3-amino-2-oxo-1-piperidineacetic derivatives as enzyme inhibitorsThe present invention discloses peptide aldehydes which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.A compound is characterized in that, it has following structural formula: wherein (a) x is selected from-s (o) 2-,-n (r ')-s (o) 2-,-c (=o)-,-oc (=o)-,-nh-c (=o)-,-p (o) (r ')-and direct connecting key; the aryl of r ' hydrogen atom wherein, 1 alkyl, about 6 to 14 carbon atoms or the aralkyl of about 6 to 16 carbon atoms; r to about 4 carbon atoms ' be nr ', or ', r ' or sr ', condition is r ' not nh, oh, h or sh; (b) r 1be selected from (1) 1 alkyl to about 12 carbon atoms, (2) through 1 alkyl of the cycloalkyl substituted of about 5 to 8 carbon atoms to about 3 carbon atoms, its available ring carbon atom is arbitrarily by hydroxyl, amino, guanidine radicals, amidino groups or 1 alkoxyl group or alkyl to about 3 carbon atoms replace, (3) 3 cycloalkyl to about 15 carbon atoms, its available ring carbon atom is arbitrarily by hydroxyl, amino, guanidine radicals, amidino groups or 1 alkoxyl group or alkyl to about 3 carbon atoms replace, (4) 4 heterocyclylalkyls to about 10 annular atomses, annular atoms is selected from carbon atom and heteroatoms, and heteroatoms wherein is selected from oxygen, nitrogen and s (o) ii wherein is 0,1 or 2, and available ring carbon atom is replaced (5) 4 heterocyclic radicals to about 10 annular atomses by hydroxyl, 1 alkoxyl group or alkyl, amino, guanidine radicals or amidino groups to about 3 carbon atoms arbitrarily, annular atoms is selected from carbon atom and heteroatoms, and heteroatoms wherein is selected from oxygen, nitrogen and s (o) ii wherein is 0,1 or 2, available ring carbon atom is replaced by hydroxyl, 1 alkoxyl group or alkyl, amino, guanidine radicals or amidino groups to about 3 carbon atoms arbitrarily, (6) can be through the alkenyl of about 3 to 6 carbon atoms of the cycloalkyl substituted of about 5 to 8 carbon atoms, ring carbon atom can be replaced by hydroxyl, amino, guanidine radicals, amidino groups or 1 alkoxyl group or alkyl to about 3 carbon atoms, (7) about 6 aryl to about 14 carbon atoms can be respectively by y 1, y 2and/or y 3single replacement, two replaces or three replacements, the heteroaryl of (8) 5 to 14 atoms, and annular atoms is selected from carbon atom and heteroatoms, and heteroatoms wherein is selected from oxygen, nitrogen and s (o) i, i wherein is 0,1 or 2, can be respectively by y 1, y 2and/or y 3single replacement, two replaces or three replacements, can be respectively by y on (9) aromatic ring 1, y 2and/or y 3the aralkyl of single replacement, two replacements or trisubstituted about 7 to 15 carbon atoms, the heteroaralkyl of (10) 6 to 11 atoms, annular atoms are carbon atom and heteroatoms, heteroatoms wherein is selected from oxygen, nitrogen and s (o) i, i wherein is 0,1 or 2, can be respectively by y 1, y 2and/or y 3single replacement, two replaces or three replacements, can be respectively by y on (11) aromatic ring 1, y 2and/or y 3the aralkenyl of single replacement, two replacements or trisubstituted about 8 to 15 carbon atoms, the heteroaralkenyl of (12) 7 to 12 atoms, annular atoms are carbon atom and heteroatoms, heteroatoms wherein is selected from oxygen, nitrogen and s (o) i, i wherein is 0,1 or 2, can be respectively by y 1, y 2and/or y 3single replacement, two replaces or three replacements, (17) 1 perfluoroalkyls to about 12 carbon atoms, (18) about 6 are to the perfluor aryl of about 14 carbon atoms, perfluor aralkyl, (20) hydrogen atom and (21) of (19) about 7 to 15 carbon atoms , wherein be 5 to 7 yuan heterocycle with 3 to 6 ring carbon atoms, v wherein is-ch 2-,-o-,-s (=o)-,-s (o) 2-or s, y wherein 1, y 2and y 3be: (i) be selected from hydrogen atom, halogen atom, cyano group, tetrazyl, amino, guanidine radicals, amidino groups, methylamino and methyl guanidine radicals ,-cf separately 3,-cf 2h ,-cf 2cf 3,-ch (cf 3) 2,-c (oh) (cf 3) 2,-ocf 3,-ocf 2cf 3,-oc (o) nh 2,-oc (o) nhz 1,-oc (o) nz 1z 2,-nhc (o) z 1,-nhc (o) nh 2,-nhc (o) nhz 1,-nhc (o) nz 1z 2,-c (o) oh ,-c (o) nh 2,-c (o) nhz 1,-c (o) oz 1,-p (o 3) h ,-p (o) 3h 2,-p (o) 3(z 1) 2,-s (o) 3h ,-s (o) mz 1,-z 1,-oz 1,-oh ,-nh 2,-nhz 1with-nz 1z 2, wherein m is 0,1 or 2, z 1and z 2be selected from the aryl of 1 alkyl, about 6 to 14 carbon atoms separately, wherein the aralkyl of 1 heteroaryl to about 5 to 14 atoms of about 9 carbon atoms, about 7 to 15 carbon atoms and the heteroaralkyl of about 6 to 11 atoms (wherein have an appointment 3 to 9 and be carbon atom) arranged to about 12 carbon atoms, or (ii) y 1and y 2be together-oc (z 3) (z 4) o-, wherein z 3and z 4be selected from separately hydrogen atom, 1 alkyl, about 6 to 14 carbon atoms to about 12 carbon atoms aryl, have the heteroaralkyl (wherein have an appointment 3 to 9 for carbon atom) of 15 heteroaryls, the aralkyl of about 7 to 15 carbon atoms, about 6 to 11 atoms to about 14 atoms to about 9 carbon atoms (c) q is-(ch 2) n-(wherein n is an integer 1 to 4), or-(ch 2) qr 4-, wherein q is 1 or 2, r 4be-s (o) p-,-o-,-n (r 5)-, wherein p is 0,1 or 2, r 5be selected from the alkyl of ...
효소 억제제로서 3-아미노-2-옥소-1-피페리딘아세트산 유도체본 발명은 강력하고 특이적인 트롬빈 억제제인 펩티드 알데히드, 이들의 제약상 허용되는 염, 이들의 제약 조성물, 및 비정상적인 혈전증으로 특징되는 포유동물에서의 질병 상태에 대한 치료제로서 이들을 사용하는 방법에 관한 것이다.하기 화학식의 화합물 및 이들의 제약상 허용되는 염 [이미지] 상기 식에서 (a)X는 -S(O)2,-N(R′)-S(O)2-,-C(=O)-,-OC(=O)-,NH-C(=O)-,-P(O)(R″)- 및 직접 결합 (여기서 R′는 수소, 탄소수 1 내지 약 4의 알킬, 탄소수 약 6 내지 약 14의 아릴 또는 탄소수 약 6 내지 약 16의 아르아킬이고, R″는 NR′,OR′,R′,또는 SR′이고, 단 R″는 NH, OH, H, 또는 SH가 아님)이고; (b) R′은 (1)탄소 1내지 약 12의 알킬, (2) 탄소수 1내지 약 3의 알킬(이는 환 탄소가 히드록실, 아미노, 구이니디노, 아미디노, 또는 탄소수 1내지 약 3의 알콕시 또는 알킬로 임의로 치환된 탄소수 약 5 내지 약 8의 시클릭 알킬로 치환됨). (3) 탄소수 3 내지 약 15의 시클릭 알킬(이는 환 탄소가 히드록실, 아미노, 구아니디노, 아미디노, 또는 탄소수 1내지 약 3의 알콕시 또는 알킬로 임의로 치환됨). (4) 환 탄소가 히드록실, 탄수소 1 내지 약 3의 알콜실 또는 알킬, 아미노, 구아니디노, 또는 아미디노로 임의로 치환되며, 탄소 및 헤테로원자 중에서 선택된 환 원자를 갖는 환 원자수 4 내지 약 10의 헤테로시클로알킬 (여기서 헤테로원자는 산소, 질소, 및 S(O)로 이루어진 군으로부터 선택되며, 1는 0.1. 또는 2임) [이미지] 약 3 내지 약 9인 원자수 약 6 내지 약 11의 헤테로아르알킬로 이루어진 군으로부터 선택됨)이도록 선택되고, (c) Q는 -(CH2)n- (여기서 n은 1 내지 4의 정수임), 또는 -(CH2)qR4- (여기서 q는 1 또는 2이고, R4는 -S(O) p-, -O-, -N(R5)- (여기서 p는 0, 1 또는 2이고, R5는 수소, 탄소수 1 내지 4의 알킬, 및 탄소수 1 내지 4의 아실임)이고; (d) R2는 수소, 탄소수 1 내지 4의 알킬 또는 탄소수 2 내지 4의 알케닐로 이루어진 군으로부터 선택되고; (e) Y는 R1 치환체의 군으로부터 선택되는데, 단, Y는 [이미지] ,가 아니다.