Cyclopeptide derivatives

Details Cyclopeptide derivatives Cyclopeptide derivatives

1998-08-18

2003-05-20

Borin, Michael (Department: 1634)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

C514S009100, C514S011400

Reexamination Certificate

active

06566491

ABSTRACT:

The invention relates to compounds of the formula I
R
1
—Q
1
—X—Q
2
—R
2
  I
in which
Q
1
, Q
2
are, in each case independently of each other, either absent or —NH—(CH
2
)
n
—CO—,
R
1
, R
2
are, in each case independently of each other, either absent or cyclo-(Arg-Gly-Asp-Z)(SEQ ID NO: 173), where Z is bonded in the side chain to Q
1
or Q
2
or, if Q
1
and/or Q
2
is/are absent, to X, and
where at least one of the radicals R
1
or R
2
must always be present,
X is —CO—R
18
—CO—, and if R
1
—Q
1
— or R
2
—Q
2
— is absent, R
10
, R
13
, R
16
, Het-CO or a fluorescent dye residue which is linked by way of a —CONH—, —COO—, —NH—C(═S)—NH—, —NH—C—(O)—NH—, —SO
2
NH— or —NHCO— bond,
Z is, in each case independently of each other, an amino acid residue or a di-, tri- or tetra-peptide residue, where the amino acids are selected, independently of each other, from a group consisting of Ala, Asn, Asp, Arg, Cys, Gin, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Val or M,
where the said amino acids can also be derivatized and the amino acid residues are linked to each other, in peptide manner, by way of the &agr;-amino and &agr;-carboxyl groups, and
where M is always present,
M is NH(R
8
)—CH(R
3
)—COOH,
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 carbon atoms,
R
6
is alkylenephenylene having 7-14 carbon atoms,
R
7
is alkylenephenylalkylene having 8-15 carbon atoms,
R
8
is H, A or alkylenephenyl having 7-12 carbon atoms,
A is alkyl having 1-6 carbon atoms,
R
10
is alkanoyl having 1-18 carbon atoms which is unsubstituted or substituted once by COOH, COOA, SR
11
or NR
12
R
12
,
R
11
is H or trityl, pyridyl-2-thio or alkylthio having 1-6 carbon atoms,
R
12
, R
12
′ are, in each case independently of each other, H, alkyl having 1-8 carbon atoms or an amino-protecting group,
R
13
is aroyl having 7-11 carbon atoms which is unsubstituted or substituted once or twice by alkyl having 1-6 carbon atoms, alkoxy having 1-4 carbon atoms, alkanoyl having 1-8 carbon atoms, Hal, SR
14
or NR
15
R
15
′,
R
14
is H or A,
R
15
, R
15
′ are, in each case independently of each other, H or A,
R
16
is aralkanoyl having 7-19 carbon atoms which is unsubstituted or substituted once, twice or three times in the aryl moiety by Hal, alkoxy having 1-6 carbon atoms or OH and in which the aryl moiety can also be a
 group,
E is CH
2
or O,
D is carbonyl or [C(R
17
R
17
′)]
m
,
R
17
, R
17
′ are, in each case independently of each other, H or A,
R
18
is absent, or is R
19
, R
20
, R
19
—R
20
—R
19
, or phenylene which is unsubstituted or substituted once or twice by R
5
, where the chain length of R
5
is in each case independent of each other,
R
19
is alkylene having 1-8 carbon atoms, where 1 or 2 methylene groups can be replaced by S, —CH═CH— or —C≡C—,
R
20
is cycloalkylene having 3-7 carbon atoms,
Hal is F, Cl, Br or I,
Het is a mononuclear or binuclear saturated, unsaturated or aromatic heterocycle having from 1 to 4 N, O and/or S atoms, bonded via N or C, which can be unsubstituted or substituted once, twice or three times by Hal, A, R
3
, NR
4
R
4
′, CN, NO
2
and/or carbonyl oxygen,
n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and
m is 1 or 2,
where, provided that the residues are residues of optically active amino acids and amino acid derivatives, both the D and the L forms are included, and the salts thereof.
Similar compounds of cyclic peptides are disclosed in DE 43 10 643.
The invention was based on the object of discovering novel compounds possessing valuable properties, in particular those compounds which can be used for preparing pharmaceuticals.
It was found that the compounds of the formula I, and their salts, possess very valuable pharmacological properties while being well tolerated. In particular, they act as integrin inhibitors, in which connection they particularly inhibit the interactions of the &agr;
v
-, &bgr;
3
- or &bgr;
5
-integrin receptors with ligands, such as the binding of fibrinogen to the &bgr;
3
-integrin receptor. The compounds exhibit particular activity in the case of the &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
and &agr;
IIb
&bgr;
3
integrins and also the &agr;
v
&bgr;
1
, &agr;
v
&bgr;
6
and &agr;
v
&bgr;
8
integrins. This effect can be demonstrated, for example, using the method described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). PC Brooks, R. A. Clark and D. A. Cheresh have reported, in Science 264, 569-71 (1994), that the development of angiogenesis depends on the interaction between vascular integrins and extracellular matrix proteins.
The possibility of using a cyclic peptide to inhibit this interaction, and thereby initiate apoptosis (programmed cell death) of angiogenic vascular cells, has been 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 that of fibrinogen to the fibrinogen receptor (Glycoprotein IIb/IIIa), prevent, as GPIIb/IIIa antagonists, the spread of tumour cells as a result of metastasis. This is substantiated by the following observations:
The compounds can inhibit the binding of metalloproteinases to integrines and thereby prevent the cells from being able to use the enzymatic activity of the proteinase. An example is provided by the ability of a cyclo-RGD peptide to inhibit the binding of MMP 2 (matrix metalloproteinase 2) to the vitro-nectin receptor &agr;
v
&bgr;
3
, as described in P. C. Brooks et al., Cell 85, 683-693 (1996).
The spread of tumour cells from a local tumour into the vascular system takes place by the formation of microaggregates (microthrombi) as a result of the interaction of the tumour cells with blood platelets. The tumour cells are shielded as a result of the protection afforded by the microaggregate and are not recognized by the cells of the immune system. The microaggregates can settle on vessel walls, thereby facilitating further penetration of tumour cells into the tissue. Since the formation of the microthrombi is mediated by the binding of fibrinogen to the fibrinogen receptors on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as effective inhibitors of metastasis.
The compounds of the formula I may be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the prophylaxis and/or therapy of thrombosis, myocardial infarct, arteriosclerosis, inflammations, stroke, angina pectoris, tumour diseases, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases such as inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis following angioplasty, viral infection, bacterial infection, fungal infection, in acute liver failure and for supporting the healing processes in wound healing.
The compounds of the formula I may be employed as substances having an antimicrobial effect in operations in which biomaterials, implants, catheters or heart pacemakers are used. In this context, they have an antiseptic effect. The efficacy of the antimicrobial activity can be demonstrated using the method described by P. Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
The amino acid residue abbreviations which are cited in the above text and in that which follows represent the residues of the following amino acids:
Abu
4-Aminobutyric acid
Aha
6-Aminohexanoic acid, 6-aminocaproic acid
Ala
Alanine
Asn
Asparagine
Asp
Aspartic acid
Arg
Arginine
Cys
Cysteine
Dab
2,4-Diaminobutyric acid
Dap
2,3-Diaminopropionic acid
Gln
Glutamine
Glp
Pyroglutamic acid
Glu
Glutamic acid
Gly
Glycine
His
Histidine
homo-Phe
homo-Phenylalanine
Ile
Isoleucine
Leu
Leucine
Lys
Lysine
Met
Methionine
Nle
Norleucine
Orn
Ornithine
Phe
P

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