Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-27
2004-03-02
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S274100
Reexamination Certificate
active
06699888
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to small molecules that are potent inhibitors of &agr;
L
&bgr;
2
mediated cell adhesion which could be useful for the treatment of inflammatory diseases.
2. Description of Related Art
The integrin family of proteins are heterodimeric receptors which are expressed on all cell types to mediate cell to cell binding and adhesion to extracellular matrix. The &bgr;
2
(CD18) integrin subfamily is comprised of 3 members, &agr;
L
&bgr;
2
integrin (LFA-1, CD11a/CD18), &agr;
M
&bgr;
2
integrin (Mac-1, CD11b/CD18), and gp 150 &bgr;
2
integrin (&agr;
X
&bgr;
2
integrin, CD11c/CD18) that are primarily expressed on leukocytes (Sanchez-Madrid et al., J. Exp. Med., 158, 1785-1803 (1983)). &agr;
L
&bgr;
2
integrin is found mostly on T and B lymphocytes, while &agr;
M
&bgr;
2
integrin is present on activated neutrophils, NK cells and some myeloid cells. The &agr;
L
&bgr;
2
integrin binds to intracellular adhesion molecules ICAM-1, 2 and 3 found on multiple cell types such as vascular endothelial cells, dendritlc cells, epithelial cells, macrophage and T lymphoblasts (Dustin et al., J. Immunology, 137, 245-254 (1986)). Recently there has been evidence presented that &agr;
L
&bgr;
2
integrin binds to ICAM-4 and a novel ligand expressed in brain telencephalin. It has been shown that the I domain or the alpha chain is the major recognition site for its ligands.
&agr;
L
&bgr;
2
integrin adhesion to ICAM-1 is necessary for immune responsiveness of T-lymphocytes to antigens, lymphocyte homing and circulation, and cell emigration to sites or inflammation (Springer, Ann. Rev. Physiol., 57, 827 (1995)). A dominant role of &agr;
L
&bgr;
2
integrin in mediating inflammatory events is shown in several different animal models of inflammatory diseases in which antibodies to &agr;
L
&bgr;
2
integrin or ICAM-1 significantly inhibit development of therapeutic end points (Rothlein et al., Kidney International, 41, G17 (1992); Iigo et al., J. Immunology, 147, 4167 (1991); Bennet et al., J. Pharmacol. and Exp. Therapeutics, 280, 988 (1997)).
Also, &bgr;
2
integrin subfamily are thought to play a critical role in several types of inflammatory disease processes by interacting with ICAMs. Support for the importance of &bgr;
2
integrin in mediating inflammatory responses has been demonstrated by the evidence that transendothelial migration in vitro is markedly inhibited by monoclonal antibodies against &bgr;
2
integrin or ICAM-1 (Smith, Can. J. Physiol. Pharmacol., 71, 76 (1993)). Furthermore, blockade of &agr;
L
&bgr;
2
integrin has been shown to inhibit neutrophil influx in almost every system, including skin, peritoneum, synovium, lung, kidney, and heart. As one of the primary ligands for the &bgr;
2
integrin, it would also be expected that blockade of ICAM-1 would inhibit the inflammatory response (Albelda et al., The FASEB Journal, 8, 504 (1994)).
Moreover, it has been shown that antibodies against &agr;
L
&bgr;
2
integrin suppress rejection after transplantation. WO 94/04188 discloses the use of monoclonal antibodies directed against &agr;
L
&bgr;
2
integrin for all transplantations, including graft vs. host or host vs. graft diseases.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula (I):
or a pharmaceutically acceptable salt thereof, wherein R
1
is selected from
1) hydrogen atom, or
2) a C
1-6
alkyl group which may be optionally substituted
with a carboxyl group or a C
1-6
alkoxycarbonyl group; R
2a
and R
2b
are independently hydrogen atom, a halogen atom, hydroxyl group, cyano group, a C
1-6
alkyl group which may be optionally substituted with 1 to 3 halogen atoms, a C
1-6
alkylthio group which may be optionally substituted with 1 to 3 halogen atoms, a C
1-6
alkylsulfinyl group which may be optionally substituted with 1 to 3 halogen atoms, a C
1-6
alkylsulfonyl group which may be optionally substituted with 1 to 3 halogen atoms, or a C
1-6
alkoxy group which may be optionally substituted with 1 to 3 halogen atoms; R
3
is a C
1-6
alkyl group; and R
4
and R
5
are independently a halogen atom.
The compound of the present invention has potent inhibitory activity against &agr;
L
&bgr;
2
mediated cell adhesion, and shows excellent in vivo improvements against the unfavorable conditions caused by &agr;
L
&bgr;
2
mediated cell adhesion.
DETAILED DESCRIPTION OF THE INVENTION
The desired compound of the present invention may exist in he form of optical isomers based on asymmetric atoms thereof, and the present invention also includes these optical isomers and mixtures thereof.
In an embodiment of the present invention, the steric configuration of a bond need not be fixed. The compound of the present invention may be a compound with a sole configuration or a mixture with several different configurations.
In a preferred embodiment of the compound (I), R
1
is hydrogen atom or a C
1-6
alkyl group which may be optionally substituted with carboxyl group or a C
1-6
alkoxycarbonyl group, R
2a
and R
2b
are independently hydrogen atom, a halogen atom, hydroxyl group, cyano group or a C
1-6
alkoxy group which may be optionally substituted with 1-3 halogen atoms, R
3
is a C
1-6
alkyl group, and R
4
and R
5
are independently a halogen atom.
In a more preferred embodiment of the compound (I), R
1
is hydrogen atom or a C
1-6
alkyl group, one of R
2a
and R
2b
is hydrogen atom, and the other is a halogen atom, cyano group, or a C
1-6
alkoxy group which may be optionally substituted with 1-3 halogen atoms, R
3
is a C
1-6
alkyl group, and R
4
and R
5
are independently a halogen atom.
In a further preferred embodiment of the compound (I), R
1
is hydrogen atom or methyl group, one of R
2a
and R
2b
is hydrogen atom and the other is bromine atom, cyano group, a C
1-6
alkoxy group or trifluoromethoxy group, R
3
is methyl group, R
4
and R
5
are chlorine atom.
In another more preferred embodiment of the compound (I), R
1
is hydrogen atom or C
1-6
alkyl group which may be substituted with carboxyl or C
1-6
alkoxycarbonyl, one of R
2a
and R
2b
is hydrogen atom, and the other is cyano group or C
1-6
alkoxy group which may be substituted with 1-3 halogen atoms.
In another further preferred embodiment of the compound (I), R
1
is hydrogen atom or methyl group, one of R
2a
and R
2b
is hydrogen atom and the other is C
1-6
alkoxy group or trifluoromethoxy group, R
3
is methyl group, R
4
and R
5
are chlorine atom.
In another preferred embodiment of the compound (I), R
1
is a C
1-6
alkyl group which is substituted with a C
1-6
alkoxycarbonyl group or carboxyl group, one of R
2a
and R
2b
is hydrogen atom, and the other is a halogen atom, cyano group, or C
1-6
alkoxy group which may be optionally substituted with 1-3 halogen atoms, R
3
is a C
1-6
alkyl group, and R
4
and R
5
are independently a halogen atom.
In a more preferred embodiment of the compound (I), R
3
is methyl group, and R
4
and R
5
are chlorine atom.
Most preferred compound of the present invention is selected from:
3-(2,6-Dichloro-4-pyrydyl)-5-(4-bromobenzyl)-1,5-dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-propoxybenzyl)-1,5-dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-ethoxybenzyl)-1,5-dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-(1,1,1trifluoromethoxybenzyl)]-5-methyl-2,4-imidazolidinedione,
3-(2,6-dichloro-4-pyrydyl)-5-[4-(1,1,1trifluoromethoxybenzyl)]-1,5-Dimethyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-Cyanobenzyl)-5-methyl-2,4-imidazolidinedione,
3-(2,6-Dichloro-4-pyrydyl)-5-(4-Cyanobenzyl)-1,5-dimethyl-2,4-imidazolidinedione; and
a pharmaceutically acceptable salt of these compounds.
The compound of the present invention has potent inhibitory activity against &agr;
L
&bgr;
2
mediated cell adhesion, and also shows excellent bioavailability after oral administration which reflects the overall improvement in plasma protein binding and solubility. The compound of the present invention therefore s
Furth Paul S.
Sircar Ila
Smith Nicholas
Xie Yun Feng
Aulakh Charanjit S.
Birch & Stewart Kolasch & Birch, LLP
Tanabe Seiyaku Co. Ltd.
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