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WO2013049591A2 - Composés doublement inhibiteurs et procédés d'utilisation de ceux-ci - Google Patents

Composés doublement inhibiteurs et procédés d'utilisation de ceux-ci Download PDF

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Publication number
WO2013049591A2
WO2013049591A2 PCT/US2012/057951 US2012057951W WO2013049591A2 WO 2013049591 A2 WO2013049591 A2 WO 2013049591A2 US 2012057951 W US2012057951 W US 2012057951W WO 2013049591 A2 WO2013049591 A2 WO 2013049591A2
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Prior art keywords
triazol
carbonyl
methyl
amine
chlorothiophen
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WO2013049591A3 (fr
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Kevin Michael Short
Son Minh Pham
David Charles Williams
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Verseon Corp
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Verseon Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • multisubstituted aromatic compounds which exhibit dual inhibitory action against thrombin (i.e., activated blood-coagulation factor II; EC 3.4.21.5) and coagulation factor Xa (i.e., "fXa,” activated Stuart-Prower factor, factor Xa, EC 3.4.21.6).
  • fVIIa plasma factor VII
  • TF exposed tissue factor
  • fXa Factor Xa
  • FXa then serves as the catalyst for formation of thrombin (flla), which in turn is the direct precursor to fibrinolysis.
  • thrombin thrombin
  • the outcome is a fibrinolytic clot, which stops the bleeding. Fibrinolysis of the polymeric clot into fibrin monomers leads to dissolution and a return of the system to 'normal'
  • the cascade is a complex balance of factors and co-factors and is tightly regulated.
  • heparin the naturally-occurring polysaccharide that activates antithrombin III (AT III), the endogenous inhibitor of many of the factors in the coagulation cascade.
  • AT III antithrombin III
  • DTIs direct thrombin inhibitors
  • d-Phe-Pro-Arg motif a sequence that mimics fibrinogen, thrombin's natural substrate.
  • the development of DTIs is very well established, such as with the hirudin-based anticoagulants, and thus there is strong commercial interest in the discovery and development of novel DTIs.
  • fXa is a promising therapeutic target, with potential advantages over thrombin.
  • thrombin also promotes platelet activation, promoting concern that thrombin inhibition may result in thrombocytopenia, a lack of platelets.
  • fXa is centrally located in the coagulation cascade, and its sole function is in the promotion of coagulation.
  • the previously described generation and subsequent amplification of fXa has led to the recognition that generation of a single molecule of fXa leads to the generation of greater than 1000 molecules of thrombin.
  • fXa inhibition has been reasoned to be more effective than thrombin inhibition.
  • R 1 and R 2 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 3 is hydrogen, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 4 is unsubstituted alkyl.
  • L 1 and L 2 are each independently a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -S0 2 -, -NHC0 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene.
  • L 3 is a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -S0 2 -, -NHC0 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or -L 3a -L 3b -.
  • L 3a is substituted or unsubstituted heterocycloalkylene, and L 3b is -C(O)-, -S(0) 2 -, or -C(0)0.
  • the compound inhibits both thrombin and coagulation factor Xa (fXa).
  • a method for inhibiting thrombin or coagulation factor Xa (fXa) includes contacting thrombin or fXa with a compound according to Formula (II), thereby inhibiting thrombin or fXa.
  • a method for treating a thrombotic disorder includes administering to a subject in need thereof an effective amount of a compound according to Formula (II), thereby treating the thrombotic disorder.
  • a method for ameliorating wound healing includes administering to a subject in need thereof an effective amount of a compound according to Formula (II), thereby ameliorating wound healing.
  • a method for mediating tissue repair includes administering to a subj ect in need thereof an effective amount of a compound according to Formula (II), thereby mediating tissue repair.
  • a method for treating a disease or disorder in a subject includes administering a compound according to Formula (II) to a subject in need thereof in an amount effective to treat the disease or disorder.
  • a pharmaceutical composition including a compound according to Formula (II) and a pharmaceutically acceptable excipient.
  • halogen and halo include fluorine, chlorine, bromine, and iodine.
  • haloalkyl include all levels of halogenation, e.g., monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like.
  • alkyl alone or in combinational form, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3 -(1,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • alkyl can refer to Q-Ci 6 straight chain saturated, Q-C16 branched saturated, C3-C8 cyclic saturated and O-C16 straight chain or branched saturated aliphatic hydrocarbon groups substituted with C 3 -C 8 cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec -butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, and the like.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, e.g., -CH2CH2CH2CH2- and the like.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • -CH CH-N(CH 3 )-CH 3 , -0-CH 3 , -0-CH 2 -CH 3 , and -CN.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • heteroalkylene alone or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, e.g., -CH 2 -CH 2 -S-CH 2 -CH 2 -, -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -, and the like.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • alkylene and heteroalkylene linking groups no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
  • the formula -C(0) 2 R'- represents both -C(0) 2 R'- and -R'C(0) 2 -, wherein "R"' represents the remainder of the alkylene or heteroalkylene.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R, -C(0)NR, -NR'R", -OR', -SR', -S0 2 R, and the like.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like wherein “R"' and “R”” represent substituents, it will be understood that the terms heteroalkyl and -NR'R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • cycloalkyl and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic “alkyl” and “heteroalkyl,” respectively.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, aziridine, azetidine, pyrrolidine, azepane, l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • cycloalkylene and “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
  • heterocycloalkyl as customary in the art, the term
  • heterocyclyl is generic to and synonymous with “heterocycloalkyl,” and the term
  • heterocyclyl is further generic to and synonymous with “heteroaryl.” Heterocyclyl functionalities may be optionally substituted with one or more substituents selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, oxo, alkyloxy, alkylthio, alkyloxycarbonyl, alkylamino, alkylaminoalkyl, alkyloxy(alkyl)amino, alkylcarbonyl, alkylcarboxy, alkylcarboxyalkyl, alkylcarbonylamino, and the like.
  • alkenyl includes C 2 -Ci 6 straight chain unsaturated, C 2 -Cn branched unsaturated, Cs-Cs unsaturated cyclic, and C2-C16 straight chain or branched unsaturated aliphatic hydrocarbon groups substituted with C3-C8 cyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Double bonds may occur in any stable point along the chain and the carbon-carbon double bonds may have either the cis or trans configuration.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5- octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, l-pentenyl-3 -cyclohexenyl, and the like.
  • cycloalkenyl refers to cycloalkyl additionally having one or more double bonds.
  • heterocycloalkenyl refers to heterocycloalkyl additionally having one or more double bonds.
  • alkynyl refers in the customary sense to alkyl additionally having one or more triple bonds.
  • acyl means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • alkyloxy e.g., methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy
  • alkylthio e.g., methylthio, ethylthio, propylthio, cyclohexylthio and the like
  • alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.
  • alkylamino represents one or two alkyl groups as defined above having the optionally indicated number of carbon atoms attached through an amine bridge.
  • the two alkyl groups maybe taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one Ci-Ci 6 alkyl, arylCo-Ci 6 alkyl, or C 0 - Ci 6 alkylaryl substituent.
  • alkylaminoalkyl represents an alkylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkyloxy(alkyl)amino e.g., methoxy(methyl)amine, ethoxy(propyl)amine
  • alkyloxy(alkyl)amino represents an alkyloxy group as defined above attached through an amino group, the amino group itself having an alkyl substituent.
  • alkylcarbonyl e.g., cyclooctylcarbonyl, pentylcarbonyl, 3-hexylcarbonyl
  • alkylcarbonyl represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • alkylcarboxy (e.g., heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen.
  • alkylcarboxy alkyl represents an alkylcarboxy group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • alkylcarbonylamino e.g., hexylcarbonylamino
  • cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group.
  • the nitrogen group may itself be substituted with an alkyl or aryl group.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • the term "furanyl,” “thiophenyl,” “pyridinyl,” “pyrimidinyl,” and “pyridazinyl” refer to the combinational forms of the terms furan, thiophene, pyridine, pyrimidine, and pyridazine, respectively.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquino
  • aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
  • the aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, Ci_i 6 alkyl, arylCi_i 6 alkyl, Co-i 6 alkyloxyCo- i 6 alkyl, arylCo-i6alkyloxyCo-i6alkyl, Co-i6alkylthioCo-i6alkyl, arylCo-i6alkylthioCo-i6alkyl, Co-i6alkylaminoCo-i6alkyl, arylCo-i6alkylaminoCo-i6alkyl, di(arylCi-i6alkyl)aminoCo-i6alkyl, Ci-i6alkylcarbonylCo-i6alkyl, arylCi_i6alkylcarbonylCo-i6alkyl, Ci-i6alkylcarboxyCo-i6alkyl, arylCi-i 6 alky
  • aryl includes but is not limited to triazolyl.
  • aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl e.g., benzyl, phenethyl, pyridylmethyl, and the like
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl, and the like
  • alkyl groups e.g., benzyl, phenethyl, pyridylmethyl, and the like
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like
  • sulfur atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like
  • arylalkyl and the like (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group attached through an alkyl group having the optional indicated number of carbon atoms.
  • alkylsulfonyl as used herein, means a moiety having the formula -S(02)- , where R is an alkyl group as defined above. R may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").
  • arylalkyl e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl
  • arylalkyl represents an aryl group attached through an alkyl group having the optional indicated number of carbon atoms.
  • carbonyloxy represents a carbonyl group attached through an oxygen bridge.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • alkyl and “alkenyl” may be used interchangeably in so far as a stable chemical entity is formed, as obvious to those skilled in the art.
  • linker refers to divalent attachment groups interposed between substituents, e.g., R 1 , R 2 , R 3 of Formula (I) described herein, e.g., Formula (II), generically referred to following as R n , and the group which is substituted, e.g., the triazole ring of Formula (II).
  • the linker includes amido (-CONH-R" or -NHCO-R”), thioamido
  • a linker is a bond, -NH-, -NR m - wherein "R m " is a nitrogen substituent as disclosed herein, -CONH-, -CSNH-, -C(O)-, -C(0)0-, - NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -S0 2 -, -NHC0 2 -, substituted or
  • a “substituent group,” as used herein, means a group selected from the following moieties:
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C 2 o alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or
  • a "lower substituent” or " lower substituent group,” as used herein, means a group selected from all of the substituents described herein for a "substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl.
  • the compounds of the present invention also include racemic mixtures, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds. See e.g., Goding; MONOCLONAL ANTIBODIES PRINCIPLES AND PRACTICE, Academic Press, p. 104 (1986). Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral chromatography. See e.g., Eliel, E. L. & Wilen S. H., 1993,
  • terapéuticaally effective amount refers to an amount of a compound, drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • Linker groups L 1 and L 2 are each independently a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0 2 -, - ⁇ -, -S-, -S(O)-, -SO2-, -NHCO2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene.
  • L 3 is a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, - NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -S0 2 -, -NHC0 2 -, substituted or
  • L 3a is substituted or unsubstituted heterocycloalkylene
  • L 3b is -C(O)-, -S(0) 2 -, or -C(0)0-.
  • R 1 and R 2 are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 3 is hydrogen, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 4 if present, is alkyl, preferably C1-C6 alkyl, more preferably methyl, or ethyl. Contemplated compounds of Formula (I) inhibit both thrombin and fXa.
  • linker groups L 1 and L 2 are each independently a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -S0 2 -, -NHC0 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted
  • L 3 is a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-,
  • L 3a is substituted or unsubstituted heterocycloalkylene
  • L 3b is -C(O)-, -S(0) 2 -, or -C(0)0-.
  • R 1 and R 2 are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 3 is hydrogen, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 4 if present, is alkyl, preferably C -Ce alkyl, more preferably methyl, or ethyl. Contemplated compounds of Formula (II) inhibit both thrombin and fXa.
  • the compound has IC5 0 > 1.0 ⁇ for thrombin inhibition. In one embodiment, the compound has IC5 0 > 1.0 ⁇ for fXa inhibition. In one embodiment, the compound has IC5 0 > 0.1 ⁇ and ⁇ 1.0 ⁇ for thrombin inhibition. In one embodiment, the compound has IC50 > 0.1 ⁇ and ⁇ 1.0 ⁇ for fXa inhibition. In one embodiment, the compound has IC5 0 ⁇ 0.1 ⁇ for thrombin inhibition. In one embodiment, the compound has IC5 0 ⁇ 0.1 ⁇ for fXa inhibition. The term "IC5 0 " refers in the customary sense to half maximal inhibitory concentration.
  • L 1 is a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, - NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -S0 2 -, -NHC0 2 -, substituted or
  • L 1 is a bond, -NH-, or substituted or unsubstituted heteroalkylene.
  • the compound of Formula (II) has the structure of Formula (Ha) following, wherein L 1 is -NH-(CH 2 ) n -, n is 0 to 6, preferably 1-2, more preferably 1 , and R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.
  • L 1 is -NHCH 2 - or -NH(CH 2 ) 2 -, and R 1 is substituted or unsubstituted aryl.
  • R 1 is unsubstituted aryl, preferably phenyl.
  • R 1 is aryl, preferably phenyl, substituted with halogen.
  • R 1 is unsubstituted alkyl, preferably lower alkyl, more preferably methyl or ethyl.
  • n is 0, and R 1 is hydrogen.
  • R 1 is substituted or unsubstituted heteroaryl.
  • R 1 is unsubstituted heteroaryl, preferably thiophenyl.
  • R 1 is substituted heteroaryl, preferably thiophenyl substituted with halogen.
  • the compound of Formula (II) has the structure of Formula (lib) following, wherein L 1 is -S-(CH 2 ) n -, n is 0 to 6, preferably 1-2, more preferably 1, and R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.
  • n is 0, and R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 1 is unsubstituted alkyl, preferably methyl.
  • n is 1, and R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 1 is substituted or unsubstituted aryl, preferably phenyl.
  • R 1 is halogen substituted phenyl.
  • L 2 is a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -SO2-, -NHCO2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene.
  • L 2 is -C(O)-, and the compound of Formula (II) has the structure of Formula (lie) following:
  • R 2 is substituted or unsubstituted aryl.
  • R 2 is unsubstituted aryl, preferably phenyl.
  • R 2 is substituted aryl, preferably substituted phenyl.
  • R 2 is aryl substituted with alkyl (preferably methyl), alkyloxy (preferably methoxy at 1 or 2 substitutions), halogen, or heteroalkyl.
  • R 2 is aryl substituted at two positions with alkyl (preferably methyl), alkyloxy (preferably methoxy at 1 or 2 substitutions), or halogen.
  • R 2 is 2,3-dihydrobenzo[b][l,4]dioxine.
  • R 2 is substituted or unsubstituted alkyl.
  • R 2 is unsubstituted alkyl, preferably methyl, ethyl, propyl, or tert- butyl.
  • R 2 is substituted alkyl, preferably phenylmethyl.
  • R 2 is substituted or unsubstituted heteroaryl.
  • R 2 is unsubstituted heteroaryl, preferably furanyl, thiophenyl, or pyridinyl.
  • R 2 is substituted heteroaryl, preferably substituted furan or substituted thiophene.
  • R 2 is furan substituted with halogen.
  • R 2 is thiophene substituted with halogen.
  • L 2 is a bond
  • R 2 is hydrogen
  • L 3 is a bond, -NH-, -NR 4 -, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0 2 -, -0-, -S-, -S(O)-, -S0 2 -, -NHC0 2 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or -L 3a -L 3b -.
  • L 3 is a bond
  • R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.
  • R 3 is substituted or unsubstituted alkyl.
  • R 3 is unsubstituted alkyl, preferably C 1 -C 4 alkyl.
  • R 3 is substituted or unsubstituted cycloalkyl. In one embodiment, R 3 is unsubstituted cycloalkyl, preferably cyclopentyl or cyclohexyl. [0076] In one embodiment, R 3 is substituted or unsubstituted aryl. In one embodiment, R 3 is unsubstituted aryl, preferably phenyl. In one embodiment, R 3 is aryl, preferably phenyl, substituted with alkyl or halogen.
  • R 3 is substituted or unsubstituted heterocycloalkyl. In one embodiment, R 3 is unsubstituted heterocycloalkyl, preferably tetrahydrofuran or tetrahydrogen- 2H-pyran. In one embodiment, R 3 is substituted heterocycloalkyl, preferably tetrahydrofuran or tetrahydrogen-2H-pyran substituted with alkyl or halogen.
  • R 3 is substituted or unsubstituted heterocycloaryl. In one embodiment, R 3 is unsubstituted heterocycloaryl, preferably furanyl, thiophenyl, pyridinyl, or pyrimidinyl, or pyridazinyl. In one embodiment, R 3 is furanyl, thiophenyl, pyridinyl, pyrimidinyl, or pyridazinyl.
  • L 3 is -L 3a -L 3b -, and the compound of Formula (II) has the structure of Formula (lid):
  • L 3a is unsubstituted heterocycloalkylene, and L 3b is -C(O)-, -S(0) 2 -, or -C(0)0-.
  • L 3a is azetidine-diyl; see e.g, Cmpd 20 and the like.
  • L 3a is piperidine-diyl; see e.g, Cmpd 24 and the like.
  • L 3b is -C(O)-, -S(0) 2 -, or -C(0)0-. In one embodiment, L 3b is -C(O)-. In one embodiment, L 3b is -S(0) 2 -. In one embodiment, L 3b is -C(0)0-.
  • R 3 is hydrogen, -NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.
  • R 3 is substituted or unsubstituted alkyl. In one embodiment, R 3 is unsubstituted alkyl, preferably C 1 -C4 alkyl. In one embodiment, R 3 is methyl. In one embodiment, R 3 is substituted or unsubstituted aryl. In one embodiment, R 3 is unsubstituted aryl, preferably phenyl. In one embodiment, R 3 is substituted or unsubstituted heteroalkyl. In one embodiment, R 3 is unsubstituted heteroalkyl, preferably -N(CH 3 ) 2 . In one embodiment, R 3 is -NH 2 .
  • R 3 is substituted or unsubstituted cycloalkyl. In one embodiment, R 3 is unsubstituted cycloalkyl, preferably cyclopentyl or cyclohexyl.
  • L 1 is -NH-(CH 2 ) n -, n is 0 to 6, preferably 1-2, L 2 is -C(O)-, and the compound has the structure of Formula (He) following.
  • Cmpds compounds of compounds (Cmpds) 1-93, and the pharmaceutically acceptable salts, solvates, acids or esters thereof.
  • Cmpds 1-93 are listed in Table A and Table B following, with corresponding calculated and observed (mass spectrometric) molecular weights (MW, Dalton) and inhibition activity levels against thrombin and fXa.
  • ACTIVITY inhibition activity
  • the compound is selected from Table A; i.e., any one of Cmpds 1, 3-18, 20-27, 29, or 31-80.
  • the compound is selected from Table B, i.e., any one of Cmpds 3, 19, 28, 30, and 81-93. Table A:
  • the compounds of the present invention may have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • Pharmaceutically acceptable salts of the compounds above, where a basic or acidic group is present in the structure are also included within the scope of this invention.
  • an acidic substituent such as-NHSOsH, COOH and P(0)(OH) 2
  • Basic groups such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
  • esters can be employed, e.g., methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations .
  • prodrug is used according to its plain ordinary meaning and is intended to mean compounds that require a chemical or enzymatic transformation in order to release the active parent drug in vivo prior to producing a pharmacological effect.
  • some of the compounds of the instant invention may be metabolized. Such metabolites are also encompassed within the scope of the invention.
  • a given compound can be used in a variety of forms, including a pharmaceutically acceptable prodrug, metabolite, analogue, derivative, solvate or salt.
  • compounds described herein exhibit inhibitory activity against thrombin and fXa with activities > 1 ⁇ , e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 ⁇ , or even greater.
  • the compounds exhibit inhibitory activity against thrombin and fXa with activities between 0.1 ⁇ and 1 ⁇ , e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 ⁇ .
  • compounds described herein exhibit inhibitory activity against thrombin and fXa with activities ⁇ 0.1 ⁇ , e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values using a combination of any of the values recited herein as upper and/or lower limits are also contemplated, for example, but not limited to, 1-10 nM, 10-100 nM, 0.1-1 ⁇ , 1-10 ⁇ , 10-100 ⁇ , 100-200 ⁇ , 200-500 ⁇ , or even 500-1000 ⁇ .
  • the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 ⁇ , 1-10 ⁇ , 10-100 ⁇ , 100-200 ⁇ , 200-500 ⁇ , or even 500-1000 ⁇ . It is understood that for purposes of quantification, the terms "activity,"
  • inhibitory activity inhibitory activity
  • biological activity biological activity
  • thrombin activity thrombin activity
  • fXa activity a activity of an inhibitory compound disclosed herein
  • IC5 0 Inhibition of thrombin and fXa inhibits the blood coagulation process. Accordingly, the compounds disclosed herein are indicated in the treatment or management of thrombotic disorders or other disorders involving the blood coagulation process.
  • a method for inhibiting thrombin and coagulation factor Xa includes contacting thrombin or fXa with a compound as set forth herein, thereby inhibiting thrombin or fXa.
  • the compound is as set forth in Table A or Table B. In one embodiment, the compound is selected from any one of Cmpds 1, 3-18, 20-27, 29, or 31-80.
  • Clinical indications e.g., diseases and disorders
  • contemplated herein include the following.
  • Thrombosis are the primary indications for thrombin and fXa inhibition, because of their location in the coagulation cascade and, in turn, the importance of the coagulation cascade in the progression of blood clotting processes.
  • thrombin and fXa are important in a variety other disease states.
  • This inhibitory action is useful in the treatment of a variety of thrombotic disorders, such as, but not limited to, acute vascular diseases such as acute coronary syndromes; venous-, arterial- and cardiogenic thromboembolisms; the prevention of other states such as disseminated intravascular coagulation, or other conditions that involve the presence or the potential formation of a blood clot thrombus.
  • acute vascular diseases such as acute coronary syndromes
  • venous-, arterial- and cardiogenic thromboembolisms the prevention of other states such as disseminated intravascular coagulation, or other conditions that involve the presence or the potential formation of a blood clot thrombus.
  • Other indications for methods described herein include the following.
  • LMWHs low molecular weight heparins
  • dabigatran etexilate treatment led to a 50% reduction in tumor volume at 4 weeks with no weight loss in treated mice. Dabigatran etexilate also reduced tumor cells in the blood and liver micrometastases by 50-60%. These investigators concluded that dabigatran etexilate may be beneficial in not only preventing thrombotic events in cancer patients, but also as adjunct therapy to treat malignant tumors.
  • hirudin and the LMWH nadroparin dramatically reduced the number of lung metastases when administered prior to cancer cell inoculation. See e.g., Hu, L., et al, 2004, Blood, 104:2746-51.
  • the de novo thrombin inhibitor d-Arg-Oic-Pro-d-Ala-Phe(p-Me) has been found to block thrombin-stimulated invasion of prostate cancer cell line PC-3 in a concentration dependent manner. See e.g., Nieman, M. T., et al, 2008, J Thromb Haemost, 6:837-845. A reduced rate of tumor growth was observed in mice dosed with the pentapeptide through their drinking water. The mice also showed reduced fold rate in tumor size and reduced overall tumor weight compared to untreated mice. Microscopic examination of treated tumors showed reduced number of large blood vessels thus concluding that the pentapeptide interfered with tumor angiogenesis. Nieman, M.
  • Fibrosis Several studies have shown the utility of anticoagulant therapy in fibrotic disorders. For example, in a rat model of CCl 4 -induced chronic liver injury, the DTI SSR182289 decreased liver fibrogenesis significantly after 7 weeks of administration. Similar observations were made in other studies using the LMWHs nadroparin, tinzaparin, enoxaparin, and dalteparin sodium. See e.g., Duplantier, J. G., et al, 2004, Gut, 53: 1682-1687; Abdel-Salam, O.
  • the DTI melagatran greatly reduced ischemia reperfusion injury in a kidney transplant model in the large white pig. This led to a drastically improved kidney graft survival at 3 months. See e.g., Favreau, F., et al, 2010, Am J Transplant, 10:30-39.
  • Alzheimer's Disease Very recent experiments confirm higher thrombin levels in brain endothelial cells of patients with Alzheimer's disease. While 'normal' thrombin levels are connected to regulatory CNS functions, thrombin accumulation in the brain is toxic. It has also been found that the neural thrombin inhibitor Protease Nexin 1 (PN-1) is significantly reduced in the Alzheimer's disease brain, despite the fact that PN-1 mRNA levels are unchanged. These observations have led some investigators to suggest that reduction of CNS-resident thrombin will prove useful in Alzheimer's Disease (AD) treatment. See e.g., Vaughan, P.
  • AD Alzheimer's Disease
  • a method for treating a thrombotic disorder in a subject in need includes administering to a subject in need an effective amount of a compound of Formula (II), thereby treating the thrombotic disorder.
  • the compound is any one of Cmpds 1-93.
  • the present disclosure contemplates methods for ameliorating wound healing and for mediating tissue repair (including but not limited to treatment of peripheral and coronary vascular disease).
  • a subject having a wound or in need of tissue repair is treated at the site of the wound or damaged tissue or treated systemically, with a compound of the present invention in the form of a free compound or a pharmaceutically- acceptable prodrug, metabolite, analogue, derivative, solvate or salt.
  • a method for ameliorating wound healing in a subject in need includes administering to a subject in need thereof a compound of Formula (II) as described herein, thereby ameliorating wound healing.
  • the compound is selected from any one of the compounds set forth in Table A or Table B.
  • the compound is any one of Cmpds 1-93.
  • a method for mediating tissue repair in a subject in need includes administering to a subject in need thereof a compound of Formula (II) as described herein, thereby mediating tissue repair.
  • the compound is selected from any one of the compounds set forth in Table A or Table B.
  • the compound is any one of Cmpds 1-93.
  • a method for treating a disease or disorder in a subject includes administering a compound according to Formula (II) to a subject in need thereof in an amount effective to treat the disease or disorder.
  • the compound is selected from any one of the compounds set forth in Table A or Table B.
  • the compound is any one of Cmpds 1-93.
  • the disease or disorder is a thrombotic disorder.
  • the thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism.
  • the disease or disorder is fibrosis.
  • the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.
  • the disease or disorder is Alzheimer's Disease. In one embodiment, the disease or disorder is Alzheimer's Disease. In one
  • the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93. [0124] In one embodiment, the disease or disorder is multiple sclerosis. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.
  • the disease or disorder is pain.
  • the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.
  • the disease or disorder is cancer. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.
  • a method for preventing a disease or disorder in a subject includes administering a compound according to Formula (II) to a subject in need thereof in an amount effective to prevent the disease or disorder.
  • the disease or disorder is a thrombotic disorder.
  • the thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism.
  • the thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism.
  • the thrombotic disorder is disseminated intravascular coagulation.
  • the thrombotic disorder involves the presence or the potential formation of a blood clot thrombus.
  • the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93. V. Preparation and formulations
  • a pharmaceutical composition including a compound according to Formula (II) and a pharmaceutically acceptable excipient.
  • the present disclosure has the objective of providing suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention.
  • the compounds disclosed herein may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs.
  • the composition for oral use may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations.
  • the tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • pharmaceutically acceptable refer in the customary sense to salts, esters, solvates, prodrugs, carriers, excipients, compounds and the like which are acceptable for administration to a subject, e.g., a human subject, as judged by a medical or veterinary practitioner.
  • excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating may also be performed using techniques described in the U. S. Pat. Nos. 4,256, 108; 4,160, 452; and 4,265, 874 to form osmotic therapeutic tablets for control release.
  • a compound of the present invention in the form of a free compound or a
  • pharmaceutically-acceptable prodrug, metabolite, analogue, derivative, solvate or salt can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time. Administration may be intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. For in vitro studies the compounds may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, growth factors and inert gases and the like.
  • the terms “treating”, “treatment” and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or disorder or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure for a disorder and/or adverse effect attributable to it.
  • Treating covers any treatment of, or prevention of a disease or disorder in a vertebrate, a mammal, particularly a human, and includes: (a) preventing the disease or disorder from occurring in a subject that may be predisposed to the disease or disorder, but has not yet been diagnosed as having it; (b) inhibiting the disease or disorder, i.e., arresting its development; or (c) relieving or ameliorating the disease or disorder, i.e., cause regression of the disease or disorder.
  • the invention includes various pharmaceutical compositions useful for ameliorating diseases and disorders, including thrombosis and the like.
  • the pharmaceutical compositions according to one embodiment of the invention are prepared by formulating a compound of the present invention, in the form of a free compound or a pharmaceutically-acceptable prodrug, metabolite, analogue, derivative, solvate or salt, either alone or together with other
  • Suitable for administration to a subject using carriers, excipients and additives or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in REMINGTON'S PHARMACEUTICAL SCIENCES, 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975) and THE NATIONAL FORMULARY XIV, 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference and for all purposes.
  • the pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art . See, e.g., Goodman and Gilman's THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).
  • the pharmaceutical compositions are preferably prepared and administered in dose units.
  • Solid dose units are tablets, capsules and suppositories.
  • different daily doses can be used for treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the disease or disorder, age and body weight of the subject.
  • the administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administrations of subdivided doses at specific intervals.
  • compositions according to the invention may be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease or disorder and the weight and general state of the subject. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders. [0139] Various considerations are described, e.g., in Langer, 1990, Science 249: 1527; Gilman et al. (eds. ), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.), each of which is herein incorporated by reference in its entirety and for all purposes.
  • Dosages for parenteral administration of active pharmaceutical agents can be converted into corresponding dosages for oral administration by multiplying parenteral dosages by appropriate conversion factors.
  • the parenteral dosage in mg/m 2 times 1.8 the corresponding oral dosage in milligrams ("mg"), where "m 2 " is the surface area of the subject (meters 2 ).
  • the parenteral dosage in mg/m 2 times 1.6 the corresponding oral dosage in mg.
  • An average adult weighs about 70 kg. See the MILLER-KEANE ENCYCLOPEDIA & DICTIONARY OF MEDICINE, NURSING & ALLIED HEALTH, 5th Ed., (W. B. Saunders Co. 1992), pp. 1708 and 1651.
  • the method by which the compound of the present invention may be administered for oral use would be, for example, in a hard gelatin capsule wherein the active ingredient is mixed with an inert solid diluent, or soft gelatin capsule, wherein the active ingredient is mixed with a co-solvent mixture, such as PEG 400 containing Tween-20.
  • a compound of the present invention may also be administered in the form of a sterile injectable aqueous or oleaginous solution or suspension.
  • the compound of the present invention can generally be administered intravenously or as an oral dose of 0.5 to 20 mg/kg given, for example, every 3 - 12 hours.
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension.
  • excipients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose,
  • dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate ; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
  • phosphatide such as lecithin
  • a condensation product of an alkylene oxide with a fatty acid for example, polyoxyethylene stearate
  • a condensation product of ethylene oxide with a long chain aliphatic alcohol
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • a compound of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • the compounds of the present invention as used in the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
  • Dosage levels of the compounds of the present invention as used in the present invention are of the order of about 0.5 mg to about 20 mg per kilogram body weight, an average adult weighing 70 kilograms, with a preferred dosage range between about 5 mg to about 20 mg per kilogram body weight per day (from about 0.3 gms to about 1.2 gms per patient per day).
  • the amount of the compound of the present invention that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for oral administration to humans may contain about 5 mg to 1 g of a compound of the present invention with an appropriate and convenient amount of carrier material that may vary from about 5 to 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 5 mg to 500 mg of the present invention active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • compositions comprising a compound of the present invention in the form of pharmaceutically-acceptable prodrugs, metabolites, analogues, derivatives, solvates or salts, either alone or in admixture with other active pharmaceutical agents, together with a pharmaceutically acceptable diluent, adjuvant, or carrier.
  • Examples herein are meant to illustrate certain embodiments and not to limit the scope thereof.
  • Phenylacetic acid 60 ⁇ ⁇ , 0.48 mmol, 1.2 eq was added to a solution containing Int 4 (100 mg, 0.4 mmol), EDCI (93 mg, 0.60 mmol, 1.5 eq) and HOBt (162 mg, 1.2 mmol, 3 eq) in DMF (4 mL) and the resulting mixture was stirred for 16 h at RT.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL). The organic layer washed with water (10 mL), saturated aqueous aHC03 (10 mL), brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated in vacuo.
  • Int 9 Int 10 [0178] Int 9 (1.6 g, 10.5 mmol) was added drop-wise to a vigorously stirring mixture of aminoguanidine sulfate (10.3 g, 42.1 mmol, 4 eq) in freshly prepared NaOMe (using 968 mg, 42.1 mmol of Na in 28 mL of dry MeOH) at 0°C. The resulting mixture was heated to reflux for 20 h. The mixture was then cooled to RT, carefully poured over ice cold water (20 mL) and concentrated in vacuo. The crude residue was purified over neutral alumina using 4-10%
  • Oxalyl chloride (2.36 niL, 24.2 mmol, 1.5 eq) and a catalytic quantity of DMF were added to a solution of pyrimidine-2-carboxylic acid (2 g, 16.1 mmol) in dry DCM (30 mL) at 0°C. The resulting mixture was allowed to warm to RT and stirred for 3 h. The volatiles were removed in vacuo and the residue was thoroughly dried to afford pyrimidine-2-carboxylic acid chloride (2.1 g, 14.8 mmol) as a black solid.
  • the crude material was added portion-wise to a solution of aminoguanidine sulfate (5.5 g, 22.2 mmol, 1.5 eq) in pyridine (20 mL) at 0°C. The resulting mixture was allowed to warm to RT and stir for 14 h. The mixture was then neutralized with saturated aqueous aHC0 3 , extracted with ?-BuOH (5 x 50 mL), dried over Na 2 S0 4 , filtered and concentrated in vacuo. The crude material was dissolved in water (45 mL) and the resulting solution was heated to 100°C for 24 h.

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Abstract

L'invention concerne inter alia des composés aromatiques multisubstitués qui montrent une double action inhibitrice contre la thrombine (facteur II activé de coagulation du sang ; EC 3.4.21.5) et le facteur de coagulation Xa (facteur Stuart-Prower activé, facteur Xa, EC 3.4.21.6), et le procédé d'utilisation de ceux-ci.
PCT/US2012/057951 2011-09-29 2012-09-28 Composés doublement inhibiteurs et procédés d'utilisation de ceux-ci Ceased WO2013049591A2 (fr)

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US9156831B2 (en) 2013-01-23 2015-10-13 Astrazeneca Ab Chemical compounds
WO2016044662A1 (fr) * 2014-09-17 2016-03-24 Verseon Corporation Composés de pyridone substituée par pyrazolyl en tant qu'inhibiteurs de sérine protéase
US9533970B2 (en) 2013-03-15 2017-01-03 Verseon Corporation Multisubstituted aromatic compounds as serine protease inhibitors
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JP2018506563A (ja) * 2015-02-27 2018-03-08 ヴァーセオン コーポレイション セリンプロテアーゼ阻害剤としての置換ピラゾール化合物
US9951025B2 (en) 2013-03-15 2018-04-24 Verseon Corporation Halogenopyrazoles as inhibitors of thrombin
US10681909B2 (en) 2014-08-29 2020-06-16 Fmc Corporation Herbicidal triazoles
WO2023018694A1 (fr) * 2021-08-10 2023-02-16 Revela, Inc. Compositions, formulations et méthodes de traitement capillaire
WO2024123668A1 (fr) * 2022-12-05 2024-06-13 Oddity Labs, Llc Compositions, formulations et méthodes de traitement capillaire
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US4256887A (en) * 1978-04-06 1981-03-17 Merck & Co., Inc. 1,2,4-Triazoles and a method for their preparation
EP1112070B1 (fr) * 1998-08-20 2004-05-12 Smithkline Beecham Corporation Nouveaux composes de triazole substitues
AR042052A1 (es) * 2002-11-15 2005-06-08 Vertex Pharma Diaminotriazoles utiles como inhibidores de proteinquinasas
US8338392B2 (en) * 2008-02-20 2012-12-25 The Wistar Institute MicroRNA modulators and method for identifying and using the same

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US10058541B2 (en) 2013-03-15 2018-08-28 Verseon Corporation Multisubstituted aromatic compounds as serine protease inhibitors
US9951025B2 (en) 2013-03-15 2018-04-24 Verseon Corporation Halogenopyrazoles as inhibitors of thrombin
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US9533970B2 (en) 2013-03-15 2017-01-03 Verseon Corporation Multisubstituted aromatic compounds as serine protease inhibitors
WO2014195244A1 (fr) * 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Triazolopyridines utilisées comme inhibiteurs de la thrombine pour traiter des maladies thromboemboliques
US10681909B2 (en) 2014-08-29 2020-06-16 Fmc Corporation Herbicidal triazoles
JP2017528486A (ja) * 2014-09-17 2017-09-28 ヴァーセオン コーポレイション セリンプロテアーゼ阻害剤としてのピラゾリル置換ピリドン化合物
US10189810B2 (en) 2014-09-17 2019-01-29 Verseon Corporation Pyrazolyl-substituted pyridone compounds as serine protease inhibitors
WO2016044662A1 (fr) * 2014-09-17 2016-03-24 Verseon Corporation Composés de pyridone substituée par pyrazolyl en tant qu'inhibiteurs de sérine protéase
JP2020143112A (ja) * 2014-09-17 2020-09-10 ヴァーセオン コーポレイション セリンプロテアーゼ阻害剤としてのピラゾリル置換ピリドン化合物
JP2018506563A (ja) * 2015-02-27 2018-03-08 ヴァーセオン コーポレイション セリンプロテアーゼ阻害剤としての置換ピラゾール化合物
US10532995B2 (en) 2015-02-27 2020-01-14 Verseon Corporation Substituted pyrazole compounds as serine protease inhibitors
CN109311824A (zh) * 2016-03-10 2019-02-05 北京生命科学研究所 激酶抑制剂
WO2017152842A1 (fr) * 2016-03-10 2017-09-14 National Institute Of Biological Sciences, Beijing Inhibiteurs de kinases
WO2023018694A1 (fr) * 2021-08-10 2023-02-16 Revela, Inc. Compositions, formulations et méthodes de traitement capillaire
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WO2024123668A1 (fr) * 2022-12-05 2024-06-13 Oddity Labs, Llc Compositions, formulations et méthodes de traitement capillaire

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