Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-15
2003-02-18
Padmanabhan, Sreeni (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S275000, C514S510000, C514S564000, C514S569000, C560S021000, C560S055000, C562S435000, C562S466000, C546S285000
Reexamination Certificate
active
06521646
ABSTRACT:
The invention relates to compounds of the formula I
in which
R
1
is OR
4
, NHR
4
or NA″
2
,
R
2
is H, Hal, NO
2
, NHR
4
, NA″
2
, OR
4
, SO
3
R
4
, SO
2
R
4
or SR
4
,
R
3
is NH
2
, H
2
N—C(═NH) or H
2
N—(C═NH)—NH, where the primary amino groups can also be provided with conventional amino protective groups, or R
5
—NH—,
R
4
is H, A, Ar or Aralk,
R
5
is a mono- or binuclear heterocycle having 1 to 4 N, O and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A″, —CO—A′, OA′, CN, COOA′, CONH
2
, NO
2
, ═NH or ═O,
A is alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or mono-, di- or trisubstituted by R
6
, and in which one, two or three methylene groups can be replaced by N, O and/or S
R
6
is Hal, NO
2
, NHA′, NA″
2
, OA′, phenoxy, CO—A′, SO
3
A′, CN, NHCOA′, COOA′, CONA′
2
or SO
2
A′,
A′ is H or alkyl having 1-6 C atoms,
A″ is alkyl having 1-6 C atoms,
Ar is a mono- or binuclear aromatic ring system, which is unsubstituted or mono-, di- or trisubstituted by alkyl having 1-6 C atoms and/or an R
6
-substituted mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms,
Aralk is aralkylene having 7-14 C atoms, which is unsubstituted or mono-, di- or trisubstituted by R
6
and in which one, two or three methylene groups can be replaced by N, O and/or S,
Hal is F, Cl, Br or I,
m, n in each case independently of one another are 0, 1, 2, 3 or 4,
and their physiologically acceptable salts and solvates.
Similar compounds are disclosed, for example, in WO 97/01540.
The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts and solvates have very valuable pharmacological properties, together with good tolerability. They act especially as integrin inhibitors, where they particularly inhibit the interactions of the &agr;
v
integrin receptors with ligands.
The compounds show particular activity in the case of the integrins &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
. The compounds are very particularly active as adhesion receptor antagonists for the vitronectin receptor &agr;
v
&bgr;
3
.
This action can be demonstrated, for example, according to the method which is described by J. W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990). In Curr. Opin. Cell. Biol. 5, 864 (1993), B. Felding-Habermann and D. A. Cheresh describe the importance of the integrins as adhesion receptors for very different phenomena and syndromes, especially with respect to the vitronectin receptor &agr;
v
&bgr;
3
.
The dependence of the formation of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 264, 569-71 (1994).
The possibility of inhibition of this interaction and thus of the initiation of apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is 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 proof that the compounds according to the invention also prevent the attachment of living cells to the corresponding matrix proteins, and accordingly also the attachment of tumour cells to matrix proteins, can be furnished in a cell adhesion test which is carried out analogously to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).
In J. Clin. Invest. 96, 1815-1822 (1995), P. C. Brooks et al. describe &agr;
v
&bgr;
3
antagonists for the control of 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 pharmaceutical active compounds, in particular for the treatment of oncoses, osteoporosis, osteolytic disorders 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 on 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) by interaction of the tumour cells with blood platelets. The tumour cells are screened by protection in the microaggregate and are not recognized by the cells of the immune system. The microaggregates can fix themselves to vessel walls, as a result of which further penetration of tumour cells into the tissue is facilitated. Since the formation of microthrombi by fibrinogen binding to the fibrinogen receptors is mediated on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as effective metastasis inhibitors.
Besides the binding of fibrinogen, fibronectin and the von 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, apoplexy, cardiac infarct, inflammation and arteriosclerosis.
The properties of the compounds can also be demonstrated according to methods which are described in EP-A1-0 462 960. The inhibition of fibrinogen binding to the fibrinogen receptor can be detected by the method which is indicated in EP-A1-0 381 033.
The platelet aggregation-inhibiting action can be demonstrated in vitro according to the method of Born (Nature 4832, 927-929, 1962).
The invention accordingly relates to the compounds of the formula I according to claim 1 and their physiologically acceptable salts and solvates as GPIIb/IIIa antagonists for the control of thromboses, cardiac infarct, coronary heart disorders and arteriosclerosis.
The invention furthermore relates to the compounds of the formula I according to claim 1 and their physiologically acceptable salts and solvates for the production of a medicament for use as an integrin inhibitor.
The invention relates in particular to compounds of the formula I according to claim 1 and their acceptable salts and solvates for the production of a medicament for controlling pathologically angiogenic disorders, tumours, osteoporosis, inflammation and infections.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, oncoses, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases such as, for example, inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing for assisting the healing process.
The compounds of the formula I can be employed as antimicrobially active substances in operations where biomaterials, implants, catheters or heart pacemakers are used. They have an antiseptic action here. The efficacy of the antimicrobial activity can be demonstrated by the process described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The invention further relates to a process for the preparation of compounds of the formula I according to claim 1, and of their salts and solvates, characterized in that
a) a compound of the formula I is set free from one of it
Goodman Simon
Gottschlich Rudolf
Stähle Wolfgang
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
Padmanabhan Sreeni
Zucker Paul A.
LandOfFree
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