ES2529653T3 - Sales de 2,3-dihidroimidazo[1,2-c]quinazolina sustituidas - Google Patents
Sales de 2,3-dihidroimidazo[1,2-c]quinazolina sustituidas Download PDFInfo
- Publication number
- ES2529653T3 ES2529653T3 ES12712104.4T ES12712104T ES2529653T3 ES 2529653 T3 ES2529653 T3 ES 2529653T3 ES 12712104 T ES12712104 T ES 12712104T ES 2529653 T3 ES2529653 T3 ES 2529653T3
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- Prior art keywords
- slightly colored
- solution
- colored solution
- dihydroimidazo
- week
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Classifications
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- 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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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Sal de dihidrocloruro de 2-amino-N-[7-metoxi-8-(3-morfolin-4-ilpropoxi)-2,3-dihidroimidazo-[1,2-c]quinazolin-5- il]pirimidin-5-carboxamida de fórmula (II):**fórmula** o un solvato, hidrato o tautómero de la misma.
Description
Tampón pH 4,5 8900 mg/100 ml soluble Tampón pH 7,0 8700 mg/100 ml soluble Agua 9400 mg/100 ml soluble
Estabilidad en disolución:
Estabilidad hidrolítica
Las diferentes disoluciones acuosas (0,05% de base libre de fórmula (I); tras la adición de 2-propanol al 50%, [disolución tampón filtrada con filtro de membrana de 0,5 m]) se almacenaron a 25ºC y 70ºC durante 24 h y una semana.
- Condiciones
- Aspecto Impurezas orgánicas, suma de todas [% de área] Impurezas orgánicas, individuales [% de área]
- Agua:
- Inicial
- disolución ligeramente coloreada 2,79 0,25
- 24 h, 25ºC
- disolución ligeramente coloreada 3,43 0,23
- 24 h, 70ºC
- disolución ligeramente coloreada 58,00 25,89
- 1 semana, 25ºC
- disolución ligeramente coloreada 5,33 0,54
- 1 semana, 70ºC
- disolución ligeramente coloreada 98,59 45,44
- Tampón pH 7:
- Inicial
- disolución turbia ligeramente coloreada 3,15 0,23
- 24 h, 25ºC
- disolución turbia ligeramente coloreada 3,22 0,20
- 24 h, 70ºC
- disolución ligeramente coloreada 56,06 23,25
- 1 semana, 25ºC
- disolución turbia ligeramente coloreada 4,85 0,82
- 1 semana, 70ºC
- disolución ligeramente coloreada 97,65 39,01
- HCl 0,9M:
- Inicial
- disolución ligeramente coloreada 5,87 1,13
- 24 h, 25ºC
- disolución ligeramente coloreada 8,75 1,90
- 24 h, 70ºC
- disolución ligeramente coloreada 92,49 22,82
- 1 semana, 25ºC
- disolución ligeramente coloreada 24,27 7,15
- 1 semana, 70ºC
- disolución ligeramente coloreada 100,00 25,48
- NaOH 0,1 M:
- Inicial
- disolución ligeramente coloreada 30,72 6,51
- 24 h, 25ºC
- disolución ligeramente coloreada 45,40 10,02
- 24 h, 70ºC
- disolución ligeramente coloreada 99,88 23,94
- 1 semana, 25ºC
- disolución ligeramente coloreada 86,64 22,03
- 1 semana, 70ºC
- disolución ligeramente coloreada 99,90 32,63
Espectroscopía IR y Raman
10
- Espectrómetro RMN
- Bruker, modelo Avance
- Frecuencia de trabajo
- 500,13 MHz
- Disolvente
- Dimetilsulfóxido (DMSO-d6)
- Compuesto de referencia interna
- Tetrametilsilano (TMS)
- Concentración
- Disolución 3,08 mg/ml
- Diámetro del tubo de muestra
- 5 mm
- Temperatura
- aprox. 25ºC
- Técnica
- Modo transformada de Fourier
- Anchura espectral
- 20,65 ppm
- Resolución digital
- 0,079 Hz/Pt
- Longitud del pulso
- 4,5 s, ángulo de rotación de la magnetización longitudinal 30º
- Tiempo de adquisición
- 6,34 s
- Tiempo de relajación
- 0,5 s
- Nº de decaimientos de inducción libre
- 32
Fórmula estructural para la asignación de señales de RNM
Desplazamiento químico, multiplicidad de señales, número relativo de núcleos:
- Átomos de H (a)
- Desplazamiento químico Multiplicidad y constantes de Nº de núcleos de H /molécula
- (ppm)
- acoplamiento (b)
- H-26
- 2,32 M 2
- H-29; H-33
- 3,11; 3,48 M; M 2; 2
- H-30; H-32
- 3,83; 3,98 M; M 2; 2
- H-27
- 3,29 M 2
- -OCH3
- 4,00 S 3
- H-25
- 4,37 T 2
- H-2; H-3
- 4,47; 4,19 T; T 2; 2
- H-9
- 7,39 D 1
- NH2
- 7,54 S 2
- H-10
- 8,21 D 1
12
Átomos de H (a) Desplazamiento químico Multiplicidad y constantes de Nº de núcleos de H /molécula (ppm) acoplamiento (b)
- H-16; H-20
- 8,97 S 1; 1
- HCl
- 11,1; 12,6 bS; bS 1; 1
- H-12
- 13,4 bS 1
a) La numeración se refiere a la fórmula estructural para la asignación de señales de RMN. b) S = Singlete bS = Singlete ancho D = Doblete T = Triplete M = Multiplete
El espectro de RMN 1H del dihidrocloruro de fórmula (II) se da en la Figura 4. Espectroscopía de RMN 13C Equipo y parámetros experimentales
- Espectrómetro RMN
- Bruker, modelo Avance
- Frecuencia de trabajo
- 125,76 MHz
- Disolvente
- Dimetilsulfóxido-d6 (DMSO)
- Compuesto de referencia interna
- Tetrametilsilano (TMS)
- Concentración
- Disolución 37,2 mg/ml
- Diámetro del tubo de muestra
- 5 mm
- Temperatura
- aprox. 27ºC
- Técnica
- Modo transformada de Fourier
- Anchura espectral
- 240,95 ppm
- Resolución digital
- 0,4624 Hz/Pt
- Longitud del pulso
- 11,0 s, ángulo de rotación de la magnetización longitudinal 90º
- Tiempo de adquisición
- 1,08 s
- Tiempo de relajación
- 4 s
- Nº de decaimientos de inducción libre
- 256
- 5
- Desplazamiento químico, multiplicidad de señales, número relativo de núcleos:
- Átomos de C (a)
- Desplazamiento químico (ppm) Multiplicidad yacoplamiento (b) constantes de Nº de núcleos /molécula de C
- C-26
- 22,73 T 1
- C-2; C-3
- 44,96; 45,65 T;T 1; 1
- C-29; C-33
- 50,84 T 1; 1
- C-27
- 53,01 T 1
- OCH3
- 61,24 Q 1
- 13
Tabla 5
- Propiedad
- Ácido cítrico (Ej. Comp. 3) Ácido succínico (Ej. Comp. 4) Ácido maleico (Ej. Comp. 5) Ácido mesulfónico (Ej. Comp. 6) Ácido clorhídrico (Ej. 1) Compuesto de fórmula (I) (base libre) Criterios
- estequiometría
- 1: 1 1: 1 1: 2 1: 2 1: 2 Basado en HPLC/IC
- procedimiento quím.
- ○ - ○ - ○ - rendimiento, procesamiento final
- pureza
- + + ○ ○ + ○ HPLC % de área
- estabilidad de la sal
- ○ - + n.d. ++ n.a. disgregación con/en agua
- cristalinidad
- ○ - + ○ ++ ○ XRPD
- hidratos
- 4 H2O 1 w a 95% r.h.; solub. ac
- solubilidad ac.
- 8,5. 5,5 > 8,1 > 8,3 > 8,8 - 16 h a 25ºC (mg/100ml)
- estab. term. disolución
- n.d. n.d. n.d. n.d. n.d. ○ 24 h a 70ºC; 1 w a 25ºC
- estab. term. sólido
- + -- + + + ++ 1 w a 90ºC
- CD global
- ○ -- ○ -- + ○
- -- muy desventajoso - desventajoso ○: indiferente +: ventajoso ++: muy ventajoso n.a.: no aplicable n.f.: no encontrado n.d.: no determinado; sin disolución transparente tras la filtración, probablemente debido a la formación de micelas.
En primer lugar, como se observa a partir del Ejemplo 1 Comparativo, inesperadamente, los resultados indican que no se formó un monohidrocloruro cristalino del compuesto de fórmula (I): fue predominantemente amorfo. Por el
5 contrario, como se observa a partir del Ejemplo 1, la sal de dihidrocloruro de fórmula (II) puede formar una sal de dihidrocloruro estable, cristalina. La sal de dihidrocloruro cristalina es estable frente a reversión en agua hacia la base libre.
Además, la sal de dihidrocloruro de la presente invención tiene una estabilidad superior en agua en comparación con las otras sales mencionadas. Eso significa que la sal no revierte en agua a la base libre en las condiciones
10 ensayadas, es decir, no se produce la precipitación de la base libre.
La cristalinidad de la sal de dihidrocloruro de la presente invención fue superior frente a la sal de monohidrocloruro (que se encontró predominantemente amorfa en XRPD).
En segundo lugar, como se observa a partir del Ejemplo 5 Comparativo, (tabla de caracterización), a partir de los
20
Tabla B. Actividad antiproliferativa de la base libre y del dihidrocloruro en ensayos de proliferación de estirpes celulares tumorales
- Estirpe celular
- Tejido IC50 de la base libre (nM) IC50 de la sal de dihidrocloruro (nM) Relación de IC50
- KPL4
- Mama 3 3 1,0
- BT474
- 5 10 0,5
- T47D
- 6 2 2,8
- BT20
- 6 2 3,1
- MCF7
- 27 9 3,0
- MDA-MB-468
- 760 256 3,0
- SK-Br-3
- 2 1 1,5
- LNCaP
- Próstata 69 67 1,0
- PC3
- 100 90 1,1
- Colo205
- Colon 48 110 0,4
- HT29
- 27 10 2,7
- HCT116
- 56 72 0,8
- A549
- Pulmón 37 44 0,8
- H460
- 46 67 0,7
- U87MG
- Cerebro 85 85 1,0
- 786O
- Riñón 116 247 0,5
Referencia:
Fuchikami K, Togame H, Sagara A, Satoh T, Gantner F, Bacon KB, Reinemer P. J Biomol Screen. 7(5):441-50 (2002). A versatile high-throughput screen for inhibitors of lipid kinase activity: development of an immobilized phospholipid plate assay for phosphoinositide 3-kinase gamma.
31
Claims (1)
-
imagen1 imagen2 imagen3 imagen4
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11161111 | 2011-04-05 | ||
| EP11161111A EP2508525A1 (en) | 2011-04-05 | 2011-04-05 | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts |
| PCT/EP2012/055600 WO2012136553A1 (en) | 2011-04-05 | 2012-03-29 | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2529653T3 true ES2529653T3 (es) | 2015-02-24 |
Family
ID=43984137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES12712104.4T Active ES2529653T3 (es) | 2011-04-05 | 2012-03-29 | Sales de 2,3-dihidroimidazo[1,2-c]quinazolina sustituidas |
Country Status (42)
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR064106A1 (es) | 2006-12-05 | 2009-03-11 | Bayer Schering Pharma Ag | Derivados de 2,3-dihidroimidazo [1,2-c] quinazolina sustituida utiles para el tratamiento de enfermedades y trastornos hiper-proliferativos asociados con la angiogenesis |
| EP2168583A1 (en) | 2008-09-24 | 2010-03-31 | Bayer Schering Pharma Aktiengesellschaft | Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines for the treatment of myeloma |
| JO3733B1 (ar) | 2011-04-05 | 2021-01-31 | Bayer Ip Gmbh | استخدام 3,2-دايهيدروايميدازو[1, 2 -c]كوينازولينات مستبدلة |
| EP2508525A1 (en) * | 2011-04-05 | 2012-10-10 | Bayer Pharma Aktiengesellschaft | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts |
| ES2708350T3 (es) * | 2013-04-08 | 2019-04-09 | Bayer Pharma AG | Uso de 2,3-dihidroimidazo[1,2-c]quinazolinas para el tratamiento de linfomas |
| SG11201509116VA (en) | 2013-06-14 | 2015-12-30 | Bayer Pharma AG | Anti-tweakr antibodies and uses thereof |
| CN103694319B (zh) * | 2013-12-20 | 2018-02-27 | 深圳翰宇药业股份有限公司 | 一种布舍瑞林的纯化方法 |
| EP3018131A1 (en) * | 2014-11-07 | 2016-05-11 | Bayer Pharma Aktiengesellschaft | Synthesis of copanlisib and its dihydrochloride salt |
| EP3018127A1 (en) * | 2014-11-07 | 2016-05-11 | Bayer Pharma Aktiengesellschaft | Synthesis of copanlisib and its dihydrochloride salt |
| SG11201707240SA (en) * | 2015-03-09 | 2017-10-30 | Bayer Pharma AG | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline-containing combinations |
| US20180042929A1 (en) * | 2015-03-09 | 2018-02-15 | Bayer Pharma Aktiengesellschaft | Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines |
| RS59878B1 (sr) | 2015-03-23 | 2020-03-31 | Bayer Pharma AG | Anti-ceacam6 antitela i njihova primena |
| EP3824908A1 (en) | 2015-04-10 | 2021-05-26 | Capsugel Belgium NV | Abiraterone acetate lipid formulations |
| MX2018009367A (es) | 2016-02-01 | 2018-11-09 | Bayer Pharma AG | Biomarcadores de copanlisib. |
| CA3012890A1 (en) | 2016-02-01 | 2017-08-10 | Bayer Pharma Aktiengesellschaft | Copanlisib biomarkers |
| EP3423105B1 (en) | 2016-03-02 | 2021-05-05 | Eisai R&D Management Co., Ltd. | Eribulin-based antibody-drug conjugates and methods of use |
| US10844066B2 (en) | 2016-03-08 | 2020-11-24 | Bayer Pharma Aktiengesellschaft | 2-amino-N-[7-methoxy-2, 3-dihydroimidazo-[1,2-c] quinazolin-5-yl] pyrimidine-5-carboxamides |
| EP3219329A1 (en) | 2016-03-17 | 2017-09-20 | Bayer Pharma Aktiengesellschaft | Combinations of copanlisib |
| JP2019532922A (ja) | 2016-09-23 | 2019-11-14 | バイエル ファーマ アクチエンゲゼルシャフト | Ｐｉ３ｋ−阻害剤の組み合わせ |
| US11241500B2 (en) | 2016-12-14 | 2022-02-08 | Tarveda Therapeutics, Inc. | HSP90-targeting conjugates and formulations thereof |
| US11684672B2 (en) | 2017-02-24 | 2023-06-27 | Bayer Pharma Aktiengesellschaft | Combinations of copanlisib with anti-PD-1 antibody |
| WO2019002068A1 (en) | 2017-06-28 | 2019-01-03 | Bayer Consumer Care Ag | COMBINATION OF A PI3K INHIBITOR AND AN ANDROGEN RECEPTOR ANTAGONIST |
| EP3498266A1 (en) | 2017-12-15 | 2019-06-19 | Bayer Consumer Care AG | Formulations of copanlisib |
| IL272857B2 (en) | 2017-09-08 | 2024-03-01 | Bayer Consumer Care Ag | Cofanalisib formulations |
| WO2019105734A1 (en) | 2017-11-28 | 2019-06-06 | Bayer Consumer Care Ag | Combinations of copanlisib |
| WO2019105835A1 (en) | 2017-11-29 | 2019-06-06 | Bayer Consumer Care Ag | Combinations of copanlisib and anetumab ravtansine |
| WO2019197269A1 (en) | 2018-04-11 | 2019-10-17 | Bayer Aktiengesellschaft | Combinations of copanlisib with triazolone derivatives and their use in the treatment of cancer |
| CA3110754A1 (en) | 2018-08-28 | 2020-03-05 | Bayer As | Combination of pi3k-inhibitors and targeted thorium conjugates |
| CA3116230A1 (en) * | 2018-10-16 | 2020-04-23 | Bayer Aktiengesellschaft | Combination of atr kinase inhibitors with 2,3-dihydroimidazo[1,2-c]quinazoline compounds |
| BR112021007377A2 (pt) | 2018-10-17 | 2021-07-20 | Sandoz Ag | cocristal, uso do cocristal e composição farmacêutica |
| KR102468480B1 (ko) * | 2018-12-27 | 2022-11-18 | 홀로스메딕 주식회사 | 신규한 화합물 및 이를 포함하는 항암 활성 증진용 약학 조성물 |
| WO2020164997A1 (en) | 2019-02-12 | 2020-08-20 | Bayer Aktiengesellschaft | Combination of pi3k-inhibitors |
| WO2023218032A1 (en) | 2022-05-13 | 2023-11-16 | Synthon B.V. | Solid forms of copanlisib salts |
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| AR064106A1 (es) | 2006-12-05 | 2009-03-11 | Bayer Schering Pharma Ag | Derivados de 2,3-dihidroimidazo [1,2-c] quinazolina sustituida utiles para el tratamiento de enfermedades y trastornos hiper-proliferativos asociados con la angiogenesis |
| PE20091174A1 (es) | 2007-12-27 | 2009-08-03 | Chugai Pharmaceutical Co Ltd | Formulacion liquida con contenido de alta concentracion de anticuerpo |
| CA2713388C (en) | 2008-01-14 | 2016-03-29 | William Scott | Sulfone substituted 2,3-dihydroimidazo [1,2-c] quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
| EP2168583A1 (en) * | 2008-09-24 | 2010-03-31 | Bayer Schering Pharma Aktiengesellschaft | Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines for the treatment of myeloma |
| EP2168582A1 (en) * | 2008-09-24 | 2010-03-31 | Bayer Schering Pharma Aktiengesellschaft | Combinations of substituted 2,3-dihydroimidazo[1,2-c]quinazolines |
| HUP0800765A2 (en) | 2008-12-18 | 2010-11-29 | Richter Gedeon Nyrt | A new process for the preparation of piperazine derivatives and their hydrochloric salts |
| WO2011128407A2 (en) | 2010-04-16 | 2011-10-20 | Bayer Pharma Aktiengesellschaft | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline-containing combinations |
| UA113280C2 (xx) | 2010-11-11 | 2017-01-10 | АМІНОСПИРТЗАМІЩЕНІ ПОХІДНІ 2,3-ДИГІДРОІМІДАЗО$1,2-c]ХІНАЗОЛІНУ, ПРИДАТНІ ДЛЯ ЛІКУВАННЯ ГІПЕРПРОЛІФЕРАТИВНИХ ПОРУШЕНЬ І ЗАХВОРЮВАНЬ, ПОВ'ЯЗАНИХ З АНГІОГЕНЕЗОМ | |
| JO3733B1 (ar) * | 2011-04-05 | 2021-01-31 | Bayer Ip Gmbh | استخدام 3,2-دايهيدروايميدازو[1, 2 -c]كوينازولينات مستبدلة |
| EP2508525A1 (en) * | 2011-04-05 | 2012-10-10 | Bayer Pharma Aktiengesellschaft | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts |
| ES2708350T3 (es) * | 2013-04-08 | 2019-04-09 | Bayer Pharma AG | Uso de 2,3-dihidroimidazo[1,2-c]quinazolinas para el tratamiento de linfomas |
| JP6499657B2 (ja) | 2013-12-03 | 2019-04-10 | バイエル ファーマ アクチエンゲゼルシャフト | Ｐｉ３ｋ阻害剤の組み合わせ |
| EP3018127A1 (en) | 2014-11-07 | 2016-05-11 | Bayer Pharma Aktiengesellschaft | Synthesis of copanlisib and its dihydrochloride salt |
| EP3018131A1 (en) | 2014-11-07 | 2016-05-11 | Bayer Pharma Aktiengesellschaft | Synthesis of copanlisib and its dihydrochloride salt |
| US20180042929A1 (en) * | 2015-03-09 | 2018-02-15 | Bayer Pharma Aktiengesellschaft | Use of substituted 2,3-dihydroimidazo[1,2-c]quinazolines |
| SG11201707240SA (en) | 2015-03-09 | 2017-10-30 | Bayer Pharma AG | Substituted 2,3-dihydroimidazo[1,2-c]quinazoline-containing combinations |
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