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US 6,492,368 B1Granted
Benzamidine derivatives as factor XA inhibitors
AssigneeMerck Patent GmbH
InventorsDieter Dorsch, Hanns Wurziger, Guido Melzer, Horst Juraszyk, Sabine Bernotat-Danielowski
Life of this patent
Estimating the term…
Abstract
Novel compounds of the formula I in which X, Y, R1, R2 and R3 are as defined in Patent Claim 1 are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic disorders.
Claims31
A compound of formula I
- in which
- R1 is —C(═NH)—NH2 which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, or —COOA, or R1 is
- R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
- R3 is A, cycloalkyl, —[C(R6)2]nAr, or —[C(R6)2]n—O—Ar,
- R6 is H, A or benzyl,
- X is absent, —C(R6)2—, —C(R6)2—C(R6)2—, —C(R6)2—CO—, —C(R6)2—C(R6)2—CO—, —C(R6)2═C(R6)—CO—, —NR6CO—, —N{[C(R6)2]n—COOR6}—CO— or —C(COOR6)R6—C(R6)2—CO—,
- Y is —C(R6)2—, —SO2—, —CO—, or —COO—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Hal is F, Cl, Br or I,
- n is 0, 1 or 2, or
- a salt thereof.
10 more elements
A compound of formula I
- wherein
- R1 is —C(═NH)—NH2, which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, —COOA, or by an amino-protective group, or R1 is
- R2 is H,
- R3 is A, cycloalkyl, Ar, —CH2Ar, —CH2OAr, —CH2CH2Ar, —CH2Het, —CH2CH2Het or —CH═CH—Ar,
- R6 is H or A,
- X is —CH2—CO—, —CH2—CH2—CO—, —CH2—, —CH2—CH2—, —CH═CH—CO—, —NHCO—, —N{CH2COOR6}—CO— or —CH(COOR6)—CH2—CO—,
- Y is —SO2—, —CO—, —COO—, —CO—NH— or —CH2—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Het is thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole or benzothiophene, which in each case is unsubstituted or mono- or polysubstituted by Hal, A, Ar′, COOR6, CN, N(R6)2, NO2, Ar—CONH—CH2 and/or carbonyl oxygen,
- Hal is F, Cl, Br or I, and
- n is 0, 1 or 2;
- or
- a salt thereof.
12 more elements
A compound of formula I
- wherein
- R1 is —C(═NH)—NH2, which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, —COOA, or by an amino-protective group, or R1 is
- R2 is H,
- R3 is A, cycloalkyl, Ar, —CH2Ar, —CH2OAr, —CH2CH2Ar, —CH2Het, —CH2CH2Het or —CH═CH—Ar,
- R6 is H or A,
- X is —CH2—CO—, —CH2—CH2—CO—, —CH2—, —CH2—CH2—, —CH═CH—CO—, —NHCO—, —N{CH2COOR6}—CO— or —CH(COOR6)—CH2—CO—,
- Y is —SO2—, —CO—, or —CO—NH—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is phenyl,
- Het is thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran, which in each case is unsubstituted or mono- or polysubstituted by Hal, A, Ar′, COOR6, CN, N(R6)2, NO2, Ar—CONH—CH2 and/or carbonyl oxygen,
- Hal is F, Cl, Br or I, and
- n is 0, 1 or 2;
- or
- a salt thereof.
12 more elements
A compound of formula I
- wherein
- R1 is —C(═NH)—NH2, which is optionally monosubstituted by COOA,
- R2 is H,
- R3 is A, cycloalkyl, Ar, —CH2Ar, —CH2OAr, —CH2CH2Ar, —CH2Het, —CH2CH2Het or —CH═CH—Ar,
- R6 is H or A,
- X is absent or is —CH2—CO—, —CH2—CH2—CO—, —CH2—, —CH2—CH2—, —NHCO—, —N{CH2COOR6}—CO— or —CH(COOR6)—CH2—CO—,
- Y is —SO2—, —CO—, or —CH2—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is phenyl,
- Het is thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran, which in each case is unsubstituted or mono- or polysubstituted by Hal, A, Ar′, COOR6, CN, N(R6)2, NO2, Ar—CONH—CH2 and/or carbonyl oxygen,
- Hal is F, Cl, Br or I, and
- n is 0, 1 or 2;
- or
- a salt thereof.
12 more elements
A compound of formula I
- in which
- R1 is —C(═NH)—NH2 which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, or —COOA, or R1 is
- R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
- R3 is A, cycloalkyl, —[C(R6)2]nAr, or —[C(R6)2]n—O—Ar,
- R6 is H, A or benzyl,
- X is —C(R6)2—, —C(R6)2—C(R6)2—, —C(R6)2—CO—, —C(R6)2—C(R6)2—CO—, —C(R6)2═C(R6)—CO—, —NR6CO—, —N{[C(R6)2]n—COOR6}—CO— or —C(COOR6)R6—C(R6)2—CO—,
- Y is —C(R6)2—, —SO2—, —CO—, —COO— or —CONR6—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Hal is F, Cl, Br or I,
- n is 0, 1 or 2, or
- a salt thereof.
10 more elements
A compound of formula I
- in which
- R1 is —C(═NH)—NH2 which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, or —COOA, or R1 is
- R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
- R3 is A, cycloalkyl, —[C(R6)2]nAr, or —[C(R6)2]n—O—Ar,
- R6 is H, A or benzyl,
- X is absent, —C(R6)2—, —C(R6)2—, —C(R6)2—CO—, —C(R6)2—C(R6)2—CO—, —C(R6)2═C(R6)—CO—, —NR6CO—, —N{[C(R6)2]n—COOR6}—CO— or —C(COOR6)R6—C(R6)2—CO—,
- Y is —C(R6)2—, —SO2—, —CO—, —COO— or —CONR6—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Hal is F, Cl, Br or I,
- n is 0, 1 or 2, or
- a salt thereof.
10 more elements
A compound of formula I
- in which
- R1 is —C(═NH)—NH2 which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, or —COOA, or R1 is
- R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
- R3 is A, cycloalkyl, —[C(R6)2]nAr, or —[C(R6)2]n—O—Ar,
- R6 is H, A or benzyl,
- X is absent, —CO—, —C(R6)2—, —C(R6)2—C(R6)2—, —C(R6)2—CO—, —C(R6)2—C(R6)2—CO—, —C(R6)2═C(R6)—CO—, —NR6CO—, —N{[C(R6)2]n—COOR6}—CO— or —C(COOR6)R6—C(R6)2—CO—,
- Y is —C(R6)2—, —CO—, or —COO—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Hal is F, Cl, Br or I,
- n is 0, 1 or 2, or
- a salt thereof.
10 more elements
A compound of formula I
- wherein
- R1 is —C(═NH)—NH2, which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, —COOA, or by an amino-protective group, or R1 is
- R2 is H,
- R3 is A, cycloalkyl, Ar, —CH2Ar, —CH2OAr, —CH2CH2Ar, —CH2Het, —CH2CH2Het or —CH═CH—Ar,
- R6 is H or A,
- X is —CO—, —CH2—CO—, —CH2—CH2—CO—, —CH2—, —CH2—CH2—, —CH═CH—CO—, —NHCO—, —N{CH2COOR6}—CO— or —CH(COOR6)—CH2—CO—,
- Y is —CO—, —COO—, —CO—NH— or —CH2—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Het is thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole or benzothiophene, which in each case is unsubstituted or mono- or polysubstituted by Hal, A, Ar′, COOR6, CN, N(R6)2, NO2, Ar—CONH—CH2 and/or carbonyl oxygen,
- Hal is F, Cl, Br or I, and
- n is 0, 1 or 2;
- or
- a salt thereof.
12 more elements
A compound of formula I
- wherein
- R1 is —C(═NH)—NH2, which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, —COOA, or by an amino-protective group, or R1 is
- R2 is H,
- R3 is A, cycloalkyl, Ar, —CH2Ar, —CH2OAr, —CH2CH2Ar, —CH2Het, —CH2CH2Het or —CH═CH—Ar,
- R6 is H or A,
- X is —CO—, —CH2—CO—, —CH2—CH2—CO—, —CH2—, —CH2—CH2—, —CH═CH—CO—, —NHCO—, —N{CH2COOR6}—CO— or —CH(COOR6)—CH2—CO—,
- Y is —CO— or —CO—NH—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is phenyl,
- Het is thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran, which in each case is unsubstituted or mono- or polysubstituted by Hal, A, Ar′, COOR6, CN, N(R6)2, NO2, Ar—CONH—CH2 and/or carbonyl oxygen,
- Hal is F, Cl, Br or I, and
- n is 0, 1 or 2;
- or
- a salt thereof.
12 more elements
A compound of formula I
- wherein
- R1 is —C(═NH)—NH2, which is optionally monosubstituted by COOA,
- R2 is H,
- R3 is A, cycloalkyl, Ar, —CH2Ar, —CH2OAr, —CH2CH2Ar, —CH2Het, —CH2CH2Het or —CH═CH—Ar,
- R6 is H or A,
- X is absent or is —CO—, —CH2—CO—, —CH2—CH2—CO—, —CH2, —CH2—CH2—, —NHCO—, —N{CH2COOR6}—CO— or —CH(COOR6)—CH2—CO—,
- Y is —CO— or —CH2—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is phenyl,
- Het is thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran, which in each case is unsubstituted or mono- or polysubstituted by Hal, A, Ar′, COOR6, CN, N(R6)2, NO2, Ar—CONH—CH2 and/or carbonyl oxygen,
- Hal is F, Cl, Br or I, and
- n is 0, 1 or 2;
- or
- a salt thereof.
12 more elements
A compound of formula I
- in which
- R1 is —C(═NH)—NH2 which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, or —COOA, or R1 is
- R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
- R3 is A, cycloalkyl, —[C(R6)2]nAr, or —[C(R6)2]n—O—Ar,
- R6 is H, A or benzyl,
- X is —CO—, —C(R6)2—, —C(R6)2—C(R6)2—, —C(R6)2—CO—, —C(R6)2—C(R6)2—CO—, —C(R6)2═C(R6)—CO—, —NR6CO—, —N{[C(R6)2]n—COOR6}—CO— or —C(COOR6)R6—C(R6)2—CO—,
- Y is —C(R6)2—, —CO—, —COO— or —CONR6—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Hal is F, Cl, Br or I,
- n is 0, 1 or 2, or
- a salt thereof.
10 more elements
A compound of formula I
- in which
- R1 is —C(═NH)—NH2 which is optionally monosubstituted by —COA, —CO—[C(R6)2]n—Ar, or —COOA, or R1 is
- R2 is H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,
- R3 is A, cycloalkyl, —[C(R6)2]nAr, or —[C(R6)2]n—O—Ar,
- R6 is H, A or benzyl,
- X is absent, —CO—, —C(R6)2—, —C(R6)2—C(R6)2—, —C(R6)2—CO—, —C(R6)2—C(R6)2—CO—, —C(R6)2═C(R6)—CO—, —NR6CO—, —N{[C(R6)2]n—COOR6}—CO— or —C(COOR6)R6—C(R6)2—CO—,
- Y is —C(R6)2—, —CO—, —COO— or —CONR6—,
- A is alkyl having 1-20 C atoms in which one or two CH2 groups are optionally replaced in each case by O or S atoms or by —CR6═CR6— groups, and 1-7 H atoms are optionally replaced by F,
- Ar is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr′, NHSO2A, NHSO2Ar′, COOR6, CON(R6)2, CONHAr′, COR6, COAr′, S(O)nA or S(O)nAr,
- Ar′ is naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
- Hal is F, Cl, Br or I,
- n is 0, 1 or 2, or
- a salt thereof.
10 more elements
Dependencies are inferred from the claim text.