ES2553255T3 - Procedimiento para fabricar materiales de partida para N-hidroxi-3-[4-[2-(2-metil-1H-indol-3-il)-etilaminometil]-fenil]-2E-2-propenamida - Google Patents
Procedimiento para fabricar materiales de partida para N-hidroxi-3-[4-[2-(2-metil-1H-indol-3-il)-etilaminometil]-fenil]-2E-2-propenamida Download PDFInfo
- Publication number
- ES2553255T3 ES2553255T3 ES11179043.2T ES11179043T ES2553255T3 ES 2553255 T3 ES2553255 T3 ES 2553255T3 ES 11179043 T ES11179043 T ES 11179043T ES 2553255 T3 ES2553255 T3 ES 2553255T3
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- Prior art keywords
- methyl
- phenyl
- mixture
- indol
- hydroxy
- Prior art date
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- 238000000034 method Methods 0.000 title abstract description 9
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 title description 2
- 239000007858 starting material Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 abstract description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 abstract description 3
- XVXVAVCOKYEXMZ-ZHACJKMWSA-N (e)-3-[4-[[2-(2-methyl-1h-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enoic acid Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(O)=O)C=C1 XVXVAVCOKYEXMZ-ZHACJKMWSA-N 0.000 abstract description 2
- -1 2-methyl-1H-indole-3-yl Chemical group 0.000 abstract description 2
- 150000004702 methyl esters Chemical class 0.000 abstract description 2
- 150000002466 imines Chemical class 0.000 abstract 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- KVXMLLMZXPRPNG-VOTSOKGWSA-N methyl (e)-3-(4-formylphenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(C=O)C=C1 KVXMLLMZXPRPNG-VOTSOKGWSA-N 0.000 abstract 1
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract 1
- 239000012279 sodium borohydride Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- CPVSLHQIPGTMLH-UHFFFAOYSA-N 2-(2-methyl-1h-indol-3-yl)ethanamine Chemical compound C1=CC=C2C(CCN)=C(C)NC2=C1 CPVSLHQIPGTMLH-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XVRIEWDDMODMGA-UHFFFAOYSA-N 5-chloropentan-2-one Chemical compound CC(=O)CCCCl XVRIEWDDMODMGA-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 3
- 229940067157 phenylhydrazine Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Un método para fabricar sal de hidrocloruro de éster metílico de ácido (E)-3 -(4- {[2-(2-metil-1H-indol-3-il)- etilamino]-metil]-fenil)-acrílico que comprende las etapas de: (a) combinar 2-metiltriptamina y éster metílico de ácido (E)-3-(4-formil-fenil)-acrílico para formar una mezcla; (b) agitar la mezcla durante un tiempo y a una temperatura suficiente para formar un intermedio imina; y (c) reducir el intermedio imina para formar la sal de hidrocloruro de éster metílico de ácido (E)-3-(4-{[2-(2-metil-1Hindol- 3-il)-etilamino]-metil]-fenil)-acrílico; en donde la etapa (c) comprende las sub-etapas de: (c1) enfriar la mezcla; (c2) añadir borohidruro sódico a la mezcla; y (c3) combinar la mezcla con ácido clorhídrico para precipitar la sal de hidrocloruro de éster metílico de ácido (E)-3- (4-{[2-(2-metil-1H-indol-3-il)-etilamino]-metil]-fenil)-acrílico.
Description
5
15
25
35
45
55
equimolares de fenilhidracina y 5-cloro-2-pentanona. Así, la fenilhidracina se usa preferiblemente en una cantidad que oscila de aproximadamente ,5 a aproximadamente 1,5, y la 5-cloro-2-pentanona se usa preferiblemente en una cantidad que oscila de aproximadamente 1 a aproximadamente 2. En una realización preferida de la presente descripción, la etapa (a) comprende las sub-etapas de: (a1) proporcionar una disolución de fenilhidracina en etanol; (a2) calentar la disolución a una temperatura que oscila de aproximadamente 30°C a aproximadamente 40°C, más preferiblemente una temperatura de aproximadamente 30-40°C; (a3) mantener la reacción a una temperatura que oscila de aproximadamente 35°C a aproximadamente 45°C, mientras se añade 5-cloro-2-pentanona a la mezcla de reacción, típicamente durante un periodo de tiempo de aproximadamente 15-45 minutos; y (a4) mantener la reacción durante un periodo de aproximadamente 30-60 minutos] a la temperatura de la etapa (a3). En esta etapa, el control cuidadoso de los parámetros de temperatura y tiempo es importante en términos de control de impurezas.
En la segunda etapa del método de la tercera realización de referencia, se añade etanol a la mezcla y la mezcla se pone a reflujo. Se añade etanol preferiblemente en una cantidad que oscila de aproximadamente 10 a aproximadamente 20 partes. Típicamente, la mezcla de reacción se calienta inmediatamente a reflujo y se deja durante 50-60 minutos mínimo. Después de reflujo, la mezcla de reacción se enfría típicamente a temperatura ambiente durante un periodo de aproximadamente 20 minutos.
En la tercera etapa del método de la tercera realización de referencia, se destila etanol. La destilación puede conseguirse usando cualquier medio adecuado; la destilación al vacío se prefiere particularmente para este propósito. La destilación parcial de etanol se realiza típicamente midiendo el volumen en el matraz.
En la cuarta etapa del método de la tercera realización de referencia, se añade agua a la disolución residual. Se añade agua preferiblemente en una cantidad que oscila de aproximadamente 10 a aproximadamente 20 partes. En un procedimiento típico, la destilación se continúa en las mismas condiciones eliminando etanol y después se añade agua adicional a la mezcla residual. Se añade agua preferiblemente en una cantidad que oscila de aproximadamente 10 a aproximadamente 20 partes.
En la quinta etapa del método de la tercera realización de referencia, la disolución residual se enfría para formar 2metiltriptamina. Típicamente, la disolución residual se enfría a una temperatura de menos de aproximadamente 25°C.
El método de la tercera realización de referencia puede comprender además la etapa de (f) aislar y purificar la 2metiltriptamina. En realizaciones preferidas de la presente descripción, la etapa (f) incluye las sub-etapas de: (f1) lavar la disolución residual con tolueno; (f2) aislar la 2-metiltriptamina; (f3) lavar la 2-metiltriptamina con tolueno; y (f4) secar la 2-metiltriptamina.
En la etapa (f1), la disolución residual se lava con tolueno. En la etapa (f2), la 2-metiltriptamina se aísla. El aislamiento puede conseguirse por cualquier medio adecuado. En la etapa (f3), la 2-metiltriptamina se lava con tolueno, preferiblemente tolueno frío, es decir, ≤ 0°C. En la etapa (f4), la 2-metiltriptamina se seca. El secado puede conseguirse por cualquier medio adecuado. El secado al vacío a 45°C hasta que se obtiene un LOD de < 1% se prefiere particularmente.
El método de la tercera realización de referencia puede usarse para producir 2-metiltriptamina que es un material de partida en la síntesis de sal de hidrocloruro de éster metílico de ácido (E)-3-(4-{[2-(2-metil-1H-indol-3-il)-etilamino]metil]-fenil)-acrílico.
Las realizaciones específicas de la invención se demostrarán ahora por referencia a los siguientes ejemplos. Debería entenderse que estos ejemplos se describen solamente como medio de ilustración de la invención y no deberían tomarse de ninguna forma para limitar el alcance de la presente invención.
Ejemplo de referencia 1
Preparación de N-hidroxi-3-[4-[[[2-(2-metil-1H-indol-3-il)etil]amino]metil]fenil]-2E-2-propenamida
La sal de hidrocloruro de éster metílico de ácido (E)-3-(4-{[2-(2-metil-1H-indol-3-il)-etilamino]-metil]-fenil)-acrílico (90 g, 233,8 mmoles) se coloca en un matraz de reacción de 4 cuellos y se añade metanol (475 g). La suspensión se enfría a -15°C. Una disolución de hidróxido sódico (28,2 g, 705 mmoles) en metanol (419,2 g) se añade a la suspensión a -15°C (tiempo de adición alrededor de 30 minutos), seguido por la adición de la disolución de hidroxilamina (100,3 g de una disolución al 50% en agua, que corresponde a 50,15 g de hidroxilamina, 1518 mmoles) a esta temperatura (tiempo de adición alrededor de 30 minutos). Advertencia: es importante usar diferentes embudos de adición para las disoluciones de hidróxido sódico e hidroxilamina respectivamente. La agitación se continua a -15°C durante unas 7 horas adicionales hasta que se alcanza una conversión de >99,5% en área según el HPLC. La mezcla de reacción se calienta a 0°C, se agita durante 5 horas a 0-5°C, se calienta a 20°C y la agitación se continúa durante 8 horas a 20-25°C. Se añade agua desmineralizada (225 g) a la suspensión a 20-25°C durante 30 minutos para obtener una disolución. La disolución se filtra y el filtro además del conducto del filtro se lava con agua desmineralizada (225 g). El pH de la disolución se ajusta a 10,3-10,7 mediante la adición de una disolución acuosa de ácido clorhídrico (alrededor de 140 g de una disolución de 7,8% en m/m en agua). Se añaden cristales de siembra a una suspensión de base libre de N-hidroxi-3-[4-[[[2-(2-metil-1H-indol-3-il)etil]amino]metil]fenil]-2E-2
7
Claims (1)
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imagen1 imagen2
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80452706P | 2006-06-12 | 2006-06-12 | |
| US804527P | 2006-06-12 | ||
| US86787806P | 2006-11-30 | 2006-11-30 | |
| US867878P | 2006-11-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2553255T3 true ES2553255T3 (es) | 2015-12-07 |
Family
ID=38832681
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES07784350T Active ES2416286T3 (es) | 2006-06-12 | 2007-06-07 | Proceso para la fabricación de N-hidroxi-3-[4-[[[2-(2-metil-1H-indol-3-il)etil]amino]metil] fenil]-2E-2-propenamida y los materiales de partida para la misma |
| ES11179043.2T Active ES2553255T3 (es) | 2006-06-12 | 2007-06-07 | Procedimiento para fabricar materiales de partida para N-hidroxi-3-[4-[2-(2-metil-1H-indol-3-il)-etilaminometil]-fenil]-2E-2-propenamida |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES07784350T Active ES2416286T3 (es) | 2006-06-12 | 2007-06-07 | Proceso para la fabricación de N-hidroxi-3-[4-[[[2-(2-metil-1H-indol-3-il)etil]amino]metil] fenil]-2E-2-propenamida y los materiales de partida para la misma |
Country Status (31)
| Country | Link |
|---|---|
| US (2) | US20090306405A1 (es) |
| EP (2) | EP2032533B8 (es) |
| JP (2) | JP5431926B2 (es) |
| KR (2) | KR101540194B1 (es) |
| CN (4) | CN102167678B (es) |
| AR (1) | AR061296A1 (es) |
| AU (1) | AU2007257883B2 (es) |
| BR (1) | BRPI0712847A2 (es) |
| CA (1) | CA2653657C (es) |
| CL (2) | CL2007001691A1 (es) |
| DK (1) | DK2032533T3 (es) |
| EC (1) | ECSP088978A (es) |
| ES (2) | ES2416286T3 (es) |
| GT (1) | GT200800282A (es) |
| HR (1) | HRP20130798T1 (es) |
| IL (2) | IL195211A (es) |
| IN (1) | IN2015DN00910A (es) |
| JO (1) | JO2900B1 (es) |
| MA (1) | MA30513B1 (es) |
| MX (2) | MX2008015898A (es) |
| MY (1) | MY147576A (es) |
| NO (1) | NO341870B1 (es) |
| NZ (1) | NZ572707A (es) |
| PE (2) | PE20080851A1 (es) |
| PL (1) | PL2032533T3 (es) |
| PT (1) | PT2032533E (es) |
| RU (1) | RU2448090C2 (es) |
| TN (1) | TNSN08507A1 (es) |
| TW (1) | TWI395734B (es) |
| WO (1) | WO2007146718A2 (es) |
| ZA (1) | ZA200809490B (es) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202000004075A1 (it) * | 2020-02-27 | 2021-08-27 | Flamma Spa | Processo per la preparazione di panobinostat |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB146260A (en) | 1918-07-11 | 1921-08-11 | Elektro Osmose Ag | A process for preparing proteids charged with immune substances |
| GB8531612D0 (en) * | 1985-12-23 | 1986-02-05 | Beecham Wuelfing Gmbh & Co Kg | Compounds |
| PE20020354A1 (es) * | 2000-09-01 | 2002-06-12 | Novartis Ag | Compuestos de hidroxamato como inhibidores de histona-desacetilasa (hda) |
| WO2002055742A2 (en) | 2001-01-09 | 2002-07-18 | Novartis Ag | Rapid method for screening compounds for in vivo activity |
| IL160970A0 (en) | 2001-11-06 | 2004-08-31 | Novartis Ag | Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination |
| KR20090026282A (ko) * | 2006-06-12 | 2009-03-12 | 노파르티스 아게 | Ｎ-히드록시-３-[４-[[[２-(２-메틸-1ｈ-인돌-３-일)에틸]아미노]메틸]페닐]-2ｅ-２-프로펜아미드의 염을 제조하는 방법 |
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2007
- 2007-06-07 CN CN2011100629486A patent/CN102167678B/zh active Active
- 2007-06-07 ES ES07784350T patent/ES2416286T3/es active Active
- 2007-06-07 HR HRP20130798TT patent/HRP20130798T1/hr unknown
- 2007-06-07 EP EP07784350.6A patent/EP2032533B8/en active Active
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