IP Library › Granted Patent US 9,138,486

Granted Patent B2

US 9,138,486 · App. 14/322,262 · Granted Sep 22, 2015

Cytotoxic peptides and antibody drug conjugates thereof

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Quick Facts

Patent No.: US 9,138,486
App. No.: 14/322,262
Granted: Sep 22, 2015
Kind: B2

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Abstract

The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

Claims (172)

1. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; and R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly or C 6 -C 14 aryl, optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl; or R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene-C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl; R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

2. The method of claim 1 , wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, salivary gland, thyroid gland, skin, stomach, and testes; and blood born cancers selected from the group consisting of leukemias and lymphomas.

3. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z is

L is an antibody;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly or C 6 -C 14 aryl, optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S;

wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, salivary gland, thyroid gland, skin, stomach, and testes; and blood born cancers selected from the group consisting of leukemias and lymphomas.

4. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

R 11 is

Z is

L is an antibody; and

X is O or S.

5. The method of claim 4 , wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, salivary gland, thyroid gland, skin, stomach, and testes; and blood born cancers selected from the group consisting of leukemias and lymphomas.

6. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IIc:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

R 1 is

Z′ is

L is an antibody;

D is —C(R 4A′ )(R 4B′ )— or is absent;

R 2′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, or is absent if

is present;

R 3A′ and R 3B′ are either of the following:

(i) R 3A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and R 3B′ is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl, or R 3B′ is C 2 -C 4 alkylene and forms 5-7 member ring as indicated by

(ii) R 3A′ and R 3B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A′ and R 4B′ are either of the following:

(i) R 4A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and R 4B′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A′ and R 4B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly or C 6 -C 14 aryl, optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

7. The method of claim 6 , wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, salivary gland, thyroid gland, skin, stomach, and testes; and blood born cancers selected from the group consisting of leukemias and lymphomas.

8. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IIIc:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

R 11′ is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —O 3 —C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z′ is

L is an antibody; and

X is O or S.

9. The method of claim 8 , wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, salivary gland, thyroid gland, skin, stomach, and testes; and blood born cancers selected from the group consisting of leukemias and lymphomas.

10. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IId:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

L is an antibody;

[linker] is a divalent linker;

D is —C(R 4A′ )(R 4B′ )— or is absent;

R 2′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, or is absent if

is present;

R 3A′ and R 3B′ are either of the following:

R 3A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and R 3B′ is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl, or R 3B′ is C 2 -C 4 alkylene and forms 5-7 member ring as indicated by

(ii) R 3A′ and R 3B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A′ and R 4B′ are either of the following:

R 4A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and R 4B′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A′ and R 4B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly or C 6 -C 14 aryl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —O 1 —C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene-C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

11. The method of claim 10 , wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, salivary gland, thyroid gland, skin, stomach, and testes; and blood born cancers selected from the group consisting of leukemias and lymphomas.

12. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IIId:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

[linker] is a divalent linker;

L is an antibody; and

X is O or S.

13. The method of claim 12 , wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, salivary gland, thyroid gland, skin, stomach, and testes; and blood born cancers selected from the group consisting of leukemias and lymphomas.

14. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound: