Water soluble prodrugs of azole compounds

Details Water soluble prodrugs of azole compounds Water soluble prodrugs of azole compounds

1999-05-20

2001-07-24

Oswecki, Jane C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S205000, C548S263200, C548S264600, C548S266600, C548S267600, C548S267800, C548S268200, C548S268600, C548S373100, C548S377100

Reexamination Certificate

active

06265584

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a new class of azole derivatives, methods for their use, and processes for their production. The compounds described herein are useful for the treatment of fungal infections in humans and other mammals. The present invention provides a compound represented by the general 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 R
1
and R
2
are hydrogen, C
1
-C
6
alkyl or C
2
-C
6
alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R
1
and R
2
taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula
where R
7
is hydrogen, CHO, COR
13
or C
1
-C
6
alkyl in which the alkyl group may be optionally interupted by an oxygen atom or NR
14
and may be substituted by hydroxy, R
8
, R
9
, R
10
, R
11
and R
12
are each independently hydrogen, hydroxy, CONH
2
, or C
1
-C
6
alkyl, said alkyl group being optionally substituted by hydroxy, R
13
is C
1
-C
6
alkyl and R
14
is hydrogen or C
1
-C
6
alkyl; or a pharmaceutically acceptable salt thereof.
DESCRIPTION OF THE PRIOR ART
Triazole antifungal compounds are well known in the prior art. Of the several classes known, one particularly potent class contains a tertiary hydroxyl group. For example, U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol has anti-fungal activity.
The utility of this class of compounds is limited by their low water solubility. One method of addressing this problem was disclosed in European Patent Application 829478, where the water solubility of an azole antifungal agent was increased by attaching a linked amino-acid to the azole portion of the molecule.
Alternatively, WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula
Examples describing the use of N-N-dialkylaminomethyl benzoate derivatives as prodrugs can be found in H. Bundgaard et al, J. Med Chem. 32, 2503 (1989); E. Jensen et. al. Int. J. Pharmaceut. 58, 143 (1990); and H. Bundgaard, Drugs of the Future 16, 443 (1991).
SUMMARY OF THE INVENTION
It has now been found that triazole anti-fungal compounds containing a secondary or tertiary hydroxyl group, including (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, may be converted into prodrugs with superior properties to those previously disclosed by attaching an amino-containing moiety via a linking group. Specifically, the invention covers compounds 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 R
1
and R
2
are hydrogen, C
1
-C
6
alkyl or C
2
-C
6
alkenyl, said alkyl or alkenyl group being optionally substituted by a hydroxy or dimethylamino group, or R
1
and R
2
taken together with the nitrogen to which they are attached forms a heterocyclic group of the formula
where R
7
is hydrogen, CHO, COR
13
or C
1
-C
6
alkyl in which the alkyl chain may be optionally interupted by either an oxygen atom or NR
14
and may be substituted by a hydroxy group, R
8
, R
9
, R
10
, R
11
and R
12
are each independently hydrogen, hydroxy, CONH
2
or C
1
-C
6
alkyl said R
8
, R
9
, R
10
, R
11
or R
12
alkyl group being optionally substituted by hydroxy, R
13
is C
1
-C
6
alkyl and R
14
is hydrogen or C
1
-C
6
alkyl; or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
The various methylamine substituents of formula I may be attached in either an ortho, meta, or para relationship to the ester substituent, with the preferred attachment being either meta or para.
In a preferred embodiment A can be
wherein R
3
represents phenyl substituted by one or more (preferably 1-3) halogen atoms;
R
4
represents H or CH
3
;
R
5
represents H, or taken together with R
4
may represent ═CH
2
;
R
6
represents a 5- or 6 membered nitrogen containing ring which may be optionally substituted by one or more groups selected from halogen, ═O, phenyl substituted by one or more groups selected from CN, (C
6
H
4
)—OCH
2
CF
2
CHF
2
and CH═CH—(C
6
H
4
)—OCH
2
CF
2
CHF
2
, or phenyl substituted by one or more groups selected from halogen and methylpyrazolyl.
Nitrogen containing heterocycles which R
6
may represent include triazolyl, pyrimidinyl, and thiazolyl.
Specific examples of A include, but are not limited to, the following:
In addition to the application of the present invention to structures containing a tertiary alcohol, it should also be understood that this discovery can be applied to anti-fungal agents which contain secondary alcohols. Some examples include, but are not limited to, the following:
Representative R
1
, R
2
and n values are shown below:
(where A represents the non-hydroxy portion of a triazole anti-fungal compound of the type containing a tertiary or secondary hydroxyl group)
R










































DEFINITIONS
The term “pharmaceutically acceptable salt” as used herein is intended to include the non-toxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like.
The term “halogen” includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro, and most preferably fluoro.
The aliphatic “alkyl” and “alkenyl” groups may be straight or branched chains having the specified number of carbon atoms, e.g. in the case of C
1
-C
6
alkyl, the alkyl group may have from 1 to 6 carbon atoms.
DETAILED DESCRIPTION
Preferred embodiments of the present invention, including in each case pharmaceutically acceptable salts thereof are:
(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 (compound of example 1)
(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 (compound of example 2)
(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 (compound of example 3)
(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 (compound of example 4)
(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 (compound of example 5)
(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 (compound of example 6)
(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 (compound of example 7)
(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 (compound of example 8)
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-&lsqb

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