CA2385859A1 - 2'-substituted 1,1'-biphenyl-2-carboxamides, processes for their preparation, their use as medicament, and pharmaceutical preparations comprising them - Google Patents

2'-substituted 1,1'-biphenyl-2-carboxamides, processes for their preparation, their use as medicament, and pharmaceutical preparations comprising them Download PDF

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CA2385859A1
CA2385859A1 CA002385859A CA2385859A CA2385859A1 CA 2385859 A1 CA2385859 A1 CA 2385859A1 CA 002385859 A CA002385859 A CA 002385859A CA 2385859 A CA2385859 A CA 2385859A CA 2385859 A1 CA2385859 A1 CA 2385859A1
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alkyl
hydrogen
phenyl
alkoxy
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CA2385859C (en
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Joachim Brendel
Wolfgang Schmidt
Peter Below
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Sanofi Aventis Deutschland GmbH
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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Abstract

2'-substituted 1,1'-biphenyl-2-carboxamides, processes for their preparation, their use as medicament, and pharmaceutical preparations comprising them Compounds of the formula I, (see formula I) in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30) and R(31) have the meanings indicated in the claims, are very particularly suitable as novel and antiarrythmic active compounds, in particular for the treatment and prophylaxis of atrial arrythmias, e.g. atrial fibrillation (AF), or atrial flutter.

Claims (17)

1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1,
2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3-, or 4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
or R(3) is CHR(18)R(19);
R(18) is hydrogen or C z H2z-R(16), where R(16) is defined as indicated in claim 1 above;

z is 0, 1, 2 or 3;
R(19) is CONH2, CONR(20)R(21), COOR(22), CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C v H2v-CF3 or C w H2w-phenyl, where the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2,
3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(4) is hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF3;
R(5), R(6), R(7) and R(8) independently of one another are hydrogen, F, Cl, Br, CF3, NO2, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethyl-amino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31) independently of one another are hydrogen or alkyl having 1, 2 or 3 carbon atoms;
or R(30) and R(31) together are a chain of 2 methylene groups;
or its pharmaceutically acceptable salts.
3. A compound of the formula I as claimed in claims 1 or 2, in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
R(9) is C x H2x-R(14);
x is 0, 1, 2, 3 or 4, where x cannot be 0 if R(14) is OR(15);
R(14) is cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1 or 2 carbon atoms, cyclo-alkyl having 3, 4, 5 or 6 carbon atoms, CF3 or phenyl, which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methyl-sulfonyl and methylsulfonylamino;
R(10), R(11) and R(12) independently of one another are defined as R(9);
R(13) is hydrogen;
R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R(3) is CHR(18)R(19);
R(18) is hydrogen or C z H2z-R(16);
z is 0, 1, 2 or 3;
R(19) is CONH2, CONR(20)R(21), COOR(22) or CH2OH;
R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms, C v H2v-CF3 or C w H2w-phenyl, where the phenyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selec-ted from the group consisting of F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methyl-sulfonylamino;
v is 0, 1, 2 or 3;
w is 0, 1, 2 or 3;
R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substitutents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3- or 4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methyl-sulfonyl and methylsulfonylamino;
R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;
R(5), R(6), R(7) and R(8) independently of one another are hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31) independently of one another are hydrogen or methyl or R(30) and R(31) together are a chain of 2 methylene groups;
or its pharmaceutically acceptable salts.
4. A compound of the formula I as claimed in claims 1 or 2, in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
R(9) is C x H2x-R(14);
x is 0, 1, 2, 3 or 4, where x cannot be 0 if R(14) is OR(15);
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(15) is alkyl having 1 or 2 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3 or phenyl, which is unsubstituted or substitu-ted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(10), R(11) and R(12) independently of one another are defined as R(9);
R(13) is hydrogen;
R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;
R(3) is C y H2y-R(16);
y is 0, 1, 2, 3 or 4, where y cannot be 0 if R(16) is OR(17);
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, OR(17), phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and the N-containing heteroaromatic are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF3, phenyl or 2-, 3- or 4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, CF3, OCF3, NO2, CN, COOMe, CONH2, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;
R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;
R(5), R(6), R(7) and R(8) independently of one another are hydrogen, F, Cl, Br, CF3, CN, COOMe, CONH2, COMe, NH2, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino;
R(30) and R(31) independently of one another are hydrogen or methyl;
or R(30) and R(31) together are a chain of 2 methylene groups;
or its pharmaceutically acceptable salts.
5. A compound of the formula I as claimed in one or more of claims 1, 2 or 4, in which:
R(1) is C(O)OR(9), SO2R(10), COR(11) or C(O)NR(12)R(13);
R(9) is C x H2x-R(14);
x is 0, 1, 2 or 3;
R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF3, phenyl or pyridyl, where phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(10), R(11) and R(12) independently of one another are defined as R(9);
R(13) is hydrogen;
R(2) is hydrogen;
R(3) is C y H2y-R(16);
y is 0, 1 or 2;
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF3, phenyl or pyridyl, where phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(4) is hydrogen;
R(5), R(6), R(7) and R(8) independently of one another are hydrogen, F, CF3, CN, COOMe, CONH2, NH2, OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;
R(30) and R(31) independently of one another are hydrogen or methyl;
or R(30) and R(31) together are a chain of 2 methylene groups;
or its pharmaceutically acceptable salts.
6. A compound of the formula I as claimed in one or more of claims 1, 2, 4 or 5, in which:
R(1) is C(O)OR(9) or COR(11);
R(9) is C x H2x-R(14);
x is 0, 1, 2 or 3;
R(14) is cycloalkyl having 5 or 6 carbon atoms or phenyl, where phenyl is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(11) is defined as R(9);
R(2) is hydrogen;
R(3) is C y H2y-R(16);
y is 0, 1 or 2;
R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF3, phenyl or pyridyl where phenyl and pyridyl are unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of F, Cl, CF3, OCF3, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbon atoms;
R(4) is hydrogen;
R(5), R(6), R(7) and R(8) independently of one another are hydrogen, F, CF3, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;
R(30) and R(31) are hydrogen;
or its pharmaceutically acceptable salts.
7. A compound of the formula I as claimed in one or more of claims 1 to 6, and its pharmaceutically acceptable salts for use as a pharmaceutical.
8. A pharmaceutical preparation, comprising an efficacious amount of at least one compound of the formula I as claimed in one or more of claims 1 to 6 and/or a pharmaceutically acceptable salt thereof as active compound, together with pharmaceutically acceptable vehicles and additives and, if appropriate, additionally one or more other pharmacological active compounds.
9. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof for the production of a medicament having K+ channel-blocking action for the therapy and prophylaxis of K+ channel-mediated illnesses.
10. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof for the production of a medicament for the therapy or prophylaxis of cardiac arrythmias which can be eliminated by action potential prolongation.
11. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof for the production of a medicament far the therapy or prophylaxis of re-entry arrythmias.
12. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof for the production of a medicament for the therapy or prophylaxis of supraventricular arrythmias.
13. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof for the production of a medicament for the therapy or prophylaxis of atrial fibrillation or atrial flutter.
14. The use of a compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof for the production of a medicament for the termination of atrial fibrillation or atrial flutters (cardioversion).
15. A pharmaceutical preparation comprising an efficacious amount of at least one compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof and of an IKr channel blocker as active compounds, together with pharmaceutically acceptable vehicles and additives.
16. A pharmaceutical preparation comprising an efficacious amount of at least one compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof and of an IKs channel blocker as active compounds, together with pharmaceutically acceptable vehicles and additives.
17. A pharmaceutical preparation comprising an efficacious amount of at least one compound of the formula I as claimed in one or more of claims 1 to 6 and/or of a pharmaceutically acceptable salt thereof and of a beta-blocker as active compounds, together with pharmaceutically acceptable vehicles and additives.
CA002385859A 1999-10-02 2000-09-19 2'-substituted 1,1'-biphenyl-2-carboxamides, processes for their preparation, their use as medicament, and pharmaceutical preparations comprising them Expired - Fee Related CA2385859C (en)

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DE19947457A DE19947457A1 (en) 1999-10-02 1999-10-02 New 2'-aminomethyl-biphenyl-2-carboxamide derivatives, are potassium channel blockers especially useful for treating re-entry or supraventricular arrhythmia or atrial fibrillation or flutter
PCT/EP2000/009151 WO2001025189A1 (en) 1999-10-02 2000-09-19 2'-substituted 1,1'-biphenyl-2-carbonamides, method for the production thereof, use thereof as a medicament and pharmaceutical preparations containing said compounds

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