Methods to modulate Rac1 import and to treat pulmonary fibrosis

Patent metadata

Field	Value
Publication number	US-9416149-B2
Application number	US-201414262448-A
Country	US
Kind code	B2
Filing date	Apr 25, 2014
Priority date	Apr 25, 2013
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

The invention provides methods for treating fibrosis, as well as methods for modulating mitochondrial peroxide production in a cell, and methods for modulating the import of Rac1 into the mitochondria of a cell.

First claim

What is claimed is:

1. A method to treat pulmonary fibrosis in an animal in need thereof comprising administering to the animal an effective amount of a compound of formula I, formula II or formula III:

wherein:
R 1 is a saturated or unsaturated (C 5 -C 20 )alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —OR a , —P(═O)(OR a ) 2 , or —NR b R c ;
R 2 is a saturated or unsaturated (C 5 -C 20 )alkyl chain that optionally comprises one or more aryl rings in the chain and that is optionally substituted with one or more halo, trifluoromethyl, —OR a , —P(═O)(OR a ) 2 , or —NR b R c ;
each R 3 , R 4 , R 5 , and R 6 is independently OH or (C 1 -C 6 )alkoxy;
each R a is independently H, (C 1 -C 6 )alkyl, or aryl; and
each R b and R c is independently H, (C 1 -C 6 )alkyl, or aryl; or R b and R c together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
wherein any aryl of R 1 , R 2 , R a , R b or R c is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR d R e or S(O) 2 NR d R e , wherein each R d and R e is independently H or (C 1 -C 6 )alkyl;
X is (C 1 -C 6 )alkyl;
Y is (C 1 -C 6 )alkyl;
R 7 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;
R 8 is H or a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;
each R 9 , R 10 , R 11 , and R 12 is independently OH or (C 1 -C 6 )alkoxy;
R 13 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , aryl, heteroaryl, or S(O) 2 NR c1 R d1 ;
R 14 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , aryl, heteroaryl, or S(O) 2 NR c1 R d1 ;
R 15 is a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;
R 16 is H or a saturated or unsaturated (C 1 -C 20 )alkyl chain that optionally comprises one or more aryl or heteroaryl rings in the chain wherein (C 1 -C 20 )alkyl is optionally substituted with one or more halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, NR m R n , or S(O) 2 NR p R q and wherein any aryl or heteroaryl is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR a1 R b1 , or S(O) 2 NR c1 R d1 ;
each R a1 and R b1 is independently H, (C 1 -C 6 )alkyl, or aryl; or R a1 and R b1 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R c1 and R d1 is independently H, (C 1 -C 6 )alkyl, or aryl; or R c1 and R d1 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R p and R q is independently H, (C 1 -C 6 )alkyl, or aryl; or R p and R q together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring;
each R p and R q is independently H, (C 1 -C 6 )alkyl, or aryl; or R p and R q together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; and
wherein any aryl of R a1 , R b1 , R c1 , R d1 , R m , R n , R p or R q is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR s R t , or S(O) 2 NR s R t wherein each R s and R t is independently H or (C 1 -C 6 )alkyl;
or a pharmaceutically acceptable salt or prodrug thereof.

2. The method of claim 1 , comprising administering to the animal a compound of formula I:

or a pharmaceutically acceptable salt or prodrug thereof.

3. The method of claim 1 , wherein R 1 is of the formula,

wherein:
n is 0, 1, or 2; and
R g and R h together with the atoms to which they are attached form an aryl ring that is optionally substituted with one or more (e.g. 1, 2, 3, or 4) (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, NR d R e , or S(O) 2 NR d R e , wherein each R d and R e is independently H or (C 1 -C 6 )alkyl.

4. The method of claim 1 , wherein R 1 is of the formula,

wherein:
n is 0, 1, 2, or 3;
each bond designated by ----- is independently either present or is absent; and R b is phenyl or naphthyl and is optionally substituted with one or more carboxy or S(O) 2 NR d R

Assignees

• Univ Iowa Res Found

Inventors

• Hohl Raymond J
• Carter A Brent

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/663

  Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid · CPC title

• C07F9/65318 Primary

  having the two nitrogen atoms in positions 1 and 3 · CPC title

• C07F9/653

  Five-membered rings · CPC title

• C07F9/3839

  Polyphosphonic acids · CPC title