RU2008136209A - POLYRETHROBRATIC POLYMERIC CONJUGATES OF 7-ETHYL-10-HYDROXYCAMPTOTECINE FOR THE TREATMENT OF BREAST CANCER, OVARIES AND LUNGS - Google Patents

Abstract

1. The compound of formula (I)! ! where R1, R2, R3 and R4 independently represent OH or (L) m-D; ! L is a bifunctional linker; ! D represents a camptothecin or camptothecin analogue residue; ! m is 0 or a positive integer; and! n is a positive integer; ! provided that R1, R2, R3, and R4, not all are OH. ! 2. The compound according to claim 1, where D is the remainder of the compounds of formula! ! where R7 is selected from the group consisting of NO2, NH2, N3, hydrogen, halogen (F, Cl, Br, I), COOH, OH, O-C1-8 alkyl, SH, S-C1-3 alkyl, CN, CH2NH2, NH -C1-3 alkyl, CH2-NH-C1-3 alkyl, N (C1-3 alkyl) 2, CH2N (C1-3 alkyl), O-, NH- and S-CH2CH2N (CH2CH2OH) 2, O-, NH- and S- CH2CH2CH2N (CH2CH2OH) 2, O-, NH- and S-CH2CH2N (CH2CH2CH2OH) 2, O-, NH- and S-CH2CH2CH2N (CH2CH2CH2OH) 2, O-, NH- and S-CH2CH2N (C1-3 alkyl) 2, O-, NH- and S-CH2CH2CH2N (C1-3alkyl) 2, CHO or C1-3alkyl; and! R8 is selected from the group consisting of H, C1-8 alkyl and CH2NR9R10, where! R9 is selected from the group consisting of hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-6alkyl, C2-6alkenyl, hydroxy-C1-6alkyl and C1-6alkoxy-C1-6alkyl; ! R10 is selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-6 alkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl and -COR11,! where R11 is selected from the group consisting of hydrogen, C1-6 alkyl, perhalo-C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-6 alkyl, C2-6 alkenyl, hydroxy-C1-6 alkyl, C1-6 alkoxy and C1-6 alkoxy C1-6alkyl; or ! R9, R10 and the nitrogen atom of ring B form a saturated 3-7 membered heterocyclic ring containing O, S or NR12,! where R12 is selected from the group consisting of hydrogen, C1-6 alkyl, perhalo-C1-6 alkyl, aryl, aryl substituted with one or more groups selected from the group consisting of C1-6 alkyl, halogen, nitro, amino, C1-6 alkylamino, perhalogen-C1-6alkyl, g

Claims (26)

1. The compound of formula (I)

, where R ₁ , R ₂ , R ₃ and R ₄ independently represent OH or (L) _m —D; L is a bifunctional linker; D represents a camptothecin or camptothecin analogue residue; m is 0 or a positive integer; and n is a positive integer; provided that R ₁ , R ₂ , R ₃ and R ₄ , not all are OH. 2. The compound according to claim 1, where D represents the remainder of the compounds of formula

, where R _{7 is} selected from the group consisting of NO ₂ , NH ₂ , N ₃ , hydrogen, halogen (F, Cl, Br, I), COOH, OH, O-C _1-8 alkyl, SH, S-C _{1- 3} alkyl, CN, CH ₂ NH ₂ , NH-C _1-3 alkyl, CH ₂ -NH-C _1-3 alkyl, N (C _1-3 alkyl) ₂ , CH ₂ N (C _1-3 alkyl), O-, NH- and S-CH ₂ CH ₂ N (CH ₂ CH ₂ OH) ₂ , O-, NH- and S-CH ₂ CH ₂ CH ₂ N (CH ₂ CH ₂ OH) ₂ , O-, NH - and S-CH ₂ CH ₂ N (CH ₂ CH ₂ CH ₂ OH) ₂ , O-, NH- and S-CH ₂ CH ₂ CH ₂ N (CH ₂ CH ₂ CH ₂ OH) ₂ , O-, NH - and S-CH ₂ CH ₂ N (C _1-3 alkyl) ₂ , O-, NH- and S-CH ₂ CH ₂ CH ₂ N (C _1-3 alkyl) ₂ , CHO or C _1-3 alkyl; and R ₈ selected from the group consisting of H, C _1-8 alkyl and CH ₂ NR ₉ R ₁₀ where R _{9 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl and C _{1 -6} alkoxy-C _1-6 alkyl; R _{10 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl, C _2-6 alkenyl, hydroxy-C _1-6 alkyl, C _{1 -6} alkoxy-C _1-6 alkyl and -COR ₁₁ , where R _{11 is} selected from the group consisting of hydrogen, C _1-6 alkyl, perhalo-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl, C _2-6 alkenyl, hydroxy C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkoxy-C _1-6 alkyl; or R ₉ , R ₁₀ and the nitrogen atom of ring B form a saturated 3-7 membered heterocyclic ring containing O, S or NR ₁₂ , where R _{12 is} selected from the group consisting of hydrogen, C _1-6 alkyl, perhalogen-C _1-6 alkyl, aryl, aryl substituted with one or more groups selected from the group consisting of C _1-6 alkyl, halogen, nitro , amino, C _1-6 alkylamino, perhalo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 alkyl and -COR ₁₃ , where R ₁₃ selected from the group consisting of hydrogen, C _1-6 alkyl, perhalogen-C _1-6 alkyl, C _1-6 alkoxy, aryl and aryl substituted with one or more C _1-6 alkyl, perhalogen-C _1-6 alkyl, hydroxy-C _1-6 alkyl and C _1-6 alkoxy-C _1-6 alkyl; each of R ₁₁₀ -R _{111 is} independently selected from the group consisting of hydrogen, halogen, acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, azido, amido, hydrazine, amino, substituted amino, hydroxycarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, carbamoyloxy, arylsulfonyloxy, alkylsulfonyloxy, -C (R ₁₁₇ ) = N- (O) _j -R ₁₁₈ , where R ₁₁₇ is H, alkyl, alkenyl, cycloalkyl or aryl, j is 0 or 1, and R ₁₁₈ is H, alkyl, alkenyl, cycloalkyl or hetero ikl, R ₁₁₉ C (O) O-, where R ₁₁₉ represents halogen, amino, substituted amino, heterocycle, substituted heterocycle, and R ₁₂₀ -O- (CH ₂ ) _k -, where k is an integer of 1-10, and R ₁₂₀ represents alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocycle or substituted heterocycle; or R ₇ together with R ₁₁₀ or R ₁₁₀ together with R ₁₁₁ form a substituted or unsubstituted methylenedioxy, ethylenedioxy or ethyleneoxy; and R ₁₁₂ represents H or OR ′, where R ′ represents alkyl, alkenyl, cycloalkyl, haloalkyl or hydroxyalkyl. 3. The compound according to claim 1, where the remainder of the camptothecin analogue is

. 4. The compound according to claim 1, where L is the residue of an amino acid or amino acid derivative, wherein the amino acid derivative is selected from the group consisting of 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, beta-aminopropionic acid, 2-aminobutyric acid , 4-aminobutyric acid, piperidic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-aminobutyric acid, desmosine, 2,2-diaminopimelic acid, 2,3-diamino propionic acid, n-ethylglycine, N-ethylasparagine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylglycine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine and. 5. The compound according to claim 4, where L is a residue of glycine, alanine, methionine or sarcosine. 6. The compound according to claim 1, where L is a glycine residue. 7. The compound according to claim 1, where L is selected from the group consisting of - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ O) _t -, - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ O) _t (CR ₂₄ R ₂₅ ) _y O-, - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ O) _t (CR ₂₄ R ₂₅ ) _y -, - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ ) _t O-, - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ ) _t (CR ₂₄ R ₂₅ O) _y NR ₂₆ -, - [C (O)] _v O (CR ₂₂ R ₂₃ ) _t NR ₂₆ -, - [C (O)] _v O (CR ₂₂ R ₂₃ ) _t O-, - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ ) _t NR ₂₆ -, - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ ) _t (CR ₂₄ R ₂₅ O) _y -, - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ O) _t (CR ₂₄ R ₂₅ ) _y NR ₂₆ -, - [C (O)] _v O (CR ₂₂ R ₂₃ ) _y

(CR ₂₄ R ₂₅ ) _t NR ₂₆ - - [C (O)] _v O (CR ₂₂ R ₂₃ ) _y

(CR ₂₄ R ₂₅ ) _t O- - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ ) _y

(CR ₂₄ R ₂₅ ) _t NR ₂₆ and - [C (O)] _v NR ₂₁ (CR ₂₂ R ₂₃ ) _y

(CR ₂₄ R ₂₅ ) _t O-, where R ₂₁ -R _{26 are} independently selected from the group consisting of hydrogen, C _1-6 alkyls, C _2-6 alkenyls, C _2-6 alkynyls, branched C _3-19 alkyls, C _3-8 cycloalkyls, substituted C _{1- 6} alkyl, substituted C _2-6 alkenyl, substituted C _2-6 alkynyl, substituted C _3-8 cycloalkyl, aryl, substituted aryl, aralkyl, C _1-6 heteroalkyl, substituted C _1-6 heteroalkyl, C _1-6 alkoxy, phenoxy and C _1-6 heteroalkoxy; R _{27 is} selected from the group consisting of hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, branched C _3-19 alkyl, C _3-8 cycloalkyl, substituted C _1-6 alkyl, substituted C _2-6 alkenyls, substituted C _2-6 alkynyls, substituted C _3-8 cycloalkyls, aryls, substituted aryls, aralkyls, C _1-6 heteroalkyls, substituted C _1-6 heteroalkyls, C _1-6 alkoxy, phenoxy, C _{1- 6} heteroalkoxy, NO ₂ , haloalkyl and halogen; t and y are selected individually from positive numbers from about 1 to about 4; and v is 0 or 1. 8. The compound according to claim 1, where m is equal to a number from about 1 to about 10. 9. The compound according to claim 1, where m is approximately 1. 10. The compound according to claim 1, where n is equal to a number from about 28 to about 341. 11. The compound according to claim 1, where n is equal to a number from about 114 to about 227. 12. The compound according to claim 1, where n is approximately 227. 13. The compound according to claim 1, having a load (L) _m -D of at least about 3.9. 14. The compound according to claim 1, selected from the group consisting of

and

15. The compound according to claim 1, having the formula

16. A method of treating a mammal, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1. 17. The method according to clause 16, where D is a residue of 7-ethyl-10-hydroxycamptothecin. 18. A method of treating a metastatic disease selected from the group consisting of solid tumors, lymphomas, lung cancer, small cell lung cancer, acute lymphocytic leukemia (ALL), breast cancer, colorectal cancer, pancreatic cancer, glioblastoma, ovarian cancer and stomach cancer comprising administering to a patient in need thereof an effective amount of a compound according to claim 1. 19. The method of claim 18, wherein the metastatic disease is breast cancer and the compound of claim 1 is

20. The method according to claim 19, where the compound is administered in amounts of from about 5 to about 20 mg / kg / dose. 21. The method of claim 18, wherein the metastatic disease is colorectal cancer and the compound of claim 1 is

22. The method according to item 21, where the compound is administered in amounts of from about 10 to about 30 mg / kg / dose. 23. The method of claim 18, wherein the metastatic disease is pancreatic cancer and the compound of claim 1 is

24. The method according to item 23, where the compound is administered in amounts of from about 10 to about 30 mg / kg / dose. 25. A method of obtaining a polybranched polymer prodrug, including (a) providing one equivalent of camptothecin or an analogue of camptothecin containing an available 20-hydroxyl group and one or more equivalents of a bifunctional linker containing an available carboxy group; (b) the interaction of the two reagents under conditions effective for the formation of an intermediate compound camptothecin-bifunctional linker containing an available amino group; (c) the interaction of one or more equivalents on the active site of the obtained intermediate compound and one equivalent of the activated polymer of formula (I), where formula (I) is

, under conditions effective for the formation of a polybranched polymer prodrug having the structure

, where R ₁ , R ₂ , R ₃ and R ₄ independently represent OH or (L) _m —D; L is a bifunctional linker; D represents a camptothecin or camptothecin analogue residue; m is 0 or a positive integer; and n is a positive integer; provided that R ₁ , R ₂ , R ₃ and R ₄ , not all are OH. 26. A method of obtaining a polybranched polymer prodrug, including (a) the interaction of one equivalent of camptothecin or an analogue of camptothecin containing an available 20-hydroxyl group, with one or more equivalents of a bifunctional linker containing an available carboxyl group, under conditions effective to form an intermediate compound camptothecin-bifunctional linker containing an available amino group; and (b) the interaction of one or more equivalents on the active site of the obtained intermediate compound from step (a) with one equivalent of an activated polymer of formula (I), where formula (I) is

, under conditions effective for the formation of a polybranched polymer prodrug having the structure

, where R ₁ , R ₂ , R ₃ and R ₄ independently represent OH or (L) _m —D; L is a bifunctional linker; D represents a camptothecin or camptothecin analogue residue; m is 0 or a positive integer; and n is a positive integer; provided that R ₁ , R ₂ , R ₃ and R ₄ , not all are OH.