Patent EA-005204-B1 (EA)
Title: Fap-activated anti-tumor compounds
Inventor: PARK JOHN EDWARD
IPC: A61K47/48
Filed: 2000-05-11
Abstract: 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R<1> represents a residue of formula Cg-A, Cg-B-A or Cg-(D)m-B-A, in which Cg represents a capping group selected from the group consisting of R<5>-CO, R<5>O-CO-, R<5>-NH-CO-, R<5>-SO2- or R<5>-, wherein R<5> is an optionally substituted C1-C6-alkyl, C3-C8-cycloalkyl, aryl, aralkyl or heteroaryl group; A is a moiety being an amino carboxylic acid derivative from L-proline, glycine, L-norleucine, L-cyclohexylglycine, L-5-hydroxynorleucine, L-6-hydroxynorleucine, L-5-hydroxylysine, L-arginine, or L-lysine; and B and D each independently represent moieties derived from amino carboxylic acids of the formula -[NR<6>-(X)p-CO]- wherein X represents CR<7>R<8> and wherein R<6>, R<7> and R<8> each independently represent a hydrogen atom, an optionally substituted C1-C6-alkyl, C3-C8-cycloalkyl, aryl or heteroarylgroup, and p is 1, 2, 3, 4, 5; or B and D each independently represent moieties derived from cyclic amino carboxylic acids of formula wherein R<9> represents C1-C6-alkyl, OH, or NH2, m is an integer from 1 to 10; q is 0, 1 or 2; and r is 0, 1 or 2; R<A> and R<B> together with the interjacent N-C group form an optionally substituted, optionally benzo- or cyclohexano-condensed 3- to 7-membered saturated or unsaturated heterocyclic ring, in which one or two CH2 groups may also be replaced by NH, O or S, R<4> represents H, C1-C6-alkyl, C3-C8-cycloalkyl, aryl or heteroaryl; and Cyt' represents the residue of a cytotoxic or cytostatic compound. 2. A compound of formula I according to claim 1, wherein the heterocyclic ring formed by R<A>, R<B> and the interjacent N-C is substituted by R<2> and R<3>, wherein R<2> and R<3> 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, formyl, C1-C6-alkoxy carbonyl, amino carbonyl, C3-C8-cycloalkyl, aryl, or heteroaryl group. 3. A compound of formula IA wherein R<1>, R<4> and Cyt' are as defined in any of the preceding claims, R<2> and R<3> are as defined in claim 2 and X-Y represents CHR<2>-CH2, CR<2>=CH, NH-CH2, CH2-NH, -CR<2>-, CH2-CHR<2>-CH2. 4. A compound of formula IA1 wherein R<1> and Cyt' are as defined in claim 1. 5. A compound of formula I wherein R<1> and Cyt' are as defined in claim 1, R<4> is H, selected from the formulae IA2, IA3, IA4 and IA5 6. A compound according to any of the preceding claims wherein R<1> is a group selected from the formulae (21), (22) and (34): Cg-Gly (21) Cg-Nle (22) Cg-(Xaa)m-Xaa-Gly (34), wherein Cg represents a hydrogen atom or a capping group selected from benzoyloxycarbonyl, phenylacetyl, phenylmethylsulfonyl and benzylaminocarbonyl; Xaa represents a moiety derived from an amino carboxylic acid; and m is an integer from 1 to 6. 7. A compound according to claim 6 wherein the amino alkanoic acid moieties exist in the (L)-configuration. 8. A compound of any one of claims 1 to 7, wherein HN-Cyt' is an anthracycline derivative. 9. A compound of claim 8 selected from the formulae (IIIA), (IIIB), (IIIE) and (IIIF): 10. Use of a compound according to any one of the preceding claims as a therapeutical gent. 11. Pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and optionally one or more pharmaceutically acceptable excipients. 12. Use of a compound according to any one of claims 1 to 9 in the preparation of a pharmaceutical composition for the treatment of cancer. 13. A process for the production of a compound of formula I according to claim 1, characterised in that a compound of formula (V) wherein R<1>, R<A> and R<B> are as defined in claim 1, X<1> represents OH, or a leaving group which is suitable to be substituted by a amino group, is reacted with a compound HN(R<4>)-Cyt', wherein Cyt' is the residue of a cytotoxic or cytostatic compound, and R<4> is as defined in claim 1 followed by isolation of a final product. 14. Method of cancer treatment, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 11 during time and under conditions effective for inhibiting prolifiration of tumor cells. 15. Method of cancer treatment, comprising administering to a patient in need thereof a pharmaceutical composition according to claim 1 in an amount effective for inhibiting prolifiration of tumor cells during time and under conditions effective for inhibiting prolifiration of tumor cells. 16. Method of treatment a disease comprising epithelial carcinomas including breast, lung, colorectal, head and neck, pancreatic, ovarian, bladder, gastric, skin, endometrial, ovarian, testicular, esophageal, prostatic and renal origin; bone and soft-tissue sarcomas including osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma (MFH), leiomyosarcoma; hematopoietic malignancies including Hodgkin's and non-Hodgkin's lymphomas; neuroectodermal tumors including Peripheral nerve tumors, astrocytomas, melanomas; and mesotheliomas, comprising administering to a patient in need thereof a compound in an amount effective g for inhibiting prolifiration of tumor cells.