AU2015237840B2 - Novel fused imidazobenzothiazole compounds - Google Patents
Novel fused imidazobenzothiazole compounds Download PDFInfo
- Publication number
- AU2015237840B2 AU2015237840B2 AU2015237840A AU2015237840A AU2015237840B2 AU 2015237840 B2 AU2015237840 B2 AU 2015237840B2 AU 2015237840 A AU2015237840 A AU 2015237840A AU 2015237840 A AU2015237840 A AU 2015237840A AU 2015237840 B2 AU2015237840 B2 AU 2015237840B2
- Authority
- AU
- Australia
- Prior art keywords
- imidazo
- alkyl
- butyl
- pyrazol
- tert
- 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.)
- Ceased
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- HWAXRLFNEXLBSN-UHFFFAOYSA-N 2h-imidazo[4,5-g][1,3]benzothiazole Chemical class C1=CC2=NCSC2=C2N=CN=C21 HWAXRLFNEXLBSN-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 275
- 239000003814 drug Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 76
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 claims description 76
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 64
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 62
- 229910052736 halogen Inorganic materials 0.000 claims description 57
- -1 (C3-Cio)carbocycle Chemical group 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 45
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 39
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 239000004202 carbamide Substances 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 150000002367 halogens Chemical class 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 150000002431 hydrogen Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 18
- 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 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 208000006673 asthma Diseases 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 230000000172 allergic effect Effects 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 208000028004 allergic respiratory disease Diseases 0.000 claims description 9
- 208000010668 atopic eczema Diseases 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 7
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- JAORDPHDFCRJHV-UHFFFAOYSA-N C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(C=CC=C1)OC1=CC2=C(N3C(S2)=NC=C3CN3CCOCC3)C=C1)C1=CC(=C(C=C1)O)Cl Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(C=CC=C1)OC1=CC2=C(N3C(S2)=NC=C3CN3CCOCC3)C=C1)C1=CC(=C(C=C1)O)Cl JAORDPHDFCRJHV-UHFFFAOYSA-N 0.000 claims description 5
- 229910004727 OSO3H Inorganic materials 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003003 spiro group Chemical group 0.000 claims description 5
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 4
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 4
- YDUMNFRWCTXYIB-UHFFFAOYSA-N C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(OC2=CC3=C(N4C(S3)=NC=C4C(=O)O)C=C2)C=CC=C1)C1=CC(=C(C=C1)O)Cl Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(OC2=CC3=C(N4C(S3)=NC=C4C(=O)O)C=C2)C=CC=C1)C1=CC(=C(C=C1)O)Cl YDUMNFRWCTXYIB-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 3
- SCMZUKWXQZOOQG-UHFFFAOYSA-N imidazo[2,1-b][1,3]benzothiazole-2-carboxamide Chemical compound C1=CC=C2N3C(SC2=C1)=NC(=C3)C(=O)N SCMZUKWXQZOOQG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 3
- LYASTVLDAJIXBL-UHFFFAOYSA-N 1,3-benzothiazole-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=NC2=C1 LYASTVLDAJIXBL-UHFFFAOYSA-N 0.000 claims description 2
- VKDFZZFOIADGKO-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-chloro-4-hydroxyphenyl)pyrazol-3-yl]-3-[[2-[1-(morpholin-4-ylmethyl)-3-oxidoimidazo[2,1-b][1,3]benzothiazol-3-ium-6-yl]oxyphenyl]methyl]urea Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(C=CC=C1)OC1=CC2=C(N3C(S2)=[N+](C=C3CN2CCOCC2)[O-])C=C1)C1=CC(=C(C=C1)O)Cl VKDFZZFOIADGKO-UHFFFAOYSA-N 0.000 claims description 2
- DHMKOBRWQFRCQY-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-chloro-4-hydroxyphenyl)pyrazol-3-yl]-3-[[2-[1-[[2-hydroxyethyl(methyl)amino]methyl]imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyphenyl]methyl]urea Chemical compound CN(CCO)CC1=CN=C2SC3=CC(OC4=C(CNC(=O)NC5=CC(=NN5C5=CC(Cl)=C(O)C=C5)C(C)(C)C)C=CC=C4)=CC=C3N12 DHMKOBRWQFRCQY-UHFFFAOYSA-N 0.000 claims description 2
- HKZTXWXVZJJHKU-UHFFFAOYSA-N C(C)(C)(C)C1=NN(C(=C1)NC(=O)NC1=CC=C(C=C1)OC1=CC2=C(N3C(S2)=NC=C3CO)C=C1)C1=CC(=C(C=C1)O)Cl Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NC1=CC=C(C=C1)OC1=CC2=C(N3C(S2)=NC=C3CO)C=C1)C1=CC(=C(C=C1)O)Cl HKZTXWXVZJJHKU-UHFFFAOYSA-N 0.000 claims description 2
- FCGGFCRDJUMZIV-UHFFFAOYSA-N C(C)(C)(C)C1=NN(C(=C1)NC(=O)NC1=CC=C(OC2=CC3=C(N4C(S3)=NC=C4C(=O)OCC)C=C2)C=C1)C1=CC(=C(C=C1)O)Cl Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NC1=CC=C(OC2=CC3=C(N4C(S3)=NC=C4C(=O)OCC)C=C2)C=C1)C1=CC(=C(C=C1)O)Cl FCGGFCRDJUMZIV-UHFFFAOYSA-N 0.000 claims description 2
- KHXIAIOLOJFQKV-UHFFFAOYSA-N C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(C=CC=C1)OC1=CC2=C(N3C(S2)=NC=C3CSCCO)C=C1)C1=CC(=C(C=C1)O)Cl Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(C=CC=C1)OC1=CC2=C(N3C(S2)=NC=C3CSCCO)C=C1)C1=CC(=C(C=C1)O)Cl KHXIAIOLOJFQKV-UHFFFAOYSA-N 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 2
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 claims description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 2
- LMNTYLGPYHWPQZ-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-chloro-4-hydroxyphenyl)pyrazol-3-yl]-3-[[2-[1-(chloromethyl)imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyphenyl]methyl]urea Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(C=CC=C1)OC1=CC2=C(N3C(S2)=NC=C3CCl)C=C1)C1=CC(=C(C=C1)O)Cl LMNTYLGPYHWPQZ-UHFFFAOYSA-N 0.000 claims 1
- GRDMHLZPXKGZIL-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-chloro-4-hydroxyphenyl)pyrazol-3-yl]-3-[[2-[1-[(4-hydroxypiperidin-1-yl)methyl]imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyphenyl]methyl]urea Chemical compound CC(C)(C)C1=NN(C(NC(=O)NCC2=C(OC3=CC=C4N5C(CN6CCC(O)CC6)=CN=C5SC4=C3)C=CC=C2)=C1)C1=CC(Cl)=C(O)C=C1 GRDMHLZPXKGZIL-UHFFFAOYSA-N 0.000 claims 1
- IZQXOSMRXXJOKD-UHFFFAOYSA-N 1-[5-tert-butyl-2-(3-chloro-4-hydroxyphenyl)pyrazol-3-yl]-3-[[2-[2-methyl-1-(morpholin-4-ylmethyl)imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyphenyl]methyl]urea Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NCC1=C(C=CC=C1)OC1=CC2=C(N3C(S2)=NC(=C3CN2CCOCC2)C)C=C1)C1=CC(=C(C=C1)O)Cl IZQXOSMRXXJOKD-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
- 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 1
- NTJQHNKNRDZZOQ-UHFFFAOYSA-N C(C)(C)(C)C1=NN(C(=C1)NC(=O)NC1=CC=C(OC2=CC3=C(N4C(S3)=NC(=C4)C(=O)NC(CO)C4=CC=CC=C4)C=C2)C=C1)C1=CC=C(C=C1)C Chemical compound C(C)(C)(C)C1=NN(C(=C1)NC(=O)NC1=CC=C(OC2=CC3=C(N4C(S3)=NC(=C4)C(=O)NC(CO)C4=CC=CC=C4)C=C2)C=C1)C1=CC=C(C=C1)C NTJQHNKNRDZZOQ-UHFFFAOYSA-N 0.000 claims 1
- HVPWBZBWZKZCPT-UHFFFAOYSA-N COCCOC(=O)NC1=CN=C2SC3=CC(OC4=C(CNC(=O)NC5=CC(=NN5C5=CC(Cl)=C(O)C=C5)C(C)(C)C)C=CC=C4)=CC=C3N12 Chemical compound COCCOC(=O)NC1=CN=C2SC3=CC(OC4=C(CNC(=O)NC5=CC(=NN5C5=CC(Cl)=C(O)C=C5)C(C)(C)C)C=CC=C4)=CC=C3N12 HVPWBZBWZKZCPT-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
- RBQGKSWYSQGVDV-UHFFFAOYSA-N imidazo[2,1-b][1,3]benzothiazole Chemical compound C1=CC=C2N3C=CN=C3SC2=C1 RBQGKSWYSQGVDV-UHFFFAOYSA-N 0.000 claims 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 26
- 150000004677 hydrates Chemical class 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 239000002904 solvent Substances 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
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Classifications
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Public Health (AREA)
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Saccharide Compounds (AREA)
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| PE20161035A1 (es) | 2013-03-15 | 2016-11-13 | Global Blood Therapeutics Inc | Compuestos y usos de estos para la modulacion de la hemoglobina |
| EA201992707A1 (ru) | 2013-11-18 | 2020-06-30 | Глобал Блад Терапьютикс, Инк. | Соединения и их применения для модуляции гемоглобина |
| TWI648282B (zh) * | 2014-03-27 | 2019-01-21 | 印度商托仁特生技有限公司 | 新熔合咪唑苯并噻唑化合物 |
| DE102016209204A1 (de) | 2016-05-27 | 2017-11-30 | Robert Bosch Gmbh | Vorrichtung zur Regelung mindestens eines Fluidstroms in einem Fahrzeug |
| KR102630959B1 (ko) * | 2016-10-31 | 2024-01-29 | 엘지디스플레이 주식회사 | 유기 화합물과 이를 이용한 발광다이오드 및 유기발광다이오드 표시장치 |
| CN106727538A (zh) * | 2017-02-20 | 2017-05-31 | 潘连香 | 一种治疗2型糖尿病的药物组合物 |
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| GB8908845D0 (en) * | 1989-04-19 | 1989-06-07 | Roussel Lab Ltd | Chemical compounds |
| WO1995029922A1 (en) * | 1994-04-29 | 1995-11-09 | Pharmacia & Upjohn Company | Methanol derivatives for treatment of retroviral infections especially hiv infections |
| AU2001294515A1 (en) * | 2000-08-11 | 2002-02-25 | The Regents Of The University Of California | Use of stat-6 inhibitors as therapeutic agents |
| US7601846B2 (en) * | 2001-06-26 | 2009-10-13 | The Regents Of The University Of California | Compounds having activity as inhibitors of apoptosis |
| AU2003300800A1 (en) * | 2002-11-25 | 2004-06-18 | Pharmacia Corporation | Heteroarylsulfonylmethyl hydroxamic acids and amides and their use as protease inhibitors |
| GB0320244D0 (en) * | 2003-05-06 | 2003-10-01 | Aventis Pharma Inc | Pyrazoles as inhibitors of tumour necrosis factor |
| TWI648282B (zh) * | 2014-03-27 | 2019-01-21 | 印度商托仁特生技有限公司 | 新熔合咪唑苯并噻唑化合物 |
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