Bicyclic amino acids

Details Bicyclic amino acids Bicyclic amino acids

2001-04-26

2003-05-06

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S311000, C514S312000, C514S315000, C514S456000, C514S452000, C544S049000, C544S106000, C544S349000, C544S353000, C546S152000, C546S153000, C549S357000, C549S377000

Reexamination Certificate

active

06559144

ABSTRACT:

The invention relates to compounds of the formula I
in which
R
1
is H, alkyl having 1-6 C atoms or benzyl,
R
2
is R
10
, CO—R
10
, COOR
6
, COOR
10
, SO
2
R
6
or SO
2
R
10
,
R
3
is H, Hal, OA, NHR
10
, N(R
10
)
2
, —NH-acyl, —O-acyl, CN, NO
2
, OR
10
, SR
10
, R
2
or CONHR
10
,
R
4
is H, ═O, ═S, C
1
-C
6
-alkyl or acyl,
R
5
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 can be mono-, di- or trisubstituted by R
10
, CO—R
10
, COOR
10
or SO
2
R
10
, or R
6
,
R
7
, R
8
are each independently of one another absent or H,
R
7
and R
8
together are also a bond,
X, Y are each independently of one another ═N—, —N—, O, S, —CH
2
— or ═C—, with the proviso that at least one of the two definitions X, Y is ═N—, —N—, O or S,
W, z are each independently of one another absent, O, S, NR
1
, C(═O), CONH, NHCO, C(═S)NH, NHC (═S), C (═S), SO
2
NH, NHSO
2
or CA═CA′,
R
6
is a mono- or binuclear heterocycle which has 1 to 4 N, O and/or S atoms and can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO—A, OH, CN, COOH, COOA, CONH
2
, NO
2
, ═NH or ═O,
R
9
is H, Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO
2
, SA, SOA, SO
2
A, SO
2
Ar or SO
3
H,
R
10
is H, A, Ar or aralkyl having 7-14 C atoms,
R
11
is H or alkyl having 1-6 C atoms,
A, A′ are each independently of one another H or unsubstituted or mono-, di- or tri-R
9
-substituted alkyl or cycloalkyl, each of which has 1-15 C atoms and in which one, two or three methylene groups can be replaced by N, O and/or S,
Ar is unsubstituted or mono-, di- or tri-A-and/or R
9
-substituted mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms,
Hal is F, Cl, Br or I and
m, n are each independently of one another 0, 1, 2, 3 or 4,
and the physiologically acceptable salts thereof.
Similar compounds are disclosed, for example, in WO 94/29273, WO 96/00730 and WO 96/18602.
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, inhibiting in particular 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 effect 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). B. Felding-Habermann and D. A. Cheresh describe, in Curr. Opin. Cell. Biol. 5, 864 (1993), the significances of the integrins as adhesion receptors for a wide variety of phenomena and pathological states, specifically relating to the vitronectin receptor &agr;
v
&bgr;
3
.
The dependence of the initiation 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 inhibiting this interaction and thus initiating 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).
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 by a cell adhesion assay carried out in analogy to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).
P. C. Brooks et al. describe, in J. Clin. Invest. 96, 1815-1822 (1995), &agr;
v
&bgr;
3
antagonists for controlling cancer and for treating tumour-induced angiogenic disorders. The compounds of the formula I according to the invention can therefore be employed as pharmaceutical agents, in particular for treating oncoses, osteoporoses and 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) prevent, as GPIIb/IIIa antagonists, the spread of tumour cells by metastasis. This is proved by the following observations: The spread of tumour cells from a local tumour into the vascular system takes place by formation of microaggregates (microthrombi) by the tumour cells interacting 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 become attached to vessel walls, facilitating further penetration of tumour cells into the tissue. Since the formation of microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as effective metastasis inhibitors.
Compounds of the formula I inhibit not only the binding of fibrinogen, fibronectin and Willebrand factor to the fibrinogen receptor of the blood platelets but also the binding of other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various types of cells. They prevent, in particular, the development of blood platelet thrombi and can therefore be employed to treat thromboses, stroke, myocardial infarct, inflammations are 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 platelet aggregation-inhibiting effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
The invention accordingly relates to compounds of the formula I according to claim 1 and/or their physiologically acceptable salts for producing a pharmaceutical for use as integrin inhibitors. The invention particularly relates to compounds of the formula I according to claim 1 and/or their acceptable salts in which R
2
is camphor-10-sulfonyl for producing a pharmaceutical for controlling pathologically angiogenic disorders, tumours, osteoporosis, inflammations and infections.
The compounds of the formula I can be employed as pharmaceutical agents in human and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarct, arteriosclerosis, inflammations, stroke, angina pectoris, oncoses, osteolytic disorders such as osteoporosis, pathologically angiogenic disorders such as, for example, inflammations, ophthalmological disorders, 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 to assist the healing processes.
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 have an antiseptic effect in such cases. The efficacy 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 invention furthermore relates to a process for preparing compounds of the formula I according to claim 1 and salts thereof, characterized
a) in that a compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
or

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