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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to novel inhibitors of Factor VIIa, pharmaceutical compositions comprising these inhibitors, and methods for using these inhibitors for treating or preventing disorders mediated by Factor VIIa. Processes for preparing these inhibitors are also disclosed.
• 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 VIIa (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 VIIa catalyzes the formation of the serine protease Factor Xa, which subsequently forms the final protease in the cascade, thrombin.
• FVIIa serine protease Factor VIIa
• TF tissue factor
• thrombosis ranges 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 and which often follows orthopedic surgery on the hip and knee, as well as general abdominal surgery and paralysis.
• AMI acute myocardial infarction
• U unstable angina
• DVT deep vein thrombosis
• 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.
• PE pulmonary embolism
• Thrombosis can also be generalized systemically, with microclot formation occurring throughout the vascular system.
• This condition known as disseminated intravascular coagulation (DIC)
• DIC disseminated intravascular coagulation
• Ebola certain cancers
• sepsis certain cancers
• rheumatoid arthritis rheumatoid arthritis
• 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.
• this invention is directed to a compound of Formula I:
• X 1 , X 2 , X 3 , and X 4 are independently —N— or CR 4 — wherein R 4 is hydrogen, alkyl, or halo with the proviso that not more than three of X 1 , X 2 , X 3 and X 4 are —N—;
• R 1 is hydrogen, alkyl, halo, carboxy or aminocarbonyl
• R 2 is hydrogen, alkyl, or halo
• R 3 is dicarboxyalkylaminocarbonylalkyl or dicarboxyalkylaminocarbonylcycloalkyl
• R x is hydrogen, alkyl, alkylthio, halo, hydroxy, hydroxyalkyl, alkoxy, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, or nitro;
• R y is hydrogen, alkyl, or halo
• R z 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, heteroarylsulfonyl, carbamimidoyl, hydroxy-carbamimidoyl, alkoxycarbamimidoyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, alkoxysulfonylamino, alkoxysul
• R 13 is hydrogen, hydroxy, (C 1-10 )alkoxy, —C(O)R 35 where R 35 is alkyl, aryl, haloalkyl, or cyanoalkyl, or —C(O)OR 36 where R 36 is alkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyl, aryl, or haloalkyl; or
• this invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I, or a zwitterion thereof, or a pharmaceutically acceptable salt thereof.
• this invention is directed to a method of treating a disease in an animal that is mediated by Factors VIIa, IXa, Xa and/or XIa, preferably VIIa, which method comprises administering to said animal a therapeutically effective amount of a compound of Formula I, or a zwitterions thereof, or a pharmaceutically acceptable salt thereof.
• the disorder is a thromboembolic disorder or cancer or rheumatoid arthritis, more preferably a thromboembolic disorder, even more preferably the disorder is deep vein thrombosis.
• the compound of the invention is administered prophylactically.
• this invention is directed to a method of treating a thromboembolic disorder in an animal which method comprises administering to said animal a therapeutically effective amount of a compound of Formula I, or a zwitterion thereof, or a pharmaceutically acceptable salt thereof in combination with another anticoagulant agent(s) independently selected from a group consisting of a thrombin inhibitor, factor IXa inhibitor, factor Xa inhibitor, Aspirin®, and Plavix®.
• this invention is directed to a method for inhibiting the coagulation of a biological sample (e.g., stored blood products and samples) comprising the administration of a compound of Formula I, or a zwitterion thereof, or a pharmaceutically acceptable salt thereof.
• a biological sample e.g., stored blood products and samples
• this invention directed to the use of a compound of Formula I, or a zwitterion thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament.
• the medicament is useful in the treatment of a thromboembolic disorder or cancer or rheumatoid arthritis in an animal.
• the disorder is a thromboembolic disorder such as deep vein thrombosis.
• this invention is directed to an intermediate of formula (II):
• PG 1 is a suitable oxygen-protecting group and PG 2 is a suitable amino-protecting group.
• PG 1 is alkyl or aralkyl, more preferably benzyl.
• PG 2 is alkyl, more preferably tert-butyl.
• this invention is directed to a process of preparing a compound of Formula I where R 3 is dicarboxyalkylaminocarbonylalkyl comprising:
• R 1 , R 2 , R 13 , R x , R y , R z , X 1 —X 4 are as defined in the Summary of the Invention or a suitably protected derivative thereof; with dicarboxyalkylamino where the carboxy groups are optionally protected;
• step (iii) optionally converting the product from step (ii) or (iii) above, to an acid addition salt
• step (iv) optionally converting the product from step (ii) or (iii) above, to a free base
• step (v) optionally converting the product from step (ii) or (iii) above, to a zwitterions.
• this invention is directed to a process of preparing a compound of Formula Ib or Ic:
• the carboxy groups are protected with benzyl groups and the compound being prepared is Ib.
• this invention is directed to a method of preparing an intermediate of formula (II):
• PG 1 is a suitable oxygen-protecting group and PG 2 is a suitable amino-protecting group comprising: (i) reacting a compound of formula (III):
• PG 1 and PG 2 are as defined above and X is halo; with one equivalent of an organometallic agent of formula RLi or RMgX 1 where R is alkyl or aryl and X 1 is halo to deprotonate the —SO 2 NHPG2 group; (ii) transmetallating the compound generated in Step (i) above with one equivalent of an organometallic agent of formula RLi or RMgX 1 where R is alkyl or aryl; (iii) treating the compound generated in Step (ii) above with trialkylborate to generate a compound of formula (II).
• methylmagnesium bromide is used in Step (i) above; i-propylmagnesium bromide is used in Step (ii) above and the trialkylborate is trimethylborate.
• PG 1 is benzyl, PG 2 is tert-butyl and X is iodo.
• 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), pentyl (including all isomeric forms), and the like.
• 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-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
• Alkylthio means a radical —SR where R is alkyl as defined above, e.g., methylthio, ethylthio, propylthio (including all isomeric forms), butylthio (including all isomeric forms), and the like.
• Amino means the radical —NRR′ where R and R′ are independently hydrogen, alkyl, or —COR a where R a is alkyl, e.g., —NH 2 , methylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the like.
• Alkylamino means a radical —NHR where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino (including all isomeric forms), and the like.
• “Acyl” means a radical —COR′ where R′ is alkyl, alkoxy, haloalkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl as defined herein, e.g., acetyl, trifluoroacetyl, hydroxymethylcarbonyl, and the like.
• Aminosulfonyl or “sulfamoyl” means a radical —SO 2 NH 2 .
• Alkylaminosulfonyl means a radical —SO 2 NHR where R is alkyl as defined above, e.g., methylaminosulfonyl, ethylamino-sulfonyl, and the like.
• Alkylsulfonyl means a radical —SO 2 R where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, n- or iso-propylsulfonyl, and the like.
• Alkylsulfonylalkyl means a radical -(alkylene)-SO 2 R where R is alkyl as defined above, e.g., methylsulfonylmethyl, ethylsulfonylmethyl, n- or iso-propylsulfonylethyl, and the like.
• Alkylsulfonylamino means a radical —NHSO 2 R where R is alkyl as defined above, e.g., methylsulfonylamino, ethylsulfonylamino, n- or iso-propylsulfonylamino, and the like.
• Alkylsulfonylaminoalkyl means a radical -(alkylene)-NHSO 2 R where R is alkyl as defined above, e.g., methylsulfonylaminomethyl, ethylsulfonylaminomethyl, n- or iso-propylsulfonylaminoethyl, and the like.
• Alkoxysulfonylamino means a radical —NHSO 2 R where R is alkoxy as defined herein, e.g., methoxysulfonylamino, ethoxysulfonylamino, and the like.
• Alkoxysulfonylaminoalkyl means a radical -(alkylene)-NHSO 2 R where R is alkoxy as defined herein, e.g., methoxysulfonylaminomethyl, ethoxysulfonylaminomethyl, and the like.
• Alkoxy means a radical —OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
• Alkoxycarbonyl means a radical —COOR where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
• Alkoxycarbonylalkyl means a radical -(alkylene)-COOR where R is alkyl as defined above, e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl, and the like.
• 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, 2-ethoxyethyl, and the like.
• 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 —COR a where R a is alkyl, e.g., aminomethyl, methylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the like.
• 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 —COR a where R a is alkyl, e.g., aminocarbonylmethyl, methylaminocarbonylmethyl, acetylaminocarbonylpropyl, and the like.
• Alkoxyalkyloxy means a radical —OR where R is alkoxyalkyl, as defined above, e.g., 2-methoxyethyloxy, 1-, 2-, or 3-methoxypropyloxy, 2-ethoxyethyloxy, and the like.
• Aminoalkyloxy means a radical —OR where R is aminoalkyl, as defined above, e.g., 2-aminoethyloxy, 1-, 2-, or 3-methylaminopropyloxy, and the like.
• Aminocarbonyl or “carbamoyl” means a radical —CONH 2 .
• Aminocarbonylalkyloxy means a radical —O-(alkylene)-CONRR′′ where R and R′ are independently hydrogen or alkyl, as defined above, e.g., 2-aminocarbonylethyloxy, aminocarbonylmethyloxy, and the like.
• Alkylureido means a radical —NRCONHR′ where R is hydrogen or alkyl and R′ is alkyl, e.g., methylureidomethyl, and the like.
• Alkylureidoalkyl means a radical -(alkylene)-NRCONHR′ where R is hydrogen or alkyl and R′ is alkyl, e.g., methylureidomethyl, and the like.
• 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.
• Arylsulfonyl means a radical —SO 2 R where R is aryl as defined above, e.g., phenylsulfonyl, and the like.
• Alkyl means a radical -(alkylene)-R where R is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
• Alkoxycarbamimidoyl means a radical —C( ⁇ NH)NHOR or —C( ⁇ NOR)NH 2 where R is alkyl as defined above, e.g., methoxycarbamimidoyl.
• Cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., cyclopropyl, cyclobutyl, and the like, preferably cyclopropyl.
• Carboxyalkyl means a radical -(alkylene)-COOH, e.g., carboxymethyl, carboxyethyl, 1-, 2-, or 3-carboxypropyl, and the like.
• Carboxyalkyloxy means a radical —O-(alkylene)-COOH, e.g., carboxymethyloxy, carboxyethyloxy, and the like.
• Carbamimidoyl means a radical —C( ⁇ NH)NH 2 , or a protected derivative thereof.
• Cyanoalkyl means a radical -(alkylene)-CN, e.g., cyanomethyl, cyanoethyl, cyanopropyl, and the like.
• “Dicarboxyalkylaminocarbonylalkyl” means a radical -(alkylene)-CONHR where R is alkyl, as defined herein, substituted with two carboxy groups, e.g., —CH 2 CONHCH(COOH)(CH 2 COOH), —CH 2 CONHCH(CH 2 COOH) 2 , —C(CH 3 ) 2 —CONHCH(COOH)(CH 2 COOH), —C(CH 3 ) 2 —CONHCH(CH 2 COOH) 2 , and the like.
• Dicarboxyalkylamino means a radical —NHR where R is alkyl, as defined herein, substituted with two carboxy groups
• Dicarboxyalkyaminocarbonylcycloalkyl means radical of the formula:
• n 1 to 4 and R is alkyl, as defined herein, substituted with two carboxy groups.
• Dialkylamino means a radical —NRR′ where R and R′ are independently alkyl as defined above, e.g., dimethylamino, methylethylamino, methylopropylamino (including all isomeric forms), and the like.
• Dialkylaminosulfonyl means a radical —SO 2 NRR′ where R and R′ are independently alkyl as defined above, e.g., dimethylaminosulfonyl, methylethylamino-sulfonyl, and the like.
• Dialkylureido means a radical —NRCONR′R′′ where R is hydrogen or alkyl and R′ and R′′ are independently alkyl, e.g., dimethylureido, and the like.
• Dialkylureidoalkyl means a radical -(alkylene)-NRCONR′R′′ where R is hydrogen or alkyl and R′ and R′′ are independently alkyl, e.g., dimethylureidomethyl, and the like.
• “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 —COR a where R a is alkyl, e.g., guanidinomethyl, N-methylaminoethyl, 2-(N′,N′,N′′,N′′-tetramethyl-guanidino)-ethyl, and the like.
• Halo means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
• 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., —CH 2 Cl, —CF 3 , —CHF 2 , and the like.
• Haloalkoxy means a radical —OR where R is haloalkyl as defined above, e.g., —OCH 2 Cl, —OCF 3 , —OCHF 2 , and the like.
• Hydroalkyl 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-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 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-(hydroxymethyl)-2-hydroxyethyl.
• Haldroxyalkyloxy means a radical —OR where R is hydroxyalkyl as defined above, e.g., 2-hydroxyethyloxy, 3-hydroxypropyloxy, and the like.
• Haldroxyalkoxyalkylaminocarbonyl means a radical —CONH-(alkylene)-O-(alkylene)OH where alkylene is as defined above, e.g., —CONH—(CH 2 ) 2 —O—(CH 2 ) 2 OH and the like.
• 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(O)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-hydroxymethyl-tetrahydropyran-3-yl, 4,5-dihydroxy-2-hydroxymethyl-6-(4,5,6-trihydroxy-2-hydroxymethyl-tetrahydro-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 —CONR a R b (where R a and R b are independently hydrogen or alkyl), or a protected derivative thereof. More specifically the term heterocycloalkyl includes, but is not
• 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.
• 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-piperidinocarbonylmethyl, 4-morpholinocarbonylethyl, 1-piperazinocarbonylmethyl, and the derivatives thereof.
• 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.
• Heterocycloalkylalkylaminocarbonyl means a radical —CONH-(alkylene)-R where R is heterocycloalkyl as defined above. More specifically the term heterocycloalkylalkylamino-carbonyl includes, but is not limited to, 1-pyrrolidinoethyl-aminocarbonyl, 1-piperidinoethyl-aminocarbonyl, 4-morpholinoethylcarbonyl, 1-piperazinoethylaminocarbonyl, and 4-thiomorpholinopropylaminocarbonyl, and the derivatives thereof.
• 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.
• heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, imidazolyl, thienyl, furanyl, indolyl, quinolyl, pyrazine, pyrimidine, pyradizine, oxazole, isooxazolyl, benzoxazole, quinoline, isoquinoline, benzopyranyl, and thiazolyl.
• Heteroarylsulfonyl means a radical —SO 2 R where R is heteroaryl as defined above, e.g., pyridylsulfonyl, furanylsulfonyl, and the like.
• Heteroaralkyl means a radical -(alkylene)-R where R is a heteroaryl group as defined above e.g., pyridylmethyl, furanylmethyl, indolylmethyl, pyrimidinylmethyl, and the like.
• 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(O)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 or two substituents, independently selected from alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, guanidinoalkyl, halo, haloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, haloalkyl, halo, cyano, carboxy, —CONR a R b (where R a and R b 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.
• Haldroxycarbamimidoyl means a radical —C( ⁇ NH)NHOH or —C( ⁇ NOH)NH 2 .
• the present invention also includes the prodrugs of compounds of Formula I.
• the term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula I, when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
• Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups by routine manipulation or in vivo.
• Prodrugs of compounds of Formula I include compounds wherein a hydroxy, carbamimidoyl, guanidino, amino, carboxylic, or a similar group is modified.
• prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I and the like.
• esters e.g., acetate, formate, and benzoate derivatives
• carbamates e.g., N,N-dimethylaminocarbonyl
• Prodrugs of compounds of Formula I are also within the scope of this invention.
• the present invention also includes (derivatives and protected derivatives of compounds of Formula I.
• 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.
• 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.
• suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis , John Wiley & Sons, Inc. 1999, the disclosure of which is incorporated herein by reference in its entirety.
• the protected derivatives of compounds of Formula I can be prepared by methods well known in the art.
• 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, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic 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, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid,
• a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
• organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
• 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, and the like 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.
• Certain compounds that contain a basic group such as an amine portion and an acid portion e.g., carboxylic acid portion, depending upon the pH of the solution, may exist as a free amine and a free carboxylic acid or as a zwitterion in which the amine is protonated to form an ammonium ion and the carboxylic acid is deprotonated to form a carboxylate ion. All such zwitterions are included in this invention.
• 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(O)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 ⁇ O) 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.
• 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.
• 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-oxomorpholin-4-yl-(methyl, ethyl, or propyl), 2-oxopiperazin-1-yl-(methyl, ethyl, or propyl), 2-oxotetrahydro-pyran-3-yl-(methyl, ethyl, or propyl), 3-oxothiomorpholin-4-yl-(methyl, ethyl, or propyl), 2-imi
• 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.
• 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.
• Treating” or “treatment” of a disease includes:
• 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.
• 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.
• Thioureido means a radical —NRC(S)NR′R′′ where R, R′, and R′′ are independently hydrogen or alkyl.
• Thioureidoalkyl means a radical -(alkylene)-NRC(S)NR′R′′ where alkylene is as defined above. Representative examples include but are not limited to thioureidomethyl, thioureidoethyl, and the like.
• “Ureido” means a radical —NHCONH 2 .
• “Ureidoalkyl” means a radical -(alkylene)-NHCONH 2 where alkylene is as defined above. Representative examples include but are not limited to ureidomethyl, ureidoethyl, and the like.
• R 1 , R 2 and R y are hydrogen;
• X 1 is —N—, X 2 , X 3 , and X 4 are carbon are disclosed in Table I below.
• R 3 , R 13 and R z are as defined in the Summary of the Invention.
• R 3 is dicarboxyalkylaminocarbonylalkyl, preferably —CH 2 CONHR or —C(CH 3 ) 2 CONHR wherein R is dicarboxyalkyl, more preferably 1,2-dicarboxyethyl or 1,3-dicarboxyprop-2-yl, even more preferably (R)-1,2-dicarboxyethyl or (S)-1,2-dicarboxyethyl.
• R z is halo, hydroxyalkyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, alkylsulfonyl, aminosulfonyl, heterocycloalkylcarbonylalkyl, oxoheterocycloalkyl, carboxyalkyl, oxoheterocycloalkylalkyl, heteroaralkyl, ureido, alkylureido, dialkylureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, thioureido, thioureidoalkyl, —COR 12 (where R 12 is alkyl, hydroxyalkyl, or haloalkyl), -(alkylene)-COR 12 (where R 12 is alkyl or haloalkyl), —CONR 14 R 15 (where R 14 is hydrogen or
• R z is aminosulfonyl, alkylsulfonylaminoalkyl, halo, carboxyalkyl, hydroxyalkyl, heterocycloalkylcarbonylalkyl, ureido, ureidoalkyl, alkylureidoalkyl, dialkylureidoalkyl, —CONR 14 R 15 (where R 14 is hydrogen or alkyl and R 15 is hydrogen or alkyl), -(alkylene)-CONR 16 R 17 (where R 16 is hydrogen or alkyl and R 17 is hydrogen, alkyl, or hydroxyalkyl), or -(alkylene)-NR 20 R 21 (where R 20 is hydrogen or alkyl and R 21 is hydrogen, alkyl, hydroxyalkyl or acyl).
• R z is fluoro, aminosulfonyl, ureidomethyl, tert-butylureidomethyl, 3,3-dimethylureidomethyl, aminomethyl, piperazin-1-ylcarbonyl-methyl, carboxymethyl, hydroxymethylcarbonylaminomethyl, aminocarbonyl, acetylaminomethyl, aminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-hydroxyethylaminocarbonylmethyl, morpholin-4-yl-carbonylmethyl, methoxycarbonylaminomethyl, R or S, or RS-1-hydroxyethylcarbonyl-aminomethyl, hydroxymethyl, or methylsulfonylaminomethyl.
• R 13 is hydrogen, hydroxy, methoxy, or ethoxycarbonyl, more preferably hydrogen.
• R 1 and R 2 are hydrogen, X 1 is nitrogen, X 2 —X 4 are carbon and R 3 is dicarboxyaminocarbonylalkyl, preferably —CH 2 CONHR or —C(CH 3 ) 2 CONHR wherein R is 1,2-dicarboxyethyl or 1,3-dicarboxyprop-2-yl, even more preferably (R)-1,2-dicarboxyethyl.
• R z is fluoro, aminosulfonyl, ureidomethyl, —CH 2 NHCONCH 3 , —CH 2 NHCONHC(CH 3 ) 3 , N,N-dimethylureidomethyl, aminomethyl, piperazin-1-ylcarbonylmethyl, carboxymethyl, —CH 2 NHCOCH 2 OH, aminocarbonyl, acetylaminomethyl, aminocarbonylmethyl, methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-hydroxyethylaminocarbonylmethyl, morpholin-4-ylcarbonylmethyl, methoxycarbonylaminomethyl, hydroxymethyl, or methylsulfonylaminomethyl.
• 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 Supplementals (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.
• 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, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
• 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.
• Formylation of a phenol derivative of formula 1 (where R is hydrogen or hydroxy protecting group, preferably hydroxy, and R′ is alkyl) provides a compound of formula 2.
• the formylation reaction is carried out in the presence of magnesium chloride and an organic base such as triethylamine, and the like, and in a suitable organic solvent such as acetonitrile, and the like.
• Halogenation of 2 with a suitable halogenating agent such as N-bromosuccinimide, N-iodosuccinimide, and the like and in a suitable organic solvent such as dimethylformamide, and the like provides a compound of formula 3 where X is halo.
• hydroxy group in 3 (where R is hydrogen) with a suitable hydroxy protecting group such as alkyl, methyoxyethoxymethyl, benzyl, and the like, provides a compound of formula 4.
• a suitable hydroxy protecting group such as alkyl, methyoxyethoxymethyl, benzyl, and the like.
• Preferred hydroxy protecting groups are 2-methoxyethoxymethyl and benzyl.
• the reaction is typically carried out in the presence of a base such as diisopropylethylamine, and the like, and in a halogenated organic solvent such as dichloromethane, carbon tetrachloride, chloroform, and the like.
• a base such as diisopropylethylamine, and the like
• a halogenated organic solvent such as dichloromethane, carbon tetrachloride, chloroform, and the like.
• 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, potassium carbonate and the like.
• a palladium catalyst such as tetrakis(triphenylphosphine)palladium
• a suitable organic solvent such as toluene or dimethoxyethane
• a base such as aqueous sodium carbonate, potassium carbonate and the like.
• reaction can be carried out in the presence of PdCl 2 (dppf).CH 2 Cl 2 complex in the presence of diisopropylamine in a suitable organic solvent such as tetrahydrofuran, and the like.
• suitable organic solvent such as tetrahydrofuran, and the like.
• Compounds of formula 5 are either commercially available or they can be prepared by methods well known in the art. For example, 5-fluoro-2-methoxyboronic acid is commercially available.
• Others can be prepared by treating a halogenated benzene of the formula Ph-(R x , R y R z )X where X is halo and R x , R y and R z are as defined in the Summary of the Invention with organic metallic reagent such as n-butyl lithium to generate a organic metallic species which upon treatment with trimethylborate provides the corresponding boronic acid.
• organic metallic reagent such as n-butyl lithium
• Halogenated benzene of the formula Ph-(R x , R y R z )X is either commercially available or it 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-tert-butyl urea can be prepared by treating 3-bromo-4-hydroxybenzonitrile with methoxyethoxymethyl chloride in the presence of a base such as diisopropylamine, and the like, followed by reduction of the resulting 3-bromo-4-methylethoxymethoxy)benzonitrile to 3-bromo-4-methoxyethoxymethoxybenzylamine with a suitable reducing agent such as diborane. Treatment of 3-bromo-4-methylethoxybenzylamine with tert-butylisocyanate then provides the desired compound.
• 1-(3-Bromo-4-methoxyethoxymethoxybenzyl)-3-tert-butyl urea can be converted to 1-(3-bromo-4-methoxyethoxymethoxybenzyl)urea by removal of the tert-butyl group under acidic hydrolysis reaction conditions.
• a suitable oxidant such as benzoquinone, air oxidation, or FeCl 3 and O 2
• a suitable organic solvent such as methanol, ethanol, and the like
• the reaction is carried out utilizing aqueous solution of sodium metabisulfite in an alcoholic solvent such as isopropanol, and in the presence of oxygen.
• the amination reaction is carried out reacting in the presence of a suitable coupling agent e.g., benzotriazole-1-yloxytris-pyrrolidinophosphonium hexafluorophosphate (PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of 1-hydroxybenzotriazole (HOBT), and a base such as N,N-diisopropylethylamine, triethylamine, N-methylmorpholine,
• hydroxy protecting group Protection of the hydroxy group in a compound of formula 7 with a suitable hydroxy protecting group provides a compound of formula 11.
• a comprehensive list of suitable hydroxy protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis , John Wiley & Sons, Inc. 1999, the disclosure of which is incorporated herein by reference in its entirety.
• Preferred hydroxy protecting group is 2-methoxyethoxymethyl.
• the reaction is typically carried out in the presence of a base such as N,N-diisopropylethylamine, and the like, and in a halogenated organic solvent such as dichloromethane, carbon tetrachloride, chloroform, and the like.
• Deprotection of the amino group in 14 provides a 5-cyano-2-(biphenyl-3-yl)-1H-indole compound of formula 15.
• 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, potassium hydroxide, and the like. The reaction is carried out in an alcoholic solution such as methanol, ethanol, and the like. If the protecting group is tert-butoxycarbonyl it is removed under acidic hydrolysis reaction conditions.
• Compounds of formula 13 are either commercially available or they can be prepared by methods well known in the art.
• the hydroxy-protecting group in 15 is then removed to provide 5-cyano-2-(2-hydroxybiphenyl-3-yl)-1H-indole 16.
• 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 16 with an acid under non-aqueous reaction conditions, in a suitable alcoholic solvent.
• the cyano group in compound 16 is then converted into the carbamimidoyl group by first treating 16 with hydrogen chloride gas in an anhydrous alcoholic solvent such as methanol, ethanol and the like, and then treating the resulting (5-methoxycarbonimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole 17 with an inorganic base such as ammonium carbonate, and the like in an alcoholic solvent such as methanol, ethanol, or with excess ammonia to give resulting (5-carbamimidolyl)-2-(2-hydroxybiphenyl-3-yl)-1H-indole of formula 18 which is then converted to a compound of Formula I as described in Scheme I above.
• anhydrous alcoholic solvent such as methanol, ethanol and the like
• Compounds of Formula I can be converted to other compounds of Formula I.
• a compound of Formula I where R x is alkoxy can be converted to corresponding compound of Formula I where R x is hydroxy by hydrolysis of the alkoxy group by a suitable dealkylating reagent such as hydrobromic acid, and the like.
• a compound of Formula I where R z is cyano can be converted to a corresponding compound of Formula I where R z 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 R z is ureidomethyl or thioureidomethyl respectively.
• a compound of Formula I where R 13 is hydrogen can be converted to a corresponding compound of Formula I where R 13 is hydroxy or alkoxy by reacting it with hydroxylamine or alkoxyamine under conditions well known in the art.
• the compounds of this invention inhibit Factors VIIa, IXa, Xa, and XIa, in particular Factor VIIa, and are therefore useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals.
• venous thrombosis e.g. DVT
• pulmonary embolism e.g. in myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis
• 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
• thrombosis after thrombolysis, percutaneous trans-luminal angioplasty (PTA) and coronary bypass operations
• PTA percutaneous trans-luminal angioplasty
• coronary bypass operations the prevention of rethrombosis after microsurgery and vascular surgery in general.
• Further indications 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 is in 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,
• the compounds of Formula I can also be used in the treatment of cancer or rheumatoid arthritis.
• 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.
• 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, even more preferably about 0.25 mg/kg/day to 10 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.
• 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.
• routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
• parenteral e.g., intramuscular, intravenous or subcutaneous
• the preferred manner of administration is oral or parenteral using a convenient 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 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.
• 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.
• the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
• 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.
• the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula I are described below.
• 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).
• 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.
• the thrombin inhibitor is Inogatran®, Melagatran® or prodrugs thereof which are disclosed in PCT Application Publication Nos. WO 94/29336 and WO 97/23499, the disclosures of which are incorporated herein by reference in their entirety.
• 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,
• 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, the specific and generic disclosures in all of which documents are hereby incorporated by reference, 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 U.S. Pat. No.
• 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, which are incorporated herein by reference in their entirety.
• 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, the disclosures in which documents are hereby incorporated by reference.
• 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, the disclosures in which documents are hereby incorporated by reference. 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.
• 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.
• Suitable doses of melagatran, Factor Xa 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 (or derivatives (including prodrugs) thereof), and to Factor Xa inhibitors, that are mentioned hereinbefore, the disclosures in which documents are hereby incorporated by reference.
• the reaction mixture was diluted with isopropylacetate (3 L), and the resulting solution was extracted with water to remove the DMF. Concentration of the organic phase afforded a reddish solid that was dissolved in hot isopropanol (400 mL) and allowed to cool while stirring. The resulting off-white crystalline product was filtered and washed with cold IPA ( ⁇ 20° C.; 400 mL) to yield methyl (3-bromo-5-formyl-4-hydroxyphenyl)acetate (368 g, 84.7%) as off-white crystals.
• Paraformaldehyde (95% w/w as prills; Aldrich #44,124-4; 63.2 g, 2.00 mols, 2.00 eq.) was added portionwise over 30 min. After heating to 80° C. for 2 h, the reaction was found to be incomplete and hence a further portion of paraformaldehye (6.00 g, 0.20 mols, 0.2 eq.) was added portion-wise. After 2 h, the reaction mixture was concentrated in situ (T int ⁇ 70° C.; approx. 30-40 Torr) to approx. 1 ⁇ 3 its original volume and then allowed to cool to room temperature. Water (500 mL) was added over a few minutes and a thick yellow slurry formed.
• 4-Amino-3-nitro-benzimidic acid ethyl ester hydrochloride (84.5 g, 344 mmol) was suspended in absolute ethanol (750 mL) and then cooled to 0° C. Ammonia was then passed through the solution for a period of 2 h. The flask was tightly sealed and allowed to warm up to room temperature over an 18 h period with stirring. The product was crystallized with diethyl ether and the resulting solid was filtered, washed and dried to give 4-amino-3-nitrobenzamidine monohydrochloride (70.7 g) as an off-white powder.
• the reaction mixture was treated with phosphorus pentachloride (217.8 g, 1.045 mol) and stirred at room temperature for 2 h.
• the reaction mixture was concentrated in vacuo to remove most of the volatile components then further concentrated at a bath temperature of 100° C. to remove POCl 3 produced in the reaction.
• the resulting oily residue was dissolved in CH 2 Cl 2 (2.8 L) and this solution was stirred with water (3 L) while solid sodium bicarbonate was added to maintain the pH around 7.
• the layers were separated and the organic phase was cooled to 0° C., then tert-butylamine (230 mL, 160 g) was added at such a rate to maintain the internal temperature ⁇ 10° C.
• N-tert-Butyl 3-iodo-4-methoxybenzenesulfonamide (335 g, 907 mmol) was dissolved in dichloromethane (3 L) and the resulting solution was cooled to an internal temperature of ⁇ 20° C.
• the solution was treated with a 3.0 M solution of methylmagnesium bromide in diethyl ether (308 mL, 925 mmol) dropwise over 0.5 h to maintain the internal temperature of the flask at ⁇ 20 ⁇ 5° C.
• the reaction mixture was allowed to stir at ⁇ 20 ⁇ 5° C.
• the reaction mixture was treated with trimethylborate (320 mL; 2.90 mol) in THF (175 mL) in one portion, resulting in a temperature increase to 27° C.
• the reaction mixture was stirred at this temperature for 4 h, then poured into water (1.3 L) and 85% phosphoric acid was added until the solution was pH 2.
• the layers were separated and the organic phase was washed with 1.5 N aqueous NaOH (2 L), followed by 1% aqueous NaOH (2 L).
• the combined aqueous phases were acidified with phosphoric acid to pH 2 and the resulting acidic solution was extracted with 9:1 dichloromethane/THF solution (2 L followed by 1 L).
• the reaction mixture was diluted with 0.5 N aqueous HCl (1 L) and the solution was allowed to stir at ambient temperature for 0.25 h, then the layers were separated. The organic layer was washed with additional 0.5 N aqueous HCl, followed by saturated aqueous sodium chloride (1 L). The organic layer was concentrated under vacuum to give an oil, which later solidified upon standing. The solid could be crystallized from ethyl acetate and hexane to yield methyl[3-bromo-5-formyl-4-(2-methoxyethoxymethoxy)phenyl]-acetate (237 g) as a colorless solid.
• Tetrahydrofuran (17 mL) and trimethyl borate (6 mL) were then added precipitating a white solid and raising the internal temperature of the reaction mixture to 0° C.
• the reaction mixture was allowed to warm to room temperature and after 12 h phosphoric acid (250 mL of 1M in 500 mL of water) was added.
• the organic layer was separated and basified with 2.5% aqueous sodium hydroxide (500 mL) causing some of the product to precipitate.
• the aqueous layer along with some of the precipitated solids was then acidified with concentrated phosphoric acid to a pH of 2 and extracted with 10% tetrahydrofuran in dichloromethane.
• a 3-neck, 3 L-round-bottom flask was equipped with an over-head stirrer, thermometer, N 2 line, 250 mL pressure-equalizing dropping funnel, and gas-exit scrubber to a NaOH solution.
• the flask was flushed with N 2 and charged with 2-iodophenol (Alfa Aesar; 201.95, 0.918 mol) and dry dichloromethane (920 mL).
• a gentle stream of N 2 was established through the reaction head-space, the reaction vessel then immersed in a brine-ice bath and cooled to ⁇ 5° C.
• the dropping funnel was charged with dry dichloromethane (175 mL), then chlorosulfonic acid (Aldrich; 106.96 g, 0.918 mol, 1.00 eq.), and the resulting mixture was stirred with a Teflon rod.
• the dilute solution of chlorosulfonic acid was then added dropwise to the reaction mixture over a period of approx. 90 mins. A thick pink slurry formed during the addition.
• the ice bath was removed and the reaction mixture was allowed to stir at ambient temperature. After 2 h, the reaction vessel was immersed in a cold-water bath and water (500 mL) was added to the reaction mixture over a few minutes.
• the resulting mixture was stirred vigorously until it was biphasic/homogenous upon settling.
• the mixture was transferred to a separating funnel along with water and was extracted with dichloromethane.
• the aqueous layer containing 4-hydroxy-3-iodo-benzenesulfonic acid was transferred back to the original reaction vessel for the next step.
• a 3-neck, 3 L, round-bottom flask was equipped with an over-head stirrer, reflux condenser (with gas exit to NaOH scrub solution), and a pressure-equalizing dropping-funnel with N 2 line.
• the flask was flushed with N 2 , charged with sodium 4-benzyloxy-3-iodo-benzenesulfonate (234 g, 0.568 mol), dichloromethane (1.15 L), and catalytic amount of dimethylformamide (910 mg, 11.7 mmol, 2.1 mol %).
• the white suspension was stirred under a gentle stream of nitrogen and heated in an oil-bath set between 40 and 45° C.
• Oxalyl chloride (90.1 g, 0.710 mol, 1.25 eq) was then added over 3-5 min. After 2.5 h, the reaction was allowed to cool to 25° C. in a cold-water bath and then quenched drop-wise with water (60 mL) over approx. 5 min. A further portion of water (450 mL) was added in a single portion and the reaction mixture stirred vigorously for 5 to 10 min. The organic layer was separated and washed with water until the aqueous pH had increased to pH 4 to 5). The resulting dichloromethane solution of 4-benzyloxy-3-iodo-benzenesulfonyl chloride was used in the next step.
• a 3-neck, 3 L, round-bottom flask was equipped with an over-head stirrer, thermometer, and a pressure-equalizing dropping-funnel was charged with the solution of 4-benzyloxy-3-iodo-benzenesulfonyl chloride.
• T int no change The resulting reaction mixture was stirred overnight at the ambient water-bath temperature. After 17 h, the reaction mixture was worked-up and the organic layer was separated and concentrated to approx.
• a 3-neck, 2 L-round-bottom flask was equipped with an over-head stirrer, thermometer, pressure-equalizing dropping-funnel, and an N 2 line.
• the flask was flushed with N 2 and then charged with 4-benzyloxy-N-tert-butyl-3-iodo-benzenesulfonamide (198.6 g, 0.446 mol) and dichloromethane (600 mL).
• the white suspension was stirred under a gentle stream of N 2 and cooled in an ice-water bath (0° C. ⁇ T int ⁇ 5° C.).
• the dry, solid product was transferred to a 3 L 3-neck round bottom flask fitted with a Dean-Stark trap, a stirring shaft and a nitrogen inlet.
• the flask was flushed with nitrogen then pyridine hydrochloride (412 g, 3.57 mol) and toluene (100 mL) were added.
• the reaction mixture was heated under reflux to remove residual water from the pyridine salt and solvent.
• the solution was heated to 150° C. to melt the pyridine hydrochloride after which the temperature was increased to 180° C. over 0.5 h. After 1.5 h, the solution was cooled under a positive pressure of nitrogen until it solidified and reached room temperature. Water (3 L) was added and the solution was allowed to stir at room temperature overnight.
• reaction mixture was filtered and the solid was washed with water (200 mL) and isopropanol (100 mL). The solid was dried in a vacuum chamber overnight to yield [5-(5-carbamimidoyl-1H-benzimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-yl]-acetic acid (38.15 g) which was contaminated with about 4% sulfonic acid.
• the reaction mixture was placed under a nitrogen atmosphere and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.68 g, 0.832 mmol) was added.
• the reaction mixture was heated to reflux for 16 h at which time it was complete by HPLC.
• the solution was concentrated to a solid and methyl tert-butyl ether (500 ml) was added to dissolve the solid.
• the solution was washed twice with 3% cold aqueous sodium hydroxide solution (500 mL).
• the organic layer was filtered through a plug of Celite (200 g) and silica gel (100 g).
• the reaction mixture was heated to reflux with an oil bath and the top of the reflux condenser was left open to the air.
• the solution was heated to reflux overnight, at which time it was complete by HPLC.
• Darco 5 g
• the solution was filtered hot through celite (100 g).
• the celite was washed with isopropanol (100 mL) and the resulting solution was extracted with ethyl acetate (300 mL) and brine (70 mL).
• Crystalline material (5.2 g) was filtered at room temperature, was washed with water until washings were neutral (pH 7). Elemental analysis and chloride content analysis revealed absence of any chloride counter ion, indicating that the material is zwitter-ionic.
• Rats with pre-implanted jugular vein 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.
• 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.
• Plasma 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.
• 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.
• 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-Pleasantville, N.Y.). 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.
• 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. to 100 mL
• 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 HCl (1 N) or NaOH (1 N) q.s. to suitable pH water (distilled, sterile) q.s. to 20 mL
• Suppository Formulation 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 Parenteral Formulation Compound (Ib) 40 mg/mL Hydroxypropyl- ⁇ -cyclodextrin 200 mg/mL Adjust pH with 1.0 N sodium hydroxide to 7.4

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