HUE025683T2 - VIIA faktor inhibitor 2-(2-hidroxi-bifenil-3-il)-1H-benzoimidazol-5-karboxamidin-származékok - Google Patents

VIIA faktor inhibitor 2-(2-hidroxi-bifenil-3-il)-1H-benzoimidazol-5-karboxamidin-származékok Download PDF

Info

Publication number
HUE025683T2
HUE025683T2 HUE03810056A HUE03810056A HUE025683T2 HU E025683 T2 HUE025683 T2 HU E025683T2 HU E03810056 A HUE03810056 A HU E03810056A HU E03810056 A HUE03810056 A HU E03810056A HU E025683 T2 HUE025683 T2 HU E025683T2
Authority
HU
Hungary
Prior art keywords
alkyl
group
hydrogen
heteroaryl
alkylene
Prior art date
Application number
HUE03810056A
Other languages
English (en)
Inventor
Aleksandr Kolesnikov
Roopa Rai
William Dvorak Shrader
Steven M Torkelson
Kieron E Wesson
Wendy B Young
Original Assignee
Pharmacyclics Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacyclics Llc filed Critical Pharmacyclics Llc
Publication of HUE025683T2 publication Critical patent/HUE025683T2/hu

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/094—Esters of phosphoric acids with arylalkanols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65128—Six-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Diabetes (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Neurosurgery (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Description
BACKGROUND OF THE INVENTION
Field of invention [0001] The present invention relates to novel inhibitors of Factors Vila, IXa, Xa, Xla, in particular Factor Vila, pharmaceutical compositions comprising these inhibitors, and methods for using these inhibitors for treating or preventing thromboembolic disorders. Processes for preparing these inhibitors are also disclosed. The invention is directed to the scope of the subject-matter as defined in the claims.
State of the Art [0002] Thrombosis results from a complex sequence of biochemical events, known as the coagulation cascade. A triggering event in coagulation is the binding of the serine protease Factor Vila (FVIIa) found in the circulation, to tissue factor (TF), a receptor which is found on the surface of blood vessels after damage or inflammation. Once bound to TF, Factor Vila catalyzes the formation of the serine protease Factor Xa, which subsequently forms the final protease in the cascade, thrombin.
[0003] The clinical manifestations of thrombosis range from acute myocardial infarction (AMI or heart attack) and unstable angina (UA) which occur in the key blood vessels of the heart (coronary vasculature) to deep vein thrombosis (DVT) which is the formation of blood clots in lower extremities which often follows orthopedic surgery on the hip and knee, as well as general abdominal surgery and paralysis. Formation of DVT is a risk factor for the development of pulmonary embolism (PE) in which part of a blood clot formed in the lower extremities, breaks off and travels to the lung where it blocks the flow of blood. The unpredictable development of PE often leads to a fatal outcome. Thrombosis can also be generalized systemically, with microclot formation occurring throughout the vascular system. This condition, known as disseminated intravascular coagulation (DIC), can be a consequence of certain viral diseases such as Ebola, certain cancers, sepsis and rheumatoid arthritis. Severe DIC can lead to a dramatic reduction in the coagulation factors due to the excessive activation of the clotting response which may result in multiple organ failure, hemorrhage and death.
[0004] The formation or embolization of blood clots in the blood vessels of the brain is the key event resulting in ischemic stroke. Triggering factors that lead to stroke are atrial fibrillation or abnormal rhythm of the atria of the heart and atherosclerosis followed by thrombosis in the main artery leading from the heart to the brain (carotid artery). Over 600,000 individuals suffer strokes each year in the U.S. Two-thirds of these stroke victims suffer some disability, and one-third suffer permanent and severe disability. Accordingly, there is a need for antithrombotic agents for the treatment of a variety of thrombotic conditions. The present invention fulfills this and related needs.
SUMMARY OF THE INVENTION
[0005] 1. In one aspect this invention is directed to a compound of Formula I:
Formula I wherein: X1 is -N- or -CR5 - wherein R5 is hydrogen, alkyl, or halo; R1 is hydrogen, alkyl, halo, carboxy or aminocarbonyl; R2 is hydrogen, alkyl, or halo; R3 is -CONR7R8, (where R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phospho-noalkyl; and R8 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylamino-carbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino), or -(alkylene)-CONR9R10 (where R9 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyl; and R10 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylaminocarbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R9 and R10 together with the nitrogen atom to which they are attached form heterocycloalkylamino);
Rx is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl, alkoxy, aminosulfonyl, alkylaminosulfonyl, di-alkylaminosulfonyl, or nitro;
Ry is hydrogen, alkyl, or halo;
Rz is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, het-eroarylsulfonyl, carbamimidoyl, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfo-nylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hydroxy-alkoxyalkylaminocarbonyl, heterocycloalkyIcarbonyl, heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocy-cloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido, alkylureido, di-alkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, -COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -(alkylene)-COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -CONR14R15 (where R14 is hydrogen or alkyl; and R15 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R14 and R15 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-CONR16R17 (where R16 is hydrogen, alkyl or hydroxyalkyl; and R17 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R16 and R17 together with the nitrogen atom to which they are attached from heterocycloamino), -NR18R19 (where R18 is hydrogen or alkyl; and R19 is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR20R21 (where R20 is hydrogen, alkyl, or hydroxyalkyl; and R21 is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), - S02NR22R23 (where R22 is hydrogen or alkyl; and R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R22 and R23 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-S02NR24R25 (where R24 is hydrogen or alkyl; and R25 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R24 and R25 together with the nitrogen atom to which they are attached from heterocycloamino), -NR26S02NR27R28 (where R26 and R27 are independently hydrogen or alkyl; and R28 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R27 and R28 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-NR29SO2NR30R31 (where R29 and R30 are independently hydrogen or alkyl; and R31 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R30 and R31 together with the nitrogen atom to which they are attached from heterocycloamino), -CONH-(alkylene)-NR32R33 (where R32 is hydrogen or alkyl; and R33 is alkyl), or aralkyl; and R13 is hydrogen, hydroxy, (C.|_10)alkoxy, -C(0)R35 (where R35 is alkyl, aryl, haloalkyl, or cyanoalkyl), or -C(0)0R36 (where R36 is alkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyl, aryl, or haloalkyl); or individual steroisomer, mixture of steroisomers, or a pharmaceutically acceptable salt thereof, provided that when R3 is -CONR7R8 (where R7 is hydrogen or alkyl; and R8 is hydrogen or alkyl), -(alkylene)-CONR9R10 (where R9 and R10 together with the nitrogen atom to which they are attached form pyrrolidinyl), and Rz is hydrogen, alkyl, haloalkyl, halo, nitro, alkoxy, haloalkyl, carboxy, alkoxycarbonyl, -NR19R19 (where R18 is hydrogen or alkyl; and R19 is hydrogen, alkyl, aryl or aralkyl), pyrrolidinylcarbonyl, -S02NR22R23 (where R22 and R23 are alkyl), carbamimidoyl, alkylsulfonylamino, alkylthio, ureido, -NHC(S)NH2 or heterocycloamino, then Rx is hydroxy or hydroxyalkyl; wherein alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms; alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms; alkylthio means a radical -SR where R is alkyl; amino means the radical -NRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; acyl means a radical -COR’ where R’ is alkyl, alkoxy, haloalkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; aminosulfonyl means a radical -S02NH2; alkylaminosulfonyl means a radical -S02NHR where R is alkyl; alkylsulfonyl means a radical -S02R where R is alkyl; alkylsulfonylalkyl means a radical -(alkylene)-S02R where R is alkyl; alkylsulfonylamino means a radical -NHS02R where R is alkyl; alkylsulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkyl; alkoxysulfonylamino means a radical -NHS02R where R is alkoxy; alkoxysulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkoxy; alkoxy means a radical -OR where R is alkyl; alkoxycarbonyl means a radical -COOR where R is alkyl; alkoxycarbonylalkyl means a radical -(alkylene)-COOR where R is alkyl; alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group; aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one -NRR’ where R and R’ are independently hydrogen, alkyl, or-CORa where Ra is alkyl; aminocarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -NRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylcarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -CONRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two -CONRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; alkoxyalkyloxy means a radical -OR where R is alkoxyalkyl; aminoalkyloxy means a radical -OR where R is aminoalkyl; aminocarbonyl means a radical -CONH2; aminocarbonylalkyloxy means a radical - O-alkylene-CONRR’ where R and R’ are independently hydrogen or alkyl; aminocarbonylalkyl means a radical -(alkylene)-CONH2; alkylureido means a radical-NRCONHR’ where R is hydrogen or alkyl and R’ is alkyl; alkylureidoalkyl means a radical -(alkylene)-NRCONHR’ where R is hydrogen or alkyl and R’ is alky; aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents, selected from alkyl, haloalkyl, alkoxy, alkylthio, halo, nitro, -COR (where R is alkyl), cyano, amino, alkylamino, dialkylamino, hydroxy, carboxy, or-COOR where R is alkyl; arylsulfonyl means a radical -S02R where R is aryl; aralkyl means a radical - (alkylene)-R where R is an aryl group; alkoxycarbamimidoyl means a radical -C(=NH)NHOR or-C(=NOR)NH2 where R is alkyl; cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms; carboxyalkyl means a radical -(alkylene)-COOH; carboxyalkyloxy means a radical -0-(alkylene)-C00H; carbamimidoyl means a radical - C(=NH)NH2; cyanoalkyl means a radical -(alkylene)-CN; diatkylaminosulfonyl means a radical - S02NRR’ where R and R’ are independently alkyl; dialkylureido means a radical -NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; dialkylureidoalkyl means a radical -(alkylene)-NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; guanidinoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms ora branched monovalent hydrocarbon radical of three to six carbons substituted with at least one -NRC(NRR’)NRR’ where R and R’ are independently hydrogen, alkyl, or -CORawhere Ra is alkyl; halo means fluoro, chloro, bromo, and iodo; haloalkyl means alkyl substituted with one or more halogen atoms; haloalkoxy means a radical -OR where R is haloalkyl; hydroxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one to five hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom; hydroxyalkyloxy means a radical -OR where R is hydroxyalkyl; hydroxyalkoxyalkylaminocarbonyl means a radical -0ONH-(alkylene)-O-(alkylene)OH; heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C; heterocycloalkylcarbonyl means a radical -COR where R is heterocycloalkyl; heterocycloalkylcarbonylalkyl means a radical -(alkylene)-COR where R is heterocycloalkyl; heterocycloalkylalkyl means a radical -(alkylene)-R where R is heterocycloalkyl; heterocycloalkylalkylaminocarbonyl means a radical -CONH-(alkylene)-R where R is heterocycloalkyl; heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being carbon, the heteroaryl ring being optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, guanidinoalkyl, halo, nitro, cyano, amino, alkyl or dialkylamino, hydroxy, carboxy, or-COOR where R is alkyl; heteroarylsulfonyl means a radical -S02R where R is heteroaryl; heteroaralkyl means a radical -(alkylene)-R where R is a heteroaryl; heterocycloamino means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C provided that at least one of the heteroatom is nitrogen and wherein one or two carbon atoms are optionally replace by a carbonyl group, the heterocycloamino ring being optionally substituted with one or more substituents independently selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo, cyano, carboxy, -CONRaRb (where Ra and Rb are independently hydrogen or alkyl), or -COOR where R is alkyl; hydroxycarbamimidoyl means a radical -C(=NH)NHOH or-C(=NOH)NH2. 2. Optionally, wherein: R3 is -CONR7R8 (where R7 is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl; and R8 is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH2CH2)nRb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl, aminocarbo-nylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl, hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonio-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or hetereocycloalkylalkyl; or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino), or-(alkylene)-CONR9R10 (where R9 is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl; and R10 is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH2CH2)nRb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl, aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl, hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl; or R9 and R10 together with the nitrogen atom to which they are attached form heterocycloalkylamino), wherein any rings comprising R3 are optionally substituted with one to six groups independently selected from hydroxy, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminoalkyl, guanidinoalkyl, alkyl or -CONRaRb (where Ra and Rb are independently hydrogen or alkyl); and Rz is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, het-eroarylsulfonyl, carbamimidoyl, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfo-nylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hydroxy-alkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido, alkylureido, di-alkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, -COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -(alkylene)-COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -CONR14R15 (where R14 is hydrogen or alkyl; and R15 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R14 and R15 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-CONR16R17 (where R16 is hydrogen, alkyl or hydroxyalkyl; and R17 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R16 and R17 together with the nitrogen atom to which they are attached from heterocycloamino), -NR18R19 (where R18 is hydrogen or alkyl; and R19 is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR20R21 (where R20 is hydrogen, alkyl, or hydroxyalkyl; and R21 is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl),-S02NR22R23 (where R22is hydrogen or alkyl; and R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R22 and R23 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-S02NR24R25 (where R24 is hydrogen or alkyl; and R25 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R24 and R25 together with the nitrogen atom to which they are attached from heterocycloamino), -NR26S02NR27R28 (where R26 and R27 are independently hydrogen or alkyl; and R28 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R27 and R28 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-NR29SO2NR30R31 (where R29 and R30 are independently hydrogen or alkyl; and R31 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R30 and R31 together with the nitrogen atom to which they are attached from heterocycloamino), -CONH-(alkylene)-NR32R33 (where R32 is hydrogen or alkyl; and R33 is alkyl), or aralkyl; and R13 is hydrogen, hydroxy, (C^^Jalkoxy, -C(0)R35 (where R35 is alkyl, aryl, haloalkyl, or cyanoalkyl), or -C(0)0R36 (where R36 is alkyl, hydroxyalkyl, acyl, or haloalkyl); or a pharmaceutically acceptable salt thereof. 3. In one aspect this invention is directed to a compound of Formula la wherein:
Formula la R3 is -CONR7R8, -CH2CONR9R10 or -C(CH3)2CONR9R10 ; R7 is hydrogen or methyl; R9 is hydrogen or methyl; R8 is aminocarbonylmethyl, 1,2-diaminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carbox-ypentyl, 2-carboxyethyl, carboxymethyl, 2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminome-thyl, 3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethyl-ethyl, 2-hydroxy-1-hydroxymethylethyl, 1,2-di-carboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl, 2-sulfoethyl, 3,4,5,6-tetrahydroxytetrahydro-pyran-2-ylmethyl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahy-dro-pyran-3-ylcarbamoyl-methyl, trimethylammonioethyl or 2-phosphonoethyl; R10 is aminocarbonylmethyl, 1,2-diaminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carbox-ypentyl, 2-carboxyethyl, carboxymethyl, 2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminome-thyl, 3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethyl-ethyl, 2-hydroxy-1-hydroxymethylethyl, 1,2-di-carboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl, 2-sulfoethyl, 3,4,5,6-tetrahydroxytetrahydro-pyran-2-ylmethyl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahy-dro-pyran-3-ylcarbamoyl-methyl, trimethylammonioethyl or 2-phosphonoethyl;
Rz is aminosulfonyl or ureidomethyl; and R13 is hydrogen; or a pharmaceutically acceptable salt thereof. 4. Optionally, wherein: R3 is -CONR7R8, -CH2CONR9R10 or -C(CH3)CONR9R10 ; R7 is hydrogen; R9 is hydrogen; R8 is aminocarbonylmethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, or 1,2-dicarboxyethyl; R10 is aminocarbonylmethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, or 1,2-dicarboxyethyl; and Rz is aminosulfonyl; or a pharmaceutically acceptable salt thereof. 5. Optionally, wherein the compound of Formula la is: {2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-suc-cinic acid, or a pharmaceutically acceptable salt thereof. 6. In one aspect, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any of paragraph 1. to 5. above, or a pharmaceutically acceptable salt thereof. 7. In one aspect, the present invention is directed to the use of a therapeutically effective amount of the compound of any one of paragraphs 1. to 6., or a pharmaceutically acceptable salt thereof, to manufacture a medicament for use in a method of treating a disease in an animal mediated by Factor Vila. 8. Optionally, wherein the disorder is a thromboembolic disorder. 9. In one aspect, the present invention is directed to the use of the compound of any one of paragraphs 1. to 5., or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a thromboembolic disorder, wherein the medicament is to be used with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a factor IXa, a factor Xa inhibitor, Aspirin®, and Plavis®. 10. In one aspect, the present invention is directed to the compound of claim any one of paragraphs 1. to 5., or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease in an animal mediated by Factor Vila. 11. Optionally, wherein the disorder is a thromboembolic disorder. 12. In one aspect, the present invention is directed to the compound of any one of paragraphs 1. to 5., or a pharmaceutically acceptable salt thereof, for use in treating a thromboembolic disorder, wherein the compound is to be administered in combination with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a factor IXa, a factor Xa inhibitor, Aspirin®, and Plavis®. 13. In one aspect, the present invention is directed to a method of inhibiting the coagulation of a biological sample in vitro comprising the administration of a compound of any one of paragraphs 1. to 5., or a pharmaceutically acceptable salt thereof. 14. In one aspect, the present invention is directed to a process of preparing a compound of paragraph 1 where X1 is -N- comprising reacting a compound of Formula II:
Formula II with a compound of Formula III:
Formula III wherein: R3 is -CONR7R8, (where R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phospho-noalkyl; and R8 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylamino-carbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino), or -(alkylene)-CONR9R10 (where R9 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyl; and R10 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, ami-nocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylaminocarbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R9 and R10 together with the nitrogen atom to which they are attached form heterocycloalkylamino); and
Rz is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkoxyloxy, aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, car-boxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfo-nyl, heteroarylsulfonyl, carbamimidoyl, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkyl-sulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hy-droxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl, heterocycloalkyl, het-erocycloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, -COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -(alkylene)-COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -CONR14R15 (where R14 is hydrogen or alkyl; and R15 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-CONR16R17 (where R16 is hydrogen, alkyl or hydroxyalkyl; and R17 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -NR18R19 (where R18 is hydrogen oralkyl; and R19 is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR20R21 (where R20 is hydrogen, alkyl, or hydroxyalkyl; and R21 is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), - S02NR22R23 (where R22 is hydrogen or alkyl; and R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R22 and R23 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-S02NR24R25 (where R24 is hydrogen or alkyl; and R25 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R24 and R25 together with the nitrogen atom to which they are attached from heterocycloamino), -NR26S02NR27R28 (where R26 and R27 are independently hydrogen or alkyl; and R28 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R27 and R28 together with the nitrogen atom to which they are attached from heterocycloam-inO),-(alkylene)-NR29SO2NR30R31 (where R29and R30are independently hydrogen or alkyl; and R31 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R30 and R31 together with the nitrogen atom to which they are attached from heterocycloamino), -CONH-(alkylene)-NR32R33 (where R32 is hydrogen or alkyl; and R33 is alkyl), or aralkyl; and R13 is hydrogen; (i) optionally modifying any of the R1, R2, R3, Rx, Ry, Rz, and R13 groups; (ii) optionally isolating individual steroisomers; (iii) optionally preparing an acid addition salt; and (iv) optionally preparing a free base; wherein alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms ora branched saturated monovalent hydrocarbon radical of three to six carbon atoms; alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms; alkylthio means a radical -SR where R is alkyl; amino means the radical -NRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; acyl means a radical -COR’ where R’ is alkyl, alkoxy, haloalkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; aminosulfonyl means a radical -S02NH2; alkylaminosulfonyl means a radical -S02NHR where R is alkyl; alkylsulfonyl means a radical -S02R where R is alkyl; alkylsulfonylalkyl means a radical -(alkylene)-S02R where R is alkyl; alkylsulfonylamino means a radical -NHS02R where R is alkyl; alkylsulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkyl; alkoxysulfonylamino means a radical -NHS02R where R is alkoxy; alkoxysulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkoxy; alkoxy means a radical -OR where R is alkyl; alkoxycarbonyl means a radical -COOR where R is alkyl; alkoxycarbonylalkyl means a radical -(alkylene)-COOR where R is alkyl; alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group; aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydro carbon radical of three to six carbons substituted with at least one -NRR’ where R and R’ are independently hydrogen, alkyl, or-CORa where Ra is alkyl; aminocarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -NRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylcarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -CONRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two -CONRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; alkoxyalkyloxy means a radical -OR where R is alkoxyalkyl; aminoalkyloxy means a radical -OR where R is aminoalkyl; aminocarbonyl means a radical -CONH2; aminocarbonylalkyloxy means a radical - O-alkylene-CONRR’ where R and R’ are independently hydrogen or alkyl; aminocarbonylalkyl means a radical -(alkylene)-CONH2; alkylureido means a radical -NRCONHR’ where R is hydrogen or alkyl and R’ is alkyl; alkylureidoalkyl means a radical -(alkylene)-NRCONHR’ where R is hydrogen or alkyl and R’ is alky; aryl means a monovalent monocyclicor bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents, selected from alkyl, haloalkyl, alkoxy, alkylthio, halo, nitro, -COR (where R is alkyl), cyano, amino, alkylamino, dialkylamino, hydroxy, carboxy, or-COOR where R is alkyl; arylsulfonyl means a radical -S02R where R is aryl; aralkyl means a radical - (alkylene)-R where R is an aryl group; alkoxycarbamimidoyl means a radical -C(=NH)NHOR or-C(=NOR)NH2 where R is alkyl; cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms; carboxyalkyl means a radical -(alkylene)-COOH; carboxyalkyloxy means a radical -0-(alkylene)-C00H; carbamimidoyl means a radical - C(=NH)NH2; cyanoalkyl means a radical -(alkylene)-CN; dialkylaminosulfonyl means a radical - S02NRR’ where R and R’ are independently alkyl; dialkylureido means a radical -NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; dialkylureidoalkyl means a radical -(alkylene)-NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; guanidinoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one -NRC(NRR’)NRR’ where R and R’ are independently hydrogen, alkyl, or -CORawhere Ra is alkyl; halo means fluoro, chloro, bromo, and iodo; haloalkyl means alkyl substituted with one or more halogen atoms; haloalkoxy means a radical -OR where R is haloalkyl; hydroxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one to five hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom; hydroxyalkyloxy means a radical -OR where R is hydroxyalkyl; hydroxyalkoxyalkylaminocarbonyl means a radical -CONH-(alkylene)-0-(alkylene)OH; heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C; heterocycloalkylcarbonyl means a radical -COR where R is heterocycloalkyl; heterocycloalkylcarbonylalkyl means a radical -(alkylene)-COR where R is heterocycloalkyl; heterocycloalkylalkyl means a radical -(alkylene)-R where R is heterocycloalkyl; heterocycloalkylalkylaminocarbonyl means a radical -CONH-(alkylene)-R where R is heterocycloalkyl; heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being carbon, the heteroaryl ring being optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, guanidinoalkyl, halo, nitro, cyano, amino, alkyl or dialkylamino, hydroxy, carboxy, or -COOR where R is alkyl; heteroarylsulfonyl means a radical -S02R where R is heteroaryl; heteroaralkyl means a radical -(alkylene)-R where R is a heteroaryl; heterocycloamino means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C provided that at least one of the heteroatom is nitrogen and wherein one or two carbon atoms are optionally replace by a carbonyl group, the heterocycloamino ring being optionally substituted with one or more substituents independently selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo, cyano, carboxy, -CONRaRb (where Ra and Rb are independently hydrogen or alkyl), or -COOR where R is alkyl; hydroxycarbamimidoyl means a radical -C(=NH)NHOH or-C(=NOH)NH2.
DETAILED DESCRIPTION OF THE INVENTION
Definitions [0006] The following terms, as used in the present specification and claims, are intended to have the meanings as defined below, unless indicated otherwise or used in naming a compound.
[0007] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), and pentyl (including all isomeric forms).
[0008] "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms e.g., methylene, ethylene, propylene, 1-methylpro-pylene, 2-methylpropylene, butylene, and pentylene.
[0009] "Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms containing one or two double bonds e.g., ethenylene, prope-nylene, and 2-methylpropenylene.
[0010] "Alkylthio" means a radical-SR where R is alkyl as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), and butylthio (including all isomeric forms).
[0011] "Amino" means the radical-NRR’where R and R’ are independently hydrogen, alkyl, or-CORawhere Ra is alkyl, e.g., -NH2, methylaminoethyl, 1,3-diaminopropyl, and acetylaminopropyl.
[0012] "Acyl" means a radical -COR’ where R’ is alkyl, alkoxy, haloalkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl as defined herein, e.g., acetyl, trifluoroacetyl, and hydroxymethylcarbonyl.
[0013] "Aminosulfonyl" or "sulfamoyl" means a radical -S02NH2.
[0014] "Alkylaminosulfonyl" means a radical -S02NHR where R is alkyl as defined above, e.g., methylaminosulfonyl, and ethylamino-sulfonyl.
[0015] "Alkylsulfonyl" means a radical -S02R where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and n- or /'so-propylsulfonyl.
[0016] "Alkylsulfonylalkyl" means a radical -(alkylene)-S02R where R is alkyl as defined above, e.g., methylsulfonyl-methyl, ethylsulfonylmethyl, and n- or/so-propylsulfonylethyl.
[0017] "Alkylsulfonylamino" means a radical -NHS02R where R is alkyl as defined above, e.g., methylsulfonylamino, ethylsulfonylamino, and n-or /so-propylsulfonylamino.
[0018] "Alkylsulfonylaminoalkyl" means a radical -(alkylene)-NHS02R where R is alkyl as defined above, e.g., meth-ylsulfonylaminomethyl, ethylsulfonylaminomethyl, and n- or /so-propylsulfonylaminoethyl.
[0019] "Alkoxysulfonylamino" means a radical -NHS02R where R is alkoxy as defined herein, e.g., methoxysulfo-nylamino, and ethoxysulfonylamino.
[0020] "Alkoxysulfonylaminoalkyl" means a radical -(aikyiene)-NHS02R where R is alkoxy as defined herein, e.g., methoxysulfonylaminomethyl, and ethoxysulfonylaminomethyl.
[0021] "Alkoxy" means a radical -OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or2-propoxy, η-, iso-, or ferf-butoxy.
[0022] "Alkoxycarbonyl" means a radical -COOR where R is alkyl as defined above, e.g., methoxycarbonyl and ethox-ycarbonyl.
[0023] "Alkoxycarbonylalkyl" means a radical -(alkylene)-COOR where R is alkyl as defined above, e.g., methoxycar-bonylmethyl, and ethoxycarbonylmethyl.
[0024] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, preferably one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, and 2-ethoxyethyl.
[0025] "Aminoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl, e.g., amino methyl, methylaminoethyl, 1,3-diaminopropyl, and acetylaminopropyl.
[0026] "Aminocarboxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -NRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or-CORa where Ra is alkyl, e.g., 1-amino-1-carboxypentyl.
[0027] "Aminocarbonylcarboxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -CONRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORawhere Ra is alkyl, e.g., 1-aminocarbonyl-1-carboxypentyl.
[0028] "Aminocarbonylalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atomsora branched monovalent hydrocarbon radical of three to six carbons substituted with one or two -CONRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl, e.g., aminocarbonylmethyl, methylaminocarbonylmethyl, and acetylaminocarbonylpropyl.
[0029] "Alkoxyalkyloxy" means a radical -OR where R is alkoxyalkyl, as defined above, e.g., 2-methoxyethyloxy, 1-, 2-, or 3-methoxypropyloxy, and 2-ethoxyethyloxy.
[0030] "Aminoalkyloxy" means a radical -OR where R is aminoalkyl, as defined above, e.g., 2-aminoethyloxy, 1-, 2-, or 3-methylaminopropyloxy.
[0031] "Aminocarbonyl" or "carbamoyl" means a radical -CONH2.
[0032] "Aminocarbonylalkyloxy" means a radical -O-alkylene-CONRR" where R and R’ are independently hydrogen or alkyl, as defined above, e.g., 2-aminocarbonylethyloxy, and aminocarbonylmethyloxy.
[0033] "Aminocarbonylalkyl" means a radical -(alkylene)-CONH2, e.g., aminocarbonylmethyl, aminocarbonylethyl, 1-, 2- , or 3-aminocarbonylpropyl.
[0034] "Alkylureido" means a radical -NRCONHR’where R is hydrogen or alkyl and R’ is alkyl, e.g., methylureidomethyl.
[0035] "Alkylureidoalkyl" means a radical -(alkylene)-NRCONHR’ where R is hydrogen or alkyl and R’ is alkyl, e.g., methylureidomethyl.
[0036] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents, preferably one, two, or three substituents, selected from alkyl, haloalkyl, alkoxy, alkylthio, halo, nitro, - COR (where R is alkyl), cyano, amino, alkylamino, dialkylamino, hydroxy, carboxy, or-COOR where R is alkyl. Representative examples include, but are not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl and the derivatives thereof.
[0037] "Arylsulfonyl" means a radical -S02R where R is aryl as defined above, e.g., phenylsulfonyl.
[0038] "Aralkyl" means a radical -(alkylene)-R where R is an aryl group as defined above e.g., benzyl, phenylethyl, 3- (3-chlorophenyl)-2-methylpentyl.
[0039] "Alkoxycarbamimidoyl" means a radical -C(=NH)NHOR or -C(=NOR)NH2 where R is alkyl as defined above, e.g., methoxycarbamimidoyl.
[0040] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., cyclopropyl, cyclobutyl, preferably cyclopropyl.
[0041] "Carboxyalkyl"meansa radical-(alkylene)-COOH, e.g., carboxymethyl, carboxyethyl, 1-,2-,or3-carboxypropyl.
[0042] "Carboxyalkyloxy" means a radical -0-(alkylene)-COOH, e.g., carboxymethyloxy, carboxyethyloxy.
[0043] "carbamimidoyl" means a radical -C(=NH)NH2, or a protected derivative thereof.
[0044] "Cyanoalkyl" means a radical -(alkylene)-CN, e.g., cyanomethyl, cyanoethyl, cyanopropyl.
[0045] "Dialkylaminosulfonyl" means a radical -S02NRR’ where R and R’ are independently alkyl as defined above, e.g., dimethylaminosulfonyl or methylethylamino-sulfonyl.
[0046] "Dialkylureido" means a radical -NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl, e.g., dimethylureido.
[0047] "Dialkylureidoalkyl" means a radical -(alkylene)-NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl, e.g., dimethylureidomethyl.
[0048] "Guanidinoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -NRC(NRR’)NRR’ where R and R’ are independently hydrogen, alkyl, or-CORa where Ra is alkyl, e.g., guanidinomethyl, N’-methylaminoethyl, 2-(A/’,/V’,/\/",/\/"-tetramethyl-guanidino)-ethyl.
[0049] "Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
[0050] "Haloalkyl" means alkyl substituted with one or more halogen atoms, preferably one to three halogen atoms, preferably fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2.
[0051] "Haloalkoxy" means a radical -OR where R is haloalkyl as defined above, e.g., -OCH2CI, -OCF3, -OCHF2.
[0052] "Haloalkylthio" means a radial -SR where R is haloalkyl as defined above.
[0053] "Haloalkylsulfonyl" means a radial -S02R where R is haloalkyl as defined above.
[0054] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one to five hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyI, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hy-droxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hy-droxymethyl)-2-hydroxyethyl.
[0055] "Hydroxyalkyloxy" means a radical -OR where R is hydroxyalkyl as defined above, e.g., 2-hydroxyethyloxy, 3-hydroxypropyloxy.
[0056] "Hydroxyalkylcarbonyl" means a radical -COR where R is hydroxyalkyl as defined above. Respresentative examples include, but are not limited to, hydroxymethylcarbonyl, 2-hydroxyethylcarbonyl.
[0057] "Hydroxyalkoxyalkylaminocarbonyl" means a radical -CONH-(alkylene)-0-(alkylene)OH where alkylene is as defined above, e.g., -C0NH-(CH2)2-0-(CH2)20H.
[0058] "Heterocycloalkyl" means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C. The heterocycloalkyl ring may be optionally substituted with one or more substituents, preferably one or two substituents, independently selected from alkyl, aryl, heteroaryl, aralkyl, 3,5,6-trihydroxy-2-hydroxymethyltetrahy-dropyran-3-yl, 4,5-dihydroxy-2-hydroxymthyl-6-(4,5,6-trihydroxy-2-hydroxymthyltetrahydro-pyran-3-yloxy)-tetrahydro- pyran-3-yl, heteroaralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, cyano, carboxy, -COOR (where R is alkyl as define above), or -CONRaRb (where Ra and Rb are independently hydrogen or alkyl), or a protected derivative thereof. More specifically the term heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, tetrahydropyranyl, and thiomorpholino.
[0059] "Heterocycloalkylcarbonyl" means a radical -COR where R is heterocycloalkyl as defined above. More specifically the term heterocycloalkylcarbonyl includes, but is not limited to, 1-pyrrolidinocarbonyl, 1-piperidinocarbonyl, 4-morpholinocarbonyl, 1-piperazinocarbonyl, 2-tetrahydropyranylcarbonyl, and 4-thiomorpholinocarbonyl, and the derivatives thereof.
[0060] "Heterocycloalkylcarbonylalkyl" means a radical -(alkylene)-COR where R is heterocycloalkyl as defined above. More specifically the term heterocycloalkylcarbonyl includes, but is not limited to, 1-pyrrolidinocarbonylmethyl, 1-pipe-ridinocarbonylmethyl, 4-morpholinocarbonylethyl, 1-piperazinocarbonylmethyl, and the derivatives thereof.
[0061] "Heterocycloalkylalkyl" means a radical -(alkylene)-R where R is heterocycloalkyl as defined above. More specifically the term heterocycloalkylalkyl includes, but is not limited to, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, 2-morpholin-1-ylethyl, piperazin-1-ylethyl, and the derivatives thereof.
[0062] "Heterocycloalkylalkylaminocarbonyl" means a radical -CONH-(alkylene)-R where R is heterocycloalkyl as defined above. More specifically the term heterocycloalkylalkylaminocarbonyl includes, but is not limited to, 1-pyrrolid-inoethyl-aminocarbonyl, 1-piperidinoethylaminocarbonyl, 4-morpholinoethylcarbonyl, 1-piperazinoethylaminocarbonyl, and 4-thiomorpholinopropylaminocarbonyl, and the derivatives thereof.
[0063] "Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more, preferably one or two ring heteroatoms selected from N, O, or S, the remaining ring atoms being carbon. The heteroaryl ring is optionally substituted with one or more substituents, preferably one or two substituents, independently selected from alkyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, guanidinoalkyl, halo, nitro, cyano, amino, alkyl or dialkylamino, hydroxy, carboxy, or -COOR where R is alkyl as define above. More specifically the term heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazine, pyrimidine, pyradizine, oxazole, isoox-azolyl, benzoxazole, quinoline, isoquinoline, benzopyranyl, and thiazolyl.
[0064] "Heteroarylsulfonyl" means a radical -S02R where R is heteroaryl as defined above, e.g., pyridylsulfonyl, fura-nylsulfonyl.
[0065] "Heteroaralkyl" means a radical -(alkylene)-R where R is a heteroaryl group as defined above e.g., pyridylmethyl, furanylmethyl, indolylmethyl, pyrimidinylmethyl.
[0066] "Heterocycloamino" means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C provided that at least one of the heteroatom is nitrogen and wherein one or two carbon atoms are optionally replace by a carbonyl group. The heterocycloamino ring may be optionally substituted with one or more substituents, preferably one ortwo substituents, independently selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo, cyano, carboxy, -CONRaRb (where Ra and Rb are independently hydrogen or alkyl), or -COOR where R is alkyl as define above. More specifically the term heterocycloamino includes, but is not limited to, pyrrolidino, piperidino, piperazino, and thiomorpholino, and the derivatives thereof.
[0067] "Hydroxycarbamimidoyl" means a radical -C(=NH)NHOH or -C(=NOH)NH2.
[0068] The present disclosure also includes (derivatives and protected derivatives of compounds of Formula I. For example, when compounds of Formula I contain an oxidizable nitrogen atom (e.g., when a compound of Formula I contains a pyridine, amino, alkylamino, piperidino, piperazino, morpholino, or dialkylamino group), the nitrogen atom can be converted to an N-oxide by methods well known in the art.
[0069] Also when compounds of Formula I contain groups such as hydroxy, carboxy, carbonyl, thiol or any group containing a nitrogen atom(s), these groups can be protected with a suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. The protected derivatives of compounds of Formula I can be prepared by methods well known in the art.
[0070] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepro-pionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesul-fonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucohep-tonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985.
[0071] The compounds of the present invention may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Many geometric isomers of olefins, C=C double bonds, can be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, enantiomeric, diastereomeric, racemic forms and all geometric isomeric forms of a structure (representing a compound of Formula I) are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
[0072] Certain compounds of Formula I exist in tautomeric equilibrium. Compounds of Formula I, which exist as tautomers are named, illustrated or otherwise described in this application as one possible tautomer. However, it is to be understood that all possible tautomers are meant to be encompassed by such names, illustrations and descriptions and are within the scope of this invention. For example, in compound of Formula I, the group -C(=NR13)NH2 can tau-tomerize to -C(=NH)NHR13 group. Additionally, as used herein the terms alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl, heteroaryl, heterocycloalkyl are substituted, they include all the positional isomers albeit only a few examples are set forth.
[0073] "Oxoheterocycloalkyl" means a saturated or unsaturated (provided that it is not aromatic) monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C wherein one or two of the carbon atoms is/are replaced with an oxo (C=0) group. The oxoheterocycloalkyl ring may be optionally substituted with one or more substituents, preferably one or two substituents, independently selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, guanidinoalkyl, alkoxy, cyano, carboxy, or -COOR where R is alkyl as define above. More specifically the term heterocycloalkyl; includes, but is not limited to, 2 or 3-oxopyrrolidin-1-yl, 2, 3, or 4-oxopiperidino, 3-oxomorpholino, 2-oxo-piperazino, 2-oxotetrahydropyranyl, 3-oxothiomorpholino, 2-imidazolidone, and the derivatives thereof.
[0074] "Oxoheterocycloalkylalkyl" means a radical -(alkylene)-R where R is a oxoheterocycloalkylalkyl group as defined above e.g., More specifically the term oxoheterocycloalkylalkyl; includes, but is not limited to, 2 or 3-oxopyrrolidin-1-yl-(methyl, ethyl, or propyl), 2, 3, or 4-oxopiperidin-1-yl-(methyl, ethyl, or propyl), 3-oxomorpholin4-yl-(methyl, ethyl, or propyl), 2-oxopiperazin-1-yl-(methyl, ethyl, or propyl), 2-oxotetrahydro-pyran-3-yl-(methyl, ethyl, or propyl), 3-oxothio-morpholin-4-yl-(methyl, ethyl, or propyl), 2-imidazolidon-1-yl-(methyl, ethyl, or propyl), and the derivatives thereof.
[0075] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocycloalkyl group optionally mono- or di-substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is mono-or disubstituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with the alkyl group.
[0076] A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes both one and more than one such excipient.
[0077] "Phosphoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -P(0)(OH)2, e.g., phosphomethyl, 2-phosphoethyl, 1-methyl-2-phosphoethyl, and 1,3-diphosphopropyl.
[0078] "Sulfoalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one, preferably one or two, -SOOH, e.g., sulfomethyl, 2-sulfoethyl, 1-methyl-2-sulfoethyl, and 1,3-disulfopropyl.
[0079] "Treating" or "treatment" of a disease includes, according to aspects of the present disclosure: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
[0080] A "therapeutically effective amount" means the amount of a compound of Formula I that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease according to aspects of the present disclosure. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
[0081] "Thioureido" means a radical -NRC(S)NR’R" where R, R’, and R" are independently hydrogen or alkyl.
[0082] "Thioureidoalkyl" means a radical-(alkylene)-NRC(S)NR’R" where alkylene is asdefined above. Representative examples include but are not limited to thioureidomethyl, and thioureidoethyl.
[0083] "Trimethylammonioalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -N+(CH3), e.g., trimethylammo-niomethyl, 2-ammonioethyl.
[0084] "Ureido" means a radical -NHCONH2.
[0085] "Ureidoalkyl" means a radical -(alkylene)-NHCONH2 where alkylene is as defined above. Representative examples include but are not limited to ureidomethyl, and ureidoethyl.
[0086] The compounds of the present disclosure are numbered as follows:
[0087] Representative compounds of Formula I of the present disclosure where R1, R2 and RV are hydrogen; X1 is -N-, X2, X3 , and X4 are carbon are disclosed in Table I below.
Table I
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
(continued)
[0088] Representative compounds of Formula I of the present disclosure where R1, R2 and Ry are hydrogen; X2 is -N-, X1, X3, and X4 are carbon are disclosed in Table II below.
Table II
[0089] The compounds of Formula I and the intermediates and starting materials used in their preparation are named generally by AutoNom 4.0 (Beilstein Information Systems, Inc.).
Preferred Embodiments [0090] While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula I are preferred. For example: (I) One preferred group of compounds is represented by the Formula la, as defined in paragraph 3. above. (a) Within the above group la, a more preferred group of compounds is that wherein R3 is hydrogen. (b) Within the above group la, another more preferred group of compounds is that wherein R3 is halo, preferably chloro orfluoro, more preferably fluoro. (c) Within the above group la, another more preferred group of compounds is that wherein R3 is -S02NHCOR6 where R6 is as defined in its broadest terms in the Summary of the Invention. Preferably R6 is alkyl, aralkyl, aryl, heteroaralkyl or heterocycloalkylalkyl. More preferably R3 is aminosulfonyl, -S02NHC0CH3,2-phenyethyl-carbonyl-aminosulfonyl, phenylcarbonylaminosulfonyl, 3-phenylpropylcarbonylaminosulfonyl, benzylcarbo-nylaminosulfonyl, 2-(3,4-dichlorophenyl)ethylcarbonylaminosulfonyl, 2-pyridin-3-ylethylcarbonylaminosulfonyl, 2-piperidin-3-ylethylcarbonylaminosulfonyl. Even more preferably R3 is -S02NHC0CH3. (d) Within the above group la, yet another more preferred group of compounds is that wherein R3 is -CONR7R8 (where R7 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl and R8 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or hetereocycloalkylalkyl or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino, wherein any rings comprising R3 are optionally substituted with one or two groups independently selected from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or -CONRaRb where Ra and Rb are independently hydrogen or alkyl). Preferably R7 is hydrogen or alkyl, and R8 is hydrogen, alkyl, aralkyl, or heteroaralkyl, or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino. More preferably, R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino, optionally substituted with one or two groups independently selected from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or-CONRaRb where Ra and Rb are independently hydrogen or alkyl. Even more preferably, R3 is aminocarbonyl, dimethylaminoc-arbonyl, 2-morpholin-4-ylethylaminocarbonyl, 2-phenethylaminocarbonyl, methylaminocarbonyl, pyridin-2-yl-methylaminocarbonyl, furan-2-ylmethylaminocarbonyl, 2-pyridin-4-ylethylaminocarbonyl, 2-pyridin-3-ylethyl-aminocarbonyl, 2-pyridin-2-ylethylaminocarbonyl, pyridin-4-ylmethylamino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl or thiazolidin-1 -ylcarbonyl , wherein any rings comprising R3 are optionally substituted with one or two groups independently selected from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or -CONRaRb where Ra and Rb are independently hydrogen or alkyl. Particularly, R3 is 4-hydroxypiperidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, 2-methoxycarbonylpyrrolidin- 1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, (2R) or(2S)-ami-nocarbonylpyrrolidin-1-ylcarbonyl, (2R) or (2S)-carboxypyrrolidin-1-ylcarbonyl, (2R) or (2S)-methoxycarbonyl, pyrrolidin-1-ylcarbonyl, dimethylaminocarbonyl, 3RS-aminocarbonylpiperidin-1-ylcarbonyl, 2S-methoxycarbo-nyl-4R-hydroxypyrrolidin-1-ylcarbonyl, (2R) or (2S)-dimethylaminocarbonylpyrrolidin-l-ylcarbonyl, 2-(S)-hy-droxymethylpyrrolidin-1-ylcarbonyl, 3R-hydroxypyrrolidin-1-ylcarbonyl, 2S-methoxycarbonyl-4S-hydroxypyrro-lidin-1-ylcarbonyl, 2S-carboxy-4R-hydroxypyrrolidin-1-ylcarbonyl, 2S-aminocarbonyl-4R-hydroxypyrrolidin-1-ylcarbonyl, 2S-carboxy-4S-hydroxypyrrolidin-1-ylcarbonyl, 2R-methoxycarbonyl-4R-hydroxypyrrolidin-1-ylcarbonyl or 2R-carboxy-4R-hydroxypyrrolidin-1-ylcarbonyl. (e) Within the above group la, yet another more preferred group of compounds is that wherein R3 is -(alkylene)-CONR9R10 (where R9 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl and R10 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl, or R9 and R10 together with the nitrogen atom to which they are attached form heterocycloalkylamino), wherein any rings comprising R3 are optionally substituted with one or two groups independently selected from hydroxy, hydroxyalkyl, carboxy, alkoxycarbonyl, alkyl or -CONRaRb where Ra and Rb are independently hydrogen or alkyl. (f) Within the above group la, yet another more preferred group of compounds is that wherein R3 is haloalkyl or haloalkoxy, preferably trifluoromethyl or trifluoromethoxy. (g) Within the above group la, yet another more preferred group of compounds is that wherein R3 is alkyl or alkoxy, preferably methyl or methoxy. (h) Within the above group la, yet another more preferred group of compounds is that wherein R3 is tetrazol-5-y or tetrazol-5-ylmethyl. (i) Within the above group la, another more preferred group of compounds is that wherein R3 is aminosulfonyl or dimethylaminosulfonyl, preferably aminosulfonyl.
Within the above preferred and more preferred groups (a-i), a particularly preferred group of compounds is that wherein:
Rx is fluoro, chloro, or hydrogen, preferably hydrogen; and
Rz is aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, aminosulfonylmethyl, methylaminosulfonyl-methyl, or dimethylaminosulfonylmethyl.
Within the above preferred, more preferred, and even more preferred groups, a particularly preferred group of compounds is that wherein: R13 is hydrogen, hydroxy, methoxy, or ethoxycarbonyl, preferably hydrogen. (Ill) Yet another preferred group of compounds of Formula I are those wherein the moiety:
is 3’-acetylphenyl, 3’-hydroxyphenyl, 2’-hydroxyphenyl, 3’-aminocarbonylphenyl, 3’-cyanophenyl, 5’-fluoro-2’-hy-droxyphenyl, 5’-chloro-2’-hydroxyphenyl, 2’-hydroxy-methylphenyl, 2’-hydroxyphenyl, 5’-carboxy-2’-hydroxyphenyl, 2’,5’-dihydroxyphenyl, 5’-cyano-2’-methoxyphenyl, 5’-aminocarbonyl-2’-methoxyphenyl, 2’,6’-dihydroxyphenyl, 2’-hydroxy-5’-nitrophenyl, 2’-cyanophenyl, 3’-hydroxymethylphenyl, 5’-cyano-2’-hydroxy-phenyl, 5’-aminocarbonyl-2’-hydroxyphenyl, 2’,6’-dihydroxyphenyl, 5’-aminomethyl-2’-hydroxyphenyl, 2’-hydroxy-5’-ureidomethylphenyl, 2’-hy-droxy-5’-imidazol-2-ylphenyl, 5’-amino-2’-hydroxyphenyl, 2’-hydroxy-5’-ureidophenyl,2’-hydroxy-5’-(2-morpholin-4-ylethyl)aminocarbonyl-phenyl, 3’-bromo-2’-hydroxy-5’-hydroxymethylphenyl, 5’-(2-cyanoethyl)- 2’-hydroxyphenyl, 3’-bromo-5’-carboxymethyl-2’-hydroxyphenyl, 5’-(2-carboxyethyl)-2’-hydroxyphenyl, 5’-aminocarbonylmethyl-2’-hy-droxyphenyl, 3’,5’-dichloro-2’-hydroxyphenyl, 2’-hydroxy-5’-[2-(2-hydroxyethoxy)ethylaminocarbonyl]phenyl, 5’-dimethylaminosulfonylamino-2’-hydroxy-phenyl, 3’-bromo-5’-chloro-2’-hydroxyphenyl, 2’-hydroxy-5’-(4-methyl-piperazin-1-ylcarbonyl)phenyl, 2’-hydroxy-5’-(4-methylpiperazin-1-ylemthyl)phenyl, 5’-carbamimidoyl-2’-hydroxy-phenyl, 5’-(2-dimethylaminoethylaminocarbonyl)-2’-hydroxyphenyl, or 5’-aminocarbonyl-2’-hydroxyphenyl. Preferably 2’-hydroxyphenyl, 5’-fluoro-2’-hydroxyphenyl, 5’-chloro-2’-hydroxyphenyl, 2’-hydroxymethylphenyl, 2’-hydrox-yphenyl, 5’-carboxy-2’-hydroxyphenyl, 2’,5’-dihydroxyphenyl, 2’,6’-dihydroxy-phenyl, 2’-hydroxy-5’-nitrophenyl, 5’-cyano-2’-hydroxyphenyl, 5’-aminocarbonyl-2’-hydroxyphenyl, 2’,6’-dihydroxyphenyl, 5’-aminomethyl-2’-hydroxy-phenyl, 2’-hydroxy-5’-ureidomethylphenyl, 2’-hydroxy-5’-imidazol-2-ylphenyl, 5’-amino-2’-hydroxyphenyl, 2’-hy-droxy-5’-ureidophenyl, 2’-hydroxy-5’-(2-morpholin-4-ylethyl)aminocarbonyl-phenyl, 3’-bromo-2’-hydroxy-5’-hy-droxymethylphenyl, 5’-(2-cyanoethyl)- 2’-hydroxyphenyl, 3'-bromo-5’-carboxymethyl-2’-hydroxyphenyl, 5’-(2-car-boxyethyl)-2’-hydroxyphenyl, 5’-aminocarbonylmethyl-2’-hydroxyphenyl, 3’,5’-dichloro-2’-hydroxyphenyl, 2’-hy-droxy-5’-[2-(2-hydroxyethoxy)ethylaminocarbonyl]phenyl, 5’-dimethylaminosulfonylamino-2’-hydroxyphenyl, 3’-bromo-5’-chloro-2’-hydroxyphenyl, 2’-hydroxy-5’-(4-methylpiperazin-1-ylcarbonyl)phenyl, 2’-hydroxy-5’-(4-methyl-piperazin-1-ylmethyl)phenyl, 5’-carbamimidoyl-2’-hydroxyphenyl, 5’-methylaminocarbonylmethyl-2’-hydroxyphe-nyl, 5’-(2-dimethylaminoethylaminocarbonyl)-2’-hydroxyphenyl, or 5’-aminocarbonyl-2’-hydroxyphenyl. More preferably, 2’,6’-dihydroxyphenyl, 5’-fluoro-2’-hydroxyphenyl, 3’-aminosulfonylphenyl, 5’-aminocarbonyl-2’-hydroxyphe-nyl, 5’-aminocarbonylmethyl-2’-hydroxyphenyl, 5’-methylaminocarbonylmethyl-2’-hydroxyphenyl, 5’-hydroxyme-thyl-2’-hydroxyphenyl, 5’-acetylaminomethyl-2’-hydroxyphenyl, 2’-hydroxy-5’-ureidophenyl; 2’-hydroxy-5’-ureid-omethylphenyl, 2’-hydroxy-5’-N-methylureidomethyl-phenyl, 2’-hydroxy-5’-N,N-dimethylureidomethylphenyl, or 5’-methylsulfonylamino-2’-hydroxyphenyl.
Within this group, a more preferred group of compounds is that wherein R and R2 are hydrogen, X1 is nitrogen, X2-X4 are carbon and R3 is hydrogen, fluoro, chloro, methyl, trifluoromethyl, trifluoromethoxy, methoxy, aminocar-bonyl, dimethylaminocarbonyl,tetrazol-5-yl,tetrazol-5-ylmethylcyanomethyl,acetylaminosulfonyl,oraminosulfonyl. (IV) Yet another preferred group of compounds of Formula I are those wherein the moiety:
is a group of the formula:
where Rz isfluoro, aminosulfonyl, ureidomethyl, -CH2NHCONCH3, -CH2NHCON-ferf-butyl, N,N-dimethylureidome-thyl, aminomethyl, piperazin-1-ylcarbonylmethyl, carboxymethyl, -CH2NHCOCH2OH, aminocarbonyl, acetylami-nomethyl, aminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-hydroxyethylami-nocarbonylmethyl, morpholin-4-ylcarbonylmethyl, methoxycarbonylaminomethyl, hydroxymethyl, or methylsulfo-nylaminomethyl.
Reference to the preferred embodiments set forth above is meant to include all combinations of particular and preferred groups unless stated otherwise. (V) Another preferred group of compounds of Formula I are the following: 2-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylami-no}-succinamic (Compound 121); ({2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetyl}-car-boxymethyl-amino)-acetic acid (Compound 122); 2-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylami-no}-succinic acid (Compound 123); 1-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetyl}-pyrrolid-ine-2-carboxamide (Compound 124); 1- {2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetyl}-4-hy-droxy-pyrrolidine-2-carboxylic acid (Compound 125); 2- [5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetamide (Compound 126); 2-[5-(5-carbamimidoyl-1F/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/,A/-dimethyl-aceta-mide (Compound 127); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-/\/-(2-hydroxy-1-hy-droxymethyl-ethyl)-acetamide (Compound 128); {2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-ace-tic acid (Compound 129); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-carbamoylmethyl-acetamide (Compound 130); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-dimethylamino-ethyl)-acetamide (Compound 131); 2- [5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-/\/-(3-dimethylamino-propyl)-acetamide (Compound 132); 3- {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-pro-pionic acid (Compound 133); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-A/-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-acetamide (Compound 134); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(S,4,5,6-tetrahy-droxy-tetrahydro-pyran-2-ylmethyl)-acetamide (Compound 135); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2,4,5-tri hydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-acetamide (Compound 136); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-acetamide (Compound 137); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-acetamide (Compound 138); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-acetamide (Compound 139); 2-{2-[5-(5-carbamimidoyl-1 H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylami-no}-succinamide (Compound 140); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-acetamide (Compound 141); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-acetamide (Compound 142); (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylami-no}-ethyl)-phosphonic acid (Compound 143); {2-[{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonic acid (Compound 144); 2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio- nylamino}-succinamic acid (Compound 145); ({2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio-nyl}-carboxymethyl-amino)-acetic acid (Compound 146); 2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio-nylamino}-succinic acid (Compound 147); 1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio-nylJ-pyrrolidine-2-carboxamide (Compound 148); 1- {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio-nyl}-4-hydroxy-pyrrolidine-2-carboxylic acid (Compound 149); 2- [5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-isobutyramide (Compound 150); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N,N-dimethyl-isobu-tyramide (Compound 151); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-/V-(2-hydroxy-1-hy-droxymethyl-ethyl)-isobutyramide (Compound 152); {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio-nylamino}-acetic acid (Compound 153); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-carbamoylmethyl-isobutyramide (Compound 154); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-dimethylamino-ethyl)-isobutyramide (Compound 155); 2- [5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N-(3-dimethylamino-propyl)-isobutyramide (Compound 156); 3- {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio-nylaminoj-propionic acid (Compound 157); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-A/-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-isobutyramide (Compound 158); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(3,4,5,6 -tetrahy-droxy-tetrahydro-pyran-2-ylmethyl)-isobutyramide (Compound 159); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-isobutyramide (Compound 161); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isobutyramide (Compound 162); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-isobutyra-mide (Compound 163); 2S-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propi-onylamino}-succinamide (Compound 164); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-isobutyramide (Compound 165); 2-[5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-isobutyramide (Compound 166); (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propio-nylamino}-ethyl)-phosphonic acid (Compound 167); {2-[{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-2-methyl-propi-onyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonic acid (Compound 168); 2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-pro-pionylaminoj-succinamic acid (Compound 169); ({2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-propi-onyl}-carboxymethyl-amino)-acetic acid (Compound 170); 2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-pro-pionylaminoj-succinic acid (Compound 171); 1-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-pro-pionyl}-pyrrolidine-2-carboxamide (Compound 172); 1- {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-pro-pionyl}-4-hydroxy-pyrrolidine-2-carboxylic acid (Compound 173); 2- [5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-isobutyramide (Compound 174); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/,A/-dimethyl- isobutyramide (Compound 175); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-/V-(2-hydroxy-1-hydroxymethyl-ethyl)-isobutyramide (Compound 176); {2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-propi-onylaminoj-acetic acid (Compound 177); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-carbamoylme-thyl-isobutyramide (Compound 178); 2-[5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-(2-dimethyl-amino-ethyl)-isobutyramide (Compound 179); 2- [5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-(3-dimethyl-amino-propyl)-isobutyramide (Compound 180); 3- {2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-pro-pionylaminoj-propionic acid (Compound 181); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-N-(3,4,5,6-tet-rahydroxy-tetrahydro-pyran-2-ylmethyl)-isobutyramide (Compound 182); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-methyl-N-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-isobutyramide (Compound 183); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-(2,4,5-trihy-droxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-isobutyramide (Compound 184); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-methyl-N-(2,3,4,5,6-pentahydroxy-hexyl)-isobutyramide (Compound 185); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-isobutyramide (Compound 186); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-methyl-isobu-tyramide (Compound 187); 2-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-pro-pionylaminoj-succinamide (Compound 188); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-[(2,4,5-trihy-droxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-isobutyramide (Compound 189); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-A/-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-isobutyramide (Compound 190); (2-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-pro-pionylamino}-ethyl)-phosphonic acid (Compound 191); {2-[{2-[5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl]-2-methyl-propionyl}-(2-phosphono-ethyl)-amino]-ethyl}-phosphonic acid (Compound 192); 2-{[5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-amino}-suc-cinamic acid (Compound 193); {[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-carboxyme-thyl-amino}-acetic acid (Compound 194); 2- {[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-amino}-suc-cinic acid (Compound 195); 1-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetyl}-pyiTolid-ine-2-carboxylic acid (Compound 196); 1-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetyl}-4-hy-droxy-pyrrolidine-2-carboxylic acid (Compound 197); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 198); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-A/,A/-dimethyl-3-carboxam-ide (Compound 199); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-N-(2-hydroxy-1-hydroxymethyl-ethyl)-5’-sulfa-moyl-biphenyl-3-carboxamide (Compound 200); {[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-amino}-acetic acid (Compound 201); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-A/-carbamoylmethyl-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-car-boxamide (Compound 202); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-/\/-(2-dimethylamino-ethyl)-5’-sulfamoyl-biphenyl- 3- carboxamide (Compound 203); 3-{[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-amino}-pro- pionic acid (Compound 204); 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-/V-methyl-/V-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 205); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-N-(3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-ylme-thyl)-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 206); 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-A/-(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 207); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-N-methy/-N-(2,3,4,5,6-pentahydroxy-hexyl)-5’-sul-famoyl-biphenyl-3-carboxamide (Compound 209); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-5’-sul-famoyl-biphenyl-3-carboxamide (Compound 210); 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-A/-methyl-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 211); 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-/V-[(2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-methyl]-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 213); 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-/\/-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-5’-sulfa-moyl-biphenyl-3-carboxamide (Compound 214); (2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-ami-no}-ethyl)-phosphonic acid (Compound 214); {2-[[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-(2-phospho-no-ethyl)-amino]-ethyl}-phosphonic acid (Compound 215); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-N,N-bis-(2-hydroxy-ethyl)-5’-methyl-biphenyl-3-carboxyamide (Compound 217); (2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-ami-no}-ethyl)-trimethyl-ammonium (Compound 218); 2-{5-[4-(2-amino-ethyl)-piperazine-1-carbonyl]-2,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl}-1H-benzoimidazole-5-carboxamidine (Compound 219); 2-amino-6-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbon-yl]-amino}-hexanoic acid (Compound 220); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-/\/-hydroxy-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 221); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-/V,/V-dimethyl-5’-sulfamoyl-biphenyl-3-carboxam-ide (Compound 222); 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 223); 1- [5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-pyrrolidine-2-carboxamide (Compound 224); 2- [2,2’-dihydroxy-5-(morpholine-4-carbonyl)-5’-sulfamoyl-biphenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine (Compound 225); 1- [5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-pyrrolidine-2-carboxylic acid (Compound 226); [(2-{4-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carbonyl]-piper-azin-1-yl}-ethylamino)-dimethylamino-methylene]-dimethyl-ammonium (Compound 228); 2- {2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylami-no}-ethanesulfonic acid (Compound 234); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide (Compound 235); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetamide (Compound 238); 2-amino-6-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-hexanoic acid (Compound 112); 2- {2,2’-dihydroxy-5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-5’-sulfamoyl-biphenyl-3-yl}-1 H-benzoimidazole-5-carboxamidine (Compound 113); (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylami-no}-ethyl)-trimethyl-ammonium (Compound 105); 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-A/-carbamoylmethyl-methyl-5’-sulfamoyl-biphenyl- 3- carboxamide (Compound 106); 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-A/-(2-piperazin-1-yl-ethyl)-5’-sulfamoyl-biphenyl-3- carboxamide (Compound 107); and 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-A/-methyl-5’-sulfamoyl-biphenyl-3-carboxamide (Compound 229).
GENERAL SYNTHETIC SCHEME
[0091] Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
[0092] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
[0093] The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. Such materials may be characterized using conventional means, including physical constants and spectral data.
[0094] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C and most preferably at about room (or ambient) temperature, e.g., about 20 °C.
[0095] Compounds of Formula I in which X1 is -N-, R13 is hydrogen, R3 is hydrogen, halo, alkyl, haloalkyl, cyanoalkyl, tetrazol-5-yl, tetrazol-5-ylalkyl, aminosulfonyl, -S02NHC0R6, - CONHS02R11 or-(alkylene)-CONHS02R11 where R6 and R11 are as described in the Summary of the Invention and X2, X3, X4, R1, R2, Rx, RV, and Rz are as defined in the Summary of the Invention can be prepared as described in Scheme I below.
Scheme I
[0096] A compound of formula 4 where R1 and R2 are as defined in the Summary of the Invention and R3 is hydrogen, halo, alkyl, haloalkyl, cyanoalkyl, tetrazol-5-yl, tetrazo l-5-y I a I ky I, aminosulfonyl, -S02NHC0R6, -CONHS02R11 or -(alkylene)-CONHS02R11 where R6 and R11 are as described in the Summary of the Invention and X is halo, preferably bromo or iodo can be prepared as disclosed in method (a) above, by halogenating a compound of formula 1 (where R is hydrogen or hydroxy protecting group) with a suitable halogenating agent such as N-bromosuccinimide or N-iodosuc-cinimide. The reaction is carried out in a suitable organic solvent such as dimethylformamide.
[0097] Alternately, a compound of formula 4 can be prepared as disclosed in method (b) above, by formylating of a phenol derivative of formula 2 (where R1 and R2 are as defined in the Summary of the Invention and R3 is hydrogen, halo, alkyl, haloalkyl, cyanoalkyl, tetrazol-5-yl, tetrazol-5-ylalkyl, or-(alkylene)-CONHS02R11 where R6 and R11 are as described in the Summary of the Invention) to provide a compound of formula 3 which is then halogenated under the reaction conditions described in method (a) above. The formylation reaction is carried out in the presence of magnesium chloride and an organic base such as triethylamine and in a suitable organic solvent such as acetonitrile.
[0098] Compounds of formulae 1 and 2 are either commercially available or they can be prepared by methods well known in the art. For example, compounds of formula 1 such as 5-fluoro-2-hydroxybenzaldehyde, 5-methyl-2-hydroxy-benzaldehyde, and salicyaldehyde are commercially available. Compounds of formula 2 such as 4-fluorophenol, phenol, p-cresol, and 4-hydroxybenzyl cyanide are commercially available. Compounds of formula 2 where R3 is tetrazolyl or tetrazol-5-ylalkyl can be prepared from 4-hydroxybenzonitrile and 4-hydroxybenzyl cyanide respectively, by first protecting the hydroxy group with a suitable hydroxy protecting group and then treating the resulting compound with azidotrib- utyltin in an aromatic organic solvent such as toluene. Compounds of formula 4 where R3 is -C0NHS02R11 or -(alkylene)-CONHS02R11 can be readily prepared from 3-formyl-4-methoxy-5-bromobenzoic acid and 2-(3-formyl-4-methoxy-5-bromophenyl)acetic acid by first converting the acid to an acid halide such as acid chloride with a suitable halogenating agent such as oxalyl chloride. Treatment of the acid halide with a sulfonamide of the formula R11S02 NH2 where R11 is as defined in the Summary of the Invention then provides the desired compound. 3-Formyl-4-methoxy-5-bromobenzoic acid and 2-(3-formyl-4-methoxy-5-bromophenyl)acetic acid can be prepared by the procedures disclosed in Applicants’ Patent Application 10/190,147. Compounds of formula 4 where R3 is aminosulfonyl or-S02NHC0R6 can be prepared as described in working Examples 12-14 below.
[0099] Protection of the hydroxy group in 4 (where R is hydrogen) with a suitable hydroxy protecting group such as alkyl or methyoxyethoxymethyl, provides a compound of fomula 5. A comprehensive list of suitable hydroxy protective groups can be found in T.W. Greene, Projective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. Preferred hydroxy protecting group is 2-methoxyethoxymethyl. The reaction is typically carried out in the presence of a base such as diispropylethylamine, and in a halogenated organic solvent such as dichloromethane, carbon tetrachloride, or chloroform.
[0100] Compound 5 is converted into phenyl (4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl) derivative 6 by heating 5 with bispinacolato diboron in the presence of potassium acetate in the presence of Pd(dppf)CI2.
[0101] Treatment of 6 with a halobenzene of formula Ph(Rx, RV, RZ)X where X is halo and Rx, RV and Rzare as defined in the Summary of the Invention provides a biphenyl compound of formula 8. The reaction is carried out in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium and in a suitable organic solvent such as toluene or dimethoxyethane and a base such as aqueous sodium carbonate or potassium carbonate. Compounds of formula 7 are either commercially available or they can be prepared by methods well known in the art. For example, 2-bromo-4-fluorophenol is commercially available. 1-(3-Bromo-4-methoxyethoxymethoxybenzyl)-3-ferf-butyl urea can be prepared by treating 3-bromo-4-hydroxybenzonitrile with methoxyethoxymethyl chloride in the presence of a base such as diisopropylamine followed by reduction of the resulting 3-bromo-4-methylethoxymethoxy)benzonitrile to 3-bromo-4-methox-yethoxymethoxybenzylamine with a suitable reducing agent such as diborane. Treatment of 3-bromo-4-methylethoxy-benzylamine with tert-butylisocyanate then provides the desired compound. 1-(3-bromo-4-methoxyethoxymethoxyben-zyl)-3-ferf-butyl urea can be converted to 1-(3-bromo-4-methoxyethoxymethoxybenzyl)urea, if desired, by removal of the tert-butyl group under acidic hydrolysis reaction conditions.
[0102] Condensation of 8 with a 1,2-diamino compound of formula 9 provides a compound of Formula I where X1 is -N-. The reaction is carried out in the presence of a suitable oxidant such as benzoquinone, air oxidation, or FeCI3 and 02 and in a suitable organic solvent such as methanol or ethanol.
[0103] Compounds of formula 9 are commercially available or they can be prepared by methods well known in the art. For example, synthesis of 3,4-diaminobenzamidine monohydrochloride is known in the art.
[0104] Compounds of Formula I in which X1 is -CH-, R13 is hydrogen, and X2, X3, X4, R1, R2, Rx, RV, and Rz are as defined in the Summary of the Invention can be prepared as described in Scheme II below.
Scheme II
[0105] Protection of the hydroxy group in a compound of formula 8 with a suitable hydroxy protecting group provides a compound of formula 10. A comprehensive list of suitable hydroxy protective groups can be found in T.W. Greene, Projective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. Preferred hydroxy protecting group is 2-meth-oxyethoxymethyl. The reaction is typically carried out in the presence of a base such as diispropylethylamine, and in a halogenated organic solvent such as dichloromethane, carbon tetrachloride, or chloroform.
[0106] Ethynylation of 10 utilizing a modified procedure described in Muller, S.; Liepold , B.; Roth G. J.; Bestmann H. J. Synlett 1996, 6, 521-522 provides a ethynylbiphenyl compound of formula 11.
[0107] Reaction of a compound of formula 11 with a cyano compound of formula 12 where PG1 is a suitable nitrogen protecting group such as methylsulfonyl, ferf-butoxycarbonyl, ortrifluoroacetyl, and X is halo, utilizing the reaction conditions described in Sakamoto, T; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1305 provides 5-cyano-2-biphenyl-3-ylindole compound of formula 13 (where X1, X2, X3 and X4 are carbon and PG1 is not hydrogen). Deprotection of the amino group in 13 provides a 5-cyano-2-biphenyl-3-yl-1H-indole compound of formula 14. The reaction conditions utilized in the deprotection step depends on the nature of the nitrogen protecting group. For example, if the protecting group is methylsulfonyl it is removed under basic hydrolysis reaction conditions. Suitable bases are aqueous sodium hydroxide or potassium hydroxide. The reaction is carried out in an alcoholic solution such as methanol or ethanol. Ifthe protecting group is ferf-butoxycarbonyl it is removed underacidic hydrolysis reaction conditions. Compounds of formula 12 are either commercially available or they can be prepared by methods well known in the art.
[0108] The hydroxy-protecting group in 14 is then removed to provide 5-cyano-2-(2-hydroxybiphenyl-3-yl)-1H-indole 15. The reaction conditions employed for the deprotection reaction depend on the nature of the hydroxy protecting group. For example, if the protecting group is 2-methoxyethoxymethyl, it is removed by treating 15 with an acid under non-aqueous reaction conditions, in a suitable alcoholic solvent.
[0109] The cyano group in compound 15 is then converted into the carbamimidoyl group by first treating 15 with hydrogen chloride gas in an anhydrous alcoholic solvent such as methanol or ethanol, and then treating the resulting (5-methoxycarbonimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1 H-indole 16 with an inorganic base such as ammonium carbonate in an alcoholic solvent such as methanol, ethanol, or with excess ammonia to give resulting (5-carbamimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1 H-indole of Formula I. Alternatively, compound 15 can be converted to a compound of Formula I by first refluxing it with hydroxylamine in an alcoholic solvent such as ethanol and then treating the resulting (N-hydroxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1 H-indole with acetic anhydride in acetic acid to give (N-acetoxycar-bamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1 H-indole. The acetoxy group is then removed under hydrogenation reaction conditions by treating (N-acetoxycarbamimidoyl)-2-(2-hydroxybiphenyl-3-yl)-1 H-indole with 10% palladium in an alcoholic solvent such as methanol or ethanol.
[0110] Compounds of Formula I in which X1 is -N-, R13 is hydrogen, R3 is -CONR7R8 or- (alkylene)-CONR9R10 where R7, R8, R9 and R10 are as described in the Summary of the Invention and X2, X3, X4, R1, R2, Rx, RV, Rz and R11 are as defined in the Summary of the Invention can be prepared as described in Scheme III below.
Scheme III
[0111] Compounds of Formula I in which X1 is -N-, R13 is hydrogen, R3 is -CONR7R8 or-(alkylene)-CONR9R10 where R7, R8, R9 and R10 are as described in the Summary of the Invention and X2, X3, X4, R1, R2, Rx, Ry, Rz and R11 are as defined in the Summary of the Invention can be prepared by first converting a compound of formula 18 (where R is hydroxy protecting group and R3 is a -COOR’ or-alkylene-COOR’ group where R’ is alkyl) to a compound of formula 19 (where R3 is an -COOR’ or-alkylene-COOR’ group where R’ is alkyl) as described in Scheme I. Compounds of formula 18 are either commercially available or they can be prepared by methods well known in the art. Some such methods are described in Applicant’s PCT Application Publication No. WO 00/35886.
[0112] Hydrolysis of the ester group provides a corresponding compound of formula 20 (where R3 is an -COOH or -alkylene-COOH). Amination of 20 with an amine of formula NHR7R8 or NHR9R then provides a compound of Formula I. The amination reaction is carried out reacting 20 with the amine in the presence of a suitable coupling agent e.g., benzotriazole-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (PyBOP®), 0-benzotriazol-1-yl-N,N,N’,N’-te- tramethyl-uronium hexafluorophosphate (HBTU), 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or 1,3-dicyclohexylcarbodiim-ide (DCC), optionally in the presence of 1-hydroxybenzotriazole (HOBT), and a base such as N,N-diisopropylethylamine, triethylamine, or N-methylmorpholine. The reaction is typically carried out at 20 to 30 °C, preferably at about 25 °C, and requires 2 to 24 h to complete. Suitable reaction solvents are inert organic solvents such as dimethylformamide.
[0113] Compounds of Formula I can be converted to other compounds of Formula I. For example, a compound of Formula I where Rx is alkoxy, can be converted to corresponding compound of Formula I where Rx is hydroxy by hydrolysis of the alkoxy group by a suitable dealkylating reagent such as hydrobromic acid. A compound of Formula I where Rz is cyano can be converted to a corresponding compound of Formula I where Rz is aminocarbonyl under hydrolysis reaction conditions. The cyano group can also be reduced to give aminomethyl group which can be treated with isocyanate or thiocyanate to give corresponding compound of Formula I where Rz is ureidomethylorthioureidomethyl respectively. A compound of Formula I where R13 is hydrogen can be converted to a corresponding compound of Formula I where R13 is hydroxy or alkoxy by reacting it with hydroxylamine or alkoxyamine under conditions well known in the art.
Utility [0114] The compounds of this invention inhibit Factors Vila, IXa.Xa, andXIa, in particular Factor Vila, and are therefore in aspects of the present dicslosure useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals.
[0115] Particular disease states which may be mentioned according to aspects of the present disclosure include the therapeutic and/or prophylactic treatment of venous thrombosis (e.g. DVT) and pulmonary embolism, arterial thrombosis (e.g. in myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis), and systemic embolism usually from the atrium during atrial fibrillation or from the left ventricle after transmural myocardial infarction, or caused by congestive heart failure; prophylaxis of reocclusion (i.e., thrombosis) after thrombolysis, percutaneous trans-luminal angioplasty (PTA) and coronary bypass operations; the prevention of rethrombosis after microsurgery and vascular surgery in general.
[0116] Further indications according to aspects of the present disclosure include the therapeutic and/or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mechanism; anticoagulant treatment when blood isin contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological prosthetic valves or any other medical device; and anticoagulant treatment when blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in haemodialysis; the therapeutic and/or prophylactic treatment of idiopathic and adult respiratory distress syndrome, pulmonary fibrosis following treatment with radiation or chemotherapy, septic shock, septicemia, inflammatory responses, which include, but are not limited to, edema, acute or chronic atherosclerosis such as coronary arterial disease and the formation of atherosclerotic plaques, cerebral arterial disease, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral arterial disease, ischaemia, angina (including unstable angina), reperfusion damage, restenosis after percutaneous trans-luminal angioplasty (PTA) and coronary artery bypass surgery.
[0117] The compounds of Formula I can also be used in aspects of the present disclosure in the treatment of cancer or rheumatoid arthritis.
Testing [0118] The ability of the compounds of this invention to inhibit factor Vila and Xa can be tested in vitro and in vivo assays described in biological assays Example 1 and 2 below.
Administration and Pharmaceutical Compositions [0119] In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
[0120] Therapeutically effective amounts of compounds of Formula I may range from approximately 0.01-50 mg per kilogram body weight of the recipient per day; preferably about 0.1-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 7 mg to 1.4 g per day.
[0121] In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral or parenteral using a con venient daily dosage regimen, which can be adjusted according to the degree of affliction. Oral compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
[0122] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[0123] The compositions are comprised of in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula I. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one skilled in the art.
[0124] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, and dried skim milk. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
[0125] Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
[0126] Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
[0127] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula I based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80wt%. Representative pharmaceutical formulations containing a compound of Formula I are described below.
[0128] The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s). For example, a compound of Formula I can be administered in combination with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a factor IXa, and a factor Xa inhibitor. Preferably, the thrombin inhibitor is Inogatran®, Melagatran® or prodrugs thereof which are disclosed in PCT Application Publication Nos. WO 94/29336 and WO 97/23499. Factor Xa inhibitors that may be used in the combination products according to the invention include those described in Current Opinion in Therapeutic Patents, 1993, 1173-1179 and in international patent applications WO 00/20416, WO 00/12479, WO 00/09480, WO 00/08005, WO 99/64392, WO 99/62904, WO 99/57096, WO 99/52895, WO 99/50263, WO 99/50257, WO 99/50255, WO 99/50254, WO 99/48870, WO 99/47503, WO 99/42462, WO 99/42439, WO 99/40075, WO 99/37304, WO 99/36428, WO 99/33805, WO 99/33800, WO 99/32477, WO 99/32454, WO 99/31092, WID 99/26941, WO 99/26933, WO 99/26932, WO 99/26919, WO 99/26918, WO 99/25720, WO 99/16751, WO 99/16747, WO 99/12935, WO 99/12903, WO 99/11658, WO 99/11617, WO 99/10316, WO 99/07732, WO 9/07731, WO 99/05124, WO 99/00356, WO 99/00128, WO 99/00127, WO 99/00126, WO 9/00121, WO 98/57951, WO 98/57937, WO 98/57934, WO 98/54164, WO 98/46591, WO 98/31661, WO 98/28282, WO 98/28269, WO 98/25611, WO 98/24784, WO 98/22483, WO 98/16547, WO 98/16525, WO 98/16524, WO 98/16523, WO 98/15547, WO 98/11094, WO 98/07725, WO 98/06694, WO 98/01428, WO 7/48706, WO 97/46576, WO 97/46523, WO 97/38984, WO 97/30971, WO 97/30073, WO 97/29067, WO 97/24118, WO 97/23212, WO 97/21437, WO 97/08165, WO 97/05161, WO 96/40744, WO 96/40743, WO 96/40679, WO 96/40100, WO 96/38421, WO 96/28427, WO 96/19493, WO 96/16940, WO 95/28420, WO 94/13693, WO 00/24718, WO 99/55355, WO 99/51571, WO 99/40072, WO 99/26926, WO 98/51684, WO 97/48706, WO 97/24135, WO 97/11693, WO 00/01704, WO 00/71493, WO 00/71507, WO 00/71508, WO 00/71509, WO 00/71511, WO 00/71512, WO 00/71515, WO 00/71516, WO 00/13707, WO 00/31068, WO 00/32590, WO 00/33844, WO 00/35859, WO 00/35886, WO 00/38683, WO 00/39087, WO 00/39092, WO 00/39102, WO 00/39108, WO 00/39111, WO 00/39117, WO 00/39118, WO 00/39131, WO 00/40548, WO 00/40571, WO 00/40583, WO 00/40601, WO 00/47207, WO 00/47553, WO 00/47554, WO 00/47563, WO 00/47578, WO 00/51989, WO 00/53264, WO 00/59876, WO 00/59902, WO 00/71510, WO 00/76970, WO 00/76971, WO 00/78747, WO 01/02356, WO 01/02397, WO 01/05784, WO 01/09093, WO 01/12600, WO 01/19788, WO 01/19795, WO 01/19798, WO 93/15756, WO 94/17817, WO 95/29189, WO 96/18644, WO 96/20689, WO 96/39380, WO 97/22712, WO 97/36580, WO 97/36865, WO 97/48687, WO 98/09987, WO 98/46626, WO 98/46627, WO 98/46628, WO 98/54132, WO 99/07730, WO 99/33458, WO 99/37643 and WO 99/64446; in US patents Nos. 6,034,093, 6,020,357, 5,994,375, 5,886,191,5,849,519, 5,783,421,5,731,315, 5,721,214, 5,693,641, 5,633,381, 5,612,378, 6,034,127, 5,670,479, 5,658,939, 5,658,930, 5,656,645, 5,656,600, 5,639,739, 5,741,819, 6,057,342, 6,060,491, 6,080,767, 6,087,487, 6,140,351,6,395,731, and 5,646,165; in Japanese patent applications Nos. JP 99152269, JP 10017549, JP 10001467, JP 98017549, JP 00178243, JP 11140040, JP 12143623, JP 12204081, JP 12302765, JP 6327488 and JP 98001467; in European patent applications EP 937 723, EP 937 711, EP 874 629, EP 842 941, EP 728 758, EP 540 051, EP 419 099, EP 686 642, EP 1 016 663 and EP 529 715; and in German patent applications Nos. DE 19845153, DE 19835950, DE 19743435, DE 19829964, DE 19834751, DE 19839499, DE19900355, DE19900471 and DE 19530996.
[0129] Factor Xa inhibitors also include those disclosed in international patent applications WO 96/10022, WO 97/28129, WO 97/29104, WO 98/21188, WO 99/06371, WO 99/57099, WO 99/57112, WO 00/47573, WO 00/78749, WO 99/09027 and WO 99/57113, as well as 4- {4-[4-(5-chloroindol-2-ylsulfonyl) piperazine-1 -carbonyl]phenyl}-pyridine-1-oxide and pharmaceutically acceptable derivatives thereof. Preferred Factor Xa inhibitors include antistatin, tick anticoagulant protein and those known as SQ-311 and SQ-315 (see international patent application WO 98/57951); SN-292 (see international patent application WO 98/28282); SN-429 and SN 116 (see international patent application WO 98/28269); RPR-208707 (see international patent application WO 98/25611 at Example 48); XU-817 (see international patent application WO 98/01428); SF-324 and SF-303 (see international patent application WO 97/23212); YM 60828 (see international patent application WO 96/16940 at Example 75); FACTOREX (see US patent No. 5,783,421); SF-324 (see European patent application EP 874 629); DX9065A (see European patent application EP 540 051 at Example 39); 1-(4-carbamimidoylbenzyl)-4-(6-chloronaphthalene-2-ylsulfonyl)-piperazin-2-one (see JP 12204081 at Example 2); M55555 (see international patent application WO 99/33805 at Example 39); DPC423 (1-(3-carbamimidoylphenyl)-2-(2’-aminolsulfonyl[1,1’-biphenyl]-4-ylaminocarbonyl)-4-bromopyrrole, see international patent application WO 98/28269); 3-(3,5-difluoro-6-[3-(4,5dihydro-1-methylimidazol-2-yl)-phenoxy]-4-[2,3-dihydroxy-propoxy]-pyridin-2-yloxy)-4-hydroxy-benzamidine (see international patent application WO 00/31068); ZK-807834 (see international patent application WO 7/29067); 1,4-diaza-4-(6-chloronaphthalene-2-ylsulfonyl)-6-(methoxymethyl)-7-oxa-1’-(pyridin-4-yl)spiro[bicyc- lo-[4-3.0]-nonane-8,4’-piperidine]-2-one (see international patent application WO 01/02397); (S)-1-(4-aminoquinazolin-7-ylmethyl)-4-[2-(5-chlorothien-2-yloxy)acetyl]-3-methoxy-methylpiperazin-2-one (see international patent application WO 00/32590); 3-(2-[4-(2-aminosulfonyl-phenyl)benzoylphenoxy)-benzamidine(see international patent application WO 01/19788); and 4-(2-[4-(5-chloroindol-2-yl-sulfonyl)-2-(pyrrolidin-1-ylcarbonylmethyl)piperazin-1-yl-carbonyl]-thiazol-5-yl)pyridine N-oxide (see Japanese patent application No. JP 12143623); as well as the compounds of Example 7 of international patent application WO 98/21188, of Examples 3 and 6 of WO 99/57113, of Example 6 of international patent application WO 00/78747, of Examples 188, 211 and 167 of US patent No. 6,080,767, of Examples 40, 54 and 55 of international patent application WO 99/33805, of Examples 5,6,8,9,10,11,12,13,15,16 and 17 of international patent application WO 01/05784, of Examples 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 22, 23, 25, 26, 28, 29, 30, 31,32, 33, 34,38,39,40,41,42 and 43 of international patent application WO 01/12600, and of Examples 802 and 877 of international patent application WO 00/35886. Other anticoagulant agents that can be used in the combination therapy are those disclosed in U.S. Patent Applications Publication Nos. 20020065303, 20020061842, 20020058677, 20020058657, 20020055522, 20020055469, 20020052368, 20020040144, 20020035109, 20020032223, 20020028820, 20020025963,20020019395,20020019394,20020016326,20020013314,20020002183,20010046974,20010044537, 20010044536, 20010025108, 20010023292, 20010023291, 20010021775, 20010020020033, 20010018423, 20010018414, and 20010000179.
[0130] Suitable formulations for use in administering melagatran and derivatives (including prodrugs) thereof are described in the literature, for example as described in inter alia international patent applications WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO 97/39770, WO 97/45138, WO 98/16252, WO 99/27912, WO 99/27913, WO 00/12043 and WO 00/13671.
[0131] Similarly, suitable formulations for use in administering Factor Xa inhibitors and derivatives (including prodrugs) thereof are described in the literature, for example as described in the prior art documents relating to Factor Xa inhibitors that are mentioned hereinbefore. Otherwise, the preparation of suitable formulations, and in particular combined preparations including both melagatran/derivative and Factor Xa inhibitor/derivative may be achieved non-inventively by the skilled person using routine techniques. The amounts of melagatran, Factor Xa inhibitor, or derivative of either, in the respective formulation(s) will depend on the severity of the condition, and on the patient to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
[0132] Suitable doses of melagatran, FactorXa inhibitors and derivatives of either, in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients may be determined routinely by the medical practitioner or other skilled person, and include the respective doses discussed in the prior art documents relating to melagatran (orderivatives (including prodrugs) thereof), and to FactorXa inhibitors, that are mentioned hereinbefore.
EXAMPLES
[0133] The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
Synthetic Examples
Reference 1
Synthesis of 2-methoxymethylether-5-fluoro-phenylboronic acid [0134] 2-Bromo-4-fluorophenol (25.0 g, 0.13 mol) was dissolved in dry dichloromethane (100 mL) and dimethoxymeth-ane (115 mL, 1.30 mol). Phosphorus pentoxide (110.8 g, 0.39 mol) was added portion-wise to the solution such that the reaction temperature remained below 40 °C. The mixture was stirred vigorously at room temperature for 2 hours and then carefully poured into IN aqueous NaOH (50 mL). The organic layer was separated, washed with water and then brine, dried over anhydrous MgS04, filtered and concentrated to give 2-bromo-4-fluoro-1-methoxymethoxy-benzene (30.1 g) as a colorless oil.
[0135] A 500 mL round bottom flask was charged with a 1.6 M solution of n-butyllithium in hexanes (100 mL, 0.16 mol) and flushed with nitrogen. The solution was cooled to -78 °C and a solution of 2-bromo-4-fluoro-1-methoxymethoxy-benzene (30.1 g, 0.13 mol) in dry tetrahydrofuran (50 mL) was added dropwise over one hour. The mixture was stirred at -78 °C and then trimethylborate (20 mL, 0.175 mol) was added very slowly via syringe. The reaction was allowed to gradually warm to room temperature and after two hours the mixture was poured into ice. The mixture was acidified to pH 4 with 5% aqueous citric acid and extracted with ethyl acetate (x3). The combined organic extracts were washed with water and brine, dried over MgS04 and filtered. The solvent was evaporation under reduced pressure and the residue was recrystallized from hexanes give 2-methoxymethoxy-5-fluorophenylboronic acid (18.9 g).
Reference 2
Synthesis of fert-butyl 2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate [0136] 2-Hydroxy-5-nitropyridine (50 g, 357 mmol) and N-chlorosuccinimide (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-chloro-5-nitro-2-hydroxypyridine (59 g, 95% yield).
[0137] 3-Chloro-5-nitro-2-hydroxy-pyridine (20 g) was added in small portions to thionylchloride (200 mL) under vigorous stirring. The suspension was heated to 100 °C within 1 hour, stirred at 100 °C for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water (3 x 200 mL) and the organic layer was dried over MgS04. The solvent was removed under reduced pressure to give 2,3-dichloro-5-nitropyridine (18 g) was obtained as a pale yellow solid.
[0138] A solution of 2,3-dichloro-5-nitropyridine (9.75 g) and potassium iodide (29 g) in acetic acid (120 mL, degassed with nitrogen) was heated to 100 °C for 1.5 hours under nitrogen. The brown solution was cooled to room temperature and then ethyl acetate (300 mL) added. The organic phase was separated and washed with water (2 x 100 mL) and dilute aqueous sodium sulfite (100 mL). Evaporation of the solventgave crystalline 3-chloro-2-iodo-5-nitro-pyridine (13.11 g)· [0139] A suspension of copper cyanide (7 g) and 3-chloro-2-iodo-5-nitro-pyridine (7 g) in acetonitrile (200 mL) was heated to 80 °C within 1 hour and stirred at 80 °C for 5 hours. The solvent was evaporated and the residue was filtered in ethyl acetate over silicon dioxide gave 3-chloro-2-cyano-5-nitro-pyridine (4.26 g).
[0140] A solution of tin chloride (52 g) and 3-chloro-2-cyano-5-nitro-pyridine (10.3 g) was stirred in ethyl acetate (200 mL) at room temperature for 10 minutes and at 70 °C for 4 hours. The solution was cooled to room temperature and diluted with ethyl acetate (500 mL). Sodium bicarbonate (100 g) added in four portions to the mixture within 4 hours. The mixture was stirred vigorously for 20 hours. The suspension was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The solvent was evaporated to give 5-amino-3-chloro-2-cyanopyridine (4.34 g) as an off-white powder.
Step (f) [0141] Bromine (7.22 g) was added to a stirring mixture of 5-amino-3-chloro-2-cyanopyridine (4.61 g) and sodium acetate (4.81 g) in anhydrous acetic acid (150 mL) at room temperature. The mixture was stirred at 60°C for 2 hours. The solvents and excess bromine were evaporated and the residue was recrystalliezed from ethyl acetate to give 5- amino-6-bromo-3-chloro-2-cyano-pyridine (6.23 g).
[0142] 5-Amino-6-bromo-3-chloro-2-cyano-pyridine (1.6 g) was dissolved in tetrahydrofuran (5 mL) at room temperature. /\/,/\/-dimethylaminopyridine (0.5 g) followed by di-tert-butyl dicarbonate (3.78 g) in small portions were added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue was dissolved in dicloromethane (60 mL). Trifluoroacetic acid (1 g) was added to the solution and the mixture was stirred for 1 hour. The solvent was removed by evaporation and product was purified from the residue by column chromatography (EtOAc/hexanes 1/1) to give ferf-butyl 2-bromo-5-chloro-6-cyano-pyridin-3-yl-carbamate (1 g). MS (obs.): 333 (M + 1).
Reference 3
Synthesis of 5-cyano-2-methoxybenzeneboronic acid [0143] 3-Bromo-4-methoxybenzonitrile (3.0 g, 14.2 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (10 mLs). The solution cooled at -10° C and stirred while isopropylmagnesium chloride (17.7 mmol, 8.8 mLs, 2.0 M in THF, 1.25 eq.) was added. The mixture was stirred for 1 hour and then trimethyl borate (1.87 g, 17.7 mmol, 2.0 mL) was added dropwise. The mixture was allowed to warm slowly to room temperature for 1 hour. The solvent was evaporated and the residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to a minimum volume under reduced pressure. The residue was recrystallized from hexanes to give 5-cyano-2-methoxybenzeneboronic acid (2.48 g, 99%) as a fluffy white powder.
Reference 4
Lithium 2-aminoethanesulfonate [0144] Lithium hydroxide monohydrate (0.42 g, 0.10 mol) was dissolved in water (15 mL) and the solution was treated with 2-amino-ethanesulfonic acid (1.25 g, 0.10 mol). The mixture was stirred until all solids dissolved and then for an additional 30 minutes. The water solvent was evaporated off in vacuo and the resulting wet solid was heated at 70 °C under vacuum (1 Torr) overnight to give lithium 2-aminoethanesulfonate as a dry, free-flowing colorless solid.
Reference 5 ferf-Butyl 6-amino-2-ferf-butoxycarbonylamino-hexanoate [0145] ferf-Butyl 2-amino-6-benzyloxycarbonylamino-hexanoate (1.0 g, 2.68 mmol) was dissolved in N,N-dimethylfor-mamide (50 mL) and then triethylamine (5.35 mmol, 0.75 mL) followed by N-(tert-butoxycarbonyloxy)succinimide (0.72 g, 3.35 mmol) was added to the solution. The mixture was stirred overnight and then concentrated. The product was purified from the residue by silica gel chromatography (20% MeOH/chloroform) to give ferf-butyl 6-benzyloxycarbo-nylamino-2-ferf-butoxycarbonylamino-hexanoate. The tri-protected product was reduced on a Parr hydrogenator (50 psi) to remove the benzyloxycarbonyl protecting group. The solvents were removed to give ferf-butyl 6-amino-2-ferf-bu-toxycarbonylamino-hexanoate (0.65 g, 80%).
Reference 6 3-Bromo-A/-ferf-butyl-4-methoxybenzenesulfonamide [0146] 1-Bromo-2-methoxy-benzene (1.87 g, 10.0 mmol) was dissolved in chloroform (5 mL) and the solution was cooled in an ice-salt bath to -5° C to 0° C. The cooled solution was carefully charged with chlorosulfonic acid (2.0 mL, 30.0 mmol) over 30 minutes and the mixture was allowed to warm to room temperature over 1 hour. The mixture then was poured onto chopped ice and transferred to a separatory funnel. The aqueous layer was separated and extracted (X2). The combined organic layers were dried and concentrated to give 3-bromo-4-methoxyphenylsulfonyl chloride (2.80 g, 98%).
[0147] 3-Bromo-4-methoxyphenylsulfonyl chloride (2.80 g, 9.8 mmol) was dissolved in dichloromethane (30 mL) and the solution was treated with triethylamine (1.76 mL, 12.6 mmol), followed by the dropwise addition of f-butylamine (1.33 mL, 12.6 mmol). The mixture was allowed to stand for 2 hours and then was poured onto a mixture of 5% citric acid solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (X2). The combined organic layers were dried and concentrated. Crystallization of the crude solid from ethyl ace- tate/hexane gave 3-bromo-A/-iert-butyl-4-methoxybenzenesulfonamide (2.43 g, 77%).
Reference 7
Synthesis of 1-[3-bromo-4-(2-methoxyethoxymethoxy)benzyl]-3-ferf-butylurea [0148] Diisopropylethylamine (21.8 mL, 151.5 mmol) was added slowly to a magnetically stirred solution of 3-bromo- 4-hydroxybenzonitrile (10 g, 50.5 mmol) and 2-methoxyethoxymethyl chloride (6.9 mL, 60.6 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with 5% citric acid solution until the washings were acidic, dried and concentrated. Product was purified from the residue by chromatography (silica gel, 30% ethyl acetate/hexanes) gave 3-bromo-4-(2-methoxyethoxymethoxy)-benzonitrile (11.5 g).
[0149] Borane-tetrahydrofuran complex (280 mL, 1 M, 280 mmol) was added to a magnetically stirred solution of 3-bromo-4-(2-methoxyethoxymethoxy)-benzonitrile (10 g, 35 mmol) in tetrahydrofuran (20 mL) and the reaction mixture was refluxed for 30 minutes. The mixture was cooled to 0 °C and 1 N HCI was added very slowly until the pH was acidic. The tetrahydrofuran was removed by evaporation and the residual aqueous layer was washed with ethyl ether. The aqueous extract was basified with 2 N sodium hydroxide until alkaline pH and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated by evaporation to give 3-bromo-4-(2-methoxy-ethoxymethoxy)benzylamine (5.6 g).
[0150] ferf-Butylisocyanate (2.9 mL, 25.5 mmol) followed by triethylamine (9.8 mL, 68 mmol) was added to a magnetically stirred solution of 3-bromo-4-(2-methoxyethoxymethoxy)benzylamine (5 g, 17 mmol) in DMF (50 mL) and the mixture was stirred at room temperature for 15 minutes. The mixture was diluted with water (10 mL) and the dilution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatographic (silica gel) employing 100% ethyl acetate as eluent to give 1-[3-bromo-4-(2-methoxyethoxymethoxy)benzyl]-3-ferf-butylurea (5.3 g).
Reference 8
Synthesis of 3-bromo-2-hydroxybenzaldehyde [0151] 2-Bromophenol (2 g, 11.5 mmol) was dissolved in anhydrous acetonitrile (25 mL) and the solution was charged with anhydrous (< 1.5% water) magnesium chloride (4.4 g, 46 mmol) and dry triethylamine (12.5 mL, 86.3 mmol). The mixture was stirred for 5 minutes and paraformaldehyde (2.8 g, 92 mmol) was added. The mixture was heated to a gentle reflux for 1 to 3 hours and then cooled. The mixture was poured onto an ether/5% citric acid mixture and the ether layer separated. The ether layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product purified from the residue by chromatography on silica gel employing 30% ethyl acetate/hexanes to give 3-bromo-2-hydroxybenzaldehyde (1.6 g).
[0152] Proceeding as in Reference 8, but substituting 4-hydroxyphenylacetonitrile(2.09g, 15 mmol) and formaldehyde (3.6 g, 120 mmol) gave 3-formyl-4-hydroxyphenylacetonitrile (1.8 g).
[0153] Proceeding as in Reference 8, but substituting methyl 4-hydroxybenzoate (30.4g, 0.20 mol, 1.0 eq.) and paraformaldehyde (42.0 g, 1.40 mol, 7.0 eq.), gave methyl 3-formyl-4-hydroxybenzoate (16.7 g) as a white solid.
[0154] Proceeding as in Reference 8, but substituting methyl 4-hydroxyphenylacetate (42.9 g, 0.258 mol) and paraformaldehyde (77.5 g, 2.58 mole), gave methyl 3-formyl-4-hydroxy-phenylacetate (50.0 g, ~100%).
[0155] Proceeding as in Reference 8, but substituting methyl-3-bromo-4-hydroxyphenylacetate, gave methyl-3-formyl-4-hydroxy-5-bromophenylacetate.
Reference 9 3-bromo-5-fluoro-2-hydroxybenzaldehyde [0156] N-bromosuccinimide (1.51 g, 8.52 mmol) was added to a magnetically stirred solution of 5-fluoro-2-hydroxy-benzaldehyde (1 g, 7.1 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 5 hour. The mixture was diluted with ethyl acetate and the organic layer was washed with 5% citric acid, brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatography over silica gel employing 50% ethyl acetate/hexanes to give 3-bromo-5-fluoro-2-hydroxybenzaldehyde (1.2 g).
[0157] Proceeding as in Reference 9, but substituting 3-formyl-4-hydroxyphenylacetonitrile (1 g, 6.2 mmol) and A/-bro-mosuccinimide (1.7 g, 9.3 mmol), gave 3-bromo-5-formyl-4-hydroxyphenylacetonitrile (1.2 g).
[0158] Proceeding as in Reference 9, but substituting 5-methyl salicylaldehyde (3 g, 22 mmol) and N-bromosuccinimide (4.7 g, 26.4 mmol), gave 3-bromo-2-hydroxy-5-methylbenzaldehyde (3.6 g).
[0159] Proceeding as in Reference 9, but substituting methyl 3-formyl-4-hydroxybenzoate (12.0 g, 66.6 mmol, 1 eq.) and N-bromosuccinimide (12.45 g, 69.9 mmol, 1.05 eq.) gave methyl 3-bromo-5-formyl-4-hydroxybenzoate (12.6 g) as a white solid.
[0160] Proceeding as in Reference 9, but substituting methyl 3-formyl-4-hydroxy-phenylacetate (50 g, 0.258 mol) and N-bromosuccinimde (45.92 g, 0.258 mole), gave methyl 3-bromo-5-formyl-4-hydroxyphenylacetate (56.4 g, 80 %) as a yellow amorphous solid.
Reference 10
Synthesis of 3-bromo-4-hydroxyphenylacetate [0161] Methyl 4-hydroxyphenylacetate (10.5 g, 63.0 mmol) was dissolved in acetic acid (200 mL) and the solution was stirred while bromine (150 mL, 0.463 M in acetic acid, 69.5 mmol) was added over 60 minutes. The mixture was stirred overnight and then concentrated by evaporation. Product was purified from the residue over 300 g of silica gel (hex-anes/ethyl acetate 5:1) to give methyl 3-bromo-4-hydroxyphenylacetate (11.9 g).
[0162] Proceeding as in Reference 14, but substituting 4-methoxyphenylacetic acid (16.6g, 0.1 mol) amd bromine (16.0 g, 0.1 mol), gave 3-bromo-4-methoxyphenylacetic acid (24.24 g, 98%) as a yellow powder.
Reference 11
Synthesis of 3-bromo-/\/-butyl-5-formyl-4-methoxy-benzenesulfonamide [0163] 5-Bromo-3-formyl-4-methoxybenzoic acid (480 mg, 1.84 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and the solution was flushed with dry nitrogen for 5 minutes. Oxalyl chloride (1.2 mL, 2.4 mmol, 1.3 eq) was added slowly to the solution while vigorous stirring and then a catalytic amount of dry dimethylformamide was added. The mixture was stirred for 1 hour and then concentrated by rotary evaporation and dried on high vacuum to give 5-bromo-3-formyl-4-methoxybenzoyl chloride (501 mg) as yellow crystals.
[0164] 5-Bromo-3-formyl-4-methoxybenzoyl chloride (501 mg, 1.8 mmol) was dissolved in in dichloromethane (5 mL) and the solution was added dropwise to a vigorously stirring solution of /V-butylsulfonamide (272 mg, 2.0 mmol), triethyl-amine (2.5 mmol) and a catalytic amount of Ν,Ν’-dimethylaminopyridine (10 mL in dichloromethane). The mixture was stirred at room temperature until the reaction was complete and concentrated under reduced pressure. The residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the filtrate was evaporated to give 3-bromo-A/-butyl-5-formyl-4-methoxy-benzenesul-fonamide as a white solid (650 mg).
Reference 12
Synthesis of 3-bromo-2-(2-methoxy-ethoxymethoxy)benzaldehyde [0165] 3-Bromo-2-hydroxybenzaldehyde (1.5 g, 7.5 mmol) was dissolved in dichloromethane (25 mL) and diisopro-pylethylamine (2 mL, 11.3 mmol) was added to the solution. The mixture was stirred while 2-methoxyethoxymethyl chloride (0.94 mL, 8.3 mmol) was added dropwise. The mixture was stirred for 1 hour and then washed with 5% citric acid solution (5 mL) until the washings were acidic, dried and concentrated by evaporation. Product was purified from the residue by chromatography (silica gel, 30% ethyl acetate/hexanes) to give 3-bromo-2-(2-methoxy-ethoxymeth-oxy)benzaldehyde (1.7 g).
[0166] Proceeding as in Reference 12, but substituting 3-bromo-5-fluoro-2-hydroxybenzaldehyde, gave 3-bromo-5-fluoro-2-(2-methoxy-ethoxymethoxy)-benzaldehyde; and substituting 3-bromo-5-formyl-4-hydroxyphenylacetonitrile (1.2 g, 5 mmol) to give 3-bromo-5-formyl-4-(2-methoxy-ethoxymethoxy)-phenyl-acetonitrile (1.4 g).
[0167] Proceeding as in Reference 12, but substituting methyl 3-bromo-5-formyl-4-hydroxybenzoate (12.6 g, 48.6 mmol, 1.0 eq.) and methoxyethoxymethyl chloride (6.8 mL, 7.26 g, 58.3 mmol, 1.2 eq.), gave methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-benzoate (16.2 g) as a colorless oil which solidified upon standing.
[0168] Proceeding as in Reference 12, but substituting methyl 3-bromo-4-hydroxyphenylacetate (22.33 g, 91.14 mmol) and 2-methoxyethoxymethyl chloride (13.62 g, 12.49 mL, 0.11 mol), gave 3-bromo-4-(2-methoxyethoxymethoxy)-phe-nylacetate (32.67 g).
[0169] Proceeding as in Reference 12, but substituting methyl 3-bromo-5-formyl-4-hydroxyphenylacetate (27.32 g, 0.10 mole) and 2-methoxyethoxymethyl chloride (0.125 mol, 14.3 mL), gave methyl 3-bromo-5-formyl-4-(2-methox-yethoxymethoxy)-phenylacetate (31.4 g (87 %).
Reference 13
Synthesis of 3-bromo-2-(methoxyethoxymethoxy)-5-(1 -(methoxyethoxymethyl)-l H-tetrazol-5-yl)benzaldehyde [0170] A solution of 3-bromo-2-hydroxy-5-(1H-tetrazol-5-yl)benzaldehyde in dichloromethane (25 mL) was treated with diisopropylethylamine (1.2 mL, 6.4 mmol) and 2-methoxyethoxymethyl chloride (0.72 mL, 6.4 mmol) under a stream of nitrogen and the mixture was stirred at room temperature for 2 hours. Workup involved rotovaping off most of the dichloromethane, followed by usual extractive workup with ethyl acetate and 5% aqueous citric acid. Collection and drying of the organic extracts gave a regioisomeric mixtures of 3-bromo-2-(methoxyethoxymethoxy)-5-(1-(methox-yethoxymethyl)-1 H-tetrazol-5-yl)benzaldehyde (0.93 g) as an oil.
Reference 14
Synthesis of methyl 4-benzyloxy-3-bromo-5-formyl-benzoate [0171] Methyl 3-bromo-5-formyl-4-hydroxybenzoate (11.5 g, 44.39 mmol) was dissolved in acetone (100 mL) and then benzylbromide (8.35 g, 48.83 mmol) and potassium bicarbonate (6.74 g, 48.83 mmol) were added. The mixture was stirred overnight and the organic layer was washed with water. The organic layer was separated, dried over MgS04 and concentrated. Product was purified from the residue by flash silica gel chromatography to give methyl 4-benzyloxy-3-bromo-5-formyl-benzoate (10.0 g).
Reference 15
Synthesis of ferf-butyl (3-bromo-benzyl)carbamate [0172] A mixture of 3-aminomethylbromobenzene (22.11 g, 99.5 mmol), di-tert-butyl dicarbonate (26.07 g, 119.45 mmol), sodium hydroxide (8.76 g, 219 mmol) in tetrahydrofuran (75 mL) and water (100 mL) were stirred at room temperature for 30 minutes. Extraction and work-up with methylene chloride and water, followed by drying gave ferf-butyl (3-bromo-benzyl)carbamate (34.9 g).
[0173] Proceeding as in Reference 15, but substituting 3-bromo-4-(2-methoxyethoxymethoxy)benzylamine (2.40 g, 8.27 mmol) and di-tert-butyl dicarbonate (3.56g, 16.3 mmol), gave ferf-bi/fy/[3-bromo-4-(2-methoxyethoxymethoxy)-ben-zyl]carbamate (2.36 g).
Reference 16
Synthesis of A/-acetyl-5-bromo-3-formyl-4-methoxybenzenesulfonamide [0174] A 100 mL round-bottom flask was charged with 5-bromo-3-formyl-4-methoxy-benzenesulfonamide (586 mg, 2.0 mmol) dissolved in dichloromethane (40 mL) and the solution was stirred vigorously while triethylamine (252 mg, 2.50 mmol) was added, followed by acetic anhydride (224 mg, 2.2 mmol) and a catalytic amount of A/,A/-dimethylami-nopyridine. The mixture was stirred for 1 hour and then concentrated by evaporation. The residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was separated, washed with water and brine and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give A/-acetyl-5-bromo-3-formyl-4-methoxybenzenesulfonamide (616 mg) as a white solid.
Reference 17
Synthesis of methyl-3-bromo-4-hydroxyphenylacetate [0175] 3-Bromo-4-hydroxyphenylacetic acid (12.0 g, 0.052 mol) was dissolved in methanol and the solution was stirred at room temperature while thionyl chloride (ten drops) was added. The mixture was stirred for two hours and then concentrated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate and the solution extracted with diethyl ether (x3). The organic layers were collected, washed with water and brine, dried over MgS04-and concentrated in vacuo to give methyl-3-bromo-4-hydroxyphenylacetate as a golden oil (12.6 g).
Reference 18
Preparation of 3-bromo-5-formyl-4-methoxybenzenesulfonamide [0176] 3-Bromo-2-hydroxy-benzaldehyde (27 g, 134 mmol), prepared as described in N. Hofsloekken, L. Skatteboel, "Convenient Method for the ortho-Formylation of Phenols", Acta Chemica Scandinavica, 1999, v.53, p.258-262), was dissolved in dimethylformamide (150 mL) and then cesium carbonate (54.7 g, 170 mmol) was added to the solution portionwise. The mixture was stirred for 30 minutes and then methyl iodide (28.5 g, 201 mmol) was added. The mixture was stirred for 20 hours and poured into water. The product was extracted with ethyl ether and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to give 3-bromo-2-methoxybenzaldehyde (28 g).
[0177] 3 -Bromo-2-methoxybenzaldehyde (28 g, 130 mmol) was combined with trimethylorthoformate (27.5 g, 28.6 mL, 260 mmol) in methanol (150 mL) and then chlorosulfonic acid (0.5 mL) was added dropwise to the mixture. The mixture was stirred for 3 hours and then concentrated by rotoevaporation. The residue was partitioned between ethyl ether and 5% aqueous sodium bicarbonate and the organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated to give 1-bromo-3-dimethoxymethyl-2-methoxybenzene (27.5 g).
[0178] 1-Bromo-3-dimethoxymethyl-2-methoxybenzene (9 g, 35 mmol) was dissolved in methylene chloride (3 mL) and the solution was added dropwise to a 0 EC, vigorous stirring solution of chlorosulfonic acid (50 mL). The mixture then was stirred for 3 hours at 0 EC and let stand for 20 hours at room temperature. The reaction was quenched by pouring the mixture portionwise onto ice (1 kg). The product was extracted with ethyl ether and the organic layer was washed with cold water (x 3) and brine, dried over sodium sulfate, filtered and treated with a stream of gaseous ammonia. Product was purified by flash silica column using hexanes/ethyl acetate mixture (7:3) as an eluent to give 3-bromo-5-formyl-4-methoxybenzenesulfonamide (3.2 g).
Reference 17
Synthesis of /\/-ferf-butyl-3-bromobenzenesulfonamide [0179] ferf-Butylamine (3.14 g, 3.0 mmol, 1.1 eq) and triethylamine (5.94 g, 58.6 mmol, 1.5 eq.) were dissolved in dichloromethane (20 mL) and stirred at room temperature while 3-bromobenzenesulfonyl chloride (10.0 g, 39.1 mmol) was added slowly. The mixture was stirred for 1 hour and then concentrated by evaporation under reduced pressure. The residue was taken up in 5% citric acid and ethyl acetate. The organic layer is washed repeatedly with brine and water, dried over anhydrous magnesium sulfate and concentrated to give A/-ferf-butyl-3-bromobenzenesulfonamide (10.94 g) as a white powder.
Reference 18
Synthesis of 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde [0180] Bispinacolato diboron (3.3 g, 12.8 mmol) and potassium acetate (3.2 g, 32.1 mmol) was added to a stirring solution of 3-bromo-2-(2-methoxyethoxymethoxy)benzaldehyde (3.1 g, 10.7 mmol) in anhydrous dioxane (100 mL) and the mixture was heated at 90 °C for 5 minutes. The mixture was flushed with nitrogen and then dichloro[1,1’-bix(diphe-nylphosphino)ferrocene]Palladium (II) dichloromethane adduct (0.218 g, 0.27 mmol) was added and the reaction was refluxed for 7 to 8 hours. The mixture was cooled to room temperature and then diluted with ethyl acetate. The organic layer was washed with 5% citric acid, brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatography (silica gel) with 100% ethyl acetate to give 2-(2-methox-yethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (40% yield).
[0181] Proceeding as in Reference 18, but substituting 3-bromo-5-fluoro-2-(2-methoxy-ethoxymethoxy)-benzalde-hyde, gave 5-fluoro-2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde.
[0182] Proceeding as in Reference 18, but substituting 3-bromo-5-formyl-4-(2-methoxy-ethoxymethoxy)-phenyl-ace-tonitrile, gave [3-formyl-4-(2-methoxy-ethoxymethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ace-tonitrile.
[0183] Proceeding as in Reference 18, but substituting A/-ferf-butyl-3-bromobenzenesulfonamide (4.4 g, 15.1 mmol) and bispinacolato diboron (5.0 g, 19.7 mmol), gaves A/-fert-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ben-zenesulfonamide (5.31 g) as peach colored crystals.
[0184] Proceeding as in Reference 18, but substituting 3-bromo-4-methoxybenzonitrile (4.77 g, 22.5 mmol) and bis(pi-nacolato)diboron (6.85 g, 27.0 mmol)gave 4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile.
[0185] Proceeding as in Reference 18, but substituting methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-phe- nylacetate (5.0 g, 13.8 mmol) and bis(pinacolato)diboron (4.22 g) gave methyl 3-formyl-4-(2-methoxyethoxy-methoxy)- 5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenylacetate and methyl 5-formyl-4-(2-methoxyethoxymethoxy)-pheny-lacetate in a 2:1 ratio.
[0186] Proceeding as in Reference 18, but substituting 3-bromo-4-methoxyethoxy-methoxybenzonitrile (5.9 g, 20.33 mmol) and bis(pinacolato)diboron (6.2 g, 24.4 mmol), gave 4-methoxyethoxymethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]di-oxaborolan-2-yl)benzonitrile as a crude brown oil.
Reference 19
Synthesis of 1-ferf-butyl-3-[3’-formyl-6,2’-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl]-urea [0187] A 2 M solution of potassium carbonate (2.1 mL) was added to a magnetically stirred mixture of 1-[3-bromo-4-(2-methoxyethoxymethoxy)benzyl]-3-ferf-butylurea (1.4 g, 4.1 mmol), prepared as in Reference 11, and 2-(2-methox-yethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (42 mL, 0.1 mM in toluene, 4.2 mmol), prepared as in Reference 15. The mixture was flushed with nitrogen and then tetrakis(thphenylphosphine)palladium(0) (118 mg, 0.1025 mmol) was added. The mixture was refluxed for 7 hours, cooled and then poured into a mixture of ethyl acetate and 5% citric acid. The organic phase was separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phase was dried and concentrated by evaporation. Product was purified from the residue by chromatography on silica gel utilizing 100% ethyl acetate to give 1-ferf-butyl-3-[3’-formyl-6,2’-bis-(2-methox-yethoxymethoxy)-biphenyl-3-ylmethyl]-urea (1.2 g).
[0188] Proceeding as in Reference 19, but substituting 1-[3-bromo-4-(2-ethoxyethoxymethoxy)benzyl]-3-ferf-butylurea (1,0g, 2.9 mmol) and 5-fluoro-2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzalde-hyde (29 mL, 0.1 mM in toluene, 2.9 mmol) gave 1-ferf-butyl-3-[5’-fluoro-3’-formyl-6,2’-bis-(2-methoxyethoxymethoxy)bi-phenyl-3-ylmethyl]-urea (0.854 g).
[0189] Proceeding as in Reference 19, but substituting 3-bromo-2-hydroxy-5-methylbenzaldehyde (0.60 g, 2.5 mmol) and /V-ferf-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (0.846 g, 2.5 mmol), gave N-ferf-butyl-3’-formyl-2’-(2-methoxyethoxymethoxy)-5’-methyl-biphenyl-3-sulfonamide (0.87 g) [0190] Proceeding as in Reference 19, but substituting methyl 3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)-ben-zoate (2.00 g, 5.76 mmol, 1.0 eq.) and A/-ferf-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (1.95 g, 5.76 mmol, 1.0 eq.), gave methyl 3’-ferf-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymethoxy)-biphenyl-3-car-boxylate (2.16 g) as a yellow gum.
[0191] Proceeding as in Reference 19, but substituting 4-benzyloxy-3-bromo-5-formyl-benzoic acid methyl ester (1.0 g, 2.71 mmol) and 5-fluoro-2-methoxyphenyl boronic acid (0.691 g, 4.16 mmol), gave 6-benzyloxy-5’-fluoro-5-formyl-2’-methoxybiphenyl-3-carboxylic acid methyl ester (0.620 g).
[0192] Proceeding as in Reference 19, but substituting 3-bromo-4-(2-methoxyethoxymethoxy)phenylacetate (2.43 g, 7.28 mmol) and 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzaldehyde in toluene (7.28 mmol, 0.1 M, 73 mL), gave methyl [3’-formyl-6,2’-bis(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (2.42 g).
[0193] Proceeding as in Reference 19, but substituting 3-bromo-/V-fert-butyl-4-methoxybenzenesulfonamide (1.45 g, 4.5 mmol) and methyl 3-formyl-4-(2-methoxyethoxy-methoxy)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyla-cetate, gave [5’-ferf-butylsulfamoyl-5-formyl-2’-methoxy-6-(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (1.56 g, 77%). LCMS: Calcd 451.53; Obsd (M+23) = 474.0, (MH-) = 450.1.
[0194] Proceeding as in Reference 19, but substituting 3-bromo-/\/-ferf-butyl-4-methoxybenzenesulfonamide and methyl 3-formyl-4-(2-methoxyethoxy-methoxy)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzoate, gave methyl 6-benzyloxy-5’-ferf-butylsulfamoyl-5-formyl-2’-methoxy-biphenyl-3-carboxylate.
[0195] Proceeding as in Reference 19, but substituting ferf-butyl (3-bromo-benzyl)-carbamate (0.9 g, 3.2 mmol) and 4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.9 g, 3.5 mmol), gave tert-butyl (5’-cyano-2’-methoxybiphenyl-3-ylmethyl)carbamate (0.73 g, 68%) as white foam.
[0196] Proceeding as in Reference 19, but substituting 3-bromo-2-(methoxyethoxymethoxy)-5-[1-(methoxyethoxyme-thyl)-1H-tetrazol-5-yl]benzaldehyde (0.93 g, 2.09 mmol) and 4-methoxyethoxymethoxy-3-(4,4,5,5-tetramethyl-[1,3,2]di-oxaborolan-2-yl)benzonitrile (1.04 g, 3.14 mmol), gave a regioisomeric mixture of 3’-formyl-6,2’-(methoxyethoxymeth-oxy)-5’-(1-methoxyethoxymethyl-1 H-tetrazol-5-yl)biphenyl-3-ylcarbonitrile (0.3 g).
[0197] Proceeding as in Reference 19, but substituting A/-acetyl-3-bromo-5-formyl-4-methoxy-benzenesulfonamide (335 mg, 1.0 mmol) and N-ferf-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (373 mg, 1.1 mmol), gave A/-acetyl-/\/’-fert-butyl-5-formyl-6-methoxy-biphenyl-3,3’-disulfonamide (242 mg) as a pale yellow oil.
[0198] Proceeding as in Reference 19, but substituting 3-bromo-A/-butyl-5-formyl-4-methoxy-benzenesulfonamide (0.65 g, 1.72 mmol) and N-ferf-butyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzenesulfonamide (0.64 g, 1.90 mmol, 1.1 eq.), gave A/-butyl-/\/’-ferf-butyl-5-formyl-6-methoxy-biphenyl-3,3’-disulfonamide (0.74 g) as on orange oil.
[0199] Proceeding as in Reference 19, but substituting 2-bromo-6-(2-methoxy-ethoxymethoxy)-benzaldehyde provid- ed 3’-formyl-4’-(methoxyethoxymethoxy)-A/-ferf-butyl-biphenylsulfonamide.
[0200] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide (0.9 g, 3.1 mmol) and 2-methoxybenzene boronic acid (0.51 g, 3.37 mmol), gave 5-formyl-6,2=-dimethoxy-biphenyl-3-sulfonamide (0.75 g).
[0201] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-nitrobenzene boronic acid, gave 5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide.
[0202] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-chlorobenzene boronic acid, gave 3’-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
[0203] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-ami-nobenzene boronic acid, gave 3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
[0204] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-ure-idobenzene boronic acid, gave 5-formyl-6-methoxy-3’-ureido-biphenyl-3-sulfonamide.
[0205] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-meth-oxybenzene boronic acid, gave 5-formyl-3’,6-dimethoxy-biphenyl-3-sulfonic acid amide.
[0206] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 3-chlo-robenzene boronic acid, gave 3’-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
[0207] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and benzene boronic acid, gave 5-formyl-6-methoxy-biphenyl-3-sulfonic acid amide.
[0208] Proceeding as in Reference 19, but substituting 3-bromo-5-formyl-4-methoxy-benzenesulfonamide and 5-cy-ano-2-methoxy-benzeneboronic acid, gave 5’-cyano-5-formyl-6,2’-dimethoxybiphenyl-3-sulfonamide.
[0209] Proceeding as in Reference 19, but substituting methyl-3-formyl-4-hydroxy-5-bromophenylacetate (2.47 g, 9.0 mmol) and 2-methoxymethoxy-5-fluorophenylboronic acid (2.0 g, 10.0 mmol), gave methyl 5’-fluoro-5-formyl-6-hydroxy-2’-methoxymethoxy-biphenyl-3-yl)-acetate (2.2 g, 70%) as a yellow oil which crystallized overnight.
[0210] Proceeding as in Reference 19, but substituting ferf-butyl [3-bromo-4-(2-methoxyethoxymethoxy)-benzyl]car-bamate (2.3 g, 5.9 mmol) and 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzalde-hyde (60 mL, 0.1 M in toluene), gave ferf-butyl [3’-formyl-6,2’-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]car-bamate (2.96 g).
Reference 20
Synthesis of 1-tert-butyl-3-[3’-formyl-2’-hydroxy-5’-(1/-/-tetrazol-5-yl)-biphenyl-3-ylmethyl]urea [0211] ferf-Butyl (5’-cyano-2’-methoxy-biphenyl-3-yl-methyl)-carbamate(0.73g, 2.16 mmol), prepared as in Reference 19, and azidotributyltin (0.9 mL, 3.2 mmol) was dissolved in toluene (5 mL) and the solution was refluxed for 14 hours. The mixture cooled to room temperature and then workup with ethyl acetate and IN HCI gave a slurry. The slurry was dried by rotovap and then triturated with hexanes. The solids were collected by filtration and treated with hydrobromic acid (48% aqueous, 15 mL). The mixture was refluxed for 14 hours at 120 °C and then diluted with water (50 mL). The dilution was dried by lyophilization to give 3’-aminomethyl-5-(1/-/-tetrazol-5-yl)-biphenyl-2-ol (0.4 g).
[0212] 3’-aminomethyl-5-(1/-/-tetrazol-5-yl)-biphenyl-2-ol (0.31 g, 1.16 mmol) was dissolved in dimethylformamide (10 mL) and the solution was treated with triethylamine (0.8 mL, 5.8 mmol) and ferf-butylisocyanate (0.14 mL, 1.27 mmol). The mixture was stirred at room temperature for 2 hours. Workup with ethyl acetate and water, followed by drying afforded 0.56 g (quant.) of the crude 1-ferf-butyl-3-[2’-hydroxy-5’-(1/-/-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea.
[0213] 1-ferf-Butyl-3-[2’-hydroxy-5’-(1/-/-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea (0.56 g, 1.5 mmol) was dissolved in a mixture of chloroform (0.2 mL, 3 mmol) and sodium hydroxide (10% aqueous, 5 mL, 12 mmol) and the mixture was refluxed for 5 days. The mixture was worked up with IN hydrochloric acid and ethyl acetate. Some solids precipitated out of solution and were filtered and dried. The organic layer from the extraction was dried and combined with the solids above gives 1-ferf-butyl-3-[3’-formyl-2’-hydroxy-5’-(1/-/-tetrazol-5-yl)-biphenyl-3-ylmethyl]-urea as a 3:1 mixture of starting material to product.
Reference 21
Synthesis of A/-(3-Phenylpropionyl)-5-formyl-6,2=-dimethoxy-biphenyl-sulfonamide [0214] 5-Formyl-6,2=-dimethoxy-biphenyl-3-sulfonamide(0.32g, 1 mmol), prepared as in Reference 19, was dissolved along with triethylamine (0.125 g, 1.25 mmol) and 4-dimethylaminopyridine (0.012 g, 0.1 mmol) in methylene chloride (30 mL) and then 3-phenylpropionyl chloride (0.2 g, 1.15 mmol) was added dropwise to the solution. The mixture was stirred for 12 hours and concentrated by rotoevaporation in vacuum. The residue was partitioned between ethyl acetate and 5% aqueous citric acid and the organic layer was separated washed with water and brine, dried over magnesium sulfate and then concentrataed in vacuum to give N-(3-phenylpropionyl)-5-formyl-6,2=-dimethoxy-biphenyl-sulfonamide (0.4 g).
[0215] Proceeding as in Reference 21, but substituting 3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenylpropionyl chloride, gave N-(3-phenylpropionyl)-3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
[0216] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide and acetyl chloride, gave A/-acetyl-5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide.
[0217] Proceeding as in Reference 21, but substituting 3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and acetyl chloride, gave A/-acetyl-3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
[0218] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide and benzoyl chloride, gave A/-benzoyl-5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide.
[0219] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide and 4-phenylbutyryl chloride, gave 5-formyl-6-methoxy-3’-nitro-/\/-(4-phenylbutyryl)-biphenyl-3-sulfonamide.
[0220] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide and 2-phenylacetyl chloride, gave 5-formyl-6-methoxy-3’-nitro-/V-(2-phenylacetyl)-biphenyl-3-sulfonamide.
[0221] Proceeding as in Reference 21, but substituting 3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 4-phenylbutyryl chloride, gave 3’-amino-5-formyl-6-methoxy-/\/-(4-phenylbutyryl)-biphenyl-3-sulfonamide.
[0222] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide and 3-(3,4-dichlorophenyl)-propanoyl chloride, gave /\/-[3-(3,4-dichlorophenyl)-propanoyl]-5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide.
[0223] Proceeding as in Reference 21, but substituting 3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamideand benzoyl chloride, gave N-benzoyl-3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
[0224] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-ureido-biphenyl-3-sulfonamide and 2-phenylacetyl chloride, gave 5-formyl-6-methoxy-/\/-(2-phenylacetyl)-3’-ureido-biphenyl-3-sulfonamide.
[0225] Proceeding as in Reference 21, but substituting 5-formyl-6,2’-dimethoxy-biphenyl-3-sulfonamide and 3-phe-nylpropionyl chloride, gave 5-formyl-6,2’-dimethoxy-A/-(3-phenylpropionyl)-biphenyl-3-sulfonamide.
[0226] Proceeding as in Reference 21, but substituting 3’-chloro-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenylpropanoyl chloride, gave 3’-chloro-5-formyl-6-methoxy-/\/-(3-phenylpropanoyl)-biphenyl-3-sulfonamide.
[0227] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenyl-propanoyl chloride, gave 5-formyl-6-methoxy-/\/-(3-phenyl-propanoyl)-biphenyl-3-sulfonamide.
[0228] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-nitro-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 5-formyl-6-methoxy-3’-nitro-A/-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
[0229] Proceeding as in Reference 21, but substituting 3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 3’-amino-5-formyl-6-methoxy-A/-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
[0230] Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3’-ureido-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 5-formyl-6-methoxy-A/-(3-pyridin-3-ylpropanoyl)-3’-ureido-biphenyl-3-sulfonamide.
[0231] Proceeding as in Reference 21, but substituting 3’-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-piperidin-3-ylpropanoyl chloride, gave 3’-amino-5-formyl-6-methoxy-A/-(3-piperidin-3-ylpropanoyl)-biphenyl-3-sulfona-mide.
Reference 22
Synthesis of A/-(3-phenylpropionyl)-5-formyl-6,2=-dihydroxy-biphenyl-3-sulfonamide [0232] A/-(3-Phenylpropionyl)-5-formyl-6,2=-dimethoxy-biphenyl-sulfonamide (0.4 g, 0.88 mmol) was dissolved in methylene chloride (5 mL) and the solution was stirred while a boron tribromide (2 mL, 1 M in methylenechloride, 2 mmol) was added. The mixture was stirred for 36 hours and then concentrated in vacuum. The residue was dissolved in ethyl acetate and the solution was shaken with 5% aqueous sodium bicarbonate (10 mL). The mixture was acidified to pH 3 with 5% aqueous citric acid. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated in vacuum to a minimal volume. The residue was passed through short silica column, using hexanes/ethyl acetate (1:1) to give A/-(3-phenylpropionyl)-5-formyl-6,2=-dihydroxy-biphenyl-3-sulfonamide (0.21 g, 53%). MS: found (M-H) 424.1, (M+H) 426.2, calc 425.09.
[0233] Proceeding as in Reference 22, but substituting 3-bromo-4-methoxyphenylacetic acid (14.0 g, 0.057 mol) and boron tribromide (63 mL, 1M in dichloromethane, 0.063 mol), gave 3-bromo-4-hydroxyphenylacetic acid (12 g).
Reference 23 [5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoylbiphenyl-3-yl]acetic acid [0234] Methyl [5’-ferf-butylsulfamoyl-5-formyl-2’-methoxy-6-(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (0.496 g, 1.1 mmol), prepared as in Reference 8, was dissolved in methanol (20 mL) and the solution was charged with 3,4-diaminobenzamidine-HCI (1.25 mmol, 0.23 g) and 1,4-benzoquinone (1.25 mmol, 0.135 g). The mixture was refluxed for 2 hours and then concentrated by evaporation. This residue was taken up in trifluoroacetic acid (10 mL) and the mixture was stirred for 1 hour. Evaporation and further pumping down yielded a purple amorphous residue. Pyridine hydrochloride (5.0 g) was added and the reaction mixture was heated at 180° C for 30 minutes. The mixture was cooled and a resulting solid was dissolved in 20 mL of preparative hplc sample solvent (20% acetonitrile/20 mmol HCI). The product was purified by preparative hplc (C-18, 2,2,25 acetonitrile). The fractions containing the pure product were collected and lyophilized to give [5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoylbiphenyl-3-yljacetic acid (0.31 g, 59 %). LCMS: Calcd 481.49; Obsd (MH+) = 482.0, (MH-) = 480.2. NMR (DMSO-d6) d 3.621 (s, 2H), 7.07 (d, J=8 Hz, 1H), 7.15 (brs, 2H), 7.27 (d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.65 (m, 2H), 7.73 (d of d, J=2, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.08 (d, J=2 Hz, 1H), 8.17 (s, 1H), 9.10, 9.39 (2s, 4H).
[0235] Proceeding as in Reference 23, but substituting 3’-ferf-butylsulfamoyl-5-formyl-6-(2-methoxyethoxymeth-oxy)-biphenyl-3-carboxylic acid methyl ester (1.64g, 3.42 mmol, 1.0 eq.) and 3,4-diamino-benzamidine hydrochloride (638 mg, 3.42 mmol, 1.0 eq.), gave 5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6-hydroxy-3’-sulfamoyl-biphenyl-3-car-boxylic acid hydrochloride (650 mg) as a brown solid.
[0236] Proceeding as in Reference 23, but substituting 6-benzyloxy-5’-fluoro-5-formyl-2’-methoxybiphenyl-3-carbox-ylic acid methyl ester (1.3 g, 3.30 mmol) and 3, 4-diaminobenzamidine hydrochloride (0.739 g, 3.96 mmol), gave 5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-carboxylic acid (0.780 g).
[0237] Proceeding as in Reference 23, but substituting methyl 5’-fluoro-5-formyl-6-hydroxy-2’-methoxymethoxy-bi-phenyl-3-yl)-acetate (400 mg, 1.1 mmol) and 3,4-diaminobenzamidine hydrochloride (235 mg, 1.2 mmol), gave 3-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-2-yl-acetic acid (201 mg, 40%). EXAMPLE 1
Synthesis of 2-(2,2’-dihydroxy-5’-ureidomethylbiphenyl-3-yl)-1 H-benzoimidazole-5-carboxamidine hydrochloride (Compound 10) [0238]
[0239] 1-ferf-Butyl-3-[3’-formyl-6,2’-bis-(2-methoxyethoxymethoxy)-biphenyl-3-ylmethyl]-urea (0.6g, 1.15 mmol), prepared as in Reference 19, diaminobenzamidine hydrochloride (0.3 g, 1.6 mmol) and 1,4-benzoquinone (0.124 g, 1.15 mmol) were combined in methanol (15 mL) and the mixture was heated at 60 °C and stirred for 2 hours. The mixture was cooled to room temperature and the solvent was removed by evaporation to yield 2-[5’-(3-ferf-butylureidomethyl)-2,2’- bis-(2-methoxyethoxymethoxy)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxami-dine.
[0240] 2-[5’-(3-ferf-Buty lureidomethy 1)-(2,2’-bis-(2-methoxyethoxymethoxy)-biphenyl-3-yl]-1H-benzoimidazole-5-car-boxamidine was dissolved in 4 M hydrogen chloride indioxane(4 mL) and the solution was a stirred at room temperature for 1 hour. Solvent was removed by evaporation and the residue was dissolved in neat trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 8 hours and then concentrated by evaporation. Product was purified from the residue by reverse preparative HPLC (acetonitrile/HCl/water) to give 2-(2,2’-dihydroxy-5’-ureidomethylbiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine hydrochloride (33 mg). MS LCMS Q+ 417.439 (M+1) (calc.), Q" 415.439 (M-1) (calc.), (obs.); Q+ 417.3 (M+1), Q“ 415.3 (M-1). 1H-NMR (d6-DMSO) δ ppm: 4.03 (2 H, s), 6.78 (1 H, d, J = 8 Hz), 6.99 (3 H, m), 7.25 (1 H, dd, J = 7.6, 2 Hz), 7.65 (1 H, dd, J = 8.8,1.6 Hz), 7.76 (1 H, d, J = 8.4 Hz), 8.06 (1 H, dd, J = 7.6, 0.8 Hz), 8.09 (1 H, br s), 8.91 (2 H, br s) and 9.27 (2 H, br s).
[0241] Proceeding as in Example 1, but substituting 1-ferf-butyl-3-[5’-fluoro-3’-formyl-6,2’-bis-(2-methoxyethoxymeth-oxy)biphenyl-3-ylmethyl]-urea, gave 2-(5-fluoro-2,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl)-1 H-benzoimidazole-5-carboxamidine hydrochloride (Compound 1). MS LCMS 433.423 (M-1) (calc.), 435.423 (M+1) (calc.), (obs.); Q+ 435.3 (M+1), Q-433.3 (M-1). 1H-NMR (d6-DMSO) δ ppm: 4.17 (2 H, s), 6.38 (1 H, brs), 6.87 (1 H, d, J= 8.4 Hz), 7.07 (1 H, dd, J = 8.4, 2.4 Hz), 7.12 (1 H, d, J = 2 Hz), 7.2 (1 H, dd, J = 9.2, 3.2 Hz), 7.73 (1 H, br d, J = 8 Hz), 7.86 (1 H, d, J = 8 Hz), 8.01 (1 H, dd, J = 9.2, 2.8 Hz), 8.18 (1 H, br s), 8.96 (2 H, br s) and 9.35 (2 H, br s) [0242] Proceeding as in Example 1, but substituting [3-formyl-4-(2-methoxy-ethoxymethoxy)-5-(4,4,5,5-tetrame-thyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile and 1-[3-bromo-4-(2-ethoxyethoxymethoxy)-benzyl]-3-ferf-butylurea, gave 2-(5-cyanomethyl-2,2’-dihydroxy-5’-ureidomethyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine hydrochloride (Compound 21). MS LCMS Q+ 456.476 (M+1) (calc.), Q‘ 454.476 (M-1) (calc.), (obs.); Q+ 456.3 (M+1), Q“ 454.3 (M-1). 1H-NMR (d6-DMSO) δ ppm: 4.14 (2 H, s), 4.17 (2 H, s), 6.92 (1 H, d, J= 9.2 Hz), 7.12 (2 H, m), 7.36 (1 H, d, J = 2.4 Hz), 7.77 (1 H, d, J = 8.4 Hz), 7.90 (1 H, d, J = 8.8 Hz), 8.14 (1 H, d, J= 1.6 Hz), 8.23 (1 H, br s), 9.0 (2 H, br s) and 9.4 (2 H, brs).
[0243] Proceeding as in Example 1, but substituting N-ferf-butyl-3’-formyl-2’-(2-methoxyethoxymethoxy)-5’-methyl-biphenyl-3-sulfonamide, gave 2-(5-methyl-2-hydroxy-3’-aminosulfonylbiphenyl-3-yl)-1H-benzoimidazole-5-carboxami-dine hydrochloride (Compound 52). MS LCMS Q+ 422.479 (M+1) (calc.), Q' 420.479 (M-1) (calc.), (obs.); Q+ 422.3 (M+1), Q-420.3 (M-1). 1H-NMR (d6-DMSO) δ ppm: 2.34 (3 H, s), 7.3 (1 H, d, J = 1.6 Hz), 7.32 (2 H, brs), 7.56 (1 H, t, J= 8 Hz), 7.64 (1 H, br m), 7.73 (1 H, t of d, J = 8.8,1.2 Hz), 7.77 (2 H, m), 7.98 (1 H, brs), 8.03 (1 H, t, J= 1.2 Hz), 8.88 (2 H, brs) and 9.28(2 H, brs).
[0244] Proceeding as in Example 1, but substituting 1-ferf-butyl-3-[3’-formyl-2’-hydroxy-5’-(1H-tetrazol-5-yl)-biphenyl-3-ylmethyl]urea, gave 2-[2-hydroxy-5-(1 H-tetrazol-5-yl)-3’-ureidomethylbiphenyl-3-yl]-1 H-benzoimidazole-5-carboxami-dine (0.01 g) as a brown solid (Compound 56). LCMS calcd. 468.48; obsvd. (M+H) 469.1, (M-H) 467.2. EXAMPLE 2
Synthesis of 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6-hydroxy-A/-dimethyl-3’-sulfamoyl-biphenyl-3-carboxamide hydrochloride (Compound 9) [0245]
[0246] 5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6-hydroxy-3’-sulfamoyl-biphenyl-3-carboxylic acid hydrochloride (29 mg, 60 μπιοΙ, 1.0 eq.), prepared as in Reference 23, triethylamine (17 mg, 120 μπιοΙ, 2.0 eq.), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (29 mg, 66 μπιοΙ, 1.1 eq.) and S-pyrrolidine-2-carboxamide (6.9 mg, 60 μπιοΙ, 1.0 eq.) in anhydrous dimethyformamide (4 mL) were stirred at ambient temperature for 21 hours and then a further half-equivalent of each reagent was added to the reaction mixture. The mixture was stirred for 28 hours and then concentrated. A dimethyl amide by-product was purified from the residue by reverse-phase preparative HPLC (5—>30% acetonitrile/20mM aqueous hydrochloric acid). Fractions containing product were concentrated by lyophilization to give 5-(5-carbamimidoyl-1 /-/-benzoimidazol-2-yl)-6-hydroxy-A/-dimethyl-3’-sulfamoyl-biphenyl-3-carboxamide hydrochloride (1.8 mg, 6%) as a yellow-brown solid. 1H NMR (400 MHz, d6-DMS0/D20): δ 9.40-9.32 (brs, 2H), 8.95-8.86 (brs, 2H), 8.29 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.88-7.84 (m, 2H), 7.82 (d, J= 7.3 Hz, 1H), 7.72 (d, J= 8.4 Hz, 1H), 7.65 (t, J = 7.3Hz, 1H), 7.57 (s, 1H). 3.04 (brs, 1H). m/z (LCMS-ESI): Q+4.79 (M+H); CM77(M-H). EXAMPLE 3
Synthesis of 2-[5-(2S-aminocarbonylpyrrolidin-1-ylcarbonyl)-2,2’-dihydroxy-5’-fluorobiphenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine hydrochloride (Compound 22) [0247]
[0248] 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-carboxylicacid (0.030g, 0.068 mmol), prepared as in Reference 23, was dissolved in dimethylformamide (5 mL) and then S-pyrrolidine-2-carboxamide (0.0074 g, 0.065 mmol) and benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.032 g, 0.072 mmol) were added to the solution. Triethylamine (0.018 mL, 0.130 mmol) was added and the mixture was stirred for 24 hours and then was concentrated. Product was purified from the residue by reverse phase HPLC to give (S)- 1-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-carbonyl]-pyrrolidine-2-carboxam-ide hydrochloride (9 mg) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (br-s, 1H), 8.93 (br-s, 1H), 8.42 (br-s, 1H), 8.17(br-s, 1H), 7.83 (br-d, J=8.35,1H),7.72(m, 1H), 7.42 (br-s, 1H), 7.05 (m, 2H), 6.93 (m, 1H),4.39 (t, J = 7.12, 1H), 3.79 (m, 1H), 3.59 (m, 1H), 2.20 (m, 2H), 1.85 (m, 2H). ESIMS m/z: M+ 503.1. EXAMPLE 4
Synthesis of 1-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-carbonyl]-4R-hydroxy-pyrrolidine-2S-carboxylic acid hydrochloride (Compound 7) [0249]
[0250] 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-carboxylie acid (0.250 g, 0.565 mmol), prepared as in Reference 23, was dissolved in A/,A/-dimethylformamide (7 mL) and then methyl (S)-trans-4-hydroxypyrrolidine-2-carboxylate (0.098 g, 0.538 mmol) and 2,3,4-trimethyl-pyridine (0.228 g, 1.88 mmol) were added to the solution. The mixture was cooled to 0 °C and 0-(7-azabenzotrizol-1-yl)-1,2,3,3-tetramethyluroniumhexafluoro-phosphate (0.225 g, 0.592 mmol) was added. The mixture was stirred at 0 °C for one hour and then at room temperature for 20 hours. The mixture was concentrated and the residue taken up in 0.5 N hydrochloric acid (20 mL). The mixture was heated to 80 °C and stirred for 6 hours. The mixture was concentrated and product purified from the residue by reverse phase HPLC to give 1-[5-(5-carbamimidoyl-1 H-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-carbon-yl]-4R-hydroxy-pyrrolidine-2S-carboxylic acid hydrochloride (0.064 g) as a yellow powder. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (br-s, 1H), 9.13 (br-s, 1H), 8.42 (br-s, 1H), 8.20(br-s, 1H), 7.85 (br-d, J=8.71, 1 H), 7.75 (br-d, J = 8.37, 1H), 7.58 (br-s, 1H), 7.10 (m, 1H), 7.03 (m, 1H), 6.96 (m, 1H), 4.54 (t, J= 8.39, 1H), 4.31 (br-s, 1H), 3.97 (dd, J = 11.64, 3.85, 1 H), 3.50 (d,J= 10.99, 1H), 2.23 (m, 1H), 1.97 (m, 1H). ESIMS m/z: M+ 520.3 EXAMPLE 5
Synthesis of 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-/\/-pyridin-4-ylmethyl-biphenyl-3-car-boxamide hydrochloride (Compound 4) [0251]
[0252] 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-carboxylic acid hydrochloride (100 mg, 0.226 mmol), prepared as in Reference 23, 0-(7-azabenzotrizol-1-yl)-1,2,3,3-tetramethyluroniumhexafluoro-phosphate monohydrate (37 mg, 0.242 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (46 mg, 0.237 mmol) were dissolved in anhydrous A/,A/-dimethylformamide (10 mL). The mixture was stirred at room temperature for 1 hour and then 4-aminomethylpyridine (27 mg, 0.248 mmol) was added to the mixture. The mixture was stirred at ambient temperature for 18 hours and then concentrated to a gum under high vacuum. The residue was dissolved in 5% acetonitrile/95% 20 mM hydrochloric acid (10 mL) and product purified via preparative C18 reverse phase HPLC (5% to 35% acetonitrile gradient, 20 mM HCI aqueous to give 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-A/-pyridin-4-ylmethyl-biphenyl-3-carboxamide hydrochloride (50 mg) as a tan powder. 1H-NMR (d6-DMSO) δ ppm: 9.45 (bs, 2H), 9.20 (bs, 2H) 9.11 (d, J = 1.6 Hz, 1H), 8.86 (d, J = 6.4 Hz, 2H), 8.22 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 6.4 Hz, 2H), 8.00 (d, J= 2.0 Hz, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.78 (dd, J= 8.8, 1.6 Hz, 1H), 7.14-6.96 (m, 3H), 4.79 (d, J= 5.6 Hz, 2H): MS LCMS Q+ 497.174 (calc.), 497.2 (obs.), Q‘ 495.158 (calc.), 454.9 (obs). EXAMPLE 6
Synthesis of 2-[3’-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-biphenyl-3-yl]-acetamide (Compound 11) [0253]
[0254] Methyl [3’-formyl-6,2’-bis(2-methoxyethoxymethoxy)biphenyl-3-yl]acetate (1.2 g, 2.59 mmol), prepared as in Reference 19, was dissolved in methanol (20 mL) and the solution was charged with 3,4-diaminobenzamidine hydro-chlroide (0.58 g, 3.11 mmol) and 1,4-benzoquinone (0.28 g, 2.59 mmol). The mixture was refluxed for 3 hours and then concentrated by evaporation. The residue was dissolved in methanol (10 mL) and treated with 4 M hydrogen chloride in dioxane (10 mL). The solution was stirred for two hours and then concentrated by evaporation. The residue was dissolved in ammonia in methanol (20 mL, 7 M). The solution was transferred to a sealed tube and heated at 60° for two days while stirring. The solution was cooled and concentrated. Product was purified from the residue by preparative hplc (2, 2, 30) acetonitrile. The desired fractions containing product were pooled and concentrated by evaporation to give 2-[3’-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-biphenyl-3-yl]-acetamide (420 mg). LCMS: Calcd 401.4; Obsd (MH+) 402.2, (MH-) 400.0. NMR (DMSO-d6) d 3.26 (s, 2H), 6.80 (s, 1H), 6.83 (d, J = 9 Hz, 1H), 7.07 (m, 2H), 7.38 (m,2H), 7.73 (d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 8.16 (d, J = 1 Hz, 1H), 8.18 (s, 1H), 9.03 (s, 2H), 9.39 (s, 2H). EXAMPLE 7
Synthesis of 2-(2,2’-dihydroxy-5-(1 /-/-tetrazol-5-yl)-3’-aminomethylbiphenyl-3-yl]-1 /-/-benzoimidazole-5-carboxamidine (Compound 57) [0255]
[0256] 3’-Formyl-6,2’-(2-methoxyethoxymethoxy)-5’-(2-methoxyethoxymethyl)-1/-/-tetrazol-5-ylbiphenyl-3-ylcarboni-trile (0.3 g, 0.5 mmol), 3,4-diaminobenzamidine hydrochloride (0.11 g, 0.6 mmol) and 1,4-benzoquinone (0.05 g, 0.5 mmol) were combined in methanol (15 mL) and the mixture was refluxed for 4 hours. 4M hydrogen chloride in dioxane (3 mL) was added to the mixture and stirring was continued at room temperature for 14 hours. The mixture was concentrated by evaporation. The residue was dried under high vacuum and then dissolved in methanol (50 mL). The solution was subjected to hydrogenation (balloon) using 10% Pearlman’s catalyst. Filtration and drying afforded 2-(2,2’-dihydroxy-5-(1/-/-tetrazol-5-yl)-3’-aminomethylbiphenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine as the crude product (0.2 g,, 88%). LCMS calcd. 441.17, obsrvd. (M+H) 442.2, (M-H) 440.2. EXAMPLE 8
Synthesis of 2-(2,2’-dihydroxy-5-(1 /-/-tetrazol-5-yl)-3’-ureidomethylbiphenyl-3-yl]-1 /-/-benzoimidazole-5-carboxamidine (Compound 13) [0257]
[0258] 2-(2,2’-Dihydroxy-5-(1 /-/-tetrazol-5-yl)-3’-aminomethylbiphenyl-3-yl]-1 /-/-benzoimidazole-5-carboxamidine (0.2 g 0.2 mmol), prepared as in Example 7, was dissolved in methanol (10 mL). The solution was treated with triethylamine (0.2 mL, 1.5 mmol) and then potassium cyanate (0.09 g, 1.1 mmol aqueous solution, 0.5 mL) was added in 3 portions over 1 hour. IN hydrochloric acid (5mL) was added and the mixture was stirred at 50 °C over 3 days. Drying afforded crude product, which was subjected to purification by reverse phase HPLC to give 2-(2,2’-dihydroxy-5-(1/-/-tetrazol-5-yl)-3’-ureidomethylbiphenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine (0.008 g) as a brown solid. LCMS calcd. 484.47, obsrvd. (M+H) 485.1, (M-H) 483.1. EXAMPLE 9
Synthesis of 2-(5-acetylsulfamoyl-2-hydroxy-3’-sulfamoyl-biphenyl-3-yl)-1/-/-benzoimidazole-5-carboxamidine (Compound 31) [0259]
[0260] /\/-acetyl-/\/-ferf-butyl-5-formyl-6-methoxy-biphenyl-3,3’-disulfonamide (100 mg, 0.21 mmol), prepared as in Reference 19, was dissolved in dichloromethane (10 mL). The solution was flushed with nitrogen for 5 minutes and then boron tribromide (1.0 mL, 1M solution in dichloromethane) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under by evaporation under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The residue was passed through a short silica plug with pure ethyl acetate to give A/-acetyl 5-formyl-6-hydroxy-biphenyl-3,3’-disul-fonamide (74 mg) as a colorless oil.
[0261] A/-acetyl 5-formyl-6-hydroxy-biphenyl-3,3’-disulfonamide (74 mg, 0.19 mmol) was dissolved in methanol (10 mL)and stirred at room temperature. 3,4-Diaminobenzamidine (39 mg, 0.21 mmol) and 1,4-benzoquinone (20 mg, 0.2 mmol) were added to the solution and the mixture was refluxed for 1 hour. The solvent was removed by rotary evaporation under reduced pressure and the residue was dissolved in water and acetonitrile and purified by reverse phase HPLC (0.02N HCI / ACN) to give 2-(5-acetylsulfamoyl-2-hydroxy-3’-sulfamoyl-biphenyl-3-yl)-1 /-/-benzoimidazole-5-carboxami-dine (14.1 mg) as a yellow amorphous powder. MS mlz: 527.4 (M-H+) and 529.3 (M+H+). 1H NMR (400 MHz, DMSO-d6): 6 9.36 (bs, 2H), 8.94 (bs, 2H), 8.08 (d, J = 2.2 Hz, 1H), 8.22 (bs, 1H), 8.10 (t, J= 1.5 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H) 7.89 (d, J= 1.8 Hz, 1H), 7.87-7.85 (m, 2H), 7.76 (dd, J= 10, 1.5 Hz, 1H), 7.71 (t, J= 7.7 Hz, 1H), 7.46 (s, 2H) and 1.96 (s, 3H).
[0262] Proceeding as in Example 9, but substituting A/-butyl-/\/-ferf-butyl-5-formyl-6-methoxy-biphenyl-3,3’-disulfona-mide (352 mg, 0.69 mmol) gave 2-(5-butylsulfamoyl-2-hydroxy-3’-sulfamoyl-biphenyl-3-yl)-1H-benzoimidazole-5-car-boxamidine (Compound 15). MS mlz: 569.2 (M-H+) and 571.2 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 9.35 (bs, 2H), 8.91 (bs, 2H), 8.80 (s, 1H), 8.21 (t, J = 1.5 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.95 (t, J = 1.5 Hz, 1H), 7.93 (t, J = 1.5 Hz, 1H), 7.87 (t, J= 1.5 Hz, 1H), 7. 85 (t, J= 1.5 Hz, 1H), 7.75 (d, J = 12.2 Hz, 1H) 7.70 (t, J = 8.0 Hz, 1H), 7.21 (s, 2H), 3.57 (t, J= 8.0 Hz, 2H), 1.71 (q, J= 11.1,11.1,7.6 Hz, 2H), 1.43 (sext, J = 22.2,11.1,7.6 Hz, 2H), and 0.89 (t, J= 7.3 Hz, 3H).
[0263] Proceeding as in Example 9, but substituting 3’-formyl-4’-(methoxyethoxymethoxy)-A/-ferf-butyl-biphenylsul-fonamide which was dissolved in neat TFA (5 mL) and stirred overnight to give 3’-formyl-4’-hydroxybiphenyl-3-sulfonic acid amide which was converted to 2-(2-hydroxy-3’-aminosulfonylbiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine (Compound 14). MS mlz: 406.2 (M-H+) and 408.3 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 9.35 (bs, 2H), 8.97 (bs, 2H), 8.23 (d, J = 7.3 Hz, 1H), 8.11 (t, J= 1.5 Hz, 1H), 7.85 (t, J = 1.5 Hz, 1H), 7.83 (t, J= 1.5 Hz, 1H), 7.82 (t, J = 1.5 Hz, 1H), 7.80 (t, J= 1.5 Hz, 1H), 7.31 (d, J=9.1 Hz, 1H) 7.64 (t,J = 8A Hz, 1H), 7.54 (dd, J= 8.1, 1.5 Hz, 1H), 7.39 (s, 2H) and 7.19 (t, J = 7.7 Hz, 1H). EXAMPLE 10
Synthesis of 2-[2,2’-dihydroxy-5-(3-phenylpropionylaminosulfonyl)biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (Compound 114) [0264]
[0265] A/-(3-Phenylpropionyl)-5-formyl-6,2=-dihydroxy-biphenyl-3-sulfonamide (0.065 g, 0.15 mmol), prepared as in Reference 22, 3,4-diaminobenzamidine hydrochloride (0.043 g 0.23 mmol) and benzoquinone (0.018 g, 0.16 mmol) were combined in ethanol (15 mL) and the mixture was heated under reflux for 1 hour. The solvent was evaporated in vacuum and the product was purified from the residue by reverse phase HPLC (acetonitrile/0.02N HCI gradient) to give 2- [2,2’-dihydroxy-5-(3-phenylpropionylaminosulfonyl)biphenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine (0.033 g). 1H NMR (DMSO-d6): δ 2.50 (t, J= 7.7 Hz, 2H), 2.63 (t, J= 7.7 Hz, 2H), 6.82-7.22 (m, 9H), 7.72 (dd, J! = 9.2 Hz, J2 = 1.7 Hz, 1H), 7.78 (d, J= 2.5 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 8.18 (s, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.99 (s,2H), 9.34 (s,2H), 12.06 (s, 1H). MS: found (M+H+) 556.4, (M-H+) 554.4, calc 555.16.
[0266] Proceeding as in Example 10, but substituting 5-formyl-6-methoxy-3’-nitro-/\/-(4-phenylbutyryl)-biphenyl-3-sul-fonamide, gave 2-[2-hydroxy-3’-nitro-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxami-dine, Compound 115. MS: found (M+H+) 600.0, (M-H+) 597.6, calc. 598.16.
[0267] Proceeding as in Example 10, but substituting 5-formyl-6-hydroxy-3’-nitro-/\/-(3-pyridin-3-yl-propionyl)-biphenyl- 3- sulfonamide, gave 2-[2-hydroxy-3’-nitro-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1-H-benzoimidazole-5-carboxamidine (Compound 116). MS: found (M+H+) 586.4, (M-H+) 584.3, calc. 585.14.
[0268] Proceeding as in Example 10, but substituting 3’-amino-5-formyl-6-hydroxy-/\/-(3-pyridin-3-yl-propionyl)-biphe- nyl-3-sulfonamide, gave 2-[3’-amino-2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1 H-benzoimida-zole-5-carboxamidine (Compound 117). MS: found (M+H+) 556. 2, (M-H+) 554.3, calc. 555.17. EXAMPLE 11
Synthesis of 2-[3’-amino-2-hydroxy-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine (Compound 118) [0269]
[0270] 2-[2-Hydroxy-3’-nitro-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.063 g, 0.1 mmol), prepared as in Example 10 was dissolved in methanol (3 mL) and saturated aqueous ammonium chloride (1 mL) was added to the solution. The mixture was heated with iron powder (1 g) for 5-10 minutes, filtered through celite and concentrated under reduced pressure. Product was purified from the residue by reverse phase HPLC (acetonitrile gradient) to give 2-[3’-amino-2-hydroxy-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.017 g). MS: found (M+H+) 569.3, (M-H+) 567.4, calc. 568.19. EXAMPLE 12
Synthesis of 2-[2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-3’-ureido-biphenyl-3-yl]-1H-benzoimidazole-5-carboxa-midine (Compound 119) [0271]
[0272] 2-[3’-Amino-2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1/-/-benzoimidazole-5-carboxami-dine (0.015 g, 0.023 mmol), prepared as in Example 10, was dissolved in a mixture of methanol and water and then triethylamine was added to bring the soluytion to pH 9. The mixture was heated with potassium cyanate (0.018 g, 0.23 mmol) for 12 hour at 40 °C, concentrated by evaporation under reduced pressure and the crude product was purified by reversed phase HPLC (acetonitrile gradient) to give 2-[2-hydroxy-5-(3-pyridin-3-yl-propionylsulfamoyl)-3’-ureido-bi-phenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine (0.01 g). MS: found (M+H+) 599.5, (M-H+) 597.7, calc. 598.17. EXAMPLE 13
Synthesis of2-[3’-amino-2-hydroxy-5-(3-piperidin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1/-/-benzoimidazole-5-carbox-amidine (Compound 120) [0273]
[0274] 2-[2-Hydroxy-3’-nitro-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxami-dine (0.031 g, 0.05 mMol), prepared as in Example 10, was dissolved in trifluoroacetic acid (5 mL) and the solution was subjected to hydrogenation at 50 psi over Pt02 catalyst for 12 hours. The mixture was concentrated in vacuum and product was purified from the residue by reverse phase HPLC (acetonitrile gradient) to give 2-[3’-amino-2-hydroxy-5-(3-piperidin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.01 g). MS: found (M+H+) 562.4, (M-H+) 560.6, calc. 561.22. EXAMPLE 14
Synthesis of 2-(2,2’-dihydroxy-5-sulfamoyl-5’-ureidomethyl-biphenyl-3-yl)-1/-/-benzoimidazole-5-carboxamidine (Compound 12) [0275]
[0276] 5’-Cyano-5-formyl-6,2’-dimethoxybiphenyl-3-sulfonic acid amide (0.35 g, 1 mmole), prepared as in Reference 19, was heated with pyridine hydrochloride (3.5 g) at 185°C for 2 hours. The melt was dissolved in IN hydrochloric acid (15 mL) and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (25 mL) along with 3,4-diami-nobenzamidine hydrochloride (0.21 g, 1.1 mmol) and benzoquinone (0.11 g, 1.0 mmol). The mixture was heated for 4 hours and concentrated. The residue was washed with ethyl ether and then dissolved in a 2:1 mixture of methanol and IN hydrochloric acid (25 mL). The solution was subjected to hydrogenation at atmospheric pressure over Pearlman’s catalyst (0.1 g) for 2 hours. The mixture was and the mother liquor was concentrated by evaporation under reduced pressure. The residue was dissolved in 2:1 mixture of methanol and water and triethylamine was added to bring the solution to pH 10.
[0277] The mixture was heated with potassium cyanate (0.32g, 4 mmol) for 16 hours at 40 to 50 ° C and then concentrated by evaporation. Product was purified from the residue by reversed phase HPLC (acetonitrile gradient) to give 2-(2,2’-dihydroxy-5-sulfamoyl-5’-ureidomethyl-biphenyl-3-yl)-1/-/-benzoimidazole-5-carboxamidine (0.035 g). 1H NMR (DMSO-dg) 6 4.11 (s, 2H), 6.39 (br.s, 1H), 6.88 (d, J=8.8 Hz, 1H), 7.09-7.11 (m, 2H),7.32 (br.s, 2H), 7.74 (dd, J-, = 8.4 Hz, J2= 1.5 Hz, 1H), 7.81 (d, J= 2.2 Hz, 1H), 7.85 (d, J= 8.4 Hz, 1H), 8.18 (s, 1H), 8.61 (d, J= 2.2 Hz, 1H), 8.99 (s, 2H), 9.36 (s, 2H), 12.06 (s, 1H). MS: found (M+H+) 496.3, (M-H+) 494.2, calc 495.13. EXAMPLE 15
Synthesis of 2-[5-(5-carbamimidoyl-1/-/ benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-yl]-/V-(2-hydroxy-ethyl)-acetamide (Compound 45) [0278]
[0279] 3-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-2-yl-acetic acid (0.04 g, 0.09 mmol), prepared as in Reference 9, was dissolved in dimethylformamide (1 mL) and then diisopropylethylamine (0.03 mL, 0.18 mmol), 2-aminoethanol (0.008 mL, 0.14 mmol) and bromotripyrrolidinophos-phonium hexafluorophosphate (0.05 g, 0.12 mmol) was added to the solution. The mixture was stirred for 1 hour and then concentrated under vacuum. Product was purified from the residue by reverse phase HPLC to give 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5’-fluoro-6,2’-dihydroxy-biphenyl-3-yl]-A/-(2-hydroxy-ethyl)-acetamide (0.025 g, 61 %) as an off-white solid. LCMS calcd. 463.47, obsrvd. (M+H) 464.2, (M-H) 462.4.
[0280] Proceeding as in Example 15, but substituting 2-amino-propane-1,3-diol (0.013 g, 0.14 mmol), gave 2-[2,2’-dihydroxy-5’-fluoro-5-(N-(1-hydroxymethyl-2-hydroxyethylaminocarbonylmethyl)biphenyl-3-yl]-1/-/-benzoimidazole-5-carboxamidine (0.015 g, 34%) as an off-white solid. LCMS calcd. 493.49, obsrvd. (M+H) 494.1, (M-H) 492.3. EXAMPLE 16
Synthesis of A/-[3’-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxybiphenyl-3-ylmethyl]-2-hydroxy-acetamide (Compound 79) [0281]
[0282] íerí-Butyl [3’-formyl-6,2’-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate (0.284 g, 0.55 mmol) was dissolved in methanol (15 mL) and the solution was treated with diamino-benzamidine hydrocloride (0.112 g, 6.0 mmol) and 1,4-benzoquinone (65 mg, 6.0 mmol). The mixture was refluxed for 3 hours and then concentrated by evaporation. The residue was dissolved in methanol (15 mL) and hydrogen chloride (15 mL, 4M in dioxane) was added to the solution. The mixture was stirred for one hour and then concentrated. Product was purified from the crude by preparative HPLC (2,2,25) (acetonitrile) to give 2-(5’-aminomethyl-2,2’-dihydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine (210 mg).
[0283] 2-(5’-Aminomethyl-2,2’-dihydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine (25 mg, 0.056 mmol) was dissolved in dimethylformamide (5 mL) and triethylamine (0.030 g, 0.30 mmol, 0.042 mL) and 2,5-dioxo-pyrrolidin- 1- y acetoxyacetate (0.0215 g, 0.10 mmol) were added to the solution. The mixture was stirred for 30 minutes and then concentrated by evaporation. The residue was combined with methanol (5 mL) and potassium carbonate (1.0 mL, 1 M) and the mixture was stirred for 1 hour. The reaction mixture was acidified to pH~3 and then concentrated by evaporation. The residue was prepped at (2,2,25) (acetonitrile) to give N-[3’-(5-carbamimidoyl-1 H-benzoimidazol-2-yl)-6,2’-dihydroxy-biphenyl-3-ylmethyl]-2-hydroxy-acetamide (17 mg). LCMS: Calcd = 431.5; Obsd, (MH+) = 432.2, (MH-) = 430.2. NMR (DMSO-d6) d 3.80 (s, 2H), 4.22 (d, J=6 Hz, 2H), 6.84 (d, J=8 Hz, 1H), 7.07 (m, 2H), 7.33 (d of d, J=1.5, 8 Hz, 1H), 7.72 (d of d, J=3, 8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.12 (m, 2H), 8.16 (brs, 1H), 8.98, 9.35 (2s, 4H). EXAMPLE 17 2- [5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-morpholin-4-yl-ethyl)-acetamide (Compound 43) [0284]
[0285] [5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetic acid (96 mg, 0.20 mmol), prepared as in Reference 9, was dissolved in dry A/,A/-dimethylformamide (20 mL) and the solution was treated with 0-(7-azabenzotriazol-1-yl)-/\/,/\/,/\/,/\/-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) and 2,3,4-trimethyl-pyridine (0.106 mL, 0.80 mmol). The mixture was stirred for one hour and then 4-(2-aminoethyl)-mor-pholine (29 uL, 0.22 mmol) was added. The mixture was stirred until the reaction was complete (1/2 to 1 hours) and then neutralizated with IN hydrochloric acid to pH ~ 3. The solvents were evaporated at 30 °C to give an oily residue. The crude amide then was prepped at 2:30 (acetonitrile/20 mmol HCI) and the solvents were lyophilized to give 2-(5-(5- carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-morpholin-4-yl-ethyl)-aceta-midé (63.0 mg, 53%). LCMS: (MH+) = 594.3; (MH-) = 592.2. NMR (DMSO-d6) d2.78 (m, 4H), 3.12 (m, 2H), 3.26 (t, J = 3 Hz, 2H), 3.57 (m, 4H), 3.59 (s, 2H), 7.17 (d, J = 5 Hz, 1H), 7.23 (br s, 1H), 7.37 (d, J = 1.5 Hz, 1H), 7.70 (m, 2H), 7.79 (döfd, J = 1,5 Hz, 1H), 7.88 (d, J = 5 Hz, 1H), 8.22 (d, J = 1 Hz, 1H), 8.24 (s, 1H), 8.59 (t, J = 3 Hz, 1H), 9.18, 9.43 (2s, 4H).
[0286] Proceeding as in Example 17, but substituting lithium 2-aminoethanesulfonate (54 mg), prepared as in Reference 4, in hot dimethyl sulfoxide (4 mL) and triethylamine (200 uL), gave 2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-ethanesulfonic acid (55 mg, 45%) (Compound 234). LCMS: (MH+) = 589.1. (MH-) = 587.2, NMR (DMSO-d6) d 2.71 (t, J = 6 Hz, 2H), 3.43 (t, J = 6 Hz, 2H), 3.46 (t, J = 6 Hz, 1H), 7.03 (d, J = 5 Hz, 1H), 7.18 (brs, 1H), 7.24 (d, J = 1 Hz, 1H), 7.63 (d of d, J = 1,5 Hz, 1H), 7.68-7.75 (m, 2H), 7.85 (d, J = 5 Hz, 1H), 8.19 (s, 1H), 8.26 (d, J = 1 Hz, 1H), 8.43 (t, J = 5 Hz, 1H), 8.86, 9.37 (2s, 4H).
[0287] Proceeding as in Example 17, but substituting ferf-butyl 6-amino-2-ferf-butoxycarbonylamino-hexanoate (0.65 g), prepared as in Reference 5, gave 2-amino-6-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sul-famoyl-biphenyl-3-yl]-acetylamino}-hexanoic acid (68 mg, 53%) (Compound 112). LCMS: (MH+) = 610.4. (MH-) = 608.6, NMR (DMSO-d6) d 1.3-1.5 (m, 2H), 1.8 (m, 2H), 3.08 (q, J = 6 Hz, 2H), 3.51 (s, 2H), 3.89 (q, J = 6Hz, 1H), 7.05 (d, J = 5 Hz, !H), 7.18 (brs, 1H), 7.31 (d, J = 1Hz, 1H), 7.65 (m, 2H), 7.77 (d of d, J = 1,5 Hz, 1H), 7.83 (d, J = 5 Hz, 1H), 8.14 (d, J = 1Hz, 1H), 8.21 (s, 1H), 8.38 (d, J = 5Hz, 2H), 9.15, 9.42 (2s, 4H).
[0288] Proceeding as in Example 17, but substituting 1-methylpiperazine (25 uL) and triethylamine (40 uL), gave 2- {2,2’-dihydroxy-5-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-5’-sulfamoyl-biphenyl-3-yl}-1H-benzoimidazole-5-carbox-amidine (55 mg, 48%), Compound 113. LCMS: (MH+) = 564.2; (MH-) = 562.1; NMR (DMSO-d6) d 2.79 (s, 3H), 2.9-3.2 (m, 2H), 3.43 (t, J = 6 Hz, 2H), 3.55 (t, J = 14 Hz, 1H), 3.70 (m, 1H), 3.80 (s, 2H), 4.33 (d, J = 14 Hz, 1H), 4.47 (d, J = 14 Hz, 1H), 7.12 (d, J = 5 Hz, 1H), 7.20 (brs, 1H), 7.24 (d, J = 1 Hz, 1H), 7.6-7.8 (m, 2H), 7.75 (d, J = 5 Hz, 1H), 7.84 (d, J = 5 Hz, 1H), 8.13 (d, J = 1 Hz, 1H), 8.21 (s, 1H), 9.02, 9.41 (2s, 4H).
[0289] Proceeding as in Example 17, but substituting (2-aminoethyl)-trimethylammonium chloride (73 mg, 0.41 mmol) in a mixture of dimethyl sulfoxide (4 mL) and triethylamine (57 uL) heated to 80 C which mixture was added in a dropwise fashion to the reaction mixture, gave (2-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-bi-phenyl-3-yl]-acetylamino}-ethyl)-trimethyl-ammonium (53 mg, 43%), Compound 105. NMR (DMSO-d6) d 3.05 (s, 9H), 3.42 (q, J = 6 Hz, 2H), 3.55 (m, 6H), 7.12 (d, J = 5 Hz, 1H), 7.20 (brs, 1H), 7.30 (d, J = 1 Hz, 1H), 7.67 (m,2H), 7.78 (d of d, J = 1,5 Hz, 1H), 7.83 (d, J = 5Hz, 1H), 8.20 (m, 2H), 8.61 (t, J = 6 Hz, 1H), 9.11,9.41 (2s, 4H).
[0290] Proceeding as in Example 17, but substituting 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoylbiphenyl-3-carboxylic acid, prepared as in Reference 10, gave A/-(2-morpholin-4-yl-ethyl) 5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-carboxamide as a yellow solid, Compound 110. RP-HPLC (1-90S) RT = 2.26 min. 1H NMR (400 MHz, d6-DMSO, selected signals): δ 10.40* (1H, v brs), 10.27* (1H, v br s), 9.36* (2H, s), 8.96* (3H, m), 8.80* (1H, br t, J= 5.7 Hz), 8.18 (1H s), 7.94 (1H, d, J = 2.0 Hz), 7.85 (1H, d, J = 8.4 Hz), 7.74 (1H, dd, J = 8.4, 1.6 Hz), 7.69 (1H, d, J = 2.0 Hz), 7.68 (1H, dd, J = 8.4, 1.6 Hz), 7.18* (2H, s), 7.08 (1H, d, J = 8.4 Hz), 3.99 (2H, br m), 3.79 (2H, br m), 3.71 (2H, br m), 3.58 (2H, m), 3.15 (2H, m); mlz (LCMS-ESI): Q+580 (M+H); Q- 578 (M-H).
[0291] Proceeding as in Example 17, but substituting 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoylbiphenyl-3-carboxylic acid (20 mg, 40 μηιοΙ), prepared as in Reference 10, and lithium 2-aminoethanesulfonate, prepared as in Reference 4, gave 2-{[5-(5-carbamimidoyl-1 H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl- 3- carbonyl]-amino}-ethanesulfonic acid as a yellow solid, Compound 111. RP-HPLC (1-90S) RT = 2.21 min; 1H NMR (400 MHz, d6-DMSO, selected signals): δ 9.36* (2H, s), 8.98* (2H, s), 8.74 (1H, J= 1.6 Hz), 8.74 (1H, d, J = 2.0 Hz), 8.49* (1H, br t, J= 5.0 Hz), 8.17 (1H, s), 7.85 (1H, d, J = 8.4 Hz), 7.81 (1H d, J= 2.0 Hz), 7.75 (1H, dd, J = 8.4 Hz, 0.8 Hz), 7.70 (1H, dd, J = 2.4 Hz), 7.67 (1H, dd, J= 8.4, 2.4 Hz); 7.16* (2H, brs), 7.07 (1H, d, J = 8.4 Hz); mlz (LCMS-ESI): Q+ 575 (M+H); Q~ 573 (M-H).
[0292] Proceeding by analogous methods provided in the Examples set forth herein gave: 2S-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-succi-namic acid hydrochloride, Compound 121,1H NMR: 9.30 (2 H, brs), 8.87 (2 H, brs), 8.23 (d, 1 H, J = 7.6 Hz), 8.09 (1 H,brs),7.92(1 H, br s), 7.76 (d, 1 H,J = 7.2 Hz),7.65(1 H, d, J = 8.4 Hz), 7.6-7. 57 (2 H, m), 7.38 (1 H,s),7.20 (1 H, d, J = 2.4 Hz), 7.08 (1 H, br s), 6.97 (1 H, d, J = 9.2 Hz), 6.865 (1 H, br s), 4.47 (1 H, dd, J = 7.6 and 5.6 Hz), 3.62 (2 H br s), 2.48 (2 H, d of ABq, J = 15.2 and 5.6 Hz); 2R-{2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-suc-cinic acid, Compound 123, H1 NMR (CD3DO-d4) 9.33 (s, 2 H) 8.94 (s, 2 H) 8.46 (d, 1 H, J=7.8 Hz) 7.99 (d, 1 H, J=1.6 Hz) 7.839 (d, 1 H, J=8.6 Hz) 7.73 (dd, 1 H, J=1.2 Hz, 8.6 Hz) 7.66 (d, 1 H, J=2.3 Hz) 7.661 (dd, 1H, J=2.7 Hz, 8.6 Hz) 7.285 (d, 1 H,J=2.3 Hz) 7.051 (d, 1 H, 8.2 Hz) 4.57 (q, 1 H, J=7.0Hz, 14.1 Hz) 3.542 (s, 2 H) 2.741 (m, 1 H); 1-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetyl}-pyrrolidine-2R-carboxamide, Compound 124,1H NMR (400 MHz, DMSO-dg) δ 10.24 (br-s, 1H), 9.30 (br-s, 1H), 8.85 (br-s, 1H), 8.15 (br-s, 1H), 7.98 (d, J=1.75, 1H), 7.83 (br-d, J= 9.3, 1H), 7.70 (br-d, J=9.17, 1H), 7.64 (m, 2H), 7.36 (br-s, 1H), 7.25 (d, J=2.02, 1H), 7.15 (s, 1H), 7.03 (d, J=8.08, 1H), 6.94 (br-s, 1H), 4.25 (dd, J= 5.64, 3.16, 1H), 3.72 (s, 2H), 3.59 (m, 1H), 3.30 (obsc-m, 1H), 2.03 (m, 2H), 1.85 (m, 2H). ESIMS m/z: M+ 578.5; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetamide, Compound 126, H1 NMR (CD3DO-d4) 3.621 (s, 2H) 7.07 (d, J=8 Hz, 1H) 7.15 (brs, 2H) 7.27 (d, J=2 Hz, 1H) 7.63 (d, J=2 Hz, 1H) 7.65 (m, 2H) 7.73 (d of d, J=2, J=8, 1H) 7.83 (d, J=8 Hz, 1H) 8.08 (d, J=2 Hz, 1H) 8.17 (s, 1H) 9.10 (s, 2H) 9.39 (s, 2H); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N,N-dimethyl-aceta-mide, Compound 127, H1 NMR (CD3DO-d4) 9.49(s,1H), 9.00(s,1H), 8.30(s,1H), 8.03(d,1H, J=8.7 Hz), 7.95(m, 2H, J=10.4 Hz), 7.87(m,2H, J=10.4 Hz), 7.51(d,1H, J=2Hz), 7.12(d,1H, J=8.4 Hz), 3.93(s,2H), 3.23(s,3H), 3.05(s,3H); MS: calc 508.55; found 509.2 (M+1), 507.3 (M-1); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-hydroxy-1-hy-droxymethyl-ethyl)-acetamide, Compound 128, 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.97 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H), 7.86 (t, 1H), 7.73 (dd, 1H), 7.67 (t, 1H), 7.64 (d, 1H), 7.30 (d, 1H), 7.16 (br-s, 1H), 7.06 (d, 1H), 3.72 (m, 4H), 3.52 (s, 2H) ESIMS m/z: M+ 555.2, M“ 553.4; 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-dimethylamino-ethyl)-acetamide (Compound 131), LCMS Calcd: 551; Obsd (MH) 551, H’-NMR: DMSO-d6: 2.7 (d, 6H), 3.1 (q, 2H), 3.4 (q, 2H), 3.45 (s, 2H), 7.0 (d, 1H), 7.1 (s, 1H), 7.25 (s, 1H), 7.6 (d, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 8.1 (s, 1H), 8.15 (s, 1H), 8.4 (t, 1H), 9.0 (s, 2H), 9.3 (s, 2H), 10.2 (s, 1H); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(3-dimethylamino-pro-pyl)-ace tarn ide, Compound 132, LCMS Calcd: 565; Obsd (MH+) 566, H’-NMR: DMSO_d6:1.85 (m, 2H), 2.5(s, 6H), 2.8 (m, 2H), 3.1 (m, 2H), 3.2 (m, 2H), 4.6 (s, 2H), 7.1 (d, 1H), 7.2 (s, 1H), 7.3 (s,1H), 7.7 (s, 1H), 7.75 (d, 1H), 7.85 (d, 1H), 8.1 (s, 1H), 8.2 (s, 1H), 8.3 (t, 1H), 9.0 (s, 2H), 9.4 (s, 2H), 10.4 (s, 1H); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-/\/-{2-[2-(2-methylamino-ethoxy)-ethoxy]-ethyl}-acetamide (Compound 134), LC-MS: Calcd. 639.25, Observed. 640.6 (M+1), 638.5 (M-1); 2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(3S,4S,5R,6S-tetrahy-droxy-tetrahydro-pyran-2R-ylmethyl)-acetamide (Compound 135), RP-HPLC (1-90S) RT = 2.17 min; 1H NMR (400 MHz, dg-DMSO+D20, selected signals, as a 40:60 mixture of α:β anomers): δ 8.14 (1H, br s), 7.94 (1H, br d, J = 2.0 Hz), 7.84 (1H, d, J = 8.4 Hz), 7.71 (1H, m), 7.68-7.66 (2H, m), 7.28 (1H, d, J = 2.0 Hz), 7.05 (1H, d, J = 8.4 Hz), 4.91 (0.4H, d, J - 3.6 Hz, a-anomer), 4.30 (0.6H, d, J= 8.0 Hz, β-anomer; m/z (LCMS-ESI): Q+ 643.4 (M+H, calc. 643.2); Q- 641.5 (M-H, calc. 641.2); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N-(2,4R,SS-trihydroxy-6R-hydroxymethyl-tetrahydro-pyran-3-yl)-acetamide (Compound 136), LCMS: Calcd 642.65; Obsd (MH+) = 643.4, (MH-) = 641.3. NMR (DMSO-d6) d 3.18 (m, 1H), 3.4-3.8 (m, 8H), 4.8-5.3 (brs, 7H), 7.11 (d, J=8 Hz, 1H), 7.20 (brs, 1H), 7.32 (d, J=2 Hz, 1H), 7.65 (d, J=2 Hz, 1H), 7.68 (m, 2H), 7.77 (d of d, J=2, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 1H), 8.12 (d of d, J=2, J=8 Hz, 1H), 8.22 (s, 1H), 9.11,9.42 (2s, 4H); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-N-methyl-N-(2R,3R,4R,5S,6-pentahydroxy-hexyl)-acetamide (Compound 137), RP-HPLC (1-90S) RT = 2.20 min; 1H NMR (400 MHz, d6-DMS0+D20, selected signals, as 60:40 mixture of amide rotamers): δ 8.14 (1H, s), 7.8 (1H, m), 7.84 (1H, d, J = 8.8 Hz), 7.70 (1H, dd, J = 8.4, 1.6 Hz), 7.69-7.66 (2H, m), 7.25 (0.4H, d, J = 2.0 Hz, 1st rotamer), 7.20 (0.6H, d, J = 2.0 Hz, 2nd rotamer), 7.05 (1H, m), 3.68-3.40 (8H, m), 3.14 (1.2H, s, 1st rotamer), 2.88 (1.8H, s, 2nd rotamer); m/z (LCMS-ESI): Q+ 659.6 (M+H, calc. 659.2); Q" 657.6 (M-H, calc. 657.2); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-(2-hydroxy-1,1-bis-hy-droxymethyl-ethyl)-acetamide (Compound 138), 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.98 (s, 1H), 8.17 (d, 1H), 8.03 (d, 1H), 7.86 (d, 1H), 7.73 (dd, 1H), 7.67 (dd, 1H), 7.50 (s, 1H), 7.30 (d, 1H), 7.16 (br-s, 1H), 7.06 (d, 1H), 4.21 (t, 1H), 3.98 (m, 6H), 3.83 (s, 2H), ESIMS m/z: M+ 585.4, M‘ 583.4; 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-A/-methyl-acetamide (Compound 139), LCMS: Calcd 494.53; Obsd (MH+) = 495.1, (MH-) = 493.1, NMR (DMSO-d6) d2.62 (s, 3H), 3.49 (s, 2H), 7.08 (d, J=8 Hz, 1H), 7.18 (brs, 2H), 7.30 (d, J=2 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 7.69 (m, 1H), 7.78 (d ofd, J=2, J=8 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 8.04 (m, 1H), 8.10 (d, J=2 Hz, 1H), 8.21 (s, 1H), 9.08, 9.41 (2s, 4H); 2S-{2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-succi-namide (Compound 140), 1H NMR (DMSO-d6): 10.23 (brs, 1H),9.33 (s, 2H), 8.94 (s, 2H), 8.32 (d, 1H,J=8.4 Hz), 8.16 (s, 1H), 8.00 (s, 1H), 8.83 (d, 1H, J = 8.4 Hz), 7.71 (d, 1H, J = 8.8 Hz), 7.66 (m, 2H), 7.62 (d, 1H, J =2.4 Hz), 7.44 (s, 1H), 7.27 (d, 2H, J = 2.0 Hz), 7.15 (s, 2H), 7.04 (d, 1H, J = 8.4 Hz), 6.94 (s, 1H), 4.53 (dd, 1H, J = 7.6, 8.4 Hz), 3.53 (brs, underwater peak), 2.56 (dd, 1H, J = 5.2, 15.6 Hz), 2.42 (dd, 1H, J =8.4, 15.6 Hz). LC-MS: Calcd. 594.16, Observed. 595.3 (M+1), 593.1 (M-1); 2-[5-(5-carbamimidoyl-1/-/-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-/\/-{3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl}-acetamide hydrochloride (Compound 141), 1H NMR : 9.40 (2 H, brs), 9.07 (2 H, brs), 8.20 (1 H, brs), 8.14-8.05 (2 H, m), 7.87 (1 H, d, J = 8 Hz), 7.76 (1 H, dd, J = 8 and 2 Hz), 7.70-7.65 (3 H, m), 7.31 (1 H, d, J = 2.4 Hz), 7.09 (8.4 Hz), 3.58-3.38 (14 H, m), 3.14 (2 H, q, J = 6.8 Hz), 1.67 (2 H, quintet, J= 6.4 Hz), 1.10 (3 H, t,J = 7.2 Hz). 3’-(5-carbamimidoyl-1/-/-pyrrolo[3,2-b]pyridin-2-yl)-6,2’-dihydroxy-biphenyl-3-carbox amide (Compound 239), Mass: Observed m/z. 417 (M+1) Calculated m/z416 (M+); and 2-(2,2’-dihydroxy-5’-ureido-biphenyl-3-yl)-1/-/-pyrrolo[3,2-b]pyridine-5-carboxamidine, Mass: Observed m/z 402 (M+2) Calculated m.z401 (M+).
Biological Examples EXAMPLE 1
In Vitro Factor Vila Inhibitor Assay [0293] Mixtures of human Factor VI la (typically supplied at 7 nM) and test compound (present at varying concentrations) in assay medium (comprising: NaCI, 150 mM (pH 7.4); CaCI2, 5 mM ; Tween-20, 0.05% ; Dade Innovin tissue factor [Dade Behring, Newark, DE, USA]; EDTA, 1.5 mM; and dimethylsulfoxide, 10 %) were incubated for 30 minutes at room temperature. Next, reactions were initiated with the addition of substrate [500 μΜ of CH3S02-D-Cha-But-Arg-pNA (from Centerchem, Norwalk, CT, USA)]. Hydrolysis of the chromogenic substrate was followed spectrophotometrically at 405 nm for five minutes. Initial velocity measurements calculated from the progress curves by a kinetic analysis program (Batch Ki; BioKin, Ltd., Pullman, WA) were used to determine apparent inhibition constants (apparent Kj’s).
[0294] Compounds of the invention tested by the above-described assay exhibited inhibition of Factor Vila. EXAMPLE 2
In Vitro Factor Xa Inhibitor Assay [0295] Mixtures of human Factor Xa (typically supplied at 3 nM) (from Haematologic Technologies, Essex Junction, VT, USA) and test compound (varying concentrations) in assay medium (comprising: Tris, 50 mM (pH 7.4); NaCI, 150 mM; CaCI2, 5 mM; Tween-20, 0.05%; EDTA, 1mM; and dimethylsulfoxide, 10%) were incubated for 30 minutes at room temperature. Next, reactions were initiated with the addition of substrate [500 μΜ of CH3C02-D-Cha-Gly-Arg-pNA (from Centerchem, Norwalk, CT, USA], Hydrolysis of the chromogenic substrate was followed spectrophotometrically at (405 nm) for five minutes. Apparent inhibition constants (apparent Kj’s) were calculated from the enzyme progress curves using standard mathematical models.
[0296] Compounds of the invention tested by the above-described assay exhibited inhibition of Factor Xa. EXAMPLE 3
Pharmacokinetic Assay [0297] Rats with pre-implanted jugularvein catheters, which were filled with heparin/saline/PVP lock prior to shipment, were bought from Charles River. Three rats were selected for each study, weighed, and injected with test compound by tail vein injection. Any residual test compound was retained and stored at -70 °C for later analysis.
[0298] Blood samples (0.25 mL each) were collected from the indwelling catheters at specified times over 120 h. The catheters were flushed with physiological saline immediately after each collection and filled with heparinized saline after each 8,24 and 48 h collection. In the event that a catheter failed, blood samples were collected via the retro-orbital sinus under isoflurane anesthesia at the appropriate time.
[0299] Blood samples were placed in 0.5 mL Microtainer® tubes (lithium heparin), shaken gently and stored on wet ice. The samples were centrifuged for 10 minutes at 2400 rpm in a refrigerated centrifuged. Plasma samples (0.1 mL) from each tube were transferred to 0.5 mL Unison polypropylene vials (Sun - 500210) and stored below -70 °C for later analysis by LC/MS-MS. EXAMPLE 4
In vitro Clotting Assays.....aPTT and PT
[0300] Coagulation assays, activated partial thromboplastin time (aPTT) and prothrombin time (PT) were carried out based on the procedure described in Hougie, C. Hematology (Williams, W. J., Beutler, B., Erslev, A. J., and Lichtman, M. A., Eds.), pp. 1766-1770 (1990), McGraw-Hill, New York.
[0301] Briefly, the assays were performed using normal human citrated plasma and were performed at 37 °C on a coagulometer (Electra 800) in accordance with the manufacturer’s instructions (Medical Laboratory Automation- Pleas-antville, New York). The instrument was calibrated with plasma immediately prior to collecting clotting times for samples with inhibitors. The aPTT and PT doubling concentrations were calculated by fitting inhibitor dose response curves to a modified version of the Hill equation.
Pharmaceutical Composition Examples [0302] The following are representative pharmaceutical formulations containing a compound of Formula I.
Tablet Formulation [0303] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet, mg compound of this invention 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5
Capsule Formulation [0304] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantitypercapsule, mg compound ofthis invention 200 lactose, spray-dried 148 magnesium stearate 2
Suspension Formulation [0305] The following ingredients are mixed to form a suspension for oral administration.
Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 mL colorings 0.5 mg
distilled water q.s.tolOOmL
Injectable Formulation [0306] The following ingredients are mixed to form an injectable formulation.
Ingredient Amount compound of this invention 1.2 g
sodium acetate buffer solution, 0.4 M 2.0 mL
HCI (1 N) or NaOH (1N) q.s. to suitable pH
water (distilled, sterile) q.s.to 20 mL
[0307] All of the above ingredients, except water, are combined and heated to 60-70 °C. with stirring. A sufficient quantity of water at 60 °C is then added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. to 100 g.
Suppository Formulation [0308] A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg
Witepsol® H-15 balance
Claims 1. A compound of Formula I:
Formula I wherein: X1 is -N- or -CR5- wherein R5 is hydrogen, alkyl, or halo; R1 is hydrogen, alkyl, halo, carboxy or aminocarbonyl; R2 is hydrogen, alkyl, or halo; R3 is -CONR7R8, (where R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phospho-noalkyl; and R8 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylamino-carbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino), or -(alkylene)-CONR9R10 (where R9 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyl; and R10 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, ami- nocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylaminocarbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R9 and R10 together with the nitrogen atom to which they are attached form heterocy-cloalkylamino);
Rx is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl, alkoxy, aminosulfonyl, alkylaminosulfonyl, di-alkylaminosulfonyl, or nitro; RV is hydrogen, alkyl, or halo;
Rz is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, het-eroarylsulfonyl, carbamimidoyl, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfo-nylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hydroxy-alkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocy-cloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido, alkylureido, di-alkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, -COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -(alkylene)-COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -CONR14R15 (where R14 is hydrogen or alkyl; and R15 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R14 and R15 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-CONR16R17 (where R16 is hydrogen, alkyl or hydroxyalkyl; and R17 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R16 and R17 together with the nitrogen atom to which they are attached from heterocycloamino), -NR18R19 (where R18 is hydrogen or alkyl; and R19 is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR20R21 (where R20 is hydrogen, alkyl, or hydroxyalkyl; and R21 is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), - S02NR22R23 (where R22 is hydrogen or alkyl; and R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R22 and R23 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-S02NR24R25 (where R24 is hydrogen or alkyl; and R25 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R24 and R25 together with the nitrogen atom to which they are attached from heterocycloamino), -NR26S02NR27R28 (where R26 and R27 are independently hydrogen or alkyl; and R28 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R27 and R28 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-NR29SO2NR30R31 (where R29 and R30 are independently hydrogen or alkyl; and R31 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R30 and R31 together with the nitrogen atom to which they are attached from heterocycloamino), -CONH-(alkylene)-NR32R33 (where R32 is hydrogen or alkyl; and R33 is alkyl), or aralkyl; and R13 is hydrogen, hydroxy, (C.|_10)alkoxy, -C(0)R35 (where R35 is alkyl, aryl, haloalkyl, or cyanoalkyl), or -C(0)OR36 (where R36 is alkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyl, aryl, or haloalkyl); or individual stereisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, provided that when R3 is -CONR7R8 (where R7 is hydrogen or alkyl; and R8 is hydrogen or alkyl), -(alkylene)-CONR9R10 (where R9 and R10 together with the nitrogen atom to which they are attached form pyrrolidinyl), and Rz is hydrogen, alkyl, haloalkyl, halo, nitro, alkoxy, haloalkyl, carboxy, alkoxycarbonyl, -NR18R19 (where R18 is hydrogen or alkyl; and R19 is hydrogen, alkyl, aryl or aralkyl), pyrrolidinylcarbonyl, -S02NR22R23 (where R22 and R23 are alkyl), carbamimidoyl, alkylsulfonylamino, alkylthio, ureido, -NHC(S)NH2 or heterocycloamino, then Rx is hydroxy or hydroxyalkyl; wherein alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms ora branched saturated monovalent hydrocarbon radical of three to six carbon atoms; alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms; alkylthio means a radical -SR where R is alkyl; amino means the radical -NRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; acyl means a radical -COR’ where R’ is alkyl, alkoxy, haloalkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; aminosulfonyl means a radical -S02NH2; alkylaminosulfonyl means a radical -S02NHR where R is alkyl; alkylsulfonyl means a radical -S02R where R is alkyl; alkylsulfonylalkyl means a radical -(alkylene)-S02R where R is alkyl; alkylsulfonylamino means a radical -NHS02R where R is alkyl; alkylsulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkyl; alkoxysulfonylamino means a radical -NHS02R where R is alkoxy; alkoxysulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkoxy; alkoxy means a radical -OR where R is alkyl; alkoxycarbonyl means a radical -COOR where R is alkyl; alkoxycarbonylalkyl means a radical -(alkylene)-COOR where R is alkyl; alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group; aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one -NRR’ where R and R’ are independently hydrogen, alkyl, or-CORa where Ra is alkyl; aminocarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -NRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylcarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -CONRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two-CONRR’where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; alkoxyalkyloxy means a radical -OR where R is alkoxyalkyl; aminoalkyloxy means a radical -OR where R is aminoalkyl; aminocarbonyl means a radical -CONH2; aminocarbonylalkyloxy means a radical - O-alkylene-CONRR’ where R and R’ are independently hydrogen or alkyl; aminocarbonylalkyl means a radical -(alkylene)-CONH2; alkylureido means a radical-NRCONHR’ where R is hydrogen or alkyl and R’ is alkyl; alkylureidoalkyl means a radical -(alkylene)-NRCONHR’ where R is hydrogen or alkyl and R’ is alky; aryl means a monovalent monocyclicor bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents, selected from alkyl, haloalkyl, alkoxy, alkylthio, halo, nitro, -COR (where R is alkyl), cyano, amino, alkylamino, dialkylamino, hydroxy, carboxy, or-COOR where R is alkyl; arylsulfonyl means a radical -S02R where R is aryl; aralkyl means a radical - (alkylene)-R where R is an aryl group; alkoxycarbamimidoyl means a radical-C(=NH)NHORor-C(=NOR)NH2 where R is alkyl; cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms; carboxyalkyl means a radical -(alkylene)-COOH; carboxyalkyloxy means a radical -0-(alkylene)-C00H; carbamimidoyl means a rad-ical-C(=NH)NH2; cyanoalkyl means a radical -(alkylene)-CN; diatkylaminosulfonyl means a radical - S02NRR’ where R and R’ are independently alkyl; dialkylureido means a radical -NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; dialkylureidoalkyl means a radical -(alkylene)-NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; guanidinoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one -NRC(NRR’)NRR’ where R and R’ are independently hydrogen, alkyl, or-CORa where Ra is alkyl; halo means fluoro, chloro, bromo, and iodo; haloalkyl means alkyl substituted with one or more halogen atoms; haloalkoxy means a radical -OR where R is haloalkyl; hydroxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one to five hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom; hydroxyalkyloxy means a radical -OR where R is hydroxyalkyl; hydroxy-alkoxyalkylaminocarbonyl means a radical -CONH-(alkylene)-0-(alkylene)OH; heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C; heterocy-cloalkylcarbonyl means a radical -COR where R is heterocycloalkyl; heterocycloalkylcarbonylalkyl means a radical -(alkylene)-COR where R is heterocycloalkyl; heterocycloalkylalkyl means a radical -(alkylene)-R where R is heterocycloalkyl; heterocycloalkylalkylaminocarbonyl means a radical -CONH-(alkylene)-R where R is heterocycloalkyl; heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being carbon, the heteroaryl ring being optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, guanidinoalkyl, halo, nitro, cyano, amino, alkyl or dialkylamino, hydroxy, carboxy, or -COOR where R is alkyl; heteroarylsulfonyl means a radical -S02R where R is heteroaryl; heteroaralkyl means a radical -(alkylene)-R where R is a heteroaryl; heterocycloamino means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C provided that at least one of the heteroatom is nitrogen and wherein one or two carbon atoms are optionally replace by a carbonyl group, the heterocycloamino ring being optionally substituted with one or more substituents independently selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo, cyano, carboxy, -CONRaRb (where Ra and Rb are independently hydrogen or alkyl), or -COOR where R is alkyl; hydroxycarbamimidoyl means a radical -C(=NH)NHOH or -C(=NOH)NH2. 2. The compound of Claim 1 wherein: R3 is -CONR7R8 (where R7 is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl; and R8 is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl, aminocarbo-nylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl, hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonio-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or hetereocycloalkylalkyl; or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino), or-(alkylene)-CONR9R10 (where R9 is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, hydroxyalkyl or phosphonoalkyl; and R10 is hydrogen, alkyl, alkoxyalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aminoalkyl, aminocarbonylalkyl, aminocarbonylcarboxyalkyl, aminocarboxyalkyl, carboxyalkyl, hydroxyalkyl, phosphonoalkyl, sulfoalkyl, trimethylammonioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkylalkyl; or R9 and R10 together with the nitrogen atom to which they are attached form heterocycloalkylamino), wherein any rings comprising R3 are optionally substituted with one to six groups independently selected from hydroxy, hydroxyalkyl, alkoxyalkyl, carboxy, alkoxycarbonyl, aminoalkyl, guanidi-noalkyl, alkyl or -CONRaRb (where Ra and Rb are independently hydrogen or alkyl); and Rz is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonyl, het-eroarylsulfonyl, carbamimidoyl, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfo-nylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hydroxy-alkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl, heterocycloalkyl, heterocycloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido, alkylureido, di-alkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, -COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -(alkylene)-COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -CONR14R15 (where R14 is hydrogen or alkyl; and R15 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R14 and R15 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-CONR16R17 (where R16 is hydrogen, alkyl or hydroxyalkyl; and R17 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R16 and R17 together with the nitrogen atom to which they are attached from heterocycloamino), -NR18R19 (where R18 is hydrogen or alkyl; and R19 is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR20R21 (where R20 is hydrogen, alkyl, or hydroxyalkyl; and R21 is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), - S02NR22R23 (where R22 is hydrogen or alkyl; and R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R22 and R23 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-S02NR24R25 (where R24 is hydrogen or alkyl; and R25 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R24 and R25 together with the nitrogen atom to which they are attached from heterocycloamino), -NR26S02NR27R28 (where R26 and R27 are independently hydrogen or alkyl; and R28 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R27 and R28 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-NR29SO2NR30R31 (where R29 and R30 are independently hydrogen or alkyl; and R31 is hydrogen, alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; or R30 and R31 together with the nitrogen atom to which they are attached from heterocycloamino), -CONH-(alkylene)-NR32R33 (where R32 is hydrogen or alkyl; and R33 is alkyl), or aralkyl; and R13 is hydrogen, hydroxy, (C^^Jalkoxy, -C(0)R35 (where R35 is alkyl, aryl, haloalkyl, or cyanoalkyl), or -C(0)OR36 (where R36 is alkyl, hydroxyalkyl, acyl, or haloalkyl); or a pharmaceutically acceptable salt thereof. 3. A compound of Formula la wherein:
Formula la R3 is -CONR7R8, -CH2CONR9R10 or-C(CH3)2CONR9R10 ; R7 is hydrogen or methyl; R9 is hydrogen or methyl; R8 is aminocarbonylmethyl, 1,2-diaminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carbox-ypentyl, 2-carboxyethyl, carboxymethyl, 2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminome-thyl, 3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethylethyl, 2-hydroxy-1-hydroxymethylethyl, 1,2-di-carboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl, 2-sulfoethyl, 3,4,5,6-tetrahydroxy-tetrahydropyran-2-ylmethyl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahy-dro-pyran-3-ylcarbamoyl-methyl, trimethylammonioethyl or 2-phosphonoethyl; R10 is aminocarbonylmethyl, 1,2-diaminocarbonylethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carbox-ypentyl, 2-carboxyethyl, carboxymethyl, 2-carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, dimethylaminome-thyl, 3-dimethylaminopropyl, 2-hydroxy-1,1-bis-hydroxymethylethyl, 2-hydroxy-1-hydroxymethylethyl, 1,2-di-carboxyethyl, methyl, 2-[2-(2-methylaminoethoxy)ethoxy]ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-morpholin-4-ylethyl, 2,3,4,5,6-pentahydroxy-hexyl, 2-piperazin-1-ylethyl, 2-sulfoethyl, 3,4,5,6-tetrahydroxy-tetrahydropyran-2-ylmethyl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl, 2,4,5-trihydroxy-6-hydroxymethyl-tetrahy-dro-pyran-3-ylcarbamoyl-methyl, trimethylammonioethyl or 2-phosphonoethyl;
Rz is aminosulfonyl or ureidomethyl; and R13 is hydrogen; or a pharmaceutically acceptable salt thereof 4. The compound of claim 3, wherein: R3 is -CONR7R8, -CH2CONR9R10 or-C(CH3)2CONR9R10 ; R7 is hydrogen; R9 is hydrogen; R8 is aminocarbonylmethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, or 1,2-dicarboxyethyl; R10 is aminocarbonylmethyl, 2-aminocarbonyl-1-carboxyethyl, 5-amino-5-carboxypentyl, 2-carboxyethyl, carboxymethyl, or 1,2-dicarboxyethyl; and Rz is aminosulfonyl; or a pharmaceutically acceptable salt thereof 5. The compound of claim 4, wherein the compound of Formula la is: {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphenyl-3-yl]-acetylamino}-suc-cinic acid, or a pharmaceutically acceptable salt thereof 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any of claims 1 to 5, or a pharmaceutically acceptable salt thereof 7. The use of a therapeutically effective amount of the compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, to manufacture a medicament for use in a method of treating a disease in an animal mediated by Factor Vila. 8. The use of Claim 7 wherein the disorder is a thromboembolic disorder. 9. The use of the compound of any one of claim 1 through 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a thromboembolic disorder, wherein the medicament is to be used with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a factor IXa, a factor Xa inhibitor, Aspirin®, and Plavis®. 10. The compound of claim any one of claims 1 through 5, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease in an animal mediated by Factor Vila. 11. The compound of claim 10 wherein the disorder is a thromboembolic disorder. 12. The compound of any one of claim 1 through 5, or a pharmaceutically acceptable salt thereof, for use in treating a thromboembolic disorder, wherein the compound is to be administered in combination with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, a factor IXa, a factor Xa inhibitor, Aspirin®, and Plavis®. 13. A method of inhibiting the coagulation of a biological sample in vitro comprising the administration of a compound of any one of claims 1 through 5, or a pharmaceutically acceptable salt thereof. 14. A process of preparing a compound of Claim 1 where X1 is -N- comprising reacting a compound of Formula II:
Formula II with a compound of Formula III:
Formula III wherein: R3 is -CONR7R8, (where R7 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, sulfoalkyl or phospho-noalkyl; and R8 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, aminocarboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkylene)-(OCH2CH2)n Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylamino-carbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R7 and R8 together with the nitrogen atom to which they are attached form heterocycloalkylamino), or -(alkylene)-CONR9R10 (where R9 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl or phosphonoalkyl; and R10 is hydrogen, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxyalkyl, sulfoalkyl, phosphonoalkyl, amino carboxyalkyl, aminocarbonylcarboxyalkyl, trimethylammonioalkyl, aminocarbonylalkyl, -(alkyleneHOCF^Chy,, Rb (where n is an integer from 1 to 6 and Rb is hydrogen, alkyl, hydroxy, alkoxy, amino or alkylcarbonylamino), aryl, aralkyl, heteroaryl, heteroaralkyl, hetereocycloalkylalkyl, hetereocycloalkylaminocarbonylalkyl or 3-heterocycloalkyl-2-hydroxypropyl; or R9 and R10 together with the nitrogen atom to which they are attached form heterocycloalkylamino); and
Rz is hydrogen, alkyl, haloalkyl, cycloalkyl, alkylthio, halo, hydroxy, hydroxyalkyl, nitro, cyano, alkoxy, alkoxyalkyl, alkoxyalkyloxy, hydroxyalkoxyloxy, aminoalkyloxy, carboxyalkyloxy, aminocarbonylalkyloxy, haloalkoxy, car-boxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfo-nyl, heteroarylsulfonyl, carbamimidoyl, hydroxycarbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkyl-sulfonylaminoalkyl, alkoxysulfonylamino, alkoxysulfonylaminoalkyl, heterocycloalkylalkylaminocarbonyl, hy-droxyalkoxyalkylaminocarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonylalkyl, heterocycloalkyl, het-erocycloalkylalkyl, oxoheterocycloalkyl, oxoheterocycloalkylalkyl, heteroaryl, heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, -COR12 (where R12 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl), -(alkylene)-COR12 (where R12 is alkyl, haloalkyl, hy-droxyalkyl, alkoxyalkyl, or aminoalkyl), -CONR14R15 (where R14 is hydrogen or alkyl; and R15 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-CONR16R17 (where R16 is hydrogen, alkyl or hydroxyalkyl; and R17 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -NR18R19 (where R18 is hydrogen or alkyl; and R19 is hydrogen, alkyl, acyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), -(alkylene)-NR20R21 (where R20 is hydrogen, alkyl, or hydroxyalkyl; and R21 is hydrogen, alkyl, acyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), - S02NR22R23 (where R22 is hydrogen or alkyl; and R23 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R22 and R23 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-S02NR24R25 (where R24 is hydrogen or alkyl; and R25 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R24 and R25 together with the nitrogen atom to which they are attached from heterocycloamino), -NR26S02NR27R28 (where R26 and R27 are independently hydrogen or alkyl; and R28 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R27 and R28 together with the nitrogen atom to which they are attached from heterocycloamino), -(alkylene)-NR29SO2NR30R31 (where R29 and R30 are independently hydrogen or alkyl; and R31 is hydrogen, alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R30 and R31 together with the nitrogen atom to which they are attached from heterocycloamino), -CONH-(alkylene)-NR32R33 (where R32 is hydrogen or alkyl; and R33 is alkyl), or aralkyl; and R13 is hydrogen; (i) optionally modifying any of the R1, R2, R3, Rx, RV, Rz, and R13 groups; (ii) optionally isolating individual stereoisomers; (iii) optionally preparing an acid addition salt; and (iv) optionally preparing a free base; wherein alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms; alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms; alkylthio means a radical -SR where R is alkyl; amino means the radical -NRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; acyl means a radical -COR’ where R’ is alkyl, alkoxy, haloalkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; aminosulfonyl means a radical -S02NH2; alkylaminosulfonyl means a radical -S02NHR where R is alkyl; alkylsulfonyl means a radical -S02R where R is alkyl; alkylsulfonylalkyl means a radical -(alkylene)-S02R where R is alkyl; alkylsulfonylamino means a radical -NHS02R where R is alkyl; alkylsulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkyl; alkoxysulfonylamino means a radical -NHS02R where R is alkoxy; alkoxysulfonylaminoalkyl means a radical -(alkylene)-NHS02R where R is alkoxy; alkoxy means a radical -OR where R is alkyl; alkoxycarbonyl means a radical -COOR where R is alkyl; alkoxycarbonylalkyl means a radical -(alkylene)-COOR where R is alkyl; alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group; aminoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one -NRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -NRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylcarboxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one -CONRR’ and -COOH where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; aminocarbonylalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two -CONRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; alkoxyalkyloxy means a radical -OR where R is alkoxyalkyl; aminoalkyloxy means a radical -OR where R is aminoalkyl; aminocarbonyl means a radical -CONH2; aminocarbonylalkyloxy means a radical - O-alkylene-CONRR’ where R and R’ are independently hydrogen or alkyl; aminocarbonylalkyl means a radical -(alkylene)-CONH2; alkylureido means a radical-NRCONHR’ where R is hydrogen or alkyl and R’ is alkyl; alkylureidoalkyl means a radical -(alkylene)-NRCONHR’ where R is hydrogen or alkyl and R’ is alky; aryl means a monovalent monocyclicor bicyclic aromatic hydrocarbon radical of 6 to 12 ring atoms, and optionally substituted independently with one or more substituents, selected from alkyl, haloalkyl, alkoxy, alkylthio, halo, nitro, -COR (where R is alkyl), cyano, amino, alkylamino, dialkylamino, hydroxy, carboxy, or-COOR where R is alkyl; arylsulfonyl means a radical -S02R where R is aryl; aralkyl means a radical - (alkylene)-R where R is an aryl group; alkoxycarbamimidoyl means a radical -C(=NH)NHOR or-C(=NOR)NH2 where R is alkyl; cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms; carboxyalkyl means a radical -(alkylene)-COOH; carboxyalkyloxy means a radical -0-(alkylene)-C00H; carbamimidoyl means a radical - C(=NH)NH2; cyanoalkyl means a radical -(alkylene)-CN; dialkylaminosulfonyl means a radical - S02NRR’ where R and R’ are independently alkyl; dialkylureido means a radical -NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; dialkylureidoalkyl means a radical -(alkylene)-NRCONR’R" where R is hydrogen or alkyl and R’ and R" are independently alkyl; guanidinoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms ora branched monovalent hydrocarbon radical of three to six carbons substituted with at least one -NRC(NRR’)NRR’ where R and R’ are independently hydrogen, alkyl, or -CORa where Ra is alkyl; halo means fluoro, chloro, bromo, and iodo; haloalkyl means alkyl substituted with one or more halogen atoms; haloalkoxy means a radical -OR where R is haloalkyl; hydroxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one to five hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom; hydroxyalkyloxy means a radical -OR where R is hydroxyalkyl; hydroxy-alkoxyalkylaminocarbonyl means a radical -CONH-(alkylene)-0-(alkylene)OH; heterocycloalkyl means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C; heterocy-cloalkylcarbonyl means a radical -COR where R is heterocycloalkyl; heterocycloalkylcarbonylalkyl means a radical -(alkylene)-COR where R is heterocycloalkyl; heterocycloalkylalkyl means a radical -(alkylene)-R where R is heterocycloalkyl; heterocycloalkylalkylaminocarbonyl means a radical -CONH-(alkylene)-R where R is heterocycloalkyl; heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being carbon, the heteroaryl ring being optionally substituted with one or more substituents independently selected from alkyl, haloalkyl, alkoxy, alkylthio, aminoalkyl, guanidinoalkyl, halo, nitro, cyano, amino, alkyl or dialkylamino, hydroxy, carboxy, or -COOR where R is alkyl; heteroarylsulfonyl means a radical -S02R where R is heteroaryl; heteroaralkyl means a radical -(alkylene)-R where R is a heteroaryl; heterocycloamino means a saturated or unsaturated monovalent cyclic group of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C provided that at least one of the heteroatom is nitrogen and wherein one or two carbon atoms are optionally replace by a carbonyl group, the heterocycloamino ring being optionally substituted with one or more substituents independently selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo, cyano, carboxy, -CONRaRb (where Ra and Rb are independently hydrogen or alkyl), or -COOR where R is alkyl; hydroxycarbamimidoyl means a radical -C(=NH)NHOH or -C(=NOH)NH2.
Patentanspriiche 1. Verbindung mit dér Formel I:
Formula I worin: X1 -N- Oder -CR5- ist, worin R5 Wasserstoff, Alkyl Oder Halo ist; R1 Wasserstoff, Alkyl, Halo, Carboxy Oder Aminocarbonyl ist; R2 Wasserstoff, Alkyl Oder Halo ist; R3-CONR7R8 (wobei R7 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Carboxyalkyl, Sulfoalkyl oderPhospho-noalkyl ist; und R8 Wasserstoff, Hydroxy, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aminoalkyl, Carboxyalkyl, Sulfoalkyl, Phosphonoalkyl, Aminocarboxyalkyl, Aminocarbonylcarboxyalkyl, Trimethylammonioalkyl, Aminocarbonylal-kyl, -(Alkylen)-(OCH2CH2)n Rb (wobei n ein Integer von 1 bis 6 ist und Rb Wasserstoff, Alkyl, Hydroxy, Alkoxy, Amino Oder Alkylcarbonylamino ist), Aryl, Aralkyl, Heteroaryl, Heteroaralkyl, Hetereocycloalkylalkyl, Hetereo-cycloalkylaminocarbonylalkyl Oder 3-Heterocycloalkyl-2-hydroxypropyl ist; Oder R7 und R8 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloalkylaminobilden)oder-(Alkylen)-CONR9R10 (wobei R9 Wasserstoff, Hydroxy, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aminoalkyl, Carboxyalkyl, Sulfoalkyl Oder Phosphonoalkyl ist; und R10 Wasserstoff, Hydroxy, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aminoalkyl, Carboxyalkyl, Sulfoalkyl, Phosphonoalkyl, Aminocarboxyalkyl, Aminocarbonylcarboxyalkyl, Trimethylammonioalkyl, Aminocarbonylal-kyl, - (Alkylen)-(OCH2CH2)n Rb (wobei n ein Integer von 1 bis 6 ist und Rb Wasserstoff, Alkyl, Hydroxy, Alkoxy, Amino Oder Alkylcarbonylamino ist), Aryl, Aralkyl, Heteroaryl, Heteroaralkyl, Hetereocycloalkylalkyl, Hetereo-cycloalkylaminocarbonylalkyl Oder 3-Heterocycloalkyl-2-hydroxypropyl ist; Oder R9 und R10 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloalkylamino bilden) ist;
Rx Wasserstoff, Alkyl, Alkylthio, Halo, Hydroxy, Hydroxyalkyl, Alkoxy, Aminosulfonyl, Alkylaminosulfonyl, Dial-kylaminosulfonyl oder Nitro ist; RV Wasserstoff, Alkyl oder Halo ist;
Rz Wasserstoff, Alkyl, Haloalkyl, Cycloalkyl, Alkylthio, Halo, Hydroxy, Hydroxyalkyl, Nitro, Cyano, Alkoxy, Alkoxyalkyl, Alkoxyalkyloxy, Hydroxyalkyloxy, Aminoalkyloxy, Carboxyalkyloxy, Aminocarbonylalkyloxy, Haloalk-oxy, Carboxy, Carboxyalkyl, Alkoxycarbonyl, Alkoxycarbonylalkyl, Cyanoalkyl, Alkylsulfonyl, Alkylsulfonylalkyl, Arylsulfonyl, Heteroarylsulfonyl, Carbamimidoyl, Hydroxycarbamimidoyl, Alkoxycarbamimidoyl, Alkylsulfonyla-mino, Alkylsulfonylaminoalkyl, Alkoxysulfonylamino, Alkoxysulfonylaminoalkyl, Heterocycloalkylalkylaminocar-bonyl, Hydroxyalkoxyalkylaminocarbonyl, Heterocycloalkylcarbonyl, Heterocycloalkylcarbonylalkyl, Heterocycloalkyl, Heterocycloalkylalkyl, Oxoheterocycloalkyl, Oxoheterocycloalkylalkyl, Heteroaryl, Heteroaralkyl, Urei-do, Alkylureido, Dialkylureido, Ureidoalkyl, Alkylureidoalkyl, Dialkylureidoalkyl, Thioureido, Thioureidoalkyl, -COR12 (wobei R12 Alkyl, Haloalkyl, Hydroxyalkyl, Alkoxyalkyl oder Aminoalkyl ist), -(Alkylen)-COR12 (wobei R12 Alkyl, Haloalkyl, Hydroxyalkyl, Alkoxyalkyl oder Aminoalkyl ist), - CONR14R15 (wobei R14 Wasserstoff oder Alkyl ist; und R15 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R14 und R15 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -(Alkylen)-CONR16R17 (wobei R16 Wasserstoff, Alkyl oder Hydroxyalkyl ist; und R17 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R16 und R17 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), - NR18R19 (wobei R18 Wasserstoff oder Alkyl ist; und R19 Wasserstoff, Alkyl, Acyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist), -(Alky-len)-NR20R21 (wobei R20 Wasserstoff, Alkyl oder Hydroxyalkyl ist; und R21 Wasserstoff, Alkyl, Acyl, Alkoxycarbonyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist), -S02NR22R23 (wobei R22 Wasserstoff oder Alkyl ist; und R23 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R22 und R23 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -(Alky-
Ien)-S02NR24R25 (wobei R24 Wasserstoff Oder Alkyl ist; und R25 WasserstofF, Alkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist; Oder R24 und R25 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -NR26S02NR27R28 (wobei R26 und R27 unabhángig WasserstofFoder Alkyl sind; und R28 WasserstofF, Alkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R27 und R28 zusammen mit dem StickstofFatom, an welches sie angehángt sind, Heterocycloamino bilden), - (Alkylen)-NR29SO2NR30R31 (wobei R29 und R30 unabhángig WasserstofF oder Alkyl sind; und R31 WasserstofF, Alkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R30 und R31 zusammen mit dem StickstofFatom, an welches sie angehángt sind, Heterocycloamino bilden), -CONH-(Alkylen)-NR32R33 (wobei R32 WasserstofF oder Alkyl ist; und R33 Alkyl ist) oder Aralkyl ist; und R13 WasserstofF, Hydroxy, (C^^J-Alkoxy, -C(0)R35 (wobei R35 Alkyl, Aryl, Haloalkyl oder Cyanoalkyl ist) oder -C(0)0R36 (wobei R36 Alkyl, Hydroxyalkyl, Alkoxyalkyl, Alkoxycarbonylalkyl, Acyl, Aryl oder Haloalkyl ist) ist; oder individuelles Stereoisomer, Gemisch von Stereoisomeren oder ein pharmazeutisch annehmbares Salz davon, sofern, wenn R3 -CONR7R8 (wobei R7 WasserstofF oder Alkyl ist; und R8 WasserstofF oder Alkyl ist), -(Alky-len)-CONR9R10 (wobei R9 und R10 zusammen mit dem StickstofFatom, an welches sie angehángt sind, Pyrro-lidinyl bilden) ist, und Rz WasserstofF, Alkyl, Haloalkyl, Halo, Nitro, Alkoxy, Haloalkyl, Carboxy, Alkoxycarbonyl, -NR18R19 (wobei R18 WasserstofF oder Alkyl ist; und R19 WasserstofF, Alkyl, Aryl oder Aralkyl ist), Pyrrolidinyl-carbonyl, -S02NR22R23 (wobei R22 und R23 Alkyl sind), Carbamimidoyl, Alkylsulfonylamino, Alkylthio, Ureido, -NHC(S)NH2 oder Heterocycloamino ist, Rx dann Hydroxy oder Hydroxyalkyl ist; worin Alkyl ein linearesgesáttigtes monovalentes KohlenwasserstofFradikal mit ein bissechs KohlenstofFatomen oder ein verzweigtes gesáttigtes monovalentes KohlenwasserstofFradikal mitdrei bis sechs KohlenstofFatomen bedeutet; Alkylen ein lineares gesáttigtes divalentes KohlenwasserstofFradikal mit ein bis sechs KohlenstofFatomen oder ein verzweigtes gesáttigtes divalentes KohlenwasserstofFradikal mit drei bis sechs KohlenstofFatomen bedeutet; Alkylthio ein Radikal -SR bedeutet, wobei R Alkyl ist; Amino das Radikal -NRR bedeutet, wobei R und R’ unabhángig WasserstofF, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Acyl ein Radikal -COR’ bedeutet, wobei R’ Alkyl, Alkoxy, Haloalkyl, Aminoalkyl, Hydroxyalkyl oder Alkoxyalkyl ist; Aminosulfonyl ein Radikal -S02NH2 bedeutet; Alkylaminosulfonyl ein Radikal - S02NHR bedeutet, wobei R Alkyl ist; Alkylsulfonyl ein Radikal -S02R bedeutet, wobei R Alkyl ist; Alkylsulfonylalkyl ein Radikal -(Alkylen)-S02R bedeutet, wobei R Alkyl ist; Alkylsulfonylamino ein Radikal -NHS02R bedeutet, wobei R Alkyl ist; Alkylsulfonylaminoalkyl ein Radikal -(Alkylen)-NHS02R bedeutet, wobei R Alkyl ist; Alkoxysulfonylamino ein Radikal -NHS02R bedeutet, wobei R Alkoxy ist; Alkoxysulfonylaminoalkyl ein Radikal -(Alkylen)-NHS02R bedeutet, wobei R Alkoxy ist; Alkoxy ein Radikal -OR bedeutet, wobei R Alkyl ist; Alkoxycarbonyl ein Radikal -COOR bedeutet, wobei R Alkyl ist; Alkoxycarbonylalkyl ein Radikal - (Alkylen)-COOR bedeutet, wobei R Alkyl ist; Alkoxyalkyl ein lineares monovalentes KohlenwasserstofFradikal mit ein bis sechs KohlenstofFatomen oder ein verzweigtes monovalentes KohlenwasserstofFradikal mit drei bis sechs KohlenstofFen, die durch zumindest eine Alkoxy-Gruppe substituiert werden, bedeutet; Aminoalkyl ein lineares monovalentes KohlenwasserstofFradikal mit ein bis sechs KohlenstofFatomen oder ein verzweigtes monovalentes KohlenwasserstofFradikal mit drei bis sechs KohlenstofFen, die durch zumindest ein -NRR’ substituiert werden, bedeutet, wobei R und R’ unabhángig WasserstofF, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Aminocarboxyalkyl ein lineares monovalentes KohlenwasserstofFradikal mit ein bis sechs KohlenstofFatomen oder ein verzweigtes monovalentes KohlenwasserstofFradikal mit drei bis sechs KohlenstofFen, die durch ein -NRR’ und -COOH substituiert werden, bedeutet, wobei R und R’ unabhángig Was-serstofF, Alkyl oder-CORa sind, wobei Ra Alkyl ist; Aminocarbonylcarboxyalkyl ein lineares monovalentes KohlenwasserstofFradikal mit ein bis sechs KohlenstofFatomen oder ein verzweigtes monovalentes KohlenwasserstofFradikal mitdrei bis sechs KohlenstofFen, die durch ein -CONRR’ und -COOH substituiert werden, bedeutet, wobei R und R’ unabhángig WasserstofF, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Aminocarbonylalkyl ein lineares monovalentes KohlenwasserstofFradikal mit ein bis sechs KohlenstofFatomen oder ein verzweigtes monovalentes KohlenwasserstofFradikal mit drei bis sechs KohlenstofFen, die durch ein oder zwei -CONRR’ substituiert werden, bedeutet, wobei R und R’ unabhángig WasserstofF, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Alkoxyalkyloxy ein Radikal -OR bedeutet, wobei R Alkoxyalkyl ist; Aminoalkyloxy ein Radikal -OR bedeutet, wobei R Aminoalkyl ist; Aminocarbonyl ein Radikal -CONH2 bedeutet; Aminocarbonylalkyloxy ein Radikal -O-Alkylen-CONRR’ bedeutet, wobei R und R’ unabhángig WasserstofF oder Alkyl sind; Aminocarbonylalkyl ein Radikal - (Alkylen)-CONH2 bedeutet; Alkylureido ein Radikal -NRCONHR’ bedeutet, wobei R WasserstofF oder Alkyl ist und R’ Alkyl ist; Alkylureidoalkyl ein Radikal - (Alkylen)-NRCONHR’ bedeutet, wobei R WasserstofF oder Alkyl ist und R’ Alky ist; Aryl ein monovalentes monozyklisches oder bizyklisches aromatisches KohlenwasserstofFradikal mit 6 bis 12 Ringatomen bedeutet, und wahlweise unabhángig durch ein oder mehr Substi-tuenten substituiert, die aus Alkyl, Haloalkyl, Alkoxy, Alkylthio, Halo, Nitro, -COR (wobei R Alkyl ist), Cyano, Amino, Alkylamino, Dialkylamino, Hydroxy, Carboxy oder-COOR ausgewáhlt werden, wobei R Alkyl ist; Aryl-sulfonyl ein Radikal -S02R bedeutet, wobei R Aryl ist; Aralkyl ein Radikal -(Alkylen)-R bedeutet, wobei R eine
Aryl-Gruppe ist; Alkoxycarbamimidoyl ein Radikal -C(=NH)NHORoder-C(=NOR)NH2 bedeutet, wobei R Alkyl ist; Cycloalkyl ein zyklisches gesáttigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoff-atomen bedeutet; Carboxyalkyl ein Radikal -(Alkylen)-COOH bedeutet; Carboxyalkyloxy ein Radikal -0-(Alky-len)-COOH bedeutet; Carbamimidoyl ein Radikal -C(=NH)NH2 bedeutet; Cyanoalkyl ein Radikal -(Alkylen)-CN bedeutet; Dialkylaminosulfonyl ein Radikal -S02NRR’ bedeutet, wobei R und R’ unabhángig Alkyl sind; Dialky-lureido ein Radikal -NRCONR’R" bedeutet, wobei RWasserstoff Oder Alkyl ist und R’ und R" unabhangig Alkyl sind; Dialkylureidoalkyl ein Radikal -(Alkylen)-NRCONR’R" bedeutet, wobei RWasserstoffoder Alkyl ist und R’ und R" unabhangig Alkyl sind; Guanidinoalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen Oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Koh-lenstofFen, diedurch zumindestein-NRC(NRR’)NRR’substituiertwerden, bedeutet, wobei R und R’ unabhangig WasserstofF, Alkyl oder-CORa sind, wobei Ra Alkyl ist; Halo Fluoro, Chloro, Bromo und Jodo bedeutet; Haloalkyl Alkyl bedeutet, das durch ein oder mehr Halogenatome substituiert wird; Haloalkoxy ein Radikal -OR bedeutet, wobei R Haloalkyl ist; Hydroxyalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffen, die durch eine bis fiinf Hydroxy-Gruppen substituiert werden, bedeutet, sofern, wenn zwei Hydroxy-Gruppen zugegen sind, sie nicht beide auf demselben KohlenstofFatom sind; Hydroxyalkyloxy ein Radikal -OR bedeutet, wobei R Hydroxyalkyl ist; Hydroxyalkoxyalkylaminocarbonyl ein Radikal -CONH-(Alkylen)-0-(Alkylen)OH bedeutet; Heterocycloalkyl eine gesáttigte oder ungesáttigte monovalentezyklische Gruppé mit 3 bis 8 Ringatomen bedeutet, worin ein oder zwei Ringatome Heteroatome sind, die aus N, O oder S(0)n ausgewáhlt werden, wobei n ein Integer von 0 bis 2 ist, wobei die verbleibenden Ringatome C sind; Heterocycloalkylcarbonyl ein Radikal -COR bedeutet, wobei R Heterocycloalkyl ist; Heterocycloalkylcarbonylalkyl ein Radikal -(Alkylen)-COR bedeutet, wobei R Heterocycloalkyl ist; Heterocycloalkylalkyl ein Radikal - (Alkylen)-R bedeutet, wobei R Heterocycloalkyl ist; Heterocycloalkylalkylaminocarbonyl ein Radikal -CONH-(Alkylen)-R bedeutet, wobei R Heterocycloalkyl ist; Heteroaryl eine monovalentes monozyklisches oder bizyklisches aromatisches Radikal mit 5 bis 10 Ringatomen bedeutet, die ein oder mehr Ring-Heteroatome enthalten, die aus N, O oder S ausgewahlt werden, wobei die verbleibenden Ringatome Kohlenstoff sind, wobei der Heteroaryl-Ring wahlweise durch ein oder mehr Substituenten substituiert wird, die aus Alkyl, Haloalkyl, Alkoxy, Alkylthio, Aminoalkyl, Guanidinoalkyl, Halo, Nitro, Cyano, Amino, Alkyl oder Dialkylamino, Hydroxy, Carboxy oder-COOR ausgewahlt werden, wobei R Alkyl ist; Heteroarylsulfonyl ein Radikal -S02R bedeutet, wobei R Heteroaryl ist; Heteroaralkyl ein Radikal -(Alkylen)-R bedeutet, wobei R ein Heteroaryl ist; Heterocycloamino eine gesáttigte oder ungesáttigte mono-valente zyklische Gruppé mit 3 bis 8 Ringatomen bedeutet, worin ein oder zwei Ringatome Heteroatome sind, die aus N, O oder S(0)n ausgewáhlt werden, wobei n ein Integer von 0 bis 2 ist, wobei die verbleibenden Ringatome C sind, sofern zumindest eines der Heteroatome Stickstoff ist, und worin ein oder zwei Kohlenstoff-atome wahlweise durch eine Carbonyl-Gruppe ersetzt werden, wobei der Heterocycloamino-Ring wahlweise durch einen oder mehr Substituenten substituiert wird, die unabhángig aus Alkyl, Hydroxy, Hydroxyalkyl, Alkoxy, Alkoxyalkyl, Aminoalkyl, Guanidinoalkyl, Halo, Haloalkyl, Aryl, Heteroaryl, Aralkyl, Heteroaralkyl, Haloalkyl, Halo, Cyano, Carboxy, -CONRaRb (wobei Ra und Rb unabhángig Wasserstoff oder Alkyl sind) oder -COOR ausgewáhlt werden, wobei R Alkyl ist; Hydroxycarbamimidoyl ein Radikal -C(=NH)NHOH oder - C(=NOH)NH2 bedeutet. 2. Verbindung nach Anspruch 1, worin: R3 -CONR7R8 (wobei R7 Wasserstoff, Alkyl, Alkoxyalkyl, Carboxyalkyl, Hydroxyalkyl oder Phosphonoalkyl ist; und R8 Wasserstoff, Alkyl, Alkoxyalkyl, - (Alkylen)-(OCH2CH2)n Rb (wobei n ein Integer von 1 bis 6 ist und Rb Wasserstoff, Alkyl, Hydroxy, Alkoxy, Amino oder Alkylcarbonylamino ist), Aminoalkyl, Aminocarbonylalkyl, Ami-nocarbonylcarboxyalkyl, Aminocarboxyalkyl, Carboxyalkyl, Hydroxyalkyl, Phosphonoalkyl, Sulfoalkyl, Trime-thylammonioalkyl, Aryl, Aralkyl, Heteroaryl, Heteroaralkyl oder Hetereocycloalkylalkyl ist; oder R7 und R8 zu-sammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloalkylamino bilden) oder -(Alky-len)-CONR9R10 (wobei R9 Wasserstoff, Alkyl, Alkoxyalkyl, Carboxyalkyl, Hydroxyalkyl oder Phosphonoalkyl ist; und R10 Wasserstoff, Alkyl, Alkoxyalkyl, -(Alkylen)-(OCH2CH2)n Rb (wobei n ein Integer von 1 bis 6 ist und Rb Wasserstoff, Alkyl, Hydroxy, Alkoxy, Amino oder Alkylcarbonylamino ist), Aminoalkyl, Aminocarbonylalkyl, Ami-nocarbonylcarboxyalkyl, Aminocarboxyalkyl, Carboxyalkyl, Hydroxyalkyl, Phosphonoalkyl, Sulfoalkyl, Trime-thylammonioalkyl, Aryl, Aralkyl, Heteroaryl, Heteroaralkyl oder Heterocycloalkylalkyl ist; oder R9 und R10 zu-sammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloalkylamin bilden) ist, worin irgend-welche Ringe, die R3 umfassen, wahlweise durch eine bis sechs Gruppén substituiert werden, die unabhangig aus Hydroxy, Hydroxyalkyl, Alkoxyalkyl, Carboxy, Alkoxycarbonyl, Aminoalkyl, Guanidinoalkyl, Alkyl oder -CONRaRb (wobei Ra und Rb unabhángig Wasserstoff oder Alkyl sind) ausgewahlt werden; und Rz Wasserstoff, Alkyl, Haloalkyl, Cycloalkyl, Alkylthio, Halo, Hydroxy, Hydroxyalkyl, Nitro, Cyano, Alkoxy, Aik- oxyalkyl, Alkoxyalkyloxy, Hydroxyalkyloxy, Aminoalkyloxy, Carboxyalkyloxy, Aminocarbonylalkyloxy, Haloalk-oxy, Carboxy, Carboxyalkyl, Alkoxycarbonyl, Alkoxycarbonylalkyl, Cyanoalkyl, Alkylsulfonyl, Alkylsulfonylalkyl, Arylsulfonyl, Heteroarylsulfonyl, Carbamimidoyl, Hydroxycarbamimidoyl, Alkoxycarbamimidoyl, Alkylsulfonyla-mino, Alkylsulfonylaminoalkyl, Alkoxysulfonylamino, Alkoxysulfonylaminoalkyl, Heterocycloalkylalkylaminocar-bonyl, Hydroxyalkoxyalkylaminocarbonyl, Heterocycloalkylcarbonyl, Heterocycloalkylcarbonylalkyl, Heterocycloalkyl, Heterocycloalkylalkyl, Oxoheterocycloalkyl, Oxoheterocycloalkylalkyl, Heteroaryl, Heteroaralkyl, Urei-do, Alkylureido, Dialkylureido, Ureidoalkyl, Alkylureidoalkyl, Dialkylureidoalkyl, Thioureido, Thioureidoalkyl, -COR12 (wobei R12 Alkyl, Haloalkyl, Hydroxyalkyl, Alkoxyalkyl Oder Aminoalkyl ist), -(Alkylen)-COR12 (wobei R12 Alkyl, Haloalkyl, Hydroxyalkyl, Alkoxyalkyl Oder Aminoalkyl ist), - CONR14R15 (wobei R14 Wasserstoff Oder Alkyl ist; und R15 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist; Oder R14 und R15zusammen mitdem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -(Alkylen)-CONR16R17 (wobei R16 Wasserstoff, Alkyl oder Hydroxyalkyl ist; und R17 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist; Oder R16 und R17 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), - NR18R19 (wobei R18 Wasserstoff oder Alkyl ist; und R19 Wasserstoff, Alkyl, Acyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist), -(Alky-len)-NR20R21 (wobei R20 Wasserstoff, Alkyl oder Hydroxyalkyl ist; und R21 Wasserstoff, Alkyl, Acyl, Alkoxycarbonyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist), -S02NR22R23 (wobei R22 Wasserstoff oder Alkyl ist; und R23 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R22 und R23 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -(Alky-len)-S02NR24R25 (wobei R24 Wasserstoff oder Alkyl ist; und R25 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R24 und R25 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -NR26S02NR27R28 (wobei R26 und R27 unabhángig Wasserstoff oder Alkyl sind; und R28 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R27 und R28 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), - (Alkylen)-NR29SO2NR30R31 (wobei R29 und R30 unabhángig Wasserstoff oder Alkyl sind; und R31 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl oder Heteroaralkyl ist; oder R30 und R31 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -CONH-(Alkylen)-NR32R33 (wobei R32 Wasserstoff oder Alkyl ist; und R33 Alkyl ist) oder Aralkyl ist; und R13 Wasserstoff, Hydroxy, (C.|_10)-Alkoxy, -C(0)R35 (wobei R35 Alkyl, Aryl, Haloalkyl oder Cyanoalkyl ist) oder -C(0)0R36 (wobei R36 Alkyl, Hydroxyalkyl, Acyl oder Haloalkyl ist); oderein pharmazeutisch annehmbares Salz davon ist. 3. Verbindung mit der Formel la, worin:
Formel la R3 -CONR7R8, -CH2CONR9R10 oder -C(CH3)2CONR9R10 ist; R7 Wasserstoff oder Methyl ist; R9 Wasserstoff oder Methyl ist; R8 Aminocarbonylmethyl, 1,2-Diaminocarbonylethyl, 2-Aminocarbonyl-1-carboxyethyl, 5-Amino-5-carboxypen-tyl, 2-Carboxyethyl, Carboxymethyl, 2-Carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, Dimethylaminomethyl, 3-Dimethylaminopropyl, 2-Hydroxy-1,1-bis-hydroxymethyl-ethyl, 2-Hydroxy-1-hydroxymethylethyl, 1,2-Dicarb-oxyethyl, Methyl, 2-[2-(2-Methylaminoethoxy)ethoxy]ethyl, 2-(4-Methylpiperazin-1-yl)ethyl, 2-Morpholin-4-yle-thyl, 2,3,4,5,6-Pentahydroxy-hexyl, 2-Piperazin-1-ylethyl, 2-Sulfoethyl, 3,4,5,6-Tetrahydroxy-tetrahydro-pyran-2-ylmethyl,2,4,5-Trihydroxy-6-hydroxymethyltetrahydro-pyran-3-yl,2,4,5-Trihydroxy-6-hydroxymethyl-tetrahy- dro-pyran-3-ylcarbamoyl-methyl, Trimethylammonioethyl Oder 2-Phosphonoethyl ist; R10 Aminocarbonylmethyl, 1,2-Diaminocarbonylethyl, 2-Aminocarbonyl-1-carboxyethyl, 5-Amino-5-carboxy-pentyl, 2-Carboxyethyl, Carboxymethyl, 2-Carboxy-3-[2-(2-ethoxy-ethoxy)-ethoxy]-propyl, Dimethylaminome-thyl, 3-Dimethylaminopropyl, 2-Hydroxy-1,1-bis-hydroxymethyl-ethyl, 2-Hydroxy-1-hydroxymethylethyl, 1,2-Di-carboxyethyl, Methyl, 2-[2-(2-Methylaminoethoxy)ethoxy]ethyl, 2-(4-Methylpiperazin-1-yl)ethyl, 2-Morpholin-4-ylethyl, 2,3,4,5,6-Pentahydroxy-hexyl, 2-Piperazin-1 -ylethyl, 2-Sulfoethyl, 3,4,5,6-Tetrahydroxy-tetrahydro-py-ran-2-ylmethyl, 2,4,5-Trihydroxy-6-hydroxymethyltetrahydro-pyran-3-yl, 2,4,5-Trihydroxy-6-hydroxymethyl-te-trahydro-pyran-3-ylcarbamoyl-methyl, Trimethylammonioethyl Oder 2-Phosphonoethyl ist;
Rz Aminosulfonyl Oder Ureidomethyl ist; und R13 Wasserstoff; Oder ein pharmazeutisch annehmbares Salz davon ist. 4. Verbindung nach Anspruch 3, worin: R3 -CONR7R8, -CH2CONR9R10 Oder -C(CH3)2CONR9R10 ist; R7 Wasserstoff ist; R9 Wasserstoff ist; R8 Aminocarbonylmethyl, 2-Aminocarbonyl-1-carboxyethyl, 5-Amino-5-carboxypentyl, 2-Carboxyethyl, Carboxymethyl Oder 1,2-Dicarboxyethyl ist; R10 Aminocarbonylmethyl, 2-Aminocarbonyl-1-carboxyethyl, 5-Amino-5-carboxypentyl, 2-Carboxyethyl, Carboxymethyl Oder 1,2-Dicarboxyethyl ist; und Rz Aminosulfonyl; Oder ein pharmazeutisch annehmbares Salz davon ist. 5. Verbindung nach Anspruch 4, worin die Verbindung mit der Formel la lautet: {2-[5-(5-Carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoylbiphenyl-3-yl]-acetylamino}-Bern-steinsáure oder ein pharmazeutisch annehmbares Salz davon. 6. Pharmazeutische Zusammensetzung umfassend einen pharmazeutisch annehmbaren Tráger und eine therapeu-tisch wirksame Menge einer Verbindung nach irgendeinem der Anspriiche 1 bis 5, oder ein pharmazeutisch annehmbares Salz davon. 7. Verwendung einer therapeutisch wirksamen Menge der Verbindung nach einem beliebigen der vorhergehenden Anspriiche, oder eines pharmazeutisch annehmbaren Salzes davon, urn ein Medikamentzur Verwendung bei einem Verfahren zur Behandlung einer Erkrankung in einem Tier, die durch Faktor Vila vermittelt wird, herzustellen. 8. Verwendung nach Anspruch 7, worin die Erkrankung eine thromboembolische Erkrankung ist. 9. Verwendung derVerbindung nach einem beliebigen der Anspriiche 1 bis 5, odereines pharmazeutisch annehmbaren Salzes davon, fiir die Flerstellung eines Medikaments zur Behandlung einerthromboembolischen Erkrankung, worin das Medikament mit einem anderen Antikoagulans oder anderen Antikoagulanzien zu verwenden ist, das oder die unabhángig aus einer Gruppé ausgewáhlt wird oder werden, die aus einem Thrombin-Hemmer, einem Faktor IXa, einem Faktor-Xa-Flemmer, Aspirin® und Plavis® besteht. 10. Verbindung nach einem beliebigen der Anspriiche 1 bis 5, oder ein pharmazeutisch annehmbares Salz davon, zur Verwendung bei einem Verfahren zur Behandlung einer Erkrankung in einem Tier, die durch Faktor Vila vermittelt wird. 11. Verbindung nach Anspruch 10, worin die Erkrankung eine thromboembolische Erkrankung ist. 12. Verbindung nach einem beliebigen der Anspriiche 1 bis 5, oder ein pharmazeutisch annehmbares Salz davon, zur Verwendung bei der Behandlung einer thromboembolischen Erkrankung, worin die Verbindung zusammen mit einem anderen Antikoagulans oder anderen Antikoagulanzien zu verabreichen ist, das oder die unabhángig aus einer Gruppé ausgewáhlt wird oder werden, die aus einem Thrombin-Hemmer, einem Faktor IXa, einem Faktor-Xa-Hemmer, Aspirin® und Plavis® besteht. 13. Verfahren zum Hemmen der Koagulation einer biologischen Probe in vitro, umfassend die Verabreichung einer
Verbindung nach einem beliebigen derAnspriiche 1 bis 5, odereines pharmazeutisch annehmbaren Salzesdavon. 14. Prozess zur Preparation einer Verbindung nach Anspruch 1, wobei X1 -N- ist, umfassend das Reagieren einer
Verbindung mit dér Formel II:
Formula II mit einer Verbindung mit der Formel III:
Formula III worin: R3-CONR7R8 (wobei R7 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Carboxyalkyl, Sulfoalkyl Oder Phospho-noalkyl ist; und R8 Wasserstoff, Hydroxy, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aminoalkyl, Carboxyalkyl, Sulfoalkyl, Phosphonoalkyl, Aminocarboxyalkyl, Aminocarbonylcarboxyalkyl, Trimethylammonioalkyl, Aminocarbonylal-kyl, -(Alkylen)-(OCH2CH2)n Rb (wobei n ein Integer von 1 bis 6 ist und Rb Wasserstoff, Alkyl, Hydroxy, Alkoxy, Amino Oder Alkylcarbonylamino ist), Aryl, Aralkyl, Heteroaryl, Heteroaralkyl, Hetereocycloalkylalkyl, Hetereo-cycloalkylaminocarbonylalkyl Oder 3-Heterocycloalkyl-2-hydroxypropyl ist; Oder R7 und R8 zusammen mit dem Stickstoffatom, an welches sieangehángtsind, Heterocycloalkylaminobilden)oder-(Alkylen)-CONR9R10 (wobei R9 Wasserstoff, Hydroxy, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aminoalkyl, Carboxyalkyl, Sulfoalkyl Oder Phosphonoalkyl ist; und R10 Wasserstoff, Hydroxy, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aminoalkyl, Carboxyalkyl, Sulfoalkyl, Phosphonoalkyl, Aminocarboxyalkyl, Aminocarbonylcarboxyalkyl, Trimethylammonioalkyl, Aminocarbonylal-kyl, - (Alkylen)-(OCH2CH2)n Rb (wobei n ein Integer von 1 bis 6 ist und Rb Wasserstoff, Alkyl, Hydroxy, Alkoxy, Amino Oder Alkylcarbonylamino ist), Aryl, Aralkyl, Heteroaryl, Heteroaralkyl, Hetereocycloalkylalkyl, Hetereo-cycloalkylaminocarbonylalkyl Oder 3-Heterocycloalkyl-2-hydroxypropyl ist; Oder R9 und R10 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloalkylamino bilden) ist; und Rz Wasserstoff, Alkyl, Haloalkyl, Cycloalkyl, Alkylthio, Halo, Hydroxy, Hydroxyalkyl, Nitro, Cyano, Alkoxy, Alkoxyalkyl, Alkoxyalkyloxy, Hydroxyalkoxyloxy, Aminoalkyloxy, Carboxyalkyloxy, Aminocarbonylalkyloxy, Halo-alkoxy, Carboxy, Carboxyalkyl, Alkoxycarbonyl, Alkoxycarbonylalkyl, Cyanoalkyl, Alkylsulfonyl, Alkylsulfonylal-kyl, Arylsulfonyl, Heteroarylsulfonyl, Carbamimidoyl, Hydroxycarbamimidoyl, Alkoxycarbamimidoyl, Alkylsulfo-nylamino, Alkylsulfonylaminoalkyl, Alkoxysulfonylamino, Alkoxysulfonylaminoalkyl, Heterocycloalkylalkylami-nocarbonyl, Hydroxyalkoxyalkylaminocarbonyl, Heterocycloalkylcarbonyl, Heterocycloalkylcarbonylalkyl, Heterocycloalkyl, Heterocycloalkylalkyl, Oxoheterocycloalkyl, Oxoheterocycloalkylalkyl, Heteroaryl, Heteroaralkyl, Ureido, Alkylureido, Dialkylureido, Ureidoalkyl, Alkylureidoalkyl, Dialkylureidoalkyl, Thioureido, Thioureidoalkyl, -COR12 (wobei R12 Alkyl, Haloalkyl, Hydroxyalkyl, Alkoxyalkyl Oder Aminoalkyl ist), -(Alkylen)-COR12 (wobei R12 Alkyl, Haloalkyl, Hydroxyalkyl, Alkoxyalkyl Oder Aminoalkyl ist), -CONR14R15 (wobei R14 Wasserstoff Oder
Alkyl ist; und R15 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist), -(Alkylen)-CONR16R17 (wobei R16 Wasserstoff, Alkyl Oder Hydroxyalkyl ist; und R17 Wasserstoff, Alkyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist), - NR18R19 (wobei R18 Wasserstoff Oder Alkyl ist; und R19 Wasserstoff, Alkyl, Acyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist), -(Alkylen)-NR20R21 (wobei R20 Wasserstoff, Alkyl Oder Hydroxyalkyl ist; und R21 Wasserstoff, Alkyl, Acyl, Alkoxycarbonyl, Hydroxyalkyl, Alkoxyalkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist), -S02NR22R23 (wobei R22 Wasserstoff Oder Alkyl ist; und R23 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist; Oder R22 und R23zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -(Alkylen)-S02NR24R25 (wobei R24 Wasserstoff Oder Alkyl ist; und R25 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist; Oder R24 und R25 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -NR26S02NR27R28 (wobei R26 und R27 unabhángig Wasserstoff Oder Alkyl sind; und R28 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist; Oder R27 und R28 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), - (Alkylen)-NR29SO2NR30R31 (wobei R29 und R30 unabhángig Wasserstoff Oder Alkyl sind; und R31 Wasserstoff, Alkyl, Aryl, Aralkyl, Heteroaryl Oder Heteroaralkyl ist; Oder R30 und R31 zusammen mit dem Stickstoffatom, an welches sie angehángt sind, Heterocycloamino bilden), -CONH-(Alkylen)-NR32R33 (wobei R32 Wasserstoff Oder Alkyl ist; und R33 Alkyl ist) Oder Aralkyl ist; und R13 Wasserstoff ist; (i) wahlweises Modifizieren einer beliebigen der R1-, R2-, R3-, Rx-, RY-, Rz-und R13-Gruppen; (ii) wahlweises Isolieren individueller Stereoisomere; (iii) wahlweises Práparieren eines Sáureadditionssalzes; und (iv) wahlweises Práparieren einer freien Base; worin Alkyl ein linearesgesáttigtes monovalentes Kohlenwasserstoffradikal mit ein bissechs Kohlenstoffatomen oder ein verzweigtes gesáttigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffatomen bedeutet; Alkylen ein lineares gesáttigtes divalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes gesáttigtes divalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffatomen bedeutet; Alkylthio ein Radikal -SR bedeutet, wobei R Alkyl ist; Amino das Radikal -NRR’ bedeutet, wobei R und R’ unabhángig Wasserstoff, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Acyl ein Radikal -COR’ bedeutet, wobei R’ Alkyl, Alkoxy, Haloalkyl, Aminoalkyl, Hydroxyalkyl oder Alkoxyalkyl ist; Aminosulfonyl ein Radikal -S02NH2 bedeutet; Alkylaminosulfonyl ein Radikal - S02NHR bedeutet, wobei R Alkyl ist; Alkylsulfonyl ein Radikal -S02R bedeutet, wobei R Alkyl ist; Alkylsulfonylalkyl ein Radikal -(Alkylen)-S02R bedeutet, wobei R Alkyl ist; Alkylsulfonylamino ein Radikal -NHS02R bedeutet, wobei R Alkyl ist; Alkylsulfonylaminoalkyl ein Radikal -(Alkylen)-NHS02R bedeutet, wobei R Alkyl ist; Alkoxysulfonylamino ein Radikal -NHS02R bedeutet, wobei R Alkoxy ist; Alkoxysulfonylaminoalkyl ein Radikal -(Alkylen)-NHS02R bedeutet, wobei R Alkoxy ist; Alkoxy ein Radikal -OR bedeutet, wobei R Alkyl ist; Alkoxycarbonyl ein Radikal -COOR bedeutet, wobei R Alkyl ist; Alko-xycarbonylalkyl ein Radikal - (Alkylen)-COOR bedeutet, wobei R Alkyl ist; Alkoxyalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffen, die durch zumindest eine Alkoxy-Gruppe substituiert sind, bedeutet; Aminoalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffen, die durch zumindest ein -NRR’ substituiert werden, bedeutet, wobei R und R’ unabhángig Wasserstoff, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Aminocarboxyalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffen, die durch ein -NRR’ und -COOH substituiert werden, bedeutet, wobei R und R’ unabhángig Wasserstoff, Alkyl oder-CORa sind, wobei Ra Alkyl ist; Aminocarbonylcarboxyalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffen, die durch ein -CONRR’ und -COOH substituiert werden, bedeutet, wobei R und R’ unabhángig Wasserstoff, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Aminocarbonylalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffen, die durch ein oder zwei -CONRR’ substituiert werden, bedeutet, wobei R und R’ unabhángig Wasserstoff, Alkyl oder -CORa sind, wobei Ra Alkyl ist; Alkoxyalkyloxy ein Radikal -OR bedeutet, wobei R Alkoxyalkyl ist; Aminoalkyloxy ein Radikal -OR bedeutet, wobei R Aminoalkyl ist; Aminocarbonyl ein Radikal -CONH2 bedeutet; Aminocarbonylalkyloxy ein Radikal -O-Alkylen-CONRR’ bedeutet, wobei R und R’ unabhángig Wasserstoff oder Alkyl sind; Aminocarbonylalkyl ein Radikal - (Alkylen)-CONH2 bedeutet; Alkylureido ein Radikal -NRCONHR’ bedeutet, wobei R Wasserstoff oder Alkyl ist und R’ Alkyl ist; Alkylureidoalkyl ein Radikal - (Alkylen)-NRCONHR’ bedeutet, wobei R Wasserstoff oder Alkyl ist und R’ Alky ist; Aryl ein monovalentes monozyklisches oder bizyklisches aromatisches Kohlén- wasserstoffradikal mit 6 bis 12 Ringatomen bedeutet, und wahlweise unabhángig durch ein Oder mehr Substi-tuenten substituiert, die aus Alkyl, Haloalkyl, Alkoxy, Alkylthio, Halo, Nitro, -COR (wobei R Alkyl ist), Cyano, Amino, Alkylamino, Dialkylamino, Hydroxy, Carboxy Oder -COOR, wobei R Alkyl ist, ausgewáhlt werden; Aryl-sulfonyl ein Radikal -S02R bedeutet, wobei R Aryl ist; Aralkyl ein Radikal -(Alkylen)-R bedeutet, wobei R eine Aryl-Gruppe ist; Alkoxycarbamimidoyl ein Radikal -C(=NH)NHORoder-C(=NOR)NH2 bedeutet, wobei R Alkyl ist; Cycloalkyl ein zyklisches gesáttigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoff-atomen bedeutet; Carboxyalkyl ein Radikal -(Alkylen)-COOH bedeutet; Carboxyalkyloxy ein Radikal -0-(Alky-len)-COOH bedeutet; Carbamimidoyl ein Radikal -C(=NH)NH2 bedeutet; Cyanoalkyl ein Radikal -(Alkylen)-CN bedeutet; Dialkylaminosulfonyl ein Radikal -S02NRR’ bedeutet, wobei R und R’ unabhángig Alkyl sind; Dialky-lureido ein Radikal -NRCONR’R" bedeutet, wobei RWasserstoff Oder Alkyl ist und R’ und R" unabhángig Alkyl sind; Dialkylureidoalkyl ein Radikal -(Alkylen)-NRCONR’R" bedeutet, wobei RWasserstoffoder Alkyl ist und R’ und R" unabhángig Alkyl sind; Guanidinoalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Koh-lenstoffen, die durch zumindestein-NRC(NRR’)NRR’substituiertwerden, bedeutet, wobei R und R’ unabhángig Wasserstoff, Alkyl oder-CORasind, wobei Ra Alkyl ist; HaloFluoro, Chloro, Bromo und Jodo bedeutet; Haloalkyl Alkyl bedeutet, das durch ein oder mehr Halogenatome substituiert wird; Haloalkoxy ein Radikal -OR bedeutet, wobei R Haloalkyl ist; Hydroxyalkyl ein lineares monovalentes Kohlenwasserstoffradikal mit ein bis sechs Kohlenstoffatomen oder ein verzweigtes monovalentes Kohlenwasserstoffradikal mit drei bis sechs Kohlenstoffen, die durch eine bis fünf Hydroxy-Gruppen substituiert werden, bedeutet, sofern, wenn zwei Hydroxy-Gruppen zugegen sind, sie nicht beide auf demselben Kohlenstoffatom sind; Hydroxyalkyloxy ein Radikal -OR bedeutet, wobei R Hydroxyalkyl ist; Hydroxyalkoxyalkylaminocarbonyl ein Radikal -CONH-(Alkylen)-0-(alkylen)OH bedeutet; Heterocycloalkyl eine gesáttigteoder ungesáttigte monovalentezyklische Gruppé mit 3 bis 8 Ringatomen bedeutet, worin ein oder zwei Ringatome Heteroatome sind, die aus N, O oder S(0)n ausgewáhlt werden, wobei n ein Integer von 0 bis 2 ist, wobei die verbleibenden Ringatome C sind; Heterocycloalkylcarbonyl ein Radikal -COR bedeutet, wobei R Heterocycloalkyl ist; Heterocycloalkylcarbonylalkyl ein Radikal -(Alkylen)-COR bedeutet, wobei R Heterocycloalkyl ist; Heterocycloalkylalkyl ein Radikal - (Alkylen)-R bedeutet, wobei R Heterocycloalkyl ist; Heterocycloalkylalkylaminocarbonyl ein Radikal -CONH-(Alkylen)-R bedeutet, wobei R Heterocycloalkyl ist; Heteroaryl ein monovalentes monozyklisches oder bizyklisches aromatisches Radikal mit 5 bis 10 Ringatomen bedeutet, das ein oder mehr Ring-Heteroatome enthált, die aus N, O oderS ausgewáhlt werden, wobei die verbleibenden Ringatome Kohlenstoff sind, wobei der Heteroaryl-Ring wahlweise durch ein oder mehr Substituenten substituiert wird, die unabhángig aus Alkyl, Haloalkyl, Alkoxy, Alkylthio, Aminoalkyl, Guanidinoalkyl, Halo, Nitro, Cyano, Amino, Alkyl oder Dialkylamino, Hydroxy, Carboxy oder -COOR ausgewahlt werden, wobei R Alkyl ist; Heteroarylsulfonyl ein Radikal -S02R bedeutet, wobei R Heteroaryl ist; Heteroaralkyl ein Radikal -(Alkylen)-R bedeutet, wobei R ein Heteroaryl ist; Heterocycloamino eine gesáttigte oder ungesáttigte monovalente zyklische Gruppé mit 3 bis 8 Ringatomen bedeutet, worin ein oder zwei Ringatome Heteroatome sind, die aus N, O oder S(0)n ausgewáhlt werden, wobei n ein Integer von 0 bis 2 ist, wobei die verbleibenden Ringatome C sind, sofern zumindest eines der Heteroatome Stickstoff ist und worin ein oder zwei Kohlenstoff-atome wahlweise durch eine Carbonyl-Gruppe ersetzt werden, wobei der Heterocycloamino-Ring wahlweise durch ein oder mehr Substituenten substituiert wird, die unabhángig aus Alkyl, Hydroxy, Hydroxyalkyl, Alkoxy, Alkoxyalkyl, Aminoalkyl, Guanidinoalkyl, Halo, Haloalkyl, Aryl, Heteroaryl, Aralkyl, Heteroaralkyl, Haloalkyl, Halo, Cyano, Carboxy, -CONRaRb (wobei Ra und Rb unabhángig Wasserstoff oder Alkyl sind) oder -COOR, wobei R Alkyl ist, ausgewahlt werden; Hydroxycarbamimidoyl ein Radikal -C(=NH)NHOH oder - C(=NOH)NH2 bedeutet.
Revendications 1. Composé de formule I :
Formula I dans laquelle : X1 est -N- ou -CR5-, öli R5 est de l’hydrogéne, un alkyle ou un groupe haló ; R1 est de l’hydrogéne, un alkyle, un groupe halo, un carboxy ou un aminocarbonyle ; R2 est de l’hydrogéne, un alkyle ou un groupe halo ; R3 est -CONR7R8 (ou R7 est de l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un carboxyalkyle, un sulfoalkyle ou un phosphonoalkyle ; et R8 est de l’hydrogéne, un hydroxy, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aminoalkyle, un carboxyalkyle, un sulfoalkyle, un phosphonoalkyle, un aminocarboxyalkyle, un aminocarbonylcarboxyalkyle, un triméthylammonioalkyle, un aminocarbonylalkyle, -(alkylé-ne)-(OCH2CH2)nRb (ou n est un entierde 1 á 6 et Rb est de l’hydrogéne, un alkyle, un hydroxy, un alcoxy, un amino ou un alkylcarbonylamino), un aryle, un aralkyle, un hétéroaryle, un hétéroaralkyle, un hétérocycloalky-lalkyle, un héterocycloalkylaminocarbonylalkyle ou 3-hétérocycloalkyl-2-hydroxypropyle ; ou R7 et R8 conjoin-tement avec Tatomé d’azote auquel ils sont liés forment un groupe hétéocycloalkylamino), ou -(alkylé-ne)-CONR9R10 (ou R9 est de l’hydrogéne, un hydroxy, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aminoalkyle, un carboxyalkyle, un sulfoalkyle ou un phosphonoalkyle ; et R10 est de l’hydrogéne, un hydroxy, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aminoalkyle, un carboxyalkyle, un sulfoalkyle, un phosphonoalkyle, un aminocarboxyalkyle, un aminocarbonylcarboxyalkyle, un triméthylammonioalkyle, un aminocarbonylalkyle, -(alkyléne)-(OCH2CH2)nRb (oü n est un entier de 1 á 6 et Rb est de l’hydrogéne, un alkyle, un hydroxy, un alcoxy, un amino ou un alkylcarbonylamino), un aryle, un aralkyle, un hétéroaryle, un hétéroaralkyle, un hété-rocycloalkylalkyle, un héterocycloalkylaminocarbonylalkyle ou 3-hétérocycloalkyl-2-hydroxypropyle ; ou R9 et R10 conjointement avec Tatomé d’azote auquel ils sont liés forment un groupe hétérocycloalkylamino) ;
Rx est de l’hydrogéne, un alkyle, un alkylthio, un groupe halo, un hydroxy, un hydroxyalkyle, un alcoxy, un aminosulfonyle, un alkylaminosulfonyle, un dialkylaminosulfonyle ou un groupe nitro ; RV est de l’hydrogéne, un alkyle ou un groupe halo ;
Rz est de l’hydrogéne, un alkyle, un haloalkyle, un cycloalkyle, un alkylthio, un groupe halo, un hydroxy, un hydroxyalkyle, un groupe nitro, un groupe cyano, un alcoxy, un alcoxyalkyle, un alcoxyalkyloxy, un hydroxyalk-yloxy, un aminoalkyloxy, un carboxyalkyloxy, un aminocarbonylalkyloxy, un haloalcoxy, un carboxy, un carboxyalkyle, un alcoxycarbonyle, un alcoxycarbonylalkyle, un cyanoalkyle, un alkylsulfonyle, un alkylsulfonylalk-yle, un arylsulfonyle, un hétéroarylsulfonyle, un carbamimidoyle, un hydroxycarbamimidoyle, un alcoxycarba-mimidoyle, un alkylsulfonylamino, un alkylsulfonylaminoalkyle, un alcoxysulfonylamino, un alcoxysulfonylami-noalkyle, un hétérocycloalkylalkylaminocarbonyle, un hydroxyalcoxyalkylaminocarbonyle, un hétérocycloalkyl-carbonyle, un hétérocycloalkylcarbonylalkyle, un hétérocycloalkyle, un hétérocycloalkylalkyle, un oxohétérocy-cloalkyle, un oxohétérocycloalkylalkyle, un hétéroaryle, un hétéroaralkyle, un uréido, un alkyluréido, un dialk-yluréido, un uréidoalkyle, un alkyluréidoalkyle, un dialkyluréidoalkyle, un thiouréido, un thiouréidoalkyle, -COR12 (ou R12 est un alkyle, un haloalkyle, un hydroxyalkyle, un alcoxyalkyle ou un aminoalkyle), -(alkyléne)-COR12 (ou R12 est un alkyle, un haloalkyle, un hydroxyalkyle, un alcoxyalkyle ou un aminoalkyle), -CONR14R15 (oü R14 est de l’hydrogéne ou un alkyle ; et R15 est de l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R14 et R15 conjointement avec Tatomé d’azote auquel ils sont liés forment un groupe hétérocycloamino), -(alkyléne)-CONR16R17 (oü R16 est de l’hydrogéne, un alkyle ou un hydroxyalkyle ; etR17estde l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R16 et R17 conjointement avec Tatomé d’azote auquel ils sont liés forment un groupe hétérocycloamino), -NR18R19 (ou R18 est de l’hydrogéne ou un alkyle ; et R19 est de l’hydrogéne, un alkyle, un acyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -(alkylé-ne)-NR20R21 (ou R20 est de l’hydrogéne, un alkyle ou un hydroxyalkyle ; et R21 est de l’hydrogéne, un alkyle, un acyle, un alcoxycarbonyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -S02NR22R23 (ou R22 est de l’hydrogéne ou un alkyle ; et R23 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R22 et R23 conjointement avec Tatomé d’azote auquel ils sont liés forment un groupe hétérocycloamino), -(alkyléne)-S02NR24R25 (oü R24 est de l’hydrogéne ou un alkyle ; et R25 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R24 et R25 conjointement avec Tatomé d’azote auquel ils sont liés forment un groupe hétérocycloamino), -NR26S02NR27R28 (oü R26 et R27 sont indépendamment de l’hydrogéne ou un alkyle ; et R28 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R27 et R28 conjointement avec Tatomé d’azote auquel ils sont liés forment un groupe hétérocycloamino), (alkyléne)-NR29SO2NR30R31 (oü R29 et R30 sont indépendamment de l’hydrogéne ou un alkyle ; et R31 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R30 et R31 conjointement avec l’atome d’azote auquel ils sont liés forment un groupe hétérocycloamino), -CONH-(alkyléne)-NR32R33 (oü R32 est de l’hydrogéne ou un alkyle ; et R33 est un alkyle) ou un aralkyle ; et R13 est de l’hydrogéne, un hydroxy, un alcoxy en (C1_10), -C(0)R35 (oü R35 est un alkyle, un aryle, un haloalkyle ou un cyanoalkyle) ou - C(0)0R36 (oü R36 est un alkyle, un hydroxyalkyle, un alcoxyalkyle, un alcoxycarbony-lalkyle, un acyle, un aryle ou un haloalkyle) ; ou un stéréoisomére individuel, un mélange de stéréoisoméres, ou un sel pharmaceutiquement acceptable correspondent, á condition quesi R3est-CONR7R8(oü R7 est de l’hydrogéneou un alkyle ; et R8 est de l’hydrogéne ou un alkyle), -(alkyléne)-CONR9R10 (oü R9 et R10 conjointement avec Tatomé d’azote auquel ils sont liés forment un pyrrolidinyle), et R7 est de l’hydrogéne, un alkyle, un haloalkyle, un groupe halo, un groupe nitro, un alcoxy, un haloalkyle, un carboxy, un alcoxycarbonyle, -NR18R19 (oü R18 de l’hydrogéne ou un alkyle ; et R19 est de l’hydrogéne, un alkyle, un aryle ou un aralkyle), un pyrrolidinylcarbonyle, -S02NR22R23 (oü R22 et R23 sont un alkyle), un carbamimidoyle, un alkylsulfonylamino, un alkylthio, un uréido, - NHC(S)NH2 ou un hétérocycloamino, alors Rxsoit un hydroxy ou un hydroxyalkyle ; oü alkyle désigne un radical d’hydrocarbure monovalent saturé linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent saturé ramifié de trois á six atomes de carbone ; alkyléne désigne un radical d’hydrocarbure divalent saturé linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure divalent saturé ramifié de trois á six atomes de carbone ; alkylthio désigne un radical -SR oü R est un alkyle ; amino désigne le radical -NRR’ oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; acyle désigne un radical -COR’ oü R’ est un alkyle, un alcoxy, un haloalkyle, un aminoalkyle, un hydroxyalkyle ou un alcoxyalkyle ; aminosulfonyle désigne un radical -S02NH2 ; alkylaminosulfonyle désigne un radical -S02NHR oü R est un alkyle ; alkylsulfonyle désigne un radical -S02R oü R est un alkyle ; alkylsulfo-nylalkyle désigne un radical - (alkyléne)-S02R oü R est un alkyle ; alkylsulfonylamino désigne un radical -NHS02R oü R est un alkyle ; alkylsulfonylaminoalkyle désigne un radical -(alkyléne)-NHS02R oü R est un alkyle ; alcoxysulfonylamino désigne un radical -NHS02R oü R est un alcoxy ; alcoxysulfonylaminoalkyle désigne un radical -(alkyléne)-NHS02R oü R est un alcoxy ; alcoxy désigne un radical -OR oü R est un alkyle ; alcoxycarbonyle désigne un radical - COOR oü R est un alkyle ; alcoxycarbonylalkyle désigne un radical -(alkyléne)-COOR oü R est un alkyle ; alcoxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par au moins un groupe alcoxy ; aminoalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par au moins un -NRR’ oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; aminocarboxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par un -NRR’ et -COOH oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; aminocarbonylcarboxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par un -CONRR’ et -COOH oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; aminocarbonylalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par un ou deux -CONRR’ oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; alcoxyalk-yloxy désigne un radical -OR oü R est un alcoxyalkyle ; aminoalkyloxy désigne un radical -OR oü R est un aminoalkyle ; aminocarbonyle désigne un radical -CONH2 ; aminocarbonylalkyloxy désigne un radical -O-alk-yléne-CONRR’ oü R et R’ sont indépendamment de l’hydrogéne ou un alkyle ; aminocarbonylalkyle désigne un radical -(alkyléne)-CONH2 ; alkyluréido désigne un radical - NRCONHR’ oü R est de l’hydrogéne ou un alkyle et R’ est un alkyle ; alkyluréidoalkyle désigne un radical -(alkyléne)-NRCONHR’ oü R est de l’hydrogéne ou un alkyle et R’ est un alkyle ; aryle désigne un radical d’hydrocarbure aromatique bicyclique ou monocyclique monovalent de 6 á 12 atomes cycliques, et éventuellement substitués indépendamment par un ou plusieurs substituants choisis parmi un alkyle, un haloalkyle, un alcoxy, un alkylthio, un groupe halo, un groupe nitro, -COR (ou R est un alkyle), un groupe cyano, un groupe amino, un alkylamino, un dialkylamino, un hydroxy, un carboxy ou -COOR ou R est un alkyle ; arylsulfonyle désigne un radical -S02R ou R est un aryle ; aralkyle désigne un radical -(alkyléne)-R ou R est un groupe aryle ; alcoxycarbamimidoyle désigne un radical -C(=NH)NHOR ou - C(=NOR)NH2 oü R est un alkyle ; cycloalkyle désigne un radical d’hydrocarbure monovalent saturé cyclique de trois á six atomes de carbone ; carboxyalkyle désigne un radical -(alkyléne)-COOH ; car-boxyalkyloxy désigne un radical -0-(alkyléne)-COOH ; carbamimidoyle désigne un radical -C(=NH)NH2 ; cya-noalkyle désigne un radical - (alkyléne)-CN ; dialkylaminosulfonyle désigne un radical -S02NRR’ ou R et R’ sont indépendamment un alkyle ; dialkyluréido désigne un radical - NRCONR’R" ou R est de l’hydrogéne ou un alkyle et R’ et R" sont indépendamment un alkyle; dialkyluréidoalkyle désigne un radical -(alkyléne)-NRCONR’R" ou R est de l’hydrogéne ou un alkyle et R’ et R" sont indépendamment un alkyle ; guanidinoalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par au moins un -NRC(NRR’)NRR’ ou R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa ou Ra est un alkyle ; halo désigne un groupe fluoro, chloro, bromo et iodo ; haloalkyle désigne un alkyle substitué par un ou plusieurs atomes d’halogéne ; haloalcoxy désigne un radical -OR oü R est un haloalkyle ; un hydroxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six carbones substitués par un á cinq groupes hydroxy, á condition que si deux groupes hydroxy sont présents, ils ne soient pás tous les deux sur le mérne atomé de carbone ; hydroxyalkyloxy désigne un radical -OR ou R est un hydroxyalkyle ; hydroxyalcoxyalkylaminocarbonyle désigne un radical -CONH-(alkyléne)-0-(alkyléne)OH ; hétérocycloalkyle désigne un groupe cyclique monovalent saturé ou non saturé de 3 á 8 atomes cycliques dans lequel un ou deux atomes cycliques sont des hétéroatomes choisis parmi N, Oou S(0)n, ou n est un entierde 0 á 2, les atomes restantsétantC ; hétérocycloalkylcarbonyle désigne un radical - COR oil R est un hétérocycloalkyle ; hétérocycloalkylcarbonylalkyle désigne un radical -(alkylé-ne)-COR ou R est un hétérocycloalkyle ; hétérocycloalkylalkyle désigne un radical -(alkyléne)-R oü R est un hétérocycloalkyle ; hétérocycloalkylalkylaminocarbonyle désigne un radical -CONH-(alkyléne)-R oü R est un hétérocycloalkyle ; hétéroaryle désigne un radical aromatique monocyclique ou bicyclique monovalent de 5 á 10 atomes cycliques consistant en un ou plusieurs hétéroatomes choisis parmi N, O ou S, les atomes cycliques restants étant du carbone, le cycle hétéroaryle étant éventuellement substitué par un ou plusieurs substituants choisis indépendamment parmi un alkyle, un haloalkyle, un alcoxy, un alkylthio, un aminoalkyle, un guanidinoalkyle, un groupe halo, un groupe nitro, un groupe cyano, un groupe amino, un alkyle ou un dialkylamino, un hydroxy, un carboxy ou -COOR oü R est un alkyle ; hétéroarylsulfonyle désigne un radical -S02R oü R est un hétéroaryle ; hétéroaralkyle désigne un radical -(alkyléne)-R oü R est un hétéroaryle ; hétérocycloamino désigne un groupe cyclique monovalent saturé ou non saturé de 3 á 8 atomes cycliques parmi lesquels un ou deux atomes cycliques sont des hétéroatomes choisis parmi N, O ou S(0)n, oü n est un entier de 0 á 2, les atomes cycliques restants étant C, á condition qu’au moins un des hétéroatomes sóit de l’azote, et un ou deux atomes de carbone étant éventuellement remplacés par un groupe carbonyle, le cycle hétérocycloamino étant éventuellement substitué par un ou plusieurs substituants choisis indépendamment parmi un alkyle, un hydroxy, un hydroxyalkyle, un alcoxy, un alcoxyalkyle, un aminoalkyle, un guanidinoalkyle, un groupe halo, un haloalkyle, un aryle, un hétéroaryle, un aralkyle, un hétéroaralkyle, un haloalkyle, un groupe halo, un groupe cyano, un carboxy, -CONRaRb (oü Ra et Rb sont indépendamment de l’hydrogéne ou un alkyle) ou -COOR oü R est un alkyle ; hydroxycarbamimidoyle désigne un radical -C(=NH)NHOH ou - C(=NOH)NH2. 2. Composé selon la revendication 1, dans lequel : R3 est -CONR7R8 (oü R7 est de l’hydrogéne, un alkyle, un alcoxyalkyle, un carboxyalkyle, un hydroxyalkyle ou un phosphonoalkyle ; et R8 est de l’hydrogéne, un alkyle, un alcoxyalkyle, -(alkyléne)-(OCH2CH2)nRb (oü n est un entierde 1 á 6etRbestde l’hydrogéne, un alkyle, un hydroxy, un alcoxy, un amino or un alkylcarbonylamino), un aminoalkyle, un aminocarbonylalkyle, un aminocarbonylcarboxyalkyle, un aminocarboxyalkyle, un carboxyalkyle, un hydroxyalkyle, un phosphonoalkyle, un sulfoalkyle, un triméthylammonioalkyle, un aryle, un aralkyle, un hétéroaryle, un hétéroaralkyle ou un hétéocycloalkylalkyle ; ou R7 et R8 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétéocycloalkylamino), ou -(alkyléne)-CONR9R10 (oü R9 est de l’hydrogéne, un alkyle, un alcoxyalkyle, un carboxyalkyle, un hydroxyalkyle ou un phosphonoalkyle ; et R10 est de l’hydrogéne, un alkyle, un alcoxyalkyle, -(alkyléne)-(OCH2CH2)nRb (oü n est un entierde 1 á 6 et Rb est de l’hydrogéne, un alkyle, un hydroxy, un alcoxy, un amino or un alkylcarbonylamino), un aminoalkyle, un aminocarbonylalkyle, un aminocarbonylcarboxyalkyle, un aminocarboxyalkyle, un carboxyalkyle, un hydroxyalkyle, un phosphonoalkyle, un sulfoalkyle, un triméthylammonioalkyle, un aryle, un aralkyle, un hétéroaryle, un hété-roaralkyle ou un hétéocycloalkylalkyle ; ou R9 et R10 conjointement avec l’atome d’azote auquel ils sont liés torment un groupe hétérocycloalkylamino), chaque cycle comprenant R3 étant éventuellement substitué par un á six groupes choisis indépendamment parmi un hydroxy, un hydroxyalkyle, un alcoxyalkyle, un carboxy, un alcoxycarbonyle, un aminoalkyle, un guanidinoalkyle, un alkyle ou - CONRaRb (oü Ra et Rb sont indépendamment de l’hydrogéne ou un alkyle); et
Rz est de l’hydrogéne, un alkyle, un haloalkyle, un cycloalkyle, un alkylthio, un groupe halo, un hydroxy, un hydroxyalkyle, un groupe nitro, un groupe cyano, un alcoxy, un alcoxyalkyle, un alcoxyalkyloxy, un hydroxyalk-yloxy, un aminoalkyloxy, un carboxyalkyloxy, un aminocarbonylalkyloxy, un haloalcoxy, un carboxy, un car-boxyalkyle, un alcoxycarbonyle, un alcoxycarbonylalkyle, un cyanoalkyle, un alkylsulfonyle, un alkylsulfonylalk-yle, un arylsulfonyle, un hétéroarylsulfonyle, un carbamimidoyle, un hydroxycarbamimidoyle, un alcoxycarba-mimidoyle, un alkylsulfonylamino, un alkylsulfonylaminoalkyle, un alcoxysulfonylamino, un alcoxysulfonylami-noalkyle, un hétérocycloalkylalkylaminocarbonyle, un hydroxyalcoxyalkylaminocarbonyle, un hétérocycloalkyl-carbonyle, un hétérocycloalkylcarbonylalkyle, un hétérocycloalkyle, un hétérocycloalkylalkyle, un oxohétérocy-cloalkyle, un oxohétérocycloalkylalkyle, un hétéroaryle, un hétéroaralkyle, un uréido, un alkyluréido, un dialk-yluréido, un uréidoalkyle, un alkyluréidoalkyle, un dialkyluréidoalkyle, un thiouréido, un thiouréidoalkyle, -COR12 (oü R12 est un alkyle, un haloalkyle, un hydroxyalkyle, un alcoxyalkyle ou un aminoalkyle), -(alkyléne)-COR12 (oü R12 est un alkyle, un haloalkyle, un hydroxyalkyle, un alcoxyalkyle ou un aminoalkyle), -CONR14R15 (oü R14 est de l’hydrogéne ou un alkyle ; et R15 est de l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R14 et R15 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), -(alkyléne)-CONR16R17 (oü R16 est de l’hydrogéne, un alkyle ou un hydroxyalkyle ; etR17estde l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R16 et R17 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), -NR18R19 (oü R18 est de l’hydrogéne ou un alkyle ; et R19 est de l’hydrogéne, un alkyle, un acyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -(alkylé-ne)-NR20R21 (oü R20 est de l’hydrogéne, un alkyle ou un hydroxyalkyle ; et R21 est de l’hydrogéne, un alkyle, un acyle, un alcoxycarbonyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -S02NR22R23 (oü R22 est de l’hydrogéne ou un alkyle ; et R23 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R22 et R23 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), -(alkyléne)-S02NR24R25 (oü R24 est de l’hydrogéne ou un alkyle ; et R25 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R24 et R25 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), -NR26S02NR27R28 (oü R26 et R27 sont indépendamment de l’hydrogéne ou un alkyle ; et R28 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R27 et R28 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), (alkyléne)-NR29SO2NR30R31 (oü R29 et R30 sont indépendamment de l’hydrogéne ou un alkyle ; et R31 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R30 et R31 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), -CONH-(alkyléne)-NR32R33 (oü R32 est de l’hydrogéne ou un alkyle ; et R33 est un alkyle) ou un aralkyle ; et R13 est de l’hydrogéne, un hydroxy, un alcoxy en (C.|_10), -C(0)R35 (oü R35 est un alkyle, un aryle, un haloalkyle ou un cyanoalkyle) ou - C(0)0R36 (oü R36 est un alkyle, un hydroxyalkyle, un acyle ou un haloalkyle) ; ou sel pharmaceutiquement acceptable correspondant. 3. Composé de formule la, dans laquelle :
Formule la R3 est -CONR7R8, -CH2CONR9R10 ou -C(CH3)2CONR9R10; R7 est de l’hydrogéne ou un méthyle ; R9 est de l’hydrogéne ou un méthyle ; R8 est un aminocarbonylméthyle, 1,2-diaminocarbonyléthyle, 2-aminocarbonyl-1-carboxyéthyle, 5-amino-5-carboxypentyle, 2-carboxyéthyle, un carboxyméthyle, 2-carboxy-3-[2-(2-éthoxy-éthoxy)-éthoxy]-propyle, un di-méthylaminométhyle, 3-diméthylaminopropyle, 2-hydroxy-1,1-bis-hydroxyméthyl-éthyle, 2-hydroxy-1-hydroxy-méthyléthyle, 1,2-dicarboxyéthyle, un méthyle, 2-[2-(2-méthylaminoéthoxy)éthoxy]éthyle, 2-(4-methylpipéra-zin-1 -yl)éthyle, 2-morpholin-4-yléthyle, 2,3,4,5,6-pentahydroxy-hexyle, 2-pipérazin-1-yléthyle, 2-sulfoéthyle, 3.4.5.6- tétrahydroxy-tétrahydro-pyran-2-ylméthyle, 2,4,5-trihydroxy-6-hydroxyméthyl-tétrahydro-pyran-3-yle, 2.4.5- trihydroxy-6-hydroxyméthyl-tétrahydro-pyran-3-ylcarbamoyl-méthyle, un triméthylammonioéthyle ou 2-phosphonoéthyle ; R10 est un aminocarbonylméthyle, 1,2-diaminocarbonyléthyle, 2-aminocarbonyl-1-carboxyéthyle, 5-amino-5-carboxypentyle, 2-carboxyéthyle, un carboxyméthyle, 2-carboxy-3-[2-(2-éthoxy-éthoxy)-éthoxy]-propyle, un di-méthylaminométhyle, 3-diméthylaminopropyle, 2-hydroxy-1,1-bis-hydroxyméthyl-éthyle, 2-hydroxy-1-hydroxy-méthyléthyle, 1,2-dicarboxyéthyle, un méthyle, 2-[2-(2-méthylaminoéthoxy)éthoxy]éthyle, 2-(4-methylpipéra-zin-1 -yl)éthyle, 2-morpholin-4-yléthyle, 2,3,4,5,6-pentahydroxy-hexyle, 2-pipérazin-1-yléthyle, 2-sulfoéthyle, 3.4.5.6- tétrahydroxy-tétrahydro-pyran-2-ylméthyle, 2,4,5-trihydroxy-6-hydroxyméthyl-tétrahydro-pyran-3-yle, 2.4.5- trihydroxy-6-hydroxyméthyl-tétrahydro-pyran-3-ylcarbamoyl-méthyle, un triméthylammonioéthyle ou 2-phosphonoéthyle ;
Rz est un aminosulfonyle ou un uréidométhyle ; et R13 est de l’hydrogéne ; ou sel pharmaceutiquement acceptable correspondant. 4. Composé selon la revendication 3, dans lequel: R3 est -CONR7R8, -CH2CONR9R10 ou -C(CH3)2CONR9R10; R7 est de l’hydrogéne ; R9 est de l’hydrogéne ; R8 est un aminocarbonylméthyle, 2-aminocarbonyl-1-carboxyéthyle, 5-amino-5-carboxypentyle, 2-carboxyéthyle, un carboxyméthyle ou 1,2-dicarboxyéthyle ; R10 est un aminocarbonylméthyle, 2-aminocarbonyl-1-carboxyéthyle, 5-amino-5-carboxypentyle, 2-carboxyéthyle, un carboxyméthyle ou 1,2-dicarboxyéthyle ; et Rz est un aminosulfonyle ; ou sel pharmaceutiquement acceptable correspondant. 5. Composé selon la revendication 4, dans lequel le composé de formule la est: acide {2-[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2’-dihydroxy-5’-sulfamoyl-biphényl-3-yl]-acétylamino}-succinique, ou sel pharmaceutiquement acceptable correspondant. 6. Composition pharmaceutique comprenant un support pharmaceutiquement acceptable et une quantité pharmaceutiquement acceptable d’un composé selon l’une quelconque des revendications 1 á 5, ou sel pharmaceutiquement acceptable correspondant. 7. Utilisation d’une quantité pharmaceutiquement acceptable du composé selon l’une quelconque des revendications précédentes, ou sel pharmaceutiquement acceptable correspondant, pour fabriquer un médicament destiné á étre utilisé dans un procédé de traitement d’une maladie médiée par le facteur Vila chez un animal. 8. Utilisation selon la revendication 7, dans laquelle le trouble est un trouble thromboembolique. 9. Utilisation du composé selon l’une quelconque des revendications 1 á 5, ou d’un sel pharmaceutiquement acceptable correspondant, pour la fabrication d’un médicament pour le traitement d’un trouble thromboembolique, le médicament devant étre utilisé avec un ou plusieurs autres agents anticoagulants choisis indépendamment dans le groupe constitué d’un inhibiteur de la thrombine, d’un facteur IXa, d’un inhibiteur du facteur Xa, d’Aspirin® et de Plavis®. 10. Composé selon l’une quelconque des revendications 1 á 5, ou sel pharmaceutiquement acceptable correspondant, destiné á étre utilisé dans un procédé de traitement d’une maladie médiée par le facteur Vila chez un animal. 11. Composé selon la revendication 10, dans lequel le trouble est un trouble thromboembolique. 12. Composé selon l’une quelconque des revendications 1 á 5, ou sel pharmaceutiquement acceptable correspondant, destiné á étre utilisé dans un traitement d’un trouble thromboembolique, le composé devant étre administré en combinaison avec un ou plusieurs autres agents anticoagulants choisis indépendamment dans le groupe constitué d’un inhibiteur de la thrombine, d’un facteur IXa, d’un inhibiteur du facteur Xa, d’Aspirin® et de Plavis®. 13. Procédé d’inhibition de la coagulation d’un échantillon biologique in vitro consistant á administrer un composé selon l’une quelconque des revendications 1 á 5, ou un sel pharmaceutiquement acceptable correspondant. 14. Procédé de préparation d’un composé selon la revendication 1, dans lequel X1 est -N-, consistant á fairé réagir un composé de formule II :
Formula Π avec un composé de formule III :
Formula III dans laquelle : R3 est -CONR7R8 (oü R7 est de l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un carboxyalkyle, un sulfoalkyle ou un phosphonoalkyle ; et R8 est de l’hydrogéne, un hydroxy, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aminoalkyle, un carboxyalkyle, un sulfoalkyle, un phosphonoalkyle, un aminocarboxyalkyle, un aminocarbonylcarboxyalkyle, un triméthylammonioalkyle, un aminocarbonylalkyle, -(alkylé-ne)-(OCH2CH2)NRb (oü n est un entierde 1 á 6 et Rb est de l’hydrogéne, un alkyle, un hydroxy, un alcoxy, un amino ou un alkylcarbonylamino), un aryle, un aralkyle, un hétéroaryle, un hétéroaralkyle, un hétérocycloalky-lalkyle, un héterocycloalkylaminocarbonylalkyle ou 3-hétérocycloalkyl-2-hydroxypropyle ; ou R7 et R8 conjoin-tement avec Tatomé d’azote auquel ils sont liés forment un groupe hétéocycloalkylamino), ou -(alkylé-ne)-CONR9R10 (oü R9 est de l’hydrogéne, un hydroxy, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aminoalkyle, un carboxyalkyle, un sulfoalkyle ou un phosphonoalkyle ; et R10 est de l’hydrogéne, un hydroxy, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aminoalkyle, un carboxyalkyle, un sulfoalkyle, un phosphonoalkyle, un aminocarboxyalkyle, un aminocarbonylcarboxyalkyle, un triméthylammonioalkyle, un aminocarbonylalkyle, -(alkyléne)-(OCH2CH2)nRb (oü n est un entier de 1 á 6 et Rb est de l’hydrogéne, un alkyle, un hydroxy, un alcoxy, un amino ou un alkylcarbonylamino), un aryle, un aralkyle, un hétéroaryle, un hétéroaralkyle, un hété-rocycloalkylalkyle, un héterocycloalkylaminocarbonylalkyle ou 3-hétérocycloalkyl-2-hydroxypropyle ; ou R9 et R10 conjointement avec Tatomé d’azote auquel ils sont liés forment un groupe hétérocycloalkylamino) ; et
Rz est de l’hydrogéne, un alkyle, un haloalkyle, un cycloalkyle, un alkylthio, un groupe halo, un hydroxy, un hydroxyalkyle, un groupe nitro, un groupe cyano, un alcoxy, un alcoxyalkyle, un alcoxyalkyloxy, un hydroxyal-coxyloxy, un aminoalkyloxy, un carboxyalkyloxy, un aminocarbonylalkyloxy, un haloalcoxy, un carboxy, un carboxyalkyle, un alcoxycarbonyle, un alcoxycarbonylalkyle, un cyanoalkyle, un alkylsulfonyle, un alkylsulfo-nylalkyle, un arylsulfonyle, un hétéroarylsulfonyle, un carbamimidoyle, un hydroxycarbamimidoyle, un alcoxy-carbamimidoyle, un alkylsulfonylamino, un alkylsulfonylaminoalkyle, un alcoxysulfonylamino, un alcoxysulfo-nylaminoalkyle, un hétérocycloalkylalkylaminocarbonyle, un hydroxyalcoxyalkylaminocarbonyle, un hétérocy-cloalkylcarbonyle, un hétérocycloalkylcarbonylalkyle, un hétérocycloalkyle, un hétérocycloalkylalkyle, un oxo-hétérocycloalkyle, un oxohétérocycloalkylalkyle, un hétéroaryle, un hétéroaralkyle, un uréido, un alkyluréido, un dialkyluréido, un uréidoalkyle, un alkyluréidoalkyle, un dialkyluréidoalkyle, un thiouréido, un thiouréidoalkyle, -COR12 (oü R12 est un alkyle, un haloalkyle, un hydroxyalkyle, un alcoxyalkyle ou un aminoalkyle), -(alkylé-ne)-COR12 (oü R12 est un alkyle, un haloalkyle, un hydroxyalkyle, un alcoxyalkyle ou un aminoalkyle), -CONR14R15 (oü R14 est de l’hydrogéne ou un alkyle ; et R15 est de l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -(alkyléne)-CONR16R17 (oü R16 est de l’hydrogéne, un alkyle ou un hydroxyalkyle ; et R17 est de l’hydrogéne, un alkyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -NR18R19 (oü R18 est de l’hydrogéne ou un alkyle ; et R19 est de l’hydrogéne, un alkyle, un acyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -(alkyléne)-NR20R21 (oü R20 est de l’hydrogéne, un alkyle ou un hydroxyalkyle ; et R21 est de l’hydrogéne, un alkyle, un acyle, un alcoxycarbonyle, un hydroxyalkyle, un alcoxyalkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle), -S02NR22R23 (oü R22 est de l’hydrogéne ou un alkyle ; et R23 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R22 et R23 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), -(alkyléne)-S02NR24R25 (oü R24 est de l’hydrogéne ou un alkyle ; et R25 est de l’hydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R24 et R25 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), - NR26S02NR27R28 (oü R26 et R27 sont indépendamment de Thydrogéne ou un alkyle ; et R28 est de Thydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R27 et R28 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), (alkylé-ne)-NR29SO2NR30R31 (oü R29 et R30 sont indépendamment de Thydrogéne ou un alkyle ; et R31 est de Thydrogéne, un alkyle, un aryle, un aralkyle, un hétéroaryle ou un hétéroaralkyle ; ou R30 et R31 conjointement avec Tatomé d’azote auquel ils sont liés torment un groupe hétérocycloamino), -CONH-(alkyléne)-NR32R33 (oü R32 est de Thydrogéne ou un alkyle ; et R33 est un alkyle) ou un aralkyle ; et R13 est de Thydrogéne ; (i) modifier éventuellement un quelconque des groupes R1, R2, R3, Rx, RV, Rz et R13 ; (ii) isoler éventuellement des stéréoisoméres individuels ; (iii) préparer éventuellement un sel d’addition acide ; et (iv) préparer éventuellement une base libre ; oü alkyle désigne un radical d’hydrocarbure monovalent saturé linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent saturé ramifié de trois á six atomes de carbone ; alkyléne désigne un radical d’hydrocarbure divalent saturé linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure divalent saturé ramifié de trois á six atomes de carbone ; alkylthio désigne un radical -SR oü R est un alkyle ; amino désigne le radical -NRR’ oü R et R’ sont indépendamment de Thydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; acyle désigne un radical -COR’ oü R’ est un alkyle, un alcoxy, un haloalkyle, un aminoalkyle, un hydroxyalkyle ou un alcoxyalkyle ; aminosulfonyle désigne un radical -S02NH2 ; alkylaminosulfonyle désigne un radical -S02NHR oü R est un alkyle ; alkylsulfonyle désigne un radical - S02R oü R est un alkyle ; alkylsulfo-nylalkyle désigne un radical - (alkyléne)-S02R oü R est un alkyle ; alkylsulfonylamino désigne un radical -NHS02R oü R est un alkyle ; alkylsulfonylaminoalkyle désigne un radical -(alkyléne)-NHS02R oü R est un alkyle ; alcoxysulfonylamino désigne un radical -NHS02R oü R est un alcoxy ; alcoxysulfonylaminoalkyle désigne un radical -(alkyléne)-NHS02R oü R est un alcoxy ; alcoxy désigne un radical -OR oü R est un alkyle ; alcoxycarbonyle désigne un radical - COOR oü R est un alkyle ; alcoxycarbonylalkyle désigne un radical -(alkyléne)-COOR oü R est un alkyle ; alcoxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par au moins un groupe alcoxy ; aminoalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par au moins un -NRR’ oü R et R’ sont indépendamment de Thydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; aminocarboxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par un - NRR’ et -COOH oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; aminocarbonylcarboxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de car-bone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par un -CONRR’ et -COOH oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; aminocarbonylalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par un ou deux -CONRR’ oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; alcoxyalk-yloxy désigne un radical -OR oü R est un alcoxyalkyle ; aminoalkyloxy désigne un radical -OR oü R est un aminoalkyle ; aminocarbonyle désigne un radical -CONH2 ; aminocarbonylalkyloxy désigne un radical -O-alk-yléne-CONRR’ oü R et R’ sont indépendamment de l’hydrogéne ou un alkyle ; aminocarbonylalkyle désigne un radical -(alkyléne)-CONH2 ; alkyluréido désigne un radical - NRCONHR’ oü R est de l’hydrogéne ou un alkyle et R’ est un alkyle ; alkyluréidoalkyle désigne un radical -(alkyléne)-NRCONHR’ oü R est de l’hydrogéne ou un alkyle et R’ est un alkyle ; aryle désigne un radical d’hydrocarbure aromatique bicyclique ou monocyclique monovalent de 6 á 12 atomes cycliques, et éventuellement substitués indépendamment par un ou plusieurs substituants choisis parmi un alkyle, un haloalkyle, un alcoxy, un alkylthio, un groupe halo, un groupe nitro, -COR (oü R est un alkyle), un groupe cyano, un groupe amino, un alkylamino, un dialkylamino, un hydroxy, un carboxy ou -COOR oü R est un alkyle ; arylsulfonyle désigne un radical -S02R oü R est un aryle ; aralkyle désigne un radical -(alkyléne)-R oü R est un groupe aryle ; alcoxycarbamimidoyle désigne un radical -C(=NH)NHOR ou - C(=NOR)NH2 oü R est un alkyle ; cycloalkyle désigne un radical d’hydrocarbure monovalent saturé cyclique de trois á six atomes de carbone ; carboxyalkyle désigne un radical -(alkyléne)-COOH ; car-boxyalkyloxy désigne un radical -0-(alkyléne)-C00H ; carbamimidoyle désigne un radical -C(=NH)NH2 ; cya-noalkyle désigne un radical - (alkyléne)-CN ; dialkylaminosulfonyle désigne un radical -S02NRR’ oü R et R’ sont indépendamment un alkyle ; dialkyluréido désigne un radical - NRCONR’R" oü R est de l’hydrogéne ou un alkyle et R’ et R" sont indépendamment un alkyle; dialkyluréidoalkyle désigne un radical -(alkyléne)-NRCONR’R" oü R est de l’hydrogéne ou un alkyle et R’ et R" sont indépendamment un alkyle ; guanidinoalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six atomes de carbone substitués par au moins un -NRC(NRR’)NRR’ oü R et R’ sont indépendamment de l’hydrogéne, un alkyle ou -CORa oü Ra est un alkyle ; halo désigne un groupe fluoro, chloro, bromo et iodo ; haloalkyle désigne un alkyle substitué par un ou plusieurs atomes d’halogéne ; haloalcoxy désigne un radical -OR oü R est un haloalkyle ; un hydroxyalkyle désigne un radical d’hydrocarbure monovalent linéaire d’un á six atomes de carbone ou un radical d’hydrocarbure monovalent ramifié de trois á six carbones substitués par un á cinq groupes hydroxy, á condition que si deux groupes hydroxy sont présents, ils ne soient pás tous les deux sur le mérne atomé de carbone ; hydroxyalkyloxy désigne un radical -OR oü R est un hydroxyalkyle; hydroxyalcoxyalkylaminocarbonyle désigne un radical -CONH-(alkyléne)-0-(alkyléne)OH ; hétérocycloalkyle désigne un groupe cyclique monovalent saturé ou non saturé de 3 á 8 atomes cycliques dans lequel un ou deux atomes cycliques sont des hétéroatomes choisis parmi N, Oou S(0)n, oü n est un entierde 0 á 2, les atomes restantsétantC ; hétérocycloalkylcarbonyle désigne un radical - COR oü R est un hétérocycloalkyle ; hétérocycloalkylcarbonylalkyle désigne un radical -(alkylé-ne)-COR oü R est un hétérocycloalkyle ; hétérocycloalkylalkyle désigne un radical -(alkyléne)-R oü R est un hétérocycloalkyle ; hétérocycloalkylalkylaminocarbonyle désigne un radical -CONH-(alkyléne)-R oü R est un hétérocycloalkyle ; hétéroaryle désigne un radical aromatique monocyclique ou bicyclique monovalent de 5 á 10 atomes cycliques consistant en un ou plusieurs hétéroatomes choisis parmi N, O ou S, les atomes cycliques restants étant du carbone, le cycle hétéroaryle étant éventuellement substitué par un ou plusieurs substituants choisis indépendamment parmi un alkyle, un haloalkyle, un alcoxy, un alkylthio, un aminoalkyle, un guanidinoalkyle, un groupe halo, un groupe nitro, un groupe cyano, un groupe amino, un alkyle ou un dialkylamino, un hydroxy, un carboxy ou -COOR oü R est un alkyle ; hétéroarylsulfonyle désigne un radical -S02R oü R est un hétéroaryle ; hétéroaralkyle désigne un radical -(alkyléne)-R oü R est un hétéroaryle ; hétérocycloamino désigne un groupe cyclique monovalent saturé ou non saturé de 3 á 8 atomes cycliques parmi lesquels un ou deux atomes cycliques sont des hétéroatomes choisis parmi N, O ou S(0)n, oü n est un entier de 0 á 2, les atomes cycliques restants étant C, á condition qu’au moins un des hétéroatomes sóit de l’azote, et un ou deux atomes de carbone étant éventuellement remplacés par un groupe carbonyle, le cycle hétérocycloamino étant éventuellement substitué parunou plusieurs substituants choisis indépendamment parmi un alkyle, un hydroxy, un hydroxyalkyle, un alcoxy, un alcoxyalkyle, un aminoalkyle, un guanidinoalkyle, un groupe halo, un haloalkyle, un aryle, un hétéroaryle, un aralkyle, un hétéroaralkyle, un haloalkyle, un groupe halo, un groupe cyano, un carboxy, -CONRaRb (oü Ra et Rb sont indépendamment de l’hydrogéne ou un alkyle) ou -COOR oü R est un alkyle ; hydroxycarbamimidoyle désigne un radical -C(=NH)NHOH ou - C(=NOH)NH2.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • US 10190147 B [0098] • WO 0035886 A [0111] [0128] [0129] • US 4107288 A [0122] • US 5145684 A [0122] • WO 9429336 A [0128] [0130] • WO 9723499 A [0128] [0130] • WO 0020416 A [0128] • WO 0012479 A [0128] • WO 0009480 A [0128] • WO 0008005 A [0128] • WO 9964392 A [0128] • WO 9962904 A [0128] • WO 9957096 A [0128] • WO 9952895 A [0128] • WO 9950263 A [0128] • WO 9950257 A [0128] • WO 9950255 A [0128] • WO 9950254 A [0128] • WO 9948870 A [0128] • WO 9947503 A [0128] • WO 9942462 A [0128] • WO 9942439 A [0128] • WO 9940075 A [0128] • WO 9937304 A [0128] • WO 9936428 A [0128] • WO 9933805 A [0128] [0129] • WO 9933800 A [0128] • WO 9932477 A [0128] • WO 9932454 A [0128] • WO 9931092 A [0128] • WO 9926941 A [0128] • WO 9926933 A [0128] • WO 9926932 A [0128] • WO 9926919 A [0128] • WO 9926918 A [0128] • WO 9925720 A [0128] • WO 9916751 A [0128] • WO 9916747 A [0128] • WO 9912935 A [0128] • WO 9912903 A [0128] • WO 9911658 A [0128] • WO 9911617 A [0128] • WO 9910316 A [0128] • WO 9907732 A [0128] • WO 907731 A [0128] • WO 9905124 A [0128] • WO 9900356 A [0128] • WO 9900128 A [0128] • WO 9900127 A [0128] • WO 9900126 A [0128] • WO 900121 A [0128] • WO 9857951 A [0128] [0129] • WO 9857937 A [0128] • WO 9857934 A [0128] • WO 9854164 A [0128] • WO 9846591 A [0128] • WO 9831661 A [0128] • WO 9828282 A [0128] [0129] • WO 9828269 A [0128] [0129] • WO 9825611 A [0128] [0129] • WO 9824784 A [0128] • WO 9822483 A [0128] • WO 9816547 A [0128] • WO 9816525 A [0128] • WO 9816524 A [0128] • WO 9816523 A [0128] • WO 9815547 A [0128] • WO 9811094 A [0128] • WO 9807725 A [0128] • WO 9806694 A [0128] • WO 9801428 A [0128] [0129] • WO 748706 A [0128] • WO 9746576 A [0128] • WO 9746523 A [0128] • WO 9738984 A [0128] • WO 9730971 A [0128] • WO 9730073 A [0128] • WO 9729067 A [0128] • WO 9724118 A [0128] • WO 9723212 A [0128] [0129] • WO 9721437 A [0128] • WO 9708165 A [0128] • WO 9705161 A [0128] • WO 9640744 A [0128] • WO 9640743 A [0128] • WO 9640679 A [0128] • WO 9640100 A [0128] • WO 9638421 A [0128] • WO 9628427 A [0128] • WO 9619493 A [0128] • WO 9616940 A [0128] [0129] • WO 9528420 A [0128] • WO 9413693 A [0128] • WO 0024718 A [0128] • WO 9955355 A [0128] • WO 9951571 A [0128] • WO 9940072 A [0128] • WO 9926926 A [0128] • WO 9851684 A [0128] • WO 9748706 A [0128] • WO 9724135 A [0128] • WO 9711693 A [0128] • WO 0001704 A [0128] • WO 0071493 A [0128] • WO 0071507 A [0128] • WO 0071508 A [0128] • WO 0071509 A [0128] • WO 0071511 A [0128] • WO 0071512 A [0128] • WO 0071515 A [0128] • WO 0071516 A [0128] • WO 0013707 A [0128] • WO 0031068 A [0128] [0129] • WO 0032590 A [0128] [0129] • WO 0033844 A [0128] • WO 0035859 A [0128] • WO 0038683 A [0128] • WO 0039087 A [0128] • WO 0039092 A [0128] • WO 0039102 A [0128] • WO 0039108 A [0128] • WO 0039111 A [0128] • WO 0039117 A [0128] • WO 0039118 A [0128] • WO 0039131 A [0128] • WO 0040548 A [0128] • WO 0040571 A [0128] • WO 0040583 A [0128] • WO 0040601 A [0128] • WO 0047207 A [0128] • WO 0047553 A [0128] • WO 0047554 A [0128] • WO 0047563 A [0128] • WO 0047578 A [0128] • WO 0051989 A [0128] • WO 0053264 A [0128] • WO 0059876 A [0128] • WO 0059902 A [0128] • WO 0071510 A [0128] • WO 0076970 A [0128] • WO 0076971 A [0128] • WO 0078747 A [0128] [0129] • WO 0102356 A [0128] • WO 0102397 A [0128] [0129] • WO 0105784 A [0128] [0129] • WO 0109093 A [0128] • WO 0112600 A [0128] [0129] • WO 0119788 A [0128] [0129] • WO 0119795 A [0128] • WO 0119798 A [0128] • WO 9315756 A [0128] • WO 9417817 A [0128] • WO 9529189 A [0128] • WO 9618644 A [0128] • WO 9620689 A [0128] • WO 9639380 A [0128] • WO 9722712 A [0128] • WO 9736580 A [0128] • WO 9736865 A [0128] • WO 9748687 A [0128] • WO 9809987 A [0128] • WO 9846626 A [0128] • WO 9846627 A [0128] • WO 9846628 A [0128] • WO 9854132 A [0128] • WO 9907730 A [0128] • WO 9933458 A [0128] • WO 9937643 A [0128] • WO 9964446 A [0128] • US 6034093 A [0128] • US 6020357 A [0128] • US 5994375 A [0128] • US 5886191 A [0128] • US 5849519 A [0128] • US 5783421 A [0128] [0129] • US 5731315 A [0128] • US 5721214 A [0128] • US 5693641 A [0128] • US 5633381 A [0128] • US 5612378 A [0128] • US 6034127 A [0128] • US 5670479 A [0128] • US 5658939 A [0128] • US 5658930 A [0128] • US 5656645 A [0128] • US 5656600 A [0128] • US 5639739 A [0128] • US 5741819 A [0128] • US 6057342 A [0128] • US 6060491 A [0128] • US 6080767 A [0128] [0129] • US 6087487 A [0128] • US 6140351 A [0128] • US 6395731 B [0128] • US 5646165 A [0128] • JP 99152269 B [0128] • JP 10017549 B[0128] • JP 10001467 B[0128] • JP 98017549 B [0128] • JP 00178243 A [0128] • JP 11140040 B[0128] • JP 12143623 B [0128] [0129] • JP 12204081 B [0128] [0129] • JP 12302765 B[0128] • JP 6327488 B [0128] • JP 98001467 B [0128] • EP 937723 A [0128] • EP 937711 A [0128] • EP 874629 A [0128] [0129] • EP 842941 A [0128] • EP 728758 A [0128] • EP 540051 A [0128] [0129] • EP 419099 A [0128] • EP 686642 A [0128] • EP 1016663 A [0128] • EP 529715 A [0128] • DE 19845153 [0128] • DE 19835950 [0128] • DE 19743435 [0128] • DE 19829964 [0128] • DE 19834751 [0128] • DE 19839499 [0128] • DE 19900355 [0128] • DE 19900471 [0128] • DE 19530996 [0128] • WO 9610022 A [0129] • WO 9728129 A [0129] • WO 9729104 A [0129] • WO 9821188 A [0129] • WO 9906371 A [0129] • WO 9957099 A [0129] • WO 9957112 A [0129] • WO 0047573 A [0129] • WO 0078749 A [0129] • WO 9909027 A [0129] • WO 9957113 A [0129] • WO 729067 A [0129] • US 20020065303 A[0129] • US 20020061842 A[0129] • US 20020058677 A[0129] • US 20020058657 A[0129] • US 20020055522 A[0129] • US 20020055469 A[0129] • US 20020052368 A[0129]
Non-patent literature cited in the description • Fieser and Fieser’s Reagents for Organic Synthesis. John Wiley and Sons, 1991, vol. 1-17 [0092] • Rodd’s Chemistry of Carbon Compounds. Elsevier Science Publishers, 1989, vol. 1-5 [0092] • Organic Reactions. John Wiley and Sons, vol. 1-40 [0092] • March’s Advanced Organic Chemistry. John Wiley and Sons [0092] • Larock’s Comprehensive Organic Transformations. VCH Publishers Inc, 1989 [0092] • T.W. GREENE. Projective Groups in Organic Synthesis. John Wiley &amp; Sons, Inc, 1981 [0099] • T.W. GREENE. Projective Groups in Organic Synthesis,. John Wiley &amp; Sons, Inc, 1981 [0105] • US 20020040144 A [0129] • US 20020035109 A [0129] • U S 20020032223 A [0129] • U S 20020028820 A [0129] • U S 20020025963 A [0129] • US 20020019395 A [0129] • US 20020019394 A [0129] • US 20020016326 A [0129] • US 20020013314 A [0129] • US 20020002183 A [0129] • U S 20010046974 A [0129] • U S 20010044537 A [0129] • U S 20010044536 A [0129] • US 20010025108 A [0129] • U S 20010023292 A [0129] • US 20010023291 A [0129] • US 20010021775 A [0129] • US 20010020020033 A[0129] • US 20010018423 A [0129] • US 20010018414 A [0129] • US 20010000179 A [0129] • WO 9614084 A [0130] • WO 9616671 A [0130] • WO 9739770 A [0130] • WO 9745138 A [0130] • WO 9816252 A [0130] • WO 9927912 A [0130] • WO 9927913 A [0130] • WO 0012043 A [0130] • WO 0013671 A [0130] • MULLER, S.; LIEPOLD , B.; ROTH G. J.; BEST-MANN H. J. Synlett, 1996, vol. 6, 521-522 [0106] • SAKAMOTO, T ; KONDO, Y.; IWASHITA, S.; NAGANO, T.; YAMANAKA, H. Chem. Pharm. Bull., 1988, vol. 36, 1305 [0107] • Remington’s Pharmaceutical Sciences. Mack Publishing Company, 1990 [0126] • Current Opinion in Therapeutic Patents, 1993, 1173-1179 [0128] • N. HOFSLOEKKEN ; L. SKATTEBOEL. Convenient Method for the ortho-Formylation of Phenols. Acta Chemica Scandinavica, 1999, vol. 53, 258-262 [0176] • HOUGIE, C. Hematology. McGraw-Hill, 1990, 1766-1770 [0300]

Claims (14)

szmmmM igénypontok
1, Az (I) képlet szerinti vegyüiet: SBötC Srsíbsíst&amp;km Uövví-í^í 5
(I) képlet ahol; to X1 jelentése ~N~ vagy *GR\ atel R8jelentése hidrogénatom, alkii- vagy R1 jeíea^sa hldfögénatöm, alkik halogén-, karboxü- vagy; amino-karhonkcsoporf; 15 R2 Jelentése hidrogénatom, alkii- vagy halogéncsoport; R3 Jaianíése -CONFER8 (ahol R' Jelentése hidrogénatom, alkik hidroxi-alkih, alkoxí-alki-, karboxí-alkil-, szulfö-alkii- vagy foszfono-alkil-csoport; és R8 20 Jelentése hidrogénatom, hidroxik alkii-, hidroxí-aikil-, alkoxi-alklk amino-aikik karboxi-aikih szuífö-alkik foszfono-aikík amino-karboxi-alkik amino-karbonil-kartmxl-aikik irimetll-amméni u m-al ki l· , am In o- ka rboη I l-aI kil-, -(aiki ién}- |ahol h Jelentése 1 és β közötti egész szám, és Rb jelentése hídmginafem, aikl-j hídroxi-, aikoxi-, amlno- vagy aikii-karhonii-amino-csoport}, 25 aril-, araíkik hi^roank heíeroaraikik hetemciktoaikih heterocikloalkil-a mi no-karboatl-aífcih vagy 3-heterocikíoalkil-2~hidroxi-propii-csoport; vagy R' és R8 azzal a nlírpgénatmnmaí egyöít, amelyhez kapcsolódnak heterocikíoaikiS-amirio- csoportot képeznek) vagy -(aikílén}~C<öNR8R’° (ahol R8 jelentése hidrogénatom, hidroxíl·. aikil-, hidroxi-aikil-, aikoxi-aSksh amino-aikíí-, karboxi-alkíl-, szulfo-alkií-vagy foszförso-aikil-csoport; és R10 jelentése hidrogénatom, hldroxii-, aikil-, hídroxí-atkíi-, ilkoxí-aíkií-, amíno-alkíl-, karboxi-alkil-, szulfö-alkik foszíono-sikil-, 5 amino-karboxi-alkíh amino-karl^pli-karbcpti-alkll-, trlmetíkammóníum-alkil-, araino-karbonii-aikih -(alkilénj-ÍOCHaCHakR0 (ahol n jelentése 1 és 6 közéit! egész szám, és R^ feientése hidrogénatom, alklí-, hidroxíh aikoxk amino- vagy aikíí~karhoni ha mi ne-esopo rí), ai-s araik!!-, heteroaril-, heteroaraikil-, heterodkloaíkíl-alk!!t heterocikloalkil-amíno-karbonil-aikll- vagy 3-heíe rod kíoaiki I-iö: 2~hidroxi-propS!~csoport; vagy R9 és R1C azzal a nitrogénatommal együtt, amelyhez kapcsolódnak heteroclkioaíkil-amino-osoportot képeznek); R* jelentése hidrogénatom, aikil-, aikiHio-, halogén-, hidrox!!-, hidroxi-afkil-, alkoxf, amino-szultáni!-, alkil-amino-szulfonih dsaikii-amino-szuííonil- vagy is hitröcsoport; R* jelentése hidrogénatom, aikil- vagy halogén csoport; R2 jétéhtése hidrogénatom, aikil-, halogén-aiki!-, cikloalkil-, alkii-tio-, halogén-, 20 hidroxil", hidraxi-alkf!-, nitre·-, ciano-, alkoxi-, aíkoxi-alkil·, aikoxl-alkiídxh hidroxi-alkiioxi-, amino-alküoxi-, karboxí-alkiloxs-, aminQ-karhonílbsiklpxk haiogin-alkexh, karboxll·, karboxi-alkii-, alkoxi-karbonik, alkoxi-karbonil-alkik ciano-alkik, aikil-szulfonil-, alklí-szblídnií-alkil-, arii-szuifonil-, heteroarii-szuífonih karbamimidois-, hidroxi-karbamimidölk aikoxi-karbamimidoik alkil-szulfonil-amíno-, aikil-szulfoni!-25 aroino-alkil-, aikoxi-szulfoml-amlno-, alkoxi-szuifonil-amlno-alki!-, heíerocikioaikil-alkii-amino-karbohiK bídíMí-afkox^ hetanxákloaikíl-karbonll-, hetemoíktoaikll-karbonii-aildl-, heíerodkioaikik heterocikloalkíi-aíkil-, oxo-heteroclkloalkil-, oxo-heíerocikloalkil-aíki!-, heteroaril-, heteroaraiktl-, ureido-, alkii-ureido-, dialkii-ureido-, uroido-alkíi-, alkü-ureido-alkll-, dialkil-ureido-aikil-, tio-ureido-, 30 iío-ureido-alkik -COR12 (ahol R12 jelentése aikil-, halogén-alkík hídroxi-aikik alkoxi-alkii- vagy amino-alkil-csoportj, -(alkilén)-COR12 (ahol R12je!entése aikil-. halogén-alkil- hidroxt-aíkíh, alkoxi-alkii- vagy amino-alkil-csoport), -CÖNRt4R1a (ahol R14 jelentése hidrogénatom vagy alkiS-csoport; és R55 jelentése hidrogénatom, aikil-, hidn^i-alkt!-, aíkoxi-alkik ad!-, araikig heteroant- vagy heíeroaralkl-csopod; vagy R14 és R15 azzal a niírogénaíomma! együtt, amelyhez kapcsolódnak heíerocikloamino-csoportöt képeznek). -{aMíén)-£öNR1#r (ahol R18 jelentése hidrogénatom, alkil-vagy hidroxi-atkikcsoport; és R17 jelentése hidrogénatom, alkii- hidroxí-alkik aíkoxl-alkii-, ahk araik!!-, heteroarií- vagy heteroaralkii-csopod; vagy R':6 és R1? azzal a 5 nltrogéhaÍ3mrrlat együtt, amelyhez kapcsolódnak heterocikioamino-esopoftot képeznek), -NRiaR19 (ahol R18 jelentése hidrogénatom vagy aikiicsoport; és R1S jelentése hidmgénatorn, alkii-, ad!-, aril-, aralkii-, heieroanl- vagy heteroaraikif-csoport), -(alkiién)- MR20!?21 (ahol R20 jelentése hidrogénatom, alkii- vagy hidroxi-alkii-csoporí; és R21 jelentése hidrogénalom, alkii-, acil~, alkoxi-karbonli- hidroxi-alkik, ίο aíkoxéalkil·, an!-, araikii-, heteroaril- vagy heteroaralkii-osoport), -SC^NR22#3 (ahol R22 jelentése hidrogénatom vagy aikiicsoport; és R23 jelentése hidrogénatom, aíkik ári!-, aralki!-, heteroaril- vagy heteroaraikii-csoport: vagy R22 és R23 azzal a nítfo^énalomrnal együtt, amelyhez kapcsolódnak heterodkloamíno-csoportot képeznek), -{alkiién j-SO^N R24R25 (aho! R24 jelentése hidrogénatom vagy aikiicsoport; i $ és R23 jelentése hidrogénatom, alkif-, ari!~, araitól-, heteroaril- vagy heteroaralkíl-csoport; vagy#4 és #s azzal a nitrogénatommal együtt, amelyhez kapcsolódnak heterocíkloamino-csoportot képeznek), -NR26SOaNR27R28 (ahol R2S és R27 jelentése egymástól függetlenül hidrogénatom vagy aikiicsoport; és R28 jelentése hidrogénatom, alkii-, áriig araikii-, heíéröanh vagy heteroaMlkii-csopod:; vagy R2í és so R28 azzal a nitrogénatommai együtt, amelyhez kapcsolódnak heterocikloamino- csoportot képeznek),: -{aIkilén }-NR23S(¾ N R30R''1 (ahol R28 és R30 jelentése egymástól függetlenül hidrogénatom vagy alktjcsopprt; és R'í1 jelentése hidrogénatom, sikli-, ári!-, araitól-, heteroaril- vagy heteroaraikii-csoport; vagy R30 és R31 azzal a nltrögénaiomma! együtt, amelyhez kapcsolódnak heterodkloamino-CvSoportot 25 képeznek), -CONH-ialkilenj-NR^R83 {ahol R32 jelentése hidrogénatom vagy aikiicsoport; és R33 jelentése aikiicsoport) vagy araikil-escport; és R18 jelentése hidrogénatom, hidroxll-, :pMí>}alkoxt-:, ~C{0)R35 (ahol R35 jelentése alkii-, aril··, halogén-aikíl- vágy eiánö-atkil-csoport) vagy -C{Ö)ÖR3ii 30 {ahol f# jelentése alkii-, hidroxl-alkil-, alkoxi-alkil-, alkoxi-karbonil-aikik acil-, adl·* vagy halogén-aikil-csoport); vagy egyedi sztereoizomer, sztereoizomerek keveréke vagy azok gjíégyszereszétíteg elfogadható sója, azzal a megkötéssel, hogy ha R3 jelentése - CÖNR7R8 (ahol R' jelentése hidrogénatom vagy alkilcsoport; és Rs jelentése hidrogénatom vagy alkilcsoport}, ~{alkiién)-CÖMR8R1<Í (ahol R2 és R10 azzal a nkrogénatommaí együtt, amelyhez kapcsolódnak pirrolídinílcsoportot képesnek), és Rz jelentése hidm|Énaíom, slkil-, halogén-alkil-, halogén-, niíro-, alkox!-, halogén-S alkil-, karboxll-, slkoxi-karbonil-, -NRiaR19 (ahol Rls jelentése hidrogénatom vagy alkilcsoport; és B!tj©iehtésé hidrogénatom, alkil-, aril- vagy aralkilcsoporí), plrmiiirnlkkarböhil·, -S02NR22R23 (ahoi R22 és R22 jelentése alkilcsoport), káíbernimíböil-, aiki!~szulfoni!~amtno~, aíkil-tiö-, ureido-, -NHC(S)NH2 vagy heierodkloamino-csoport, akkor R* jelentése hidroxií* vagy hldroxi-alkil-esoporí; to ahol az aíkiicsöpórt kifejezés egyenes láncú, telített, egyértékű, 1-6 szénatomot tartalmazó szénhidrogéncsoportot vagy elágazó láncú, telített, ©gyértiki, 3-6 szénatomot tartalmazó szónhidrögénesopöioí jelent; az aiksiénosoport kifejezés egyenes láncú, telített, kétértékű. 1-6 szénatomét 15 tartalmazó szénhldrogénésoporfot «agy elágazó láncú, telített, kétértékű, 3-6 szénatomot tartalmazó szénhfbmgénesoporíot jelent; az aíkíl-íio-csoport kifejezés -SR csoportot jetenf, ahol R jeientése aíkiicsopoft; az arninocsoport kifejezés -NRR’ csoportot jelent, ahol R és R'jelentése egymástól függetlenül hidrogénatom, alktl-vagy -0101¾3 csoport, ahol R8 jelentése alkilcsoport; az acilcsoport kifejezés CÖR1 20 csoportot jelent, ahol R‘ jeientése alkil-, alkpxh halogén-alkil-, amino-aíkif-, hídroxí-alkií- vagy alkoxi-aiksl-oseport; az amino^szulfdnii-csópört kifejezés -SOgNHg csoportot jelent;, az aikii-amino-szulfonii~csoport kifejezés -SO2NHR csoportot jelent, ahol R jelentése alklicsoport; az alkll-szuifoníi-csoport kifejezés -SO?R csoportot jelenig ahol R jelentése alkilcsoport; az alkil-szulfonii-alkii-csoport 20 kifejezés -(alkíiénj-SÖaR csoportot jelent, ahol R jelentése alkilcsoport; az alkil-szulfoníl-amino-csoport kiélezés -RH$OaR csoportot jelent, ahol R jelentése alkiicsöport; az aíkii-szülfoníl-amíno-alkii-csoport kifejezés -(alkiiénj-NHSC^R Csoportot jelent, ahol R jelentése alkticsoport; az aikoxi-szolfonli-amino-csoport kifejezés ^NHSQaR csoportot jelent, ahol R jelentése alkoxicsoport; az aikoxi-3ö szülfonli-amíno-alkíl-csoport kifejezés -{aíkilénj-NHSOsR csoportot jelent, ahol R jelentése alkoxicsoport; az alkoxicsoport kifejezés ~ÖK csoportot jelent, ahol R jelentése alklicsoport; az alkoxi-karbonil-csoport kifejezés -COOR csoportot jelent, ahol R jelentése aíkicsöpöi; az alkoxi-karbonij-aikil-csoport kifejezés -(alkilén)-CÖÖR csoportot jelent, ahol R jeientése alkilcsoport; az aíkoxi-alkihcsoport kifejezés egyenes láncú, egyértékü, 1-6 szénatomot tartalmazó szénbidrogéncsoportot vagy elágazd láncú, egyértékü, 3-8 szénatomot tartaImázó szénhidrogéncsopodot jelent, amely szubsztltúálvá Várt legalább egy sikoxiesapOrttai: az amino-alktl-csoport kiélezés egyenes láncú, egyértékü, 1-6 szénatomot tartalmazó s szénhirtrögéoesopQrtet vagy elágazd láncú, egyértékü, 3-6 szénatomot tartalmazó szénhlrtrogéoesGpQrtoí jelent, amely szubszfSaálva van legalább egy -NRR' csoporttal, ahol R és R* jelentése egymástól függetlenül hidrogénatom, alkii-vagy -GGRa csoport, ahol Re jelentése alktícsoport; az amino-karboxi-aíkií-csoport kjfépzés egyenes láncú, egyértékü, 1-6 szénatomot tartalmazó i(j szénhldrogéncsoportot vagy elágazó láncú, egyértékü, 3-8 szénatomot tartalmazó szénhidreginesöporíoí jelent, amely szubsztitusfva van egy -NRR’ és egy -COÖH csoporttal, ahol R és R' jelentése egymástól függetlenül hidrogénatom, alkii- vagy ~ GÓR9 csoport, ahol Ra jelentése aikllcsoport; az amíno-karbonil-karboxi-alklé csoport tévézés egyenes láncú, egyértékü, 1 --8 szénatomot tartalmazó 15 szén hidrogéncsoportöt vagy elágazó láncú, egyértékü, 3-8 szénatomot tartalmazó szénhldrogéncsoportot jelent, amely szobsztítuÉlya van egy -CONRR’ és agy -CGQH csöpörttal, ahol R és R' jelentése egymástól függetlenül hidrogénatom, aiklh va§y -CORa csoport, ahol Ra jelentése aikllcsoport; az anrino-karboníl-alkíi-csoport kifejezés egyenes láncú, egyértékü, 1-8 szénatomot tartalmazó 20 szénhidmgéncsoportöt vagy elágazó láncú, egyértékü, 3-β szénatomot tartalmazó szénbldrogéncsoportOi jelent, amely szubsztltuáíva: van egy vagy két -GONRR' csoporttal, ahol R és R! jelentése egymástól függetlenül hidrogénatom, aikii- vagy -CÖR® csoport, ahol R9 jelentése alkiiesoport; az atkoxhafkijoxi-osoport kifejezés -DR csoportot jelent, ahol R jelentése alkoxi-alkii-csopori; az amino-aíkiloxi -25 csoport kifejezés -OR csoportot jelent, ahol R jelentése amíno-aíkil-csoport; az amioo-karbonii-csoport kifejezés -CONHs csoportot jelent; az amino-karbonil-aiklloxi·csoport kifejezés -O-alkiién-CONRR’ csoportot jelent, ahol R és R' jelentése egymástól függetlenül hidrogénatom vagy alkílcsoport; az amino-karbonil-alkll-csoporí kifejezés -(alkilénj-CONHa csoportot jelent; az alkli-ureido-30 csoport kifejezés -NRGÖfsIHR1 csoportot jelent, ahol R jéléntésé hidrogénatom vagy aikllcsoport, és R‘ je!éntése aikllcsoport; az sikiRereldc-atkil-csoport kiejezés ~(alkilén}-NRCONHR! csoportot jeleni ahol Rjelentése hidrogénatom vagy aikllcsoport, és Rr jelentése aikllcsoport; az árucsoport kifejezés egyértékü, monociklosos vagy blctfeíusos:, aromás. 8 -12 gyyrűatomot tsrtalmazó szén hid rogéncsoportot jelent, amely adott esetben egymástól függetlenül szubsztituálva lehet a következők közül választott egy vagy több szubsztiíuenssel: aíklí-, baiogén-attcfb, atkoxi- alkít-tio-, halogén-, nitro-, -CöR {ahol Ft jelentése alkiicsoport), eiano-, amino-, aíkií-amlno-, diatkil-amino-, hsdroxii-, karhoxii- vagy -5 COÖR csoport, ahol R jelentése alkiicsoport; az aril-szulfonii-csoporl kifejezés -SOjR csoportot jelent, ahol R jelentése ahlcsoport; az aralkílcsoport kifejezés * (aikílén)-R csoportot jelent abo! R jelentése ahicsoport az aikcxi-karbamirnidoii-csoport kifejezés -€{~NH)NHOR vagy~C{~NOR)NHz csoportot jelent, ahol R jelentése alkiicsoport; a cMoalkilcsoport kifejezés ciklusos, teíiieit.egyértékö, 3-6 to szénatomot tartalmazó szénhidrogéncsoport jelent; a karboxi-aikil-csoport ktfejezés>|aiki!énj-^OöH csöpörtöí jelent; a karboxi-aikiioxl-csoportkifejezés -ö-|aikiién}-£GGH csoportot jeleni; a karbamimídoil-csoport kifejezés -Cf-NHjNHs esöportot jelent; a ciano-alkil-csopori kifejezés ~(aiki!én}~CR csoportot jelent; a diiéikl^mtncNe^uífonlN^öpört kifejezés -SCpNRR1 csoportot jeleni, ahol R és R! is jelentése egymástól függetlenül alkiicsoport; a dsalkíl-ureido-csoport kifejezés -RRCÖNRW'csoportot jelent, ahol R jelentése hidrogénatom vagy alkiicsoport, és R' és R!! jelentése egymástól függetlenül alKlícsoport; a diaikil -ureldo-alkll-csoporf kifejezés ^aik!lé?h)-HR¢ϊp^tR‘R,, csoportot jelent ahol R jelentése hidrogénatom vagy alkilosoport,: és R* és R" jelentése egymástól függetlenül alkiicsoport; a so panidino-alkil-csoport kifejezés egyenes láncú, egyértékű, 1-6 szénatomot tartalmazó szénhldrogéncsoportot vagy elágazó láncú, egyértékű, 3-6 szénatomot tartalmazó szénhldrogéncsöpprtot jelént, amely szubsztituálva van legalább egy -NRPPRH^RR* csoporttal, ahol R és R' jelentése egymástól függetlenül hidrogénatom, alkil- vagy -CÖR8 csoport, ahol Ra jelentése alkiicsoport; a balogén-25 csoport kifejezés: fluor-, klór-, bróm- és jódcsoportot jelent; a haiogén-alkll-csoport kifejezés alkilosoportot jéient, amely szubsztituálva van egy vagy főbb haiöiénáíommal; a balogen-alkoxi-csopoirt kifejezés -ÖR csoportot jelent, ahol R jelentése halogén-atkU-csoport; a hidroxi-aikii-csoport kifejezés egyenes láncú, egyértékű, IMI szénatomot tartalmazó szénhídroaéncsoportot vagy elágazó láncú, so egyértékű, 3-6 szénatomot lártiíhiazó azénhídrogéncseporfet jelent, amely szubsztiíuélvá vart 1-5 hidmxilcsoporttal, azzal a megkötéssel, hogy ha két hidroxiicsoport van jelen, akkor azok nem ugyanazon a szénatomon találhatok; a hidroxí-atklloxhcsoport kifefez^s -GR csoportot jelent, ahol R jelentése hidroxi-aikii-csoport; a hidroxi-alkoxi-afkll-amino-karbonil-csoport kifejezés ~GÖNH~CalkiÍén)--Ö- (alkiién)ÖH exportot jelent; a heterocikio-alkihcsopori kifejezés olyan telített vagy íettteieo, epyértéM, eikipsps csoportot jelent, amelynek 3-8 györűatomjá: közöl egy vagy kettő a következők közül választott héíferöatom: fsí^ 0 vagy S(0)n, ahol π jelentése 0 is 2 közötti egész szám, a további gyűruaíomok pedig: C atomok; a :S hetercmíkioalkikkarbonihcsopori kifejezés -COR csoportot jelent, ahol R jelentése heterodkioalkikesopott; a beterooikioaikll^karbonií-aiklbcsoport kifejezés -{aíkíién}-COR csoportot jelent, ahol R jelentése heterocikloolkikcsoport; a heterocikioaikih aikii-csoport kifejezés *Íatkiién}'R csoportot jelent, ahol R jelentése heterocikloaíkH-csoport: a heterocikloaikll'-alkil-amino-karbonii-csoport kifejezés -ίο COblH-Caikitén^R csoportot jelent, ahol R jelentése heíerocikloaIkil-csoport; a heteroaribesoport kifejezés olyan egyértékű, monociklusos vagy bicikiusos, aromás csoportot jelent, amelynek S~1G gyűmaiomja közöl egy vagy több a következők közöl választott heteroatom: N, Ö vagy 8, a további gyűrüatomok pedig szénatomok, a heteroarii-gyűrű adott esetben szuhsztituálva van a i5 következők közöl egymásföl függetleni! választott egy vagy több szubsztitoenssal: alkil·, hafogén-alkil·, aiköxh alkií-tíü-, amíno-alkíl·, guanidino-aikíl·, balogén-, nítro-, ciano", amino-, afkfl·, diafkii-amino-, hidroxík karboxil- vagy -ODOR csoport, ahol R jelentése alkücsoport; a heteroaríkszulfonü-csoport kifejezés -SG^R csoportot jelent, elol R jelentése beleroaribosoport; a heieroaralkíl-esoport kifejezés -20 plkiléh j-R csoportot jelent, ahol R jelentése heteroarll-csoporí; a hetorocikloamino-csoport kifejezés olyan telített vagy telítetlen, egyéneke, ciklusos osopörtöt jelent, amelynek 3-8 györűatomja közöl egy vagy kettő a következők közöl yÉiasZíptt .heíeroatom: M, 0 vagy S(ö)n, ahol n jelentése 0 és 2 közötti egész szám, a íevihbi gyüruaiomok pedig C atomok, azzal a megkötessél, hogy a 25 beteroaíomok közül legalább egy nítrogénatom, és ahol egy vagy két szénatom adott esetben szubszíítuálva van egy karhonilcsoporttal, a heterocikloamino-gyűrö pedig adott esetben szuöszfituálva van a következők közül egymástól függetlenül választott egy vagy több szubsztítuenssel: alkil-, hidraxil·, hidrozeaikil-, alkoxí-, alkoxi-átkii-, amlno-aikii-, guanidino-aikíl-, halogén-, halogén-alkil-, aril··, heleroarih 30 araikik, heteroaralkií-, halogén-alkll·, halogén-, ciano-, karboxil-, -CONR8Rb (ahol R3 és Rí;' jelentése egymástól függetlenül hidrogénatom vagy alkllcsoport} vagy -ODOR csoport, ahol R jelentése alkilcsoport; a hidroxi-karbamímídoii-csoport kifejezés -C(~NH)NHOH vagy -C(~NOH)NH2 csoportot jelent.
2, Az 1. igénypont szerinti vegyuiei ahol: R3jeientése ~CÖNR7R8 csoport (also! R7 Jelentése hidrogénalorn, alkik alkoxi-alkik karfeoxí-aSkih hidroxi-alkil- vagy foszfono-alkil-csoport; és R* jelentése &amp; hidrogénatom, alkik aSkoxl-afkils, ^IkitéhHOCíHsCHglnR^ (ahol n jelentése 1 és 8 közötti egész szám, és Rb jelentése hidrogénatom, alkik, hidroxih aikoxl-, amino-vagy alkjl-karbonil-amino-csoport), amino-alkil-, amino-karbonil-aíkik, amino-karbonii-kaffedxi-aíktk amino-karboxlmilh karboxi-alkik hldroxí -a I ki d fosztοπο-aIkil-, szuiío-alkil-, thmei-ammónsum-atkik árié, araikik, heteroanh heteroaratkii- vagy i ö hetereodkioalkil-alkii-csoport; vagy R7 és R8 jelentése azzal a nitrogénatommal eg^t, amelyhez kapcsotédnak heterocikioalkif-amino-csoport) vagy -(alkilén)-CÖNRSR10 csoport (ahol R3 jelentése hidrogénatom, aikil-, alkoxi-alkik karhoxí-alkik iidroxi-éfkli- vagy foszfono-alksi-Gsoport; és R10 jelentése hidrogénatom, aikil-, áíkpxk aíkíl-, -(alkílénHOCHaCHa^R0 (ahol n jelentése 1 és 8 közötti egész szám, és Rb 15 jelentése hidrogénatom, alkik hidroxil--, alkoxk amino* vagy aíkil-kamonil-amíno-csoport), amíno-aíkik ardno-karbonil-aikik aminG-ka:&amp;oníl-karbGxí-aíkih amino-karboxl-alkil-, karboxi-alkik hidroxi-alkll*·, foszfono-aMk szuifo-aikih támetif-amménium-alkik and, araikid, heteroanl-, heteroaralkii*· vagy heterocikloaíkihalkii-csopod; vagy R9 és R10 jelentése azzal a nitrogénatommal együtt, amelyhez m kapcsolódnak, hetemcíkio-aikil-a?nino-csopod), ahol bármely olyan gyűrő, amely R3 csoportot tartalmaz, adott esetben a következők közöl egymástól függetlenül választott 1~i csoporttal saMiifea van: hidroxil-, hidroxi-alkil-, alkoxi-alkik karboxíí-, alkoxl-karbonik amino-alkih guanidino-iíkik aikil- vagy -CGNRaRb csoport (ahol Ra és Rfe jelentése egymástól függetlenül hidrogénatom vagy aikífcsoport); és 25 Rí: jelentése hidrogénatom, aikil-, halogén-alkil-, cikloalkih alkil-tío-, halogén-, hidroxil-, hidroxi-alkid nitro-, ciano-, alkoxí-, alkoxi-aikil-, aíkoxi-alkíloxi-, hidroxi-alkíioxk amino-alklloxk karhoxi-aikiloxi-, amino-karbonil-alkiioxi-, hafogén-alkoxi-, karboxl!-, karboxi-alkti-, alkoxi-karteonií-, alkoxi-karbonil-aJkik dano-alkíh, 30 alkil-szulfonil-, aikíi-szulfonil-aSkil-, aril-szuifonik heteroarii-szuifoniS-, karbamlmidoik hidroxi-karbamimídoík aikoxi-karbamimidGih alkidszutfonii-amino-, sikií-szuSfom!-amíno-alkil-, alkoxl-szulfonii-amino-, alkoxi-szulfonil-amíno-aíkil~, heterodkloalkíl-álklI-amlho-kaÉonlh, hídroxi-a^oxs-alkikamino-karboník, heterocikloalkü-karhonii-, Heteröcikbalkil-karbonii-alkii-, heterocikloalkii-. heteröcikloaíkil-alkik oxo- heterocskloalkíh oxo-fieteisciklöátoNilíll·, beteroarík heteroaraikil-, ureido-, aikíi-ureido--, diáikíi-ureido-, ureido-aíkík aíkil-ureidü-alkí!-, díalkii-ufeldo-alkih tio-ureido-, tio-ureída-alkík -€Ö:Rt2 (ahol R12 jelentése aíkil-, haíogén-aSkii-, hídroxi-aikih alkoxí-aikíi- vagy arnino-alkií-esoporí), -{aikíién)-COR12 {ahol R12 jelentése aíkil-, halogén-s aíkil-, hkiroxi-aíklk aikoxl-aíksl- vagy amino-alkikcsoport), -CONR14R1b (ahol R14 jáíéntése éídrogáaatom vagy aíkíídsdpott; és R13 jelentése hidrogénatom, aíkil-, hídroxí-alkl-, altekalkíí-, aríí-, afaíkik heteroaril- vagy heíeroaraikíí-csoport; vagy Ru és R13 azzal a nkrogénatommal együtt, amelyhez kapcsolódnak heterocikloamino-csoportot képeznek), ~(a!kílén}-CONRi6R17 (ahol R13 jelentése io hidrogénatom, aíkil- vagy hídroxi-aikit-csoport; és R17 jelentése hidrogénatom, alklh hidroxi-aíkii-, alkoxí-alkík arik araikik heteroaril- vagy heteroaralkkcsoport; vagy R;1S és R17 azzal a nítrogénalornrnal együtt, amelyhez kapcsolódnak heterocikioamino-csoportot képeznek). NR'8R'9 (ahol R1S jelentése hidrogénatom vagy alki lesöpört; és R1S jelentése hidrogénatom, aíkil-, acii-, arik aralkil-, heteroarif-ts vagy heteroaralkil-csoport), -(alkílénk NR20R2· (ahol R2u jelentése hidrogénatom, aikíi- vagy hidrOxí-alkií-esöport; és R21 jelentése hidrogénatom, aíkil-, acll-, alkoxl-karbonk hidroxi-aíkik aikoxi-aikík aríl-, aralkil-, heteroari- vagy heteroaralkil-csoport), -SOsMR^R23 (ahol R22 jelentése hidrogénatom vagy aíkil-csoporl; és R23 jelentése hidrogénem, alki!-, ahi-, aralkil-, heteroanl- vagy heteroaralklí-osoport; 20 vagy R22 és R23 azzal a nitrogénatommal együtt, amelyhez kapcsolódnak hetertókloamlno-éSí^dotMpeznek), -(alkí^ (ahol R24 jelentése hidrogénatom vagy alki lesöpört; és R&amp; jaíenfés© hidrogénatom, aikíi-, arií-, araikil-, heteroarit* vagy hetemaraíkil'-csoptt; vagy R24 és R25 azzal a nítragénatommaí együtt, amelyhez kapcsolódnak heterocikioamino-csoportot képeznek!, -25 NR2SSÖ2NR27R2S (ahöl R23 és R27 jelentése egymástól függetlenül hidrogénatom vagyaikitesoport; és R28 jelentése hidrogénatom, aík^-, aril-, aralkil- heteroanl- vagy heteroaraikil-csoport; vagy R27 és Rm azzal a nitrogénatommal együtt, amelyhez kapcsolódnák heterocikioamino-csoportot képeznek), -|alkiíén)~hlR2%Ö2NRsöR34 (áhoí R^ és R33 jeíéhíése egymástóí függetlenO! hidrogénatom vagy alkiiesoport; és so R31 jelentése hidrogénatom, aikíi-, arik araiki!-, heteroaríl- vagy heteroaraikíí-csoport; vagy R30 és R34 azzal a nitrogénatommal együtt, amelyhez kapcsolódnak heteröískíoarníno-csöportót képeznek). -CÖNH-(aíkilén)~NR32R33 (ahol R32 jelentése hidrogénatom vagy aikiiesoport; és R33 jelentése aikilcsoport) vagy aralkíí-csoport, és R13 píentése hiclPöiénatorri, fridroxík íC1.1olalkoxí·', ~C(Ü)R35 (ahol R38 jelentése alklk, arlk, haiegén-afkii- vagy biano-atkll-csoporl;} vagy -C{0)0R36 phot R36 jelentése alkíh Ndroxí-alkik acil- vagy haiogén-afkil-csopori); vagy 5 azok gyógyszerészeííieg elfogadható sója.
3. Az (ía) képlet szerinti vegyülei ahol:
no pa) képlet R3 jelentése -CONR7R8( -CH;€ÖNRSR10 vagy -C{CH;i)2CONR3R’0 csoport; R7 jelen lése hidrogénatom vagy metllcsoport; ;f§ Rs jelentésé hidrogénatom vagy metiícsoport; Rs jelentése amino-karbonIhméik, 1,2~dia míno-karóon ii-étik 2~amlno-karfconiM -karboxl-etik S-amlnadkkartsoxi-pentik 2'karboxi~eíik karboxs-metil·, 20 2~karböxíkk2R2~etoxi~eioxi)~etoxn~pröpik dimet í i -a m I η o -métiI-1 3-dimet.il-amino-propík 2>-hfdrox!“1 Jsbisshldi^xhmeif-eih, 2~hídroxí~1-fn!droxi'-met!Í-etii-5 1,2-díkarboxi-etih( metik 2p2~p-meÉ Namine-etox!)eiox|atit~, 2~|4-metii-pi perazi η- ϊ~ Hjetík 2-morfolin~4-IÍ8tík 2:3,4,5,6-pe nta hidroxí -hexlk S-ptperazin-l -Itétík 2-:szoÍÉo--etík 3,4,5,8-feírahidröxí4eir8hidrö~piran“2-iímetik 2,4(54πΝόη3χΝ8-25 hidroxí-metildetrahsdro-'piran'-S-ih, 2,4,5-trihidroxi~6·' hídroxi-metiS-tetrahidro-piran' 3~ilkatbamoií-nnetik trímelii~ammónium“etil” vagy 2-foszfono-etil-csoport; R10 jelentése^ amiho^kerhóriikmétik, 1^-diamíno-karbonil-etlk 2-amino-karbonlM-karboxikrisk 5~aminQ-5~karboxi~pentlk 2-karfeöxhetlk karboxi-metik 2-karboxí"3-(2-(2~etoxí~eíox!)'etoxí]--propil"( dimetif-amíno-meii.!-, 3-dfmeíii-amino-propíK 2 -hid rox? -1~ híd ro xi~me ti l-etí l~, 1,2- dtkarboxheib, meifi-, 2-P'{2-niadl~amloo-'eloxi}aíoxi]etll·, 2~(4--rneti;-pipefazin-1 -íl>étí{~, 2~morfotin-4~iletli-, 2,3,4,5,6~peníahidröXHhexíÍ~, 2~piperazin-1 -ijetil~, 2-5 szufeelln 3,4,5,6-ietrahídroxi~tetrahid ro-piran-2~iImet;4, 2,4,54rshidroxi-6" hídmxi-rnettíRetrah^ S^é^fíbídroxhó- hídmxi»^«íjMefráhldm-piran- 34ikarbamoii-melik trlraetil-ammonium-etih vagy 2-ioszfonG~etil~csopori; Rz jelentése amino-sztílfoni!- vagy ureido-metíl-csüport; és H) R13 jelentése hidrogénatom; vagy annak gyögpzeréSEetilég gifogadhato sója. í 5
4. A 3. Igénypont szerinti vegyidet, ahol: ^jelentése -Göf^R® -CH2CONR3R10 vagy -C(CH3)2CÖNRSR10 csoport; R7 jeíéntésf hidrogénatom; 20 R9 jelentése hidrogénatom; R8 jelentése amino-karbanil-metih 2~amino~karhonii-1~karbox4etih S-aminö-5~karboxí-pentih 24:arboxk?tlh karboxi-metíl·· vagy 1,2-dikarboxi-eiil-csoport; 2S R10 jeléntése amtno^arhöhi^meüh, 2-aminO“karhoníi'-1~karboxi-etík.
5~amtno~ 5-karboxi-pentik S-karboxi-etll·, karboxl-metíí- vagy 1,2-dikarboxi-etíl-csöport; és Rz jelentese amino-szulfonll-csopoh; vagy 30 annak gyógyszerészetfeg elfogadható sója. 5. A 4. igénypont szerinti vegyidet, azzal jellemezve, hogy az (la) képlet szerinti vegyidet: bifeni!-3*íl] - acéli!~amino}-szukeini í sav vagy annak egy gyógyszerészetíleg elfogadható sója. 5
6. Gyógyszerészeti készítmény, amely gyogyszerészetiieg elfogadható hordozóból és az 1-5. igénypontok szerinti bármelyike szerinti vegyület terápiásán hatékony mennyiségéből vagy annak gyógyszerészetíleg elfogadható sójából áll. te
7. Az előző Igénypontok bármelyike szerinti vegyület terápiásán hatékony-mén nyíségének vagy gyógyszerészéfiieg elfogadható sójának alkalmazása gyógyszerkészstmény éSSáliiásáhőz a Vila faktor által szabályozod folyamatot érintő, állatokban előforduló betegség kezelésére szolgáló módszerhez. is
8. A 7. igénypont szerinti alkalmazás, azzal jellemezve, hogy a betegség tromboembóiiás betegség.
9. Az 1~5. Igénypontok bármelyike szerinti vegyüleinek vagy gyógyszerészeti lég elfogadható sójának alkalmazása tromboembóiiás bétepég n kezelésére szolgáló gyógyszerkészítmény előállítására, azzal jellemezve, hogy a gyógyszerkésziminyf más, a kővetkezők közül egymástól függetlenül választott antikoaguláns szerrel/szerekkei együtt alkalmazzák: trombsn-nhsbkor, IXa faktor, Xa faktor Inhibitor, Aspirin® és PlavIsÉk
10. Az 1~5. Igénypontok bármelyike szerinti vegyűleinek vagy gyogyszerészetiteg efogadható sójának alkalmazása a Vita faktor által szabályozott folyamatot érintő, állatokban előforduló betegség kezelésére szolgáló módszerhez.
11. A 10. igénypont szerinti vegyület, azzal jellemezve, hogy a betegség 36 ímmböemhéilás betegség.
12. Az f-S, Igénypontok bármelyike szerinti vagyületnek vagy gyógyszerészetiéi elfogadható sójának alkalmazása tromboembóiiás betegség kezelésére, azzal jellemezve, hogy a vegyü letet másik, a kővetkezők közül egymástól függetlenül választott aniikoaguláns szerrel!szewkkel együtt alkalmazzák; trombininhibitor, IXa faktor, Xa faktor inhibitor, Aspirin® és Plavis®.
13. Egy biológiai mintában végzett in vitro véraivadásgátlásra szolgáló 5 módszer, amely magában foglalja az 1-5. igénypont szerinti bármely vegyületnek vagy gyógyszerészetíleg elfogadható sójának alkalmazását.
14, Az 1. igénypont szerinti végyütel előállítására szolgáló eljárás, ahol X1 jelentése -N-, és amely eljárás magában foglalja a fi) képiét szerinti vegyüfet
(i| képlet i5 a (III) képlet szerinti vegyülettei;
(Üt) képlet 20 ahol: f*·5 jelentése ~CÖNR7R3 (ahol R7 jelentése hidrogénatom, alkih hidroxl-álkíi-,: atkoxi-alkil-, :karboxi~atk!l", szuífo-aikil- vagy foszfono-alkíl-csoport; és R8 jelentése hidrogénatom, hidroxik atkíl-, hidroxi-alkH-, mkoxbalkík amino-alkih karboxi-aíkil·, szulfckalkil·, foszfone-aikik amlno-karboxi-aikik amino-karbonil· karboxl-alklk, trirnetiS-ammonsum'-alkik, amino-karbonil-slkik -{alküén)" :(OCH2;CH2:}s^'^b:d::R]ateatéM I és 8 közötti egész szám, és Rb jelentése hidrogénatom, aikik, hidroxik, alkoxk amino- vagy aIkit-karbonikamino-csoport), s arik aralkík, heteroarí!-, heteroaralkik, heterocikloalkii-aíkil, heieroctkioalkik aminokarbonikalkik vagy 3-heterocikloaikii--2-hsdroxi~propii; vagy Fi7 és R8 azzal a nitrogénatommal agyőit, amelyhez kapcsolódnak h et e rocl ktoaf ki ka m s η o ~ csoportot képeznek) vagy ~(alkiién)-CöNR9R10 (ahol R9 jelentése hidrogénatom, Éídiröxik aikik, hidroxkaikik, alkoxi-alkii-, amino-aikil·, karboxkalksk, szulfö-alkík ío vagy toszlono^atkíl-csopod; és R10 jelentése hidrogénatom, hidroxik, aíkii··, bidföxi-alkík, alkoxkalkik, amino-aikik karboxkaíkik, szuifo-aikil·, foszfono-alkik aniino-karboxbalkk, aminokarbonikkarboxnalkik tnmeiikammónkim-alkik amino-karbonikalkik, kaikllén)-(OCH2CH2)riRb (ahol n jelentése 1 és 6 közötti egész szám:, és Rfe jelentése hidrogénatom, alki!-, hidroxik álkoxi-, amlno- vagy II aikil-karbonll-amino-csoport), aril·, átaiikik hetstoarih, heíeroarafkik, feetemtiktoatklkátkil, heterocikioalkil-aniino-karbopll-alkil- vagy S-beterocIkloaíkil-2 - h idrox kpropikcsoport; vagy R9 és R10 azzal a nitrogénatommal együtt, amelyhez kaposoíódnak heterocikioaikibamino-'csoportot képeznek); és 20 R* jelentése hidrogénatom, alkil··, halogén-atkik eikloalklk aikil-tio-, halogérK hidroxik, hidroxi-alkik hitre-, ciano-, aikoxk aikoxhatktk attexi-aíikííoxk , hidroxi-aikoxiloxk, amino-aiktioxl·, karboxi-atklioxk, amino-karbonikatldlöxj-, haiogén-aikoxl·, karboxík karboxkaikik alkoxi-karbonik alkozkkarboníkafkik ciano-alkik, alkii-szulfonlk, aikíi-szuffönskaíkik anl-szuitonik neteroani-szuifonik, 25 karbamimidöih hldroxi-karbamimidoik·, aikoxi-karbamimidoik, alkil-szulfonil-amino-, aikü-szuifonikamlno-aikik, aikcxi-szulfonlkamino-.. aikoxi-szulfoníl-amlno-aiklt-, heterocikioalklkalkii-amino-karbonik, hidroxi-alkoxi-aikikamino-karbonik·, heteroclkioaikii-karhomk heterocikloalkikkarbonikalkik, heterocikloalkik, hetérocikíoaíkikalkii", oxo-heterocikioaikik, oxo-heterocíkioalkil-aikik, heíeroarík, 30 heteroarajkik ereiden, atkikuíeido-, dialkikureído-, ureido-alkik, alkikureldo-alki!-, dlalkikurétdo-alkiik, tio-ureído-, iio-ureido-alkik -CÖR12 (ahol R12 jelentése alklk, haiogén-alkik, hidroxi-alkih aikoxi-alkll· vagy amíno-aikií-csoport), -(•aikilén)~ COR12 (aböi: R12 jelentése alkil·, halogén-aikik hidroxi-aikil·, alkoxi-alkik vagy amino-alkii-csoport), -CÖNR14RÍS (ahoi R14 jelentése hidrogénatom vagy alklícsoport; és R1S jelentése hidrogénatom, alkil-, hidrcxbalkíl·, alkoxi-aíkil·, aril-, aralkil·. heteroaríl- vagy heíeroaraíkií-csöpori). -{alkiíénj-CÖNR^'R17 (ahol R16 jelentése hidrogénatom, alkil- vagy hidroxi-aikil-csoporí; és R17 jelentése hidrogénatom, alkil-, hidroxí-aíkii-, atkexi-alkil·, aril-, aralkil-, heteroarii- vagy 5 heíeroaraíkíí-csopori), -NR'aR;3 (ahol R18 jelentése hidrogénatom vagy aíkiícsoporí; és R1S jelentése hidrogénatom, alkil-, acíí-, aril-, araiki!-, heterosni-vagy neteroaralkihesoportí,: -Caikiién)- NR20R21 (ahol R20 jelentése hidrogénatom* alkil·· vagy hldroxi-aikil-esopórt; és R21 jelentése hidrogénatom, alkil-, acil-, alkoxi-karhonil-, hidroxi-alki!-, aikoxRalkil-, aril-, aralkil-, heteroarii- vagy heteroaraíkií-10 csoport), -SG2NR22R23 (ahol ff2 jelentése hidrogénatom vagy aikílcsoport is R23 jelentésé nidrogénaíom, aikíh, aril-, aralkil·, heteroarii- vagy heteroaralkíl-Gsoport; vagy R22 és R23 azzal a nitrogénatommal együtt, amelyhez kapcsolódnak heterodkloamino-csoportot képeznék), -(alki!én)-S02HR24R25 (ahol R24 jelentése hidrogénatom vagy alkilOSöpöá; és ! $ R2S jelentése hidrogénatom, alkik aril-, aralkil-, heleroaril- vagy heteroaralkil-csoport: vagy R24 és R28 azzal a nkrogénatommai együtt, amelyhez kapcsolódnak heferödkioamino-csoportot képeznek), -NR^SChNR^R''3 (ahol R28 és R27 jelentése egymástól függetlenül hidrogénatom vagy aikílcsoport; és jelentése 20 hidrogénatom, alkik, aril-, aralkil-, heteroarii- vagy heíerearalkíi-esöport; vagy R27 és R28 azzal a nitrogénatommal együtt, amelyhez kapcsolódnak heterocikloamino-csoportot képeznek), -(alkílénj-lslR^SOsNR^R2,1 (ahol R29 és R30 jeientése egymástól függetlenül hidrogénatom vagy aikílcsoport; és R31 jeientése hidrogénatom, alkil·, ah!-, aralkil-, heteroarii- vagy heteroaralkil-csoport; vagy R^és R35 azzal a 25 nitrogénatommal épül, amelyhez kapcsolódnak heteroclkJoamino-csoportot képeznek), (ahol R32 jelentése hidrogénatom vagy éíkííosepört; és R33 jelentése aíklcsoport) vagy araíkli-csoport; és Rr3 jelentése hidrogénatom; 30 I) adod esetben az R1, R2, R3, R\ Ry, R* és R13 csoport bármelyikének módosításával; (11) adói esetben az egyedi sztereoizomerek elkülönítésével; (iií) adott esetben savadd idős sót kialakításával; és (ív) adott esetben egy szabad bázist kialakításával; 5 ahol az alkíicsoport kifejezés egyenes láncú, teíítettegyérfékö, i--6 szénatomot tartalmazó szénhidrogéncsopörtot vagy elágazó láncú, telített, egyéríékű, 3--8 szénatomottartalmazó szénhidrogéncsoportotjeíent; az alkiiéncscporf kifejezés egyenes láncú, telített, kétértékű, 1-6 szénatomot to tartalmazó szénbldrogéncsoportot vagy elágazó láncú, telített, kétértékű, 3 -8 szénatomot tartalmazó szénbldrogéncsoportot jelent; az aíkii-ilo-csoport kifejezés ~SR csoportot jelent, ahol R jelentése alkllcsoport; az aminocsoport kifejezés -NRR' csoportot plant, ahol R és R' jelentése egymástól függetlenül hidrogénatom, alkil- vagy ~CORa csoport, ahol Ra jelentése ajkílcsoport; az 15 adicsoport kifejezés -CQR’ csoportéi jelent, ahol R’ jelentése alkil-, aikoxí-, haiogén-alkü-, amino-aikii-, hldroxl-alkil- vagy alkoxi-aikil-csoport; az amino-szulfonlbesoport kifejezés csoportot jelent; az aikil-amino-szelfonil·* csoport kifejezés -SÖ-jNHR csoportot jeleni ahol R jelentése alkllcsoport; az áilI-Szoirtmil-csoport kifejezés -fÖgR Csoportot jelent, ahol R jelentése 20 alkílcsoport; az alkíl-szulfonii-aíkíl-csoport kiiejfzéf tepertői jelent, ábol R jelentése alkílcsoport; az alklkszuifonii-aniino-csoport kifejezés ~ NHSOgiR csoportot Jelent, ahol R jelentése alkifcsopört; az alkíí-szulfonil-amino-alkii-csoport kifejezés -{aikilénj-NHSÖzR csoportot jelent, ahol R jelentése alkllcsoport; az aikcxi-szulfonil-amino-csopört kifejezés -NNSO^R csoportot 25 jelent, ahol R jelentése alkoxicsoport; m 81 koxí-szultoní hanii no-a Ikti-csoport kifejezés -{alkilénj-NHSOjR csoportot jélént, adót R jelentése alkoxicsoport; az alkoxicsoport kifejezés ~ÖR csoportot jelent, ahol R jelentése alkilcsopört; az áfkoxi-karböhil-csoport kifejezés -COÖR csoportot jelent, ahol R jelentésé alkilcsopört; az alkoxi-karbonil-alkii--csoport kifejezés -(alkilén)-COOR csoportot :io jelent, ahol R jelentésé alkllcsoport; m alkoxi-alkil-csoporí kifejezés egyenes láncú, egyértékü, 1-8 szénatomot tartalmazó szénhfdfogéncsoportot vagy elágazó láncú, egyértékü, 3-6 szénatomot tartalmazó szénhldmgóncsoprtót jelent, amely szubszíituálva van legalább egy alköxlcsiporttai; az amino-afkil-csoport kifejezés egyenes láncú, egyértékü, 1-8 szénatomot tartalmazó szénhkfrogáncsoportot vagy elágazó láncú, egyértékű, 3-6 szénatomot tartalmazó szénhidrogénesoportot jelent, amely szubszíituáiva van legalább egy csapórttal, ahol R és Rs jelentése egymástól függetlenül hidrogénatom, alkil· vagy -COR3 csoport, ahol Ra jelentése alkilcsoport; az amlno-karbokealii-s csoport kifejezés egyenes láncú, egyértéki, t-6 szénatomot tartalmazó szári híd rogénoseportot vagy elágazó láncú, egyértékű, 3-6 szénatomot tartalmazó szénhidrogéncsoportot jelent, amely szubsztltuálva van egy -fsfRR* és -COOH csoporttal, ahol R és R! jelentése egymástól függetlenül hidrogénatom, alkil- vagy -CGRa csoport, ahol Ra jelentése alkllcsoport; az amino-karbonil-10 karboxbalkll-csoport kifejezés egyenes láncú, egyértékű, 1-6 szénatomot tartalmazó szénhidrogéncsoportot vagy elágazó láncé, egyértékű, 3-8 szénatomot tartalmazó szénéIdrogéhcsöjpöidldl.léiiót; amely szubsztltuálva van egy wÖCjNRR' és -CÖÖH csoporttal, ahol R és R’ jelentése egymástól függetlenül hidrogénatom, alkil- vagy -COR3 csoport, ahol Ra jelentése alkllcsoport; az 15 amino-karbonikalkiscsoport kifejezés egyenes iáncú, egyértékű, 1 -6 szénatomot tartalmazó szén h idrogén cső portot vagy elágazó láncú, egyértékű, 3-6 szénatomot tartalmazó szénhidrogéncsoportot Jelent, amely szuhszfituálva van egy vagy két ^ONRR’ csoporttal, ahol R és R' Jelentése egymástól függetlenül hidrogénatom, alkil- vágy ~CORa csoport, ahol R® jelentése alkllcsoport; az 20 alkoxi-aíkíloxi-csoport kiefezés -ÖR csoportot Jelent, ahol R jelentése aikoxi-afkil· csoport; az amíno-alkio)d~csoport kifejezés -ÖR csoportot jelent, ahol R jelentése amino-alk í i-csoport; az amino-karboniΙ-csoport kifejezés -CGNHa csoportot jelent; az amino-karbonü-alkiloxi-csoport kifejezés -ö-alkilén-CGNRR! csoportot jelent, ahol R és R" jelentése egymástól függetlenül hidrogénatom vagy alkilcsoport; az 25 amino-karhonii-alkll-csoport kifejezés “Calkilénj-CQNH:? csoportot jelent; az alkil-ureldp^csoport kifejezés -NRCONHR* csoportot jelent, ahol R jelentése hidrogénatom vagy alkilcsoport, és R* jelentése alkllcsoport; az alkH-ureido-afkii-csoport kifejezés -{alkilénj-NRCONHR1 csoportot jelent, ahol R jelentése hidmgénaíem vagy alkilcsoport, és R’ jelentése alkllcsoport; az árucsoport 30 kifejezés egyértékű, monoeíklusos vagy biciklusos, aromás, 8-12 gyürűatomot tartalmazó szénhidrogéncsoportot jelent, amely adott esetben egymástól függelenilszübsztltüálva lehet a következik közül választott egy vagy több szubszltuenssei; alkil-, haiogén-alkil·, alkoxl· aíkii-ίίο-, halogén-, nitro- -COR |ahol R jelentése alkilcssport}, ciano-, amino-, alkil-amino-, dialkihamino-, hidroxi!-, karboxi)- vagy -CÖÖI^ csoport, ahol R jelentése aiksicsoport; az aril-szulfoníl-csoport kifejezés -SO^R csoportot jeleni, ahol R jelentése árucsoport; az amlklí-csoport kifejezés -(aíkiiénj-R csoportot jelent, ahol R jelentése árucsoport; az alkoxókarbamímidoü-csoport kifejezés ~€{~NH)NHÖR vagy -C(~í\íOR}NH2 5 csoportot jelent, ahol R jelentése alkiícsoport; a clkioalkil-csoport kifejezés ciklusos, Ipihei, egyértékű, 3 -6 szénatomot tartalmazó szénhidrogéncsopori jelent; a karfeoxi-atkikesoport kifejezés -{aíkiiém-COOH csoportot jelent; a karböxs-aíkiíoxí-csGpürt kifejezés ~ö~{alkiíén)'COOH csoportot jelent; a karbamimldoií-esoport kifejezés ~C{~NH)NH2 csoportot jelent a ciano-alkli-m csoport kifejezés -(aikiíénj-CN csoportot jeleni; a diaíkil-amsno-szuifoniécsopori kifejezés -SÖjNRR* csoportot jelent, ahol R és R* jelentése egymástól függetlenül alkiícsoport; a dlalkil-ureido-csoport kifejezés -NRCONR^* csoportot jelent, ahol R jelentése hidrogénatom vagy alkiícsoport;, és R! és R” jelentése egymástól függetlenül alkiícsoport; a díalkil-ureido-aíkíí-csöport kifejezés -15 {aikilénj-NRCÖMR’R” csoportot jelent, ahol R jelentése hidrogénatom vagy álkilcsopcrt, és R’ és R" jelentése egymástól függetlenül alkiícsoport; a guanidino-aikil-Gsoport kifejezés egyenes láncé, egyértékű, 1-6 szénatomot tartalmazó szén hidrogén csoportot vagy elágazó láncú, egyértékű, 3-6 sZépatomot tartalmazó szénhidrogéncsoportot jelent, amely szubsztítuálva van >o legalább egy ~NRC(NRRS}NRR' csoporttal, ahol R és R' jeteriise egymástól függetlenül hidrogénatom, aikil- vagy -C0R3 csoport, ahol Rs jelentése alkiícsoport; a halogén-csoport kifejezés fluor-, klór-, bróm~ és jodcsoportot jelent; a halegén-atkiNsoport kifejezés alklicsoportot jelent, amely szubsztítuálva van egy vagy tdbb halogénatommel; a halogén-alkoxi-csoport kifejezés -OR 25 csoportot Jelent, ahol R jelentése haíogén-aíkií-csöporl; a hidroxi-aikil-csoport kifejezés egyenes láncú, egyértékű, 1-8 szénatomot tartalmazó szénbidrogénosGportdí vagy elágazó láncú, egyértékű, 3-8 szénatomot tartalmazó szén hid rogéncsoportot jele nt, amely szubsztítuálva van 1-5 hídroxílcsoporttak azzal a megkötéssel, hogy ha két hidroxílcsoport van jelén, 30 azok nem ugyanahhoz a szénatomhoz kapcsolódnak; a hidroxí-alklloxi-csoport kifejezés -0R csoportot jelent, ahol R jelentése hidroxbaíkihcsopori; a hldroxi-aikoxi-alkil-amino-karbonii-csopori kifejezés -CORH-(alkllén}-ö~{alkilén}OH csoportot jeienl; a heterocikloalkii-csoport kifejezés teli lei! vagy telítetlen, egyértékű, ciklusos csoportot jelent, amelynek 3-8 gyűröatomja közül egy vagy kettő györöatöm a kővetkezők közöl választott heteroatónv. N, O vagy S(0}n, ahol n jelentése ö és 2 közötti eg ész szám, a tovább! gyurüatemok pedig C atomok; a heíéröcikloaikii-kartjonikcsoport kifejezés -CÖR csoportot jelent, ahol R jelentése heteroclkioaikil-csoport; a heteroclklloalkil-karbonil-aikil-csopGrt 5 kifejezés -(alkiSénVCÖR csoportot jelent, ahol R jelentése heterocikloaikil- csoport; a heterocíklöalkii-alkli-GSOpOft kifejezés -(aikliénj-R csoportot jelent, ahol R jelentése heteröeikloalkGcsoport; a heterodkioalkikalkíi-amino-kafbonii-csoport kifejezés -GÖNH-(a!kfíén;hR csoportot jelent, aho! R jelentése heterocikloalkii-esoport; a heleroarihcsoport kifejezés olyan egyértékö, to monodklusos vagy biolkiusos, aromás csoportot jeleni, amelynek 5-Ί ö gyürűatomja közül egy vagy több a következők közöl választott heíeroatorn: N, Ö vagy §, a további gyürüatömök pedig szénatomok, a betefoaiikgyörü adott esetben szubsztiluáiva van a következők közöl egymástól függetlenül választott egy vagy több szubsztituenssel: SlkiS-, halogén-alkil-, alkoxh aíkií-tio-, amino-15 alklh guanidíno-aíkih halogén-, nitro-, ciano-, amino-, aikik dlalkikarnino-, hldroxli-, karboxii- vagy -COOR csoport, ahol R jelentése; aíkitesopertpa heteroari i-szuIfoni 1-csoporí kifejezés -SOgR csoportot jelent, ahol R jelentése heieroarihcsöport; a heteroaraikiS-csoport kifejezés -{aikilénVR csoportot jelent, abol R jelentése heteroaril-csoport; a heterodkioamino-csoport kifejezés olyan 20 téliéit vagy telítetlen, egyértékű,, olldösoscsoportot jelent, amelynek 3-8 gyürűatomja közül egy vagy kettő a kővetkezők közül választott heieroalom: M, ö vagy spjn, ahol n jelentése 0 és 2 közötti egész szám, a további gyürüatömök pedig G atomok, azzal a megkötéssel, hogy a heteroatomok közül legalább egy nirogénatom, és ahol egy vagy két szénatom adott esetben 25 szubsztituáiva van egy karbonHcsoportfal, a heterocikloanilno-gyCírü pedig adott esetben szubsztituáiva van a következők közül egymástól függetlenül választott egy vagy több szubsztitueossel: aikil-, hidroxil-, bidroxkaikil-, alkoxi-, alkoxi-alkil··, smino-alkih guanidtno-afkib, balogén-, halogén-atkil-, ani-t heteroaril-, araik)!-, heterearalklk, halogén-alkil», halogén-, ciano-, karboxii-, -CONRaRb (ahol Rs és 30 R&amp; jelentése egymástól függetlenül hidrogénatom vagy alkiicsoport} vagy -CÖOR csoport, ahol R jelentése alkiicsoport; a hidroxi-karbamimidoil-csopDrt kifejezés -G|=NldpblDH vagy -Cf-NÖHjNHs csoportot jelent.
HUE03810056A 2002-12-03 2003-12-03 VIIA faktor inhibitor 2-(2-hidroxi-bifenil-3-il)-1H-benzoimidazol-5-karboxamidin-származékok HUE025683T2 (hu)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US43098102P 2002-12-03 2002-12-03

Publications (1)

Publication Number Publication Date
HUE025683T2 true HUE025683T2 (hu) 2016-04-28

Family

ID=32469576

Family Applications (1)

Application Number Title Priority Date Filing Date
HUE03810056A HUE025683T2 (hu) 2002-12-03 2003-12-03 VIIA faktor inhibitor 2-(2-hidroxi-bifenil-3-il)-1H-benzoimidazol-5-karboxamidin-származékok

Country Status (12)

Country Link
US (5) US7479502B2 (hu)
EP (2) EP2982668A3 (hu)
JP (3) JP4744149B2 (hu)
CN (1) CN100513398C (hu)
AU (1) AU2003302238A1 (hu)
CA (1) CA2507707C (hu)
DK (1) DK1569912T3 (hu)
ES (1) ES2543588T3 (hu)
HU (1) HUE025683T2 (hu)
PT (1) PT1569912E (hu)
SI (1) SI1569912T1 (hu)
WO (1) WO2004050637A2 (hu)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7479502B2 (en) 2002-12-03 2009-01-20 Pharmacyclics, Inc. 2-(2-hydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors
US7129264B2 (en) 2003-04-16 2006-10-31 Bristol-Myers Squibb Company Biarylmethyl indolines and indoles as antithromboembolic agents
EP1656158B1 (en) 2003-08-14 2016-03-09 Novo Nordisk Health Care AG Liquid, aqueous pharmaceutical composition of factor vii polypeptides
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
US8729117B2 (en) 2004-06-02 2014-05-20 Pharmacyclics, Inc. Factor VIIa inhibitor
CN1976903A (zh) * 2004-06-02 2007-06-06 法莫西克立克斯公司 因子VⅡa抑制剂
CN102417484A (zh) * 2004-06-02 2012-04-18 法莫西克立克斯公司 因子VIIa抑制剂
WO2006076575A2 (en) 2005-01-13 2006-07-20 Bristol-Myers Squibb Company Substituted biaryl compounds as factor xia inhibitors
JP5406525B2 (ja) * 2005-07-04 2014-02-05 ツァナン・サイテック・カンパニー・リミテッド ルテニウム錯体配位子、ルテニウム錯体、固定化ルテニウム錯体触媒及びその調製方法と用途
US20100285516A1 (en) * 2007-04-13 2010-11-11 Pharmacyclics, Inc. Calcium flux as a pharmacoefficacy biomarker for inhibitors of histone deacetylase
CN102015606B (zh) 2007-06-08 2015-02-04 满康德股份有限公司 IRE-1α抑制剂
EA201370191A1 (ru) 2007-10-16 2014-05-30 Фармасайкликс, Инк. КОМПОЗИЦИИ, СОДЕРЖАЩИЕ МОДУЛЯТОРЫ ФАКТОРА КОАГУЛЯЦИИ VIIa, И ИХ ПРИМЕНЕНИЕ
CN101903355B (zh) * 2007-12-17 2014-05-14 霍夫曼-拉罗奇有限公司 咪唑取代的芳基酰胺
WO2014057069A1 (en) * 2012-10-10 2014-04-17 Novo Nordisk Health Care Ag Liquid pharmaceutical composition of factor vii polypeptide
FR2996845A1 (fr) * 2012-10-12 2014-04-18 Servier Lab Nouveau procede de synthese du 3-(2-bromo-4,5-dimethoxyphenyl)propanenitrile, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
WO2016094260A1 (en) * 2014-12-10 2016-06-16 Merck Sharp & Dohme Corp. Factor ixa inhibitors
TW201838974A (zh) 2017-04-19 2018-11-01 印度商Ｐｉ工業公司 具殺菌性質之雜環化合物
WO2019048988A1 (en) 2017-09-08 2019-03-14 Pi Industries Ltd. NOVEL FUNGICIDE HETEROCYCLIC COMPOUNDS
CN111655687A (zh) 2017-09-08 2020-09-11 Pi工业有限公司 新型杀真菌杂环化合物
UY38940A (es) 2019-11-11 2021-06-30 Pi Industries Ltd Nuevas piridiniloxi piperidiniletanonas sustituidas
AR120376A1 (es) 2019-11-11 2022-02-09 Pi Industries Ltd Heteroaril piperidiniletanonas sustituidas con actividad fungicida
AR120377A1 (es) 2019-11-11 2022-02-09 Pi Industries Ltd Derivados heteroaromáticos de sulfiliminas o sulfoximinas con actividad fungicida
CN113683480B (zh) * 2021-08-28 2024-02-27 山东三牧新材料科技有限公司 一种4-乙基苄氯的制备方法
CN114195640B (zh) * 2021-12-27 2024-03-12 攀枝花学院 羟基酪醇及其中间体的合成工艺

Family Cites Families (245)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
EP0139773B1 (de) * 1983-10-19 1987-01-21 GebràœDer Sulzer Aktiengesellschaft Schwingungsisolierende und -dämpfende Lagerung einer Webmaschine
CA2024697A1 (en) 1989-09-07 1991-03-08 George P. Vlasuk Protein having anticoagulant properties
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
IL102758A (en) 1991-08-23 1997-03-18 Akzo Nv Glycosaminoglycanoid derivatives, their preparation and pharmaceutical compositions comprising them
ZA928276B (en) 1991-10-31 1993-05-06 Daiichi Seiyaku Co Aromatic amidine derivates and salts thereof.
DE69321344D1 (de) 1992-02-14 1998-11-05 Corvas Int Inc Inhibitoren der thrombose
US5492895A (en) 1992-02-14 1996-02-20 Corvas International, Inc. Inhibitors of thrombosis
CA2151044A1 (en) 1992-12-15 1994-06-23 Terence K. Brunck Novel inhibitors for factor xa
US5563127A (en) 1993-03-24 1996-10-08 The Dupont Merck Pharmaceutical Company Boronic acid and ester inhibitors of thrombin
US5656600A (en) 1993-03-25 1997-08-12 Corvas International, Inc. α-ketoamide derivatives as inhibitors of thrombosis
US5863534A (en) 1993-04-09 1999-01-26 Bio-Technology General Corp. Polypeptide having factor Xa inhibitory method of reducing blood coagulation with a novel polypeptide having factor Xa inhibitory activity
JP3388803B2 (ja) 1993-05-20 2003-03-24 第一製薬株式会社 光学活性７−アミジノナフタレン誘導体の製造法
SE9301916D0 (sv) 1993-06-03 1993-06-03 Ab Astra New peptides derivatives
US5681844A (en) 1994-04-18 1997-10-28 Corvas International, Inc. Methionine sulfone and s-substituted cysteine sulfone derivatives as enzyme inhibitors
CN1181091C (zh) 1994-04-26 2004-12-22 西莱克泰德公司 因子Xa抑制剂
US5561146A (en) 1994-06-10 1996-10-01 Bristol-Myers Squibb Company Modified guanidino and amidino thrombin inhibitors
US5633381A (en) 1994-07-05 1997-05-27 Berlex Laboratories, Inc. (Z,Z), (Z,E) and (E,Z) isomers of substituted bis(phenylmethylene)cycloketones
IL115420A0 (en) 1994-09-26 1995-12-31 Zeneca Ltd Aminoheterocyclic derivatives
ATE346928T1 (de) 1994-10-18 2006-12-15 Dendreon Corp Aus nematoden extrahierte serinprotease- inhibitoren und die koagulation hemmende proteine
SE504185C2 (sv) 1994-11-08 1996-12-02 Astra Ab Lagringsstabil vattenlösning för infusion av trombininhibitorer
SE9404196D0 (sv) 1994-12-02 1994-12-02 Astra Ab New antithrombotic formulation
ES2193202T3 (es) 1994-12-02 2003-11-01 Yamanouchi Pharma Co Ltd Nuevo derivado de amidinonaftilo o sal de este.
BR9509994A (pt) 1994-12-13 1997-12-30 Corvas Int Inc Derivados heterocíclicos aromáticos como inibidores de enzimas
US5656645A (en) 1994-12-13 1997-08-12 Corvas International, Inc. Aromatic heterocyclic derivatives as enzyme inhibitors
US5658930A (en) 1994-12-13 1997-08-19 Corvas International, Inc. Aromatic heterocyclic derivatives as enzyme inhibitors
US6025472A (en) 1994-12-21 2000-02-15 Corvas International, Inc. N-substituted glycine derivatives as enzyme inhibitors
DE59610771D1 (de) 1995-02-27 2003-11-20 Hoffmann La Roche Dioxopyrrolo-pyrrolderivate
DK0813525T3 (da) 1995-03-10 2004-02-16 Berlex Lab Benzamidinderivater, deres fremstilling og anvendelse som antikoagulanter
US5639739A (en) 1995-03-24 1997-06-17 The Dupont Merck Pharmaceutical Company Imidazole containing aminoboronic acids
US5612363A (en) 1995-06-02 1997-03-18 Berlex Laboratories, Inc. N,N-di(aryl) cyclic urea derivatives as anti-coagulants
US5612378A (en) 1995-06-06 1997-03-18 3-Dimensional Pharmaceuticals, Inc. Bis-arylsulfonylaminobenzamide derivatives and the use thereof as factor Xa inhibitors
US5919765A (en) 1995-06-07 1999-07-06 Cor Therapeutics, Inc. Inhibitors of factor XA
US5612353A (en) 1995-06-07 1997-03-18 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
US6069130A (en) 1995-06-07 2000-05-30 Cor Therapeutics, Inc. Ketoheterocyclic inhibitors of factor Xa
US5741819A (en) 1995-06-07 1998-04-21 3-Dimensional Pharmaceuticals, Inc. Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
US6034093A (en) 1995-06-07 2000-03-07 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
US5731315A (en) 1995-06-07 1998-03-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted sulfonic acid n- (aminoiminomethyl)phenylalkyl!-azaheterocyclamide compounds
US5721214A (en) 1995-06-07 1998-02-24 Cor Therapeutics, Inc. Inhibitors of factor Xa
GB9515489D0 (en) 1995-07-28 1995-09-27 Sandoz Ltd Organic compounds
DE19530996A1 (de) 1995-08-23 1997-02-27 Boehringer Mannheim Gmbh Cyclische Guanidine, Verfahren zu ihrer Herstellung und Arzneimittel
EP0859607B1 (en) 1995-09-29 2002-12-18 3-Dimensional Pharmaceuticals, Inc. Guanidino protease inhibitors
US5849759A (en) 1995-12-08 1998-12-15 Berlex Laboratories, Inc. Naphthyl-substituted benzimidazole derivatives as anti-coagulants
AU717995B2 (en) 1995-12-20 2000-04-06 Aventis Pharmaceuticals Inc. Novel process for preparing N-acetyl(L)-4-cyanophenylalanine Ac-(l)-Phe(4-CN)-OH and N-Acetyl-(L)-p-amidinophenylalanine -cyclohexylglycine-beta-(3-N-methylpyridinium)-alanine Ac- (L)-pAph-Cgh-PalMe(3)-NH2
EP0874629B1 (en) 1995-12-21 2004-05-19 Bristol-Myers Squibb Pharma Company ISOXAZOLINE, ISOTHIAZOLINE AND PYRAZOLINE FACTOR Xa INHIBITORS
AR005245A1 (es) 1995-12-21 1999-04-28 Astrazeneca Ab Prodrogas de inhibidores de trombina, una formulación farmaceutica que las comprende, el uso de dichas prodrogas para la manufactura de un medicamento y un procedimiento para su preparacion
CA2256309C (en) 1995-12-29 2006-08-15 3-Dimensional Pharmaceuticals, Inc. Amidino protease inhibitors
RO117913B1 (ro) 1996-01-02 2002-09-30 Aventis Pharmaceuticals Inc. Derivaţi de n-[(amino-(imino)metil)fenil]propil amide substituite, compoziţie farmaceutică care îi conţine şi metodă de tratament
US6080767A (en) 1996-01-02 2000-06-27 Aventis Pharmaceuticals Products Inc. Substituted n-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides
GB9602166D0 (en) 1996-02-02 1996-04-03 Zeneca Ltd Aminoheterocyclic derivatives
GB9602294D0 (en) 1996-02-05 1996-04-03 Zeneca Ltd Heterocyclic compounds
US5994375A (en) 1996-02-12 1999-11-30 Berlex Laboratories, Inc. Benzamidine derivatives substituted by amino acid and hydroxy acid derivatives and their use as anti-coagulants
CN1212706A (zh) 1996-02-13 1999-03-31 阿克佐诺贝尔公司 丝氨酸蛋白酶抑制剂
EP0892780B1 (en) 1996-02-22 2002-11-20 Bristol-Myers Squibb Pharma Company M-AMIDINO PHENYL ANALOGS AS FACTOR Xa INHIBITORS
EP0906091B1 (en) 1996-03-29 2006-10-04 Ortho-McNeil Pharmaceuticals, Inc. Amidinohydrazones as protease inhibitors
DE19612828C1 (de) 1996-03-30 1997-02-27 Boehringer Mannheim Gmbh Verfahren zur Herstellung von Naphthonitrilderivaten und deren Verwendung zur Herstellung von Faktor-Xa-Inhibitoren
FR2754260B1 (fr) * 1996-10-04 1998-10-30 Adir Nouveaux derives substitues de biphenyle ou de phenylpyridine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
ES2218677T3 (es) 1996-04-17 2004-11-16 Bristol-Myers Squibb Pharma Company Derivados de n-(amidinofenil)-n'-(subst.)-3h-2,4-benzodiazepin-3-ona como inhibidores del factor xa.
SE9601556D0 (sv) 1996-04-24 1996-04-24 Astra Ab New pharmaceutical formulation of a thrombin inhibitor for parenteral use
SE9602145D0 (sv) 1996-05-31 1996-05-31 Astra Ab New improved formulation for treatment of thromboembolism
HU224315B1 (hu) 1996-06-05 2005-07-28 Gyógyszerkutató Intézet Kft. Véralvadásgátló hatású peptidil-arginin-aldehid-származékok és a vegyületeket tartalmazó gyógyszerkészítmények
HU222199B1 (hu) 1996-06-05 2003-05-28 Gyógyszerkutató Intézet Kft. Véralvadásgátló hatású peptid-aldehid-származékok és a vegyületeket tartalmazó gyógyszerkészítmények
JPH101467A (ja) 1996-06-13 1998-01-06 Banyu Pharmaceut Co Ltd ビフェニルアミジン誘導体
US6124291A (en) 1996-06-18 2000-09-26 Warner-Lambert Company Pyrrolo[1,2-a]pyrazine-1,4-dione serine protease inhibitors
JP2000513354A (ja) 1996-06-18 2000-10-10 ワーナー―ランバート・コンパニー キラルな塩基性アミノ酸ケト―複素環化合物の製造方法
US6200967B1 (en) 1996-06-25 2001-03-13 Eli Lilly And Company Anticoagulant agents
JPH1017549A (ja) 1996-07-02 1998-01-20 Banyu Pharmaceut Co Ltd 二環性芳香族アミジン誘導体
WO1998001428A1 (en) 1996-07-08 1998-01-15 Du Pont Pharmaceuticals Company AMIDINOINDOLES, AMIDINOAZOLES, AND ANALOGS THEREOF AS INHIBITORS OF FACTOR Xa AND OF THROMBIN
US6057342A (en) 1996-08-16 2000-05-02 Dupont Pharmaceutical Co. Amidinophenyl-pyrrolidines, -pyrrolines, and -isoxazolidines and derivatives thereof
US5753635A (en) 1996-08-16 1998-05-19 Berlex Laboratories, Inc. Purine derivatives and their use as anti-coagulants
ATE230392T1 (de) 1996-08-16 2003-01-15 Bristol Myers Squibb Pharma Co Amidinophenyl-pyrrolidine, -pyrroline und - isoxazolidine und ihre derivate
US5693641A (en) 1996-08-16 1997-12-02 Berlex Laboratories Inc. Bicyclic pyrimidine derivatives and their use as anti-coagulants
AU4172397A (en) 1996-09-06 1998-03-26 Biochem Pharma Inc. Lactam inhibitors of thrombin
PT929547E (pt) 1996-09-12 2003-03-31 Schering Ag Derivados da benzamidina substituidos por derivados de aminoacidos ciclicos e de hidroxiacidos ciclicos e seu uso como anticoagulantes
US6004985A (en) 1996-10-09 1999-12-21 Berlex Laboratories, Inc. Thio acid derived monocylic N-heterocyclics as anticoagulants
WO1998016547A1 (en) 1996-10-11 1998-04-23 Cor Therapeutics, Inc. SELECTIVE FACTOR Xa INHIBITORS
SE9603724D0 (sv) 1996-10-11 1996-10-11 Astra Ab New pharmaceutical parenteral formulation of a thrombin inhibitor
WO1998016524A1 (en) 1996-10-11 1998-04-23 Cor Therapeutics, Inc. HETEROCYCLIC DERIVATIVES AS FACTOR Xa INHIBITORS
CA2268281A1 (en) 1996-10-11 1998-04-23 Cor Therapeutics, Inc. Selective factor xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
JP2001502674A (ja) 1996-10-11 2001-02-27 シーオーアール・セラピューティックス・インコーポレーテッド 選択的Ｘａ因子阻害物質
UA56197C2 (uk) 1996-11-08 2003-05-15 Зенека Лімітед Гетероциклічні похідні
EP0842941A1 (de) 1996-11-16 1998-05-20 Roche Diagnostics GmbH Neue Phosphonate, Verfahren zu ihrer Herstellung und Arzneimittel
US6602864B1 (en) 1996-12-13 2003-08-05 Aventis Pharma Deutschland Gmbh Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds
AU726637B2 (en) 1996-12-13 2000-11-16 Aventis Pharmaceuticals Inc. Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds
WO1998028282A2 (en) 1996-12-23 1998-07-02 Du Pont Pharmaceuticals Company OXYGEN OR SULFUR CONTAINING 5-MEMBERED HETEROAROMATICS AS FACTOR Xa INHIBITORS
US6020357A (en) 1996-12-23 2000-02-01 Dupont Pharmaceuticals Company Nitrogen containing heteroaromatics as factor Xa inhibitors
EA003056B1 (ru) 1996-12-23 2002-12-26 Дюпон Фармасьютикалз Компани АЗОТСОДЕРЖАЩИЕ ГЕТЕРОАРОМАТИЧЕСКИЕ СОЕДИНЕНИЯ В КАЧЕСТВЕ ИНГИБИТОРОВ ФАКТОРА Ха, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И СПОСОБ ЛЕЧЕНИЯ
TW542822B (en) 1997-01-17 2003-07-21 Ajinomoto Kk Benzamidine derivatives
WO1998046591A1 (en) 1997-04-14 1998-10-22 Cor Therapeutics, Inc. SELECTIVE FACTOR Xa INHIBITORS
US6133256A (en) 1997-04-14 2000-10-17 Cor Therapeutics Inc Selective factor Xa inhibitors
EP0977773A1 (en) 1997-04-14 2000-02-09 Cor Therapeutics, Inc. SELECTIVE FACTOR Xa INHIBITORS
NZ500353A (en) 1997-04-14 2002-02-01 Cor Therapeutics Inc Cyclic diaza compounds that are selective inhibitors of factor Xa
CA2289625A1 (en) 1997-05-15 1998-11-19 Charles Van Jackson Antithrombotic compound
TW513402B (en) 1997-05-30 2002-12-11 Daiichi Seiyaku Co Process for preparing 3-(7-amidino-2-naphthyl)-2-phenylpropionic acid derivatives
WO1998054164A1 (en) 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US20010046974A1 (en) 1997-06-06 2001-11-29 Hamilton Civic Hospitals Res Dev., Inc. Modified low molecular weight heparin that inhibits clot associated coagulation factors
US6060491A (en) 1997-06-19 2000-05-09 Dupont Pharmaceuticals 6-membered aromatics as factor Xa inhibitors
ES2239806T3 (es) 1997-06-19 2005-10-01 Bristol-Myers Squibb Pharma Company Inhibidores del factor xa con un grupo de especificidad neutro p1.
AU7976998A (en) 1997-06-19 1999-01-04 Du Pont Merck Pharmaceutical Company, The (amidino)6-membered aromatics as factor xa inhibitors
ZA985247B (en) 1997-06-19 1999-12-17 Du Pont Merck Pharma Guanidine mimics as factor Xa inhibitors.
US6339099B1 (en) 1997-06-20 2002-01-15 Dupont Pharmaceuticals Company Guanidine mimics as factor Xa inhibitors
JP2002506462A (ja) 1997-06-26 2002-02-26 イーライ・リリー・アンド・カンパニー 抗血栓物質
US6372759B1 (en) 1997-06-26 2002-04-16 Eli Lilly And Company Antithrombotic agents
WO1999000121A1 (en) 1997-06-26 1999-01-07 Eli Lilly And Company Antithrombotic agents
JP2002510313A (ja) 1997-06-26 2002-04-02 イーライ・リリー・アンド・カンパニー 抗血栓物質
AU735144B2 (en) 1997-07-23 2001-07-05 Yamanouchi Pharmaceutical Co., Ltd. Novel hexahydro-1,4-diazepine derivatives or their salts
GB9715894D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic derivatives
GB9715895D0 (en) 1997-07-29 1997-10-01 Zeneca Ltd Heterocyclic compounds
JP2001515842A (ja) 1997-08-11 2001-09-25 シーオーアール セラピューティクス インコーポレイテッド 選択的Ｘａ因子阻害剤
NZ502877A (en) 1997-08-11 2001-11-30 Cor Therapeutics Inc Bicyclic aryl azepinone selective factor Xa inhibitors for treating thrombosis related diseases
NZ502803A (en) 1997-08-11 2001-11-30 Cor Therapeutics Inc Selective factor Xa inhibitors for treating diseases such as angina, myocardial infarction, transient ischemic attacks or diseases associated with undesired thrombosis
US5886191A (en) 1997-08-18 1999-03-23 Dupont Pharmaceuticals Company Amidinoindoles, amidinoazoles, and analogs thereof
IL134394A0 (en) 1997-08-27 2001-04-30 Kissei Pharmaceutical 3-amidinoaniline derivatives, activated blood coagulation factor x inhibitors, and intermediates for producing both
US6262069B1 (en) 1997-08-29 2001-07-17 Protherics Molecular Design Limited 1-amino-7-isoquinoline derivatives as serine protease inhibitors
US6740682B2 (en) 1997-08-29 2004-05-25 Tularik Limited Meta-benzamidine derivatives as serine protease inhibitors
WO1999011617A1 (fr) 1997-09-01 1999-03-11 Yamanouchi Pharmaceutical Co., Ltd. Nouveaux derives de naphtamide et sels de ces derives
ATE266636T1 (de) 1997-09-09 2004-05-15 Bristol Myers Squibb Pharma Co Benzimidazolinone, benzoxazolinone, benzopiperazinone, indanone und deren derivate als faktor xa inhibitoren
GB9719161D0 (en) 1997-09-09 1997-11-12 Glaxo Group Ltd New therapeutic method
IL135180A0 (en) 1997-09-30 2001-05-20 Daiichi Seiyaku Co Sulfonyl derivatives
DE19743435A1 (de) 1997-10-01 1999-04-08 Merck Patent Gmbh Benzamidinderivate
US6693075B1 (en) 1997-10-23 2004-02-17 Regents Of The University Of Minnesota Modified vitamin K-dependent polypeptides
JPH11140040A (ja) 1997-11-06 1999-05-25 Kissei Pharmaceut Co Ltd ３−アミジノフェニルエーテル誘導体、活性化血液凝固第ｘ因子阻害剤およびそれらの製造中間体
IL126893A (en) 1997-11-19 2003-05-29 Akzo Nobel Nv Sulfated pentasaccharide derivatives and pharmaceutical compositions containing them
JPH11152269A (ja) 1997-11-20 1999-06-08 Teijin Ltd ビフェニルアミジン誘導体
AU736112B2 (en) 1997-11-20 2001-07-26 Teijin Limited Biphenylamidine derivatives
ID24846A (id) 1997-11-20 2000-08-24 Teijin Ltd Turunan-turunan bifenilamidina
US6150379A (en) 1997-11-26 2000-11-21 Axys Pharmaceuticals, Inc. Compounds and compositions as anticoagulants
AU1608399A (en) 1997-11-26 1999-06-15 Axys Pharmaceuticals, Inc. Substituted amidinoaryl derivatives and their use as anticoagulants
WO1999026932A1 (en) 1997-11-26 1999-06-03 Axys Pharmaceuticals, Inc. By amidino group substituted heterocyclic derivatives and their use as anticoagulants
WO1999026926A1 (en) 1997-11-26 1999-06-03 3-Dimensional Pharmaceuticals, Inc. Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors
SE9704401D0 (sv) 1997-11-28 1997-11-28 Astra Ab Matrix pellets for greasy, oily or sticky drug substances
SE9704400D0 (sv) 1997-11-28 1997-11-28 Astra Ab Porous inorganic particles as carriers for drug substances
US6686364B2 (en) 1997-12-08 2004-02-03 Berlex Laboratories, Inc. Benzamidine derivatives and their use as anti-coagulants
DE19755268A1 (de) 1997-12-12 1999-06-17 Merck Patent Gmbh Benzamidinderivate
US6140351A (en) 1997-12-19 2000-10-31 Berlex Laboratories, Inc. Ortho-anthranilamide derivatives as anti-coagulants
RU2226529C2 (ru) 1997-12-19 2004-04-10 Шеринг Акциенгезельшафт Производные ортоантраниламида в качестве антикоагулянтов, фармацевтическая композиция и способ лечения
BR9813835A (pt) 1997-12-22 2000-10-10 Du Pont Pharm Co Composto, composição farmacêutica e método de tratamento ou prevenção de uma desordem tromboembólica
US6271237B1 (en) 1997-12-22 2001-08-07 Dupont Pharmaceuticals Company Nitrogen containing heteromatics with ortho-substituted P1s as factor Xa inhabitors
RU2225397C2 (ru) 1997-12-24 2004-03-10 Авентис Фарма Дойчланд Гмбх Производные индола как ингибиторы фактора Ха
EP1043020A1 (en) 1997-12-25 2000-10-11 Daiichi Pharmaceutical Co., Ltd. Medicinal composition for percutaneous administration
AU1692399A (en) 1997-12-26 1999-07-19 Mochida Pharmaceutical Co., Ltd. Aromatic compounds having cyclic amino or salts thereof
FR2773801B1 (fr) 1998-01-19 2000-05-12 Sanofi Sa Nouveaux pentasaccharides, procedes pour leurs preparations et compositions pharmaceutiques les contenant
AU2074699A (en) 1998-01-26 1999-08-09 Yamanouchi Pharmaceutical Co., Ltd. Novel benzene-fused heterocyclic derivatives or salts thereof
KR20010034442A (ko) 1998-01-27 2001-04-25 아벤티스 파마슈티칼즈 프로덕츠 인코포레이티드 치환된 옥소아자헤테로사이클릴 인자 Ｘａ 억제제
EP1060166A1 (de) 1998-02-03 2000-12-20 Boehringer Ingelheim Pharma KG 5-gliedrige benzokondensierte heterocyclen als antithrombotika
EP1054005A4 (en) 1998-02-05 2003-02-05 Takeda Chemical Industries Ltd SULFAMIDE DERIVATIVES, THEIR PRODUCTION PROCESS AND THEIR USE
JP2000204081A (ja) 1998-02-05 2000-07-25 Takeda Chem Ind Ltd スルホンアミド誘導体、その製造法及び用途
EP0937723A1 (de) 1998-02-18 1999-08-25 Roche Diagnostics GmbH Neue Sulfonamide, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel
EP0937711A1 (de) 1998-02-18 1999-08-25 Roche Diagnostics GmbH Neue Thiobenzamide, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel
EP1065200A4 (en) 1998-03-19 2003-01-02 Ajinomoto Kk Aminoisoquinoline DERIVATIVES
JP4495339B2 (ja) 1998-03-23 2010-07-07 アベンティス・ファーマスーティカルズ・インコーポレイテツド ピペリジニルおよびｎ−アミジノピペリジニル誘導体
JP2002509924A (ja) 1998-03-27 2002-04-02 デュポン ファーマシューティカルズ カンパニー 第Ｘａ因子阻害剤としてのジ置換ピラゾリン類およびトリアゾリン類
BR9815784A (pt) 1998-03-31 2000-11-21 Warner Lambert Co Benzoxazinonas/benzotiazinonas como inibidores de protease de serina
US6855726B1 (en) 1998-03-31 2005-02-15 Warner-Lambert Company Llc Quinolones as serine protease inhibitors
JP2002509923A (ja) 1998-03-31 2002-04-02 ワーナー−ランバート・カンパニー Ｘａ因子およびトロンビンのようなセリンプロテアーゼ阻害剤としてのキノキサリノン
US6344486B1 (en) 1998-04-03 2002-02-05 3-Dimensional Pharmaceuticals, Inc. Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors
SK15072000A3 (sk) 1998-04-10 2001-08-06 Japan Tobacco Inc. Amidové zlúčeniny
US20020061842A1 (en) 1998-04-10 2002-05-23 Octapharma Ag Method for sterilizing a native collagen in liquid medium, sterile native collagen obtained, compositions containing it and uses
US6417161B1 (en) 1998-04-24 2002-07-09 3-Dimensional Pharmaceuticals, Inc. Amino acid amidinohydrazones, alkoxyguanidines and aminoguanidines as protease inhibitors
DE19819548A1 (de) 1998-04-30 1999-11-04 Merck Patent Gmbh Biphenylderivate
GB9809350D0 (en) 1998-05-02 1998-07-01 Zeneca Ltd Novel salt
US6753331B1 (en) 1998-05-02 2004-06-22 Astrazeneca Ab Heterocyclic derivatives which inhibit factor Xa
GB9809349D0 (en) 1998-05-02 1998-07-01 Zeneca Ltd Heterocyclic derivatives
EP1086946A4 (en) 1998-06-08 2003-03-05 Ajinomoto Kk BENZAMIDINE DERIVATIVE
SI1086122T1 (sl) 1998-06-11 2006-02-28 Pment L L C Johnson & Johnson Inhibitorji pirazinon-proteaze
TWI248435B (en) 1998-07-04 2006-02-01 Boehringer Ingelheim Pharma Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
DE19829964A1 (de) 1998-07-04 2000-01-05 Boehringer Ingelheim Pharma Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel
DE19834751A1 (de) 1998-08-01 2000-02-03 Boehringer Ingelheim Pharma Disubstituierte bicyclische Heterocyclen, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19835950A1 (de) 1998-08-08 2000-02-10 Merck Patent Gmbh Piperazinonderivate
CA2340100A1 (en) 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Novel sulfonyl derivatives
JP2000143623A (ja) 1998-08-28 2000-05-26 Dai Ichi Seiyaku Co Ltd 新規なスルホニル誘導体およびその塩
DE19839499A1 (de) 1998-08-29 2000-03-02 Merck Patent Gmbh 2-Oxo-2H-chinolinderivate
SE9802938D0 (sv) 1998-09-01 1998-09-01 Astra Ab Improved stability for injection solutions
SE9802973D0 (sv) 1998-09-03 1998-09-03 Astra Ab Immediate release tablet
JP2000080046A (ja) 1998-09-03 2000-03-21 Dai Ichi Seiyaku Co Ltd 多臓器障害の予防・治療剤
DE19845153A1 (de) 1998-10-01 2000-04-06 Merck Patent Gmbh Imidazo[4,5]-pyridin-4-on-derivate
TW575567B (en) 1998-10-23 2004-02-11 Akzo Nobel Nv Serine protease inhibitor
US6262088B1 (en) 1998-11-19 2001-07-17 Berlex Laboratories, Inc. Polyhydroxylated monocyclic N-heterocyclic derivatives as anti-coagulants
JP2003529531A (ja) 1998-11-25 2003-10-07 アヴェンティス ファーマシューティカルズ インコーポレイテッド 置換オキソアザへテロシクリルＸａ因子阻害剤
US6127376A (en) 1998-12-04 2000-10-03 Berlex Laboratories, Inc. Aryl and heterocyclyl substituted pyrimidine derivatives as anti-coagulants
JP2000178243A (ja) 1998-12-14 2000-06-27 Teijin Ltd ビフェニルアミジン誘導体
CA2353151A1 (en) 1998-12-16 2000-06-22 Boehringer Ingelheim Pharma Kg Substituted aryl and heteroaryl derivatives, the preparation thereof and their use as medicaments
BR9916363A (pt) * 1998-12-18 2001-12-11 Axys Pharm Inc Composto, composição farmacêutica e método paratratar ou prevenir um distúrbio tromboembólico
KR100628407B1 (ko) 1998-12-23 2006-09-26 브리스톨-마이어스 스퀴브 파마 컴파니 Ｘａ 인자 억제제로서의 질소 함유 헤테로비시클릭 화합물
JP2002533453A (ja) 1998-12-23 2002-10-08 イーライ・リリー・アンド・カンパニー Ｘａ因子のインヒビターとしてのヘテロ芳香族アミド
CA2320730A1 (en) 1998-12-23 2000-07-06 Renhua Li Thrombin or factor xa inhibitors
AU2054700A (en) 1998-12-23 2000-07-31 Eli Lilly And Company Antithrombotic amides
ES2226485T3 (es) 1998-12-23 2005-03-16 Eli Lilly And Company Amidas aromaticas.
KR20010086461A (ko) 1998-12-24 2001-09-12 오흘러 로스 제이. 인자 ｘａ 억제제로서의 치환된 (아미노이미노메틸 또는아미노메틸)벤조헤테로아릴 화합물
CA2356214A1 (en) 1998-12-24 2000-07-06 Eli Lilly And Company Heterocyclic amides as inhibitors of factor xa
EP1155033A1 (en) 1998-12-30 2001-11-21 Aventis Pharmaceuticals Products Inc. Process for preparing a stable non-hygroscopic crystalline n-[n-[n-(piperdin-4-yl)butanoyl)-n-ethylglycyl]-(l)-aspartyl]-ss-cyclohexylalanine amide
DE69924527T2 (de) 1999-01-02 2006-02-09 Sanofi-Aventis Deutschland Gmbh Arylalkanoylderivate, verfahren zu ihrer herstellung, ihre verwendung und diese enthaltende pharmazeutische zubereitungen
KR20010101355A (ko) 1999-01-02 2001-11-14 로버트 흐라이탁, 미쉘 베스트 신규한 말론산 유도체, 이의 제조 방법, 이의 용도 및이를 함유하는 약제학적 조성물(인자 ｘａ 활성 억제)
EP1016663A1 (en) 1999-01-02 2000-07-05 Aventis Pharma Deutschland GmbH Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor Xa activity)
DE19900355A1 (de) 1999-01-07 2000-07-13 Merck Patent Gmbh Benzimidazolderivate
DE19900471A1 (de) 1999-01-08 2000-07-13 Merck Patent Gmbh Imidazo[4,5c]-pyridin-4-on-derivate
WO2000047207A1 (en) 1999-02-09 2000-08-17 Bristol-Myers Squibb Company LACTAM INHIBITORS OF FXa AND METHOD
EP1175405A4 (en) 1999-02-09 2002-05-15 Bristol Myers Squibb Co LACTAM INHIBITORS OF FACTOR Xa AND ASSOCIATED METHOD
PL351767A1 (en) 1999-02-09 2003-06-16 Dimensional Pharmaceuticals 3 Heteroaryl amidines, methylamidines and guanidines as protease inhibitors
JP2003522733A (ja) 1999-02-11 2003-07-29 コア セラピューティクス，インコーポレイティド Ｘａ因子の阻害剤としてのアルケニルおよびアルキニル化合物
GB9902989D0 (en) 1999-02-11 1999-03-31 Zeneca Ltd Heterocyclic derivatives
DE19909237A1 (de) 1999-03-03 2000-09-07 Merck Patent Gmbh Pyrazol-3-on-derivate
EP1161279A1 (en) 1999-03-11 2001-12-12 Du Pont Pharmaceuticals Company Treatment of thrombosis by combined use of a factor xa inhibitor and aspirin, tissue plasminogen activator (tpa), a gpiib/iiia antagonist, low molecular weight heparin or heparin
AU3329400A (en) 1999-03-31 2000-10-23 Kissei Pharmaceutical Co. Ltd. 3-amidinobenzenesulfonamide derivatives, medicinal compositions containing the same and intermediates in the production thereof
WO2000059902A2 (en) 1999-04-02 2000-10-12 Du Pont Pharmaceuticals Company Aryl sulfonyls as factor xa inhibitors
JP4390024B2 (ja) 1999-04-23 2009-12-24 アステラス製薬株式会社 新規なジアゼパン誘導体又はその塩
CA2374793A1 (en) 1999-05-24 2000-11-30 Penglie Zhang Inhibitors of factor xa
CA2374820A1 (en) 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibitors of factor xa
AU5283900A (en) 1999-05-24 2000-12-12 Cor Therapeutics, Inc. Inhibitors of factor xa
JP2003500390A (ja) 1999-05-24 2003-01-07 シーオーアール セラピューティクス インコーポレイテッド Ｘａ因子阻害剤
WO2000076970A2 (en) 1999-06-14 2000-12-21 Eli Lilly And Company Serine protease inhibitors
DE60022508T2 (de) 1999-06-14 2006-06-08 Eli Lilly And Co., Indianapolis Inhibitoren von serin proteasen
GB9914342D0 (en) 1999-06-19 1999-08-18 Zeneca Ltd Compound
US6723722B1 (en) 1999-06-22 2004-04-20 Takeda Chemical Industries, Ltd. Acylhydrazine derivatives, their production and use
TR200103853T2 (tr) 1999-06-30 2002-11-21 Mochida Pharmaceutical Co., Ltd Spiro bağlı trisiklik bileşikler.
WO2001002356A1 (fr) 1999-07-01 2001-01-11 Sankyo Company, Limited Dérivés d'indoline ou tétrahydroquinoline
BR0013200A (pt) 1999-07-16 2002-05-07 Bristol Myers Squibb Pharma Co Compostos derivados de heterobiciclos contendo nitrogênio, composições farmacêuticas, método de tratamento ou prevenção de uma disfunção tromboembólica e uso dos compostos
US6350761B1 (en) 1999-07-30 2002-02-26 Berlex Laboratories, Inc. Benzenamine derivatives as anti-coagulants
AU6762400A (en) 1999-08-12 2001-03-13 Cor Therapeutics, Inc. Inhibitors of factor xa
DE60006407T2 (de) 1999-09-13 2004-09-09 3-Dimensional Pharmaceuticals, Inc. Azazykloalkanone serin-protease-hemmer
EP1216228B1 (en) 1999-09-17 2008-10-29 Millennium Pharmaceuticals, Inc. BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa
TR200201413T2 (tr) 1999-09-17 2003-02-21 Millennium Pharmaceuticals, Inc. Faktör Xa' nın inhibitörleri.
AU2079901A (en) 1999-12-06 2001-06-12 Smithkline Beecham Corporation Thrombopoietin mimetics
WO2001056989A2 (en) 2000-02-01 2001-08-09 Cor Therapeutics, Inc. Inhibitors of factor xa
EP1255743A1 (en) 2000-02-01 2002-11-13 Millenium Pharmaceuticals, Inc. 3,4-DIHYDRO-2H-BENZO[1,4]OXAZINE INHIBITORS OF FACTOR Xa
US20020019395A1 (en) 2000-02-01 2002-02-14 Bing-Yan Zhu Indalone and benzimidazolone inhibitors of factor Xa
AU2001234690A1 (en) 2000-02-01 2001-08-14 Cor Therapeutics, Inc. 2-(1h)-quinolone and 2-(1h)-quinoxalone inhibitors of factor xa
EP1259485B1 (en) 2000-02-29 2005-11-30 Millennium Pharmaceuticals, Inc. BENZAMIDES AND RELATED INHIBITORS OF FACTOR Xa
US6548517B2 (en) 2000-03-24 2003-04-15 Millennium Pharmaceuticals, Inc. Oxindole inhibitors of factor Xa
US20020019394A1 (en) 2000-03-24 2002-02-14 Wenhao Li Bicyclic sulfonyl amino inhibitors of factor Xa
US6469026B2 (en) 2000-03-24 2002-10-22 Millennium Pharmaceuticals, Inc. Isoquinolone inhibitors of factor Xa
US20020037912A1 (en) 2000-08-11 2002-03-28 Leahy Ellen M. Factor viia inhibitors
US6465503B2 (en) * 2000-08-11 2002-10-15 Axys Pharmaceuticals, Inc. Selective urokinase inhibitors
US6410733B1 (en) 2000-09-11 2002-06-25 Genentech, Inc. Amidine inhibitors of serine proteases
US20030114457A1 (en) 2001-07-09 2003-06-19 Axys Pharmaceuticals, Inc. 2- [5- (5-carbamimidoyl-1H-heteroaryl)-6-hydroxybiphenyl-3-yl]-succinic acid derivatives as factor viia inhibitors
KR20040065278A (ko) 2001-12-21 2004-07-21 노보 노르디스크 에이/에스 변경된 인자 ⅶ 폴리펩티드의 액체 조성물
US20050203094A1 (en) 2002-02-13 2005-09-15 Aleksandr Kolesnikov 2-[5-(5-carbamimidoyl-1h-heteroaryl)]-6-hydroxybiphenyl-3-yl derivatives as factor viia inhibitors
PL373850A1 (en) 2002-04-08 2005-09-19 Guilford Pharmaceuticals, Inc. Pharmaceutical compositions containing water-soluble prodrugs of propofol and methods of administering same
US7479502B2 (en) 2002-12-03 2009-01-20 Pharmacyclics, Inc. 2-(2-hydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors
AU2003300106A1 (en) 2003-01-08 2004-08-10 Axys Pharmaceuticals, Inc. 2-'5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl!- carboxylic acid derivatives as factor viia inhibitors
CN102417484A (zh) 2004-06-02 2012-04-18 法莫西克立克斯公司 因子VIIa抑制剂
US8729117B2 (en) 2004-06-02 2014-05-20 Pharmacyclics, Inc. Factor VIIa inhibitor
CN1976903A (zh) 2004-06-02 2007-06-06 法莫西克立克斯公司 因子VⅡa抑制剂
EA201370191A1 (ru) 2007-10-16 2014-05-30 Фармасайкликс, Инк. КОМПОЗИЦИИ, СОДЕРЖАЩИЕ МОДУЛЯТОРЫ ФАКТОРА КОАГУЛЯЦИИ VIIa, И ИХ ПРИМЕНЕНИЕ

Also Published As

Publication number Publication date
US20140378453A1 (en) 2014-12-25
AU2003302238A1 (en) 2004-06-23
JP4744149B2 (ja) 2011-08-10
PT1569912E (pt) 2015-09-15
CA2507707A1 (en) 2004-06-17
JP2011157362A (ja) 2011-08-18
ES2543588T3 (es) 2015-08-20
US20060205942A1 (en) 2006-09-14
DK1569912T3 (en) 2015-06-29
US20110269806A1 (en) 2011-11-03
AU2003302238A8 (en) 2004-06-23
US9162986B2 (en) 2015-10-20
JP2006515839A (ja) 2006-06-08
US20090054432A1 (en) 2009-02-26
CN100513398C (zh) 2009-07-15
EP2982668A3 (en) 2016-04-13
SI1569912T1 (sl) 2015-09-30
EP2982668A2 (en) 2016-02-10
EP1569912B1 (en) 2015-04-29
EP1569912A2 (en) 2005-09-07
CA2507707C (en) 2011-06-21
WO2004050637A3 (en) 2004-09-02
US8299110B2 (en) 2012-10-30
US7479502B2 (en) 2009-01-20
WO2004050637A2 (en) 2004-06-17
US20130157298A1 (en) 2013-06-20
US8778625B2 (en) 2014-07-15
CN1745070A (zh) 2006-03-08
JP2014088446A (ja) 2014-05-15

Similar Documents

Publication Publication Date Title
HUE025683T2 (hu) VIIA faktor inhibitor 2-(2-hidroxi-bifenil-3-il)-1H-benzoimidazol-5-karboxamidin-származékok
JP3277170B2 (ja) メタロプロテアーゼ阻害剤
US20030114457A1 (en) 2- [5- (5-carbamimidoyl-1H-heteroaryl)-6-hydroxybiphenyl-3-yl]-succinic acid derivatives as factor viia inhibitors
US8415328B2 (en) Factor VIIa inhibitor
US9181280B2 (en) Factor VIIa inhibitor
WO2004062661A1 (en) 2-‘5-(5-carbamimidoyl-1h-heteroaryl)-6-hydroxybiphenyl-3-yl!- carboxylic acid derivatives as factor viia inhibitors
US20050203094A1 (en) 2-[5-(5-carbamimidoyl-1h-heteroaryl)]-6-hydroxybiphenyl-3-yl derivatives as factor viia inhibitors