IP Library Granted Patent US 10,155,728
Granted Patent B2
US 10,155,728 · App. 15/858,183 · Granted Dec 18, 2018

Compounds for treatment of cancer

Inventors: Yan Lu (Bartlett, TN); James T Dalton (Ann Arbor, MI); Wei Li (Germantown, TN); Duane D Miller (Collierville, TN)
Assignees: GTX INC.; UNIVERSITY OF TENNESSEE RESEARCH FOUNDATION
C07D235/18A61K31/4184A61K31/426A61K31/437A61K45/06C07D277/24C07D403/04C07D417/12C07D471/04
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Quick Facts
Patent No.
US 10,155,728
App. No.
15/858,183
Granted
Dec 18, 2018
Kind
B2
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.

Claims (32)

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.

Assignments (3)
CHANGE OF NAME Recorded Mar 17, 2020
From: GTX, INC
To: ONCTERNAL THERAPEUTICS, INC
Reel/Frame 052184/0092 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2018
From: LU, YAN; DALTON, JAMES T
To: GTX INC.
Reel/Frame 046469/0695 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 26, 2018
From: LI, WEI; MILLER, DUANE D.
To: UNI VERSITY OF TENNESSEE RESEARCH FOUNDATION
Reel/Frame 046470/0072 →
Continuity (3)
Division 15309357
Provisional Application 61989294 · May 6, 2014
Related Publication 20180118693A1 · May 3, 2018