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US 7,598,241 B2Granted
Carboxamide derivatives and their use as factor Xa inhibitors
AssigneeMerck Patent GmbH
InventorsDieter Dorsch, Bertram Cezanne, Werner Mederski, Christos Tsaklakidis, Johannes Gleitz, Christoph van Amsterdam
Life of this patent
Estimating the term…
Abstract
Novel compounds of the formula (I) in which R1, D, X, W, Y and T have the meaning indicated in Patent Claim (1), e.g. (II), are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumors.
Claims33
A compound of formula I
- in which
- D denotes phenyl or pyridyl, each of which is unsubstituted or mono- or polysubstituted by Hal, A, OR2, N(R2)2, NO2, CN, COOR2 or CON(R2)2,
- R1 denotes A, which is mono-, di- or trisubstituted by S(═O)(═NR2)R2, NR2SO2R2, OSO2R2, OSO2N(R2)2 or PO(OR2)2, and may additionally be mono- or disubstituted by OR3, N(R3)2, CN, COOR3 or CON(R3)2, and may additionally be mono-, di- or trisubstituted by S(O)mR2, SO2N(R2)2, or SO3R2,
- R2 denotes H, A, —[C(R3)2]n—Ar′, —[C(R3)2]n-Het′, —[C(R3)2]ncycloalkyl, —[C(R3)2]n—N(R3)2 or [C(R3)2]n—OR3,
- R3 denotes H or A,
- W denotes —[C(R3)2]n—,
- X denotes NR3 or O,
- Y denotes alkylene, cycloalkylene, Het-diyl or Ar-diyl,
- T denotes a mono- or bicyclic saturated, unsaturated or aromatic carbo- or heterocycle having 0 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted by ═O, R2, Hal, A, —[C(R3)2]n—Ar, —[C(R3)2]n-Het, —[C(R3)2]n-cycloalkyl, OR2, N(R2)2,NO2, CN, COOR2, CON(R2)2, NR2COA, NR2CON(R2)2, NR2SO2A, COR2, SO2NR2 and/or S(O)nA,
- or N(R2)2
- and, if Y=piperidine-1,4-diyl, also R2 or cycloalkyl,
- A denotes unbranched or branched alkyl having 1-10 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and/or by —CH═CH— groups and/or also 1-7 H atoms may be replaced by F,
- Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2, NR2COA, NR2SO2A, COR2, SO2N(R2)2, —[C(R3)2]n—COOR2, —O—[C(R3)2]o—COOR2, SO3H or S(O)nA,
- Ar′ denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR3, N(R3)2, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3CON(R3)2, NR3SO2A, COR3, SO2N(R3)2, S(O)nA, —[C(R3)2]n—COOR3 or —O—[C(R3)2]o—COOR3,
- Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen (═O), ═S, ═N(R2)2, Hal, A, —[C(R3)2]n—Ar, —[C(R3)2]n-Het′, —[C(R3)2]n-cycloalkyl, —[C(R3)2]n-OR2, —[C(R3)2]n—N(R3)2, NO2, CN, —[C(R3)2]n—COOR2, —[C(R3)2]n-CON(R2)2, —[C(R3)2]n-NR2COA, NR2CON(R2)2, —[C(R3)2]n-NR2SO2A, COR2, SO2N(R2)2 and/or S(O)nA,
- Het′ denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by carbonyl oxygen, ═S, ═N(R3)2, Hal, A, OR3, N(R3)2, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3CON(R3)2, NR3SO2A, COR3, SO2N(R3)2 and/or S(O)nA,
- Hal denotes F, Cl, Br or I,
- m denotes 1 or 2,
- n denotes 0, 1 or 2, and
- o denotes 1, 2 or 3,
- or a pharmaceutically acceptable salt or stereoisomer thereof.
18 more elements
A compound, which is
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-4-methanesulfonylbutyramide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxo-2H-pyrazin-1-yl)phenyl]-4-methanesulfonylbutyramide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-4-methanesulfonylbutyramide,
- (R)-2-[3(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-4-methanesulfonylbutyramide,
- (R)-2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-methanesulfonyipropionamide,
- (S)-2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-methanesulfonyipropionamide,
- (S)-2-[N-(4-chlorophenyl)carbamoyloxy]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-methanesulfonylpropionamide,
- (R)-2-[N-(4-chlorophenyl)carbamoyloxy]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-methanesulfonyipropionamide,
- (R)-2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-4-methanesulfonylbutyramide,
- (S)-2-[3-(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-methanesulfonyipropionamide,
- 2-[N-4-chlorophenyl)carbamoyloxy]—N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-methanesulfonylpropionamide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-sulfopropionamide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-3-sulfopropionamide,
- (S)-2-[3(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-(dimethoxyphosphoryl)propionamide,
- 2-[3(4-chlorophenyl)ureido]—N-[4-(2-oxomorpholin-1-yl)phenyl]-3-(dimethoxyphosphoryl)propionamide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(3-oxopiperidin-4-yl)phenyl]-3-phosphonopropionamide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxopiperidin-4-yl)phenyl]-3-(methanesulfoximinyl)butyramide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(2-oxo-2H-pyridin-1-yl)phenyl]3-sulfamoylpropionamide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-methanesulfonylaminopropionamide,
- 2-[3-(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-sulfamoyloxypropionamide,
- (R)-2-[3-(4-chlorophenyl)ureido]—N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-3-methanesulfonyipropionamide,
- (R)-2-[3-(4-chlorophenyl)ureido]—N-[2-oxo-1,3-oxazinan-3-yl)phenyl-]3-methanesulfonylpropionamide,
- (R)-2-[3-(4-chlorophenyl)ureido]—N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-4-methanesulfonylbutyramide,
- (R)-2-[3-(4-chlorophenyl)ureido]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3-sulfamoyloxypropionamide,
- (R)-2-[3-(4-chlorophenyl)ureidp]—N-[4-(3-oxomorpholin-4-yl)phenyl]-3(dimethoxyphosphoryl)propionamide,
- (R)-2-[3-(4-chlorophenyl)ureido]—N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-3-(dimethoxyphosphoryl)propionamide, or
- (S)-2-[3-(4-chlorophenyl)ureido]—N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]-3-(dimethoxyphosphoryl)propionamide.
24 more elements
A compound of formula I
- in which
- D denotes phenyl or pyridyl, each of which is unsubstituted or mono- or polysubstituted by Hal, A, OR2, N(R2)2, NO2, CN, COOR2 or CON(R2)2,
- R1 denotes A, which is mono-, di- or trisubstituted by SO2N(R2′)2, SO3R2′, S(═O)(═NR2′)R2, NR2SO2R2, OSO2R2,OSO2N(R2)2 or PO(OR2)2 and may additionally be mono- or disubstituted by OR3, N(R3)2, CN, COOR3 or CON(R3)2, and may additionally be mono-, di- or trisubstituted by S(O)mR2, SO2N(R2)2 or SO3R2,
- R2 denotes H, A, —[C(R3)2]n—Ar′, —[C(R3)2]n-Het′, —[C(R3)2]n-cycloalkyl, —[C(R3)2]n—N(R3)2 or —[C(R3)2]n-OR3,
- R2′ denotes —[C(R3)2]n-Ar′, —[C(R3)2]n-Het′, —[C(R3)2]n-cycloalkyl, —[C(R3)2]n—N(R3)2 or —[C(R3)2]nOR3,
- R3 denotes H or A,
- W denotes —[C(R3)2]n—,
- X denotes NR3 or O,
- Y denotes alkylene, cycloalkylene, Het-diyl or Ar-diyl,
- T denotes a mono- or bicyclic saturated, unsaturated or aromatic carbo- or heterocycle having 0 to 4 N, O and/or S atoms, which may be mono-, di- or trisubstituted by ═O, R2, Hal, A, —[C(R3)2]n-AR,—[C(R3)2]n -Het, —[C(R3)2]n-cycloalkyl, OR2, N(R2)2, NO2,CN, COOR2, CON(R2)2, NR2COA, NR2CON(R2)2,NR2SO2A, COR2, SO2NRw and/or S(O)nA,
- or N(R2)2
- and, if Y=piperidine-1,4-diyl, also R2 or cycloalkyl,
- A denotes unbranched or branched alkyl having 1-10 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and/or by —CH═CH— groups and/or also 1-7 H atoms may be replaced by F,
- Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2, NR2COA, NR2SO2A, COR2, SO2N(R2)2—[C(R3)2]n—COOR2, —O—[C(R3)2]o—COOR2, SO3H or S(O)nA,
- Ar′ denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR3, N(R3)2, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3CON(R3)2, NR3SO2A, COR3, SO2N(R3)2, S(O)nA, —[C(R3)2]nCOOR3 or —O—[C(R3)2]o—COOR3,
- Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen (═O), ═S, ═N(R2)2, Hal, A, —[C(R3)2]n-Het′, —[C(R32]n-cycloalkyl, —[C(R3)2]n-OR2, —[C(R3)2]nN(R3)2, NO2, CN, —[C(R3)2]n—COOR2, —[C(R3)2]n-CON(R2)2, —[C(R3)2]n-NR2COA, NR2CON(R2)2, —[C(R3)2]n-NR2SO2A, COR2, SO2N(R2)2 and/or S(O)nA,
- Het′denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by carbonyl oxygen, (═)), ═S, ═N(R3)2, Hal, A, OR3, N(R3)2, CN, COOR3, CON(R3)2, NR3COA, NR3CON(R3)2, NR3SO2A, COR3, SO2N(R3)2 and/or S(O)nA,
- Hal denotes F, Cl, Br or I,
- m denotes 1 or 2,
- n denotes 0, 1 or 2, and
- o denotes 1, 2 or 3,
- or a pharmaceutically acceptable salt thereof
19 more elements
A compound of formula I
- in which
- D denotes phenyl or pyridyl, each of which is unsubstituted or mono- or polysubstituted by Hal, A, OR2, N(R2)2, NO2, CN, COOR2 or CON(R2)2,
- R1 denotes A, which is mono-, di- or trisubstituted by S(O)mR2, SO2N(R2)2, SO3R2, S(═O)(═NR2)R2, NR2SO2R2, OSO2N(R2, OSO2N(R2)2 or PO(OR2)2 and may additionally be mono- or disubstituted by OR3, N(R3)2, CN, COOR3 or CON(R3)2,
- R2 denotes H, A, —[C(R3)2]n—Ar′, —[C(R3)2]n-Het′, —[C(R3)2]n-cycloalkyl, —[CR3)2]n—N(R3)2 or —[C(R3)2]n-OR3,
- R3 denotes H or A,
- W denotes —[C(R3)2]n,
- X denotes NR3 or O,
- Y denotes alkylene, cycloalkylene, Het-diyl or Ar-diyl,
- T denotes a mono- or bicyclic saturated, unsaturated or aromatic carbo- or heterocycle having 0 to 4 N, O and/or S atoms, which is mono-, di- or trisubstituted by ═O, and which in addition may be mono-, di- or trisubstituted by R2, Hal, A, —[C(R3)2]n—Ar, —[C(R3)2]n-Het, —[C(R3)2]n-cycloalkyl, OR2, N(R2)2, NO2,CN, COOR2, CON(2)2, NR2COA, NR2CON(R2)2, NR2SO2A, COR2, SO2NR2 and/or S(O)nA, or N(R2)2and, if Y=piperidine-1,4-diyl, also R2 or cycloalkyl,
- A denotes unbranched or branched alkyl having 1-10 C atoms, in which one or two CH2 groups may be replaced by O or S atoms and/or by —CH═CH— groups and/or also 1-7 H atoms may be replaced by F,
- Ar denotes phenyl, naphthyl or biphenyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR2, N(R2)2, NO2, CN, COOR2, CON(R2)2 NR2COA, NR2SO2A, COR2, SO2N(R2)2, —[C(R3)2]n—COOR2, —O—[C(R3)2]o—COOR2,SO2H or S(O)nA,
- Ar′ denotes phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A, OR3, N(R3)2, NO2, CN, COOR3, CON(R3)2, NR3COA, NR3CON(R3)2, NR3SO2A, COR3, SO2N(R3)2, S(O)nA, —[C(R3)2]n-COOR3 or —O—[C(R3)2]o—COOR3,
- Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen (═O), ═S, ═N(R2)2, Hal, A, —[C(R3)2]n—Ar, —[C(R3)2]n-Het′, —[C(R3)2]n-cycloalkyl, —[C(R3)2]n-OR2, —[C(R3)2]n—N(R32, NO2, CN, —[C(R3)2]n—COOR2, —[C(R3)2]n-CON(R2)2—[C(R3)2]n-NR2COA, NR2CON(R2)2, —[C(R3)2]n-NR2SO2A, COR2, SO2N(R22 and/or S(O)nA,
- Het′ denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by carbonyl oxygen, ═S, ═N(R3)2, Hal, A, OR3, N(R3)2, CN, COOR3, CON(R3)2, NR3COA, NR3CON(R3)2, NR3SO2A, COR3, SO2N(R3)2 and/or S(O)nA,
- Hal denotes F, Cl, Br or I,
- m denotes 1 or 2,
- n denotes 0, 1 or 2, and
- o denotes 1, 2 or 3,
- or a pharmaceutically acceptable salt thereof
16 more elements
Dependencies are inferred from the claim text.