KR101059379B1 - 아미노사이클로헥실 에테르 화합물, 이의 제조방법 및 이를 포함하는 약제학적 조성물 - Google Patents
아미노사이클로헥실 에테르 화합물, 이의 제조방법 및 이를 포함하는 약제학적 조성물 Download PDFInfo
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- KR101059379B1 KR101059379B1 KR1020057020862A KR20057020862A KR101059379B1 KR 101059379 B1 KR101059379 B1 KR 101059379B1 KR 1020057020862 A KR1020057020862 A KR 1020057020862A KR 20057020862 A KR20057020862 A KR 20057020862A KR 101059379 B1 KR101059379 B1 KR 101059379B1
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Abstract
Description
구조식 | 화학명 | |
(1R,2R)/(1S,2S)-2-[(3R)/(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)/(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1- (3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)/(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1- (3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 |
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(1R,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 |
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(1R,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 |
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(1S,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 |
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(1S,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 |
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(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1- (3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2S)/(1S,2R)-2-[(3R)/(3S)-하이드록시 피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
화합물 번호 |
구조식 | 화합물명 |
1 | (1R,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
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2 | (1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
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3 | (1R,2R)/(1S,2S)-2-[(3R)/(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
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4 | (1R,2R)/(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1- (3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
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5 | (1R,2R)/(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1- (3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
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6 | (1R,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
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7 | (1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
구조식 | 화합물명 | |
(1R,2R)/(1S,2S)-2-[(3R)/(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)/(1S,2S)-2-[(3R)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)/(1S,2S)-2-[(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)-2-[(3R)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2R)-2-[(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2S)-2-[(3R)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2S)-2-[(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1S,2R)-2-[(3R)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1S,2R)-2-[(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
(1S,2S)-2-[(3R)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1S,2S)-2-[(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 |
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(1R,2S)/(1S,2R)-2-[(3R)/(3S)-하이드록시 피롤리디닐]-1-(3,4-디메톡시펜에톡시)- 사이클로헥산 |
화합물 번호 |
구조식 | 화합물명 |
1 | (1R,2R)-2-[(3R)-하이드록시 피롤리디닐]-1-(3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
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2 | (1S,2S)-2-[(3R)-하이드록시 피롤리디닐]-1-(3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
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3 | (1R,2R)/(1S,2S)-2-[(3R)/(3S)-하이드록시 피롤리디닐]-1-(3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
4 | (1R,2R)/(1S,2S)-2-[(3R)-하이드록시 피롤리디닐]-1-(3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
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5 | (1R,2R)/(1S,2S)-2-[(3S)-하이드록시 피롤리디닐]-1-(3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
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6 | (1R,2R)-2-[(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
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7 | (1S,2S)-2-[(3S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
다른 양태로, 화학식 (75)의 입체이성체적으로 거의 순수한 트랜스 아미노사이클로헥실 에테르 화합물의 제조는 G1이 수소가 아닌 화학식 (86)의 화합물을 출발로 한 다음, 도 104에 기술된 적용 가능한 부분과 유사한 반응 순서를 따르는 단계(여기서, 모든 화학식 및 심볼은 상기 기술한 바와 같다)를 포함하는, 도 113에 제시된 바와 같은 공정에 의해 적절한 조건하에 수행할 수 있다.
흑연 단상
등급 | 설명 |
0 | 0-49회 VPB |
1 | 50-499회 VPB |
2 | > 499회 VPS 및/또는 자발적으로 회복되는 VT 또는 VF의 1 에피소드 |
3 | VT 또는 VF나, 이 둘 모두의 > 1 에피소드(> 60초 총 합한 지속기간) |
4 | VT 또는 VF나, 이 둘 모두(60-119초 총 지속 기간) |
5 | VT 또는 VF나, 이 둘 모두(> 119초 총 지속 기간) |
6 | 폐색후 > 15분에 시작되는 치명적인 VF |
7 | 폐색후 4분 내지 14분 59초 후에 시작되는 치명적인 VF |
8 | 폐색후 1분 내지 3분 59초 후에 시작되는 치명적인 VF |
9 | 폐색후 < 1분에 시작되는 치명적인 VF |
약제 | 시험되는 용량 범위 (μmol/㎏) |
AF를 종결하기 위한 유효 용량 (μmol/㎏) |
AF를 종결하는데 필요한 평균 용량 (μmol/㎏) |
AF를 종결하는데 필요한 중간 용량 (μmol/㎏) |
플레카이니드 | 1.25-10 | 4-2.5:1-10 | 4±2 | 2.5 |
화합물 번호 | Kv1.5 | hERG | Kv4.2 | H1Na | Kv2.1 |
1 | 3.2 | 7 | 50 | 18.6 | |
2 | 6 | 20 | 36.4 | ||
3 | 5 | 35 | 30.3 | ||
6 | 6 | 20 | 25.4 | ||
7 | 6 | 35 | 37.2 |
화합물 번호 |
구조식 | 화학명 | 경련 용량 (umol/ kg/ min) |
누적 경련 용량 (umol/ kg) |
ED50AA (umol/ kg/ min) |
치료 학적 지수* |
1 | (1R,2R)-2-[(3R)-하이드록시 피롤리디닐]-1-(3,4-디메톡시 펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
64 | 507 | 1.4 | 18.1 | |
2 | (1R,2S)-2-[(3R)-하이드록시 피롤리디닐]-1-(3,4-디메톡시 펜에톡시)-사이클로헥산 모노하이드로클로라이드 |
64 | 500.67 | 1.2 | 20.9 | |
3 | (1R,2R)/(1S,2S)-2-[(3R)/ 3(S)-하이드록시피롤리디닐]- 1-(3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
64 | 502 | 1.3 | 19.3 | |
4 | (1R,2R)/(1S,2S)-2-[(3R)- 하이드록시피롤리디닐]-1- (3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
64 | 502 | 0.8 | 31.4 | |
5 | (1R,2R)/(1S,2S)-2-[(3S)- 하이드록시피롤리디닐]-1- (3,4-디메톡시펜에톡시)- 사이클로헥산 모노하이드로클로라이드 |
64 | 438 | 0.7 | 31.3 | |
6 | (1R,2R)-2-[(3S)-하이드록시 피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로 헥산 모노하이드로클로라이드 |
64 | 472.24 | 1.6 | 14.8 | |
7 | (1S,2S)-2-[(3S)-하이드록시 피롤리디닐]-1-(3,4- 디메톡시펜에톡시)-사이클로 헥산 모노하이드로클로라이드 |
64 | 451.67 | 0.9 | 25.1 |
비교 실시예 화합물 번호 |
구조식 | 화학명 | 경련 용량 (umol/ kg/ min) |
누적 경련 용량 (umol/ kg) |
ED50AA (umol/ kg/ min) |
치료 학적 지수* |
8 | 4-{(1R,2R)/(1S,2S)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}모르폴린 하이드로클로라이드 |
16 | 113 | 1.5 | 38 | |
9 | 7-{(1R,2R)/(1S,2S)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}-1,4-디옥사- 7-아자스피로[4.4]노난 하이드로클로라이드 |
16 | 91.33 | 1.6 | 2.9 | |
10 | 1-{(1R,2R)/(1S,2S)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}피롤리딘 하이드로클로라이드 |
21.33 | 118 | 1.33 | 4.4 | |
11 | (3S)-3-벤질옥시-1-{(1R,2R)/ (1S,2S)-2-[2-(3,4- 디메톡시페닐)에톡시] 사이클로헥실}피롤리딘 하이드로클로라이드 |
8 | 38.13 | 0.5 | 3.8 | |
12 | (3R)-3-벤질옥시-1-{(1R,2R)/(1S,2S)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}피롤리딘 하이드로클로라이드 |
8 | 51.1 | 1 | 2.6 | |
13 | (3S)-1-{(1R,2R)/(1S,2S)-2-[2-(3,4-디메톡시페닐) 에톡시]사이클로헥실} 피롤리딘-3-일 아세테이트 하이드로클로라이드 |
8 | 51.9 | 1.3 | 2 | |
14 | (3R)/(3S)-1-{(1R,2R)/(1S,2S)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}-3-플루오로 피롤리딘 하이드로클로라이드 |
10.67 | 63.33 | 1.4 | 2.3 |
15 | {(2R)-1-{(1R,2R)/(1S,2S)- 2-[2-(3,4-디메톡시페닐) 에톡시]사이클로헥실}- 피롤리딘-2-일}메탄올 하이드로클로라이드 |
16 | 142.33 | 0.8 | 8.9 | |
16 | 1-{(1R,2R)/(1S,2S)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}-2,5- 디하이드로-1H-피롤 하이드로클로라이드 |
8 | 44.4 | 2.4 | 0.9 | |
17 | (3R)-1-{(1R,2R)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}-피롤리딘- 3-일 아세테이트 하이드로클로라이드 |
13.33 | 74.3 | 2.1 | 1.8 | |
18 | 1-{(1R,2R)/(1S,2S)-2-[2- (3,4-디메톡시페닐)에톡시] 사이클로헥실}-피롤리딘-3- 온 하이드로클로라이드 |
32 | 235 | 4.5 | 2.6 | |
19 | 4-{(1R,2R)/(1S,2S)-2-[3- (3,4-디메톡시페닐)프로폭시] 사이클로헥실}모르폴린 하이드로클로라이드 |
16 | 109 | 1.5 | 3.6 | |
20 | 4-{(1R,2R)/(1S,2S)-2-[4- (3,4-디메톡시페닐)부톡시] 사이클로헥실}모르폴린 하이드로클로라이드 |
10.7 | 66.8 | 1.5 | 2.2 |
21 | (3R)-1-{(1R,2R)/(1S,2S)- 2-[3-(3-클로로-4,5- 디메톡시페닐)프로폭시] 사이클로헥실}-피롤리딘- 3-올 하이드로클로라이드 |
13.33 | 90.9 | 0.6 | 7.6 | |
22 | 1-[(3,4-디메톡시페닐) 아세틸]-4-{(1R,2R)/ (1S,2S)-2-[2-(3,4-디메톡시 페닐)에톡시]사이클로헥실}- 피페라진 하이드로클로라이드 |
21.33 | 133 | 0.6 | 11.1 | |
23 | (3R)/(3S)-1-{(1R,2R)/(1S,2S)-2-[2- (2,6-디클로로페닐)-에톡시] 사이클로헥실}-피롤리딘-3- 올 하이드로클로라이드 |
8 | 65 | 0.6 | 5.4 | |
24 | (3R)/(3S)-1-{(1R,2R)/(1S,2S)-2-[2- (2-브로모페닐)-에톡시] 사이클로헥실}-피롤리딘- 3-올 하이드로클로라이드 |
13 | 67 | 0.4 | 8.4 | |
25 | (3R)/(3S)-1-{(1R,2S)/(1S,2R)-2-[2- (1-나프틸)에톡시]- 사이클로헥실}-피롤리딘-3- 올 하이드로클로라이드 |
16 | 70 | 0.4 | 8.8 |
26 | (3R)/(3S)-1-{(1R,2R)/ (1S,2S)-2-[2-(1-나프틸) 에톡시]-사이클로헥실}- 피롤리딘-3-올 하이드로클로라이드 |
8 | 67.33 | 0.78 | 4.3 | |
27 | (3R)-1-{(1R,2R)/(1S,2S)- 2-[2-(2-트리플루오로 메틸페닐)에톡시]- 사이클로헥실}-피롤리딘- 3-올 하이드로클로라이드 |
16 | 101.93 | 0.7 | 7.3 | |
28 | (3R)/(3S)-1-{(1R,2R)/ (1S,2S)-2-[2-(1H-인돌- 1-일)에톡시]사이클로헥실} 피롤리딘-3-올 하이드로클로라이드 |
16 | 113 | 0.6 | 9.4 | |
29 | (3R)-1-{(1R,2R)/(1S,2S)- 2-[2-(1-벤조푸란-2-일) 에톡시]-사이클로헥실}- 피롤리딘-3-올 하이드로클로라이드 |
10.67 | 65.67 | 1 | 3.3 | |
30 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-(2- 나프텐에톡시)]- 사이클로헥산 |
13.3 | 85 | 0.8 | 53 | |
31 | (1R,2R)/(1S,2S)-[2-(4- 모르폴리닐)-1-(1-나프텐 에톡시)]-사이클로헥산 |
16 | 93 | 1 | 4.7 |
32 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-(4- 브로모펜에톡시)]- 사이클로헥산 |
12 | 91 | 2.1 | 2.2 | |
33 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-[2- (2-나프톡시)에톡시]]- 사이클로헥산 |
8 | 61.63 | 2 | 1.5 | |
34 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-[2-(4- 브로모페녹시)-에톡시]]- 사이클로헥산 |
10.7 | 83 | 3 | 1.4 | |
35 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-(3,4- 디메톡시-펜에톡시)]- 사이클로헥산 |
16 | 113 | 4 | 1.4 | |
36 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-(2- (벤조[b]티오펜-3-일)] 사이클로헥산 |
8 | 65 | 1 | 3.3 | |
37 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-(2- (벤조[b]티오펜-4-일) 사이클로헥산 |
8 | 54 | 1 | 2.7 | |
38 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-(3- 브로모펜에톡시)]- 사이클로헥산 |
16 | 131 | 2 | 3.3 |
39 | (1R,2R)/(1S,2S)-[2- (4-모르폴리닐)-1-(2- 브로모펜에톡시)]-사이클로헥산 |
16 | 125 | 1 | 6.3 | |
40 | (1R,2R)/(1S,2S)-2-(4- 모르폴리닐)-1-(3,4- 디클로로펜에톡시)-사이클로헥산 |
16 | 118 | 1.5 | 3.9 | |
41 | (1R,2R)/(1S,2S)-2-(3-케토 피롤리디닐)-1-(2,6-디클로로 펜에톡시)사이클로헥산 모노하이드로클로라이드 |
32 | 190 | 1.1 | 8.6 | |
42 | (1R,2S)/(1S,2R)-2-(4- 모르폴리닐)-1-[(2-트리 플루오로메틸)-펜에톡시]- 사이클로헥산 모노하이드로클로라이드 |
16 | 102 | 1.4 | 3.6 | |
43 | (1R,2R)/(1S,2S)-2-(3-아세톡시 피롤리디닐)-1-(1-나프텐 에톡시)사이클로헥산 모노하이드로클로라이드 |
8 | 65 | 1.4 | 2.3 | |
44 | (1R,2R)/(1S,2S)-2-(4- 모르폴리닐)-1-[(2,6-디클로로 페닐)메톡시]사이클로헥산 모노하이드로클로라이드 |
16 | 97 | 1.8 | 2.7 |
45 | (1R,2R)/(1S,2S)-2-(3-케토 피롤리디닐)-1-[(2,6- 디클로로페닐)메톡시] 사이클로헥산 모노하이드로클로라이드 |
32 | 214 | 2.1 | 5.1 | |
46 | (1R,2R)/(1S,2S)-2-(3- 하이드록시피롤리디닐)-1- (2,6-디클로로펜에톡시) 사이클로헥산 모노하이드로클로라이드 |
8 | 65 | 0.6 | 5.4 | |
47 | (1R,2R)/(1S,2S)-2-(3-케토 피롤리디닐)-1-(2,2- 디페닐에톡시)사이클로헥산 모노하이드로클로라이드 |
21 | 155 | 2.5 | 3.1 | |
48 | (1R,2R)/(1S,2S)-2-(3- 티아졸리디닐)-1-(2,6- 디클로로펜에톡시) 사이클로헥산 모노하이드로클로라이드 |
43 | 331 | 6.5 | 2.5 |
Claims (121)
- 제1항에 있어서, R4 및 R5가 독립적으로 C1-C3 알콕시로부터 선택되는 화학식 IE의 화합물.
- 제1항에 있어서, R4 및 R5가 C1 알콕시인 화학식 IE의 화합물.
- 제1항에 있어서, 다음 화합물로 이루어진 그룹으로부터 선택되는 화학식 IE의 화합물.
화학식 화학명
(1R,2R)/(1S,2S)-2-[(3R)/(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2R)/(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2R)/(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1S,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1S,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2S)/(1S,2R)-2-[(3R)/(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산
(1R,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드
(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산모노하이드로클로라이드
(1R,2R)/(1S,2S)-2-[(3R)/(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드
(1R,2R)/(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드
(1R,2R)/(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드
(1R,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드
(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 - 제1항에 있어서,(1R,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물,(1R,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물,(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물,(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산, 또는 이의 약제학적으로 허용되는 염 또는 용매화물,(1R,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 또는 이의 용매화물,(1R,2R)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 또는 이의 용매화물,(1S,2S)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 또는 이의 용매화물, 및(1S,2S)-2-[(3S)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 모노하이드로클로라이드 또는 이의 용매화물로부터 선택되는 화합물.
- 제1항에 있어서, (1R,2R)-2-[(3R)-하이드록시피롤리디닐]-1-(3,4-디메톡시펜에톡시)-사이클로헥산 또는 이의 약제학적으로 허용되는 염인 화합물.
- 제1항 내지 제6항 중 어느 하나의 항에 따르는 유효량의 화합물을 시험관내 투여함을 포함하는, 시험관내 세팅에서 이온 채널 활성의 조절 방법.
- 제7항에 있어서, 조절이 차단/억제를 의미하고, 활성이 이온 채널의 활성/전도도를 의미하는 방법.
- 제7항에 있어서, 이온 채널이 칼륨 채널인 방법.
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 삭제
- 제4항에 따르는 화합물을 포함하는, 온혈동물에서의 부정맥, 심방 부정맥, 온혈 동물에서의 심실 부정맥, 온혈 동물에서의 심방 세동, 온혈 동물에서의 심방 조동, 온혈 동물에서의 심실 세동, 또는 온혈 동물에서의 심실 조동 치료 및/또는 예방용 약제학적 조성물.
- 제5항에 따르는 화합물을 포함하는, 온혈동물에서의 부정맥, 심방 부정맥, 온혈 동물에서의 심실 부정맥, 온혈 동물에서의 심방 세동, 온혈 동물에서의 심방 조동, 온혈 동물에서의 심실 세동, 또는 온혈 동물에서의 심실 조동 치료 및/또는 예방용 약제학적 조성물.
- 제6항에 따르는 화합물을 포함하는, 온혈동물에서의 부정맥, 심방 부정맥, 온혈 동물에서의 심실 부정맥, 온혈 동물에서의 심방 세동, 온혈 동물에서의 심방 조동, 온혈 동물에서의 심실 세동, 또는 온혈 동물에서의 심실 조동 치료 및/또는 예방용 약제학적 조성물.
- 화학식 55 또는 74의 화합물을 화학식 56의 화합물과 반응시켜 각각 화학식 57 또는 75의 화합물을 수득함을 포함하여, 아미노사이클로헥실 에테르를 입체 선택적으로 제조하는 방법.화학식 55화학식 74화학식 56화학식 57화학식 75위의 화학식 55, 56, 57, 74 및 75에서,R1 및 R2는 화학식 57 또는 75에서 이들이 직접 결합된 질소 원자와 함께, 화학식 II의 환을 형성하며,화학식 IIR3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없으며,O-J는 이탈 그룹이다.
- 제19항에 있어서, 반응 단계 전에, 화학식 53 또는 84의 화합물을 화학식 54의 화합물로 알킬화시켜 각각 화학식 55 또는 74의 화합물을 수득하고,알킬화 단계 전에, 화학식 53 또는 84의 화합물을 임의로 보호하는 단계를 추가로 포함하는 방법.화학식 53화학식 84화학식 54위의 화학식 53, 54 및 84에서,O-J는 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,O-Q는 화학식 53 또는 84의 화합물의 입체 화학 배위가 각각 화학식 55 또는 74의 화합물에 유지되도록, 화학식 55 또는 74의 화합물을 형성하기 위해 화학식 53 또는 84에서 -OH와 반응하는 이탈 그룹이다.
- 제20항에 있어서, R3, R4 및 R5 중의 하나 이상이 C1-C6 알콕시인 방법.
- 제20항에 있어서,O-J가 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,R3, R4 및 R5 중의 하나 이상이 C1-C6 알콕시이고,O-Q가 트리클로로아세트이미데이트인 방법.
- 제26항에 있어서, R3, R4 및 R5 중의 하나 이상이 C1-C6 알콕시이고, 하이드록시 활성화 시약이 토실 클로라이드인 방법.
- 제20항에 있어서, 알킬화 단계 전에, 화학식 53 및 84의 화합물의 라세믹 혼합물을 분리하는 단계를 추가로 포함하는 방법.
- 제46항에 있어서, 분리 단계가 화합물을 분할할 수 있도록 화학식 53 및 84의 화합물 중 어느 하나 또는 둘 다를 작용화하고, 분할하여 화합물을 분리한 다음, 작용화된 화합물 중 어느 하나 또는 둘 다의 작용성 그룹을 임의로 제거하는 단계를 추가로 포함하는 방법.
- 화학식 53 또는 84의 화합물을 화학식 54의 화합물로 알킬화시켜 각각 화학식 55 또는 74의 화합물을 수득하는 단계, 및알킬화 단계 전에, 화학식 53 또는 84의 화합물을 임의로 보호하는 단계를 포함하는, 화학식 55 또는 74의 화합물의 제조 방법.화학식 55화학식 74화학식 53화학식 84화학식 54위의 화학식 53, 54, 55, 74 및 84에서,O-Q는 화학식 53 또는 84의 화합물의 입체 화학 배위가 각각 화학식 55 또는 74의 화합물에 유지되도록, 화학식 55 또는 74의 화합물을 형성하기 위해 화학식 53 또는 84에서 -OH와 반응하는 이탈 그룹이고,R3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없고,O-J는 이탈 그룹이다.
- 화학식 51의 화합물을 화학식 54의 화합물로 알킬화시켜 화학식 72의 화합물을 수득하는 단계를 포함하는, 화학식 72의 화합물의 제조 방법.화학식 72화학식 51화학식 54위의 화학식 51, 54 및 72에서,X는 할라이드이고,R3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없고,O-Q는 화학식 51의 화합물의 입체 화학 배위가 화학식 72의 화합물에 유지되도록, 화학식 72의 화합물을 형성하기 위해 화학식 51에서 -OH와 반응하는 이탈 그룹이다.
- 화학식 92의 화합물을 화학식 54의 화합물로 알킬화시켜 화학식 93의 화합물을 수득하는 단계를 포함하는 화학식 93의 화합물의 제조 방법.화학식 93화학식 92화학식 54위의 화학식 54, 92 및 93에서,Pro는 보호 그룹이고,R3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없고,O-Q는 화학식 92의 화합물의 입체 화학 배위가 화학식 93의 화합물에 유지되도록, 화학식 93의 화합물을 형성하기 위해 화학식 92에서 -OH와 반응하는 이탈 그룹이다.
- 제62항에 있어서, 분리 단계가 화합물을 분할할 수 있도록 화학식 52 및 84의 화합물 중 어느 하나 또는 둘 다를 작용화하고, 분할하여 화합물을 분리한 다음, 작용화된 화합물 중 어느 하나 또는 둘 다의 작용성 그룹을 임의로 제거하는 단계를 추가로 포함하는 방법.
- (a) 화학식 53의 화합물을 화학식 54의 화합물과 반응시키는 단계,(b) 제1 반응 단계(a) 전에, 화학식 53의 화합물을 임의로 보호하는 단계, 및(c) 화학식 55의 화합물을 화학식 56의 화합물과 반응시켜 화학식 57의 아미노사이클로헥실 에테르를 수득하는 단계를 포함하여, 화학식 57의 아미노사이클로헥실 에테르를 입체 선택적으로 제조하는 방법.화학식 57화학식 53화학식 54화학식 55화학식 56위의 화학식 53 내지 57에서,R1 및 R2는 화학식 57에서 이들이 직접 결합되는 질소 원자와 함께, 화학식 II의 환을 형성하며,화학식 IIR3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없으며,O-J는 이탈 그룹이고,O-Q는 화학식 53의 화합물의 입체 화학 배위가 화학식 55의 화합물에 유지되도록, 화학식 55의 화합물을 형성하기 위해 화학식 53에서 하이드록시 그룹(-OH)과 반응하는 이탈 그룹이다.
- 제68항에 있어서, 분리 단계가 효소적 분할, 결정화 및/또는 크로마토그래피 분할을 포함하는 방법.
- 제68항에 있어서, 분할이 리파제 매개되는 방법.
- 제65항 내지 제70항 중 어느 하나의 항에 있어서,R3, R4 및 R5 중의 하나 이상이 C1-C6 알콕시이고,O-J가 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,O-Q가 트리클로로아세트이미데이트이고,존재하는 경우, X가 Cl인 방법.
- (a) 화학식 84의 화합물을 화학식 54의 화합물과 반응시키는 단계,(b) 제1 반응 단계(a) 전에, 화학식 84의 화합물을 임의로 보호하는 단계, 및(c) 화학식 74의 화합물을 화학식 56의 화합물과 반응시켜 화학식 75의 아미노사이클로헥실 에테르를 수득하는 단계를 포함하여, 화학식 75의 아미노사이클로헥실 에테르를 입체 선택적으로 제조하는 방법.화학식 75화학식 84화학식 54화학식 74화학식 56위의 화학식 54, 56, 74, 75 및 84에서,R1 및 R2는 화학식 75에서 이들이 직접 결합되는 질소 원자와 함께, 화학식 II의 환을 형성하며,화학식 IIR3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없으며,O-J는 이탈 그룹이고,O-Q는 화학식 84의 화합물의 입체 화학 배위가 화학식 74의 화합물에 유지되도록, 화학식 74의 화합물을 형성하기 위해 화학식 54에서 하이드록시 그룹(-OH)과 반응하는 이탈 그룹이다.
- 제78항에 있어서, 분리 단계가 효소적 분할, 결정화 및/또는 크로마토그래피 분할을 포함하는 방법.
- 제78항에 있어서, 분할이 리파제 매개되는 방법.
- 제75항 내지 제80항 중 어느 하나의 항에 있어서,R3, R4 및 R5 중의 하나 이상이 C1-C6 알콕시이고,O-J가 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,O-Q가 트리클로로아세트이미데이트이고,존재하는 경우, Pro가 3급 부틸디페닐실릴(TBDPS)이고,존재하는 경우, X가 Cl인 방법.
- 제75항 내지 제80항 중 어느 하나의 항에 있어서,화학식 56의 화합물이 화학식 65의 화합물이고,R3이 수소이고, R4가 페닐 그룹의 C3에서 메톡시이고, R5가 페닐 그룹의 C4에서 메톡시이고,O-J가 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,O-Q가 트리클로로아세트이미데이트이고,존재하는 경우, Pro가 3급 부틸디페닐실릴(TBDPS)이고,존재하는 경우, X가 Cl이어서,화학식 75의 아미노사이클로헥실 에테르가 화학식 79의 화합물인 방법.화학식 65화학식 79
- (a) 화학식 73의 화합물을 하이드록시 활성화 시약과 반응시켜 화학식 74의 화합물을 수득하는 단계, 및(b) 제1 반응 단계(a)의 생성물인 화학식 74의 화합물을 화학식 56의 화합물과 반응시켜 화학식 75의 아미노사이클로헥실 에테르를 수득하는 단계를 포함하여, 화학식 75의 아미노사이클로헥실 에테르를 입체 선택적으로 제조하는 방법.화학식 75화학식 73화학식 74화학식 56위의 화학식 56, 73, 74 및 75에서,R1 및 R2는 화학식 75에서 이들이 직접 결합되는 질소 원자와 함께, 화학식 II의 환을 형성하며,화학식 IIR3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없으며,O-J는 이탈 그룹이다.
- 제85항 내지 제87항 중 어느 하나의 항에 있어서,R3, R4 및 R5 중의 하나 이상이 C1-C6 알콕시이고,O-J가 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,O-Q가 트리클로로아세트이미데이트이고,존재하는 경우, X가 Cl인 방법.
- (a) 화학식 91의 화합물을 수소화 및 가수소분해시켜 화학식 92의 화합물을 수득하는 단계,(b) 화학식 92의 화합물을 화학식 54의 화합물로 알킬화시키는 단계,(c) 화학식 93의 화합물을 탈보호하여 화학식 94의 화합물을 수득하는 단계,(d) 화학식 94의 화합물을 활성화시켜 화학식 55의 화합물을 수득하는 단계,(e) 화학식 55의 화합물을 화학식 56의 화합물과 반응시켜 화학식 57의 아미노사이클로헥실 에테르를 수득하는 단계를 포함하여, 화학식 57의 아미노사이클로헥실 에테르를 입체 선택적으로 제조하는 방법.화학식 57화학식 91화학식 92화학식 54화학식 93화학식 94화학식 55화학식 56위의 화학식 54, 55, 56, 57, 91, 92, 93 및 94에서,R1 및 R2는 화학식 57에서 이들이 직접 결합되는 질소 원자와 함께, 화학식 II의 환을 형성하며,화학식 IIR3, R4 및 R5는 독립적으로 수소, 하이드록시 및 C1-C6 알콕시로부터 선택되고, 단 R3, R4 및 R5는 모두 수소일 수 없으며,Pro는 보호 그룹이고,X는 할라이드이고,O-Q는 화학식 92의 화합물의 입체 화학 배위가 화학식 93의 화합물에 유지되도록, 화학식 93의 화합물을 형성하기 위해 화학식 92에서 하이드록시 그룹(-OH)과 반응하는 이탈 그룹이고,O-J는 이탈 그룹이다.
- 제91항 또는 제92항에 있어서,O-J가 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,O-Q가 트리클로로아세트이미데이트이고,존재하는 경우, Pro가 3급 부틸디페닐실릴(TBDPS)이고,존재하는 경우, X가 Cl인 방법.
- 제91항 또는 제92항에 있어서,R3, R4 및 R5 중의 하나 이상이 C1-C6 알콕시이고,O-J가 메실레이트 그룹, 토실레이트 그룹, 노실레이트 그룹, 2-브로모페닐설포네이트 그룹 또는 4-브로모페닐설포네이트 그룹이고,O-Q가 트리클로로아세트이미데이트이고,존재하는 경우, Pro가 3급 부틸디페닐실릴(TBDPS)이고,존재하는 경우, X가 Cl인 방법.
- (b) 화합물 1R을 적합한 조건하에 벤질 브로마이드와 반응시켜 화학식 2R의 화합물을 수득하는 단계,(c) 화합물 2R을 적합한 조건하에 가수분해시켜 화학식 3R의 화합물을 수득하는 단계,(f) 화합물 5R을 적합한 조건하에 분할하여 화학식 5RRR 및 5SSR의 화합물을 수득하는 단계, 및(g) 화합물 5RRR을 적합한 조건하에 가수소분해시켜 화학식 1의 화합물을 수득하고, 화합물 5SSR을 적합한 조건하에 가수소분해시켜 화학식 2의 화합물을 수득하는 단계를 포함하는, 화학식 1 또는 2의 화합물의 제조 방법.화학식 1화학식 2화학식 1R화학식 2R화학식 3R화학식 4R화학식 5R화학식 5RRR화학식 5SSR
- (b) 화합물 1R을 적합한 조건하에 벤질 브로마이드와 반응시켜 화학식 2R의 화합물을 수득하는 단계,(c) 화합물 2R을 적합한 조건하에 가수분해시켜 화학식 3R의 화합물을 수득하는 단계,(f) 화합물 5R을 적합한 조건하에 분할하여 화학식 5RRR 및 5SSR의 화합물을 수득하는 단계를 포함하는, 화학식 5RRR 또는 5SSR의 화합물의 제조 방법.화학식 5RRR화학식 5SSR화학식 1R화학식 2R화학식 3R화학식 4R화학식 5R
- (b) 화합물 1R을 적합한 조건하에 벤질 브로마이드와 반응시켜 화학식 2R의 화합물을 수득하는 단계,(c) 화합물 2R을 적합한 조건하에 가수분해시켜 화학식 3R의 화합물을 수득하는 단계,화학식 5R화학식 1R화학식 2R화학식 3R화학식 4R
- (g) 단계(f)에서 수득한 화학식 의 화합물을 적합한 조건하에 가수소분해시켜 화학식 6의 화합물을 수득하고, 단계(f)에서 수득한 화학식 의 화합물을 적합한 조건하에 가수소분해시켜 화학식 7의 화합물을 수득하는 단계를 포함하는, 화학식 6 또는 7의 화합물의 제조 방법.화학식 6화학식 7
- 화학식 3
Applications Claiming Priority (15)
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---|---|---|---|
US46715903P | 2003-05-02 | 2003-05-02 | |
US60/467,159 | 2003-05-02 | ||
US47608303P | 2003-06-04 | 2003-06-04 | |
US60/476,083 | 2003-06-04 | ||
US47644703P | 2003-06-05 | 2003-06-05 | |
US47588403P | 2003-06-05 | 2003-06-05 | |
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PCT/US2003/034655 WO2004099137A1 (en) | 2003-05-02 | 2003-10-31 | Aminocyclohexyl ether compounds and uses thereof |
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EP (3) | EP1666459B1 (ko) |
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AT (2) | ATE325789T1 (ko) |
AU (2) | AU2003287378B2 (ko) |
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SG (2) | SG167670A1 (ko) |
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