Triazole derivatives useful in therapy

Details Triazole derivatives useful in therapy Triazole derivatives useful in therapy

2003-01-09

2004-09-14

Morris, Patricia L. (Department: 1625)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

Reexamination Certificate

active

06790957

ABSTRACT:

This invention relates to triazole derivatives useful in therapy (in particular in the treatment of fungal infections in humans and other mammals), methods for their use, formulations including them and processes for their production.
A large number of triazole antifungal compounds are known. For example, European Patent Application 0440372, Example 7, discloses (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol (also known as voriconazole) which has particularly good activity against the clinically important Aspergillus spp fungi. However, the compound has low solubility in aqueous media, necessitating the use of complexing agents to achieve satisfactory aqueous formulations, such as intravenous formulations. European Patent Application 0440372 suggests co-formulation with cyclodextrin derivatives to improve solubility; however, it is always desirable to keep the number of ingredients in a formulation to a minimum so as to minimize possible adverse reactions in patients.
UK Patent Application 2,128,193 discloses phosphoric acid esters for use as plant fungicides and insecticides.
Maurin et al [Int J Pharm, 1993, 94(1-3), 11-14] disclose &agr;-(2,4-difluorophenyl)-&agr;-[(1-(2-(3pyridyl)phenylethenyl)]-1H-1,2,4-triazole-1-ethanol bismesylate, which is stated to be an antifungal agent having high solubility.
Other triazole antifungal agents are known from European Patent Application 0576201 and international Patent Application WO 97/01552.
European Patent Application 0413674 discloses formation of prodrugs of therapeutic glycosidase inhibitors by phophorylating a free hydroxy group in the molecule. However, phosphorylation of tertiary hydroxy groups is not described.
It has now been found that triazole antifungal compounds of the type comprising a tertiary hydroxy group, including (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, may be converted into pro-drugs having greatly enhanced solubility, but which are converted readily in vivo to give the desired active moiety.
According to the invention, there is provided a compound of formula I,
R
1
—OP(O)(OH)
2
  I
wherein R
1
represents the non-hydroxy portion of a triazole antifungal compound of the type comprising a tertiary hydroxy group;
or a pharmaceutically acceptable salt thereof (referred to herein as “the compounds of the invention”).
The compounds of the invention are distinct from the prior art because the tertiary hydroxy group in triazole antifungal compounds of this type has not previously lent itself to functionalization.
Pharmaceutically acceptable salts that may be mentioned include alkali metal salts of the phosphate group, for example disodium or dipotassium salts; and salts with an amine counter ion, for example ethylenediamine, glycine or choline salts.
Preferably, R
1
represents a group of formula Ia,
in which
R
2
represents phenyl substituted by one or more halogen atoms;
R
3
represents H or CH
3
;
R
3a
represents H, or together with R
3
it may represent ═CH
2
; and
R
4
represents a 5- or 6-membered nitrogen-containing heterocyclic ring which is optionally substituted by one or more groups selected from halogen, ═O, phenyl [substituted by a group selected from CN and (C
6
H
4
)—OCH
2
CF
2
CHF
2
] or 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.
When R
1
represents a group of formula Ia, as defined above, R
2
is preferably 2,4-difluorophenyl, and R
3
is preferably H or methyl.
Nitrogen-containing heterocyclic rings that R
4
may represent or comprise include triazolyl, pyrimidinyl and thiazolyl.
Preferred specific groups that R
1
may represent include:
The triazole antifungal compounds corresponding to the groups (a)-(g) above are: (a) D-0870 (under development by Zeneca, see also Example 19, European Patent Application 0472392); (b) fluconazole (sold by Pfizer, see also UK Patent Application 2099818); (c) Example 7 of European Patent Application 0440372, also known as voriconazole; (d) Example 35 of U.S. Pat. No. 4,952,232; (e) the compound of Example 8 of the present application; (f) Compound A of WO 95/22973 (see page 29), originally disclosed as Compound 30 in Example 27 of EP 567982; and (g) ER-30346 (see Drugs of the Future, 1996, 21(1): 20-24, Tetrahedron Letters, Vol 37, 45, pp 8117-8120, 1996 AND European Patent Application 0667346, Example 88).
The present invention also provides a process for the production of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, which comprises phosphorylating a compound of formula II,
R
1
OH  II
wherein R
1
is as defined above;
and where desired or necessary converting the resulting compound into a pharmaceutically acceptable salt or vice versa.
The phosphorylation may be carried out using the following steps (1)-(3):
(1) Reacting a compound of formula II, as defined above, with a compound of formula III,
R
a
R
b
N—P(OR
c
)(OR
d
)  III
wherein R
a
and R
b
independently represent C
1-6
alkyl, phenyl or substituted phenyl, or together with the nitrogen atom to which they are attached they may represent a ring such as a morpholine ring; and R
c
and R
d
independently represent hydroxy protecting groups selected from benzyl optionally subsituted by one or more halogen atoms; to give a phosphite compound of formula IV,
R
i
—O—P(OR
c
)(OR
d
)  IV
wherein R
i
, R
c
and R
d
are as defined above.
The reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. methylene chloride) in the presence of a mild acid (for example tetrazole, 5-methyltetrazole or pyridinium hydrobromide) and optionally 4-dimethylaminopyridine, at room temperature or above.
(2) Reacting the resulting phosphite of formula IV with an oxidant (for example a peracid such as 3-chloroperoxybenzoic acid, or H
2
O
2
), to give a phosphate of formula V,
R
1
—OP(O)(OR
c
)(OR
d
)  V
wherein R
1
, R
c
and R
d
are as defined above. The reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. methylene chloride or ethyl acetate) below room temperature (for example 0-−20° C.).
(3) Removing the hydroxy protecting groups from the compound of formula V to give a compound of formula I, as defined above.
As an alternative to step (1), phosphites of formula IV may be prepared according to steps (1A) and (1B):
(1A) Reaction of a compound of formula II, as defined above, with PCl
3
in the presence of a base to give a postulated intermediate compound of formula VI,
R
1
—O—PCl
2
  VI
wherein R
1
is as defined above. The reaction may be carried out in a solvent which does not adversely affect the reaction (e.g. methylene chloride or ethyl acetate) at a temperature in the range −20 to +20° C. (for example 0° C.). Suitable bases include pyridine and N-methylimidazole.
(1B) Reaction of the compound of formula VI with a compound of formula R
c
OH and/or R
d
OH (in which R
c
and R
d
are as defined above) to give a compound of formula IV, as defined above. The reaction is performed without isolation of the compound of formula VI, at a temperature around room temperature.
Hydroxy protecting groups which R
c
and R
d
may represent include 2,6-dichlorobenzyl and 2-chloro-6-fluorobenzyl. Benzyl groups may be removed using catalytic hydrogenation (e.g. over Pearlman's catalyst or palladium-on-carbon) or bromotrimethylsilane.
If step(3) is carried out in the presence of sodium acetate or sodium hydroxide, the disodium salt may be obtained directly.
Process step (3) above, and the intermediate compounds of formula V from further aspects of the invention. Compounds of formulae II and III are either known or are available using known techniques.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This ma

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