JP3983662B2 - ピリミジン誘導体 - Google Patents
ピリミジン誘導体 Download PDFInfo
- Publication number
- JP3983662B2 JP3983662B2 JP2002512174A JP2002512174A JP3983662B2 JP 3983662 B2 JP3983662 B2 JP 3983662B2 JP 2002512174 A JP2002512174 A JP 2002512174A JP 2002512174 A JP2002512174 A JP 2002512174A JP 3983662 B2 JP3983662 B2 JP 3983662B2
- Authority
- JP
- Japan
- Prior art keywords
- trifluoro
- benzyloxymethyl
- pyrrolidine
- pyrimidin
- thiol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title 1
- 150000003230 pyrimidines Chemical class 0.000 title 1
- -1 diarylalkyl Chemical group 0.000 claims description 135
- 150000001875 compounds Chemical class 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 56
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 46
- 238000010511 deprotection reaction Methods 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 15
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 12
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 9
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 208000002249 Diabetes Complications Diseases 0.000 claims description 8
- 206010012655 Diabetic complications Diseases 0.000 claims description 8
- 206010019280 Heart failures Diseases 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000005120 alkyl cycloalkyl alkyl group Chemical group 0.000 claims description 8
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 8
- 208000031225 myocardial ischemia Diseases 0.000 claims description 8
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 8
- 150000003573 thiols Chemical class 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 208000010412 Glaucoma Diseases 0.000 claims description 7
- 206010040047 Sepsis Diseases 0.000 claims description 7
- 206010052779 Transplant rejections Diseases 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000005127 aryl alkoxy alkyl group Chemical group 0.000 claims description 7
- 208000006673 asthma Diseases 0.000 claims description 7
- 210000000056 organ Anatomy 0.000 claims description 7
- WUEPMEXUMQVEGN-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;2,2,2-trifluoro-n-[2-[2-[(2,2,2-trifluoroacetyl)amino]ethylamino]ethyl]acetamide Chemical compound OC(=O)C(F)(F)F.FC(F)(F)C(=O)NCCNCCNC(=O)C(F)(F)F WUEPMEXUMQVEGN-UHFFFAOYSA-N 0.000 claims description 6
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 206010040070 Septic Shock Diseases 0.000 claims description 6
- 206010043540 Thromboangiitis obliterans Diseases 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 6
- 206010003119 arrhythmia Diseases 0.000 claims description 6
- 230000006793 arrhythmia Effects 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 6
- 239000000824 cytostatic agent Substances 0.000 claims description 6
- 230000001085 cytostatic effect Effects 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 230000002175 menstrual effect Effects 0.000 claims description 6
- 201000011461 pre-eclampsia Diseases 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 230000029663 wound healing Effects 0.000 claims description 6
- LDWBMEMUYZSWCV-ZVWHLABXSA-N (3r,5s)-1-pyrimidin-2-yl-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=CC=CN=2)C[C@H](S)C1 LDWBMEMUYZSWCV-ZVWHLABXSA-N 0.000 claims description 5
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 5
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 5
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- XRXDLCUAVFZZIZ-ZWKOTPCHSA-N (3r,5s)-1-(5-phenylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=CC(=CN=2)C=2C=CC=CC=2)C[C@H](S)C1 XRXDLCUAVFZZIZ-ZWKOTPCHSA-N 0.000 claims description 4
- HHQGKVFJHXBAAD-JKSUJKDBSA-N (3r,5s)-1-(5-pyridin-2-ylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=CC(=CN=2)C=2N=CC=CC=2)C[C@H](S)C1 HHQGKVFJHXBAAD-JKSUJKDBSA-N 0.000 claims description 4
- NQHHCMKGFMKOFU-DLBZAZTESA-N (3r,5s)-1-(6-phenylpyridazin-3-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=NC(=CC=2)C=2C=CC=CC=2)C[C@H](S)C1 NQHHCMKGFMKOFU-DLBZAZTESA-N 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 239000000539 dimer Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
- IPMQDYQBJGYCOR-WDEREUQCSA-N (3r,5s)-1-(2-chloropyrimidin-4-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=C(Cl)N=CC=2)C[C@H](S)C1 IPMQDYQBJGYCOR-WDEREUQCSA-N 0.000 claims description 3
- AYBXHWXTWCIHTP-NWDGAFQWSA-N (3r,5s)-1-(2-methylsulfanylpyrimidin-4-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound CSC1=NC=CC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)=N1 AYBXHWXTWCIHTP-NWDGAFQWSA-N 0.000 claims description 3
- VYOCXHUFKWXORO-DLBZAZTESA-N (3r,5s)-1-(5-pyridin-4-ylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=CC(=CN=2)C=2C=CN=CC=2)C[C@H](S)C1 VYOCXHUFKWXORO-DLBZAZTESA-N 0.000 claims description 3
- WERIMYMQPAGYPE-ZWKOTPCHSA-N (3r,5s)-1-[2-(benzylamino)pyrimidin-4-yl]-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=C(NCC=3C=CC=CC=3)N=CC=2)C[C@H](S)C1 WERIMYMQPAGYPE-ZWKOTPCHSA-N 0.000 claims description 3
- YBZULUMQYLZWJD-NWDGAFQWSA-N (3r,5s)-1-[2-(methylamino)pyrimidin-4-yl]-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound CNC1=NC=CC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)=N1 YBZULUMQYLZWJD-NWDGAFQWSA-N 0.000 claims description 3
- PASHRVSSGDGACB-UHFFFAOYSA-N 1-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COCN1CC(S)CC1 PASHRVSSGDGACB-UHFFFAOYSA-N 0.000 claims description 3
- BNDSAUJQUBQEMB-NWDGAFQWSA-N 6-methyl-2-[(2s,4r)-4-sulfanyl-2-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidin-1-yl]pyrimidine-4-carboxylic acid Chemical compound CC1=CC(C(O)=O)=NC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)=N1 BNDSAUJQUBQEMB-NWDGAFQWSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 3
- 125000001769 aryl amino group Chemical group 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 230000001681 protective effect Effects 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- ZJAMIEIOACGWIT-RBUKOAKNSA-N s-[(3r,5s)-5-[[(2,5-difluorophenyl)methylamino]methyl]-1-(5-propylpyrimidin-2-yl)pyrrolidin-3-yl] ethanethioate Chemical compound N1=CC(CCC)=CN=C1N1[C@H](CNCC=2C(=CC=C(F)C=2)F)C[C@@H](SC(C)=O)C1 ZJAMIEIOACGWIT-RBUKOAKNSA-N 0.000 claims description 3
- XPRQARNOXVFIAN-NWDGAFQWSA-N (3r,5s)-1-(2-methoxypyrimidin-4-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound COC1=NC=CC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)=N1 XPRQARNOXVFIAN-NWDGAFQWSA-N 0.000 claims description 2
- QRPSWQVMTOZSIC-DOTOQJQBSA-N (3r,5s)-1-(2-phenoxypyrimidin-4-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=C(OC=3C=CC=CC=3)N=CC=2)C[C@H](S)C1 QRPSWQVMTOZSIC-DOTOQJQBSA-N 0.000 claims description 2
- TVYWICRWPUGEFD-NWDGAFQWSA-N (3r,5s)-1-(4,6-dimethoxypyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound COC1=CC(OC)=NC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)=N1 TVYWICRWPUGEFD-NWDGAFQWSA-N 0.000 claims description 2
- ZBYVKAQKUFSUHI-VHSXEESVSA-N (3r,5s)-1-(4-amino-5-fluoropyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(N)=NC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)=N1 ZBYVKAQKUFSUHI-VHSXEESVSA-N 0.000 claims description 2
- CDWMLPFDROZTPB-DLBZAZTESA-N (3r,5s)-1-(5-pyridin-3-ylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=CC(=CN=2)C=2C=NC=CC=2)C[C@H](S)C1 CDWMLPFDROZTPB-DLBZAZTESA-N 0.000 claims description 2
- JBISUVFYOSMVQM-LSDHHAIUSA-N (3r,5s)-1-[2-(butylamino)pyrimidin-4-yl]-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound CCCCNC1=NC=CC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)=N1 JBISUVFYOSMVQM-LSDHHAIUSA-N 0.000 claims description 2
- UNKNXSFMYAROAL-PKOBYXMFSA-N (3r,5s)-1-[5-(4-methoxyphenyl)pyrimidin-2-yl]-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=CC(OC)=CC=C1C1=CN=C(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)N=C1 UNKNXSFMYAROAL-PKOBYXMFSA-N 0.000 claims description 2
- ANQXBYLDYFYYSO-NWDGAFQWSA-N (3r,5s)-1-pyrazin-2-yl-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=CC=NC=2)C[C@H](S)C1 ANQXBYLDYFYYSO-NWDGAFQWSA-N 0.000 claims description 2
- HCAPHMKDDMUESA-DLBZAZTESA-N (3r,5s)-5-[(2,4,5-trifluorophenyl)methoxymethyl]-1-[5-(2-trimethylsilylethynyl)pyrimidin-2-yl]pyrrolidine-3-thiol Chemical compound N1=CC(C#C[Si](C)(C)C)=CN=C1N1[C@H](COCC=2C(=CC(F)=C(F)C=2)F)C[C@@H](S)C1 HCAPHMKDDMUESA-DLBZAZTESA-N 0.000 claims description 2
- VPNROZRRPDMWDL-QWHCGFSZSA-N (3r,5s)-5-[(2,5-difluoro-4-methoxyphenyl)methoxymethyl]-1-(2-methoxypyrimidin-4-yl)pyrrolidine-3-thiol Chemical compound COC1=NC=CC(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(OC)=C(F)C=2)F)=N1 VPNROZRRPDMWDL-QWHCGFSZSA-N 0.000 claims description 2
- CDWMLPFDROZTPB-UHFFFAOYSA-N 1-(5-pyridin-3-ylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COCC1N(C=2N=CC(=CN=2)C=2C=NC=CC=2)CC(S)C1 CDWMLPFDROZTPB-UHFFFAOYSA-N 0.000 claims description 2
- UVUJLMKBKHBROX-UHFFFAOYSA-N 1-(5-thiophen-3-ylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COCC1N(C=2N=CC(=CN=2)C2=CSC=C2)CC(S)C1 UVUJLMKBKHBROX-UHFFFAOYSA-N 0.000 claims description 2
- JSFXXFMQIMIOTA-UONOGXRCSA-N 2-[(2s,4r)-4-sulfanyl-2-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidin-1-yl]pyridine-3-carbonitrile Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2C(=CC=CN=2)C#N)C[C@H](S)C1 JSFXXFMQIMIOTA-UONOGXRCSA-N 0.000 claims description 2
- LXTWYFDYKSBOCX-NWDGAFQWSA-N 2-[(2s,4r)-4-sulfanyl-2-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidin-1-yl]pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1N1[C@H](COCC=2C(=CC(F)=C(F)C=2)F)C[C@@H](S)C1 LXTWYFDYKSBOCX-NWDGAFQWSA-N 0.000 claims description 2
- BWNXXAWAZSGSRS-NWDGAFQWSA-N 2-[(2s,4r)-4-sulfanyl-2-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidin-1-yl]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1N1[C@H](COCC=2C(=CC(F)=C(F)C=2)F)C[C@@H](S)C1 BWNXXAWAZSGSRS-NWDGAFQWSA-N 0.000 claims description 2
- ADZVOMVMIAGCJA-ZWKOTPCHSA-N 4-[2-[(2s,4r)-4-sulfanyl-2-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidin-1-yl]pyrimidin-5-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CN=C(N2[C@@H](C[C@@H](S)C2)COCC=2C(=CC(F)=C(F)C=2)F)N=C1 ADZVOMVMIAGCJA-ZWKOTPCHSA-N 0.000 claims description 2
- 239000005973 Carvone Substances 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000006287 difluorobenzyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- TZVFQFLWFZUIQS-UHFFFAOYSA-N pyrrolidine-3-thiol Chemical compound SC1CCNC1 TZVFQFLWFZUIQS-UHFFFAOYSA-N 0.000 claims description 2
- FRYMCZDMUBETNT-DLBZAZTESA-N s-[(3r,5s)-1-(5-propylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidin-3-yl] ethanethioate Chemical compound N1=CC(CCC)=CN=C1N1[C@H](COCC=2C(=CC(F)=C(F)C=2)F)C[C@@H](SC(C)=O)C1 FRYMCZDMUBETNT-DLBZAZTESA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 8
- UVUJLMKBKHBROX-JKSUJKDBSA-N (3r,5s)-1-(5-thiophen-3-ylpyrimidin-2-yl)-5-[(2,4,5-trifluorophenyl)methoxymethyl]pyrrolidine-3-thiol Chemical compound C1=C(F)C(F)=CC(F)=C1COC[C@H]1N(C=2N=CC(=CN=2)C2=CSC=C2)C[C@H](S)C1 UVUJLMKBKHBROX-JKSUJKDBSA-N 0.000 claims 1
- 208000001106 Takayasu Arteritis Diseases 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 125000006493 trifluoromethyl benzyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000011734 sodium Substances 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 description 25
- 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000007429 general method Methods 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
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- 235000011056 potassium acetate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- 230000009257 reactivity Effects 0.000 description 1
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- 238000006722 reduction reaction Methods 0.000 description 1
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- 239000011347 resin Substances 0.000 description 1
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- 208000037803 restenosis Diseases 0.000 description 1
- BNPPOCAFGWAXTH-IZZNHLLZSA-N s-[(3r,5s)-5-[[(2,5-difluorophenyl)methyl-phenylmethoxycarbonylamino]methyl]-1-(5-propylpyrimidin-2-yl)pyrrolidin-3-yl] ethanethioate Chemical compound N1=CC(CCC)=CN=C1N1[C@H](CN(CC=2C(=CC=C(F)C=2)F)C(=O)OCC=2C=CC=CC=2)C[C@@H](SC(C)=O)C1 BNPPOCAFGWAXTH-IZZNHLLZSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- SQNZXWCEBYTVBZ-XZWHSSHBSA-N tert-butyl (2s,4r)-2-[(2,4,5-trifluorophenyl)methoxymethyl]-4-tritylsulfanylpyrrolidine-1-carboxylate Chemical compound C([C@@H]1C[C@H](CN1C(=O)OC(C)(C)C)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)OCC1=CC(F)=C(F)C=C1F SQNZXWCEBYTVBZ-XZWHSSHBSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 125000006510 trifluorobenzyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- BNCVEHSRHRBTPQ-OIDHKYIRSA-N trimethyl-[2-[2-[(2s,4r)-2-[(2,4,5-trifluorophenyl)methoxymethyl]-4-tritylsulfanylpyrrolidin-1-yl]pyrimidin-5-yl]ethynyl]silane Chemical compound N1=CC(C#C[Si](C)(C)C)=CN=C1N1[C@H](COCC=2C(=CC(F)=C(F)C=2)F)C[C@@H](SC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C1 BNCVEHSRHRBTPQ-OIDHKYIRSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 230000004572 zinc-binding Effects 0.000 description 1
Classifications
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- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
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- A61P9/12—Antihypertensives
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Ophthalmology & Optometry (AREA)
- Hematology (AREA)
- Neurology (AREA)
- Pregnancy & Childbirth (AREA)
- Obesity (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Transplantation (AREA)
- Neurosurgery (AREA)
- Vascular Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Emergency Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00114950 | 2000-07-19 | ||
| PCT/EP2001/008059 WO2002006271A1 (en) | 2000-07-19 | 2001-07-12 | Pyrimidine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2004504317A JP2004504317A (ja) | 2004-02-12 |
| JP2004504317A5 JP2004504317A5 (enExample) | 2005-02-03 |
| JP3983662B2 true JP3983662B2 (ja) | 2007-09-26 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002512174A Expired - Lifetime JP3983662B2 (ja) | 2000-07-19 | 2001-07-12 | ピリミジン誘導体 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US6660738B2 (enExample) |
| EP (1) | EP1303507A1 (enExample) |
| JP (1) | JP3983662B2 (enExample) |
| KR (1) | KR100551853B1 (enExample) |
| CN (1) | CN1443184A (enExample) |
| AR (1) | AR030940A1 (enExample) |
| AU (1) | AU2001285836A1 (enExample) |
| BR (1) | BR0112656A (enExample) |
| CA (1) | CA2415681C (enExample) |
| MX (1) | MXPA03000504A (enExample) |
| PA (1) | PA8522201A1 (enExample) |
| PE (1) | PE20020484A1 (enExample) |
| UY (1) | UY26845A1 (enExample) |
| WO (1) | WO2002006271A1 (enExample) |
| ZA (1) | ZA200300161B (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2537514T3 (es) | 2003-04-04 | 2015-06-09 | Incyte Corporation | Composiciones, métodos y kits relacionados con la escisión de HER-2 |
| US7678363B2 (en) | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| US20110053907A1 (en) * | 2008-03-27 | 2011-03-03 | Auckland Uniservices Limited | Substituted pyrimidines and triazines and their use in cancer therapy |
| SG11201505631PA (en) | 2013-01-23 | 2015-08-28 | Astrazeneca Ab | Chemical compounds |
| WO2019226213A2 (en) | 2018-03-08 | 2019-11-28 | Incyte Corporation | AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS |
| WO2020010003A1 (en) | 2018-07-02 | 2020-01-09 | Incyte Corporation | AMINOPYRAZINE DERIVATIVES AS PI3K-γ INHIBITORS |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0182213B1 (en) * | 1984-11-08 | 1990-09-26 | Sumitomo Pharmaceuticals Company, Limited | Carbapenem compounds and production thereof |
| AU631671B2 (en) * | 1989-08-04 | 1992-12-03 | Banyu Pharmaceutical Co., Ltd. | 2-(2-vinylpyrrolidinylthio)carbapenem derivatives |
| US5360798A (en) * | 1991-07-04 | 1994-11-01 | Shionogi Seiyaku Kabushiki Kaisha | Aminooxypyrrolidinylthiocarbapenem compounds |
| US5317016A (en) * | 1991-08-20 | 1994-05-31 | Shionogi Seiyaku Kabushiki Kaisha | Pyrrolidylthiocarbapenem derivative |
| BR9609744A (pt) * | 1995-07-31 | 1999-03-02 | Shionogi & Co | Derivados de pirrolidina tendo atividade inibitória de fosfolipase a2 |
| JP2000514041A (ja) * | 1996-07-26 | 2000-10-24 | ドクター・レディーズ・リサーチ・ファウンデーション | 抗糖尿病、低脂血、抗高血圧特性を有するチアゾリジンジオン化合物、それらの調製法、及びその薬学的組成物 |
| BR9712792A (pt) * | 1996-08-28 | 1999-12-14 | Procter & Gamble | Inibidores de metaloprotease bidentada. |
| JP4368524B2 (ja) * | 1997-09-12 | 2009-11-18 | メルク フロスト カナダ リミテツド | シクロオキシゲナーゼ−２阻害薬としての２−アミノピリジン類 |
| US6329418B1 (en) * | 1998-04-14 | 2001-12-11 | The Procter & Gamble Company | Substituted pyrrolidine hydroxamate metalloprotease inhibitors |
-
2001
- 2001-07-12 EP EP01965123A patent/EP1303507A1/en not_active Withdrawn
- 2001-07-12 CN CN01812970A patent/CN1443184A/zh active Pending
- 2001-07-12 MX MXPA03000504A patent/MXPA03000504A/es active IP Right Grant
- 2001-07-12 AU AU2001285836A patent/AU2001285836A1/en not_active Abandoned
- 2001-07-12 WO PCT/EP2001/008059 patent/WO2002006271A1/en not_active Ceased
- 2001-07-12 KR KR1020037000727A patent/KR100551853B1/ko not_active Expired - Fee Related
- 2001-07-12 CA CA002415681A patent/CA2415681C/en not_active Expired - Fee Related
- 2001-07-12 BR BR0112656-3A patent/BR0112656A/pt not_active IP Right Cessation
- 2001-07-12 JP JP2002512174A patent/JP3983662B2/ja not_active Expired - Lifetime
- 2001-07-16 PE PE2001000709A patent/PE20020484A1/es not_active Application Discontinuation
- 2001-07-16 PA PA20018522201A patent/PA8522201A1/es unknown
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- 2001-07-17 AR ARP010103414A patent/AR030940A1/es unknown
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2003
- 2003-01-07 ZA ZA200300161A patent/ZA200300161B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1303507A1 (en) | 2003-04-23 |
| CA2415681A1 (en) | 2002-01-24 |
| CN1443184A (zh) | 2003-09-17 |
| WO2002006271A1 (en) | 2002-01-24 |
| CA2415681C (en) | 2008-05-20 |
| US20020055632A1 (en) | 2002-05-09 |
| JP2004504317A (ja) | 2004-02-12 |
| PA8522201A1 (es) | 2002-04-25 |
| KR100551853B1 (ko) | 2006-02-13 |
| UY26845A1 (es) | 2002-01-31 |
| BR0112656A (pt) | 2003-06-24 |
| MXPA03000504A (es) | 2003-06-24 |
| AR030940A1 (es) | 2003-09-03 |
| ZA200300161B (en) | 2004-04-07 |
| KR20030022289A (ko) | 2003-03-15 |
| PE20020484A1 (es) | 2002-06-06 |
| AU2001285836A1 (en) | 2002-01-30 |
| US6660738B2 (en) | 2003-12-09 |
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