Indol-3-yl derivatives

Details Indol-3-yl derivatives Indol-3-yl derivatives

2002-08-09

2004-06-01

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S422000, C546S277400, C548S152000, C548S204000, C548S465000, C548S506000, C548S509000

Reexamination Certificate

active

06743810

ABSTRACT:

The invention relates to indol-3-yl derivatives of the formula I
in which
A and B are each, independently of one another, O, S, NH, NR
7
, CO, CONH, NHCO or a direct bond,
X is alkylene having 1 to 2 carbon atoms which is unsubstituted or monosubstituted by R
4
or R
5
, or a direct bond,
R
1
is H, Z or —(CH
2
)
o
—Ar,
R
2
is H, R
7
or —C(O)Z,
R
3
is NHR
6
, —NR
6
—C(═NR
6
)—NHR
6
, —C(═NR
6
)—NHR
6
, —NR
6
—C(═NR
9
)—NHR
6
, —C(═NR
9
)—NHR
6
or Het
1
,
R
4
and R
5
are each, independently of one another, H, oxo, R
7
, —(CH
2
)
o
—Ar, —C(O)—(CH
2
)
o
—Ar, —C(O)—(CH
2
)
o
—R
7
, —C(O)—(CH
2
)
o
—Het, Het, NHR
6
, NHAr, NH—Het, CONH—R
7
, CONH—(CH
2
)
o
—Ar, CONH—(CH
2
)
o
—Het, OR
7
, OAR, OR
6
or O—Het,
R
6
is H, —C(O)R
7
, —C(O)—Ar, —C(O)—Het, R
7
, COOR
7
, COO—(CH
2
)
o
—Ar, COO—(CH
2
)
o
—Het, SO
2
—Ar, SO
2
R
7
or SO
2
—Het,
R
7
is alkyl having 1 to 10 carbon atoms or cycloalkyl having 3 to 10 carbon atoms,
R
8
is Hal, NO
2
, CN, Z, —(CH
2
)
o
—Ar, COOR
1
, OR
1
, CF
3
, OCF
3
, SO
2
R
1
, NHR
1
, N(R
1
)
2
, NH—C(O)R
1
, NHCOOR
1
, COOH, COOZ or C(O)R
1
,
R
9
is CN or NO
2
,
Z is alkyl having 1 to 6 carbon atoms,
Ar is aryl which is unsubstituted or monosubstituted or polysubstituted by R
8
,
Hal is F, Cl, Br or l,
Het is a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms may be present and the heterocyclic radical may be monosubstituted or disubstituted by R
8
,
Het
1
is a saturated, partially or fully unsaturated monocyclic or bicyclic heterocyclic radical having 5 to 10 ring members and 1 to 4 N atoms which may be unsubstituted or monosubstituted or disubstituted by Hal, R
7
, OR
7
, CN, NHZ, oxo or NO
2
,
n is 0, 1 or 2,
m is 0, 1, 2, 3, 4, 5 or 6, and
o is 0, 1 or 2,
and their physiologically acceptable salts and solvates.
Some similar compounds are disclosed in WO 99/30713 and WO 94/12478.
The object of the invention was to discover novel compounds having valuable properties, in particular those which are used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts are well tolerated and have very valuable pharmacological properties. In particular, they act as integrin inhibitors, inhibiting, in particular, the interactions of the &agr;v-, &bgr;3- and &bgr;5-integrin receptors with ligands, such as, for example, the binding of vitronectin to the integrin receptor. Integrins are membrane-bound, heterodimeric glycoproteins consisting of an &agr; subunit and a smaller &bgr; subunit. The relative affinity and specificity for ligand binding is determined by recombination of the various &agr; and &bgr; subunits. Particular efficacy is exhibited by the compounds according to the invention in the case of integrins &agr;v&bgr;1, &agr;v&bgr;3, &agr;v&bgr;5, &agr;IIb&bgr;3, &agr;v&bgr;6 and &agr;v&bgr;8, preferably &agr;v&bgr;3, &agr;v&bgr;5 and &agr;IIb&bgr;3. The compounds according to the invention are particularly potent inhibitors of the vitronectin receptor &agr;v&bgr;3 and/or &agr;v&bgr;5 and/or of the fibrinogen receptor &agr;IIb&bgr;3. The compounds according to the invention are particularly preferably inhibitors of the vitronectin receptor &agr;v&bgr;3.
An essential factor for the activity of integrin inhibitors is the presence of an acid function at a suitable distance from a base centre. The activity and specificity can be controlled by adjusting the spacer length and the type of the base centre. A suitable central template is indole.
&agr;v&bgr;3 integrin is expressed in a number of cells, for example endothelium cells, cells of smooth vascular muscles, for example the aorta, cells for breaking down bone matrix (osteoclasts) or tumour cells.
The action of the compounds according to the invention can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 1990, 265,12267-12271.
B. Felding-Habermann and D. A. Cheresh in Curr. Opin. Cell. Biol. 1993, 5, 864, describe the significance of the integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially in relation to the vitronectin receptor &agr;v&bgr;3.
The dependence of formation of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins has been described by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 1994, 264, 569-571.
The possibility of inhibiting this interaction and so initiating apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide has been described by P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Hu, G. Klier and D. A. Cheresh in Cell 1994, 79, 1157-1164. In this, for example, &agr;v&bgr;3 antagonists or antibodies against &agr;v&bgr;3 were described which cause shrinkage of tumours due to the initiation of apoptosis.
The experimental evidence that the compounds according to the invention also prevent the attachment of living cells to the corresponding matrix proteins and accordingly also prevent the attachment of tumour cells to matrix proteins can be provided in a cell adhesion test analogously to the method of F. Mitjans et al., J. Cell Science 1995, 108, 2825-2838.
P. C. Brooks in J. Clin. Invest. 1995, 96, 1815-1822, describe &agr;
v
&bgr;3 antagonists for combating cancer and for the treatment of tumour-induced angiogenic diseases.
The compounds are able to inhibit the binding of metal proteinases to integrins and thus prevent the cells utilizing the enzymatic activity of the proteinase. An example can be found in the ability of a cyclo-RGD peptide to inhibit the binding of MMP-2 (matrix-metallo-proteinase-2) to the vitronectin receptor &agr;v&bgr;3, as described in P. C. Brooks et al., Cell 1996, 85, 683-693.
The compounds of the formula I according to the invention can therefore be employed as medicament active ingredients, in particular for the treatment of tumour diseases, osteoporosis, osteolytic diseases and for suppressing angiogenesis.
Compounds of the formula I which block the interaction of integrin receptors and ligands, such as, for example, of fibrinogen to the fibrinogen receptor (glycoprotein IIb/IIIa or &agr;II&bgr;3), prevent the spread of tumour cells by metastasis and can therefore be employed as antimetastatic substances in operations in which tumours are removed or attacked surgically. This is confirmed by the following observations:
The spread of tumour cells from a local tumour into the vascular system occurs through the formation of microaggregates (microthromboses) due to the interaction of the tumour cells with blood platelets. The tumour cells are masked by the protection in the microaggregate and are not recognized by the immune system cells. The microaggregates are able to attach to vessel walls, simplifying further penetration of tumour cells into the tissue. Since the formation of microthromboses is promoted by ligand binding to the corresponding integrin receptors, for example &agr;v&bgr;3 or &agr;IIb&bgr;3, on activated blood platelets, the corresponding antagonists can be regarded as effective metastasis inhibitors.
Besides the binding of fibrinogen, fibronectin and von Willebrand factor to the fibrinogen receptor of blood platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as victronectin, collagen and laminin, to the corresponding receptors on the surface of various types of cell. In particular, they prevent the formation of blood platelet thromboses and can therefore be employed for the treatment of thromboses, apoplexia, cardiac infarction, inflammations and arteriosclerosis.
The thrombocyte aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature 1962, 4832, 927-929).
The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine, in particular for the prophylaxis and/or therapy of circulation disorders, thromboses, cardiac infarction, arteriosclerosis, apoplexia, angina pectori

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