Compounds for treatment of cancer

Patent metadata

Field	Value
Publication number	US-10155728-B2
Application number	US-201715858183-A
Country	US
Kind code	B2
Filing date	Dec 29, 2017
Priority date	May 6, 2014
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

The present invention relates to colchicine-binding site compounds having anti-cancer activity, compositions comprising the same, and their use for treating various forms of cancer.

First claim

What is claimed:

1. A method of treating a cancer comprising administering a therapeutically effective amount of a compound of Formula II to a subject suffering from cancer under conditions effective to treat the cancer, wherein the compound of Formula II has the following formula:

wherein
Q is S, NH, or O;
Z is CH or N;
A is substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl, and the substituents include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO 2 , haloalkyl, CF 3 , CN, —CH 2 CN, NH 2 , hydroxyl, —(CH 2 ) i NHCH 3 , —(CH 2 ) i NH 2 , —(CH 2 ) i N(CH 3 ) 2 , —OC(O)CF 3 , —SO 2 -aryl, C 1 -C 5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH 2 Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH 2 or a combination thereof;
R 1 is independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF 3 , CN, NO 2 , —CH 2 CN, NH 2 , hydroxyl, COOH, C(O)H, NHCO-alkyl, —O(CH 2 ) j OCH 3 , —O(CH 2 ) j OH, —O(CH 2 ) j NHCH 3 , —O(CH 2 ) j NH 2 , —O—(CH 2 ) j N(CH 3 ) 2 , —OC(O)CF 3 , —OC(O)CH 2 Cl, —OCH 2 Ph, —O(CH 2 ) j NH 2 , —O(CH 2 ) j N-phthalimide or a combination thereof;
R 2 is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF 3 , CN, NO 2 , —CH 2 CN, NH 2 , hydroxyl, COOH, C(O)H, NHCO-alkyl, —O(CH 2 ) k OCH 3 , —O(CH 2 ) k OH, —O(CH 2 ) k NHCH 3 , —O(CH 2 ) k NH 2 , —O—(CH 2 ) k N(CH 3 ) 2 , —OC(O)CF 3 , —OC(O)CH 2 Cl, —OCH 2 Ph, —O(CH 2 ) k NH 2 or —O(CH 2 ) k N-phthalimide;
i, j, and k are independently an integer between 0 to 5;
n is an integer between 1 to 4;
or a hydrate, isomer, N-oxide, pharmaceutically acceptable salt, polymorph, or a combination thereof;
and wherein the cancer is selected from prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer, melanoma, drug-resistant melanoma, lung cancer, colon cancer, glioma, leukemia, lymphoma, renal cancer, CNS cancer, uterine cancer, drug-resistant uterine cancer, or a combination thereof.

2. The method according to claim 1 , wherein R 1 is OCH 3 , n is 3 and R 2 is hydrogen.

3. The method according to claim 1 , wherein the compound is compound 3 represented by the structure:

4. The method according to claim 1 , wherein the compound of claim 1 , or a pharmaceutically acceptable salt thereof, is compound 4, 5, 6 or 7:

5. The method according to claim 1 , wherein cancer is melanoma, metastatic melanoma, or prostate cancer.

6. A method of treating a drug resistant tumor comprising administering a therapeutically effective amount of a compound of Formula II to a subject in need thereof under conditions effective to treat the drug resistant tumor or tumors wherein the compound of Formula II has the following formula:

wherein
Q is S, NH, or O;
Z is CH or N;
A is substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl, and the substituents include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO 2 , haloalkyl, CF 3 , CN, —CH 2 CN, NH 2 , hydroxyl, —(CH 2 ) i NHCH 3 , —(CH 2 ) i NH 2 , —(CH 2 ) i N(CH 3 ) 2 , —OC(O)CF 3 , —SO 2 -aryl, C 1 -C 5 linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH 2 Ph, —NHCO-alkyl, COOH, —C(O)Ph, C(O)O-alkyl, C(O)H, —C(O)NH 2 or a combination thereof;
R 1 is independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF 3 , CN, NO 2 , —CH 2 CN, NH 2 , hydroxyl, COOH, C(O)H, NHCO-alkyl, —O(CH 2 ) j OCH 3 , —O(CH 2 ) j OH, —O(CH 2 ) j NHCH 3 , —O(CH 2 ) j NH 2 , —O—(CH 2 ) j N(CH 3 ) 2 , —OC(O)CF 3 , —OC(O)CH 2 Cl, —OCH 2 Ph, —O(CH 2 ) j NH 2 , —O(CH 2 ) j N-phthalimide or a combination thereof;
R 2 is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF 3 , CN, NO 2 , —CH 2 CN, NH 2 , hydroxyl, COOH, C(O)H, NHCO-alkyl, —O(CH 2 ) k OCH 3 , —O(CH 2 ) k OH, —O(CH 2 ) k NHCH 3 , —O(CH 2 ) k NH 2 , —O—(CH 2 ) k N(CH 3 ) 2 , —OC(O)CF 3 , —OC(O)CH 2 Cl, —OCH 2 Ph, —O(CH 2 ) k NH 2 or —O(CH 2 ) k N-phthalimide;
i, j, and k are independently an integer between 0 to 5;
n is an integer between 1 to 4;
or a hydrate, isomer, N-oxide, pharmaceutically acceptable salt, polymorph, or a combination thereof;
wherein the cancer is selected from prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer, melanoma, drug-resistant melanoma, lung cancer, colon cancer, glioma, leukemia, lymphoma, renal cancer, CNS cancer, uterine cancer, drug-resistant uterine cancer, or a combination thereof.

7. The method according to claim 6 , wherein R 1 is OCH 3 , n is 3 and R 2 is hydrogen.

8. The method according to claim 6 , wherein the compound is compound 3 represented by the structure:

9. The method according to claim 6 , wherein the compound of claim 1 , or a pharmaceutically acceptable salt thereof, is compound 4, 5, 6 or 7:

10. The method according to claim 6 , wherein the tumor is drug-resistant prostate cancer tumor, drug-resistant breast cancer tumor, drug-resistant ovarian cancer tumor, drug-resistant melanoma tumor, drug-resistant uterine cancer tumor, or a combination thereof.

11. The method according to claim 6 , wherein cancer is melanoma tumor, metastatic melanoma tumor, or prostate cancer tumor.

12. The method according to claim 6 further comprising a second cancer therapy.

Assignees

• Lu Yan
• Dalton James T
• Li Wei
• Miller Duane D
• Gtx Inc
• Univ Tennessee Res Found

Inventors

• Lu Yan
• Dalton James T
• Li Wei
• Miller Duane D

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D235/18 Primary

  with aryl radicals directly attached in position 2 · CPC title