US 6,486,159 B2 · Water soluble prodrugs of azole compounds

Abstract

Water-soluble prodrugs of triazole antifungal compounds having a secondary or tertiary hydroxy group are provided. More particularly, new water-soluble triazole antifungal compounds are provided having the general formula wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxyl group and n, R1 and R2 are as defined in the specification.

Claims17

Dependent claims

A compound of the formula

wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, and R1 and R2 are hydrogen, C1-C6alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or a pharmaceutically acceptable salt thereof.

A compound selected from:

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-N,N-diethylaminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N,-di-(2-hydroxyethyl)aminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-dimethylaminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-[[p-N-methyl-N-(2-hydroxyethyl)aminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N-ethyl-N-butyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-dipropyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-diallyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-ethyl-N-(2-dimethylaminoethyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N-methyl-N-(3-dimethylaminopropyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N-methyl-N-(2-dimethylaminoethyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-bis-(2RS-hydroxypropyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-(N,N-diethylaminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[N,N-bis(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-diethylaminomethyl]benzoyloxy) methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4,-triazol-1-yl)-2-[[[m-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N-methyl-N-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application

09/789,986Filed 21 Feb 2001 · division

Priority

22 May 1998

Published

US 2001/0039353 A18 Nov 2001

Granted

26 Nov 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification3 codes

C07D 417/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms
C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…
C07D
Heterocyclic compounds

Family

Application60/086,435Us provisional application · filed 22 May 1998

Application60/103,560Us provisional application · filed 7 Oct 1998

Application09/315,606Parent of this division · filed 20 May 1999

US 2001/0039353 A1Pre-grant publication · published 8 Nov 2001

US 6,265,584 B1Parent of this division

US 6,486,159 B2This patent

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

Abstract

Claims17

Dependent claims

A compound of the formula

wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, and R1 and R2 are hydrogen, C1-C6alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or a pharmaceutically acceptable salt thereof.

A compound selected from:

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-N,N-diethylaminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N,-di-(2-hydroxyethyl)aminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N,N-dimethylaminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-[[p-N-methyl-N-(2-hydroxyethyl)aminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-(N-ethyl-N-butyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-dipropyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N,N-diallyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-ethyl-N-(2-dimethylaminoethyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N-methyl-N-(3-dimethylaminopropyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[(N-methyl-N-(2-dimethylaminoethyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-(4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[p-[N-bis-(2RS-hydroxypropyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-(N,N-diethylaminomethyl)benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[m-[N,N-bis(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-diethylaminomethyl]benzoyloxy) methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N,N-bis-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4,-triazol-1-yl)-2-[[[m-[N,N-diethylaminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[N-methyl-N-(2-hydroxyethyl)aminomethyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof.

15 more elements

Dependencies are inferred from the claim text.

Water soluble prodrugs of azole compounds

Life of this patent

Abstract

Claims17

Water soluble prodrugs of azole compounds

Life of this patent

Abstract

Claims17