| US 7,491,825 B2 | ||
| Basic non-peptide bradykinin antagonists and pharmaceutical compositions therefrom | ||
| Federico Calvani, Pomezia (Italy); Fernando Catrambone, Pomezia (Italy); Patrizia Felicetti, Pomezia (Italy); Christopher Ingo Fincham, Pomezia (Italy); Alessandro Giolitti, Pomezia (Italy); Carlo Alberto Maggi, Pomezia (Italy); Laura Quartara, Pomezia (Italy); Cristina Rossi, Pomezia (Italy); and Rosa Terracciano, Pomezia (Italy) | ||
| Assigned to Menarini Ricerche S.p.A., Pomezia (Italy) | ||
| Appl. No. 10/516,681 PCT Filed Jun. 05, 2003, PCT No. PCT/EP03/05893 § 371(c)(1), (2), (4) Date Jul. 11, 2005, PCT Pub. No. WO03/103671, PCT Pub. Date Dec. 18, 2003. |
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| Claims priority of application No. MI2002A1247 (IT), filed on Jun. 07, 2002. | ||
| Prior Publication US 2006/0205712 A1, Sep. 14, 2006 | ||
| Int. Cl. C07D 215/38 (2006.01); A61K 31/47 (2006.01) | ||
| U.S. Cl. 546—172 [514/311; 514/314] | 10 Claims |
1. A compound of general formula (I):
 R1 is a hydrogen atom or a C1-C4 alkyl group;
R2 and R3, which can be the same or different, are a C1-C4 alkyl group, or R2 and R3, together with the carbon atom which they are linked to, form a cyclic aliphatic group having 3 to 7 carbon atoms or a heterocyclic
aliphatic group having 3 to 7 atoms, one or two of which are selected from the group N, O, S and the others being C atoms;
R4 and R5, which can be the same or different, are a hydrogen atom or a C1-C4 alkyl group;
X is selected from the group consisting of halogen, OR1, SR1, CN, and a C1-C4 alkyl group;
B has at least one amino group with basic characteristics or a tetraalkylammonium group and is selected from the group consisting
of:
 R6 is a hydrogen atom or a C1-C6 alkyl group;
Y is selected from the group consisting of hydrogen, (CH2)pY1, (CH2)pNR6Y1, (CH2)pN(Y1)2, NR5R6, —NR6(CH2)pY1, and a residue selected from the group consisting of:
 T is selected from the group consisting of —NR7R8, —NR14R18R19, and —OR6;
R7 and R8, which can be the same or different, are a hydrogen atom, a C1-C4 alkyl group, or NR7R8 is a group selected from: i) guanidine optionally substituted with 1 or 2 C1-C4 alkyl groups, cyclohexyl, ii) a 5-7 membered nitrogen heterocycle optionally containing another heteroatom selected from O,
N, S;
Y1 is selected from the group consisting of NR7R8, NR14R18R19, and a residue selected from the group consisting of:
 Z is selected from the group consisting of H, C1-C6 alkyl, OR6, SR6, CF3, OCOR6, COR10, NHCOR6, SO2R6, SOR6, CO2R6, N(R6)2, C1, Br, NO2, NH2, CN, F, imidazole, phenyl, amidine, guanidine, and guanidyl-methyl;
R9 is hydrogen or —(CH2)q-L, wherein L is selected from the group consisting of —OH, —NR5R6, —NR14R18R19, amidine optionally substituted with 1 or 2 C1-C4 alkyl groups, and guanidine optionally substituted with 1 or 2 C1-C4 alkyl groups;
R10 is OR6 or NR6R12;
R11 is selected from the group consisting of hydrogen, —(CH2)q-L, and —(CH2)p—NR4—(CH2)q-L;
R12 is selected from the group consisting of a hydrogen atom, a C1-C6 alkyl group, and COR6;
R13 is selected from the group consisting of H, a —C1-C6 alkyl group, —(CH2)pW(CH2)qY1, —Y, —COY, and —CH2—Y;
R14 is a straight or branched C1-C4 alkyl group;
R15 is selected from the group consisting of hydrogen and straight or branched C1-C4 alkyl groups;
the —NR16R17 group is a 5-7 membered nitrogen aliphatic heterocycle optionally containing another heteroatom selected from the group consisting
of O, S, and N;
the —NR14R18R19 group is a quaternary ammonium group in which: R14 is selected from the group consisting of straight or branched C1-C4 alkyl groups, R18 and R19, which can be the same or different, are a straight or branched C1-C4 alkyl group, or —NR18R19 is a 5-7 membered nitrogen heterocycle optionally containing another heteroatom selected from the group consisting of O, N,
and S;
W is selected from the group consisting of CH2, O, S, NR4, and N(R4)2;
p=1-6, q=1-6.
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