Water soluble prodrugs of azole compounds

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

2001-09-28

2002-10-01

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S205000

Reexamination Certificate

active

06458961

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, m can be 0 to 6; p is 1 or 2; R
1
, R
2
, R
3
and R
4
can each independently be hydrogen, C
1
-C
6
alkyl, hydroxy, OR
5
, NH
2
, NR
6
R
7
, or halogen; R
5
, R
6
and R
7
can each independently be hydrogen, C(O)R8, or C
1
-C
6
alkyl; R
8
is 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 known classes of such compounds, 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 potent anti-fungal activity.
The utility of this class of compounds is limited by their low water solubility. Various prior art methods have attempted to address this problem in order to prepare water-soluble forms of these compounds, e.g. for parenteral administration.
WO 97/28169 discloses compounds of the general formula
R′—OP(O)(OH)
2
wherein R′ represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
EP 829478 discloses compounds of the general formula
wherein
Q is the remainder of an azole compound of the formula
possessing antifungal activity;
Z is nitrogen or methine;
R
1
and R
2
are each independently a hydrogen atom or a group —OY in which Y is a group easily hydrolyzable under physiological condition;
R
3
and R
4
are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower alkylcarbonyl)-thiomethyl, carboxy or methoxycarbonyl; and X
−
is a pharmaceutically acceptable anion.
WO 99/15522 discloses compounds of the general formula
wherein G is H or PO
3
H
2
.
WO 98/34934 discloses compounds of the formula
the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein —A—B— forms a divalent radical of formula:
—N═CH—  (a),
—CH═N—  (b),
—CH═CH—  (c),
wherein one hydrogen atom in the radicals (a) and (b) may be replaced with a C
1-6
alkyl-radical and up to two hydrogen atoms in radical (c) may be replaced by a C
1-6
alkyl-radical;
L represents the acyl moiety of an amino acid, and thus —O—L represents an amino acid ester group;
D is a radical of formula
wherein
X is N or CH;
R
1
is halo;
R
2
is hydrogen or halo.
U.S. Pat. No. 5,707,977 discloses compounds of the formula
an acid or base addition salt thereof or a stereochemically isomeric form thereof, wherein A and B taken together form —N═CH—, —CH═N—, —CH
2
—CH
2
, CH═CH—, —C(═O)—CH
2
—, —CH
2
—C(═O); D is a radical of formula
Alk is a C
1-4
alkanediyl radical; R
1
is halo; R
2
is hydrogen or halo; R
3
is hydrogen, C
1-6
alkyl, phenyl or halophenyl; R
4
is hydrogen, C
1-6
alkyl phenyl or halophenyl; R
5
is hydrogen or C
1-6
alkyl; R
6
is hydrogen, C
1-6
alkyl, C
1-6
alkyloxycarbonyl, or R
5
and R
6
taken together with the nitrogen atom to which they are attached form a heterocyclic ring.
WO 96/38443 discloses compounds of the formula
wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl;
R
1
is a straight or branched chain (C
4
-C
5
) alkyl group substituted by one or two groups convertible in vivo into hydroxy moieties or a pharmaceutically acceptable salt thereof.
WO 98/43970 discloses a quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound wherein one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo to be converted into an antifungal azole compound. The preferred compounds have the formula
(wherein Q is an imidazol-1-yl or 1,2,4-triazol-1-yl group in which one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo; Ar is an optionally substituted phenyl group; A is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X
1
is an oxygen atom or a methylene group; X
2
is an optionally oxidized sulfur atom; m and p respectively represent 0 or 1; Y is an anion; and (1) R
3
, R
4
and R
5
may be the same or different and represent a hydrogen atom or a lower alkyl group, or (2) R
3
is a hydrogen atom or a lower alkyl group and R
4
and R
5
are combined with each other to form a lower alkylene group, or (3) R
5
is a hydrogen atom or a lower alkyl group and R
3
and R
4
are combined with each other to form a lower alkylene group) or a salt thereof.
WO 99/33846 discloses compounds of the formula
wherein R
1
, R
2
and R
3
are substituents which comprise the parent secondary or tertiary amine such that one of R
1
, R
2
or R
3
may be hydrogen, R
4
and R
5
are each hydrogen, or an organic or inorganic residue.
U.S. Pat. No. 5,883,097 discloses the water-soluble lactic acid addition salt of the compound represented by the formula
as suitable for preparation of pharmaceutical formulations for intravenous use.
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 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, n is 0 or 1, m can be 0 to 6; p is 1 or 2; R
1
, R
2
, R
3
and R
4
can each independently be hydrogen, C
1
-C
6
alkyl, hydroxy, OR
5
, NH
2
, NR
6
R
7
, or halogen; R
5
, R
6
and R
7
can each independently be hydrogen, C(O)R8, or C
1
-C
6
alkyl; R
8
is C
1
-C
6
alkyl, or a pharmaceutically acceptable salt thereof. The preferred formula I compounds are those where R
1
, R
2
, R
3
and R
4
are each independently hydrogen, C
1
-C
6
alkyl, OR
5
or halogen. Most preferred are the formula I compunds where R
1
, R
2
, R
3
and R
4
are each hydrogen.
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 phosphate containing 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
9
represents phenyl substituted by one or more (preferably 1-3) halogen atoms;
R
10
represents H or CH
3
;
R
11
represents H, or taken together with R
10
may represent ═CH
2
;
R
12
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
12
may represent include triazolyl, pyrimidinyl, and thiazolyl.
Preferred embodiments comprise:
(1) A compound of formula I where A is a group of formula II and R
9
is 2,4-difluorophenyl; or a pharmaceutically acceptable salt thereof;
(2) A compound of (1) above where R
10
is methyl and R
11
is hydrogen; or a pharmaceutically

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