RU2006125632A - DIPHENYLASETIDININE DERIVATIVES, PERFORMING AN INHIBITING SUCTION OF CHOLESTEROL - Google Patents

Claims (20)

1. The compound of formula (I)

where R ¹ represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or aryl; wherein said C _1-6 alkyl may optionally be substituted with one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _{1 -6} alkyl) ₂ amino, C ₁ -C ₆ alkylcarbonylamino, C _1-6 alkyl S (O) _a , where a is 0-2, C _3-6 cycloalkyl or aryl; and where any aryl group may optionally be substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; R ² and R ⁵ independently represent hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; wherein said C _1-6 alkyl may optionally be substituted with one or more hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C _1-6 alkoxy, aryl C _1-6 alkoxy, (C ₁ -C ₄ ) ₃ Si, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkylS (O) _a , C _3-6 cycloalkyl, aryl or arylC _1-6 alkylS (O ) _a , where a is 0-2; and where any aryl group may optionally be substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; R ³ represents hydrogen, alkyl, halogen, C _1-6 alkoxy or C _1-6 alkylS-; R ⁴ represents hydrogen, C _1-6 alkyl, halogen or C _1-6 alkoxy; R ⁶ represents hydrogen, C _1-6 alkyl or arylC _1-6 alkyl; where R ⁵ and R ² can form a ring of 2-7 carbon atoms, and where R ⁶ and R ² can form a ring of 3-6 carbon atoms, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug thereof; with the proviso that said compound is not 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- [4- (N- {N - [(R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one or 3- (R) -4- (R) -1- (phenyl ) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N - ((R) -α- {N - [(S) -1- (carboxy) -2- ( hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one. 2. The compound of formula (I2)

where R ¹ represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or aryl; wherein said C _1-6 alkyl may optionally be substituted with one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _{1 -6} alkyl) ₂ amino, C ₁ -C ₆ alkylcarbonylamino, C _1-6 alkyl S (O) _a , where a is 0-2, C _3-6 cycloalkyl or aryl; and where any aryl group may optionally be substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; R ² and R ⁵ independently represent hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; wherein said C _1-6 alkyl may optionally be substituted with one or more hydroxy, amino, guanidino, cyano, carbamoyl, carboxy, C _1-6 alkoxy, aryl C _1-6 alkoxy, (C ₁ -C ₄ ) ₃ Si, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkylS (O) _a , C _3-6 cycloalkyl, aryl or arylC _1-6 alkylS (O ) _a , where a is 0-2; and where any aryl group may optionally be substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; R ³ represents hydrogen, alkyl, halogen, C _1-6 alkoxy or C _1-6 alkylS-; R ⁴ represents hydrogen, C _1-6 alkyl, halogen or C _1-6 alkoxy; R ⁶ represents hydrogen, C _1-6 alkyl or aryl C _1-6 alkyl; where R ⁵ and R ² can form a ring of 2-7 carbon atoms, and where R ⁶ and R ² can form a ring of 3-6 carbon atoms, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug thereof; with the proviso that said compound is not 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- [4- (N- {N - [(R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one or 3- (R) -4- (R) -1- (phenyl ) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N - ((R) -α- {N - [(S) -1- (carboxy) -2- ( hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one. 3. The compound according to claim 1 or 2, where R ¹ represents hydrogen or phenyl. 4. The compound according to claim 1 or 2, where R ² represents hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; where the specified C _1-6 alkyl may optionally be substituted with one or more hydroxy, amino, acylamino, C _1-6 alkylS (O) _a , where a is 0-2, C _3-6 cycloalkyl or aryl; and where any aryl group may optionally be substituted with hydroxy, alkyl, alkoxy or cyano. 5. The compound according to claim 1 or 2, where R ³ represents hydrogen, C ₁ -C ₂ alkyl, halogen or methoxy. 6. The compound according to claim 1 or 2, where R ³ represents hydrogen, methyl, chloro, fluoro, C _1-6 alkylS - or methoxy. 7. The compound according to claim 1 or 2, where R ⁴ represents hydrogen or halogen. 8. The compound according to claim 1 or 2, where R ⁴ represents chlorine or fluorine. 9. The compound according to claim 1 or 2, where R ⁶ represents hydrogen, C _1-6 alkyl, aryl C _1-6 alkyl, or R ⁶ and R ² form a ring of 3-6 carbon atoms. 10. The compound according to claim 1, where R ¹ represents hydrogen; R ² represents a branched or unbranched C _1-4 alkyl, possibly substituted by C _3-6 cycloalkyl, alkyl S-, aryl, possibly substituted by hydroxy or cyano, amino, N- (C _1-6 alkyl) amino, N, N- ( C _1-6 alkyl) ₂ amino or aryl C _1-6 alkylS (O) _a , where a is 0-2; R ³ and R ⁴ are halogen; R ⁵ represents hydrogen or C _1-6 alkyl; and R ⁶ represents hydrogen. 11. One or more than one compound selected from N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-N ⁶ -acetyl-D-pisine; 1- (4-fluorophenyl) -3- (R) - [2- (4-fluorophenyl) -2-hydroxyethylthio] -4- (R) - {4- [N- {N- [2- (phenyl) - 1- (R) - (carboxy) ethyl] carbamoylmethyl} carbamoylmethoxy] phenyl} azetidin-2-one; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-D-tyrosine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-D-proline; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-D-lysine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2-hydroxy-2- (4-methoxyphenyl) ethyl] thio} -4-oxoazetidin-2-yl) phenoxy ] acetyl} glycyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-2-butylnorleucine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-S-methyl-L-cysteine; N-4 [4 - ((2R, 3R) -1- (4-chlorophenyl) -3 {[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl } glycyl-3-cyclohexyl-D-alanine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-3-cyclohexyl-D-alanine, N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-4-methylleucine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} -L-alanyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2-hydroxy-2- (4-methylphenyl) ethyl] thio} -4-oxoazetidin-2-yl) phenoxy ] acetyl} glycyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-chlorophenyl) -3 - {[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-chlorophenyl) -3 - {[2- (4-chlorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-3- (2-naphthyl) -D-alanine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-3-methyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl- (3R, 4S, 5R) -3,4,5,6-tetrahydroxy-D-norleucine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-N, 2-dimethylalanine; N - ({4 - [(2R, 3R) -1- (4-fluorophenyl) -3 - ({2-hydroxy-2- [4- (methylthio) phenyl] ethyl} thio) -4-oxoazetidin-2- yl] phenoxy} acetyl) glycyl-3-methyl-D-valine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-S- (4-methylbenzyl) -D-cysteine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-S- (tert-butyl) -D-cysteine; N - {[4 - ((2R, 3R) -1- (4-fluorophenyl) -3 - {[2- (4-fluorophenyl) -2-hydroxyethyl] thio} -4-oxoazetidin-2-yl) phenoxy] acetyl} glycyl-b, b-dimethyl-D-phenylalanine. 12. The compound of formula (XV) or its hydrolyzable esters or amides

where R ¹ represents hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or aryl; wherein said C _1-6 alkyl may optionally be substituted with one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, N- (C _1-6 alkyl) amino, N, N- (C _{1 -6} alkyl) ₂ amino, C ₁ -C ₆ alkylcarbonylamino, C _1-6 alkyl S (O) _a , where a is 0-2, C _3-6 cycloalkyl or aryl; and where any aryl group may optionally be substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; R ² and R ⁵ independently represent hydrogen, branched or unbranched C _1-6 alkyl, C _3-6 cycloalkyl or aryl; wherein said C _1-6 alkyl may optionally be substituted with one or more hydroxy, amino, guanidino, carbamoyl, carboxy, C _1-6 alkoxy, aryl C _1-6 alkoxy, (C ₁ -C ₄ ) ₃ Si, N- (C _1-6 alkyl) amino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkylS (O) _a , arylC _1-6 alkylS (O) _a , where a is 0-2, With _3-6 cycloalkyl or aryl; and where any aryl group may optionally be substituted with one or two substituents selected from halo, hydroxy, C _1-6 alkyl or C _1-6 alkoxy; R ³ represents hydrogen, alkyl, halogen, C _1-6 alkoxy or C _1-6 alkylS-; R ⁴ represents hydrogen, C _1-6 alkyl, halogen or C _1-6 alkoxy; R ⁶ represents hydrogen, C _1-6 alkyl or aryl C _1-6 alkyl; R ⁷ is hydroxy or C _1-3 alkoxy; where R ⁵ and R ² can form a ring of 2-7 carbon atoms, and where R ⁶ and R ² can form a ring of 3-6 carbon atoms, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug thereof; with the proviso that said compound is not 3- (R) -4- (R) -1- (phenyl) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- [4- (N- {N - [(R) -1- (carboxy) -2- (hydroxy) ethyl] carbamoylmethyl} carbamoylmethoxy) phenyl] azetidin-2-one or 3- (R) -4- (R) -1- (phenyl ) -3- [2- (4-fluorophenyl) -2-hydroxyethylsulfanyl] -4- {4- [N - ((R) -α- {N - [(S) -1- (carboxy) -2- ( hydroxy) ethyl] carbamoyl} benzyl) carbamoylmethoxy] phenyl} azetidin-2-one. 13. A method of treating or preventing hyperlipidemic conditions, comprising administering an effective amount of a compound according to any one of claims 1 to 12 to a mammal in need thereof. 14. A method of treating or preventing atherosclerosis, comprising administering an effective amount of a compound according to any one of claims 1 to 12 to a mammal in need thereof. 15. A method of treating or preventing Alzheimer's disease, comprising administering an effective amount of a compound according to any one of claims 1-12 to a mammal in need thereof. 16. A method of treating or preventing cholesterol-associated tumors, comprising administering an effective amount of a compound according to any one of claims 1 to 12 to a mammal in need thereof. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 in a mixture with pharmaceutically acceptable adjuvants, diluents and / or carriers. 18. The combination of a compound of formula (I) or (I2) with a PPAR alpha and / or gamma agonist (receptors activated by the peroxisome alpha and / or gamma proliferator). 19. The combination of a compound of formula (I) or (I2) with an HMG-CoA reductase inhibitor (hydroxymethylglutaryl coenzyme A reductase). 20. A method of obtaining a compound of formula (I) or a pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug thereof (where variable groups, unless otherwise stated, are as defined in formula (I)), including method 1) the interaction of the compounds of formula (II)

with a compound of formula (III)

where L represents a substituted group; method 2) the interaction of the acid of the formula (IV)

or an activated derivative thereof with an amine of formula (V)

method 3) the interaction of the acid of formula (VI)

or an activated derivative thereof with an amine of formula (VII)

Method 4) Reduction of a Compound of Formula (VIII)

method 5) the interaction of the compounds of formula (IX)

with a compound of formula (X)

where L represents a substituted group; method 6) the interaction of the compounds of formula (XI)

where L represents a substituted group, with a compound of formula (XII)

Method 7) Deesterification of a Compound of Formula (XIII)

where the group C (O) OR is an ester group; and after that, if necessary or desirable: 1) the conversion of a compound of formula (I) into another compound of formula (I); 2) removal of any protective groups; 3) the formation of a pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug; or 4) separation of two or more enantiomers. L is a substitutable group, suitable values for L are, for example, a halogen or sulfonyloxy group, for example chloro, bromo, methanesulfonyloxy or toluene-4-sulfonyloxy. C (O) OR is an ester group, suitable values for C (O) OR are methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and benzyloxycarbonyl.