル法、カルボニルジイミダゾール法、酸
化還元法、ウッドワード試薬Ｋを用いる方法等が挙げら
れる。
縮合反応を行なう前に、それ自体公知の手段により、反
応に関与しないカルボキシル基、アミノ基等を保護した
り、また反応に関与するカルボキシル基、アミノ基を活
性化してもよい。
カルボキシル基の保護基としては、例えば、メチル、エ
チル、ベンジル、ｐ−ニトロベンジル、ｔ−ブチル、シ
クロヘキシル等のエステルを挙げることができる。
アミノ基の保護基としては、例えば、ベンジルオキシカ
ルボニル基、ｔ−ブトキシカルボニル基、イソボルニル
オキシカルボニル基、９−フルオレニルメチルオキシカ
ルボニル基等を挙げることができる。
グアニジノ基の保護基としては、例えば、ニトロ基、ベ
ンジルオキシカルボニル基、トシル基、ｐ−メトキシベ
ンゼンスルホニル基、メシチレンスルホニル基等を挙げ
ることができる。
メルカプト基ゐ保護基としては、例えば、トリチル基、
アセトアミドメチル基、ベンジル基、ｐ−メトキシベン
ジル基、３−ニトロ−２−ピリジンスルフェニル基等を
挙げることができる。
カルボキシル基の活性化されたものとしては、例えば、
対応する酸無水物、アジド、活性エステル［アルコール
（例、ペンタクロロフェノール、２．４−ジニトロフェ
ノール、シアノメチルアルコール、ｐ−ニトロフェノー
ル、Ｎ−ヒドロキシ−５−ノルボルネン−２，３−ジカ
ルボキシイミド、Ｎ−ヒドロキシコハク酸イミド、Ｎ−
ヒドロキシフタルイミド、１−ヒドロキシベンゾトリア
ゾール）とのエステル］等が挙げられる。アミノ基の活
性化されたものとしては、例えば、対応する燐酸アミド
が挙げられる。
反応は、通常溶媒中で行なわれ、例えば、クロロホルム
、ジクロルメタン、酢酸エチル、Ｎ、 Ｎ−ジメチルホ
ルムアミド、ジメチルスルホキシド、ピリジン、ジオキ
サン、テトラヒドロフラン、水、メタノール等の溶媒、
又は、これらの混合物中で行なうことができる。
反応温度は、一般に使用される約−３０℃〜約５０℃の
範囲で行なうことができる。
本発明のペプチドの保護基脱離反応は、使用する保護基
の種類によって異なるが、ペプチド結合に影響を与えず
、保護基が除かれることが必要である。
保護基の脱離方法としては、例えば、塩化水素、無水フ
ッ化水素、メタンスルホン酸、トリフルオロメタンスル
ホン酸、トリフルオロ酢酸、又は、これらの混合物等に
よる酸処理が挙げられるが、この他に、液体アンモニア
中ナトリウム、パラジウム炭素による還元等も挙げられ
る。上記酸処理による脱保護基反応においては、アニソ
ール、フェノール、チオアニソールの如きカチオン捕捉
剤の添加が有効である。
このようにして製造された本発明のペプチド誘導体は、
反応終了後、それ自体公知のペプチドの分離手段、例え
ば、抽出、分配、再沈殿、再結晶、カラムクロマトグラ
フィー等によって収得することができる。
また、本発明のペプチド誘導体は、それ自体公知の方法
により、前記のような、その官能基における誘導体、又
は、それらの薬理学的に許容され得る塩にすることがで
きる。
本発明のペプチド誘導体としては、例えば、下記のもの
が挙げられる。
１１−八ｓｎ−Ｇｙｓ−Ｐｒｏ−Ａｒｇ−ＤＨＷ[Industrial Field of Application] The present invention relates to a peptide derivative that exhibits a nootropic effect and is therefore useful as a medicine, particularly as an anti-dementia agent. [Prior Art] It has been known for a long time that pap pressin has a nootropic effect. Peptides that are known or can recently be regarded as fragments of pap pressin, e.g. pGIu-Asn-Cys-Pro-1, -Arg-G
ly-NII2Cys-011, also 11-85n-Cys-Pro-^rg-O111t
It has been reported that the peptide represented by -(: y s -Of+ also has a nootropic effect similar to pap pressin [Science
ce) 221.1310-+312 (1983)
] [Brain Research (Brain Re5ear
ch) 371.17 (1986)]. [Problems to be Solved by the Invention] An object of the present invention is to provide a novel peptide derivative that has an even better nootropic effect than such pap pressin and pap pressin fragment peptides. [Means for solving the problem] The present invention provides the following general formula (I): Q'-Asn-Cys-Pro-Am02
(I) [wherein A represents G or Lys, Ql represents pGlu or H, and Q2 represents cry-
o++ or OH, W represents the following general formula (■): Y'-Gys-Yl(H) (wherein, Yl is H or Co-T, Yl is OH or T, (however, T is the following general formula (III) 2R'S C110 (wherein, R1 is an alkylcarbonyl group having 2 to 7 carbon atoms, an arylcarbonyl group having 7 to 10 carbon atoms, and an alkylthio group having 1 to 6 carbon atoms) ), or the following general formula (■) -S - a group selected from the group consisting of 10 arylcarbonyl groups), a group represented by (at least one of Yl and Y2 contains T), and the peptide-constituting amino acids are L-type But, P
ro and 8rg may be D-type], or a functional group derivative thereof, or a pharmacologically acceptable salt thereof. The present invention also provides an effective amount of the peptide derivative represented by the above general formula (I), a functional group derivative thereof, or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier or The present invention relates to an anti-dementia agent containing a diluent. -]] The derivative in the functional group of the peptide derivative represented by general formula I) means the following. a) N-acyl derivatives derived from aliphatic carboxylic acids having 1 to 6 carbon atoms, preferably acetic acid; b) amides or mono-alkyl or di-alkyl derivatives having alkyl groups of 1 to 6 carbon atoms; Esters derived from alkyl-substituted amides and c) alcohols having 1 to 18 carbon atoms, preferably aliphatic alcohols having 1 to 6 carbon atoms. The pharmacologically acceptable salts of the above peptide derivatives or functional group derivatives thereof include acid addition salts and basic salts. Such acid addition salts include inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid) or organic acids such as acetic acid, propionic acid, citric acid, tartaric acid, malic acid,
Examples include salts such as oxalic acid and methanesulfonic acid. Further, examples of the basic salt include sodium salt, potassium salt, triethylamine salt, and the like. In this specification, amino acids, peptides, protective groups, solvents, etc. are referred to by abbreviations commonly used in the technical field or IU
Abbreviations adopted by the PAC-IUB nomenclature committee are used. For example, the following abbreviations are used: Furthermore, if the optical configuration is not indicated, the amino acid shall mean the L-type. Asn: to asparagine rg: arginine to ys + cysteine Gl, y nigericin 11 GIIJ: pyroglutamic acid Lys: lysine Pro Nibroline Boc: t-butoxycarbonyl Z: benzyloxycarbonyl Mbs ・ρ-methoxybenzenesulfonyl MBzl
:P-methoxybenzyl AC[Il :acetamidomethyl5crn :carbomethoxysulfenyl O5u:N
-Hydroxysuccinimide ester D (:C:N,
N'-dicyclohexylcarbodiimide DGIJrea
: N,N'-dicyclohexylurea 1101]t
: 1-Hydroxyhencytriazole NMM : N
-Methylmorpholine TFA: Trifluoroacetic acid MSΔ: Methanesulfonic acid 8cOEt: Ethyl acetate Ac011: Acetic acid DMF: N,N-dimethylformamide MeOH
:methanol The peptide derivative of the present invention is first prepared by a method commonly used in peptide chemistry, for example, 5chr6derand.
"The Peptid" by Lubke
es)” Volume, Acaden+ic Press,
New York, U, S, A, (+965), “Basics and Experiments of Peptide Synthesis” by Nobuo Izumiya et al., Maruzen @) (1
985) etc. (liquid phase method and solid phase method), and then reacting a cysteine derivative containing a thiamin group with the mercapto group of the cysteine side chain of the peptide skeleton, It can be produced by forming disulfide bonds. Furthermore, a peptide bond may be formed by a condensation reaction using a cystine derivative having thiamine as the amino acid constituting the peptide skeleton. Condensation methods for forming peptide bonds include azide method, acid chloride method, acid anhydride method, mixed acid anhydride method, N
, N'-dicyclohexylcarbodiimide method, N,N
'-dicyclohexylcarbodiimide-additive method, active ester method, carbonyldiimidazole method, redox method, method using Woodward reagent K, and the like. Before carrying out the condensation reaction, carboxyl groups, amino groups, etc. that do not participate in the reaction may be protected, or carboxyl groups, amino groups that participate in the reaction may be activated by means known per se. Examples of the carboxyl protecting group include esters such as methyl, ethyl, benzyl, p-nitrobenzyl, t-butyl, and cyclohexyl. Examples of protecting groups for amino groups include benzyloxycarbonyl group, t-butoxycarbonyl group, isobornyloxycarbonyl group, and 9-fluorenylmethyloxycarbonyl group. Examples of the protecting group for the guanidino group include a nitro group, a benzyloxycarbonyl group, a tosyl group, a p-methoxybenzenesulfonyl group, and a mesitylenesulfonyl group. Examples of mercapto group-protecting groups include trityl group,
Examples include acetamidomethyl group, benzyl group, p-methoxybenzyl group, and 3-nitro-2-pyridinesulfenyl group. Examples of activated carboxyl groups include:
Corresponding acid anhydrides, azides, active esters [alcohols (e.g., pentachlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, p-nitrophenol, N-hydroxy-5-norbornene-2,3-dicarboximide) , N-hydroxysuccinimide, N-
esters with hydroxyphthalimide, 1-hydroxybenzotriazole), and the like. Examples of activated amino groups include the corresponding phosphoric acid amides. The reaction is usually carried out in a solvent, such as chloroform, dichloromethane, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, pyridine, dioxane, tetrahydrofuran, water, methanol, etc.
Alternatively, it can be carried out in a mixture of these. The reaction temperature can be within the commonly used range of about -30°C to about 50°C. The protecting group removal reaction for the peptide of the present invention varies depending on the type of protecting group used, but it is necessary that the protecting group be removed without affecting the peptide bond. Examples of methods for removing the protecting group include acid treatment with hydrogen chloride, anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture thereof; Examples include reduction with sodium in liquid ammonia, palladium on carbon, and the like. In the deprotection reaction by acid treatment, it is effective to add a cation scavenger such as anisole, phenol, and thioanisole. The peptide derivative of the present invention thus produced is
After the reaction is completed, the peptide can be obtained by known peptide separation means such as extraction, partitioning, reprecipitation, recrystallization, column chromatography, etc. Furthermore, the peptide derivative of the present invention can be made into a derivative at its functional group or a pharmacologically acceptable salt thereof, as described above, by a method known per se. Examples of the peptide derivatives of the present invention include the following. 11-8sn-Gys-Pro-Arg-DHW
【
）１−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−八ｒｇ−Ｎｌ１２ｐＧ
ｌｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−八ｒｇ−ＯＨＨ−Ａｓ
ｎ−Ｃｙｓ−Ｐｒｏ−Ａｒｇ−Ｇｌｙ−Ｎｉｌ□ｐＧＩ
ｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−八ｒｇ−Ｇｌｙ−Ｎｉ１
２ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−Ｄ−八ｒｇ−Ｇ
ｌｙ−ＮＨ２ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｄ−Ｐｒｏ−
＾ｒｇ−Ｇｌｙ−ＮｌｌｚｐＧｌｕ−Ａｓｎ−Ｇｙｓ−
Ｐｒｏ−Ｌｙｓ−Ｇｌｙ−Ｎｉ１２本発明のペプチド誘
導体は、ラットにおける受動的回避試験において強い向
知能作用を示す。
本発明のペプチド誘導体の有用な対象疾病名としては、
例えば、老年痴呆（アルツハイマー型痴呆）、脳血管性
痴呆、ならびに、アルツハイマー病、ビック病、ハンチ
ントン舞踏病、クロイツフェルト・ヤコブ病、パーキン
ソン病、小脳を髄変性症、等に基く痴呆症などが挙げら
れ、これらの疾病の予防又は治療に用いることができる
。
本発明のペプチド誘導体の毒性は、極めて低く、薬効有
効量を道かに上回る投与量でも死亡例はない。
本発明のペプチド誘導体は、遊離体として、又はその官
能基における誘導体として投与できる。
その没！ｇ、量は、遊離体又はその塩の何れであっても
、遊離体の量として、一般に０．１ｎｇ−１ｍｇ／日の
範囲の量が適当である。特に、非経口投与、経鼻投与で
は、０．１ｎｇ〜１００μｇ／日が好ましく、経口投与
、直腸役作では、非経Ｌ】投与の１０〜１００倍役学す
ることが好ましい。
本発明のペプチド誘導体は、主として、非経口的に投与
（例、静脈又は皮下注射、脳室内又はを髄腔内投与、経
鼻投与、直腸投与）されるが、場合によっては、経口投
与されてもよい。
剤型としては、例えば、注射剤、平削、散剤、点鼻剤、
火剤、錠剤等が挙げられる。本発明、のペプチド誘導体
は生理食塩水の溶液として保存することができるが、マ
ンニトール、ソルビトールを添加して凍結乾燥アンプル
とし、使用時に溶解することもできる。
以下に実施例を示す。
各実施例において、薄層クロマトグラフィーの展開溶媒
は下記の通りであり、メルク社製ＴＬＣプレートシリカ
ゲル６０ Ｆ ２５４を用いた。
Ｒ「１：クロロホルム−メタノール−酢酸−水（８０：
２０：２．５：５ ）下層
Ｒ，”：クロロホルムーメタノールー水（７０：：ＩＱ
：５ ）
Ｒ，３，ｎ−ブタノール−酢酸−水（２：ｌ：ｌ ）ま
た、高速液体クロマトグラフィーによる精製は、
カラム： μＢｏｎｄａｐａｋ Ｃ＋ａ １．９
Ｘｌ５ｃｍ移動相： Ａ）０．０５％ ＴＦＡ、Ｂ）ア
セトニトリルを使用して行なった。
［参考例１］
Ｈ−Ｃｙｓ （Ｓｃｍ） −Ｔ ’・塩債塩（但し、Ｔ
１は、式中のＲ１がベンゾイル基である前記一般式（Ｉ
ＩＩ）で表わされる基である）（１） Ｂｏａ４：
ｙｓ（八ｃｍ）−Ｔ’３０ｃｍＣｙｓ （八ｃｍ）−０
１１１，Ｏｇ、 Ｓ−ベンゾイルチアミン １．３ｇ及
び４−ジメチルアミノピリジン２０ｍｇの（：ｔｈＣ１
２５０ｍ ＪＺ温溶液水冷下Ｄ（：Ｇ Ｏ，７８ｇのＯ
Ｈ□（：１２５＋ｎｊＺ溶液を滴下した。
水冷下で３０分間、更に室温で１時間攪拌した後、ＤＣ
Ｕｒｅａを濾別し、飽和炭酸水素ナトリウム水、及び水
にて洗浄した。
無水硫酸ナトリウムで乾燥した後、溶媒を留去し、エー
テルで結晶を濾集し、標記の化合物を得た。
収量：１．Ｂｇ
融点＝７１〜７５℃
Ｒｆ’： ０．７４ Ｒｆ２： ｏ、８２［αコ
。 ： −３９、２” （ｃ−０，５，ＤＭＦ）（
２） Ｂｏａ−Ｃｙｓ （ＳｃｒＭ） −Ｔ’１１ｏ
ｃｌ；ｙｓ（Ａｃ＋＋＋）−Ｔ’ ６００ｍ ｇのＭｃ
Ｏｌｌ −に１１２Ｇ１２（１： ｌｖ／ｖ ） ６ｍ
ｆｌ溶液にＣｌ−５ｃｍ ０．１４ ｍ ｌを加え、室
温で２０分間攪拌した。
溶媒を留去した後、ＣＨＣＩ ３−ＭｃＯｌｌを用いて
シリカゲルカラム精製し、油状物として標記の化合物を
得た。
収量＋ ５８０ｍｇ
Ｒｒ’： ０．８２ Ｒｅ’： ０．８８［ｆｆ
］ｏ： ４４．０° （ｃ＝０．５． ＤＭＦ）（３
） ＩトＣｙｓ（Ｓｃｍ）−Ｔ’ ・塩酸塩１１ｏｃ
−Ｃｙｓ（Ｓｃｍ）−Ｔ’ ４７０ｍ ｇ を４Ｎ１
１にｌ−へｃＯＥｔ２ｍｆｌ中に３０分間室温で放置後
、溶媒を留去した。残留物をｅｌｌ（： １１−ＭｅＯ
ｔｌを用いてシリカゲルカラム精製し、油状物として標
記の化合物を得た。
収ｉｉｔ ： ２５０ ｍ ｇ
Ｒ，’： ０．３８ Ｒ，’： ０．５４［α
コ 。 ：＋３８． ４ ° （ｃ−０，５、
ＤＭＦ）［実施例１］
１ｌ−Ｃｙｓ−Ｔ’
ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−Ｄ−Ａｒｇ−Ｇｌ
ｙ−ＮＨ□−酢酸塩（１）Ｚ−Ｄ−Ａｒｇ（Ｍｂｓ）−
Ｇｌｙ−Ｎｌｌ□Ｚ−Ｄ−Ａｒｇ（Ｍｂｓ）−０Ｈジシ
クロヘキシルアミン塩３０ｇを、へｃＯＥｔ５００ｍｕ
＋５％クエン酸水２００ｍ１２中で攪拌溶解させた後、
ＡｃｏＥｔ層を水洗し、無水硫酸す］・リウムで乾燥し
た。
溶媒を留去し、得られた残留物をＤＭＦ ３００ｍｆｌ
に溶解し、水冷下にＩｔ−Ｇｌｙ−Ｎｌｈ塩酸塩５ｇ、
８ＭＭ５ｍｆｔ、ｌｌ０Ｂｔ、 ８ｇ及びＤＧＣ９，
８ｇを添加した。混合物を室温で１８時間攪拌した後、
Ｄ Ｉ： ＩＪ ｒ ｅ ａを濾別し、ＤＭＦを留去し
た。
残留物を２−ブタノール−ＣＩＩ２ＣＩ２（５： １
ｖ／ｖ）に溶解し、飽和炭酸水素ナトリウム水、食塩飽
和希塩酸水、飽和食塩水にて順次洗浄の後、無水硫酸ナ
トリウムで乾燥した。
溶媒を留去の後、残留物をＭｅｏｌｌ−エーテルより結
晶化させ標記の化合物を波乗した。
収量：１４．６ｇ
融点＝１９４〜１９６℃
Ｒ，’：０．２４ Ｒ，２：０．５２［ａ］ｏ：
２．９°（ｃ＝０．５． ＤＭＦ）（２）Ｉｌｏｃ−
Ｐｒｏ−Ｄ−Ａｒｇ（Ｍｂｓ）−Ｇｌｙ−Ｎｌｌ、。
Ｚ−Ｄ−Ａｒｇ（Ｍｂｓ）−Ｇｌｙ−Ｎｌｌｚ １０．
７ ｇを、８０％Ａｃ０１１２００ｍｆｉ中で１０％パ
ラジウム炭素の存在下に、６時間水素気流中で攪拌した
。
パラジウム炭素を濾別した後、溶媒を留去した。残留物
を減圧乾燥した後、ＤＭＦ１００ｍｌ！に溶解し、ＮＭ
Ｍ ３ ｍ Ｑ 、Ｂｏｃ−Ｐｒｏ−Ｏ５ｕ ６．２
ｇを加え、室温にて１８時間攪拌した。
ＤＭＦを留去し、残留物を２−ブタノール−Ｃｌｈ（：
１２（５： １ ｖ ／ ｖ ）に溶解し、飽和炭酸水
素ナトリウム水、食塩飽和希塩酸水、飽和食塩水にて順
次洗浄の後、無水硫酸ナトリウムで乾燥した。
溶媒を留去の後、残留物にエーテルを加え結晶化させ標
記の化合物を波乗した。
収量：１１．９ｇ
融点°１０８〜１１１℃
Ｒ，’：０．３２ Ｒｒ２：０．５６［ａ］ｏ
ニー６．９°（ｃ−０，５，ＤｈｌＦ）（３） Ｂｏ
ｃ−Ｃｙｓ（ＭＢｚｌ）−Ｐｒｏ−Ｄ−八ｒｇ（Ｍｂｓ
）−Ｇｌｙ−Ｎｔｌ□１１ｏｃ−Ｐｒｏ−Ｄ−Ａｒｇ（
Ｍｂｓ）−Ｇｌｙ−Ｎｉｌ□２．９ｇを、４ＮＨ（：ｌ
−Ａｃ０Ｅｔ： ２５ ｍ Ｅ中に室温で３０分間放置
した後、溶媒を留去した。
残留物を減圧乾燥した後、ＤＭＦ５０ｍ１２に溶解し水
冷下でＮＭＭ Ｏ，５３ｍ ｌ 、 Ｂｏｃ−Ｇｙｓ（
ＭＢｚｌ）−Ｏｆｆ １．８ｇ、ＨＯＢｔ Ｏ，８５ｇ
及びＤＩ：Ｃ１，１ｇを加え、室温にて１８時間攪拌し
た。
ＤＣｌｌｒｅａを濾別し、ＤＭＦを留去し、残留物を２
−ブタノール−ａｎ□Ｃ：＋２（５： １ ｖ／ｖ）に
溶解し、飽和炭酸水素ナトリウム水、食塩飽和希塩酸水
、飽和食塩水にて順次洗浄の後、無水硫酸ナトリウムで
乾燥した。
溶媒を留去の後、残留物にエーテルを加え結晶化させ標
記の化合物を濾集した。
収量：３．３ｇ
融点：１２７〜１３０℃
Ｒ，’： ０．４７ Ｒ，”： ０．６３［ａｌＤ
ニー７．６° （ｃ＝１．０． ＤＭＦ）Ｚ−ｐＧｌ
ｕ−Ａｓｎ−Ｃｙｓ （ＭＢｚｌ）−Ｐｒｏ−Ｄ−八ｒ
ｇ（Ｍｂｓ）−Ｇｌｙ−ＮＨ２Ｂｏｃ−Ｇｙｓ（ＭＢｚ
ｉ）−Ｐｒｏ−Ｄ−Ａｒｇ（Ｍｂｓ）−Ｇｌｙ−Ｎｔｌ
ｚ ３．１８ｇを４ Ｎ １１１１：１−ＡｃＯＥｔ
２０ ｍ ｔｌ中に室温で３０分間放置した後、溶媒
を留去した。
残留物に２−ブタノール−にＩｔ。Ｃｌ２（５： １
ｖ／ｖ）及び飽和炭酸水素ナトリウム水を加え、有機層
を分取し、飽和食塩水にて洗浄の後、無水硫酸ナトリウ
ムで乾燥した。
溶媒を留去し残留物をＤＭＦ３０ｍｆｆｉに溶解し、水
冷下でＺ−ｐＧｌｕ−Ａｓｎ−ＯＨ１，７７ｇ、ｌｌ０
Ｂｔ Ｏ，６３ｇ及びＤ（：Ｃ０，９７ｇを加えた。
室温にて１８時間攪拌した後、ＤＧＵｒｅａを濾別しＤ
ＭＦを留去した。
残留物を２−ブタノール−ｃｌ１２ｃ１２ （５： １
ｖ／ｖ）に溶解し、飽和炭酸水素ナトリウム水、食塩
飽和希塩酸水、飽和食塩水にて順次洗浄の後、無水硫酸
ナトリウムで乾燥した。
溶媒を留去の後、残留物にエーテルを加え結晶化させ標
記の化合物を波乗した。
収量：３．４ｇ
融点：１４３〜１４５℃
Ｒｆ蔦 ：０．２４ Ｒ，２：０．４５
［α］ 、 ニー２５． ６° （Ｃ＝１．０．
ＤＭＦ）ｔｌ −（： ｙ ｓ −Ｔ ’
ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−Ｄ−Ａｒｇ−Ｇｌ
ｙ−ＮＨ２−酢酸塩Ｚ−ｐＧ Ｉｎ−Ａｓｎ−Ｃｙｓ
（ＭＨｚ Ｉ） −Ｐｒｏ−Ｄ −Ａ ｒｇ （Ｍｂｓ
）−Ｇ Ｉｙ−Ｎｌ１２２００ｍｇをアニソール０．２
ｍ ｌ及びＭＳＡ２ｍｆ！、中に加え、室温で１時間攪
拌した後、エーテルを加えた。
上澄みを除去し、沈殿物を水に溶解した後、Ｄｏｗｅｘ
ｌｘ２ （アセテート型）処理し凍結乾燥した。
凍結乾燥ペプチドを０．０５％ＴＦ＾５ｍｊ２．に溶解
し、参考例１で製造したＨ−にｙｓ （Ｓｃｍ）−Ｔ’
・塩酸塩８８ｍｇを水冷下に添加した。
２０分間攪拌した後、ｌ ２ｍｆｆ１／分（流量）、１
０から２０％Ｂ）２０分直線グラジェント（移動相）に
て、高速液体クロマトグラフィー特製の後、Ｄｏｗｅｘ
ｌｘ２（アセテート型）処理し、凍結乾燥して標記の化
合物を得た。
収量：１０４ｍｇ
Ｒｒ３：０．０８
［α］Ｄ ニー４１．６° （ｃ−０，６，水）し実施
例２］
１ｌ−Ｃｙｓ−Ｔ’
ト＾ｓｎ−［：ｙｓ−Ｐｒｏ−＾ｒｇ−Ｏｌｌ ・酢酸
塩Ｉｔ−Ａｓｎ−ｆ；ｙｓ−Ｐｒｏ−Ａｒｇ−Ｏｌｌ
−酢酸塩２７ｍｇと参考例１で製造したトＧｙｓ （Ｓ
ｃｍ） −Ｔ’ ・塩酸塩３１ｍｇとから、実施例１（
５）におけると同様にして標記の化合物を得た。
収量：１８ｍｇ
Ｒ，３：０．０７
［ａ］ｎ： ６０．７°（ｃ−０，５，水）「実施例
３］
）１−Ｃｙｓ−Ｔ’
）１−Ａｓｎ−（１：ｙｓ−Ｐｒｏ−＾ｒｇ−ＮＨ，−
酢酸塩トＡｓｎ−Ｃｙｓ−Ｐｒｏ−Ａｒｇ−ＮＨ２−酢
酸塩９７ｍｇと参考例１で製造した１Ｉ−Ｃｙｓ （Ｓ
ｃｍ） −Ｔ’ ・塩酸塩４９ｍｇとから、実施例１（
５）におけると同様にして標記の化合物を得た。
収量：４９ｍｇ
Ｒ，”：０．０６
［α］。ニー５４．６°（ｃ−０，５，水）［実施例４
］
１ｌ−Ｇｙｓ−Ｔ’
ｐＧｌｕ−八５ｎ−Ｃｙｓ−Ｐｒｏ−＾ｒｇ−０１１・
酢酸塩ｐ Ｇ Ｉ ｕ−＾５ｎ−Ｃｙｓ−Ｐｒｏ−Δｒ
ｇ−Ｏ１１・酢酸塩３２ｍｇと参考例１て製造したＩｔ
−Ｃｙｓ （ＳＣ［０）−Ｔ’・塩酸塩３２ｍｇとから
、実施例１（５）におけると同様にして標記の化合物を
得た。
収量：３３ｍｇ
Ｒ，３：０．１１
［α］。ニー６５．１“（ｃ−０，５，水）［実施例５
］
ｔｌ−Ａｓｎ−（：ｙｓ−Ｐｒｏ−Ａｒｇ−Ｇｌｙ−Ｎ
Ｈ，−酢酸塩６５ｍｇと参考例１で製造したＨ−Ｃｙｓ
（Ｓｃ＋＋＋） −Ｔ ’・塩酸塩６０ｍｇとから、
実施例１（５）におけると同様にして標記の化合物を得
た。
収量：４２ｍｇ
Ｒ，’：０．０５
［α］ｏ ニー５７．０°（ｃ−０，５，水）［実施例
６］
１ｌ−Ｇｙｓ−Ｔ’
ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−Ａｒｇ−Ｇｌｙ−
ＮＨ２・酢酸塩ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−Ａ
ｒｇ−Ｇｌｙ−ＮＨ□−酢酸塩２８ｍｇと参考例１で製
造した１ｌ−（：ｙｓ （ＳＣＤＩ） −Ｔ’−塩酸塩
２７ｍｇとから、実施例１（５）におけると同様にして
標記の化合物を得た。
収量：２５ｍｇ
Ｒｒ３：０．１０
［α］ｏ ニー６６．４°（ｃ−０，５，水）［実施例
７］
Ｈ−Ｇｙｓ−Ｔ’
ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｐｒｏ−Ｌｙｓ−Ｇｌｙ−
ＮＨ２−酢酸塩ｐＧｌｕ−Ａｓｎ−（：ｙｓ−Ｐｒｏ−
Ｌｙｓ−Ｇｌｙ−Ｎｔ１２Ｈ酢酸塩６７ｍｇと参考例１
で製造したＨ−（：ｙｓ （Ｓｃｍ） −Ｔ’ ・塩酸
塩５０ｍｇとから、実施例１（５）におけると同様にし
て標記の化合物を得た。
収量：３５ｍｇ
Ｒ，’：０．２２
［α］。ニー５１．９°（ｃ−０，６，水）［実施例８
］
１１−（：ｙｓ−Ｔ’
ｐＧｌｕ−Ａｓｎ−Ｃｙｓ−Ｄ−Ｐｒｏ−＾ｒｇ−Ｇｌ
ｙ−Ｎｉ１２−酢酸塩（１）Ｚ−Ａｒｇ（Ｍｂｓ）−Ｇ
ｌｙ−ＮＨ２２−八ｒｇ （Ｍｂｓ）−ＯＨジシクロヘ
キシルアミン塩１０ｇを、ＩＩ−Ｇｌｙ−ＮＨ２塩酸塩
１．７ｇ、 ＮＭＭ １．７ ｍｌｌ、１１０Ｂｔ ２
ｇ及びＤ［；ｌ； ３．４ ｇから、実施例１（１）
におけると同様にして、標記の化合物を得た。
収量：５．０ｇ
融点＝２０１〜２０２℃
Ｒ，Ｉ：０．２６ Ｒ，２：０．５５［α］。：＋
２．１°（ｃ−０，５，ＤＭＦ）（２） Ｂｏｃ−Ｄ
−Ｐｒｏ−八ｒｇ（Ｍｂｓ）−Ｇｌｙ−ＮＨ□２−八ｒ
ｇ（Ｍｂｓ）−Ｇｌｙ−ＮＨ□ ５．２ｇ 、 Ｂ
ｏｃ−Ｄ−Ｐｒｏ−Ｏ５ｕ３．１ ｇ、 ＮＭＭ ２．
２ ｍｌから、実施例１（２）におけると同様にして、
標記の化合物を得た。
収量：５．７ｇ
融点：８８〜９１”Ｃ
Ｒｒ’： ０． ３ ５ Ｒｆ２： ｏ、
５９［ｃｚ］、：＋８．７° （ｃＪ、６． Ｄ
ＭＦ）（３）Ｂｏｒ、−Ｃｙｓ（ＭＢｚｌ）−Ｄ−Ｐｒ
ｏ−Ａｒｇ（Ｍｂｓ）−Ｇｌｙ−ＮＨ□Ｂｏｃ−Ｄ−Ｐ
ｒｏ−Ａｒｇ（Ｍｂｓ）−Ｇｌｙ−ＮＨ２５，Ｏｇ、
Ｂｏｃ−Ｃｙｓ（ＭＢｚｌ）−０ｔｌ ３．４ ｇ
、 ＮＭＭ ２．３ ｍ ｌ、ＨＯＢｔ １．５ｇ及び
、Ｄ（：Ｇ ２．１ ｇから、実施例１（３）における
と同様にして、標記の化合物を得た。
収量：３−８ｇ
融点：１０１〜１０３℃
Ｒ，’： ０．４７ Ｒ，２： ０．６３［ａＥ
ｏ ： −１６，４” （ｃ＝１．ｏ、 ＤＭＦ）Ｚ−
ｐＧ １ｕ−Ａｓｎ−Ｃｙｓ （ＭＢｚ Ｉ）−Ｄ−Ｐ
ｒｏ−八ｒｇ（Ｍｂｓ）−Ｇｌｙ−ＮＨ２Ｂｏｃ−Ｃｙ
ｓ（ＭＢｚｌ）−Ｄ−Ｐｒｏ−Ａｒｇ（Ｍｂｓ）−Ｇｌ
ｙ−ＮＨ，３，５ｇ、 Ｚ−ｐＧｌｕ−Ａｓｎ−Ｏｆ
ｆ １．６ ｇ、 ＮＭＭ ０．４６ｍｆ、
１ｌＯＢｔＯ，７５ｇ及び、ＤＣ（： ０．９２ｇから
、実施例１（４）におけると同様にして、標記の化合物
を得た。
収＠：３．１ｇ
融点＝１４７〜１４９℃
Ｒｆ’： ０． ２５ Ｒｒ”： ｏ、
５０［αｌ、 ニー２４． ６° （ｃ＝１．０．
ＤＭＦ）Ｈ−Ｃｙｓ−Ｔ’
ｐＧｌｕ−Ａｓｎｌｌ：ｙｓ−Ｄ−Ｐｒｏ−Ａｒｇ−Ｇ
ｌｙ−ＮＨ２・酢酸塩Ｚ−ｐＧｌｕ−八５ｎ−Ｃｙｓ
（ＭＢｚｌ）−Ｄ−Ｐｒｏ−八ｒｇ（Ｍｂｓ）−Ｇｌｙ
−Ｎｉ１２２００ｍｇ及び参考例１で製造したＩＩ−Ｃ
ｙｓ （Ｓｃｍ）−Ｔ’・塩酸塩６０ｍｇから実施例１
（５）におけると同様にして、標記の化合物を得た。
収量： ５４ｍｇ
Ｒｒ３：０．０８
［α］ｏ ニー２１．４°（ｃ−０，６，水）次に、本
発明のペプチド誘導体の有効性を示す薬理学的試験例を
示す。
［薬理学的試験例］
記憶固定に対する作用はＷｉｓｔａｒ系雄性ラットを用
いて、プルバッハ（Ｂｕｒｂａｃｈ）ら［サイエンス（
Ｓｒ、１ｅｎｃｅ）、 ２２］、 １３１０−１３１２
（１９８３年）１の方法に準じたー試行受動的回避実験
により検討した。実験装置は、明室と暗室とから成り、
床はステンレス製グリッドでできている。明室に入れら
れたラットは自由に暗室へ移動できる。この装置を用い
、ラットが暗室に入ると一回の電気ショックを経験させ
る。電気ショックに対する受動的回避行動の保持は、一
定時間後に再び明室に置かれたラットが暗室に入るまで
の時間（反応潜時）によって判定した。
サイクロへキシミド（ｃｙｃｌｏｈｅｘｉａ＋１ｄｅ）
による実験的逆向性健忘の改善効果の検討
本発明のペプチド誘導体または生理食塩水を皮下投与し
１時間後に電気ショック（０，５ｍＡ）を経験させ、そ
の直後にサイクロヘキシミド２゜７〜３ 、０ ｍｇ／
ｋｇまたは生理食塩水を皮下投与し、４８時間後に記
憶保持試験を行った。生理食塩水のみを投与したラット
は一般に３００秒前後の反応潜時を示し、サイクロへキ
シミドのみを投与した対照群のラットは５０秒前後の反
応潜時を示し逆向性健忘を発現した。
本発明のペプチド誘導体投与群の反応潜時の平均値と対
照群のそれとを比較した。各群の試験にに使用したラッ
トの数は６〜８匹である。最大測定時間は６００秒とし
た。
各実施例で得られたペプチド誘導体について、その投与
量及び効果（対照群の反応潜時に対する各側の反応潜時
の割合を％で示す）を第１表に示す。
以下余白
第１表
上記の試験結果から、本発明のペプチド誘導体は、チア
ミンを有しないペプチドに比べて、１／１０乃至１／１
００の投与量で同等の効果を奏しており、優れた記憶促
進効果及び逆向性健忘に対する改善効果を示した。
次に本発明のペプチド誘導体を含有する薬剤の製剤例を
示す。
［実施例９］ （注射剤）
注射用蒸留水１００ｒｎＪＺ中に、実施例１で得られた
ペプチド誘導体０．１ｍｇ、及び塩化ナトリウム０．９
ｇを含有させ、ｐＨを水酸化ナトリウムで６．０〜８．
０に調節した水溶液を調製した。これを、細菌濾過後１
ｒｎＪＺアンプルに充填、溶閉し加熱滅菌して、注射剤
を製造した。
［実施例１０］ （凍乾製剤）
注射用蒸留水１００ｍｊＺ中に、実施例１で得られたペ
プチド誘導体５ｍｇ、及びＤ−マンニット５ｇを含有さ
せ、ｐ）（をリン酸緩衝液で６．０〜８．０に調節した
水溶液を調製した。これを、細菌濾過し、バイアル瓶に
１ｍ４２分注した後、凍結乾燥を行ない、凍結乾燥注射
剤を製造した。
［実施例１１］ （点鼻剤）
生理食塩水１００ｒｎＩＬ中に、実施例１で得られたペ
プチド誘導体１０ｍｇを含有させ、ｐＨをクエン酸緩衝
液で３．０〜６．０に調節し、１回投与量０．Ｓｍｆｆ
１中に５０μｇ含有する点鼻剤を製造した。
［実施’１１１２］（平削）
ハードファツト（飽和脂肪酸のトリグリセライド）９８
．５ｇに卵黄レシチン０．５ｇを加え、４０〜４５℃に
て溶融させた後、実施例１で得られたペプチド誘導体５
ｍｇをＰＥＧ４００のＩｇに溶解させた液をこれに添加
し攪拌分散させた後、その１ｇを平削型に注入し、固化
後型から分離して平削を製造した。
［発明の効果］
本発明のペプチド誘導体は、新規な化合物であり、優れ
た向知能性作用を有しており、医薬として有用である。
特許出願人 ［１本ケミファ株式会社特許出願人
富士レビオ株式会社
代 理 人 弁理士 柳川 秦男[ )1-Asn-Cys-Pro-8rg-Nl12pG
lu-Asn-Cys-Pro-8rg-OHH-As
n-Cys-Pro-Arg-Gly-Nil□pGI
u-Asn-Cys-Pro-8rg-Gly-Ni1
2pGlu-Asn-Cys-Pro-D-8rg-G
ly-NH2pGlu-Asn-Cys-D-Pro-
^rg-Gly-NllzpGlu-Asn-Gys-
The peptide derivative of the present invention, Pro-Lys-Gly-Ni12, exhibits a strong nootropic effect in a passive avoidance test in rats. Useful target diseases for the peptide derivatives of the present invention include:
Examples include senile dementia (Alzheimer's dementia), cerebrovascular dementia, and dementias caused by Alzheimer's disease, Vick's disease, Huntington's disease, Creutzfeldt-Jakob disease, Parkinson's disease, myelin degeneration of the cerebellum, etc. and can be used for the prevention or treatment of these diseases. The toxicity of the peptide derivatives of the present invention is extremely low, and there have been no cases of death even at doses far exceeding the medicinally effective dose. The peptide derivatives of the invention can be administered as free forms or as derivatives at their functional groups. Its death! The amount of the educt is generally in the range of 0.1 ng to 1 mg/day, regardless of whether it is the educt or its salt. In particular, for parenteral administration and nasal administration, the dose is preferably 0.1 ng to 100 μg/day, and for oral administration and rectal administration, the dose is preferably 10 to 100 times the parenteral administration. The peptide derivative of the present invention is mainly administered parenterally (e.g., intravenous or subcutaneous injection, intraventricular or intrathecal administration, nasal administration, rectal administration), but in some cases, it may be administered orally. Good too. Dosage forms include, for example, injections, tablets, powders, nasal drops,
Examples include gunpowder and tablets. The peptide derivative of the present invention can be stored as a solution in physiological saline, but it can also be prepared into a lyophilized ampoule by adding mannitol or sorbitol, and then dissolved at the time of use. Examples are shown below. In each example, the developing solvent for thin layer chromatography was as follows, and Merck & Co. TLC plate silica gel 60 F 254 was used. R "1: Chloroform-methanol-acetic acid-water (80:
20:2.5:5) Lower layer R, ”:Chloroform-methanol-water (70::IQ
:5) R,3,n-butanol-acetic acid-water (2:l:l) Also, for purification by high performance liquid chromatography, column: μBondapak C+a 1.9
Performed using Xl5cm mobile phase: A) 0.05% TFA, B) Acetonitrile. [Reference Example 1] H-Cys (Scm) -T'・Salt bond salt (However, T
1 represents the general formula (I) in which R1 is a benzoyl group.
II) (1) Boa4:
ys (8cm)-T'30cmCys (8cm)-0
111,Og, S-benzoylthiamine 1.3g and 4-dimethylaminopyridine 20mg (:thC1
250m JZ hot solution under water cooling D(:GO, 78g O
H□(:125+njZ solution was added dropwise. After stirring for 30 minutes under water cooling and further stirring at room temperature for 1 hour, DC
Urea was filtered off and washed with saturated sodium bicarbonate water and water. After drying over anhydrous sodium sulfate, the solvent was distilled off, and the crystals were collected by filtration with ether to obtain the title compound. Yield: 1. Bg Melting point = 71-75°C Rf': 0.74 Rf2: o, 82[αko. : -39,2" (c-0,5,DMF)(
2) Boa-Cys (ScrM) -T'11o
cl;ys(Ac+++)-T' 600 mg Mc
Oll-112G12 (1: lv/v) 6m
0.14 ml of Cl-5cm was added to the fl solution, and the mixture was stirred at room temperature for 20 minutes. After evaporating the solvent, the residue was purified on a silica gel column using CHCI 3-McOll to obtain the title compound as an oil. Yield + 580 mg Rr': 0.82 Re': 0.88 [ff
]o: 44.0° (c=0.5. DMF) (3
) ItoCys(Scm)-T' Hydrochloride 11oc
-Cys(Scm)-T' 470mg in 4N1
After standing in 2 mfl of cOEt for 30 minutes at room temperature, the solvent was distilled off. The residue was ell (: 11-MeO
Purification was performed on a silica gel column using tl to obtain the title compound as an oil. Yield: 250 mg R,': 0.38 R,': 0.54[α
Ko . :+38. 4 ° (c-0,5,
DMF) [Example 1] 1l-Cys-T' pGlu-Asn-Cys-Pro-D-Arg-Gl
y-NH□-acetate (1) Z-D-Arg(Mbs)-
30 g of Gly-Nll□Z-D-Arg(Mbs)-0H dicyclohexylamine salt was added to 500 mu of cOEt.
After stirring and dissolving in 200ml of +5% citric acid water,
The AcoEt layer was washed with water and dried over anhydrous sulfuric acid. The solvent was distilled off, and the resulting residue was added to 300 mfl of DMF.
5 g of It-Gly-Nlh hydrochloride dissolved in and cooled with water,
8MM5mft, 110Bt, 8g and DGC9,
8g was added. After the mixture was stirred at room temperature for 18 hours,
DI: IJ rea was filtered off and DMF was distilled off. The residue was diluted with 2-butanol-CII2CI2 (5:1
(v/v), washed successively with saturated aqueous sodium bicarbonate, saturated aqueous dilute hydrochloric acid, and saturated brine, and then dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was crystallized from Meoll-ether to give the title compound. Yield: 14.6g Melting point = 194-196°C R,': 0.24 R,2: 0.52[a]o:
2.9° (c=0.5. DMF) (2) Iloc-
Pro-D-Arg(Mbs)-Gly-Nll. Z-D-Arg(Mbs)-Gly-Nllz 10.
7 g were stirred in 80% Ac011200 mfi in the presence of 10% palladium on carbon for 6 hours under a stream of hydrogen. After filtering off the palladium on carbon, the solvent was distilled off. After drying the residue under reduced pressure, 100ml of DMF! Dissolved in NM
M3mQ, Boc-Pro-O5u 6.2
g and stirred at room temperature for 18 hours. DMF was distilled off, and the residue was dissolved in 2-butanol-Clh (:
12 (5:1 v/v), washed successively with saturated sodium bicarbonate water, salt-saturated dilute hydrochloric acid water, and saturated salt water, and then dried over anhydrous sodium sulfate. After evaporating the solvent, ether was added to the residue to crystallize it to give the title compound. Yield: 11.9g Melting point °108-111°C R,': 0.32 Rr2: 0.56[a]o
Knee 6.9° (c-0,5, DhlF) (3) Bo
c-Cys(MBzl)-Pro-D-8rg(Mbs
)-Gly-Ntl□11oc-Pro-D-Arg(
Mbs)-Gly-Nil□2.9g was added to 4NH(:l
-Ac0Et: After standing in 25 mE at room temperature for 30 minutes, the solvent was distilled off. After drying the residue under reduced pressure, it was dissolved in 50 ml of DMF and mixed with NMMO, 53 ml, Boc-Gys (
MBzl)-Off 1.8g, HOBt O, 85g
and DI:C1.1g were added, and the mixture was stirred at room temperature for 18 hours. DCllrea was filtered off, DMF was distilled off, and the residue was
-Butanol-an□C:+2 (5:1 v/v), washed successively with saturated sodium bicarbonate water, salt-saturated dilute hydrochloric acid water, and saturated salt water, and then dried over anhydrous sodium sulfate. After evaporating the solvent, ether was added to the residue to crystallize it, and the title compound was collected by filtration. Yield: 3.3g Melting point: 127-130°C R,': 0.47 R,'': 0.63 [alD
Knee 7.6° (c=1.0. DMF) Z-pGl
u-Asn-Cys (MBzl)-Pro-D-8r
g(Mbs)-Gly-NH2Boc-Gys(MBz
i)-Pro-D-Arg(Mbs)-Gly-Ntl
z 3.18g to 4N 1111:1-AcOEt
After standing in 20 m tl for 30 minutes at room temperature, the solvent was evaporated. It was added to the residue in 2-butanol. Cl2(5:1
v/v) and saturated sodium bicarbonate water were added, and the organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was dissolved in 30 mffi of DMF, and 1.77 g of Z-pGlu-Asn-OH was added under water cooling.
63 g of Bt O and 97 g of D (:C) were added. After stirring at room temperature for 18 hours, DGUrea was filtered out and D
MF was distilled off. The residue was dissolved in 2-butanol-cl12c12 (5:1
(v/v), washed successively with saturated aqueous sodium bicarbonate, saturated aqueous dilute hydrochloric acid, and saturated brine, and then dried over anhydrous sodium sulfate. After evaporating the solvent, ether was added to the residue to crystallize it to give the title compound. Yield: 3.4g Melting point: 143-145°C Rf ivy: 0.24 R,2:0.45
[α], Knee 25. 6° (C=1.0.
DMF)tl-(:ys-T'pGlu-Asn-Cys-Pro-D-Arg-Gl
y-NH2-acetate Z-pG In-Asn-Cys
(MHz I) -Pro-D -A rg (Mbs
)-G Iy-Nl 12200mg anisole 0.2
m l and MSA2mf! After stirring at room temperature for 1 hour, ether was added. After removing the supernatant and dissolving the precipitate in water, Dowex
lx2 (acetate type) treatment and lyophilization. Lyophilized peptide was added to 0.05% TF^5mj2. ys (Scm)-T' to the H- produced in Reference Example 1.
- 88 mg of hydrochloride was added under water cooling. After stirring for 20 minutes, l 2mff1/min (flow rate), 1
0 to 20% B) in a 20 min linear gradient (mobile phase), after high performance liquid chromatography, Dowex
Treatment with lx2 (acetate form) and lyophilization gave the title compound. Yield: 104 mg Rr3: 0.08 [α]D knee 41.6° (c-0,6, water) and Example 2] 1l-Cys-T'to^sn-[:ys-Pro-^rg- Oll ・Acetate It-Asn-f;ys-Pro-Arg-Oll
- 27 mg of acetate and Gys (S) produced in Reference Example 1
cm) -T' ・From 31 mg of hydrochloride, Example 1 (
The title compound was obtained in the same manner as in 5). Yield: 18 mg R, 3:0.07 [a]n: 60.7° (c-0,5, water) "Example 3")1-Cys-T')1-Asn-(1:ys- Pro-＾rg-NH,-
Acetate Asn-Cys-Pro-Arg-NH2-acetate 97 mg and 1I-Cys (S
cm) -T' ・From 49 mg of hydrochloride, Example 1 (
The title compound was obtained in the same manner as in 5). Yield: 49 mg R,'': 0.06 [α]. Knee 54.6° (c-0,5, water) [Example 4
] 1l-Gys-T' pGlu-85n-Cys-Pro-＾rg-011・
Acetate p G I u-^5n-Cys-Pro-Δr
32 mg of g-O11 acetate and It produced in Reference Example 1
The title compound was obtained from 32 mg of -Cys (SC[0)-T' hydrochloride in the same manner as in Example 1 (5). Yield: 33 mg R, 3:0.11 [α]. Knee 65.1" (c-0,5, water) [Example 5
] tl-Asn-(:ys-Pro-Arg-Gly-N
65 mg of H,-acetate and H-Cys produced in Reference Example 1
(Sc+++) -T'・From 60 mg of hydrochloride,
The title compound was obtained in the same manner as in Example 1 (5). Yield: 42 mg R,': 0.05 [α] o knee 57.0° (c-0,5, water) [Example 6] 1l-Gys-T' pGlu-Asn-Cys-Pro-Arg-Gly −
NH2/acetate pGlu-Asn-Cys-Pro-A
From 28 mg of rg-Gly-NH□-acetate and 27 mg of 1l-(:ys (SCDI)-T'-hydrochloride produced in Reference Example 1), the title compound was prepared in the same manner as in Example 1 (5). Yield: 25 mg Rr3: 0.10 [α]o knee 66.4° (c-0,5, water) [Example 7] H-Gys-T' pGlu-Asn-Cys-Pro-Lys- Gly-
NH2-Acetate pGlu-Asn-(:ys-Pro-
67 mg of Lys-Gly-Nt12H acetate and Reference Example 1
From 50 mg of H-(:ys (Scm) -T' .hydrochloride produced in Example 1 (5)), the title compound was obtained in the same manner as in Example 1 (5). Yield: 35 mg R,': 0.22 [ α]. Knee 51.9° (c-0,6, water) [Example 8
] 11-(:ys-T' pGlu-Asn-Cys-D-Pro-^rg-Gl
y-Ni12-acetate (1) Z-Arg(Mbs)-G
ly-NH22-8rg (Mbs)-OH dicyclohexylamine salt 10g, II-Gly-NH2 hydrochloride 1.7g, NMM 1.7ml, 110Bt2
g and D[;l; from 3.4 g, Example 1(1)
The title compound was obtained in the same manner as in . Yield: 5.0 g Melting point = 201-202°C R, I: 0.26 R, 2: 0.55 [α]. :+
2.1° (c-0,5,DMF) (2) Boc-D
-Pro-8rg(Mbs)-Gly-NH□2-8r
g(Mbs)-Gly-NH□ 5.2g, B
oc-D-Pro-O5u3.1 g, NMM 2.
From 2 ml, as in Example 1(2),
The title compound was obtained. Yield: 5.7g Melting point: 88-91"C Rr': 0.35 Rf2: o,
59[cz], :+8.7° (cJ, 6.D
MF) (3) Bor, -Cys(MBzl)-D-Pr
o-Arg(Mbs)-Gly-NH□Boc-D-P
ro-Arg(Mbs)-Gly-NH25,Og,
Boc-Cys(MBzl)-0tl 3.4 g
From 2.3 ml of NMM, 1.5 g of HOBt, and 2.1 g of D(:G), the title compound was obtained in the same manner as in Example 1(3). Yield: 3-8 g Melting point: 101-103°C R,': 0.47 R,2: 0.63 [aE
o: -16,4" (c=1.o, DMF)Z-
pG 1u-Asn-Cys (MBz I)-D-P
ro-8rg(Mbs)-Gly-NH2Boc-Cy
s(MBzl)-D-Pro-Arg(Mbs)-Gl
y-NH, 3.5 g, Z-pGlu-Asn-Of
f 1.6 g, NMM 0.46mf,
From 75 g of 11OBtO and 0.92 g of DC, the title compound was obtained in the same manner as in Example 1 (4). Yield: 3.1 g Melting point = 147-149°C Rf': 0.25 Rr”: o,
50 [αl, knee 24. 6° (c=1.0.
DMF) H-Cys-T' pGlu-Asnll:ys-D-Pro-Arg-G
ly-NH2 Acetate Z-pGlu-85n-Cys
(MBzl)-D-Pro-8rg(Mbs)-Gly
-Ni 12200mg and II-C produced in Reference Example 1
Example 1 from 60 mg of ys (Scm)-T' hydrochloride
The title compound was obtained in the same manner as in (5). Yield: 54 mg Rr3: 0.08 [α]o knee 21.4° (c-0,6, water) Next, pharmacological test examples showing the effectiveness of the peptide derivative of the present invention will be shown. [Pharmacological test example] The effect on memory consolidation was determined using Wistar male rats by Burbach et al.
Sr, 1ence), 22], 1310-1312
(1983) conducted a trial passive avoidance experiment based on method 1. The experimental equipment consists of a bright room and a dark room.
The floor is made of stainless steel grid. Rats placed in the light room can freely move to the dark room. Using this device, rats are given a single electric shock when they enter a dark room. Retention of passive avoidance behavior in response to electric shock was determined by the time it took for the rat, placed in the light room again after a certain period of time, to enter the dark room (response latency). Cycloheximide (cyclohexia+1de)
Examination of the effect of improving experimental retrograde amnesia by administering the peptide derivative of the present invention or physiological saline subcutaneously, 1 hour later, an electric shock (0.5 mA) was administered, and immediately thereafter, cycloheximide 2.7-3. ,0 mg/
kg or physiological saline was administered subcutaneously, and a memory retention test was conducted 48 hours later. Rats administered only with physiological saline generally exhibited a response latency of around 300 seconds, while rats in the control group administered only with cycloheximide exhibited a response latency of around 50 seconds and developed retrograde amnesia. The average response latency of the group administered with the peptide derivative of the present invention was compared with that of the control group. The number of rats used for testing each group is 6-8. The maximum measurement time was 600 seconds. For the peptide derivatives obtained in each example, the dosage and effects (ratio of response latency on each side to response latency of the control group is shown in %) are shown in Table 1. Table 1 in the margin below From the above test results, the peptide derivative of the present invention is 1/10 to 1/1 of the thiamine-free peptide.
The same effect was achieved at the dose of 0.00, showing an excellent memory promoting effect and an improving effect on retrograde amnesia. Next, examples of formulations of drugs containing the peptide derivatives of the present invention will be shown. [Example 9] (Injection) 0.1 mg of the peptide derivative obtained in Example 1 and 0.9 mg of sodium chloride in 100 rnJZ of distilled water for injection.
g and the pH was adjusted to 6.0-8.g with sodium hydroxide.
An aqueous solution adjusted to 0 was prepared. After bacterial filtration, 1
An injection was prepared by filling an rnJZ ampoule, sealing it, and sterilizing it by heat. [Example 10] (Freeze-dried preparation) 5 mg of the peptide derivative obtained in Example 1 and 5 g of D-mannitol were added to 100 mjZ of distilled water for injection, and 6. An aqueous solution adjusted to 0 to 8.0 was prepared. This was subjected to bacterial filtration, dispensed into 1 m42 vials, and then lyophilized to produce a lyophilized injection. [Example 11] (Nasal Drop) Agent) 10 mg of the peptide derivative obtained in Example 1 was contained in 100 rnIL of physiological saline, the pH was adjusted to 3.0 to 6.0 with a citrate buffer, and the single dose was 0.Smff.
A nasal spray containing 50 μg in 1 was produced. [Implementation '1112] (Planning) Hard fat (triglyceride of saturated fatty acids) 98
．． After adding 0.5 g of egg yolk lecithin to 5 g and melting at 40 to 45°C, the peptide derivative 5 obtained in Example 1 was added.
A solution prepared by dissolving PEG400 in Ig was added thereto, stirred and dispersed, and then 1 g of the solution was poured into a planing mold, and after solidification, it was separated from the mold to produce a planing. [Effects of the Invention] The peptide derivative of the present invention is a novel compound, has excellent nootropic activity, and is useful as a medicine. Patent Applicant [Ippon Chemifa Co., Ltd. Patent Applicant
Fujirebio Co., Ltd. Representative Patent Attorney Hatao Yanagawa
Claims (1)
ｌｕ又はＨを示し、Ｑ＾２は、Ｇｌｙ−ＯＨ又はＯＨを
示し、Ｗは下記一般式（II）： Ｙ＾１−Ｃｙｓ−Ｙ＾２（II） （式中、Ｙ＾１はＨ又はＣＯ−Ｔであり、Ｙ＾２はＯＨ
又はＴであり、 （但し、Ｔは下記一般式（III）： ▲数式、化学式、表等があります▼（III） （式中、Ｒ＾１は、炭素原子数２〜７のアルキルカルボ
ニル基、炭素原子数７〜１０のアリールカルボニル基及
び炭素原子数１〜６のアルキルチオ基からなる群から選
ばれた基である）、 又は、下記一般式（IV）： ▲数式、化学式、表等があります▼（IV） （式中、Ｒ＾２は、水素原子、炭素原子数２〜７のアル
キルカルボニル基、炭素原子数７〜１０のアリールカル
ボニル基からなる群から選ばれた基である）、 で表わされる基である） Ｙ＾１及びＹ＾２の少なくとも一方はＴを含む）で表わ
される基であり、ペプチド構成アミノ酸はＬ型であるが
、Ｐｒｏ及びＡｒｇはＤ型であってもよい］ で表わされるペプチド誘導体、若しくはその官能基にお
ける誘導体、又はそれらの薬理学的に許容され得る塩。 ２、下記一般式（ I ）： ▲数式、化学式、表等があります▼（ I ） ［式中、ＡはＡｒｇ又はＬｙｓを示し、Ｑ＾１は、ｐＧ
ｌｕ又はＨを示し、Ｑ＾２は、Ｇｌｙ−ＯＨ又はＯＨを
示し、Ｗは下記一般式（II）： Ｙ＾１−Ｃｙｓ−Ｙ＾２（II） （式中、Ｙ＾１はＨ又はＣＯ−Ｔであり、Ｙ＾２はＯＨ
又はＴであり、 （但し、Ｔは下記一般式（III）： ▲数式、化学式、表等があります▼（III） （式中、Ｒ＾１は、炭素原子数２〜７のアルキルカルボ
ニル基、炭素原子数７〜１０のアリールカルボニル基及
び炭素原子数１〜６のアルキルチオ基からなる群から選
ばれた基である）、 又は、下記一般式（IV）： ▲数式、化学式、表等があります▼（IV） （式中、Ｒ＾２は、水素原子、炭素原子数２〜７のアル
キルカルボニル基、炭素原子数７〜１０のアリールカル
ボニル基からなる群から選ばれた基である）、 で表わされる基である） Ｙ＾１及びＹ＾２の少なくとも一方はＴを含む）で表わ
される基であり、ペプチド構成アミノ酸はＬ型であるが
、Ｐｒｏ及びＡｒｇはＤ型であってもよい］ で表わされるペプチド誘導体、若しくはその官能基にお
ける誘導体、又はそれらの薬理学的に許容され得る塩の
有効量、及び薬理学的に許容され得る担体若しくは希釈
剤を含有してなる抗痴呆剤。[Claims] 1. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A represents Arg or Lys, and Q^1 represents pG
lu or H, Q^2 represents Gly-OH or OH, and W represents the following general formula (II): Y^1-Cys-Y^2 (II) (wherein, Y^1 is H or CO-T and Y^2 is OH
or T, (However, T is the following general formula (III): ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (In the formula, R^1 is an alkylcarbonyl group having 2 to 7 carbon atoms, A group selected from the group consisting of an arylcarbonyl group having 7 to 10 carbon atoms and an alkylthio group having 1 to 6 carbon atoms), or the following general formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(IV) (wherein R^2 is a group selected from the group consisting of a hydrogen atom, an alkylcarbonyl group having 2 to 7 carbon atoms, and an arylcarbonyl group having 7 to 10 carbon atoms), At least one of Y^1 and Y^2 contains T), and the peptide-constituting amino acids are L-type, but Pro and Arg may be D-type.] A peptide derivative represented by, or a functional group derivative thereof, or a pharmacologically acceptable salt thereof. 2. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, A represents Arg or Lys, and Q^1 represents pG
lu or H, Q^2 represents Gly-OH or OH, and W represents the following general formula (II): Y^1-Cys-Y^2 (II) (wherein, Y^1 is H or CO-T and Y^2 is OH
or T, (However, T is the following general formula (III): ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (In the formula, R^1 is an alkylcarbonyl group having 2 to 7 carbon atoms, A group selected from the group consisting of an arylcarbonyl group having 7 to 10 carbon atoms and an alkylthio group having 1 to 6 carbon atoms), or the following general formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(IV) (wherein R^2 is a group selected from the group consisting of a hydrogen atom, an alkylcarbonyl group having 2 to 7 carbon atoms, and an arylcarbonyl group having 7 to 10 carbon atoms), At least one of Y^1 and Y^2 contains T), and the peptide-constituting amino acids are L-type, but Pro and Arg may be D-type.] An anti-dementia agent comprising an effective amount of a peptide derivative represented by the above formula, a functional group derivative thereof, or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier or diluent.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63201356A JPH0826068B2 (en) | 1988-08-12 | 1988-08-12 | Peptide derivative and anti-dementia agent containing the same |
| ZA896145A ZA896145B (en) | 1988-08-12 | 1989-08-11 | Novel peptide and anti-dementia agent |
| KR1019890011534A KR0141693B1 (en) | 1988-08-12 | 1989-08-12 | Peptide derivatives and anti-dementia agents |
| CA000608307A CA1339756C (en) | 1988-08-12 | 1989-08-14 | Peptide derivatives and antidementia agents |
| DK397989A DK397989A (en) | 1988-08-12 | 1989-08-14 | PEPTIDE DERIVATIVES AND MEDICINES AGAINST DEMENS WITH CONTENT OF SUCH RELATIONSHIPS |
| AU39907/89A AU632496B2 (en) | 1988-08-12 | 1989-08-14 | Novel peptide derivatives and antidementia agents |
| EP89308222A EP0354820B1 (en) | 1988-08-12 | 1989-08-14 | Novel peptide derivatives and anti-dementia agents |
| US07/393,515 US5312811A (en) | 1988-08-12 | 1989-08-14 | Peptide derivatives and antidemetia agents |
| AT89308222T ATE104315T1 (en) | 1988-08-12 | 1989-08-14 | PEPTIDE DERIVATIVES AND AGENTS AGAINST DEMENTIA. |
| DE68914545T DE68914545T2 (en) | 1988-08-12 | 1989-08-14 | Peptide derivatives and anti-dementia drugs. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63201356A JPH0826068B2 (en) | 1988-08-12 | 1988-08-12 | Peptide derivative and anti-dementia agent containing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0253797A true JPH0253797A (en) | 1990-02-22 |
| JPH0826068B2 JPH0826068B2 (en) | 1996-03-13 |
Family
ID=16439686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63201356A Expired - Lifetime JPH0826068B2 (en) | 1988-08-12 | 1988-08-12 | Peptide derivative and anti-dementia agent containing the same |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH0826068B2 (en) |
| ZA (1) | ZA896145B (en) |
-
1988
- 1988-08-12 JP JP63201356A patent/JPH0826068B2/en not_active Expired - Lifetime
-
1989
- 1989-08-11 ZA ZA896145A patent/ZA896145B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0826068B2 (en) | 1996-03-13 |
| ZA896145B (en) | 1990-05-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3853837A (en) | Novel nonapeptide amide analogs of luteinizing hormone releasing factor | |
| US4619916A (en) | Tripeptide compounds containing pyroglutamic acid and tryptophan, process for their production and therapeutic applications | |
| JPS6340199B2 (en) | ||
| EP0393934B1 (en) | Novel peptides, and antidementia agents containing the same | |
| KR940006768B1 (en) | Process for the preparation of spergualin related compound | |
| EP0354820B1 (en) | Novel peptide derivatives and anti-dementia agents | |
| EP0227410A2 (en) | Peptide derivatives, their production and use | |
| JPS60231697A (en) | Peptide | |
| JPH0631314B2 (en) | Novel gonadobereline derivative | |
| EP0354819B1 (en) | Novel peptide and anti-dementia agent | |
| JPH0253797A (en) | Peptide derivative and antidement agent containing same derivative | |
| JP2654673B2 (en) | Peptides and anti-dementia agents | |
| JP2640778B2 (en) | Peptide and anti-dementia agent containing the same | |
| JPH0253734A (en) | Agent for alleviating dementia | |
| SK57693A3 (en) | Linear peptides and pharmaceutical agents on their base | |
| CA1284550C (en) | Retro-inverso analogs of the bradykinin potentiating peptide bpp*in5a*xx | |
| JP2590005B2 (en) | Anti-dementia agent | |
| EP0406931B1 (en) | New analogues of all-bond retroinverted thymopentin, the method for the synthesis of the same and their employment for the preparation of pharmaceutical compositions | |
| JPH02273694A (en) | Peptide derivative and antidemential agent containing the same | |
| JPH02273698A (en) | Peptide and antidemential agent containing the same | |
| JPH02273699A (en) | Peptide and antidemential agent containing the same | |
| JP2542241B2 (en) | peptide | |
| JP2542254B2 (en) | Peptide and anti-dementia drug containing the same | |
| JPH02273697A (en) | Peptide and antidemential agent containing the same | |
| DD298410A5 (en) | RENININHIBITIC PEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |