Catechol diethers as potent anti-HIV agents

Patent metadata

Field	Value
Publication number	US-9487476-B2
Application number	US-201214348952-A
Country	US
Kind code	B2
Filing date	Oct 12, 2012
Priority date	Oct 12, 2011
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention is directed to novel catechol diether compounds, pharmaceutical compositions therefrom and methods for inhibiting reverse transcriptase and treating HIV infections, especially included drug resistant strains of HIV 1 and 2 and/or secondary disease states and/or conditions which occur as a consequence of HIV infection.

First claim

We claim:

1. A compound according to the chemical structure:

wherein R 1 is H, OH, a halogen, CN, NO 2 , morpholinylethoxy, an optionally substituted alkyl group, an optionally substituted C 2 -C 6 alkene group, an optionally substituted C 2 -C 6 alkyne group, —(CH 2 ) m —NR A R B , —(CH 2 ) m —C(O)NR A R B1 , —(CH 2 ) m —NR A C(O)R C , —(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —O—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —O—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted,
—(CH 2 ) m —C(O)—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —OC(O)—C 1 -C 6 alkyl which is optionally substituted, or —(CH 2 ) m —C(O)O—C 1 -C 6 alkyl which is optionally substituted;
R A and R B are each independently H or an optionally substituted C 1 -C 6 alkyl group;
R B1 is H, an optionally substituted C 1 -C 6 alkyl group or an optionally substituted —(CH 2 ) m —O—(C 1 -C 6 ) alkyl group;
R C is H, an optionally substituted C 1 -C 6 alkyl group, or an optionally substituted —(CH 2 ) m —O—(C 1 -C 6 ) alkyl group;
R′ is H, OH, a halogen, CN, NO 2 , an optionally substituted C 1 -C 6 alkyl group, —(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —O—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —C(O)—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —OC(O)—C 1 -C 6 alkyl which is optionally substituted, or —(CH 2 ) m —C(O)O—C 1 -C 6 alkyl which is optionally substituted;
X′ and Y′ are each independently a bond (absent), O, S, S(O) (sulfoxide) or S(O)(O)(sulfone);
R 3 is H, OH, a C 1 -C 3 alkyl group which is optionally substituted with up to three halogens, —O—C 1 -C 3 alkyl, which is optionally substituted with up to three halogens, a halogen, NO 2 or CN;
j, j 1 , m, n and n 1 are each independently 0, 1, 2 or 3;
X and Y are each independently H, OH, a halogen, CN, NO 2 , an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 2 -C 6 alkene group, an optionally substituted C 2 -C 6 alkyne group, —(CH 2 ) m —NR A R B , —(CH 2 ) m —C(O)NR A R B1 , —(CH 2 ) m —NR A C(O)R C , —(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —O—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted,
—(CH 2 ) m —C(O)—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —OC(O)—C 1 -C 6 alkyl which is optionally substituted, or —(CH 2 ) m —C(O)O—C 1 -C 6 alkyl which is optionally substituted, or X and Y, together with W, form an optionally substituted pyrrole ring, an optionally substituted dihydrofuran ring or an optionally substituted dihydropyrrole ring;
W is N or C, wherein when W is N, W, X and Y together form an optionally substituted five-membered pyrrole ring and when W is C, C is optionally substituted with X, Y or R 3 , or alternatively, W, X and Y form an optionally substituted dihydrofuran ring or an optionally substituted dihydropyrrole ring; and
R p is an optionally substituted C 1 -C 6 alkyl group or an optionally substituted 6 membered heteroaryl group, or
a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate or polymorph thereof.

2. The compound according to claim 1 wherein R 1 and is H, halogen, CN, NO 2 , NH 2 , NHCH 3 , or morpholinylethoxy.

3. The compound according to claim 1 wherein either of R 1 or R′ is H.

4. The compound according to claim 1 wherein R 1 and R′ are each independently H or a halogen.

5. The compound according to claim 4 wherein R 1 is Cl or F and R′ is H.

6. The compound according to claim 1 wherein X and Y are each independently H, halogen, CN, NO 2 , (E)-cyanovinyl, methoxyethoxy or 3-hydroxypropan-1-oxy.

7. The compound according to claim 1 wherein X′ and Y′ are both O, j, j 1 and n 1 are each 0 and n is 1 or 2.

8. The compound according to claim 1 wherein Rp is a pyrimidine group attached at the N-1 position of the pyrimidine group and contains a substituent R 2a , attached at the 5- or 6-position of the pyrimidine group, wherein the R 2a is H, CH 3 , F, Cl, Br or I.

9. The compound according to claim 1 wherein Rp is a uracil group attached at the N-1 position of the uracil group and contains a substituent R 2a , attached at the 5-position of the uracil group, wherein the R 2a is H or CH 3 .

10. The compound according to claim 1 wherein the compound is

11. A compound according to the chemical structure:

wherein W is N or C;
R 1 is H, OH, a halogen, a morpholinylethoxy group, an optionally substituted alkyl group, an optionally substituted C 2 -C 6 alkene group, an optionally substituted C 2 -C 6 alkyne group, —(CH 2 ) m —NR A R B , —(CH 2 ) m —C(O)NR A R B1 , —(CH 2 ) m —NR A C(O)R C , —(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —O—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —O—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —C(O)—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —OC(O)—C 1 -C 6 alkyl which is optionally substituted, or —(CH 2 ) m —C(O)O—C 1 -C 6 alkyl which is optionally substituted;
R A and R B are each independently H or an optionally substituted C 1 -C 6 alkyl group;
R B1 is H, an optionally substituted C 1 -C 6 alkyl group, or an optionally substituted —(CH 2 ) m —O—(C 1 -C 6 ) alkyl group;
R C is H, an optionally substituted C 1 -C 6 alkyl group or an optionally substituted —(CH 2 ) m —O—(C 1 -C 6 ) alkyl group;
R′ is H, OH, a halogen, CN, NO 2 , an optionally substituted C 1 -C 6 alkyl group,
—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —O—(CH 2 ) m —O—(C 1 -C 6 ) alkyl which is optionally substituted, —(CH 2 ) m —C(O)—(C 1 -C 6 ) alkyl which is optionally substituted,
—(CH 2 ) m —OC(O)—C 1 -C 6 alkyl which is optionally substituted, or —(CH 2 ) m —C(O)O—C 1 -C 6 alkyl which is optionally substituted;
X′ and Y′ are each independently a bond (absent), O, S, S(O) (sulfoxide) or S(O)(O)(sulfone);
R 3 is H, OH, a C 1 -C 3 alkyl group which is optionally substituted with up to three halogens,
—O—C 1 -C 3 alkyl which is optionally substituted with up to three halogens, a halogen, NO 2 or CN;
j, j 1 , m, n and n 1 are each independently 0, 1, 2 or 3;
X 1 is

or N—R X when W is C, or

when W is N;
Z is

Y 1 is

O or N—R Y when W is C, or

when W is N;
R 2 is H, a C 1 -C 3 alkyl optionally substituted with up to three fluorines, CN or halogen; and
R X and R Y are each independently H or a C 1 -C 6 alkyl (or a C 1 -C 3 alkyl) group, optionally substituted with one or two hydroxyl groups, and
R p is an optio

Assignees

• Univ Yale

Inventors

• Jorgensen William L
• Anderson Karen S

Classifications

• A61K31/5377

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

• C07D239/553

  with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil · CPC title

• C07D239/54

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title