WO1999026932A1 - Derives heterocycliques substitues par un groupe amidino et leur utilisation en tant qu'anticoagulants - Google Patents

Derives heterocycliques substitues par un groupe amidino et leur utilisation en tant qu'anticoagulants Download PDF

Info

Publication number
WO1999026932A1
WO1999026932A1 PCT/US1998/025216 US9825216W WO9926932A1 WO 1999026932 A1 WO1999026932 A1 WO 1999026932A1 US 9825216 W US9825216 W US 9825216W WO 9926932 A1 WO9926932 A1 WO 9926932A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzoimidazol
compound
carboxamidine
benzoimidazole
ylmethyl
Prior art date
Application number
PCT/US1998/025216
Other languages
English (en)
Other versions
WO1999026932A8 (fr
Inventor
Paul R. Fatheree
Thomas E. Jenkins
Yong Li
Martin S. Linsell
Roopa Rai
William D. Shrader
Sean G. Trapp
Wendy B. Young
Original Assignee
Axys Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Axys Pharmaceuticals, Inc. filed Critical Axys Pharmaceuticals, Inc.
Priority to AU16071/99A priority Critical patent/AU1607199A/en
Publication of WO1999026932A1 publication Critical patent/WO1999026932A1/fr
Publication of WO1999026932A8 publication Critical patent/WO1999026932A8/fr

Links

Classifications

    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine 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 fibrinolysis.
  • 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 concert with tissue factor, catalyzes the conversion of factor X to factor Xa.
  • the formation of factor Xa represents a convergence of the intrinsic 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.
  • 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,
  • each R 3 is independently hydrogen, cyano, halo, nitro, perhalo(C, .3 )alkyl or perhalo(C,.
  • 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, .6 )alkylamino, di(C,_ 6 )alkylamino, (C,_ 6 )alkylcarbamoyl, di(C,.
  • R 2 , R 3 , R 4 , R 5 , R 7 and R 8 are not all hydrogen and/or (C, .3 )alkyl when A together with B comprises lH-benzoimidazol-2yl, C comprises lH-benzoimidazol-2yl and X 3 is -CR 7 R S -; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
  • 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 anticoagulation can prevent, inhibit or ameliorate 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, arylalkyl, alkylcarbamoyl, and the like.
  • Alkyl 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,
  • Alkyloxy means the radical -OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C, .6 )alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, ⁇ ec-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 above, having the number of carbon atoms indicated (e.g., (C,.
  • alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propenylsulfonyl, isopropenylsulfonyl, 1-butenylsulfonyl, 2-butenylsulfonyl, 3-butenylsulfonyl, 2-methylallylsulfonyl, ethynylsulfonyl, 1 -propynylsulfonyl, 2-propynylsulfonyl, etc.).
  • 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,
  • 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 arylalkyl, 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[2.2J]hept-l-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, 2-oxobicyclo[2.2J]heptylene, etc.).
  • “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 8 to 18 annular atoms and the carbocyclic ketone and thioketone derivatives thereof includes lH-benzoimidazol-2-yl, lH-naphtho[2,3-c/]imidazol-2-yl, lH-imidazo[4,5-
  • Heteroatom means an atom selected from N, O, S and P.
  • Heteroalkyl means alkyl, as defined above, 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.I2 )alkyl includes methoxy, ethoxy, ethylthio, 2-(2-methoxyethoxy)ethoxy,
  • Heterocycloalkyl means cycloalkyl, as defined above, 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 (e.g., the term heterocyclo(C 5.14 )alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, etc.).
  • Heterocycloalkylene means cycloalkylene, as defined above, except one or more of the annular carbon atoms indicated is replaced by a heteroatom moiety, as defined in this
  • any carbocyclic ketone, thioketone or iminoketone derivative thereof e.g., the term heterocyclo(C 3 _ 14 )alkylene includes piperidylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, mo holinylene, etc.).
  • Heteropolycycloaryl means polycycloaryl, as defined in this Section, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety, as set defined in this Section, 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,
  • Heteropolycycloarylene means polycycloarylene, as defined in this Section, except one or more of the annular carbon atoms indicated is replaced by a heteroatom moiety, as set defined in this Section, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., heteropolycyclo(C 8 _, 0 )alkylene includes 3,4-dihydro-2H-quinolinylene, 5,6,7,8-tetrahydroquinolinylene, 3,4-dihydro-2H-[l,8]naphthyridinylene,
  • 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.
  • the name 2-[6-fluoro-4-(5-oxopyrrolidin-2-ylmethoxy)- lH-benzoimidazol-2-ylmethyl]-lH-benzoimidazole-5-carboxamidine is meant to include (S)-2-[6-fluoro-4-(5-oxopyrrolidin-2-ylmethoxy)-lH-benzoimidazol-2-ylmethyl]- lH-benzoimidazole-5-carboxamidine and (i?)-2-[6-fluoro-4-(5-oxopyrrolidin-2-ylmethoxy)- lH-benzoimidazol-2-ylmethyl]-lH-benzoimidazole-5-carboxamidine and any mixture, racemic or otherwise, thereof.
  • 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.
  • alkylsulfonloxy e.g., mesyloxy, ethanesulfonyloxy, etc.
  • arylsulfonyloxy e.g., benzenesulfonyloxy and tosyloxy, thienyloxy
  • dihalophosphinoyloxy tetrahalopho
  • 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 9 )S(O) 2 - -S(O) 2 NR 9 -, -OP(O)(OR 9 )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 9 )C(O)-, -C(O)NR 9 -, -N(R 9 )C(O)O- -OC(O)NR 9 -, -N
  • 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 .
  • Niro means the radical -NO 2 .
  • 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 j.3 )alkyl means alkyl, as defined above, except all of the hydrogen atoms are replaced by haloatoms (e.g., trifluoromethyl, etc.).
  • “Pharmaceutically acceptable salts” means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, 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, ⁇ -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benz
  • 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
  • any carbocyclic ketone, thioketone or iminoketone derivative thereof e.g., polycyclo(C 9.]0 )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 polycyclic 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 j . ⁇ 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 or “treating” refers to any administration of a compound of the present invention and includes:
  • a together with B comprises 5-amidino-lH-benzoimidazol-2-yl
  • C comprises 6-fluoro-4-[2-(2-oxoimidazolidin-l-yl)ethoxy]-lH-benzoimidazol-2-yl
  • X 3 is -CH 2 - is named 2- ⁇ 6-fluoro-4-[2-(2-oxoimidazolidin-l-yl)ethoxy]-lH-benzoimidazol-2-ylmethyl ⁇ - lH-benzoimidazole-5-carboxamidine;
  • a together with B comprises 5-amidino-l//-benzoimidazol-2-yl
  • C comprises 5-(2-methoxy)acetylammo-lH-benzoimidazol-2-yl
  • X 3 is -CH 2 - is named N-[2-(5-amidino-lH-benzoimidazol-2-ylmethyl)-lH-benzoimidazol-5-ylmethyl]- 2-methoxyacetamide.
  • N-[2-(5-amidino- lH-benzoimidazol-2-ylmethyl)-lH-benzoimidazol-5-ylmethyl]-2-methoxyacetamide is meant to include its tautomers N-[2-(5-amidino-lH-benzoimidazol-2-ylmethyl)- 3H-benzoimidazol-5-ylmethyl]-2-methoxyacetamide, N-[2-(6-amidino- lH-benzoimidazol-2-ylmethyl)-3H-benzoimidazol-5-ylmethyl]-2-methoxyacetamide and N-[2-(6-amidino-lH-benzoimidazol-2-ylmethyl)-lH-benzoimidazol-5-ylmethyl]- 2-methoxyacetamide.
  • a preferred aspect of the Invention is a compound of Formula I in which: n2 is 1 ; 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 heteromonocyclic or fused heteropolycyclic radical containing from 5 to 18
  • each ring contains 5 to 6 annular atoms
  • X 3 is -C(O)-, - ⁇ R 7 - or -CR 7 R 8 -;
  • R 2 is hydrogen, (C ].3 )alkyl or halo;
  • each R 3 is independently hydrogen, cyano, halo, nitro or perhalo(C,. 3 )alkyl;
  • each R 4 , R 5 and R 8 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 .
  • a further preferred aspect of the Invention is a compound of Formula II:
  • D together with the vinylene moiety to which it is fused comprises a monocyclic or heteromonocyclic divalent radical containing 6 annular atoms; and X 1 and X 5 are independently a heteroatom moiety selected from -NR 5 -, -O- and -S-.
  • a further preferred aspect of the Invention is a compound of Formula II in which each R 4 , R 5 and/or R 8 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 )polycycloaryl or (C 9 . 14 )polycycloaryl, or -X 6 -R 6 , wherein X 6 is (C,_ 10 )alkylene or (C 2.10 )heteroalkylene and R 6 is hydrogen, (C 6 . 14 )aryl, cyclo(C 3 .
  • a further prefeoed 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 9 or -OP(O)(OR 9 )OH, wherein R 9 is hydrogen or (C, .6 )alkyl.
  • a further prefeoed 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
  • 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. For further details of the assays for measuring factor Xa inhibitor and/or anticoagulant activity see Examples 18, 19 and 20, infra.
  • compositions In general, 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 OJ 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 OJ mg/kg/day.
  • a therapeutically effective amount for a 80 kg human patient may range from 10 ⁇ g/day to 10 mg/day, typically 0J mg/day to 10 mg/day.
  • a therapeutically effective amount for a 80 kg human patient may range from 10 ⁇ g/day to 10 mg/day, typically 0J mg/day to 10 mg/day.
  • 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.).
  • Prefeoed liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • compositions of a compound of Formula I for treating a given disease will comprise from
  • 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 21. Chemistry:
  • L is a leaving group
  • D 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 7 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 heteropolycyclic 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 10 and 11, infra.).
  • DMPU l,3-dimethyl-3,4,5,6-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 10 and 11, infra.).
  • Compounds of Formula I in which C comprises lH-imdazol-2-yl, thiazol-2-yl or oxazol-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 q, R 3 , R 4 and R 5 is as defined in the Summary of the Invention.
  • L is a leaving group
  • X 7 is -O-, -N(R 5 )- 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.
  • n2, n3, n4, A, B, C, X 1 , X 2 , X 3 , X 4 , X 5 , R 2 , R 3 and R 4 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-hydroxycarboxamidine and then dehydroxylating to give the unsubstituted carboxamidine.
  • 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 (see Example 12, infra).
  • the dehydroxylation can be effected by reacting the N-hydroxycarboxamidine with zinc in the presence of acetic acid at reflux temperature and requires 3 to 4 hours to complete (see Example 13, infra.).
  • 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 ethoxy, X 3 is -CH 2 - and X 1 and X 2 or X 4 and X 5 are adjacent members of an imidazole, thiazole or oxazole ring can be prepared by reacting an appropriate compound of Formula 4 or Formula 2, respectively, with ethyl ethoxycarbonimidoylacetate hydrochloride. The reaction is carried out in the presence of a suitable solvent (e.g., anhydrous ethanol) at 80 °C and typically requires approximately 18 hours to complete (see Example 2, infra.).
  • a suitable solvent e.g., anhydrous ethanol
  • Compounds of Formula 2(a) can be prepared by reducing a cooesponding 2- nitroaniline.
  • the reduction can be effected with catalytic hydrogenation in the presence of a suitable catalyst (e.g, 10% palladium on carbon) and in a suitable solvent (e.g., methanol, ethanol, acetic acid, etc.) and requires 3 to 24 hours to complete (see Examples 3, 4, 5 and 6, infra.).
  • a suitable catalyst e.g, 10% palladium on carbon
  • a suitable solvent e.g., methanol, ethanol, 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 cooespondingly appropriate amine, alcohol, thiol or heterocycloalkane with a cooesponding halo-subsituted nitroaniline and then reducing.
  • the reaction with the halo-substituted nitroaniline typically is carried out in a suitable solvent (e.g., THF) at 0 to 25 °C and requires 4 to 5 hours to complete (see Example 3, infra.).
  • Compounds of Formula 2(a) in which R 10 is -NHR 5 can be prepared by reacting a cooespondingly appropriate amine of the formula NH 2 R 5 with a cooesponding 1-halo- 2-nitrobenzene and then reducing.
  • the reaction with the 1 -halo-2-nitrobenzene typically is caoied out in a suitable solvent (e.g., dimethyl sulfoxide) at 0 to 25 °C and requires 4 to 5 hours to complete (see Example 4, infra.).
  • a suitable solvent e.g., dimethyl sulfoxide
  • a non-nucleophillic base e.g., N-methylmo ⁇ holine, N,N-diisopropylethylamine, etc.
  • a suitable solvent e.g., N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, etc., preferably DMF
  • R 4 , R 5 or R 8 comprises -X 8 ⁇ R 9 C(O)X 9 R 6
  • R 4 , R 5 or R 8 comprises -X 8 NHR 9
  • R 6 X 9 C(O)OH a compound having the formula R 6 X 9 C(O)OH, wherein X ⁇ and X 9 are linking groups containing n8 and n9 contiguous linking atoms, respectively, wherein the sum of n8 and n9 is 0 to 10
  • R 9 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 J -carbonyldumidazole, etc.) and a non-nucleophillic base (e.g., N-methylmo ⁇ holine, N,N-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 (see Example 14, infra.).
  • a coupling agent e.g., PyBOP, EDCI, 1 J -carbonyldumidazole, etc.
  • a non-nucleophillic base e.g., N-methylmo ⁇ holine, N,N-diisopropylethylamine, etc.
  • a suitable solvent e.g., DMF, THF, dichloromethane, etc.,
  • the reaction typically is carried out in the presence of a non-nucleophillic base (e.g., N-methylmo ⁇ holine, N,N-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 (see Example 15, infra.).
  • a non-nucleophillic base e.g., N-methylmo ⁇ holine, N,N-diisopropylethylamine, etc.
  • a suitable solvent e.g., DMF, THF, dichloromethane, etc., preferably DMF
  • the reaction typically is carried out in the presence of a reducing agent (e.g., sodium cyanoborohydride) and in a suitable solvent (e.g., methanol) at 20 to 25 °C and requires 12 to 24 hours to complete (see Example 16, infra.).
  • a reducing agent e.g., sodium cyanoborohydride
  • a suitable solvent e.g., methanol
  • 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.
  • the 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 cooesponding base addition salt or acid addition salt form.
  • compounds of Formula I in an acid addition salt form may be converted to the cooesponding 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 cooesponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
  • 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
  • N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
  • 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.,
  • 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 prefeoed (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 chromatography 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 :
  • L is a leaving group
  • D 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
  • 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 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 10 in which L is a leaving group, 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, 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 (c) reacting a compound of Formula 5 :
  • n2, n3, n4, A, B, C, X 1 , X 2 , X 3 , X 4 , X 5 , R 2 , R 3 and R 4 are as defined in the Summary of the Invention with hydroxylamine hydrochloride to give a corresponding
  • R 4 or R 5 comprises -X 8 C(O)NR 9 X 9 R 6 , wherein X 8 and X 9 are linking groups containing n8 and n9 contiguous linking atoms, respectively, wherein the sum of n8 and n9 is 0 to 10, R 9 is hydrogen or (C, .6 )alkyl and R 6 is as defined in the Summary of the Invention;
  • EXAMPLE 2 Ethyl (5-amidino-lH-benzoimidazol-2-yl)acetate, a compound of Formula 1 in which L is ethoxy, A together with B comprises 5-amidino- lH-benzoimidazol-2-yl and X 3 is -CH 2 -
  • 5-Fluoro-3-(lH-imidazol-l-yl)benzene-l,2-diamine a compound of Formula 2(a) in which D together with the vinylene moiety to which it is fused comprises 5-fluoro-3-(lH-imidazol-l-yl)-l,2-phenylene and R 10 is amino
  • the 4-amino-3-nitrobenzylamine hydrochloride (9.16 g, 45 mmol) was dissolve in methanol (250 mL) and then acetic anhydride (9J9 g, 8.5 mL, 90 mmol, 2 equiv) and 1 M sodium hydroxide (180 mL, 4 equiv) were sequentially added to the solution.
  • the mixture was stioed for 18 hours and then 1 M sodium hydroxide (45 mL, 1 eq) and acetic anyhydride (4.3 mL, 1 eq) was added.
  • the reaction was allowed to proceed 20 minutes and then the mixture was concentrated by roto-evaporation.
  • the N-(4-amino-3-nitrobenzyl)acetamide (7.07 g, 34 mmol) and 10% palladium on carbon (200 mg) were suspended in acetic acid (200 mL) and the mixture was hydrogenated for 18 hours, filtered and concentrated to provide N-(3,4-diaminobenzyl)acetamide (6.3 g, 35.2) as a red oil.
  • 2,5-Dichlorobenzenesulfonyl chloride (1.0 g, 4.07 mmol) was dissolved in concentrated H 2 SO 4 (5 mL) and fuming H ⁇ O 3 (5 mL). The mixture was heated for 18 hours at 80 °C, cooled to ambient temperature and poured over ice (250 mL). The mixture was extracted with ethyl acetate and the extract was dried (MgSO 4 ) and concentrated to an oil. The residue was purified by flash chromatography (10% ethyl acetate:hexanes) to provide 2,5-dichloro-3-nitrobenzenesulfonyl chloride (0.6 g, 51%) as a light yellow oil.
  • N,N-Diisopropylethylamine (1.2 mL, 6.88 mmole, 2.0 equiv) was added to a solution comprising ammonia (1 J equiv), 2,5-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmol) and ethyl acetate (50 mL) and the mixture was stioed for 30 minutes at ambient temperature.
  • 4-Benzoimidazol-l-ylbenzene-l,2-diamine a compound of Formula 2(a) in which D together with the vinylene moiety to which it is fused comprises 4-benzoimidazol-l-yl-l,2-phenylene and R 10 is amino
  • a mixture comprising 5-chloro-2-nitro-phenylamine (1.46 g, 8.47 mmol, 1.0 eq), benzoimidazole (1.0 g, 8.47 mmol, 1.0 eq), DMPU (4 mL) and sodium tert-butoxide (0.95 g, 9.89 mmol, 1.2 eq) was heated at 160 °C for 1 hour, cooled to ambient temperature and diluted with water (100 mL) to give a precipitate. The precipitate was collected and dried to provide an orange solid. The solid was purified by chromatography (Silica) with ethyl acetate to provide 5-benzoimidazol-l-yl-2-nitrophenylamine.
  • a mixture comprising the purified 5-benzoimidazol-l-yl-2-nitrophenylamine, 10% palladium on carbon and methanol (200 mL) was hydrogenated for 18 hours, filtered and concentrated to provide 4-benzoimidazol-l-ylbenzene-l,2-diamine (0.9 g, 47%) as a brown amo ⁇ hous solid.
  • Methyl 8-hydroxyquinolin-2-ylacetate a compound of Formula 3 in which L is ethoxy, C comprises 8-hydroxyquinolin-2-yl and X 3 is -CH 2 -
  • Compound 1 a compound of Formula I in which A together with B comprises 5-amidino- lH-benzoimidazol-2-yl, C comprises 5-benzolyl-lH-benzoimidazol-2-yl and X 3 is -C ⁇ 2 -
  • X 3 is -C ⁇ 2 -
  • N-tert-butyl-3-methoxy-4-nitrobenzamide (51.5 g, 204 mmol) as an off-white solid.
  • the N-tert-butyl-3-methoxy-4-nitrobenzamide and sodium chloride 60. Og was dissolved in 1 ,2-dichloroethane (250 mL) and then POCl 3 (12.45 mL, 0J34 mol, 1 J equiv) was added dropwise to the solution at ambient temperature and under an atmosphere of nitrogen. The mixture was heated at reflux for 18 hours, then cooled to ambient temperature and poured onto a 1:1 mixture of methylene chloride and ice (200 mL each).
  • a mixture comprising ethyl 6-cyano— [2-(l ,3-dioxo-l ,3-dihydroisoindol-2-yl)ethyl]- lH-benzoimidazol-2-ylacetate (5.0 g, 12.43 mmole, 1 eq) and benzene- 1,2-diamine ( 1.88 g, 17.4 mmol, 1.4 eq) was heated at 180 °C in a sealed tube for 3 hours. The mixture was cooled to ambient temperature to give a precipitate.
  • a mixture comprising the 2-(lH-benzoimidazol-2-ylmethyl)-3-[2-(l,3-dioxo- l,3-dihydroisoindol-2-yl)ethyl]-3H-benzoimidazole-5-carbonitrile (5.0 g, 11.2 mmol, 1 eq) and hydrazine monohydrate (2.24 g, 44.8 mmol, 4 eq) was stioed at ambient temperature for 8 hours and then additional hydrazine monohydrate (4 eq) was added. The mixture was stioed for 2 hours and then concentrated under reduced pressure.
  • Compound 241 a compound of Formula I in which A together with B comprises 5-amidino- lH-benzoimidazol-2-yl, C comprises l-[2-(p-tolylsulfonylaminoacetylamino)ethyl]- lH-benzoimidazol-2-yl and X 3 is -C ⁇ 2 -
  • Compound 280 a compound of Formula I in which A together with B comprises 5-amidino- lH-benzoimidazol-2-yl, C comprises l-[2-(3,5-dimethyl-2,3-dihydroisoxazole- 4-sulfonylamino)ethyl]-lH-benzoimidazol-2-yl and X 3 is -C ⁇ 2 -
  • Compound 304 a compound of Formula I in which A together with B comprises 5-amidino- lH-benzoimidazol-2-yl, C comprises l-[2-(lH-Imidazol-2-ylmethylamino)ethylj- lH-benzoimidazol-2-yl and X 3 is -C ⁇ 2 -
  • a mixture comprising 2-[l-(2-aminoethyl)-lH-benzoimidazol-2-ylmethylj- lH-benzoimidazole-5-carboxamidine (250 mg, 0.615 mmol, 1 eq), methanol (5 mL), Na 2 CO 3 (65 mg, 0.615 mmol, 1 eq) and lH-imidazole-2-carboxaldehyde (63 mg, 0.646 mmol, 1.05 eq) was stioed for 5 minutes and then sodium cyanoborohydride (41 mg, 0.646 mmol, 1.05 eq) was added.
  • Hypnorm® fluanisone 10 mg/mL and phentanylcitrate 0.315 mg/mL; 0.05 mL/kg, i.m.
  • a catheter (Nenflon®2, ⁇ 0.8/25 mm) was inserted into a marginal ear vein for adminstration of test compound.
  • a second catheter (Venflon®2, ⁇ 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.
  • 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. The concentration of test compounds necessary to double ACT was determined.
  • ACT was measured as described in Example 19. 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. The concentration of test compounds necessary to effect a doubling of the ACT (EC ⁇ ) was determined.
  • EC x2human 35 ⁇ M
  • Compound 157, EC ⁇ , ⁇ 45 ⁇ M, EC X2human 29 ⁇ M;
  • Citric Acid Monohydrate 1.05 mg

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dérivés bihétérocycliques inhibiteurs du facteur Xa, leurs oxydes de N et leurs sels pharmaceutiquement acceptables, leurs utilisations en tant qu'agents thérapeutiques et leurs méthodes de production.
PCT/US1998/025216 1997-11-26 1998-11-25 Derives heterocycliques substitues par un groupe amidino et leur utilisation en tant qu'anticoagulants WO1999026932A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16071/99A AU1607199A (en) 1997-11-26 1998-11-25 By amidino group substituted heterocyclic derivatives and their use as anticoagulants

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US7265497P 1997-11-26 1997-11-26
US60/072,654 1997-11-26
US19370498A 1998-11-17 1998-11-17
US09/193,704 1998-11-17

Publications (2)

Publication Number Publication Date
WO1999026932A1 true WO1999026932A1 (fr) 1999-06-03
WO1999026932A8 WO1999026932A8 (fr) 1999-09-10

Family

ID=26753594

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/025216 WO1999026932A1 (fr) 1997-11-26 1998-11-25 Derives heterocycliques substitues par un groupe amidino et leur utilisation en tant qu'anticoagulants

Country Status (1)

Country Link
WO (1) WO1999026932A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000009480A1 (fr) * 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle
WO2000020401A1 (fr) * 1998-10-01 2000-04-13 Bayer Aktiengesellschaft Nouveaux bis-benzimidazoles
WO2000075117A1 (fr) * 1999-06-04 2000-12-14 Elan Pharma International Ltd. Compositions et methodes permettant d'inhiber la mort cellulaire
WO2001053291A1 (fr) * 2000-01-17 2001-07-26 Teijin Limited Derives benzimidazoles
WO2001079197A1 (fr) * 2000-04-14 2001-10-25 Nippon Chemiphar Co.,Ltd. Activateurs de ppar$g(d) (peroxisome proliferator activated receptor $g(d))
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
US7176320B2 (en) 2000-01-17 2007-02-13 Teijin Limited Benzimidazole derivative
US7268145B2 (en) 1998-07-15 2007-09-11 Teijin Pharma Limited Thiobenzimidazole derivatives
US7410990B2 (en) * 2002-10-15 2008-08-12 Synta Pharmaceuticals Corp. Heterocyclic compounds
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
JP2015532308A (ja) * 2012-10-22 2015-11-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４−アミノベンゾアミジン二塩酸塩の製造方法
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
US10172840B2 (en) 2014-12-01 2019-01-08 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
WO2019109132A1 (fr) * 2017-12-05 2019-06-13 Bionomics Limited Composés d'isoxazolyle utilisés en tant que composés modulateurs du récepteur, procédés et utilisations de ceux-ci
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2839989A1 (de) * 1978-09-14 1980-04-03 Hoechst Ag Substituierte bisbenzimidazolylverbindungen, ihre herstellung und ihre verwendung
EP0540051A1 (fr) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Dérivés aromatiques à fonction amidines et leurs sels
US5693515A (en) * 1995-04-28 1997-12-02 Arris Pharmaceutical Corporation Metal complexed serine protease inhibitors
WO1998001428A1 (fr) * 1996-07-08 1998-01-15 Du Pont Pharmaceuticals Company AMIDINOINDOLES, AMIDINOAZOLES ET LEURS ANALOGUES AGISSANT EN TANT QU'INHIBITEURS DU FACTEUR Xa ET DE LA THROMBINE
WO1998045275A1 (fr) * 1997-04-07 1998-10-15 Axys Pharmaceuticals Corporation Composes et compositions pour traitement de maladies associees a une serine protease, en particulier une activite de tryptase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2839989A1 (de) * 1978-09-14 1980-04-03 Hoechst Ag Substituierte bisbenzimidazolylverbindungen, ihre herstellung und ihre verwendung
EP0540051A1 (fr) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Dérivés aromatiques à fonction amidines et leurs sels
US5693515A (en) * 1995-04-28 1997-12-02 Arris Pharmaceutical Corporation Metal complexed serine protease inhibitors
WO1998001428A1 (fr) * 1996-07-08 1998-01-15 Du Pont Pharmaceuticals Company AMIDINOINDOLES, AMIDINOAZOLES ET LEURS ANALOGUES AGISSANT EN TANT QU'INHIBITEURS DU FACTEUR Xa ET DE LA THROMBINE
WO1998045275A1 (fr) * 1997-04-07 1998-10-15 Axys Pharmaceuticals Corporation Composes et compositions pour traitement de maladies associees a une serine protease, en particulier une activite de tryptase

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CAUGHEY G H ET AL: "BIS(5-AMIDINO-2-BENZIMIDAZOLYL)METHANE AND RELATED AMIDINES. ARE POTENT, REVERSIBLE INHIBITORS OF MAST CELL TRYPTASES", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 264, no. 2, 1993, pages 676 - 682, XP002064911 *
CHEMICAL ABSTRACTS, vol. 89, no. 17, 23 October 1978, Columbus, Ohio, US; abstract no. 141219c, GERATZ J. ET AL: "SPECIFIC INHIBITION OF PLATELET AGGLUTINATION AND AGGREGATION BY AROMATIC AMIDINO COMPOUNDS" page 129; XP002094821 *
CHEMICAL ABSTRACTS, vol. 94, no. 1, 5 January 1981, Columbus, Ohio, US; abstract no. 232t, TIDWELL R. R. ET AL: "STRATEGIES FOR ANTICOAGULATION WITH SYNTHETIC PROTEASE INHIBITORS. XA INHIBITORS VERSUS THROMBIN INHIBITORS" page 237; XP002094822 *
NAGAHARA T ET AL: "DiBASIC (AMIDINOARY) PROPANOIC ACID DERIVATIVES AS NOVEL BLOOD COAGULATION FACTOR XA INHIBITORS", JOURNAL OF MEDICINAL CHEMISTRY, vol. 37, no. 8, 15 April 1994 (1994-04-15), pages 1200 - 1207, XP000608128 *
THROB. RES., vol. 19, no. 3, 1980, pages 339 - 349 *
THROMB.HAEMOSTASIS, vol. 39, no. 2, 1978, pages 4 *
TIDWELL R -R ET AL: "DIARYLAMIDINE DERIVATIVES WITH ONE OR BOTH OF THE ARYL MOIETIES CONSISTING OF AN INDOLE OR INDOLE-LIKE RING. INHIBITORS OF ARGININE-SPECIFIC ESTEROPROTEASES", JOURNAL OF MEDICINAL CHEMISTRY, vol. 21, no. 7, 1 July 1978 (1978-07-01), pages 613 - 623, XP000573913 *
TIDWELL R.R. ET AL: "AROMATIC AMIDINES: COMPARISON OF THEIR ABILITY TO BLOCK RESPIRATORY SYNCYTIAL VIRUS INDUCED CELL FUSION AND TO INHIBIT PLASMIN ,UROKINASE THROMBIN, AND TRYPSIN", JOURNAL OF MEDICINAL CHEMISTRY., vol. 26, no. 2, 1983, WASHINGTON US, pages 294 - 298, XP002094820 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7268145B2 (en) 1998-07-15 2007-09-11 Teijin Pharma Limited Thiobenzimidazole derivatives
WO2000009480A1 (fr) * 1998-08-11 2000-02-24 Daiichi Pharmaceutical Co., Ltd. Nouveaux derives sulfonyle
WO2000020401A1 (fr) * 1998-10-01 2000-04-13 Bayer Aktiengesellschaft Nouveaux bis-benzimidazoles
WO2000075117A1 (fr) * 1999-06-04 2000-12-14 Elan Pharma International Ltd. Compositions et methodes permettant d'inhiber la mort cellulaire
WO2001053291A1 (fr) * 2000-01-17 2001-07-26 Teijin Limited Derives benzimidazoles
US7176320B2 (en) 2000-01-17 2007-02-13 Teijin Limited Benzimidazole derivative
CZ301504B6 (cs) * 2000-01-17 2010-03-24 Teijin Limited Benzimidazolové deriváty
WO2001079197A1 (fr) * 2000-04-14 2001-10-25 Nippon Chemiphar Co.,Ltd. Activateurs de ppar$g(d) (peroxisome proliferator activated receptor $g(d))
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
US7410990B2 (en) * 2002-10-15 2008-08-12 Synta Pharmaceuticals Corp. Heterocyclic compounds
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
US10570126B2 (en) 2010-02-18 2020-02-25 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US10030011B2 (en) 2010-02-18 2018-07-24 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US11649230B2 (en) 2010-02-18 2023-05-16 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US11130753B2 (en) 2010-02-18 2021-09-28 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US10287284B2 (en) 2010-02-18 2019-05-14 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
JP2015532308A (ja) * 2012-10-22 2015-11-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４−アミノベンゾアミジン二塩酸塩の製造方法
US10040750B2 (en) 2012-10-22 2018-08-07 Boehringer Ingelheim International Gmbh Process for the manufacture of 4-aminobenzoamidine dihydrochloride
US10280133B2 (en) 2012-10-22 2019-05-07 Boehringer Ingelheim International Gmbh Process for the manufacture of 4-aminobenzoamidine dihydrochloride
US10463652B2 (en) 2014-12-01 2019-11-05 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US10898475B2 (en) 2014-12-01 2021-01-26 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
US10172840B2 (en) 2014-12-01 2019-01-08 Vtv Therapeutics Llc Bach1 inhibitors in combination with Nrf2 activators and pharmaceutical compositions thereof
WO2019109132A1 (fr) * 2017-12-05 2019-06-13 Bionomics Limited Composés d'isoxazolyle utilisés en tant que composés modulateurs du récepteur, procédés et utilisations de ceux-ci
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors

Also Published As

Publication number Publication date
WO1999026932A8 (fr) 1999-09-10

Similar Documents

Publication Publication Date Title
WO1999026932A1 (fr) Derives heterocycliques substitues par un groupe amidino et leur utilisation en tant qu'anticoagulants
EP2049518B1 (fr) Derives de l'indazole et de l'isoindazole comme agents de l'activation de glucokinase
US9199965B2 (en) Benzoimidazole derivatives and pharmaceutical composition comprising the same
US20110070297A1 (en) Glucokinase activators
EP1608628A2 (fr) Inhibiteurs d'histone deacetylase
HU211524A9 (en) Benzimidazole compounds
CA2724116A1 (fr) Activateurs de la glucokinase
WO2005065681A1 (fr) Derives de n-hydroxy-3-(3-(1h-imidazol-2-yl)-phenyl)-acrylamide et composes associes en tant qu'inhibiteurs d'histone deacetylase pour le traitement du cancer
US5354759A (en) Angiotenin II antagonizing heterocyclic compounds
KR20070113207A (ko) 신규한 벤조이미다졸 유도체 및 이를 함유하는 약제학적조성물
JPH11514361A (ja) Ｈ＋−ＡＴＰａｓｅとしての複素環式化合物
JP4092732B2 (ja) ブラジキニン作動薬としてのキノリンおよびベンズイミダゾール誘導体
EP3585772B1 (fr) Dérivés de 2-alkyl-1h-benzo[d]imidazole, 1, 4,6-trisubstitués comme inhibiteurs de dihydro-orotate-oxygénase
DE4408497A1 (de) Benzimidazole, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
US20030139450A1 (en) Substituted benzimidazole antiviral agents
AU752064B2 (en) Compounds and compositions for treating diseases associated with serine protease, particularly tryptase, activity
US6150379A (en) Compounds and compositions as anticoagulants
WO2004060367A1 (fr) Derives d'imidazole et de triazole utiles en tant qu'inhibiteurs de cox-1 selectifs
US4962200A (en) Nitrogen-containing compound
WO1999026933A1 (fr) Derives d'amidinoaryle substitue et leur utilisation comme anticoagulants
US6562854B2 (en) Compositions comprising a substituted benzimidazole useful for treating immunomediated inflammatory disorders
US8148367B2 (en) Renin inhibitors
US5554624A (en) Imidazopyridine derivatives as angiotensin II antagonists
CA2921298C (fr) Imidazoles substitues en tant que bloqueurs des canaux calciques de type n
DE69836427T2 (de) Heterozyclische ketonen als npy y5 antagonisten

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: C1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: C1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i

Free format text: PAT. BUL. 22/99 UNDER (30) REPLACE "NOT FURNISHED" BY "09/193704"

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase