[go: up one dir, main page]

US20110130432A1 - Heterocyclic Carboxamides For Use As Thrombin Inhibitors - Google Patents

Heterocyclic Carboxamides For Use As Thrombin Inhibitors Download PDF

Info

Publication number
US20110130432A1
US20110130432A1 US13/000,637 US200913000637A US2011130432A1 US 20110130432 A1 US20110130432 A1 US 20110130432A1 US 200913000637 A US200913000637 A US 200913000637A US 2011130432 A1 US2011130432 A1 US 2011130432A1
Authority
US
United States
Prior art keywords
tetrazol
chloro
benzyl
carboxamide
alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US13/000,637
Other languages
English (en)
Inventor
Jonas Branalt
David Gustafsson
Ingemar NILSSON
Magnus Polla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Priority to US13/000,637 priority Critical patent/US20110130432A1/en
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRANALT, JONAS, GUSTAFSSON, DAVID, NILSSON, INGEMAR, POLLA, MAGNUS
Publication of US20110130432A1 publication Critical patent/US20110130432A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel pharmaceutically useful compounds, in particular compounds that are competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.
  • Blood coagulation is the key process involved in both haemostasis (i.e. the prevention of blood loss from a damaged vessel) and thrombosis (i.e. the formation of a blood clot in a blood vessel, sometimes leading to vessel obstruction).
  • Coagulation is the result of a complex series of enzymatic reactions.
  • One of the ultimate steps in this series of reactions is the conversion of the proenzyme prothrombin to the active enzyme thrombin.
  • Thrombin is known to play a central role in coagulation. It activates platelets, leading to platelet aggregation, converts fibrinogen into fibrin monomers, which polymerise spontaneously into fibrin polymers, and activates factor XIII, which in turn crosslinks the polymers to form insoluble fibrin. Furthermore, thrombin activates factor V, factor VIII and factor XI leading to a “positive feedback” generation of thrombin from prothrombin.
  • Thrombin inhibitors based (at the P1-position of the molecule) upon the 2-heteroaromatic substituted 1-yl-benzylamide structural unit are disclosed in U.S. Pat. No. 7,144,899 and WO2004032834.
  • Thrombin inhibitors based (at the P2-position of the molecule) upon the 1-acetyl-pyrrolidine-2-carboxylic acid amide, 1-acetyl-piperidine-2-carboxylic acid amide or 1-acetyl-azepane-2-carboxylic acid amide structural units are disclosed in U.S. Pat. No. 7,144,899.
  • Thrombin inhibitors based (at the P2-position of the molecule) upon the 1-acetyl-pyrrolidine-2-carboxylic acid amide or 1-acetyl-dihydropyrrole-2-carboxylic acid amide structural units are disclosed in U.S. Pat. No. 6,515,011 and WO2004032834.
  • Thrombin inhibitors based (at the P2-position of the molecule) upon the 1-acetyl-azepane-2-carboxylic acid amide structural unit are disclosed in U.S. Pat. No. 6,528,503.
  • Thrombin inhibitors based (at the P2-position of the molecule) upon the aza-bicyclo[3.1.0]hexane-1-carboxylic acid amide structural unit are disclosed in U.S. Pat. No. 6,288,077.
  • Thrombin inhibitors based (at the P2-position of the molecule) upon the 1,3-thiazolidine-2-carboxylic acid amide, 1,3-thiazolidine-4-carboxylic acid amide, pyrazolidine-3-carboxylic acid amide and 4,5-dihydro-1H-pyrazole-5-carboxylic acid amide structural units are disclosed in U.S. Pat. No. 6,740,647 and also described by Lange et al. in Bioorganic & Medicinal Chemistry Letters 16, 2648-2653 (2006).
  • Thrombin inhibitors based (at the P2-position of the molecule) upon 4-fluoroprolines are described by Staas et al. in Bioorganic & Medicinal Chemistry 14, 6900-6916 (2006).
  • Thrombin inhibitors based (at the P2-position of the molecule) upon pyrazinones carrying various aryl-heterocycles at the P1-position of the molecule are described by Young et al. in Journal of Medicinal Chemistry 47, 2995-3008 (2004).
  • X is N, O or NH
  • Y is CH 2 when X is O or NH, with X and Y connected via a single bond, or, alternatively,
  • Y is CH when X is N, with X and Y connected via a double bond;
  • R 1 is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S, wherein said 5-membered heteroaryl ring is substituted, at any carbon ring atom, by 0, 1 or 2 substituents independently selected from C 1-6 alkyl and a 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms, wherein said 6-membered heteroaryl ring is substituted, at any carbon ring atom, by 0, 1, 2 or 3 substituents independently selected from C 1-6 alkyl;
  • R 2 is H, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1-6 alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen;
  • R 3 is H, R 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl are independently substituted by 0, 1, 2, 3, 4 or 5 substituents selected from halogen and 0, 1 or 2 substituents selected from OH, oxo, cyano, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 3-6 cycloalkyl, C 4-7 cycloalkenyl, cycloheteroalkyl, R 5 and R 6 ;
  • R 5 is phenyl
  • R 6 is C 1-6 alkoxy, wherein said C 1-6 alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen;
  • R 7 is C 1-6 alkyl
  • R 4 is OH, OC(O)R 7 , OC(O)R 8 or NHR 9 ;
  • R 8 is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, cyano, F, CF 3 , CHF 2 and CH 2 F or
  • C 1-4 alkyl wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from methyl and ethyl and 0 or 1 substituents selected from phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, cyano F, CF 3 , CHF 2 , CH 2 F and OC(O)R 7 ;
  • R 9 is H, COOR 7 or SO 2 R 7 wherein said R 7 is substituted by 0, 1, 2 or 3 substituents independently selected from OH, halogen, cyano, R 6 and C 3-7 cycloalkyl;
  • Q is O, CH 2 or S(O) n ;
  • W is C or N
  • n is independently 0, 1 or 2;
  • t is independently 0, 1 or 2;
  • u is independently 0 or 1;
  • R 10 is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, R 5 and R 6 , wherein said C 1-4 alkyl is substituted by 0 or 1 substituent selected from R 5 , NH 2 , NH(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ; and
  • R 11 is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, R 5 and R 6 , wherein said C 1-4 alkyl is substituted by 0 or 1 substituent selected from R 5 , NH 2 , NH(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;
  • the compounds of formula (I) have chiral centres and some have geometric isomeric centres (E- and Z-isomers), and it is understood that the invention encompasses all such optical, diastereoisomeric and geometric isomers.
  • a method of treatment of a condition where inhibition of thrombin is beneficial comprises administration of a therapeutically effective amount of a compound of formula (I) to a person suffering from, or susceptible to, such a condition.
  • a method of treatment and prevention of thromboembolic disorders comprises administration of a therapeutically effective amount of a compound of formula (I) to a person suffering from, or susceptible to, thrombophilia conditions.
  • compositions comprising a therapeutically effective amount of a compound of formula (I), in admixture with at least one pharmaceutically acceptable diluent, excipients and/or inert carrier.
  • a pharmaceutical formulation comprising a compound of formula (I) for use in the treatment of those conditions where inhibition of thrombin is beneficial, such as thrombo-embolism and/or conditions where anticoagulant therapy is indicated.
  • the object of the present invention is to provide compounds that are competitive inhibitors of trypsin-like serine proteases, especially thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes to their production.
  • C 1-6 means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms and “C 1-4 ” means a carbon group having 1, 2, 3 or 4 carbon atoms.
  • alkyl includes both straight and branched chain alkyl groups and may be, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl or t-hexyl.
  • cycloalkyl refers to a saturated cyclic hydrocarbon ring system.
  • C 3-6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • alkenyl includes both straight and branched chain alkenyl groups.
  • the term C 2-6 alkenyl includes alkenyl groups having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, vinyl, allyl, propenyl, butenyl, crotyl, pentenyl, or hexenyl, and a butenyl group may for example be buten-2-yl, buten-3-yl or buten-4-yl.
  • alkynyl includes both straight and branched chain alkynyl groups.
  • the term C 2-6 alkynyl includes alkynyl groups having 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to, etynyl, propargyl, pentynyl or hexynyl and a butynyl group may for example be butyn-3-yl or butyn-4-yl.
  • cycloalkenyl refers to a non-aromatic cyclic hydrocarbon ring system containing one or two double bonds.
  • C 4-7 cycloalkenyl may be, but is not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl and a cyclopentenyl group may for example be cyclopenten-3-yl or cyclopenten-4-yl.
  • alkoxy includes both straight or branched alkoxy groups.
  • C 1-6 alkoxy may be, but is not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, t-pentoxy, neo-pentoxy, n-hexyloxy, i-hexyloxy or t-hexyloxy.
  • the term “5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S” includes aromatic heterocyclic rings. Examples of such rings are imidazole, tetrazole, triazole, thiadiazole or oxadiazole.
  • 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms includes pyridine, pyridazine, pyrimidine or pyrazine.
  • the term “4-, 5- or 6-membered cycloheteroalkyl ring having 1 or 2 heteroatoms selected from O, S and N” includes oxetane, azetidine, oxazetidine, pyrrolidine, imidazoline, tetrahydrofuran, oxazolidine, piperidine, piperazine, hexahydropyridazine, hexahydropyrimidine, morpholine, oxazinane, thietane, thietane 1-oxide, thietane 1,1-dioxide, tetrahydra-thiophene, tetrahydra-thiophene 1-oxide, tetrahydra-thiophene 1,1-dioxide, tetrahydra-thiopyran, tetrahydra-thiopyran 1-oxide or tetrahydra-thiopyran
  • the term “5 or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from O, S and N” includes furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine or triazine.
  • phenyl-fused 5- or 6-membered cycloheteroalkyl ring containing 1 or 2 heteroatoms independently selected from O, S and N includes indoline, dihydroisoindole, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydrobenzoimidazole, dihydroindazole, dihydrobenzooxazole, dihydrobenzothiazole, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroquinoxaline, tetrahydraquinazoline, tetrahydrophtalazine, chroman, isochroman, thiochroman, isothiochroman, dihydrobenzooxazine or dihydrobenzothiazine.
  • halogen may be fluoro, chloro, bromo or iodo.
  • R 1 is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatoms are O or S, wherein said 5-membered heteroaryl ring is substituted, at any carbon ring atom, by 0, 1 or 2 substituents independently selected from C 1-6 alkyl and a 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms, wherein said 6-membered heteroaryl ring is substituted, at any carbon ring atom, by 0, 1, 2 or 3 substituents independently selected from C 1-6 alkyl.
  • R 1 is a 5-membered heteroaryl ring containing 2, 3 or 4 heteroatoms, selected from N, O and S, wherein at least 2 heteroatoms are N, and 0 or 1 heteroatom is O or S.
  • R 1 is tetrazole.
  • R 2 is H, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1-6 alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen.
  • R 2 is H or halogen.
  • R 2 is H, Cl or F.
  • the stereochemical configuration around the carbon in the pyrazolidine, dihydropyrazole or isoxazolidine, i.e. the ring containing X and Y, which is covalently bound to the carbonyl is (S).
  • R 3 is H, R 5 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl, wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are independently substituted by 0, 1, 2, 3, 4 or 5 substituents selected from halogen and 0, 1 or 2 substituents selected from OH, oxo, cyano, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 3-6 cycloalkyl, C 4-7 cycloalkenyl, cycloheteroalkyl, R 5 and R 6 ,
  • R 4 is OH, OC(O)R 7 , OC(O)R 8 or NHR 9 ;
  • R 8 is phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, cyano, F, CF 3 , CHF 2 and CH 2 F or
  • C 1-4 alkyl wherein said C 1-4 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from methyl and ethyl and 0 or 1 substituents selected from phenyl, wherein said phenyl is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from C 1-4 alkyl, C 1-4 alkoxy, cyano, F, CF 3 , CHF 2 , CH 2 F and OCOR 7 ;
  • R 9 is H, COOR 7 or SO 2 R 7 wherein said R 7 is substituted by 0, 1, 2 or 3 substituents independently selected from OH, halogen, cyano, R 6 and C 3-7 cycloalkyl;
  • R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, a 5 or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from O, S and N,
  • R 4 is OH, OC(O)R 7 , OC(O)R 8 or NH 2 ,
  • R 3 is C 3-6 cycloalkyl, R 12 or C 1-6 alkyl, wherein said C 1-6 alkyl is substituted by 0 or 1 substituents selected from C 3 cycloalkyl, N(C 1-4 alkyl) 2 , R 6 or R 12 ,
  • R 4 is OH or OC(O)R 7 .
  • stereochemical configuration around the carbon substituted by R 3 and R 4 in G is (R).
  • R 10 is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, R 5 and R 6 , wherein said C 1-4 alkyl is substituted by 0 or 1 substituent selected from R 5 , NH 2 , NH(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;
  • R 5 is phenyl, which is substituted, by 0, 1, 2, 3, 4 or 5 substituents independently selected from COOH, OH, halogen, CF 3 , cyano, C 1-6 alkyl, R 6 and SO 2 R 7 ,
  • Q is O, CH 2 or S(O) n ;
  • n is independently 0, 1 or 2;
  • each t is independently 0, 1 or 2.
  • Q is O or CH 2 ;
  • each t is independently 0 or 1;
  • R 10 is 0, 1 or 2 substituents selected from oxo, C 1-4 alkyl, R 5 and R 6 ;
  • R 5 is phenyl, which is substituted by 0, 1, 2, 3, 4 or 5 substituents independently selected from COOH, OH, halogen, CF 3 , cyano, C 1-6 alkyl, R 6 and SO 2 R 7 ;
  • Q is O or CH 2 ;
  • each t is independently 0 or 1;
  • R 10 is 0, 1 or 2 substituents selected from oxo and C 1-4 alkyl.
  • R 4 is OH, OC(O)R 7 , OC(O)R 8 or NHR 9 ;
  • Q is O, CH 2 or S(O) n ;
  • W is C or N
  • n is independently 0, 1 or 2;
  • u is independently 0 or 1;
  • R 10 is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, oxo, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, R 5 and R 6 , wherein said C 1-4 alkyl is substituted by 0 or 1 substituent selected from R 5 , NH 2 , NH(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;
  • R 11 is 0, 1, 2, 3, 4 or 5 substituents selected from halogen, OH, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, R 5 and R 6 , wherein said C 1-4 alkyl is substituted by 0 or 1 substituents selected from R 5 , NH 2 , NH(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;
  • R 4 is OH, OC(O)R 7 , OC(O)R 8 or NH 2 ,
  • Q is O or CH 2 ;
  • u is independently 0 or 1;
  • R 10 is 0, 1 or 2 substituents selected from C 1-4 alkyl, halogen and R 6 ;
  • R 11 is 0, 1 or 2 substituents selected from C 1-4 alkyl, halogen and R 6 ,
  • R 4 is OH or OC(O)R 7 ;
  • R 10 is 0, 1 or 2 substituents selected from C 1-4 alkyl, F, Cl, OCH 3 , OCF 3 , OCHF 2 and OCH 2 F;
  • R 11 is 0, 1 or 2 substituents selected from C 1-4 alkyl, F, Cl, OCH 3 , OCF 3 , OCHF 2 and OCH 2 F;
  • Q is O or CH 2 ;
  • u is independently 0 or 1.
  • the compound of formula (I) is selected from:
  • X is N, O or NH
  • Y is CH 2 when X is O or NH, with X and Y connected via a single bond, or
  • Y is CH when X is N, with X and Y connected via a double bond;
  • R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, a 5 or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from O, S and N,
  • R 6 is C 1-6 alkoxy, wherein said C 1-6 alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen;
  • R 12 is phenyl, wherein said phenyl is substituted by 0, 1 or 2 substituents selected from halogen and R 6 .
  • X is N, O or NH
  • Y is CH 2 when X is O or NH, with X and Y connected via a single bond, or
  • Y is CH when X is N, with X and Y connected via a double bond;
  • Q is O or CH 2 ;
  • u is independently 0 or 1;
  • R 10 is 0, 1 or 2 substituents selected from C 1-4 alkyl, halogen and R 6 ;
  • R 11 is 0, 1 or 2 substituents selected from C 1-4 alkyl, halogen and R 6 ;
  • R 6 is C 1-6 alkoxy, wherein said C 1-6 alkoxy is substituted by 0, 1, 2, 3, 4 or 5 halogen.
  • the present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:
  • R 1 and R 2 are as defined in formula (I) to deliver a compound of formula (IV), or a derivative thereof that is protected at the amino group,
  • R 3 is as hereinbefore defined and R 4 is OH, or a derivative thereof that is either protected at the hydroxy substituent or at both the hydroxy substituent and at the carboxylic acid, to deliver a compound of formula (I);
  • R 10 , R 11 , W, Q and u are as hereinbefore defined and R 4 is OH, or a derivative thereof that is either protected at the hydroxy substituent or at both the hydroxy substituent and at the carboxylic acid, to deliver a compound of formula (I);
  • R 3 is as hereinbefore defined and R 4 is NHR 9 , wherein R 9 is as hereinbefore defined, or a derivative thereof that is protected at the amino substituent, to deliver a compound of formula (I);
  • R 10 , R 11 , W, Q and u are as hereinbefore defined and R 4 is NHR 9 , wherein R 9 is as hereinbefore defined, or a derivative thereof that is protected at the amino substituent, to deliver a compound of formula (I);
  • R 10 , Q and t are as hereinbefore defined, or a derivative thereof that is protected at the amino group, to deliver a compound of formula (I);
  • R 3 is as hereinbefore defined and R 4 is OH, or a derivative thereof that is either protected at the hydroxy substituent or at both the hydroxy substituent and at the carboxylic acid, to deliver a compound of formula (VIII);
  • R 10 , R 11 , W, Q and u are as hereinbefore defined and R 4 is OH, or a derivative thereof that is either protected at the hydroxy substituent or at both the hydroxy substituent and at the carboxylic acid, to deliver a compound of formula (IX)
  • R 10 , R 11 , X, Y, W, Q and u are as hereinbefore defined and R 4 is OH, or a derivative thereof that is protected at the OH group, to deliver a compound of formula (XI)
  • R 12 is OH, alkoxy, aryloxy or R 13 , wherein R 13 is a chiral auxiliary, e.g., 2,10-camphorsultam, 6,6-dimethyl-7,10-methylen-3-oxa-1-azaspiro[4.5]decan-2-one or 4-benzyl-2-oxazolidinone, with trimethylsilyldiazomethane to deliver a compound of formula (XV)
  • R 12 is OH or alkoxy
  • L is Cl, Br, I or OSO 2 CF 3
  • X is O, N or a protected derivative thereof, in the presence of base to deliver a compound of formula (XV)
  • Y is CH 2 , X is N or O, R 12 is OH or alkoxy and the bond between X and Y is a single bond.
  • Processes (A)-(H) and (L) may be carried out using known procedures for preparation of amides from carboxylic acids, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in a solvent, e.g. DCM, MeCN, H 2 O, EtOAc or DMF, in the presence of an appropriate base, e.g. pyridine, DMAP, NMM, TEA, NaHCO 3 , 2,4,6-collidine or DIPEA, and a suitable reagent, e.g. oxalyl chloride, cyanuric fluoride, EDC/HOBt, DCC/HOBt, HBTU, HATU, PyBOP, T3P or TBTU.
  • the reaction temperature may be from 0° C. to 100° C., or at the reflux temperature of the solvent if ⁇ 100° C., but conveniently room temperature.
  • Processes (I) and (J) may be carried out using known procedures for preparation of lactones, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. CHCl 3 , benzene, toluene, EtOH or THF, in the presence of a suitable reagent, e.g. TsOH, MsOH, NaOH, pivaloyl chloride/TEA or DMAP/BOP.
  • the reaction temperature may be from 0° C. to 100° C., or at the reflux temperature of the solvent if ⁇ 100° C., but conveniently room temperature.
  • Process (K) may be carried out using known procedures for preparation of amides from lactones, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. DCM, THF or MeOH, in the presence of a suitable reagent, e.g. TEA.
  • the reaction temperature may be from 0° C. to 100° C., or at the reflux temperature of the solvent if ⁇ 100° C., but conveniently room temperature.
  • Process (M) may be carried out using known procedures for preparation of alcohols from ketones, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. THF, in the presence of a suitable reagent, e.g. NaBH 4 , Zn(BH 4 ) 2 , Ph 2 SiH 2 in the presence of a suitable catalyst, e.g. Rh(PPh 3 ) 3 Cl or Rh(I)-2-(2-pyridyl)-4-carbomethoxy-1,3-thiazolidine, or, alternatively, in the presence of H 2 and a suitable catalyst, e.g. Ru/C, Rh-DIOP or Rh-CYDIOP.
  • the reaction temperature may be from 0° C. to 100° C., or at the reflux temperature of the solvent if ⁇ 100° C., but conveniently room temperature.
  • Process (N) may be carried out using known procedures for preparation of pyrazolines from olefins, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. methylene chloride, hexane or THF.
  • the reaction temperature may be from ⁇ 100° C. to 100° C., or at the reflux temperature of the solvent if ⁇ 100° C., but conveniently room temperature.
  • Process (O) may be carried out using known procedures for preparation of pyrazolidines or isoxazolidines, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in an organic solvent, e.g. THF, in the presence of a suitable reagent, e.g. NaHMDS, LiHMDS or tetrabutylammoniumfluoride.
  • the reaction temperature may be from 0° C. to 100° C., or at the reflux temperature of the solvent if ⁇ 100° C., but conveniently room temperature.
  • Processes used for hydrolyzing carboxylic esters to carboxylic acids may be carried out using known procedures, or analogously, e.g. as hereinafter described in the Examples. It may be carried out in a solvent, e.g. MeCN or H 2 Od 2 O in the presence of an appropriate base, e.g. TEA or DIPEA, or a suitably acid, e.g. HCl, and optionally a suitable reagent, e.g. LiBr.
  • the reaction temperature may be from 0° C. to 100° C., or at the reflux temperature of the solvent if ⁇ 100° C., but conveniently room temperature.
  • a further embodiment of the invention encompasses pharmaceutically acceptable salts of the compounds of formula (I).
  • pharmaceutically-acceptable salts include, but are not limited to, an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine.
  • pharmaceutically acceptable salts include, but are not limited to, acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate salt.
  • the compounds of formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
  • Certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).
  • Prodrugs of formula (I) may display improved physicochemical, biopharmaceutical or pharmacokinetic properties. Examples of prodrugs include in vivo hydrolysable esters of a compound of the formula (I).
  • An in vivo hydrolysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • ester prodrugs derivatives see: Curr. Drug. Metab. 2003, 4, 461.
  • prodrug derivatives see: Rautio, J. et al. Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein.
  • the compounds of the invention are thus expected to be useful in those conditions where inhibition of thrombin is beneficial (as determined by reference to a clinically relevant end-point, e.g. conditions, such as thrombo-embolisms, where inhibition of thrombin is required or desired, and/or conditions where anticoagulant therapy is indicated), including the following:
  • thrombophilia conditions include, but are not limited to, inherited or acquired activated protein C resistance, such as the factor V-mutation (factor V Leiden), inherited or acquired deficiencies in antithrombin III, protein C, protein S, protein Z, heparin cofactor II, and conditions with increased plasma levels of the coagulation factors such as caused by the prothrombin G20210A mutation.
  • factor V-mutation factor V Leiden
  • inherited or acquired deficiencies in antithrombin III protein C
  • protein S protein S
  • protein Z protein Z
  • heparin cofactor II heparin cofactor II
  • thrombo-embolic disease Other conditions known to be associated with hypercoagulability and thrombo-embolic disease include circulating antiphospholipid antibodies (Lupus anticoagulant), homocysteinemi, heparin induced thrombocytopenia and defects in fibrinolysis, as well as coagulation syndromes (e.g. disseminated intravascular coagulation (DIC)) and vascular injury in general (e.g. due to trauma or surgery).
  • DIC intravascular coagulation
  • low physical activity, low cardiac output or high age are known to increase the risk of thrombosis and hypercoagulability may be just one of several factors underlying the increased risk. These conditions include, but are not limited to, prolonged bed rest, prolonged air travelling, hospitalisation for an acute medical disorder such as cardiac insufficiency or respiratory insufficiency.
  • Further conditions with increased risk of thrombosis with hypercoagulability as one component are pregnancy and hormone treatment (e.g. oestrogen).
  • venous thrombosis e.g. deep venous thrombosis, DVT
  • pulmonary embolism e.g. in myocardial infarction, unstable angina and acute coronary syndrome, thrombosis-based stroke and peripheral arterial thrombosis
  • systemic embolism which may lead to stroke usually from the atrium during atrial fibrillation (e.g. non-valvular or valvular atrial fibrillation) or from the left ventricle after transmural myocardial infarction, or caused by congestive heart failure
  • prophylaxis of re-occlusion i.e. thrombosis
  • thrombolysis thrombolysis
  • PTI percutaneous trans-luminal interventions
  • coronary bypass operations the prevention of thrombosis after microsurgery and vascular surgery in general, organ transplantation and plastic surgery.
  • Further indications include the therapeutic and/or prophylactic treatment of disseminated intravascular coagulation caused by bacteria, multiple trauma, intoxication or any other mechanism; anticoagulant treatment when blood is in contact with foreign surfaces in the body such as vascular grafts, vascular stents, vascular catheters, mechanical and biological prosthetic valves or any other medical device; and anticoagulant treatment when blood is in contact with medical devices outside the body such as during cardiovascular surgery using a heart-lung machine or in haemodialysis; the therapeutic and/or prophylactic treatment of idiopathic and adult respiratory distress syndrome, pulmonary fibrosis following treatment with radiation or chemotherapy, chronic obstructive pulmonary disease, septic shock, septicaemia, inflammatory responses, which include, but are not limited to, edema, acute or chronic atherosclerosis such as coronary arterial disease and the formation of atherosclerotic plaques, cardiac insufficiency, cerebral arterial disease, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral arterial disease
  • the compounds of the invention are thus indicated both in the therapeutic and/or prophylactic treatment of these conditions.
  • a method of treatment of a condition where inhibition of thrombin is beneficial comprises administration of a therapeutically effective amount of a compound of formula (I) to a person suffering from, or susceptible to, such a condition.
  • a method of treatment and prevention of thromboembolic disorders comprises administration of a therapeutically effective amount of a compound of formula (I) to a person suffering from, or susceptible to, thrombophilia conditions.
  • the compounds of the invention have the advantage that they may be more efficacious, be less toxic, be more selective (e.g. for inhibiting thrombin over other serine proteases, in particular trypsin and those involved in haemostasis), be more potent, produce fewer side effects, be more easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than compounds known in the prior art.
  • a method of treatment of a condition where inhibition of thrombin is required comprises administration of a therapeutically effective amount of a compound of the invention to a person suffering from, or susceptible to, such a condition.
  • the compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route or via inhalation, in the form of pharmaceutical preparations comprising a compound of the invention either as a free base, or a pharmaceutically acceptable non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form.
  • Preferred route of administration of compounds of the invention is oral.
  • compositions may be administered at varying doses.
  • the compounds of the invention may also be combined and/or co-administered with any antithrombotic agent(s) with a different mechanism of action, such as one or more of the following: the anticoagulants unfractionated heparin, low molecular weight heparin, other heparin derivatives, synthetic heparin derivatives (e.g. fondaparinux), vitamin K antagonists, synthetic or biotechnological inhibitors of other coagulation factors than thrombin (e.g.
  • PAI-1 plasminogen activator inhibitor-1
  • the compounds of the invention may further be combined and/or co-administered with thrombolytics such as one or more of tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisoylated plasminogen-streptokinase activator complex (APSAC), animal salivary gland plasminogen activators, and the like, in the treatment of thrombotic diseases, in particular myocardial infarction.
  • tissue plasminogen activator naturally, recombinant or modified
  • streptokinase urokinase
  • prourokinase prourokinase
  • anisoylated plasminogen-streptokinase activator complex APSAC
  • animal salivary gland plasminogen activators and the like
  • a pharmaceutical formulation comprising a compound of formula (I), in admixture with at least one pharmaceutically acceptable adjuvant, diluent or carrier.
  • Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.001-100 mg/kg body weight at peroral administration and 0.001-50 mg/kg body weight at parenteral administration.
  • treatment includes therapeutic and/or prophylactic treatment.
  • ethyl acrylate (288 g, 2877 mmol) was dissolved in dichloromethane (4000 mL) at 20° C. with a stirring rate of 150 rpm.
  • Trimethylsilyldiazomethane (2M in hexanes, 1150 mL, 2301 mmol) was added over a period of 30 min, after which the mixture was stirred at 20° C. for 19.5 h. After cooling to ⁇ 30° C., trifluoroacetic acid (443 mL, 5752 mmol) was slowly added aver a period of 35 min.
  • a crude mixture of (R)-2-(4-fluorophenyl)-2-(trimethylsilyloxy)acetyl chloride (600 g, 2301 mmol) in dichloromethane (4000 ml) was slowly added during 110 min, during which time the temperature was allowed to raise to 20° C. The mixture was stirred at 20° C.
  • tert-butyl 5-chloro-2-(1H-tetrazol-1-yl)benzylcarbamate 14 g, 45.20 mmol, prepared as described in J. Med. Chem. 2004, 47, 2995, was suspended in acetonitrile (80 mL) HCl (6 M aqueous solution, 37.7 mL, 225.99 mmol) was added and the mixture was then stirred at room temperature for 4 hours. Water (200 mL) and TBME (100 mL) were added.
  • Examples 2-22 were prepared in a manner analogous to Example 1 described above using the appropriate starting materials.
  • Examples 24-27 were prepared in a manner analogous to Example 23 described above using the appropriate starting materials.
  • Examples 32-48 were prepared in a manner analogous to Example 31 described above using the appropriate starting materials.
  • Examples 50-57 were prepared in a manner analogous to Example 49 described above using the appropriate starting materials.
  • the thrombin inhibitor potency is measured with a chromogenic substrate method, in a Plato 3300 robotic microplate processor (Rosys AG, CH-8634 Hombrechtikon, Switzerland), using 96-well, half volume microtitre plates (Costar, Cambridge, Mass., USA; Cat No 3690).
  • Stock solutions of test substance in DMSO (72 ⁇ L), 0.1-1 mmol/L, are diluted serially 1:3 (24+48 ⁇ L) with DMSO to obtain ten different concentrations, which are analyzed as samples in the assay.
  • test sample 2 ⁇ L is diluted with 124 ⁇ L assay buffer, 12 ⁇ L of chromogenic substrate solution (S-2366, Chromogenix, Mölndal, Sweden) in assay buffer and finally 12 ⁇ L of ⁇ -thrombin solution (Human ⁇ -thrombin, Sigma Chemical Co. or Hematologic Technologies) in assay buffer, are added, and the samples mixed.
  • the final assay concentrations are: test substance 0.00068-133 ⁇ mol/L, S-2366 0.30 mmol/L, ⁇ -thrombin 0.020 NIHU/mL
  • the linear absorbance increment during 40 minutes incubation at 37° C. is used for calculation of percentage inhibition for the test samples, as compared to blanks without inhibitor.
  • the IC 50 value corresponding to the inhibitor concentration which causes 50% inhibition of the thrombin activity, is calculated from a log concentration vs. % inhibition curve.
  • APTT is determined in pooled normal human citrated plasma with the reagent PTT Automated 5 manufactured by Stago.
  • the inhibitors are added to the plasma (10 ⁇ L, inhibitor solution to 90 ⁇ L, plasma) and incubated with the APTT reagent for 3 minutes followed by the addition of 100 ⁇ L, of calcium chloride solution (0.025 M) and APTT is is determined by use of the coagulation analyzer KC10 (Amelung) according to the instructions of the reagent producer.
  • the clotting time is expressed as absolute values (seconds) as well as the ratio of APTT without inhibitor (APTT 0 ) to APTT with inhibitor (APTT i ).
  • the latter ratios range 1-0 are plotted against the concentration of inhibitor (log transformed) and fitted to sigmoidal dose-response curves according to the equation
  • IC 50 APTT is defined as the concentration of inhibitor in human plasma that doubled the Activated Partial Thromboplastin Time.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
US13/000,637 2008-06-23 2009-06-22 Heterocyclic Carboxamides For Use As Thrombin Inhibitors Abandoned US20110130432A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/000,637 US20110130432A1 (en) 2008-06-23 2009-06-22 Heterocyclic Carboxamides For Use As Thrombin Inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US7473608P 2008-06-23 2008-06-23
US10238108P 2008-10-03 2008-10-03
US13/000,637 US20110130432A1 (en) 2008-06-23 2009-06-22 Heterocyclic Carboxamides For Use As Thrombin Inhibitors
PCT/SE2009/050778 WO2009157860A1 (en) 2008-06-23 2009-06-22 New heterocyclic carboxamides for use as thrombin inhibitors

Publications (1)

Publication Number Publication Date
US20110130432A1 true US20110130432A1 (en) 2011-06-02

Family

ID=41431868

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/000,637 Abandoned US20110130432A1 (en) 2008-06-23 2009-06-22 Heterocyclic Carboxamides For Use As Thrombin Inhibitors
US12/489,458 Expired - Fee Related US8119673B2 (en) 2008-06-23 2009-06-23 Compounds 148

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/489,458 Expired - Fee Related US8119673B2 (en) 2008-06-23 2009-06-23 Compounds 148

Country Status (20)

Country Link
US (2) US20110130432A1 (zh)
EP (1) EP2321301A4 (zh)
JP (1) JP2011525487A (zh)
KR (1) KR20110025970A (zh)
CN (1) CN102131802A (zh)
AR (1) AR072278A1 (zh)
AU (1) AU2009263076B2 (zh)
BR (1) BRPI0914323A2 (zh)
CA (1) CA2727925A1 (zh)
CO (1) CO6321275A2 (zh)
CR (1) CR11873A (zh)
DO (1) DOP2010000402A (zh)
EA (1) EA018502B1 (zh)
EC (1) ECSP10010710A (zh)
IL (1) IL210076A0 (zh)
MX (1) MX2010014229A (zh)
TW (1) TW201002689A (zh)
UY (1) UY31923A (zh)
WO (1) WO2009157860A1 (zh)
ZA (1) ZA201100568B (zh)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8354444B2 (en) 2008-09-18 2013-01-15 Hoffmann-La Roche Inc. Substituted pyrrolidine-2-carboxamides
RU2570896C2 (ru) * 2013-04-23 2015-12-20 Общество с ограниченной ответственностью "Химико-фармацевтические технологии" (ООО "ХимФармТех") (4-фтор-бензил)-этил-(2-тетразол-1-ил-фенил)-амин и способ его получения
CN104610184A (zh) * 2015-01-13 2015-05-13 佛山市赛维斯医药科技有限公司 苯二烯四氮唑类化合物、其制备方法和用途
CN104529923B (zh) * 2015-01-13 2016-06-01 佛山市赛维斯医药科技有限公司 二烯四氮唑硝基苯类化合物、其制备方法和用途
US10717703B2 (en) * 2017-08-21 2020-07-21 Celgene Corporation Processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate
CN113636982A (zh) * 2021-04-28 2021-11-12 合肥工业大学 一种肉桂酸衍生物及其制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288077B1 (en) * 1999-05-03 2001-09-11 Adir Et Compagnie 2,3-methano-amino acid compounds
US6515011B2 (en) * 2000-12-18 2003-02-04 Merck & Co., Inc. Thrombin inhibitors
US6528503B2 (en) * 2000-12-18 2003-03-04 Merck & Co., Inc. Thrombin inhibitors
US20040073025A1 (en) * 2001-02-09 2004-04-15 Selnick Harold G Thrombin inhibitors

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW394760B (en) 1993-09-07 2000-06-21 Hoffmann La Roche Novel Carboxamides, process for their preparation and pharmaceutical composition containing the same
WO1996031504A1 (en) * 1995-04-04 1996-10-10 Merck & Co., Inc. Thrombin inhibitors
AR013084A1 (es) * 1997-06-19 2000-12-13 Astrazeneca Ab Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados
DE69824433D1 (en) 1997-08-28 2004-07-15 Biovitrum Ab Proteintyrosinphosphatase inhibitoren
CA2317761A1 (en) * 1998-01-26 1999-07-29 Basf Aktiengesellschaft Thrombin inhibitors
US6482921B1 (en) 1999-01-28 2002-11-19 Essential Therapeutics, Inc. Uridyl peptide antibiotic (UPA) derivatives, their synthesis and use
SE0001803D0 (sv) * 2000-05-16 2000-05-16 Astrazeneca Ab New compounds i
UA78195C2 (uk) * 2001-08-30 2007-03-15 Astrazeneca Ab Похідні мигдалевої кислоти та їх застосування як інгібіторів тромбіну, фармацевтична композиція на їх основі
WO2004032834A2 (en) * 2002-10-04 2004-04-22 Merck & Co., Inc. Thrombin inhibitors
GB0327761D0 (en) 2003-11-29 2003-12-31 Astrazeneca Ab Compounds
PL2104497T3 (pl) 2006-12-06 2015-07-31 Sanofi Sa Pochodne sulfamidu jako inhibitory TAFIa
TW200911787A (en) 2007-07-03 2009-03-16 Astrazeneca Ab New aza-bicyclohexane compounds useful as inhibitors of thrombin
EP2300462B1 (de) 2008-06-06 2014-05-21 Sanofi Makrocyclische harnstoff- und sulfamidderivate als inhibitoren von tafia

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6288077B1 (en) * 1999-05-03 2001-09-11 Adir Et Compagnie 2,3-methano-amino acid compounds
US6515011B2 (en) * 2000-12-18 2003-02-04 Merck & Co., Inc. Thrombin inhibitors
US6528503B2 (en) * 2000-12-18 2003-03-04 Merck & Co., Inc. Thrombin inhibitors
US20040073025A1 (en) * 2001-02-09 2004-04-15 Selnick Harold G Thrombin inhibitors
US7144899B2 (en) * 2001-02-09 2006-12-05 Merck & Co., Inc. Thrombin inhibitors

Also Published As

Publication number Publication date
ZA201100568B (en) 2012-06-27
AU2009263076B2 (en) 2012-07-26
ECSP10010710A (es) 2011-01-31
JP2011525487A (ja) 2011-09-22
US8119673B2 (en) 2012-02-21
TW201002689A (en) 2010-01-16
MX2010014229A (es) 2011-06-20
WO2009157860A1 (en) 2009-12-30
CO6321275A2 (es) 2011-09-20
CA2727925A1 (en) 2009-12-30
UY31923A (es) 2010-01-29
EA018502B1 (ru) 2013-08-30
IL210076A0 (en) 2011-02-28
CR11873A (es) 2011-02-28
US20090318517A1 (en) 2009-12-24
DOP2010000402A (es) 2011-01-15
KR20110025970A (ko) 2011-03-14
CN102131802A (zh) 2011-07-20
BRPI0914323A2 (pt) 2017-03-28
AR072278A1 (es) 2010-08-18
EP2321301A1 (en) 2011-05-18
EA201001823A1 (ru) 2011-06-30
EP2321301A4 (en) 2011-09-28
AU2009263076A1 (en) 2009-12-30

Similar Documents

Publication Publication Date Title
US5414013A (en) Trifluoromethyl mercaptan and mercaptoacyl derivatives and method of using same
JP4199309B2 (ja) 新規アセトアミド誘導体およびプロテアーゼ阻害
EP0910573B1 (en) New amino acid derivatives and their use as thrombin inhibitors
US6515011B2 (en) Thrombin inhibitors
US20090012087A1 (en) New Aza-Bicyclohexane Compounds Useful As Inhibitors Of Thrombin
JPWO1998009949A1 (ja) 新規アセトアミド誘導体およびプロテアーゼ阻害剤
SK73898A3 (en) Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation
KR20060056352A (ko) 안지오텐신ⅱ 수용체 차단제 유도체들
MXPA06003248A (es) Sulfonamida-indoles substituidos.
US8119673B2 (en) Compounds 148
CA3008023A1 (en) Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists
CN101384585B (zh) 治疗血栓栓塞病症的氨酰前体药物衍生物和药物
HRP980096A2 (en) Reverse hydroxamate derivatives as matrix metalloprotease inhibitors, metalloprotease inhibitors, and tnf alpha inhibitors
US4946839A (en) Azetidine derivatives, compositions and methods of treating
KR100483869B1 (ko) 신규한 아미노산 유도체 및 트롬빈 억제제로서의 그의 용도
HK40072612B (zh) 安眠蛋白α和β的新型抑制剂
JP2006527729A (ja) 急性血管疾患の治療用のｘａ因子阻害剤としての１−フェニル−２−オキソ−３−スルホニルアミノ−ピロリジン誘導体および関連化合物
JP2006056830A (ja) ２−アリールアミノベンゾオキサゾール誘導体
JPWO1994001400A1 (ja) ピロリジン誘導体およびその塩の製造方法
JP2008512365A (ja) 第Ｘａ因子阻害物質として使用する、Ｎ−（１−（２，３−ジヒドロ−１Ｈ−インデン−５イル）−２−オキソ−３−ピロリジニル）−スルホンアミド誘導体
HUP9903675A2 (hu) Új acetamid-származékok és proteáz inhibitorok

Legal Events

Date Code Title Description
AS Assignment

Owner name: ASTRAZENECA AB, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BRANALT, JONAS;GUSTAFSSON, DAVID;NILSSON, INGEMAR;AND OTHERS;REEL/FRAME:025786/0454

Effective date: 20110204

STCB Information on status: application discontinuation

Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION