Adhesion receptor antagonists

Details Adhesion receptor antagonists Adhesion receptor antagonists

1996-05-03

2002-09-24

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S254020, C514S326000, C514S221000, C514S252110, C514S253010, C514S316000, C514S330000, C514S331000, C514S392000, C514S424000, C514S616000, C544S364000, C544S369000, C544S357000, C544S360000, C546S209000, C546S191000, C546S226000, C546S231000, C548S229000, C548S230000, C548S232000, C548S550000, C540S513000

Reexamination Certificate

active

06455529

ABSTRACT:

The invention relates to novel adhesion receptor antagonists of the formula I
in which
R is
 with
B=CH
2
, CO or CS, R
10
=OH or H and
m=0, 1, 2, 3 or 4;
 with
B=CH
2
, CO or CS, U=CH
2
or CO,
R
9
=H, CO
2
H or CO
2
A and q=0, 1, 2 or 3;
 with
n=1, 2, 3 or 4;
 with
R
4
=H, A—SO
2
, Ar—SO
2
, A—CO, Ar—CO or
Het—CO;
 with
R
5
=H, A, alkynyl or alkenyl with in each
case 2-5 C atoms, or Ar;
 with
D, E, F and G each, independently of one another, CH or N and
k and 1 each, independently of one another, 0, 1, 2, 3 or 4, where k=0 is excluded when E and F are each N and 1=0 is excluded when G=N;
where AA is an amino acid residue selected from a group consisting of residues of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val, which is bonded by peptide linkages;
 with
R
6
=H or A and
m in each case independently of one another 0, 1, 2, 3 or 4;
 with
R
7
=OH, OA, OAr, OHet, NHOH, NH
2
, NHA or NA
2
,
R
8
=H or A and
n in each case independently of one another 1, 2, 3 or 4; or
 where R
4
has the meaning already indicated under (d), and p is 2, 3, 4, 5 or 6;
R
1
is H, A, Ar—CO, A—CO, OH, OA or AO—CO;
R
2
is OH, OA, OAr, OHet, NHOH, NH
2
, NHA or NA
2
;
R
3
is A—CO, Ar—CO, Het—CO, Het—O—CO, Ar—O—CO, A—O—CO, Ar—SO
2
or A—SO
2
;
A is alkyl with 1 to 6 C atoms;
Ar is aryl of 6 to 10 C atoms, e.g., phenyl, naphthyl, or diphenylmethyl or benzyl, which are unsubstituted or substituted once, twice or three times by A, F, Cl, Br, I, OA, —O—CH
2
—O—, COOA, COOH, CF
3
, OH, NO
2
, CN, O—CO—A, NH
2
, NHA or NA
2
, and
Het is a mono- or binuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and/or S atoms, which can be unsubstituted or substituted once by F, Cl, Br, CF
3
, A, OH, OA, CN or NO
2
,
and their physiologically acceptable salts and solvates.
Similar compounds are disclosed in EP-A1-0 623 615 (DE 43 14 378).
The invention has an object of finding novel compounds with valuable properties, in particular those which can be used to produce pharmaceuticals.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
This object has been achieved by the invention. It has been found that the compounds of the formula I and their solvates and salts have valuable pharmacological properties while being well tolerated. In particular, they act as integrin inhibitors, and they inhibit, in particular, the interactions of the &bgr;
3
or &bgr;
5
integrin receptors with ligands. The compounds show particular activity in the case of the integrins &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
and &agr;
IIb
&bgr;
3
. This effect can be demonstrated, for example, by the method described in J. W. Smith et al. in J. Biol. Chem., 2265, 12267-12271 (1990). In particular, they inhibit the binding of fibrinogen, fibronectin and von-Willebrand factor to the fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa) and the binding thereof and of other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various types of cells. The compounds thus influence cell-cell and cell-matrix interactions. They prevent, in particular, the development of blood platelet thrombi and can therefore be used for the treatment of thromboses, stroke, myocardial infarct, angina pectoris, osteolytic disorders, especially osteoporosis and restenosis after angioplasty, ischemias, inflammations, arteriosclerosis and acute kidney failure, for example. The compounds inhibit or prevent vessel development and thus also show an antiangiogenetic effect. The compounds furthermore have an effect on tumor cells by inhibiting metastasis thereof. They can thus also be used as antitumor agents.
There is evidence that tumor cells gain access to vessels through microthrombi and thus are protected from detection by the cells of the immune system. Likewise, microthrombi act to assist the binding of tumour cells to vessel walls. Since the formation of microthrombi is connected with the binding of fibrinogen to the fibrinogen receptor (glycoprotein IIb/IIIa), fibrinogen binding inhibitors are regarded as also being metastasis inhibitors. Their antiangiogenetic capabilities mean that they prevent tumor cells from being supplied with blood and nutrients.
The compounds are additionally suitable as antimicrobial agents which are able to prevent infections like those caused, for example, by bacteria, fungi or yeasts. The substances can therefore be preferably given as concomitant antimicrobial agents when interventions are performed on organisms in which exogenous substances such as, for example, biomaterials, implants, catheters or cardiac pacemakers are inserted. They act as antiseptics. Antimicrobial activities of the compounds can be demonstrated, for example, by the method of P. Valentin-Weigand et al., described in Infection and Immunity, 2851-2855 (1988).
The other properties of the compounds can be demonstrated by methods described in EP-A1-0 462 960. Inhibition of the binding of fibrin 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 furthermore relates to a process for the preparation of a compound of the stated formula I and of its salts, characterized in that
(i) a compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolyzing or hydrogenolyzing agent, or in that
(ii) a compound of the formula II
 in which
R, R
1
and R
2
have the stated meanings, is reacted with a compound of the formula III
R
3
—X  III,
 in which
R
3
has the stated meaning, and
X is OH, F, Cl, Br, I or another easily displaceable leaving group, or in that
(iii) to prepare a compound of the formula I with R=(a), (b), (c) or (d),
a compound of the formula IV
 above,
R* is
 where R
1
and R
3
, as well as B, have the meanings stated above, and
Z is Cl, Br, I, OH or a reactively esterified OH group,
is reacted with a compound of the formula Va
 in which
Y is —CH—(CH
2
)
m
—COR
2
, —N—CHR
9
—(CH
2
)
q
—COR
2
or —N—(CH
2
)
n
—COR
2
, where U, R
2
, R
9
, m, q and n have the meanings stated above,
or with a compound of the formula Vb
 in which
L is —(CH
2
)
n
—COR
2
or —CH
2
—CH(NHR
4
)—COR
2
, where R
2
, R
4
and n have the meanings stated above, and
X′ is OH or a salt-like radical which can be derived from OH, or in that
a compound of the formula VI
 in which
T is
 or
 where B, L, U and Y, and
R
1
and R
3
have the meanings already stated, is reacted with a reactive derivative of carbonic acid, or in that
(iv) to prepare a compound of the formula I with R=(e), (f), (g), (h), (i) or (k), a compound of the formula VII
 in which
R
1
and R
3
have the meanings already stated, and
M is
 —NR
6
H or —CONR
8
H, where D, E, F, X, X′, AA, R
6
, R
8
and k have the meanings already stated,
is reacted with a compound of the formula VIII
R
2
—CO—Q  VIII,
 in which
R
2
has the stated meaning, and
Q is
—CH
2
—CHR
5
—NHCO—(CH
2
)
2
—COX, —CH
2
—CHR
5
—NH
2
,
where F, G, X, R
5
, R
7
, AA, k, l, m and n have the meanings already stated, or in that
(v) to prepare a compound of the formula I with R=(1), a compound of the formula IX
 in which
R
1
, R
3
, X and p have the stated meanings,
is reacted with a compound of the formula X
 in which
R
2
, R
4
and X′ have the stated meanings,
or in that to prepare a compound of the formula I, in a compound which corresponds per se to the formula I
(vi) a radical R
1
is converted into a different radical R
1
by
alkylation or acylation, or in that
(vii) a radial R
2
is converted into a different radical R
2

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