US2003045516A1PendingUtilityA1
Chemokine receptor antagonists and methods of use therefor
Est. expiryJan 21, 2018(expired)· nominal 20-yr term from priority
A61P 37/08A61P 9/10A61P 7/00A61P 43/00A61P 3/10A61P 31/18A61P 37/06A61P 37/00A61P 29/00A61P 25/28A61P 1/04A61P 19/02A61P 17/06A61P 11/06C07D 405/06C07D 401/06C07D 211/46C07D 495/04C07D 471/04C07D 313/12C07D 409/06C07D 491/04C07D 211/52A61K 31/55
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Claims
Abstract
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: and physiologically acceptable salts thereof.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
and physiologically acceptable salts thereof, wherein:
n is an integer from one to about four;
M is >NR 2 , >CR 1 R 2 , —O—CR 1 R 2 —O— or —CH 2 —CR 1 R 2 —O—;
The ring containing M is substituted or unsubstituted;
q 1 is an integer, such as an integer from zero to about three;
q 2 is an integer from zero to about 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 —H, —OH, 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 represented by:
wherein:
X, is a bond, —O—, —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— 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; and
Ring A and Ring B are independently substituted or unsubstituted.
2 . The method of claim 1 wherein
R 1 is —H, —OH, —N 3 , —CN, a halogen, a substituted aliphatic group, an aminoalkyl group —O-(aliphatic group), —O-(substituted aliphatic group), —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 —NR 5 R 6 , a substituted acyl group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, —O-(substituted or unsubstituted aromatic group); or
R 1 and R 2 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
3 . The method of claim 1 wherein q 1 and q 2 are zero, and the compound is represented by the structural formula:
4 . The method of claim 3 wherein M is >CR1R 2 .
5 . The method of claim 1 wherein q 1 is one and q 2 is zero, and the compound is represented by the structural formula:
6 . The method of claim 5 wherein M is >CR 1 R 2 .
7 . The method of claim 1 wherein q 1 is one and q 2 is two, and the compound is represented by the structural formula:
8 . The method of claim 7 wherein M is >NR 2 .
9 . The method of claim 1 wherein q 1 is one and q 2 is two, and the compound is represented by the structural formula:
10 . The method of claim 9 wherein M is —O—CR 1 R 2 —O— or —CH 2 —CR 1 R 2 —O—.
11 . The method of claim 9 wherein
M is >NR 2 or >CR 1 R 2 ; and
R 1 is a substituted aliphatic group or an aminoalkyl group.
12 . The method of claim 9 wherein
M is >NR 2 or >CR 1 R 2 ; and
R 2 is —O-(substituted or unsubstituted aromatic group).
13 . The method of claim 1 wherein Z is represented by the structural formula:
wherein:
X, is —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NRC—CH 2 —, —CH 2 —NRC—, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NRC—CO—, a bond, —O—, or —CO—NRC—;
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; and
Ring A and Ring B are independently substituted or unsubstituted.
14 . The method of claim 13 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphatic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ), —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to about 3.
15 . The method of claim 14 wherein R 40 is represented by —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 .
16 . The method of claim 15 wherein u is zero and t one to about three.
17 . The method of claim 15 wherein u is zero and t one to about three u is one and t is zero.
18 . The method of claim 15 wherein u and t are both zero.
19 . The method of claim 14 wherein R 40 is a aliphatic group that is substituted with —NR 24 R 25 or —CONR 24 R 25 .
20 . The method of claim 14 wherein R 40 is —O-(aliphatic group) or —O-(substituted aliphatic group).
21 . The method of claim 14 wherein R 40 is —COOH.
22 . The method of claim 1 wherein X, is —CH 2 —O—.
23 . A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
and physiologically acceptable salts thereof, wherein:
n is an integer from one to about four;
M is >NR 2 , >CR 1 R 2 , —O—CR 1 R 2 —O— or —CH 2 —CR 1 R 2 —O—;
The ring containing M is substituted or unsubstituted;
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 —H, —OH, 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 represented by:
wherein:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
24 . The method of claim 23 wherein Z is represented by the structural formula:
wherein:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
25 . The method of claim 24 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(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 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to about 3.
26 . A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
and physiologically acceptable salts thereof, wherein:
n is an integer from one to about four;
R 50 and R 51 are each, independently, —H, R 50 and R 51 are each independently —H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —NR 3 R 4 , 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, or a covalent bond between the nitrogen atom an adjacent carbon atom;
R 3 and R 4 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;
Z is represented by:
wherein:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
27 . The method of claim 26 wherein
R 50 is a substituted aliphatic group; and
R 51 is —H, an aliphatic group or a substituted aliphatic group.
28 . The method of claim 27 wherein R 50 is a substituted aliphatic group bearing an aromatic substituent.
29 . The method of claim 27 wherein R 50 is a an aliphatic group which is substituted with a 4-chlorophenyl group.
30 . The method of claim 26 wherein Z is represented by the structural formula:
wherein:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
31 . The method of claim 30 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 2 , —(O) u —(CH 2 ), —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to about 3.
32 . A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR1R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
R 40 is
33 . A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR 1 R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
R 40 is —COOH.
34 . A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR 1 R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
R 40 is
35 . A compound represented by the following structural formula:
and physiologically acceptable salts thereof, wherein:
n is an integer from one to about four;
M is >NR 2 , >CR 1 R 2 , —O—CR 1 R 2 —O— or —CH 2 —CR 1 R 2 —O—;
The ring containing M is substituted or unsubstituted;
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 —H, —OH, 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 represented by:
wherein:
X, 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—NRC—;
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; and
Ring A and Ring B are independently substituted or unsubstituted.
36 . The compound of claim 35 wherein
R 1 is —H, —OH, —N 3 , —CN, a halogen, a substituted aliphatic group, an aminoalkyl group —O-(aliphatic group), —O-(substituted aliphatic group), —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 —NR 5 R 6 , a substituted acyl group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, —O-(substituted or unsubstituted aromatic group); or
R 1 and R 2 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
37 . The compound of claim 35 wherein q 1 and q 2 are zero, and the compound is represented by the structural formula:
38 . The compound of claim 37 wherein M is >CR 1 R 2 .
39 . The compound of claim 35 wherein q 1 is one and q 2 is zero, and the compound is represented by the structural formula:
40 . The compound of claim 39 wherein M is >CR 1 R 2 .
41 . The compound of claim 35 wherein q 1 is one and q 2 is two, and the compound is represented by the structural formula:
42 . The compound of claim 41 wherein M is >NR 2 .
43 . The compound of claim 35 wherein q 1 is one and q 2 is two, and the compound is represented by the structural formula:
44 . The compound of claim 43 wherein M is —O—CR 1 R 2 —O— or —CH 2 —CR 1 R 2 —O—.
45 . The compound of claim 43 wherein
M is >NR 2 or >CR 1 R 2 ; and
R 1 is a substituted aliphatic group or an aminoalkyl group.
46 . The compound of claim 43 wherein
M is >NR 2 or >CR 1 R 2 ; and
R 2 is —O-(substituted or unsubstituted aromatic group).
47 . The compound of claim 35 wherein Z is represented by the structural formula:
wherein:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
48 . The compound of claim 47 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(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 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to about 3.
49 . The compound of claim 48 wherein R 40 is represented by —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 .
50 . The compound of claim 49 wherein u is zero and t one to about three.
51 . The compound of claim 49 wherein u is zero and t one to about three u is one and t is zero.
52 . The compound of claim 49 wherein u and t are both zero.
53 . The compound of claim 48 wherein R 40 is a aliphatic group that is substituted with —NR 24 R 25 or —CONR 24 R 25 .
54 . The compound of claim 48 wherein R 40 is —O-(aliphatic group) or —O-(substituted aliphatic group).
55 . The compound of claim 48 wherein R 40 is —COOH.
56 . The compound of claim 35 wherein X 1 is —CH 2 —O—.
57 . A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
and physiologically acceptable salts thereof, wherein:
n is an integer from one to about four;
M is >NR 2 , >CR 1 R 2 , —O—CR 1 R 2 —O— or —CH 2 —CR 1 R 2 —O—;
The ring containing M is substituted or unsubstituted;
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 —H, —OH, 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 represented by:
wherein R 40 is —OH, —COOH, —NO, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 21 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to about 3.
60 . A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
and physiologically acceptable salts thereof, wherein:
n is an integer from one to about four;
R 50 and R 51 are each, independently, —H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —NR 3 R 4 , 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, or a covalent bond between the nitrogen atom an adjacent carbon atom;
R 3 and R 4 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;
Z is represented by:
wherein:
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 —;
wherein:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
58 . The compound of claim 57 wherein Z is represented by the structural formula:
wherein:
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—NRC—;
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; and
Ring A and Ring B are independently substituted or unsubstituted.
59 . The compound of claim 58 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X, in ring C, and Z is represented by the structural formula:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
61 . The compound of claim 60 wherein R 50 is a substituted aliphatic group; and
R 50 is —H, an aliphatic group or a substituted aliphatic group.
62 . The compound of claim 61 wherein R 50 is a substituted aliphatic group bearing an aromatic substituent.
63 . The method of claim 61 wherein R 50 is a an aliphatic group that is substituted with a 4-chlorophenyl group.
64 . The compound of claim 60 wherein Z is represented by the structural formula:
wherein:
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; and
Ring A and Ring B are independently substituted or unsubstituted.
65 . The compound of claim 64 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:
wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O) u —(CH 2 ) t —C(O)OR 2 ”, —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or —(O) u —(CH 2 ) t —NHC(O)O—R 20 ;
R 20 , R 21 or R 22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or
R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;
Q is —NR 24 C(O)— or —NR 24 S(O) 2 —;
R 24 and R 25 are independently —H, —OH, an aliphatic group or a substituted aliphatic group;
u is zero or one; and
t is an integer from zero to about 3.
66 . A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR1R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
R 40 is
67 . A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR 1 R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
R 40 is —COOH.
68 . A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:
or a physiologically acceptable salt thereof, wherein:
M is CR 1 R 2 ;
R 1 is —OH;
R 2 is 4-chlorophenyl;
n is two;
Z is represented by:
X 1 is —CH 2 —O—; and
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