RU2011110745A - [4-(5-аминометил-2-фторфенил)-пиперидин-1-ил]-[7-фтор-1-(2-метоксиэтил)-4-трифторметокси-1н-индол-3-ил]-метанон как ингибитор триптазы тучных клеток - Google Patents
[4-(5-аминометил-2-фторфенил)-пиперидин-1-ил]-[7-фтор-1-(2-метоксиэтил)-4-трифторметокси-1н-индол-3-ил]-метанон как ингибитор триптазы тучных клеток Download PDFInfo
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- RU2011110745A RU2011110745A RU2011110745/04A RU2011110745A RU2011110745A RU 2011110745 A RU2011110745 A RU 2011110745A RU 2011110745/04 A RU2011110745/04 A RU 2011110745/04A RU 2011110745 A RU2011110745 A RU 2011110745A RU 2011110745 A RU2011110745 A RU 2011110745A
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- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 title 1
- -1 5-AMINOMETHYL-2-fluorophenyl Chemical group 0.000 title 1
- 210000001789 adipocyte Anatomy 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract 8
- 238000000034 method Methods 0.000 claims abstract 7
- 150000003839 salts Chemical class 0.000 claims abstract 6
- 102000001400 Tryptase Human genes 0.000 claims abstract 4
- 108060005989 Tryptase Proteins 0.000 claims abstract 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract 4
- 230000004962 physiological condition Effects 0.000 claims abstract 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910019142 PO4 Inorganic materials 0.000 claims abstract 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims abstract 2
- 229930195712 glutamate Natural products 0.000 claims abstract 2
- 239000000155 melt Substances 0.000 claims abstract 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract 2
- 239000010452 phosphate Substances 0.000 claims abstract 2
- 239000000651 prodrug Substances 0.000 claims abstract 2
- 229940002612 prodrug Drugs 0.000 claims abstract 2
- 239000012453 solvate Substances 0.000 claims abstract 2
- 229940095064 tartrate Drugs 0.000 claims abstract 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 6
- 239000002904 solvent Substances 0.000 claims 6
- 238000009835 boiling Methods 0.000 claims 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- ZTYPULSVPPCCAY-UHFFFAOYSA-N 2,2,2-trifluoro-n-[(4-fluoro-3-pyridin-4-ylphenyl)methyl]acetamide;hydrochloride Chemical compound Cl.FC1=CC=C(CNC(=O)C(F)(F)F)C=C1C1=CC=NC=C1 ZTYPULSVPPCCAY-UHFFFAOYSA-N 0.000 claims 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 2
- 208000032544 Cicatrix Diseases 0.000 claims 2
- 206010010741 Conjunctivitis Diseases 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims 2
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims 2
- 230000035790 physiological processes and functions Effects 0.000 claims 2
- 231100000241 scar Toxicity 0.000 claims 2
- 230000037387 scars Effects 0.000 claims 2
- 206010002198 Anaphylactic reaction Diseases 0.000 claims 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 claims 1
- 206010012689 Diabetic retinopathy Diseases 0.000 claims 1
- 206010016654 Fibrosis Diseases 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- 208000029523 Interstitial Lung disease Diseases 0.000 claims 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims 1
- 229940122142 Lipoxygenase inhibitor Drugs 0.000 claims 1
- 206010028594 Myocardial fibrosis Diseases 0.000 claims 1
- 201000004404 Neurofibroma Diseases 0.000 claims 1
- 206010039085 Rhinitis allergic Diseases 0.000 claims 1
- 206010039710 Scleroderma Diseases 0.000 claims 1
- 208000036142 Viral infection Diseases 0.000 claims 1
- 239000000808 adrenergic beta-agonist Substances 0.000 claims 1
- 201000010105 allergic rhinitis Diseases 0.000 claims 1
- 230000036783 anaphylactic response Effects 0.000 claims 1
- 208000003455 anaphylaxis Diseases 0.000 claims 1
- 230000001078 anti-cholinergic effect Effects 0.000 claims 1
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 1
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 210000001188 articular cartilage Anatomy 0.000 claims 1
- 208000006673 asthma Diseases 0.000 claims 1
- 208000019425 cirrhosis of liver Diseases 0.000 claims 1
- 239000003246 corticosteroid Substances 0.000 claims 1
- 230000006378 damage Effects 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000004761 fibrosis Effects 0.000 claims 1
- 201000005917 gastric ulcer Diseases 0.000 claims 1
- 230000001969 hypertrophic effect Effects 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 201000006417 multiple sclerosis Diseases 0.000 claims 1
- 208000028169 periodontal disease Diseases 0.000 claims 1
- 239000003880 polar aprotic solvent Substances 0.000 claims 1
- 208000005069 pulmonary fibrosis Diseases 0.000 claims 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 claims 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical group FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 claims 1
- 229960002586 roflumilast Drugs 0.000 claims 1
- 230000004614 tumor growth Effects 0.000 claims 1
- 230000009385 viral infection Effects 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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Abstract
1. Соединение формулы I: ! (I) ! или его пролекарство, фармацевтически приемлемая соль или сольват. ! 2. Соединение по п.1 в виде фармацевтически приемлемой соли, выбранной из: гидрохлорида, фумарата, безилата, тозилата, сульфата, цитрата, метансульфоната, тартрата, фосфата, глютамата и бензоата. ! 3. Соединение по п.2, где соль представляет собой бензоат. ! 4. Кристаллическая форма А соединения по п.3. ! 5. Кристаллическая форма по п.4, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, двух углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88. ! 6. Кристаллическая форма по п.5, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, трех углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88. ! 7. Кристаллическая форма по п.6, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, четырех углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88. ! 8. Кристаллическая форма по п.7, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, пяти углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88. ! 9. Кристаллическая форма по п.4, отличающаяся тем, что данная кристаллическая форма плавится при 162°С. ! 10. Применение соединения по п.1 для лечения нуждающегося в улучшении пациента, страдающего от физиологического состояния или подверженного такому состоянию, путем ингибирования триптазы. ! 11. Способ лечения нуждающегося в улучшении пациента, страдающего от физиологического состояния или подверженного такому состоянию, путем ингибирования триптазы, включающий в себя: введение пациенту терапевтически эффективного к
Claims (21)
1. Соединение формулы I:
или его пролекарство, фармацевтически приемлемая соль или сольват.
2. Соединение по п.1 в виде фармацевтически приемлемой соли, выбранной из: гидрохлорида, фумарата, безилата, тозилата, сульфата, цитрата, метансульфоната, тартрата, фосфата, глютамата и бензоата.
3. Соединение по п.2, где соль представляет собой бензоат.
4. Кристаллическая форма А соединения по п.3.
5. Кристаллическая форма по п.4, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, двух углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88.
6. Кристаллическая форма по п.5, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, трех углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88.
7. Кристаллическая форма по п.6, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, четырех углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88.
8. Кристаллическая форма по п.7, отличающаяся тем, что данная кристаллическая форма имеет пики XRPD при, по меньшей мере, пяти углах из следующих углов 2Θ: 7,75, 10,13, 17,03, 17,16, 18,39, 21,33 и 21,88.
9. Кристаллическая форма по п.4, отличающаяся тем, что данная кристаллическая форма плавится при 162°С.
10. Применение соединения по п.1 для лечения нуждающегося в улучшении пациента, страдающего от физиологического состояния или подверженного такому состоянию, путем ингибирования триптазы.
11. Способ лечения нуждающегося в улучшении пациента, страдающего от физиологического состояния или подверженного такому состоянию, путем ингибирования триптазы, включающий в себя: введение пациенту терапевтически эффективного количества соединения, заявленного в п.1.
12. Способ по п.11, в котором физиологическое состояние выбрано из группы, состоящей из воспалительного заболевания, болезни, выражающейся в разрушении суставного хряща, глазного конъюнктивита, весеннего конъюнктивита, воспалительной болезни кишечника, астмы, аллергического ринита, интерстициальной болезни легких, фиброза, хронической обструктивной болезни легких (ХОБЛ), склеродермы, легочного фиброза, цирроза печени, фиброза миокарда, нейрофибромы, гипертрофических рубцов или шрамов, дерматологического состояния, состояния, связанного с разрушением атеросклеротических бляшек, периодонтальной болезни, диабетической ретинопатии, роста опухоли, анафилаксии, рассеянного склероза, язвы желудка и синцитиальной вирусной инфекции.
13. Способ по п.12, в котором физиологическим состоянием является ХОБЛ.
14. Фармацевтическая композиция, содержащая терапевтически эффективное количество соединения по п.1 и фармацевтически приемлемый носитель для него.
15. Фармацевтическая композиция по п.14, дополнительно содержащая терапевтически эффективное количество второго соединения, выбранного из группы, включающей бета- адренергический агонист, антихолинергик, противовоспалительный кортикостероид, антагонист рецептора лейкотриена, ингибитор липоксигеназы, ингибитор фосфодиэстеразы-4 и противовоспалительное средство.
16. Фармацевтическая композиция по п.15, где ингибитор фосфодиэстеразы-4 выбирают из рофлумиласта и цифлумоласта.
17. Соединение, выбранное из группы соединений, имеющих формулу:
18. Соединение, имеющее формулу:
19. Способ получения гидрохлорида 2,2,2-трифтор-N-(4-фтор-3-пиридин-4-ил-бензил)-ацетамида, заявленного в п.2, включающий в себя сочетание гидрохлорида 3-бром-4-фторбензиламина и пиридин-4-бороновой кислоты в условиях сочетания с получением гидрохлорида 2,2,2-трифтор-N-(4-фтор-3-пиридин-4-ил-бензил)-ацетамида.
20. Способ по п.19, в котором для условий сочетания Судзуки используют растворитель сочетания Судзуки, выбранный из спиртового растворителя с точкой кипения, равной, по меньшей мере, точке кипения изо-пропилового спирта, полярного апротонного растворителя или простого эфирного растворителя, или смеси любых из названных выше растворителей с водой или толуолом.
21. Способ по п.20, в котором растворителем сочетания Судзуки является спиртовой растворитель с точкой кипения равной, по меньшей мере, точке кипения изо-пропилового спирта.
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| FR2955324A1 (fr) * | 2010-01-15 | 2011-07-22 | Sanofi Aventis | [4-(5-aminomethyl-phenyl)-piperidin-1-yl]-1h-indol-3-yl]-methanones disubstituees |
| EP2516428A1 (en) * | 2009-12-23 | 2012-10-31 | Sanofi | Tropinone benzylamines as beta-tryptase inhibitors |
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| RU2012131327A (ru) * | 2009-12-23 | 2014-02-10 | Санофи | Лечение воспалительного заболевания кишечника |
| RU2012131341A (ru) * | 2009-12-23 | 2014-01-27 | Санофи | Индол-пиперидинилбензиламины как ингибиторы бета-триптазы |
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| AR065858A1 (es) * | 2007-03-29 | 2009-07-08 | Sanofi Aventis | Metodo para preparar el inhibidor de triptasa [ 4-(5-aminoetil-2-fluoro-fenil)-piperidin-1-il]-(4-bromo-3-metil-5-propoxi-tiofen-2-il)-metanona. |
| AR065859A1 (es) * | 2007-03-29 | 2009-07-08 | Sanofi Aventis | Ester de 2,5-dioxo-pirrolidin-1-ilo de acido 4-bromo-3-metil-5-propoxitiofen-2- carboxilico ,su sintesis regioespecifica y un intermedio del mismo |
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