WO1993013065A1 - Derive de proline - Google Patents
Derive de proline Download PDFInfo
- Publication number
- WO1993013065A1 WO1993013065A1 PCT/JP1992/001711 JP9201711W WO9313065A1 WO 1993013065 A1 WO1993013065 A1 WO 1993013065A1 JP 9201711 W JP9201711 W JP 9201711W WO 9313065 A1 WO9313065 A1 WO 9313065A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- pyrrolidine
- prolyl
- phenoxyacetyl
- compound
- Prior art date
Links
- 150000003147 proline derivatives Chemical class 0.000 title claims abstract description 17
- -1 nitro, hydroxy Chemical group 0.000 claims abstract description 128
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 206010012289 Dementia Diseases 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 208000000044 Amnesia Diseases 0.000 claims abstract description 5
- 208000031091 Amnestic disease Diseases 0.000 claims abstract description 5
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 5
- 230000006986 amnesia Effects 0.000 claims abstract description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 164
- 150000001875 compounds Chemical class 0.000 claims description 112
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims description 40
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000000638 benzylaminocarbonyl group Chemical group C(C1=CC=CC=C1)NC(=O)* 0.000 claims description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 9
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
- KPPVNWGJXFMGAM-UUILKARUSA-N (e)-2-methyl-1-(6-methyl-3,4-dihydro-2h-quinolin-1-yl)but-2-en-1-one Chemical compound CC1=CC=C2N(C(=O)C(/C)=C/C)CCCC2=C1 KPPVNWGJXFMGAM-UUILKARUSA-N 0.000 claims 1
- 229940122344 Peptidase inhibitor Drugs 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 33
- 230000002401 inhibitory effect Effects 0.000 abstract description 16
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 abstract description 12
- 101710178372 Prolyl endopeptidase Proteins 0.000 abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 11
- 101800004623 Thyrotropin-releasing hormone Proteins 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 5
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 230000002779 inactivation Effects 0.000 abstract description 4
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 abstract description 4
- 101800001814 Neurotensin Proteins 0.000 abstract description 3
- PCJGZPGTCUMMOT-ISULXFBGSA-N neurotensin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 PCJGZPGTCUMMOT-ISULXFBGSA-N 0.000 abstract description 3
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 abstract description 2
- 108010004977 Vasopressins Proteins 0.000 abstract description 2
- 102000002852 Vasopressins Human genes 0.000 abstract description 2
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract description 2
- 229960003726 vasopressin Drugs 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical group 0.000 abstract 2
- 102000050267 Neurotensin Human genes 0.000 abstract 1
- 102100032251 Pro-thyrotropin-releasing hormone Human genes 0.000 abstract 1
- 238000000354 decomposition reaction Methods 0.000 abstract 1
- 150000002431 hydrogen Chemical class 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 78
- 239000000243 solution Substances 0.000 description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 125000006239 protecting group Chemical group 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- 239000007853 buffer solution Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 239000012442 inert solvent Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 239000003480 eluent Substances 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000006482 condensation reaction Methods 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- CCZWSTFVHJPCEM-UHFFFAOYSA-N 2-iodopyridine Chemical compound IC1=CC=CC=N1 CCZWSTFVHJPCEM-UHFFFAOYSA-N 0.000 description 7
- 102000035195 Peptidases Human genes 0.000 description 7
- 108091005804 Peptidases Proteins 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 229960002429 proline Drugs 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 150000003462 sulfoxides Chemical class 0.000 description 6
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- XNSAINXGIQZQOO-UHFFFAOYSA-N L-pyroglutamyl-L-histidyl-L-proline amide Natural products NC(=O)C1CCCN1C(=O)C(NC(=O)C1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-UHFFFAOYSA-N 0.000 description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- 239000000627 Thyrotropin-Releasing Hormone Substances 0.000 description 4
- 102400000336 Thyrotropin-releasing hormone Human genes 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000002858 neurotransmitter agent Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XNSAINXGIQZQOO-SRVKXCTJSA-N protirelin Chemical compound NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H]1NC(=O)CC1)CC1=CN=CN1 XNSAINXGIQZQOO-SRVKXCTJSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229940034199 thyrotropin-releasing hormone Drugs 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108090000317 Chymotrypsin Proteins 0.000 description 3
- 229930182821 L-proline Natural products 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- PHENPABYBHPABM-UHFFFAOYSA-N acetic acid;octane Chemical compound CC(O)=O.CCCCCCCC PHENPABYBHPABM-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- VVCLBQFBKZQOAF-NSHDSACASA-N benzyl (2s)-pyrrolidine-2-carboxylate Chemical compound O=C([C@H]1NCCC1)OCC1=CC=CC=C1 VVCLBQFBKZQOAF-NSHDSACASA-N 0.000 description 3
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 229960002376 chymotrypsin Drugs 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 3
- ASHGTUMKRVIOLH-UHFFFAOYSA-L potassium;sodium;hydrogen phosphate Chemical compound [Na+].[K+].OP([O-])([O-])=O ASHGTUMKRVIOLH-UHFFFAOYSA-L 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 102000004225 Cathepsin B Human genes 0.000 description 2
- 108090000712 Cathepsin B Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000002704 Leucyl aminopeptidase Human genes 0.000 description 2
- 108010004098 Leucyl aminopeptidase Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 102400001103 Neurotensin Human genes 0.000 description 2
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- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- UPQNPBHYPACBSK-UHFFFAOYSA-N methylsulfinylmethane;sodium Chemical compound [Na].CS(C)=O UPQNPBHYPACBSK-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 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
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- FQROAMAHRSNCHM-UHFFFAOYSA-N oxane;hydrochloride Chemical compound Cl.C1CCOCC1 FQROAMAHRSNCHM-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- GGROONUBGIWGGS-UHFFFAOYSA-N oxygen(2-);zirconium(4+);hydrate Chemical compound O.[O-2].[O-2].[Zr+4] GGROONUBGIWGGS-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- NFNGYUXIXLYXKH-QRPNPIFTSA-N pyrrolidin-1-yl-[(2s)-pyrrolidin-2-yl]methanone;hydrochloride Chemical compound Cl.C1CCCN1C(=O)[C@@H]1CCCN1 NFNGYUXIXLYXKH-QRPNPIFTSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MXTOPOMDACBNLV-UEWDXFNNSA-N tert-butyl (2s)-2-(1-hydroxy-2-pyridin-2-yloxyethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COC1=CC=CC=N1 MXTOPOMDACBNLV-UEWDXFNNSA-N 0.000 description 1
- FDMCEXDXULPJPG-MERQFXBCSA-N tert-butyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 FDMCEXDXULPJPG-MERQFXBCSA-N 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
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
Definitions
- the present invention relates to a proline compound having a prolyl endopeptidase inhibitory activity, and is used in the field of medicine.
- Prolyl endopeptidase (EC. 3. 4.21.26) is an enzyme that acts on peptides containing proline and is known to specifically cleave the carboxyl group side of proline.
- This enzyme acts on neurotransmitters such as thyrotropin-releasing hormone (TRH), substance P, and neurotensin, and also acts on vasobresin, which is thought to be involved in learning and memory processes. It is known to decompose and inactivate them.
- TRH thyrotropin-releasing hormone
- substance P substance P
- neurotensin and also acts on vasobresin, which is thought to be involved in learning and memory processes. It is known to decompose and inactivate them.
- amyloid Proteins have been shown to play an essential role in the development of Alzheimer's disease by exhibiting neurotoxic effects.
- prolylendopeptidase is a beta-amyloid cleaving enzyme from pre-amyloid cucumbers (FEBS Lett,, 260, 131-134 (1990)), or substance P suppresses the neurotoxic effects of beta-amyloid (Pro Natl. Acad. Sci. USA, 88, 7247-7251 (1991)) suggests that a prolyl endopeptidase inhibitor may be an effective therapeutic agent for Alheimer's disease.
- the present inventors have conducted intensive studies to find a compound which has an amino acid, particularly a proline residue as a fragment, and which specifically and strongly inhibits the action of prolylendopeptidase.
- the present inventors have found that a proline derivative represented by the following general formula [1] has a specific and potent prolyl endopeptidase inhibitory activity, and completed the present invention.
- Honkiaki has the following general formula: (1)
- ⁇ is 10—, 1 CHR 1— or 1 NR 2 — (where R 1 is a hydrogen atom or a heterocycle, and R 2 is a lower alkoxycarbonyl lower alkyl group); B is Or —NR 3 —CHR 4 —, wherein R 3 and R 4 are the same or different and are a hydrogen atom or a lower alkyl group;
- W is a phenyl group, an adamantyl group, a lower alkyl group or a heterocyclic ring which may be substituted with a halogen atom, a lower alkyl group or a lower alkoxy group;
- U is — ⁇ , 1 S—, 1 NH— or —CHR 5 — (where R 5 is a hydrogen atom or a lower alkoxycarbonyl group);
- X is - S-, one S_ ⁇ one, -S0 2 one, a one hundred and one or one NH-;
- D is a benzene ring or a hetero ring
- Y and Z are the same or different and may be substituted with a hydrogen atom, a halogen atom, a fluorine atom, a lower alkyl group, an amino group, a nitro group, a hydroxyl group, a lower alkoxy group. Is a group).
- U is —CH 2 —
- W is an adamantyl group or a heterocycle
- A is —CHR 1 — or 1 NR 2 — (where R 1 is a heterocycle) R 2 is a lower alkoxycarbonyl-lower alkyl group)
- B is thiazolidine or R represents a heterocyclic ring.
- the present invention provides a pharmaceutical composition containing the above proline derivative [1] as an active ingredient, which is useful as a prolyl lendopeptidase inhibitor.
- “Lower alkyl group” means a straight or branched hydrocarbon chain having 1 to 5 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, sec- Butyl, tert-butyl, pentyl and the like.
- the “lower alkoxy group” is an alkoxy group having 1 to 5 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, a tert-butoxy group. And the like.
- the “lower alkoxycarbonyl group” is an alkoxycarbonyl group having 2 to 6 carbon atoms, specifically, a methoxycarbonyl group, an ethoxyquincarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group. , Sec-butoxycarbonyl group, tert_butoxycarbonyl group and the like.
- the “lower alkoxycarbonyl lower alkyl group” is an alkyl group having 1 to 5 carbon atoms substituted by a lower alkoxycarbonyl group as described above, specifically, a methoxycarbonylmethyl group, a 2- (methoxycarbonylcarbonyl group). ) Ethyl, 3- (methoxycarbonyl) propyl, ethoxycarbonylmethyl, 2- (ethoxycarbonyl) ethyl, 3- (ethoxycarbonyl) propyl, propoxycarbonylmethyl, 2- (propoxycarbonyl) ethyl And 3- (propoxycarbonyl) propyl.
- Halogen atoms are chlorine, bromine, fluorine and iodine.
- a phenyl group J which may be substituted with a halogen atom, a lower alkyl group or a lower alkoxy group is a phenyl group which may be substituted with one or two halogen atoms, a lower alkyl group or an alkoxy group as described above.
- Heterocycle refers to a saturated or unsaturated 4- to 7-membered ring containing one or more heteroatoms (nitrogen atom, oxygen atom or sulfur atom).
- Thiofen, pyrazole, isoxabul, imidazole, oxazole, thiabour, pyridine, pyrimidine, pyrazine, azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, morpholine, homopiperidine, etc. 1] can be produced, for example, according to the following reaction steps.
- R 6 is a benzyloxycarbonyl group, a tert-butoxycarbonyl group, or a 9-fluorenylmethyloxy group. It is an amino protecting group such as a carbonyl group, and may be any amino protecting group as long as it does not hinder the reaction.
- compound [3] was obtained by subjecting compound [2] to a Wittig reaction to form an olefin. Thereafter, it can also be obtained by epoxidation with a peracid, for example, methyltrif using n-butyllithium or the like in an inert solvent such as tetrahydrofuran or getyl ether.
- An olefin is obtained by generating the corresponding ylide from enylphosphonium halide and then reacting with compound [2] The reaction is carried out at a reaction temperature of 170 to reflux temperature as appropriate.
- This olefin is dissolved in a solvent such as methylene chloride, benzene, hexane, or methanol at a temperature of from 120 ° C. to a reflux temperature, preferably from 0 ° C. to a room temperature.
- the target compound [3] can be obtained by performing an epoxidation reaction using aqueous hydrogen peroxide.
- An alcohol derivative represented by the general formula [5] is obtained.
- the reaction with HS-R, where X is a zeo atom is carried out in the presence of tertiary amines such as triethylamine and N-methylmorpholine in the presence of methanol, 4-dioxane, N, N-dimethylformamide. This is performed in a solvent such as a solvent.
- HO-R where is an oxygen atom
- a solvent such as 1,4-dioxane or N, N-dimethylformamide
- HO-R is converted to anion ⁇ ⁇ -R, and then reacts with [3].
- the reaction with H 2 N—R where X is NH is carried out in a solvent such as methanol or 1,4-dioxane.
- the reaction temperature is from room temperature to reflux temperature in each case.
- the Amino protecting group R 6 of the intermediate represented by general formula (5) is removed according to known methods, which by compound condensation reaction represented by the formula (6), is also to obtain a compound (7).
- the compound [10] can be obtained from the compound represented by the general formula [9].
- the amino-protecting group R 6 is, for example, a tert-butoxycarbonyl group (B oc group)
- removal of the intermediate represented by the formula [5] or [9] can be carried out by a known method.
- the thus obtained deprotected product is subjected to a condensation reaction with the compound [6] by a conventional method to obtain the amino acid derivative [7] or [10].
- Q means a W—U—A—CO—B— group.
- This peptide formation reaction can employ a method known per se.
- Commonly available techniques include N, N'-dicyclohexylcarpoimide (DCC), water-soluble ruposimid hydrochloride (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( EDC ⁇ HC 1))) as a condensing agent, active ester method, mixed acid anhydride method, and the like.
- DCC N'-dicyclohexylcarpoimide
- EDC ⁇ HC 1 water-soluble ruposimid hydrochloride
- active ester method ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
- the reaction is carried out in an inert solvent at a temperature of from 0 to under heating. Suitable solvents include black form, getyl ether, N, N-dimethylform Amides, ethyl acetate, dichlor
- the active ester method comprises reacting the above compound [6] with p-12-trophenol, thiophenol, p-nitrothiophenol, N-hydroxysuccinimide and the like in an inert solvent in the presence of DCC.
- an ester with N-hydroxysuccinimide), and without isolation or isolation further react with the above deprotected product in an inert solvent at 0 to 4 (TC reaction). It forms a peptide bond.
- the compound [6] and an acid halide are prepared in an inert solvent in the presence of a tertiary amine (eg, pyridine, triethylamine).
- a mixed acid anhydride is formed by reacting an acid derivative (eg, ethyl ethyl chloroformate, isobutyl chloroformate) at 0 ° C. to 40 ° C., and the mixed acid anhydride is further converted to the above deprotected compound. With 0 ° C. to 40 ° C. to form peptide bonds.
- the DCC method is carried out in the presence or absence of the above-mentioned tertiary amine such as triethylamine in an inert solvent, or a suitable additive (for example, 1-hydroxybenzotriazole (HOBt), N-hydroxy-5— Under the conditions of addition or non-addition of norbornene-2,3-dicarboxylic acid imide (HONB)), the above deprotected product is reacted with [6] using DCC or EDCHC1 as a condensing agent. It forms the desired disulfide bonds.
- a suitable additive for example, 1-hydroxybenzotriazole (HOBt), N-hydroxy-5—
- HONB norbornene-2,3-dicarboxylic acid imide
- the final target compound [1] is obtained by oxidizing the alcohol compound represented by the general formula [7] obtained in the above reaction (C) using an appropriate oxidizing agent. Similarly, the final target compound [1] can be obtained by oxidizing the compound [8] or the compound [I 1] described later.
- This reaction is carried out, for example, in an inert solvent such as benzene, methylene chloride, N, N-dimethylformamide at 0 ° C. to reflux temperature, preferably at 0 ° C. to room temperature, in the presence of peroxidic sieve.
- an inert solvent such as benzene, methylene chloride, N, N-dimethylformamide
- pyridinium chromate chromate Dimethyl sulfoxide is used in the presence of oxalyl chloride and triethylamine at a temperature of 180 ° C to room temperature, preferably 180 ° C to 0 ° C, in an inert solvent such as methylene chloride using pyridinium dichromate.
- DCC in the presence of pyridine, trifluoroacetic acid, dimethyl sulfoxide at 0 ° C to room temperature in the presence or absence of an inert solvent (eg, benzene) or in the absence of an inert solvent (eg, benzene)
- an inert solvent eg, benzene
- a compound in which X is a zeo atom is oxidized using a peracid such as m-chloroperbenzoic acid, and a sulfoxide derivative represented by the general formula [8] It is what gains the body. Specifically, 1 equivalent or 2 equivalents of m-chloroperbenzoic acid at 120 ° C to reflux temperature, preferably 0 ° C to room temperature, in an inert solvent such as methylene chloride, chloroform and benzene. By using, a sulfoxide form or a sulfone form can be obtained, respectively.
- X is a compound represented by the general formula [5] is NH, and using methods known in peptide chemistry, is intended to obtain compound by introducing Amino protecting group R 8 to [9].
- Various amino protecting groups R 8 can be considered.
- R 6 an acid for de-B 0 c conversion in the next reaction ([9] ⁇ [10]) is used. It must be stable to the processing, for example, formyl group, trifluoroacetyl group, etc., which are an acyl-type protecting group, and 9-fluorenylmethyloxycarbonyl group, which is a urethane-type protecting group, and methylsulfonylethyl.
- an oxycarbonyl group formyl group, trifluoroacetyl group, etc., which are an acyl-type protecting group, and 9-fluorenylmethyloxycarbonyl group, which is a urethane-type protecting group, and methylsulfonylethyl.
- the introduction of these protecting groups can be achieved by a known method (“Basic and Experimental Peptide Synthesis”, Izumiya et al., Maruzen).
- introduction of a trifluoroacetyl group is carried out by reaction with trifluoroacetic acid ethyl ester in a solvent such as methanol in the presence of a tertiary amine such as triethylamine at 0 ° C. to room temperature, preferably room temperature.
- a tertiary amine such as triethylamine at 0 ° C. to room temperature, preferably room temperature.
- R 8 may be introduced.
- Amino method for removing the protecting group R 8 varies depending on the type of protecting group can be used Oite methods known to peptide chemistry. For example, triflates Ruo b dividing the acetyl groups removed by the solvent such as methanol, potassium carbonate as a base, sodium carbonate, using a completion Nmonia, 0 e C to the reflux temperature, preferably takes place at room temperature.
- the solvent such as methanol, potassium carbonate as a base, sodium carbonate
- a completion Nmonia 0 e C to the reflux temperature
- R 7 -B-COOH R 7 is an appropriate amino protecting group
- R 7 is subjected to a condensation reaction with the compound [5] in the same manner as in the reaction (C) to obtain a compound represented by the general formula [17].
- the compound shown is obtained.
- the desired compound [7] can be obtained by reacting with the compound represented by WUA-COOH (when A is —CHR 1 —).
- a in the former one 0, in the case of -NR 2 scratch, for example, W- U- A- H 1, 4 one Jiokisan, in a suitable solvent such as tetrahydrofuran, tertiary Amin such Toriechiruamin
- phosgene, trichloromethylchloroformate, carbonyldiimidabour and the like at ⁇ 20 ° C. to room temperature in the presence of and then reacting with the deprotected compound of compound [17].
- a in the latter is —CHR 1 —
- the deprotected compound of compound [17] is converted to W—U—A—COOH or the corresponding acid chloride using the method described in the aforementioned reaction (C). Achieved by performing a condensation reaction with W—U—A—COC1.
- the compound [9] is converted to the compound represented by the general formula [19] in the same manner as in the above reaction (K), and then the reaction (L) is performed in the same manner as above. As a result, the desired compound [10] can be prepared.
- optically active sulfinyl compound represented by can be produced according to the following steps.
- the compound represented by the general formula [12] was prepared by the method described in the literature (P. Pitchen et.al., J. Am. Chem. Soc., 106, 8188-8193 (1984); SH Zhao et. Al., Tetrahedron) .43.5135-5144 (1987)) to obtain an optically active sulfoxide represented by the general formula [13].
- This reaction is, for example, methylene chloride, 1, 2-titanium Te Bok La isopropoxide Boki Sid in a solvent such as Jikuroroetan, the presence of an optically active tartaric acid Jechiru and water, 0 e C or less, preferably from one 4 0 ° C At 20 ° C, use tert-butyl hydroperoxide or cumene hydroperoxide.
- An optically active sulfoxide represented by the general formula [13] is treated with a base to give a corresponding carbodione, which is converted into an ester or compound represented by the general formula [14] (R 9 represents a carboxyl protecting group) [14] condensation with an aldehyde represented by the general formula [15] derived by a known method to obtain an optically active sulfinyl compound represented by the general formula [1] or [16], respectively. .
- the reaction is carried out, for example, by converting the optically active sulfoxide [13] into an inert organic solvent such as THF, 1,4-dioxane at a temperature of from 178 to room temperature, preferably at a reaction temperature of 0 ° C.
- N-protected prolinal [2], HX-R [4], Q-COOH [6], IT-B-COOH, W—U—A—H, W—U—A—C00H , CH 3 S—R [12] and proline ester [18] can be obtained as known substances or can be obtained by a known method from a known syrup. It can be easily derived and synthesized.
- a protecting group may be introduced at an appropriate stage as necessary, and a suitable step (preferably, the final step reaction (D) or reaction (J)) may be carried out. Before ()), the protecting group may be removed.
- Simplification and purification of the thus obtained compound represented by the general formula [1] from the reaction mixture can be carried out by using any means commonly used in the field of synthetic organic chemistry. For example, it can be isolated and purified by methods such as column chromatography, solvent extraction, and recrystallization. The singulation and purification may be performed for each reaction, or may be performed after completion of some reactions.
- Each of the above series of compounds has one to three asymmetric centers in the molecule.
- the configuration of each asymmetric center is either R or S, or a mixture thereof. It may be.
- Each optically active substance can be obtained by using an optically active compound as a starting material or by purifying the obtained diastereomer mixture by a method such as column chromatography or recrystallization.
- the compound of the present invention is used as a pharmaceutical, it is usually administered systemically or locally, orally or parenterally.
- the dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, etc., but is usually in the range of lmg to 100mg at a time per adult, once or several times daily. It is administered orally or parenterally once per adult per day in the range of 0.2 rag to 2 nig.
- the compound of the present invention is used in the form of a solid composition or liquid composition for oral administration or an injection or suppository for parenteral administration.
- Solid compositions for oral administration include tablets, pills, capsules, powders, granules and the like.
- one or more active substances are used in admixture with at least one inert diluent, and may include excipients, binders, lubricants, disintegrants, You may contain a solubilizing agent, a stabilizer, etc. Tablets or pills may be coated with a film of a gastric or enteric material, if necessary.
- the capsules include hard capsules and soft capsules.
- Liquid compositions for oral administration include solutions, emulsions, suspensions, syrups, and elixirs. Such liquid compositions will include commonly used inert diluents, as well as auxiliary agents such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents, preservatives An agent may be contained.
- Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- one or more active substances are used in a mixture with at least one inert aqueous diluent or inert non-aqueous diluent. It may contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers and solubilizers. These are usually sterilized by filtration (such as a bacteria-retaining filter), blending of a bactericide or gamma-irradiation, or after these treatments, solidified by a method such as freeze-drying, and used immediately before use. Sterile water or a sterile injectable diluent is used.
- the extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated.
- the residue was purified by silica gel column chromatography (eluent: ethyl hexane monoacetate) to obtain two diastereomers of the title compound, 3.12 g of a low-polar compound and 1.28 g of a high-polar compound (both of them).
- the three-dimensional structure of the epoxy part has not been determined). In the following reactions, a low-polar substance was used.
- (2S) 1 2 [1-Hydroxy-2- (4-methoxyphenoxy) ethyl] 1 1 CN- (phenoxyacetyl) 1; L-prolyl] pyrrolidine (478 mg) in DMSO (3.5 m 1) And benzene (1.5 ml) and triethylamine (0.7 ml) were added. After the mixture was cooled on ice, iodopyridine complex (730 mg) was added little by little, and triethylamine (0.25 m 1) was added to keep the reaction solution neutral. After stirring at 5 to 10 for 1 hour, the reaction solution was poured into ice water and extracted with ethyl acetate.
- Example 5 Prepared in the same manner as in a) of Example 5 with trichloromethyl chromate formate (0.37 ml), N-benzylglycineethyl ester (1.2 ml) and c) of Example 1 (2S).
- L-prolyl) 12- (1-hydroxy-2-phenyloxethyl) pyrrolidine obtained by treating with hydrochloric acid (2S) -2- (1-hydroxyl)
- the title compound (2.12 g) was obtained using 2-phenoxetyl) 1-111 (L-prolyl) pyrrolidine hydrochloride (1.75 g).
- the proline derivative represented by the general formula [1] according to the present invention was tested for its prolyl endopeptidase inhibitory activity and inhibitory activity against various proteases in an in vitro system.
- the mixture (100-1) was pre-cubated at 0.30 ° C for 30 minutes (using the method described in (1980)).
- 125 1 was added and incubated at 30 ° C for 1 hour. Stop the reaction by immersing the reaction mixture in ice (0 ° C).
- Inhibition rate (%) 1 x 1 0 0
- the compound of the present invention was found to have excellent inhibitory activity on prolylendopeptidase.
- the method for measuring the activity of inhibiting various proteases except for prolylendopeptidase and the method for calculating the inhibition rate are as follows. Measurement of Hata trypsin inhibitory activity
- a 5 OmM Tris-HCl buffer (pH 8.0) was used as the measurement buffer, and a 0.2 M buffer solution of leucine aminopeptidase (derived from Bushu Kidney, manufactured by Sigma) was used as the enzyme solution.
- a 0.2 M buffer solution of leucine aminopeptidase derived from Bushu Kidney, manufactured by Sigma
- 20 0 / M the same buffer solution of 7-mouth Ishiru 4 one Mechirukumari N'ami de (manufactured Ltd. peptide Institute) as, in the same manner as above, each fluorescence intensity was measured d 2 and d 3.
- I mM Tris-HCl buffer pH 8.5
- 0.2% elastase derived from pig kidney, manufactured by Sigma
- substrate solution 200 Iv of 7- (N-succinylol-lanilupol-lilualanil)-4--methylcoumarinamide (manufactured by Peptide Research Laboratories) [Use the same buffer solution as above, in the same manner, each fluorescence intensity was measured e 2 and e 3. Measurement of catabstin B inhibitory activity
- Fluorescence intensity X measured in this way, (the chi b, c, d, representative of e and f) chi 2 and chi 3 used, and the percent inhibition for various proteolytic enzymes was calculated by the following equation.
- the novel proline derivative represented by the general formula [1] has a very strong inhibitory activity on prolyl peptidase, but has trypsin, chymotrypsin, leucine aminopeptidase, elastase, cathepsin B, etc. It has been shown that it does not act at all on the protease, which degrades and inactivates hormones in the brain containing proline residues and neurotransmitters such as TRH, substance P, neurotensin, and vasobrescine. It is considered to be a compound that specifically suppresses the conversion.
- the compound of the present invention can be expected to make an effective contribution to the improvement of symptoms of various diseases mediated by hormones and neurotransmitters, and as an anti-dementia drug or an anti-amnesic agent that directly acts on the core symptoms of dementia, Alzheimer's disease It can be used for prevention and Z or treatment of dementia and amnesia including
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Abstract
L'invention se rapporte à un dérivé de proline représenté par la formule générale (I), où A représente -O-, -CHR1- ou -NR2-, R1 représentant hydrogène ou hétérocycle et R2 représentant alcoxycarbonyle inférieur-alkyle inférieur; W représente phényle qui peut être substitué par halogène, alkyle inférieur ou alcoxy inférieur, adamantyle, alkyle inférieur ou hétérocycle; U représente -O-, -S-, -NH- ou -CHR5-, R5 représentant hydrogène ou alcoxycarbonyle inférieur; X représente -S-, -SO-, -SO¿2?-, -O- ou -NH-; D représente benzène ou hétérocycle; et Y et Z, qui peuvent être identiques ou différents l'un de l'autre, représentent chacun hydrogène, halogène, alkyle inférieur éventuellement fluoré, amino, nitro, hydroxy ou alcoxy inférieur. Ce dérivé possède un pouvoir inhibiteur spécialement puissant contre la prolyle endopeptidase et il inhibe la décomposition et l'inactivation de la TRH (hormone thyréolibérine), de la substance P, de la neurotensine, de la vasopressine, etc.. Ce dérivé peut par conséquent être utilisé pour prévenir et/ou traiter les états de démence, tels que la maladie d'Alzheimer et l'amnésie.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/026,311 US5506256A (en) | 1990-07-27 | 1993-02-26 | Proline derivatives possessing prolyl endopeptidase-inhibitory activity |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3/361355 | 1991-12-27 | ||
JP3361355A JPH05186498A (ja) | 1991-12-27 | 1991-12-27 | プロリン誘導体 |
Publications (1)
Publication Number | Publication Date |
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WO1993013065A1 true WO1993013065A1 (fr) | 1993-07-08 |
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ID=18473247
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1992/001711 WO1993013065A1 (fr) | 1990-07-27 | 1992-12-25 | Derive de proline |
Country Status (2)
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JP (1) | JPH05186498A (fr) |
WO (1) | WO1993013065A1 (fr) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996018643A1 (fr) * | 1994-12-13 | 1996-06-20 | Novartis Ag | Antagonistes de la tachykinine |
US5536737A (en) * | 1992-11-20 | 1996-07-16 | Japan Tobacco Inc. | Compound having prolyl endopeptidase inhibitory activity and pharmaceutical use thereof |
WO1998035960A1 (fr) * | 1997-02-14 | 1998-08-20 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Inhibiteurs de prolylendopeptidase |
WO2004098591A2 (fr) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibiteurs de glutaminyl-cyclase |
WO2005049027A2 (fr) | 2003-11-03 | 2005-06-02 | Probiodrug Ag | Combinaisons utiles au traitement de troubles neuronaux |
WO2005075436A2 (fr) | 2004-02-05 | 2005-08-18 | Probiodrug Ag | Nouveaux inhibiteurs de la glutaminyl-cyclase |
WO2008055945A1 (fr) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies |
WO2008065141A1 (fr) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Nouveaux inhibiteurs de glutaminylcyclase |
WO2008104580A1 (fr) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase |
WO2011029920A1 (fr) | 2009-09-11 | 2011-03-17 | Probiodrug Ag | Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase |
WO2011107530A2 (fr) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2011110613A1 (fr) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (fr) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2012123563A1 (fr) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase |
EP2865670A1 (fr) | 2007-04-18 | 2015-04-29 | Probiodrug AG | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
EP3461819A1 (fr) | 2017-09-29 | 2019-04-03 | Probiodrug AG | Inhibiteurs de la glutaminyl-cyclase |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS63258852A (ja) * | 1987-04-11 | 1988-10-26 | ヘキスト・アクチエンゲゼルシヤフト | 新規なピロリジン‐2‐(1,3‐ジカルボニル)誘導体 |
JPS6442475A (en) * | 1987-08-08 | 1989-02-14 | Kissei Pharmaceutical | Thiazolidine derivative |
JPS6442465A (en) * | 1987-08-07 | 1989-02-14 | Wakunaga Pharma Co Ltd | N-acylprolylpyrrolidine derivative, production and use thereof |
-
1991
- 1991-12-27 JP JP3361355A patent/JPH05186498A/ja active Pending
-
1992
- 1992-12-25 WO PCT/JP1992/001711 patent/WO1993013065A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS63258852A (ja) * | 1987-04-11 | 1988-10-26 | ヘキスト・アクチエンゲゼルシヤフト | 新規なピロリジン‐2‐(1,3‐ジカルボニル)誘導体 |
JPS6442465A (en) * | 1987-08-07 | 1989-02-14 | Wakunaga Pharma Co Ltd | N-acylprolylpyrrolidine derivative, production and use thereof |
JPS6442475A (en) * | 1987-08-08 | 1989-02-14 | Kissei Pharmaceutical | Thiazolidine derivative |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5536737A (en) * | 1992-11-20 | 1996-07-16 | Japan Tobacco Inc. | Compound having prolyl endopeptidase inhibitory activity and pharmaceutical use thereof |
WO1996018643A1 (fr) * | 1994-12-13 | 1996-06-20 | Novartis Ag | Antagonistes de la tachykinine |
WO1998035960A1 (fr) * | 1997-02-14 | 1998-08-20 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Inhibiteurs de prolylendopeptidase |
WO2004098591A2 (fr) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibiteurs de glutaminyl-cyclase |
EP2338490A2 (fr) | 2003-11-03 | 2011-06-29 | Probiodrug AG | Combinaisons utiles pour le traitement de désordres neuronales |
WO2005049027A2 (fr) | 2003-11-03 | 2005-06-02 | Probiodrug Ag | Combinaisons utiles au traitement de troubles neuronaux |
WO2005075436A2 (fr) | 2004-02-05 | 2005-08-18 | Probiodrug Ag | Nouveaux inhibiteurs de la glutaminyl-cyclase |
US7897633B2 (en) | 2004-02-05 | 2011-03-01 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
WO2008055945A1 (fr) | 2006-11-09 | 2008-05-15 | Probiodrug Ag | Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies |
WO2008065141A1 (fr) | 2006-11-30 | 2008-06-05 | Probiodrug Ag | Nouveaux inhibiteurs de glutaminylcyclase |
WO2008104580A1 (fr) | 2007-03-01 | 2008-09-04 | Probiodrug Ag | Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase |
EP2481408A2 (fr) | 2007-03-01 | 2012-08-01 | Probiodrug AG | Nouvelle utilisation d'inhibiteurs glutaminyle cyclase |
EP2865670A1 (fr) | 2007-04-18 | 2015-04-29 | Probiodrug AG | Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase |
WO2011029920A1 (fr) | 2009-09-11 | 2011-03-17 | Probiodrug Ag | Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase |
WO2011107530A2 (fr) | 2010-03-03 | 2011-09-09 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2011110613A1 (fr) | 2010-03-10 | 2011-09-15 | Probiodrug Ag | Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5) |
WO2011131748A2 (fr) | 2010-04-21 | 2011-10-27 | Probiodrug Ag | Nouveaux inhibiteurs |
WO2012123563A1 (fr) | 2011-03-16 | 2012-09-20 | Probiodrug Ag | Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase |
EP3461819A1 (fr) | 2017-09-29 | 2019-04-03 | Probiodrug AG | Inhibiteurs de la glutaminyl-cyclase |
Also Published As
Publication number | Publication date |
---|---|
JPH05186498A (ja) | 1993-07-27 |
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