JP4996926B2 - グルタミニルシクラーゼの新規の阻害剤 - Google Patents
グルタミニルシクラーゼの新規の阻害剤 Download PDFInfo
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- JP4996926B2 JP4996926B2 JP2006551809A JP2006551809A JP4996926B2 JP 4996926 B2 JP4996926 B2 JP 4996926B2 JP 2006551809 A JP2006551809 A JP 2006551809A JP 2006551809 A JP2006551809 A JP 2006551809A JP 4996926 B2 JP4996926 B2 JP 4996926B2
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- Prior art keywords
- phenyl
- inhibitor
- group
- compound
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003112 inhibitor Substances 0.000 title claims description 142
- 108010081484 glutaminyl-peptide cyclotransferase Proteins 0.000 title description 15
- 102000003642 glutaminyl-peptide cyclotransferase Human genes 0.000 title description 15
- -1 4- (trifluoromethyl) -phenyl Chemical group 0.000 claims description 189
- 150000001875 compounds Chemical class 0.000 claims description 164
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 57
- 102000004190 Enzymes Human genes 0.000 claims description 51
- 108090000790 Enzymes Proteins 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 108010016626 Dipeptides Proteins 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 230000033228 biological regulation Effects 0.000 claims description 15
- 230000008482 dysregulation Effects 0.000 claims description 15
- 208000012902 Nervous system disease Diseases 0.000 claims description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 13
- 239000003446 ligand Substances 0.000 claims description 13
- 208000024827 Alzheimer disease Diseases 0.000 claims description 12
- 208000025966 Neurological disease Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 201000010374 Down Syndrome Diseases 0.000 claims description 10
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 claims description 10
- 230000037149 energy metabolism Effects 0.000 claims description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 208000019901 Anxiety disease Diseases 0.000 claims description 9
- 208000012639 Balance disease Diseases 0.000 claims description 9
- 208000030814 Eating disease Diseases 0.000 claims description 9
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 9
- 208000023105 Huntington disease Diseases 0.000 claims description 9
- 208000018737 Parkinson disease Diseases 0.000 claims description 9
- 206010044688 Trisomy 21 Diseases 0.000 claims description 9
- 230000036506 anxiety Effects 0.000 claims description 9
- 210000001124 body fluid Anatomy 0.000 claims description 9
- 239000010839 body fluid Substances 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 235000014632 disordered eating Nutrition 0.000 claims description 9
- 230000013632 homeostatic process Effects 0.000 claims description 9
- 201000000980 schizophrenia Diseases 0.000 claims description 9
- 208000007848 Alcoholism Diseases 0.000 claims description 8
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 claims description 8
- 208000028698 Cognitive impairment Diseases 0.000 claims description 8
- 206010012289 Dementia Diseases 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 8
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 8
- 208000028017 Psychotic disease Diseases 0.000 claims description 8
- 206010037660 Pyrexia Diseases 0.000 claims description 8
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 8
- 201000007930 alcohol dependence Diseases 0.000 claims description 8
- 125000002837 carbocyclic group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 208000010877 cognitive disease Diseases 0.000 claims description 8
- 239000003395 histamine H3 receptor antagonist Substances 0.000 claims description 8
- 230000001717 pathogenic effect Effects 0.000 claims description 8
- 239000005541 ACE inhibitor Substances 0.000 claims description 7
- 229940125373 Gamma-Secretase Inhibitor Drugs 0.000 claims description 7
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 7
- 239000002439 beta secretase inhibitor Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003623 enhancer Substances 0.000 claims description 7
- 206010015037 epilepsy Diseases 0.000 claims description 7
- 239000003540 gamma secretase inhibitor Substances 0.000 claims description 7
- 125000006413 ring segment Chemical group 0.000 claims description 7
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 6
- 208000022531 anorexia Diseases 0.000 claims description 6
- 210000004899 c-terminal region Anatomy 0.000 claims description 6
- 206010061428 decreased appetite Diseases 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000002899 monoamine oxidase inhibitor Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 5
- 102000009091 Amyloidogenic Proteins Human genes 0.000 claims description 5
- 108010048112 Amyloidogenic Proteins Proteins 0.000 claims description 5
- 206010013752 Drug withdrawal convulsions Diseases 0.000 claims description 5
- 102100028656 Sigma non-opioid intracellular receptor 1 Human genes 0.000 claims description 5
- 101710104750 Sigma non-opioid intracellular receptor 1 Proteins 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 230000008021 deposition Effects 0.000 claims description 5
- 239000002792 enkephalinase inhibitor Substances 0.000 claims description 5
- 239000002658 neuropeptide Y receptor agonist Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- WHGMHGPIJZTKTI-UHFFFAOYSA-N 3h-1,2-benzodithiole Chemical compound C1=CC=C2CSSC2=C1 WHGMHGPIJZTKTI-UHFFFAOYSA-N 0.000 claims description 4
- ZOLNSECVOZFNLU-UHFFFAOYSA-N 3h-1,2-benzoxathiole Chemical compound C1=CC=C2CSOC2=C1 ZOLNSECVOZFNLU-UHFFFAOYSA-N 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 claims description 4
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 claims description 4
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical class OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 claims description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 3
- 150000007860 aryl ester derivatives Chemical class 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 230000003054 hormonal effect Effects 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000004474 valine Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical class ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 claims description 2
- AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- YKRQYGZEUVWOFN-UHFFFAOYSA-N 3a,4,5,9b-tetrahydro-1h-benzo[e]indol-2-amine Chemical group C1CC2=CC=CC=C2C2C1N=C(N)C2 YKRQYGZEUVWOFN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- QSAIYEIQUKKBDM-VYRBHSGPSA-N 9H-fluoren-9-ylmethyl N-[(2S)-1-(2-cyanopyrrolidin-1-yl)-1-oxopropan-2-yl]carbamate Chemical group C1=CC=CC=2C3=CC=CC=C3C(C1=2)COC(=O)N[C@@H](C)C(=O)N1C(CCC1)C#N QSAIYEIQUKKBDM-VYRBHSGPSA-N 0.000 claims description 2
- ULEBESPCVWBNIF-BYPYZUCNSA-N L-arginine amide Chemical compound NC(=O)[C@@H](N)CCCNC(N)=N ULEBESPCVWBNIF-BYPYZUCNSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- KUWBXRGRMQZCSS-HSZRJFAPSA-N bibp-3226 Chemical compound N([C@H](CCCN=C(N)N)C(=O)NCC=1C=CC(O)=CC=1)C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 KUWBXRGRMQZCSS-HSZRJFAPSA-N 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical group COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 claims description 2
- 229950005741 rolipram Drugs 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims 3
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims 3
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 3
- FSUYMKXZLQOFQY-UHFFFAOYSA-N 3,4-dihydro-1,2-benzodithiine Chemical compound C1=CC=C2SSCCC2=C1 FSUYMKXZLQOFQY-UHFFFAOYSA-N 0.000 claims 2
- NTOIMCSZPGZTND-UHFFFAOYSA-N 3,4-dihydro-1,2-benzoxathiine Chemical compound C1=CC=C2OSCCC2=C1 NTOIMCSZPGZTND-UHFFFAOYSA-N 0.000 claims 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims 2
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- 102100031674 Protein-L-isoaspartate(D-aspartate) O-methyltransferase Human genes 0.000 claims 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 2
- 150000003147 proline derivatives Chemical class 0.000 claims 2
- 108010018276 trimethylguanosine synthase Proteins 0.000 claims 2
- OWWNABDDYQLERE-RFZPGFLSSA-N (1r,2r)-2-(1h-imidazol-5-yl)cyclopropan-1-amine Chemical compound N[C@@H]1C[C@H]1C1=CNC=N1 OWWNABDDYQLERE-RFZPGFLSSA-N 0.000 claims 1
- XGNBIYXILDDDQR-DTWKUNHWSA-N (2s)-1-[(2s)-2-amino-3,3-dimethylbutanoyl]pyrrolidine-2-carbonitrile Chemical compound CC(C)(C)[C@H](N)C(=O)N1CCC[C@H]1C#N XGNBIYXILDDDQR-DTWKUNHWSA-N 0.000 claims 1
- ICULFJDHZQTNRB-HOTGVXAUSA-N (2s)-n-benzyl-2-[(2s)-2-(2-hydroxyacetyl)pyrrolidine-1-carbonyl]pyrrolidine-1-carboxamide Chemical compound OCC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)NCC=2C=CC=CC=2)CCC1 ICULFJDHZQTNRB-HOTGVXAUSA-N 0.000 claims 1
- RICKQPKTSOSCOF-HKUYNNGSSA-N (3s)-2-[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1C2=CC=CC=C2C[C@@H](C(O)=O)N1C(=O)[C@@H](N)CC1=CNC2=CC=CC=C12 RICKQPKTSOSCOF-HKUYNNGSSA-N 0.000 claims 1
- FNCPECYULVHYCJ-PAFCVIRNSA-N (4e,6e,8e,10z,12z,14e,16e)-3-[(3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19-[7-(4-aminophenyl)-5-hydroxy-7-oxoheptan-2-yl]-23,25,29,31,33,35,37-heptahydroxy-18-methyl-21-oxo-20,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10,12,14,16-heptaene Chemical compound O1C(=O)CC(O)CC(O)CCCC(O)CC(O)CC(O)CC(O2)(O)CC(O)C(C(O)=O)C2CC(OC2[C@H]([C@@H](N)[C@H](O)[C@@H](C)O2)O)\C=C\C=C\C=C\C=C/C=C\C=C\C=C\C(C)C1C(C)CCC(O)CC(=O)C1=CC=C(N)C=C1 FNCPECYULVHYCJ-PAFCVIRNSA-N 0.000 claims 1
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims 1
- GWHQHAUAXRMMOT-MERQFXBCSA-N 2,3-dihydroxybutanedioic acid;[3-[(1s)-1-(dimethylamino)ethyl]phenyl] n-ethyl-n-methylcarbamate Chemical group OC(=O)C(O)C(O)C(O)=O.CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 GWHQHAUAXRMMOT-MERQFXBCSA-N 0.000 claims 1
- OTBYLNCJHFPRTL-RQJHMYQMSA-N 2-[(1s,2s)-2-(1h-imidazol-5-yl)cyclopropyl]ethanamine Chemical compound NCC[C@@H]1C[C@@H]1C1=CNC=N1 OTBYLNCJHFPRTL-RQJHMYQMSA-N 0.000 claims 1
- GRUVVLWKPGIYEG-UHFFFAOYSA-N 2-[2-[carboxymethyl-[(2-hydroxyphenyl)methyl]amino]ethyl-[(2-hydroxyphenyl)methyl]amino]acetic acid Chemical compound C=1C=CC=C(O)C=1CN(CC(=O)O)CCN(CC(O)=O)CC1=CC=CC=C1O GRUVVLWKPGIYEG-UHFFFAOYSA-N 0.000 claims 1
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- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 1
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- PTKHFRNHJULJKT-UHFFFAOYSA-N jnj-5207852 Chemical compound C1CCCCN1CCCOC(C=C1)=CC=C1CN1CCCCC1 PTKHFRNHJULJKT-UHFFFAOYSA-N 0.000 claims 1
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- CSOBIBXVIYAXFM-UHFFFAOYSA-N rpl-554 Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN(C(N2CCNC(N)=O)=O)C1=CC2=NC1=C(C)C=C(C)C=C1C CSOBIBXVIYAXFM-UHFFFAOYSA-N 0.000 claims 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 claims 1
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- 238000003786 synthesis reaction Methods 0.000 description 33
- 235000002639 sodium chloride Nutrition 0.000 description 29
- 125000002252 acyl group Chemical group 0.000 description 28
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
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Classifications
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D417/12—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 chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US54213304P | 2004-02-05 | 2004-02-05 | |
| US60/542,133 | 2004-02-05 | ||
| US10/838,993 US7371871B2 (en) | 2003-05-05 | 2004-05-05 | Inhibitors of glutaminyl cyclase |
| US10/838,993 | 2004-05-05 | ||
| US63436404P | 2004-12-08 | 2004-12-08 | |
| US60/634,364 | 2004-12-08 | ||
| PCT/EP2005/001153 WO2005075436A2 (en) | 2004-02-05 | 2005-02-04 | Novel inhibitors of glutaminyl cyclase |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2007520520A JP2007520520A (ja) | 2007-07-26 |
| JP2007520520A5 JP2007520520A5 (enExample) | 2008-03-06 |
| JP4996926B2 true JP4996926B2 (ja) | 2012-08-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2006551809A Expired - Fee Related JP4996926B2 (ja) | 2004-02-05 | 2005-02-04 | グルタミニルシクラーゼの新規の阻害剤 |
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| Country | Link |
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| US (2) | US7304086B2 (enExample) |
| EP (1) | EP1713780B1 (enExample) |
| JP (1) | JP4996926B2 (enExample) |
| KR (1) | KR101099206B1 (enExample) |
| CN (1) | CN1918131B (enExample) |
| AU (1) | AU2005210004B2 (enExample) |
| BR (1) | BRPI0507485A (enExample) |
| CA (1) | CA2554809C (enExample) |
| WO (1) | WO2005075436A2 (enExample) |
Families Citing this family (87)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100376573C (zh) * | 2002-12-04 | 2008-03-26 | 卫材R&D管理有限公司 | 稠合的1,3-二氢-咪唑环化合物 |
| US20040242566A1 (en) | 2003-03-25 | 2004-12-02 | Syrrx, Inc. | Dipeptidyl peptidase inhibitors |
| US8338120B2 (en) | 2003-05-05 | 2012-12-25 | Probiodrug Ag | Method of treating inflammation with glutaminyl cyclase inhibitors |
| KR20100106630A (ko) * | 2003-05-05 | 2010-10-01 | 프로비오드룩 아게 | 글루타미닐 및 글루타메이트 사이클라제의 이펙터의 용도 |
| JP4806628B2 (ja) * | 2003-05-05 | 2011-11-02 | プロビオドルグ エージー | グルタミニルシクラーゼ阻害剤 |
| US7732162B2 (en) * | 2003-05-05 | 2010-06-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases |
| AU2004265341A1 (en) | 2003-08-13 | 2005-02-24 | Takeda Pharmaceutical Company Limited | 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors |
| WO2005026148A1 (en) | 2003-09-08 | 2005-03-24 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
| EP1824846A2 (en) * | 2003-11-03 | 2007-08-29 | Probiodrug AG | Novel compounds for the treatment of neurological disorders |
| US20100099721A1 (en) * | 2003-11-03 | 2010-04-22 | Probiodrug Ag | Novel compounds for the treatment of neurological disorders |
| US20050171112A1 (en) * | 2003-11-03 | 2005-08-04 | Probiodrug Ag | Combinations useful for the treatment of neuronal disorders |
| US7667044B2 (en) | 2003-11-03 | 2010-02-23 | Probiodrug Ag | Compounds for the treatment of neurological disorders |
| JP4996926B2 (ja) | 2004-02-05 | 2012-08-08 | プロビオドルグ エージー | グルタミニルシクラーゼの新規の阻害剤 |
| WO2005095381A1 (en) * | 2004-03-15 | 2005-10-13 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| JP2008524331A (ja) | 2004-12-21 | 2008-07-10 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼ阻害剤 |
| KR100650278B1 (ko) * | 2004-12-27 | 2006-11-27 | 김성진 | 엔-아릴 엔' 모르폴리노/ 피페리디노 티오카르바마이드유도체를 유효성분으로 함유하는 당뇨병, 당뇨병 합병증,인슐린저항성 및 그로 인한 인슐린 저항성 증후군의 예방및 치료용 약학적 조성물 |
| BRPI0608469A2 (pt) | 2005-04-22 | 2010-01-05 | Alantos Pharmaceuticals Holding Inc | inibidores de dipeptidil peptidase-iv |
| PL1942898T5 (pl) | 2005-09-14 | 2014-10-31 | Takeda Pharmaceuticals Co | Inhibitory peptydazy dipeptydylowej do leczenia cukrzycy |
| CN102675221A (zh) | 2005-09-16 | 2012-09-19 | 武田药品工业株式会社 | 用于制备嘧啶二酮衍生物的方法中的中间体 |
| US8324383B2 (en) * | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
| DK2073810T3 (da) * | 2006-09-13 | 2011-10-31 | Takeda Pharmaceutical | Anvendelse af 2-6-(3-aminio-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl-4-fluor-benzonitril til behandling af diabetes, cancer, autoimmune sygdomme og HIV infektion |
| KR101432848B1 (ko) * | 2006-09-21 | 2014-08-27 | 프로비오드룩 아게 | 글루타미닐 사이클라제에 관련된 신규한 유전자 |
| US9277737B2 (en) | 2006-09-21 | 2016-03-08 | Probiodrug Ag | Mouse models carrying a knock-out mutation of the QPCTL-gene |
| CN101573450B (zh) * | 2006-09-21 | 2015-12-16 | 前体生物药物股份公司 | 与谷氨酰环化酶相关的新基因 |
| US8889709B2 (en) | 2006-09-21 | 2014-11-18 | Probiodrug Ag | Use of isoQC inhibitors in the treatment and prevention of inflammatory diseases or conditions |
| JP5379692B2 (ja) * | 2006-11-09 | 2013-12-25 | プロビオドルグ エージー | 潰瘍、癌及び他の疾患の治療のためのグルタミニルシクラーゼの阻害薬としての３−ヒドロキシ−１，５−ジヒドロ−ピロール−２−オン誘導体 |
| US8420684B2 (en) * | 2006-11-09 | 2013-04-16 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
| WO2008055950A1 (en) * | 2006-11-09 | 2008-05-15 | Probiodrug Ag | Novel inhibitors of glutaminyl cyclase |
| TW200838536A (en) | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| EP2091948B1 (en) | 2006-11-30 | 2012-04-18 | Probiodrug AG | Novel inhibitors of glutaminyl cyclase |
| KR100867978B1 (ko) * | 2006-12-12 | 2008-11-10 | 이화여자대학교 산학협력단 | 이중 작용기를 가지는 새로운 이온성 액체 및 그의제조방법 |
| WO2008087197A1 (en) * | 2007-01-19 | 2008-07-24 | Probiodrug Ag | In vivo screening models for treatment of alzheimer's disease and other qpct-related disorders |
| EP2117540A1 (en) * | 2007-03-01 | 2009-11-18 | Probiodrug AG | New use of glutaminyl cyclase inhibitors |
| BRPI0808170A2 (pt) * | 2007-03-01 | 2014-07-08 | Probiodrug Ag | Uso de inibidores de glutaminil ciclase |
| GB2447017A (en) * | 2007-03-01 | 2008-09-03 | Probiodrug Ag | New use for inhibitors of glutaminyl peptide cyclotransferinase |
| US7803810B2 (en) * | 2007-03-09 | 2010-09-28 | Probiodrug Ag | Inhibitors |
| MX2009009703A (es) * | 2007-03-13 | 2010-03-03 | Takeda Pharmaceutical | Preparacion solida que comprende 2-[[6-[(3r)-3-amino-1-piperidinil ]-3,4-dihidro-3-metil-2,4-dioxo-1(2h)-pirimidinil]metil]-4-fluoro benzonitrilo. |
| US8093236B2 (en) * | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
| ES2474693T3 (es) * | 2007-04-18 | 2014-07-09 | Probiodrug Ag | Derivados de ciano-guanidina como inhibidores de glutaminil ciclasa |
| JP5675343B2 (ja) * | 2007-04-18 | 2015-02-25 | プロビオドルグ エージー | グルタミニルシクラーゼ阻害剤としての尿素誘導体 |
| JP5667440B2 (ja) * | 2007-04-18 | 2015-02-12 | プロビオドルグ エージー | グルタミニルシクラーゼ阻害剤としてのチオ尿素誘導体 |
| ES2478673T3 (es) * | 2007-04-18 | 2014-07-22 | Probiodrug Ag | Derivados de tioxoquinazolinona como inhibidores de la glutaminil ciclasa |
| JP5675344B2 (ja) * | 2007-04-18 | 2015-02-25 | プロビオドルグ エージー | グルタミニルシクラーゼ阻害剤としてのニトロビニルジアミン誘導体 |
| DK2142513T3 (da) * | 2007-04-18 | 2014-06-10 | Probiodrug Ag | Nitrovinyl-diamin-derivater som glutaminyl-cyclase-inhibitorer |
| US8188094B2 (en) * | 2007-04-20 | 2012-05-29 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
| WO2008144748A1 (en) * | 2007-05-21 | 2008-11-27 | The Uab Research Foundation | Prolyl endopeptidase inhibitors for reducing or preventing neutrophilic inflammation |
| NZ583799A (en) * | 2007-09-12 | 2011-12-22 | Probiodrug Ag | Transgenic mice comprising a DNA transgene encoding ABeta peptide |
| AU2009204864A1 (en) * | 2008-01-14 | 2009-07-23 | Probiodrug Ag | Mouse models carrying a knock-out mutation of the glutaminyl cyclase gene |
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- 2005-02-04 US US11/051,760 patent/US7304086B2/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| EP1713780B1 (en) | 2012-01-18 |
| US20050215573A1 (en) | 2005-09-29 |
| CN1918131B (zh) | 2011-05-04 |
| KR20060125884A (ko) | 2006-12-06 |
| US20090018087A1 (en) | 2009-01-15 |
| JP2007520520A (ja) | 2007-07-26 |
| BRPI0507485A (pt) | 2007-07-10 |
| CN1918131A (zh) | 2007-02-21 |
| CA2554809C (en) | 2014-04-29 |
| US7304086B2 (en) | 2007-12-04 |
| WO2005075436A2 (en) | 2005-08-18 |
| WO2005075436A3 (en) | 2005-12-08 |
| US7897633B2 (en) | 2011-03-01 |
| KR101099206B1 (ko) | 2011-12-27 |
| EP1713780A2 (en) | 2006-10-25 |
| CA2554809A1 (en) | 2005-08-18 |
| AU2005210004A1 (en) | 2005-08-18 |
| AU2005210004B2 (en) | 2010-10-28 |
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