Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-20
2003-06-10
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S352000, C544S330000, C544S332000, C546S304000, C546S309000
Reexamination Certificate
active
06576637
ABSTRACT:
The invention relates to &bgr;-alanine derivatives of the formula I
in which
Q
1
, Q
2
,
Q
3
or Q
4
is, in each case, independently of one another, CH or N,
R
1
is H, A, Ar, Hal, OH, OA, CF
3
or OCF
3
,
R
2
is H or A,
R
4
and R
5
are, in each case independently of one another H, A, Hal, OH, OA, CF
3
, OCF
3
, CN, NH
2
, NHA, NA
2
or NH—C (O) A,
R
6
is H, A, —(CH
2
)
m
—OH, —(CH
2
)
m
—O—C (O) A or —(CH
2
)
m
—Ar,
A is alkyl with 1 to 6 C atoms,
Ar is unsubstituted or mono-, di- or trisubstituted aryl,
Hal is F, Cl, Br or I,
n is 2, 3, 4, 5 or 6,
m is 1, 2, 3 or 4,
and their physiologically acceptable salts and solvates.
Partly similar compounds are disclosed in WO 97/26250 or WO 97/24124.
The invention was based on the object of finding novel compounds with valuable properties, in particular those which can be used to produce pharmaceuticals.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties while being well tolerated. In particular, they act as integrin inhibitors, in particular inhibiting the interactions with the &agr;&ugr;&bgr;3 or &agr;&ugr;&bgr;5 integrin receptors with ligands such as, for example, the binding of vitronectin to the &agr;&ugr;&bgr;3 integrin receptor. Integrins are membrane-bound, heterodimeric glycoproteins which consist of an &agr; subunit and of a smaller. &bgr; subunit. The relative affinity and specificity for ligand binding is determined by the combination of the various &agr; and &bgr; subunits. The compounds according to the invention show particular activity in the case of the integrins &agr;&ugr;&bgr;1, and &agr;&ugr;&bgr;3, &agr;&ugr;&bgr;5, &agr;IIb&bgr;3, and &agr;&ugr;&bgr;6 and &agr;&ugr;&bgr;8, preferably of &agr;&ugr;&bgr;3 and &agr;&ugr;&bgr;5. In particular, potent selective inhibitors of the integrin &agr;&ugr;&bgr;3 have been found. The &agr;&ugr;&bgr;3 integrin is expressed on a number of cells, for example endothelial cells, smooth vascular muscle cells, for example of the aorta, cells for breaking down bone matrix (osteoclasts) or tumour cells.
The effect of the compounds according to the invention can be detected, for example, by the method described by J. W. Smith et al., in J. Biol. Chem. 1990, 265, 12267-12271. The dependence of the development 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 1994, 264, 569-571.
The possibility of inhibiting this interaction and thus for inducing 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. Reisfield, T. Hu, G. Klier and D. A. Cheresh in Cell 1994, 79, 1157-1164. Descriptions are given therein of, for example, &agr;&ugr;&bgr;3 antagonists or antibodies against &agr;&ugr;&bgr;3 which bring about shrinkage of tumours through induction of apoptosis.
The experimental demonstration that the compounds according to the invention also prevent adhesion of living cells to the appropriate matrix proteins, and accordingly, also prevent the adhesion of tumour cells to matrix proteins can be provided in a cell adhesion test in analogy to the method of F. Mitjans et al., Cell Science 1995, 108, 2825-2838.
The compounds of the formula I are able to inhibit the binding of metalloproteinases to integrins and thus prevent the cells being able to utilize the enzymatic activity of the proteinase. One example is to be found in the ability to inhibit the binding of MMP-2 (matrix metalloproteinase
2
) to the vitronectin receptor &agr;
&ugr;
&bgr;
3
by a cylcic RGD peptide, as described in P. C. Brooks et al., Cell 1996, 85, 683-693.
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 antagonists, the spread of tumour cells by metastasis and can therefore be employed as substances with antimetastatic activity in operations in which the tumours are surgically removed of dealt with. This is demonstrated by the following observations:
The spread of tumour cells from a local tumour into the vascular system takes place by the formation of microaggregates (microthrombi) through the interaction of the tumour cells with blood platelets. The tumour cells are shielded by the protection in the microaggregate and are not recognized by the cells of the immune system. The microaggregates are able to attach to vessel walls, which facilitates further penetration of tumour cells into the tissue. Since the formation of microthrombi is mediated by a ligand binding to the corresponding integrin receptors, for example &agr;&ugr;&bgr;3 or &agr;IIb&bgr;3, on activated blood platelets, the appropriate antagonists can be regarded as effective metastasis inhibitors.
The compounds of formula I can be employed as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and/or therapy of circulatory disorders, thrombosis, myocardial infarct, arteriosclerosis, stroke, angina pectoris, tumorous disorders such as tumour development or tumour metastasis, osteolytic diseases such as osteoporosis, diseases with pathological angiogenesis, such as, for example, inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing to assist the healing process.
The compounds of the formula I can be employed as substances with antimicrobial activity in operations where biomaterials, implants, catheters or heart pacemakers are used.
They moreover have an antiseptic effect. The antimicrobial activity can be demonstrated by the method described by P. Valentin-Weigund et al. in Infection and Immunity, 1988, 2851-2855.
Selected compounds of the formula I are, in particular, selective &agr;&ugr;&bgr;3 and &agr;&ugr;&bgr;6 integrin receptor inhibitors.
Selected compounds of the formula I are, in particular, selective &agr;&ugr;&bgr;5 and &agr;&ugr;&bgr;6 integrin receptor inhibitors. Selected compounds of the formula I are, in particular, selective &agr;&ugr;&bgr;3 and &agr;&ugr;&bgr;5 and &agr;&ugr;&bgr;5 integrin receptor inhibitors.
The effect of a compound on an &agr;&ugr;&bgr;5 integrin receptor and thus the activity as inhibitor can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271. The effect of a compound on an &agr;&ugr;&eegr;6 integrin receptor and thus the activity as inhibitor can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271.
These selected compounds are particularly suitable for therapy or for controlling pathological processes which can be influenced by the integrins &agr;&ugr;&bgr;3 and/or &agr;&ugr;&bgr;5 and &agr;&ugr;&bgr;6 . Examples of angiogenic pathologies are skin disorders such as psoriasis, bullous pemphigus, dermatitis and erythemas, as well as pulmonary fibrosis, cystic fibrosis, endometriosis, cirrhosis or the liver of periodontitis, and they can be influenced through &agr;&ugr;&bgr;3 and/or &agr;&ugr;&bgr;5 inhibitors, and pathologies of epithelial cells which can be influenced through &agr;&mgr;&bgr;6 inhibitors are, in particular, carcinomas and the abovementioned skin disorders and pulmonary fibrosis (Lit.: Healy D. L. et al., Hum. Reprod. Update 1998, 4 (5), 736-40; Creamer D. et al., Br. J. Dermatol. 1997, 137, 851-5; Norrby K., APMIS, 1997, 105, 417-37; Creamer D. et al., Br. J. Dermatol. 1997, 136, 859-65; Polverini P. J., Crit. Rev. Oral. Biol. Med, 1995, 6, 230-47; Brown L. F. et al., J. Invest. Dermatol. 1995, 104, 744-9; Hoyt D. G. et al., Am. J. Physiol., 1997, 273, L612-7; Pilewski J. M. et
Goodmann Simon
Hölzemann Günter
Jonczyk Alfred
Stähle Wolfgang
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
Rao Deepak
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