Cyclic peptide derivatives

Details Cyclic peptide derivatives Cyclic peptide derivatives

1999-10-07

2001-12-25

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S317000, C530S323000, C530S330000, C530S331000

Reexamination Certificate

active

06333308

ABSTRACT:

The invention relates to compounds of the formula I
cyclo-(Arg-X-Asp-R
1
)  I
in which
X is Gly, Ala or NH—NH—CO,
where the amino acids mentioned can also be derivatized, and the amino acid residues are linked to one another in a peptide-like manner via the &agr;-amino and &agr;-carboxyl groups,
R
1
is a radical of the formula II
 R
2
,R
3
,R
4
in each case independently of one another are H, A, Ar, R
5
-Ar, Het or R
5
-Het,
A is alkyl having 1-6 C atoms,
Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted by R
7
,R
8
or R
9
, or unsubstituted naphthyl,
R
5
is alkylene having 1-6 C atoms,
R
6
,R
6′
in each case independently of one another are H, A, benzyl or phenyl,
R
7
,R
8
,R
9
in each case independently of one another are R
6
, OR
6
, Hal, NO
2
, NR
6
R
6
, NHCOR
6
, CN, NHSO
2
R
6
, COOR
6
or COR
6
,
Hal is F, Cl, Br or I and
Het is a mono- or binuclear heterocycle having 1 to 4 N, O, and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, NR
6
R
6′
, CN or NO
2
,
where, providing the residues are optically active amino acids and amino acid derivatives, both the D- and the L-forms are included,
and their salts.
Similar cyclic peptide compounds are disclosed, for example, in DE 43 10 643 or EP 0 683 173.
The invention was based on the object of discovering 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, inhibiting, 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 exhibit particular efficacy in the case of the integrins &agr;
v
&bgr;
1
, &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
, &agr;
IIb
&bgr;
3
and also &agr;
v
&bgr;
6
and &agr;
v
&bgr;
8
.
This action can be detected, for example, by the method which is described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990).
The dependency of the origin of angiogenesis on the interaction between vascular integrins and extracellular 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 through the formation of microaggregates (microthrombi) by interaction of the tumour cells with blood platelets. The tumour cells are shielded by protection in the microaggregate and are not recognized by the cells of the immune system. The microaggregates can fix to vascular walls, whereby a further penetration of tumour cells into the tissue is facilitated. Since the formation of microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as effective metastasis inhibitors.
The compounds of the formula I can 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, apoplexy, angina pectoris, oncoses, osteolytic diseases such as osteoporosis, pathologically angiogenic diseases such as, for example, inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing for assisting the healing process.
The compounds of the formula I can be employed as substances having antimicrobial activity in operations where biomaterials, implants, catheters or heart pacemakers are used. They have an antiseptic effect here. The efficacy of the antimicrobial activity can be demonstrated by the method described by P.Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).
Since the compounds of the formula I are inhibitors of fibrinogen binding and thus ligands of the fibrinogen receptors on blood platelets, they can be used as diagnostics for the detection and localization of thrombi in the vascular system in vivo, provided they are substituted, for example, by a radioactive or Uv-detectable radical.
As inhibitors of fibrinogen binding, the compounds of the formula I can also be used as efficacious medicaments for the study of the metabolism of blood platelets in different activation stages or of intracellular signal mechanisms of the fibrinogen receptor. The detectable unit of a “label” to be incorporated, e.g. an isotope labelling by
3
H, allows the mechanisms mentioned to be investigated, after binding to the receptor.
The abbreviations of amino acid residues mentioned above and below stand for the radicals of the following amino acids:
Ala
Alanine
AMP
Aminomethylphenyl residue
Asn
Asparagine
Asp
Aspartic acid
Arg
Arginine
Cys
Cysteine
Gln
Glutamine
Glu
Glutamic acid
Gly
Glycine
His
Histidine
homo-Phe
homo-Phenylalanine
Ile
Isoleucine
Leu
Leucine
Lys
Lysine
Met
Methionine
Nle
Narleucine
Orn
Ornithine
Phe
Phenylalanine
Phg
Phenylglycine
4-Hal-Phe
4-Halaphenylalanine
Pro
Proline
Ser
Serine
Thr
Threonine
Trp
Tryptophan
Tyr
Tyrosine
Val
Valine.
The 3-AMP radical has the following structure:
The following radicals have the meanings below:
Ac
Acetyl
BOC
tert-Butoxycarbonyl
CBZ or Z
Benzyloxycarbonyl
DCCI
Dicyclohexylcarbodiimide
DMF
Dimethylformamide
EDCI
N-Ethyl-N,N′-dimethylaminopropyl) carbodiimide
Et
Ethyl
FCA
Fluoresceincarboxylic acid
Fmoc
9-Fluorenylmethoxycarbonyl
HOBt
1-Hydroxybenzotriazole
Me
Methyl
MBHA
4-Methylbenzhydrylamine
Mtr
4-Methoxy-2,3,6-trimethylphenylsulfonyl
HONSu
N-Hydroxysuccinimide
OBzl
Benzyl ester
OtBu
tert-Butyl ester
Oct
Octanoyl
OMe
Methyl ester
OEt
Ethyl ester
POA
Phenoxyacetyl
Sal
Salicyloyl
TFA
Trifluoroacetic acid
Trt
Trityl (Triphenylmethyl).
Provided the abovementioned amino acids can occur in a number of enantiomeric forms, all these forms and also their mixtures (e.g. the DL-forms) are included above and below, e.g. as a constituent of the compounds of the formula I. Furthermore, the amino acids, e.g. as a constituent of compounds of the formula I, can be provided with appropriate protective groups known per se.
In the compounds according to the invention, so-called prodrug derivatives are also included, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the body to give the active compounds according to the invention.
These also include biodegradable polymer derivatives of the compounds according to the invention, such as is described, for example, in Int. J. Pharm. 115, 61-67 (1995).
Amino acids whose configuration is not specifically indicated have the (S)- or (L)-configuration.
The invention further relates to a process for the preparation of compounds of the formula I according to claim
1
, and their salts, characterized in that
(a) a compound of the formula III
H—Z—OH  III
 in which
Z is -Arg-X-Asp-R
1
-
—X-Asp-R
1
-Arg-
—Asp-R
1
-Arg-X- or
—R
1
-Arg-X-Asp,
and X and R
1
have the meanings indicated in Claim
1
,
or a reactive derivative of a compound

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