Ketone ligands for modulating the expression of exogenous genes via an ecdysone receptor complex

Patent metadata

Field	Value
Publication number	US-9802936-B2
Application number	US-86947407-A
Country	US
Kind code	B2
Filing date	Oct 9, 2007
Priority date	Jul 5, 2002
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

This invention relates to a method to modulate exogenous gene expression in which an ecdysone receptor complex comprising: a DNA binding domain; a ligand binding domain; a transactivation domain; and a ligand is contacted with a DNA construct comprising: the exogenous gene and a response element; wherein the exogenous gene is under the control of the response element and binding of the DNA binding domain to the response element in the presence of the ligand results in activation or suppression of the gene. The ligands comprise a class of ketones.

First claim

What we claim is:

1. A compound of formula I:

wherein Q 1 is selected from the group consisting of O and S;
R 1 is selected from the group consisting of 2-methyl-3,4-methylenedioxyphenyl, 2-ethyl-3,4-methylenedioxyphenyl, 2-methyl-3,4-ethylenedioxyphenyl, 2-ethyl-3,4-ethylenedioxyphenyl, and 2-methyl-3,4-oxydimethylenephenyl;
R 2 and R 3 are independently:
(a) cyano, aminocarbonyl, carboxy, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )halocycloalkyl, (C 2 -C 6 )alkenyl, (C 3 -C 6 )cycloalkenyl, (C 2 -C 6 )haloalkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkylcarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylaminocarbonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkoxycarbonyl(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, or carboxy(C 1 -C 6 )alkyl; or
(b) unsubstituted or substituted phenyl, phenyl(C 1 -C 6 )alkyl, benzoyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thiophenyl, benzothiophenyl, benzofuranyl, isoxazolyl, or imidazolyl, heterocyclylcarbonyl, wherein the substituents are independently selected from the group consisting of cyano, nitro, halo, aminocarbonyl, aminothiocarbonyl, carboxy, formyl, hydroxy, amino, carbamoyl, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkythio, (C 1 -C 3 )haloalkylthio, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, (C 1 -C 2 )alkoxy(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylthio(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylsulfonyl(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, di(C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, (C 1 -C 3 )alkylcarbonyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylaminocarbonyl, di(C 1 -C 3 )alkylaminocarbonyl, and cyano(C 1 -C 3 )alkyl; or

R 2 and R 3 may be joined together with the carbon to which they are attached to form an unsubstituted or substituted, partially unsaturated or saturated 3-, 4-, 5-, 6-, 7- or 8-membered carbocyclic or heterocyclic ring wherein the heterocyclic ring contains from one to three heteroatoms selected from O, N, or S; and the substituents are independently selected from the group consisting of cyano, nitro, halo, aminocarbonyl, aminothiocarbonyl, carboxy, formyl, hydroxy, amino, carbamoyl, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkythio, (C 1 -C 3 )haloalkylthio, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, (C 1 -C 2 )alkoxy(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylthio(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylsulfonyl(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, di(C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, (C 1 -C 3 )alkylcarbonyl, (C 1 -C 4 )alkoxycarbonyl, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxycarbonylcarbonyl, (C 1 -C 3 )alkylaminocarbonyl, di(C 1 -C 3 )alkylaminocarbonyl, cyano(C 1 -C 3 )alkyl, oxo, methoxyimino, and spiro-(C 1 -C 4 )alkadioxy; and
R 4 is unsubstituted or substituted phenyl or pyridyl, wherein the substituents are independently selected from the group consisting of cyano, nitro, halo, aminocarbonyl, aminothiocarbonyl, carboxy, formnyl, hydroxy, amino, carbamoyl, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )haloalkyl, (C 3 -C 6 )halocycloalkyl, (C 2 -C 6 )alkenyl, (C 3 -C 6 )cycloalkenyl, (C 3 -C 6 )alkadienyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, (C 1 -C 6 )haloalkoxy, (C 3 -C 6 )cyclohaloalkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 1 -C 6 )alkythio, (C 3 -C 6 )cycloalkylthio, (C 1 -C 6 )haloalkylthio, (C 3 -C 6 )halocycloalkythio, (C 2 -C 6 )alkenylthio, (C 2 -C 6 )alkynylthio, (C 1 -C 6 )alkylsulfinyl, (C 3 -C 6 )cycloalkysulfinyl, (C 1 -C 6 )haloalkylsulfinyl, (C 3 -C 6 )halocycloalkylsulfinyl, (C 2 -C 6 )alkenylsulfinyl, (C 3 -C 6 )cycloalkenylsulfinyl, (C 2 -C 6 )alkynylsulfinyl, (C 1 -C 6 )alkylsulfonyl, (C 3 -C 6 )cycloalkysulfonyl, (C 1 -C 6 )haloalkylsulfonyl, (C 3 -C 6 )halocycloalkylsulfonyl, (C 1 -C 6 )alkylsulfinyl, (C 3 -C 6 )cycloalkysulfinyl, (C 1 -C 6 )haloalkylsulfinyl, (C 3 -C 6 )halocycloalkylsulfinyl, (C 1 -C 6 )alkylamino, (C 3 -C 6 )cycloalkylamino, di(C 1 -C 6 )alkylamino, di(C 3 -C 6 )(cycloalkyl)amino, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkoxyalkyl, (C 1 -C 6 )alkoxy(C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfonyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, (C 3 -C 6 )cycloalkylcarbonyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylaminocarbonyl, (C 3 -C 6 )cycloalkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, di(C 3 -C 6 )(cycloalkyl)aminocarbonyl, cyano(C 1 -C 6 )alkyl, and tri(C 1 -C 6 )alkylsilyl;
wherein in said substituted phenyl or pyridyl, two adjacent substituted positions may be joined together with the atoms to which they are attached to form an unsubstituted or substituted, unsaturated, partially unsaturated, or saturated 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring wherein the heterocyclic ring contains from one to three heteroatoms selected from N, O, or S; and the substituents are independently selected from the group consisting of cyano, nitro, halo, aminocarbonyl, aminothiocarbonyl, carboxy, fonnuyl, hydroxy, amino, carbamoyl, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkoxy, (C 1 -C 3 )alkythio, (C 1 -C 3 )haloalkylthio, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, (C 1 -C 2 )alkoxy(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylthio(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylsulfonyl(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, di(C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, (C 1 -C 3 )alkylcarbonyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylaminocarbonyl, di(C 1 -C 3 )alkylaminocarbonyl, cyano(C 1 -C 3 )alkyl, oxo, and methoxyimino.

2. The compound of claim 1 wherein:
Q 1 is O; and
R 4 is unsubstituted or substituted phenyl or pyridyl, wherein the substituents are independently selected from the group consisting of cyano, nitro, halo, carboxy, formyl, hydroxy, amino, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkoxy, (C 3 )alkenyloxy, (C 3 )alkynyloxy, (C 1 -C 3 )alkythio, (C 1 -C 3 )haloalkylthio, (C 1 -C 3 )alkylsulfinyl, (C 1 -C 3 )haloalkylsulfinyl, (C 1 -C 3 )alkylsulfonyl, (C 1 -C 3 )haloalkylsulfonyl, (C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, (C 1 -C 2 )alkoxy(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylthio(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylsulfinyl(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylsulfonyl(C 1 -C 2 )alkyl, (C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, di(C 1 -C 2 )alkylamino(C 1 -C 2 )alkyl, (C 1 -C 3 )alkylcarbonyl, (C 1 -C 3 )alkoxycarbonyl, (C 1 -C 3 )alkylaminocarbonyl, di(C 1 -C 3 )alkylaminocarbonyl, and cyano(C 1 -C 3 )alkyl;
wherein in said substituted phenyl or pyridyl, two adjacent positions may be joined together with the atoms to which they are attached to form an unsubstituted or substituted, unsaturated, partially unsaturated, or saturated 4-,5-, 6- or 7-membered carbocyclic or heterocyclic ring wherein the heterocyclic ring contains from one to three heteroatoms selected from N, O, or S; and the substituents are independently selected from the group consisting of cyano, nitro, halo, aminocarbonyl, amin

Assignees

• Tice Colin M
• Michelotti Enrique L
• Hormann Robert E
• Intrexon Corp

Inventors

• Tice Colin M
• Michelotti Enrique L
• Hormann Robert E

Classifications

• C07D211/58

  attached in position 4 · CPC title

• C07C311/20

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title

• C07D211/56

  Nitrogen atoms (nitro radicals C07D211/38) · CPC title

• C07D319/18

  Ethylenedioxybenzenes, not substituted on the hetero ring · CPC title

• C07C233/76

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms · CPC title