Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-01
2002-04-23
Morris, Patricia L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S266200, C548S266600
Reexamination Certificate
active
06376526
ABSTRACT:
This invention relates to triazole derivatives which have antifungal activity and are useful in the treatment of fungal infections in animals, including human beings.
Thus the invention provides compounds of formula (I):
pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of either entity, wherein
X is CH or N;
R
1
is phenyl subsituted with 1 to 3 substituents each independently selected from halo and CF
3
;
R
2
is (hydroxy)C
1
-C
4
alkyl, CONH
2
, S(O)
m
(C
1
-C
4
alkyl), Ar or Het; m is 1 or 2;
Ar is phenyl optionally monosubstituted with halo or CF
3
; and
Het is a C-linked 6-membered nitrogen-containing aromatic heterocyclic group containing 1 or 2 nitrogen atoms, or a C- or N-linked 5-membered nitrogen-containing aromatic heterocyclic group containing from 2 to 4 nitrogen atoms, wherein either of said heterocyclic groups is optionally substituted with C
1
-C
4
alkyl or (C
1
-C
4
alkoxy)methyl.
In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms may be straight or branched chain; halo means fluoro, chloro, bromo or iodo. In addition. Het is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl.
The compounds of formula (I) contain at least two chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formula (I) together with mixtures thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid.
The preferred stereoisomers of formula (I) have the (2R,3S)-configuration of formula (IA):
Furthermore, the compounds of formula (I) may exist as cis- or trans-alkene isomers and the invention also includes both separate individual isomers and mixtures thereof. The preferred isomers are the trans-isomers.
Certain compound of formula (I) may also exist in tautomeric forms and the invention includes both separate individual tautomers and mixtures thereof.
Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
The pharmaceutically acceptable salts of the compounds of formula (I) are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with organo-carboxylic acids, or with organo-sulphonic acids. Certain compounds of formula (I) can also provide pharmaceutically acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include the sodium and potassium salts. For a review of suitable pharmaceutical salts, see J. Pharm. Sci., 1977, 66, 1.
A preferred group of compounds of formula (I) is that wherein R
1
is phenyl substituted by 1 or 2 substituents each independently selected from F and Cl; R
2
is hydroxypropyl, CONH
2
, SO
2
CH
3
, Ar or Het; Ar is fluorophenyl; Het is a pyridyl, pyrazolyl, imidazolyl or triazolyl group, wherein, said pyrazolyl group is substituted with methyl and said triazolyl group is optionally substituted with ethoxymethyl; and X is as previously defined for formula (I).
A more preferred group of compounds of formula (I) is that wherein R
1
is 2,4-difluorophenyl; R
2
is C(CH
3
)
2
OH, CONH
2
, SO
2
CH
3
, 4-fluorophenyl, 2-pyridyl, 1-methylpyrazol-5-yl, imidazol-1-yl, 1,2,3-triazol-4-yl or 1-ethoxymethyl-1,2,3-triazol-5-yl; and X is as previously defined for formula (I).
Particularly preferred compounds of the invention include:
trans-(2R,3S)-1-(1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{4-[2-(1-methylpyrazol-5-yl)ethenyl]phenyl}butan-2-ol;
trans-(2R,3S/2S,3R)-1-(1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-{4-[2-(imidazol-1-yl)ethenyl]phenyl}butan-2-ol; and
trans-(2R,3S/2S,3R)-1-(1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-[5-(2-carbamoylethenyl)pyrid-2-yl]butan-2-ol;
and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of either entity.
In another aspect, the present invention provides processes for the preparation of compounds of formula (I), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity.
A compound of formula (I) may be prepared from a compound of formula (II):
wherein Z is bromo or iodo, and X and R
1
are as previously defined for formula (I), by treatment with a compound of formula (III):
CH
2
═CHR
2
(III)
wherein R
2
is as previously defined for formula (I), under typical Heck reaction conditions. The reaction is generally carried out using from about a 20 to about a 100% excess of the required alkene and from about a 50 to about a 100% excess of a tertiary amine, in the presence of from about 0.05 to about 0.60 equivalent of a palladium salt and from about 0.10 to about 1.10 equivalents of a tertiary arylphosphine, in a suitable solvent such as acetonitrile or dimethylformamide, at from about 80 to about 160° C. Preferably the tertiary amine is triethylamine, the palladium salt is palladium acetate, the phosphine is either tri-o-tolylphosphine or 1,1′-bis(diphenylphosphino)ferrocene, and the reaction is conducted in refluxing acetonitrile.
A compound of formula (II) may be prepared by a variety of synthetic procedures. For example one such procedure, which is preferred when X is N, involves the reaction of a compound of formula (IV):
wherein R
1
is as previously defined for formula (II), with an organometallic compound of formula (V):
wherein M is a suitable metal (e.g. lithium, sodium or potassium) or metal halide (e.g. magnesium halide or zinc halide), and X and Z are as previously defined for formula (II).
An organometallic compound of formula (V) wherein M is a suitable metal is preferably generated in situ by deprotonation of the corresponding alkane precursor (i.e. a compound of formula (V) wherein M is hydrogen) with a suitable base, e.g. lithium or potassium diisopropylamide or lithium, sodium or potassium bis(trimethylsilyl)amide.
An organometallic compound of formula (V) wherein M is a suitable metal halide, e.g. a Grignard reagent or organozincate, can be prepared either by treatment in situ of the corresponding organometallic compound of formula (V) wherein M is lithium with a suitable metal halide, e.g. magnesium bromide or zinc iodide, or by treatment of the corresponding alkyl halide precursor (i.e. a compound of formula (V) wherein M is chloro, bromo or iodo) with magnesium or zinc respectively, optionally using iodine to promote the reaction.
Preferably (V) wherein M is chloro, bromo or iodo is converted to the corresponding zincate in the presence of (IV) in a suitable solvent at about room temperature in an inert atmosphere by treating it with zinc in the presence of iodine. This may be achieved in tetrahydrofuran as solvent using about 2.6 equivalents of zinc powder, followed by 0.2 equivalent of iodine, which leads to an exothermic reaction.
The compounds of formula (IV) are either known, e.g. see EP-A-044605, EP-A-069442 or GB-A-1464224, or may be prepared by methods similar to those described therein.
An alternative synthetic procedure for preparing a compound of formula (II), which is preferred when X is CH, involves the reduction of a compound of formula (VI):
wherein Z, X and R
1
are as previously defined for formula (II).
The reduction is conveniently effected using diimide generated in situ. Thus diimide precursor, such as p-toluenesulphonylhydrazi
Bell Andrew Simon
Stephenson Peter Thomas
Ginsburg Paul H.
Morris Patricia L.
Myers Jeffrey N.
Pfizer Inc.
Richardson Peter C.
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