JP2005533803A - システインプロテアーゼ活性と関連する疾患の処置のためのピリミジン−またはトリアジン−２−カルボニトリルの新規使用および新規ピリミジン−２−カルボニトリル誘導体 - Google Patents
システインプロテアーゼ活性と関連する疾患の処置のためのピリミジン−またはトリアジン−２−カルボニトリルの新規使用および新規ピリミジン−２−カルボニトリル誘導体 Download PDFInfo
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- JP2005533803A JP2005533803A JP2004515328A JP2004515328A JP2005533803A JP 2005533803 A JP2005533803 A JP 2005533803A JP 2004515328 A JP2004515328 A JP 2004515328A JP 2004515328 A JP2004515328 A JP 2004515328A JP 2005533803 A JP2005533803 A JP 2005533803A
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- Prior art keywords
- amino
- carbonitrile
- chlorophenyl
- alkyl
- morpholin
- 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.)
- Pending
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- 108010005843 Cysteine Proteases Proteins 0.000 title claims abstract description 11
- 102000005927 Cysteine Proteases Human genes 0.000 title claims abstract description 11
- IIHQNAXFIODVDU-UHFFFAOYSA-N pyrimidine-2-carbonitrile Chemical class N#CC1=NC=CC=N1 IIHQNAXFIODVDU-UHFFFAOYSA-N 0.000 title claims description 3
- 201000010099 disease Diseases 0.000 title abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 8
- 230000000694 effects Effects 0.000 title abstract description 5
- GJAXSOVBBPZKHH-UHFFFAOYSA-N 1h-triazine-2-carbonitrile Chemical compound N#CN1NC=CC=N1 GJAXSOVBBPZKHH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 32
- 108090000613 Cathepsin S Proteins 0.000 claims abstract description 12
- 102100035654 Cathepsin S Human genes 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- -1 amino, hydroxy Chemical group 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- JLEVFFZEGQVAOR-UHFFFAOYSA-N 5-chloro-4-(4-chloroanilino)-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(C#N)=NC(N2CCOCC2)=C1Cl JLEVFFZEGQVAOR-UHFFFAOYSA-N 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims description 5
- WUUXAWFBPPBXII-UHFFFAOYSA-N 4-(4-chloroanilino)-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N2CCNCC2)C(OC)=C1NC1=CC=C(Cl)C=C1 WUUXAWFBPPBXII-UHFFFAOYSA-N 0.000 claims description 4
- GJHNZJNXSKYROP-UHFFFAOYSA-N 5-amino-4-(4-chloroanilino)-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N2CCOCC2)C(N)=C1NC1=CC=C(Cl)C=C1 GJHNZJNXSKYROP-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- HRXPLNARFGLXAV-UHFFFAOYSA-N 1-(4-cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-n,n-diethylpiperidine-3-carboxamide Chemical compound C1C(C(=O)N(CC)CC)CCCN1C1=NC(C#N)=NC(N2CCOCC2)=N1 HRXPLNARFGLXAV-UHFFFAOYSA-N 0.000 claims description 3
- CMRHBNMOCLQRSF-UHFFFAOYSA-N 4-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(C#N)=NC(NC=2C=C3OCCOC3=CC=2)=NC=1N1CCOCC1 CMRHBNMOCLQRSF-UHFFFAOYSA-N 0.000 claims description 3
- XWCQLQFUUUVLRU-UHFFFAOYSA-N 4-(4-aminopiperidin-1-yl)-6-(4-chloroanilino)-5-methoxypyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N2CCC(N)CC2)C(OC)=C1NC1=CC=C(Cl)C=C1 XWCQLQFUUUVLRU-UHFFFAOYSA-N 0.000 claims description 3
- YPDSLCXUIXJXNJ-UHFFFAOYSA-N 4-(4-aminopiperidin-1-yl)-6-(4-chloroanilino)pyrimidine-2-carbonitrile Chemical compound C1CC(N)CCN1C1=CC(NC=2C=CC(Cl)=CC=2)=NC(C#N)=N1 YPDSLCXUIXJXNJ-UHFFFAOYSA-N 0.000 claims description 3
- NMABGHZGYRXDKI-UHFFFAOYSA-N 4-(4-chloroanilino)-5-methoxy-6-(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N2CC(=O)NCC2)C(OC)=C1NC1=CC=C(Cl)C=C1 NMABGHZGYRXDKI-UHFFFAOYSA-N 0.000 claims description 3
- BTZKIHBFNQJXTB-UHFFFAOYSA-N 4-(4-chloroanilino)-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N2CCOCC2)C(OC)=C1NC1=CC=C(Cl)C=C1 BTZKIHBFNQJXTB-UHFFFAOYSA-N 0.000 claims description 3
- PQVMVGGJDJIQEL-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(2-piperidin-1-ylethylamino)-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(NCCN2CCCCC2)=NC(C#N)=N1 PQVMVGGJDJIQEL-UHFFFAOYSA-N 0.000 claims description 3
- ZPTOAFOTEBXFRX-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(3-hydroxypyrrolidin-1-yl)-1,3,5-triazine-2-carbonitrile Chemical compound C1C(O)CCN1C1=NC(NC=2C=CC(Cl)=CC=2)=NC(C#N)=N1 ZPTOAFOTEBXFRX-UHFFFAOYSA-N 0.000 claims description 3
- LNLMQGVSOHPCFR-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(3-pyrrolidin-1-ylpropylamino)pyrimidine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=CC(NCCCN2CCCC2)=NC(C#N)=N1 LNLMQGVSOHPCFR-UHFFFAOYSA-N 0.000 claims description 3
- XFOOFOWYROOZEA-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-carbonitrile Chemical compound C1CN(C)CCN1C1=NC(NC=2C=CC(Cl)=CC=2)=NC(C#N)=N1 XFOOFOWYROOZEA-UHFFFAOYSA-N 0.000 claims description 3
- XJKDWNYTZZEYQD-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(C#N)=NC(N2CCC(CC2)C=2C=CC=CC=2)=N1 XJKDWNYTZZEYQD-UHFFFAOYSA-N 0.000 claims description 3
- BBAKVKGWOAPQKH-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=CC(N2CCC(CC2)N2CCCC2)=NC(C#N)=N1 BBAKVKGWOAPQKH-UHFFFAOYSA-N 0.000 claims description 3
- NMWMRLWGNJUBRC-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile Chemical compound N#CC1=NC(N(C)C)=NC(NC=2C=CC(Cl)=CC=2)=N1 NMWMRLWGNJUBRC-UHFFFAOYSA-N 0.000 claims description 3
- FKNPVHLJQRYZPP-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(dimethylamino)-5-methoxypyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N(C)C)C(OC)=C1NC1=CC=C(Cl)C=C1 FKNPVHLJQRYZPP-UHFFFAOYSA-N 0.000 claims description 3
- VCUKMSHUJDBTKR-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(dimethylamino)pyrimidine-2-carbonitrile Chemical compound N#CC1=NC(N(C)C)=CC(NC=2C=CC(Cl)=CC=2)=N1 VCUKMSHUJDBTKR-UHFFFAOYSA-N 0.000 claims description 3
- CFTYWZFVQURLDD-UHFFFAOYSA-N 4-(4-chloroanilino)-6-(ethylamino)-1,3,5-triazine-2-carbonitrile Chemical compound N#CC1=NC(NCC)=NC(NC=2C=CC(Cl)=CC=2)=N1 CFTYWZFVQURLDD-UHFFFAOYSA-N 0.000 claims description 3
- VSBXRTMJVIITDW-UHFFFAOYSA-N 4-(4-chloroanilino)-6-[4-[3-(dimethylamino)propyl]piperazin-1-yl]-5-methoxypyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N2CCN(CCCN(C)C)CC2)C(OC)=C1NC1=CC=C(Cl)C=C1 VSBXRTMJVIITDW-UHFFFAOYSA-N 0.000 claims description 3
- GKWVLGLOAVNKNN-UHFFFAOYSA-N 4-(4-chloroanilino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(C#N)=NC(N2CCOCC2)=N1 GKWVLGLOAVNKNN-UHFFFAOYSA-N 0.000 claims description 3
- ARIOMJSONVMVHM-UHFFFAOYSA-N 4-(4-chloroanilino)-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=CC(N2CCOCC2)=NC(C#N)=N1 ARIOMJSONVMVHM-UHFFFAOYSA-N 0.000 claims description 3
- PHRFVDJKWANIIJ-UHFFFAOYSA-N 4-(4-chloroanilino)-6-piperazin-1-ylpyrimidine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=CC(N2CCNCC2)=NC(C#N)=N1 PHRFVDJKWANIIJ-UHFFFAOYSA-N 0.000 claims description 3
- XUABEUVVOXVCEQ-UHFFFAOYSA-N 4-(4-chloroanilino)-6-piperidin-1-yl-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(C#N)=NC(N2CCCCC2)=N1 XUABEUVVOXVCEQ-UHFFFAOYSA-N 0.000 claims description 3
- FNIDFZPHGCXTQD-UHFFFAOYSA-N 4-(4-chloroanilino)-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(C#N)=NC(N2CCCC2)=N1 FNIDFZPHGCXTQD-UHFFFAOYSA-N 0.000 claims description 3
- JBJHOQKLHPKKNE-UHFFFAOYSA-N 4-(4-chloroanilino)-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=CC(N2CCCC2)=NC(C#N)=N1 JBJHOQKLHPKKNE-UHFFFAOYSA-N 0.000 claims description 3
- RCCAPSQQOVDJIJ-UHFFFAOYSA-N 4-(4-chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1OC1=CC(N2CCOCC2)=NC(C#N)=N1 RCCAPSQQOVDJIJ-UHFFFAOYSA-N 0.000 claims description 3
- ICWNIFGBCIVBTL-UHFFFAOYSA-N 4-(4-imidazol-1-ylpiperidin-1-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(C#N)=NC(N2CCOCC2)=NC=1N(CC1)CCC1N1C=CN=C1 ICWNIFGBCIVBTL-UHFFFAOYSA-N 0.000 claims description 3
- NLPJWWPRAXCQIW-UHFFFAOYSA-N 4-(7-azabicyclo[2.2.1]heptan-7-yl)-6-(4-chloroanilino)-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(C#N)=NC(N2C3CCC2CC3)=N1 NLPJWWPRAXCQIW-UHFFFAOYSA-N 0.000 claims description 3
- ZOZJTLLDGHUBPY-UHFFFAOYSA-N 4-(azetidin-1-yl)-6-(4-chloroanilino)-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1NC1=NC(C#N)=NC(N2CCC2)=N1 ZOZJTLLDGHUBPY-UHFFFAOYSA-N 0.000 claims description 3
- JACOZRXEUWTVOP-UHFFFAOYSA-N 4-(cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound C=1C(N2CCOCC2)=NC(C#N)=NC=1NC1CCCCC1 JACOZRXEUWTVOP-UHFFFAOYSA-N 0.000 claims description 3
- SWHVKIKRWPLXPK-UHFFFAOYSA-N 4-[(1-methylpiperidin-4-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound C1CN(C)CCC1NC1=CC(N2CCOCC2)=NC(C#N)=N1 SWHVKIKRWPLXPK-UHFFFAOYSA-N 0.000 claims description 3
- WOXKHFVEAVYTRX-UHFFFAOYSA-N 4-[(3-chlorophenyl)methylamino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile Chemical compound N#CC1=NC(N(C)C)=NC(NCC=2C=C(Cl)C=CC=2)=N1 WOXKHFVEAVYTRX-UHFFFAOYSA-N 0.000 claims description 3
- KJLDVJFLNOBWQC-NSHDSACASA-N 4-[(3s)-3-aminopyrrolidin-1-yl]-6-(4-chloroanilino)-5-methoxypyrimidine-2-carbonitrile Chemical compound N1=C(C#N)N=C(N2C[C@@H](N)CC2)C(OC)=C1NC1=CC=C(Cl)C=C1 KJLDVJFLNOBWQC-NSHDSACASA-N 0.000 claims description 3
- QTUPPQQZNILLGV-UHFFFAOYSA-N 4-[(4-methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound C1CC(C)CCC1NC1=CC(N2CCOCC2)=NC(C#N)=N1 QTUPPQQZNILLGV-UHFFFAOYSA-N 0.000 claims description 3
- FBBDIKHSVMXWNJ-UHFFFAOYSA-N 4-[(6-chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile Chemical compound C1=NC(Cl)=CC=C1NC1=CC(N2CCOCC2)=NC(C#N)=N1 FBBDIKHSVMXWNJ-UHFFFAOYSA-N 0.000 claims description 3
- HKYNATOIQKWVMA-UHFFFAOYSA-N 4-[2-(furan-2-yl)ethylamino]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(N2CCOCC2)=NC(C#N)=NC=1NCCC1=CC=CO1 HKYNATOIQKWVMA-UHFFFAOYSA-N 0.000 claims description 3
- AGZVGTBMPVFJME-UHFFFAOYSA-N 4-[4-(2-methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile Chemical compound COC1=CC=CC=C1N1CCN(C=2N=C(N=C(N=2)C#N)N2CCOCC2)CC1 AGZVGTBMPVFJME-UHFFFAOYSA-N 0.000 claims description 3
- QBVCDJOMJPOECH-UHFFFAOYSA-N 4-[4-(4-chlorobenzoyl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(C=2N=C(N=C(N=2)C#N)N2CCOCC2)CC1 QBVCDJOMJPOECH-UHFFFAOYSA-N 0.000 claims description 3
- NSXYUBSJTLTVOX-UHFFFAOYSA-N 4-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile Chemical compound N1=CC(Cl)=CC=C1N1CCN(C=2N=C(N=C(N=2)C#N)N2CCOCC2)CC1 NSXYUBSJTLTVOX-UHFFFAOYSA-N 0.000 claims description 3
- VVFZSWNCOHTYQS-UHFFFAOYSA-N 4-morpholin-4-yl-6-(2-pyridin-3-ylethylamino)-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(N2CCOCC2)=NC(C#N)=NC=1NCCC1=CC=CN=C1 VVFZSWNCOHTYQS-UHFFFAOYSA-N 0.000 claims description 3
- ACPGGAROWYBYCA-UHFFFAOYSA-N 4-morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(C#N)=NC(N2CCOCC2)=NC=1N(C1)CCCC1C1=CC=CC=C1 ACPGGAROWYBYCA-UHFFFAOYSA-N 0.000 claims description 3
- RSBVTQNOBXLYGL-UHFFFAOYSA-N 4-morpholin-4-yl-6-(4-morpholin-4-ylanilino)-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(N2CCOCC2)=NC(C#N)=NC=1NC(C=C1)=CC=C1N1CCOCC1 RSBVTQNOBXLYGL-UHFFFAOYSA-N 0.000 claims description 3
- KHPHMGJSXDODOC-UHFFFAOYSA-N 4-morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(C#N)=NC(N2CCOCC2)=NC=1N(CC1)CCC1OC1=CC=CC=C1 KHPHMGJSXDODOC-UHFFFAOYSA-N 0.000 claims description 3
- URMHHFDWPPZHIV-UHFFFAOYSA-N 4-morpholin-4-yl-6-(4-piperidin-1-ylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile Chemical compound N=1C(C#N)=NC(N2CCOCC2)=NC=1N(CC1)CCC1N1CCCCC1 URMHHFDWPPZHIV-UHFFFAOYSA-N 0.000 claims description 3
- JORNRTNWRASXHW-UHFFFAOYSA-N 4-morpholin-4-yl-6-[3-(2-oxopyrrolidin-1-yl)propylamino]-1,3,5-triazine-2-carbonitrile Chemical compound O=C1CCCN1CCCNC1=NC(C#N)=NC(N2CCOCC2)=N1 JORNRTNWRASXHW-UHFFFAOYSA-N 0.000 claims description 3
- HLVUUIRENGTYML-UHFFFAOYSA-N 5-amino-4-(4-chloroanilino)-6-(ethylamino)pyrimidine-2-carbonitrile Chemical compound CCNC1=NC(C#N)=NC(NC=2C=CC(Cl)=CC=2)=C1N HLVUUIRENGTYML-UHFFFAOYSA-N 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 150000002780 morpholines Chemical class 0.000 claims description 2
- 125000004193 piperazinyl group Chemical class 0.000 claims description 2
- 241001024304 Mino Species 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- HXDJGRYZPYELDQ-UHFFFAOYSA-N C(#N)C1=NC(=NC(=N1)N1CCOCC1)N(CC(=O)N1C(COCC1)NCC(=O)NC(C)(C)C)CC(C)C Chemical compound C(#N)C1=NC(=NC(=N1)N1CCOCC1)N(CC(=O)N1C(COCC1)NCC(=O)NC(C)(C)C)CC(C)C HXDJGRYZPYELDQ-UHFFFAOYSA-N 0.000 claims 1
- 230000001939 inductive effect Effects 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 25
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 229910052700 potassium Inorganic materials 0.000 abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 abstract description 2
- 239000013037 reversible inhibitor Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 238000005160 1H NMR spectroscopy Methods 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 9
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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| PCT/SE2003/001078 WO2004000819A1 (en) | 2002-06-24 | 2003-06-23 | New use of pyrimidine - or triazine- 2-carbonitiles for treating diseases associated with cysteine protease activity and novel pyrimidine-2-carbonitile derivatives |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2006500385A (ja) * | 2002-08-30 | 2006-01-05 | ノバルティス アクチエンゲゼルシャフト | ヘテロアリールニトリル誘導体 |
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| AR036375A1 (es) | 2001-08-30 | 2004-09-01 | Novartis Ag | Compuestos pirrolo [2,3-d] pirimidina -2- carbonitrilo, un proceso para su preparacion, una composicion farmaceutica y el uso de dichos compuestos para la preparacion de medicamentos |
| SE0201980D0 (sv) * | 2002-06-24 | 2002-06-24 | Astrazeneca Ab | Novel compounds |
| RS20050532A (sr) * | 2003-01-14 | 2007-12-31 | Arena Pharmaceuticals Inc., | Derivati 1,2,3-trisupstituisanog arila i heteroarila kao modulatori metabolizma za profilaksu i tretman poremećaja povezanih sa njim, kao što su dijebetes i hiperglikemija |
| SI1599468T1 (sl) | 2003-01-14 | 2008-02-29 | Arena Pharm Inc | 1,2,3-trisubstituirani arilni in heteroarilni derivati kot modulatorji metabolizma ter profilaksa in zdravljenje motenj v zvezi z njim, kot diabetesain hiperglikemije |
| US20040242568A1 (en) | 2003-03-25 | 2004-12-02 | Syrrx, Inc. | Dipeptidyl peptidase inhibitors |
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| KR20060056944A (ko) | 2003-07-14 | 2006-05-25 | 아레나 파마슈티칼스, 인크. | 대사 조절제로서 융합된 아릴 및 헤테로아릴 유도체 및이에 관련된 장애의 예방 또는 치료 |
| MXPA06001601A (es) | 2003-08-13 | 2006-08-25 | Takeda Pharmaceutical | Derivados de 4-pirimidona y su uso como inhibidores de dipeptidilpeptidasa. |
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| US7687515B2 (en) | 2006-01-17 | 2010-03-30 | N.V. Organon | 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives |
| 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 |
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| JP6838744B2 (ja) | 2015-06-22 | 2021-03-03 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Ｓ１Ｐ１レセプター関連障害における使用のための（Ｒ）−２−（７−（４−シクロペンチル−３−（トリフルオロメチル）ベンジルオキシ）−１，２，３，４−テトラヒドロシクロペンタ［ｂ］インドール−３−イル）酢酸（化合物１）の結晶性Ｌ−アルギニン塩 |
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| JP2004525129A (ja) * | 2001-03-12 | 2004-08-19 | バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト | 置換フルオロアルコキシフェニルスルホニルウレア |
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| JPH11512399A (ja) | 1995-09-01 | 1999-10-26 | シグナル ファーマシューティカルズ，インコーポレイテッド | ピリミジンカルボキサミドおよび関連化合物ならびに炎症状態を処置するための方法 |
| EA200100972A1 (ru) | 1999-03-15 | 2002-02-28 | Аксис Фармасьютикалз, Инк. | Новые соединения и композиции как ингибиторы протеаз |
| WO2002032879A1 (en) | 2000-10-19 | 2002-04-25 | Naeja Pharmaceutical Inc. | Dihydropyrimidine derivatives as cysteine protease inhibitors |
| AR036375A1 (es) * | 2001-08-30 | 2004-09-01 | Novartis Ag | Compuestos pirrolo [2,3-d] pirimidina -2- carbonitrilo, un proceso para su preparacion, una composicion farmaceutica y el uso de dichos compuestos para la preparacion de medicamentos |
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2002
- 2002-06-24 SE SE0201976A patent/SE0201976D0/xx unknown
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2003
- 2003-06-23 US US10/518,817 patent/US7125881B2/en not_active Expired - Fee Related
- 2003-06-23 JP JP2004515328A patent/JP2005533803A/ja active Pending
- 2003-06-23 AT AT03761001T patent/ATE353880T1/de not_active IP Right Cessation
- 2003-06-23 EP EP03761001A patent/EP1532121B1/en not_active Expired - Lifetime
- 2003-06-23 ES ES03761001T patent/ES2280794T3/es not_active Expired - Lifetime
- 2003-06-23 WO PCT/SE2003/001078 patent/WO2004000819A1/en not_active Ceased
- 2003-06-23 AU AU2003243095A patent/AU2003243095A1/en not_active Abandoned
- 2003-06-23 DE DE60311820T patent/DE60311820T2/de not_active Expired - Fee Related
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| JP2006500385A (ja) * | 2002-08-30 | 2006-01-05 | ノバルティス アクチエンゲゼルシャフト | ヘテロアリールニトリル誘導体 |
Also Published As
| Publication number | Publication date |
|---|---|
| US7125881B2 (en) | 2006-10-24 |
| US20050222152A1 (en) | 2005-10-06 |
| WO2004000819A1 (en) | 2003-12-31 |
| ATE353880T1 (de) | 2007-03-15 |
| EP1532121A1 (en) | 2005-05-25 |
| EP1532121B1 (en) | 2007-02-14 |
| AU2003243095A1 (en) | 2004-01-06 |
| ES2280794T3 (es) | 2007-09-16 |
| SE0201976D0 (sv) | 2002-06-24 |
| DE60311820D1 (de) | 2007-03-29 |
| DE60311820T2 (de) | 2007-11-22 |
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