Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis

1. A method for treating acute kidney failure or chronic kidney failure, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof

wherein:

R1 and R2 are, independently, H, F, Cl, Br, I, CN, NO 2 , —(X) n —C q H 2q —Z, cycloalkyl having 3, 4, 5 or 6 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl, or alkylalkynyl having 3 or 4 carbon atoms, wherein

n is zero or 1;

X is oxygen, NH, N—CH 3 , or S(O) k , wherein k is zero, 1 or 2;

q is zero, 1, 2, 3, 4, 5 or 6; and

Z is hydrogen or C m F 2m+1 , wherein m is zero, 1, 2, 3 or 4;

R3 is hydrogen, methyl, F, Cl, Br, I, CN, S(O) k —CH 3 , —NO 2 , or —O—CH 3 , wherein

k is zero, 1 or 2;

R4 is hydrogen, cycloalkyl having 3, 4, 5, or 6 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl, alkylalkynyl having 3 or 4 carbon atoms, or —C r H 2r —Y, wherein

r is zero, 1, 2, 3 or 4; and

Y is hydrogen or trifluoromethyl;

R5 and R6 are hydrogen or are together a bond; and

R7 and R8 are, independently, (C 3 -C 5 )-alkyl, (C 2 -C 5 )-alkenyl, (C 2 -C 5 )-alkynyl, (C 3 -C 6 )-cycloalkyl or (C 4 -C 6 )-cycloalkenyl; or

R7 and R8 taken together with the two carbon atoms to which R7 and R8 are attached, form a (C 5 -C 10 ) cycloalkyl ring which may be unsubstituted or substituted with one or more fluorine atoms; or

R7 and R8 taken together with the two carbon atoms to which R7 and R8 are attached, form a ring of the following formula

wherein

R10 and R11 are, independently, hydrogen, fluorine, chlorine, bromine, methyl, CN, OH, —O—CH 3 , NO 2 , NH 2 or —CF 3 ;

R9 and R12 are hydrogen or F; or

R9 is hydrogen and R12 is F, Cl, Br, I, CN, NO 2 , COOH, CO—NR13R14, SO 2 —NR13R14, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl, alkylalkynyl having 3 or 4 carbon atoms, or —(XI) n —C q H 2q —Z; or

R12 is hydrogen and R9 is F, Cl, Br, I, CN, NO 2 , COOH, CO—NR13R14, SO 2 —NR13R14, alkenyl having 2, 3 or 4 carbon atoms, alkenylalkyl having 3 or 4 carbon atoms, ethynyl, alkylalkynyl having 3 or 4 carbon atoms, or —(XI) n —C q H 2q —Z; wherein:

R13 is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms and R14 is hydrogen or alkyl having 1, 2, 3, or 4 carbon atoms; or

R13 and R14 together with the nitrogen to which they are attached form a saturated 5-, 6- or 7-membered ring;

n is zero or 1;

XI is oxygen, NH, N—CH 3 , or S(O) k ;

k is zero, 1 or 2;

q is zero, 1, 2, 3, 4, 5 or 6; and

Z is hydrogen or C m F 2m+1 , wherein m is zero, 1, 2, 3 or 4.

2. The method according to claim 1 , wherein the pharmaceutical composition further comprises one or more other drugs or active compounds.

3. The method according to claim 1 , wherein for the compound of formula I according to claim 1 ,

R1 and R2 are, independently, selected from the group consisting of H, F, Cl, Br, CH 3 , CF 3 , and SO 2 CH 3 , provided that R1 and R2 are not both hydrogen;

R3 is hydrogen, F or Cl;

R4 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or cyclopropyl; and

R7 and R8 taken together with the two carbon atoms to which R7 and R8 are attached, form a (C 5 -C 10 ) cycloalkyl ring which may be unsubstituted or substituted with one or more fluorine atoms; or

R7 and R8 taken together with the two carbon atoms to which R7 and R8 are attached, form a ring of the following formula

wherein,

R10 and R11 are, independently, hydrogen, OH, fluorine or chlorine;

R9 and R12 are both hydrogen, or

R9 is hydrogen and R12 is F, Cl, Br, CN, COOH, CO—NR13R14, SO 2 —NR13R14 or —(XI) n —C q H 2q —Z, or

R12 is hydrogen and R9 is F, Cl, Br, CN, COOH, CO—NR13R14, SO 2 —NR13R14 or —(XI) n —C q H 2q —Z, wherein

R13 and R14 are, independently, hydrogen or methyl;

n is zero or 1;

XI is oxygen, NH, N—CH 3 or S(O) k ;

k is zero, 1 or 2;

q is zero, 1, 2, 3 or 4; and

Z is hydrogen or CF 3 .

4. The method according to claim 1 , wherein for the compound of formula I according to claim 1 ,

R1 and R2 are, independently, F, Cl, Br, CH 3 or CF 3 ;

R3 is hydrogen;

R4 is hydrogen, methyl or ethyl; and

R7 and R8 taken together with the two carbon atoms to which R7 and R8 are attached, form a (C 5 -C 10 ) cycloalkyl ring which may be unsubstituted or substituted with one or more fluorine atoms; or

R7 and R8 taken together with the two carbon atoms to which R7 and R8 are attached, form a ring of the following formula:

wherein,

R10 and R11 are, independently, hydrogen, OH or fluorine;

R9 and R12 are both hydrogen, or

R9 is hydrogen and R12 is F, Cl, Br or —(XI) n —C q H 2q —Z, or

R12 is hydrogen and R9 is F, Cl, Br or —(XI) n —C q H 2q —Z, wherein:

n is zero or 1;

XI is oxygen, NH, N—CH 3 or S(O) k ;

k is zero, 1 or 2;

q is zero or 1; and

Z is hydrogen or CF 3 .

5. The method according to claim 1 , wherein the compound of formula I according to claim 1 is

trans-R,R-2-chlorine-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine,

trans-R,R-2-bromo-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-4-methyl-3-thienylamine,

2-chloro-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine,

2-bromo-3N-(2-benzimidazolyl)-4-methyl-3-thienylamine,

2-chloro-3N-(4-methyl-2-benzimidazolyl)-4-methyl-3-thienylamine,

2-chloro-3N-(5-fluoro-2-benzimidazolyl)-4-methyl-3-thienylamine,

2-chloro-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene,

2-bromo-3N-(4-chloro-2-benzimidazolylamino)-4-methylthiophene,

2-bromo-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene,

2-chloro-3N-(4-fluoro-2-benzimidazolylamino)-4-methylthiophene,

2-chloro-3N-(4-hydroxy-2-benzimidazolylamino)-4-methylthiophene,

(1H-benzimidazol-2-yl)-(2-chloro-4-methylthiophen-3-yl)-methylamine,

(2-bromo-4-methylthiophen-3-yl)-(5-fluoro-1H-benzimidazol-2-yl)-amine,

2,4-dichloro-3N-(2-benzimidazolylamino)thiophene,

2-bromo-4-chloro-3N-(2-benzimidazolylamino)thiophene,

2,4-dichloro-3N-(4-methyl-2-benzimidazolyl-amino)thiophene,

trans-R,R-2,4-dichloro-3N-(3a,4,5,6,7,7a-hexahydro-1H-2-benzimidazolyl)-3-thienylamine,

2,4-dichloro-3N-(4-chloro-2-benzimidazolyl-amino)thiophene, or

2-chloro-3N-(2-benzimidazolylamino)-4-methylthiophene.