RU2305681C2 - Производные бензотиадиазепина, способ их получения (варианты) - Google Patents
Производные бензотиадиазепина, способ их получения (варианты) Download PDFInfo
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- RU2305681C2 RU2305681C2 RU2004110716/04A RU2004110716A RU2305681C2 RU 2305681 C2 RU2305681 C2 RU 2305681C2 RU 2004110716/04 A RU2004110716/04 A RU 2004110716/04A RU 2004110716 A RU2004110716 A RU 2004110716A RU 2305681 C2 RU2305681 C2 RU 2305681C2
- Authority
- RU
- Russia
- Prior art keywords
- carbamoyl
- carbamoylmethoxy
- solvate
- formula
- alkyl
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title abstract description 13
- KAOYLRLQZXRRBD-UHFFFAOYSA-N 1,2,3-benzothiadiazepine Chemical class S1N=NC=CC2=CC=CC=C12 KAOYLRLQZXRRBD-UHFFFAOYSA-N 0.000 title abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 283
- 238000000034 method Methods 0.000 claims abstract description 136
- 239000003613 bile acid Substances 0.000 claims abstract description 63
- 238000011282 treatment Methods 0.000 claims abstract description 58
- 150000002148 esters Chemical class 0.000 claims abstract description 44
- 238000001727 in vivo Methods 0.000 claims abstract description 30
- 238000012546 transfer Methods 0.000 claims abstract description 30
- 150000001408 amides Chemical class 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 24
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims description 276
- 150000001875 compounds Chemical class 0.000 claims description 258
- -1 benzyloxycarbonylamino Chemical group 0.000 claims description 211
- 229910052739 hydrogen Inorganic materials 0.000 claims description 105
- 239000001257 hydrogen Substances 0.000 claims description 105
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 91
- 229910052757 nitrogen Inorganic materials 0.000 claims description 75
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 74
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 58
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 48
- 230000007062 hydrolysis Effects 0.000 claims description 37
- 238000006460 hydrolysis reaction Methods 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 210000003405 ileum Anatomy 0.000 claims description 27
- 125000003277 amino group Chemical group 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 230000003516 hyperlipidaemic effect Effects 0.000 claims description 18
- 230000002401 inhibitory effect Effects 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 abstract description 29
- 239000000126 substance Substances 0.000 abstract description 25
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- 201000005577 familial hyperlipidemia Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 210000000936 intestine Anatomy 0.000 abstract 1
- 229940002612 prodrug Drugs 0.000 description 119
- 239000000651 prodrug Substances 0.000 description 119
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 239000000203 mixture Substances 0.000 description 64
- 241001465754 Metazoa Species 0.000 description 61
- 239000000243 solution Substances 0.000 description 54
- 239000002904 solvent Substances 0.000 description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 43
- 239000012317 TBTU Substances 0.000 description 42
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 40
- 235000019439 ethyl acetate Nutrition 0.000 description 39
- 238000002953 preparative HPLC Methods 0.000 description 38
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
- 239000003480 eluent Substances 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 239000000872 buffer Substances 0.000 description 31
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 30
- 239000005695 Ammonium acetate Substances 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 235000019257 ammonium acetate Nutrition 0.000 description 30
- 229940043376 ammonium acetate Drugs 0.000 description 30
- 239000007787 solid Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000002552 dosage form Substances 0.000 description 27
- 239000000047 product Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 241000282414 Homo sapiens Species 0.000 description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 23
- 150000001721 carbon Chemical group 0.000 description 21
- 239000012267 brine Substances 0.000 description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 229940123934 Reductase inhibitor Drugs 0.000 description 18
- 125000004429 atom Chemical group 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- 125000003396 thiol group Chemical group [H]S* 0.000 description 18
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 17
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 17
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 16
- 125000004093 cyano group Chemical group *C#N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
- 102000023984 PPAR alpha Human genes 0.000 description 14
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- 239000000556 agonist Substances 0.000 description 14
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- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 10
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- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 9
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 125000000213 sulfino group Chemical group [H]OS(*)=O 0.000 description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
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Classifications
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- 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
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- 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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Landscapes
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- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Steroid Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| GB0121768.6 | 2001-09-08 | ||
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| GB0209463A GB0209463D0 (en) | 2002-04-25 | 2002-04-25 | Chemical compounds |
| GB0209463.9 | 2002-04-25 |
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| RU2004110716A RU2004110716A (ru) | 2005-05-10 |
| RU2305681C2 true RU2305681C2 (ru) | 2007-09-10 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2591188C2 (ru) * | 2010-11-04 | 2016-07-10 | Альбирео Аб | Ингибиторы ibat для лечения заболеваний печени |
| RU2814570C2 (ru) * | 2019-02-06 | 2024-03-01 | Альбирео Аб | Соединения бензотиадиазепина и их применение в качестве модуляторов желчных кислот |
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| SE0000772D0 (sv) | 2000-03-08 | 2000-03-08 | Astrazeneca Ab | Chemical compounds |
| EG26979A (en) | 2000-12-21 | 2015-03-01 | Astrazeneca Ab | Chemical compounds |
| 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 |
| SE0104333D0 (sv) | 2001-12-19 | 2001-12-19 | Astrazeneca Ab | Therapeutic agents |
| GB0209467D0 (en) * | 2002-04-25 | 2002-06-05 | Astrazeneca Ab | Chemical compounds |
| GB0213669D0 (en) * | 2002-06-14 | 2002-07-24 | Astrazeneca Ab | Chemical compounds |
| TWI282784B (en) * | 2002-06-20 | 2007-06-21 | Astrazeneca Ab | Therapeutic agents |
| GB0304194D0 (en) | 2003-02-25 | 2003-03-26 | Astrazeneca Ab | Chemical compounds |
| AU2008202120B2 (en) * | 2003-04-05 | 2009-12-17 | Albireo Ab | Use of an IBAT inhibitor for the treatment of prophylaxis of constipation |
| GB0307918D0 (en) * | 2003-04-05 | 2003-05-14 | Astrazeneca Ab | Therapeutic use |
| GB0314131D0 (en) * | 2003-06-18 | 2003-07-23 | Astrazeneca Ab | Therapeutic agents |
| AR057828A1 (es) * | 2005-09-29 | 2007-12-19 | Astrazeneca Ab | Compuestos derivados de azetidina, su preparacion y composicion farmaceuutica |
| US8062824B2 (en) * | 2006-07-17 | 2011-11-22 | E. I. Du Pont De Nemours And Company | Thermally imageable dielectric layers, thermal transfer donors and receivers |
| US7528448B2 (en) * | 2006-07-17 | 2009-05-05 | E.I. Du Pont De Nemours And Company | Thin film transistor comprising novel conductor and dielectric compositions |
| JP5404429B2 (ja) * | 2007-03-08 | 2014-01-29 | アルビレオ・アクチボラグ | ２−置換３−フェニルプロピオン酸誘導体および炎症性腸疾患の治療におけるそれらの使用 |
| US7666568B2 (en) * | 2007-10-23 | 2010-02-23 | E. I. Du Pont De Nemours And Company | Composition and method for providing a patterned metal layer having high conductivity |
| US7666567B2 (en) | 2007-10-23 | 2010-02-23 | E. I. Du Pont De Nemours And Company | Negative imaging method for providing a patterned metal layer having high conductivity |
| CN102316872B (zh) | 2008-11-26 | 2016-12-21 | 萨蒂奥根制药公司 | 治疗肥胖症和糖尿病的胆汁酸再循环抑制剂 |
| EP3593802A3 (en) | 2010-05-26 | 2020-03-25 | Satiogen Pharmaceuticals, Inc. | Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions |
| US20120114588A1 (en) * | 2010-11-08 | 2012-05-10 | Albireo Ab | Ibat inhibitors for treatment of metabolic disorders and related conditions |
| CN103228270B (zh) * | 2010-11-08 | 2016-02-10 | 阿尔比里奥公司 | 含ibat抑制剂和胆汁酸结合剂的药物组合 |
| MY176863A (en) * | 2010-11-08 | 2020-08-24 | Albireo Ab | Ibat inhibitors for treatment of metabolic disorders and related conditions |
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Cited By (2)
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|---|---|---|---|---|
| RU2591188C2 (ru) * | 2010-11-04 | 2016-07-10 | Альбирео Аб | Ингибиторы ibat для лечения заболеваний печени |
| RU2814570C2 (ru) * | 2019-02-06 | 2024-03-01 | Альбирео Аб | Соединения бензотиадиазепина и их применение в качестве модуляторов желчных кислот |
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