Compounds as modulator of JAK-STAT pathway, methods and applications thereof

Patent metadata

Field	Value
Publication number	US-9604974-B2
Application number	US-201615004114-A
Country	US
Kind code	B2
Filing date	Jan 22, 2016
Priority date	Jan 22, 2015
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

The present disclosure relates to compound of structural Formula I and a method for preparing said compounds. The disclosure further relates to a method of employing the Formula I compounds for modulation of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway in cancer cells, and the corresponding use of compound of Formula I as anti-cancer agents.

First claim

We claim:

1. A compound of Formula I

where, ‘R’ is selected from a group consisting of 1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl, 2-butyl-5-chloro-3-(4-benzyloxy-1-benzyl)-imidazol-4-yl, 2,6-dichlorophenyl and chromene-4-one;
‘R 1 ’ is hydrogen or 4-(2-cyanophenyl)benzyl;
or its tautomers, isomers, or salts thereof.

2. The compound as claimed in claim 1 , wherein said compound is selected from a group comprising:
2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-aza spiro(5,5) undecane;
2-(2-butyl-5-chloro-3-(4-benzyloxy-1-benzyl)-imidazol-4-yl)-5-(4-methoxy-phenyl)-1-oxa-3-aza spiro(5, 5) undecane;
3-[5-(4-Methoxy-phenyl)-1-oxa-3-aza-spiro[5.5]undec-2-yl]-chromen-4-one;
2-(2,6-dichlorophenyl)-5-(4-methoxy-phenyl)-1-oxa-3-(4-(2-cyanophenyl)benzyl azaspiro(5,5) undecane.

3. The compound as claimed in claim 1 , wherein said compound is crystalline and has a melting point ranging from about 55° C. to about 160° C.

4. The compound as claimed in claim 1 , wherein said compound is soluble in solvent selected from a group comprising DMSO, CDCl 3 , methanol, DMF, ethanol and combinations thereof.

5. A method for preparing a compound of Formula I,

where, ‘R’ is selected from a group consisting of 1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl, 2-butyl-5-chloro-3-(4-benzyloxy-1-benzyl)-imidazol-4-yl, 2,6-dichlorophenyl, and chromene-4-one;
‘R 1 ’ is hydrogen or 4-(2-cyanophenyl)benzyl;
or its tautomers, isomers, or salts thereof;
said method comprising steps of:
a) reacting amino alcohol with an aldehyde in presence of a base to obtain the compound of Formula I wherein ‘R 1 ’ is hydrogen, ‘R’ is selected from a group consisting of 1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl, 2-butyl-5-chloro-3-(4-benzyloxy-1-benzyl)-imidazol-4-yl, 2,6-dichlorophenyl and chromene-4-one; and
b) optionally, reacting the compound of Formula I of step (a) with 4-(2-cyanophenyl) benzyl halide to obtain the compound of Formula I, wherein ‘R’ is 2,6-dichlorophenyl, and ‘R 1 ’ is 4-(2-cyanophenyl) benzyl moiety.

6. The method as claimed in claim 5 , wherein the amino alcohol is 1-(2-amino)-1-(4-methoxy-phenyl-ethyl)-cyclohexanol; the 4-(2-cyanophenyl) benzyl halide is 4-(2-cyanophenyl)benzyl bromide; the base is selected from a group comprising potassium carbonate, sodium carbonate and a combination thereof; and the aldehyde is selected from a group comprising

7. The method as claimed in claim 5 , wherein the reaction is carried out in a solvent selected from a group comprising methanol, ethanol, DMSO, DMF, Ethyl acetate, Ether and combinations thereof.

8. The method as claimed in claim 5 , wherein the reaction is carried out at temperature ranging from about 25° C. to about 30° C.; and for time period ranging from about 4 hours to about 5 hours.

9. The method as claimed in claim 5 , wherein the compound of Formula I is extracted, dried and re-crystallized.

10. A method of inhibiting a protein selected from a group comprising tyrosine kinase, Signal Transducer and Activator of Transcription (STAT) and a combination thereof in a cancer cell, said method comprising act of contacting the compound of claim 1 with the cancer cell for inhibiting the protein.

11. The method as claimed in claim 10 , wherein the tyrosine kinase is selected from a group comprising Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), c-Src kinase and combinations thereof; and the STAT is Signal Transducer and Activator of Transcription 3 (STAT3).

12. The method as claimed in claim 10 , wherein concentration of the compound of Formula I ranges from about 7.3 μM to about 50 μM.

13. The method as claimed in claim 10 , wherein the inhibition of the tyrosine kinase leads to inhibition of STAT3 activation.

14. The method as claimed in claim 13 , wherein the inhibition of STAT3 activation is carried out by suppressing STAT3 phosphorylation at tyrosine 705 (Y705) residue.

15. The method as claimed in claim 14 , wherein the phosphorylation is selected from a group comprising constitutive phosphorylation, interleukin-6 (IL-6) induced phosphorylation and a combination thereof; and the constitutive phosphorylation is regulated by tyrosine kinase.

16. The method as claimed in claim 13 , wherein inhibition of STAT3 activation result in reduction in nuclear localization of STAT3 in cancer cell.

17. The method as claimed in claim 10 , wherein said method inhibits Janus kinase—Signal Transducer and Activator of Transcription (JAK-STAT) pathway in the cancer cell.

18. The method as claimed in claim 10 , wherein said method treats cancer; and the cancer is selected from a group comprising hepatocellular carcinoma (HCC), leukemia, lymphoma, prostate cancer, breast cancer, ovarian cancer, multiple myeloma, head and neck cancer, gastric cancer and combinations thereof.

Assignees

• Univ Of Mysore
• Nat Univ Singapore
• Bangalore Univ
• Cambridge Entpr Ltd
• Nat Univ Of Singpore

Inventors

• Rangappa Kanchugarakoppal Subbegowda
• Basappa
• Mohan Chakrabhavi Dhananjaya
• RANGAPPA Shobith
• Bharathkumar Hanumantharayappa
• Sethi Gautam
• Bender Andreas
• Lobie Peter Edward
• Hui Kam Man
• Kumar Alan Prem
• Pandey Vijay Kumar
• Fuchs Julian
• SHANMUGAM Muthu Kumaraswamy
• Bulusu Krishna
• Dai Xiaoyun
• Li Feng
• Deivasigamani Amudha

Classifications

• C07D413/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D265/16

  with only hydrogen or carbon atoms directly attached in positions 2 and 4 · CPC title