Peptide and peptide mimetic derivatives with integrin-inhibitors properties II

1. A compound of formula I

B-Q-X 1   I

in which

B is a bioactive, cell adhesion-mediating molecule of formula (i), (ii) (SEQ ID NO 1), (iii) (SEQ ID NO 2), (iv) (SEQ ID NO 3), (v) (SEQ ID NO 4), (vi) (SEQ ID NO 5), or (vii) (SEQ ID NO 6),

Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys

(ii)

Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys

(iii)

Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys

(iv)

Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg

(v)

Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn

(vi)

Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg

(vii),

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 C 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 C 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, NH 2 , OA, CF 3 , OCF 3 , CN, NO 2 or Hal, which can be substituted by a phenyl which is mono-, di- or trisubstituted by A, OH, OA, OCF 3 , CN, NO 2 or Hal in such a way that an unsubstituted or substituted biphenyl results,

Hal is F, Cl, Br or I,

Het is a saturated, partly or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 to 3 N and/or an S or O atom(s) can be present 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 can be 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 0, 1 or 2,

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

Q is absent or is of formula (xvii), (xviii), (xix), (xx), (xxi), or (xxii),

[CO—(CH 2 ) x —NH—] m,

(xvii)

[CO—CH 2 —(O—CH 2 CH 2 ) y —NH—] m,

(xviii)

[CO—(CH 2 ) z —CO—]

(xix)

[NH—(CH 2 ) z —NH—]

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

(xxi)

[NH—CH 2 CH 2 —(OCH 2 CH 2 ) y —NH—]

(xxii)

or a combination thereof,

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

x is 1 to 12,

y is 1 to 50, and

z is 1 to 12,

X 1 is an anchor molecule of formula (viii), (ix), (x), (xi), (xii), (xiii) or (xiv),

—CO—CH═CH 2

(viii)

—CO—(CH 2 ) 1-20 —CO—CH═CH 2

(ix)

—CO—(CH 2 ) 1-20 —SH

(x)

—CO—CH(NH 2 )—CH 2 —SH

(xi)

—NH—(CH 2 ) 1-20 —CO—CH═CH 2

(xii)

—NH—(CH 2 ) 2-20 —SH

(xiii)

—NH—CH(CO 2 H)—CH 2 —SH

(xiv),

where

in the case of the compounds with anchor molecules (viii) to (xi), a free amino group of the group B is linked by forming a peptide bond with a free carboxyl group of the spacer molecule Q or of the anchor molecule X 1 , or a free amino group of the radical Q is linked by forming a peptide bond with a free carboxyl group of the radical X 1 is linked to one another, and

in the case of the compounds with anchor molecules (xii) to (xiv), a free carboxyl group of the group B is linked by forming a peptide bond with a free amino group of the spacer molecule Q or of the anchor molecule X 1 , or a free carboxyl group of the radical Q is linked by forming a peptide bond with a free amino group of the radical X 1 ,

or a salt thereof.

2. A compound according to claim 1 , in which Q is of formula (xvii), (xviii), (xix), (xx), (xxi), or (xxii),

[CO—(CH 2 ) x —NH—] m,

(xvii)

[CO—CH 2 —(O—CH 2 CH 2 ) y —NH—] m,

(xviii)

[CO—(CH 2 ) z —CO—]

(xix)

(NH—(CH 2 ) z —NH—]

(xx)

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

(xxi)

[NH—CH 2 CH 2 —(OCH 2 CH 2 ) y —NH—]

(xxii)

or a combination thereof,

in which

m in each case independently of one another is 1 to 8,

x is 1 to 5,

y is 1 to 6and

z is 1 to 6.

3. A compound according to claim 1 , which is a compound of formula a), b) (SEQ ID NO 7), c) (SEQ ID NO 8), d) (SEQ ID NO 9), e) (SEQ ID NO 10), e) (SEQ ID NO 11), or f) (SEQ ID NO 12),

b)

Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys-Aca-Aca-Cys

c)

Cys-Aca-Aca-Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys

d)

Lys-Ile-Ala-Phe-Gln-Arg-Asn-Arg-Lys-Aca-Aca-Cys

e)

Cys-Aca-Aca-Thr-Trp-Tyr-Lys-Ile-Ala-Phe-Gln-Arg

f)

Phe-Gln-Arg-Asn-Arg-Lys-Aca-Aca-Cys

g)

Cys-Aca-Aca-Thr-Trp-Tyr-Lys-Ile-Ala.

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. An implant, which is suitable for a human or an animal organ, consisting essentially of a carrier matrix and a layer of a bioactive, cell adhesion-mediating molecule of formula I according to claim 1 surrounding this matrix, wherein a covalent bond or adsorptive binding is present between the carrier matrix and the compound of formula I.

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

7. An implant according to claim 5 , wherein the carrier matrix and/or its surface is a polymer.

8. An implant according to claim 7 , wherein characterized in that the polymer is polymethyl methacrylate, polyhydroxyethyl methacrylate or copolymers thereof.

9. A process for preparing a compound of the formula I according to claim 1 , or a salt thereof, comprising:

conjugating via a peptide bond a bioactive molecule B, with protecting groups, and a spacer-anchor molecule (Q-X 1 ) or an anchor molecule (X 1 ) with protecting groups;

removing the protecting groups; and

optionally converting a basic or acidic compound of the formula I into one of its salts by treating with an acid or base.

10. A method for treating a disorder, defect or inflammation caused by an implant, or for treating an osteolytic disorder, osteoporosis, thrombosis, cardiac infarct or arteriosclerosis or for the acceleration and strengthening of an integration process of an implant or of a biocompatible surface into a tissue, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1 .

11. A method of preparing an implant for a human or an animal organ comprising coating said implant with a compound of formula I according to claim 1 , wherein the compound of formula I binds to the implant by covalent bond or by adsorptive binding.