NZ573015A - Triazolopyrazine compounds useful for the treatment of degenerative & inflammatory diseases - Google Patents

Info

Publication number

NZ573015A

NZ573015A NZ573015A NZ57301507A NZ573015A NZ 573015 A NZ573015 A NZ 573015A NZ 573015 A NZ573015 A NZ 573015A NZ 57301507 A NZ57301507 A NZ 57301507A NZ 573015 A NZ573015 A NZ 573015A

Authority

NZ

New Zealand

Prior art keywords

pyrazin

triazolo

substituted

pyrazol

piperazin

Prior art date

2006-05-31

Links

• Espacenet
• Global Dossier
• Discuss

• 238000011282 treatment Methods 0.000 title claims description 53
• CJGGKSPGRJHZNP-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyrazine Chemical class C1=CN=C2NN=NC2=N1 CJGGKSPGRJHZNP-UHFFFAOYSA-N 0.000 title abstract description 4
• 208000027866 inflammatory disease Diseases 0.000 title description 4
• 230000003412 degenerative effect Effects 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 779
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 60
• 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 55
• 201000010099 disease Diseases 0.000 claims abstract description 54
• 150000003839 salts Chemical class 0.000 claims abstract description 32
• 239000000651 prodrug Substances 0.000 claims abstract description 31
• 229940002612 prodrug Drugs 0.000 claims abstract description 31
• 230000015556 catabolic process Effects 0.000 claims abstract description 26
• 238000006731 degradation reaction Methods 0.000 claims abstract description 26
• 239000012453 solvate Substances 0.000 claims abstract description 23
• 230000000155 isotopic effect Effects 0.000 claims abstract description 13
• 206010061218 Inflammation Diseases 0.000 claims abstract description 9
• 230000004054 inflammatory process Effects 0.000 claims abstract description 9
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 302
• 125000000217 alkyl group Chemical group 0.000 claims description 147
• -1 CH2CONH2 Chemical group 0.000 claims description 99
• 229910052739 hydrogen Inorganic materials 0.000 claims description 69
• 239000001257 hydrogen Substances 0.000 claims description 66
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 65
• 230000014509 gene expression Effects 0.000 claims description 49
• 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 41
• 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 41
• 125000003118 aryl group Chemical group 0.000 claims description 41
• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 37
• 230000000694 effects Effects 0.000 claims description 34
• 229910052757 nitrogen Inorganic materials 0.000 claims description 33
• 125000003545 alkoxy group Chemical group 0.000 claims description 31
• 150000001412 amines Chemical class 0.000 claims description 31
• 125000001072 heteroaryl group Chemical group 0.000 claims description 31
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
• 239000003814 drug Substances 0.000 claims description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims description 23
• PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 21
• 229910052760 oxygen Inorganic materials 0.000 claims description 21
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 20
• 238000004519 manufacturing process Methods 0.000 claims description 20
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 18
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 15
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 15
• 108090000623 proteins and genes Proteins 0.000 claims description 15
• 238000011321 prophylaxis Methods 0.000 claims description 14
• 230000002159 abnormal effect Effects 0.000 claims description 13
• 102000004169 proteins and genes Human genes 0.000 claims description 13
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 12
• 150000003053 piperidines Chemical class 0.000 claims description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 11
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 229910052777 Praseodymium Inorganic materials 0.000 claims description 10
• 239000003112 inhibitor Substances 0.000 claims description 10
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
• KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
• 150000001408 amides Chemical class 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
• 230000001413 cellular effect Effects 0.000 claims description 6
• 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 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 150000003230 pyrimidines Chemical class 0.000 claims description 5
• 108091000080 Phosphotransferase Proteins 0.000 claims description 4
• 230000001668 ameliorated effect Effects 0.000 claims description 4
• 125000001041 indolyl group Chemical group 0.000 claims description 4
• 102000020233 phosphotransferase Human genes 0.000 claims description 4
• 238000006467 substitution reaction Methods 0.000 claims description 4
• 125000002947 alkylene group Chemical group 0.000 claims description 3
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
• 150000002460 imidazoles Chemical class 0.000 claims description 3
• 125000002971 oxazolyl group Chemical group 0.000 claims description 3
• 150000003216 pyrazines Chemical class 0.000 claims description 3
• 150000003217 pyrazoles Chemical class 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 150000003233 pyrroles Chemical class 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 230000000699 topical effect Effects 0.000 claims description 3
• 125000004474 heteroalkylene group Chemical group 0.000 claims description 2
• 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 5
• JGGDMMYPOPZHLL-UHFFFAOYSA-N 4-[8-[4-(4-methylpiperazin-1-yl)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]thiophene-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC(C1=NC=NN11)=NC=C1C1=CSC(C(N)=O)=C1 JGGDMMYPOPZHLL-UHFFFAOYSA-N 0.000 claims 2
• HEAMBSUSRXMHHW-UHFFFAOYSA-N 5-[8-[4-(4-methylpiperazin-1-yl)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]thiophene-2-carboxamide Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC(C1=NC=NN11)=NC=C1C1=CC=C(C(N)=O)S1 HEAMBSUSRXMHHW-UHFFFAOYSA-N 0.000 claims 2
• VKUVJWJZEWKBRP-UHFFFAOYSA-N 2-fluoro-4-[8-(4-morpholin-4-ylanilino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]benzamide Chemical compound C1=C(F)C(C(=O)N)=CC=C1C(N1N=CN=C11)=CN=C1NC1=CC=C(N2CCOCC2)C=C1 VKUVJWJZEWKBRP-UHFFFAOYSA-N 0.000 claims 1
• GIAQJIIDNXNNSY-UHFFFAOYSA-N 3,3-dimethyl-5-[8-[4-(4-propan-2-ylpiperazin-1-yl)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2h-isoindol-1-one Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1NC(C1=NC=NN11)=NC=C1C1=CC=C(C(=O)NC2(C)C)C2=C1 GIAQJIIDNXNNSY-UHFFFAOYSA-N 0.000 claims 1
• ZSUFWZOCGCTTBU-UHFFFAOYSA-N 3-fluoro-4-[8-(4-morpholin-4-ylanilino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]benzamide Chemical compound FC1=CC(C(=O)N)=CC=C1C(N1N=CN=C11)=CN=C1NC1=CC=C(N2CCOCC2)C=C1 ZSUFWZOCGCTTBU-UHFFFAOYSA-N 0.000 claims 1
• MDGOPRLPIZCNLF-UHFFFAOYSA-N 4-[8-[(6-morpholin-4-ylpyridin-3-yl)amino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]thiophene-2-carboxamide Chemical compound S1C(C(=O)N)=CC(C=2N3N=CN=C3C(NC=3C=NC(=CC=3)N3CCOCC3)=NC=2)=C1 MDGOPRLPIZCNLF-UHFFFAOYSA-N 0.000 claims 1
• CBDPFOMIDRBHPG-UHFFFAOYSA-N 4-[8-[4-(2-morpholin-4-ylethoxy)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]thiophene-2-carboxamide Chemical compound S1C(C(=O)N)=CC(C=2N3N=CN=C3C(NC=3C=CC(OCCN4CCOCC4)=CC=3)=NC=2)=C1 CBDPFOMIDRBHPG-UHFFFAOYSA-N 0.000 claims 1
• ULADOTYNHIXXPX-UHFFFAOYSA-N 4-[8-[4-(4-methylpiperazin-1-yl)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-1h-pyridin-2-one Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC(C1=NC=NN11)=NC=C1C1=CC(=O)NC=C1 ULADOTYNHIXXPX-UHFFFAOYSA-N 0.000 claims 1
• RPTBHZFWKPSPBV-UHFFFAOYSA-N 4-[8-[4-(4-methylpiperazin-1-yl)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]benzamide Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC(C1=NC=NN11)=NC=C1C1=CC=C(C(N)=O)C=C1 RPTBHZFWKPSPBV-UHFFFAOYSA-N 0.000 claims 1
• CEQGCMHVEDNLEF-UHFFFAOYSA-N 4-[8-[4-[4-(cyclopropylmethyl)piperazin-1-yl]anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]thiophene-2-carboxamide Chemical compound S1C(C(=O)N)=CC(C=2N3N=CN=C3C(NC=3C=CC(=CC=3)N3CCN(CC4CC4)CC3)=NC=2)=C1 CEQGCMHVEDNLEF-UHFFFAOYSA-N 0.000 claims 1
• ZDLDULHTZCUMMG-UHFFFAOYSA-N 5-[8-(4-morpholin-4-ylanilino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydroisoindol-1-one Chemical compound C=1C=C2C(=O)NCC2=CC=1C(N1N=CN=C11)=CN=C1NC(C=C1)=CC=C1N1CCOCC1 ZDLDULHTZCUMMG-UHFFFAOYSA-N 0.000 claims 1
• BFAUVRNFXIHEFU-UHFFFAOYSA-N 5-[8-[(6-morpholin-4-ylpyridin-3-yl)amino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydroisoindol-1-one Chemical compound C=1C=C2C(=O)NCC2=CC=1C(N1N=CN=C11)=CN=C1NC(C=N1)=CC=C1N1CCOCC1 BFAUVRNFXIHEFU-UHFFFAOYSA-N 0.000 claims 1
• TYBOWYHKKVNQIB-UHFFFAOYSA-N 5-[8-[4-(2-morpholin-4-ylethoxy)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]thiophene-2-carboxamide Chemical compound S1C(C(=O)N)=CC=C1C(N1N=CN=C11)=CN=C1NC(C=C1)=CC=C1OCCN1CCOCC1 TYBOWYHKKVNQIB-UHFFFAOYSA-N 0.000 claims 1
• QWICPTNWZITFIH-UHFFFAOYSA-N 5-[8-[[2-(4-propan-2-ylpiperazin-1-yl)pyrimidin-5-yl]amino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydroisoindol-1-one Chemical compound C1CN(C(C)C)CCN1C(N=C1)=NC=C1NC(C1=NC=NN11)=NC=C1C1=CC=C(C(=O)NC2)C2=C1 QWICPTNWZITFIH-UHFFFAOYSA-N 0.000 claims 1
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• XMGJRIGZLBBPSS-UHFFFAOYSA-N [4-[8-[4-(4-propan-2-ylpiperazin-1-yl)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]pyridin-2-yl]methanol Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1NC(C1=NC=NN11)=NC=C1C1=CC=NC(CO)=C1 XMGJRIGZLBBPSS-UHFFFAOYSA-N 0.000 claims 1
• 125000002541 furyl group Chemical group 0.000 claims 1
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims 1
• WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims 1
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