CN1059674C - 降低血脂的苯并硫氮杂䓬 - Google Patents
降低血脂的苯并硫氮杂䓬 Download PDFInfo
- Publication number
- CN1059674C CN1059674C CN95196304A CN95196304A CN1059674C CN 1059674 C CN1059674 C CN 1059674C CN 95196304 A CN95196304 A CN 95196304A CN 95196304 A CN95196304 A CN 95196304A CN 1059674 C CN1059674 C CN 1059674C
- Authority
- CN
- China
- Prior art keywords
- phenyl
- benzothiazepine
- tetrahydrochysene
- ethyl
- butyl
- 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.)
- Expired - Fee Related
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- 210000004369 blood Anatomy 0.000 title description 6
- 239000008280 blood Substances 0.000 title description 6
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 title description 2
- 150000002632 lipids Chemical class 0.000 title description 2
- 230000002829 reductive effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 198
- 238000000034 method Methods 0.000 claims abstract description 61
- 238000002360 preparation method Methods 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- -1 methoxyl group Chemical group 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 230000035790 physiological processes and functions Effects 0.000 claims description 21
- 239000012453 solvate Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- KCPBOWHYNQITMZ-UHFFFAOYSA-N 3-butyl-3-ethyl-5-phenyl-2,4-dihydro-1,5-benzothiazepine Chemical compound C1C(CCCC)(CC)CSC2=CC=CC=C2N1C1=CC=CC=C1 KCPBOWHYNQITMZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- LUVVTXKGSGRAKA-UHFFFAOYSA-N 3,3-diethyl-5-phenyl-2,4-dihydro-1,5-benzothiazepine Chemical compound C1C(CC)(CC)CSC2=CC=CC=C2N1C1=CC=CC=C1 LUVVTXKGSGRAKA-UHFFFAOYSA-N 0.000 claims description 5
- HZLURQUSSCQKEY-UHFFFAOYSA-N 3,3-dimethyl-5-phenyl-2,4-dihydro-1,5-benzothiazepine Chemical compound C1C(C)(C)CSC2=CC=CC=C2N1C1=CC=CC=C1 HZLURQUSSCQKEY-UHFFFAOYSA-N 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
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- 230000000055 hyoplipidemic effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 96
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
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- 239000012141 concentrate Substances 0.000 description 16
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- 239000002253 acid Substances 0.000 description 14
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic 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)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 14
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 13
- 239000004380 Cholic acid Substances 0.000 description 13
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- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
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- 239000003826 tablet Substances 0.000 description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 235000012000 cholesterol Nutrition 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 210000002381 plasma Anatomy 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 6
- 239000002702 enteric coating Substances 0.000 description 6
- 238000009505 enteric coating Methods 0.000 description 6
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- 239000007864 aqueous solution Substances 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229920003136 Eudragit® L polymer Polymers 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004902 Softening Agent Substances 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
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- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
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Classifications
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- 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 System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
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- 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
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- 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
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- 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
- C07D417/04—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
- C07D513/00—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
- 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
- C07D513/04—Ortho-condensed systems
Abstract
本发明涉及通式(Ⅰ)的新降血脂化合物,涉及它们的制备方法和制备这类化合物的新中间体,涉及含它们的药物组合物,涉及它们在医学中的应用,特别是涉及它们在预防和治疗高血脂症和诸如动脉粥样硬化一类的相关疾病中的应用。
Description
本发明涉及新的降血脂的化合物、涉及它们的制备方法和制备它们的新的中间体、涉及含有它们的药物组合物以及涉及它们在医学上的应用,特别是涉及它们在预防和治疗高血脂症和诸如动脉粥样硬化一类的相关的疾病中的应用。
高血脂症经常与血浆中低密度脂肪蛋白(LDL)胆固醇的浓度升高有关,这类浓度可以通过减少吸收肠内的胆汁酸而降低。可以达到该目的的一个办法是通过抑制回肠末端的胆汁酸活化摄取体系。这种抑制可以刺激肝脏将胆固醇转化为胆汁酸,结果要求胆固醇产生的对应的LDL胆固醇从血浆或血清中的清除率增高。
已经鉴定了一类新的杂环化合物,这类化合物能够降低血浆或血清中LDL胆固醇的浓度,因而是特别有用的降脂药。通过降低血浆中胆固醇和胆固醇酯的浓度,本发明的化合物能够阻止动脉粥样硬化损伤的发生并降低与冠心病有关的疾病的发病率。后者被定义为与血浆或血清中胆固醇和胆固醇酯的浓度升高有关。
国际专利申请No.WO 93/16055描述了1,4-苯并硫氮杂化合物具有降低血脂的活性。现在发现了一组新的取代1,5-苯并硫氮杂化合物,它们也具有降低血脂的活性。
其中,R1和R2是相同的或不同的,并且各自为随意取代的C1-6烷基,C3-6环烷基,或R1和R2和与它们相连的碳原子一起形成随意取代的C3-6螺环烷基;
R4是C6-14芳基,或是C3-13杂芳基,这些基团均被1-8个取代基随意取代,这些取代基是相同的或是不同的,并各自选自卤素,羟基,硝基,苯基-C1-6烷氧基,C1-6烷氧基,随意取代的C1-6烷基,S(O)nR8,SO2NR8R9,CO2R8,O(CH2CH2O)nR8,OSO2R8,O(CH2)pSO3R8,O(CH2)pNR9R10和O(CH2)pN+R9R10R11,其中R8至R11是相同的或不同的,并各自独立选自氢或随意取代的C1-6烷基;其中p为1-4的整数;n为0-3的整数。
R5a,R5b,R5c和R5d各自为原子或基团,这些原子或基团可以是相同的或不同的,并且各自为氢,卤素,氰基,R8-乙炔化物,OR8,随意取代的C1-6烷基,COR8,CH(OH)R8,S(O)nR8,SO2NR8R9,P(O)(OR8)2,OCOR8,OCF3,OCN,SCN,NHCN,CH2OR8,CHO,(CH2)pCN,CONR9R10,(CH2)pCO2R8,(CH2)pNR9R10,CO2R8,NHCOCF3,NHSO2R8,OCH2OR8,OCH=CHR8,O(CH2CH2O)nR8,OSO2R8,O(CH2)pSO3R8,O(CH2)pNR9R10和O(CH2)pN+R9R10R11,其中R8至R11,n和p的定义与上面定义相同;或R5a和R5b,R5b和R5c,或R5c和R5d一起与和它们相连的环形成一个环基-O(CR9R10)mO-,其中R9和R10的定义与上面的定义相同,m是1或2;
R6和R7是相同的或不同的,并各自为氢,随意取代的C1-6烷基,C3-6环烷基,或R6和R7一起与它们相连的碳原子形成随意取代的C3-6螺环烷基;
X是CH2,C=O,C=S,或C=NR8,其中R8的定义与上面的定义相同;并且l为0-2的整数,本发明还提供了这类化合物的盐,溶剂化物或具有生理功能的衍生物。
合适的R1是C1-6烷基,优选的R1是甲基,乙基或正丙基,R1最好是乙基。
合适的R2是C1-6烷基,优选的R2是甲基,乙基,正丙基,正丁基或正戊基,R2最好是乙基或正丁基。
合适的R4是1-5个取代基随意取代的苯基,优选的R4是1至2个取代基随意取代的苯基,这些取代基是相同的或不同的,并各自选自卤素,羟基,硝基,苯基-C1-6烷氧基,C1-6烷氧基,随意取代的C1-6烷基,S(O)nR8,CO2R8,O(CH2CH2O)nR8,OSO2R8,O(CH2)pSO3R8,O(CH2)pNR9R10和O(CH2)pN+R9R10R11,优选的是卤素,羟基,硝基,苯基-C1-6烷氧基,C1-6烷氧基,或随意取代的C1-6烷基。优选的的R4是在3位和/或4位随意取代的苯基,取代基可以是卤素,羟基,甲基,乙基,甲氧基,乙氧基,三氟甲基,羟基,羧基或O(CH2)3SO3H。最优选的R4是未被取代的苯基或在3位和/或4位用卤素,羟基或C1-6烷氧基,例如甲氧基或乙氧基取代的苯基。
合适的R5a,R5b,R5c和R5d是相同的或不同的,并各自为氢,C1-4烷氧基,卤素,羟基或氟随意取代的C1-4的烷基。优选的R5a,R5b,R5c和R5d是相同的或不同的,并各自为氢,甲基,甲氧基,羟基,三氟甲基或卤素。更优选的R5a和R5d是氢,R5b和R5c是相同的或不同的,并各自为氢,C1-4烷氧基,卤素,羟基,或氟随意取代的C1-4的烷基。最优选的R5a和R5d是氢,R5b和R5c是相同的或不同的,并各自为氢,甲基,甲氧基,羟基,三氟甲基或卤素。
合适的R6和R7是相同的或不同的,并各自为氢或C1-6烷基,例如甲基或乙基,最优选的R6和R7都是氢。
合适的X是CH2或C=0。
合适的R9至R11是相同的或不同的,并各自为氢或甲基。
合适的1是0或2,并且优选的是2。
当R1,R2,R4至R11中1个或多个是取代的C1-6烷基时,或包括C1-6烷基时,这些取代基可以是相同的或不同的,并各自选自羟基,卤素,C1-6烷基,C1-6烷氧基,COR12,氰基,CO2R12,SO3R12,NR13R14,N+R13R14R15,其中R12至R15是相同的或不同的,并各自选自氢或C1-6烷基,优选甲基。
通式(I)进一步优选的化合物是:
(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;
(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-3-正丁基-2-异丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
3,3-二乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;
3,3-二乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物;
3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂;
3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
3,3-二甲基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;
3,3-二甲基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物;
3,3-二甲基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂;
3,3-二甲基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7,8-二甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
3,3-二乙基-2,3,4,5-四氢-7,8-二甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
3,3-二乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;
3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;
3,3-二乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;
(±)-7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
7-溴-3,3-二乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7,8-二醇-1,1-二氧化物;
3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7,8-二醇-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1-一氧化物;
3,3-二乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1-一氧化物;
(±)3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1-一氧化物;
3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1-一氧化物;
(±)-3-正丁基-3-乙基-2,3-二氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-4-酮;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-羟基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-7-溴-3-正丁基-3-乙基-2,3-二氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-4-酮;
(±)-7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7,8-二甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7,8-二醇-1,1-二氧化物;
(±)-7-溴-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;和
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7-醇-1,1-二氧化物;
特别优选的化合物包括:
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;和
(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-羟基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;
药物可以接受的盐特别适宜于在医学上应用,因为相对于母体化合物即碱性化合物,它们具有较高的水溶性。这些盐必须具有明确的药物可以接受的阴离子或阳离子。适合的药物可以接受的本发明的化合物的酸加合盐包括那些从无机酸衍生来的盐,例如从氯化氢,溴化氢,磷酸,偏磷酸,硝酸,磺酸和硫酸衍生的盐,以及从有机酸衍生来的盐,例如从乙酸,苯磺酸,苯甲酸,柠檬酸,乙磺酸,反式丁烯二酸,葡糖酸,乙醇酸,isothionic acid,乳酸,乳糖酸,顺式丁烯二酸,羟基丁二酸,甲磺酸,丁二酸,对甲苯磺酸,2,3-二羟基丁二酸和三氟乙酸衍生来的盐。盐酸盐特别适合于医学目标。合适的药物可以接受的碱的盐包括铵盐;碱金属盐,如钠盐和钾盐;碱土金属盐,例如镁盐和钙盐。具有非药物可以接受的阴离子盐作为制备或纯化药物可以接受的盐的有用中间体和/或作为非治疗应用,例如用于体外,仍属于本发明的范围。
“通式(I)的化合物”,“本发明的化合物”,“根据本发明的化合物”等的任何含义都是指上面描述的通式(I)的化合物加上它们的盐,它们的溶剂化物和上面定义的有生理功能的衍生物。
这里使用的“生理功能衍生物”术语是指任何生理上可以接受的本发明的化合物的衍生物,例如,一种酯,当给哺乳动物(如人)服用该酯时,可能直接或间接提供这类化合物或它们的活性代谢物。
本发明的另一个方面是本发明的化合物的前药。这些前药可能在体内代谢生成相应的本发明的化合物,这些前药从它自身的实情上看可以有活性,也可以没有活性。
本发明的化合物还可以不同的多形态的形式存在,例如,以非晶形和晶形的多形态形式存在。本发明的化合物的所有多形态的形式都属于本发明的范围,也是本发明的另一方面。
只要不作说明,这里使用的的术语“烷基”就是指一价的直链或支链基。类似地,只要不作说明,术语“环烷基”和“螺环烷基”是分别指二价环基和二价螺环基。术语“烷氧基”是指通过氧原子连接到母体分子残基上的一价直链或支链基。术语“芳基”是指一价的单环,双环或三环芳环。术语“杂芳基”是指一价的含有一个或多个杂原子(如氮、氧、硫)的单环,双环或三环芳环。术语“苯烷氧基”是指与二价C1-6亚烷基相连的一价苯基,该二价C1-6亚烷基本身通过氧原子与母体分子残基相连。术语“卤素”是指氟、氯、溴、或碘。
在通式(I)的化合物的存在形式中,定位于-C(R1)(R2)-和-C(R6)(R7)-中的碳可以是手性碳。在本发明的范围内包括每种可能的本质上不含其它光学异构体的光学异构体,即其它光学异构体的量应少于5%,包括一种或多种光学异构体按任何比例的混合物,包括外消旋体混合物。
如果-C(R1)(R2)-和-C(R6)(R7)-的绝对构型尚未确定,那么本发明的化合物就按R1/R2和R6/R7取代基的相对位置定义。其中大取代基,即两个较大质量的取代基处在硫氮杂环的同一侧的化合物这里指定为“顺式”,两个较大取代基处在硫氮杂环异侧的化合物称为“反式”。对专业人员来说应当是明显的,即本发明的“顺式”和“反式”两种化合物各自可以以按照偏振光通过化合物的样品时偏振光平面偏转的方向各自记作“(+)”或“(-)”的两种对映异构体存在。其中各对映异构体尚未拆分的本发明的顺式或反式化合物用前缀“(+-)”指定。
本发明还进一步提供了:
(a)通式(I)的化合物和它们的药物上可以接受的盐,溶剂化物及生理功能衍生物用作治疗剂,尤其是在临床的预防和治疗中用作胆酸摄入抑制剂,例如预防和治疗高血脂症和相关的疾病例如动脉粥样硬化;
(b)含通式(I)的化合物或一种它们的药物上可以接受的盐,溶剂化物或生理功能衍生物的药物组合物,该组合物至少含一种药物上可以接受的载体,以及随意地含一种或多种其它生理活性剂;
(c)使用通式(I)的化合物或它们的药物上可以接受的盐、溶剂化物或生理功能衍生物制备在临床预防和治疗中作为胆酸摄入抑制剂的药物,例如制备预防和治疗高血脂症以及相关的疾病例如动脉粥样硬化的药物;
(d)一种抑制哺乳动物例如人从肠胃道吸收胆酸的方法,该方法包括给哺乳动物服用有效量的一种抑制胆酸吸收的通式(I)的化合物或它们的药物上可以接受的盐,溶剂化物或生理功能衍生物;
(e)降低哺乳动物例如人的血浆或血清中LDL胆固醇浓度的方法,该方法包括给哺乳动物服用有效量的降低胆固醇的通式(I)的化合物,或它们的药物上可以接受的盐,溶剂化物或生理功能衍生物;
(f)降低哺乳动物例如人的血浆或血清中胆固醇和胆固醇酯浓度的方法,该方法包括给哺乳动物服用有效量的降低胆固醇和胆固醇酯的通式(I)的化合物,或它们的药物上可以接受的盐,溶剂化物或生理功能衍生物;
(g)增加哺乳动物例如人的胆酸粪便排泄的方法,该方法包括给哺乳动物服用有效量的增加胆酸粪便排泄的通式(I)的化合物或它们的药物上可以接受的盐,溶剂化物或生理功能衍生物;
(h)用胆酸摄入抑制剂在临床上预防或治疗哺乳动物例如人的疾病的方法,例如预防或治疗高血脂症和相关的动脉粥样硬化疾病,该方法包括给哺乳动物服用有效治疗量的通式(I)的化合物或它们的药物上可以接受的盐,溶剂化物或生理功能衍生物;
(i)降低哺乳动物例如人与冠心病相关的意外事件发病率的方法,该方法包括给哺乳动物服用有效量的降低冠心病相关意外事件发病率的通式(I)的化合物或它们的药物上可以接受的盐,溶剂化物或生理功能衍生物;
(j)降低哺乳动物例如人的血浆或血清胆固醇浓度的方法,该方法包括给哺乳动物服用有效量的降低胆固醇的通式(I)的化合物;
(k)制备通式(I)的化合物(包括这里定义的它们的盐,溶剂化物和生理功能衍生物)的方法;
(l)制备通式(I)的化合物的新的化学中间体;和
(m)后面描述的合成实施例1-27的化合物。
达到期待的生理效应所需的通式(I)的化合物的量当然取决于一系列因素,例如取决于选择的特定化合物,采取的用法,给药方式以及患者的病情,一般情况下,每天每公斤体重的剂量范围为0.001mg-100mg(典型的是0.01mg-50mg),例如0.01-10mg/kg/日。这样,口服的单位剂型,例如片剂或胶囊可以含例如0.1-100mg,典型地含0.1-10mg,最好含0.1-5mg。使用它们的药物上可以接受的盐时,上面给出的重量是指从盐中衍生出的苯并硫氮杂离子的重量。
为预防或治疗上面指出的疾病,虽然可以单独使用通式(I)的化合物,但最好是通式(I)的化合物与一种可以接受的载体一道以药物组合物的形式使用。从与组合物的其它辅料可比的意义上说,这类载体当然必须是可以接受的,而且对患者必须无害。载体可以是固体或液体,或两种同时使用,最好与化合物作为单位剂型组合物配方,例如作为片剂配方,该片剂可以含有活性化合物(按重量计)的0.05%-95%载体。其它药理活性化合物,包括通式(I)的其它化合物亦可存在。可以使用本质上由混合化合物构成的任何以已知制剂技术制备本发明的药物组合物。
虽然在任何给定的条件下最适合的给药途径将取决于治疗的疾病的性质和严重程度,取决于使用的通式(I)特定的化合物的性质,但本发明的药物组合物包括适于口服,直肠,局部,口腔(例如舌下)和非肠道(例如皮下,肌肉,真皮内或静脉)给药的组合物。肠溶包衣和肠溶包衣控释剂型也包括在本发明的范围内。适宜的肠溶包衣包括醋酸-邻苯二甲酸纤维素,聚醋酸-邻苯二甲酸乙烯酯,邻苯二甲酸羟丙基甲基纤维素和甲基丙烯酸和甲基丙烯酸甲酯的阴离子型共聚物。适宜的肠溶包衣和肠溶包衣控释剂型包括片剂和胶囊。
适于口服给药的药物组合物可以是分离的剂型,例如胶囊剂,扁囊剂,锭剂,或片剂,各含预定量的通式(I)的化合物;可以是粉剂或颗粒剂;可以是溶液剂或水性或非水性液体的悬浮液;或为水包油或油包水的乳浊液。正如指出的那样,这类组合物可以按照任何适宜的制剂方法制备,包括将活性化合物与载体(可以由一种或多种附加成分构成)联合的步骤。一般来说,制备组合物时,将活性化合物与液体或精细粉碎的固体载体或同时与二者均匀地紧密地混合,必要时然后可以将产品成形。例如制备片剂时,可以将化合物的粉末或颗粒随意与一种或多种辅加成分经压或模印制备。压片可以使用适宜的压片机将自由流动型的化合物例如粉末或颗粒随意与黏合剂,润滑剂,惰性稀释剂和/或表面活性剂/分散剂混合压片。模印片可以使用适宜的模印机将粉状化合物用惰性液体稀释剂湿润后进行模印。可以按照相同的方式并加羟丙基甲基纤维素制备控释片。
制备肠溶包衣片时可以将片剂用肠溶高聚物,例如用醋酸-邻苯二甲酸纤维素,聚醋酸-邻苯二甲酸乙烯酯,邻苯二甲酸羟丙基甲基纤维素或甲基丙烯酸和甲基丙烯酸甲酯的阴离子型共聚物(Eudragit LTM)包衣。除Eudragit L外,这些高聚物还应包括10%(按使用的高聚物的重量计)的增塑剂,以便防止在使用或保存中发生裂膜。适宜的增塑剂包括邻苯二甲酸二乙酯,柠檬酸三丁酯和甘油三醋酸酯。
制备肠溶包衣控释片时,可以用肠溶高聚物,例如用醋酸-邻苯二甲酸纤维素,聚醋酸-邻苯二甲酸乙烯酯,邻苯二甲酸羟丙基甲基纤维素或甲基丙烯酸和甲基丙烯酸甲酯的阴离子型共聚物(Eudragit L)将控释片包衣。除Eudragit L外,这些高聚物还应包括10%(按使用的高聚物的重量计)的增塑剂,以便防止在使用或保存中发生裂膜。适宜的增塑剂包括邻苯二甲酸二乙酯,柠檬酸三丁酯和甘油三醋酸酯。
制备胶囊时,可以通过将通式(I)的化合物与例如硬脂酸镁,非胶凝性淀粉,淀粉乙醇酸钠,和/或硬脂酸镁混合,生成的混合物装入分成两部分的硬质明胶胶囊。
制备控释的胶囊组合物时,可将通式(I)的化合物与例如微晶纤维素和/或乳糖混合,用挤压器挤压,然后将挤压物进行球状化并干燥。干丸用控释膜包衣,例如用乙基纤维素包衣,然后装入分成两部分的硬质明胶胶囊。
制备肠溶胶囊组合物时,可将通式(I)的化合物与例如微晶纤维素和/或乳糖混合,用挤压器挤压,然后将挤压物进行球状化并干燥。干丸用肠溶膜包衣,例如用含增塑剂例如邻苯二甲酸二乙酯的醋酸-邻苯二甲酸纤维素包衣,然后装入分成两部分的硬质明胶胶囊。
适合于口腔(舌下)给药的药物组合物包括含存在于芳香基质中的通式(I)的化合物的锭剂和存在于明胶和甘油或蔗糖和金合欢胶一类惰性基质中的芳香薰剂。
适合于肠道外给药的药物组合物适宜地包括由通式(I)的化合物制备的灭菌水剂最好是与患者的血液等渗的灭菌水剂。虽然皮下给药,肌肉给药或真皮内注射也有效,但最好是静脉给药。制备这类剂型时,可以适宜地将化合物与水混合,得到的溶液然后进行灭菌并配成与血液等渗。本发明的可以注射的组合物按重量计算一般含0.1-5%的活性化合物。
适合于直肠给药的药物组合物最好以单剂量的栓剂存在。制备时可将通式(I)的化合物与一种或多种适宜的固体载体混合,例如与可可油混合,然后将得到的混合物成形。
也可能透皮给药。适合于透皮给药的药物组合物可以作为适宜于长期与患者的表皮紧密接触的分离的药胶存在。这类药膏适当地含有存在于随意缓冲的水溶液中的活性化合物,并溶解和/或分散于一种粘附物或分散到一种高聚物中。活性化合物的适宜的浓度为大约1%至35%,最好是大约3%至15%。作为一种特殊的可能性,活性化合物可以通过电荷转移或电离子透入从药膏中释放,例如见于PharmaceuticalResearch,3(6),318(1986)。
通式(I)的化合物可以按照专业人员熟知的方法制备或按照与文献类似的方法制备。
例如其中l为0,R6和R7为氢,X为CH2的通式(I)的化合物可以通过将通式(II)的化合物的羰基还原来制备,
其中R1,R2,R4,和R5a,b,c,d的定义同前,还原剂为例如氢化铝(AlH3),氢化二异丁基铝(DIBAL)或硼烷(BH3),还原反应在适宜的有机溶剂中例如在THF中进行。
这里按前面定义的通式(II)的化合物是新化合物,并构成了本发明的另一个方面。
通式III的化合物在碱存在下,例如在碳酸钾(K2CO3)的存在下,并随意地在碘化铜(CuI)一类的催化剂存在下与适宜的R4-Z反应,其中R4的定义同前,Z为适宜的离去基,例如为卤素可制备通式(II)的化合物
在通式(III)中,R1,R2,和R5a,b,c,d的定义同前。R4-Z一般可买到或者可以按文献中的已知方法制备或者专业人员容易得到。
这里按前面定义的通式III的化合物为新化合物,并构成了本发明的另一个方面。
通式(IV)的化合物与酸反应,例如与甲苯磺酸(tosic acid)一类的有机酸反应进行环化可制得通式(III)的化合物,反应温度最好是高温,例如为255℃。
通式(IV)中,R1,R2,和R5a,b,c,d的定义同前。
R1,R2,和Ra,b,c,d的定义同前,Z为适宜的离去基,例如为卤素。通式(V)和(Va)的化合物或可以买到,或可按已知的方法制备,或对于专业人员是容易得到的。
其中l为1或2的通式(I)的化合物,可以由对应的其中l为0的通式(I)的化合物使用适宜的氧化剂,例如使用过氧化氢,有机过氧酸,Oxone(过氧化单硫酸钾),或四氧化锇(OsO4)将硫氧化制备。
其中R6和/或R7不为氢的通式(I)的化合物可以通过用碱,例如用正丁基锂处理其中l′为1或2,R6和R7为氢的对应的通式(I)的化合物,然后与适宜的R6-Z或R7-Z反应制备,其中这里定义的R6和R7不为氢,这里的定义的Z为适宜的离去基。
在通式(VII)中,R1,R2,和R5a,b,c,d的定义同前。
通式(VIII)的化合物在酸存在下例如在硫酸(H2SO4)存在下环化可以制备通式(VII)的化合物,在通式(VIII)中,R1,R2,和R5a,b,c,d的定义同前。
在通式(IX)中,R5a,b,c,d的定义同前。
通式(IX)的化合物或者可以买到,或者可按照已知方法制备,或者专业人员容易得到。
由通式(XI)的化合物与通式(Va)的化合物按类似于制备通式(IV)的化合物的方法可以制得通式(X)的化合物,在通式(XI)中,R4,和R5a,b,c,d的定义同前。
通式(XI)的化合物可按照已知方法制备,例如按照H.Gilman和J.Dietrich发明的方法制备,见于J,Am.Chem.Soc.,80,380-383(1958)。
其中X为C=O的通式(I)的化合物可以按前面描述的制备通式(II)的化合物的方法制备。
其中X为C=S的通式(I)的化合物可以由对应的其中X为C=O的通式(I)的化合物通过用Lawesson’s试剂(2,4-双(4-甲氧苯基)-1,3-二硫代-2,4-diphosphetane-2,4-二硫醚)将C=O残基转化制得。
本质上不含别的光学异构体的通式(I)的化合物或者通过手性合成,例如使用适宜的手性原料例如通式(Va)的手性化合物进行合成,或通过拆分非手性合成得到的产物来制备,例如通过手性HPLC分离,通过酶拆分,或用手性酸进行经典的拆分。
通式(I)的化合物或含碱性取代基的通式(I)的化合物与适宜的酸溶液反应,例如与前面引述的酸反应,可以随意有效地转化为对应的酸加合盐。含酸性取代基的通式(I)的化合物与适宜的碱溶液反应,例如与氢氧化钠反应可以随意有效地转化为对应的碱盐。按照专业人员熟知的方法或化学文献中可以参考的方法,通式(I)的化合物可随意转化为生理功能的衍生物,例如转化为酯。
此外,通过标准方法或专业人员从文献中可以找到的方法,例如将羟基烷基化可将通式(I)的化合物转变为通式(I)的不同的化合物。
为更好地理解本发明,给出下面的实施例对本发明进行解释,但决不限制本发明的范围。
一般方法。
用300MHz仪器测定1HNMR。MS使用LCMS在大气压化学电离(APCI)条件下测定,或由Oneida Research Services,Inc测定,在化学电离(CI)条件下用甲烷作载气。元素分析由Atlantic Microlab,Inc测定。所有反应都在氮气保护下完成。TLC板为Whatman MK6F硅胶60板,而且在紫外灯下可见。用EM Science silica Gel 60(230-400目)进行柱层析。只要不加指明,化学试剂都是购自Aldrich Chemical CO,而且不经纯化直接使用。溶剂为Aldrich的无水溶剂。实施例1(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮的制备(a)(±)-2-((叔丁基二甲基硅)氧基)甲基-乙基-己醇
往60%的NaH(7.5g,187.2mmol)与400mlTHF的泥浆中分三次加2-正丁基-2-乙基-1,3-丙二醇(30.0g,187.2mmol),搅拌45分钟。往得到的胶体中加叔丁基二甲基氯硅烷(28.2g,187.2mmol)并搅拌2小时。蒸发除去溶剂,残留物用水和乙醚分配,乙醚层用碳酸氢钠水溶液和饱和食盐水洗涤并浓缩。柱层析(5%乙酸乙酯/石油醚)得到无色油状物的标题化合物(50.12g,182.6mmol,98%)。
1H NMR(DMSO-d6)δ4.19(t,1H);3.29(s,2H);3.13(d,2H);1.15(m,8H);0.84(s,9H);0.83(t,3H);0.73(t,3H);-0.01(s,6H).MS Da/e=275(MH+)C15H34O2Si:计算值:C,65.63;H,12.48;实测值:C,65.87;H,12.47。(b)(±)-2-乙基-2-(羟甲基)-己酸
实施例1(a)的产物(4.43g,16.0mmol)溶解在16mlCCl4,16mlCH3CN和24ml水中,往该溶液中加NaIO4(13.69g,64mmol)和RuCl3(0.16g,0.8mmol),并搅拌16小时。该泥浆浓缩除去溶剂,残留物用水和CH2Cl2分配,水相用CH2Cl2萃取三次,有机相干燥,浓缩。残留物溶解于3ml的THF中,加入1M的氟化四丁基铵的THF溶液(1.75ml,1.75mmol),该溶液搅拌1小时。蒸发除去溶剂,得到的油状物用水和CH2Cl2分配。水相用CH2Cl2萃取三次,有机相干燥后浓缩。柱层析(95%CH2Cl2/4%MeOH/0.5%水/0.5%醋酸)得到油状产物2.26g(13.0mmol,81%)。
1H NMR(DMSO-d6)δ 11.95(br s,1H);4.74(br s,1H);3.42(s,2H);1.53-1.03(m,8H);0.84(t,3H);0.73(t,3H).MS Da/e=175(MH+)and 129(M-CO2H)C9H18O3,计算值:C,62.04;H,10.41。实测值:C,61.94;H,10.44。(c)(±)-2-(溴甲基)-2-乙基-己酸
实施例1(b)的产物(2.30g,13.2mmol)溶解在48%的HBr(40ml)中,回流20小时。冷却到室温后将溶液转移到分液漏斗中,用乙酸乙酯萃取三次,用Na2SO4干燥后浓缩。在高真空下吸去痕量的HBr后得到标题化合物(2.46g,10.4mmol,79%)。
1H NMR(DMSO-d6)δ3.60(s,2H);1.62-1.04(m,8H);0.85(t,3H);0.75(t,3H).MS Da/e=157(M-Br),237(M),238,239(M+2).C9H17O2Br计算值:C,45.59;H,7.23;Br,33.70。实测值:C,46.27;H,7.17;Br,32.94。(d)(±)-2-(((2-氨基苯基)硫代)甲基)-2-乙基己酸
实施例1(c)的产物(0.52g,2.19mmol)溶解在THF(4ml)中,并加入2-氨基硫代苯酚(0.41g,3.29mmol,新蒸馏的)和吡咯烷(或三乙胺,3.29mmol),搅拌48小时。将反应混合物转移到分液漏斗中用水和氯仿分配,水层用氯仿萃取三次。柱层析(30%乙酸乙酯的石油醚溶液)得到标题化合物(0.50g,1.78mmol,81%)。1H NMR(DMSO-d6)δ12.40(br s,1H);7.25(d,1H);7.00(t,1H);6.67(d,1H);6.48(t,1H);5.23(br,s,2H);2.91(s,2H);1.66-0.99(m,8H);0.77(t,3H);0.67(t,3H).MS Da/e=282(MH+),264(M-H2O),236(M-CO2H);C15H23NSO2x(0.8乙酸乙酯)计算值:C,62.12;H,8.42;N,3.98;S,9.11。实测值:C,62.41;H,8.28;N,3.83;S,8.91。(e)(±)-3-正丁基-3-乙基-2.3-二氢-1.5-苯并硫氮杂-4-酮
实施例1(d)的产物(0.66g,2.35mmol)和对甲苯磺酸(0.15g,0.79mmol)溶解在十四烷(30ml)中,回流3小时。冷却到室温后,反应混合物直接装到硅胶柱上,用10%乙酸乙酯/石油醚洗脱产品,得到标题化合物(0.44g,167mmol,71%)。 M.P.=90.0℃.1H NMR(DMSO-d6)δ9.71(s,1H);7.39(d,1H);7.23(t,1H);7.10(d,1H);6.95(t,1H);2.92(s,2H);1.72-1.20(m,4H);1.15(m,4H);0.78(m,6H).MS Da/e=264(MH+).C15H21NSO计算值:C,68.40;H,8.40;N,5.32;S,12.17。实测值:C,68.25;H,8.11;N,5.29;S,12.09。(f)(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮
往实施例1(e)的产物(4.07g,15.45mmol)的碘苯(17ml,154mmol)的溶液中加入碘化铜(0.28g,1.5mmol)和碳酸钾(2.13g,15.45mmol),混合物回流16小时。反应混合物冷却后直接装硅胶柱,用5%乙酸乙酯/石油醚洗脱得到标题化合物(5.14g,15.14mmol,98%收率)。
M.P.=159.4℃.1H NMR(DMSO-d6)δ7.67-6.86(m,9H);3.11(s,2H);1.58-1.13(m,8H);0.77(m,6H).MS Da/e=340(MH+).C21H25NSO计算值:C,74.30;H,7.42;N,4.13;S,9.44。实测值:C,74.11;H,7.49;N,4.03;S,9.36。实施例2(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物的制备
实施例1(f)的产物(0.95g,2.80mmol)的三氟乙酸(9.5ml)溶液在0℃加入30%的过氧化氢(1.60g,14mmol)搅拌16小时。溶液用碳酸钠溶液中和,产品用乙酸乙酯萃取三次,有机相用Na2SO4干燥后浓缩,得到的油状物直接装上硅胶柱,用20%乙酸乙酯/石油醚洗脱产品,得到标题化合物为白色粉末。(0.96g,2.58mmol,92%)。
M.P.=57.6℃.1H NMR(DMSO-d6)δ7.94-7.06(m,9H);3.73(s,2H);1.72-
0.98(m,8H);0.77(m,6H).MS Da/e=372 (MH+).C21H25NSO3计算值:C,67.90;H,6.78;N,3.77;S,8.63。实测值:C,67.61;H,6.92;N,3.62;S,8.57。实施例3(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂的制备
在0℃下往AlH3(44mmol,用硫酸(22mmol)和LiAlH4(44mmol)原地产生)的乙醚(44ml)溶液中加入实施例1(f)的化合物(5.00g,14.60mmol)的THF(40ml)溶液。将反应混合物升温到室温,升温时间2小时,并在室温下搅拌15小时,TLC(20%乙酸乙酯/石油醚)显示反应完全。反应瓶冷至0℃,先滴加30份体积滴水/THF 1∶2溶液,随后加5ml 1M NaOH破坏过量的AlH3。混合物转移到分液漏斗中,用乙醚萃取三次,合并乙醚萃取液,干燥,浓缩。柱层析(石油醚)得到标题化合物(4.74g,14.55mmol,99%)。
1H NMR(DMSO-d6)δ7.26-6.69(m,9H);3.67(br s,2H);2.78(m,2H);1.21-1.05(m,8H);0.71(m,6H).MSDa/e=325(M+),326(MH+).C21H27NS计算值:C,77.49;H,8.36;N,4.30;S,9.85。实测值:C,77.51;H,8.40;N,4.31;S,9.73。实施例4(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
实施例3的化合物(4.73g,.14.53mmol)溶解在100ml THF和23ml叔丁醇中,再加入N-甲基-吗啉-N-氧化物(5.1g,43.6mmol)和四氧化锇[0.8mmol,2.5%的2-甲基-2-丙醇溶液(重量百分比)]。混合物在室温搅拌16小时,然后加入50ml NaHCO3溶液中和任何酸。混合物转移到分液漏斗中用乙酸乙酯萃取三次,有机相用连二亚硫酸钠和饱和食盐水洗涤,用Na2SO4干燥后浓缩。柱层析(10%乙酸乙酯/石油醚)得到标题化合物(4.76g,13.3mmol,92%的收率)。
1H NMR(DMSO-d6)δ7.87-6.81(m,9H);3.72(m,
2H);3.33(s,2H);1.55-0.97(m,8H);0.69(m,6H).MS Da/e=358(MH+).C21H27NSO2计算值:C,70.55;H,7.61;N,3.92;S,8.97。实测值:C,70.37;H,7.59;N,3.84;S,9.07。实施例5(±)-3-正丁基-2-异丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
在-78℃将实施例4的化合物(0.565g,1.58mmol)溶解在10ml THF中,再加入正丁基锂(2.5M/THF,1.74mmol)。在-78℃搅拌20分钟后滴加碘代-2-甲基丙烷(1.3M/THF,6.32mmol)。反应混合物恢复到0℃并搅拌16小时。加入饱和食盐水(10ml)破坏过量的碱,产物用乙醚(3×20ml)萃取。乙醚萃取液干燥,浓缩,残留物上硅胶柱,用10%乙酸乙酯/石油醚洗脱产品得到黄色油状物(0.48g,1.16mmol,74%)。
1H NMR(DMSO-d6)δ7.89-6.80(m,9H);3.30(br m,2H);3.09(br s,1H);1.88-0.63(m,23H).MS Da/e=414(MH+),436(M+Na).)Calcdfor C25H35NSO2:C,72.60;H,8.53;N,3.39;S,7.75.Found:C,72.39;H,8.56;N,3.27;S,7.88.C25H35NSO2计算值:C,72.60;H,8.53;N,3.39;S,7.75。实测值:C,72.39;H,8.56;N,3.27;S,7.88。实施例63,3-二乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮的制备(a)2-((叔丁基二甲基硅)氧基)甲基-2-乙基丁醇
根据实施例1(a)的方法从2,2-二乙基-1,3-丙二醇制得标题化合物。
1H NMR(DMSO-d6)δ 4.20(t,1H);3.29(s,2H);3.14(d,2H);1.13(q,4H);0.84(s,9H);0.73(t,6H);0.73(t,3H);-0.01(s,6H).MS Da/e=247(MH+).C13H30O2Si计算值:C,63.35;H,12.26。实测值:C,63.27;H,12.25。(b)2-乙基-2-(羟甲基)-丁酸
用实施例1(b)的方法从实施例6(a)的产物(41.28g,189mmol)制备标题化合物(24.4g,167mmol,88%收率)。
1H NMR(DMSO-d6)δ3.42(s,2H);1.89(s,1H);1.44(q,4H);0.73(t,6H).MS Da/e=147(MH+).C7H14O3×0.3(乙酸)计算值:C,55.39;H,9.33。实测值:C,55.38;H,9.17。(c)2-(溴甲基)-2-乙基-丁酸
根据实施例1(c)的方法从实施例6(b)的产物(22.2g,151mmol)制备标题化合物,减压除去HBr后得到10B(19.8g,94.7mmol,63%)。
1H NMR(DMSO-d6)δ3.60(s,2H);1.58(q,4H);0.75(t,3H).MS Da/e=209(M),211(M+2).C7H13O2Br计算值:C,40.21;H,6.27,Br,38.21。实测值:C,40.92;H,6.38,Br,37.17。(d)2-(((2-氨基苯基)硫代)甲基)-2-乙基丁酸
根据实施例1(d)的方法从实施例6(c)的化合物(19.7g,94mmol)制得标题化合物,柱层析得到产物(9.77g,40mmol,43%)。
1H NMR(DMSO-d6)δ7.24(d,1H);7.00(t,1H);6.69(d,1H);6.49(t,1H);2.91(s,2H);1.60(q,4H);0.68(t,3H).MS Da/e=254(MH+).C13H19NSO2计算值:C,61.62;H,7.57;N,5.52;S,12.65。实测值:C,61.34;H,7.62;N,5.33;S,12.40。(e)3,3-二乙基-2,3-二氢-1,5-苯并硫氮杂-4-酮
按照实施例1(e)的方法,用实施例6(d)的产物(9.7g,38mmol)热关环制备标题化合物。经柱层析(50%乙酸乙酯/石油醚)得标题化合物(6.22g,26.4mmol,70%的收率)。
1HNMR(DMSO-d6)δ9.73(s,1H);7.40(d,1H);7.23(t,1H);7.10(d,1H);6.97(t,1H);2.92(s,2H);1.71-1.48(m,4H);0.76(m,6H).MS Da/e=236(MH+).C13H17NSO计算值:C,66.34;H,7.28;N,5.95;S,13.67。实测值:C,66.34;H,7.37;N,5.96;S,13.58。(f)3,3-二乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮
按照实施例1(f)的方法,实施例6(e)的化合物(5.40g,23mmol)N-苯基化后经柱层析得标题化合物(7.04g,22.6mmol,99%的收率)。
M.P.=86.4℃.1H NMR(DMSO-d6)δ7.66-6.87(m,9H);3.09(s,2H);1.45(m,4H);0.76(m,6H).MS Da/e=312(MH+).C19H21NSO计算值:C,73.21;H,6.79;N,4.49;S,10.29。实测值:C,73.36;H,6.90;N,4.49;S,10.42。实施例73,3-二乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物的制备
按照实施例2的方法,实施例6(f)的化合物(2.00g,6.4mmol)氧化成砜后经柱层析(50%乙酸乙酯/石油醚)得标题化合物(1.92g,5.59mmol,88%的收率)。
M.P.=163.0-165.6℃.1H NMR(DMSO-d6)δ7.94-7.07(m,9H);3.72(s,2H);1.80-1.22(brm,4H);0.76(m,6H).MS Da/e=344(MH+),366(M+Na+)C19H21NSO3计算值:C,66.44;H,6.16;N,4.07;S,9.33。实测值:C,66.22;H,6.21;N,4.06;S,9.42。实施例83,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂的制备
按照实施例3的方法,实施例6(f)的化合物(2.43g,7.80mmol)还原后经柱层析(20%乙酸乙酯/石油醚)得标题化合物(2.01g,6.76mmol,87%的收率)。
1HNMR(DMSO-d6)δ7.29-6.71(m,9H);3.65(br s,2H);2.77(s,2H);1.36-1.15(m,4H);0.67(m,6H).MS Da/e=298(MH+).C19H23NS计算值:C,76.71;H,7.79;N,4.70;S,10.77。实测值:C,76.64;H,7.82;N,4.69;S,10.72。实施例93,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
按照实施例4的方法,实施例8的化合物(0.53g,1.80mmol)氧化后经柱层析(50%乙酸乙酯/石油醚)得标题化合物(0.55g,1.67mmol,93%的收率)为黄色固体。
M.P.=128.0-130.2℃.1H NMR(DMSO-d6)δ7.88-6.84(m,9H);3.73(br s,2H);3.32(s,2H);1.55-1.30(m,4H);0.68(m,6H).MS Da/e=330(MH+),352(M+Na+).C19H23NSO2计算值:C,69.27;H,7.04;N,4.25;S,9.73。实测值:C,69.06;H,7.16;N,4.16;S,9.56。实施例103,3-二甲基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮的制备(a)溴代新戊酸
用实施例1(c)的方法,从羟基新戊酸(美国TCI,50.0g,423mmol)制备标题化合物,在高真空下除去HBr后得产物(66.42g,367mmol,87%的收率)。
1H NMR(DMSO-d6)δ12.3(br s);3.57(s,2H);1.19(s,6H).MS Da/e=181(M),183(M+2)C5H9O2Br计算值:C,33.17;H,5.01;Br,44.13。实测值:C,34.07;H,5.08;Br,42.45。(b)2-(((2-氨基苯基)硫代)甲基)-2-甲基丙酸
根据实施例1(d)的方法,溴新戊酸(实施例10(a))(59.4g,328mmol)与2-氨基硫代苯酚(41g,328mmol,新蒸馏)反应,经柱层析后得标题化合物(52.3g,232mmol,71%)
1HNMR(DMSO-d6)δ12.44(br s,1H);7.22(d,1H);6.99(t,1H);6.63(d,1H);6.47(t,1H);5.27(br s,2H);2.88(s,2H);1.14(s,6H).MS Da/e=226(MH+),208(M-H2O),180(M-CO2).C11H15NSO2计算值:C,58.64;H,6.71;N,6.22;S,14.23。实测值:C,58.41;H,6.78;N,6.13;S,14.29。(c)3,3-二甲基-2,3-二氢-1,5-苯并硫氮杂-4(5H)-酮
按照实施例1(e)的方法,实施例10(b)的化合物(33.4g,148mmol)热关环制备标题化合物,经柱层析(25%乙酸乙酯/石油醚)得标题化合物(25.39g,122mmol,83%的收率)。
M.P.=112.6℃.1H NMR(DMSO-d6)δ9.71(s,1H);7.40(d,1H);7.23(t,1H);7.11(d,1H);6.96(t,1H);2.95(s,2H);1.18(s,6H).MS Da/e=208(MH+).C11H13NSO计算值:C,63.74;H,6.32;N,6.76;S,15.47。实测值:C,63.94;H,6.37;N,6.56;S,15.28。(d)3,3-二甲基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮
按照实施例1(f)的方法,实施例10(c)的化合物(22.0g,106mmol)N-苯基化后经柱层析得标题化合物(28.69g,101mmol,96%的收率)。
M.P.=103.8℃.1HNMR(DMSO-d6)δ7.68-6.88(m,9H);3.19(s,2H);1.05(s,6H).MS Da/e=284(MH+),306(M+Na+).C17H17NSO计算值:C,72.05;H,6.05;N,4.94;S,11.31。实测值:C,71.85;H,6.13;N,4.85;S,11.26。实施例113,3-二甲基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物的制备
按照实施例2的方法,实施例10(d)的化合物(8.69g,30.7mmol)氧化后经柱层析,烘箱干燥,得白色粉末样产物(8.80g,27.9mmol,91%的收率)。
M.P.=140.8℃.1H NMR(DMSO-d6)δ7.95-7.04(m,9H;3.81(s,2H);1.10(s,6H).MS Da/e=316(MH+),338(M+Na+).C17H17NSO3×(0.5水)计算值:C,62.94;H,5.59;N,4.32;S,9.88。实测值:C,62.98;H,5.28;N,4.26;S,9.68。实施例123,3-二甲基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂的制备
按照实施例3的方法,实施例11的化合物(8.88g,31.05mmol)还原后得到的产物经柱层析(5%乙酸乙酯/石油醚)得黄色油状物(8.02g,29.77mmol,96%的收率)。
1HNMR(DMSO-d6)δ7.44-6.68(m,9H);3.31(br s,2H);2.65(s,2H);0.93(s,6H).MSDa/e=270(MH+).C17H19NS计算值:C,75.79;H,7.11;N,5.20;S,11.90。实测值:C,75.82;H,7.06;N,5.28;S,11.86。实施例132,3,4,5-四氢-3,3-二甲基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
按照实施例4的方法,实施例12的化合物(5.66g,21.01mmol)氧化后经柱层析(20%乙酸乙酯/石油醚)得白色粉末(5.56g,18.45mmol,88%的收率)。
M.P.=168.0-168.6℃.1H NMR(DMSO-d6)δ7.92-6.83(m,9H);3.66(br s,2H);3.33(s,2H);1.03(s,6H).MS Da/e=302(MH+),324(M+Na+).C17H19NSO2计算值:C,67.75;H,6.35;N,4.65;S,10.65。实测值:C,67.85;H,6.44;N,4.68;S,10.71。实施例14(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮的另一种制备方法(a)2-苯胺基苯硫醇
根据H.Gilman and J.Dietrich,J.Am.Chem.Soc.80(1958)pp.380-383中的方法制备标题化合物。往吩噻嗪(10.0g,50.2mmol)与50ml THF溶液中加入锂条(2.0g,288mmol),加锂条时间为45分钟。混合物搅拌1小时以后,吸去溶液中未反应的锂,转至分液漏斗中用水和乙醚分配,产物用4N NaOH萃取,从乙醚层收集未反应的吩噻嗪(4.02g,20mmol,40%)。碱水溶液层中和至pH4,用乙醚萃取3次,乙醚层干燥,浓缩,残留物层析纯化(5%乙酸乙酯/石油醚)得标题化合物(5.49g,27.3mmol,55%的收率)。
1H NMR(DMSO-d6)δ7.65-6.74(m,9H).MS Da/e=202(MH+).C12H11NS计算值:C,71.61;H,5.51;N,6.96;S,15.93。实测值:C,71.66;H,5.46;N,6.92;S,15.90。(b)(±)-2-(((2-苯胺基苯基)硫代)甲基)-2-乙基己酸
根据实施例1(d)的方法,通过实施例14(a)的化合物(3.06g,15.2mmol)与实施例1(c)的化合物(3.50g,15.0mmol)反应制备标题化合物。经柱层析(50%乙酸乙酯/石油醚)得标题化合物(3.70g,10.4mmol,70%)。
1H NMR(DMSO-d6)δ 12.48(br s,1H);7.46-6.83(m,9H);3.01(s,2H);1.55-1.03(m,8H);0.73(m,6H).MS Da/e=358(MH+).C21H27NSO2计算值:C,70.55;H,7.61;N,3.91;S,8.96。实测值:C,70.61;H,7.62;N,3.85;S,8.88。(c)(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮
使用实施例1(e)的方法进行实施例14(b)化合物(0.59g,1.65mmol)的关环反应,得到标题化合物(0.17g,0.51mmol,31%的收率)。1HNMR(DMSO-d6)与上面描述的实施例1(f)的产物一致。实施例15(±)-3-正丁基-3-乙基-2,3-二氢-8-甲氧基-5-苯基-1.5-苯并硫氮杂-4-酮的制备(a)2-氨基-5-甲氧基硫代苯酚
2-氨基-6-甲氧基苯并噻唑(36g,200mmol;Aldrich Chemical Co.)和400ml 30%的氢氧化钾水溶液回流16小时,黑色溶液冷却至0℃,然后用50%醋酸水溶液中和至pH6并搅拌1小时。过滤得到的浆状物,从滤纸上收集产品并干燥(25.29g,81%的收率)。
1H NMR(DMSO-d6)δ6.91-6.44(m,3H),5.90(br s,2H),3.52(s,3H).MS Da/e=154(M-H).(b)(±)-3-正丁基-3-乙基-2,3-二氢-8-甲氧基-1,5-苯并硫氮杂-4(5H)-酮
实施例1(c)的化合物(25.1g,105.8mmol)溶解在150ml二甲基甲酰胺后加入实施例15(a)的化合物(13.7g,88.2mmol)和13ml三乙胺。混合物搅拌过夜,然后转移至装有200ml水的分液漏斗内。用0.1N HCl调pH至4,产物用6×50ml乙醚萃取,合并萃取液,干燥,蒸发除去溶剂得到粘稠的油。该粘稠的油中加入200ml十四烷和825mg对甲苯磺酸,混合物回流1.5小时。冷却反应混合物并装入硅胶柱中,用20%乙酸乙酯/石油醚洗脱得产品(15.15g,59%的收率)。
1H NMR(DMSO-d6)δ9.51(s,1H);7.96-6.81(m,3H);3.70(s,3H);2.94(S,2H);1.71-1.39(m,4H);1.19-1.13(m,4H);0.79(t,3H);0.74(t,3H).MS Da/e=294(MH+)C16H23NSO2计算值:C,65.49;H,7.90;N,4.77;S,10.93。实测值:C,65.39;H,7.94;N,4.80;S,10.85。(c)(±)-3-正丁基-3-乙基-2.3-二氢-8-甲氧基-5-苯基-1.5-苯并硫氮杂-4-酮
用实施例1(f)的方法,实施例15(b)的化合物(11.0g,37.5mmol)与碘苯反应得到产物(13.07g,94%的收率)。
1H NMR(DMSO-d6)δ7.54-6.79(m,8H);3.75(s,3H);3.11(s,2H);1.51-1.13(m,8H);0.77(m,6H).MS Da/e=370(MH+).C22H27NSO2×0.75水计算值:C,68.99;H,7.50;N,3.66;S,8.35。实测值:C,68.95;H,7.14;N,3.63;S,8.25。实施例16(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂的制备
用实施例3的方法,实施例15(c)的化合物(2.25g,6.10mmol)与AlH3反应得到产物(1.95g,90%的收率)。
1H NMR(DMSO-d6)δ7.11-6.65(m,8H,);3.70(s,3H);3.51(br s,2H);2.66(s,2H);1.40-1.10(m,8H);0.72(m,6H).MS Da/e=356(MH+).C22H29NSO计算值:C,74.32;H,8.22;N,3.94;S,9.02。实测值:C,74.20;H,8.16;N,3.88;S,8.95。实施例17(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
用类似实施例4的方法,实施例16的化合物(1.52g,4.28mmol)氧化成砜得到产物(1.61g,97%的收率)。
1HNMR(DMSO-d6)δ7.35-6.79(m,8H);3.80(5,3H);3.65(br s,2H);3.26(s,2H);1.51-1.02(m,8H);0.73(m,6H).MS Da/e=388(MH+).
C22H29NSO3计算值:C,68.18;H,7.54;N,3.61;S,8.27。实测值:C,68.13;H,7.59;N,3.57;S,8.21。实施例18(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-羟基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
溴化铝(1M/CH2Cl2,16mmol)和乙硫醇(7.4ml,100mmol)的混合物在0℃时加入实施例17化合物(0.78g,2.01mmol)与30ml二氯甲烷的溶液。混合物在0℃搅拌1小时,然后加入25ml水,产物用3×20ml二氯甲烷萃取,有机相干燥,蒸发除去溶剂。残留物用硅胶柱纯化,产品(0.74g,98%)用35%乙酸乙酯/石油醚洗脱。
1H NMR(DMSO-d6)δ10.00(s,1H),7.28-6.74(m,8H);3.6(br s,2H);3.21(s,2H);1.55-1.02(m,8H);0.73(m,6H).MSDa/e=374(MH+).C21H27NSO3×0.4水计算值:C,66.25;H,7.36;N,3.68;S,8.42。实测值:C,66.12;H,7.37;N,3.61;S,8.30。实施例19(±)-7-溴-3-正丁基-3-乙基-2,3,-二氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-4-酮的制备(a)(±)-7-溴-3-正丁基-3-乙基-2,3,-二氢-8-甲氧基-1,5-苯并硫氮杂-4(5H)-酮
实施例15(c)的化合物(5.59g,19.05mmol)的二氯甲烷(120ml)溶液在0℃时加入N-溴代琥珀酰亚胺(6.78g,38.10mmol)搅拌30分钟,反应混合物用水洗涤一次,有机相干燥,浓缩,残留物装硅胶柱,用10%乙酸乙酯/石油醚洗脱产物(6.60g,93%的收率)。
M.P=102.0℃.1HNMR(DMSO-d6)δ9.60(s,1H);7.31(s,1H);7.09(s,1H);3.80(s,3H);2.91(S,2H);1.71-1.39(m,4H);1.19-1.13(m,4H);0.80(t,3H);0.75(t,3H).MS Da/e=372,374(MH+).C16H22BrNSO2计算值:C,51.62;H,5.96;N,3.76;S,8.61。实测值:C,51.33;H,5.87;N,3.65;S,8.44。(b)(±)-7-溴-3-正丁基-3-乙基-2,3,-二氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-4-酮
实施例19(a)的化合物(6.60g,17.7mmol)溶于在35ml的溴苯中,加入溴化铜(500mg)和碳酸钾(2.5g),混合物回流20小时。将反应混合物装硅胶柱,用10%乙酸乙酯/石油醚洗脱产物(5.05g,64%的收率)。
M.P.=131.0-132.8℃.1H NMR(DMSO-d6)δ7.40-7.05(m,7H);3.88(s,3H);3.14(s,2H);1.55-1.03(m,8H);0.77(m,6H).MS Da/e=448,450(MH+)C22H26BrNSO2×0.3水 计算值:C,58.23;H,5.91;N,3.09;Br,17.61。实测值:C,58.25;H,5.96;N,3.05;Br,17.56。实施例20(±)-7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
AlH3(29mmol,从H2SO4(15.5mmol)和LiAlH4(29mmol))原地产生)的乙醚(29ml)溶液在0℃加入实施例19(b)的化合物(4.38g,9.77mmol)的THF(15ml)溶液。反应混合物升温至室温,历时2小时,然后在室温搅拌15小时,TLC(20%乙酸乙酯/石油醚)显示反应完全。反应瓶冷至0℃,先滴加25ml H2O/THF(1∶2),随后加5ml 1M NaOH破坏过量的AlH3。混合物转移至分液漏斗中用乙醚萃取3次。合并乙醚萃取液,干燥,浓缩,柱层析(5%乙酸乙酯/石油醚)。含有产品的馏分旋转蒸发,所得到的油状物溶解在50ml四氢呋喃和叔丁醇中,该溶液中加入四氧化锇(2.5%的2-甲基-2-丙醇溶液5.1ml)和N-甲基吗啉-N-氧化物(2.7g,22.9mmol),混合物在室温下搅拌18小时,然后加入50ml NaHCO3溶液中和酸。混合物转移至分液漏斗中用乙酸乙酯萃取3次,有机相用饱和食盐水洗涤,干燥(NaSO4),浓缩。经柱层析(10%乙酸乙酯/石油醚)得到产物(3.41g,7.30mmol,75%的收率)。
M.P.=107.5-110.0℃.1H NMR(DMSO-d6)δ7.42-6.81(m,7H);3.90(s,3H);3.65(s,2H);3.31(s,2H);1.51-0.97(m,8H);0.71(m,6H).MS Da/e=466,468(MH+).C22H28BrNSO3计算值:C,56.65;H,6.05;N,3.00;S,6.87。实测值:C,56.80;H,6.19;N,3.01;S,6.80。实施例21(±)-7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物的制备
用实施例18的方法,实施例20的化合物(3.19g,6.84mmol)去甲基化得到产物(2.48g,77%收率)。
1HNMR(DMSO-d6)δ10.87(br s,1H),7.46-6.82(m,7H);3.62(br s,2H);3.25(s,2H);1.49-1.02(m,8H);0.71(m,6H).MS Da/e=452,454(MH+).C21H26BrNSO3计算值:C,56.75;H,5.79;N,3.10;S,7.09。实测值:C,55.79;H,5.93;N,3.15;S,7.17。实施例22(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物的制备
实施例21的化合物(0.50g,1.10mmol)溶于乙酸乙酯(2.0ml)中,加入甲醇钠(10ml,25%,重量比)和溴化铜(I)(57mg),混合物回流2小时。反应混合物用1N HCl中和,用3×15ml的乙醚萃取,乙醚层干燥,浓缩。残留物装硅胶柱,用20%乙酸乙酯/石油醚洗脱产品(0.44g,99%的收率)。
1H NMR(DMSO-d6)δ 9.69(s,1H),7.26-6.52(m,7H);3.60
(s,5H);1.53-1.02(m,8H);0.71(m,6H).MS Da/e=404(MH+).C22H29NSO4计算值:C,65.48;H,7.24;N,3.47;S,7.94。实测值:C,65.41;H,7.26;N,3.53;S,8.02。实施例23(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7,8-二甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
用实施例22的方法,实施例20的化合物(2.62g,5.62mmol)与甲醇钠反应得到产物(1.95g,83%的收率)。
1H NMR(DMSO-d6)δ7.30(s,1H);7.21-6.79(m,5H);6.52(s,1H);3.80(s,3H);3.62(br s,2H);3.59(s,3H);3.20(s,2H);1.53-0.98(m,8H);0.73(m,6H).MS Da/e=418(MH+)C23H31NSO4计算值:C,66.16;H,7.48;N,3.35;S,7.68。实测值:C,66.10;H,7.50;N,3.42;S,7.74。实施例24(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7,8-二醇-1,1-二氧化物的制备
氢化钠(60%,0.19g,4.79mmol)溶解在二甲基甲酰胺(20ml)中,加入乙硫醇(0.35ml,4.79mmol)和实施例23的化合物(0.50g,1.19mmol)。反应混合物回流3小时,然后加入饱和的醋酸胺水溶液25ml,调pH到7,用乙酸乙酯(3×10ml)萃取,有机相干燥,浓缩,上硅胶柱,产物用50%乙酸乙酯/石油醚洗脱(0.40g,收率为86%).
1H NMR(DMSO-d6)δ9.79(br,2H);7.23(s,1H);7.19-6.76(m,5H);6.37(s,1H);3.58(br s,2H);3.11(s,2H);1.50-0.98(m,8H);0.72(m,6H).MS Da/e=390(MH+).
C21H27NSO4×0.5水 计算值:C,63.29;H,7.08;N,3.51;S,8.05。实测值:C,63.47;H,7.21;N,3.36;S,7.92。实施例25(±)-7-溴-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮的制备(a)(±)-7-溴-3-正丁基-3-乙基-2,3-二氢-1,5-苯并硫氮杂-4(5H)-酮
实施例1(e)的化合物(8.28g,31.1mmol)溶解在30ml乙酸中,室温下滴加溴(1.75ml,34.2mmol)搅拌18小时。反应混合物用水洗涤一次,用2×20ml乙醚萃取,有机相干燥,浓缩,残留物上硅胶柱,用50%乙酸乙酯/石油醚洗脱产物(9.23g,87%的收率)。
M.P=104.4℃.1HNMR(DMSO-d6)δ9.81(s,1H);7.58(s,1H);7.42(s,1H);7.04(d,1H);2.96(S,2H);1.73-1.40(m,4H);1.19-1.15(m,4H);0.80(t,3H);0.76(t,3H).MS Da/e=342,344(MH+)C15H20BrNSO计算值:C,52.63;H,5.89;N,4.09;S,9.37。实测值:C,52.76;H,5.93;N,4.17;S,9.21。(b)(±)-7-溴-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮
用实施例1(f)的方法,实施例25(a)的化合物(8.8g,23.61mmol)与碘苯反应得产品(8.96g,收率为91%),该产品中7-溴化物与7-碘化物的比例是3∶1。用10当量LiBr和10mol%溴化铜(I)在DMF中回流18小时可以将7-碘化物完全转化为7-溴化物。1H NMR(DMSO-d6)δ7.84(d,1H);7.52(dd,1H);7.37-7.03(m,5H);6.84(d,1H);3.15(S,2H);1.57-1.13(m,8H);0.77(m,6H).MS Da/e=418,420(MH+).C21H24BrNSO计算值:C,60.29;H,5.78;N,3.35;Br,19.10。实测值:C,60.56;H,5.83;N,3.25;Br,18.83。实施例26(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物的制备
用实施例3的方法,实施例25(b)的化合物(7.71g,18.4mmol)与AlH3反应得到一油状物,根据实施例4的方法,该油状物直接与OsO4反应,得到的砜用实施例22的方法与甲醇钠反应得到产品(三步的总收率为67%)。
1H NMR(DMSO-d6)δ7.35-6.79(m,8H);3.79(s,3H);3.62(br s,2H);3.26(s,2H);1.53-1.00(m,8H);0.73(m,6H).MS Da/e=388(MH+).) Calcd forC22H29NSO3:C,68.18;H,7.54;N,3.61;S,8.27.Found:C,67.89;H,7.65;N,3.42;S,8.20.C22H29NSO3计算值:C,68.18;H,7.54;N,3.61;S,8.27。实测值:C,67.89;H,7.65;N,3.42;S,8.20。实施例27(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7-醇-1.1-二氧化物的制备
根据实施例18的方法,实施例26的化合物(1.05g,2.71mmol)与AlBr3和乙硫醇反应得到标题化合物(0.90g,89%)。
1H NMR(DMSO-d6)δ9.99(s,1H);7.27-6.74(m,8H);3.61(br s,2H);3.20(s,2H);1.50-1.00(m,8H);0.73(m,6H).MS Da/e=374(MH+).C21H27NSO3×(0.25水)计算值:C,66.73;H,7.33;N,3.71;S,8.48。实测值:C,66.67;H,7.32;N,3.67;S,8.49。生物检测胆汁酸再吸收的体内抑制
重220-260mg的雄性Spraque-Dawley大鼠(CD,Charles Rrver),单笼饲养正常喂食。上午9点和下午3:30将检测化合物与0.5%甲基纤维素的悬浮液经口用管饲法给药(1ml/100g体重)连续2天。对照组给药(1ml/100g体重)连续2天。对照组服用0.5%甲基纤维素。第二天早剂量2小时后大鼠口服给予示踪量(1.3nmoles)23.25-75Se-同型胆酸牛磺酸(75SeHCAT)与1.0ml生理盐水。75SeHCAT是合成的γ-放射性胆酸类似物,类似于牛磺胆酸可以被回肠中的胆酸活泼摄取系统吸收,临床用于测定回肠胆酸的吸收。服用75SeHCAT后收集粪便,收集的时间为24小时。用Packard Auto-Gamma 500 Series γ-计数器测定粪便中75SeHCAT的含量。按下式计算抑制胆酸吸收的%:
实施例2,4,7和9的化合物在10mg/kg浓度下,使用75SeHCAT的大鼠的胆酸抑制的百分数分别为7%,36%,20%和29%。在相同的测定中,实施例18,22,23和27的化合物在1mg/kg浓度下的胆酸再吸收的抑制百分数在50%至65%之间。
Claims (11)
1.通式(I)的化合物或其盐、溶剂化物或具有生理功能的衍生物:
其中,R1和R2是相同的或不同的,并且各自为C1-6烷基,该C1-6烷基被一个或多个选自羟基、卤素、C1-6烷基、C1-6烷氧基、COR12、腈、CO2R12、SO3R12、NR13R14和N+R13R14R15的基团任选取代,C3-6环烷基,或R1和R2和与它们相连的碳原子一起形成C3-6螺环烷基;
R4是C6-14芳基,或是C3-13杂芳基,这些基团均被1-8个取代基任选取代,这些取代基是相同的或是不同的,并各自选自卤素,羟基,硝基,苯基-C1-6烷氧基,C1-6烷氧基,被一个或多个选自羟基、卤素、C1-6烷基、C1-6烷氧基、COR12、腈、CO2R12、SO3R12、NR13R14和N+R13R14R15的基团任选取代的C1-6烷基,S(O)nR8,SO2NR8R9,CO2R8,O(CH2CH2O)nR8,OSO2R8,O(CH2)pSO3R8,O(CH2)pNR9R10和O(CH2)pN+R9R10R11,其中R8至R11是相同的或不同的,并各自独立选自氢或被一个或多个选自羟基、卤素、C1-6烷基、C1-6烷氧基、COR12、腈、CO2R12、SO3R12、NR13R14和N+R13R14R15的基团任选取代的C1-6烷基;其中p为1-4的整数;n为0-3的整数。
R5a,R5b,R5c和R5d各自为相同的或不同的原子或基团,各自为氢,卤素,氰基,R8-乙炔化物,OR8,被一个或多个选自羟基、卤素、C1-6烷基、C1-6烷氧基、COR12、腈、CO2R12、SO3R12、NR13R14和N+R13R14R15的基团任选取代的C1-6烷基,COR8,CH(OH)R8,S(O)nR8,SO2NR8R9,P(O)(OR8)2,OCOR8,OCF3,OCN,SCN,NHCN,CH2OR8,CHO,(CH2)pCN,CONR9R10,(CH2)pCO2R8,(CH2)pNR9R10,CO2R8,NHCOCF3,NHSO2R8,OCH2OR8,OCH=CHR8,O(CH2CH2O)nR8,OSO2R8,O(CH2)pSO3R8,O(CH2)pNR9R10和O(CH2)pN+R9R10R11,其中R8至R11,n和p的定义与上面定义相同;或R5a和R5b,R5b和R5c,或R5c和R5d一起与和它们相连的环形成一个环基-O(CR9R10)mO-,其中R9和R10的定义与上面的定义相同,m是1或2;
R6和R7是相同的或不同的,并各自为氢,被一个或多个选自羟基、卤素、C1-6烷基、C1-6烷氧基、COR12、腈、CO2R12、SO3R12、NR13R14和N+R13R14R15的基团任选取代的C1-6烷基,C3-6环烷基,或R6和R7一起与它们相连的碳原子形成C3-6螺环烷基;
X是CH2,C=O,C=S,或C=NR8,其中R8的定义与上面的定义相同;
R12-R15是相同的或不同的,并且各自选自氢或C1-6烷基;和
l为0-2的整数。
2.权利要求1的通式(I)的化合物或其盐、溶剂化物或具有生理功能的衍生物,其中R1为甲基或乙基;R2为甲基,乙基或正丁基;R4为苯基;R5a和R5d为氢R5b和R5c是相同的或不同的,且各自为氢,甲基,甲氧基,羟基,三氟甲基或卤素;R6和R7是相同的或不同的,且各自为氢,甲基,乙基,或异丁基;X为CH2或C=O;l为2。
3.权利要求1或2的通式(I)的化合物,其中R1是乙基和R2是正丁基。
4.权利要求1至3中任一通式(I)的化合物,其中R4是苯基。
5.权利要求1至4中任一通式(I)的化合物,其中R5a和R5d是氢,R5b和R5c是相同的或不同的且各自为氢、甲基、甲氧基、羟基、三氟甲基或卤素。
6.权利要求1至5中任一通式(I)的化合物,其中R6和R7都是氢。
7.权利要求1的化合物,选自:(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;(±)-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)-3-正丁基-2-异丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;3,3-二乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;3,3-二乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物;3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂;3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;3,3-二甲基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;3,3-二甲基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮-1,1-二氧化物;3,3-二甲基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂;3,3-二甲基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7,8-二甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;3,3-二乙基-2,3,4,5-四氢-7,8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;3,3-二乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;3,3-二乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;(±)-7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;7-溴-3,3-二乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7,8-二醇-1,1-二氧化物;3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7,8-二醇-1,1-二氧化物;(±)3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1-一氧化物;3,3-二乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1-一氧化物;(±)3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1-一氧化物;3,3-二乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1-一氧化物;(±)3-正丁基-3-乙基-2,3-二氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-4-酮;(±)3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂;(±)3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)3-正丁基-3-乙基-2,3,4,5-四氢-8-羟基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)7-溴-3-正-丁基-3-乙基-2,3-二氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-4-酮;(±)7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-8-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)7-溴-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7,8-二甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7,8-二醇-1,1-二氧化物;(±)7-溴-3-正丁基-3-乙基-2,3-二氢-5-苯基-1,5-苯并硫氮杂-4-酮;(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物;和(±)-3-正丁基-3-乙基-2,3,4,5-四氢-5-苯基-1,5-苯并硫氮杂-7-醇-1,1-二氧化物;
8.权利要求1的化合物或其盐,溶剂化物和具有生理功能的衍生物,选自:(±)-3-正丁基-3-乙基-2,3,4,5-四氢-7-甲氧基-5-苯基-1,5-苯并硫氮杂-8-醇-1,1-二氧化物;和(±)-3-正丁基-3-乙基-2,3,4,5-四氢-8-羟基-5-苯基-1,5-苯并硫氮杂-1,1-二氧化物。
9.权利要求1至8中任一通式(I)的化合物或它们的药物上可以接受的盐,溶剂化物或具有生理功能的衍生物在制造治疗高血脂症的药物中的应用。
10.一种药物组合物,该药物组合物含权利要求1至8中任一通式(I)的化合物或它们的药物上可以接受的盐,溶剂化物或生理功能的衍生物和至少一种药物上可以接受的载体。
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GB9423172A GB9423172D0 (en) | 1994-11-17 | 1994-11-17 | Hypolipidemic benzothiazepines |
GB9423172.7 | 1994-11-17 |
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JP2023537285A (ja) | 2020-08-03 | 2023-08-31 | アルビレオ・アクチボラグ | ベンゾチア(ジ)アゼピン化合物及び胆汁酸モジュレータとしてのそれらの使用 |
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GB9704208D0 (en) * | 1997-02-28 | 1997-04-16 | Glaxo Group Ltd | Chemical compounds |
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- 1994-11-17 GB GB9423172A patent/GB9423172D0/en active Pending
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1995
- 1995-11-16 EP EP95937940A patent/EP0792268B1/en not_active Expired - Lifetime
- 1995-11-16 US US08/836,405 patent/US5998400A/en not_active Expired - Fee Related
- 1995-11-16 CZ CZ971473A patent/CZ147397A3/cs unknown
- 1995-11-16 PT PT95937940T patent/PT792268E/pt unknown
- 1995-11-16 BR BR9509683A patent/BR9509683A/pt not_active IP Right Cessation
- 1995-11-16 MX MX9703546A patent/MX9703546A/es not_active IP Right Cessation
- 1995-11-16 DK DK95937940T patent/DK0792268T3/da active
- 1995-11-16 HU HU9702189A patent/HUT77412A/hu unknown
- 1995-11-16 JP JP51666196A patent/JP2868623B2/ja not_active Expired - Fee Related
- 1995-11-16 CN CN95196304A patent/CN1059674C/zh not_active Expired - Fee Related
- 1995-11-16 AT AT95937940T patent/ATE189891T1/de not_active IP Right Cessation
- 1995-11-16 WO PCT/GB1995/002700 patent/WO1996016051A1/en not_active Application Discontinuation
- 1995-11-16 DE DE69515183T patent/DE69515183T2/de not_active Expired - Fee Related
- 1995-11-16 AU AU38762/95A patent/AU706325B2/en not_active Ceased
- 1995-11-16 PL PL95320093A patent/PL320093A1/xx unknown
- 1995-11-16 NZ NZ295426A patent/NZ295426A/en unknown
- 1995-11-16 ES ES95937940T patent/ES2144151T3/es not_active Expired - Lifetime
-
1997
- 1997-05-15 FI FI972085A patent/FI972085A0/fi unknown
- 1997-05-16 KR KR1019970703298A patent/KR970707111A/ko not_active Application Discontinuation
- 1997-05-16 NO NO972261A patent/NO308470B1/no unknown
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2000
- 2000-05-19 GR GR20000401138T patent/GR3033450T3/el not_active IP Right Cessation
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US8008292B2 (en) | 2004-07-15 | 2011-08-30 | Japan Tobacco Inc. | Condensed benzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity |
US7906508B2 (en) | 2005-12-28 | 2011-03-15 | Japan Tobacco Inc. | 3,4-dihydrobenzoxazine compounds and inhibitors of vanilloid receptor subtype 1 (VRI) activity |
Also Published As
Publication number | Publication date |
---|---|
EP0792268A1 (en) | 1997-09-03 |
WO1996016051A1 (en) | 1996-05-30 |
HUT77412A (hu) | 1998-04-28 |
NO308470B1 (no) | 2000-09-18 |
DE69515183D1 (de) | 2000-03-30 |
EP0792268B1 (en) | 2000-02-23 |
ES2144151T3 (es) | 2000-06-01 |
US5998400A (en) | 1999-12-07 |
JP2868623B2 (ja) | 1999-03-10 |
CN1164230A (zh) | 1997-11-05 |
PT792268E (pt) | 2000-06-30 |
FI972085A (fi) | 1997-05-15 |
BR9509683A (pt) | 1997-09-16 |
JPH11500102A (ja) | 1999-01-06 |
PL320093A1 (en) | 1997-09-15 |
NZ295426A (en) | 1997-10-24 |
FI972085A0 (fi) | 1997-05-15 |
GB9423172D0 (en) | 1995-01-04 |
KR970707111A (ko) | 1997-12-01 |
DE69515183T2 (de) | 2000-08-17 |
AU3876295A (en) | 1996-06-17 |
DK0792268T3 (da) | 2000-07-31 |
ATE189891T1 (de) | 2000-03-15 |
NO972261D0 (no) | 1997-05-16 |
CZ147397A3 (en) | 1997-11-12 |
MX9703546A (es) | 1997-08-30 |
AU706325B2 (en) | 1999-06-17 |
GR3033450T3 (en) | 2000-09-29 |
NO972261L (no) | 1997-07-16 |
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