&agr;v&bgr;3 integrin inhibitors

Details &agr;v&bgr;3 integrin inhibitors &agr;v&bgr;3 integrin inhibitors

2002-06-21

2003-11-11

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S275000, C514S393000, C514S398000, C544S316000, C546S307000, C546S312000, C548S307400, C548S328500, C548S335100, C548S335500, C548S341500

Reexamination Certificate

active

06645991

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims benefit of PCT/EP00/07590, filed Aug. 4, 2000, under 35 U.S.C. §371.
The invention relates to novel compounds of the formula I
X—Y—Z—R
1
—CH
2
—R
2
(R
4
)—CH
2
—CO—R
5
in which
X is H
2
N—C(═NH)—, H
2
N—C(═NH)—NH—, A—C(═NH)—NH—, Het
1
— or Het
1
—NH—, where the primary amino groups may also be provided with conventional amino-protecting groups,
Y is —(CH
2
)
n
—,
in which one, two, three or four methylene groups may be replaced by N, O and/or S,
Z is absent, —O—, —NH—, —NA—, —CH(OH)—, —CH(OA)—, —CHA—, —CA
2
— or —S—,
R
1
is phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF
3
or CN,
R
2
is N, CH or CA,
R
3
is H, F, Cl, Br, A, OA or OCF
3
,
R
4
is phenyl, naphthyl or Het
2
, each of which is unsubstituted or mono- or polysubstituted by A, aryl or CF
3
,
R
5
is OH, OA, NH
2
, NHA or NA
2
,
Het
1
is a mono- or bicyclic heterocyclic radical having from 1 to 4 N atoms, which may be unsubstituted or mono- or disubstituted by NH
2
,
Het
2
is an aromatic mono- or bicyclic heterocyclic radical having from 1 to 3 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF
3
, —CO—A, CN, COOA, CONH
2
, CONHA, CONA
2
or NO
2
,
aryl is phenyl which is unsubstituted or mono-, di- or trisubstituted by Hal, A or OA,
A is alkyl having 1-12 carbon atoms,
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,
m, o are each, independently of one another, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,
and their physiologically acceptable salts and solvates.
The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties and are well tolerated. In particular, they act as integrin inhibitors, inhibiting, in particular, the interactions of the &agr;
v
integrin receptors with ligands. The compounds exhibit particular efficacy in the case of integrins &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
. The compounds are very particularly effective as adhesion receptor antagonists for the &agr;
v
&bgr;
3
receptor.
This action can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
Inhibition of vitronectin binding to the receptor &agr;
v
&bgr;
3
has been demonstrated experimentally for 3-phenyl-4-{4-[3-(pyridin-2-ylamino)propoxy]phenyl}-butyric acid.
B. Felding-Habermann and D. A. Cheresh in Curr. Opin. Cell. Biol. 5, 864 (1993), describe the importance of the integrins as adhesion receptors for a wide variety of phenomena and syndromes, especially in relation to the receptor &agr;
v
&bgr;
3
.
Other inhibitors of integrin &agr;
v
&bgr;
3
are described in EP 0820988. The compounds according to the invention should be regarded as an invention of selection in relation to the said application. Vitronectin receptor antagonists are also described in WO 97/24124 and in EP 0820991.
The dependence of the occurrence 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 264, 569-71 (1994).
The possibility of inhibiting this interaction and thus 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 79, 1157-64 (1994).
The experimental evidence that the compounds according to the invention also prevent the adhesion of living cells to the corresponding matrix proteins and accordingly also prevent the adhesion of tumour cells to matrix proteins can be provided in a cell adhesion test carried out analogously to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).
P. C. Brooks et al. in J. Clin. Invest. 96, 1815-1822 (1995) describe &agr;
v
&bgr;
3
antagonists for combating cancer and for the treatment of tumour-induced angiogenic diseases.
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 and other osteolytic diseases, and for the suppression of angiogenesis.
Compounds of the formula I which block the interaction of integrin receptors and ligands, such as, for example, of fibrinogen with the fibrinogen receptor (glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists, the spread of tumour cells by metastasis. This is confirmed by the following observations:
The spread of tumour cells from a local tumour into the vascular system takes place through the formation of microaggregates (microthrombi) through interaction of the tumour cells with blood platelets. The tumour cells are screened by the protection in the microaggregate and are not recognised by the cells of the immune system.
The microaggregates are able to attach themselves to vessel walls, facilitating further penetration of tumour cells into the tissue. Since the formation of the microthrombi is promoted by fibrinogen binding to the fibrinogen receptors on activated blood platelets, the GPIIb/IIIa antagonists can be regarded as effective metastasis inhibitors.
Besides the binding of fibrinogen, fibronectin and Willebrand factor to the fibrinogen receptor of the blood platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent the formation of blood platelet thrombi and can therefore be employed for the treatment of thromboses, apoplexia, cardiac infarction, inflammation and arteriosclerosis.
The properties of the compounds can also be demonstrated by methods described in EP-A1-0 462 960. The inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the method indicated in EP-A1-0 381 033.
The thrombocyte aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962). The inhibition of bone resorption by the compounds according to the invention can take place with the aid of an osteoclast resorption test analogously to WO 95/32710.
The invention accordingly relates to compounds of the formula I according to claim 1 and/or their physiologically acceptable salts for the preparation of a medicament for use as integrin inhibitor. In particular, the invention relates to compounds of the formula I according to claim 1 and/or their acceptable salts for the preparation of a medicament for combating pathologically angiogenic diseases, tumours, osteoporosis, inflammation and infections.
The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine, for the prophylaxis and/or therapy of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, tumour diseases, osteolytic diseases, such as osteoporosis, hypercalcaemia, pathologically angiogenic illnesses, such as, for example, inflammation, ophthalmological illnesses, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infections, bacterial infections, fungal infections, in acute renal failure and in wound healing for supporting the healing processes.
The compounds of the formula I can be employed as antimicrobially active substances in operations where biomaterials, implants, catheters or cardiac pacemakers are used. They have an antiseptic action here. The effectiveness of the antimicrobial activity can be demonstrated by the method described by P. Valentin-Weigund et al. in Infection and Immunity, 2851-2855 (1988).
The invent

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