Triazines with suitable spacers for treatment and/or prevention of HIV infections

Patent metadata

Field	Value
Publication number	US-9650348-B2
Application number	US-201314385843-A
Country	US
Kind code	B2
Filing date	Mar 18, 2013
Priority date	Mar 19, 2012
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present invention relates to the field of HIV-1 infections, and in particular provides novel compounds containing triazine rings and suitable spacers. The compounds according to this invention are very suitable for the prevention and/or treatment of HIV-1 infection and in particular show improved activity against NNRTI-resistant viruses of HIV-1.

First claim

The invention claimed is:

1. A compound represented by Formula (Ia) or (Ib) or a stereoisomer, tautomer, racemic, salt, hydrate, or solvate thereof,

Wherein
R 1 , R 2 , and R 3 are each independently selected from the group consisting of —C 1-6 alkyl, -halo, and —CH═CH—CN;
R 4 and R 5 are each independently selected from the group consisting of —H, —CN, and —CH═CH—CN;
R 6 is selected from the group consisting of —H, and —NR 7 R 8 ;
R 7 and R 8 are each independently selected from the group consisting of —H, —C 1-6 alkyl, and -phenyl; said -phenyl being optionally substituted with —CN; or
R 7 and R 8 taken together with the N atom to which they are attached form a 5- or 6-membered heterocycle comprising from 1 to 3 heteroatoms selected from N, S and O;
X is selected from the group consisting of —NH—, —NC 1-6 alkyl-, —O—; and
wherein at least one of R 1 -R 5 is —CH═CH—CN.

2. A compound according to claim 1 wherein
R 1 and R 2 are each independently selected from the group consisting of —C 1-6 alkyl, and -halo;
R 3 is —CH═CH—CN;
R 4 and R 5 are each independently selected from the group consisting of —H, and —CN;
R 6 is selected from the group consisting of —H, and —NR 7 R 8 ;
R 7 and R 8 are each independently selected from the group consisting of —H, —C 1-6 alkyl, and -phenyl; said -phenyl being optionally substituted with —CN; or
R 7 and R 8 taken together with the N atom to which they are attached form a 5- or 6-membered heterocycle comprising from 1 to 3 heteroatoms selected from N, S and O;
X is selected from the group consisting of —NH—, —NC 1-6 alkyl-, —O—.

3. A compound according to claim 1 wherein
R 1 , R 2 , and R 3 are each independently selected from the group consisting of —C 1-6 alkyl, -halo, and —CH═CH—CN;
R 4 and R 5 are each independently selected from the group consisting of —H, and —CN;
R 6 is —NR 7 R 8 ;
R 7 and R 8 are each independently selected from the group consisting of —H, —C 1-6 alkyl, and -phenyl; said -phenyl being optionally substituted with —CN; or
R 7 and R 8 taken together with the N atom to which they are attached form a 5- or 6-membered heterocycle comprising from 1 to 3 heteroatoms selected from N, S and O;
X is selected from the group consisting of —NH—, —NC 1-6 alkyl-, —O—; and
wherein at least one or R 1 -R 3 is —CH═CH—CN.

4. A compound according to claim 1 wherein
R 1 and R 2 are each independently selected from the group consisting of —C 1-6 alkyl, and -halo;
R 3 is —CH═CH—CN;
R 4 and R 5 are each independently selected from the group consisting of —H, —CN, and —CH═CH—CN;
R 6 is —NR 7 R 8 ;
R 7 and R 8 are each independently selected from the group consisting of —H, —C 1-6 alkyl, and -phenyl; said -phenyl being optionally substituted with —CN; or
R 7 and R 8 taken together with the N atom to which they are attached form a 5- or 6-membered heterocycle comprising from 1 to 3 heteroatoms selected from N, S and O;
X is selected from the group consisting of —NH—, —NC 1-6 alkyl-, and —O—.

5. A compound according to claim 1 wherein
R 1 and R 2 are each independently selected from the group consisting of —C 1-6 alkyl, and -halo;
R 3 is —CH═CH—CN;
R 4 is —CN;
R 5 is —H;
R 6 is —NR 7 R 8 ;
R 7 and R 8 are each independently selected from the group consisting of —H and —C 1-6 alkyl;
X is selected from the group consisting of —NH— and —O—.

6. A compound according to claim 1 wherein the compound is the E-isomer.

7. A pharmaceutical composition comprising a compound according to claim 1 .

8. A method of inhibiting HIV reverse transcriptase comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 .

9. A method of treating HIV infection comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 .

10. A method of treating HIV infection in a subject in need thereof, comprising administering to said subject an effective amount of a composition according to claim 7 .

11. A method of inhibiting HIV reverse transcriptase comprising administering to a subject in need thereof an effective amount of a composition according to claim 7 .

Assignees

• Univ Antwerpen
• Shakturana Cv
• Heeres Jan

Inventors

• Heeres Jan
• Augustyns Koen
• Van Der Veken Pieter
• Joossens Jurgen
• Muthusamy Venkatraj
• Arien Kevin Karel Florentina
• Vanham Guido Louis Emile
• Lewi Paulus

Classifications

• C07D251/52

  with an oxygen or sulfur atom attached to the third ring carbon atom · CPC title

• A61P31/18

  for HIV · CPC title

• C07D251/70 Primary

  Other substituted melamines · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title