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WO2000071512A1 - Inhibiteurs du facteur xa - Google Patents

Inhibiteurs du facteur xa Download PDF

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Publication number
WO2000071512A1
WO2000071512A1 PCT/US2000/014207 US0014207W WO0071512A1 WO 2000071512 A1 WO2000071512 A1 WO 2000071512A1 US 0014207 W US0014207 W US 0014207W WO 0071512 A1 WO0071512 A1 WO 0071512A1
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Prior art keywords
alkyl
group
cycloalkyl
phenyl
member selected
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PCT/US2000/014207
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English (en)
Inventor
Yonghong Song
Lane Clizbe
Charles Marlowe
Robert M. Scarborough
Ting Su
Bing-Yan Zhu
James Kanter
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Cor Therapeutics, Inc.
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Priority to CA002374820A priority Critical patent/CA2374820A1/fr
Priority to EP00936235A priority patent/EP1189879A1/fr
Priority to AU51581/00A priority patent/AU5158100A/en
Priority to JP2000619769A priority patent/JP2003500387A/ja
Publication of WO2000071512A1 publication Critical patent/WO2000071512A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • This invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fNIIa, flXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin).
  • the present invention relates to novel monoamidino-containing compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals.
  • the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by coagulation disorders.
  • Hemostasis the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation.
  • This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption.
  • platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition.
  • Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., " Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5, 411-436 (1994).
  • Several classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and coumarins).
  • a prothrombinase complex including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family), converts the zymogen prothrombin into the active procoagulant thrombin.
  • Factor Xa a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family
  • Ga carboxyglutamyl
  • Polypeptides derived from hematophagous organisms have been reported which are highly potent and specific inhibitors of factor Xa.
  • United States Patent 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria of icinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al. , "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structure", J. Biol. Chem., 262, 10162-10167 (1988).
  • ATS antistasin
  • tick anticoagulant peptide Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata, as reported by Waxman, L., et al, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa" Science, 248, 593-596 (1990).
  • Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R.R. et al., "Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res., 19, 339-349 (1980); Turner, A.D. et al., "p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry, 25, 4929-4935 (1986); Hitomi, Y.
  • Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites.
  • WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino- piperidine and 4-phenoxy-N-alkylamidino-piperidine group connected to a 3- amidinophenyl group via a carboxamidealkyleneamino bridge
  • EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piper
  • the present invention relates to novel compounds which inhibit factor Xa, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof which have particular biological properties and are useful as potent and specific inhibitors of blood coagulation in mammals.
  • the invention relates to methods of using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals which have coagulation disorders, such as in the treatment or prevention of any thrombotically mediated acute coronary or cerebrovascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples.
  • this invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents.
  • coagulation cascade e.g. thrombin, etc.
  • the present invention provides a compound of the formula I:
  • A is selected from:
  • R 1 is selected from:
  • R 2 and R 3 are independently selected from the group consisting of:
  • n is an integer of 0-2;
  • Y is a member selected from the group consisting of:
  • R 4 is selected from:
  • D is a direct link or is a member selected from the group consisting of:
  • a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R la substituents;
  • R la is selected from:
  • Halo C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ⁇ ,alkylC 3 . 8 cycloalkyl, -CN, -NO 2 , (CH 2 ) m NR 2a R 3a , SO 2 NR 2a R 3a , SO 2 R 2a , CF 3 , OR 2a , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ⁇ alkylC 3 . 8 cycloalkyl, -CN and -NO 2 .
  • n is an integer of 0-2;
  • R 2a and R 3a are independently selected from the group consisting of:
  • R 5 and R 6 are independently selected from:
  • C M alkylCOOC M alkyl wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 _ 8 cycloalkyl, C 0 ⁇ alkylC 3 . 8 cycloaU yl, -CN and -NO 2 ;
  • G is selected from:
  • R 7 , R 8 , R 7a , R 8a , R 70 and R 8b are each independently a member selected from the group consisting of:
  • alkyl-phenyl, -C 0 ⁇ ,alkyl-naphthyl, -C 0 ⁇ ,alkyl-heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of O, N and S, wherein the heterocyclic ring system is a 5-6 membered monocyclic ring or a 8-12 membered bicyclic ring, and wherein 0-4 hydrogen atoms of the phenyl ring, the naphthyl ring carbon and the heterocyclic ring system are replaced by a member selected from the group consisting of -C,.
  • R 9 , R 9a , R 9b , R 9c and R 9d are each independently a member selected from the group consisting of:
  • J is a member selected from the group consisting of:
  • R ⁇ is a member selected from the group consisting of:
  • Z is a member selected from the group consisting of:
  • a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R lb substituents;
  • R lb is selected from:
  • N(R 2b )-C( O)R 3b , N(R 2b )-SO 2 -R 3b , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 _ 8 cycloalkyl, C 0 . 4 alkylC 3 . scycloalkyl, -CN and -NO 2 ;
  • R 2b and R 3b are independently selected from the group consisting of:
  • n is an integer of 0-2;
  • R 12 and R 13 are independently selected from:
  • R 14 and R 15 are independently selected from:
  • the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
  • the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by undesired thrombosis or disorders of the blood coagulation process in mammals, or for preventing coagulation in biological samples such as, for example, stored blood products and samples.
  • the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
  • the preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives.
  • alkenyl refers to a trivalent straight chain or branched chain unsaturated aliphatic radical.
  • alkinyl (or “alkynyl”) refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • cycloalkyl refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.
  • the terms "carbocyclic ring structure " and " C 3 . 16 carbocyclic mono, bicyclic or tricyclic ring structure” or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable monocyclic ring which is aromatic ring ("aryl") having six ring atoms; a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atoms in the three rings
  • non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring stmcture may independently be saturated, partially saturated or fully saturated.
  • carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), 2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • the ring stmctures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable stmcture.
  • substituted as used in conjunction with carbocyclic ring stmctures means that hydrogen atoms attached to the ring carbon atoms of ring stmctures described herein may be substituted by one or more of the substituents indicated for that stmcture if such substitution(s) would result in a stable compound.
  • aryl which is included with the term “carbocyclic ring stmcture” refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted.
  • Prefened aryl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl.
  • arylalkyl which is included with the term “carbocyclic aryl” refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted.
  • heterocyclic ring or “heterocyclic ring system” is intended to mean a substituted or unsubstituted member selected from the group consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring stmcture having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring stmctures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring stmcture having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and
  • heterocyclic ring or “heterocyclic ring system” include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings.
  • heterocyclic ring system includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring stmcture containing at least one hetero atom, for example bicyclic ring stmctures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term "heterocyclic ring systems” as well as bicyclic ring stmctures wherein each of the two rings has at least one hetero atom.
  • the ring stmctures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure.
  • substituted means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring stmctures described herein may be replaced by one or more of the indicated substituents if such replacement(s) would result in a stable compound.
  • Nitrogen atoms in a ring stmcture may be quaternized, but such compounds are specifically indicated or are included within the term "a pharmaceutically acceptable salt" for a particular compound.
  • the total number of O and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring stmcture.
  • Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolin
  • Prefened heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, IH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocylic ring stmctures.
  • aromatic heterocyclic ring system has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring stmcture.
  • halo or halogen as used herein refer to CI, Br, F or I substituents.
  • haloalkyl refers to an aliphatic carbon radicals having at least one hydrogen atom replaced by a CI, Br, F or I atom, including mixtures of different halo atoms.
  • Trihaloalkyl includes trifluoromethyl and the like as prefened radicals, for example.
  • methylene refers to -CH2-.
  • salts includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form; both acid and base addition salts are within the scope of the present invention.
  • “Pharmaceutically acceptable acid addition salt” refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly prefened are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly prefened organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
  • Bio property for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
  • the compounds of this invention carbon atoms bonded to four non- identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof.
  • the syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art.
  • Each of the asymmetric carbon atoms when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention.
  • the present invention provides a compound of the formula I:
  • A is selected from:
  • R 1 is selected from:
  • R 2 and R 3 are independently selected from the group consisting of:
  • n is an integer of 0-2;
  • Y is a member selected from the group consisting of:
  • R 4 is selected from:
  • D is a direct link or is a member selected from the group consisting of:
  • R la is selected from: Halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0J( alkylC 3. 8 cycloalkyl, -CN, -NO 2 , (CH 2 ) m NR 2a R 3a , SO 2 NR 2a R 3a , SO 2 R 2a , CF 3 , OR 2a , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2. 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ⁇ ,alkylC 3 . 8 cycloalkyl, -CN and -NO 2 .
  • n is an integer of 0-2;
  • R 2a and R 3a are independently selected from the group consisting of:
  • E is a member selected from the group consisting of:
  • R 5 and R 6 are independently selected from:
  • G is selected from:
  • R 7 , R 8 , R 7a , R 8a , R 7 " and R 8b are each independently a member selected from the group consisting of:
  • R 7 , R 8 , R 7a , R 8a , R 713 and R 8b can combine with a nitrogen on the E group to form a 5-7 membered heterocyclic ring containing a 0-3 additional heteroatoms selected from the group consisting of O, N and S; or R 7a and R n on adjacent carbons combine to form a 3-6 membered carbocyclic ring;
  • R 9 , R 9a , R 9b , R 9c and R 9d are each independently a member selected from the group consisting of:
  • heterocycle may be a 5-6 membered ring, and wherein from 0-4 hydrogen atoms from the ring atoms of the phenyl and heterocycle groups may be independently replaced with a member selected from the group consisting of halo, -C M alkyl, -C 2 _ 6 alkenyl, -C 2 . 6 alkynyl, -C 3.8 cycloalkyl, -C 0 ⁇ alkyl-C 3 .
  • R 9a taken with R 9b or R 9c taken with R 9d when either pair of groups is attached to the same nitrogen atom may combine with that nitrogen atom to form a 5-8 membered saturated, partially saturated or unsaturated ring which contains from 0-1 additional heteroatoms selected from a group consisting of -N, -O, S, wherein any S ring atom may be present as a -S-,
  • J is a member selected from the group consisting of:
  • R ⁇ is a member selected from the group consisting of:
  • Z is a member selected from the group consisting of:
  • a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R lb substituents;
  • R 2b and R 3b are independently selected from the group consisting of:
  • L is selected from:
  • n is an integer of 0-2;
  • R 12 and R 13 are independently selected from:
  • R 14 and R 15 are independently selected from:
  • the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier.
  • the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by disorders of the blood coagulation process in mammals, or for preventing coagulation in stored blood products and samples.
  • the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant.
  • the prefened compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodmg derivatives.
  • the present invention provides a compound according to the formula I:
  • A is a member selected from the group consisting of:
  • Y is a member selected from the group consisting of:
  • D is a member selected from the group consisting of:
  • A-Y-D is a member selected from the group consisting of:
  • R la is selected from:
  • E is a member selected from the group consisting of:
  • G is -CR 7a R 8a -C b R 8b ;
  • alkyl-heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of O, N and S, wherein the heterocyclic ring system is a 5- 6 membered monocyclic ring; wherein the phenyl ring and heterocyclic ring are substituted by a member selected from the group consisting of CH 3 , halo, -CN, -NO 2 , -OMe, -CO 2 H, -CO 2 Me;
  • R 9 , R 9a and R 9b are independently selected from:
  • R 9a and R 9b may combine with that nitrogen atom to which they are attached to form a 5-6 membered ring which contains from 0-1 additional heteroatoms selected from a group consisting of -N, -O, S;
  • J is a member selected from the group consisting of:
  • Z-L is a member selected from the group consisting of:
  • the present invention provides a compound according to the formula I:
  • A is a member selected from the group consisting of:
  • Y is a member selected from the group consisting of:
  • D is a member selected from the group consisting of:
  • E is a member selected from the group consisting of:
  • G is a member selected from the group consisting of:
  • Z-L is a member selected from the group consisting of:
  • the present invention provides a compound according to the formula I:
  • A is a member selected from the group consisting of:
  • Y is a member selected from the group consisting of:
  • D is a member selected from the group consisting of:
  • E is a member selected from the group consisting of:
  • G is a member selected from the group consisting of:
  • Z-L is a member selected from the group consisting of:
  • A is a member selected from the group consisting of:
  • Y is a member selected from the group consisting of:
  • D is a member selected from the group consisting of:
  • This invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates and solvates of the compounds of the invention.
  • the compounds can exist in various isomeric and tautomeric forms, and all such forms are meant to be included in the invention, along with pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers.
  • the compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
  • the free acid or free base form of a compound of one of the formulas above can be reacted with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying.
  • the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
  • prodmg refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug.
  • Prodmgs are variations or derivatives of the compounds of this invention which have groups cleavable under metabolic conditions. Prodmgs become the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation.
  • Prodrug compounds of this invention may be called single, double, triple etc., depending on the number of biotransformation steps required to release the active dmg within the organism, and indicating the number of functionalities present in a precursor-type form.
  • Prodmg forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodmgs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of
  • Prodmgs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative.
  • the prodmg derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
  • the compounds of this invention find utility as therapeutic agents for disease states in mammals which have disorders of coagulation such as in the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, thrombotic stroke, embolic stroke, disseminated intravascular coagulation including the treatment of septic shock, deep venous thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of reperfused coronary arteries. Further, these compounds are useful for the treatment or prophylaxis of those diseases which involve the production and/or action of factor Xa/prothrombinase complex.
  • thrombotic and prothrombotic states in which the coagulation cascade is activated which include but are not limited to, deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, thromboembolic complications of surgery and peripheral arterial occlusion.
  • a method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprises administering to the mammal a therapeutically effective amount of a compound of this invention.
  • diseases treatable or preventable by the administration of compounds of this invention include, without limitation, occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty, thrombus formation in the venous vasculature, disseminated intravascular coagulopathy, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure, hemonhagic stroke, renal dialysis, blood oxygenation, and cardiac catheterization.
  • the compounds of the invention also find utility in a method for inhibiting the coagulation biological samples, which comprises the administration of a compound of the invention.
  • the compounds of the present invention may also be used in combination with other therapeutic or diagnostic agents.
  • the compounds of this invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • the compounds of the present invention may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion.
  • the compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • mammals such as primates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the biological properties of the compounds of the present invention can be readily characterized by methods that are well known in the art, for example by the in vitro protease activity assays and in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters, such as are illustrated in the examples.
  • Diagnostic applications of the compounds of this invention will typically utilize formulations in the form of solutions or suspensions.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles.
  • Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy.
  • the dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concunent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
  • Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985).
  • Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpynolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
  • buffers such as phosphate, citrate, acetate and other organic acid salts
  • antioxidants such as
  • Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution.
  • the pH of the preparations of this invention typically will be 3-11, more preferably 5-9 and most preferably 7-8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts.
  • the prefened route of administration is by injection
  • other methods of administration are also anticipated such as orally, intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally, transdermally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • the compounds of this invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone mbber or other polymers commercially available.
  • the compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled.
  • the compounds of this invention may also be coupled with suitable polymers as targetable drug carriers.
  • suitable polymers can include polyvinylpynolidinone, pyran copolymer, polyhydroxy- propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • compounds of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a dmg, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
  • Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required.
  • the range of therapeutically effective dosages will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • the determination of effective dosage levels that is, the dosage levels necessary to achieve the desired result, will be readily determined by one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved.
  • the compounds of the invention can be administered orally or parenterally in an effective amount within the dosage range of about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg kg and more preferably about 1 to 20 mg/kg on a regimen in a single or 2 to 4 divided daily doses and/or continuous infusion.
  • a compound or mixture of compounds of this invention is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice.
  • a physiologically acceptable vehicle carrier, excipient, binder, preservative, stabilizer, dye, flavor etc.
  • the amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
  • Typical adjuvants which may be inco ⁇ orated into tablets, capsules and the like are binders such as acacia, com starch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents like com starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents.
  • binders such as acacia, com starch or gelatin
  • excipients such as microcrystalline cellulose, disintegrating agents like com starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents.
  • lubricants such as magnesium stearate
  • sweetening agents such as sucrose or lactose
  • flavoring agents such as sucrose or lactose
  • flavoring agents such as sucrose or lactose
  • a dosage form is a capsule, in addition to the above materials it may also contain
  • dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
  • a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the compounds of the present invention may be synthesized by either solid or liquid phase methods described and referenced in standard textbooks, or by a combination of both methods. These methods are well known in the art. See,
  • Bodanszky "The Principles of Peptide Synthesis", Hafner, et al, Eds., Springer- Nerlag, Berlin, 1984.
  • Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated.
  • Non-limiting exemplary synthesis schemes are outlined directly below, and specific steps are described in the Examples.
  • the reaction products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent.
  • the products may be further purified by column chromatography or other appropriate methods.
  • the compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification.
  • a number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of the structures recited above with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.
  • Diagnostic applications of the compounds of this invention will typically utilize formulations such as solution or suspension.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles.
  • Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy.
  • the dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize.
  • Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remingto 's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985).
  • Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinalpyrrohdinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.
  • buffers such as phosphate, citrate, acetate and other organic acid salts
  • antioxidants such as as
  • Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution.
  • the pH of the preparations of this invention typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts.
  • While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.
  • the compounds of this invention are desirably inco ⁇ orated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available.
  • the compounds of this invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled.
  • the compounds of this invention may also be coupled with suitable polymers as targetable drug carriers.
  • suitable polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy- propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the factor Xa inhibitors of this invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
  • Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
  • Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle.
  • Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required.
  • the range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the abso ⁇ tion efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
  • the determination of effective dosage levels that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art.
  • a typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0.10 mg/kg to about 20 mg/kg.
  • the compounds of this invention may be administered several times daily, and other dosage regimens may also be useful.
  • a compound or mixture of compounds of this invention is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice.
  • a physiologically acceptable vehicle carrier, excipient, binder, preservative, stabilizer, dye, flavor etc.
  • the amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
  • Typical adjuvants which may be inco ⁇ orated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent.
  • a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil.
  • Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice.
  • dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired.
  • a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome
  • Buffers, preservatives, antioxidants and the like can be inco ⁇ orated according to accepted pharmaceutical practice.
  • the compounds of this invention may be used alone or in combination, or in combination with other therapeutic or diagnostic agents.
  • the compounds of this inventions may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.
  • the compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.
  • the preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use. Conditions characterized by undesired thrombosis would include those involving the arterial and venous vasculature.
  • abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTC A).
  • abnormal thrombus formation characterizes the condition observed in patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from thrombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism.
  • Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure.
  • the compounds of this present invention are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post- thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi
  • Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • the compounds of this invention can be added to or contacted with any medium containing or suspected to contain factor Xa and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra co ⁇ oreal circulation systems and the like.
  • N-Boc-meta-cyano-phenylalanine 200 mg, 0.69 mmol
  • 4-[(2-tert- butylaminosulfonyl)phenyl]-aniline 210 mg, 0.69 mmol
  • DMF 3 mL
  • DIEA 0.24 mL, 1.4 mmol
  • PyBOP 572 mg, 1.1 mmol
  • reaction mixture was stirred at -78° C for 20 minutes after which a solution of 3-[2-(7H-l-pyrazolyl)acetyl]- benzonitrile (330mg, 1.56mmol) in 5ml anhydrous tetrahydrofuran was added dropwise over several minutes. Reaction was gradually allowed to warm to room temperature and strrred for 5 hours. Reaction was then quenched with a saturated ammonium chloride solution (10ml) and extracted with 2x25ml diethyl ether. Combined organic layers were washed with 2x25ml water, 2x25ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to a brown residue.
  • Part E ⁇ -[4-(2-aminosulfonylphenyl)phenyl]-3-(l-pyrazolylmethyl)-3-(3- amidinophenyl)-propionamide.
  • Example 21 Preparation of N- ⁇ 4-[(2-aminosulfonyl)phenyl]phenyl ⁇ -3-(3- amidinophenyl)- 3 -isopropylpropionamide.
  • Example 22 Preparation of N-[4-(2-aminosulfonylphenyl)phenyl]-2-hydroxyl-3- methylidenyl-3-(3-amidinophenyl)-propionamide and N-[4-(2- aminosulfonylphenyl)phenyl]-2,3-dihydroxyl-3-methyl-3-(3-amidinophenyl)- propionamide.
  • Example 23 Preparation of N-[4-(2-aminosulfonylphenyl)phenyl]-2-hydroxyl-3- methyl-3-chloro-3-(3-amidinophenyl)-propionamide and N-[4-(2- aminosulfonylphenyl)phenyl]-2-hydroxyl-3-methyl-3-methoxyl-3-(3- amidinophenyl)-propionamide.
  • [l,l'-biphenyl]-2-sulfonamide in 5 mL of anhydrous CH 2 C1 2 was added 0.5 mL of a 2.0 M solution of trimethylaluminum in hexanes, and the solution was stirced at room temperature for 30 minutes.
  • a solution of 103 mg of ethyl (Z)-3-(3- cyanophenyl)-2-methyl-2-butenoate in 5 mL of anhydrous CH 2 C1 2 was then added dropwise over a few minutes, and the reaction was stirred at room temperature overnight.
  • This compound was prepared by a procedure analogous to that for 6- bromoisoquinoline N-oxide hydrochloride as in PCT WO 98/47876.
  • a solution of 7.8 g (37.5 mmol) of a 60:40 mixture of 7-bromo and 5 -bromoisoquinoline in 125 mL of CH 2 C1 2 was treated portionwise with 9.1 g (-39.4 mmol) of 3- chloroperoxybenzoic acid (-70% purity).
  • the solution which was initially homogeneous, deposited a voluminous precipitate over 1 hr. Then 100 mL of methanol were added, and the reaction was concentrated to a volume of about 100 mL.
  • This compound was prepared by a procedure analogous to that for 6-bromo- 1-chloroisoquinoline as in PCT WO 98/47876.
  • a solution of 8.07 g (31 mmol) of the mixture from Part B was taken up in 50 mL of POCl 3 , and the mixture was heated at 90 °C for 2 hr.
  • the reaction mixture was concentrated to remove most of the POCl 3 , and the residue was taken up in 100 mL of CH 2 C1 2 .
  • the solution was carefully basified to pH 10 by the slow addition of IN NaOH, and the organic layer was washed with 100 mL of H 2 O, 100 mL of sat. NaCl, and dried over MgSO 4 .
  • reaction mixture was concentrated to give a dark oil, which was subjected to flash column chromatography on silica gel with 20% EtOAc in hexanes to give 736 mg of the desired product as a light yellow solid. Also isolated were 156 mg of product as a somewhat less pure light yellow solid, making the total yield 64%.
  • Example 30 Preparation of [5-(2-aminosulfonylphenyl)indolin-l-yl] 3-(3- amidinophenyl)-propionyl amide.
  • the crude product was dissolved in dry pyridine (5 mL) and TsCl (15.7 mg, 0.08 mmol) was added. The mixture was stined at 23 C for 5 minutes. The solvent of pyridine was removed in vacuo. The residue was dissolved in ethanolamine (5 mL). The mixture was stined at 23 C for 3 h before pouring into saturated NaCl solution for partition. The organic layers were collected and concentrated in vacuo to afford a yellow residue.
  • the compounds of the present invention are dissolved in buffer to give solutions containing concentrations such that assay concentrations range from 0 to
  • a synthetic chromogenic substrate is added to a solution containing test compound and the enzyme of interest and the residual catalytic activity of that enzyme is determined spectrophotometrically.
  • the IC50 of a compound is determined from the substrate turnover.
  • the IC50 is the concentration of test compound giving 50% inhibition of the substrate turnover.
  • the compounds of the present invention desirably have an IC50 of less than 500 nM in the factor Xa assay, preferably less than 200 nM, and more prefened compounds have an IC50 of about 100 nM or less in the factor Xa assay.
  • the compounds of the present invention desirably have an IC50 of less than
  • 4.0 ⁇ M in the prothrombinase assay preferably less than 200 nM, and more prefened compounds have an IC50 of about 10 nM or less in the prothrombinase assay.
  • the compounds of the present invention desirably have an IC50 of greater than 1.0 ⁇ M in the thrombin assay, preferably greater than 10.0 ⁇ M, and more prefened compounds have an IC50 of greater than 100.0 ⁇ M in the thrombin assay.
  • the factor Xa and thrombin assays are performed at room temperature, in 0.02 M Tris-HCl buffer, pH 7.5, containing 0.15 M NaCl.
  • the prothrombinase inhibition assay is performed in a plasma free system with modifications to the method described by Sinha, U. et al., Thromb. Res., 75, 427-436 (1994). Specifically, the activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p- nitroanilide substrate Chromozym TH.
  • the assay consists of preincubation ( 5 minutes) of selected compounds to be tested as inhibitors with the complex formed from factor Xa (0.5 nM), factor Va (2 nM), phosphatidyl serine:phosphatidyl choline (25:75, 20 ⁇ M) in 20 mM Tris-HCl buffer, pH 7.5, containing 0.15 M NaCl, 5 mM CaCl2 and 0.1% bovine serum albumin. Aliquots from the complex-inhibitor mixture are added to prothrombin (1 nM) and Chromozym TH (0.1 mM). The rate of substrate cleavage is monitored at 405 nm for two minutes. Eight different concentrations of inhibitor are assayed in duplicate. A standard curve of thrombin generation by an equivalent amount of untreated complex are used for determination of percent inhibition.
  • Rabbits are anesthetized with I.M. injections of Ketamine, Xylazine, and Acepromazine cocktail.
  • a standardized protocol consists of insertion of a thrombogenic cotton thread and copper wire apparatus into the abdominal vena cava of the anesthetized rabbit.
  • a non-occlusive thrombus is allowed to develop in the central venous circulation and inhibition of thrombus growth is used as a measure of the antithrombotic activity of the studied compounds.
  • Test agents or control saline are administered through a marginal ear vein catheter.
  • a femoral vein catheter is used for blood sampling prior to and during steady state infusion of test compound.
  • Initiation of thrombus formation begins immediately after advancement of the cotton thread apparatus into the central venous circulation.
  • the rabbits are euthanized and the thrombus excised by surgical dissection and characterized by weight and histology. Blood samples are analyzed for changes in hematological and coagulation parameters.

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Abstract

L'invention concerne des composés représentés par la formule générale A-Y-D-E-G-J-Z-L, dans laquelle A-Y-D-E-G-J-Z et L sont tels que définis dans l'invention. Ces composés sont actifs contre le facteur Xa mammalien. Ils sont utilisés in vitro et in vivo pour prévenir ou traiter les troubles de la coagulation.
PCT/US2000/014207 1999-05-24 2000-05-24 Inhibiteurs du facteur xa WO2000071512A1 (fr)

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WO2002024654A1 (fr) * 2000-09-19 2002-03-28 Merck Patent Gmbh Composes amino-heterocycliques (inhibiteurs 14 du facteur xa)
WO2001070678A3 (fr) * 2000-03-24 2002-04-04 Merck Patent Gmbh Derives de biphenyle substitues
WO2002083630A1 (fr) * 2001-04-10 2002-10-24 Merck Patent Gmbh Derives d'acide oxalique
WO2003013531A1 (fr) 2001-08-08 2003-02-20 Merck Patent Gmbh Derives de phenyle en tant qu'inhibiteurs du facteur xa
WO2003101942A1 (fr) * 2001-05-22 2003-12-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives aryle et heteroaryle substitues par un groupe amidine, ces derives possedant une action antithrombotique et une action inhibitrice sur le facteur xa
US6825181B1 (en) 1998-03-19 2004-11-30 Ajinomoto Co., Inc. Aminoisoquinoline derivatives
US7005437B2 (en) 2001-05-22 2006-02-28 Boehringer Ingelheim Pharma Kg Substituted aryl and heteroaryl derivatives, the preparation thereof and the use therof as pharmaceutical compositions
US7326791B2 (en) 2002-12-19 2008-02-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg Carboxylic acid amides, the preparation thereof, and their use as pharmaceutical compositions
US7371743B2 (en) 2004-02-28 2008-05-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
US7429604B2 (en) 2004-06-15 2008-09-30 Bristol Myers Squibb Company Six-membered heterocycles useful as serine protease inhibitors
US7964732B2 (en) 2006-11-17 2011-06-21 Pfizer Inc. Substituted bicyclocarboxyamide compounds
US8772293B2 (en) 2010-07-09 2014-07-08 Pfizer Limited Chemical compounds
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WO2003042190A1 (fr) 2001-11-12 2003-05-22 Pfizer Products Inc. Derives de n-adamantylalkyle benzamide en tant qu'antagonistes du recepteur p2x7
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Publication number Priority date Publication date Assignee Title
US6825181B1 (en) 1998-03-19 2004-11-30 Ajinomoto Co., Inc. Aminoisoquinoline derivatives
WO2001062717A1 (fr) * 2000-02-23 2001-08-30 Merck Patent Gmbh Derives d'aminosulfonylbiphenyle
WO2001070678A3 (fr) * 2000-03-24 2002-04-04 Merck Patent Gmbh Derives de biphenyle substitues
US6946489B2 (en) 2000-03-24 2005-09-20 Merck Patent Gmbh Substituted biphenyl derivatives
WO2002024654A1 (fr) * 2000-09-19 2002-03-28 Merck Patent Gmbh Composes amino-heterocycliques (inhibiteurs 14 du facteur xa)
WO2002083630A1 (fr) * 2001-04-10 2002-10-24 Merck Patent Gmbh Derives d'acide oxalique
US7005437B2 (en) 2001-05-22 2006-02-28 Boehringer Ingelheim Pharma Kg Substituted aryl and heteroaryl derivatives, the preparation thereof and the use therof as pharmaceutical compositions
WO2003101942A1 (fr) * 2001-05-22 2003-12-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Derives aryle et heteroaryle substitues par un groupe amidine, ces derives possedant une action antithrombotique et une action inhibitrice sur le facteur xa
WO2003013531A1 (fr) 2001-08-08 2003-02-20 Merck Patent Gmbh Derives de phenyle en tant qu'inhibiteurs du facteur xa
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques
US7326791B2 (en) 2002-12-19 2008-02-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg Carboxylic acid amides, the preparation thereof, and their use as pharmaceutical compositions
US7371743B2 (en) 2004-02-28 2008-05-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
US7947700B2 (en) 2004-02-28 2011-05-24 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
US8445525B2 (en) 2004-02-28 2013-05-21 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
US8791103B2 (en) 2004-02-28 2014-07-29 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
US7429604B2 (en) 2004-06-15 2008-09-30 Bristol Myers Squibb Company Six-membered heterocycles useful as serine protease inhibitors
US7964732B2 (en) 2006-11-17 2011-06-21 Pfizer Inc. Substituted bicyclocarboxyamide compounds
US8772293B2 (en) 2010-07-09 2014-07-08 Pfizer Limited Chemical compounds

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