Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

Patent metadata

Field	Value
Publication number	US-2020345717-A1
Application number	US-201916719794-A
Country	US
Kind code	A1
Filing date	Dec 18, 2019
Priority date	Oct 14, 2011
Publication date	Nov 5, 2020
Grant date	—

Abstract

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-xL protein.

First claim

1 - 16 . (canceled)

17 . A process for preparing tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((1-morpholinocyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate (160F),

comprising:
combining ethyl 1-aminocyclohexanearboxylate hydrogen chloride, triethylamine, and 1-bromo-2-(2-bromoethoxy)ethane (4.21 mL) in N,N-dimethylformamide at 95° C. to produce ethyl 1-morpholinocyclohexanecarboxylate (160A),

adding lithium aluminum hydride dropwise to a solution of 160A in diethyl ether at 0° C., followed by allowing the mixture to warm to room temperature, stirring at room temperature, and cooling to 0° C. followed by adding water and 15% aqueous NaOH solution to the mixture to produce (1-morpholinocyclohexyl)methanol (160B),

adding 1H-pyrazole and cyanomethylenetributylphosphorane to a solution of 160B in toluene to produce 4-(1-((1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine (160C),

adding n-butyllithium in hexanes dropwise to a solution of 160C at −45° C., followed by allowing the mixture to warm to −20° C. and adding iodomethane dropwise to produce 4-(1-((5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine (160D),

dissolving 160D in N,N-dimethylformamide and adding N-bromosuccinimide to the solution of 160D in N,N-dimethylformamide to produce 4-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine (160E)

heating a suspension of 160E, tert-butyl 6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate, tris(dibenzylideneacetone)dipalladium(0), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane, and potassium phosphate in tetrahydrofuran and water, followed by purifying 160F from the suspension.

Assignees

• Abbvie Inc

Inventors

• Wang Le
• Doherty George
• Wang Xilu
• Tao Zhi-Fu
• Bruncko Milan
• Kunzer Aaron R
• Wendt Michael D
• Song Xiaohong
• Frey Robin
• Hansen Todd M
• Sullivan Gerard M
• Judd Andrew
• Souers Andrew

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4725 Primary

  containing further heterocyclic rings · CPC title