Cyclopeptolides

Details Cyclopeptolides Cyclopeptolides

1998-06-25

2000-01-04

Woodward, Michael P.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Cyclic peptides

530329, 514 11, 514 14, A61K 3808, A61K 3812, C07K 512

Patent

active

060111364

DESCRIPTION:

BRIEF SUMMARY
This invention relates to cyclopeptolides and to their therapeutic use as inhibitors of adhesion molecule expression.
Cellular adhesion molecules such as ICAM-1, VCAM-1 and E-selectin are expressed on the surface of endothelial cells, as well as keratinocytes for ICAM-1, in response to pro-inflammatory mediators including TNF.alpha., IFN.gamma., IL1 and LPS. Corresponding counter-ligands, e.g. LFA-1, VLA4 and SLE.sup.x, are expressed on the surfaces of circulating blood cells. Transendothelial migration of leucocytes during inflammatory processes, as well as extravascular cell-cell interactions, are regulated as a result of the interactions between these adhesion molecules and their counter-ligands. Consequently, inhibitors of adhesion molecule expression offer potential for the treatment of many disease states.
Cyclopeptolides are cyclic molecules comprising amino acid residues linked together by peptide bonds and at least one hydroxy substituted carboxylic acid residue which is linked through its hydroxyl substituent to the neighbouring acid residue by an ester linkage.
Our copending patent application, published International patent application WO 96/03430 discloses novel cycloheptapeptolides which are inhibitors of ICAM-1, VCAM-1 and E-selectin expression. We have now discovered further new cycloheptapeptolides of the same general compound class, including compounds having particularly desirable properties.
The present invention provides cycloheptapeptolides of formula I ##STR2## wherein: A is a glycolic acid residue optionally .alpha.-substituted by COOR.sub.2, vinyl, ##STR3## wherein R.sub.3 represents hydrogen, alkoxy, alkyl or benzyl, R.sub.4 represents hydrogen or single or double bond; residue, and C.sub.10) carboxylic acid residue.
In formula I the N-terminal to C-terminal orientation of the amino acid residues is in the clockwise direction, and the peptolide ester bond is between residues A and Y. When R.sub.1 is methyl, the residues R.sub.1 -Leu and Leu are N-methyl-leucine and leucine residues respectively.
Preferably A is a glycolic acid residue, which is .alpha.-substituted by H, methyl, ethyl or propyl optionally substituted by amino, hydroxy, chloro, alkoxy, optionally substituted thiazole, optionally substituted vinyl, cyclopropyl, CSNH.sub.2 or --C.tbd.CH.
Preferably C is a N-methyltryptophan residue of formula II, wherein R.sub.3 represents hydrogen, (C.sub.1 to C.sub.4)alkoxy (especially methoxy) or alkyl and R.sub.4 represents hydrogen or halogen.
Preferably X is an ox-amino-substituted (C.sub.4 to C.sub.8) carboxylic acid residue, which is optionally .beta.- or .gamma.-(C.sub.1 to C.sub.4) alkyl substituted. Most preferably X is an .alpha.-amino-.beta.- or .gamma.-(C.sub.1 to C.sub.4) alkyl-, especially methyl-, substituted octanoic or a butyric acid residue.
Preferably Y is an N-methyl-.alpha.-amino-substituted (C.sub.2 to C.sub.4) carboxylic acid residue, which is optionally .beta.- or .gamma.-(C.sub.1 to C.sub.4) alkyl-substituted. Most preferably Y is an N-methyl-alanine or N-methyl-valine residue.
The invention includes open chain peptides or peptolides corresponding to the compounds of formula I; for instance, the open chain molecules obtained by either cleavage of the ester bond between residues Y and A or cleavage of an amide linkage between any other adjacent pair of the acid residues. Preferred open-chain derivatives are compounds of formulae IV and V
Preferred compounds according to one embodiment of the invention are the compounds of formula Ip ##STR4## wherein: A.sub.p is a glycolic acid residue optionally .alpha.-substituted by H, ethyl or methyl; residue; N'-(C.sub.1 to C.sub.4) alkoxy substituted; acid residue, and to C.sub.10) carboxylic acid residue.
Preferred compounds according to a further embodiment of the invention are compounds of formula I.sub.p ' ##STR5## wherein B.sub.p, R.sub.1p, C.sub.p, X.sub.p and Y.sub.p are as defined above and A'p is an .alpha. hydroxy-substituted butyric acid residue which is .gamma. substituted by a group of formula VI ##STR6## wh

REFERENCES:
patent: 5643869 (1997-07-01), Dreyfuss et al.
patent: 5686604 (1997-11-01), Ludescher et al.
Foster, C.A., et al., J. of Dermatology, vol. 21, No. 11., pp. 847 to 854, Nov., 1994, "Pharmacological Modulation of Endothelial Cell-associated Adhesion Molecule Expression: Implications for Future Treatment of Dermatological Diseases".
Shionogi & Co., Derwent Abstract 95-196280 [26] (JP 71/9299).
Hommel, U., et al., FEBS Letters, vol. 379, No. 1, pp. 69-73, (1996) "The 3D-structure of a natural inhibitor of cell adhesion molecule expression".

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