ES2629751T3 - Derivados de pirazol novedosos - Google Patents
Derivados de pirazol novedosos Download PDFInfo
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- ES2629751T3 ES2629751T3 ES14709590.5T ES14709590T ES2629751T3 ES 2629751 T3 ES2629751 T3 ES 2629751T3 ES 14709590 T ES14709590 T ES 14709590T ES 2629751 T3 ES2629751 T3 ES 2629751T3
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- substituted
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- alkoxy
- cycloalkyl
- halogen
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- 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
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
Un compuesto de fórmula (I)**Fórmula** en la que A1 es -CH- o nitrógeno; A2 es -CH- o nitrógeno; A3 es -(CH2)n- o -CH2C(O)-; R1 es alquilo, cicloalquilo, alcoxi o halógeno; R2 es alcoxi, pirrolidinilo sustituido o dihidropirrolilo sustituido, en el que pirrolidinilo sustituido y dihidropirrolilo sustituido son pirrolidinilo y dihidropirrolilo sustituidos con uno o dos sustituyentes independientemente seleccionados de halógeno, hidroxilo, hidroxialquilo, alcoxialquilo y alquilfurazanilalcoxi; R3 es fenilo, fenilo sustituido, furazanilo sustituido, piridinilo, piridinilo sustituido, dioxotietanilo, tetrahidrofuranilo, tetrazolilo sustituido o triazolilo sustituido, en el que fenilo sustituido, piridinilo sustituido y triazolilo sustituido son fenilo, piridinilo y triazolilo sustituidos con uno o dos sustituyentes independientemente seleccionados de alquilo, alcoxi, halógeno, haloalquilo, alquilsulfonilo y cicloalquilo, y en el que tetrazolilo sustituido y furazanilo sustituido son tetrazolilo y furazanilo sustituidos con un sustituyente seleccionado de alquilo, alcoxi, halógeno, haloalquilo, alquilsulfonilo y cicloalquilo; n es 1 o 2; siempre que A1 y A2 30 no sean ambos carbono al mismo tiempo; o una sal o éster farmacéuticamente aceptable del mismo; en la que "alquilo", solo o en combinación, es un grupo alquilo de cadena lineal o cadena ramificada con 1 a 8 átomos de carbono; "cicloalquilo", solo o en combinación, es un anillo cicloalquilo con 3 a 8 átomos de carbono; y "alcoxi", solo o en combinación, es un grupo de la fórmula alquil-O-.
Description
en presencia de R2H y una base;
(b) la reacción de un compuesto de fórmula (B)
en presencia de R3-A3-X y una base;
(c) la reacción de un compuesto de fórmula (C)
15 en presencia de MR1, un catalizador de paladio y una base;
(d) la reacción de un compuesto de fórmula (D)
20 en presencia de MR1, un catalizador de paladio y una base;
en la que A1 a A3 y R1 a R3 son como se definen anteriormente, X es un grupo saliente y M es una especie de metal adecuadamente sustituida, como una especie de boro, borilo, trifluoro-borato o estannilo. 25 En la etapa (a), la base es por ejemplo DIEA.
La etapa (a) se lleva a cabo en particular ventajosamente en un disolvente inerte, tal como DMF. La etapa (a) se puede llevar a cabo convenientemente a 120 ºC. 30 En la etapa (b), la base es por ejemplo terc-butóxido, carbonato de cesio o carbonato de potasio.
La etapa (b) se lleva a cabo en particular ventajosamente en un disolvente inerte, como DMF o DMA. La etapa (b) se puede llevar a cabo convenientemente a 120 ºC.
35 En la etapa (c), el catalizador de paladio es por ejemplo acetato de paladio(II). La etapa (c) se lleva a cabo preferentemente en presencia de una fosfina, particularmente n-butil-di-adamantilfosfina.
12
6-terc-butil-1-[(2-clorofenil)metil]-4-etoxi-1H-pirazolo[3,4-d]pirimidina
5 El compuesto del título se sintetizó en analogía con los ejemplos 1c a 1f, usando 5-amino-1-[(2-clorofenil)metil]-1Hpirazol-4-carboxamida (CAN 106898-48-0), cloruro de pivaloílo y etanol como materiales de partida, y se aisló (15 mg) como un aceite incoloro; CLEM (área de pico UV, ESI) 83 %, 345,5 [MH+].
6-terc-butil-1-[(2-cloro-4-fluorofenil)metil]-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo[3,4-d]pirimidina
a) 6-terc-butil-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo[3,4-d]pirimidina 15
A una mezcla de 6-terc-butil-4-(3,3-difluoro-pirrolidin-1-il)-1-(4-metoxi-bencil)-1H-pirazolo[3,4-d]pirimidina (0,174 g, 0,43 mmol) y TFA (870 µl, 11,3 mmol) en DCM (3 ml) se le añadió ácido metanosulfónico (141 µl, 2,17 mmol). La
20 mezcla se agitó durante 1 hora a 0 ºC y durante 1,5 horas a temperatura ambiente. Después de esto, la mezcla se volvió básica con solución de hidróxido de sodio (2,5 ml, 25 %, enfriamiento) y se repartió entre agua y DCM. Se mezclaron las fases orgánicas, se secó con MgSO4, se filtró y se concentró a vacío. El residuo, 135 mg del compuesto del título como un sólido amarillo claro, se usó sin purificación adicional; CLEM (área de pico UV, ESI) 80 %, 282,5 [MH+].
25 b) 6-terc-butil-1-(2-cloro-4-fluoro-bencil)-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo [3,4-d]pirimidina
30 A una solución de 6-terc-butil-4-(3,3-difluoro-pirrolidin-1-il)-1H-pirazolo[3,4-d]pirimidina (30 mg, 107 µmol) en acetona (1 ml) y DMF (2 ml) se le añadió 2-cloro-1-(clorometil)-4-fluoro-benceno (23 mg, 128 µmol) y carbonato de potasio (44 mg, 318 µmol). La mezcla se sometió a microondas durante 45 minutos a 120 ºC, se enfrió y se repartió entre agua y acetato de etilo. Se mezclaron las fases orgánicas, se secó por filtración sobre ChemElut®, y se concentró a vacío. El residuo se purificó por HPLC preparativa (Gemini NX, gradiente de agua/acetonitrilo), para proporcionar el
18
- Ejemplo
- CE50 de CB2 humano [µM] CE50 de CB1 humano [µM]
- 1
- 0,0048 >10
- 2
- 0,0033 >10
- 3
- 0,0051 >10
- 4
- 0,0042 >10
- 5
- 0,0255 >10
- 6
- 0,0059 >10
- 7
- 0,0011 >10
- 8
- 0,0054 >10
- 9
- 0,0005 >10
- 10
- 0,0007 0,3368
- 11
- 0,0187 >10
- 12
- 0,0016 1,5741
- 13
- 0,0196 >10
- 14
- 0,0013 >10
- 15
- 0,0009 >10
- 16
- 0,0006 >10
- 17
- 0.003 >10
- 18
- 0,0262 >10
- 19
- 0,0014 >10
- 20
- 0,0016 >10
- 21
- 0,0034 >10
- 22
- 0,0084 >10
- 23
- 0,0055 >10
- 24
- 0,0175 >10
- 25
- 0,0004 >10
- 26
- 0,0356 >10
- 27
- 0,0425 >10
- 28
- 0,0019 >10
- 29
- 0,0019 >10
- 30
- 0,0024 >10
- 31
- 0,0173 >10
- 32
- 0,0015 >10
- 33
- 0,0088 >10
- 34
- 0.005 >10
- 35
- 0,0133 >10
- 36
- 0,0014 >10
- 37
- 0,0172 >10
- 38
- 0,0160 >10
Los comprimidos recubiertos con película que contienen los siguientes ingredientes se pueden fabricar de manera convencional:
- Ingredientes
- Por comprimido
- Núcleo:
- Compuesto de fórmula (I)
- 10,0 mg 200,0 mg
- Celulosa microcristalina
- 23,5 mg 43,5 mg
- Lactosa hidratada
- 60,0 mg 70,0 mg
- Povidona K30
- 12,5 mg 15,0 mg
- Glicolato sódico de almidón
- 12,5 mg 17,0 mg
- Estearato de magnesio
- 1,5 mg 4,5 mg
- (Peso del núcleo)
- 120,0 mg 350,0 mg
- Recubrimiento de película:
- Hidroxipropilmetilcelulosa
- 3,5 mg 7,0 mg
- Polietilenglicol 6000
- 0,8 mg 1,6 mg
- Talco
- 1,3 mg 2,6 mg
- Óxido de hierro (amarillo)
- 0,8 mg 1,6 mg
- Dióxido de titanio
- 0,8 mg 1,6 mg
41
Claims (1)
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imagen1 imagen2 imagen3 imagen4
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13158233 | 2013-03-07 | ||
EP13158233 | 2013-03-07 | ||
PCT/EP2014/054107 WO2014135507A1 (en) | 2013-03-07 | 2014-03-04 | Novel pyrazol derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
ES2629751T3 true ES2629751T3 (es) | 2017-08-14 |
Family
ID=47827068
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES14709590.5T Active ES2629751T3 (es) | 2013-03-07 | 2014-03-04 | Derivados de pirazol novedosos |
Country Status (35)
Country | Link |
---|---|
US (2) | US9512132B2 (es) |
EP (1) | EP2964646B1 (es) |
JP (2) | JP6514119B2 (es) |
KR (2) | KR102217297B1 (es) |
CN (1) | CN105143220B (es) |
AR (1) | AR094978A1 (es) |
AU (1) | AU2014224784B2 (es) |
BR (1) | BR112015020795B1 (es) |
CA (1) | CA2897513C (es) |
CL (1) | CL2015002387A1 (es) |
CR (1) | CR20150447A (es) |
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EA (1) | EA027935B1 (es) |
ES (1) | ES2629751T3 (es) |
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NZ (1) | NZ710052A (es) |
PE (1) | PE20151539A1 (es) |
PH (1) | PH12015501843A1 (es) |
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SG (1) | SG11201507168XA (es) |
SI (1) | SI2964646T1 (es) |
TW (1) | TWI609866B (es) |
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Families Citing this family (17)
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MA38403A1 (fr) * | 2013-03-07 | 2017-11-30 | Hoffmann La Roche | Nouveaux dérivés de pyrazole modulateurs specifiques de cb2 |
CN105121436B (zh) | 2013-03-26 | 2018-07-27 | 豪夫迈·罗氏有限公司 | 新的吡啶衍生物 |
SG11201509029PA (en) | 2013-05-02 | 2015-12-30 | Hoffmann La Roche | Pyrrolo[2,3-d]pyrimidine derivatives as cb2 receptor agonists |
SG11201509014UA (en) | 2013-05-02 | 2015-11-27 | Hoffmann La Roche | Purine derivatives as cb2 receptor agonists |
SG11201601714UA (en) | 2013-09-06 | 2016-04-28 | Hoffmann La Roche | Novel triazolo[4,5-d]pyrimidine derivatives |
WO2016149169A1 (en) * | 2015-03-13 | 2016-09-22 | Abbvie Inc. | (indazol-4-yl)hexahydropyrrolopyrrolones and method of use |
WO2016191935A1 (en) * | 2015-05-29 | 2016-12-08 | Merck Sharp & Dohme Corp. | 6-alkyl dihydropyrazolopyrimidinone compounds as pde2 inhibitors |
WO2016192083A1 (en) * | 2015-06-04 | 2016-12-08 | Merck Sharp & Dohme Corp. | Dihydropyrazolopyrimidinone compounds as pde2 inhibitors |
EP3475280B1 (en) | 2016-06-23 | 2020-04-08 | H. Hoffnabb-La Roche Ag | Novel [1,2,3]triazolo[4,5-d]pyrimidine derivatives |
CN113943297A (zh) | 2016-06-23 | 2022-01-18 | 豪夫迈·罗氏有限公司 | 对2型大麻素受体具有亲和力的[1,2,3]三唑并[4,5-d]嘧啶衍生物 |
WO2018015088A1 (en) | 2016-06-23 | 2018-01-25 | F. Hoffmann-La Roche Ag | Novel [1,2,31triazolo[4,5-d]pyrimidine derivatives |
JP7090036B2 (ja) | 2016-06-23 | 2022-06-23 | エフ.ホフマン-ラ ロシュ アーゲー | 新規な[1,2,3]トリアゾロ[4,5-d]ピリミジン誘導体 |
EP3950920A4 (en) | 2019-03-25 | 2023-02-01 | Nikon Corporation | DEVICE AND METHOD FOR CELL MANIPULATION |
MX2023002850A (es) | 2020-09-10 | 2023-07-07 | Precirix N V | Fragmento de anticuerpo contra proteina activadora de fibroblastos (fap). |
WO2023203135A1 (en) | 2022-04-22 | 2023-10-26 | Precirix N.V. | Improved radiolabelled antibody |
WO2023213801A1 (en) | 2022-05-02 | 2023-11-09 | Precirix N.V. | Pre-targeting |
CN115246832B (zh) * | 2022-06-15 | 2024-05-24 | 深圳湾实验室 | 一类去泛素化酶usp25和usp28靶向抑制剂及制备和应用 |
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US2980677A (en) * | 1961-04-18 | Certificate of correction | ||
JP2004502642A (ja) * | 2000-02-11 | 2004-01-29 | ブリストル−マイヤーズ スクイブ カンパニー | カンナビノイドレセプターモジュレーター、それらの製造方法、および呼吸系および非呼吸系疾患の処置のためのカンナビノイドレセプターモジュレーターの使用 |
CA2479744A1 (en) | 2002-03-28 | 2003-10-09 | Paul E. Finke | Substituted 2,3-diphenyl pyridines |
DE10219435A1 (de) * | 2002-05-02 | 2003-11-13 | Bayer Cropscience Ag | Substituierte Pyrazolo-pyrimidin-4-one |
AR051596A1 (es) * | 2004-10-26 | 2007-01-24 | Irm Llc | Compuestos heterociclicos condensados nitrogenados como inhibidores de la actividad del receptor canabinoide 1; composiciones farmaceuticas que los contienen y su empleo en la preparacion de medicamentos para el tratamiento de trastornos alimentarios |
EP2211619A1 (en) | 2007-10-18 | 2010-08-04 | Merck Sharp & Dohme Corp. | Substituted 1,2,4-oxadiazoles and analogs thereof as cb2 receptor modulators, useful in the treatment of pain, respiratory and non-respiratory diseases |
WO2010118367A2 (en) * | 2009-04-10 | 2010-10-14 | Progenics Pharmaceuticals, Inc. | Antiviral pyrimidines |
US9321727B2 (en) | 2011-06-10 | 2016-04-26 | Hoffmann-La Roche Inc. | Pyridine derivatives as agonists of the CB2 receptor |
UA111640C2 (uk) | 2011-11-08 | 2016-05-25 | Ф. Хоффманн-Ля Рош Аг | ПОХІДНІ [1,2,3]ТРИАЗОЛО[4,5-d]ПІРИМІДИНУ ЯК АГОНІСТИ КАНАБІНОЇДНОГО РЕЦЕПТОРА 2 |
EP2870139B1 (en) | 2012-07-04 | 2016-06-15 | F.Hoffmann-La Roche Ag | Novel adamantyl derivatives as cannabinoid receptor 2 agonists |
PT2928867T (pt) | 2012-12-07 | 2017-10-04 | Hoffmann La Roche | Piridinas-2-amidas úteis como agonistas de cb2 |
AU2013354278B2 (en) | 2012-12-07 | 2017-10-12 | F. Hoffmann-La Roche Ag | Novel pyridine derivatives |
BR112015009600A2 (pt) | 2012-12-07 | 2017-07-04 | Hoffmann La Roche | piridina-2-amidas úteis como agonistas cb2 |
UA116894C2 (uk) | 2012-12-07 | 2018-05-25 | Ф. Хоффманн-Ля Рош Аг | Похідні піразину як агоністи канабіноїдного рецептора 2 |
MA38403A1 (fr) * | 2013-03-07 | 2017-11-30 | Hoffmann La Roche | Nouveaux dérivés de pyrazole modulateurs specifiques de cb2 |
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