ES2366641T3 - Derivado de 4,4-difluoro-1,2,3,4-tetrahidro-5h-1-benzazepina o sal del mismo. - Google Patents
Derivado de 4,4-difluoro-1,2,3,4-tetrahidro-5h-1-benzazepina o sal del mismo. Download PDFInfo
- Publication number
- ES2366641T3 ES2366641T3 ES04729502T ES04729502T ES2366641T3 ES 2366641 T3 ES2366641 T3 ES 2366641T3 ES 04729502 T ES04729502 T ES 04729502T ES 04729502 T ES04729502 T ES 04729502T ES 2366641 T3 ES2366641 T3 ES 2366641T3
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- Spain
- Prior art keywords
- substituted
- lower alkyl
- aryl
- group
- groups selected
- 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 - Lifetime
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- 150000003839 salts Chemical class 0.000 title claims abstract description 24
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 81
- 125000001424 substituent group Chemical group 0.000 claims abstract description 47
- -1 -CO2alkyl lower Chemical group 0.000 claims abstract description 38
- 125000003118 aryl group Chemical group 0.000 claims abstract description 34
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 23
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 23
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 20
- 150000002367 halogens Chemical class 0.000 claims abstract description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 14
- DTSDJGNXLLPHFA-UHFFFAOYSA-N 4,4-difluoro-1,2,3,5-tetrahydro-1-benzazepine Chemical class C1C(F)(F)CCNC2=CC=CC=C21 DTSDJGNXLLPHFA-UHFFFAOYSA-N 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 12
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 11
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 6
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 239000011593 sulfur Substances 0.000 claims abstract description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims abstract 4
- 125000004429 atom Chemical group 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 146
- 238000000034 method Methods 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 17
- 201000010064 diabetes insipidus Diseases 0.000 claims description 9
- VSXSHTIGQAUGMW-VCRXTVNUSA-N (2z)-n-(2-hydroxyethyl)-2-[4,4,7-trifluoro-1-[4-[(2r)-2-fluoropropoxy]-2-(trifluoromethyl)benzoyl]-2,3-dihydro-1-benzazepin-5-ylidene]acetamide Chemical compound FC(F)(F)C1=CC(OC[C@H](F)C)=CC=C1C(=O)N1C2=CC=C(F)C=C2C(=C/C(=O)NCCO)/C(F)(F)CC1 VSXSHTIGQAUGMW-VCRXTVNUSA-N 0.000 claims description 8
- 208000028235 central diabetes insipidus Diseases 0.000 claims description 7
- 206010029446 nocturia Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims description 6
- 208000008967 Enuresis Diseases 0.000 claims description 6
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 claims description 6
- 208000003450 Neurogenic Diabetes Insipidus Diseases 0.000 claims description 6
- 201000005119 neurohypophyseal diabetes insipidus Diseases 0.000 claims description 6
- 206010036018 Pollakiuria Diseases 0.000 claims description 3
- 206010046543 Urinary incontinence Diseases 0.000 claims description 3
- 208000005346 nocturnal enuresis Diseases 0.000 claims description 3
- 208000022934 urinary frequency Diseases 0.000 claims description 3
- 230000036318 urination frequency Effects 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 239000003814 drug Substances 0.000 description 25
- 238000004519 manufacturing process Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 229940079593 drug Drugs 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 102000004136 Vasopressin Receptors Human genes 0.000 description 15
- 108090000643 Vasopressin Receptors Proteins 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 102000004190 Enzymes Human genes 0.000 description 11
- 108090000790 Enzymes Proteins 0.000 description 11
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 210000002700 urine Anatomy 0.000 description 10
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 9
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 101800001144 Arg-vasopressin Proteins 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 230000002686 anti-diuretic effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 108010000543 Cytochrome P-450 CYP2C9 Proteins 0.000 description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
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- 125000003277 amino group Chemical group 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 102100029358 Cytochrome P450 2C9 Human genes 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 229960004580 glibenclamide Drugs 0.000 description 5
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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- 239000000654 additive Substances 0.000 description 4
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
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- 239000012043 crude product Substances 0.000 description 4
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- 229960005371 tolbutamide Drugs 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 229960001134 von willebrand factor Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003-123032 | 2003-04-28 | ||
| JP2003123032 | 2003-04-28 | ||
| JP2003-401126 | 2003-12-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2366641T3 true ES2366641T3 (es) | 2011-10-24 |
Family
ID=36770628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES04729502T Expired - Lifetime ES2366641T3 (es) | 2003-04-28 | 2004-04-26 | Derivado de 4,4-difluoro-1,2,3,4-tetrahidro-5h-1-benzazepina o sal del mismo. |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN100404511C (zh) |
| ES (1) | ES2366641T3 (zh) |
| ZA (1) | ZA200508080B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012043791A1 (ja) * | 2010-10-01 | 2012-04-05 | 大正製薬株式会社 | １，２，４-トリアゾロン誘導体 |
| US9586905B2 (en) * | 2012-12-26 | 2017-03-07 | Sanwa Kagaku Kenkyusho Co., Ltd. | Benzoazepine derivative and medical use thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL182011B1 (en) * | 1993-08-26 | 2001-10-31 | Yamanouchi Pharma Co Ltd | Benzazepine derivative, pharmaceutic composition and intermediate compounds |
| JP3215910B2 (ja) * | 1994-06-15 | 2001-10-09 | 大塚製薬株式会社 | ベンゾヘテロ環誘導体 |
| JPH09221476A (ja) * | 1995-12-15 | 1997-08-26 | Otsuka Pharmaceut Co Ltd | 医薬組成物 |
| AR011913A1 (es) * | 1997-03-06 | 2000-09-13 | Yamano Masaki | Derivados de 4,4-difluoro-2,3,4,5-tetrahidro-1h-1-benzoazepina y composiciones farmaceuticas de los mismos. |
-
2004
- 2004-04-26 ES ES04729502T patent/ES2366641T3/es not_active Expired - Lifetime
- 2004-04-26 CN CNB2004800113447A patent/CN100404511C/zh not_active Expired - Fee Related
- 2004-04-26 ZA ZA200508080A patent/ZA200508080B/en unknown
- 2004-04-26 CN CNA2008100999960A patent/CN101279971A/zh active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200508080B (en) | 2007-03-28 |
| CN1780819A (zh) | 2006-05-31 |
| CN100404511C (zh) | 2008-07-23 |
| CN101279971A (zh) | 2008-10-08 |
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