OA11629A - Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake. - Google Patents

Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake. Download PDF

Info

Publication number: OA11629A
Authority: OA; OAPI
Prior art keywords: heterocycle; alkyl; quaternary; alkynyl; alkenyl
Prior art date: 1998-07-02

Application number

OA1200000365A

Other languages

English (en)

Inventor

Len F Lee

Shyamal BANERJEE

Horng-Chih Huang

Jinglin J Li

Raymond E Miller

David B Reitz

Samuel J Tremont

Original Assignee

Searle & Co

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.)

1998-07-02

Filing date

1999-06-29

Publication date

2004-11-10

1999-06-29 Application filed by Searle & Co filed Critical Searle & Co

2004-11-10 Publication of OA11629A publication Critical patent/OA11629A/en

Links

NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical class S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 title abstract description 23
239000003613 bile acid Substances 0.000 title abstract description 23
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 abstract description 14
239000003112 inhibitor Substances 0.000 title abstract description 8
230000000694 effects Effects 0.000 title abstract description 7
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 abstract 2
238000000034 method Methods 0.000 claims abstract description 77
125000000623 heterocyclic group Chemical group 0.000 claims description 453
125000000217 alkyl group Chemical group 0.000 claims description 403
125000003118 aryl group Chemical group 0.000 claims description 298
125000003342 alkenyl group Chemical group 0.000 claims description 293
125000000304 alkynyl group Chemical group 0.000 claims description 291
125000000753 cycloalkyl group Chemical group 0.000 claims description 267
125000003710 aryl alkyl group Chemical group 0.000 claims description 231
125000001072 heteroaryl group Chemical group 0.000 claims description 230
150000001875 compounds Chemical class 0.000 claims description 194
-1 ammoniumalkyl Chemical group 0.000 claims description 158
239000004721 Polyphenylene oxide Substances 0.000 claims description 145
229910052739 hydrogen Inorganic materials 0.000 claims description 145
229920000570 polyether Polymers 0.000 claims description 145
108090000765 processed proteins & peptides Proteins 0.000 claims description 138
229910052736 halogen Inorganic materials 0.000 claims description 133
150000002367 halogens Chemical class 0.000 claims description 133
125000001188 haloalkyl group Chemical group 0.000 claims description 132
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 107
125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 104
125000001424 substituent group Chemical group 0.000 claims description 89
125000004043 oxo group Chemical group O=* 0.000 claims description 87
125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 81
239000001257 hydrogen Substances 0.000 claims description 78
150000001413 amino acids Chemical class 0.000 claims description 75
125000004181 carboxyalkyl group Chemical group 0.000 claims description 72
239000000203 mixture Substances 0.000 claims description 72
RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 72
235000001014 amino acid Nutrition 0.000 claims description 69
229920001184 polypeptide Polymers 0.000 claims description 68
102000004196 processed proteins & peptides Human genes 0.000 claims description 68
229910052760 oxygen Inorganic materials 0.000 claims description 63
150000001720 carbohydrates Chemical class 0.000 claims description 62
125000003545 alkoxy group Chemical group 0.000 claims description 59
125000004122 cyclic group Chemical group 0.000 claims description 58
230000008569 process Effects 0.000 claims description 58
229910052757 nitrogen Inorganic materials 0.000 claims description 57
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 54
125000002252 acyl group Chemical group 0.000 claims description 52
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 52
VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 claims description 52
239000003795 chemical substances by application Substances 0.000 claims description 51
125000002877 alkyl aryl group Chemical group 0.000 claims description 47
229910052799 carbon Inorganic materials 0.000 claims description 45
125000004423 acyloxy group Chemical group 0.000 claims description 41
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 39
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
125000004433 nitrogen atom Chemical group N* 0.000 claims description 34
125000004948 alkyl aryl alkyl group Chemical group 0.000 claims description 31
125000004414 alkyl thio group Chemical group 0.000 claims description 31
125000004663 dialkyl amino group Chemical group 0.000 claims description 31
125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 30
150000003839 salts Chemical group 0.000 claims description 30
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
150000001768 cations Chemical class 0.000 claims description 26
150000002431 hydrogen Chemical class 0.000 claims description 25
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 23
150000001450 anions Chemical class 0.000 claims description 23
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
125000004964 sulfoalkyl group Chemical group 0.000 claims description 21
150000005171 halobenzenes Chemical class 0.000 claims description 19
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 17
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 16
229910000104 sodium hydride Inorganic materials 0.000 claims description 16
238000011282 treatment Methods 0.000 claims description 16
101150020251 NR13 gene Proteins 0.000 claims description 15
239000002253 acid Substances 0.000 claims description 15
239000002585 base Substances 0.000 claims description 15
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
239000008194 pharmaceutical composition Substances 0.000 claims description 14
LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 14
125000004946 alkenylalkyl group Chemical group 0.000 claims description 13
125000005038 alkynylalkyl group Chemical group 0.000 claims description 13
125000004966 cyanoalkyl group Chemical group 0.000 claims description 13
125000002950 monocyclic group Chemical group 0.000 claims description 13
125000003367 polycyclic group Chemical group 0.000 claims description 13
239000012312 sodium hydride Substances 0.000 claims description 13
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 12
101100379081 Emericella variicolor andC gene Proteins 0.000 claims description 11
150000001721 carbon Chemical group 0.000 claims description 11
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 11
239000007800 oxidant agent Substances 0.000 claims description 10
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
239000002552 dosage form Substances 0.000 claims description 8
239000000651 prodrug Substances 0.000 claims description 8
229940002612 prodrug Drugs 0.000 claims description 8
102220465932 Beta-1,3-glucuronyltransferase LARGE2_R13A_mutation Human genes 0.000 claims description 7
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 7
125000004429 atom Chemical group 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 5
GLNWILHOFOBOFD-UHFFFAOYSA-N lithium sulfide Chemical group [Li+].[Li+].[S-2] GLNWILHOFOBOFD-UHFFFAOYSA-N 0.000 claims description 5
LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 5
238000011321 prophylaxis Methods 0.000 claims description 5
UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 4
239000003513 alkali Substances 0.000 claims description 4
125000001309 chloro group Chemical group Cl* 0.000 claims description 4
230000001590 oxidative effect Effects 0.000 claims description 4
150000003457 sulfones Chemical class 0.000 claims description 4
HCUOEKSZWPGJIM-YBRHCDHNSA-N (e,2e)-2-hydroxyimino-6-methoxy-4-methyl-5-nitrohex-3-enamide Chemical compound COCC([N+]([O-])=O)\C(C)=C\C(=N/O)\C(N)=O HCUOEKSZWPGJIM-YBRHCDHNSA-N 0.000 claims description 3
101001109689 Homo sapiens Nuclear receptor subfamily 4 group A member 3 Proteins 0.000 claims description 3
101000598778 Homo sapiens Protein OSCP1 Proteins 0.000 claims description 3
208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
101001067395 Mus musculus Phospholipid scramblase 1 Proteins 0.000 claims description 3
102100022673 Nuclear receptor subfamily 4 group A member 3 Human genes 0.000 claims description 3
150000004703 alkoxides Chemical class 0.000 claims description 3
125000003282 alkyl amino group Chemical group 0.000 claims description 3
150000004678 hydrides Chemical class 0.000 claims description 2
125000001544 thienyl group Chemical group 0.000 claims description 2
SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 6
101150064767 NNR1 gene Proteins 0.000 claims 3
230000008878 coupling Effects 0.000 claims 2
238000010168 coupling process Methods 0.000 claims 2
238000005859 coupling reaction Methods 0.000 claims 2
125000006575 electron-withdrawing group Chemical group 0.000 claims 2
229910006074 SO2NH2 Inorganic materials 0.000 claims 1
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 1
230000003143 atherosclerotic effect Effects 0.000 claims 1
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 90
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
239000000243 solution Substances 0.000 description 78
YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
238000006243 chemical reaction Methods 0.000 description 54
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 47
229910001868 water Inorganic materials 0.000 description 47
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 46
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 36
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
239000000047 product Substances 0.000 description 34
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
238000003756 stirring Methods 0.000 description 30
235000014633 carbohydrates Nutrition 0.000 description 29
235000019439 ethyl acetate Nutrition 0.000 description 28
229940093499 ethyl acetate Drugs 0.000 description 28
239000003921 oil Substances 0.000 description 27
150000003254 radicals Chemical group 0.000 description 27
235000019198 oils Nutrition 0.000 description 26
238000005481 NMR spectroscopy Methods 0.000 description 25
238000007792 addition Methods 0.000 description 24
239000012044 organic layer Substances 0.000 description 24
229910052943 magnesium sulfate Inorganic materials 0.000 description 23
235000019341 magnesium sulphate Nutrition 0.000 description 23
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
229940073584 methylene chloride Drugs 0.000 description 22
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
238000001819 mass spectrum Methods 0.000 description 21
238000010992 reflux Methods 0.000 description 20
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
239000010410 layer Substances 0.000 description 18
229940035423 ethyl ether Drugs 0.000 description 16
239000011541 reaction mixture Substances 0.000 description 16
239000007789 gas Substances 0.000 description 15
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
235000011121 sodium hydroxide Nutrition 0.000 description 15
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
239000007787 solid Substances 0.000 description 14
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 12
239000012267 brine Substances 0.000 description 12
125000004432 carbon atom Chemical group C* 0.000 description 12
239000000284 extract Substances 0.000 description 12
235000011118 potassium hydroxide Nutrition 0.000 description 12
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 12
238000000746 purification Methods 0.000 description 12
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
201000010099 disease Diseases 0.000 description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
238000010926 purge Methods 0.000 description 11
JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 10
238000004949 mass spectrometry Methods 0.000 description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
229910052717 sulfur Inorganic materials 0.000 description 10
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 9
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
230000037396 body weight Effects 0.000 description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
235000002568 Capsicum frutescens Nutrition 0.000 description 8
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 8
ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 8
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
239000002904 solvent Substances 0.000 description 8
239000007858 starting material Substances 0.000 description 8
239000003826 tablet Substances 0.000 description 8
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
239000003643 water by type Substances 0.000 description 8
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
201000001320 Atherosclerosis Diseases 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
239000000543 intermediate Substances 0.000 description 7
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
238000004809 thin layer chromatography Methods 0.000 description 7
229940099408 Oxidizing agent Drugs 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
150000001335 aliphatic alkanes Chemical class 0.000 description 6
150000001345 alkine derivatives Chemical class 0.000 description 6
ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
125000005842 heteroatom Chemical group 0.000 description 6
230000003647 oxidation Effects 0.000 description 6
238000007254 oxidation reaction Methods 0.000 description 6
239000012071 phase Substances 0.000 description 6
229940093932 potassium hydroxide Drugs 0.000 description 6
238000010898 silica gel chromatography Methods 0.000 description 6
239000011780 sodium chloride Substances 0.000 description 6
229940083608 sodium hydroxide Drugs 0.000 description 6
229910021653 sulphate ion Inorganic materials 0.000 description 6
239000000725 suspension Substances 0.000 description 6
241000124008 Mammalia Species 0.000 description 5
XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical compound CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 description 5
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
150000001336 alkenes Chemical class 0.000 description 5
239000007864 aqueous solution Substances 0.000 description 5
239000002775 capsule Substances 0.000 description 5
238000007796 conventional method Methods 0.000 description 5
239000003814 drug Substances 0.000 description 5
238000009472 formulation Methods 0.000 description 5
125000005843 halogen group Chemical group 0.000 description 5
238000004128 high performance liquid chromatography Methods 0.000 description 5
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 5
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
229910000027 potassium carbonate Inorganic materials 0.000 description 5
229920006395 saturated elastomer Polymers 0.000 description 5
239000000741 silica gel Substances 0.000 description 5
229910002027 silica gel Inorganic materials 0.000 description 5
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
GDVUGFJXFFCXMX-UHFFFAOYSA-N (2-ethyl-2-formylhexyl) methanesulfonate Chemical compound CCCCC(CC)(C=O)COS(C)(=O)=O GDVUGFJXFFCXMX-UHFFFAOYSA-N 0.000 description 4
LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
229940077672 Ileal bile acid transport inhibitor Drugs 0.000 description 4
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
239000003153 chemical reaction reagent Substances 0.000 description 4
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
238000001816 cooling Methods 0.000 description 4
239000003085 diluting agent Substances 0.000 description 4
150000002148 esters Chemical class 0.000 description 4
238000000605 extraction Methods 0.000 description 4
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
239000007788 liquid Substances 0.000 description 4
OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 4
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
125000004585 polycyclic heterocycle group Chemical group 0.000 description 4
229920000642 polymer Polymers 0.000 description 4
235000015320 potassium carbonate Nutrition 0.000 description 4
230000035484 reaction time Effects 0.000 description 4
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
229910001220 stainless steel Inorganic materials 0.000 description 4
239000010935 stainless steel Substances 0.000 description 4
AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical group O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 4
238000005406 washing Methods 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
229920001268 Cholestyramine Polymers 0.000 description 3
AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
102000007330 LDL Lipoproteins Human genes 0.000 description 3
108010007622 LDL Lipoproteins Proteins 0.000 description 3
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Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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OA1200000365A 1998-07-02 1999-06-29 Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake. OA11629A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US09/109,551 US5994391A (en)	1994-09-13	1998-07-02	Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

Publications (1)

Publication Number	Publication Date
OA11629A true OA11629A (en)	2004-11-10

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ID=22328263

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OA1200000365A OA11629A (en)	1998-07-02	1999-06-29	Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake.

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US (1)	US5994391A (de)
EP (2)	EP1091953B1 (de)
JP (3)	JP2002519418A (de)
KR (1)	KR20010083084A (de)
CN (1)	CN1312805A (de)
AP (1)	AP2001002062A0 (de)
AR (1)	AR019880A1 (de)
AT (1)	ATE256122T1 (de)
AU (2)	AU766957B2 (de)
BG (1)	BG105206A (de)
BR (1)	BR9911737A (de)
CA (1)	CA2336315A1 (de)
CO (2)	CO4950537A1 (de)
DE (1)	DE69913530T2 (de)
DK (1)	DK1091953T3 (de)
EA (2)	EA200400149A1 (de)
EE (1)	EE200100002A (de)
ES (1)	ES2213373T3 (de)
GE (1)	GEP20032925B (de)
HK (1)	HK1039614A1 (de)
HR (1)	HRP20010004A2 (de)
HU (1)	HUP0102840A2 (de)
ID (1)	ID28221A (de)
IL (1)	IL140576A0 (de)
IS (1)	IS5798A (de)
NO (1)	NO20010016L (de)
NZ (1)	NZ509621A (de)
OA (1)	OA11629A (de)
PL (1)	PL346324A1 (de)
PT (1)	PT1091953E (de)
SG (1)	SG108309A1 (de)
SK (1)	SK20302000A3 (de)
TR (1)	TR200100824T2 (de)
TW (1)	TWI229670B (de)
WO (1)	WO2000001687A1 (de)
YU (1)	YU84400A (de)
ZA (1)	ZA200100028B (de)

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1998
- 1998-07-02 US US09/109,551 patent/US5994391A/en not_active Expired - Fee Related
1999
- 1999-06-29 EP EP99931769A patent/EP1091953B1/de not_active Expired - Lifetime
- 1999-06-29 HK HK02100948.1A patent/HK1039614A1/zh unknown
- 1999-06-29 TR TR2001/00824T patent/TR200100824T2/xx unknown
- 1999-06-29 EA EA200400149A patent/EA200400149A1/ru unknown
- 1999-06-29 SG SG200207701A patent/SG108309A1/en unknown
- 1999-06-29 SK SK2030-2000A patent/SK20302000A3/sk unknown
- 1999-06-29 EP EP03026649A patent/EP1466911A3/de not_active Withdrawn
- 1999-06-29 OA OA1200000365A patent/OA11629A/en unknown
- 1999-06-29 WO PCT/US1999/012828 patent/WO2000001687A1/en not_active Ceased
- 1999-06-29 PT PT99931769T patent/PT1091953E/pt unknown
- 1999-06-29 JP JP2000558091A patent/JP2002519418A/ja active Pending
- 1999-06-29 PL PL99346324A patent/PL346324A1/xx unknown
- 1999-06-29 ES ES99931769T patent/ES2213373T3/es not_active Expired - Lifetime
- 1999-06-29 DE DE69913530T patent/DE69913530T2/de not_active Expired - Fee Related
- 1999-06-29 GE GEAP19995707A patent/GEP20032925B/en unknown
- 1999-06-29 AP APAP/P/2001/002062A patent/AP2001002062A0/en unknown
- 1999-06-29 CA CA002336315A patent/CA2336315A1/en not_active Abandoned
- 1999-06-29 HR HR20010004A patent/HRP20010004A2/hr not_active Application Discontinuation
- 1999-06-29 YU YU84400A patent/YU84400A/sh unknown
- 1999-06-29 DK DK99931769T patent/DK1091953T3/da active
- 1999-06-29 NZ NZ509621A patent/NZ509621A/en unknown
- 1999-06-29 EA EA200100002A patent/EA004650B1/ru not_active IP Right Cessation
- 1999-06-29 BR BR9911737-1A patent/BR9911737A/pt not_active IP Right Cessation
- 1999-06-29 CN CN99809602A patent/CN1312805A/zh active Pending
- 1999-06-29 AT AT99931769T patent/ATE256122T1/de not_active IP Right Cessation
- 1999-06-29 IL IL14057699A patent/IL140576A0/xx unknown
- 1999-06-29 EE EEP200100002A patent/EE200100002A/xx unknown
- 1999-06-29 KR KR1020017000027A patent/KR20010083084A/ko not_active Ceased
- 1999-06-29 AU AU48202/99A patent/AU766957B2/en not_active Ceased
- 1999-06-29 ID IDW20010002A patent/ID28221A/id unknown
- 1999-06-29 HU HU0102840A patent/HUP0102840A2/hu unknown
- 1999-07-02 CO CO99041717A patent/CO4950537A1/es unknown
- 1999-07-02 CO CO99041717D patent/CO5080807A1/es unknown
- 1999-07-02 AR ARP990103234A patent/AR019880A1/es unknown
2000
- 2000-01-07 TW TW088111293A patent/TWI229670B/zh not_active IP Right Cessation
- 2000-12-29 IS IS5798A patent/IS5798A/is unknown
2001
- 2001-01-02 ZA ZA200100028A patent/ZA200100028B/xx unknown
- 2001-01-02 NO NO20010016A patent/NO20010016L/no not_active Application Discontinuation
- 2001-01-31 BG BG105206A patent/BG105206A/bg unknown
2004
- 2004-01-30 AU AU2004200346A patent/AU2004200346A1/en not_active Abandoned
- 2004-02-25 JP JP2004050473A patent/JP2004203891A/ja active Pending
- 2004-08-03 JP JP2004227034A patent/JP2004359694A/ja active Pending

Also Published As

Publication number	Publication date
NO20010016D0 (no)	2001-01-02
HRP20010004A2 (en)	2001-12-31
DK1091953T3 (da)	2004-04-13
EE200100002A (et)	2002-06-17
PT1091953E (pt)	2004-04-30
CA2336315A1 (en)	2000-01-13
ATE256122T1 (de)	2003-12-15
BG105206A (bg)	2001-09-28
JP2004359694A (ja)	2004-12-24
AU766957B2 (en)	2003-10-30
NZ509621A (en)	2003-08-29
EP1091953A1 (de)	2001-04-18
CO4950537A1 (es)	2000-09-01
DE69913530T2 (de)	2004-09-23
YU84400A (sh)	2002-12-10
US5994391A (en)	1999-11-30
AP2001002062A0 (en)	2001-03-31
EA004650B1 (ru)	2004-06-24
IL140576A0 (en)	2002-02-10
ES2213373T3 (es)	2004-08-16
TWI229670B (en)	2005-03-21
TR200100824T2 (tr)	2001-07-23
NO20010016L (no)	2001-03-02
DE69913530D1 (de)	2004-01-22
HK1039614A1 (zh)	2002-05-03
AU2004200346A1 (en)	2004-02-26
JP2004203891A (ja)	2004-07-22
KR20010083084A (ko)	2001-08-31
CN1312805A (zh)	2001-09-12
ID28221A (id)	2001-05-10
EP1466911A2 (de)	2004-10-13
IS5798A (is)	2000-12-29
WO2000001687A1 (en)	2000-01-13
ZA200100028B (en)	2001-07-25
GEP20032925B (en)	2003-03-25
JP2002519418A (ja)	2002-07-02
WO2000001687A9 (en)	2000-07-20
EA200400149A1 (ru)	2004-10-28
SK20302000A3 (sk)	2001-11-06
EP1466911A3 (de)	2005-09-07
AU4820299A (en)	2000-01-24
AR019880A1 (es)	2002-03-20
EP1091953B1 (de)	2003-12-10
PL346324A1 (en)	2002-02-11
BR9911737A (pt)	2001-12-11
EA200100002A1 (ru)	2001-08-27
CO5080807A1 (es)	2001-09-25
SG108309A1 (en)	2005-01-28
HUP0102840A2 (hu)	2002-01-28

Publication	Publication Date	Title
OA11629A (en)	2004-11-10	Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake.
US6784201B2 (en)	2004-08-31	Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
EP0888333B1 (de)	2005-08-31	Benzothiepinen mit wirkung als inhibitoren des ileumgallensäuretransports und der taurocholate-aufnahme
US6642268B2 (en)	2003-11-04	Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors
AU700557B2 (en)	1999-01-07	Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
RU2247579C2 (ru)	2005-03-10	Комбинированное лечение с применением бензотиепинов, ингибирующих транспорт желчной кислоты в подвздошной кишке, и ингибиторов hmg co-а редуктазы
WO1997033882A9 (en)	1998-02-26	Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6420417B1 (en)	2002-07-16	Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
AU723123B2 (en)	2000-08-17	Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
MXPA01000208A (en)	2001-09-07	Novel benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
EP1440972A1 (de)	2004-07-28	Neue Benzothiepine mit pharmazeutischer Wirkung.
HK1068342A (en)	2005-04-29	Novel benzothiepines having pharmaceutical activity
AU761249B2 (en)	2003-05-29	Novel intermediates and processes for the preparation of benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
CZ20004937A3 (cs)	2001-06-13	Benzothiepiny, které mají účinek jako inhibitory transportu žlučových kyselin v ileu a vychytávání taurocholátu