Adhesion receptor antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S376000, C544S369000, C546S209000, C548S232000

Reexamination Certificate

active

06602876

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to novel oxazolidinone derivatives of the formula I
wherein
R
1
is
R
2
is H, A, Ac, A—SO
2
—, Ar—SO
2
— or a conventional amino protective group,
R
3
is H, A, cycloalkyl having 3 to 7 C atoms, Ar or Ar—(CH
2
)
k
—,
A is alkyl having 1 to 16 C atoms,
B is H, A or H
2
N—C(═NH)—,
D is H
2
N—CH
2
—, H
2
N—C(═NH)— or H
2
N—C(═NH)—NH—CH
2
—, where the primary amino groups can also be provided with conventional amino protective groups,
Ac is alkanoyl having 1 to 10 C atoms or aroyl having 7 to 11 C atoms,
Ar is phenyl which is unsubstituted or mono- or disubstituted by A, Cl, Br, I, OA, OH, NO
2
, CN, NH
2
, NHA and/or NA
2
, or benzyl,
m is 0, 1, 2, 3 or 4,
n is 2, 3 or 4 and
k is 1, 2, 3 or 4,
and their physiologically acceptable salts.
Similar compounds are disclosed in EP-A1-0 381 033.
An object of the invention is to provide novel compounds having useful properties, in particular those which can be used for the production of medicaments.
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.
These objects are achieved by the invention. It was found that the compounds of the formula I, and their solvates and salts, have useful pharmacological properties together with good tolerability. The compounds have integrin inhibiting effects, in particular they inhibit interaction of &bgr;
3
- or &bgr;
5
-integrin receptors with ligands. Especially, they affect the a
v
&bgr;
3
, a
v
&bgr;
5
and a
IIb
&bgr;
3
integrins. The activity of the compounds can be demonstrated, for example, by the method of J. W. Smith et al., described in J. Biol. Chem. 265:12267-12271 (1990). In particular, they inhibit the binding of fibrinogen, fibronectin and of the von Willebrand factor to the fibrinogen receptor of the blood platelets (glycoprotein IIb/IIIa) and also the binding thereof and of further adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. The compounds thus affect cell-cell and cell-matrix interactions. In particular, they prevent the formation of blood platelet thrombi and can therefore be used for the treatment of thromboses, apoplexia, cardiac infarct, angina pectoris, osteolytic diseases, in particular osteoporosis, anti-angiogenesis and restenosis after angioplasty, ischaemias, inflammations, arteriosclerosis and of acute kidney failure. The compounds also have an effect on tumor cells by inhibiting their metastasization. They can thus also be employed as antitumor agents.
There are indications that tumor cells pass into the vessels by means of microthrombi and are thus protected from detection by cells of the immune system. Microthrombi also have a supportive effect on the binding of tumor cells to the vessel walls. Since the formation of the microthrombi is connected with the fibrinogen binding to the fibrinogen receptor (glycoprotein IIb/IIIa), fibrinogen binding inhibitors likewise count as metastasis inhibitors.
Also, since fibrinogen-binding inhibitors are ligands with fibrinogen receptor on platelets, they can be used as diagnostic tools for detection and localization of thrombi in the vascular in vivo. Thus, for example, in accordance with known procedures, the fibrinogen-binding inhibitors can be labeled with a signal generating or detectable moiety whereby, once the labeled fibrinogen-binding inhibitor is bound to a fibrinogen receptor on platelets, it is possible to detect and locate thrombi.
Fibrinogen-binding inhibitors are also very effective as research tools for studying the metabolism of platelets in the different activation states or intracellular signalling mechanisms of the fibrinogen receptor. For example, as described above, fibrinogen-binding inhibitor can be labeled with a signal generating or detectable moiety. The fibrinogen-binding inhibitor-signal generating/detectable moiety conjugate can then be employed in vitro as a research tool. By binding the conjugate to fibrinogen receptors, it is possible to monitor and study the metabolism of platelets, as well as the activation states and signalling mechanisms of the fibrinogen receptors.
The compounds are additionally suitable as antimicrobial agents which can prevent infections, such as can be caused, for example, by bacteria, fungi or yeasts. The substances can therefore preferably be given as accompanying antimicrobial agents when operations on bodies are performed in which exogenous substances, such as biomaterials, implants, catheters or cardiac pacemakers, are employed. 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 which are described in EP-A1-0 462 960. The inhibition of fibrin binding to the fibrinogen receptor can be demonstrated by the method which is indicated in EP-A1-0 381 033. The platelet aggregation-inhibiting action can be demonstrated in vitro by the method of Born (Nature, 4832:927-929 (1962)).
The invention also relates to a process for the preparation of a compound of the formula I indicated, and of its salts, characterized in that
(a) a compound of the formula I is liberated from one of its functional derivatives by treating with a solvolyzing or hydrogenolyzing agent, or in that
(b) a compound of the formula II
 wherein
Z is Cl, Br, I, OH or a reactive esterified OH group, and
R
1
has the meaning indicated above,
is reacted with a compound of the formula III
 wherein
R
2
and R
3
have the meanings indicated and
X is OH or a salt-like radical derivable from OH, or in that
(c) a compound of the formula IV
 wherein
R
1
R
2
and R
3
have the meanings indicated,
is reacted with a reactive derivative of carbonic acid, or in that
(d) a compound of the formula V
 wherein
R
2
and R
3
have the meanings indicated, is reacted with a compound of the formula VI
 wherein
B has the meaning indicated and
Y is
 wherein
m and n have the meanings already indicated and
X′ is Cl, Br, I or another, easily nucleophilically displaceable leaving group,
 or in that
(e) for the preparation of a guanidinomethyl compound of the formula I (R
1
=a phenyl radical monosubstituted by H
2
N—C(═NH)—NH—CH
2
—), an amino compound corresponding to the formula I, but which instead of the radical R
1
contains an aminomethylphenyl group, is treated with an amidinating agent, or in that
(f) a radical R
3
is converted into another radical R
3
by hydrolyzing an ester of the formula I, or by esterifying a carboxylic acid of the formula I, or in that
(g) (a) radical(s) R
1
and/or R
2
is (are) converted into (a) other radical(s) R
1
and/or R
2
, and/or in that
(h) a compound of the formula I is converted into one of its salts by treating with an acid or base.
The compounds of the formula I have at least one chiral center and can therefore occur in several enantiomeric forms. All these forms (e.g. D- and L-forms) and their mixtures (e.g. the DL-forms) are included in the formula I.
Hereinbefore and hereinafter, the radicals or parameters A, B, D, X, Y, Z, R
1
to R
3
, Ac, Ar, k, m and n have the meanings indicated in the formulae I to VI if not expressly stated otherwise. If several groups designated as identical are present in the molecule, they can assume various definitions independently of one another.
In the above formulae, the group A has 1-6, preferably 1, 2, 3 or 4, C atoms. Specifically, A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, or 1-, 2-, 3- or 4- methylpentyl.
R
1
is preferably a phenyl radical substituted in the 4-position, but also substituted in the 2- or 3-position as indicated, specifically preferably 2-, 3- or (in particular) 4-aminomethylp

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