Cytotoxic-drug delivering molecules targeting HIV (CDM-Hs), cytotoxic activity against the human immunodeficiency virus and methods of use

Patent metadata

Field	Value
Publication number	US-9745334-B2
Application number	US-201314396956-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	Apr 26, 2012
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as CDM-Hs, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by introducing cytotoxic moieties to gp120-expressing cells, thereby causing cell death and preventing cell infection and spread of HIV. It is shown that CDM-Hs bind to gp120 and gp-120 expressing cells competitively with CD4, and these compounds cause cell death of HIV-infected cells, thereby decreasing viral infectivity. Compounds and methods are described herein.

First claim

The invention claimed is:

1. A compound according to the chemical structure:

Where X 2 is H, C 1 -C 6 alkyl, O—C 1 -C 6 alkyl or halogen;

is

W or W′ is each independently H, —(CH 2 ) n″ OH, —(CH 2 ) n″ COOH, —(CH 2 ) n″ O—(C 1 -C 6 alkyl), NO 2 , CN or halogen;
n and n′ are each independently 2-8;
Each n″ is independently 0, 1, 2, 3, 4, 5, or 6;
i is 0 or 1;
[LL] is a labile linker according to the chemical structure:

where R is an ethylene glycol group, or a methylene group and n in this labile linker is from 0 to 10;
X is O, N—R AL or S;
R AL is H or a C 1 -C 3 alkyl group;
Y is O or S and
Z=Me, Et, iPr, tBu, Ph, each of which may be optionally substituted with one or more halogen groups and where said Ph group may be further optionally substituted with OMe or a C 1 -C 3 alkyl group which itself may be substituted with up to three halogens; or
[LL] is a group according to the chemical formula:

and
R is an ethylene glycol group, or a methylene group and n in this labile linker is from 0 to 10; or [LL] is an enzymatically cleaved labile linker according to the chemical structure:

Where the protease substrate is a peptide containing from 2 to 50 amino acid units, and
R is an ethylene glycol group, or a methylene group;
and n in this labile linker is from 0 to 10; or
[LL] is a group according to the chemical structure:

Where the points of attachment in each of the labile linkers as indicated are joined to other portions of the molecule as indicated;
[NLL] when present is a (poly)ethylene glycol linker of from 2 to 8 ethylene glycol units, or [NLL] is a group:

where each X S is independently S, O or N—R S ;
R S is H or C 1-3 alkyl;
S c is CH 2 ; CH 2 O; or CH 2 CH 2 O;
i is 0 or 1; and
m S is 0, 1, 2, 3, 4, 5, or 6; and
[CYT] is a group according to the chemical structure:

wherein X is a group —NR 1N —, —NR 1N CO—, —O—, —CH 2 —, —S—, —OCONH— or —NHCONH—
where R 1N is H or a C 1 -C 3 alkyl group optionally substituted with one or two hydroxyl groups, and
the symbol signifies a chemical attachment point of the cytotoxic moiety to a labile linker which is linked through X,
or a pharmaceutically acceptable salt or stereoisiomer thereof.

2. A compound according to claim 1 which is

or
a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound according to claim 2 wherein CYT is doxorubicin or daunorubicin.

4. The compound according to claim 3 wherein CYT is doxorubicin.

5. The compound according to claim 3 wherein CYT is daunorubicin.

6. A compound according to the chemical structure:

or the free amine or alternative pharmaceutical salt thereof.

7. A compound according to claim 6 having the chemical structure:

or the free amine or alternative pharmaceutical salt thereof.

8. A compound of claim 6 having the chemical structure:

or the free amine or alternative pharmaceutical salt thereof.

9. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

10. A pharmaceutical composition comprising an effective amount of a compound according to claim 2 in combination with a pharmaceutically acceptable carrier, additive or excipient.

11. A pharmaceutical composition comprising an effective amount of a compound according to claim 3 in combination with a pharmaceutically acceptable carrier, additive or excipient.

12. A pharmaceutical composition comprising an effective amount of a compound according to claim 4 in combination with a pharmaceutically acceptable carrier, additive or excipient.

13. A pharmaceutical composition comprising an effective amount of a compound according to claim 5 in combination with a pharmaceutically acceptable carrier, additive or excipient.

14. A pharmaceutical composition comprising an effective amount of a compound according to claim 6 in combination with a pharmaceutically acceptable carrier, additive or excipient.

15. A pharmaceutical composition comprising an effective amount of a compound according to claim 7 in combination with a pharmaceutically acceptable carrier, additive or excipient.

16. A pharmaceutical composition comprising an effective amount of a compound according to claim 8 in combination with a pharmaceutically acceptable carrier, additive or excipient.

17. The composition according to claim 9 further comprising a latent HIV activator selected from the group consisting of prostratin, bradystatin 1, bryostatin 1, bryostatin 2, IL-7, a histone deacetylase inhibitor, a DNA methylation inhibitor, a compound according to the chemical structure:

where X and Y are H, X is OH and Y is H, X is OAc and Y is H or X is OAc and Y is OH;
a compound according to the chemical structure:

where X and Y are H, X is OAc and Y is H or X is OAc and Y is OH, or a mixture thereof.

18. The composition according to claim 10 further comprising a latent HIV activator selected from the group consisting of prostratin, bradystatin 1, bryostatin 1, bryostatin 2, IL-7, a histone deacetylase inhibitor, a DNA methylation inhibitor, a compound according to the chemical structure:

where X and Y are H, X is OH and Y is H, X is OAc and Y is H or X is OAc and Y is OH;
a compound according to the chemical structure:

Assignees

• Univ Yale

Inventors

• Spiegel David
• Parker Christopher

Classifications

• A61P31/18

  for HIV · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title