TWI331143B - Benzothiadiazepine derivatives, process for preparing them, and pharmaceutical composition comprising them - Google Patents

Info

Publication number

TWI331143B

TWI331143B TW091120297A TW91120297A TWI331143B TW I331143 B TWI331143 B TW I331143B TW 091120297 A TW091120297 A TW 091120297A TW 91120297 A TW91120297 A TW 91120297A TW I331143 B TWI331143 B TW I331143B

Authority

TW

Taiwan

Prior art keywords

group

formula

alkyl

compound

carboxy

Prior art date

2001-09-08

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
• 238000004519 manufacturing process Methods 0.000 title abstract description 16
• KAOYLRLQZXRRBD-UHFFFAOYSA-N 1,2,3-benzothiadiazepine Chemical class S1N=NC=CC2=CC=CC=C12 KAOYLRLQZXRRBD-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 233
• 150000003839 salts Chemical class 0.000 claims abstract description 182
• 238000000034 method Methods 0.000 claims abstract description 129
• 238000011282 treatment Methods 0.000 claims abstract description 44
• 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 23
• 230000008569 process Effects 0.000 claims abstract description 20
• 125000000217 alkyl group Chemical group 0.000 claims description 191
• -1 azetidine-1-yl group Chemical group 0.000 claims description 132
• 239000001257 hydrogen Substances 0.000 claims description 82
• 229910052739 hydrogen Inorganic materials 0.000 claims description 82
• 239000000203 mixture Substances 0.000 claims description 73
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 70
• 241001465754 Metazoa Species 0.000 claims description 64
• 150000001412 amines Chemical group 0.000 claims description 45
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 45
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 39
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 38
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 34
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
• 125000001424 substituent group Chemical group 0.000 claims description 31
• 229910052799 carbon Inorganic materials 0.000 claims description 28
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 230000002401 inhibitory effect Effects 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
• 125000003277 amino group Chemical group 0.000 claims description 21
• 239000002253 acid Substances 0.000 claims description 20
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
• 239000003085 diluting agent Substances 0.000 claims description 19
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 17
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
• 230000002792 vascular Effects 0.000 claims description 17
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
• 150000002431 hydrogen Chemical group 0.000 claims description 14
• 125000006239 protecting group Chemical group 0.000 claims description 13
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
• 241000282412 Homo Species 0.000 claims description 11
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
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• 206010002383 Angina Pectoris Diseases 0.000 claims description 6
• 208000011775 arteriosclerosis disease Diseases 0.000 claims description 6
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
• 210000004027 cell Anatomy 0.000 claims description 6
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• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
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• 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• 150000002923 oximes Chemical class 0.000 claims description 5
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• 208000031481 Pathologic Constriction Diseases 0.000 claims description 4
• 208000007536 Thrombosis Diseases 0.000 claims description 4
• FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 claims description 4
• 238000009826 distribution Methods 0.000 claims description 4
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• 208000032456 Hemorrhagic Shock Diseases 0.000 claims description 3
• 206010049771 Shock haemorrhagic Diseases 0.000 claims description 3
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 3
• 230000035939 shock Effects 0.000 claims description 3
• 230000006492 vascular dysfunction Effects 0.000 claims description 3
• 208000005189 Embolism Diseases 0.000 claims description 2
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• 206010072810 Vascular wall hypertrophy Diseases 0.000 claims description 2
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
• 230000003394 haemopoietic effect Effects 0.000 claims description 2
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• 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
• 150000002602 lanthanoids Chemical class 0.000 claims description 2
• UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 2
• 208000019553 vascular disease Diseases 0.000 claims description 2
• 241001674044 Blattodea Species 0.000 claims 2
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
• HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims 1
• 208000037260 Atherosclerotic Plaque Diseases 0.000 claims 1
• 102100035353 Cyclin-dependent kinase 2-associated protein 1 Human genes 0.000 claims 1
• 125000002393 azetidinyl group Chemical group 0.000 claims 1
• 230000005540 biological transmission Effects 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 claims 1
• 230000001788 irregular Effects 0.000 claims 1
• 239000008267 milk Substances 0.000 claims 1
• 210000004080 milk Anatomy 0.000 claims 1
• 235000013336 milk Nutrition 0.000 claims 1
• 125000004043 oxo group Chemical group O=* 0.000 claims 1
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
• 239000012453 solvate Substances 0.000 abstract description 213
• 229940002612 prodrug Drugs 0.000 abstract description 111
• 239000000651 prodrug Substances 0.000 abstract description 111
• 239000003613 bile acid Substances 0.000 abstract description 34
• HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 abstract description 30
• 239000003112 inhibitor Substances 0.000 abstract description 8
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 177
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
• 235000019439 ethyl acetate Nutrition 0.000 description 89
• 239000002585 base Substances 0.000 description 66
• 239000000243 solution Substances 0.000 description 61
• 239000012317 TBTU Substances 0.000 description 37
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 37
• 239000002904 solvent Substances 0.000 description 34
• 238000006243 chemical reaction Methods 0.000 description 32
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
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• 239000002552 dosage form Substances 0.000 description 25
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• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
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• CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 16
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