RU2330849C2 - МАЛОНАМИДНЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ γ-СЕКРЕТАЗЫ - Google Patents

МАЛОНАМИДНЫЕ ПРОИЗВОДНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ γ-СЕКРЕТАЗЫ Download PDF

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RU2330849C2
RU2330849C2 RU2005127666/04A RU2005127666A RU2330849C2 RU 2330849 C2 RU2330849 C2 RU 2330849C2 RU 2005127666/04 A RU2005127666/04 A RU 2005127666/04A RU 2005127666 A RU2005127666 A RU 2005127666A RU 2330849 C2 RU2330849 C2 RU 2330849C2
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methyl
oxo
malonamide
dihydro
compounds
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Гуидо ГАЛЛЕЙ (DE)
Гуидо Галлей
Анник ГЁРГЛЕ (FR)
Анник ГЁРГЛЕ
Хельмут ЯКОБЗЕН (DE)
Хельмут ЯКОБЗЕН
Эрик Аргириос КИТАС (CH)
Эрик Аргириос Китас
Йенс-Уве ПЕТЕРС (DE)
Йенс-Уве Петерс
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Ф.Хоффманн-Ля Рош Аг
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Abstract

Изобретение относится к малонамидным производным формул (IA) или (IB)
Figure 00000001
Figure 00000002
и к их фармацевтически приемлемым кислотным аддитивным солям, где R1, R1', (R2)1,2,3, R3, R4, R14, L,
Figure 00000003
и

Description

Текст описания приведен в факсимильном виде.
Figure 00000009
Figure 00000010
Figure 00000011
Figure 00000012
Figure 00000013
Figure 00000014
Figure 00000015
Figure 00000016
Figure 00000017
Figure 00000018
Figure 00000019
Figure 00000020
Figure 00000021
Figure 00000022
Figure 00000023
Figure 00000024
Figure 00000025
Figure 00000026
Figure 00000027
Figure 00000028
Figure 00000029
Figure 00000030
Figure 00000031
Figure 00000032
Figure 00000033
Figure 00000034
Figure 00000035
Figure 00000036
Figure 00000037
Figure 00000038
Figure 00000039
Figure 00000040
Figure 00000041
Figure 00000042
Figure 00000043
Figure 00000044
Figure 00000045
Figure 00000046
Figure 00000047
Figure 00000048
Figure 00000049
Figure 00000050
Figure 00000051
Figure 00000052
Figure 00000053
Figure 00000054
Figure 00000055
Figure 00000056
Figure 00000057
Figure 00000058
Figure 00000059
Figure 00000060
Figure 00000061
Figure 00000062
Figure 00000063
Figure 00000064
Figure 00000065
Figure 00000066
Figure 00000067
Figure 00000068
Figure 00000069
Figure 00000070
Figure 00000071
Figure 00000072
Figure 00000073
Figure 00000074
Figure 00000075
Figure 00000076
Figure 00000077
Figure 00000078
Figure 00000079
Figure 00000080

Claims (17)

1. Соединения общей формулы
Figure 00000081
Figure 00000082
где L представляет собой связь, -(CH2)1,2-, -СН(СН3)- или
Figure 00000083
;
Figure 00000084
представляет собой циклическое кольцо, выбранное из группы, состоящей из фенила, пиридинила, фуранила, бензо[b]тиофенила, тетрагидронафтила, инданила, 2,2-диметил-[1,3]диоксоланила или тетрагидрофуранила;
R1 и R1 являются одинаковыми или различными и представляют собой водород, низший алкил, галоген, бензил или низший алкенил;
(R2)1,2,3 независимо друг от друга представляют собой водород, гидрокси, галоген, низший алкил, низший алкокси или трифторметил;
R3 представляет собой
фенил или бензил, который является незамещенным или замещен одним или двумя заместителями, выбранными из группы, состоящей из галогена или циано, или представляет собой
низший алкил,
два атома водорода,
(СН2)1,2-S-низший алкил,
(СН2)1,2-циклоалкил,
(CH2)1,2-OH, или группы
Figure 00000085
или
Figure 00000086
;
R4 представляет собой моно-, ди- или трициклическую группу, незамещенную или замещенную R5-R10, и
где группы могут быть связаны с помощью -N(CH3)(CH2)0,1,2 с -С(О) группой в формуле IB, выбранные из группы, состоящей из
Figure 00000087
,
Figure 00000088
,
Figure 00000089
,
Figure 00000090
,
Figure 00000091
,
Figure 00000092
,
Figure 00000093
,
Figure 00000094
,
Figure 00000095
,
Figure 00000096
,
Figure 00000097
,
Figure 00000098
,
Figure 00000099
,
Figure 00000100
,
Figure 00000101
,
Figure 00000102
,
Figure 00000103
,
Figure 00000104
,
Figure 00000105
или представляет собой
Figure 00000106
где (R5)1,2 независимо друг от друга представляет собой водород, галоген, низший алкил или -(CH2)1,2OH;
R6 представляет собой водород, галоген или низший алкокси;
R7 представляет собой водород или -СН2ОСН3;
R8 представляет собой водород или галоген;
R9 представляет собой водород или амино;
(R10)1,2,3 независимо друг от друга представляет собой водород, низший алкил, низший алкокси, низший циклоалкил, галоген, гидрокси, нитро, -CH2CN, -ОСН2С6Н5,
Figure 00000107
,
Figure 00000108
,
Figure 00000109
,
Figure 00000110
или
Figure 00000111
или группы
Figure 00000112
может представлять собой следующие кольца:
Figure 00000113
,
Figure 00000114
,
Figure 00000115
,
Figure 00000116
,
Figure 00000117
или
Figure 00000118
где X представляет собой -СН2, -S(О)2 или -С(О)-;
R11 представляет собой водород или низший алкил;
R12 представляет собой водород или галоген;
R13 представляет собой водород, CN,
Figure 00000119
или
Figure 00000120
;
R14 представляет собой водород, низший алкил, -(СН2)2ОН или -(CH2)2CN;
и их фармацевтически приемлемые кислотные аддитивные соли.
2. Соединения по п.1 общей формулы
Figure 00000121
Figure 00000122
где R1 и R1' являются одинаковыми или различными и представляют собой водород, низший алкил, галоген, бензил или низший алкенил;
(R2)1,2,3 независимо друг от друга представляет собой водород, галоген, низший алкил, низший алкокси или трифторметил;
R3 представляет собой фенил или бензил, которые являются незамещенными или замещены одним или двумя заместителями, выбранными из группы, состоящей из галогена или циано, или представляет собой
низший алкил,
два атома водорода,
(СН2)1,2-S-низший алкил,
(СН2)1,2-циклоалкил,
(CH2)1,2-OH, или группы
Figure 00000085
или
Figure 00000086
;
R4 представляет собой представляет собой моно-, ди- или трициклическую группу, незамещенную или замещенную R5-R10, и
где группы могут быть связаны с помощью -N(СН3)(СН2)0,1,2 с -С(O)-группой в формуле IB, выбранные из группы, состоящей из
Figure 00000087
,
Figure 00000088
,
Figure 00000089
,
Figure 00000090
,
Figure 00000091
,
Figure 00000092
,
Figure 00000093
,
Figure 00000094
,
Figure 00000095
,
Figure 00000096
,
Figure 00000097
,
Figure 00000098
,
Figure 00000099
,
Figure 00000100
,
Figure 00000101
,
Figure 00000102
,
Figure 00000103
,
Figure 00000104
,
Figure 00000105
или представляет собой
Figure 00000106
где (R5)1,2 независимо друг от друга представляет собой водород, галоген, низший алкил или -(CH2)1,2OH;
R6 представляет собой водород, галоген или низший алкокси;
R7 представляет собой водород или -СН2ОСН3;
R8 представляет собой водород или галоген;
R9 представляет собой водород или амино;
(R10)1,2,3 независимо друг от друга представляет собой водород, низший алкил, низший алкокси, низший циклоалкил, галоген, гидрокси, нитро, -СН2CN, -ОСН2С6Н5,
Figure 00000123
,
Figure 00000108
,
Figure 00000109
,
Figure 00000110
или
Figure 00000111
;
или группы
Figure 00000112
может представлять собой следующие кольца:
Figure 00000113
,
Figure 00000114
,
Figure 00000115
,
Figure 00000116
,
Figure 00000117
или
Figure 00000118
где X представляет собой -СН2, -S(O)2 или -С(O)-;
R11 представляет собой водород или низший алкил;
R12 представляет собой водород или галоген;
R13 представляет собой водород, CN
Figure 00000119
или
Figure 00000120
;
и их фармацевтически приемлемые кислотные аддитивные соли.
3. Соединения формулы IA по п.2.
4. Соединения формулы IA по п.3, где
Figure 00000112
представляет собой
Figure 00000124
и
Figure 00000084
представляет собой фенил.
5. Соединения формулы IA по п.4, где соединения представляют собой
N-(3,5-дифторбензил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(3,5-дифторбензил)-2-фтор-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(3,5-дифторбензил)-2-изопропил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(3,5-дифторбензил)-2-этил-N'-(5-метил-6-оксо-6,7-гидро-5H-дибензо[b,d]азепин-7-ил)-малонамид,
N-(3,5-дифторбензил)-2-фтор-N'-(5-метил-6-оксо-6,7-дигидро-5H-дибензо[b,d]азепин-7-ил)-малонамид,
N-(3,5-дифторбензил)-2,2-диметил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(3,5-дифторбензил)-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-2-пропил-малонамид,
N-бензил-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(4-фторбензил)-2-метил-N'-(5метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(4-хлорбензил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(3-фторбензил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(2,5-дифторбензил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5H-дибензо[b,d]азепин-7-ил)-малонамид,
2-метил-N-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-N'-(2,3,5-трифторбензил)-малонамид,
N-(2-фторбензил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-(2-хлорбензил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5H-дибензо[b,d]азепин-7-ил)-малонамид или
N-(3-хлорбензил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид.
6. Соединения формулы IA по п.1, где
Figure 00000112
представляет собой а) и
Figure 00000084
представляет собой циклическое кольцо, выбранное из группы, состоящей из фуранила, бензо[b]тиофенила или инданила.
7. Соединения формулы IA по п.6, где соединения представляют собой
N-фуран-2-илметил-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид,
N-бензо[b]тиофен-3-илметил-2-метил-N-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид или
N-(4,6-дифториндан-1-ил)-2-метил-N'-(5-метил-6-оксо-6,7-дигидро-5Н-дибензо[b,d]азепин-7-ил)-малонамид.
8. Соединения формулы IA по п.1 или 2, где
Figure 00000112
представляет собой
Figure 00000125
.
9. Соединения формулы IA по п.8, где соединения представляют собой
N-(3,5-дифторбензил)-2-метил-N'-(1-метил-2-оксо-5-фенил-2,3-дигидро-1Н-бензо[е][1,4]диазепин-3-ил)-малонамид,
N-(3,5-дифторбензил)-2-фтор-2-метил-N'-(1-метил-2-оксо-5-фенил-2,3-дигидро-1Н-бензо[е][1,4]диазепин-3-ил)-малонамид,
N-(3,5-дифторбензил)-N'-(1-метил-2-оксо-5-фенил-2,3-дигидро-1Н-бензо[е][1,4]диазепин-3-ил)-2-пропил-малонамид,
N-(3,5-дифторбензил)-2-этил-N'-(1-метил-2-оксо-5-фенил-2,3-дигидро-1Н-бензо[е][1,4]диазепин-3-ил)-малонамид или
N-(4-хлорбензил)-2-метил-N'-(1-метил-2-оксо-5-фенил-2,3-дигидро-1Н-бензо[е][1,4]диазепин-3-ил)-малонамид.
10. Соединения формулы IA по п.1 или 2, где
Figure 00000112
представляет собой
Figure 00000126
.
11. Соединения формулы IA по п.10, где соединения представляют собой
N-(5-бензил-1-метил-2-оксо-2,3,4,5-тетрагидро-1H-бензо[d][1,4]диазепин-3-ил)-N'-(3,5-дифторбензил)-2-метил-малонамид,
N-(5-бензолсульфонил-1-метил-2-оксо-2,3,4,5-тетрагидро-1Н-бензо[b][1,4]диазепин-3-ил)-N'-(3,5-дифторбензил)-2-метил-малонамид или
N-(5-бензоил-1-метил-2-оксо-2,3,4,5-тетрагидро-1Н-бензо[b][1,4]диазепин-3-ил)-N'-(3,5-дифторбензил)-2-метил-малонамид.
12. Соединения формулы IA по п.1 или 2, где
Figure 00000112
представляет собой
Figure 00000127
13. Соединения формулы IA по п.12, где соединения представляют собой
(2S-цис)-N-(3,5-дифторбензил)-2-метил-N'-{4-оксо-2-[(2-тиофен-2-ил-ацетиламино)-(2R,S)-метил]-1,2,4,5,6,7-гексагидроазепино[3,2,1-hi]индол-5-ил}-малонамид или
(2S-цис)-N-(3,5-дифторбензил)-N'-(2-{[2-(4-фторфенил)ацетиламино]метил}-4-оксо-1,2,4,5,6,7-гексагидроазепино[3,2,1-hi]индол-5-ил)-2,2-диметил-малонамид.
14. Соединения формулы IB по п.1 или 2.
15. Соединения формул IA или IB по п.1 или 2, где по крайней мере один из (R2)1,2,3 представляет собой фтор.
16. Лекарственное средство, обладающее ингибирующим действием в отношении γ-секретазы, содержащее одно или несколько соединений по любому из пп.1-15 и фармацевтически приемлемые эксципиенты.
17. Лекарственное средство по п.16 для лечения болезни Альцгеймера.
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KR20200036063A (ko) 2014-01-21 2020-04-06 얀센 파마슈티카 엔.브이. 대사 조절형 글루탐산 작동성 수용체 제2아형의 양성 알로스테릭 조절제 또는 오르토스테릭 작동제를 포함하는 조합 및 그 용도
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