Boronic acid inhibitors of HIV protease

Patent metadata

Field	Value
Publication number	US-9738664-B2
Application number	US-201514927390-A
Country	US
Kind code	B2
Filing date	Oct 29, 2015
Priority date	Oct 29, 2014
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

Protease inhibitors, particularly aspartyl protease inhibitors, and more particularly HIV protease inhibitors which are boronated to enhance activity or to enhance entry into cells. Compounds, prodrugs and salts thereof of this invention contain phenylboronate groups, in particular p -B(OH) 2 -phenyl groups, benzoxaborole groups or borono-pyridyl groups or analogous groups in which the boronate group is protected. Methods for treating AIDS and ARC as well as providing a method for treating or preventing HIV infection.

First claim

We claim:

1. A compound of formula:

or a pharmaceutically acceptable salt, ester, or solvate thereof,
wherein:
x is 0 or 1 to show the presence or absence of —XX—;
—XX—, when present, is —O—, —CO—, —SO 2 —, —CO—CO—, —O—CO—, —O—SO 2 —, —NR 10 —SO 2 —, —NR 10 —CO— or —NR 10 —CO—CO—, where each R 10 is independently H, C1-C4 alkyl or C1-C4 alkyl substituted with C3-C7 cycloalkyl;
R 20 , and R 20A are independently selected from C1-C4 alkyl, C3-C6 cycloalkyl, C5-C6-cycloalkenyl, phenyl, C1-C4 alkyl substituted with one or more phenyl, or substituted with one or more C3-C6 cycloalkyl groups, a C3-C6 cycloalkyl group substituted with or fused to a phenyl, and a C5-C6 cycloalkyl group substituted with or fused to a phenyl; R 20B is independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C5-C6-cycloalkenyl, phenyl, C1-C4 alkyl substituted with one or more phenyl, or substituted with one or more C3-C6 cycloalkyl groups, a C3-C6 cycloalkyl group substituted with or fused to a phenyl, and a C5-C6 cycloalkyl group substituted with or fused to a phenyl;
R 21 is selected from H, —PO 3 H 2 , —PO 3 H − , —PO 3 2− , —CH 2 —OPO 3 H 2 , —CH 2 —OPO 3 H − , —CH 2 —OPO 3 2− , —PO 3 (R 31 ) 2 , —PO 3 R 31 H, and pharmaceutically acceptable salts thereof, where R 31 is optionally substituted C1-C6 alkyl or optionally substituted C6-C10 aryl, and —CO—R 22 , where R 22 is selected from C1-C4 alkyl, C2-C4 alkenyl, C2-C10 alkyl, wherein one or more —CH 2 — groups are replaced with —O—, and a C2-C10 alkyl, wherein one or more —CH 2 — groups are replaced with —NH— or one or more —CH 3 groups are replaced with —NR 23 , where R 23 is H or a C1-C4 alkyl; and
A is selected from H, Het, C6-C10 aryl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, C1-C4 alkyl, C2-C4 alkenyl, and C1-C4 alkyl substituted with one or more C1-C4 alkoxy, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, C6-C10 aryl, or Het group,
wherein Het is a 5-10 membered saturated, partially saturated or unsaturated cyclic group containing one or more heteroatoms or moieties selected from —N═, —N(R 24 )—, —O—, —S—, —SO—, —SO 2 —, and —CO—, where R 24 is selected from H, C1-C4 alkyl, C1-C4 alkyl substituted with a C3-C7 cycloalkyl group, and C1-C4 alkyl substituted with a C6-C10 aryl group;
wherein each R 20 , R 22 , R 23 , R 24 , R 31 , A or Het group is optionally substituted with one or more oxo, C1-C3 alkoxy, —OH, C1-C3 alkyl, —CO—R 25 , —N(R 25 ) 2 , —CO 2 R 25 , —NR 25 —CO—R 25 , —CO—N(R 25 ) 2 ,—(CH 2 ) r —OH, where r is 1 or 2, —CN, —NO 2 , halo or —CF 3 , where R 25 is H or C1-C3 alkyl; and
BBB is

2. The compound, salt, ester, or solvate of claim 1 , wherein XX is present, x is 1 and is —O—, —CO—,—SO 2 —or —O—CO—.

3. The compound, salt, ester, or solvate of claim 1 , wherein A is a 5-10 membered saturated, partially saturated or unsaturated cyclic group containing one or more heteroatoms or moieties selected from —N═, —N(R 24 )—, —O—, —S—, —SO—, —SO 2 —, and —CO—, where R 24 is selected from H, C1-C4 alkyl, C1-C4 alkyl substituted with a C3-C7 cycloalkyl group, and C1-C4 alkyl substituted with a C6-C10 aryl group.

4. The compound, salt, ester, or solvate of claim 1 , wherein XX is present, x is 1 and is —O—CO—, R 20 is a benzyl group, R 20A is C1-C4 alkyl and R 20B is hydrogen.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound, salt, ester, or solvate of claim 1 and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound, salt, ester, or solvate of claim 1 and a pharmaceutically acceptable carrier and further comprising ritonovir.

7. The compound, salt, ester, or solvate of claim 4 , where R 21 is selected from hydrogen, —PO 3 H 2 , —PO 3 H − , —PO 3 2− , —CH 2 —OPO 3 H 2 , —CH 2 —OPO 3 H − ,—CH 2 —OPO 3 2− , —PO 3 (R 31 ) 2 , —PO 3 R 31 H, and pharmaceutically acceptable salts thereof, where R 31 is optionally substituted C1-C6 alkyl or optionally substituted C6-C10 aryl.

8. The compound, salt, ester, or solvate of claim 7 , where A is selected from A1-A4 of formulae:

9. The compound, salt, ester, or solvate of claim 7 , where A is A2 or A4 of formulae:

10. The compound, salt, ester, or solvate of claim 9 of formula:

where R 21 is hydrogen, —PO 3 H 2 or pharmaceutically acceptable salts thereof.

11. The compound, salt, ester, or solvate of claim 7 , where A is A2 or A4 of formulae:

12. The compound claim 1 which is selected from:

or
a salt, ester, or solvate thereof.

13. The compound of claim 1 of formula:

or a salt, ester, or solvate thereof.

14. The compound of claim 1 of formula:

Assignees

• Wisconsin Alumni Res Found

Inventors

• Raines Ronald T
• Windsor Ian
• Palte Michael
• Lukesh John

Classifications

• A61P31/18

  for HIV · CPC title

• A61K31/34

  having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide · CPC title

• A61K31/00

  Medicinal preparations containing organic active ingredients · CPC title

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/366

  having six-membered rings, e.g. delta-lactones · CPC title