Patent FR-2912147-A1 (FR)
Title: Multimeric compounds for use in the treatment of diseases involving the immune response, comprise a spacer with 2-4 macrocycles carrying groups for attachment to a receptor of the TNF super-family
Inventor: GUICHARD GILLES
IPC: A61K38/12
Filed: 2007-02-05
Abstract: Multimeric compounds with 2, 3 or 4 macrocycles attached to a spacer group and with substituent groups on the macrocycles enabling attachment to a receptor of the TNF super-family are new. Multimeric compounds of formula (I) are new. k, j : 0 or 1; Y' : a macrocycle with 9-36 atoms, functionalised with 3 amino groups (for the attachment of R cvia its terminal carboxylic acid group) and a chain enabling coupling with the spacer Z via a bond X; R ca unit for attachment to a receptor of the THN super-family, preferably corresponding to a sequence derived from a ligand selected from residues forming the interface with the receptor of the ligand (this sequence being able to interact with the receptor), preferably a TNF receptor ligand, especially EDA, CD40L, FasL, OX40L, AITRL, CD30L, VEGI, LIGHT, 4-IBBL, CD27L, LTalpha , TNF, LTbeta , TWEAK, APRIL, BLYS, RANKL or TRAIL; X : a linking group of formula CO-NH (1x), NH-CO (2x), a-CO-NH-CH 2-CO-b (3x), S (4x), NH-CO-NH (8x), S-S (9x), C=N-O (10x), O-N=C (11x), with (a) and (b) as the links to Y'and Z respectively; Z : a bi-, tri- or tetra-functional spacer; if j : k= 0 and X= (1x), (8x), (9x), (5x), (6x), (7x), (13x) or (15x), Z= -CH 2CH 2O-(CH 2CH 2O) m-CH 2CH 2-(Z1) or -(CH 2) m- (Z2); if j : k= 0 and X= (2x), (3x) or (4x), Z= a group of formula NH-CH 2-CH 2-O(CH 2-CH 2-O) m-CH 2-CH 2-NH (Z3), NH-(CH 2) n-NH (Z4), (NH(CH 2) u-CO) n-NH-CH 2-(CH 2) p-NH-(CO-(CH 2) u-NH) (Z5), (Pro) n-NH-(CH 2) p-CH 2-NH-(Pro) n(Z6), (NH(CH 2) u-CO) n-NH-CH 2-CH 2-O(CH 2-CH 2-O) p-CH 2-CH 2-NH-(CO-(CH 2) u-NH) (Z7) or (Pro) n-NH-CH 2-CH 2-O(CH 2-CH 2-O) p-CH 2-CH 2-NH-(Pro) n(Z8); if j : k= 0 and X= (12x) or (14x), Z= a group of formula W'-NH-CH 2-CH 2-O(CH 2-CH 2-O) p-CH 2-CH 2-NH-W'(Z9), W'-NH-(CH 2) p-NH-W'(Z10), W'-(Pro) n-NH-(CH 2) p-NH-(Pro) n-W'(Z11), W'-(NH-(CH 2) uCO) n-NH-CH 2-(CH 2)-NH-(CO-(CH 2) p-NH)-W'(Z12), W'-(NH-(CH 2) uCO) n-CH 2-CH 2-O-(CH 2-CH 2) p-CH 2-CH 2-NH-(CO-(CH 2) p-NH)-W'(Z13) or W'-(Pro) n-NH-CH 2-CH 2-O-(CH 2-CH 2-O) p-CH 2-CH 2-NH-(Pro) n-W'(Z14) with W'= -CH 2NHCO(CH 2) 2CO- (W1) or -CO- (W2); if j : k= 0 and X= 1x, 2x, 8x, 9x, 5x, 6x, 7x, 10x, 11x, 13x or 15x, Z= Z9-Z14 with W'= -(CH 2) rCO- (W3); if j or k : 1 and X= 12x or 14x, Z= a group of Z15-Z19 with W'= W1 or W2; if j or k : 1 and X= 1x, 2x, 8x, 9x, 5x, 6x, 7x, 10x, 11x, 13x or 15x, Z= Z18 or Z19 with W'= W3; Z may also : a group of formula Z20-Z24; m : 1-40; n : 1-10; p : 1-6; u, r : 1-4; if X : 1x, 8x, 9x, 5x, 6x, 7x, 13x or 15x, R (in Z20-Z24)= (CH 2-CH 2-O) m-CH 2-CH 2-COR1 (with m= 3-6), (CH 2) n-COR2 (with n= 1-10) or CH 2-CH 2-O-(CH 2-CH 2-O)-CH 2-CH 2-NH-CO-CH 2-CH 2-COR3 (with m= 1-40); if X : 2x, 3x or 4x, R= NH-CH 2-CH 2-O(CH 2-CH 2-O) m-CH 2-CH 2-NH-CO-CH 2-CH 2-COR4 (with m= 1-40), NH-(CH 2-CH 2-O) m-CH 2-CH 2-COR5 (with m= 3-6), (Pro) nR6, NH-(CH 2) n-COR7 or (NH-(CH 2) u-CO) nR8; if X : 12x or 14x, R= R4-R9 with W as above; if X : 1x, 2x, 8x, 9x, 5x, 6x, 7x, 10x, 11x, 13x or 15x, R= NH-CH 2-CH 2-O-(CH 2-CH 2-O) m-CH 2-CH 2-NH-CO-CH 2-CH 2-CO or W'-NH-(CH 2-CH 2-O) m-CH 2-CH 2-CO with W'= W3. Independent claims are also included for (1) pharmaceutical compositions or vaccine compositions containing (I) as active ingredient together with an acceptable adjuvant (2) a method for the preparation of (I) on a solid support, involving (a) the formation of a linear precursor for (Y) comprising a growing peptide chain by means of successive coupling cycles between N-protected amino-acid residues (3 of which carry an amino group) and the amino group on the growing peptide chain, followed by deprotection, so that the first amino-acid residue is attached to a solid support and the precursor contains at least one D-alanine residue substituted with a D-lysine residue in which the epsilon -NH has been acylated with a carboxylic acid carrying the required function corresponding to group X, (b) cyclisation to form a protected cyclic structure, (c) reaction with a spacer derived from Z to give a dimerised structure, (d) cleavage of protective groups, (e) coupling of the free amino groups with a peptide (already formed or formed in situ by the sequential assembly of amino-acid residues corresponding to groups R cas in (I)), and (f) cleavage of the molecule from the support after removing all protective groups on the functionalised side chains of R c. [Image] [Image] [Image] [Image] [Image] [Image].