Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Reexamination Certificate
2000-06-15
2003-08-26
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
C530S329000, C530S331000, C530S345000, C530S317000, C514S011400, C514S017400, C514S018700
Reexamination Certificate
active
06610826
ABSTRACT:
The invention relates to compounds of the formula I
R—Q—X I
n which
R is cyclo-(Arg-Gly-Asp-Z), where Z is bonded in the side chain to Q, or if Q is absent; to X,
Q is absent, or is —[CO—R
1
—NH—]
m
, —[NH—R
1
—CO—]
m
, —[CO—R
1
—CO—]
m
, —(CO—CH
2
—O—CH
2
CH
2
—O—CH
2
CH
2
—NH—)
n
, —(NH—CH
2
—O—CH
2
CH
2
—O—CH
2
CH
2
—CO—)
n
, —(NH—CH
2
CH
2
—O—CH
2
CH
2
—O—CH
2
—CO—)
n
or —(CO—CH
2
—O—CH
2
CH
2
—O—CH
2
CH
2
—NH—)
n
—[CO—R
1
—NH—]
m
,
X is —CO—CH═CH
2
, —CO—C(CH
3
)═CH
2
, —NH—CH═CH
2
, —NH—C(CH
3
)═CH
2
or —NH—(CH
2
)
p
—SR
10
,
Z is in each case independently of one another an amino acid residue or a di- or tripeptide residue, where the amino acids independently of one another are selected from a group consisting of Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, Homo-Phe, Ile, Leu, Lys, Met, Phe, Phg, Pro, Ser, Thr, Trp, Tyr, Val or M
where the amino acids mentioned can also be derivatized, and the amino acid residues are linked to one another in peptide fashion via the &agr;-amino- and &agr;-carboxyl groups, and
where M is always present,
M is NH(R
8
)—CH(R
3
)—COOH,
R
1
is absent or is R
2
, R
9
, R
2
—R
9
—R
2
, or phenylene which is unsubstituted or mono- or disubstituted by R
5
, where the chain length of R
5
is in each case independent of one another,
R
2
is alkylene having 1-10 C atoms, where 1 or 2 methylene groups can be replaced by S, —CH═CH— or —C≡C—,
R
3
is —R
5
—R
4
, —R
6
—R
4
or —R
7
—R
4
,
R
4
is OH, NH
2
, SH or COOH,
R
5
is alkylene having 1-6 C atoms,
R
6
is alkylenephenylene having 7-14 C atoms,
R
7
is alkylenephenylalkylene having 8-15 C atoms,
R
8
is H, A or alkylenephenyl having 7-12 C atoms,
R
9
is cycloalkylene having 3-7 C atoms,
R
10
is H or an S protective group,
A is alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I
m and n in each case independently of one another are 0, 1, 2 or 3 and
p is 1, 2 or 3,
where, if radicals of optically active amino acids and amino acid derivatives are concerned, both the D and the L forms are included,
and their salts.
Similar cyclic peptide compounds are disclosed in DE 43 10 643 and DE 195 38 741. The compound cyclo-(Art-Gly-Asp-Glu(&egr;-Ahx-Cys-NH
2
)-D-Val) is disclosed by D. Delforge et al. in Anal. Biochem. 242, 180-186 (1996).
The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability. They act especially as integrin inhibitors, where they inhibit, in particular, the interactions of the &agr;
v
-, &bgr;
3
- or &bgr;
5
-integrin receptors with ligands, such as, for example, the binding of fibrinogen to the &bgr;
3
-integrin receptor. The compounds show particular activity in the case of the integrins &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
, &agr;
IIb
&bgr;
3
and also &agr;
v
&bgr;
1
, &agr;
v
&bgr;
6
and &agr;
v
&bgr;
8
.
This action can be demonstrated, for example, by the method which is described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990).
The dependence of the origin 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 264, 569-71 (1994).
The possibility of the inhibition of this interaction and thus for the initiation of 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).
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 confirmed by the following observations: The spread of tumour cells from a local tumour into the vascular system takes place by means of the formation of microaggregates (microthrombi) by interaction of the tumour cells with blood platelets. The tumour cells are screened by the protection in the microaggregates and are not recognized by the cells of the immune system. The microaggregates can collect on vascular walls, whereby further penetration of tumour cells into the tissue is facilitated. Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as efficacious metastasis inhibitors.
The (meth)acrylate radical serves to bond the peptides covalently to biocompatible surfaces of, for example, implants which have free acrylate or methacrylate radicals, such as, for example, poly(methyl methacrylate) moulded articles (bone cements) or acrylate- and methacrylate-containing layers, for example on metal surfaces.
Correspondingly, the thiol radical serves for peptide bonding, for example, to gold surfaces.
The invention therefore relates in particular to the compounds of the formula I for covalent bonding via the functional group of the radical X to biocompatible surfaces.
If X=—NH—(CH
2
)
p
—SR
10
, the functional group which bonds to the surface is the SH radical, i.e. if R
10
=H.
The peptides according to the invention now make possible the biofunctionalization of biomaterials, in particular implants for all conceivable organs, by coating thereof, mainly the adhesion of those cell species being stimulated which in each case are intended to accomplish the tissue integration of the appropriate biomaterial. Using such coatings an accelerated and increased integration of various biomaterials/implants with improved long-term stability can be achieved after introduction thereof into the body.
In this connection, reference is made to the second application filed on the same date by the Applicant, in which suitable biomaterials and the coating thereof with the compounds according to the invention are described.
The peptides according to the invention bind selectively to integrins. After immobilization on biocompatible surfaces, e.g. implants, they stimulate the adhesion of cells which carry integrins. After coating of the compounds on the surfaces, those cell species can be selectively stimulated to bind which are also intended to accomplish the implant integration into the natural tissue after implantation. Thus, for example, osteoblasts, osteoclasts and endothelial cells are &agr;
v
-carrying cell species.
The invention therefore relates to the compounds of the formula I as integrin inhibitors for selective cell enrichment on implants.
After anchorage to a biocompatible surface, the compounds of the formula I can be employed as medicaments in human and veterinary medicine, in particular they can be employed as integrin inhibitors for the treatment of disorders, defects and inflammations caused by implants, such as inadequate and delayed integration of biomaterials and implants, of thrombosis caused by implants, of bone and tooth defects, and also of osteolytic disorders such as osteoporosis, thrombosis, cardiac infarct, arteriosclerosis, in wound healing for assisting the healing process, and also for the acceleration and reinforcement of the integration process of the implant or of the biocompatible surface into the tissue.
The compounds of the formula I can be employed as antimicrobially active substances in operations where biomaterials, implants, catheters or heart pacemakers are used. They have an antiseptic action here. The efficacy of the antimicrobial activity can be demonstrated by the procedure described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The invention thus relates to the compounds of the formula I as integrin inhibitors for the treatment of disorders caused by implants, defects, inflammations and of osteolytic disorders such as osteoporosis, thrombosis, cardiac infa
Finsinger Dirk
Jonczyk Alfred
Kantlehner Martin
Kessler Horst
Meyer Jörg
Low Christopher S. F.
Lukton David
Merck Patent Department
Millen White Zelano & Branigan P.C.
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