TWI648282B - 新熔合咪唑苯并噻唑化合物 - Google Patents

Info

Publication number

TWI648282B

TWI648282B TW104108329A TW104108329A TWI648282B TW I648282 B TWI648282 B TW I648282B TW 104108329 A TW104108329 A TW 104108329A TW 104108329 A TW104108329 A TW 104108329A TW I648282 B TWI648282 B TW I648282B

Authority

TW

Taiwan

Prior art keywords

alkyl

imidazole

butyl

tert

benzothiazole

Prior art date

2014-03-27

Links

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• -1 imidazole benzothiazole compound Chemical class 0.000 title claims description 71
• 230000004927 fusion Effects 0.000 title claims description 4
• 150000001875 compounds Chemical class 0.000 claims abstract description 266
• 239000003814 drug Substances 0.000 claims abstract description 21
• 150000003839 salts Chemical class 0.000 claims abstract description 18
• 238000002360 preparation method Methods 0.000 claims abstract description 9
• 239000012453 solvate Substances 0.000 claims abstract description 9
• 150000004677 hydrates Chemical class 0.000 claims abstract description 7
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 221
• KYUNTDRHCPSMOG-UHFFFAOYSA-N 2h-1,3-benzothiazole-3-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)CSC2=C1 KYUNTDRHCPSMOG-UHFFFAOYSA-N 0.000 claims description 80
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 73
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 64
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 45
• 229910052736 halogen Inorganic materials 0.000 claims description 40
• ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 claims description 38
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 38
• 229910052739 hydrogen Inorganic materials 0.000 claims description 38
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 35
• 239000001257 hydrogen Substances 0.000 claims description 34
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
• 239000004202 carbamide Substances 0.000 claims description 32
• 150000002460 imidazoles Chemical class 0.000 claims description 32
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 32
• 125000002837 carbocyclic group Chemical group 0.000 claims description 30
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 125000001072 heteroaryl group Chemical group 0.000 claims description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 21
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 20
• 125000001424 substituent group Chemical group 0.000 claims description 19
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
• 238000011282 treatment Methods 0.000 claims description 18
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 208000006673 asthma Diseases 0.000 claims description 16
• 150000002367 halogens Chemical class 0.000 claims description 15
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
• 229910052717 sulfur Inorganic materials 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 13
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
• 150000001412 amines Chemical class 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 9
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
• 230000000172 allergic effect Effects 0.000 claims description 8
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 7
• 208000028004 allergic respiratory disease Diseases 0.000 claims description 7
• 208000010668 atopic eczema Diseases 0.000 claims description 7
• 125000002950 monocyclic group Chemical group 0.000 claims description 7
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
• 239000002253 acid Substances 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
• 125000003003 spiro group Chemical group 0.000 claims description 4
• 239000002671 adjuvant Substances 0.000 claims description 3
• 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 3
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
• LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 2
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
• 239000011593 sulfur Substances 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims 9
• 150000002431 hydrogen Chemical class 0.000 claims 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 6
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 5
• SZXLBDVCHABEGD-UHFFFAOYSA-N 2h-1,3-benzothiazole-3-carboxamide Chemical compound C1=CC=C2N(C(=O)N)CSC2=C1 SZXLBDVCHABEGD-UHFFFAOYSA-N 0.000 claims 4
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 4
• 125000006720 (C1-C6) alkyl (C6-C10) aryl group Chemical group 0.000 claims 3
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
• QGRPVMLBTFGQDQ-UHFFFAOYSA-N 1-chloro-2-methoxybenzene Chemical compound COC1=CC=CC=C1Cl QGRPVMLBTFGQDQ-UHFFFAOYSA-N 0.000 claims 1
• KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
• CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 claims 1
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
• WCTJYXKKCKDIOE-UHFFFAOYSA-N [O-]C([S+]1C(C=CC=C2)=C2N=C1)=O Chemical compound [O-]C([S+]1C(C=CC=C2)=C2N=C1)=O WCTJYXKKCKDIOE-UHFFFAOYSA-N 0.000 claims 1
• KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 1
• ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 claims 1
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims 1
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims 1
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
• FFXFWNLKXAIQRM-UHFFFAOYSA-N phenyl n-benzylcarbamate Chemical compound C=1C=CC=CC=1OC(=O)NCC1=CC=CC=C1 FFXFWNLKXAIQRM-UHFFFAOYSA-N 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 22
• RDFSGGALTYXDLZ-UHFFFAOYSA-N 1,3-benzothiazole;1h-imidazole Chemical class C1=CNC=N1.C1=CC=C2SC=NC2=C1 RDFSGGALTYXDLZ-UHFFFAOYSA-N 0.000 abstract description 4
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 61
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
• 239000002904 solvent Substances 0.000 description 43
• YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 42
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
• 239000011541 reaction mixture Substances 0.000 description 37
• 238000000034 method Methods 0.000 description 32
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
• 239000002585 base Substances 0.000 description 28
• 239000007787 solid Substances 0.000 description 27
• WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 26
• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 24
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 24
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• 210000004027 cell Anatomy 0.000 description 22
• 235000019439 ethyl acetate Nutrition 0.000 description 21
• 210000004072 lung Anatomy 0.000 description 21
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• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 125000003118 aryl group Chemical group 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 15
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 15
• 238000003786 synthesis reaction Methods 0.000 description 15
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
• 239000000010 aprotic solvent Substances 0.000 description 13
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
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• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
• LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 10
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