Furanochalcones as inhibitors of cyp1a1, cyp1a2 and cyp1b1 for cancer chemoprevention

Patent metadata

Field	Value
Publication number	US-2021284618-A1
Application number	US-201716325002-A
Country	US
Kind code	A1
Filing date	Aug 11, 2017
Priority date	Aug 12, 2016
Publication date	Sep 16, 2021
Grant date	—

Abstract

The present invention relates to the furanochalcone class of compounds of general formula A. The present invention particularly relates to the synthesis of furanochalcones and their CYP1A1, CYP1A2 and CYP1B1 inhibitory activity. In addition, the invention relates to the prevention or treatment of cancer caused by polyaromatic hydrocarbons (PAHs), 4-nitroquinoline-1-oxide, and N-nitroso-N-methylurea, heterocyclic amines, estrogen and 17β-estradiol, resulting from the inhibition of CYP1A1, CYP1A2 and CYP1B1 enzymes.

First claim

1 . A compound having formula A,

wherein, Ar is selected from the group consisting of 4-bromophenyl, 4-fluoro-3-bromo-phenyl, 2,4-difluorophenyl, 2,6-dichlorophenyl, 2-ethoxy-5-bromophenyl, 2,3-dimethoxyphenyl, 3-bromo-4-methoxyphenyl, 2,4,5-trimethoxyphenyl, thiophen-3-yl, 2,4-dichlorophenyl and anthracen-2-yl.

2 . The compound as claimed in claim 1 , wherein the compound having formula A is selected from the group consisting of:

3 . A method for preventing or treating cancer via inhibition of CYP1A1, CYP1A2, and CYP1B1 in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound having formula A,

wherein, Ar is selected from the group consisting of 4-bromophenyl, 4-fluoro-3-bromo-phenyl, 2,4-difluorophenyl, 2,6-dichlorophenyl, 2-ethoxy-5-bromophenyl, 2,3-dimethoxyphenyl, 3-bromo-4-methoxyphenyl, 2,4,5-trimethoxyphenyl, thiophen-3-yl, 2,4-dichlorophenyl, anthracen-2-yl, 4-chlorophenyl, 4-fluorophenyl, pyridine-3-yl, 4-methoxyphenyl, 2-chlorophenyl, 2,4-dimethoxyphenyl, pentafluorophenyl, phenyl, 3,4-methylene-dioxy-phenyl, naphth-2-yl, and 2-fluorophenyl.

4 . The method as claimed in claim 3 , wherein the compound having Formula A is selected from the group consisting of:

5 . The method as claimed in claim 3 , wherein the administering is effective to overcome chemo-resistance to cisplatin, docetaxel and paclitaxel through the inhibition of CYP1B1.

6 . The method as claimed in claim 4 , wherein IC 50 value of compound 8 is 342 and 470 nM against CYP1A1 in Sacchrosomes and in live cells.

7 . A process for preparation of the compound having Formula A as claimed in claim 1 , wherein the process comprises:
a. reacting khellin with an alkali hydroxide in an alcohol at reflux temperature ranging between 80-120° C. over a period in the range of 12-14 hours to form a reaction mixture, followed by concentrating the reaction mixture and extracting with an aqueous solvent selected from the group consisting of DCM: H 2 O, chloroform: H 2 O, and acetone: H 2 O to obtain khellinone; and b. reacting the khellinone obtained in (a) with an aldehyde in presence of a catalytic amount of an alkali selected from the group consisting of KOH and NaOH in an alcohol selected from the group consisting of methanol and ethanol at a temperature in the range of 0° C. to 1° C. over a period ranging between 12-14 hours to obtain the compound of Formula A. c.

8 . The process as claimed in claim 7 , wherein the alkali hydroxide used in (a) is selected from the group consisting of sodium hydroxide and potassium hydroxide.

9 . The process as claimed in claim 7 , wherein the alcohol used in (a) is selected from the group consisting of ethanol and methanol.

10 . The process as claimed in claim 7 , wherein the aldehyde used in (b) is selected from the group consisting of 4-bromophenyl aldehyde, 4-fluoro-3-bromo-phenyl aldehyde, 2,4-difluorophenyl aldehyde, 2,6-dichlorophenyl aldehyde, 2-ethoxy-5-bromophenyl aldehyde, 2,3-dimethoxyphenyl aldehyde, 3-bromo-4-methoxyphenyl aldehyde, 2,4,5-trimethoxyphenyl aldehyde, thiophen-3-yl aldehyde, 2,4-dichlorophenyl aldehyde and anthracen-2-yl aldehyde, 4-chlorophenyl aldehyde, 4-fluorophenyl aldehyde, pyridine-3-yl aldehyde, 4-methoxyphenyl aldehyde, 2-chlorophenyl aldehyde, 2,4-dimethoxyphenyl aldehyde, pentafluorophenyl aldehyde, phenyl aldehyde, 3,4-methylene-dioxy-phenyl aldehyde, naphth-2-yl aldehyde, and 2-fluorophenyl aldehyde.

11 . A pharmaceutical composition for the prevention or treatment of cancer, the pharmaceutical composition comprising an effective amount of at least one of the compound having structural Formulae A as claimed in claim 1 individually or in combination thereof, optionally, along with pharmaceutically acceptable excipients and/or diluents.

12 . The pharmaceutical composition as claimed in claim 11 , wherein the pharmaceutically acceptable excipients are saccharides selected from the group consisting of lactose, starch, and dextrose; stearates selected from the group consisting of stearic acid, magnesium stearate, polyvinylpyrrolidone, dicalcium phosphate dihydrate, eudragit polymers, celluloses, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, magnesium oxide, and silicon dioxide; or carbonates selected from the group consisting of sodium carbonate, sodium bicarbonate, and talc.

Assignees

• Council Scient Ind Res
• De Montfort Univ

Inventors

• Bharate Sandip Bibishan
• Sharma Rajni
• Joshi Prashant
• Vishwakarma Ram
• Chaudhuri Bhabatosh

Classifications

• C07D409/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D307/86 Primary

  with an oxygen atom directly attached in position 7 · CPC title

• C07D405/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title