TW201343641A

TW201343641A - 用於組合療法的白三烯製造之噁二唑抑制劑

用於組合療法的白三烯製造之噁二唑抑制劑 Download PDF

Info

Publication number: TW201343641A
Authority: TW; Taiwan
Prior art keywords: group; alkyl; combination; mmol; pharmaceutically active
Prior art date: 2012-02-01

Application number

TW102103835A

Other languages

English (en)

Chinese (zh)

Inventor

Lars Anders Bylock

Original Assignee

Boehringer Ingelheim Int

Priority date

2012-02-01

Filing date

2013-01-31

Publication date

2013-11-01

2013-01-31 Application filed by Boehringer Ingelheim Int filed Critical Boehringer Ingelheim Int

2013-11-01 Publication of TW201343641A publication Critical patent/TW201343641A/zh

Links

239000003112 inhibitor Substances 0.000 title claims description 21
238000002648 combination therapy Methods 0.000 title abstract description 5
150000002617 leukotrienes Chemical class 0.000 title description 21
238000004519 manufacturing process Methods 0.000 title description 4
WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 184
238000000034 method Methods 0.000 claims abstract description 93
239000013543 active substance Substances 0.000 claims abstract description 44
150000003839 salts Chemical class 0.000 claims abstract description 36
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 28
238000011282 treatment Methods 0.000 claims abstract description 20
125000000217 alkyl group Chemical group 0.000 claims description 100
-1 -C(O)-R 6 Chemical group 0.000 claims description 66
229910052739 hydrogen Inorganic materials 0.000 claims description 35
239000001257 hydrogen Substances 0.000 claims description 34
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229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 28
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125000002837 carbocyclic group Chemical group 0.000 claims description 24
125000000623 heterocyclic group Chemical group 0.000 claims description 24
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RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 24
125000003118 aryl group Chemical group 0.000 claims description 23
201000001320 Atherosclerosis Diseases 0.000 claims description 22
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125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 20
150000002431 hydrogen Chemical class 0.000 claims description 19
125000001072 heteroaryl group Chemical group 0.000 claims description 18
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
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208000024172 Cardiovascular disease Diseases 0.000 claims description 15
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
229910052736 halogen Inorganic materials 0.000 claims description 15
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125000005843 halogen group Chemical group 0.000 claims description 12
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OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
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125000004663 dialkyl amino group Chemical group 0.000 claims description 8
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
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238000002360 preparation method Methods 0.000 claims description 8
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239000003146 anticoagulant agent Substances 0.000 claims description 7
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QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
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208000010125 myocardial infarction Diseases 0.000 claims description 7
239000003358 phospholipase A2 inhibitor Substances 0.000 claims description 7
239000000106 platelet aggregation inhibitor Substances 0.000 claims description 7
XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 6
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ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims description 5
125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 5
XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 5
PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims description 5
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PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims description 5
QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims description 5
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VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims description 5
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229960000672 rosuvastatin Drugs 0.000 claims description 5
BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 5
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
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206010040642 Sickle cell anaemia with crisis Diseases 0.000 claims description 4
208000007474 aortic aneurysm Diseases 0.000 claims description 4
125000000753 cycloalkyl group Chemical group 0.000 claims description 4
239000002552 dosage form Substances 0.000 claims description 4
229940125753 fibrate Drugs 0.000 claims description 4
208000012947 ischemia reperfusion injury Diseases 0.000 claims description 4
NRWORBQAOQVYBJ-GJZUVCINSA-N obicetrapib Chemical compound N=1C=C(OCCCC(O)=O)C=NC=1N([C@H]1C[C@@H](CC)N(C2=CC=C(C=C21)C(F)(F)F)C(=O)OCC)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 NRWORBQAOQVYBJ-GJZUVCINSA-N 0.000 claims description 4
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208000002815 pulmonary hypertension Diseases 0.000 claims description 4
OCNBSSLDAIWTKS-UHFFFAOYSA-N 3-[[[3,5-bis(trifluoromethyl)phenyl]methyl-(2-methyltetrazol-5-yl)amino]methyl]-n,n-bis(cyclopropylmethyl)-8-methylquinolin-2-amine Chemical compound C1CC1CN(CC1CC1)C=1N=C2C(C)=CC=CC2=CC=1CN(C1=NN(C)N=N1)CC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 OCNBSSLDAIWTKS-UHFFFAOYSA-N 0.000 claims description 3
YZQLWPMZQVHJED-UHFFFAOYSA-N 2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester Chemical compound C=1C=CC=C(SC(=O)C(C)C)C=1NC(=O)C1(CC(CC)CC)CCCCC1 YZQLWPMZQVHJED-UHFFFAOYSA-N 0.000 claims description 2
MZZLGJHLQGUVPN-HAWMADMCSA-N anacetrapib Chemical group COC1=CC(F)=C(C(C)C)C=C1C1=CC=C(C(F)(F)F)C=C1CN1C(=O)O[C@H](C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)[C@@H]1C MZZLGJHLQGUVPN-HAWMADMCSA-N 0.000 claims description 2
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