Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-19
2004-09-21
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252180, C514S256000, C514S318000, C514S326000, C544S122000, C544S296000, C544S333000, C546S194000, C546S210000
Reexamination Certificate
active
06794386
ABSTRACT:
The present invention relates to compounds of formula (I),
their preparation and use as pharmaceutical compositions as integrin antagonists, especially as &agr;
4
&bgr;
1
and/or &agr;
4
&bgr;
7
and/or &agr;
9
&bgr;
1
integrin antagonists and in particular for the production of pharmaceutical compositions suitable for the inhibiton or the prevention of cell adhesion and cell-adhesion mediated disorders. Examples are the treatment and the prophylaxis of arteriosclerosis, asthma, allergies, diabetes, inflammatory bowel disease, multiple sclerosis, myocardial ischemia, rheumatoid arthritis, transplant rejection and other inflammatory, autoimmune and immune disorders.
Adhesive interactions between the leukocytes and endothelial cells play a critical role in leukocyte trafficking to sites of inflammation. These events are essential for normal host defense against pathogens and repair of tissue damage, but can also contribute to the pathology of a variety of inflammatory and autoimmune disorders. Indeed, eosinophil and T cell infiltration into the tissue is known as a cardinal feature of allergic inflammation such as asthma.
The interaction of circulating leukocytes with adhesion molecules on the luminal surface of blood vessels appears to modulate leukocyte transmigration. These vascular cell adhesion molecules arrest circulating leukocytes, thereby serving as the first step in their recruitment to infected or inflamed tissue sites. Subsequently, the leukocytes reaching the extravascular space interact with connective tissue cells such as fibroblasts as well as extracellular matrix proteins such as fibronectin, laminin, and collagen. Adhesion molecules on the leukocytes and on the vascular endothelium are hence essential to leukocyte migration and attractive therapeutic targets for intervention in many inflammatory disorders.
Leukocyte recruitment to sites of inflammation occurs in a stepwise fashion beginning with leukocyte tethering to the endothelial cells lining the blood vessels. This is followed by leukocyte rolling, activation, firm adhesion, and transmigration. A number of cell adhesion molecules involved in the those four recruitment steps have been identified and characterized to date. Among them, the interaction between VCAM-1 and VLA-4 has been shown to mediate the tethering, rolling, and adhesion of lymphocytes and eosinophils, but not neutrophils, to endothelial cells under a physiologic flow condition. This suggests that the interaction between VCAM-1 and VLA-4 could predominantly mediate a selective recruitment of leukocyte sub-populations in vivo. The inhibition of this interaction is a point of departure for therapeutic intervention.
VCAM-1 is a member of immunoglobulin (Ig) superfamily and is one of the key regulators of leukocyte trafficking to sites of inflammation. VCAM-1, along with ICAM-1 and E-selectin, is expressed on inflamed endothelium activated by such cytokines as IL-1 and TNF-&agr;, as well as by LPS, via NF-&kgr;B dependent pathway. However, these molecules are not expressed on resting endothelium. Cell adhesion mediated by VCAM-1 may be involved in numerous physiological and pathological processes including myogenesis, hematopoiesis, inflammatory reactions, and the development of autoimmune disorders. Integrins VLA-4 and &agr;4&bgr;7 both function as leukocyte receptors for VCAM-1.
The integrin &agr;
4
&bgr;
1
(VLA-4) is a heterodimeric protein expressed in substantial levels on all circulating leukocytes except mature neutrophils. It regulates cell migration into tissues during inflammatory responses and normal lymphocyte trafficking. VLA-4 binds to different primary sequence determinants, such as a QIDSP motif of VCAM-1 and a ELDVP sequence of the major cell type-specific adhesion site of the alternatively spliced type III connecting segment domain (CS-1) of fibronectin.
In vivo studies with neutralizing monoclonal antibodies and inhibitor peptides have demonstrated a critical role for &agr;4 integrins interaction in leukocyte-mediated inflammation. Blocking of VLA-4/ligand interactions, thus, holds promise for therapeutic intervention in a variety of inflammatory, autoimmune and immune diseases (Zimmerman, C.;
Exp. Opin. Ther. Patents
1999, 9, 129-133).
Natural ligands for integrin receptors are for example extracellular matrix proteins such as fibronectin, laminin and collagen containing a specific binding sequence. In case of the &agr;
4
&bgr;
1
integrin receptor LDV is the specific binding sequence of the natural protein ligands (LDV is the single letter code for the &agr;-amino acid sequence leucine-aspartate-valine [N-terminus→C-terminus]). The most important structural feature for binding is the free carboxylic acid group of the aspartate. Thus, synthetic inhibitors have to mimic the natural binding sequence including a free carboxylic acid group.
Accordingly, compounds containing a dipeptide with a free carboxylic acid C-terminus as structural element were disclosed as &agr;
4
&bgr;
1
integrin receptor antagonists, such as WO 98/53817 discloses prolin-phenylalanin [N-terminus→C-terminus] derivatives, WO 98/26921 discloses prolin-&bgr;-phenylalanin [N-terminus→C-terminus] derivatives and WO 99/25685 discloses isonipecotic acid (a cyclic &ggr;-amino acid)-phenylalanin [N-terminus→C-terminus] derivatives substituted with a bisarylurea. However, no dipeptide derivatives with a &bgr;-amino acid as N-terminus have been described.
&bgr;-amino acids have been shown to stabilise helices [D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo, L. Oberer, U, Hommel, R. Amstutz, H. Widmer
Helv. Chim. Acta
1996, 79, 2043-66] and sheet-structures [S. Krauthäuser, L. A. Christianson, D. R. Powell, S. Gellman
J. Am. Chem. Soc
. 1997, 119, 11719-20] which are completely different from regular secundary structural elements like &agr;-helices or &bgr;-sheets which are observed for &agr;-amino acids. Thus &bgr;-amino acids show a conformational behavior which is significantly different from natural &agr;-amino acids and it cannot be expected that generally a &bgr;-amino acids will mimic corresponding &agr;-amino acids. Consequently, the replacement of a &agr;-amino acid within a biologically active compound containing a peptidic substructure against a &bgr;-amino acid will generally disturb the bioactive conformation, yielding compounds with significantly decreased activity.
Surprisingly, however, in the present invention it has now been found that &bgr;-amino acid derivatives of formula (I) are potent integrin antagonists, especially &agr;
4
&bgr;
1
integrin antagonists.
An object of the present invention is to provide new, alternative, &bgr;-amino acid derived integrin antagonists for the treatment of inflammatory, autoimmune and immune diseases.
The present invention therefore relates to compounds of the general formula (I):
wherein
R
1
represents hydrogen, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, C
6
or C
10
aryl, C
3
-C
7
cycloalkyl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 3 radicals R
10
, and which can furthermore be single-foldedly substituted by C
3
-C
7
cycloalkyl, C
6
or C
10
aryl, C
4
-C
9
heteroaryl or a 4-9-membered saturated or unsaturated heterocyclic residue containing up to 2 heteroatoms selected from the group oxygen, nitrogen or sulfur, which can optionally be substituted by 1 to 3 radicals R
10
,
wherein
R
10
represents C
1
-C
4
alkyl, trifluormethyl, trifluormethoxy, —OR
11
, —SR
11
, NR
13
R
14
, —C(O)R
11
, S(O)R
11
, —SO
2
R
11
, —CO
2
R
11
, —OC(O)R
11
, —C(O)NR
13
R
14
, —NR
11
C(O)R
11
, —SO
2
NR
13
R
14
, NR
11
SO
2
R
11
, —NR
11
C(O)NR
13
R
14
, —NR
11
C(O)OR
11
, —OC(O)NR
13
R
14
, halogen, cyano, nitro or oxo,
wherein
R
11
represents hydrogen, C
1
-C
4
alkyl, C
3
-C
6
cycloalkyl, C
6
or C
10
aryl which can optionally be substituted by 1 substituent select
Albers Markus
Hasegawa Haruki
Hessler Gerhard
Lehmann Thomas
Möller Gerhard
Bayer Aktiengesellschaft
McKane Joseph K.
Wright Sonya
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