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WO2009124103A2 - Thérapies de combinaison comprenant des antagonistes de récepteur 1 activé par protéase (par1) associés à des antagonistes récepteur 4 activé par protéase (par4) - Google Patents

Thérapies de combinaison comprenant des antagonistes de récepteur 1 activé par protéase (par1) associés à des antagonistes récepteur 4 activé par protéase (par4) Download PDF

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Publication number
WO2009124103A2
WO2009124103A2 PCT/US2009/039070 US2009039070W WO2009124103A2 WO 2009124103 A2 WO2009124103 A2 WO 2009124103A2 US 2009039070 W US2009039070 W US 2009039070W WO 2009124103 A2 WO2009124103 A2 WO 2009124103A2
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alkyl
group
independently selected
alkoxy
aryl
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WO2009124103A3 (fr
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Yan Xia
Samuel Chackalamannil
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Merck Sharp and Dohme LLC
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Schering Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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. Thrombin receptor antagonists have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bematowicz e/ a/, J. M ⁇ dChem., 1996, 39, pp.
  • 4879-4887 tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyH>-fluoroPhe-p- guanidinoPhe-Le ⁇ -Arg-NH2 and N ⁇ rans ⁇ dnna ⁇ )yl-p-fluoroPh ⁇ -p ⁇ uanklinoPh ⁇ -L ⁇ u- Arg-Arg-NH2.
  • Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published February 17, 1994.
  • Thrombin receptor antagonist have been suggested in the literature as being potentially useful in treating a variety of cardiovascular diseases or conditions including, for example, thrombosis, vascular restenosis, deep venous thrombosis, lung embolism, cerebral infarction, heart disease, disseminated intravascular coagulation syndrome. hypertension (Suzuki, Shuichi, PCT Int. Appls. WO 0288092 (2002). WO 0285850 (2002) and WO 0285855 (2002)), arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemic conditions (Zhang, Han-cheng, PCT Int. Appl. WO 0100659 (2001). WO 0100657(2001) and WO 0100656 (2001)).
  • Thrombin activates human platelets through proteolytic activation of two protease- activated receptors(PARS): protease-activated receptor- 1 or PAR1 and protease- activated receptor-4 or PAR4.
  • PARS protease-activated receptors
  • PAR1 protease-activated receptor- 1 or PAR1
  • PAR4 protease- activated receptor-4
  • PAR1 is a high-affinity receptor for platelet activation at low concentrations of thrombin.
  • PAR4 is a low-affinity receptor that mediates thrombin signaling at high concentrations i
  • the two or more active agents may act by very different biochemical pathways to provide particularly beneficial therapeutic results.
  • the two or more active agents may be delivered as either coadministered monotherapy formulations, or as a single co-formulation, ( ⁇ o-forrn ⁇ lations have the patient-compliance advantages of reducing the number of distinct doses and fixing fte ratio of the two active agents being administered.
  • An example of such a combination is Vytorin®, which is a single dosage form comprising simvastatin (marketed in the U.S. as Zocor®) and ezetimibe (marketed in the U.S. as Zetia ⁇ ).
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of at least one PARI antagonist, at least one PAR4 antagonist, optionally, an effective amount of at least one cardiovascular agent, and, optionally, a pharmaceutically acceptable carrier.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising i) an effective amount of at least one PAR1 antagonist which is selected from the group consisting of: a) Formula I-A:
  • the single dotted line represents an optional single bond; represents an optional double bond; n is 0-2; Q is
  • R 1 is independently selected from the group consisting of H, (C-
  • Het is a mono- or bj-cycfic heteroaryi group of 5 to 10 atoms comprised of 1 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein a ring nitrogen can form an N-oxide or a quaternary group with a C1-C4 alky! group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by W;
  • W is 1 to 4 substi tuents independently selected from the group consisting of H, (C 1 -C 6 )alkyl. fl ⁇ oro(Ci -C 6 )aJ kyK difluoro(C 1 -C 6 )alkyK trifluoro(C 1 -C 6 )alkyl-. (C 3 - C 6 )cycloalkyl. hydroxy(C 1 -C 6 )alky1- r dihydroxy(C 1 -C 6 )alkyl-. NR ⁇ R ⁇ tC 1 -C 6 Jalkyl-. thk)(C 1 -C 6 )alky ⁇ . -OH. (C 1 -C 6 )alkoxy.
  • R 4 and R 5 are independently selected from the group consisting of H, (C 1 - C 6 )aikyl, phenyl, benzyl and (C3-C 6 )cycioalkyl, or R 4 and R 5 taken together are -
  • R ⁇ is H, (C 1 -C 6 )alkyl or phenyl;
  • R 7 is H. (C 1 -C 6 )a «cyl. -C(O)-R 18 . -C(O)OR 17 or -SO 2 R 17 ;
  • R 8 is independently selected from the group consisting of R 1 and -OR 1 , provided that when the optional double bond is present, R 10 is absent;
  • R9 is H, OH or (C 1 -C 6 )a»koxy;
  • B is - ⁇ CH2)n3-, cis or trans -(CH2)n4CR 12 sCR 12 "(CH2)n5 or -(CH ⁇ OC ⁇ CH ⁇ -, wherein 03 is 0-5, 114 and 05 are independently 0-2, and R 12 and Ri2a are independently selected from the group consisting of H, (C 1 -C 6 )alkyi and halogen;
  • X is -O- or -NR 6 - when the dotted line represents a single bond, or X is -OH or - NHR20 when the bond is absent;
  • Y is sO, sS, (H, H), (H, OH) or (H, (C 1 -C 6 )alkoxy) when the dotted line represents a single bond, or when the bond is absent Y is s0, (H, H).
  • each R 13 is independently selected from H, (C 1 -C 6 )aJkyl, (CrC ⁇ )cyc(oaJkyl, - (CH 2 )n ⁇ NHC(O)OR 1 ⁇ b , -(CH2)n ⁇ NHC(O)R 1 ⁇ b , -(CH 2 ) K NHC(O)NR 4 R 6 , -(CH 2 X-NHSO 2 R 16 , -(CH 2 ) H eNHSO 2 NR 4 R 5 . and -(CH 2 ) ⁇ C(O)NR 28 R 29 where n ⁇ is 0-4, haloalkyi.
  • each R 14 is independently selected from H, (C 1 -C 6 )alky1, -OH, (C 1 -C 6 )alkoxy, R 27 -aryKC 1 -C 6 )aJky1, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylaJkyl, -(CH 2 )n ⁇ NHC(O)OR 1 ⁇ b , -KCH 2 X-NHC(O)R 1 *,
  • R 13 and R 14 taken together form a spirocydic or a heterospirocycHc ring of 3-6 atoms; wherein at least one of R 13 or R 14 is selected from the group consisting of
  • R 16 is independently selected from the group consisting of (C 1 -C 6 )alkyl, phenyl and benzyl; R 16b is H, (C 1 -C 6 )alkyi. (C 1 -C 6 )alkoxy(C 1 -C 6 )alky1-.
  • R 22 O-C(OMCi -C 6 )alkyl-, (C 3 -C ⁇ )cydoalkyl, R 21 -aryi, R ⁇ -aryKC 1 -C 6 Jalkyl, haloalkyi, alkenyl, halosubstituted alkenyl, aJkynyl, halosubstituted alkynyl, R ⁇ -heteroaryl, R 21 -(C 1 -Ce)alkyl heteroaryi, R 21 -(C 1 -C 6 )aikyl heterocycloalkyl, R 28 R 29 N-(C 1 -Ce)HIkYi 5 R 28 R 29 N-(CO)-(C 1-Ce)alkyt, R 28 R 29 N-(CO)O-(C 1-C6)alkyi, R 28 O(CO)N(R 29 HC 1 -C 6 )aIkyI !
  • the single dotted line represents an optional double bond
  • the double dotted Hne represents an optional single bond
  • n is 0-2
  • Q is wherein ni and n2 are independently 0-2; or when the double bond is not present, Q is also fused R-substituted aryi or R-substituted heteroaryl
  • R is 1 to 3 subst ' tuents independently selected from the group consisting of H, Oj- C 6 ⁇ lkyl, halogen, hydroxy, amino, (C 1 -C 6 )alkyl-amino, (C 1 -C 6 )diaJkylamino, (C 1 - C 6 )alkoxy.
  • drfluoro(C 1 -C 6 )alky1 trifluoro-(C 1 -C 6 )alkyl, C 3 -C 6 cycloalkyi, C2-C 6 alkenyl, aryl(C 1 -C 6 )alkyl f aryl(C2-C 6 )alkenyl, heteroaryl(C 1 -C 6 )alkyl, heteroaryt ⁇ -C 6 Jalkenyl, hydroxy-(C 1 -C 6 )alkyl.
  • R 1 and R 2 together form a sO group;
  • R3 is H, hydroxy, C 1 -C 6 alkoxy. -SOR 16 . -SO2R 17 .
  • R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 6 alkyi, phenyl, benzyl and C 3 -C 6 cycloalkyl, or R 4 and R 5 together are -(CH 2 )4-.
  • 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 , provided that when the optional double bond is present, R 10 is absent, and when ring Q is aromatic, 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 is -(CH2)n3-. -CH2-O-, -CH2S-, -CH2-NR 6 -, -C(O)NR 6 -. -NR 6 C(O)-. , cis or trans -(CH2)n4CR 12 sCR 12a (CH2)n5 or, -(CH2)n4 R(CH2)n5-, wherein 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 1 C 1 -C 6 alkyi and halogen;
  • X is -O- or -NR 6 - when the double dotted line represents a single bond, or X is - OH or-NHR20 when the bond is absent;
  • Y is s0, sS, (H, H), (H, OH) or (H, C 1 -C 6 alkoxy) when the double dotted line represents a single bond, or when the bond is absent, Y is s0, (H, H), (H, OH). (H, SH) or (H, C 1 -C 6 alkoxy);
  • R 16 and R 16a are independently selected from the group consisting of C 1 -C 6 lower alkyi, phenyl or benzyl;
  • R 17 , R 18 and R 19 are independently selected from the group consisting of H, C-j- C 6 aJkyl, phenyl, benzyl;
  • R 21 is 1 to 3 substutuents independently selected from the group consisting of - CF3, -OCF3, halogen, -NO2, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 )alkylamino, di-((C 1 - C 6 )
  • Z is -CH2-, -O-. -S(0)o-2-. -NR 22 -, -C(OK -C(sNOR 17 )- or -C(R 13 R 14 )-, wherein R 13 and R 14 , together with the carbon to which they are attached, form a spirocycloalkyl group of 3 to 6 carbons, or a spiroheterocycloalkyi group of 3 to 6 members, comprised of 2 to 5 carbon atoms and 1 or 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 1 6 Or -CONR 1 ⁇ R 19 ;
  • R is 1 to 3 substftuents independently selected from the group consisting of H, C 1 - C 6 alkyl, halogen, hydroxy, amino, ( C 1 -C 6 )alkyl-amino, (C 1 -C ⁇ )-dialky1 amino, (C 1 - C ⁇ )alkoxy, -C0R 16 , -COOR 17 , -SOR 1 ⁇ , -S ⁇ 2R 1 ⁇ , -SO 2 NR 17 R 18 . -NR 17 SO 2 R 1 '. - NR 1 ⁇ COR 16a . -NR 1 ⁇ COOR 1 ⁇ *.
  • R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 0 alkyi, fluoro ⁇ -C ⁇ kyi, difluoro ⁇ -CsJalkyl, trffl ⁇ oro-( ⁇ -CsJaJkyl, C 3 -C 0 cycloalkyl, C 2 -C 6 S alkeny), aryK ⁇ -Cg ⁇ kyl, hydroxy- ⁇ C 1 -C 6 )SIk
  • R 7 isH or (C 1 -C 6 )alkyl
  • R , R and R are independently selected from the group consisting of R and - OR 1
  • R 9 is H, OH, -NR 4 R 5 , C 1 -C 6 BIkOXy, halogen or halo ⁇ -C ⁇ kyl
  • B is -(CH 2 Jn 3 - or cis or trans -(CH 2 )T ⁇ CR sCR (CH 2 )n 5 , wherein n 3 is 0-5, n 4 and n 5 are independently 0-2, and R and R are independently selected from the group consisting of H, C 1 -C 6 alky! and halogen; R 1 ⁇ and R 1 ⁇ " are independently selected from the group consisting of C 1 -C 0 alkyl.
  • R 17 , R 1 ⁇ and R 19 are independently selected from the group consisting of H, C 1 - C ⁇ alkyt, phenyl and benzyl;
  • R is 1 to 3 substrtuents independently selected from the group consisting of H 1 - CF 3 , -OCF 3 , halogen, -NO 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -WH 2 , (C ⁇ J-alkyl-amino, di-
  • R 22 is -COR 23 , -S(O)R 31 , -S(O) 2 R 31 , -SO 2 NR 24 R 25 or -COOR 27 ;
  • R 23 is hato ⁇ -C ⁇ Jalkyt; C 2 -C 6 alkenyl; halo(C 2 -C 6 )alkenyl; C 2 -C 6 alkynyl; Cs-Cr-cyctoalkyl; (C r C 7 )cydoaJky1(C 1 -C ⁇ )alky1; (CrC 7 )cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of hal
  • R and R are independently selected from the group consisting of H, alky), or R 37 -substitut ⁇ d Ci-Ce alkyi, wherein R 37 is selected from the group consisting of HO-, HS-, CH 2 S-, -NH 2 , phenyl, p-hydroxyphenyl and indolyl; R 24 and R 26 are independently selected form the group consisting of H, C 1 -Ce alkyl, halofC.-C ⁇ JaJkyl.
  • R 10 is absent; or the single clotted line represents an optional double bond; the double dotted line represents an optional single bond; n is 0-2; R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 alkyi. fluoro(C 1 -C 6 )aJkyt, difluoro(C 1 -C 6 )alkyl. trifluoro-(C 1 -C 6 )alkyl.
  • C3-C7 cycloalkyl C2-C 6 alkenyl, aryl(C 1 -C 6 )alkyl, aryl(C2-C 6 )alkenyl, heteroaryl(C 1 -C 6 )alkyl, heteroaryKC2-C 6 )alkenyl, hydroxy- ⁇ C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, amino-(C 1 - C 6 )alkyi, aryi and thio(C 1 -C 6 )alkyl; or R 1 and R 2 together form a s0 group; R3 is H, hydroxy, C 1 -C 6 alkoxy, -NR 1 ⁇ R 1 ⁇ , -SOR16, -SO2R 17 .
  • Hot is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atoms comprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N 1 0 and S, wherein a ring nitrogen can form an N-oxide or a quaternary group with a C1-C4 alkyf group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by 1 to 4 substituents, W, independently selected from the group consisting of H; C 1 -C 6 alkyi; fluoro(C 1 -
  • R ⁇ is independently selected from the group consisting of H, C 1 -C 6 alkyl, 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 , provided that when the optional double bond is present, R 10 is absent;
  • Rd is H, OH, C 1 -C 6 alkoxy, halogen or halo(C 1 -C 6 )alkyl;
  • B is - ⁇ CH2)n3-.
  • n3 is 0-5, 04 and r>5 are independently 0-2, and R 12 and R 12a are independently selected from the group consisting of H, Cf-C 6 alkyl and halogen;
  • X is -O- or -NR 6 - when the double dotted line represents a single bond, or X is H, •
  • Y is sO. sS, (H, H), (H, OH) or (H, d-C 6 alkoxy) when the double dotted line represents a single bond, or when the bond is absent Y is s0, sNOR 17 , (H, H), (H, OH), (H, SH), (H, C 1 -C 6 alkoxy) or (H. -NHR 4 *); R 15 is absent when the double clotted line represents a single bond; R 15 is H, C 1 -
  • R 15 is H or Cl -C 6 alkyl
  • R 16 is 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 1 C-j- C 6 alkyl, phenyl, benzyl
  • R20 is H, C 1 -C 6 alkyl. p ⁇ enyl. benzyl, -C(O)R 6 or -SO2R 6
  • R 21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, -CF3, -OCF3, halogen, -NO2.
  • R 22 and R 23 are independently selected from the group consisting of hydrogen, R ⁇ d-doJalkyl.
  • R 24 -(C 2 -Cio)alkynyl.
  • R M -(C3-C7)cycloalkyl.
  • (d-C ⁇ )alkoxy f R ⁇ -aryl, (d-C 10 )-alkyl-C(O)-, (CrCioHilkenyl- C(O)-, (CrCi 0 )alkynyl-C(O)-, heterocycloalkyl.
  • R 26 is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, halogen and (Ci-C ⁇ )alkoxy
  • R 27 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, R M -(Ci-Cio)alkyl.
  • R ⁇ CrCioJalkenyl is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, R M -(Ci-Cio)alkyl.
  • R ⁇ CrCioJalkynyl R 28 is hydrogen, -OH or (Ci-C ⁇ )alkoxy; R 29 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, (Ci-C ⁇ )alkyl, -OH, (Ci-C ⁇ )alkoxy and halogen; R 30 , R 31 and R 32 are independently selected from the group consisting of hydrogen, (C,-C, 0 )-alkyl.
  • R 30 is hydrogen, (Ci-C ⁇ )alkyl, hatofd-C ⁇ Jalkyl. dihalofd-C ⁇ Jalkyl or trifl ⁇ oro ⁇ Ci- C ⁇ )alkyl.
  • R 37 and R 38 are independently selected from the group consisting of hydrogen, (Ci-C ⁇ )aJkyt, aryKd-C ⁇ Jalkyl, phenyl and (C 3 -C 15 )cycloalkyl, or R 37 and R 38 together are - (CH 2 V. -(CH 2 )S- or -(CHzh-NR ⁇ CHak- and form a ring with the nitrogen to which they are attached; R 39 and R 40 are independently selected from the group consisting of hydrogen,
  • R 41 is 1 to 4 substituents independently selected from the group consisting of hydrogen.
  • R 42 is 1 to 3 substituents independently selected from the group consisting of hydrogen, -OH, (C 1 -C 6 JaIlCyI and (C 1 -C 6 JaIkOXy; R 43 is -NR 30 R 31 , -NR 30 C(O)R 31 .
  • R 44 is H. C 1 -C 6 alkoxy, -S0R16. -SCfeR 17 . -C(OYDRW, -C(O)NR18R19 d-C 6 alkyt. halogen, fluoro(C 1 -C 6 )alkyl.
  • R 1 is H, Ci-Cr-alkyl. halogen or -OR; represents a ring selected from the group consisting of
  • R 2 is H, -COOR, -CH 2 OR, Ci-CraJkyl, or halogen;
  • X is -O- or -S-; represent a ring selected from the group consisting of
  • Cardiovasudar agents include, for example, thromboxane A2 biosynthesis inhibitors (e.g., thromboxane A2 biosynthesis inhibitors (e.g., thromboxane A2 biosynthesis inhibitors (e.g., thromboxane A2 biosynthesis inhibitors (e.g., thromboxane A2 biosynthesis inhibitors (e.g., thromboxane A2 biosynthesis inhibitors (e.g.
  • thromboxane antagonists e.g., seratrodast, picotamide and ramatroban
  • AOP adenosine diphosphate
  • cydooxygenase inhibitors aspirin, metoxicam, rofecoxib and ceJecoxib
  • angiotensin antagonists e.g.,0 valsartan, teimisartan, candesartran, irbesartran, losartan and eprosartan
  • endothelin antagonists e.g., tezse ⁇ tan
  • phosphodiesterase inhibitors e.g.
  • angiotensin converting enzyme (ACE) inhibitors e.g., captopril, enalapril, enaliprilat, spirapril quinapril, perindopril, ramiprfl, fesoinopril, trandolapril, Hsinopril, moexipril, and benazepril
  • neutral endopeptkJase inhibitors e.g., canodoxatrfl and S exadotril
  • anticoagulants e.g., ximelagatran, fondaparin and enoxaparin
  • diuretics e.g., chlorothiazide, hydrochlorothiazide, ethacrynic acid, f ⁇ rosemide and amiloride
  • platelet aggregation inhibitors e.g., aboiximab and eptifibatide
  • This invention also relates to the use of the of treating the following disease states0 by administering, either together or concomitantly, an effective amount of at least one PAR1 antagonist, at least one PAR4 receptor antagonist and, optionally, an effective amount of at least one cardiovascular agent to a mammal in need thereof: diseases associated with thrombosis (e.g., thrombosis, atherosclerosis, restenosis, hypertension, acute coronary syndrome, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, myocardial infarction, glomerulonephritis, thrombotic and thromboembolytic stroke, peripheral cadiovasc ⁇ lar disease, deep vein thrombosis, cerebral ischemia, venous thromboembolism, and other cardiovascular diseases); inflammatory disorders (e.g., radiation and chemotherapy induced proliferative and inflammatory disorders of the gastrointestinal tract, lungs, and other organs, inflammatory disorders of the urinary bladder); fibrotic disorders of the liver, kidney
  • R 1 is methyl; R2
  • R 10 is absent; B is -CHsCH-; X is -O-; Y is sO; R 14 is NHC(O)OR 1 * R 1 ⁇ b is alkoxy, (C 1 -C 6 )alky1. (C 1 -C 6 )alkoxy(C 1 -C 6 )alky1-, R ⁇ -O-C ⁇ OHC 1 -C 6 Jalkyl-, (QrC ⁇ JcycloalkyJ, R 28 R 29 N-(COHCi -C 6 )alkyl, R 28 R 29 N- (CO)O-(C 1 -C 6 )alkyf.
  • R 21 is 1 to 3 substituents independently selected from the group consisting of H, CN. -CF3. halogen and CONH 2 ;
  • R 22 is H or (C 1 -C 6 )alkyl; and, R 28 and R 29 are independently selected from the group consisting of H, (C 1 -C 6 )aikyl, (Ct-C 6 )alkoxy, R 27 -aryl(Ci -C 6 )alkyl, heteroaryl, heteroaryialkyl, hydroxy(Ci-C ⁇ )alkyi, and (d-C «)alkoxy(Ci-Ce)alkyi, heterocyclyl, heterocyclylalkyl, and haloalkyi; or R 28 and R 29 taken together form a spirocydic or a heterospirocyclic ring of 3-6 atoms.
  • Another embodiment of the compounds of Formula 1-A1 are those wherein the optional double bond is absent
  • Another embodiment of the compounds of Formula 1-A1 are those compounds selected from the group consisting of
  • a preferred salt is the bisutf ate salt
  • An embodiment of a compound of Formula 1 -B are compounds of the the structural formula
  • ni and n2 are independently 0-2; or when the double bond is not present, Q is also fused R-substituted aryl;
  • R is 1 to 38ubstit ⁇ ents independently selected from the group consisting of H, Cf- C 6 alkyl, halogen, hydroxy, amino, (Ct-C 6 )alkyl-amino, (C 1 -C 6 )di-alkylamino, (C-j- C 6 )alkoxy, -COR 16 . -CCOR 17 , -SOR 16 . -SO2R 16 , -NR 16 COR 16Q .
  • R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 alkyl, fluoro(C 1 -C 6 )alkyl, dffluoro(C 1 -C 6 )alkyl. trifluoro-(C 1 -C 6 )a»kyl. C 3 -C 6 cycloalkyl.
  • quinolyl or benzoquinolyl 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 1 to 4 substit ⁇ ents, W, independently selected from the group consisting of H; C 1 -C 6 alkyl; f)uoro(C 1 -C 6 )alkyl; dJftuoro(C 1 -C 6 )alkyl; trifluoro-
  • 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 are -(CH2)4-.
  • 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 1 O and R 11 are independently selected from the group consisting of R 1 and -OR 1 , provided that when the optional double bond is present, R 10 is absent, and when ring Q is aromatic, R 10 and R 11 are absent;
  • Rd is H. OH, C 1 -C 6 alkoxy. halogen or halo(C 1 -C 6 )alkyl;
  • B is -(CH2)n3-. , cis or trans -(CH2)n4CR 12 sCR 12a (CH2)n5- or -
  • Y is s0. sS, (H, H), (H, OH) or (H, C 1 -C 6 alkoxy); R 15 is absent; R16 and R 1 ⁇ 3 are independently selected from the group consisting of C 1 -C 6 lower alkyl, phenyl or benzyl; R17 ( R18 and R19 are independentiy selected from the group consisting of H, C-
  • C 1 -C 6 alkyl C 1 -C 6 alkoxy, (C 1 -C 6 )alkylamino, di-((C 1 - C 6 )aJkyl)amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )-alkylamino(C 1 -C 6 )alkyi, di-((C 1 -C 6 )a)kyl)- amino(C 1 -C 6 )alkyl t hydroxy-(C 1 -C 6 )alkyl, -CCOR 17 , -COR 17 , -NHCOR 16 , -NHS ⁇ R 16 and -NHSO2CH2CF3; and
  • Z is -CH2-, -C(Oh -C(sN0R 17 )- O ⁇ -C(R 1 3R 1 4)-, wherein R 1 3 and RTM, together with the carbon to which they are attached, form a spirocycloalkyl group of 3 to 6 carbons, or a spiroheterocycloalkyl group of 3 to 6 members, comprised of 2 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of O, S and N.
  • An alternative embodiment of compounds of Formula I-B1 are those where n is zero.
  • An alternative embodiment of compound of Formula I-B1 are those wherein R 2 and R 8 are each hydrogen and R 3 is hydrogen or C 1 -C 6 alkyl.
  • n is zero; the double dotted line represents a single bond; R 2 and R 8 are each hydrogen; R 3 is hydrogen or Ci-Ce alkyl; R 9 is H, OH or C 1 -C 6 alkoxy; X is -O -; Y iS sO; R 1 is Ci-Ce alkyl; Q is R-s ⁇ bstituted cyclohexyl and R 10 and R 11 are each hydrogen, or Q is R-s ⁇ bstituted phenyl and R 10 and R 11 are absent; B is -CHsCH-; and Het is pyridyl, W-susbtituted pyridyl, quinolyl or W-substituted quinolyl.
  • Another embodiment of compound of Formula 1-B1 are compounds of the fo ⁇ owing formula:
  • An embodiment of a compound of Formula I-C are compounds of the formula
  • R is 1 to 3 substit ⁇ ents independently selected from the group consisting of H, C 1 - C 6 aJkyi, halogen, hydroxy, amino, (C n -C 6 )aJkyl-amino, (C 1 -C ⁇ )-d'alkylamino, (C 1 - C 6 JaIkOXy, -COR 1 ⁇ , -CCOR 17 , -SOR 16 , -S ⁇ 2R 1 ⁇ , -SO 2 NR 17 R 18 , -NR 17 SO 2 R 18 . - NR 16 COR 16a . -NR 16 COOR 16 *.
  • R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 alkyl, fluorcH ⁇ -C ⁇ Jalkyt, dlfluoro ⁇ -C ⁇ ky*, trifluoro- ⁇ C 1 -C 6 JaWCyI, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, 8TyI(C 1 -C 6 JaIlCyI, hydroxy ⁇ C 1 -C 6 JaIk ⁇ , BmInO(C
  • R 9 is H, hydroxy, C 1 - ⁇ aIkOXy, arytoxy, aryKC f -C ⁇ Jalkyloxy, (C 3 -C ⁇ jcyck>alkyloxy, -SOR 16 , -SO 2 R 17 , -SO 2 NR 16 R 19 , -SR 16 , -SO 3 H, -C(O)OR 17 , -C(O)NR 16 R 19 . -OC(O)R 32 , -OC(O)NR 33 R 34 . -(CR 33 R 34 J n OR 32 .
  • R 7 is H or (C 1 -C 6 JaIKyI;
  • R , R and R are independently selected from the group consisting of R and -
  • R is H 1 OH , - -N -R-I4 4 DR5 5 , C r C 6 alkoxy, halogen or halo ⁇ -C ⁇ alkyl;
  • B is cis or trans -(CH 2 Jn 4 CR sCR (CH 2 Jn 5 , wherein n 4 is 0-2, n 5 is 0-2, and R and R are independently selected from the group consisting of H, C 1 -C 6 aikyl and halogen; R 16 and R 16a are independently selected from the group consisting of C 1 -C 6 alky!, phenyl and benzyl;
  • R 17 , R 18 and R 19 are independently selected from the group consisting of H, C 1 - C 6 alkyl, phenyl and benzyl;
  • R is 1 to 3 substituents independently selected from the group consisting of H, - CF 3 , -OCF 3 , halogen, -NO 2 , -CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NH 2 , (C j -C 8 J-afkyl-amino, di- (( C r C 6 )alkytJamino, amino(C r C 6 Jalkyl, (C 1 -C 6 J-alkylamino(C 1 -C 6 Jalkyl, di-(( C 1 -C 6 JaIkYl)- amino(C 1 -C 6 Jalkyl, hydroxy-( C ⁇ C g Jalkyl, -COOR 17 , -COR 17 , -CONR 24 R 25 , -NHCOR 16 , - NHSO 2 R 16 , -NHSOzCH 2 CF 3 , -SO 2 NR 24 R 25
  • R 23 is ha!o(C,,-C 6 Ja!kyi; C 2 -C 6 alke ⁇ yl; halo(C 2 -C 6 Jalkenyl; C 2 -C 6 alkynyl; C 3 -C 7 -cycloalkyi; (Cs-C/JcycloalkyKC ⁇ C g Jalkyl; (C 3 -C 7 Jcycloalkyl substituted by 1 to 3 substituents selected from the group consisting of halo, (C-rC 3 jaikoxy(Ci-C 3 )alkyl, hydroxy and Ci-C 3 alkoxy; aryi; aryl(C 2 -C ⁇ )alkyi; heteroaryl; heterocycloalkyl; (C r C e Jalkyl substituted by 1-3 substituents independently selected from -COOH and
  • R and R are independently selected from the group consisting of H, alkyl, or R 37 -substituted CrCe afkyl, wherein R 37 is selected from the group consisting of HO-, HS- 5 CH 2 S-, -NH 2 , phenyl, p-hydroxyphenyl and indolyl;
  • R 24 and R 25 are independently selected form the group consisting of H, C 1 -C 6 alkyl, hato(C r C ⁇ )alkyl, C 2 -C 6 alkenyl, halo(C 2 -C 6 )alkyl, C 2 -C 6 alkynyl, aryl, aryKC,- C 6 )alky), CyCrcycloalkyl, hakXQHwJcydoalkyi, (d-C 3 )alkoxy(Ci-C 3 )-alky1, hydroxy and Ci-Ce alkoxy;
  • R 26 is Cy-
  • R 27 is C ⁇ alkyl, phenyl, benzyl, (d-C 3 )alkoxy(Ci-C3)-alkyl, (CrC7)-cycloalkyl, carboxy ⁇ -C ⁇ Jalkyl, sulfo ⁇ -C ⁇ Jalkyl.
  • R 28 is H, C 1 -C 6 alkyl, phenyl, benzyl or (d-CaJalkoxyfd-CaJalkyl;
  • R 29 and R 30 are independently selected from the group consisting of H and C 1 -C 6 alkyl;
  • R 31 is (C 1 -C 6 JaIlCyI; hato ⁇ -C ⁇ ky!; C 2 -C 6 alkenyl; haJo(C 2 -C 6 )afkyl; C 2 -C 6 alkynyl; QrCr-cycloalkyl; (QrC7)cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of halo, (C 1 -C 3 JaJkOXy(C 1 -C 3 )aJkyl, hydroxy and Ci-C 0 alkoxy; aryl; aryl ⁇ -CeJa
  • R 33 and R 34 are independently selected from the group consisting of H, (C 1 -C 6 JaJlCyI and CyCr-cycloalkyl. These compounds are described in US Patent No. 7,037,920, herein incorporated by reference.
  • An embodiment of the compounds of Formula I-C1 are those wherein R 1 , R 10 and R 11 are independently selected from the group consisting of H and C 1 -Ce alkyl; R 2 and R 8 are each hydrogen; and R 0 is H, OH or Ci-Ce alkoxy.
  • R is H, halogen, OH, C 1 -Ce alkyl, Ci-C 6 alkoxy or amino.
  • a further embodiment of the compounds of Formula I-C1 are those wherein B rs - CH «CH-.
  • An embodiment of the compounds of Formula I-C1 are those wherein W is - NR 4 R 5 . -NHCOR 26 . -NHSO 2 R 16 . R ⁇ -aryl or heteroaryl.
  • R 21 is 1 to 3 substituents independently selected from the group consisting of H, -CF 3 , -OCF 3 , halogen. -CN. C 1 -C 6 alkyt, C 1 -C 6 alkoxy, -NH 2 and -CR 2 ⁇ (sNOR 2 ⁇ ).
  • An embodiment of the compounds of Formula I-C1 are those wherein R 3 is H, hydroxy. C 1 -C 6 ⁇ kOXy. halogen, C 3 -C 6 cycloalkyl. -CN. (C 1 -C 6 ⁇ KyI 1 -COOR 17 or -NR 4 R 5 .
  • An embodiment of the compounds of Formula I-C1 are those wherein R 22 is - COR 23 , -S(O) 2 R 31 or -COOR 27 .
  • An embodiment of the compounds of Formula I-C1 are those wherein R 23 Is C 3 -C 7 - cycloalkyl; (C 3 -C7)cycloaikyl substituted by 1 to 3 substituents selected from the group consisting of halo. (C-CaJalkoxytC ⁇ Jalkyi, hydroxy and C 1 -C 0 alkoxy: (C 3 - C 7 )cycloalkyl(C 1 -C 6 )alkyl; aryl; or aryl(C 2 -C 6 )alkyl.
  • An embodiment of the compounds of Formula I-C1 are those wherein R 23 is C 3 -Cr cycloalkyl; (C 3 -C 7 )cycioalkyi(C 1 -C 6 )alkyl or aryKC 2 -C 6 )alkyl.
  • An embodiment of the compounds of Formula I-C1 are those wherein R 31 is (C 1 - C ⁇ Jalkyl, CrCr-cyctoalkyl. aryl or aryKC.-C ⁇ kyl.
  • a further embodiment of the compounds of Formula I-C1 are those wherein R 27 is C f -C ⁇ alkyl. phenyl, benzyl. (Ci-Ca ⁇ kox ⁇ d-C ⁇ kyl Of (C 3 -C 7 )cycioalkyf.
  • An embodiment of the compounds of Formula I-C1 are those compounds selected from the group consisting of compounds of the formula
  • W is as defined in the following table:
  • An embodiment of the compounds of Formula I-C1 are those compounds selected from the group consisting of compounds of the formula
  • W and Z are as defined in the following table: or a pharmaceutically acceptable salt thereof.
  • the PAR-I antagonist is a compound of Formula-! 01
  • Z is -CH 2 -;
  • R1 is H, C 1 -C 6 alkyi, fluoro ⁇ C 1 -C 6 )alkyl, drfluoro ⁇ C 1 -C 6 )alkyl, t ⁇ fl ⁇ oro-(C 1 - C 6 )alkyl, C3-C7 cycloalkyl, C2-C 6 alkenyl, aryKC 1 -C 6 )alkyl ⁇ aryi(C2-C 6 )alkenyi, hydroxy- (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alky1, amino-(C 1 -C 6 )alkyt, aryl or thio(C 1 -C 6 )alkyl;
  • R 2 is H;
  • R3 is H, hydroxy, C 1 -C 6 alkoxy, -NR 1 ⁇ R 1 ⁇ .
  • Het is pyridyl, wherein the 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 1 to 4 substituents, W, independently selected from the group consisting of H; C 1 -C 6 alkyl; fluoro(C 1 -C 6 )alky1; difluoro(C 1 - C 6 )alkyl; trifl ⁇ oro-fC 1 -C 6 J-alkyl; C3-C7 cyctoalkyi; C 2 -C 6 alkenyl; R21-eryl(
  • R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, benzyl and C3-C7 cycloalkyl;
  • R ⁇ is independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, (C3-C7)cycloalkyl. (C3-C7)cydoalkyl(C 1 -C 6 )alkyl.
  • R 7 is H or (C 1 -C 6 )alkyl;
  • R8 R 1 O and R 11 are each H;
  • R 9 is H, OH. C 1 -C 6 aJkoxy, halogen or halo(C 1 -C 6 )alkyl;
  • R 16 is C 1 -C 6 lower alky), 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 21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, CN, -CF3, -OCF3, halogen. -NO2.
  • R 26 is 1. 2 or 3 substituents independently selected from the group consisting of hydrogen, halogen, -COOR 36 , -CN. -C(O)NR 37 R 36 . -NR 39 C(O)R 40 .
  • R 2 * is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, halogen and (d-C ⁇ )aJkoxy
  • R 29 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, (Ci-C ⁇ )alkyi, -OH, (Ci-C «)alkoxy and halogen
  • R 30 , R 31 and R 32 are independently selected from the group consisting of hydrogen, (Ci-Ci O )-alkyl, (d-C ⁇ )aJkoxy(Ci-Cio)-alkyl, R ⁇ -aryKd-C ⁇ Hilkyl.
  • R 33 ⁇ C 3 - d)cydoalkyf, R 34 -(C 3 -C 7 )cydoafkyi(C 1 -C ⁇ )alkyl, and R ⁇ -aryl;
  • R 33 is hydrogen, (d-C ⁇ )alkyl, OH- ⁇ d-C ⁇ )alkyl or (Ci-Ce)alkoxy;
  • R 36 is 1 to 4 substituents independently selected from the group consisting of hydrogen, (d-C ⁇ )alkyt, -OH, halogen, -CN, (Ci-C ⁇ )alkoxy, trihakHd-CeJalkoxy.
  • R 36 is hydrogen, (d-C ⁇ )alkyl, hak>(d-C ⁇ )alkyl, dihalo(Ci-C ⁇ )alkyi or triftuoro(Ci- C ⁇ )alkyl.
  • R 37 and R 38 are independently selected from the group consisting of hydrogen, (d-C ⁇ )alky ⁇ , aryKd-C ⁇ )alkyi. phenyl and (Cs-dsjcycloalkyl; R 39 and R 40 are independently selected from the group consisting of hydrogen, (Ci-C ⁇ )alkyl.
  • R 42 is 1 to 3 substituents independently selected from the group consisting of hydrogen, -OH, (d-C «)aflcyl and (d-C ⁇ )alkoxy.
  • R 0 , R 10 and R 11 are each hydrogen, and R is hydrogen, OH 1 C 1 -C 6 alkoxy, -NHR 18 or C 1 -C 6 alkyl.
  • R 9 is H, OH or C 1 - C 6 alkoxy.
  • R 1 is C 1 -C 6 alkyt.
  • W is C 1 -C 6 alkyt, or R 2 i-aryl.
  • R 22 and R 23 are independently selected from the group consisting of OH 1 (Ci-d o )aikyl, (Crdo)-alkenyl, S (C2-C 10 )alkynyf, trifluoro(d-do)-alkyl. trifluorofCr-doHrikenyl, trifluorofQrdoJalkynyl, (CrdJcycloaJkyi, R ⁇ -aryl, R ⁇ -aryKd-CeJalkyl, R ⁇ -arylriydroxyfd-CijJalkyl, R 25 - aryJalkoxyiC-C ⁇ Jalkyf.
  • R 22 and R 23 are 0 independently selected from the group consisting of (d-Cio)alkyl and OH-(Ci-Cio)alkyl.
  • R 2 is hydrogen; R3 is hydrogen OH, C 1 -C 6 alkoxy, -NHR" or C 1 -C 6 alky); R 9 is H, OH or C 1 -C 6 alkoxy; and R 1 is C 1 -C 6 alkyl.
  • R 22 and R 23 are S independently selected from the group consisting of OH, (Ci-Cio)alkyl,
  • R 22 and R 23 are independently selected from the group consisting of (d-Ci ⁇ )alkyl and OH-(d-do)aikyl.
  • Another embodiment of the compounds of Formula 1-D includes the following:
  • W is as defined in the following table:
  • Another embodiment of the compounds of formula I-D1 is a compound of the formula
  • Another embodiment of the compounds of Formula 1-01 include is a compound of the formula
  • Additional embodiments related to the compound of Formula I-O1 include:
  • Additional embodiments of Formula 1-0 include:
  • the PAR-1 antagonist is a compound of the Formula l-E-1 or l-E-2
  • the PAR1 antagonist is a compound of the Formula l-E-3
  • a preferred salt for the compound of Formula 1-1 E-1 is the hydrobromkfe salt
  • the compounds of Formulae l-E-1 to l-E-3 are made by Eisai.
  • PAR4 antagonists are known in the art Compounds that antagonize the PAR4 receptor include 1-(benzyl)-3-(substituted aryl) condensed pyrazole derivatives of the formula
  • R 1 is H, Ci-Cralkyl, halogen or -OR; represents a ring selected from the group consisting of
  • R 2 is H, -COOR, -CH 2 OR.
  • X is -O- or -S-; represent a ring selected from the group consisting of represents a ring selected from the group consisting of
  • R 2 is H, -COOR, -CH 2 OR, d-Ca-alkyl, or haJogen;
  • X is -O- or -S-; represent a ring selected from the group consisting of
  • R 3 is H, Ci-Cralkyi, halogen or -OR; X* Is -O-. -S-. or -NH-; R 3 is H, d-Cralkyl, halogen or -OR; R is H or CrCa-aJkyl; or a pharmaceutically acceptable salt thereof.
  • a preferred PAR4 antagonist is a compound of the formula
  • the PAR1 antagonist is selected from the group of compounds consisting of the following: OH H 0
  • the cardiovascular agent is selected from the group consisting of thromboxane A2 biosynthesis inhibitors, thromboxane antagonists, platelet aggregation inhibitors, cyctooxygenase inhibitors, angiotensin antagonists, endothelin antagonists, phosphodiesterase inhibitors, angiotensin converting enzyme (ACE) inhibitors, neutral endopeptidase inhibitors, anticoagulants, diuretics, Factor Xa inhibitors, statins, chlolesterol absorption inhibitors (e.g., ezetimibe), calcium antagonists, B-type natriuretic peptides, beta blockers, calcium channel blockers, phosphodiesterase inhibitors, fibrinolytics and GP llb/llla antagonists.
  • the cardiovascular agent is a thromboxane antagonist selected from the group consisting of seratrod
  • the cardiovascular agent is a platelet aggregation inhibitor selected from the group consisting of clopidogrel, cHostazol, ab ⁇ ximab, limaprost, S ticlopkJine and eptifibatide.
  • prasugrel CS-747
  • AZD-6140 AZD-6140 and CT-50547.
  • the cardiovascular agent is a cyclooxygenase inhibitor selected from the group consisting of aspirin, meloxicam, rofecoxib and celecoxib.
  • the cardiovascular agent is an angiotensin antagonist selected from the group consisting oflichartan, telrrrfsartan, candesartan, irbesartan,0 losartan and eprosartan.
  • the cardiovascular agent is tezosentan.
  • the cardiovascular agent is a phosphodiesterase inhibitor selected from the group consisting of milrinoone and enoximone.
  • the cardiovascular agent is an angiotensin converting S enzyme (ACE) inhibitor selected from the group consisting of captopril, enalapril, enalapriJ, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolaprH, iisinopril, moexipril and benazepril.
  • ACE angiotensin converting S enzyme
  • the cardiovascular agent is a neutral endopeptidase inhibitor selected from the group consisting of candoxatril and ecadotril.
  • the cardiovascular agent is an anticoagulant selected from the group consisting of warfarin, ximelagatran, fondaparin, nadroparin, dalteparin and enoxaparin.
  • the cardiovascular agent is a diuretic selected from the group consisting of chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide and amUoride.
  • the cardiovascular agent is a Factor Xa inhibitor selected from the group consisting of apixaban, razaxaban, Arixtra®, Induprux®, KFA-1982, and DX-90 6 5a.
  • the cardiovascular agent is a statin selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, fluvastatin, and pravastatin.
  • the cardiovascular agent is a calcium antagonist selected from the group consisting of verapamil and dittiazem. In some embodiments, the cardiovascular agent is a B-type natriuretic peptide selected from the group consisting of, nesiritide and ularitide.
  • the cardiovascular agent is a beta blocker selected from the group consisting of nebivolol and betaxoiol. In some embodiments, the cardiovascular agent is amlodipine.
  • the cardiovascular agent is milrinoone.
  • the cardiovascular agent is a fibrinolytic selected from the group consisting of reteplase, alteplase, and tenecteplase.
  • the cardiovascular agent is a GP llb/ll!a antagonist selected from the group consisting of Integrillin®, abciximab, and tirofiban.
  • the cardiovascular agent is aspirin or clopidogrel bisulfate.
  • the invention encompasses a method of treating a mammal in need of said treating comprising administering to said mammal pharmaceutically effective amounts of a thrombin receptor antagonist and a cardiovascular agent.
  • a method of treating a mammal in need of said treating comprising administering to said mammal pharmaceutically effective amounts of a thrombin receptor antagonist and a cardiovascular agent.
  • a thrombin receptor antagonist and a cardiovascular agent.
  • Various embodiments of the this method are in accordance with the pharmaceutical compositions above described.
  • the condition is a cardiovascular or circulatory disease or condition, an inflammatory disease or condition, a respiratory tract disease or condition, cancer, or a neurodegenerative disease.
  • the condition is a cardiovascular or circulatory disease or condition selected from the group consisting of acute coronary syndrome, secondary prevention, thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, renal ischemia, cerebral stroke, cerebral ischemia, cerebral infarction, migraine, renal vascular homeostasis and erectile dysfunction.
  • acute coronary syndrome secondary prevention, thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, deep vein thrombosis
  • the condition is an inflammatory disease or condition selected from the group consisting of irritable bowel syndrome, Crohn's disease, nephritis and a radiation- or chemotherapy- induced proliferative or inflammatory disorder of the gastrointestinal tract, lung, urinary bladder, or other organ.
  • the condition is a respiratory tract disease or condition selected from the group consisting of reversible airway obstruction, asthma, chronic asthma, bronchitis and chronic airways disease.
  • the condition is a cancer selected from the group consisting of renal cell carcinoma and an angiogenesis related disorder.
  • the condition is a neurodegenerative disease selected from the group consisting of Parkinson's disease, amyotropic lateral sclerosis, Alzheimer's disease, Huntington's disease and Wilson's disease.
  • the condition is selected from the group consisting of acute renal failure, glomerulonephritis, astrogliosis, a fibrotic disorder of the liver, kidney, lung or intestinal tract, Alzheimer's disease, diabetes, diabetic neuropathy, rheumatoid arthritis, neurodegenerative disease, neurotoxic disease, systemic lupus erythematosus, multiple sclerosis, osteoporosis, glaucoma, macular degeneration, psoriasis, radiation fibrosis, endothelial dysfunction, and a wound or a spinal cord injury, or a symptom or result thereof .
  • the condition is sepsis.
  • Subject includes both mammals and non-mammalian animals.
  • “Mammal * includes humans and other mammalian animals.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • alkyP means an aliphatic hydrocarbon group that can be straight or branched and comprises 1 to about 20 carbon atoms in the chain. Preferred alkyl groups comprise 1 to about 12 carbon atoms in the chain. More preferred alkyt groups comprise 1 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyi chain.
  • the alkyl can be substituted by one or more substituents independently selected from the group consisting of halo, aryl, cydoalkyl, cyano, hydroxy, alkoxy, alkyfthk), amino.
  • -NH(alkyl), -NH(cydoalkyl), -Nfalkylfe (which alkyls can be the same or different).
  • suitable aJkyl groups include methyl, ethyl, n-propyl, isopropyt, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl.
  • Alkenyl means an aliphatic hydrocarbon group (straight or branched carbon chain) comprising one or more double bonds in the chain and which can be conjugated or unconjugated.
  • Useful alkenyl groups can comprise 2 to about 15 carbon atoms in the chain, preferably 2 to about 12 carbon atoms in the chain, and more preferably 2 to about 6 carbon atoms in the chain.
  • the alkenyl group can be substituted by one or more substituents independently selected from the group consisting of halo, alkyl. && > cydoalkyl, cyano and alkoxy.
  • suitable alkenyl groups include ethenyt, propenyt, n-butenyl, 3-methytbut-enyl and n-pentenyl.
  • Alkoxy means an afkyl-O group in which the alkyl group is as previously described.
  • Useful alkoxy groups can comprise 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms.
  • suitable alkoxy groups include methoxy, ethoxy and isopropoxy.
  • the alkyl group of the alkoxy is finked to an adjacent moiety through the ether oxygen.
  • AJkynyT means an aliphatic hydrocarbon group comprising at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyt groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alky) groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methyfbutynyl, n-p ⁇ ntynyf, and decynyl.
  • the alkynyl group may be substituted by one or more substituents which may be the same or different, each substit ⁇ ent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • AryF means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl can be substituted with one or more substituents, as defined above, which may be the same or different Non-limiting examples of suitable aryt groups include phenyl, naphthyl, ind ⁇ nyl, tetrahydronaphthyl and indanyJ.
  • Arylene means a bivalent phenyl group, including ortho, meta and para-substitution.
  • alkyl, alkenyl and alkynyl chains depends on the length of the chain, and the size and nature of the substituent Those skilled in the art will appreciate that while longer chains can accommodate multiple substituents, shorter alkyl chains, e.g., methyl or ethyl, can have multiple substitution by halogen, but otherwise are likely to have only one or two substituents other than hydrogen. Shorter unsaturated chains, e.g., ethenyi or ethynyl, are generally unsubstituted or substitution is limited to one or two groups, depending on the number of available carbon bonds.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.
  • Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be substituted with one or more substituents, as defined above, which may be the same or different
  • suitable monocyclic cydoalkyls include cydopropyl, cydobutyl, cyclopentyt, cyclohexyl and the like.
  • suitable multicyclic cydoalkyls include 1-decalinyl, norbomyi, adamantyi and the like.
  • Cycloafkylene refers to a corresponding bivalent ring, wherein the points of attachment to other groups include all positional isomers.
  • Dihydroxy(C 1 -C 6 )alkyr refers to an alkyl chain substituted by two hydroxy groups on two different carbon atoms.
  • Fl ⁇ oroalkyT, "dtfluoroalkyf” and “t ⁇ fluoroalkyt” mean aikyi chains wherein the terminal carbon is substituted by 1, 2 or 3 fluoroatoms, respectively, e.g., -CF3, - CH2CF3, -CH2CHF2 or -CH2CH2F.
  • 'Hatoalkyl means an alkyl chain substituted by 1 to 3 hato atoms.
  • Halogen or "halo” refers to fluorine, chlorine, bromine or iodine radicals. Preferred are fl ⁇ oro, chloro or bromo, and more preferred are ftuoro and chkxo.
  • ⁇ teroaryT means an aromatic monocyclic or muiticyclic ring system comprising 5 to 14 ring atoms, preferably about 5 to 10 ring atoms, comprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms.
  • N- oxide ⁇ of the ring nitrogens are also included, as well as compounds wherein a ring nitrogen is substituted by a (C-
  • single-ring heteroaryt groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyf, pyrroryl, thienyl, irnkJazoryt, pyrazolyi, tetrazolyl, tNazoJyi, isothiazoryl, thiadiazolyi, pyrazinyl, pyrimidyl, pyridazinyt and triazoryi.
  • bicyclic heteroaryl groups are napnthyridyl (e.g., 1, 5 or 1,7), imidazopyridyl, pyrido[2,3]imidazolyl, pyridopyrimldinyl and 7-azaindolyl.
  • benzofused heteroaryt groups are indolyl, quinolyt, isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyl), benzimidazolyl, benzofuranyl, benzoxazolyi and benzofurazanyl.
  • W-substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent as defined above, or where adjacent carbon atoms form a ring with an alkylene group or a methylenedioxy group, or where a nitrogen in the Het ring can be substituted with R ⁇ -aryt or an optionally substituted alkyl substituent as defined in W.
  • Het is exemplified by the single ring, the ring substituted with another ring (which can be the same or different), benzofused heteroaryl groups as defined immediately above, as well as bicyclic groups such as benzoquinolinyl (e.g., 1,4 or 7,8) orphenanthrolinyl ( ⁇ .g., 1,7; 1,10; or 4,7). Het groups are joined to group B by a carbon ring member, e.g., Het is 2-pyridyl, 3-pyridyi or 2-quinor/i.
  • heteroaryi groups wherein adjacent carbon atoms form a ring with an alkylene group are 2,3-cydopentenopyridine, 2,3-cydohexenopyridine and 2,3- cycloheptenopyridine.
  • Heterocydoalkyt means a 4 to 6 membered saturated ring containing 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of N, S and O, provided that the heteroatoms are not adjacent.
  • heterocycloalkyi rings are pyrrolidinyl, piperidlnyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazotidinyi, 1,3- dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl and t ⁇ trahydrothiopyranyt.
  • heterospirocyclic refers to a spirocydic structure containing 3 to 5 carbon atoms and 1 or 2 heteroatoms selected from the group consisting of N, S and O, provided that the heteroatoms are not adjacent.
  • optional single bond represented by refers to the bond shown by the double dotted line between X and the carbon to which Y and R 15 are attached in the structures of Formulas I and II.
  • Optional single bond means that a single bond may be present, or that no bond is present.
  • the “optional double bond” represented by refers to the bond shown by the combined solid/single dotted line in the middle ring of the structure shown for Formulas I and Il and means that at least a single bond must be present, but that a double bond can be present When the double bond is present, R 10 is absent
  • the rings formed are 1-pyrroJklinyl, 1-piperidinyl and 1 -piperazinyl, wherein the piperazinyl ring may also be substituted at the 4-positk>n nitrogen by a group R?.
  • R 4 and R 5 are said to be independently selected from a group of substituents, means that R 4 and R 5 are independently selected when attached to the same nitrogen, but also that where an R 4 or R 5 variable occurs more than once in a molecule, those occurrences are independently selected. Similarly, each occurrence of R 13 or R 14 is independent of any other R 13 or R 14 in the same Q ring.
  • substituent(s) will affect the number of substituents which can be present.
  • Compounds of the invention have at least one asymmetrical carbon atom and therefore all isomers, including enantiomers, stereoisomers, rotamers, tautomers and racemate ⁇ of the compounds of Formula I or Il (where they exist) are contemplated as being part of this invention.
  • the invention includes d and I isomers in both pure form and S in admixture, including racemic mixtures.
  • Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of Formula I or II. Isomers may also include geometric isomers, e.g., when a double bond is present.
  • Polymorph * means a crystalline form of a substance that is distinct from another0 crystalline form but that shares the same chemical formula. Polymorphous forms of the compounds of Formula I or II, whether crystalline or amorphous, also are contemplated as being part of this invention.
  • ⁇ ffective amount or "therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in antagonism of a thrombin receptor and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect 0
  • Compounds of the invention with a basic group can form pharmaceutically acceptable salts with organic and inorganic acids.
  • acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, matonic, salicylic, malic, fumaric, succinic, ascorbic maleic, methanesutfonic and other mineral and carboxylic adds well known to those in the art
  • Preferred embodiments include bis ⁇ tfate salts.
  • the salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt
  • the free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate.
  • the free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.
  • Compounds of the invention can also form pharmaceutically acceptable solvates, including hydrates.
  • Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, fitnkjm, gold and silver salts.
  • salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkvlamines, N-methykjlucamine and the like.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or Il or a salt and/or solvate thereof (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
  • a discussion of prodrugs is provided in T. Higuchi and V. SteHa, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreverslble Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
  • Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covaJent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ⁇ thanolates. methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • Co-crystal means a crystalline structure simultaneously comprising pharmaceutically active molecules and inert molecules. Co-crystals may be formed by combining a weak base with a weak acid selected to match hydrogen bond donors with acceptors. The pKa difference of conjugate pairs may be inconsistent with salt formation in water.
  • the co-crystallizing agents used to form co-crystals are usually bifunctional adds such as fumaric acid, succinic acid, malic acid, and tartaric acid. Co-crystals are discussed in J. F. Remenar of. a/., "Crystal Engineering of Novel Cocrystals of a Triazole Drug with 1,4-Dicart>oxytfc Acids", Journal of the American Chemical Society, 2003, vol.
  • Compounds of the invention with a carboxylic acid group can form S pharmaceutically acceptable esters with an alcohol.
  • suitable alcohols include methanol and ethanol.
  • the combinations of the present invention of at least one PAR1 antagonist at least one PAR4 antagonist and optionally one or more other therapeutically effective agents, the two or more active components may each be formulated individually and co-administered simultaneously or sequentially.
  • the active agents may be formulated in a single pharmaceutical composition comprising a PAR1 antagonist and a PAR4 antagonist in a pharmaceutically acceptable carrier.
  • the components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
  • the dosage of the other S therapeutically active agents) can be determined from published material, and may range from 1 to 1000 mg per dose.
  • the term "at least one PAR1 antagonist” or “at least one PAR4 antagonist” means that one to three different compounds that are active as PAR1 antagonists or PAR4 antagonists may be used in a pharmaceutical composition or0 method of treatment Preferably one PAR1 antagonist and one PAR4 antagonist are used.
  • the term “one or more additional cardiovascular agents” means that one to three additional drugs may be administered in combination with a thrombin receptor antagonist; preferably, one additional compound is administered in combination with a PAR1 antagonist and PAR4 antagonist combination.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient Suitable solid carriers are known in the art e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20 th Edition, Lippincott Williams & Wilkins, Baltimore, MD, (2000).
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opadfiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g., nitrogen.
  • transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the administration of the above-described combinations is carried out by specifying not only the formulations, but also the modes of administration and the dosing regimen.
  • the compound is administered orally.
  • Orally dissolving formulations of thrombin receptor antagonists are disclosed in U.S. provisional application no. 60/689,207, which is herein incorporated in its entirety by reference.
  • the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g. , an effective amount to achieve the desired purpose.
  • the dosing regimen for the above-described PAR1 antagonists may comprise a loading dose followed by a series of maintenance doses.
  • the loading dose is about 1 to about 100 mg., preferably about 5 to about 40 mg., more preferably about 10 to about 30 mg., and still more preferably about 15 to about 25 mg.
  • the daily maintenance dose is about 0.1 to about 10 mg., preferably about 0.5 to about 5 mg.. more preferably about 0.5 to about 1.5 mg., most preferably about 0.75 to about 1.25 mg.
  • the daily dose of a PAR1 antagonist for treatment of a disease or condition cited above is about 0.001 to about 100 mg/kg of body weight per day, preferably about 0.001 to about 10 mg/kg.
  • the dosage level is therefore from about 0.1 to about 700 mg of drug per day, given in a single dose or 2-4 divided doses.
  • the daily dose of a PAR4 antagonist for treatment of a disease or condition cited above is about 1 to about 1000 mg per day, preferably about 5 to about 300 mg per day for oral administration and 1 to about 100 mg per day, preferably about 2 to about 15 mg per day for intravenous administration, given in a single dose or 2-4 divided closes.
  • the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.
  • a cardiovascular or circulatory disease or condition such as acute coronary syndrome, secondary prevention, thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, deep vein thrombosis, venous thromboembolism, a cardiovascular disease associated with hormone replacement therapy, disseminated intravascular coagulation syndrome, renal ischemia, cerebral stroke, cerebral ischemia, cerebral infarction, migraine, renal vascular homeostasis or erectile dysfunction; an inflammatory disease or condition, such irritable bowel syndrome, Crohn's disease, nephritis or a radiation- or chemotherapy- induced proliferative or inflammatory disorder of

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Abstract

La présente invention concerne une composition pharmaceutique comportant une quantité efficace d’au moins un antagoniste de PAR1, au moins un antagoniste de PAR4, éventuellement, une quantité efficace d’au moins un agent cardiovasculaire, et, éventuellement un support pharmaceutiquement acceptable. La présente invention concerne également l’utilisation de ces compositions pharmaceutiques pour traiter diverses maladies associées à une thrombose.
PCT/US2009/039070 2008-04-02 2009-04-01 Thérapies de combinaison comprenant des antagonistes de récepteur 1 activé par protéase (par1) associés à des antagonistes récepteur 4 activé par protéase (par4) Ceased WO2009124103A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011128420A1 (fr) * 2010-04-16 2011-10-20 Sanofi Pyridyl-vinyl-pyrazolo-quinoléines utilisées comme inhibiteurs du par1
US8871798B2 (en) 2010-04-16 2014-10-28 Sanofi Tricyclic pyridyl-vinyl pyrroles as PAR1 inhibitors
WO2014173859A2 (fr) 2013-04-22 2014-10-30 Institut National De La Recherche Agronomique Antagonistes de par4 pour l'utilisation dans le traitement ou la prévention d'infections par le virus de la grippe de type a
WO2017181993A1 (fr) * 2016-04-22 2017-10-26 江苏天士力帝益药业有限公司 Nouvel analogue d'himbacine et ses utilisations dans des médicaments
CN110407819A (zh) * 2019-08-02 2019-11-05 牡丹江医学院 一种作为预防外科手术并发症的凝血酶受体拮抗剂
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1495018E (pt) * 2002-04-16 2008-02-19 Schering Corp Antagonistas tricíclicos de receptores de trombina
US20070202140A1 (en) * 2005-12-22 2007-08-30 Veltri Enrico P Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery
PE20080183A1 (es) * 2006-04-06 2008-03-10 Schering Corp Terapias de combinacion de tra

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011128420A1 (fr) * 2010-04-16 2011-10-20 Sanofi Pyridyl-vinyl-pyrazolo-quinoléines utilisées comme inhibiteurs du par1
US8791133B2 (en) 2010-04-16 2014-07-29 Sanofi Pyridylvinylpyrazoloquinolines as PAR1 inhibitors
US8871798B2 (en) 2010-04-16 2014-10-28 Sanofi Tricyclic pyridyl-vinyl pyrroles as PAR1 inhibitors
WO2014173859A2 (fr) 2013-04-22 2014-10-30 Institut National De La Recherche Agronomique Antagonistes de par4 pour l'utilisation dans le traitement ou la prévention d'infections par le virus de la grippe de type a
WO2017181993A1 (fr) * 2016-04-22 2017-10-26 江苏天士力帝益药业有限公司 Nouvel analogue d'himbacine et ses utilisations dans des médicaments
CN107304200A (zh) * 2016-04-22 2017-10-31 江苏天士力帝益药业有限公司 一种新的喜巴辛类似物及其在医药中的应用
CN107304200B (zh) * 2016-04-22 2021-09-21 江苏天士力帝益药业有限公司 一种新的喜巴辛类似物及其在医药中的应用
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
CN110407819A (zh) * 2019-08-02 2019-11-05 牡丹江医学院 一种作为预防外科手术并发症的凝血酶受体拮抗剂

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