US 10,370,405 B2Granted

C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors

AssigneeHetero Labs Limited

InventorsParthasaradhi Reddy Bandi, Rathnakar Reddy Kura, David Krupadanam Gazula Levi, Panduranga Reddy Adulla, Eswara Rao Bammidi, Bhaskar Reddy Kasireddy, Sudhakar Neela, Carl Thomas Wild, David Eugene Martin, Theodore John Nitz

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Abstract

The invention relates to C-3 novel triterpenone with C-28 amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases (formula 1).

Claims9

Dependent claims

The A compound of the formula (1):

wherein,
R1 is
wherein Rb is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;
R2 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxylalkoxy or substituted or unsubstituted amino alkyl;
R3 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted amine, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
or R2 and R3 optionally are taken together with the N-atom and C-atom to which they are attached to form substituted or unsubstituted 4-7 membered N-contained heterocyclyl;
wherein the substituent is heterocyclyl;
R4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amine, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
W is —CH2—, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
R5 is selected from hydroxy, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
wherein the substituent is halo or hydroxyl alkyl;
‘n’ is 1;
a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, a N-oxide thereof, a tautomer thereof, a regioisomer thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof.

10 more elements

A compound selected from the group consisting of:

(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3aS)-2-(5-(4-fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3, 3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-3, 3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-[1,3′-bipyrrolidine]-1′-carbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a, 11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(((S)-2-(hydroxy methyl)pyrrolidin-1-yl)methyl)pyrrolidine-1-carbonyl)-1-isopropyl-5a,5b,8,8,11a-penta methyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclo penta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((3,3-difluoro pyrrolidin-1-yl)methyl)pyrrolidine-1-carbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a] chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4,4-difluoro piperidin-1-yl)methyl)pyrrolidine-1-carbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((2-(5-phenyl-1H-imidazol-2-yl)propan-2-yl)carbamoyl)-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-2-((4-fluoropiperidin-1-yl)methyl)pyrrolidine-1-carbonyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((2-(5-(4-chlorophenyl)-1H-imidazol-2-yl)propan-2-yl)carbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4, 5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,1a-pentamethyl-3a-((2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)carbamoyl)-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((S)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl)-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid,
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((4-chlorobenzyl)(2-(di methylamino)ethyl)carbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid and
(1R,3S)-3-((((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((1-hydroxy-2-methyl propan-2-yl)carbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a, 8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-1-carboxylic acid or
pharmaceutically acceptable salts thereof.

13 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/558,677Filed 12 Mar 2016
Published: US 2018/0237472 A123 Aug 2018
Granted: 6 Aug 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07J 63/008
Steroids in which the cyclopentahydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms: expansion of ring…
A61P 31/18
For RNA viruses: for HIV
C07J
Steroids
A61P
Therapeutic uses of medicines

Family

US 2018/0237472 A1Pre-grant publication · published 23 Aug 2018
US 10,370,405 B2This patent

From the US filing history. Foreign family members aren’t listed.

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