Cyclic adhesion inhibitors

Details Cyclic adhesion inhibitors Cyclic adhesion inhibitors

1998-10-01

2001-01-02

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S003100, C530S317000

Utility Patent

active

06169072

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to novel cyclopeptides of the formula I
cyclo-(Arg-B-Asp-D-E)  I
in which
B is Gly, Ala, or —HN—Q—CO—,
D and E in each case independently of one another are Gly, —HN—Q—CO—, Ala, Asn, Asp, Asp(OR), Arg, Cha, Cys, Gln, Glu, His, Ile, Leu, Lys, Lys(Ac), Lys(AcNH
2
), Lys(AcSH), Met, Nal, Nle, Orn, Phe, 4-Hal-Phe, Phg, Pro, Pya, Ser, Thr, Tia, Tic, Trp, Tyr or Val, where the said amino acid radicals can also be derivatized,
R is alkyl having 1-6 C atoms,
Hal is F, Cl, Br or I,
Q is alkylene having 1-6 C atoms and
Ac is alkanoyl having 1-10 C atoms,
where, if it is a case of radicals of optically active amino acids and amino acid derivatives, both the D and the L forms are included, and also their physiologically acceptable salts.
Similar compounds are known from Pharmazie 40 (8), 532-5, (1985).
An object of the invention is to find novel compounds having useful 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 useful properties. In particular, they act as integrin inhibitors, in which case they particularly inhibit the interactions of &bgr;
3
- or &bgr;
5
-integrin receptors with ligands. The compounds are particularly effective in the case of the integrins a
v
&bgr;
3
, a
v
&bgr;
5
and a
IIb
&bgr;
3
. 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). In addition, there are anti-inflammatory effects. All these actions can be demonstrated with the aid of methods which are known from the literature.
It is known that compounds which inhibit or block the &bgr;
3
-integrin receptor ligand interactions, such as the binding of fibrinogen to &bgr;
3
-integrin receptors (adhesion receptor antagonist or ARA), can be used as therapeutic agents. Furthermore, such compounds also inhibit cell adhesion in the case of the formation of osteoclasts.
Thus, the compounds can be employed as pharmaceutically active compounds in human and veterinary medicine, in particular, for the prophylaxis and the treatment of disorders of the circulation, thrombosis, cardiac infarct, arterioschlerosis, inflammations, apoplexy, angina pectoris, tumor disorders (e.g., melanoma, sarcoma, and epithelioma), osteolytic disorders, in particular, osteoporosis, antiogenesis and restenosis after angioplasty. The compounds may furthermore be employed to improve the healing of wounds.
The compounds are also suitable as antimicrobial agents which avoid infections as caused, for example, by bacteria, fungi or yeasts. The substances are useful as accompanying antimicrobial agents in cases where operations are effected in order to insert non-corporal materials, for example such as biomaterials, implants, catheters or heart-pacemakers. They act as antiseptics.
The abbreviations of amino acid radicals shown above and below stand for the radicals of the following amino acids:
Abu
4-aminobutyric acid
Aha
6-aminohexanoic acid
Ala
alanine
Asn
asparagine
Asp
aspartic acid
Asp (OR)
aspartic acid (&bgr;-ester)
Arg
arginine
Cha
3-cyclohexylalanine
Cit
citrulline
Cys
cysteine
Dab
2,4-diaminobutyric acid
Gln
glutamine
Glu
glutamic acid
Gly
glycine
His
histidine
Ile
isoleucine
Leu
leucine
Lys
lysine
Lys (Ac)
N′-alkanoyllysine
Lys(AcNH
2
)
N′-aminoalkanoyllysine
Lys(AcSH)
N′-mercaptoalkanoyllysine
Met
methionine
Nal
3-(2-naphthyl)-alanine
Nle
norleucine
Orn
ornithine
Phe
phenylalanine
4-Hal-Phe
4-halogenophenylalanine
Phg
phenylglycine
Pro
proline
Pya
3-(2-pyridyl)-alanine
Ser
serine
Tia
3-(2-thienyl)-alanine
Tic
tetrahydroisoquinoline-3-carboxylic acid
Thr
threonine
Trp
tryptophan
Tyr
tyrosine
Val
valine.
In addition, the following have the meanings below:
BOC
tert-butoxycarbonyl
CBZ
benzyloxycarbonyl
DCCI
dicyclohexylcarbodiimide
DMF
dimethylformamide
EDCI
N-ethyl-N′-(3-dimethylaminopropyl)-
carbodiimide hydrochloride
Et
ethyl
FMOC
9-fluorenylmethoxycarbonyl
HOBt
1-hydroxybenzotriazole
Me
methyl
Mtr
4-methoxy-2,3,6-trimethylphenylsulfonyl
OBut
tert-butyl ester
OMe
methyl ester
OEt
ethyl ester
POA
phenoxyacetyl
TBTU
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-
methyluronium tetrafluoroborate
TFA
trifluoroacetic acid
Trt
trityl (triphenylmethyl).
If the amino acids mentioned above can occur in several enantiomeric forms, then all of these forms and also their mixtures (e.g., the DL-forms) are included above and below, e.g., as constituents of the compounds of the formula I. The amino acids, e.g., as constituents of compounds of the formula I, may furthermore be provided with appropriate protective groups known per se.
Derivatized amino acid radicals are, for example, those radicals which are protected by one of the hydroxy or amino protecting groups discussed below. Preferred protecting groups are, for example, Boc and Fmoc for the N-terminus and OMe and OEt for the C-terminus of the amino acid radicals. Furthermore, if an amino acid residue has a functional group in its side chain, this group could be derivatized, too. The following are examples of derivatized amino acids: Ala(2-thienyl); 4-NO
2
—Phe; Lys(Aha); Asp(OEt); Lys(BOC-Aha); Tyr(OEt); Arg(Mtr); Asn(Trt); Asp(OBut); Cys(Trt); Cys(SBut); Glu(OBut); Gln(Trt); His(Trt); Lys(BOC); Ser(But); Thr(But); Tyr(But); Lys(AcH); Lys(AcNH
2
); and Lys(AcSH), wherein Ac is —CO—C
n
H
2n
— (n=2-12).
The invention further relates to a process for the preparation of a compound of the formula I or one of its salts, characterized in that it is liberated from one of its functional derivatives by treating with a solvolyzing or hydrogenolyzing agent, or in that a peptide of the formula II
H—Z—OH  II
in which
Z is
-Arg-B-Asp-D-E,
B-Asp-D-E-Arg-,
-Asp-D-E-Arg-B-,
-D-E-Arg-B-Asp, or
-E-Arg-B-Asp-D,
or a reactive derivative of such a peptide is treated with a cyclizing agent [e.g., dicyclohexylcarbodiimide (DCCI), N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide (EDCI), benzyltriazolyltetramethyluronium-tetrafluoroborate (TBTU), and diisopropylcarbodiimide (DICI)].
and/or in that a basic or acidic compound of the formula I is converted into one of its salts by treating with an acid or base.
The radicals B, D, E and Z above and below have the meanings given in the formulae I and II, if not expressly stated otherwise.
In the above formulae, alkyl is preferably methyl, ethyl, isopropyl or tert-butyl.
The group B is preferably Gly, but also —NH—(CH
2
)
2
—CO—, —NH—(CH
2
)
3
—CO—, —NH—(CH
2
)
5
—CO— or Ala. D is preferably Phe, in particular D-Phe, but also 4-Hal-Phe, particularly 4-I-Phe, and Pro, Tic, Lys, Nal or Phg, the D forms being particularly preferred.
Accordingly, the invention is particular relates to those compounds of the formula I in which at least one of the radicals has one of the preferred meanings given above.
A preferred group of compounds can be expressed by the part formula Ia, which otherwise corresponds to the formula I, but in which
B is Gly, —NH—(CH
2
)
2
—CO—, —NH—(CH
2
)
3
—CO—, —NH—(CH
2
)
5
—CO— or Ala
D is D-Pro, D-Tic, Phe, D-Nal, D-Phg or 4-I-Phe and
E is Val, Lys, Gly, Ala, Phe, Leu, Lys(Ac) or Nle.
A further preferred group of compounds can be expressed by the part formula Ib, which otherwise corresponds to the formula I, but in which
B is Gly
D is D-Phe and
E is Val, Lys or Gly.
The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by known methods, as are described in the literature (e.g., in the standard works such as Houben-Weyl, Methoden der organischen Chemie, (Methods of Organic Chemistry) Georg-Thieme-Verlag, Stuttgart), in particular under reaction conditions which are known and suitable for the reactions. In this context, use can also be made of known variants which are not mentioned in more detail here.
The starting substances can also be formed in situ, if desired, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compound

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