ZA200106252B - Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake. - Google Patents

Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake. Download PDF

Info

Publication number: ZA200106252B
Authority: ZA; South Africa
Prior art keywords: alkyl; heterocyclyl; group; aryl; independently selected
Prior art date: 1999-02-12

Application number

ZA200106252A

Other languages

English (en)

Inventor

Michael B Tollefson

Steve A Kolodziej

David B Reitz

Original Assignee

Searle Llc

Priority date (The priority date 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 date listed.)

1999-02-12

Filing date

2001-07-30

Publication date

2002-07-30

2001-07-30 Application filed by Searle Llc filed Critical Searle Llc

2002-07-30 Publication of ZA200106252B publication Critical patent/ZA200106252B/en

Links

239000003613 bile acid Substances 0.000 title description 16
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 title description 10
FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical class S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 title description 7
230000000694 effects Effects 0.000 title description 5
239000003112 inhibitor Substances 0.000 title description 4
WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 title description 2
125000000217 alkyl group Chemical group 0.000 claims description 579
125000000623 heterocyclic group Chemical group 0.000 claims description 481
229910052799 carbon Inorganic materials 0.000 claims description 429
125000003118 aryl group Chemical group 0.000 claims description 290
125000000304 alkynyl group Chemical group 0.000 claims description 228
125000003342 alkenyl group Chemical group 0.000 claims description 226
229910052739 hydrogen Inorganic materials 0.000 claims description 208
239000001257 hydrogen Substances 0.000 claims description 206
125000000753 cycloalkyl group Chemical group 0.000 claims description 194
150000003254 radicals Chemical class 0.000 claims description 194
-1 heterocyclyl radicals Chemical class 0.000 claims description 191
125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 189
150000001875 compounds Chemical class 0.000 claims description 183
125000003710 aryl alkyl group Chemical group 0.000 claims description 175
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 169
239000004721 Polyphenylene oxide Chemical group 0.000 claims description 159
229920000570 polyether Chemical group 0.000 claims description 159
229910052736 halogen Inorganic materials 0.000 claims description 115
150000002367 halogens Chemical class 0.000 claims description 114
125000001188 haloalkyl group Chemical group 0.000 claims description 111
108090000765 processed proteins & peptides Chemical group 0.000 claims description 110
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 72
125000000837 carbohydrate group Chemical group 0.000 claims description 69
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 66
125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 61
229920001184 polypeptide Polymers 0.000 claims description 55
102000004196 processed proteins & peptides Human genes 0.000 claims description 55
229910052757 nitrogen Inorganic materials 0.000 claims description 54
125000003545 alkoxy group Chemical group 0.000 claims description 48
125000000539 amino acid group Chemical group 0.000 claims description 44
125000001183 hydrocarbyl group Chemical group 0.000 claims description 43
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 41
150000002431 hydrogen Chemical class 0.000 claims description 37
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
125000002252 acyl group Chemical group 0.000 claims description 32
125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 32
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 31
125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 31
125000004948 alkyl aryl alkyl group Chemical group 0.000 claims description 31
125000004122 cyclic group Chemical group 0.000 claims description 31
125000005842 heteroatom Chemical group 0.000 claims description 31
125000001424 substituent group Chemical group 0.000 claims description 31
125000002877 alkyl aryl group Chemical group 0.000 claims description 30
125000000392 cycloalkenyl group Chemical group 0.000 claims description 30
125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
150000003839 salts Chemical group 0.000 claims description 30
125000004181 carboxyalkyl group Chemical group 0.000 claims description 26
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 24
238000011282 treatment Methods 0.000 claims description 24
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
150000001768 cations Chemical class 0.000 claims description 21
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
125000005082 alkoxyalkenyl group Chemical group 0.000 claims description 20
150000001450 anions Chemical class 0.000 claims description 18
150000005840 aryl radicals Chemical class 0.000 claims description 18
150000001721 carbon Chemical group 0.000 claims description 17
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 16
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
125000003282 alkyl amino group Chemical group 0.000 claims description 16
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
229910052760 oxygen Inorganic materials 0.000 claims description 16
239000001301 oxygen Substances 0.000 claims description 16
229910052698 phosphorus Inorganic materials 0.000 claims description 16
239000011574 phosphorus Substances 0.000 claims description 16
238000011321 prophylaxis Methods 0.000 claims description 16
229910052717 sulfur Inorganic materials 0.000 claims description 16
239000011593 sulfur Substances 0.000 claims description 16
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 15
238000000034 method Methods 0.000 claims description 15
125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 14
150000001720 carbohydrates Chemical class 0.000 claims description 14
125000004432 carbon atom Chemical group C* 0.000 claims description 14
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
125000002950 monocyclic group Chemical group 0.000 claims description 14
239000000651 prodrug Substances 0.000 claims description 14
229940002612 prodrug Drugs 0.000 claims description 14
239000012453 solvate Substances 0.000 claims description 14
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 14
239000002253 acid Substances 0.000 claims description 13
125000004423 acyloxy group Chemical group 0.000 claims description 12
125000004964 sulfoalkyl group Chemical group 0.000 claims description 12
125000005605 benzo group Chemical group 0.000 claims description 10
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 9
208000035150 Hypercholesterolemia Diseases 0.000 claims description 8
150000001413 amino acids Chemical class 0.000 claims description 8
239000003814 drug Substances 0.000 claims description 8
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
125000004966 cyanoalkyl group Chemical group 0.000 claims description 7
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 7
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
239000000203 mixture Substances 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 7
125000004103 aminoalkyl group Chemical group 0.000 claims description 6
125000005026 carboxyaryl group Chemical group 0.000 claims description 5
101150020251 NR13 gene Proteins 0.000 claims description 4
125000001624 naphthyl group Chemical group 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
125000001544 thienyl group Chemical group 0.000 claims description 4
150000001412 amines Chemical class 0.000 claims description 3
239000003795 chemical substances by application Substances 0.000 claims description 3
125000004193 piperazinyl group Chemical group 0.000 claims description 3
102220480121 H/ACA ribonucleoprotein complex subunit DKC1_R10A_mutation Human genes 0.000 claims description 2
125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 2
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
125000004663 dialkyl amino group Chemical group 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
125000002883 imidazolyl group Chemical group 0.000 claims description 2
125000001041 indolyl group Chemical group 0.000 claims description 2
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
125000001786 isothiazolyl group Chemical group 0.000 claims description 2
125000000842 isoxazolyl group Chemical group 0.000 claims description 2
125000002971 oxazolyl group Chemical group 0.000 claims description 2
229960005235 piperonyl butoxide Drugs 0.000 claims description 2
125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 2
125000003226 pyrazolyl group Chemical group 0.000 claims description 2
125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
125000000168 pyrrolyl group Chemical group 0.000 claims description 2
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
125000000335 thiazolyl group Chemical group 0.000 claims description 2
125000001425 triazolyl group Chemical group 0.000 claims description 2
125000004093 cyano group Chemical group *C#N 0.000 claims 68
125000005843 halogen group Chemical group 0.000 claims 30
125000005210 alkyl ammonium group Chemical group 0.000 claims 21
150000001335 aliphatic alkanes Chemical class 0.000 claims 14
150000001336 alkenes Chemical class 0.000 claims 9
150000001345 alkine derivatives Chemical class 0.000 claims 9
241001516584 Andrya Species 0.000 claims 8
ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 claims 8
239000002552 dosage form Substances 0.000 claims 6
239000003937 drug carrier Substances 0.000 claims 6
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 6
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 5
230000003143 atherosclerotic effect Effects 0.000 claims 5
238000004519 manufacturing process Methods 0.000 claims 5
102000017921 NTSR1 Human genes 0.000 claims 4
101150108752 Ntsr1 gene Proteins 0.000 claims 4
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 4
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 4
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
108090000629 orphan nuclear receptors Proteins 0.000 claims 3
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims 3
STSYRNZXXQMGHP-UHFFFAOYSA-N (amino-ethoxy-nitromethyl)-(diethylamino)-[dimethylamino-(ethylamino)-(methylamino)methyl]-[hydroxy(methoxy)methyl]azanium Chemical compound OC([N+](C(NCC)(N(C)C)NC)(C(N)([N+](=O)[O-])OCC)N(CC)CC)OC STSYRNZXXQMGHP-UHFFFAOYSA-N 0.000 claims 2
FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 claims 2
235000010290 biphenyl Nutrition 0.000 claims 2
239000004305 biphenyl Substances 0.000 claims 2
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 2
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims 2
125000004464 hydroxyphenyl group Chemical group 0.000 claims 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
125000006501 nitrophenyl group Chemical group 0.000 claims 2
JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims 2
125000006413 ring segment Chemical group 0.000 claims 2
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
METJFDMYWVYDOK-DNQXCXABSA-N (4r,5r)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@@H]2C3=CC(=CC=C3S(=O)(=O)NC([C@@H]2O)(CCCC)CCCC)N(C)C)=CC=CC=C1 METJFDMYWVYDOK-DNQXCXABSA-N 0.000 claims 1
TUJPZSYJLFMWCA-JWQCQUIFSA-N (4r,5r)-3,3-dibutyl-7-(dimethylamino)-2-methyl-5-(3-nitrophenyl)-1,1-dioxo-4,5-dihydro-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@H]2[C@@H](O)C(N(S(=O)(=O)C3=CC=C(C=C32)N(C)C)C)(CCCC)CCCC)=CC=CC([N+]([O-])=O)=C1 TUJPZSYJLFMWCA-JWQCQUIFSA-N 0.000 claims 1
XYVUGRAVQKLPPU-CLJLJLNGSA-N (4r,5r)-3,3-dibutyl-7-(dimethylamino)-5-(3-methoxyphenyl)-2-methyl-1,1-dioxo-4,5-dihydro-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@H]2[C@@H](O)C(N(S(=O)(=O)C3=CC=C(C=C32)N(C)C)C)(CCCC)CCCC)=CC=CC(OC)=C1 XYVUGRAVQKLPPU-CLJLJLNGSA-N 0.000 claims 1
LDZIKONCRYGLFY-DNQXCXABSA-N (4r,5r)-3,3-dibutyl-7-(dimethylamino)-5-(3-nitrophenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@@H]2C3=CC(=CC=C3S(=O)(=O)NC([C@@H]2O)(CCCC)CCCC)N(C)C)=CC=CC([N+]([O-])=O)=C1 LDZIKONCRYGLFY-DNQXCXABSA-N 0.000 claims 1
RJEHRPZAQZYFIL-DNQXCXABSA-N (4r,5r)-3,3-dibutyl-7-(dimethylamino)-5-(4-hydroxyphenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@@H]2C3=CC(=CC=C3S(=O)(=O)NC([C@@H]2O)(CCCC)CCCC)N(C)C)=CC=C(O)C=C1 RJEHRPZAQZYFIL-DNQXCXABSA-N 0.000 claims 1
WVQLVOSWPXPLRD-JWQCQUIFSA-N (4r,5r)-3,3-dibutyl-7-(dimethylamino)-5-(4-methoxyphenyl)-1,1-dioxo-4,5-dihydro-2h-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@@H]2C3=CC(=CC=C3S(=O)(=O)NC([C@@H]2O)(CCCC)CCCC)N(C)C)=CC=C(OC)C=C1 WVQLVOSWPXPLRD-JWQCQUIFSA-N 0.000 claims 1
ZCJMAJYQZWBZMJ-CLJLJLNGSA-N (4r,5r)-3,3-dibutyl-7-(dimethylamino)-5-(4-methoxyphenyl)-2-methyl-1,1-dioxo-4,5-dihydro-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@H]2[C@@H](O)C(N(S(=O)(=O)C3=CC=C(C=C32)N(C)C)C)(CCCC)CCCC)=CC=C(OC)C=C1 ZCJMAJYQZWBZMJ-CLJLJLNGSA-N 0.000 claims 1
STEYOPYSZKLUJY-DNQXCXABSA-N (4r,5r)-5-(3-aminophenyl)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6},2-benzothiazepin-4-ol Chemical compound C1([C@@H]2C3=CC(=CC=C3S(=O)(=O)NC([C@@H]2O)(CCCC)CCCC)N(C)C)=CC=CC(N)=C1 STEYOPYSZKLUJY-DNQXCXABSA-N 0.000 claims 1
FOUHQFWUUMJAKD-UHFFFAOYSA-N (amino-ethoxy-nitromethyl)-[(2-bromo-2-chloro-2-fluoroethyl)-ethylamino]-[dimethylamino-(ethylamino)-(methylamino)methyl]-(hydroxy-iodo-methoxymethyl)azanium Chemical group ClC(CN(CC)[N+](C(NCC)(N(C)C)NC)(C(N)([N+](=O)[O-])OCC)C(OC)(O)I)(Br)F FOUHQFWUUMJAKD-UHFFFAOYSA-N 0.000 claims 1
RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 claims 1
WWYVZTLIFYLZFM-UHFFFAOYSA-N 1-methylazetidine Chemical compound CN1CCC1 WWYVZTLIFYLZFM-UHFFFAOYSA-N 0.000 claims 1
PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims 1
AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims 1
KGCGCEWAJOGOQT-KAYWLYCHSA-N 2-chloro-n-[3-[(4r,5r)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-2-methyl-1,1-dioxo-4,5-dihydro-1$l^{6},2-benzothiazepin-5-yl]phenyl]acetamide Chemical compound C1([C@H]2[C@@H](O)C(N(S(=O)(=O)C3=CC=C(C=C32)N(C)C)C)(CCCC)CCCC)=CC=CC(NC(=O)CCl)=C1 KGCGCEWAJOGOQT-KAYWLYCHSA-N 0.000 claims 1
ZTNLGPOYWLKXPR-UHFFFAOYSA-N 2-ethenoxypyrimidine Chemical group C=COC1=NC=CC=N1 ZTNLGPOYWLKXPR-UHFFFAOYSA-N 0.000 claims 1
UYYGJSNWDMBJNA-UHFFFAOYSA-N 2-methylhydrazin-1-ol Chemical compound CNNO UYYGJSNWDMBJNA-UHFFFAOYSA-N 0.000 claims 1
ANJFZNGNTORFNS-LOYHVIPDSA-N 5-chloro-N-[3-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-2-methyl-1,1-dioxo-4,5-dihydro-1lambda6,2-benzothiazepin-5-yl]phenyl]pentanamide Chemical compound CCCCC1(CCCC)[C@H](O)[C@H](c2cccc(NC(=O)CCCCCl)c2)c2cc(ccc2S(=O)(=O)N1C)N(C)C ANJFZNGNTORFNS-LOYHVIPDSA-N 0.000 claims 1
CGGMXZXSAZKBDC-UHFFFAOYSA-N C1(=CC=CC=C1)CN1S(C=2C(CC(C1)O)CC=CC2)(=O)=O Chemical compound C1(=CC=CC=C1)CN1S(C=2C(CC(C1)O)CC=CC2)(=O)=O CGGMXZXSAZKBDC-UHFFFAOYSA-N 0.000 claims 1
101100310929 Caenorhabditis elegans sra-7 gene Proteins 0.000 claims 1
102100033668 Cartilage matrix protein Human genes 0.000 claims 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims 1
101001018382 Homo sapiens Cartilage matrix protein Proteins 0.000 claims 1
101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 claims 1
101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 claims 1
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims 1
PQBAWAQIRZIWIV-UHFFFAOYSA-N N-methylpyridinium Chemical compound C[N+]1=CC=CC=C1 PQBAWAQIRZIWIV-UHFFFAOYSA-N 0.000 claims 1
102100039614 Nuclear receptor ROR-alpha Human genes 0.000 claims 1
125000002015 acyclic group Chemical group 0.000 claims 1
230000000879 anti-atherosclerotic effect Effects 0.000 claims 1
230000001315 anti-hyperlipaemic effect Effects 0.000 claims 1
125000002393 azetidinyl group Chemical group 0.000 claims 1
125000001246 bromo group Chemical group Br* 0.000 claims 1
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125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
125000001309 chloro group Chemical group Cl* 0.000 claims 1
125000000068 chlorophenyl group Chemical group 0.000 claims 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
125000006125 ethylsulfonyl group Chemical group 0.000 claims 1
125000001153 fluoro group Chemical group F* 0.000 claims 1
125000001207 fluorophenyl group Chemical group 0.000 claims 1
125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
125000006303 iodophenyl group Chemical group 0.000 claims 1
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
125000002757 morpholinyl group Chemical group 0.000 claims 1
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
AEABQBMUYZBBCW-UHFFFAOYSA-N pentanamide Chemical compound CC[CH]CC(N)=O AEABQBMUYZBBCW-UHFFFAOYSA-N 0.000 claims 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 1
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
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Classifications

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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P3/06—Antihyperlipidemics
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/36—Amides thereof
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
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Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
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Molecular Biology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
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Animal Behavior & Ethology (AREA)
Veterinary Medicine (AREA)
Chemical Kinetics & Catalysis (AREA)
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Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Hematology (AREA)
Obesity (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

ZA200106252A 1999-02-12 2001-07-30 Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake. ZA200106252B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US11993399P	1999-02-12	1999-02-12

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ZA200106252A ZA200106252B (en)	1999-02-12	2001-07-30	Novel 1,2-benzothiazepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake.

Country Status (10)

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EP (1)	EP1155007A2 (fr)
JP (1)	JP2002536440A (fr)
KR (1)	KR20020000139A (fr)
CN (1)	CN1195748C (fr)
AU (1)	AU3694600A (fr)
CA (1)	CA2362147A1 (fr)
HU (1)	HUP0105409A3 (fr)
IL (1)	IL144716A0 (fr)
WO (1)	WO2000047568A2 (fr)
ZA (1)	ZA200106252B (fr)

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GB0121337D0 (en)	2001-09-04	2001-10-24	Astrazeneca Ab	Chemical compounds
GB0121622D0 (en)	2001-09-07	2001-10-31	Astrazeneca Ab	Chemical compounds
GB0121621D0 (en)	2001-09-07	2001-10-31	Astrazeneca Ab	Chemical compounds
TWI331143B (en)	2001-09-08	2010-10-01	Astrazeneca Uk Ltd	Benzothiadiazepine derivatives, process for preparing them, and pharmaceutical composition comprising them
GB0209467D0 (en)	2002-04-25	2002-06-05	Astrazeneca Ab	Chemical compounds
JP4530849B2 (ja) *	2002-06-11	2010-08-25	ワイス・エルエルシー	βアミロイド産生の置換フェニルスルホンアミド阻害剤
GB0213669D0 (en)	2002-06-14	2002-07-24	Astrazeneca Ab	Chemical compounds
US7312208B2 (en)	2002-08-28	2007-12-25	Asahi Kasei Pharma Corporation	Quaternary ammonium compounds
AU2003257578B2 (en) *	2002-08-28	2009-01-22	Asahi Kasei Pharma Corporation	Novel quaternary ammonium compounds
GB0304194D0 (en) *	2003-02-25	2003-03-26	Astrazeneca Ab	Chemical compounds
GB0307918D0 (en)	2003-04-05	2003-05-14	Astrazeneca Ab	Therapeutic use
CN102293773A (zh) *	2004-02-27	2011-12-28	旭化成制药株式会社	含有苯并硫氮杂卓和苯并虑平化合物的药物
EP2575821B1 (fr)	2010-05-26	2015-08-12	Satiogen Pharmaceuticals, Inc.	Inhibiteurs de recyclage d'acide biliaire et satiogènes pour traitement du diabète, de l'obésité et d'états inflammatoires gastro-intestinaux
PL3400944T3 (pl)	2010-11-04	2020-11-16	Albireo Ab	Inhibitory ibat w leczeniu chorób wątroby
JP6097695B2 (ja)	2010-11-08	2017-03-15	アルビレオアクチエボラグ	Ｉｂａｔ阻害剤および胆汁酸結合剤を含む薬学的組み合わせ
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CA2852957C (fr)	2011-10-28	2020-08-04	Lumena Pharmaceuticals, Inc.	Inhibiteurs du recyclage de l'acide biliaire pour traitement de l'hypercholemie et de la maladie cholestatique hepatique
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CN105228615A (zh)	2013-03-15	2016-01-06	鲁美纳医药公司	用于治疗巴雷特食管和胃食管返流疾病的胆汁酸再循环抑制剂
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CA2952406A1 (fr)	2014-06-25	2015-12-30	Ea Pharma Co., Ltd.	Preparation solide et procede d'inhibition ou d'attenuation de coloration de celle-ci
EP3012252A1 (fr)	2014-10-24	2016-04-27	Ferring BV	Formes crystallines d'Elobixibat
RU2750937C2 (ru)	2016-02-09	2021-07-06	Альбирео Аб	Пероральный состав холестирамина и его применение
US10441604B2 (en)	2016-02-09	2019-10-15	Albireo Ab	Cholestyramine pellets and methods for preparation thereof
EP3413877B1 (fr)	2016-02-09	2021-04-07	Albireo AB	Formulation orale de cholestyramine et utilisation associée
US10786529B2 (en)	2016-02-09	2020-09-29	Albireo Ab	Oral cholestyramine formulation and use thereof
US10441605B2 (en)	2016-02-09	2019-10-15	Albireo Ab	Oral cholestyramine formulation and use thereof
JP2020530448A (ja)	2017-08-09	2020-10-22	アルビレオ・アクチボラグ	コレスチラミン顆粒、経口コレスチラミン製剤、及びそれらの使用
CA3071182A1 (fr)	2017-08-09	2019-02-14	Albireo Ab	Pastilles de cholestyramine, formulations orales de cholestyramine et leur utilisation
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- 2000-02-10 JP JP2000598488A patent/JP2002536440A/ja active Pending
- 2000-02-10 EP EP00915720A patent/EP1155007A2/fr not_active Ceased
- 2000-02-10 IL IL14471600A patent/IL144716A0/xx unknown
- 2000-02-10 WO PCT/US2000/002503 patent/WO2000047568A2/fr not_active Ceased
- 2000-02-10 AU AU36946/00A patent/AU3694600A/en not_active Abandoned
- 2000-02-10 CN CNB008060282A patent/CN1195748C/zh not_active Expired - Fee Related
- 2000-02-10 KR KR1020017010201A patent/KR20020000139A/ko not_active Ceased
- 2000-02-10 HU HU0105409A patent/HUP0105409A3/hu unknown
2001
- 2001-07-30 ZA ZA200106252A patent/ZA200106252B/en unknown

Also Published As

Publication number	Publication date
JP2002536440A (ja)	2002-10-29
CN1195748C (zh)	2005-04-06
WO2000047568A2 (fr)	2000-08-17
HUP0105409A2 (hu)	2002-05-29
EP1155007A2 (fr)	2001-11-21
CA2362147A1 (fr)	2000-08-17
HUP0105409A3 (en)	2004-11-29
IL144716A0 (en)	2002-06-30
AU3694600A (en)	2000-08-29
KR20020000139A (ko)	2002-01-04
CN1346351A (zh)	2002-04-24
WO2000047568A3 (fr)	2000-12-14

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PT98421A (pt)	1992-05-29	Processo de preparacao de derivados da tetra-hidropiridinildibenzazepina e de composicoes fasrmaceuticas
NZ222401A (en)	1991-04-26	Pharmaceutical compositions which include a calcium antagonist and 7-(n-(1(s)-ethoxycarbonyl-3-phenylpropyl)-(s)-alanyl)-1,4-dithia-7-azaspiro(4,4)nonane-8-(s)-carboxylic acid