HRP20050693A2 - Compounds having prolyl oligopeptidase inhibitory activity - Google Patents
Compounds having prolyl oligopeptidase inhibitory activity Download PDFInfo
- Publication number
- HRP20050693A2 HRP20050693A2 HR20050693A HRP20050693A HRP20050693A2 HR P20050693 A2 HRP20050693 A2 HR P20050693A2 HR 20050693 A HR20050693 A HR 20050693A HR P20050693 A HRP20050693 A HR P20050693A HR P20050693 A2 HRP20050693 A2 HR P20050693A2
- Authority
- HR
- Croatia
- Prior art keywords
- amino
- aryl
- lower alkyl
- unsubstituted
- alkyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 64
- 230000002401 inhibitory effect Effects 0.000 title description 13
- 102000056251 Prolyl Oligopeptidases Human genes 0.000 title description 8
- 101001095266 Homo sapiens Prolyl endopeptidase Proteins 0.000 title description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 211
- 125000003118 aryl group Chemical group 0.000 claims description 160
- 125000003282 alkyl amino group Chemical group 0.000 claims description 106
- 125000003545 alkoxy group Chemical group 0.000 claims description 93
- 125000001424 substituent group Chemical group 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 78
- 125000000623 heterocyclic group Chemical group 0.000 claims description 65
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 63
- -1 cyano, hydroxy Chemical group 0.000 claims description 61
- 125000001769 aryl amino group Chemical group 0.000 claims description 50
- 125000004432 carbon atom Chemical group C* 0.000 claims description 50
- 125000003342 alkenyl group Chemical group 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 46
- 150000002367 halogens Chemical class 0.000 claims description 46
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 43
- 125000004104 aryloxy group Chemical group 0.000 claims description 43
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 31
- 229920006395 saturated elastomer Polymers 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 30
- 125000004043 oxo group Chemical group O=* 0.000 claims description 29
- 125000002252 acyl group Chemical group 0.000 claims description 21
- 101100295741 Gallus gallus COR4 gene Proteins 0.000 claims description 20
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 20
- 125000002837 carbocyclic group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 14
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 13
- 239000003649 prolyl endopeptidase inhibitor Substances 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000004770 neurodegeneration Effects 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 230000006386 memory function Effects 0.000 claims description 5
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 206010039966 Senile dementia Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 131
- 238000003818 flash chromatography Methods 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 238000000746 purification Methods 0.000 description 38
- 239000000243 solution Substances 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- 239000012071 phase Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 14
- 229940086542 triethylamine Drugs 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- CFTJSTPKLISBIS-UHFFFAOYSA-N 2-(benzylcarbamoyl)cyclopent-2-ene-1-carboxylic acid Chemical compound OC(=O)C1CCC=C1C(=O)NCC1=CC=CC=C1 CFTJSTPKLISBIS-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 210000004556 brain Anatomy 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 239000008057 potassium phosphate buffer Substances 0.000 description 7
- ASHGTUMKRVIOLH-UHFFFAOYSA-L potassium;sodium;hydrogen phosphate Chemical compound [Na+].[K+].OP([O-])([O-])=O ASHGTUMKRVIOLH-UHFFFAOYSA-L 0.000 description 7
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- WODLVEFJKWRNHB-VHSXEESVSA-N (2s,5r)-5-tert-butyl-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1[C@H](C(O)=O)CC[C@@H]1C(C)(C)C WODLVEFJKWRNHB-VHSXEESVSA-N 0.000 description 6
- BUFVLAUIGPPSTK-UHFFFAOYSA-N 2-(4-phenylbutanoyl)cyclopent-2-ene-1-carboxylic acid Chemical compound OC(=O)C1CCC=C1C(=O)CCCC1=CC=CC=C1 BUFVLAUIGPPSTK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- QMMOUMUWLXVWRW-UHFFFAOYSA-N 2-formylcyclopent-2-ene-1-carboxylic acid Chemical compound OC(=O)C1CCC=C1C=O QMMOUMUWLXVWRW-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 5
- 125000004492 methyl ester group Chemical group 0.000 description 5
- 229960002429 proline Drugs 0.000 description 5
- VQDQISMDUHBUFF-UHFFFAOYSA-N 4-phenylbutanoyl chloride Chemical compound ClC(=O)CCCC1=CC=CC=C1 VQDQISMDUHBUFF-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229950009215 phenylbutanoic acid Drugs 0.000 description 4
- NXLRDTHAZNPPOQ-JTQLQIEISA-N tert-butyl (2s)-2-(2-acetyloxyacetyl)pyrrolidine-1-carboxylate Chemical compound CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C NXLRDTHAZNPPOQ-JTQLQIEISA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- LHNMSWXPJFRDIE-JKSUJKDBSA-N (2s,5r)-5-tert-butyl-1-(4-phenylbutanoyl)pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)[C@H]1CC[C@@H](C(O)=O)N1C(=O)CCCC1=CC=CC=C1 LHNMSWXPJFRDIE-JKSUJKDBSA-N 0.000 description 2
- FFCHAPNQBQNUFB-RYUDHWBXSA-N 1-o-tert-butyl 2-o-ethyl (2s,5s)-5-tert-butylpyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)[C@@H]1CC[C@@H](C(C)(C)C)N1C(=O)OC(C)(C)C FFCHAPNQBQNUFB-RYUDHWBXSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- GJBUKMXCIBNPEF-UHFFFAOYSA-N 2-(1-hydroxy-2-phenylethyl)cyclopent-2-ene-1-carboxylic acid Chemical compound C=1CCC(C(O)=O)C=1C(O)CC1=CC=CC=C1 GJBUKMXCIBNPEF-UHFFFAOYSA-N 0.000 description 2
- CVNWDSRKCMNKJH-UHFFFAOYSA-N 2-(1-hydroxy-4-phenylbutyl)cyclopent-2-ene-1-carboxylic acid Chemical compound C=1CCC(C(O)=O)C=1C(O)CCCC1=CC=CC=C1 CVNWDSRKCMNKJH-UHFFFAOYSA-N 0.000 description 2
- ACXAUXAJOFPTPV-UHFFFAOYSA-N 2-(2-phenylacetyl)cyclopent-2-ene-1-carboxylic acid Chemical compound OC(=O)C1CCC=C1C(=O)CC1=CC=CC=C1 ACXAUXAJOFPTPV-UHFFFAOYSA-N 0.000 description 2
- MLSDZSSQADPSDG-VWMHFEHESA-N 2-(4-phenylbutanoyl)cyclopent-2-ene-1-carboxylic acid;(2s)-pyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1.OC(=O)C1CCC=C1C(=O)CCCC1=CC=CC=C1 MLSDZSSQADPSDG-VWMHFEHESA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 102100020751 Dipeptidyl peptidase 2 Human genes 0.000 description 2
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 2
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- UQXRFBHLDSYNCP-YQOVMPOYSA-N N1([C@@](CC[C@H]1C)(C(=O)CCCC=1C=CC=CC=1)C(=O)COC(C)=O)C(=O)[C@@H]1CCCN1 Chemical compound N1([C@@](CC[C@H]1C)(C(=O)CCCC=1C=CC=CC=1)C(=O)COC(C)=O)C(=O)[C@@H]1CCCN1 UQXRFBHLDSYNCP-YQOVMPOYSA-N 0.000 description 2
- KTPWOMHKPQIXND-XXAUWVGASA-N N1([C@H](CC[C@@]1(C(=O)COC(=O)C)C(=O)CCCC=1C=CC=CC=1)C(C)(C)C)C(=O)[C@@H]1CCCN1 Chemical compound N1([C@H](CC[C@@]1(C(=O)COC(=O)C)C(=O)CCCC=1C=CC=CC=1)C(C)(C)C)C(=O)[C@@H]1CCCN1 KTPWOMHKPQIXND-XXAUWVGASA-N 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 108090000212 dipeptidyl peptidase II Proteins 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- VHTLQGZJSMSREM-DLBZAZTESA-N methyl (2s,5r)-5-tert-butyl-1-(4-phenylbutanoyl)pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CC[C@H](C(C)(C)C)N1C(=O)CCCC1=CC=CC=C1 VHTLQGZJSMSREM-DLBZAZTESA-N 0.000 description 2
- UJEDKGJALATKHH-UHFFFAOYSA-N methyl 2-(benzylcarbamoyl)cyclopent-2-ene-1-carboxylate Chemical compound COC(=O)C1CCC=C1C(=O)NCC1=CC=CC=C1 UJEDKGJALATKHH-UHFFFAOYSA-N 0.000 description 2
- NUKZAGXMHTUAFE-UHFFFAOYSA-N methyl hexanoate Chemical compound CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 2
- 230000002887 neurotoxic effect Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI20030014A FI20030014A0 (fi) | 2003-01-03 | 2003-01-03 | Prolyylioligopeptidaasia inhiboivaa aktiivisuutta omaavia yhdisteitä |
| PCT/FI2004/000001 WO2004060862A2 (en) | 2003-01-03 | 2004-01-02 | Compounds having prolyl oligopeptidase inhibitory activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20050693A2 true HRP20050693A2 (en) | 2005-10-31 |
Family
ID=8565256
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20050693A HRP20050693A2 (en) | 2003-01-03 | 2005-08-02 | Compounds having prolyl oligopeptidase inhibitory activity |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US20060229254A1 (ko) |
| EP (1) | EP1581489A2 (ko) |
| JP (1) | JP2006516557A (ko) |
| KR (1) | KR20060027789A (ko) |
| CN (1) | CN1747930A (ko) |
| AU (1) | AU2004203788A1 (ko) |
| BR (1) | BRPI0406618A (ko) |
| CA (1) | CA2511856A1 (ko) |
| EA (1) | EA010022B1 (ko) |
| FI (1) | FI20030014A0 (ko) |
| HR (1) | HRP20050693A2 (ko) |
| IS (1) | IS7963A (ko) |
| MX (1) | MXPA05007262A (ko) |
| NO (1) | NO20053726L (ko) |
| PL (1) | PL378329A1 (ko) |
| RS (1) | RS20050514A (ko) |
| WO (1) | WO2004060862A2 (ko) |
| ZA (1) | ZA200505183B (ko) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL2513053T3 (pl) | 2009-12-18 | 2018-03-30 | Ogeda Sa | Pochodne kwasu pirolidyno-karboksylowego jako agoniści receptora 43 sprzężonego z białkiem G (GPR43), kompozycja farmaceutyczna i sposoby do zastosowania w leczeniu zaburzeń metabolicznych |
| EP2730571A1 (en) | 2012-11-12 | 2014-05-14 | Universitat De Barcelona | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
| EP3610872A1 (en) * | 2013-11-27 | 2020-02-19 | Epics Therapeutics | Compounds, pharmaceutical composition and methods for use in treating inflammatory diseases |
| KR101913506B1 (ko) * | 2017-07-18 | 2018-10-30 | 경상대학교산학협력단 | 프롤릴 올리고펩티다아제 억제제를 유효성분으로 함유하는 퇴행성 뇌질환 예방 또는 치료용 조성물 |
| CN117545738A (zh) | 2020-07-07 | 2024-02-09 | 安克瑞治疗公司 | 1-[1-(4-苄氧基-3,5-二氟-苯甲酰基)-4-氟-吡咯烷-2-羰基]吡咯烷-2-腈 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4483991A (en) * | 1983-01-17 | 1984-11-20 | American Home Products Corporation | Hypotensive agents |
| CA1309805C (en) * | 1985-04-16 | 1992-11-03 | Naoki Higuchi | Dipeptide derivative and synthesis and use thereof |
| JPH0696563B2 (ja) * | 1986-02-04 | 1994-11-30 | サントリー株式会社 | アシルアミノ酸誘導体、その製法並びに用途 |
| CA1320734C (en) * | 1986-02-04 | 1993-07-27 | Suntory Limited | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
| CA2084412C (en) * | 1990-06-04 | 2000-05-09 | W. Stephen Faraci | Pyrrolidine and thiazolidine amides |
| AU643300B2 (en) * | 1990-06-07 | 1993-11-11 | Zeria Pharmaceutical Co., Ltd. | Novel arylalkanoylamine derivative and drug containing the same |
| ES2182203T3 (es) * | 1997-10-31 | 2003-03-01 | Hoffmann La Roche | Derivados de d-prolina. |
-
2003
- 2003-01-03 FI FI20030014A patent/FI20030014A0/fi unknown
-
2004
- 2004-01-02 MX MXPA05007262A patent/MXPA05007262A/es not_active Application Discontinuation
- 2004-01-02 EA EA200501083A patent/EA010022B1/ru not_active IP Right Cessation
- 2004-01-02 WO PCT/FI2004/000001 patent/WO2004060862A2/en active Application Filing
- 2004-01-02 CA CA002511856A patent/CA2511856A1/en not_active Abandoned
- 2004-01-02 BR BR0406618-9A patent/BRPI0406618A/pt not_active IP Right Cessation
- 2004-01-02 JP JP2006500146A patent/JP2006516557A/ja active Pending
- 2004-01-02 EP EP04700047A patent/EP1581489A2/en not_active Withdrawn
- 2004-01-02 RS YUP-2005/0514A patent/RS20050514A/sr unknown
- 2004-01-02 CN CNA2004800034680A patent/CN1747930A/zh active Pending
- 2004-01-02 US US10/541,387 patent/US20060229254A1/en not_active Abandoned
- 2004-01-02 KR KR1020057012201A patent/KR20060027789A/ko not_active Application Discontinuation
- 2004-01-02 PL PL378329A patent/PL378329A1/pl unknown
- 2004-01-02 AU AU2004203788A patent/AU2004203788A1/en not_active Abandoned
-
2005
- 2005-06-27 ZA ZA200505183A patent/ZA200505183B/en unknown
- 2005-07-28 IS IS7963A patent/IS7963A/is unknown
- 2005-08-02 HR HR20050693A patent/HRP20050693A2/hr not_active Application Discontinuation
- 2005-08-03 NO NO20053726A patent/NO20053726L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI20030014A0 (fi) | 2003-01-03 |
| IS7963A (is) | 2005-07-28 |
| JP2006516557A (ja) | 2006-07-06 |
| ZA200505183B (en) | 2006-04-26 |
| BRPI0406618A (pt) | 2005-12-06 |
| US20060229254A1 (en) | 2006-10-12 |
| NO20053726L (no) | 2005-09-28 |
| EP1581489A2 (en) | 2005-10-05 |
| CN1747930A (zh) | 2006-03-15 |
| WO2004060862A2 (en) | 2004-07-22 |
| CA2511856A1 (en) | 2004-07-22 |
| NO20053726D0 (no) | 2005-08-03 |
| WO2004060862A3 (en) | 2004-11-25 |
| EA200501083A1 (ru) | 2006-02-24 |
| MXPA05007262A (es) | 2005-09-08 |
| EA010022B1 (ru) | 2008-06-30 |
| PL378329A1 (pl) | 2006-03-20 |
| RS20050514A (en) | 2007-12-31 |
| AU2004203788A1 (en) | 2004-07-22 |
| KR20060027789A (ko) | 2006-03-28 |
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