Betulinic acid proline derivatives as HIV inhibitors

Patent metadata

Field	Value
Publication number	US-9637516-B2
Application number	US-201314758309-A
Country	US
Kind code	B2
Filing date	Dec 26, 2013
Priority date	Dec 31, 2012
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The invention relates to novel betulinic acid derivatives and related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.

First claim

The invention claimed is:

1. A compound of the formula (1):

wherein,
R 1 is H, substituted or unsubstituted alkyl,

(wherein Rb is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);
R 3 and R 4 are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or R 3 and R 4 together with their adjacent carbons to form a bond or R 3 and R 4 together with their adjacent carbons to form cyclopropyl or epoxide;
W is a bond, C(O), or CR 6 R 7 ;
Rx is substituted or unsubstituted heteroaryl;
R 5 , R 6 and R 7 are independently selected from H, D, CD 3 , CH 2 CD 3 , CH(CD 3 ) 2 , CO 2 R d (wherein R d is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl;
n is an integer from 1 to 3;
pharmaceutically acceptable salts, tautomers, stereoisomers, or esters thereof.

2. The compound of claim 1 , wherein W is —C(O)—.

3. The compound of claim 1 , wherein Rx is imidazole, oxazole, oxadiazole, thiazole, thiadizole, isothiazole, isothiadiazole, pyridine, pyrazine, pyrimidine, or pyridazine.

4. A compound of the formula (1A):

wherein,
R 1 is H, substituted or unsubstituted alkyl,

(wherein Rb is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);

R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;
R 3 and R 4 are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or R 3 and R 4 can be together with their adjacent carbons to form a bond or R 3 and R 4 together with their adjacent carbons to form cyclopropyl or epoxide;
W is a bond, C(O), or CR 6 R 7 ;
R 5 , R 6 and R 7 are independently selected from H, D, CD 3 , CH 2 CD 3 , CH(CD 3 ) 2 , CO 2 R d (wherein R d is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl;
n is an integer from 1 to 3; pharmaceutically acceptable salts, tautomers, stereoisomers, or esters thereof.

5. The compound of claim 4 , wherein W is —C(O)—.

6. The compound of claim 4 , wherein R 2 is isopropyl, t-butyl, phenyl, pyridine, pyrazine, thiophene or chromene.

7. A compound of the formula (1B):

wherein,
R 1 is H, substituted or unsubstituted alkyl,

(wherein Rb is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);
R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;
R 3 and R 4 are independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or R 3 and R 4 together with their adjacent carbons to form a bond or R 3 and R 4 together with their adjacent carbons to form cyclopropyl or epoxide;
W is a bond, C(O), or CR 6 R 7 ;
R 5 , R 6 and R 7 are independently selected from H, D, CD 3 , CH 2 CD 3 , CH(CD 3 ) 2 , CO 2 R d (wherein R d is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl), or substituted or unsubstituted alkyl;
n is an integer from 1 to 3; pharmaceutically acceptable salts, tautomers, stereoisomers, or esters thereof.

8. The compound of claim 7 , wherein W is —C(O)—.

9. The compound of claim 7 , wherein R 2 is isopropyl, t-butyl, phenyl, pyridine, pyrazine, thiophene or chromene.

10. A compound selected from the group consisting of:
2,2-dimethyl-4-oxo-4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)butanoic acid,
3,3-dimethyl-5-oxo-5-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)pentanoic acid,
2,2-dimethyl-4-oxo-4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((R)-2-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)butanoic acid,
3,3-dimethyl-5-oxo-5-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((R)-2-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)pentanoic acid,
2,2-dimethyl-4-oxo-4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)butanoic acid,
3,3-dimethyl-5-oxo-5-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)pentanoic acid,
2,2-dimethyl-3-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((R)-2-(3-phenyl-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)carbonyl)cyclobutanecarboxylic acid,
2,2-dimethyl-4-oxo-4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)butanoic acid,
3,3-dimethyl-5-oxo-5-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)pentanoic acid,
2,2-dimethyl-4-oxo-4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)butanoic acid,
3,3-dimethyl-5-oxo-5-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((S)-2-(5-(pyridin-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)pentanoic acid,
2,2-dimethyl-4-oxo-4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(1-methylcyclopropyl)-3a-((S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)icosahydro-1H-

Assignees

• Hetero Research Foundation

Inventors

• Parthasaradhi Reddy Bandi
• Rathnakar Reddy Kura
• Vl Subrahmanyam Lanka
• David Krupadanam Gazula Levi
• Venkati Mukkera
• Sudhakar Neela
• Srinivas Reddy Kallem

Classifications

• C07J53/002 Primary

  Carbocyclic rings fused · CPC title

• C07J63/008 Primary

  Expansion of ring D by one atom, e.g. D homo steroids · CPC title