WO1999026933A1 - Derives d'amidinoaryle substitue et leur utilisation comme anticoagulants - Google Patents

Derives d'amidinoaryle substitue et leur utilisation comme anticoagulants Download PDF

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Publication number
WO1999026933A1
WO1999026933A1 PCT/US1998/025241 US9825241W WO9926933A1 WO 1999026933 A1 WO1999026933 A1 WO 1999026933A1 US 9825241 W US9825241 W US 9825241W WO 9926933 A1 WO9926933 A1 WO 9926933A1
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formula
compound
annular
alkyl
benzimidazol
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PCT/US1998/025241
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English (en)
Inventor
Robert F. Day
Wendy B. Young
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Axys Pharmaceuticals, Inc.
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Priority to AU16083/99A priority Critical patent/AU1608399A/en
Publication of WO1999026933A1 publication Critical patent/WO1999026933A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • This application relates to compounds and compositions for treating diseases associated with serine protease activity, particularly factor Xa activity.
  • Hemostasis is a function of the physiological processes which initiate and modulate blood coagulation and fibrino lysis.
  • Blood coagulation involves a series of highly complex, inter-related proteolytic events which culminate in the formation of a fibrin clot surrounding the platelet aggregate which makes up the primary hemostatic plug that forms to prevent loss of blood when a vessel is damaged.
  • Fibrin is the product of a proteolytic reaction catalyzed by thrombin, a serine protease, which in turn is the product of a proteolytic activation of prothrombin by factor Xa, also a serine protease.
  • Thrombin also is a potent activator of platelet aggregation.
  • Factor Xa is converted from inactive factor X by two distinct mechanisms referred to as the intrinsic and extrinsic coagulation pathways.
  • the intrinsic pathway comprises a series of proteolytic reactions catalyzed by factors originating in blood and culminates in the formation of factor IXa.
  • the extrinsic pathway comprises the activation of factor VII by tissue factor, a membrane bound protein, which is available at the site of vessel injury and culminates in the formation of factor Vila.
  • Factor IXa and factor Vila in consert with tissue factor, catalyzes the conversion of factor X to factor Xa.
  • the formation of factor Xa represents a convergence of the entrinsic and extrinsic pathways in the cascade of events which lead to blood coagulation.
  • Fibrinolysis is the mechanism by which the platelet aggregate and fibrin clot is dissolved after the vessel injury has healed.
  • the normal physiological condition results in an equilibrium between blood coagulation and anticoagulation mechanisms preventing hemorrhage while maintaining blood fluidity.
  • a pathological condition leading to the occlusion of a blood vessel i.e., thrombosis, is the equilibrium tipped in the direction of procoagulation.
  • Arterial thrombosis which deprives tissue of oxygen will result in ischemic necrosis of that tissue.
  • Venous thrombosis may result in a pulmonary embolism.
  • Agents which shift the equilibrium towards anticoagulation provide a method for treating and/or preventing thrombosis.
  • Agents which inhibit factor Xa provide a valid pharmacological mechanism for effecting anticoagulation.
  • This application relates to a compound of Formula I:
  • a together with B comprises a fused heterobicyclic radical containing 8 to 12 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X 1 and X 2 are adjacent annular members of an aromatic ring and
  • X 3 represents a linking group of Formula (a) or (b):
  • D comprises a monocyclic or polycyclic divalent radical containing 5 to 10 annular atoms
  • X 10 and X 11 together represent a linking group containing two contiguous linking atoms and R 7 is -R 6 or -X 6 -R 6 , wherein X 6 and R 6 are as defined above, with the proviso that when X 3 is a linking group of Formula (b) and R 7 is -R 6 , wherein R 6 is substituted or unsubstituted heteroaryl or heteropolycycloaryl, then the annular atom of R 6 to which X 10 or X 11 is attached is not adjacent to an annular heteroatom moiety;
  • R 1 is amidino and bonded to any annular carbon atom with an available valence comprising B; each R 2 is independently hydrogen, (C, .3 )alkyl, (C, .3 )alkyloxy, (C,. 3 )alkylsulfonyl, (C, rule 3 )alkylthio, carboxy, halo, (C 2 . 12 )heteroalkyl, hydroxy, mercapto or nitro and bonded to any annular atom with an available valence comprising B; each R 3 is independently hydrogen, cyano, halo, nitro, perhalo(C,. 3 )alkyl or perhalo(C j .
  • each R 4 is independently -R 6 or -X 6 -R 6 , wherein X 6 and R 6 are as defined above, and bonded to any annular atom with an available valence comprising C; wherein aliphatic or alicyclic moieties with an available valence comprising each X 6 and R 6 optionally are substituted with 1 to 5 substituents independently selected from (C,_ 6 )alkyl, (C ⁇ alkylamino, di(C,.
  • a second aspect of this invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer, mixture of isomers or pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
  • a third aspect of this invention is a method of treating a disease in an animal in which contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer, mixture of isomers or pharmaceutically acceptable salt thereof.
  • a fourth aspect of this invention is the processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof as set forth in "Detailed Description of the Invention".
  • Alicyclic moiety means any saturated or unsaturated, monocyclic or polycyclic portion of a radical and includes cycloalkyl, cycloalkylene, heterocycloalkyl and heterocycloalkylene, as defined in this Section.
  • alicyclic moiety refers to cycloalkyl as well as to the alicyclic portions comprising cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylcarbamoyl, polycycloaryl, and the like.
  • Aliphatic moiety means any straight or branched, saturated or unsaturated portion of a radical and includes alkyl, alkylene, heteroalkyl and heteroalkylene, as defined in this Section.
  • aliphatic moiety refers to alkyl as well as to aliphatic portions comprising alkyloxy, arylalkyi, alkylcarbamoyl, and the like.
  • Alkyl for the purposes of this application, means a straight or branched, saturated or unsaturated aliphatic radical having the number of carbon atoms indicated, and any ketone, thioketone or iminoketone derivative thereof (e.g., (C,.
  • alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, 3-oxopentyl, 3-thioxopentyl, 3-iminopentyl, etc.).
  • Alkyloxy means the radical -OR, wherein R is alkyl as defined in this Section, having the number of carbon atoms indicated (e.g., (C j.
  • ⁇ alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, etc.).
  • Alkylsulfonyl and “alkylthio” mean the radicals -S(O) 2 R and -SR, respectively, wherein R is alkyl as defined in this Section, having the number of carbon atoms indicated (e.g., (C,_ 6 )alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propenylsulfonyl, isopropenylsulfonyl, 1 -butenylsulfonyl, 2-butenylsulfonyl, 3-butenylsulfonyl
  • Amino means the radical -C(NH)NH 2 .
  • Amino means the radical -NH 2 .
  • “Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e.g., birds, etc.).
  • “Aryl” means an aromatic monocyclic or fused polycyclic radical containing the number of annular carbon atoms indicated, wherein each ring contained therein is comprised of 6 annular members (e.g., (C 6.14 )aryl includes phenyl, naphthalenyl, anthracenyl, phenanthrenyl, etc.).
  • Arylene means an aromatic monocyclic or fused bicyclic divalent radical containing 6 to 10 annular atoms, wherein each ring contained therein is comprised of 6 annular members (e.g., arylene includes 1 ,4-phenylene, 1 ,2-phenylene, 1,5-naphthalenylene, 1,8-naphthaleylene, etc.).
  • Aromatic moiety means any aromatic portion of a radical and includes aryl and heteroaryl, as defined in this Section.
  • aromatic moiety refers to aryl as well as the aromatic portions comprising arylalkyi, polycycloaryl, and the like.
  • Carbamoyl means the radical -C(O)NH 2 .
  • Carboxy means the radical -C(O)OH.
  • Cyano means the radical -CN.
  • Cycloalkyl means a saturated or unsaturated, monocyclic or fused polycyclic radical containing the number of annular carbon atoms indicated, wherein each ring contained therein is comprised of 3 to 8 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C 3.14 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, l-azabicyclo[2.2.2]oct-3-yl, etc.).
  • Cycloalkylene means a saturated or unsaturated, monocyclic or fused bicyclic divalent radical containing 3 to 14 annular atoms, wherein each ring contained therein is comprised of 3 to 8 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., cycloalkylene includes cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, 2,5-cyclohexadienylene, bicyclo[2.2.2]octylene, oxocyclohexylene, dioxocyclohexylene, thiocyclohexylene,
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.
  • “Fused heteropolycyclic radical” includes “fused heterobicyclic radical” and means a heterocyclic radical containing two or more rings having the number of annular members indicated, wherein at least two annular members of one ring are common to a second ring (e.g., a heteropolycyclic radical containing from 5 to 18 annular atoms and the carbocyclic ketone and thioketone derivatives thereof includes lH-benzimidazol-2-yl, lH-naphtho[2,3-d]imidazol-2-yl, lH-imidazo[4,5 ]quinolin-2-yl, lH-imidazo[4,5- ⁇ ]pyridin-2-yl, lH-phenanthro[9,10- ⁇ f]imidazol-2-yl, lH-imidazo[4,5-g]quinoxalin-2-yl, 2,6-dioxo-2,3,6,7-tetrahydro-l
  • Heteroatom moiety unless indicated otherwise, means a moiety selected from
  • Heteroalkyl means alkyl, as defined in this Section, except one or more of the carbon atoms indicated is replaced by a heteroatom moiety, as defined in this Section, and any ketone, thioketone or iminoketone derivative thereof (e.g., hetero(C 2 . 12 )alkyl includes methoxy, ethoxy, ethylthio, 2-(2-methoxyethoxy)ethoxy,
  • Heteroalkylene means alkylene, as defined in this Section, except one or more of the carbon atoms indicated is replaced by a heteroatom moiety, as defined in this Section, or any suitable combination thereof (e.g., -OS(O) 2 - -S(O) 2 O- -N(R 8 )S(O) 2 - -S(O) 2 NR 8 -,
  • R 8 is hydrogen or (C, .6 )alkyl
  • 3-oxo-3-phosphapentamethylene (-CH 2 OP(O)(OH)OCH 2 -), 3-aza- 2-oxo-4-carboxyhexamethylene, 4-aza-l-oxa-3-oxohexamethylene, l-thia-3-oxo-
  • Heterocycloalkyl means cycloalkyl, as defined in this Section, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as defined in this Section, and any carbocyclic ketone, thioketone or iminoketone derivative thereof
  • heterocyclo(C 5 . 14 )alkyl includes piperidyl, pyrrolidinyl, pyreolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).
  • Heterocycloalkylene means cycloalkylene, as defined in this Section, except one or more of the annular carbon atoms indicated is replaced by a heteroatom moiety, as defined in this Section, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo(C 3.14 )alkylene includes piperidylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.).
  • Heteropolycycloaryl means polycycloaryl, as defined below, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as set defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., heteropolycyclo(C 8.10 )alkyl includes 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H-[l,8]naphthyridinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 3-oxo- 2,3-dihydrobenzo[l,4]oxazinyl, etc.).
  • heteropolycycloarylene means polycycloarylene, as defined below, except one or more of the annular carbon atoms indicated is replaced by a heteroatom moiety, as set defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., heteropolycyclo(C 8.10 )alkylene includes 3,4-dihydro-2H-quinolinylene, 5,6,7,8-tetrahydroquinolinylene,
  • Iminoketone derivative refers to a radical containing the moiety -C(NR)-, wherein R is hydrogen or (C, .6 )alkyl.
  • “Isomers” mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “steroisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes "optical isomers”. A carbon atom bonded to four nonidentical substituents is termed a "chiral center”. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a "racemic mixture”.
  • a compound that has more than one chiral center has 2" "1 enantiomeric pairs, where n is the number of chiral centers.
  • Compounds with more than one chiral center may exist as ether an individual diasteromer or as a mixture of diastereomers, termed a "diastereomeric mixture".
  • a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog.
  • Ketone derivative refers to a radical containing the moiety -C(O)-.
  • "Leaving group” has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkyloxy, alkylsulfonloxy (e.g., mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy (e.g., benzenesulfonyloxy and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like.
  • Linking group means a saturated or unsaturated divalent radical having the number of contiguous linking atoms indicated, wherein “contiguous linking atoms” refers to the minimum number of connecting atoms linking the free valences, and any substituted, ketone, thioketone or iminoketone derivative thereof.
  • the linking group may contain one or more heteroatom moieties, as defined in this Section, one or more suitable combinations of heteroatom moieties (e.g., -OS(O) 2 -, -S(O) 2 O-, -N(R 8 )S(O) 2 -, -S(O) 2 NR 8 -, -OP(O)(OR 8 )O-, etc.), alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, polycycloarylene, heteropolycycloarylene, and any combination and carbocyclic ketone, thioketone and iminoketone derivative thereof (e.g., -C(O)-, -C(O)O-, -OC(O)-, -N(R 8 )C(O)-, -C(O)NR 8 -, -N(R 8 )C(O)O-, -OC(O)NR 8 -
  • a linking group containing 1 to 12 contiguous linking atoms may include one or more heteroatom moieties, one or more suitable combinations of heteroatom moieties and one or more groups selected from (C 2 _ 10 )alkylene, hetero(C 2 . 10 )alkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, polycycloarylene and heteropolycycloarylene, and any combination thereof
  • methylenephen-l,4-ylene (e.g., methylenephen-l,4-ylene (-C 6 H 4 CH 2 - or -CH 2 C 6 H 4 -), methylenepiperazin-l,4-ylene (-N 2 C 4 H 8 CH 2 - or -CH 2 N 2 C 4 H 8 -), methyleneoxaphen-l,4-ylene (-OC 6 H 4 CH 2 - or -CH 2 C 6 H 4 O-), etc.).
  • “Mercapto” means the radical -SH. "Nitro” means the radical -NO 2 . "Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase “optionally are substituted with one to three radicals” means that the group referred to may or may not be substituted in order to fall within the scope of the invention.
  • N-oxide derivatives means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i.e., O ⁇ ) and which possess the desired pharmacological activity.
  • Phathology of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
  • “Pharmaceutically acceptable” means that which is userul in preparing a pharmaceutical composition that is generall safe, non-toxic and neither biologically nor otherwise undesirabale and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Perhalo(C 1.3 )alkyl” means alkyl, as defined in this Section, except all of the hydrogen atoms are replaced by haloatoms (e.g., trifluorornefhyl, etc.).
  • “Pharmaceutically acceptable salts” means salts of compounds of Formula I which are pharmaceutically acceptable, as defined in this Section, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, -chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, />-toluene
  • 3-phenylpropionic acid trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydoxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • Polycycloaryl means a fused polycyclic radical containing the number of annular carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic and each ring contained therein is comprised of 5 to 6 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., polycyclo(C 9.10 )aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1 ,2-dihydronaphthalenyl, 2,4-dioxo-l,2,3,4-tetrahydronaphthalenyl, etc.).
  • Polycycloarylene means a fused bicyclic divalent radical containing 10 to 12 annular atoms, wherein at least one, but not both, of the fused rings comprising the radical is aromatic and each ring contained therein is comprised of 5 to 6 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., polycyclo(C 9 . 10 )arylene includes indanylene, indenylene, 1 ,2,3,4-tetrahydronaphthalenylene, 1 ,2-dihydronaphthalenylene, 2,4-dioxo-l,2,3,4-tetrahydronaphthalenylene, etc.).
  • Prodrug derivatives means derivatives of compounds of Formula I which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I.
  • suitable prodrug derivatives include compounds of Formula I wherein the R 1 amidino group is hydroxy- or (C, .6 )alkyloxy-substituted.
  • Protected derivatives means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protective groups.
  • Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active inhibitors of factor Xa.
  • a compound of Formula I may have one or more reactive amino groups.
  • Suitable protecting groups for reactive nitrogen atoms include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protective groups (e.g., see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).
  • “Therapeutically effective amount” means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • “Thioketone derivative” refers to a radical containing the moiety -C(S)-.
  • Treatment refers to any administration of a compound of the present invention and includes: (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (3) amelorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
  • Sulfo means the radical -S(O)OH.
  • Uriedo means the radical -NHC(O)NH 2 .
  • a together with B comprises 5-amidino-lH-benzimidazol-2-yl
  • C comprises 6-methoxycarbonyl-l -methyl- lH-benzimidazol-2-yl
  • X 3 is ethylene is named methyl 2-[2-(5-amidino-lH-benzimidazol-2-yl)ethyl]-3-methyl-3H-benzimidazole-5-carboxylate;
  • a together with B comprises 5-amidino-lH-benzimidazol-2-yl
  • C comprises 5-(4-aminophenoxy)-lH-benzimidazol-2-yl
  • X 3 is ethylene is named 2-[2-(5-(4-aminophenoxy)-l-H-benzimidazol-2-yl)ethyl]-lH-benzimidazole- 5-carboxamidine;
  • a together with B comprises 5-amidino-lH-benzimidazol-2-yl
  • C comprises lH-benzimidazol-2-yl
  • X 3 is ethylene
  • 2-[2-(5-chloro- lH-benzimidazol-2-yl)ethyl]-lH-benzimidazole-5-carboxamidine is meant to include its tautomers 2-[2-(6-chloro-lH-benzimidazol-2-yl)ethyl]-lH-benzimidazole-5-carboxamidine, 2-[2-(6-chloro-lH-benzimidazol-2-yl)ethyl]-3H-benzimidazole-5-carboxamidine and 2-[2-(5-chloro-lH-benzimidazol-2-yl)ethyl]-
  • a prefened aspect of the Invention are compounds of Formula I in which: n2 is l;
  • a together with B comprises a fused heterobicyclic radical containing 8 to 10 annular atoms, wherein each ring contains 5 to 6 annular members;
  • C comprises a fused heteropolycyclic radical containing from 9 to 13 annular atoms, wherein each ring contains 5 to 6 annular atoms;
  • X 3 represents a linking group of Formula (a) or (b) in which D comprises a monocyclic divalent radical containing 6 annular carbon atoms; each R 3 is independently hydrogen, halo or hydroxy; and each R 4 , R 5 and R 7 is independently -R 6 or -X 6 -R 6 , wherein X 6 is a linking group containing 1 to 10 contiguous linking atoms and R 6 is hydrogen, (C 6 . 10 )aryl, cyclo(C 3 . 6 )alkyl, hetero(C 5.10 )aryl, heterocyclo(C 5.6 )alkyl or hetero(C 8 . 10 )polycycloaryl.
  • a further preferred aspect of the Invention is a compound of Formula II:
  • E together with the vinylene moiety to which it is fused comprises a monocyclic or heteromonocyclic divalent radical containing 6 annular atoms
  • X 3 is ethylene, carbamoylethylene, methoxycarbonylethylene, tra «X ,2-methylvinylene, 1 ,2-phenylene or l-cyclohexen-l,2-ylene
  • X 1 and X 5 are independently a heteroatom moiety selected
  • a further preferred aspect of the Invention is a compound of Formula II in which each R 4 , R 5 and/or R 7 is independently -R 6 , wherein R 6 is (C 6.14 )aryl, cyclo(C 3 . 14 )alkyl, hetero(C 5.14 )aryl, heterocyclo(C 3.14 )alkyl, hetero(C 8.14 ) ⁇ olycycloaryl or (C 9 .
  • a further preferred aspect of the Invention is a compound of Formula II in which each R 3 is independently cyano, halo, nitro, perhalo(C,. 3 )alkyl or perhalo(C,_ 3 )alkyloxy and/or each R 4 is independently hydroxy, mercapto, sulfo, -NHR 8 or -OP(O)(OR 8 )OH, wherein R 8 is hydrogen or (C ⁇ alkyl.
  • a further preferred aspect of the Invention is a compound of Formula II in which one of X 1 and X 5 is -NR 5 - and the other is a heteroatom selected from -O- and -S-; in particular, compounds of Formula II wherein X 1 is -S- and X 5 is -NR 5 -.
  • the compounds of this invention are factor Xa inhibitors and, as such, are useful for treating diseases in which factor Xa activity contributes to the pathology and/or symptomatology of the disease.
  • Uses for factor Xa inhibitors include therapy in treating venous thromboembolism (obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel), to reduce the risk of myocardial infarction in patients with unstable angina, to ameliorate further loss of cardiac function in patients with acute myocardial infarction, to reduce the risk of occlusion of saphenous grafts, to reduce periprocedural thrombosis in patients undergoing angioplasty procedures, to reduce the risk of ischemic stroke in patients with atrial fibrillation, to reduce the risk of embolism associated with mechanical heart valves and valvular heart disease, to prevent ischemic strokes in patients with cerebrovascular atherosclerosis, in patients with peripheral vascular disease, and the like.
  • Suitable in vitro assays for measuring factor Xa activity and the inhibition thereof by test compounds are known. Typically, the assay measures factor Xa induced hydrolysis of a peptide base substrate. Suitable in vivo and ex vivo models for measuring the anti-coagulation activity of test compounds are known to those of ordinary skill in the art.
  • compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • therapeutically effective amounts of a compound of Formula I for anticoagulant therapy may range from 0.1 micrograms per kilogram body weight ( ⁇ g/kg) per day to 1 milligram per kilogram body weight (mg/kg) per day, typically 1 ⁇ g/kg/day to 0.1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 ⁇ g/day to 10 mg/day, typically 0.1 mg/day to 10 mg/day.
  • one of ordinary skill in the art acting in reliance upon personal knowledge and the disclosure of this application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
  • compositions can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).
  • routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and 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 active ingredient.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • 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, dried skim milk, and the like.
  • Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.).
  • Prefened liquid carriers, particularly for mjectable solutions include water, saline, aqueous dextrose and glycols.
  • a composition of a compound of Formula I for treating a given disease will comprise from 0.01 %w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients.
  • the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
  • Representative pharmaceutical formulations containing a compound of Formula I are described in Example .
  • R 9 is -C(O)L or -CN, wherein L is a leaving group
  • E together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and optionally one or more annular members is a heteroatom moiety
  • X 12 is -O-, -N(R 5 )- or -S -
  • R 10 is -OH, -NHR 5 or -SH and heteroatom moiety, n2, n3, n4,
  • A, B, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the Summary of the Invention.
  • Compounds of Formula I in which X 4 and X 5 are adjacent members of an oxazol-2- yl, lH-imidazol-2-yl or thiazol-2-yl ring comprising a fused polycyclic radical can be prepared by reacting a compound of Formula 1 with a compound of Formula 2(a).
  • the reaction may be carried out neat, but preferably is carried out in the presence of l,3-dimethyl-3, 4, 5, 6-tetrahydro-2(lH)-pyrimidinone (DMPU) or polyphosphoric acid, at 160 to 200 °C, preferably 170-180 °C, and requires 2 to 3 hours to complete (e.g., see Examples 3 and 4, infra.).
  • DMPU 6-tetrahydro-2(lH)-pyrimidinone
  • polyphosphoric acid at 160 to 200 °C, preferably 170-180 °C, and requires 2 to 3 hours to complete (e.g., see Examples 3 and 4, infra.).
  • Compounds of Formula I in which C comprises oxazol-2-yl, lH-imdazol-2-yl or thiazol-2-yl can be prepared by proceeding as in Scheme I, but replacing the compound of Formula 2(a) with a compound of Formula 2(b):
  • R 10 is -OH, -NHR 5 or -SH and each p, q, R 3 , R 4 and R 5 is as defined in the Summary of the Invention.
  • R 9 is -C(O)L or -CN, wherein L is a leaving group
  • X 12 is N(R 5 ), O or S
  • R 10 is -OH, -NHR 5 or -SH and n2, n3, n4, B, C, X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the Summary of the Invention (e.g., see Example 5, infra.).
  • n2, n3, n4, A, B, C, X 1 , X 2 , X 3 , X 4 , X 5 , R 2 , R 3 , R 4 and R 5 are as defined in the Summary of the Invention.
  • Compounds of Formula I can be prepared by reacting a corresponding nitrile with hydroxylamine hydrochloride to give a N-hydroxy amidine and then dehydroxylating to give the unsubstituted amidine.
  • the reaction with the hydroxylamine may be carried out in the presence of sodium bicarbonate and in a suitable solvent (e.g., ethanol) at reflux temperature and requires 12 to 18 hours.
  • the dehydroxylation can be effected by reacting the N-hydroxy amidine with zinc in the presence of acetic acid at reflux temperature and requires 3 to 4 hours to complete.
  • the starting materials required for preparing the compounds of Formula I are either commercially available or can be readily prepared by methods known to those of ordinary skill in the art or as described herein.
  • compounds of Formula 1 or Formula 3 in which L is hydroxy and X 1 and X 2 or X 4 and X 5 are adjacent members of an oxazole, imidazole or thiazole ring can be prepared by reacting an appropriate compound of Formula 4 or Formula 2, respectively, with an anhydride of Formula 4:
  • X 3 is as defined in the Summary of the Invention (e.g., dihydrofuran-2,5-dione, furan-2,5-dione, 3,4-dimethylfuran-2,5-dione, isobenzofuran-1 ,3-dione, 4,5,6,7-tetrahydroisobenzofuran-l,3-dione, etc.).
  • a suitable solvent e.g., acetic acid, etc.
  • Compounds of Formula 2(a) in which R 4 is -OR, -NRR' or -SR, wherein R and R' are independent or together with the nitrogen atom to which they are attached form heterocycloalkyl can be prepared by reacting a conespondingly appropriate amine, alcohol, thiol or heterocycloalkane with a co ⁇ esponding halo-subsituted nitroaniline and then reducing.
  • the reaction with the halo-substituted nitroaniline typically is canied out in a suitable solvent (e.g., THF) at 25 to 60 °C and requires 4 to 5 hours to complete.
  • a suitable solvent e.g., THF
  • R 4 , R 5 or R 7 comprises -X 13 C(O)NR 8
  • X 14 R 6 can be prepared by reacting a conesponding compound of Formula I in which R 4 , R 5 or R 7 comprises -X 13 C(O)OH with a compound having the formula R 6 X 14 NHR 8 , wherein X 13 and X 14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R 8 is hydrogen or (C, .6 )alkyl and R 6 is as defined in the Summary of the Invention.
  • the reaction typically is canied out in the presence of 1-hydroxybenzotriazole (HOBT) and a coupling agent
  • R 4 , R 5 or R 7 comprises -X I3 ⁇ R 8 C(O)X 14 R 6
  • R 6 can be prepared by reacting a conesponding compound of Formula I in which R 4 , R 5 or R 7 comprises -X 13 NHR 8 with a compound having the formula R 6 X 14 C(O)OH, wherein X 13 and X 14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R 8 is hydrogen or (C,_ 6 )alkyl and R 6 is as defined in the Summary of the Invention.
  • the reaction typically is carried out in the presence of a coupling agent (e.g., PyBOP, EDCI, 1,1-carbonyldiimidazole, etc.) and a non-nucleophillic base (e.g., N-methylmorpholine, NN-diisopropylethylamine, etc.) and in a suitable solvent (e.g., DMF, THF, dichloromethane, etc., preferably DMF) at 20 to 25 °C and requires 6 to 24 hours to complete.
  • a coupling agent e.g., PyBOP, EDCI, 1,1-carbonyldiimidazole, etc.
  • a non-nucleophillic base e.g., N-methylmorpholine, NN-diisopropylethylamine, etc.
  • a suitable solvent e.g., DMF, THF, dichloromethane, etc., preferably DMF
  • R 4 , R 5 or R 7 comprises -X 13 ⁇ R 8 S(O) 2 X 14 R 6
  • R 6 can be prepared by reacting a conesponding compound of Formula I in which R 4 , R 5 or R 7 comprises -X 13 NHR 8 with a compound having the formula R 6 X 14 S(O) 2 Cl, wherein X 13 and X 14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R 8 is hydrogen or (Cj_ 6 )alkyl and R 6 is as defined in the Summary of the Invention.
  • the reaction typically is carried out in the presence of a non-nucleophillic base (e.g., N-methylmorpholine, NN-diisopropylethylamine, etc.) and in a suitable solvent (e.g., DMF, THF, dichloromethane, etc., preferably DMF) at 20 to 25 °C and requires 12 to 24 hours to complete.
  • a non-nucleophillic base e.g., N-methylmorpholine, NN-diisopropylethylamine, etc.
  • a suitable solvent e.g., DMF, THF, dichloromethane, etc., preferably DMF
  • R 4 , R 5 or R 7 comprises -X 13 ⁇ R 8 CH 2 X 14 R 6
  • R 6 can be prepared by reacting a corresponding compound of Formula I in which R 4 , R 5 or R 7 comprises -X 13 NHR 8 with a compound having the formula R 6 X 14 C(O)H under reducing conditions, wherein X 13 and X 14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of n7 and n8 is 0 to 10, R 8 is hydrogen or (C,. 6 )alkyl and R 6 is as defined in the Summary of the Invention.
  • Compounds of Formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salts of compounds of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application.
  • the salt forms of the compounds of Formula I may be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of Formula I can be prepared from the conesponding base addition salt or acid addition salt form.
  • compounds of Formula I in an acid addition salt form may be converted to the conesponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, etc.
  • Compounds of Formula I in a base addition salt form may be converted to the conesponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
  • a suitable acid e.g., hydrochloric acid, etc.
  • the N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated such as rnethylene chloride) at approximately 0 °C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.
  • a suitable inert organic solvent e.g., a halogenated such as rnethylene chloride
  • Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 °C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, etc.
  • Prodrug derivatives of the compounds of Formula I can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et ⁇ /.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbonochloridate,/ ⁇ r ⁇ -nitrophenyl carbonate, etc.).
  • a suitable carbamylating agent e.g., l,l-acyloxyalkylcarbonochloridate,/ ⁇ r ⁇ -nitrophenyl carbonate, etc.
  • Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Son
  • Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds of Formula I, dissociable complexes are prefened (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromotography or, preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixtures can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).
  • an aspect of this Invention is a process for preparing a compound of Formula I, which process comprises: (a) reacting a compound of Formula 1 :
  • R is -C(O)L or -CN, wherein L is a leaving group
  • E together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and optionally one or more annular members is a heteroatom
  • X 5 is N(R 5 ), O or S
  • R 10 is -OH, -NHR 5 or -SH and heteroatom n2, n3, n4, B
  • X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 5 and R 4 are as defined in the Summary of the Invention, to give a compound of Formula I in which X 4 and X 5 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring; or
  • R 9 is -C(O)L or -CN, wherein L is a leaving group
  • R 10 is -OH, -NHR 5 or -SH and n2, n3, n3, B, C, X 3 , X 4 , X 5 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the Summary of the Invention, to give a compound of Formula I in which X 1 and X 2 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring; or (c) reacting a compound of Formula 5:
  • n2, n3, n3, A, B, C, X 1 , X 2 , X 3 , X 4 , X 5 , R R 2 , R 3 and R 4 are as defined above, to give a conesponding N-hydroxycarboxamidine and then dehydroxylating;
  • R 4 , R 5 or R 7 comprises -X 13 C(O)NR 8 X 14 R 6 , wherein X 13 and X 14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R 8 is hydrogen or (C, .6 )alkyl and R 6 is as defined in the Summary of the Invention;
  • Methyl 3-(8-benzyloxyquinolin-2-yl)propionate a compound of Formula 3 in which L is methoxy, C comprises 3-(8-benzyloxyquinolin-2-yl) and X 3 is -C ⁇ 2 C ⁇ 2 -
  • the following represents an assay for determining the Factor Xa inhibitory activity of compounds of Formula I.
  • Hypnorm® fluanisone 10 mg/mL and phentanylcitrate
  • a catheter (Venflon®2, ⁇ 0.8/25 mm) was inserted into a marginal ear vein for adminstration of test compound.
  • a second catheter (Venflon®2, 0 1.0/32 mm) was inserted into the artery of the other ear for blood sampling.
  • Test compounds were administered by i.v. bolus injection. Blood samples were collected (0.5 mL) prior to adminstration of test compounds and at various time points thereafter.
  • the activating clotting time (ACT) the amount of time for clot formation, was measured with a Medtronic Automated Coagulation Timer ACT II.
  • An aliquot (200 ⁇ L) of the blood sample was added to each of two reaction chambers of a disposable two-channel test cartridge containing assay buffer (comprising: 0.75% kaolin, as the activator, and
  • Clot formation was measured as a decrease in the downward motion of a plunger assembly contained by the test cartridge. The decrease in downward motion of the plunger was detected by a photo-optic system.
  • Example 9 compounds of the present Invention were assayed and found to increase ACT.
  • Rabbit blood was collected from an indwelling catheter in a ear artery into plastic containers. Human blood was collected via venipuncture into vacutainers, some of which contained 0.5 mL of 3.8%> citrate. ACT was measured as described in Example 7. Blood samples were mixed with varying concentrations of test compounds dissolved in physiological saline (30 ⁇ L for non-citrated blood and 15 ⁇ L for citrated blood). Non- citrated blood was used in the assay immediately upon its collection. Citrated blood was kept at ambient temperature for 0.5 to 2 hours and then incubated at 37 °C before used.
  • Example lOcompounds of the present Invention were assayed and found to increased ACT.
  • Citric Acid Monohydrate 18 mg Sodium Hydroxide
  • Citric Acid Monohydrate 1.05 mg

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Abstract

La présente invention concerne de nouveaux dérivés bihétérocycliques, inhibiteurs du facteur Xa; les sels et les N-oxydes pharmaceutiquement acceptables de ces dérivés; ainsi que leur utilisation comme agents thérapeutiques et leurs procédés de fabrication.
PCT/US1998/025241 1997-11-26 1998-11-25 Derives d'amidinoaryle substitue et leur utilisation comme anticoagulants WO1999026933A1 (fr)

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WO2004010996A1 (fr) * 2002-07-29 2004-02-05 Shizuoka Coffein Co., Ltd. Derive 1,3 azole et composition medicale contenant ce derive pour le traitement de thrombose
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WO2016018701A1 (fr) * 2014-07-28 2016-02-04 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xia
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
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WO2000035886A3 (fr) * 1998-12-18 2000-10-26 Axys Pharm Inc Inhibiteurs de proteases
WO2000035886A2 (fr) * 1998-12-18 2000-06-22 Axys Pharmaceuticals, Inc. Inhibiteurs de proteases
DE10048715A1 (de) * 2000-09-30 2004-05-19 Grünenthal GmbH Verwendung von Aminosäure zur Behandlung von Schmerz
JP2005530763A (ja) * 2002-05-13 2005-10-13 アイシーエージェン，インコーポレイティド カリウム・チャネル調節物質としてのビス−ベンズイミダゾール及び関連化合物
EP1511744A2 (fr) * 2002-05-13 2005-03-09 Icagen, Inc. Bis-benzimidazoles et composes associes utilises comme modulateurs des canaux potassiques
EP1511744A4 (fr) * 2002-05-13 2009-10-21 Icagen Inc Bis-benzimidazoles et composes associes utilises comme modulateurs des canaux potassiques
WO2004010996A1 (fr) * 2002-07-29 2004-02-05 Shizuoka Coffein Co., Ltd. Derive 1,3 azole et composition medicale contenant ce derive pour le traitement de thrombose
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques
GB2417955B (en) * 2003-05-13 2008-09-24 Icagen Inc Asymmetric benzimidazoles and related compounds as potassium channel modulators
US7777051B2 (en) 2003-05-13 2010-08-17 Icagen, Inc. Asymmetric benzimidazoles and related compounds as potassium channel modulators
WO2016018701A1 (fr) * 2014-07-28 2016-02-04 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xia
US10011585B2 (en) 2014-07-28 2018-07-03 Merck Sharp & Dohme Corp. Factor XIa inhibitors
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides

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