Chemokine receptor antagonists and methods of use therefor
View Patent ↗Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by: or physiologically acceptable salt thereof.
1. A compound having the formula:
or physiologically acceptable salt thereof, wherein:
n is an integer from one to four;
M is >CR 1 R 2 ;
q 1 is zero;
q 2 is one;
R 1 is —H, —OH, —N 3 , a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , —NR 3 R 4 or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
R 2 is —OH, a halogen, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 3 , R 4 , R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
Z is:
X 1 is —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—, a bond, —O—, or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl
said aliphatic group is a C 1 -C 6 alkyl, alkenyl or alkynyl;
said aromatic group is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, benzocyclopentyl, and benzocyclohexyl;
said non-aromatic heterocyclic group is a five to eight-membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;
said substituted aliphatic group is substituted with one or more substituents selected from the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, —CN, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) and -Q-(CH 2 ) p -(non-aromatic heterocyclic group);
said substituted non-aromatic heterocyclic ring is substituted with one or more substituents selected from the group consisting of ═O, ═S, electron withdrawing group, halo, azido, —CN, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) and -Q-(CH 2 ) p -(non-aromatic heterocyclic group);
said substituted aromatic group and substituted benzyl group are substituted with one or more substituents selected from the group consisting of electron withdrawing group, halo, azido, —CN, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) and -Q-(CH 2 ) p -(non-aromatic heterocyclic group);
Q is —O—, —S—, —S(O)—, —S(O) 2 —, —OS(O) 2 —, —C(O)—, —OC(O)—, —C(O)O—, —C(O)C(O)—O—, —O—C(O)C(O)—, —NHC(O)—, —OC(O)NH—, —NH—C(O)—NH—, —S(O) 2 NH—, —NHS(O) 2 —, —C(NR 23 )NHNH—, —NHNHC(NR 23 )—, —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 20 , R 21 and R 22 are independently —H, an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclic group) or R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a substituted or unsubstituted non-aromatic heterocyclic ring;
R 23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group;
R 24 and R 25 are independently —H, —OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R 24 and R 25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring;
R 60 is a —H, —OH, —NH 2 , an aromatic group or a substituted aromatic group;
t is zero to three;
u is zero or one;
p is one to five; and
R 40 is selected from the group consisting of
2. The compound of claim 1 wherein:
R 1 is —H or —OH; and
R 2 is a substituted aromatic group.
3. The compound of claim 2 wherein R 2 is phenyl substituted with a halogen.
4. The compound of claim 3 wherein R 2 is 4-chlorophenyl.
5. The compound of claim 4 wherein n is 2, X 1 is —CH 2 —O—, and R 1 is —OH.
6. A pharmaceutical composition comprising a compound of claim 1 and a physiologically acceptable carrier.
7. A compound having the formula:
or physiologically acceptable salt thereof, wherein:
n is one to four;
R 2 is —OH, a halogen, an acyl group, a substituted acyl group, —NR 5 R 6 , an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
R 5 and R 6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or
R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
Z is:
X 1 is —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—, a bond, —O—, or —CO—NR c —;
R c is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
Rings A and B are independently unsubstited or substituted;
said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
said aliphatic group is a C 1 -C 6 alkyl, alkenyl or alkynyl;
said aromatic group is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, benzocyclopentyl, and benzocyclohexyl;
said non-aromatic heterocyclic group is a five to eight-membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;
said substituted aliphatic group is substituted with one or more substituents selected from the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, —CN, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) and -Q-(CH 2 ) p -(non-aromatic heterocyclic group);
said substituted non-aromatic heterocyclic ring is substituted with one or more substituents selected from the group consisting of ═O, ═S, electron withdrawing group, halo, azido, —CN, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) and -Q-(CH 2 ) p -(non-aromatic heterocyclic group);
said substituted aromatic group, substituted benzyl group, Ring A when substituted and Ring B when substituted, are substituted with one or more substituents selected from the group consisting of electron withdrawing group, halo, azido, —CN, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) and -Q-(CH 2 ) p -(non-aromatic heterocyclic group);
Q is —O—, —S—, —S(O)—, —S(O) 2 —, —OS(O) 2 —, —C(O)—, —OC(O)—, —C(O)O—, —C(O)C(O)—O—, —O—C(O)C(O)—, —NHC(O)—, —OC(O)NH—, —NH—C(O)—NH—, —S(O) 2 NH—, —NHS(O) 2 —, —C(NR 23 )NHNH—, —NHNHC(NR 23 )—, —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 20 , R 21 and R 22 are independently —H, an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclic group) or R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring;
R 23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group;
R 24 and R 25 are independently —H, —OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R 24 and R 25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring;
R 60 is a —H, —OH, —NH 2 , an aromatic group or a substituted aromatic group;
t is zero to three;
u is zero or one;
p is one to five.
8. The compound according to claim 7 wherein R 2 is —NR 5 R 6 .
9. The compound of claim 8 wherein:
R 5 is aliphatic group or substituted aliphatic group; and
R 6 is benzyl or substituted benzyl; or
R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
10. The compound of claim 9 wherein R 5 is ethyl, and R 6 is substituted benzyl, wherein said substituted benzyl is substituted with a halogen.
11. A pharmaceutical composition comprising a compound according to claim 7 and a physiologically acceptable carrier.