RU2000116548A

RU2000116548A - THROMBINE RECEPTOR ANTAGONISTS

Info

Publication number: RU2000116548A
Application number: RU2000116548/04A
Authority: RU
Inventors: Сэмюэл ЧАКАЛАМАННИЛ; Теодрос АСБЕРОМ; Йен КСИА; Дарио Доллер; Мартин КЛАСБИ; Майкл Ф. КЗАРНИЕКИ
Original assignee: Шеринг Корпорейшн
Priority date: 1997-11-25
Filing date: 1998-11-23
Publication date: 2002-08-10

Claims

1. The compound represented by the structural formula

or its pharmaceutically acceptable salts, where the single dashed line indicates an optional double bond; double dashed line indicates an optional single bond; n is 0-2; Q means

where n ₁ and n ₂ independently mean 0-2; or, in the absence of a double bond, Q also denotes R-substituted aryl or R-substituted heteroaryl;
R means from 1 to 3 substituents independently selected from the group including H, C ₁ -C ₆ alkyl, halogen, hydroxy, amino, (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) dialkylamino , (C ₁ -C ₆ ) alkoxy-, -COR ¹⁶ , -COOR ¹⁷ , -SOR ¹⁶ , -S0 ₂ R ¹⁶ , -NR ¹⁶ COR ¹⁶ , -NR ¹⁶ COOR ^16a , -NR ¹⁶ CONR ⁴ R ⁵ , fluorine (C ₁ -C ₆ ) alkyl, difluoro (C ₁ -C ₆ ) alkyl, trifluoro (C ₁ -C ₆ ) alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl,
aryl (C ₁ -C ₆ ) alkyl, aryl (C ₂ -C ₆ ) alkenyl, heteroaryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₂ -C ₆ ) alkenyl, hydroxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₆ ) alkyl, aryl and thio (C ₁ -C ₆ ) alkyl;
R ¹ and R ^{2 are} independently selected from the group consisting of H, C ₁ -C ₆ alkyl, fluorine (C ₁ -C ₆ ) alkyl, difluoro (C ₁ -C ₆ ) alkyl, trifluoro (C ₁ -C ₆ ) alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, aryl (C ₁ -C ₆ ) alkyl, aryl (C ₂ -C ₆ ) alkenyl, heteroaryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₂ -C ₆ ) alkenyl, hydroxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₆ ) alkyl, aryl and thio (C ₁ -C ₆ ) alkyl; or R ¹ and R ² together form a = O group;
R ³ means H, hydroxy, C ₁ -C ₆ alkoxy-, -SOR ¹⁶ , -SO ₂ R ¹⁷ , -C (O) OR ¹⁷ , -CONR ¹⁸ R ¹⁹ , C ₁ -C ₆ alkyl, halogen, fluorine ( C ₁ -C ₆ ) alkyl, difluoro (C ₁ -C ₆ ) alkyl, trifluoro (C ₁ -C ₆ ) alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, aryl (C ₁ -C ₆ ) alkyl,
aryl (C ₂ -C ₆ ) alkenyl, heteroaryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₂ -C ₆ ) alkenyl, hydroxy (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₆ ) alkyl, aryl and thio (C ₁ -C ₆ ) alkyl;
Het means a mono-, bi- or tricyclic heteroaromatic group consisting of from 5 to 14 atoms, including from 1 to 13 carbon atoms and from 1 to 4 heteroatoms, independently selected from the group consisting of N, O and S, where a ring nitrogen atom can form an N-oxide or a quaternary group with a C ₁ -C ₄ alkyl group, where the Het group is bonded to B via a ring carbon atom and where the Het group is substituted with 1 to 4 substituents, W, independently selected from the group consisting of H; C ₁ -C ₆ alkyl; fluorine (C ₁ -C ₆ ) alkyl; difluoro (C ₁ -C ₆ ) alkyl; trifluoro (C ₁ -C ₆ ) alkyl; C ₃ -C ₆ cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted on C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkenyl; R ²¹ -aryl (C ₁ -C ₆ ) alkyl; R ²¹ -aryl (C ₂ -C ₆ ) alkynyl; heteroaryl (C ₁ -C ₆ ) alkyl; heteroaryl (C ₂ -C ₆ ) alkenyl; hydroxy (C ₁ -C ₆ ) alkyl; dihydroxy (C ₁ -C ₆ ) alkyl; amino (C ₁ -C ₆ ) alkyl; (C ₁ -C ₆ ) alkylamino- (C ₁ -C ₆ ) alkyl;
di - ((C ₁ -C ₆ ) alkyl) amino (C ₁ -C ₆ ) alkyl; thio (C ₁ -C ₆ ) alkyl; C ₁ -C ₆ alkoxy;
C ₂ -C ₆ alkenyloxy-; halogen; —NR ⁴ R ⁵ ; -CN; -HE; -COOR ¹⁷ ; -COR ¹⁶ ; -OSO ₂ CF ₃ ; -CH ₂ OCH ₂ CF ₃ ; (C ₁ -C ₆ ) alkylthio; -C (O) NR ⁴ R ⁵ ; -OCH ⁶ -phenyl; phenoxy- (C ₁ -C ₆ ) alkyl; -NHCOR ¹⁶ ; -NHSO ₂ R ¹⁶ ; biphenyl; —OC (R ⁶ ) ₂ COOR ⁷ ; —OC (R ⁶ ) ₂ C (O) NR ⁴ R ⁵ ; (C ₁ -C ₆ ) alkoxy; C ₁ -C ₆ alkoxy, substituted with (C ₁ -C ₆ ) alkyl; amino-; -HE; -COOR ¹⁷ ; -NHCOOR ¹⁷ ; -CONR ⁴ R ⁵ ; aryl; aryl substituted with 1-3 substituents independently selected from the group consisting of halogen, —CF ₃ , C ₁ –C ₆ alkyl, C ₁ –C ₆ alkoxy, and –COOR ¹⁷ ; aryl, where adjacent carbon atoms form a ring with a methylenedioxy group, -C (O) NR ⁴ R ⁵ and heteroaryl; R ²¹ is aryl; aryl, where adjacent carbon atoms form a ring with a methylenedioxy group;
heteroaryl; heteroaryl substituted with 1-4 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, (C ₁ -C ₆ ) alkylamino, di - ((C ₁ -C ₆ ) alkyl) amino-, -OCF ₃ , -NO ₂ , hydroxy (C ₁ -C ₆ ) alkyl, -CHO and phenyl; and heteroaryl, where adjacent carbon atoms form a ring with a C ₃ -C ₅ alkylene group or a methylenedioxy group;
R ⁴ and R ^{5 are} independently selected from the group consisting of H, C ₁ -C ₆ alkyl, phenyl, benzyl and C ₃ -C ₆ cycloalkyl, or R ⁴ and R ⁵ together represent - (CH ₂ ) ₄ -, - ( CH ₂ ) ₅ - or - (CH ₂ ) ₂ NR ⁷ - (CH ₂ ) ₂ - and form a ring with the nitrogen atom to which they are bound;
R ^{6 is} independently selected from the group consisting of H, C ₁ -C ₆ alkyl or phenyl;
R ⁷ is H or (C ₁ -C ₆ ) alkyl;
R ⁸ , R ¹⁰ and R ^{11 are} independently selected from the group consisting of R ¹ and -OR ¹ , with the proviso that when there is an optional double bond, R ^{10 is} absent, and if Q is an aromatic group, R ¹⁰ and R ^{11 are} absent;
R ⁹ is —H, —OH, C ₁ -C ₆ alkoxy, halogen or halo (C ₁ -C ₆ ) alkyl;
B means - (CH ₂ ) _{n 3} -, —CH ₂ —O—, —CH ₂ S—, CH ₂ —NR ⁶ -, —C (O) NR ⁶ -, —NR ⁶ C (O) -,

CIS - or TRANS- (CH ₂ ) _n4 CR ¹² = CH ^12a (CH ₂ ) _n5 or

where n ₃ is 0-5, n ₄ and n _{5 are} independently 0-2, and R ¹² and R ^{12a are} independently selected from the group consisting of H, C ₁ -C ₆ alkyl and halogen;
X is -O- or -NR ⁶ - if the double dashed line represents a single bond, or X is -OH or -NHR ²⁰ if there is no bond;
Y means = O, = S, (H, H), (H, OH) or (H, C ₁ -C ₆ alkoxy) if the double dashed line represents a simple bond, or if there is no connection, Y means = O, ( H, H), (H, OH), (H, SH), or (H, C ₁ -C ₆ alkoxy);
R ^{15 is} absent if the double dashed line represents a single bond, and is H, C ₁ -C ₆ alkyl, -NR ¹⁸ R ^19, or -OR ¹⁷ if there is no bond;
either Y means

and R ^{15 is} H or C ₁ -C ₆ alkyl;
R ¹⁶ and R ^{16a are} independently selected from the group consisting of C ₁ -C ₆ lower alkyl, phenyl or benzyl;
R ¹⁷ , R ¹⁸ and R ^{19 are} independently selected from the group consisting of H, C ₁ -C ₆ alkyl, phenyl, benzyl;
R ²⁰ is H, C ₁ -C ₆ alkyl, phenyl, benzyl, —C (O) R ⁶ or —SO ₂ R ⁶ ;
R ²¹ means from 1 to 3 substituents independently selected from the group comprising —CF ₃ , —OCF ₃ , halogen, —NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy-, (C ₁ -C ₆ ) alkylamino, di - ((C ₁ -C ₆ ) alkyl) amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, di - ((( C ₁ -C ₆ ) alkyl) -amino (C ₁ -C ₆ ) alkyl,
hydroxy (C ₁ -C ₆ ) alkyl, —COOR ¹⁷ , —COR ¹⁷ , —NHCOR ¹⁶ and —NHSO ₂ CH ₂ CF ₃ ;
Z means -CH ₂ -, -O-, -S (O) _0-2 ^- , NR ²² -, -C (O) -, -C (= NOR ¹⁷ ) or -C (R ¹³ R ¹⁴ ) -, where R ¹³ and R ^14, together with the carbon atom to which they are bonded, form a spirocycloalkyl group containing from 3 to 6 carbon atoms, or a spiroheterocycloalkyl group of 3-6 members, including 2 to 5 carbon atoms and from 1 to 2 heteroatoms selected from the group consisting of O, S, and N; and
R ²² is H, C ₁ -C ₆ alkyl, phenyl, benzyl, —COR ¹⁶ or —CONR ¹⁸ R ¹⁹ .

2. The compound according to claim 1, where n is 0.

3. The compound according to claim 1 or 2, wherein the double dashed line represents a simple bond, X means -O-, and Y means = O.

4. Connection on PP. 1, 2 or 3, where each of R ² and R ⁸ means a hydrogen atom; R ³ is H or C ₁ -C ₆ alkyl; and R ⁹ is H, OH or C ₁ -C ₆ alkoxy.

5. Connection on PP. 1, 2, 3, or 4, where R ¹ means C ₁ -C ₆ alkyl.

6. Connection on PP. 1, 2, 3, 4, or 5, where Q is R-substituted cyclohexyl or R-substituted phenyl.

7. Connection on PP. 1, 2, 3, 4, 5 or 6, where R is H, fluorine, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or -COOR ¹⁷ .

8. Connection on PP. 1, 2, 3, 4, 5, 6, or 7, where B means -CH = CH-.

9. Connection on PP. 1, 2, 3, 4, 5, 6, 7, or 8, where Het is pyridyl, W-substituted pyridyl, quinolyl, or W-substituted quinolyl.

10. The compound according to claim 9, wherein W is C ₁ -C ₆ alkyl, aryl, R ²¹ -aryl, or heteroaryl.

11. The compound according to claim 1, selected from the group including
12. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, and a pharmaceutically acceptable carrier.

13. A method of inhibiting thrombin receptors, comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1.

14. A method for the treatment of thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular disease, inflammatory diseases, cerebral ischemia and cancer, including a route, an inaccuracy of the disease, cerebral ischemia and cancer, including a route, an inaccurate pattern, an inaccuracy of course, a 4-year pattern, an inaccuracy of the disease, cerebral ischemia and a cancer, a stroke, an inaccurate stroke, peripheral vascular disease, inflammatory diseases, cerebral ischemia and a cancer, a stroke, a cerebral ischemia, an inflammatory disease, cerebral ischemia, and an embolism, peripheral vascular disease, inflammatory diseases, cerebral ischemia, and cancer, which is subject to the use of a route, a cerebral ischemia, an embolism, peripheral vascular disease, inflammatory diseases, cerebral ischemia, and an embarrassment the amount of the compound according to claim 1.