Claims
- 1. A compound of formula (I)
- 2. A compound of formula (I) according to claim 1 wherein the capping group exhibits one or more functional groups, which have the capability of forming salts with pharmaceutially acceptable acids or bases, selected from amino, carboxy, phospate, phophonate, sulfate and sulfonate groups.
- 3. A compound of formula (I) according to claim 1 or 2, wherein said capping group (Cg) is a group of formula
- 4. A compound of formula (I) according to claim 1 or 2, wherein
R1 represents a residue of formula Cg-A, Cg-B-A or Cg-(D)n-B-A, in which
Cg represents a capping group of formula R2—(CH2)m-Z-, wherein R2 is an optionally substituted saturated heterocyclyl or heteroaryl group; m is 0 or 1; A, B and D each independently represent moieties derived from amino carboxylic acids of the formula —[NR4—(X)p—CO]— wherein X represents CR5R6 and wherein R4, R5 and R6 each independently represent a hydrogen atom, an optionally substituted C1-C6-alkyl, C3-C8-cycloalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl group, and p is 1, 2, 3, 4, 5; or A, B and D each independently represent moieties derived from cyclic amino carboxylic acids of formula 63wherein
R7 represents C1-C6-alkyl, OH, or NH2, n is an integer from 1 to 10; q is 0, 1 or 2; and r is 0, 1 or 2.
- 5. A compound of formula I according to any of claims 1 to 3, wherein the heterocyclic ring formed by Ra, Rb and the interjacent N—C is substituted by R8 and R9, wherein R8 and R9 each independently represent a hydrogen or halogen atom or a C1-C6-alkyl, C1-C6-alkylamino, di-C1-C6-alkylamino, C1-C6-alkoxy, thiol, C1-C6-alkylthio, oxo, imino, fomyl, C1-C6-alkoxy carbonyl, amino carbonyl, C3-C8-cycloalkyl, aryl, or heteroaryl group.
- 6. A compound of fomula IA
- 7. A compound of fomula IA1
- 8. A compound of fomula IA2
- 9. Compounds of formulae I, IA, IA1 or IA2 according to any of the preceding claims, wherein
R2 represents a group selected from 67
- 10. A compound according to any of the preceding claim, wherein R1 represents an aminoalkanoyl, or an oligopeptidoyl group, which is derived from glycine (Gly), or the D- or L-forms of alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), cysteine (Cys), methionine (Met), serine (Ser), threonine (Thr), lysine (Lys), arginine (Arg), histidine (His), aspartatic acid (Asp), glutamic acid (Glu), asparagine (Asn), glutamine (Gln), proline (Pro), 4-hydroxy-proline (Hyp), 5-hydroxy-lysine, norleucine (Nle), 5-hydroxynorleucine (Hyn), 6-hydroxynorleucine, ornithine, or cyclohexylglycine (Chg) and wherein the N-terminal amino function of said aminoalkanoyl or oligopeptidoyl group is attached to a capping group Cg.
- 11. A compound of formula I according to any of the preceding claims, wherein the unit A is derived from L-proline, glycine, L-norleucine, L-cyclohexylglycine, L-5-hydroxynorleucine, L-6-hydroxynorleucine, L-5-hydroxylysine, L-arginine, or L-lysine.
- 12. A compound according to any of the preceding claims wherein R1 is a group selected from the formulae (1) to (14):
- 13. A compound according to claim 11 wherein the amino alkanoic acid moieties exist in the (L)-configuration
- 14. A compound of any one of claims 1 to 12, wherein Cyt′ is an anthracycline group.
- 15. A compound of claim 14 selected from the formulae (IIIA) to (IIIH):
- 16. A prodrug that is capable of being converted into a cytotoxic or cytostatic drug, by the catalytic action of FAPα, said prodrug exhibits an oligomeric part comprising up to 13 amino carboxylic residues, the C-terminal amino carboxylic thereof is recognised by FAPα, and a cytotoxic or cytostatic part, characterized in that
the N-terminal amino function of the oligomeric part is attached to a capping group (Cg) which is capable of enhancing the chemical stability of said prodrug under physiological conditions and the physical stability of an aqueous pharmaceutical formulations comprising said prodrug.
- 17. The prodrug of claim 16 wherein the capping group is a group of formula R2—(CH2)m-Z-, in which R2 represents
(a) a group selected from C1-C6 alkyl, C3-C8 cycloalkyl, aryl and heteroaryl, wherein each of these groups is substituted by at least one amino, carboxy or hydroxy group, or (b) an optionally substituted 5- to 7-membered saturated, unsaturated or aromatic nitrogen containing heterocyclic group, or (c) a phenyl group which is substituted by 1 to 5 fluorine atoms; Z represents —CO—, —O—CO—, —SO2—, —NH—CO— or a single bond; m is 0 or 1.
- 18. The prodrug of claim 16 or 17, wherein the C-terminal amino carboxilic residue is selected from D-proline, L-proline, D-hydroxyproline and L-hydroxyproline and the oligomeric part comprises two, three, or four amino carboxylic acid residues.
- 19. A compound of any one of the preceding claims for medical use.
- 20. Pharmaceutical composition comprising a compound according to any one of claims 1 to 19, and optionally one or more pharmaceutically acceptable excipients.
- 21. Use of a compound according to any one of claims 1 to 19 in the preparation of a pharmaceutical composition for the treatment of cancer.
- 22. Method of treatment of cancer, comprising administering a pharmaceutical composition according to claim 20 to a patient.
- 23. Method of treatment of cancer, wherein a prodrug is administered to a patient wherein said prodrug is capable of being converted into a cytotoxic or cytostatic drug by the enzymatic activity of FAPα, and said prodrug exhibits an oligomeric part comprising up to 13 amino carboxylic residues, the C-terminal amino carboxylic thereof is recognised by FAPα, and a cytotoxic or cytostatic part, characterized in that the N-terminal amino function of the oligomeric part is attached to a capping group (Cg) which is capable of enhancing the chemical stability of said prodrug under physiological conditions and the physical stability of aqueous pharmaceutical formulations comprising said prodrug.
- 24. Use of a prodrug which is capable of being converted into a cytotoxic or cytostatic drug by the enzymatic activity of FAPα, said prodrug exhibits an oligomeric part comprising up to 13 amino carboxylic residues, the C-terminal amino carboxylic thereof is recognised by FAPα, and a cytotoxic or cytostatic part, wherein the N-terminal amino function of the oligomeric part is attached to a capping group (Cg) which is capable of enhancing the chemical stability of said prodrug under physiological conditions and the physical stability of aqueous pharmaceutical formulations comprising said prodrug, for the manufacture of a stable medicament for the treatment of cancer.
Priority Claims (1)
Number |
Date |
Country |
Kind |
0027552.9 |
Nov 2000 |
GB |
|
RELATED APPLICATIONS
[0001] The benefit of priority U.S. Provisional application No. 60/262,323, filed Jan. 17, 2001 is hereby claimed.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60262323 |
Jan 2001 |
US |