US 2001/0012843 A1 · 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 1 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.

Claims25

Dependent claims

A compound of the formula 114

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-C6 alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R1 and R2 taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula 115
where R7 is hydrogen, CHO, COR13 or C1-C6 alkyl in which the alkyl chain may be optionally interupted by either an oxygen atom or NR14 and may be substituted by a hydroxy group, R8, R9, R10, R11 and R12 are each independently hydrogen, hydroxy, CONH2 or C1-C6 alkyl, said alkyl group being optionally substituted by hydroxy, R13 is C1-C6 alkyl and R14 is hydrogen or C1-C6 alkyl;
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-(4-methyl-piperazinyl)methyl]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)-2-[[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-(4-(2-hydroxyethyl)-1-piperazinylmethyl) 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-[(3RS-hydroxy)-1-piperidinylmethyl]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-[(4-(2RS-hydroxyethyl)-1-piperidinylmethyl] 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-[(4-formyl)-1-piperazinylmethyl]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-[(4RS-hydroxy)-1-piperidinylmethyl]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-[(4-ethyl)-1-piperazinylmethyl]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-[(4RS-methyl)-1-piperidinylmethyl]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-[4RS-(N-piperadinyl)-1-piperidinylmethyl] 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-[(3RS-hydroxy)-1-pyrrolidinylmethyl]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-[(2S,6R-dimethyl-1-piperidinyl)methyl] 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-[(3-thiazolidinyl)methyl]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-[(3RS-methyl-1-piperidinyl)methyl]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,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-[[p-[(1-piperidinyl)methyl]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-[(4-morpholinyl)methyl]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-[(4-morpholinyl)methyl]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-[[m-[(4-methyl-1-piperazinyl)methyl]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-[(4-morpholinyl)methyl]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-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-[(4-morpholinyl)methyl]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-[[[p-[(4-methyl-1-piperazinyl)methyl]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-[(4-methyl-1-piperazinyl)methyl]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-[(4-(2′-hydroxyethoxy)ethyl-1-piperazinyl) methyl]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
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-hydroxy-4-piperidinyl)methyl]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-[(4′-carbamyl-4-piperidinyl)methyl]benzoyloxy] methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof;
and
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2-hydroxyethyl)-1-piperazinyl) methyl]benzoyloxymethoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof.

41 more elements

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-[(4-morpholinyl)methyl]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-[[[m-[(4-morpholinyl)methyl]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-[(4-(2′-hydroxyethoxy)ethyl-1-piperazinyl) methyl]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
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-hydroxy-4-piperidinyl)methyl]benzoyloxy] methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof;
and
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-carbamyl-4-piperidinyl)methyl]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-[(4-(2-hydroxyethyl)-1-piperazinyl) methyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof.

9 more elements

Dependencies are inferred from the claim text.

Facts

Application

09/789,982Filed 21 Feb 2001

Priority

22 May 1998

Published

9 Aug 2001

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

Application09/315,606Division · filed 20 May 1999

Application09/789,982Division · filed 21 Feb 2001

US 6,265,584 B1Related patent

US 6,359,141 B2Related patent

US 2001/0012843 A1This patent

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

Abstract

Claims25

Dependent claims

A compound of the formula 114

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-C6 alkyl or C2-C6 alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R1 and R2 taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula 115
where R7 is hydrogen, CHO, COR13 or C1-C6 alkyl in which the alkyl chain may be optionally interupted by either an oxygen atom or NR14 and may be substituted by a hydroxy group, R8, R9, R10, R11 and R12 are each independently hydrogen, hydroxy, CONH2 or C1-C6 alkyl, said alkyl group being optionally substituted by hydroxy, R13 is C1-C6 alkyl and R14 is hydrogen or C1-C6 alkyl;
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-(4-methyl-piperazinyl)methyl]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)-2-[[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-(4-(2-hydroxyethyl)-1-piperazinylmethyl) 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-[(3RS-hydroxy)-1-piperidinylmethyl]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-[(4-(2RS-hydroxyethyl)-1-piperidinylmethyl] 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-[(4-formyl)-1-piperazinylmethyl]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-[(4RS-hydroxy)-1-piperidinylmethyl]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-[(4-ethyl)-1-piperazinylmethyl]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-[(4RS-methyl)-1-piperidinylmethyl]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-[4RS-(N-piperadinyl)-1-piperidinylmethyl] 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-[(3RS-hydroxy)-1-pyrrolidinylmethyl]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-[(2S,6R-dimethyl-1-piperidinyl)methyl] 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-[(3-thiazolidinyl)methyl]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-[(3RS-methyl-1-piperidinyl)methyl]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,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-[[p-[(1-piperidinyl)methyl]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-[(4-morpholinyl)methyl]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-[(4-morpholinyl)methyl]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-[[m-[(4-methyl-1-piperazinyl)methyl]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-[(4-morpholinyl)methyl]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-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-[(4-morpholinyl)methyl]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-[[[p-[(4-methyl-1-piperazinyl)methyl]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-[(4-methyl-1-piperazinyl)methyl]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-[(4-(2′-hydroxyethoxy)ethyl-1-piperazinyl) methyl]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
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-hydroxy-4-piperidinyl)methyl]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-[(4′-carbamyl-4-piperidinyl)methyl]benzoyloxy] methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof;
and
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4-(2-hydroxyethyl)-1-piperazinyl) methyl]benzoyloxymethoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof.

41 more elements

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-[(4-morpholinyl)methyl]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-[[[m-[(4-morpholinyl)methyl]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-[(4-(2′-hydroxyethoxy)ethyl-1-piperazinyl) methyl]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
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-hydroxy-4-piperidinyl)methyl]benzoyloxy] methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof;
and
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-[(4′-carbamyl-4-piperidinyl)methyl]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-[(4-(2-hydroxyethyl)-1-piperazinyl) methyl]benzoyloxy]methoxy]carbonyloxy]butane, or a pharmaceutically acceptable salt thereof.

9 more elements

Dependencies are inferred from the claim text.

Water soluble prodrugs of azole compounds

Life of this patent

Abstract

Claims25

Water soluble prodrugs of azole compounds

Life of this patent

Abstract

Claims25