N-benzyl,N'-arylcarbonylpiperazine derivatives
View Patent ↗The present invention relates to N-benzyl,N′-arylcarbonylpiperazine derivatives having the general formula I to pharmaceutical compositions comprising the same, and to the use of a these N-benzyl,N′-arylcarbonylpiperazine derivatives for the manufacture of a medicament for treating or preventing atherosclerosis and related disorders associated with cholesterol and bile acids transport and metabolism.
1. A N-benzyl,N′-arylcarbonylpiperazine derivative having the general formula I
wherein
n is 1 or 2;
A is a 6-membered aromatic ring optionally containing 1 or 2 nitrogen atoms;
X is NR 8 , O or a bond;
R 1 is H, (C 1-8 )alkyl optionally substituted with halogen, (C 1-4 )alkyloxy, (C 1-4 )alkyloxycarbonyl, (C 3-8 )cycloalkyl, OH, CF 3 , cyano or NR 9 R 10 , (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 3-8 )-cycloalkyl, phenyl optionally substituted with (C 1-4 )alkyl, (C 1-4 )alkyloxy, halogen, CN, CF 3 , OCF 3 or NO 2 , a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O and S, or a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, S and N optionally substituted with (C 1-4 )alkyl, (C 1-4 )-alkyloxy, halogen or CF 3 ; or
R 1 is (C 1-3 )alkyl substituted with phenyl optionally substituted with (C 1-4 )alkyl, (C 1-4 )-alkyloxy, halogen or with 2 substituents at adjacent positions forming O—(CH 2 )n-O, wherein n is 1 or 2, a 5- or 6-membered heteroaryl group containing 1-3 heteroatoms selected from O, S and N optionally substituted with (C 1-3 )alkyl, (C 1-3 )alkyloxy or halogen, or a 5- or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O, S and N optionally substituted with (C 1-4 )alkyl, (C 1-4 )-alkyloxy, oxo, OH or halogen; or
when X is NR 8 , R 1 may together with R 8 and the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O and S and which ring is optionally substituted with OH, (C 1-4 )alkyl, (C 1-4 )alkyloxy or halogen;
R 2 optionally represents 1-3 substituents independently selected from (C 1-4 )alkyl, (C 1-4 )-alkyloxy, CF 3 and halogen;
R 3 optionally represents 1-4 substituents independently selected from (C 1-4 )alkyl and (C 1-4 )alkyl substituted by OH or 1 or more halogens;
R 4 is H or (C 1-6 )alkyl;
R 5 optionally represents 1-3 substituents independently selected from (C 1-3 )alkyl, (C 1-3 )alkyloxy and halogen;
R 6 is H, (C 1-6 )alkyl optionally substituted with halogen, CF 3 or CN, (C 3-6 )cycloalkyl optionally containing a heteroatom selected from O and S, and optionally substituted by CN or phenyl, (C 3-6 )cycloalkyl(C 1-4 )alkyl, or a 5- or 6-membered (hetero)aryl group, optionally linked through a methylene group, and optionally substituted with (C 1-4 )alkyl, (C 1-4 )alkyloxy, (C 1-4 )alkylsulfonyl, halogen, CN, CF 3 , CF 3 O or NO 2 ;
R 7 is H or (C 1-3 )alkyl;
R 8 , when present, is H or (C 1-3 )alkyl; or
R 8 together with R 1 , and the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O and S and which ring is optionally substituted with OH, (C 1-3 )alkyl, (C 1-3 )alkyloxy or halogen;
R 9 and R 10 are independently selected from H, (C 1-3 )alkyl or (C 1-3 )alkylcarbonyl; or
R 9 and R 10 together with the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O and S;
or a pharmaceutically acceptable salt thereof.
2. The N-benzyl,N′-arylcarbonylpiperazine derivative of claim 1 , wherein X is NH and n is 1.
3. The N-benzyl,N′-arylcarbonylpiperazine derivative of claim 2 , wherein A is phenyl.
4. The N-benzyl,N′-arylcarbonylpiperazine derivative of claim 3 , wherein R 1 is (C 1-8 )alkyl optionally substituted with (C 3-8 )cycloalkyl, (C 2-6 )alkenyl, (C 3-8 )cycloalkyl or phenyl optionally substituted with halogen.
5. The N-benzyl,N′-arylcarbonylpiperazine derivative of claim 4 , wherein R 3 is absent or represents methyl, and wherein R 5 is absent or represents halogen.
6. The N-benzyl,N′-arylcarbonylpiperazine derivative of claim 5 , wherein R 6 is (C 1-6 )alkyl optionally substituted with CF 3 , and R 7 is H.
7. The N-benzyl,N′-arylcarbonylpiperazine derivative of claim 1 which is selected from the group consisting of
N-tert-butyl-3-((4-(4-(3-(cyclopropylmethyl)ureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-fluoro-4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-(cyclopropylmethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-fluoro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-fluoro-4-(3-isopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-(cyclobutylmethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-butylureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)benzamide
N-tert-butyl-3-((4-(4-(3-(2-cycopropylethyl)ureido)-3-fuorobenzoyl)piperazin-1-yl)methyl)benzamide;
3-((4-(4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
3-((4-(4-(3-butylureido)benzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
3-((4-(4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
3-((4-(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1 yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
3-((4-(4-(3-(cyclopropylmethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)-benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-(cyclopropylmethyl)ureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-butylureido)-3-chlorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-isopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(2,3-difluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(2,3-difluoro-4-(3-isopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-butylureido)-2,3-difluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(2,3-difluoro-4-(3-isobutylureido)benzoyl)piperazin-1-yl) methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-(cyclopropylmethyl)ureido)-2,3-difluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-cyclobutylureido)-2,3-difluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-(cyclopropylmethyl)ureido)-2-fluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-2-fluoro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)-2-fluorobenzamide;
N-tert-butyl-2-fluoro-3-((4-(4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-cyclobutyl-3-((4-(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide; and
(R)—N-sec-butyl-3-((4-(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide; or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a N-benzyl,N′-arylcarbonylpiperazine derivative of claim 1 and or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliaries.
9. The pharmaceutical composition of claim 8 , wherein the N-benzyl,N′-arylcarbonylpiperazine derivative is selected from the group consisting of
N-tert-butyl-3-((4-(4-(3-(cyclopropylmethyl)ureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-fluoro-4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-(cyclopropylmethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-fluoro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-fluoro-4-(3-isopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-(cyclobutylmethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-butylureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-(2-cyclopropylethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)benzamide;
-3-((4-(4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
3-((4-(4-(3-butylureido)benzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
-3-((4-(4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)—N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
-3-((4-(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide;
-3-((4-(4-(3-(cyclopropylmethyl)ureido)-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-y)benzamide hydrochloride;
N-tert-butyl-3-((4-(3-chloro-4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-(cyclopropylmethyl)ureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-butylureido)-3-chlorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-isopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(2,3-difluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(2,3-difluoro-4-(3-isopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-butylureido)-2,3-difluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(2,3-difluoro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-(cyclopropylmethyl)ureido)-2,3-difluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-cyclobutylureido)-2,3-difluorobenzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-4-(3-(cyclopropylmethyl)ureido)-2-fluorobenzoyl)piperazin-1-y)methyl)benzamide;
N-tert-butyl-3-((4-(3-chloro-2-fluoro-4-(3-isobutylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-tert-butyl-3-((4-(4-(3-cyclobutylureido)benzoyl)piperazin-1-yl)methyl)-2-fluorobenzamide;
N-tert-butyl-2-fluoro-3-((4-(4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide;
N-cyclobutyl-3-((4-(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide; and
(R)—N-sec-butyl-3-((4-(3-fluoro-4-(3-neopentylureido)benzoyl)piperazin-1-yl)methyl)benzamide; or a pharmaceutically acceptable salt thereof.