Derivatives of dolaproine-dolaisoleuine peptides

Patent metadata

Field	Value
Publication number	US-2017190735-A1
Application number	US-201515313906-A
Country	US
Kind code	A1
Filing date	May 27, 2015
Priority date	May 28, 2014
Publication date	Jul 6, 2017
Grant date	—

Abstract

Provided are peptide analogs, pharmaceutical compositions comprising such compounds, and methods of treating cancer with such compounds.

First claim

1 . A compound of Formula (I):

wherein
R 1 and R 2 are each independently —H or alkyl;
X is —O—, —NR z —, —S—, or is absent;
wherein R z is —H or alkyl;

R 3 is a group of the formula:

wherein R 15 and R 16 are each independently —H, —OH, —NH 2 , —SH, —N 3 , alkyl, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, or -alkyl-N 3 ;

R 4 is a group of the formula:

wherein R 17 and R 18 are each independently —H, —OH, —NH 2 , —SH, —N 3 , —CO 2 H, alkyl, alkenyl, alkynyl, -alkyl-OH, -alkyl-NH 2 , -alkyl-SH, -alkyl-N 3 or -alkyl-CO 2 H

R 5 is sec-butyl or isobutyl;
R 6 is —H or alkyl;
R 7 and R 8 are each independently —H, alkyl, —CO 2 R a , CONR b R c , substituted or unsubstituted phenyl, or substituted or unsubstituted heterocyclic ring;
wherein R a is —H or alkyl;
R b and R c are each independently H or alkyl;

R 9 is —H or alkyl; or R 9 is taken together with R 4 and the atoms to which they are attached to form a substituted or unsubstituted heterocycloalkyl ring;
R 10 is —H or alkyl;
R 11 is —H or alkyl;
R 12 is —H or alkyl;
R 13 is —H or alkyl; and
R 14 is —H, —OH or alkyl;
provided that when X is absent and R 15 , R 16 , R 17 and R 18 are each methyl, then R 8 is not substituted or unsubstituted phenyl, or substituted or unsubstituted heterocyclic ring; or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 wherein X is absent.

3 . The compound of claim 2 , wherein
R 15 and R 16 are each independently —H or alkyl; R 7 is —H, —CO 2 R a , —CONR b R c or substituted or unsubstituted heterocyclic ring; R 8 is substituted or unsubstituted phenyl, or substituted or unsubstituted heterocyclic ring; and R 14 is —H.

4 . The compound of claim 3 , wherein R 15 and R 16 are each methyl.

5 . The compound of claim 4 , wherein
R 17 is —OH, —NH 2 , —SH or —N 3 ; and R 18 is —H or alkyl.

6 . The compound of claim 5 , wherein
R 7 is —H, —CO 2 R a or —CONR b R x ; and R 8 is phenyl.

7 . A compound selected from the group consisting of:
(S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-hydroxy-N-methylpropanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((2S,3R)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-hydroxy-N-methylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-2-(dimethylamino)-N—((S)-3-hydroxy-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((2-(pyridin-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-1-oxopropan-2-yl)-3-methylbutanamide; (2S,3R)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-hydroxy-N— ((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((2-(pyridin-2-yl)ethyl)amino)propyl)pyffolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N-methylbutanamide; (2S)-2-(dimethylamino)-N-((2S)-3-hydroxy-1-(((3R,4S,5S)-3-methoxy-1-((2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((2-(piperidin-2-yl)ethyl)amino)propyl)pyfolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-1-oxopropan-2-yl)-3-methylbutanamide; (2S,3R)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-hydroxy-N— ((3R,4S,5S)-3-methoxy-1-((2S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((2-(piperidin-2-yl)ethyl)amino)propyl)pyffolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N-methylbutanamide; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((2S,3S)-3-azido-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-methylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-3-amino-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-methylpropanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)—N—((S)-3-amino-1-(((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((2-(pyridin-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)(methyl)amino)-1-oxopropan-2-yl)-2-(dimethylamino)-3-methylbutanamide; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-3-azido-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-methylpropanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-4-azido-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-methylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-4-amino-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-methylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-2-((S)-2-(aminooxy)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-((2-(pyridin-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide; ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-hydroxypropanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)-L-phenylalanine; ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((2S,3R)-2-(dimethylamino)-3-hydroxybutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoyl)-L-phenylalanine; (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((2S,3S)-3-azido-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-methylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid; (S)—N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((2S,3R)-2-(dimethylamino)-3-hydroxybutanamido)-N,3-dimethylbutanamide; (S)—N-((3R,4S,5S)-1-((S)-2-((1R,2R)-3-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-oxopropyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-hydroxypropanamido)-N,3-dimethylbutanamide; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((R)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-mercapto-N-methylpropanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((R)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-mercapto-N-methylpropanamido)-3-methoxy-5-methylheptanoyl)pyffolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid; (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-hydroxy-N-methylpropanamido)-3-methoxy-5-methylheptanoyl)pyffolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid; (S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((2S,3R)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-3-hydroxy-N-methylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-hydroxypropanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate; (S)-methyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((2S,3R)-2-(dimethylami

Assignees

• Agensys Inc

Inventors

• Mendelsohn Brian Alan
• Dugal-Terrier Julien
• Barnscher Stuart Daniel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/0205 Primary

  containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof · CPC title

• A61K38/07

  Tetrapeptides · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/02

  Linear peptides containing at least one abnormal peptide link · CPC title