Ingenol analogs, pharmaceutical compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10583140-B2
Application number	US-201716072278-A
Country	US
Kind code	B2
Filing date	Jan 27, 2017
Priority date	Jan 27, 2016
Publication date	Mar 10, 2020
Grant date	Mar 10, 2020

Abstract

The invention relates to compounds of Formula (I), (II), (III) or (IV), salts thereof, pharmaceutical compositions thereof, as well as methods of treating, curing or preventing HIV in subjects.

First claim

What is claimed is:

1. A compound according to formula (II):

or a pharmaceutically acceptable salt thereof:
X is selected from O or N, wherein when X is O, then R 3 is absent;

R 1 is optionally present, and when present, the group:

is represented as:

and R 1 is —C(O)R 4 ;
R 2 and R 3 are independently selected from the group consisting of —H, methyl, —C(O)R 10 , —C(O)N(R 6 ) 2 , —S(O) 2 CH 3 , (C 6 )heteroaryl and (C 9 )heteroaryl, wherein when X is N, then R 2 and R 3 may be taken together to form a pyrrolidine group optionally substituted by one or more R 12 ;
R 4 is —N(R 6 ) R 7 ;
R 6 is methyl;
R 7 is phenyl optionally substituted with one or more R 13 ;

R 10 is selected from the group consisting of (C 1 -C 4 )alkyl, (C 3 -C 9 )cyclohexyl, (C 5 -C 6 )heterocycle, and phenyl, wherein the cyclohexyl, (C 5 -C 6 ) heterocycle and phenyl are optionally substituted with one or more R 11 ; and
wherein R 11 ,R 12 and R 13 are independently selected from the group consisting of methyl, methoxy, oxo, trifluoromethyl and chloro;
with the proviso that when X is O and R 2 is H, R 1 is not present.

2. The compound according to claim 1 , wherein R 6 is methyl and R 7 is aryl substituted by chloro.

3. The compound according to claim 1 , wherein R 2 is —C(O)R 10 .

4. The compound according to claim 3 , wherein R 10 is aryl or methyl.

5. The compound according to claim 1 , wherein X is N.

6. The compound according to claim 5 , wherein R 2 and R 3 together form a (C 2 -C 9 ) heteroaryl.

7. The compound according claim 1 , wherein R 1 is absent.

8. The compound according to claim 7 , wherein X is O and R 2 is H.

9. A compound selected from the group consisting of:

((1aR,2S,5R,5aS,6S,8aS,9R, 10aR)-6-(((4-chlorophenyl) (methyl)carbamoyl)oxy)- 5,5a-dihydroxy-1,1,7,9- tetramethyl-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen- 4-yl)methyl acetate

((1aR,2S,5R,5aS,6S,8aS, 9R,10aR)-6-(((4- chlorophenyl) (methyl)carbamoyl)oxy)- 5,5a-dihydroxy-1,1,7,9- tetramethyl-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta [a]cyclopropa[e][10] annulen-4-yl)methyl benzoate

(1aR,2S,5R,5aS,6S,8aS, 9R,10aR)-4-((1,3- dioxoisoindolin-2- yl)methyl)-5,5a-dihydroxy- 1,1,7,9-tetramethyl-11- oxo-1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen- 6-yl(4-chlorophenyl) (methyl)carbamate

(1aR,2S,5R,5aS,8aS,9R, 10aR)-5,5a-dihydroxy-4- (hydroxymethyl)-1,1,7,9- tetramethyl- 1a,2,5,5a,10,10a- hexahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulene- 6,11(9H)-dione

((1aR,2S,5R,5aR,6S,8aS, 9R,10aR)-5,5a,6- trihydroxy-1,1,7,9- tetramethyl-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen-4- yl)methyl (4- chlorophenyl)(methyl) Carbamate

((1aR,2S,5R,5aR,6S,8aS, 9R,10aR)-5,5a,6- trihydroxy-1,1,7,9- tetramethyl-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen-4- yl)methyl phenylcarbamate

((1aR,2S,5R,5aR,6S,8aS, 9R,10aR)-5,5a,6- trihydroxy-1,1,7,9- tetramethyl-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen-4- yl)methyl butylcarbamate

((1aR,2S,5R,5aR,6S,8aS, 9R,10aR)-5,5a,6- trihydroxy-1,1,7,9- tetramethy1-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen-4- yl)methyl benzylcarbamate

((1aR,2S,5R,5aR,6S,8aS, 9R,10aR)-5,5a,6- trihydroxy-1,1,7,9- tetramethyl-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10] annulen-4- yl)methyl cyclohexyl(methyl) Carbamate

((1aR,2S,5R,5aR,6S,8aS, 9R,10aR)-5,5a,6- trihydroxy-1,1,7,9- tetramethyl-11-oxo- 1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen-4- yl)methyl indoline-1- carboxylate

(1aR,2S,5R,5aS,6S,8aS, 9R,10aR)-5,5a-dihydroxy-4- (((indoline-1- carbonyl)oxy)methyl)- 1,1,7,9-tetramethyl-11- oxo-1a,2,5,5a,6,9,10,10a- octahydro-1H-2,8a- methanocyclopenta[a] cyclopropa[e][10]annulen- 6-yl indoline-1-carboxylate

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Tai Vincent Wing-Fai
• Tang Jun

Classifications

• C07C271/12

  to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals · CPC title

• A61K31/325

  Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof (thiurams A61K31/145) · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• A61K9/20

  Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)} · CPC title

• C07C271/24

  with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring · CPC title