Diacylhydrazine derivatives

Details Diacylhydrazine derivatives Diacylhydrazine derivatives

2002-01-14

2003-11-18

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C562S439000, C562S561000, C544S330000, C544S331000, C544S238000, C544S407000, C544S336000, C544S224000, C546S264000, C546S276700, C546S306000, C548S312100, C548S326500, C514S565000, C514S252060, C514S255060, C514S275000, C514S332000, C514S339000, C514S397000, C514S398000, C514S407000

Reexamination Certificate

active

06649613

ABSTRACT:

The invention relates to diacylhydrazine derivatives of the formula I
in which
X is H
2
N—C(═NH)—NH—, H
3
C—C (═NH)—NH— or Het
1
—NH—,
Y is
Z is N—R
2
or CH—R
2
,
R
1
, R
2
are each independently of one another H or A,
R
3
is H, Ar or Het,
R
4
is H, A, Ar, OH, OA, OAr, arylalkyl, Hal, CN, NO
2
, CF
3
or OCF
3
A is alkyl having 1 to 6 carbon atoms,
Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF
3
, OCF
3
, CN, NO
2
or Hal and which may be substituted by a phenyl which is mono-, di- or trisubstituted by A, OH, OA, CF
3
, OCF
3
, CN, NO
2
or Hal such that an unsubstituted or substituted biphenyl is formed or naphthyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF
3
, OCF
3
, CN, NO
2
or Hal,
Hal is F, Cl, Br or I,
Het is a saturated, partially or fully unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, wherein 1 or 2 nitrogen and/or 1 or 2 sulfur or oxygen atoms may be present and wherein the heterocyclic radical may be mono- or disubstituted by CN, Hal, OH, OA, CF
3
, A, NO
2
or OCF
3
,
Het
1
is a 5- or 6-membered aromatic heterocycle having 1 to 4 nitrogen atoms which may be unsubstituted or mono- or disubstituted by Hal, A, OA, Ar, OAr, arylalkyl, CN, NO
2
, CF
3
or OCF
3
,
n is 2, 3, 4, 5 or 6,
m, o are 0, 1 or 2,
and their physiologically acceptable salts and solvates.
Partially similar compounds are known from EP 0 632 016, WO 97/26250, WO 97/24124 or DE 198 31 710.
The invention was based on the object of discovering novel compounds having valuable properties, in particular those which can be used for preparing medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties, coupled with a good tolerability. Above all, they act as integrin inhibitors, and in particular inhibit the interactions of the &agr;v-, &bgr;3-, &bgr;5- or &bgr;6-integrin receptors with ligands, such as, for example, binding of fibrinogen to the integrin receptor.
Integrins belong to the family of heterodimeric class I—transmembrane receptors which play an important role in numerous cell-matrix or cell-cell adhesion processes (Tuckwell et al., 1996, Symp. Soc. Exp. Biol. 47). Roughly, they can be divided into three classes: the &bgr;1-integrins, which are receptors for the extracellular matrix, the &bgr;2-integrins, which are activatable on leukocytes and are triggered during inflammatory processes, and the &agr;v-integrins, which influence the cellular response during wound healing and other pathological processes (Marshall and Hart, 1996, Semin. Cancer Biol. 7, 191). 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 are particularly effective in the case of the integrins &agr;v&bgr;1, &agr;v&bgr;3, &agr;v&bgr;5, &agr;IIb&bgr;3 and also &agr;v&bgr;6 and &agr;v&bgr;8, preferably of &agr;v&bgr;3, &agr;v&bgr;5 and &agr;v&bgr;6, and also &agr;IIb&bgr;3.
&agr;v&bgr;6 is a relatively rare integrin (Busk et al., J. Biol. Chem. 1992, 267(9), 5790) which is increasingly formed during reparation processes in epithelial tissue and which preferably binds the natural matrix molecules fibronectin and tenascin (Wang et al., Am. J. Respir. Cell Mol. Biol. 1996, 15(5), 664). The physiological and pathological functions of &agr;v&bgr;6 are not yet known in detail; however, it is assumed that this integrin plays an important role in physiological processes and disorders (for example inflammations, wound healing, tumours) in which epithelial cells are involved. Thus, &agr;v&bgr;6 is expressed on keratinocytes in wounds (Haapasalmi et al., J. Invest. Dermatol. 1996, 106(1), 42), which indicates that, in addition to wound-healing processes and inflammations, other pathological processes in the skin, such as, for example, psoriasis, bullous pemphigus, dermatitis and erythema, and also cystic fibrosis, endometriosis, cirrhosis of the liver or periodontitis, can also be influenced by agonists or antagonists of said integrin. Furthermore, &agr;v&bgr;6 plays a role in the epithelium of the respiratory tract (Weinacker et al., Am. J. Respir. Cell Mol. Biol. 1995, 12(5), 547) so that it may be possible to use appropriate agonists/antagonists of this integrin successfully for disorders of the respiratory tract, such as bronchitis, asthma, pulmonary fibrosis and tumours of the respiratory tract. Finally, it is known that &agr;v&bgr;6 also plays a role in the intestinal epithelium, so that appropriate integrin agonists/antagonists could be used for treating inflammations, tumours and wounds of the gastrointestinal tract.
It has been found that the compounds of the formula I according to the invention and their salts, as soluble molecules, act on cells carrying the receptor mentioned, or, if they are attached to surfaces, they are artificial ligands for the &agr;v&bgr;6-mediated cell adhesion. Especially, they act as &agr;v&bgr;6 integrin inhibitors, inhibiting in particular the interactions of the receptor with other ligands, such as, for example, binding of fibronectin.
In particular, the compounds according to the invention are potent inhibitors of the vitronectin receptor &agr;v&bgr;3 and/or potent inhibitors of the &agr;v&bgr;6-receptor.
The &agr;v&bgr;3 integrin is expressed on a number of cells, for example endothelial cells, smooth vascular muscle cells, for example of the aorta, cells which degrade the bone matrix (osteoclasts) or tumour cells.
The action of the compounds according to the invention can be demonstrated, for example, using the method described by J. W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271.
In Curr. Opin. Cell. Biol. 1993, 5, 864, B. Felding-Habermann and D. A. Cheresh describe the importance of the integrins as adhesion receptors for various phenomena and symptoms, specifically with respect to the vitronectin receptor &agr;v&bgr;3.
The dependence of the formation of angiogenesis on the interaction between vascular integrins and extra-cellular matrix proteins is described by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 1994, 264, 569-671.
P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Hu, G. Klier and D. A. Cheresh describe, in Cell 1994, 79, 1157-1164 the possibility of inhibiting this interaction, thus initiating apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide. They describe, for example, &agr;v&bgr;3 antagonists or antibodies against &agr;v&bgr;3 which cause tumours to shrink, by initiating apoptosis.
The experimental proof that the compounds according to the invention also prevent adhesion of living cells on the corresponding matrix proteins and, accordingly, also adhesion of tumour cells to matrix proteins can be obtained in a cell adhesion test, analogously to the method of F. Mitjans et al., J. Cell Science 1995, 108, 2825-2838.
In J. Clin. Invest. 1995, 96, 1815-1822, P. C. Brooks et al. describe &agr;v&bgr;3 antagonists for controlling cancer and for treating tumour-induced angiogenic disorders. The compounds are capable of inhibiting binding of metal proteinases to integrins, thus preventing the cells from utilizing the enzymatic activity of the proteinase. An example is given by the inhibition of MMP-2 (matrix metalloproteinase 2) binding to the vitronectin receptor &agr;v&bgr;3 by a cyclo-RGD peptide, as described in P. C. Brooks et al., Cell 1996, 85, 683-693.
It is therefore possible to use the compounds of the formula I according to the invention as medicinally active compounds, in particular for treating tumour disorders, osteoporoses, osteolytic disorders, and for suppressing 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), inhibit, as GPIIb/IIIa antagonists, the spreading of tumour cells by metastasis. This is demonstrated by the following observations:
tumour cells spread

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