US 6,723,743 B1 · High affinity small molecule C5a receptor modulators

Abstract

This invention relates to low molecular weight, non-peptidic, non-peptidomimetic, organic molecules that act as modulators of mammalian complement C5a receptors, preferably ones that act as high affinity C5a receptor ligands and also to such ligands that act as antagonists or inverse agonists of complement C5a receptors, preferably human C5a receptors, Preferred compounds of the invention possess one or more, and preferably two or more, three or more, four or more, or all of the following properties in that they are; 1) multi-aryl in structure (having a plurality of un-fused or fused aryl groups), 2) heteroaryl in structure, 3) orally available in vivo (such that a sub-lethal or preferably a pharmaceutically acceptable oral dose can provide a detectable in vitro effect such as a reduction of C5a-induced neutropenia), 4) comprised of fewer than four, preferably fewer than three, or fewer than two, or no amide bonds, and 5) capable of inhibiting leukocyte chemotaxis at nanomolar concentrations and preferably at sub-nanomolar concentrations. Specifically exemplified representative compounds include, but are not limited to optionally substituted arylimidazoles, optionally substituted arylpyridyls, optionally substituted aryl-substituted cycloalkylimidazoles, optionally substituted arylpyrazoles, optionally substituted benzimidazoles, optionally substituted aryl-substituted tetrahydroisoquinolines, and optionally substituted biaryl carboxamides. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders. Additionally, this invention relates to the use such compounds as probes for the localization of C5a receptors.

Claims44

Dependent claims

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
m is 0, 1, or 2;
R1 is chosen from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
R2 is chosen from optionally substituted C1-C8 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkyl(C1-C8)alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, haloalkyl, aminoalkyl, each of which may be unsubstituted or substituted with one or more substituents selected from oxo, hydroxy, alkoxy, amide, ester, cyano, acetoxy or nitro;
R3, R3A, R5, and R6 are independently selected from hydrogen, hydroxy, halogen, amino, cyano, nitro, haloalkyl, alkoxy, mono- or dialkylamino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, and optionally substituted (cycloalkyl)alkyl;
R4 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl each of which may be optionally substituted;
or
R4 is optionally substituted carbocyclic aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or heteroalicyclic group having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
Ar1 is optionally substituted carbocyclic aryl or optionally substituted arylalkyl;
and
RA represents 0 to 3 groups independently selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, haloalkyl, hydroxy, acetoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, amino, and mono- or di(C1-C6)alkylamino.

8 more elements

A compound that is:

1-(1-butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenyl methyl])aminomethylimidazole;
1-(1-butyl)-2-phenyl-5-(1-[N-{3,4-methylenedioxyphenylmethyl}-N-phenylmethyl]amino)ethylimidazole;
1-(1-Butyl)-2-phenyl-4-methyl-5-(N-[3,4-methylenedioxyphenyl-methyl]-N-phenylmethyl)aminomethylimidazole;
1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole;
1-(1-Butyl)-2-(4-fluorophenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole;
1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl) aminomethylimidazole;
1-(1-Butyl)-2-(2-methoxyphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])aminomethylimidazole;
1-(1-Butyl)-2-(2-methylphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)aminomethylimidazole;
1-(1-Butyl)-2-(4-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])aminomethylimidazole;
1-(1-Butyl)-2-(2-methylphenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])amino-methylimidazole;
1-(1-Butyl)-2-(3-fluorophenyl)-5-(N,N-di[3,4-methylenedioxyphenylmethyl])aminomethylimidazole;
1-(1-Butyl)-2-(3-methoxyphenyl)-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)-aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-{1-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)amino}ethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorophenyl]methyl)aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N,N-di[3,4-methylenedioxyphenylmethyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-methoxyphenylmethyl])-aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyl}phenylmethyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dichlorophenylethyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-nitrophenylmethyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[4-{1-propyloxy}phenylmethyl])aninomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[quinol-6-ylmethyl])-aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2,3-dichlorophenylmethyl])-aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3,4-dimethylphenylmethyl])-aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[indan-2-yl])-aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-phenylethyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)aminomethyl-imidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-ethyl)aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-propyl])aminomethyl-imidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-butyl])aminomethyl-imidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cycloheptylmethyl)amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-isobutyl)aminomethyl-imidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[2-cyclopentylethyl])amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[3-cyclopentylpropyl])amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-n-octyl])aminomethyl-imidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopropylmethyl)amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-cyclopentylmethyl)amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-N-[3,4-methylenedioxyphenylmethyl]-N-cyclohexylmethyl)amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[t-amyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{3-methyl}butyl)]amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[1-{2,2-dimethyl}butyl]) aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-methyl)aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylnethyl]-N-[2-thiophenylmethyl])amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenylmethyl]-N-[indol-5-ylmethyl])amino-methylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylendioxyphenylmethyl]-N-[{1-methylindol-5-yl}methyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[4-hydroxy-2-chlorophenyl]-methyl)aminomethylimidazole;
1-(1-Butyl)-2-(3-fluorophenyl)-5-(1-[N-{2-chloro-4-hydroxyphenyl}methyl-N-phenylmethyl])aminoethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[3,4-methylenedioxyphenyl]methyl-N-[2,3-dihydrobenzo[b]furan-5-yl]methyl)aminomethylimidazole;
1-Butyl-2-(4-fluorophenyl)-5-(1-[N-{3,4-methylenedioxyphenyl}methyl-N-phenylmethyl]-amino)ethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-phenylmethyl-N-[3,4-dimethoxyphenylmethyl])aminomethylimidazole;
1-(1-Butyl)-2-phenyl-5-(N-[6-chloro-3,4-methylenedioxyphenylmethyl]-N-phenylmethyl)-aminomethylimidazole;
Bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2,5-diphenyl-3H-imidazol-4-ylmethyl)-amine;
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-amine;
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-2-(2-methoxy-phenyl)-5-phenyl-3H-imidazol-4-ylmethyl)]-amine;
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-pentyl]-amine;
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[1-(3-butyl-2,5-diphenyl-3H-imidazol-4-yl)-ethyl]-amine;
Benzo[1,3]dioxol-5-ylmethyl-benzyl-[3-butyl-5-(4-fluoro-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-amine;
4-{5-[(Bis-benzo[1,3]dioxol-5-ylmethyl-amino)-methyl]-2,4-diphenyl-imidazol-1-yl}-butan-1-ol;
1-(1-Butyl)-2-(4-fluorophenyl)-5-(1-N,N-di[3,4-methylenedioxyphenylmethyl]amino)ethylimidazole;
or a pharmaceutically acceptable salt, prodrug or hydrate thereof.

56 more elements

A compound of the formula

wherein Ar1, R1, R2, R3, and R4 are define, as follows:
Ar1 R1 R2 R4 phenyl hydrogen butyl 4-acetoxy-benzyl;
phenyl hydrogen butyl 2-phenoxy-benzyl;
phenyl hydrogen butyl 4-benzyloxy-phenyl-ethyl;
phenyl hydrogen butyl 2-phenoxy-phenyl-ethyl;
phenyl hydrogen butyl phenoxy-ethyl;
phenyl hydrogen butyl 3-(2-fluoro-phenyl)-allyl;
phenyl hydrogen butyl 3-methyl-phenoxy-ethyl;
phenyl hydrogen butyl 3-methoxy-phenoxy-ethyl;
phenyl hydrogen butyl 3-(2,5-dimethoxy-phenyl)- allyl;
phenyl hydrogen butyl 3-(3,5-dimethoxy-phenyl)- allyl;
phenyl hydrogen butyl 3-(3-trifluoromethyl-phenyl)- allyl;
phenyl hydrogen butyl 3-(2,6-dichloro-phenyl)-allyl;
phenyl hydrogen butyl 3-(3-bromo-phenyl)-allyl;
phenyl hydrogen butyl 3-thiophen-3-yl-allyl;
phenyl hydrogen butyl 3-furan-2-yl-allyl;
phenyl hydrogen butyl 3-(4-isopropyl-phenyl)-allyl;
phenyl hydrogen butyl 2-phenyl-cyclopropylmethyl;
phenyl hydrogen butyl 2-fluoro-3-phenyl-allyl;
phenyl hydrogen butyl 2-cyclopentyl-2-phenyl-ethyl;
phenyl hydrogen butyl 2,2-diphenyl-ethyl;
phenyl hydrogen butyl 2-cyclohexyl-2-phenyl-ethyl;
phenyl hydrogen butyl 2-phenyl-ethyl-benzyl;
phenyl hydrogen butyl 3-(2-fluoro-5-bromo-phenyl)- allyl;
phenyl hydrogen butyl 3-(2-fluoro-4-bromo-phenyl)- allyl;
phenyl hydrogen butyl 3-(2-fluoro-4-chloro-phenyl)- allyl;
phenyl hydrogen butyl 3-(2-fluoro-6-chloro-phenyl)- allyl;
phenyl hydrogen butyl 3-(2-ethoxy-5-bromo-phenyl)- allyl;
4-fluoro- hydrogen butyl 2-phenoxy-phenyl-ethyl;
phenyl 4-fluoro- hydrogen butyl 2-(4-methylphenoxy)-6- phenyl methyl-pyrid-3-yl;
4-fluoro- hydrogen butyl 2-phenoxy-pyrid-3-yl;
phenyl phenyl phenyl butyl 4-aminocarboxy-benzyl;
phenyl 4-dimethylamino- butyl butyl;
ethoxy-phenyl phenyl phenyl butyl phenyl phenyl butyl phenyl butyl butyl;;
phenyl butyl butyl;
phenyl 4- butyl butyl;
dimethylaminomethyl- phenyl phenyl butyl butyl;
phenyl phenyl butyl 4-methyl-phenyl-sulfonyl;
phenyl phenyl 3-ethoxycarbonyl- 4-acetoxy-benzyl;
propyl phenyl phenyl 3-ethoxycarbonyl- benzo[1,3]dioxol-5-ylmethyl;
propyl phenyl phenyl 3-ethoxycarbonyl- 2-chloro-4-hydroxy-benzyl;
propyl phenyl phenyl 3-ethoxycarbonyl- 4-methoxy-benzyl;
propyl phenyl phenyl 3-ethoxycarbonyl- 4-dimethylamino-benzyl;
propyl phenyl phenyl 4-hydroxy-butyl 4-hydroxymethyl-benzyl;
phenyl phenyl 4-hydroxy-butyl benzo[1,3]dioxol-5-ylmethyl;
phenyl phenyl 4-hydroxy-butyl 2-chloro-4-hydroxy-benzyl;
phenyl phenyl 4-hydroxy-butyl 4-methoxy-benzyl;
phenyl phenyl 4-hydroxy-butyl 4-dimethyl-benzyl;
phenyl phenyl benzo[1,3]dioxol-5-ylmethyl;
phenyl phenyl 2-chloro-4-hydroxy-benzyl;
phenyl 4-fluoro-phenyl butyl butyl;;
phenyl 4-chloro-phenyl butyl butyl;
phenyl 4-methoxy-phenyl butyl butyl;
and phenyl 2-methoxy-phenyl butyl butyl.

51 more elements

Dependencies are inferred from the claim text.

High affinity small molecule C5a receptor modulators

Life of this patent

High affinity small molecule C5a receptor modulators

Life of this patent

Abstract

Claims44