Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers

1. A compound of Formula (I)

wherein

R 1 , R 2 , R 3 and R 4 are independently OH or (L) m -D;

L is a bifunctional linker;

D is a camptothecin or a camptothecin analog;

m is 0 or a positive integer from 1 to 10; and

n is a positive integer from about 28 to about 341;

provided that R 1 , R 2 , R 3 and R 4 are not all OH.

2. The compound of claim 1 , wherein D is a compound of Formula (II)

wherein

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 ) 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 and C 1-3 alkyl;

R 8 is selected from the group consisting of H, C 1-8 alkyl and CH 2 NR 9 R 10

wherein

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

wherein 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;

R 110 R 111 are each independently selected from the group consisting of hydrogen; halo, acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, azido, amido, hydrazine, amino, substituted amino, hydroxcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino, carbamoyloxy, arylslfonyloxy, alkylsulfonyloxy, —C(R 117 )═N—(O) j —R 118 wherein R 117 is H, alkyl, alkenyl, cycloalkyl, or aryl, j is 0 or 1, and R 118 is H, alkyl, alkenyl, cycloalkyl, or heterocycle, R 119 C(O)O— wherein R 119 is 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 is 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 substituted or unsubstituted methylenedioxy, ethylenedioxy, or ethyleneoxy; and

R 112 is H or OR′, wherein R′ is alkyl, alkenyl, cycloalkyl, haloalkyl, or hydroxyalkyl

3. The compound of claim 1 , wherein the camptothecin analog is

4. The compound of claim 1 , wherein L is 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, piperidinic 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-diaminopropionic acid, n-ethylglycine, N-ethylasparagine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine, sarcosine, N-methyl-isoleucine, 6-N-methyl-lysine, N-methylvaline, norvaline, norleucine, and ornithine.

5. The compound of claim 4 , wherein L is glycine, alanine, methionine or sarcosine.

6. The compound of claim 1 , wherein L is glycine.

7. The compound of claim 1 , wherein L is selected from the group consisting of

wherein:

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, C 3-19 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6 heteroalkyls, substituted C 1-6 heteroalkyls, C 1-6 alkoxy, phenoxy and C 1-6 heteroalkoxy;

R 27 is selected from the group consisting of hydrogen, C 1-6 alkyls, C 2-6 alkenyls, C 2-6 alkynyls, C 3-19 branched alkyls, C 3-8 cycloalkyls, C 1-6 substituted alkyls, C 2-6 substituted alkenyls, C 2-6 substituted alkynyls, C 3-8 substituted 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 individually selected positive integers from 1 to 4; and

v is 0 or 1.

8. The compound of claim 1 , wherein m is 1.

9. The compound of claim 1 , wherein the total molecular weight of the polymeric portion of the compound ranges from about 20,000 to about 40,000 Daltons.

10. The compound of claim 1 , wherein the total molecular weight of the polymeric portion of the compound is about 40,000 daltons.

11. The compound of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are (L) m -D.

12. A compound of claim 1 , selected from the group consisting of

13. A compound of claim 1 having the formula

14. A method of treating cancer in a mammal, comprising administering an effective amount of a compound of Formula (I) to a mammal in need thereof,

wherein

the compound of Formula (I) has the structure of:

wherein

R 1 , R 2 , R 3 and R 4 are independently OH or (L) m -D;

L is a bifunctional linker;

D is a camptothecin or a camptothecin analog;

m is 0 or a positive integer from 1 to 10; and

n is a positive integer from about 28 to about 341,

provided that R 1 , R 2 , R 3 and R 4 are not all OH; and

the cancer is selected from the group consisting of colorectal cancer, lung cancer pancreatic cancer, ovarian cancer and breast cancer.

15. The method of claim 14 , wherein D is 7-ethyl-10-hydroxycamptothecin.

16. The method of claim 14 , wherein the cancer is metastatic.

17. The method of claim 14 , wherein the cancer is breast cancer and the compound of Formula (I) is

18. The method of claim 17 , wherein the compound is administered in amounts of from about 5 to about 20 mg/kg/dose.

19. The method of claim 14 , wherein the cancer is colorectal cancer and the compound of Formula (I) is

20. The method of claim 19 , wherein the compound is administered in amounts of from about 10 to about 30 mg/kg/dose.

21. The method of claim 14 , wherein the cancer is pancreatic cancer and the compound of Formula (I) is

22. The method of claim 21 , wherein the compound is administered in amounts of from about 10 to about 30 mg/kg/dose.

23. A method of preparing a multi-arm polymeric prodrug, comprising:

(a) providing one equivalent of a camptothecin or camptothecin analog containing an available 20-hydroxyl group and one or more equivalents of a bifunctional linker containing an available carboxylic acid group;

(b) reacting the two reactants under conditions effective to form a camptothecin-bifunctional linker intermediate having an available amine group; and

(c) reacting one or more equivalents per active site of the resulting intermediate and one equivalent of an activated polymer of the formula,

wherein the formula is

under conditions effective to form the multi-arm polymeric prodrug having the structure of

wherein

R 1 , R 2 , R 3 and R 4 are independently OH or (L) m -D;

L is a bifunctional linker;

D is a camptothecin or a camptothecin analog;

m is 0 or a positive integer from 1 to 10; and

n is a positive integer from about 28 to about 342;

provided that R 1 , R 2 , R 3 and R 4 are not all OH.

24. A method of preparing a multi-arm polymeric prodrug, comprising:

(a) reacting one equivalent of a camptothecin or camptothecin analog containing an available 20-hydroxyl group

with one or more equivalents of a bifunctional linker containing an available carboxylic acid group under conditions effective to form a camptothecin-bifunctional linker intermediate having an available amine group; and

(b) reacting one or more equivalents per active site of the resulting intermediate from step (a)

with one equivalent of an activated polymer of the formula,

wherein the formula is

under conditions effective to form the multi-arm polymeric prodrug having the structure of

wherein

R 1 , R 2 , R 3 and R 4 are independently OH or (L) m -D;

L is a bifunctional linker;

D is a camptothecin or a camptothecin analog;

m is 0 or a positive integer from 1 to 10; and

n is a positive integer from about 28 to about 341;

provided that R 1 , R 2 , R 3 and R 4 are not all OH.

25. The compound of claim 1 , wherein the camptothecin analog is 7-ethyl-10-hydroxycamptothecin or irinotecan.

26. The method of claim 14 , wherein the compound is administered in amounts of from about 1 mg/kg/week to about 100 mg/kg/week.

27. The method of claim 14 , wherein the compound is administered in amounts of from about 2 mg/kg/week to about 60 mg/kg/week.

28. The method of claim 14 , wherein the total molecular weight of the polymeric portion of the compound is about 40,000 daltons.

29. The method of claim 14 , wherein the cancer is lung cancer and the compound of Formula (I) is

30. The method of claim 29 , wherein the compound is administered in amounts of from about 1 mg/kg/week to about 100 mg/kg/week.

31. The method of claim 29 , wherein the compound is administered in amounts of from about 2 mg/kg/week to about 60 mg/kg/week.

32. The method of claim 14 , wherein the cancer is ovarian cancer and the compound of Formula (I) is

33. The method of claim 32 , wherein the compound is administered in amounts of from about 1 mg/kg/week to about 100 mg/kg/week.

34. The method of claim 33 , wherein the compound is administered in amounts of from about 2 mg/kg/week to about 60 mg/kg/week.