# US 7,608,611 B2 · Hsp90 inhibitors, methods of making and uses therefor

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- Number: US 7,608,611 B2
- Document ID: US7608611B2
- Status: Granted
- Kind: B2
- Application number: 11/218,320
- Filed: 2005-08-31
- Published: 2006-09-14
- Granted: 2009-10-27
- Earliest claimed: 2005-03-11
- Assignees: The Regents of the University of Colorado
- Inventors: David Ross; David Siegel; Philip Reigan; Wenchang Guo; Daniel L. Gustafson
- Web page: https://patentgrep.com/patent/US7608611B2

## CPC

- C07D 225/02: not condensed with other rings
- C07D 225/06: condensed with one six-membered ring
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- C07H 19/00: Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides ; Anhydro-derivatives thereof
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The invention provides purified 18,21-didehydro-18,21-dideoxo-18,21-dihydroxy-geldanamycin derivatives, pharmaceutically acceptable salts thereof and prodrugs thereof that are potent Hsp90 binding agents that are useful for the treatment and/or the amelioration of symptoms of cancer and other proliferative tissue disorders.

## Claims

### Claim 1

A purified compound having the chemical structure:
or a pharmaceutically-acceptable salt thereof;
wherein:
R1 and R2 are independently C2-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-cycloalkyl, C(═O)(CH2)n-aryl, wherein n=1-10, alkoxy, alkylthiol, glycoside, glucuronide or sulfate, C(═O)CH(X)NH2, and C(═O)CH(X)OH wherein X=an amino acid side chain;
R3 is H, NHCH2CH═CH2, NHCH2CH2N(CH3)2, NHCH2CH2NC4H8, azetidinyl, furfuryl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofurfuryl, 2-methyl-1-aziridinyl, (dimethylamino)methyl-1-aziridinyl, 3-(dimethylamino)-1-azetidinyl, 3-hydroxy-1-pyrrolidinyl, 3,4-dihydroxy-1-pyrrolidinyl, or NR7R8, OR7, SR7, wherein R7 and R8 are independently alkenyl, alkynyl, alkoxy, alkylhalide, alkyldihalide, amine, cycloalkyl, carboxyalkyl, (acetylamino)alkyl, (dimethylamino)alkyl, 1-(methoxymethyl)alkyl, 2-(1,3-dioxolan-2-yl)alkyl, 4,4-dimethoxybutyl, [[(1,1-dimethylethoxy)carbonyl]amino]alkyl, [[(1,1-dimethylethoxy)carbonyl]alkylamino]alkyl, 1-(hydroxymethyl)alkyl, 1-(hydroxymethyl)-2-methylalkyl, 2-(hydroxymethyl)cycloalkyl, (diethylamino)alkyl, 2-(dimethylamino)-1-methylethyl, (ethylmethylamino)alkyl, [(2-fluoroethyl)methylamino]alkyl, [(2,2-difluoroethyl)methylamino]alkyl, [bis(2-hydroxyethyl)amino]alkyl, (dimethyloxidoamino)alkyl, (trimethylammonio)alkyl, (1-aziridinyl)alkyl, (1-aziridinylmethyl)alkyl, (1-azetidinyl)alkyl, (2-deoxy-D-glucos-2-yl), (6-deoxy-D-glucos-6-yl), (1H-imidazol-4-yl)alkyl, (1-methyl-1H-imidazol-4-yl)alkyl, (1-methyl-1H-imidazol-5-yl)alkyl, (4-morpholinyl)alkyl, (4-pyridinyl)alkyl, (1-piperidinyl)alkyl, (1-piperazinyl)alkyl, (1-pyrrolidinyl)alkyl, (1-ethyl-2-pyrrolidinyl)methyl, or 2-(N-methyl-pyrrolidin-2-yl)ethyl; and wherein when R1 and R2 are both H, R3 is not NH2;
R4 and R5 are independently H, C1-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-aryl, C(═O)(CH2)n-cycloalkyl, alkoxy, alkylthiol or sulfate, wherein n=1-10; and,
R6 is O, OC(═O)NH2, OC(═O)C1-10 alkyl, OSO2OH, OC(═O)OSO2OH and OC(═O)NR9R10 wherein R9 and R10 are independently H and C1-10 alkyl.

### Claim 2

A purified compound having the chemical structure:
or a pharmaceutically-acceptable salt thereof;
wherein:
R1 and R2 are independently H, C1-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-cycloalkyl, C(═O)(CH2)n-aryl, wherein n=1-10, alkoxy, alkylthiol, glycoside, glucuronide or sulfate, C(═O)CH(X)NH2, and C(═O)CH(X)OH, wherein X=an amino acid side chain;
R3 is H, NHCH2CH2N(CH3)2, NHCH2CH2NC4H8, azetidinyl, furfuryl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofurfuryl, 2-methyl-1-aziridinyl, (dimethylamino)methyl-1-aziridinyl, 3-(dimethylamino)-1-azetidinyl, 3-hydroxy-1-pyrrolidinyl, 3,4-dihydroxy-1-pyrrolidinyl, or NR7R8, OR7, SR7, wherein R7 and R8 are independently alkenyl, alkynyl, alkoxy, alkylhalide, alkyldihalide, amine, cycloalkyl, carboxyalkyl, (acetylamino)alkyl, (dimethylamino)alkyl, 1-(methoxymethyl)alkyl, 2-(1,3-dioxolan-2-yl)alkyl, 4,4-dimethoxybutyl, [[(1,1-dimethylethoxy)carbonyl]amino]alkyl, [[(1,1-dimethylethoxy)carbonyl]alkylamino]alkyl, 1-(hydroxymethyl)alkyl, 1-(hydroxymethyl)-2-methylalkyl, 2-(hydroxymethyl)cycloalkyl, (diethylamino)alkyl, 2-(dimethylamino)-1-methylethyl, (ethylmethylamino)alkyl, [(2-fluoroethyl)methylamino]alkyl, [(2,2-difluoroethyl)methylamino]alkyl, [bis(2-hydroxyethyl)amino]alkyl, (dimethyloxidoamino)alkyl, (trimethylammonio)alkyl, (1-aziridinyl)alkyl, (1-aziridinylmethyl)alkyl, (1-azetidinyl)alkyl, (2-deoxy-D-glucos-2-yl), (6-deoxy-D-glucos-6-yl), (1H-imidazol-4-yl)alkyl, (1-methyl-1H-imidazol-4-yl)alkyl, (1-methyl-1H-imidazol-5-yl)alkyl, (4-morpholinyl)alkyl, (4-pyridinyl)alkyl, (1-piperidinyl)alkyl, (1-piperazinyl)alkyl, (1-pyrrolidinyl)alkyl, (1-ethyl-2-pyrrolidinyl)methyl, or 2-(N-methyl-pyrrolidin-2-yl)ethyl;
R4 and R5 are independently H, C1-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-aryl, C(═O)(CH2)n-cycloalkyl, alkoxy, alkylthiol or sulfate, wherein n=1-10; and,
R6 is O, OC(═O)NH2, OC(═O)C1-10 alkyl, OSO2OH, OC(═O)OSO2OH and OC(═O)NR9R10 wherein R9 and R10 are independently H and C1-10 alkyl.

### Claim 3 (depends on 1)

A purified compound of claim 1, wherein:
R1 and R2 are independently C(═O)C1-10 alkyl;
R3 is NHCH2CH═CH2, NHCH2CH2N(CH3)2, or NHCH2CH2NC4H8;
R4 and R5 are H, C1-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-aryl, C(═O)(CH2)n-cycloalkyl, alkoxy, alkylthiol or sulfate, wherein n=1-10; and,
R6 is O, OC(═O)NH2, OC(═O)C1-10 alkyl, OSO2OH, OC(═O)OSO2OH and OC(═O)NR9R10 wherein R9 and R10 are independently H and C1-10 alkyl.

### Claim 4 (depends on 1)

A purified compound of claim 1, wherein:
R1 and R2 are independently SO2OR10 wherein R10 is H or C1-10 alkyl.
R3 is NHCH2CH═CH2, NHCH2CH2N(CH3)2, or NHCH2CH2NC4H8;
R4 and R5 are H, C1-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-aryl, C(═O)(CH2)n-cycloalkyl, alkoxy, alkylthiol or sulfate, wherein n=1-10; and,
R6 is O, OC(═O)NH2, OC(═O)C1-10 alkyl, OSO2OH, OC(═O)OSO2OH and OC(═O)NR9R10 wherein R9 and R10 are independently H and C1-10 alkyl.

### Claim 5 (depends on 1)

A pharmaceutical composition containing at least one of the purified compounds of claim 1 and a metal chelating agent.

### Claim 6 (depends on 2)

A pharmaceutical composition containing at least one of the purified compounds of claim 2 and a metal chelating agent.

### Claim 7 (depends on 5)

The pharmaceutical composition of claim 5 where in the metal chelating agent is a copper chelating agent.

### Claim 8 (depends on 5)

The pharmaceutical composition of claim 5 where in the metal chelating agent is D-penicillamine.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising at least one of the compounds of claim 1 and at least one pharmaceutically-acceptable carrier.

### Claim 10

A purified compound having the chemical structure:
or a pharmaceutically-acceptable salt thereof;
wherein:
R1 and R2 are independently C1-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-cycloalkyl, C(═O)(CH2)n-aryl, wherein n=1-10, alkoxy, alkylthiol, glycoside, glucuronide or sulfate, C(═O)CH(X)NH2, and C(═O)CH(X)OH wherein X=an amino acid side chain;
R3 is H, NHCH2CH═CH2, NHCH2CH2N(CH3)2, NHCH2CH2NC4H8, azetidinyl, furfuryl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofurfuryl, 2-methyl-1-aziridinyl, (dimethylamino)methyl-1-aziridinyl, 3-(dimethylamino)-1-azetidinyl, 3-hydroxy-1-pyrrolidinyl, 3,4-dihydroxy-1-pyffolidinyl, or NR7R8, SR7, wherein R7 and R8 are independently H, alkenyl, alkynyl, alkoxy, alkylhalide, alkyldihalide, amine, cycloalkyl, carboxyalkyl, (acetylamino)alkyl, (dimethylamino)alkyl, 1-(methoxymethyl)alkyl, 2-(1,3-dioxolan-2-yl)alkyl, 4,4-dimethoxybutyl, [[(1,1-dimethylethoxy)carbonyl]amino]alkyl, [[(1,1-dimethylethoxy)carbonyl]alkylamino]alkyl, 1-(hydroxymethyl)alkyl, 1-(hydroxymethyl)-2-methylalkyl, 2-(hydroxymethyl)cycloalkyl, (diethylamino)alkyl, 2-(dimethylamino)-1-methylethyl, (ethylmethylamino)alkyl, [(2-fluoroethyl)methylamino]alkyl, [(2,2-difluoroethyl)methylamino]alkyl, [bis(2-hydroxyethyl)amino]alkyl, (dimethyloxidoamino)alkyl, (trimethylammonio)alkyl, (1-aziridinyl)alkyl, (1-aziridinylmethyl)alkyl, (1-azetidinyl)alkyl, (2-deoxy-D-glucos-2-yl), (6-deoxy-D-glucos-6-yl), (1H-imidazol-4-yl)alkyl, (1-methyl-1H-imidazol-4-yl)alkyl, (1-methyl-1H-imidazol-5-yl)alkyl, (4-morpholinyl)alkyl, (4-pyridinyl)alkyl, (1-piperidinyl)alkyl, (1-piperazinyl)alkyl, (1-pyrrolidinyl)alkyl, (1-ethyl-2-pyrrolidinyl)methyl, or 2-(N-methyl-pyrrolidin-2-yl)ethyl; and wherein when R1 and R2 are both H, R3 is not NH2;
R4 and R5 are independently H, C1-6 alkyl, C3-8 cycloalkyl, C(═O)C1-10 alkyl, C(═O)(CH2)n-aryl, C(═O)(CH2)n-cycloalkyl, alkoxy, alkylthiol or sulfate, wherein n=1-10; and,
R6 is O, OC(═O)NH2, OC(═O)C1-10 alkyl, OSO2OH, OC(═O)OSO2OH and OC(═O)NR9R10 wherein R9 and R10 are independently H and C1-10 alkyl.