(19) TZZ_Z__T (11) EP 1 495 018 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 405/06 (2006.01) A61K 31/44 (2006.01) 14.11.2007 Bulletin 2007/46 A61P 7/02 (2006.01) A61P 9/00 (2006.01) A61P 9/04 (2006.01) A61P 9/06 (2006.01) (2006.01) (2006.01) (21) Application number: 03718393.6 A61P 9/10 A61P 9/12 A61P 35/00 (2006.01) A61P 43/00 (2006.01) (22) Date of filing: 14.04.2003 (86) International application number: PCT/US2003/011510 (87) International publication number: WO 2003/089428 (30.10.2003 Gazette 2003/44) (54) TRICYCLIC THROMBIN RECEPTOR ANTAGONISTS TRIZYKLISCHE THROMBIN REZEPTOR ANTAGONISTEN ANTAGONISTES TRICYCLIQUES DU RECEPTEUR DE THROMBINE (84) Designated Contracting States: • XIA, Yan AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Edison, NJ 08820 (US) HU IE IT LI LU MC NL PT RO SE SI SK TR • VELTRI, Enrico, P. Designated Extension States: Princeton, NJ 08540 (US) AL LT LV MK • CHELLIAH, Mariappan Edison, NJ 08817 (US) (30) Priority: 16.04.2002 US 373072 P • WU, Wenxue Princeton Junction, (43) Date of publication of application: NJ 08550 (US) 12.01.2005 Bulletin 2005/02 (74) Representative: Siegert, Georg (60) Divisional application: Hoffmann - Eitle 07016461.1 Patent- und Rechtsanwälte Arabellastrasse 4 (73) Proprietor: Schering Corporation 81925 München (DE) Kenilworth, New Jersey 07033-0530 (US) (56) References cited: (72) Inventors: WO-A-01/96330 WO-A-99/26943 • CHACKALAMANNIL, Samuel US-A- 6 063 847 Califon, NJ 07830 (US) • CLASBY, Martin, C. Remarks: Plainsboro, NJ 08536 (US) Thefilecontainstechnicalinformationsubmittedafter • GREENLEE, William, J. the application was filed and not included in this Teaneck, NJ 07666 (US) specification • WANG, Yuguang North Brunswick, NJ 08902 (US) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 495 018 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 495 018 B1 Description BACKGROUND OF THE INVENTION 5 [0001] The present invention relates to substituted tricyclic thrombin receptor antagonists, pharmaceutical composi- tions containing them and their use in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, inflammatory disorders, neurodegen- erative diseases and cancer. The invention also relates to the combination of novel compounds of the invention and other cardiovascular agents. 10 [0002] Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore possible that thrombin receptor antagonists, also known as protease activated receptor (PAR) antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role. 15 [0003] Thrombin receptor antagonists peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bematowicz et al, J. Med. Chem., vol. 39, pp. 4879-4887 (1996) , tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl- p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH2. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published February 17, 1994. 20 [0004] Substituted tricyclic thrombin receptor antagonists are disclosed in US 6,063,847, US 6,326,380 and U.S. Serial Nos. 09/880222 (WO 01/96330) and 10/271715. SUMMARY OF THE INVENTION 25 [0005] The present invention relates to thrombin receptor antagonists represented by the Formula I: 30 35 40 or a pharmaceutically acceptable salt or solvate thereof, wherein: 45 ----- represents an optional double bond; n is 0-2; Q is 50 55 2 EP 1 495 018 B1 5 10 15 1 R is independently selected from the group consisting of H and (C1-C6)alkyl; R2 is independently selected from the group consisting of H and (C1-C6)alkyl; 17 22 23 R3 is H, hydroxy, (C1-C6)alkoxy, -C(O)OR , (C1-C6)alkyl, halogen, (C3-C6)cycloalkyl or -NR R ; Het is pyridyl, wherein a ring nitrogen can form an N-oxide or a quaternary group with a (C1-C4)alkyl group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by W; 20 W is 1 to 4 substituents independently selected from the group consisting of R21-aryl and R21-heretoaryl; 4 5 R and R are independently selected from the group consisting of H, (C1-C6)alkyl, phenyl, benzyl and (C3-C6) 4 5 7 cycloalkyl, or R and R taken together are -(CH2)4-, -(CH2)5- or -(CH2)2NR -(CH2)2- and form a ring with the nitrogen to which they are attached; R8,R10 and R11 are independently selected from the group consisting of R1 and -OR1, provided that when the 25 optional double bond is present, R10 is absent; 9 - R is H, OH or (C1-C6)alkoxy; B is -CH=CH-; 13 16b each R is independently selected from H, (C1-C6)alkyl (C3-C8)cycloalkyl, -(CH2)n6NHC(O)OR , -(CH2)n6NHC 16b 4 5 16 4 5 28 29 (O)R , -(CH2)n6NHC(O)NR R , -(CH2)n6NHSO2R , -(CH2)n6NHSO2NR R , and -(CH2)n6C(O)NR R where 30 n6 is 0-4, haloalkyl, and halogen; 14 27 each R is independently selected from H, (C1-C6)alkyl, -OH, (C1-C6)alkoxy, R -aryl(C1-C6)alkyl, heteroaryl, het- 16b 16b 4 5 eroarylalkyl, heterocyclyl, heterocyclylalkyl, -(CH2)n6NHC(O)OR , -(CH2)n6NHC(O)R , -(CH2)n6NHC(O)NR R , 16 4 5 28 29 -(CH2)n6NHSO2R , -(CH2)n6NHSO2NR R , and -(CH2)n6C(O)N R where n6 is 0-4, halogen and haloalkyl; or R13 and R14 taken together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms; 35 13 14 16b wherein at least one of R or R is selected from the group consisting of -(CH2)n6NHC(O)OR , -(CH2)n6NHC 16b 4 5 16 4 5 (O)R , -(CH2)n6NHC(O)NR R , -(CH2)n6NHSO2R , -(CH2)n6NHSO2NR R ; n6 is 0-4; 16 R is independently selected from the group consisting of (C1-C6)alkyl, phenyl and benzyl; 16b 22 21 R is H, alkoxy, (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-, R -O-C(O)-(C1-C6)alkyl-, (C3-C6)cycloalkyl, R -aryl, 40 21 21 R -aryl(C1-C6)alkyl, haloalkyl, alkenyl, halosubstituted alkenyl, alkynyl, halosubstituted alkynyl, R -heteroaryl, 21 21 28 29 28 29 R -(C1-C6)alkyl heteroaryl, R -(C1-C6)alkyl heterocycloalkyl, R R N-(C1-C6)alkyl, R R N-(CO)-(C1-C6)alkyl, 28 29 28 29 28 29 28 29 R R N-(CO)O-(C1-C6)alkyl, R O(CO)N(R )-(C1-C6)alkyl, R S(O)2N(R )-(C1-C6)alkyl, R R N-(CO)-N 29 28 29 29 28 29 20 29N (R )- (C1-C6)alkyl, R R N-S(O)2N(R )-(C1-C6)alkyl, R -(CO)N(R )-(C1-C6)alkyl. R R -S(O)2-(C1-C6) 28 28 alkyl, HOS(O)2-(C1-C6)alkyl, (OH)2P(O)2-(C1-C6)alkyl, R -S-(C1-C6)alkyl, R -S(O)2-(C1-C6)alkyl or hydroxy 45 (C1-C6)alkyl); 17 R is independently selected from the group consisting of H, (C1-C6)alkyl, phenyl, and benzyl; 21 R is 1 to 3 substituents independently selected from the group consisting of H, -CN, -CF3, -OCF3, halogen, -NO2, 25 26 (C1-C6)alkyl, -OH, (C1-C6)alkoxy, (C1-C6)-alkylamino-, di-((C1-C6)alkyl)amino-, NR R -(C1-C6)alkyl-, hy- 17 17 16 16 25 26 25 droxy-(C1-C6)alkyl-,-C(O)OR , -C(O)R , -NHCOR , -NHSO2R , -NHSO2CH2CF3, -C(O)NR R ,-NR -C 50 25 26 13 13 13 (O)-NR R , -S(O)R , -S(O)2R and -SR ; 22 R is H or (C1-C6)alkyl; 23 24 24 24 24 R is H, (C1-C6)alkyl, -C(O)R , -SO2R , -C(O)NHR or -SO2NHR ; 24 25 26 R is (C1-C6)alkyl, hydroxy (C1-C6)alkyl or NR R -((C1-C6)alkyl)-; 25 26 R and R are independently selected from the group consisting of H and (C1-C6)alkyl; 55 27 R is 1, 2 or 3 substituents selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, halogen and -OH; and 28 29 27 R and R are independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkoxy, R -aryl(C1-C6) alkyl, heteroaryl, heteroarylalkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, heterocyclyl, heterocyclylalkyl, 3 EP 1 495 018 B1 and haloalkyl; or R28 and R29 taken together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms. [0006] Thrombin receptor antagonist compounds of the present invention can have anti-thrombotic, anti-platelet ag- 5 gregation, antiatherosclerotic, antirestenotic and/or anti-coagulant activity. Thrombosis-related diseases treated by the compounds of this invention include thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic and thromboembolytic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as other disorders in which thrombin and its receptor play a pathological role.