EA023465B1 - Новые производные 6-триазолпиридинсульфанил-бензотиазола или -бензимидазола, способ их получения, применение их в качестве лекарственных средств, фармацевтические композиции и новое применение в качестве ингибиторов мет - Google Patents

Info

Publication number

EA023465B1

EA023465B1 EA201070235A EA201070235A EA023465B1 EA 023465 B1 EA023465 B1 EA 023465B1 EA 201070235 A EA201070235 A EA 201070235A EA 201070235 A EA201070235 A EA 201070235A EA 023465 B1 EA023465 B1 EA 023465B1

Authority

EA

Eurasian Patent Office

Prior art keywords

triazolo

sulfanyl

pyridazin

radical

benzothiazol

Prior art date

2007-08-09

Links

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• 239000003814 drug Substances 0.000 title claims abstract description 27
• IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title claims abstract description 18
• 238000004519 manufacturing process Methods 0.000 title claims description 20
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
• 239000003112 inhibitor Substances 0.000 title abstract description 4
• 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title abstract 2
• 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title abstract 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 46
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 36
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 31
• 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 27
• 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 26
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 18
• 125000005843 halogen group Chemical group 0.000 claims abstract description 16
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 15
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 10
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 8
• CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 7
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
• 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 6
• TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000002619 bicyclic group Chemical group 0.000 claims abstract description 4
• -1 heterocycloalkyl radical Chemical class 0.000 claims description 371
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 262
• 235000013877 carbamide Nutrition 0.000 claims description 134
• 239000004202 carbamide Substances 0.000 claims description 133
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 132
• 150000001875 compounds Chemical class 0.000 claims description 114
• 238000000034 method Methods 0.000 claims description 109
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 107
• 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 97
• ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 86
• 239000007787 solid Substances 0.000 claims description 76
• 150000003254 radicals Chemical class 0.000 claims description 75
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 70
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 60
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 58
• 125000003545 alkoxy group Chemical group 0.000 claims description 45
• ATQVBSVAXDRWFW-HBMCJLEFSA-N [(1r)-2-(4-hydroxyphenyl)-1-[[(2s)-1-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]ethyl]phosphonic acid Chemical compound C([C@@H](C(=O)NC(=O)[C@H](C(C)C)NC)N[C@@H](CC=1C=CC(O)=CC=1)P(O)(O)=O)C1=CC=CC=C1 ATQVBSVAXDRWFW-HBMCJLEFSA-N 0.000 claims description 44
• 239000002904 solvent Substances 0.000 claims description 44
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
• 125000001424 substituent group Chemical group 0.000 claims description 37
• 125000000217 alkyl group Chemical group 0.000 claims description 29
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
• 239000012279 sodium borohydride Substances 0.000 claims description 22
• 229910000033 sodium borohydride Inorganic materials 0.000 claims description 22
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• 102000001253 Protein Kinase Human genes 0.000 claims description 20
• 108060006633 protein kinase Proteins 0.000 claims description 20
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 18
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
• 230000000694 effects Effects 0.000 claims description 15
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
• 230000035755 proliferation Effects 0.000 claims description 13
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 12
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 12
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 12
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 12
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• ADNZLWOUBQDGPQ-UHFFFAOYSA-N 6-[[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-amine Chemical compound C1=C2SC(N)=NC2=CC=C1SC(N1N=2)=NN=C1C=CC=2C1=CC=C(F)C=C1 ADNZLWOUBQDGPQ-UHFFFAOYSA-N 0.000 claims description 10
• 229940079593 drug Drugs 0.000 claims description 10
• 229910052708 sodium Inorganic materials 0.000 claims description 10
• 239000011734 sodium Substances 0.000 claims description 10
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• 230000002401 inhibitory effect Effects 0.000 claims description 9
• XEXQGVJFSNKIQS-UHFFFAOYSA-N CC1=CC(=CC2=C1N=C(S2)OC(=O)N)SC3=NN=C4N3N=C(C=C4)C5=CC=C(C=C5)F Chemical compound CC1=CC(=CC2=C1N=C(S2)OC(=O)N)SC3=NN=C4N3N=C(C=C4)C5=CC=C(C=C5)F XEXQGVJFSNKIQS-UHFFFAOYSA-N 0.000 claims description 7
• 201000011510 cancer Diseases 0.000 claims description 7
• AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 7
• 230000002265 prevention Effects 0.000 claims description 7
• MHIFGAJNWXOGBB-UHFFFAOYSA-N 6-[[6-(3-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-amine Chemical compound C1=C2SC(N)=NC2=CC=C1SC(N1N=2)=NN=C1C=CC=2C1=CC=CC(F)=C1 MHIFGAJNWXOGBB-UHFFFAOYSA-N 0.000 claims description 6
• 230000015572 biosynthetic process Effects 0.000 claims description 6
• 238000003786 synthesis reaction Methods 0.000 claims description 6
• 206010020751 Hypersensitivity Diseases 0.000 claims description 5
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
• 208000002231 Muscle Neoplasms Diseases 0.000 claims description 5
• 206010028289 Muscle atrophy Diseases 0.000 claims description 5
• 208000012902 Nervous system disease Diseases 0.000 claims description 5
• 201000004681 Psoriasis Diseases 0.000 claims description 5
• 208000017442 Retinal disease Diseases 0.000 claims description 5
• 206010038923 Retinopathy Diseases 0.000 claims description 5
• 208000007536 Thrombosis Diseases 0.000 claims description 5
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• CVZCYTQCYDQBNK-UHFFFAOYSA-N 6-[(6-cyclohexyloxy-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-amine Chemical compound C1=C2SC(N)=NC2=CC=C1SC(N1N=2)=NN=C1C=CC=2OC1CCCCC1 CVZCYTQCYDQBNK-UHFFFAOYSA-N 0.000 claims description 4
• QNIMXIKOTJYMBT-UHFFFAOYSA-N 6-[(6-ethoxy-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-amine Chemical compound C1=C2N=C(N)SC2=CC(SC2=NN=C3C=CC(=NN32)OCC)=C1 QNIMXIKOTJYMBT-UHFFFAOYSA-N 0.000 claims description 4
• IKIIPAQDNAMHLT-UHFFFAOYSA-N 6-[[6-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-amine Chemical compound C1=C2SC(N)=NC2=CC=C1SC(N1N=2)=NN=C1C=CC=2C1=CC=CC=C1F IKIIPAQDNAMHLT-UHFFFAOYSA-N 0.000 claims description 4
• JPSDZKIZFRMMSJ-UHFFFAOYSA-N 6-[[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1h-benzimidazol-2-amine Chemical compound C1=C2NC(N)=NC2=CC=C1SC(N1N=2)=NN=C1C=CC=2C1=CC=C(F)C=C1 JPSDZKIZFRMMSJ-UHFFFAOYSA-N 0.000 claims description 4
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 4
• OSQXFTFWHXZNCO-UHFFFAOYSA-N n-[6-[[6-(3-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide Chemical compound FC1=CC=CC(C2=NN3C(SC=4C=C5SC(NC(=O)C6CC6)=NC5=CC=4)=NN=C3C=C2)=C1 OSQXFTFWHXZNCO-UHFFFAOYSA-N 0.000 claims description 4
• YBKJIXLHEWSYBR-UHFFFAOYSA-N n-[6-[[6-(4-fluorophenyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-yl]cyclopropanecarboxamide Chemical compound C1=CC(F)=CC=C1C1=NN2C(SC=3C=C4SC(NC(=O)C5CC5)=NC4=CC=3)=NN=C2CC1 YBKJIXLHEWSYBR-UHFFFAOYSA-N 0.000 claims description 4
• ZUKJXYRXZAVUJV-UHFFFAOYSA-N phosphoryl trichloride trichlorophosphane Chemical compound ClP(Cl)Cl.ClP(Cl)(Cl)=O ZUKJXYRXZAVUJV-UHFFFAOYSA-N 0.000 claims description 4
• FVCTVHUIEQIQCJ-UHFFFAOYSA-N 6-[[6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-amine Chemical compound C1=NN(C)C=C1C1=NN2C(SC=3C=C4SC(N)=NC4=CC=3)=NN=C2C=C1 FVCTVHUIEQIQCJ-UHFFFAOYSA-N 0.000 claims description 3
• REJLCQNSWJSFHR-UHFFFAOYSA-N 6-[[6-(3-fluorophenyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-amine Chemical compound C1=C2SC(N)=NC2=CC=C1SC(N1N=2)=NN=C1CCC=2C1=CC=CC(F)=C1 REJLCQNSWJSFHR-UHFFFAOYSA-N 0.000 claims description 3
• AORGRYSITDHUHD-UHFFFAOYSA-N C1COC1CC2=C3C(=CC(=C2)SC4=NN=C5N4N=C(C=C5)C6=CC=C(C=C6)F)SC(=N3)OC(=O)N Chemical compound C1COC1CC2=C3C(=CC(=C2)SC4=NN=C5N4N=C(C=C5)C6=CC=C(C=C6)F)SC(=N3)OC(=O)N AORGRYSITDHUHD-UHFFFAOYSA-N 0.000 claims description 3
• 238000004113 cell culture Methods 0.000 claims description 3
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• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
• TYHRTKBUAIMRJP-UHFFFAOYSA-N n-[3-[[2-(2-morpholin-4-ylethylcarbamoylamino)-1,3-benzothiazol-6-yl]sulfanyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]acetamide Chemical compound N12N=C(NC(=O)C)C=CC2=NN=C1SC(C=C1S2)=CC=C1N=C2NC(=O)NCCN1CCOCC1 TYHRTKBUAIMRJP-UHFFFAOYSA-N 0.000 claims description 3
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• HICBPXUTWCFOKN-UHFFFAOYSA-N n-[6-[[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1SC(N1N=2)=NN=C1C=CC=2C1=CC=C(F)C=C1 HICBPXUTWCFOKN-UHFFFAOYSA-N 0.000 claims description 3
• VIGKXYUWTHILQV-UHFFFAOYSA-N 2-[6-[[6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1,3-benzothiazol-2-yl]-4-morpholin-4-ylbutanamide Chemical compound FC1=CC=C(C=C1)C=1C=CC=2N(N=1)C(=NN=2)SC1=CC2=C(N=C(S2)C(C(=O)N)CCN2CCOCC2)C=C1 VIGKXYUWTHILQV-UHFFFAOYSA-N 0.000 claims description 2
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