IMIDAZOOXAZOLE DERIVATIVE HAVING ANTITUMOR EFFECT, AND PHARMACEUTICAL COMPOSITION INCLUDING SAME

• US 20200131199A1
• Filed: 12/31/2019
• Published: 04/30/2020
• Est. Priority Date: 07/05/2016
• Status: Active Grant

• Current Assignee: Korea Advanced Institute of Science and Technology
• Original Assignee: Korea Advanced Institute of Science and Technology
• Inventors: MAHMOUD, Gamal El-din, CHOI, Hong Seok, YOO, Kyung Ho, HAN, Dong Keun, OH, Chang Hyun, MOHAMMED, Abdel-Maksoud, MOHAMMED, I. El-Gamal, AMMAR, Usama M.
• Granted Patent: US 11,332,479 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Provided is a pharmaceutical composition for preventing and treating tumors, the pharmaceutical composition including an imidazooxazole derivative compound, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition is administered to an entity which has developed a tumor or is in danger of developing a tumor, and thus tumors can be prevented or treated.

Claims

1. A compound represented by the following Chemical Formula P or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof:

2. The compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein,

R¹ is hydrogen, hydroxy, C₁-C₄ alkoxy, a halogen, nitro, or amino;

Y is hydrogen, hydroxy, C₁-C₄ alkoxy, or a halogen;

R², R³, and R⁴ are each independently hydrogen or C₁-C₄ linear or branched alkyl; and

R⁵ is M or M-Z, wherein M and Z are each independently C₅-C₁₂ aryl, C₅-C₁₂ heteroaryl, C₅-C₁₂ cycloalkyl, or C₅-C₁₂ heterocycloalkyl unsubstituted or substituted with one or more substituents,

wherein the one or more substituents are selected from the group consisting of a halogen, C₁-C₄ linear or branched alkyl, C₁-C₄ alkoxy, trifluoromethyl, and hydroxyl.

3. The compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein,

R¹ is hydrogen, 3-hydroxy, or 3-methoxy;

Y is hydrogen, 4-flouoro, or 4-chloro;

R² is hydrogen, methyl, or ethyl;

R³ and R⁴ are each hydrogen; and

R⁵ is phenyl unsubstituted or substituted with one or more substituents,

wherein the one or more substituents are selected from the group consisting of 4-fluoro, 4-chloro, 4-hydroxy, 4-methoxy, and 4-trifluoromethyl.

4. The compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein the compound represented by Chemical Formula P is selected from the group consisting of:

4-fluoro-N-(3-(4-(6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)propyl)benzenesulfonamide;

4-chloro-N-(3-(4-(6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)propyl)benzenesulfonamide;

4-fluoro-N-(2-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)ethyl)benzenesulfonamide;

4-chloro-N-(2-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)ethyl)benzenesulfonamide;

N-(2-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)ethyl)benzenesulfonamide;

4-chloro-N-(3-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)propyl)benzenesulfonamide;

N-(3-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)propyl)-4-methoxybenzenesulfonamide;

N-(3-(4-(6-(3-amino-4-fluorophenyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-2-ylamino)propyl)-4-fluorobenzenesulfonamide;

4-chloro-N-(3-(4-(6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-ylamino)propyl)benzenesulfonamide;

4-fluoro-N-(2-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-ylamino)ethyl)benzenesulfonamide;

4-chloro-N-(2-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-ylamino)ethyl)benzenesulfonamide;

4-chloro-N-(3-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-ylamino)propyl)benzenesulfonamide;

N-(3-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-ylamino)propyl)-4-methoxybenzenesulfonamide; and

N-(3-(4-(6-(4-fluoro-3-hydroxyphenyl)imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-ylamino)propyl)benzenesulfonamide.

5. A method of preparing the compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, the method comprising:

cyclizing a compound of Chemical Formula 1 and a compound of Chemical Formula 2 to prepare a compound of Chemical Formula 3;

reacting the compound of Chemical Formula 3 with 4-chloro-2-(methylthio)pyrimidine to prepare a compound of Chemical Formula 4;

oxidizing the compound of Chemical Formula 4 to prepare a compound of Chemical Formula 5; and

reacting the compound of Chemical Formula 5 with an N-aminoethylcyclic sulfonamide derivative or an N-(2-aminoethyl)benzenesulfonamide derivative in the presence of a base to prepare the compound of Chemical Formula P.

6. A pharmaceutical composition for preventing and treating tumors, the pharmaceutical composition comprising the compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.

7. The pharmaceutical composition of claim 6, wherein the compound or the solvate, stereoisomer, or pharmaceutically acceptable salt thereof inhibits protein kinase to inhibit proliferation of tumor cells.

8. The pharmaceutical composition of claim 7, wherein the protein kinase is selected from the group consisting of V600E RAF, B-RAF, C-RAF, mitogen-activated protein kinase 14 (MAPK14), Fms-like tyrosine kinase 3 (FLT3), and glycogen synthase kinase 3 beta (GSK33).

9. The pharmaceutical composition of claim 6, wherein the tumors are selected from the group consisting of lung cancer, liver cancer, esophageal cancer, stomach cancer, colorectal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, renal cancer, cervical cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, testicular cancer, hematological malignancy, lymphoma, skin cancer, psoriasis, and fibroadenoma.

10. A method of preventing or treating tumors, the method comprising administering the pharmaceutical composition of claim 6 to a subject having or at risk of developing a tumor.