Amphiphilic cyclobutenes and cylobutanes

Patent metadata

Field	Value
Publication number	US-10538475-B2
Application number	US-201314403763-A
Country	US
Kind code	B2
Filing date	May 28, 2013
Priority date	May 25, 2012
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

This disclosure relates to amphiphilic compounds containing a cyclobutene or cyclobutane moiety. In some embodiments, the compounds are useful for treating infection by Mycobacterium such as Mycobacterium tuberculosis. Cyclobutene containing compounds are also useful as monomers in the preparation of amphiphilic polymers.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
----- represents an optionally present double bond;
R 1 and R 2 are independently selected from the group consisting of: H, halo, OR 5 , and ═O;
R 3 is an optionally substituted C 5 -C 40 alkyl;
R 4 is C 2 -C 30 alkyl optionally substituted with Cy 1 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)NR c1 R d1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O) 2 R b1 and S(O) 2 NR c1 R d1 ;
each Cy 1 is independently C 6-10 aryl, C 3-10 carbocyclyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, each of which is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 S(O)NR c1 R d1 , S(O) 2 R b1 , S(O) 2 NR c1 R d1 and oxo;
each R a1 , R b1 , R c1 , R d1 , is independently selected from C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 carbocyclyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 carbocyclyl-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl or (4-10 membered heterocyclyl)-C 1-4 alkyl, wherein said C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 carbocyclyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 carbocyclyl-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl and (4-10 membered heterocyclyl)-C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR 4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR 4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR 4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR 4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR 4 R d4 , S(O) 2 R b4 NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR 4 R d4 and S(O) 2 NR 4 R d4 ;
each R a4 , R b4 , R c4 and R d4 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy; and

Z is selected from the group consisting of: COR 6 , CO 2 H, NHC(O)NR 6 R 7 , CONR 6 , OCOR 6 , OR 6 , SR 6 , NR 6 R 7 , and OPO 3 R 6 ;
R 5 is C 1 -C 6 alkyl;
R 6 and R 7 are independently H or C 1 -C 6 alkyl; and
wherein the hydrocarbon backbone formed by R 4 and R 3 —Z is amphiphilic.

2. The compound of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of: H, halo, and ═O.

3. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 4 is a C 2 -C 10 alkyl.

5. The compound of claim 1 , wherein Z is CO 2 H.

6. The compound of claim 1 , wherein the compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
---- represents an optionally present double bond;
R 1 and R 2 are independently selected from the group consisting of: H, halo, OR 5 , and =0;
R 3 is an optionally substituted C 5 -C 40 alkyl;
R 4 is C 1 -C 40 alkyl optionally substituted with Cy 1 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, C 1-6 haloalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)NR c1 R d1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 S(O) 2 R b1 and S(O) 2 NR c1 R d1 ;
each Cy 1 is independently C 6-10 aryl, C 3-10 carbocyclyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, each of which is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , S(O) 2 NR c1 R d1 and oxo;
each R a1 , R b1 , R c1 , R d1 , is independently selected from C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 carbocyclyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 carbocyclyl-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl or (4-10 membered heterocyclyl)-C 1-4 alkyl, wherein said C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 carbocyclyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 6-10 aryl-C 1-4 alkyl, C 3-10 carbocyclyl-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl and (4-10 membered heterocyclyl)-C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR 4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR 4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR 4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR 4 R d4 , NR c4 C(═NR e4 )NR 4 R d4 S(O)R b4 , S(O)NR 4 R d4 , S(O) 2 R b4 NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR 4 R d4 and S(O) 2 NR 4 R d4 ;

each R a4 , R b4 , R c4 and R d4 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, is optionally substituted with 1, 2,

Assignees

• Nutech Ventures

Inventors

• Sittiwong Wantanee
• Dussault Patrick H
• Barletta Raul
• Powers Robert

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07C67/313

  by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups · CPC title

• C07C59/11

  containing rings · CPC title

• C07C59/205

  containing rings · CPC title