ES2618939T3 - Sal de camsilato - Google Patents

Sal de camsilato Download PDF

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Publication number
ES2618939T3
ES2618939T3 ES13733415.7T ES13733415T ES2618939T3 ES 2618939 T3 ES2618939 T3 ES 2618939T3 ES 13733415 T ES13733415 T ES 13733415T ES 2618939 T3 ES2618939 T3 ES 2618939T3
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mol
strong
indene
mixture
salt
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English (en)
Inventor
Martin Hans Bohlin
Craig Robert Stewart
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AstraZeneca AB
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AstraZeneca AB
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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
    • C07D401/02—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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • 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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D401/02—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
    • C07D401/10—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 aromatic rings

Abstract

Una sal de camsilato de (1r,1'R,4R)-4-metoxi-5"-metil-6'-[5-(prop-1-in-1-il)piridin-3-il]-3'H-diespiro [ciclohexano- 1,2'-indeno-1'2"-imidazol]-4"-amina:**Fórmula**

Description

imagen1
imagen2
Ángulos corregidos
Espaciamiento d (Å) Intensidad relativa
12.83
6.89 m
14.07
6.29 w
15.05
5.88 w
15.24
5.81 m
15.47
5.72 m
16.24
5.45 w
16.68
5.31 w
17.17
5.16 m
17.33
5.11 w
17.62
5.03 vw
17.84
4.97 w
18.13
4.89 m
19.71
4.50 m
20.18
4.40 w
20.77
4.27 m
21.12
4.20 m
21.67
4.10 vw
21.88
4.06 vw
22.09
4.02 vw
22.29
3.99 w
22.73
3.91 w
23.11
3.84 vw
4
Ángulos corregidos
Espaciamiento d (Å) Intensidad relativa
23.63
3.76 m
24.50
3.63 m
26.18
3.40 m
26.54
3.36 m
27.72
3.22 vw
27.95
3.19 vw
28.80
3.10 vw
28.93
3.08 vw
29.71
3.00 vw
30.56
2.92 vw
31.14
2.87 vw
31.64
2.83 vw
31.74
2.82 vw
32.11
2.79 vw
32.84
2.72 vw
33.86
2.65 vw
34.30
2.61 m
36.78
2.44 m
37.49
2.40 w
40.23
2.24 vw
40.93
2.20 vw
41.32
2.18 vw
5
Ángulos corregidos
Espaciamiento d (Å) Intensidad relativa
42.43
2.13 w
44.54
2.03 vw
46.29
1.96 vw
48.32
1.88 vw
Otra realización de la presente invención es una sal de camsilato del compuesto (1r,1'R,4R)-4-metoxi-5"-metil-6'-[5(prop-1-in-1-il)piridin-3-il]-3'H-diespiro[ciclohexano-1,2'-indeno-1'2'-imidazole]-4"-amina, caracterizada por suministrar un patrón de difracción en polvo por rayos X, que exhibe de modo sustancial los siguientes picos muy fuertes, fuertes y medios con valores de espaciamiento d como se representan en la Tabla 2:
Tabla 2:
Picos identificados en difracción en polvo por rayos X
Ángulos corregidos
Espaciamiento d (Å) Intensidad relativa
5.66
15.60 vs
7.72
11.44 m
11.30
7.83 m
12.35
7.16 s
12.83
6.89 m
15.24
5.81 m
15.47
5.72 m
17.17
5.16 m
18.13
4.89 m
19.71
4.50 m
20.77
4.27 m
21.12
4.20 m
23.63
3.76 m
6
imagen3
imagen4
imagen5
imagen6
5
10
15
20
25
30
35
40
valores de distancia en XRPD pueden variar en el intervalo ±2 en el último lugar decimal.
Las intensidades relativas se derivan de difractogramas medidos con rendijas variables.
Las intensidades relativas medidas vs. el pico más fuerte son dados como muy fuerte (vs) por encima de 50%, como fuerte (s) entre 25 y 50%, como media (m) entre 10 y 25%, como débil (w) entre 5 y 10% y como muy débil (vw) por debajo de 5% de altura relativa de pico. Una persona experta en la técnica notará que las intensidades de XRPD pueden variar entre diferentes muestras y diferentes preparaciones de muestra por una variedad de razones, incluyendo la orientación preferida. También una persona experta en la técnica notará que pueden ocurrir desplazamientos más pequeños en el ángulo medido y por ello en el espaciamiento d, por una variedad de razones incluyendo variación del nivel de superficie de la muestra en el difractómetro.
Ejemplos
Ejemplo 1
6'-bromoespiro[ciclohexano-1,2'-indeno]-1',4(3'H)-diona
imagen7
Se cargó tert-butóxido de potasio (223 g, 1.99 mol) a un reactor de 100 L que contenía una mezcla agitada de 6bromo-1-indanona (8.38 kg, 39.7 mol) en THF (16.75 L) a 20-30 °C. Se cargó entonces metil acrilato (2.33 L, 25.8 mol) a la mezcla durante 15 minutos manteniendo la temperatura entre 20-30 °C. Se añadió una solución de tertbutóxido de potasio (89.1 g, 0.79 mol) disuelto en THF (400 mL) después se añadió metil acrilato (2.33 L, 25.8 mol) durante 20 minutos a 20-30 °C. Se añadió entonces una tercera porción de tert-butóxido de potasio (90 g, 0.80 mol) disuelto en THF (400 mL), seguido por una tercera adición de metil acrilato (2.33 L, 25.8 mol) durante 20 minutos a 20-30 °C. Se cargó al reactor tert-butóxido de potasio (4.86 kg, 43.3 mol) disuelto en THF (21.9 L), durante 1 hora a 20-30 °C. Se calentó la reacción a aproximadamente 65 °C y se retiraron por destilación 23 L de solvente. Se redujo la temperatura de reacción a 60 °C y se añadió a la mezcla hidróxido de potasio acuoso al 50% (2.42 L, 31.7 mol) disuelto en agua (51.1 L), durante 30 minutos a 55-60 °C después se agitó la mezcla por 6 horas a 60 °C, se enfrió a 20 °C durante 2 horas. Después de agitar por 12 horas a 20 °C se separó por filtración el material sólido, se lavó dos veces con una mezcla de agua (8.4 L) y THF (4.2 L) y luego se secó a 50 °C bajo vacío para dar 6'bromoespiro[ciclohexano-1,2'-indeno]-1',4(3'H)-diona (7.78 kg; 26.6 mol). 1H RMN (500 MHz, DMSO-d6) δ ppm 1.78 -1.84 (m, 2 H), 1.95 (td, 2 H), 2.32 -2.38 (m, 2 H), 2.51 -2.59 (m, 2 H), 3.27 (s, 2 H), 7.60 (d, 1 H), 7.81 (m, 1 H),
7.89 (m, 1 H).
Ejemplo 2
(1r,4r)-6'-bromo-4-metoxiespiro[ciclohexano-1,2'-indeno]-1'(3'H)-ona
imagen8
Se cargó complejo de borano tert-butilamina (845 g, 9.7 mol) disuelto en DCM (3.8 L) a una pasta de 6'bromoespiro[ciclohexano-1,2'-indeno]-1',4(3'H)-diona (7.7 kg, 26.3 mol) en DCM (42.4 L) a aproximadamente 0-5 °C durante aproximadamente 25 minutos. Se dejó la reacción con agitación a 0-5°C por 1 hora, después de análisis se confirmó que la conversión era >98%. Se cargó una solución preparada de cloruro de sodio (2.77 kg), agua (13.3 L) y ácido clorhídrico al 37% (2.61 L, 32 mol). Se calentó la mezcla a aproximadamente 15 °C y se separaron las fases después de decantarse en capas. Se devolvió la fase orgánica al reactor, junto con metil metanosulfonato (2.68 L,
31.6 mol) y cloruro de tetrabutilamonio (131 g, 0.47 mol) y se agitó vigorosamente la mezcla a 20 °C. Se cargó entonces hidróxido de sodio al 50% (12.5 L, 236 mol) a la mezcla de reacción agitada vigorosamente, durante aproximadamente 1 hora y se dejó la reacción con agitación vigorosa durante la noche a 20 °C. Se añadió agua (19 L) y después de la separación se descartó la fase acuosa. Se calentó la capa orgánica a aproximadamente 40 °C y se separaron por destilación 33 L de solvente. Se cargó etanol (21 L) y se reanudó la destilación aumentando la
11
imagen9
imagen10
imagen11
imagen12

Claims (17)

  1. REIVINDICACIONES
    1.
    Una sal de camsilato de (1r,1'R,4R)-4-metoxi-5"-metil-6'-[5-(prop-1-in-1-il)piridin-3-il]-3'H-diespiro [ciclohexano1,2'-indeno-1'2"-imidazol]-4"-amina:
  2. 2.
    Una sal de camsilato de acuerdo con la reivindicación 1 que tiene un patrón de difracción de rayos X en polvo (XRPD) que exhibe sustancialmente los siguientes picos muy fuerte, fuerte y medio con valores d:
    imagen1
    Ángulos corregidos
    Espaciamiento d (Å) Intensidad relativa
  3. 5.66
    15.60 vs
  4. 7.72
    11.44 m
  5. 11.30
    7.83 m
  6. 12.35
    7.16 s
  7. 12.83
    6.89 m
  8. 15.24
    5.81 m
  9. 15.47
    5.72 m
  10. 17.17
    5.16 m
  11. 18.13
    4.89 m
  12. 19.71
    4.50 m
  13. 20.77
    4.27 m
  14. 21.12
    4.20 m
  15. 23.63
    3.76 m
  16. 24.50
    3.63 m
  17. 26.18
    3.40 m
    16
    imagen2
ES13733415.7T 2012-06-21 2013-06-20 Sal de camsilato Active ES2618939T3 (es)

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US201261662592P 2012-06-21 2012-06-21
US201261662592P 2012-06-21
PCT/GB2013/051606 WO2013190302A1 (en) 2012-06-21 2013-06-20 Camsylate salt

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Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8415483B2 (en) 2010-12-22 2013-04-09 Astrazeneca Ab Compounds and their use as BACE inhibitors
US9650336B2 (en) 2011-10-10 2017-05-16 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
US9000182B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US9000185B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cycloalkyl ether compounds and their use as BACE inhibitors
US9000184B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-naphthalene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000183B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-indene-1′,2″-imidazol compounds and their use as BACE inhibitors
UY36347A (es) 2014-10-07 2016-04-01 Astrazeneca Ab Compuestos y su uso como inhibidores de bace
JP6546410B2 (ja) * 2015-02-23 2019-07-17 ローム株式会社 電力供給装置、ａｃアダプタ、ａｃチャージャ、電子機器および電力供給システム
AR107783A1 (es) * 2016-03-15 2018-06-06 Lilly Co Eli Terapia de combinación
CA3017418A1 (en) 2016-03-15 2017-09-21 Astrazeneca Ab Combination of a bace inhibitor and an antibody or antigen-binding fragment for the treatment of a disorder associated with the accumulation of amyloid beta
CN113573709A (zh) * 2019-03-14 2021-10-29 阿斯利康(瑞典)有限公司 用于体重减轻的兰比斯特

Family Cites Families (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100452491B1 (ko) * 2001-03-29 2004-10-12 한미약품 주식회사 신규한 결정형 암로디핀 캠실레이트 염 및 그의 제조방법
JP4273406B2 (ja) 2001-06-01 2009-06-03 小野薬品工業株式会社 アルドース還元酵素阻害剤を有効成分とする脱髄性疾患または脱髄を伴う疾患治療剤
US7592348B2 (en) 2003-12-15 2009-09-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
ATE445399T1 (de) 2004-03-22 2009-10-15 Lilly Co Eli Pyridyl-derivate und ihre verwendung als mglu5- rezeptorantagonisten
JP2008543849A (ja) 2005-06-14 2008-12-04 シェーリング コーポレイション アスパルチルプロテアーゼ阻害剤
CN101360716A (zh) 2005-11-21 2009-02-04 阿斯利康(瑞典)有限公司 新颖的2-氨基-咪唑-4-酮化合物及其在制备用于治疗认知缺损、阿尔茨海默病、神经变性和痴呆的药物中的用途
TW200734311A (en) * 2005-11-21 2007-09-16 Astrazeneca Ab New compounds
US20080318929A1 (en) 2005-12-21 2008-12-25 Barbosa Antonio J M Pyrimidine Derivatives Useful as Inhibitors of Pkc-Theta
WO2007100536A1 (en) 2006-02-24 2007-09-07 Wyeth DIHYDROSPIRO[DIBENZO[A,D][7]ANNULENE-5,4'-IMIDAZOL] COMPOUNDS FOR THE INHIBITION OF β-SECRETASE
US8168641B2 (en) 2006-06-12 2012-05-01 Schering Corporation Aspartyl protease inhibitors
WO2008076044A1 (en) 2006-12-20 2008-06-26 Astrazeneca Ab Novel 2-amino-5, 5-diaryl-imidazol-4-ones
US20090325993A1 (en) 2007-02-01 2009-12-31 Nadia Mamoona Ahmad GLYT1 Transporter Inhibitors and Uses Thereof in Treatment of Neurological and Neuropsychiatric Disorders
CN101809019A (zh) 2007-05-07 2010-08-18 先灵公司 γ分泌酶调节剂
WO2009100169A1 (en) 2008-02-06 2009-08-13 Glaxo Group Limited Dual pharmacophores - pde4-muscarinic antagonistics
FR2929943B1 (fr) * 2008-04-15 2010-09-24 Inst Rech Developpement Ird Sels de quinoleines 2-substituees
WO2010013794A1 (en) 2008-07-28 2010-02-04 Eisai R&D Management Co., Ltd. Spiroaminodihydrothiazine derivatives
EP2324032B1 (en) 2008-08-19 2014-10-01 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
CN102209721A (zh) 2008-09-11 2011-10-05 安姆根有限公司 作为β-分泌酶调节剂的螺四环化合物及其使用方法
SG173466A1 (en) 2009-03-13 2011-09-29 Vitae Pharmaceuticals Inc Inhibitors of beta-secretase
UY32751A (es) 2009-07-02 2011-01-31 Astrazeneca Ab Imidazoles sustituidos y uso de los mismos
TW201103893A (en) 2009-07-02 2011-02-01 Astrazeneca Ab New compounds
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
AR080865A1 (es) 2010-03-31 2012-05-16 Array Biopharma Inc Derivados de espirotetrahidronaftaleno, composiciones farmaceuticas que los contienen, proceso de preparacion y uso de los mismos para tratar enfermedades neurodegenerativas,tal como alzheimer.
WO2011130741A1 (en) 2010-04-16 2011-10-20 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
WO2012019056A1 (en) 2010-08-05 2012-02-09 Amgen Inc. Amino-iso-indole, amino-aza-iso-indole, amino-dihydroisoquinoline and amino-benzoxazine compounds as beta-secretase modulators and methods of use
WO2012040641A2 (en) 2010-09-24 2012-03-29 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
TW201307357A (zh) 2010-11-22 2013-02-16 Array Biopharma Inc 治療神經退化性疾病之化合物
US8415483B2 (en) 2010-12-22 2013-04-09 Astrazeneca Ab Compounds and their use as BACE inhibitors
US9650336B2 (en) 2011-10-10 2017-05-16 Astrazeneca Ab Mono-fluoro beta-secretase inhibitors
US9000182B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab 2H-imidazol-4-amine compounds and their use as BACE inhibitors
US9000184B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-naphthalene-1′,2″-imidazol compounds and their use as BACE inhibitors
US9000185B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cycloalkyl ether compounds and their use as BACE inhibitors
US9000183B2 (en) 2012-06-20 2015-04-07 Astrazeneca Ab Cyclohexane-1,2′-indene-1′,2″-imidazol compounds and their use as BACE inhibitors

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TWI588140B (zh) 2017-06-21
CN106279102A (zh) 2017-01-04
HK1206349A1 (zh) 2016-01-08
DK2864316T3 (en) 2017-03-20
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DOP2014000268A (es) 2015-04-15
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US20140031379A1 (en) 2014-01-30
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