KR20030022370A - 뉴로키닌-1 수용체 길항물질로서의 4-페닐-피리딘 유도체 - Google Patents
뉴로키닌-1 수용체 길항물질로서의 4-페닐-피리딘 유도체 Download PDFInfo
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- KR20030022370A KR20030022370A KR10-2003-7001838A KR20037001838A KR20030022370A KR 20030022370 A KR20030022370 A KR 20030022370A KR 20037001838 A KR20037001838 A KR 20037001838A KR 20030022370 A KR20030022370 A KR 20030022370A
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- methyl
- trifluoromethyl
- bis
- tolyl
- benzyl
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Abstract
Description
실시예 번호 | pKi |
8 | 9.29 |
13 | 8.79 |
16 | 8.5 |
26 | 8.65 |
38 | 8.67 |
42 | 9.08 |
62 | 8.52 |
66 | 8.57 |
99 | 8.58 |
113 | 8.78 |
㎎/정 | |
활성 물질 | 5 |
락토스 | 45 |
옥수수 전분 | 15 |
미세정질 셀룰로스 | 34 |
스테아르산 마그네슘 | 1 |
정제 중량 | 100 |
㎎/캡슐 | |
활성 물질 | 10 |
락토스 | 155 |
옥수수 전분 | 30 |
활석 | 5 |
캡슐 충전 중량 | 200 |
㎎/좌제 | |
활성 물질 | 15 |
좌제 덩어리 | 1285 |
총량 | 1300 |
Claims (22)
- 하기 화학식 I의 화합물 및 그의 약학적으로 허용가능한 산 부가염.화학식 I상기 식에서,R은 수소 또는 할로겐이고;R1은 -(C≡C)mR1'또는 -(CR'≡CR")mR1'이되, 여기서R1'는a) 할로겐,b) 시아노,c),d) -C(O)NR'R",e) -C(O)O(CH2)mR5,f) -C(O)R5,g) -N(OH)-(CH2)mR5,h) -NR'C(O)-(CH2)mR5,i) -N[C(O)-R']2,j) -OR6,k) -(CH2)m-SR6, -(CH2)m-S(O)R6또는 -(CH2)m-S(O)2R6,l) 아릴(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환됨),m) N, O 또는 S로부터 선택된 1 내지 4개의 헤테로원자를 함유하는 5원 또는 6원 헤테로아릴 그룹(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)OR', -C(O)NR'R" 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있음), 또는n) N, O 또는 S로부터 선택된 하나의 추가 헤테로원자를 함유할 수 있는 그룹의 5원 또는 6원 포화 사이클릭 3급 아민이고,R'/R"는 서로 독립적으로 수소, 하이드록시, 저급 알킬, 사이클로알킬 또는 아릴이되, 여기서 상기 저급 알킬, 사이클로알킬 또는 아릴 그룹은 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'"R"", 니트로, -(CH2)nOR'", -C(O)NR'"R"", -C(O)OR'" 또는 -C(O)R'"로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있되, R'"/R""는 서로 독립적으로 수소, 저급 알킬, 사이클로알킬 또는 아릴이고,R5는 수소, 시아노, 하이드록시, 할로겐, 트리플루오로메틸, -C(O)OR', -OC(O)R' 또는 아릴(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환됨)이거나, 또는 N, O 또는 S로부터 선택된 1 내지 4개의 헤테로원자를 함유하는 5원 또는 6원 헤테로아릴 그룹(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있음)이고,R6은 수소, 저급 알킬, 트리플루오로메틸 또는 아릴(여기서, 상기 저급 알킬 또는 아릴 그룹은 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -C(O)NR'R", -(CH2)nOR', -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있다)이거나, 또는 N, O 또는S로부터 선택된 1 내지 4개의 헤테로원자를 함유하는 5원 또는 6원 헤테로아릴 그룹(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있음)이고,R7은 -C(O)-(CH2)mOH 또는 옥소 그룹이고;R2는 수소, 저급 알킬, 저급 알콕시, 할로겐 또는 CF3이고;R3/R3'는 서로 독립적으로 수소 또는 저급 알킬이거나, 또는 이들이 부착된 탄소원자와 함께 사이클로알킬 그룹을 형성하고;R4/R4'는 서로 독립적으로 수소, 할로겐, CF3, 저급 알킬 또는 저급 알콕시이고;R과 R2또는 R4과 R4'는 함께 -CH=CH-CH=CH-(이는 저급 알킬, 할로겐 또는 저급 알콕시로부터 선택된 1 또는 2개의 치환기에 의해 선택적으로 치환됨)일 수 있고;X는 -C(O)N(R8)-, (CH2)pO-, -(CH2)pN(R8)-, -N(R8)C(O)- 또는 -N(R8)-(CH2)p-이되, 여기서 R8은 수소 또는 저급 알킬이고;n은 1 또는 2이고;m은 0, 1, 2, 3 또는 4이고;o는 1 또는 2이고;P는 1 또는 2이다.
- 하기 화학식 I의 화합물 및 그의 약학적으로 허용가능한 산 부가염.화학식 I상기 식에서,R은 수소 또는 할로겐이고;R1은 -(C≡C)mR1'또는 -(CR'≡CR")mR1'이되, 여기서R1'는a) 할로겐,b) 시아노,c),d) -C(O)NR'R",e) -C(O)O(CH2)mR5,f) -C(O)R5,g) -N(OH)-(CH2)mR5,h) -NR'C(O)-(CH2)mR5,i) -N[C(O)-R']2,j) -OR6,k) -SR6, -S(O)R6또는 -S(O)2R6,l) 아릴(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환됨),m) N, O 또는 S로부터 선택된 1 내지 4개의 헤테로원자를 함유하는 5원 또는 6원 헤테로아릴 그룹(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)OR', -C(O)NR'R" 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있음), 또는n) N, O 또는 S로부터 선택된 하나의 추가 헤테로원자를 함유할 수 있는 그룹의 5원 또는 6원 포화 사이클릭 3급 아민이고,R'/R"는 서로 독립적으로 수소, 저급 알킬, 사이클로알킬 또는 아릴(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'"R"", 니트로, -(CH2)nOR'", -C(O)NR'"R"", -C(O)OR'" 또는 -C(O)R'"로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있되, R'"/R""는 서로 독립적으로 수소, 저급 알킬, 사이클로알킬 또는 아릴임)이고,R5는 수소, 시아노, 하이드록시, 할로겐, 트리플루오로메틸, -C(O)OR' 또는 아릴(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환됨)이거나, 또는 N, O 또는 S로부터 선택된 1 내지 4개의 헤테로원자를 함유하는 5원 또는 6원 헤테로아릴 그룹(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있음)이고,R6은 수소, 저급 알킬, 트리플루오로메틸 또는 아릴(이는 할로겐, 트리플루오로메틸, 저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -C(O)NR'R", -(CH2)nOR', -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있음)이거나, 또는 N, O 또는 S로부터 선택된 1 내지 4개의 헤테로원자를 함유하는 5원 또는 6원 헤테로아릴 그룹(이는 할로겐, 트리플루오로메틸,저급 알킬, 저급 알콕시, 시아노, 하이드록시, -NR'R", 니트로, -(CH2)nOR', -C(O)NR'R", -C(O)OR' 또는 -C(O)R'로부터 선택된 하나 이상의 치환기에 의해 선택적으로 치환될 수 있음)이고,R7은 -C(O)-(CH2)mOH 또는 옥소 그룹이고;R2는 수소, 저급 알킬, 저급 알콕시, 할로겐 또는 CF3이고;R3/R3'는 서로 독립적으로 수소 또는 저급 알킬이거나, 또는 이들이 부착된 탄소원자와 함께 사이클로알킬 그룹을 형성하고;R4/R4'는 서로 독립적으로 수소, 할로겐, CF3, 저급 알킬 또는 저급 알콕시이고;R과 R2또는 R4과 R4'는 함께 -CH=CH-CH=CH-(이는 저급 알킬, 할로겐 또는 저급 알콕시로부터 선택된 1 또는 2개의 치환기에 의해 선택적으로 치환됨)일 수 있고;X는 -C(O)N(R8)-, (CH2)pO-, -(CH2)pN(R8)-, -N(R8)C(O)- 또는 -N(R8)-(CH2)p-이되, 여기서 R8은 수소 또는 저급 알킬이고;n은 1 또는 2이고;m은 0 내지 4이고;o는 1 또는 2이고;P는 1 또는 2이다.
- 제 1 항에 있어서,하기 화학식 IA의 화합물.상기 식에서,R1은 할로겐, -(CH2)mCN, -C(O)O-저급 알킬, -(CH2)m-OH, -N(OH)-(CH2)mOH, -N(R)C(O)-(CH2)mOC(O)-저급 알킬, -N[C(O)-사이클로알킬]2, -N(R)C(O)-(CH2)mOH, 피리딘-2,3,4-일 또는 페닐(이는 저급 알킬, 저급 알콕시 또는 하이드록시에 의해 선택적으로 치환됨)이거나, 또는 모폴리닐 또는 피페라지닐(이는 -C(O)-(CH2)mOH 또는 옥소 그룹(들)에 의해 치환됨)이고,R은 수소 또는 저급 알킬이고,R2는 저급 알킬 또는 할로겐이고,R3/R3'는 서로 독립적으로 수소 또는 저급 알킬이고,X는 -C(O)N(R8)- 또는 -N(R8)C(O)-이되, 여기서 R8은 수소 또는 저급 알킬이고,m은 1 또는 2이다.
- 제 1 항에 있어서,-(R4)n이 3,5-디-트리플루오로메틸인 화학식 I의 화합물.
- 제 4 항에 있어서,X가 -C(O)N(R)-인 화학식 I의 화합물.
- 제 5 항에 있어서,R3/R3'가 모두 수소이고 R2가 메틸인 화학식 I의 화합물.
- 제 6 항에 있어서,N-(3,5-비스-트리플루오로메틸-벤질)-6-(4-하이드록시아세틸-피페라진-1-일)-N-메틸-4-o-톨릴-니코틴아미드,N-(3,5-비스-트리플루오로메틸-벤질)-6-클로로-N-메틸-4-o-톨릴-니코틴아미드,N-(3,5-비스-트리플루오로메틸-벤질)-6-시아노메틸-N-메틸-4-o-톨릴-니코틴아미드,N-(3,5-비스-트리플루오로메틸-벤질)-6-요오도-N-메틸-4-o-톨릴-니코틴아미드,4-o-톨릴-[2,4']비피리디닐-5-카복실산 (3,5-비스-트리플루오로메틸-벤질)-메틸-아미드,5-[(3,5-비스-트리플루오로메틸-벤질)-메틸-카바모일]-4-o-톨릴-피리딘-2-카복실산 메틸 에스테르,N-(3,5-비스-트리플루오로메틸-벤질)-6-하이드록시메틸-N-메틸-4-o-톨릴-니코틴아미드,6-(5-아세틸-티오펜-2-일)-N-(3,5-비스-트리플루오로메틸-벤질)-N-메틸-4-o-톨릴-니코틴아미드,4-o-톨릴-1',2',3',6'-테트라하이드로-[2,4']비피리디닐-5-카복실산 (3,5-비스-트리플루오로메틸-벤질)-메틸-아미드,N-(3,5-비스-트리플루오로메틸-벤질)-6-(4-하이드록시메틸-페닐)-N-메틸-4-o-톨릴-니코틴아미드,2'-메틸-4-o-톨릴-[2,4']비피리디닐-5-카복실산 (3,5-비스-트리플루오로메틸-벤질)-메틸-아미드,N-(3,5-비스-트리플루오로메틸-벤질)-N-메틸-6-(3-메틸-[1,2,4]옥사디아졸-5-일)-4-o-톨릴-니코틴아미드,6-(3-아미노-프롭-1-이닐)-N-(3,5-비스-트리플루오로메틸-벤질)-N-메틸-4-o-톨릴-니코틴아미드,(RS)-N-(3,5-비스-트리플루오로메틸-벤질)-6-(2-하이드록시-에탄설피닐메틸)-N-메틸-4-o-톨릴-니코틴아미드,N-(3,5-비스-트리플루오로메틸-벤질)-N-메틸-6-(1-메틸-1H-이미다졸-2-일설파닐메틸)-4-o-톨릴-니코틴아미드,(RS)-N-(3,5-비스-트리플루오로메틸-벤질)-N-메틸-6-(피리딘-2-설피닐)-4-o-톨릴-니코틴아미드,N-(3,5-비스-트리플루오로메틸-벤질)-N-메틸-6-(피리딘-2-설포닐)-4-o-톨릴-니코틴아미드, 또는N-(3,5-비스-트리플루오로메틸-벤질)-6-(3-하이드록시-프로폭시)-N-메틸-4-o-톨릴-니코틴아미드인 화학식 I의 화합물.
- 제 4 항에 있어서,X가 -N(R)C(O)-인 화학식 I의 화합물.
- 제 8 항에 있어서,R3/R3'및 R2가 메틸인 화학식 I의 화합물.
- 제 9 항에 있어서,2-(3,5-비스-트리플루오로메틸-페닐)-N-{6-[하이드록시-(2-하이드록시-에틸)-아미노]-4-o-톨릴-피리딘-3-일}-N-메틸-이소부티르아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-메틸-N-[6-(3-옥소-모르폴린-4-일)-4-o-톨릴-피리딘-3-일]-이소부티르아미드,아세트산 (5-{[2-(3,5-비스-트리플루오로메틸-페닐)-2-메틸-프로피오닐]-메틸-아미노}-4-o-톨릴-피리딘-2-일카바모일)-메틸 에스테르,2-(3,5-비스-트리플루오로메틸-페닐)-N-[6-(2-하이드록시-아세틸아미노]-4-o-톨릴-피리딘-3-일]-N-메틸-이소부티르아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-[6-(하이드록시아세틸-메틸-아미노]-4-o-톨릴-피리딘-3-일]-N-메틸-이소부티르아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-[6-(2,5-디옥소-피롤리딘-1-일)-4-o-톨릴-피리딘-3-일]-N-메틸-이소부티르아미드,사이클로프로판카복실산 (5-{[2-(3,5-비스-트리플루오로메틸-페닐)-2-메틸-프로피오닐]-메틸-아미노}-4-o-톨릴-피리딘-2-일)-사이클로프로판카보닐-아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-(6-클로로-4-o-톨릴-피리딘-3-일)-N-메틸-이소부티르아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-[4-(2-클로로-페닐)-2'-메틸-[2,4']비피리디닐-5-일]-N-메틸-이소부티르아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-(6-에티닐-4-o-톨릴-피리딘-3-일)-N-메틸-이소부티르아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-[6-(3-하이드록시메틸-이속사졸-5-일)-4-o-톨릴-피리딘-3-일)-N-메틸-이소부티르아미드,2-(3,5-비스-트리플루오로메틸-페닐)-N-[6-(3-하이드록시-프롭-1-이닐)-4-o-톨릴-피리딘-3-일)-N-메틸-이소부티르아미드, 또는(RS)-2-(3,5-비스-트리플루오로메틸-페닐)-N-[6-(3-메톡시-벤젠설피닐)-4-o-톨릴-피리딘-3-일]-N-메틸-이소부티르아미드인 화학식 I의 화합물.
- 제 8 항에 있어서,R3/R3'가 모두 메틸이고 R2가 클로로인 화학식 I의 화합물.
- 제 11 항에 있어서,2-(3,5-비스-트리플루오로메틸-페닐)-N-{4-(2-클로로-페닐)-6-[하이드록시-(2-하이드록시-에틸)-아미노]-피리딘-3-일}-N-메틸-이소부티르아미드, 또는2-(3,5-비스-트리플루오로메틸-페닐)-N-[4-(2-클로로-페닐)-6-(3-옥소-모르폴린-4-일)-피리딘-3-일]-N-메틸-이소부티르아미드인 화학식 I의 화합물.
- 제 4 항에 있어서,X가 -N(R)-(CH2)p-인 화학식 I의 화합물.
- 제 4 항에 있어서,X가 -(CH2)pO-인 화학식 I의 화합물.
- 제 4 항에 있어서,X가 -(CH2)pN(R)-인 화학식 I의 화합물.
- 제 1 항 내지 제 15 항중 어느 한 항에 따른 하나 이상의 화합물 및 약학적으로 허용가능한 부형제를 함유하는 약제.
- 제 16 항에 있어서,NK-1(Neurokinin-1) 수용체 길항물질과 관련된 질환을 치료하기 위한 약제.
- a) 하기 화학식 II의 화합물을 하기 화학식 III의 화합물과 반응시켜 하기 화학식 Ia의 화합물을 수득하거나,b) 하기 화학식 IV의 화합물을 하기 화학식 V의 화합물과 반응시켜 하기 화학식 Ib의 화합물을 수득하거나,c) 하기 화학식 Ib의 화합물을 환원시켜 하기 화학식 Ic의 화합물을 수득하거나,d) 하기 화학식 VI의 화합물을 하기 화학식 VII의 화합물과 반응시켜 하기 화학식 Ib의 화합물을 수득하거나,e) 하기 화학식 VIII의 화합물을 하기 화학식 VII의 화합물과 반응시켜 하기 화학식 Id의 화합물을 수득하거나,f) 하기 화학식 Ia의 화합물을 환원시켜 하기 화학식 Ie의 화합물을 수득하거나, 또는h) 하나 이상의 치환기 R1내지 R4, R8또는 R을 상기한 정의내에서 변형시키고,필요하다면, 상기 수득된 화합물을 약학적으로 허용가능한 염으로 전환시키는 것을 포함하는 제 1 항의 화학식 I의 화합물의 제조방법.화학식 Ia화학식 Ib화학식 Ic화학식 Id화학식 Ie화학식 II화학식 III화학식 IV화학식 V화학식 VI화학식 VII화학식 VIII상기 식에서,Z는 Cl, Br, I, -OS(O)2CH3또는 -OS(O)2C6H4CH3이고,R1, R2, R3, R4, R, n 및 나머지 치환기는 제 1 항에서 제시된 의미를 갖는다.
- 제 18 항에 따른 제조방법 또는 그와 동등한 방법에 의해 제조되는, 제 1 항 내지 제 15 항중 어느 한 항에 따른 화합물.
- NK-1 수용체 길항물질과 관련된 질환을 치료하기 위한, 제 1 항 내지 제 15 항중 어느 한 항에 따른 화합물의 용도.
- NK-1 수용체 길항물질과 관련된 질환을 치료하기 위해 화학식 I의 하나 이상의 화합물을 함유하는 약제를 제조하기 위한, 제 1 항 내지 제 15 항중 어느 한 항에 따른 화합물의 용도.
- 본원에 기술된 발명.
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US6303790B1 (en) * | 1999-11-29 | 2001-10-16 | Hoffman-La Roche Inc. | Process for the preparation of pyridine derivatives |
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