Peptide and peptide mimetic conjugates with integrin-inhibitor properties

1. A compound of formula I

B-Q-X 1   1

wherein

B is a bioactive, integrin-binding molecule which is,

(1) cyclo-(Arg-Gly-Asp-Z 1 ) (iv), wherein Z 1 is, in each case independently of one another, an amino acid radical or a di- or tripeptide residue, wherein the amino acid(s) are selected independently of one another, from Ala, Asn, Asp, Arg, Cys, Gln, Glu, Gly, His, homo-Phe, Ile, Leu, Lys, Met, Orn, Phe, Phg, Pro, Ser, Thr, Trp, Tyr, and Val;

(2) wherein

X is H 2 N—C(═NH)—NH, Het-NH—, H 2 N—C(═NH)—, A-C(═NH)—NH— or Het-,

Y is —(CH 2 ) n —,

 (CH 2 ) s —CH(R 4 )—(CH 2 ) t — or (CH 2 ) p -Het 1 -(CH 2 ) q —,

Z is N—R 2 or CH—R 2 ,

R 2 is H or alkyl having 1 to 4 carbon atoms,

R 3 is H, Ar, Het or A,

R 4 is H, A, Ar, OH, OA, OAr, arylalkyl, Hal, CN, NO 2 , CF 3 or OCF 3 ,

A is COOH, NH 2 or alkyl having 1-6 carbon atoms, which is unsubstituted or substituted by COOH or NH 2 ,

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 is optionally substituted by phenyl, which is mono-, di- or trisubstituted by A, OH, OA, NH 2 , OCF 3 , CN, NO 2 or Hal in such a way as to give unsubstituted or substituted biphenyl,

Hal is F, Cl, Br or I,

Het is a saturated or partially or fully unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, 1 to 3 N atoms and/or 1 S or O atom(s) and the heterocyclic radical can be mono- or disubstituted by CN, Hal, OH, NH 2 , COOH, OA, CF 3 , A, NO 2 , Ar or OCF 3 ,

Het 1 is a 5- or 6-membered aromatic heterocycle having 1 to 4 N and/or S atoms, which is optionally unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA or OCF 3 ,

n is 4, 5 or 6,

m, o, p, and q are, each independently, 0, 1 or 2,

s, and t are, each independently, 0, 1, 2, 3, 4 or 5;

(3) Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys (vi), (SEQ. ID. NO. 1);

(4) Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys (vii), (SEQ. ID. NO. 2);

(5) Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys (viii), (SEQ. ID. NO. 3);

(6) Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg (ix), (SEQ. ID. NO. 4);

(7) Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn (x), (SEQ. ID. NO. 5); or

(8) Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg (xi), (SEQ. ID. NO. 6);

Q is absent or is an organic spacer molecule which is

[CO—(CH 2 ) x —NH—] m   (xii)

[CO—CH 2 (—O—CH 2 CH 2 ) y —] m   (xiii)

[CO—(CH 2 ) z —CO—]  (xiv)

[NH—(CH 2 ) z —NH—]  (xv)

[CO—CH 2 —(OCH 2 CH 2 ) y —O—CH 2 —CO—]  (xvi) or

[NH—CH 2 CH 2 —(OCH 2 CH 2 ) y —NH—]  (xvii)

 or a combination thereof,

wherein

m in each case independently of one another is 1-20,

x is 1-12,

y is 1-50, and

z is 1-12, and

X 1 is an anchor molecule, which is

-Lys-(CO—CH 2 —(CH 2 ) n —(PO 3 H 2 ) 2   (i)

-Lys-[Lys-(CO—CH 2 —(CH 2 ) n —PO 3 H 2 ) 2 ] 2   (ii) or

-Lys-(Lys[-Lys-(CO—CH 2 —(CH 2 ) n —PO 3 H 2 ) 2 ] 2   (iii),

wherein n, in each case independently of one another, is 0, 1, 2 or 3,

and wherein a free amino group in group B is linked in a peptide-like manner to a free carboxyl group in group Q or in group X 1 ,

or a free amino group of the group Q is linked in a peptide-like manner to a free carboxyl group of the radical X 1 , or a salt thereof or a stereoisomer thereof.

2. A compound according to claim 1 , wherein Q is

[CO—(CH 2 ) x —NH—] m   (xviii)

[CO—CH 2 (—O—CH 2 CH 2 ) y —NH—] m   (xix)

[CO—(CH 2 ) z —CO—]  (xx)

[NH—(CH 2 ) z —NH—]  (xxi)

[CO—CH 2 —(OCH 2 CH 2 ) y —O—CH 2 —CO—]  (xxii) or

[NH—CH 2 CH 2 —(OCH 2 CH 2 ) y —NH—]  (xxiii)

or a combination thereof,

wherein

m is 1-8,

x is 1-5,

y is 1-6, and

z is 1-6,

or a salt thereof or a stereoisomer thereof.

3. A compound according to claim 1 which is

a) Cyclo(Arg-Gly-Asp-DPhe-Lys( ε NH—[CO—(CH 2 ) 5 —NH] 2 -Lys-[Lys-(CO—CH 2 —(CH 2 ) n —PO 3 H 2 ) 2 ] 2 ));

b) Cyclo(Arg-Gly-Asp-DPhe-Lys( ε NH—[CO—(CH 2 ) 5 —NH] 3 -Lys-[Lys-(CO—CH 2 —(CH 2 ) n —PO 3 H 2 ) 2 ] 2 ; or

c) Cyclo(Arg-Gly-Asp-DPhe-Lys( ε NH—[CO—CH 2 (—O—CH 2 CH 2 ) 6 —NH] 2 -Lys-[Lys-(CO—CH 2 —(CH 2 ) n —PO 3 H 2 ) 2 ] 2 ));

wherein n is 1.

4. A medicament which comprises a compound of Formula I according to claim 1 and a carrier.

5. An implant which is suitable for human and animal organs, consisting of a carrier matrix and a layer of a bioactive, cell adhesion-mediating molecule surrounding said matrix, wherein a surrounding layer comprises a compound of Formula I according to claim 1 , and wherein said carrier matrix and said compound of Formula I are bound via an ionic or adsorptive bond.

6. An implant according to claim 5 , wherein the carrier matrix and/or a surface thereof is a metal or a metal oxide.

7. An implant according to claim 5 , wherein the carrier matrix and/or a surface thereof is a bone or tooth substitute material.

8. An implant according to claim 7 , wherein the bone or tooth substitute material consists of calcium phosphate mixtures.

9. A process for the preparation of a compound according to claim 1 comprising

linking, in a peptide-like manner, a bioactive molecule B optionally comprising a protective group with a spacer-anchor molecule (Q-X 1 ) or an anchor molecule (X 1 ), wherein said Q-X 1 and said X 1 groups comprise one or more protective groups;

removing said protective groups; and optionally

converting a basic or acidic compound of Formula I to a salt thereof by treating with an acid or base.

10. A method of treating a disorder, defect or inflammation caused by implants, comprising administering to a subject in need thereof, a compound according to claim 1 .

11. A method for the treatment of an osteolytic disorder, thrombosis, cardiac infarct, or arteriosclerosis, comprising administering to a subject in need thereof, a compound according to claim 1 .

12. A method for the acceleration and strengthening of the integration process of the implant or of the biocompatible surface into the tissue, comprising administering to a subject in need thereof, a compound according to claim 1 .