Water soluble prodrugs of azole compounds

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

2001-01-10

2002-03-26

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S086000, C514S093000, C544S337000, C544S243000, C548S112000

Reexamination Certificate

active

06362172

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel water-soluble azole compounds useful for the treatment of serious systemic fungal infections and suitable for both oral and, particularly, parenteral administration. More particularly, the invention relates to novel water-soluble prodrugs having 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, R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl, or pharmaceutically acceptable salts 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. For example, the solubility of the above triazole compound in water at pH 6.8 is 0.0006 mg/mL. This greatly impedes developing suitable parenteral dosage forms.
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
U.S. Pat. No. 5,707,977 and WO 95/19983 disclose water soluble prodrugs having the general formula
wherein X is OP(O)(OH)
2
or an easily hydrolyzable ester OC(O)RNR
1
R
2
.
WO 95/17407 discloses water-soluble azole prodrugs of the general formula
wherein X is P(O)(OH)
2
, C(O)—(CHR
1
)
n
—OP(O)(OH)
2
or C(O)—(CHR
1
)
n
—(OCHR
1
CHR
1
)
m
OR
2
.
WO 96/38443 discloses water-soluble azole prodrugs of the general formula
U.S. Patent No. 5,883,097 discloses water-soluble amino acid azole prodrugs such as the glycine ester
The introduction of the phosphonooxymethyl moiety into hydroxyl containing drugs has been disclosed as a method to prepare water-soluble prodrugs of hydroxyl containing drugs.
European Patent Application 604910 discloses phosphonooxymethyl taxane derivatives of the general formula
wherein at least one of R
1′
, R
2″
, R
3′
, R
6′
or R
7′
is OCH
2
OP(O)(OH)
2
.
European Patent Application 639577 discloses phosphonooxymethyl taxane derivatives of the formula T-[OCH
2
(OCH
2
)
m
OP(O)(OH)
2
]
n
wherein T is a taxane moiety bearing on the C13 carbon atom a substituted 3-amino-2-hydroxypropanoyloxy group; n is 1, 2 or 3; m is 0 or an integer from 1 to 6 inclusive, and pharmaceutically acceptable salts thereof.
WO 99/38873 discloses O-phosphonooxymethyl ether prodrugs of a diaryl 1,3,4-oxadiazolone potassium channel opener.
Golik, J. et al,
Bioorganic
&
Medicinal Chemistry Letters,
1996, 6:1837-1842 discloses novel water soluble prodrugs of paclitaxel such as
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-(1 H-1,2,4-triazol-1-yl)-butan-2-ol, may be converted into prodrugs with superior properties to those previously disclosed by attaching a phosphate 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, R and R
1
are each independently hydrogen or (C
1
-C
6
) alkyl, or pharmaceutically acceptable salts thereof.
The compounds of general formula I function as “prodrugs” when administered in vivo, being converted to the biologically active parent azole in the presence of alkaline phosphatase.
Preferred among the compounds of formula I are those wherein R and R
1
are both hydrogen.
In a preferred embodiment, A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
In a more preferred embodiment of the above type compounds, 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 of the non-hydroxy portion of triazole antifungal compounds of the type containing a secondary hydroxy group include, but are not limited to, the following:
DETAILED DESCRIPTION
As used herein “(C
1
-C
6
)alkyl” refers to a straight or branched chain saturated aliphatic group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, etc.
The term “pharmaceutically acceptable salt” as used herein is intended to include phosphate salts with such counterions as ammonium, metal salts, salts with amino acids, salts with amines and salts with other bases such as piperidine or morpholine. Both mono- and bis-salts are intended to be encompassed by the term “pharmaceutically acceptable salts”. Specific embodiments include ammonium, sodium, calcium, magnesium, cesium, lithium, potassium, barium, zinc, aluminum, lysine, arginine, histidine, methylamine, ethylamine, t-butylamine, cyclohexylamine, N-methylglucamine, ethylenediamine, glycine, procaine, benzathene, diethanolamine, triethanolamine, piperidine and morpholine. For the most preferred embodiment, (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[(dihydrogen phosphonoxy)methoxy]butane, the t-butylamine and lysine salts are especially preferred as they can be obtained as single polymorph crystalline solids of high purity with good solubility and stability.
The term “halogen” as used herein includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro, and most preferably fluoro.
The compounds of the present invention can be solvated or non-solvated. A preferred solvate is a hydrate.
A most preferred embodiment of the present invention is (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[(dihydrogen phosphonoxy)methoxy]butane or a pharmaceutically acceptable salt thereof. This prodrug exhibits much improved aqueous solubility (>10 mg/mL at pH 7, 5-6 mg/mL at pH 4.3) compared with the parent compound which enables it to be used for parenteral administration as well as oral administration. This compound is also stable in solution, can be isolated in crystalline form and is readily converted to parent drug in vivo.
The compounds of the present invention may be made by the following general reaction scheme. In this method, A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary or secondary hydroxyl group, Pr represents a conventional hydroxy-protecting groups such as t-butyl, benzyl or allyl, and R and R
1
are each independently hydrogen or (C
1
-C
6
)alkyl. Most preferably, R and R
1
are both hydrogen.
To elaborate on the method, the antifungal pare

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