Note: Descriptions are shown in the official language in which they were submitted.
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Pyrazole Derivatives
This invention relates to pyrazole derivatives, to their use in medicine, to
compositions containing them, to processes for their preparation and to
intermediates used in such processes.
Reverse transcriptase is implicated in the infectious lifecycle of Human
Immunodeficiency Virus (HIV). Compounds which interfere with the function of
this enzyme have shown utility in the treatment of conditions caused by HIV
and
genetically related retroviruses, such as Acquired Immune Deficiency Syndrome
(AIDS). There is a constant need to provide new and better modulators,
especially inhibitors, of HIV reverse transcriptase, since the virus is able
to
mutate, becoming resistant to the effects of known modulators.
Antiviral activity is ascribed to a class of N(hydroxyethyl)pyrazole
derivatives in
US patent number 3,303,200. A number of pyrazoles are disclosed as reverse
transcriptase inhibitors, including: a class of N-phenylpyrazoles (J. Med.
Chem.,
2000, 43, 1034); a class of C and S linked aryl pyrazoles (W002/04424); and a
class of O and S linked aryl pyrazoles, the O and S aryl link being adjacent
to the
nitrogen atom (W002/30907).
According to the present invention there is provided a compound of formula (I)
Ra O R'
z
O / N~R (I)
-N
R3
or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein:
R' is a five or six-membered, aromatic heterocyclic group containing (i) from
1 to
4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or
1
sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said
heterocyclic group being optionally substituted by halo, oxo, -CN, -CORS,
-CONR5R5, -S02NR5R5, -NR5S02R5, -ORS, OR", -NR5R5,
-(C1-C6 alkylene)-NR5R5, R' or R";
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R2 is H, C~-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C~ cycloalkyl,
C3_C~ cycloalkenyl, phenyl, benzyl, R8 or R9, said C~-C6 alkyl, C3-C7
cycloalkyl,
phenyl and benzyl being optionally substituted by halo, -ORS, -OR'°, -
CN,
-C02R', -OCONR5R5, -CONR5R5, -C(=NR5)NR50R5, -CONR5NR5R5, -NR6R6,
-NRSR'°, -NR5COR5, -NR5COR8, -NRSCOR'°, -NR5C02R5, -NRSCONR5R5,
-S02NR5R5, -NR5S02R5, -NR5S02NR5R5, R8 or R9;
R3 is H, C,-C6 alkyl, C3-C7 cycloalkyl, phenyl, benzyl, halo, -CN, -OR7, -
C02R5,
-CONR5R5, R8 or R9, said C,-C6 alkyl, C3-C7 cycloalkyl, phenyl and benzyl
being
optionally substituted by halo, -CN, -ORS, -C02R5, -CONR5R5, -OCONR5R5,
-NR5C02R5, -NR6R6, -NR5COR5, -S02NR5R5, -NRSCONR5R5, -NR5S02R5, R$ or
Rs.
R4 is phenyl, naphthyl or pyridyl, each being optionally substituted by R8,
halo,
-CN, C~-C6 alkyl, C~-C6 haloalkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, -CONR5R5,
OR", SoXRs, O-(C~-C6 alkylene)-CONR5R5, O-(C1-C6 alkylene)-NR5R5, or
O_(C1_C6 alkylene)-OR6;
each R5 is independently either H, C~-C6 alkyl or C3-C7 cycloalkyl or, when
two R5
groups are attached to the same nitrogen atom, those two groups taken together
with the nitrogen atom to which they are attached represent azetidinyl,
pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl or
morpholinyl, said azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,
piperazinyl,
homopiperazinyl and morpholinyl being optionally substituted by C1-C6 alkyl or
C3-C7 cycloalkyl;
each R6 is independently either H, C~-C6 alkyl or C3-C7 cycloalkyl;
R' is C~-C6 alkyl or Cs-C~ cycloalkyl;
R$ is a five or six-membered, aromatic heterocyclic group containing (i) from
1 to
4 nitrogen heteroatom(s) or (ii) 1 or 2 nitrogen heteroatom(s) and 1 oxygen or
1
sulphur heteroatom or (iii) 1 or 2 oxygen or sulphur heteroatom(s), said
heterocyclic group being optionally substituted by halo, oxo, -CN, -CORS,
-CONR5R5, -S02NR5R5, -NR5S02R5, -ORS, -NR5R5, -(C,-C6 alkylene)-NR5R5,
C~-C6 alkyl, fluoro(C~-C6)alkyl or C3-C7 cycloalkyl;
R9 is a four to seven-membered, saturated or partially unsaturated
heterocyclic
group containing (i) 1 or 2 nitrogen heteroatom(s) or (ii) 1 nitrogen
heteroatom
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and 1 oxygen or 1 sulphur heteroatom or (iii) 1 oxygen or sulphur heteroatom,
said heterocyclic group being optionally substituted by oxo, C1-Cs alkyl,
C3-C7 cycloalkyl, -S02R5, -CONRSRS, -COORS, -CO-(C1-C6 alkylene)-ORS or
-CORS and optionally substituted on a carbon atom which is not adjacent to a
heteroatom by halo, -ORS, -NRSRS, -NRSCORS, -NRSCOORS, -NRSCONRSRS,
-NRSS02R5 or -CN;
R'° is C,-C6 alkyl substituted by R8, R9, -ORS, -CONRSRS, -NRSCORS or -
NRSRS;
R" is phenyl optionally substituted by halo, -CN, -CORS, -CONRSRS, -S02NRSR5,
-NRSS02R5, -ORS, -NRSRS, -(C~-C6 alkylene)-NRSRS, C1-C6 alkyl, halo(C1-
C6)alkyl
or C3-C7 cycloalkyl; and
x is 0, 1 or 2.
In the above definitions, halo means fluoro, chloro, bromo or iodo. Unless
otherwise stated, alkyl, alkenyl, alkynyl, alkylene and alkoxy groups
containing
the requisite number of carbon atoms can be unbranched or branched chain.
Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
sec-
butyl and t-butyl. Examples of alkenyl include ethenyl, propen-1-yl, propen-2-
yl,
propen-3-yl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-
yl, 2-
buten-2-yl, 2-methylpropen-1-yl or 2-methylpropen-3-yl. Examples of alkynyl
include ethynyl, propyn-1-yl, propyn-3-yl, 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-
4-yl,
2-butyn-1-yl. Examples of alkylene include methylene, 1,1-ethylene, 1,2-
ethylene, 1,1-propylene, 1,2-propylene, 2,2-propylene and 1,3-propylene.
Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-
butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Where R' and R2 are taken
together, they form, along with the nitrogen atom and the carbon atom of the
pyrazole ring to which they are attached, a 5- or 6-membered ring. Where a
heterocyclic group R$ or R9 is attached to an oxygen, sulphur or nitrogen
heteroatom the heterocyclic group R$ or R9 must be linked through a ring
carbon
atom. Further, where a heterocyclic group R9 is attached to an oxygen, sulphur
or nitrogen heteroatom the heterocyclic group R9 must be linked through a ring
carbon atom that is not adjacent to a ring heteratom.
The pharmaceutically acceptable salts of the compounds of formula (I) include
the acid addition and the base salts thereof.
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Suitable acid addition salts are formed from acids which form non-toxic salts
and
examples are the hydrochloride, hydrobromide, hydroiodide, chloride, bromide,
iodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate,
fumarate, pamoate, aspartate, besylate, carbonate, bicarbonate/, camsylate, D
and L-lactate, D and L-tartrate, esylate, mesylate, malonate, orotate,
gluceptate,
methylsulphate, stearate, glucuronate, 2-napsylate, tosylate, hibenzate,
nicotinate, isethionate, malate, maleate, citrate, gluconate, succinate,
saccharate, benzoate, esylate, and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and
examples are the sodium, potassium, aluminium, calcium, magnesium, zinc,
choline, diolamine, olamine, arginine, glycine, tromethamine, benzathine,
lysine,
meglumine and diethylamine salts.
For reviews on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977
and
Bighley et al, Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc,
New York, 1996, Vol 13, pp453-497
The pharmaceutically acceptable solvates of the compounds of formula (I)
include the hydrates thereof.
The compound of formula (I) may be modified to provide pharmaceutically
acceptable derivatives thereof at any of the functional groups in the
compound.
Examples of such derivatives are described in: Drugs of Today, Volume 19,
Number 9, 1983, pp 499 - 538; Topics in Chemistry, Chapter 31, pp 306 - 316;
and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the
disclosures in which documents are incorporated herein by reference) and
include:
esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate
esters, sulfoxides, amides, sulphonamides, carbamates, azo-compounds,
phosphamides, glycosides, ethers, acetals and ketals.
The invention encompasses all isomers of the compound of formula (I) and
pharmaceutically acceptable salts, solvates or derivatives thereof, including
all
geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic
mixtures).
Separation of diastereoisomers may be achieved by conventional techniques,
e.g. by fractional crystallisation, chromatography or high performance liquid
chromatography (HPLC) of a stereoisomeric mixture of compounds. An
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individual enantiomer of a compound may also be prepared from a
corresponding optically pure intermediate or by resolution, such as by HPLC of
the corresponding racemate using a suitable chiral support, or by fractional
crystallisation of the diastereoisomeric salts formed by reaction of the
5 corresponding racemate with a suitable optically active acid or base, as
appropriate.
The compound of formula (I) and pharmaceutically acceptable salts, solvates or
derivatives thereof may have the ability to crystallize in more than one form,
a
characteristic known as polymorphism, and all such polymorphic forms
("polymorphs") are encompassed within the scope of the invention.
Polymorphism generally can occur as a response to changes in temperature or
pressure or both, and can also result from variations in the crystallization
process. Polymorphs can be distinguished by various physical characteristics,
and typically the x-ray diffraction patterns, solubility behaviour, and
melting point
of the compound are used to distinguish polymorphs.
Compounds of formula (I), pharmaceutically acceptable salts, solvates and
derivatives thereof, isomers thereof, and polymorphs thereof, are hereinafter
referred to as the compounds of the invention.
Preferred compounds of the invention are the compounds of formula (I) and
pharmaceutically acceptable salts and solvates thereof.
Preferably, R' is a five or six-membered, aromatic heterocyclic group
containing
(i) from 1 to 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1
oxygen
or 1 sulphur heteroatom, said heterocyclic group being optionally substituted
by
halo, oxo, -CN, -ORS, -OR", -NRSRS, -(C~-C6 alkylene)-NRSRS, R' or R".
Preferably, R' is a five or six-membered, aromatic heterocyclic group
containing
(i) from 1 to 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1
sulphur
heteroatom, said heterocyclic group being optionally substituted by -OR",
-NRSRS, R' or R".
Preferably, R' is a five or six-membered, aromatic heterocyclic group
containing
(i) from 1 to 2 nitrogen heteroatom(s) or (ii) 1 nitrogen heteroatom and 1
sulphur
heteroatom, said heterocyclic group being optionally substituted by C~-Cs
alkyl,
phenyl, phenoxy, C,-C6 alkoxyphenoxy or-NRSRS.
Preferably, R' is pyridinyl, pyrimidinyl, pyrazinyl or thiazolyl, each being
optionally
substituted by C1-C2 alkyl, phenyl, C~-C2 alkoxyphenoxy, -N(CH3)2, -N(CH2CH3)2
or N(CH3)( CH2CH3).
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Preferably, R2 is H, C1-C6 alkyl, C3-C6 alkenyl, phenyl, benzyl or R9, said
phenyl,
benzyl or C~-C6 alkyl being optionally substituted by halo, -ORS, -
OR'°, -CN,
-C02R', -OCONRSRS, -CONRSRS, -C(=NRS)NRSORS, -CONRSNRSRS, -NR6R6,
-NRSR'°, -NRSCORS, -NRSCORB, -NRSCOR'°, -NRSC02R5, -NRSCONRSRS,
-S02NRSR5, -NRSS02R5, R$ or R9.
Preferably, R2 is C1-Cs alkyl, phenyl or benzyl, said C~-Cs alkyl being
optionally
substituted by halo, -ORS, -OR'° or -CN.
Preferably, R2 is C,-C3 alkyl or benzyl, said C~-C3 alkyl being optionally
substituted by -CN.
Preferably, R3 is H, C~-C6 alkyl or C3-C~ cycloalkyl, said C,-C6 alkyl being
optionally substituted by halo, -CN, -ORS, -C02R5, -CONRSRS, -OCONRSRS,
-NRSC02R5, -NR6R6, -NRSCORS, -S02NRSR5, -NRSCONRSRS, -NRSS02R5, R8 or
R9.
Preferably, R3 is H or C~-C6 alkyl.
Preferably, R3 is H or C~-C4 alkyl.
Preferably, R3 is methyl or ethyl.
Preferably, R4 is phenyl optionally substituted by R8, halo, -CN, C1-C6 alkyl,
C1_C6 haloalkyl, C3-C~ cycloalkyl or C~-C6 alkoxy.
Preferably, R4 is phenyl substituted by R8, halo, -CN, C,-C6 alkyl, or C1-C6
alkoxy.
Preferably, R4 is phenyl substituted by -CN.
Preferably, R4 is 3,5-dicyanophenyl.
Preferably, R$ is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-
triazolyl,
tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl or
pyrazinyl,
each being optionally substituted by halo, -CN, -CORS, -CONRSRS, -S02NRSR5,
-NRSS02R5, -ORS, -NRSRS, -(C1-C6 alkylene)-NRSRS, C~-Cs alkyl,
fluoro(C,-C6)alkyl or C3-C~ cycloalkyl.
Preferably, R8 is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally
substituted by halo, -CN, -CORS, -CONRSRS, -S02NRSR5, -NRSS02R5, -ORS,
-NRSRS, -(C~-C6 alkylene)-NRSRS, C~-C6 alkyl, fluoro(C~-C6)alkyl or
Cs-C~ cycloalkyl.
Preferably, R$ is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally
substituted by -ORS, -NRSRS or C,-C6 alkyl.
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Preferably, R$ is imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, pyridinyl, pyrazinyl or pyrimidinyl, each being optionally
substituted by -OH, -NH2 or methyl.
Preferably, R9 is azetidinyl, tetrahydropyrrolyl, piperidinyl, azepinyl,
oxetanyl,
tetrahydrofuranyl, tetrahydropyranyl, oxepinyl, morpholinyl, piperazinyl or
diazepinyl, each being optionally substituted by oxo, C~-C6 alkyl, Cs-C7
cycloalkyl,
-S02R5, -CONRSRS, -COORS, -CO-(C,-C6 alkylene)-ORS or -CORS and optionally
substituted on a carbon atom which is not adjacent to a heteroatom by halo,
-ORS, -NRSRS, -NRSCORS, -NRSCOORS, -NRSCONRSRS, -NRSS02R5 or -CN.
Preferably, R9 is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or
morpholinyl, each being optionally substituted by oxo, C~-C6 alkyl,
C3-C7 cycloalkyl, -S02R5, -CONRSRS, -COORS, -CO-(C1-C6 alkylene)-ORS or
-CORS and optionally substituted on a carbon atom which is not adjacent to a
heteroatom by halo, -ORS, -NRSRS, -NRSCORS, -NRSCOORS, -NRSCONRSRS,
-NRSS02R5 or -CN.
Preferably, R9 is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or
morpholinyl, each being optionally substituted by C1-C6 alkyl, -S02R5, -
CONRSRS,
-COORS, -CO-(C1-Cs alkylene)-ORS or -CORS and optionally substituted on a
carbon atom which is not adjacent to a heteroatom by -ORS or -NRSCORS.
Preferably, R9 is azetidinyl, piperidinyl, tetrahydrofuranyl, piperazinyl or
morphoninyl, each being optionally substituted by -CH3, -S02CH3, -CONH2,
-COOCH3, -COCH20CH3 or -COCH3 and optionally substituted on a carbon atom
which is not adjacent to a heteroatom by -OCH3 or -NHCOCH3.
Preferably, R'° is C~-Ca. alkyl substituted by R8, R9, -ORS, -CONRSRS, -
NRSCORS
or -NRSRS.
Preferably, R'° is C~-C4 alkyl substituted by R9, -ORS, -NRSCORS or -
NRSRS.
Preferably, R'° is C~-C2 alkyl substituted by tetrahydrofuranyl, -OCH3,
-NHCOCHs
or -NH2.
Preferably, R" is phenyl substituted by halo, -CN, -CORS, -CONRSRS,
-S02NRSR5, -NRSS02R5, -ORS, -NRSRS, -(C,-C6 alkylene)-NRSRS, C~-C6 alkyl,
halo(C1-C6)alkyl or C3-C7 cycloalkyl.
Preferably, R" is phenyl substituted by halo, -CN, -CONRSRS, -S02NRSR5 or
-ORS.
Preferably, R" is phenyl substituted by -ORS.
Preferably, R" is phenyl substituted by C1-C2 alkoxy.
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Preferred groups of compounds according to the invention include all
combinations of the preferred definitions for individual substituents given
above.
Preferred compounds of the invention are:
5-[3-Ethyl-1-methyl-5-(pyridin-2-yloxy)-1 H pyrazol-4-yloxy]-
isophthalonitrile;
the compound of Example 6;
and its pharmaceutically acceptable salts, solvates or derivatives.
The compounds of the invention may have advantages over those of the prior art
with regard to a number of useful properties or combination thereof, such as
potency, duration of action, pharmacokinetics, spectrum of activity, side
effect
profile, solubility, chemical stability, and so on.
The compounds of the invention may be prepared by any method known in the
art for the preparation of compounds of analogous structure. The compounds of
the invention can be prepared by the procedures described in the methods
below, or by the specific methods described in the Examples, or by similar
methods to either. The invention also encompasses any one or more of these
processes for preparing the compounds of the invention, in addition to any
novel
intermediates used therein.
In the following methods, R', R2, R3 and R4 are as previously defined for a
compound of formula (I), unless otherwise stated, and Ra is an alkyl group,
such
as a lower alkyl group (e.g. methyl).
Compounds of formula (I) may be prepared according to Scheme 1.
According to Scheme 1, compounds of formula (I) may be prepared by the
reaction of a compound of formula (V) with an alcohol of formula (IV) under
conventional conditions. Conveniently, the reaction is effected in the
presence of
a catalyst, such as a transition metal catalyst, preferably a palladium
catalyst
(e.g. 1,1'-bis(diphenylphosphino)ferrocenepalladium(II)chloride); a solvent,
such
as a polar aprotic solvent (e.g. N,N-dimethylformamide); at ambient to
elevated
temperature, such as around 50°C; under an inert atmosphere, such as
carbon
monoxide; and at elevated pressure, such as around 345 kPa.
Compounds of formula (V) may be prepared from compounds of formula (III) by
derivatising the hydroxy group therein to provide a leaving group (Lg).
Conveniently, Lg is a reactive ester group, such as a sulphonic ester group,
(e.g.
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trifluoromethanesulphonate). Conveniently, the reaction is effected in the
presence of a derivatising agent, such as a sulphonic amide, (e.g.
phenyltriflamide); a base, such as a trialkylamine base (e.g. triethylamine);
a
solvent such, such as a halogenated alkane (e.g. dichloromethane); and at
ambient to elevated temperature, such as ambient temperature.
Scheme 1
ORa R ORa
CI R4-OH (VIII) O
O ---~ . O
R3 ~ (IX) R3 O (VII)
H2NNH-RZ (VI)
Ra
i
O OH
Lg-R' (II)
4 3
O R 1 R N~N~R2 (III)
OR
alcohol
R N~N\R2 derivatisation
(I) Ra
O ~g
R'-OH (IV)
R3 N~N~R2 V
()
Compounds of formula (III) may be prepared by the reaction of a compound of
formula (VII) with a hydrazine of formula (VI), or a salt or hydrate thereof.
Conveniently, the reaction is effected a solvent, such as a protic solvent
(e.g.
acetic acid); at ambient to elevated temperature, such as ambient temperature;
and optionally in the presence of an acid (e.g. acetic acid) or a base, such
as a
tertiary amine (e.g. triethylamine).
Compounds of formula (VII) may be prepared by the reaction of a compound of
formula (IX) with an alcohol of formula (VIII). Conveniently, the reaction is
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effected in the presence of a solvent, such as a polar solvent (e.g. acetone);
a
base, such as an inorganic base, preferably a metal carbonate (e.g. potassium
or
caesium carbonate); optionally, a nucleophilic catalyst, such as sodium iodide
or
tetrabutylammonium iodide; and at ambient to elevated temperature, such as
5 elevated temperature (e.g. under reflux).
Chloroketoesters of formula (IX) are either commercially available, known in
the
literature, or may be prepared by conventional methods (e.g. the chlorination
of
the corresponding ketoesters, for instance using sulphonyl chloride).
According to Scheme 1, compounds of formula (I) may also be prepared by the
reaction of an alcohol of formula (III) with a compound of formula (II) under
conventional conditions. Conveniently, the reaction is effected in the
presence of
a base, such as an inorganic base, preferably a metal carbonate (e.g.
potassium
carbonate); optionally a solvent, such as a polar aprotic solvent (e.g. N,N-
dimethylacetamide); optionally a catalyst, such as a copper(I) catalyst; and
at
ambient to elevated temperature, such as elevated temperature (e.g. under
reflux).
Alternatively, compounds of formula (I) may be prepared from compounds of
formula (III) by reaction with an alcohol of formula (IV) under dehydrating
conditions, such as afforded by the Mitsunobu reaction. Conveniently, the
reaction is effected in the presence of diethylazodicarboxylate,
triphenylphosphine, a solvent, such as an ether, (e.g. tetrahydrofuran); and
at
reduced to ambient temperature, such 0°C.
Compounds of formula (I) in which R3 is halo can be prepared from a compound
of formula (X)
Ra
O OR'
HO N~N~R2 (X)
under conventional conditions. Conveniently, the reaction is effected by an
inorganic acid halide, such as an inorganic acid chloride (e.g. POC13);
optionally
in the presence of a solvent, such as a polar aprotic solvent (e.g. N,N-
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11
dimethylformamide); and at reduced to ambient temperature, such as ambient
temperature.
Compounds of formula (X) may be prepared using the routes described above,
mutatis mutandis.
It will be appreciated by those skilled in the art that, in many cases,
compounds
of formula (I) may be converted into other compounds of formula (I) by
functional
group transformations, including for example the following interconversions.
Compounds of formula (I) in which R2 is optionally substituted C,-C6 alkyl may
be
prepared from compounds of formula (I) in R2 is H by reaction with an
alkylating
agent. Suitable alkylating agents include bromoacetonitrile, ethyl
4-chloroacetoacetate, methyl bromoacetate and chloroethylamine hydrochloride.
Conveniently, alkylation is effected in the presence of a suitable solvent,
such as
an alcohol (e.g. ethanol) or a polar aprotic solvent (e.g. N,N-
dimethylformamide);
a base, such as a metal hydride (e.g. sodium hydride) or metal alkoxide (e.g.
sodium ethoxide); and at ambient to elevated temperature, such as under
reflux.
Compounds of formula (I) in which R2 or R3 contains a hydroxy group may be
prepared from the corresponding compound of formula (I) in which R2 or R3
contains an ester group by reduction. Conveniently, the reduction is effected
by
a metal hydride agent, such as lithium aluminium hydride; in a solvent, such
as
an ether (e.g. diethyl ether); and at reduced temperature, such as from -
78°C to
0°C.
Compounds of formula (I) in which R2 or R3 are substituted by a heterocycle of
formula R8 and R9 may be prepared by standard heterocycle-forming reactions
well known to the skilled man (see, for example, Advanced Organic Chemistry,
3rd Edition, by Gerry March or Comprehensive Heterocyclic Chemistry, A.R.
Katritzky, C.W. Rees, E.F.V. Scriven, Volumes 1-11).
Compounds of formula (I) in which R3 is -C02H may be prepared by hydrolysis of
a corresponding compound of formula (I) in which R3 is -C02R5. Conveniently,
the reaction is effected in the presence of a solvent, such as an alcohol
(e.g.
aqueous ethanol), or an ether (e.g. aqueous 1,4-dioxan); and in the presence
of
a base, such as a metal hydroxide (e.g. sodium hydroxide). The skilled artisan
will appreciate that such an acid may be converted into a primary amide by
reaction with ammonia and a suitable coupling agent, such as a carbodiimide,
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12
e.g. dicyclohexylcarbodiimide, and that such a primary amide may then be
converted into a nitrite by dehydration with a suitable dehydrating agent,
such as
phosphoryl chloride.
Compounds of formula (I) in which R3 is C~-C6 alkyl may be converted into the
compounds of formula (I) in which R3 is C~-C6 alkyl substituted by halo (such
as
bromo), by halogenation, using a suitable halogenating agent. Conveniently the
reaction is effected in the presence of a solvent, such as a haloalkane (e.g.
dichloromethane) and at ambient temperature. Suitable halogenating agents
include halogens (e.g. bromine) or N-halosuccinimides (e.g. N-
bromsuccinimide).
Compounds of formula (I) containing an -OH, -NH- or -NH2 group may be
prepared by the deprotection of the corresponding compound bearing an -OP',
-NP'- or -NHP' group, respectively, wherein the group P' is a suitable
protecting
group. Examples of suitable protecting groups will be apparent to the skilled
person; see, for instance, 'Protecting groups in Organic Synthesis (Second
Edition)' by Theodora W. Green and Peter G. M. Wuts, 1991, John Wiley and
Sons. Such compounds bearing an -OP', -NP'- or -NHP' group may be
prepared using the routes described above, mutatis mutandis.
Compounds of formulae (II), (IV) and (VI) and (VIII) are either commercially
available, known in the literature or easily prepared by methods well known to
those skilled in the art, such as those described in the Preparations
hereinafter.
Compounds of formulae (III), (V) or (X) are key intermediates and form a
further
aspect of the invention.
The compounds of the invention can be administered alone, but will generally
be
administered in admixture with a suitable pharmaceutical excipient, diluent or
carrier selected with regard to the intended route of administration and
standard
pharmaceutical practice.
For example, the compounds of the invention can be administered orally,
buccally or sublingually in the form of tablets, capsules, multi-particulates,
gels,
films, ovules, elixirs, solutions or suspensions, which may contain flavouring
or
colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or
controlled-release applications. The compounds of the invention may also be
administered as fast-dispersing or fast-dissolving dosage forms or in the form
of
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13
a high energy dispersion or as coated particles. Suitable formulations of the
compounds of the invention may be in coated or uncoated form, as desired.
Such solid pharmaceutical compositions, for example, tablets, may contain
excipients such as microcrystalline cellulose, lactose, sodium citrate,
calcium
carbonate, dibasic calcium phosphate, glycine and starch (preferably corn,
potato
or tapioca starch), disintegrants such as sodium starch glycollate,
croscarmellose
sodium and certain complex silicates, and granulation binders such as
polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),
hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate
and talc may be included.
General Example
A formulation of the tablet could typically contain from 0.01 mg to 500mg of
active
compound whilst tablet fill weights may range from 50mg to 1000mg. An
example of a formulation for a l0mg tablet is illustrated below:
In_ req dient %w/w
Compound of the invention 10.000*
Lactose 64.125
Starch 21.375
Croscarmellose sodium 3.000
Magnesium Stearate 1.500
* Quantity adjusted in accordance with drug activity.
The tablets are manufactured by a standard process, for example, direct
compression or a wet or dry granulation process. The tablet cores may be
coated with appropriate overcoats.
Solid compositions of a similar type may also be employed as fillers in
gelatin or
HPMC capsules. Preferred excipients in this regard include lactose, starch, a
cellulose, milk sugar or high molecular weight polyethylene glycols. For
aqueous
suspensions and/or elixirs, the compounds of the invention may be combined
with various sweetening or flavouring agents, colouring matter or dyes, with
emulsifying and/or suspending agents and with diluents such as water, ethanol,
propylene glycol and glycerin, and combinations thereof.
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The compounds of the invention can also be administered parenterally, for
example, intravenously, intra-arterially, intraperitoneally, intrathecally,
intraventricularly, intraurethrally, intrasternally, intracranially,
intramuscularly or
subcutaneously, or they may be administered by infusion or needleless
injection
techniques. For such parenteral administration they are best used in the form
of
a sterile aqueous solution which may contain other substances, for example,
enough salts or glucose to make the solution isotonic with blood. The aqueous
solutions should be suitably buffered (preferably to a pH of from 3 to 9), if
necessary. The preparation of suitable parenteral formulations under sterile
conditions is readily accomplished by standard pharmaceutical techniques well-
known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage
level
of the compounds of the invention will usually be from 0.01 to 30 mg/kg,
preferably from 0.01 to 5 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the invention may contain from 1
to
500 mg of active compound for administration singly or two or more at a time,
as
appropriate. The physician in any event will determine the actual dosage which
will be most suitable for any individual patient and it will vary with the
age, weight
and response of the particular patient. The above dosages are exemplary of the
average case. There can, of course, be individual instances where higher or
lower dosage ranges are merited and such are within the scope of this
invention.
The skilled person will appreciate that, in the treatment of certain
conditions the
compounds of the invention may be taken as a single dose as needed or desired.
The compounds of invention can also be administered intranasally or by
inhalation and are conveniently delivered in the form of a dry powder inhaler
or
an aerosol spray presentation from a pressurised container, pump, spray,
atomiser or nebuliser, with or without the use of a suitable propellant, e.g.
dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a
hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or
1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or
other suitable gas. In the case of a pressurised aerosol, the dosage unit may
be
determined by providing a valve to deliver a metered amount. The pressurised
container, pump, spray, atomiser or nebuliser may contain a solution or
suspension of the active compound, e.g. using a mixture of ethanol and the
propellant as the solvent, which may additionally contain a lubricant, e.g.
sorbitan
trioleate. Capsules and cartridges (made, for example, from gelatin) for use
in an
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inhaler or insufflator may be formulated to contain a powder mix of a compound
of the invention and a suitable powder base such as lactose or starch.
Alternatively, the compounds of the invention can be administered in the form
of
5 a suppository or pessary, or they may be applied topically in the form of a
gel,
hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds
of
the invention may also be dermally or transdermally administered, for example,
by the use of a skin patch. They may also be administered by the pulmonary or
rectal routes.
They may also be administered by the ocular route. For ophthalmic use, the
compounds can be formulated as micronised suspensions in isotonic, pH
adjusted, sterile saline, or, preferably, as solutions in isotonic, pH
adjusted, sterile
saline, optionally in combination with a preservative such as a benzylalkonium
chloride. Alternatively, they may be formulated in an ointment such as
petrolatum.
For application topically to the skin, the compounds of the invention can be
formulated as a suitable ointment containing the active compound suspended or
dissolved in, for example, a mixture with one or more of the following:
mineral oil,
liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene
polyoxypropylene compound, emulsifying wax and water. Alternatively, they can
be formulated as a suitable lotion or cream, suspended or dissolved in, for
example, a mixture of one or more of the following: mineral oil, sorbitan
monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl
esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the invention may also be used in combination with a
cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion
complexes with drug molecules. Formation of a drug-cyclodextrin complex may
modify the solubility, dissolution rate, bioavailability and/or stability
property of a
drug molecule. Drug-cyclodextrin complexes are generally useful for most
dosage forms and administration routes. As an alternative to direct
complexation
with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a
carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are
most
commonly used and suitable examples are described in W091/11172,
W094/02518 and W098/55148.
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It is to be appreciated that all references herein to treatment include
curative,
palliative and prophylactic treatment.
Oral administration is preferred.
Included within the scope of the invention are embodiments comprising the co-
administration of a compound of the invention with one or more additional
therapeutic agents, and compositions containing a compound of the invention
along with one or more additional therapeutic agents. Such a combination
therapy is especially useful for the prevention and/or treatment of infection
by
HIV and related retroviruses which may evolve rapidly into strains resistant
to any
monotherapy. Alternatively, additional therapeutic agents may be desirable to
treat diseases and conditions which result from or accompany the disease being
treated with the compound of the invention. For example, in the treatment of
an
HIV or related retroviral infection, it may be desirable to additionally treat
opportunistic infections, neoplasms and other conditions which occur as a
result
of the immuno-compromised state of the patient being treated.
Preferred combinations of the invention include simultaneous or sequential
treatment with a compound of the invention and one or more:
(a) reverse transcriptase inhibitors such as abacavir, adefovir, didanosine,
lamivudine, stavudine, zalcitabine and zidovudine;
(b) non-nucleoside reverse transcriptase inhibitors such as capavirine,
delavirdine, efavirenz, and nevirapine;
(c) HIV protease inhibitors such as indinivir, nelfinavir, ritonavir, and
saquinavir;
(d) CCR5 antagonists such as TAK-779 or UK-427,857;
(e) CXCR4 antagonists such as AMD-3100;
(f) integrase inhibitors, such as L-870,810 or S-1360;
(g) inhibitors of viral fusion such as T-20;
(h) investigational drugs such as trizivir, KNI-272, amprenavir, GW-33908,
FTC, PMPA, MKC-442, MSC-204, MSH-372, DMP450, PNU-140690, ABT-378,
KNI-764, DPC-083, TMC-120 or TMC-125;
(i) antifungal agents, such as fluconazole, itraconazole or voriconazole; or
(j) antibacterial agents, such as azithromycin.
The activity of the compounds of the invention as reverse transcriptase
inhibitors
may be measured using the following assay.
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Inhibition of HIV-1 reverse transcriptase enzyme
Using purified recombinant HIV-1 reverse transcriptase (RT, EC, 2.7.7.49)
obtained by expression in Escherichia Coli, a 96-well plate assay system is
established for assaying a large number of samples using either the Poly(rA)
oligo(dT) Reverse Transcriptase (3H]-SPA enzyme assay system (Amersham
NK9020) or the [3H]-flashplate enzyme assay system (NEN - SMP 103) and
following the manufacturer's recommendations. The compounds are dissolved in
100% DMSO and diluted with the appropriate buffer to a 5% final DMSO
concentration. The inhibitory activity is expressed in percent inhibition
relative to
DMSO control. The concentration at which compound inhibits reverse
transcriptase by 50% is expressed as the ICSO of the compound.
The compound of Exampls 1 and 6, when tested according to the above
procedure, had an ICSO values of, respectively, 5400 and 391 nanomolar.
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Thus the invention provides:
(i) a compound of formula (I) or a pharmaceutically acceptable salt, solvate
or derivative thereof;
(ii) a process for the preparation of a compound of formula (I) or a
pharmaceutically acceptable salt, solvate or derivative thereof;
(iii) a pharmaceutical composition including a compound of formula (I) or a
pharmaceutically acceptable salt, solvate or derivative thereof, together
with a pharmaceutically acceptable excipient, diluent or carrier;
(iv) a compound of formula (I) or a pharmaceutically acceptable salt, solvate
or composition thereof, for use as a medicament;
(v) a compound of formula (I) or a pharmaceutically acceptable salt, solvate
or composition thereof, for use as a reverse transcriptase inhibitor or
modulator;
(vi) a compound of formula (I) or a pharmaceutically acceptable salt, solvate
or composition thereof, for use in the treatment of an HIV or genetically-
related retroviral infection, or a resulting acquired immune deficiency
syndrome (AIDS);
(vii) a use of the compound of formula (I) or of a pharmaceutically acceptable
salt, solvate or composition thereof, for the manufacture of a medicament
having reverse transcriptase inhibitory or modulating activity;
(viii) the use of a compound of formula (I) or of a pharmaceutically
acceptable
salt, solvate or composition thereof, for the manufacture of a medicament
for the treatment of an HIV or genetically-related retroviral infection, or a
resulting acquired immune deficiency syndrome (AIDS);
(ix) a method of treating an HIV or a genetically-related retroviral
infection, or a
resulting acquired immune deficiency syndrome (AIDS), comprising
administering an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt, solvate or composition thereof; and
(xi) certain novel intermediates disclosed herein.
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The following Examples illustrate the preparation of the compounds of formula
(I). The synthesis of certain intermediates used therein are described in the
Preparations section that follows the Examples.
'H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with
the proposed structures. Characteristic chemical shifts (8) are given in parts-
per-
million downfield from tetramethylsilane using conventional abbreviations for
designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q,
quartet; m,
multiplet; br, broad. The following abbreviations have been used: HRMS, high
resolution mass spectrometry; hplc, high performance liquid chromatography;
nOe, nuclear Overhauser effect; m.p., melting point; CDC13, deuterochloroform;
D6-DMSO, deuterodimethylsulphoxide; CD30D, deuteromethanol. Where thin
layer chromatography (TLC) has been used it refers to silica gel TLC using
silica
gel 60 F25a plates, Rf is the distance travelled by a compound divided by the
distance travelled by the solvent front on a TLC plate.
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Example 1
5-[3-Ethyl-1-methyl-5-(pyridin-2-yloxy~-1 H pyrazol-4-yloxyl-isophthalonitrile
NC
CN
N-
O O
~ iN~CH
N 3
H3C
5
The pyrazole of Preparation 5 (10 mg, 0.37 mmol) and 2-chloropyridine (55 mg,
0.49 mmol) were mixed and heated to 145°C for 1.5 hours. The mixture
was
cooled to room temperature and partitioned between ethyl acetate (10 ml) and
water (10 ml). The aqueous solution was extracted with ethyl acetate (2x10
ml).
10 The combined organic solutions were evaporated under reduced pressure and
the residue was purified by chromatography on silica gel using methanol in
dichloromethane (1:99) to give the title compound as a yellow solid (30 mg).
'H NMR (400 MHz, CD30D): 8 1.18 (m, 3H), 2.49 (m, 2H), 3.60 (s, 3H), 7.00 (m,
15 1 H), 7.15 (m, 1 H), 7.6 (s, 2H), 7.72 (m, 1 H), 7.80 (m, 1 H), 8.12 (m, 1
H).
LRMS (APCI): m/z[M+H]+346
Examples 2-10:
The compounds of Table 1 of the general formula:
NC
CN
O O-R'
NiN~R2
H3C
were prepared by a method analogous to that of Example 1 using the appropriate
pyrazole and aryl halide.
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Table 1
Example No. R' R2
N \
2 ~ i CHs
N
N \ ~CH3
3 ~ i CHs
N
4,a N \ \ CHs
i
N
N \
N~CH3 CH3
I
CH3
N \ O \
6 ~ , ~ / CH CH3
N
N
7 ~ , CH3
N
N
8 . CH3
S
N \
~N
N
~ \
i /
N
A, starting pyrimidine, see J. Het. Chem, 1980, 17(7) 1479.
B, starting pyrimidine supplied by Peakdale Fine Chemicals
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Example 2
'H NMR (400 MHz, DMSO-ds): 8 1.10 (m, 3H), 2.40 (m, 2H), 3.6 (s, 3H), 7.38 (m,
1 H), 7.8 (s, 2H), 8.05 (s, 1 H), 8.62 (m, 2H).
LRMS (APCI): m/z [M+H]+ 347
Example 3:
'H NMR (400 MHz, CDC13): 8 1.26 (m, 6H), 2.48 (m, 2H), 2.64 (m, 2H), 3.70 (s,
3H), 7.50 (m, 3H), 8.38 (m, 2H)
LRMS (APCI): m/z [M+H]+ 375.
Example 4:
'H NMR (400 MHz, CDC13): 8 1.20 (m, 3H), 2.48 (m, 2H), 3.75 (s, 3H), 7.50 (m,
8H), 8.70 (m, 2H).
LRMS (APCI): m/z [M+H]+ 423
Example 5:
'H NMR (400 MHz, CDC13): b 1.20 (m, 3H), 2.49 (m, 2H), 3.15 (m, 6H), 3.70 (s,
3H), 6.23 (m, 1 H), 7.45 (m, 2H), 8.00 (m, 2H).
LRMS (APCI): m/z [M+H]+ 390
Example 6:
'H NMR (400 MHz, CDC13): 8 1.20 (m, 3H), 2.48 (m, 2H), 3.82 (s, 3H),3.85 (s,
3H), 6.95 (m, 4H), 7.42 (s, 2H), 7.52 (s, 1 H), 8.20 (s, 2H).
LRMS (APCI): m/z [M+H]+ 469
Example 7:
'H NMR (400 MHz, CDC13): b 1.20 (m, 3H), 2.48 (m, 2H), 3.70 (s, 3H), 7.42 (s,
2H), 7.50 (s, 1 H), 8.00 (s, 1 H), 8.38 (s, 1 H), 8.42 (s, 1 H).
LRMS (APCI): m/z [M+H]+ 347
Example 8:
'H NMR (400 MHz, CDCI3): 8 1.20 (m, 3H), 2.48 (m, 2H), 3.80 (s, 3H), 6.80 (m,
1 H), 7.10 (m, 1 H), 7.42 (s, 2H), 7.50 (s, 1 H).
LRMS (APCI): m/z [M+H]+ 352
Example 9:
'H NMR (400 MHz, DMSOO-ds): 8 1.10 (m, 3H), 2.47 (m, 2H), 3.0 (m, 2H), 4.20
(m, 2H), 7.38 (m, 1 H), 7.5 (s, 2H), 8.05 (s, 1 H), 8.60 (m, 2H).
LRMS (APCI): m/z[M+H]+386
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Example 10:
'H NMR (400 MHz, CDC13): 8 1.20 (m, 3H), 2.54 (m, 2H), 5.2 (s, 2H), 7.00 (m,
1 H), 7.15-7.25 (m, 5H), 7.5 (s, 3H), 8.4 (m, 2H).
LRMS (APCI): m/z [M+H]+ 423
Example 11
5-f3-Ethyl-1- 2-hydroxy-ethyl)-5-(pyridin-2-yloxy)-1 H-pyrazol-4-yloxyl-
isoahthalonitrile
NC
CN
N_
O O
H3C
~ ,N
N
OH
Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 72 ~I, 0.07 mmol) was
added to a solution of the silyl ether of Preparation 10 (32 mg, 0.07 mmol) in
tetrahydrofuran (3 ml) and the mixture was stirred for 1.5 hours. A further
quantity of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 33 wl, 0.03
mmol)
was added and the mixture was stirred for a further 45 minutes. Brine and
dichloromethane were added and the layers were separated. The organic layer
was dried over magnesium sulphate and evaporated under reduced pressure.
The residue was purified by chromatography on silica gel using methanol in
dichloromethane (gradient from 2:98 to 3.5:96.5) to give the title compound as
a
yellow oil (21 mg).
'H NMR (400 MHz, CDC13): 8 1.18 (m, 3H), 2.49 (m, 2H), 4.07 (m, 4H), 6.90 (m,
1 H), 7.10 (m, 1 H), 7.45 (m, 3H), 7.60 (m, 1 H), 8.10 (m, 1 H).
LRMS (APCI): m/z [M+H]+ 376.
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Preparation 1
1,3-Dibromo-5-methoxybenzene
Br ~ ~~CH
3
Br
Sodium methoxide (4.5M solution in methanol, 8.80 ml, 41.0 mmol) was added
dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol,
Aldrich) in N,N dimethylformamide (95 ml) at 0°C under a nitrogen
atmosphere.
The reaction was warmed to room temperature, stirred for 1 hour and then
evaporated under reduced pressure. The residue was dissolved in diethyl ether
and was washed with water (3x300 ml) and brine (300 ml), dried over magnesium
sulphate, filtered and concentrated under reduced pressure to give the title
compound as a white solid (5.13 g).
'H-NMR (300MHz, CDC13): 8 3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, 1 H).
LRMS: m/z TS+ 266 [M+H]
Preparation 2
3,5-Dicyanomethoxybenzene
NC ~ O~CH3
CN
Tris(dibenzylideneacetone)dipalladium(0) (6.53g, 7.15mmol) was added in one
portion to a stirred solution of the bromide of Preparation 1 (38.Og,
143mmol),
1,1'-bis(diphenylphosphino)ferrocene (9.3g, 16.8mmol) and zinc cyanide (20.Og,
172mmol) in N,N dimethylformamide (300m1) at room temperature under
nitrogen. The reaction was heated at 100°C for 14 hours and cooled to
room
temperature. Water (1500m1) was added and the mixture was extracted with
ethyl acetate (3x500m1). The combined organics were filtered and the filtrate
was
washed with water (500m1), dried over magnesium sulphate, filtered and
concentrated under reduced pressure. The resulting solid was triturated with
toluene (1000m1) to provide the title compound (l8.Og) as a tan solid.
' H-NMR (300MHz, CDC13): 8 = 3.83 (3H, s), 7.31 (2H, s), 7.48 (1 H, s).
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Preparation 3
3.5-Dicyanohydroxybenzene
OH
5 N
The ether of Preparation 2 (9.60 g, 60.7 mmol) was added portionwise to a
stirred suspension of aluminium trichloride (32.4 g, 243 mmol) in
dichloromethane (250 ml) at 0°C under a nitrogen atmosphere. The
suspension
10 was stirred at 45°C for 6 days, then cooled to room temperature and
poured onto
ice (450 ml). Concentrated hydrochloric acid (450 ml) was added dropwise and
the resulting suspension was stirred for 10 minutes at room temperature. The
solid formed was isolated by filtration, washed with water and dried over
phosphorus pentoxide to give the title compound as a tan solid (7.83 g).
20
'H-NMR (400MHz, CDC13): 8 7.36 (m, 2H), 7.56 (m, 1 H).
Preparation 4
~3 5-Dicyano-phenoxy)-3-oxo-pentanoic acid methyl ester
N
O \ ~\N
HsC O~CH3
O O
A solution of 2-chloro-3-oxo-pentanoic acid methyl ester (20 g, 121.5 mmol) in
acetone (100 ml) was added to the phenol from Preparation 3 (17.5 g, 121.5
mmol) and caesium carbonate (43.5 g, 133.6 mmol) in acetone (400 ml) under a
nitrogen atmosphere. The mixture was stirred at room temperature for 15
minutes and then heated under reflux for 2.5 hours. Water was added and the
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26
solvent was evaporated under reduced pressure. The residual aqueous solution
was extracted with dichloromethane (3x300 ml) and the combined organic layers
were dried over magnesium sulphate and evaporated under reduced pressure.
The residual orange oil was pre-adsorbed onto silica gel and then purified by
chromatography on silica gel using ethyl acetate in pentane (gradient from
20:80
to 80:20) to give the title compound as a yellow solid (27 g).
M.p. 93-95°C
Found; C, 61.57; H, 4.54; N, 10.06; C,4H~2N204 requires C, 61.76; H, 4.44; N,
10.29%.
Preparation 5
5-(3-Ethyl-1-methyl-5-oxo-4 5-dihydro-1 H pyrazol-4-yloxy)-isophthalonitrile
~~ N
O O
H3C wN~N~CH3
The ester from Preparation 4 (4 g, 14.7 mmol) was dissolved in acetic acid (50
ml) and methyl hydrazine (0.87 ml, 16.2 mmol) was added. The mixture was
stirred at room temperature under a nitrogen atmosphere for 3 hours and the
solvent was evaporated under reduced pressure. The residue was triturated with
diethyl ether to give the title compound as a pink solid (2.75 g).
M. p. 235-dec
LRMS: m/z ES+ 269 [M+H]
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Preparation 6
5-[1-(2-C~ano-ethyl)-3-ethyl-5-oxo-4 5-dihydro-1 H-pyrazol-4-yloxyl-
isophthalonitrile
j \~N
0 0
HsC ~ ~N
N
~N
The title compound was obtained from the ester of preparation 4 and 3-
hydrazino-propionitrile in 57% yield following a procedure analogous to that
described in Preparation 5.
M.p.203.5-204.5°C
APCI MS m/z 308 [M+H]+
Preparation 7
5-[3-Ethyl-1-(2-hey-eth~-5-oxo-4,5-dihydro-1 H pvrazol-4-yloxyl- l
isophthalonitrile
NC
\ CN
O O
HsC ~ ~N
N
OH
The title compound was obtained in 73% yield from the ester of preparation 4
and 2-hydrazino-ethanol following a procedure analogous to that described in
Preparation 5.
M.p. 203.5-204.5°C
APCI MS m/z297 [M-H]~
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Preparation 8
5-i;1-Benzyl-3-ethyl-5-oxo-4 5-dihydro-1 H-eyrazol-4-yloxy)-isophthalonitrile
~~ N
O O
HsC ~ ~N
N
~1
The title compound was obtained from the ester of preparation 4 and benzyl
hydrazine in 52% yield following a procedure analogous to that described in
Preparation 5.
APCI MS m/z 345 [M+H]+
Preparation 9
5-{1-f2-(tert-Butyl-dimeth I-y silanYloxy)-ethyl]-3-ethyl-5-oxo-4,5-dihydro-1
H
wrazol-4-~rloxy}-isophthalonitrile
NC
CN
O O
HsC W ~N
N
O CHs
H3C S~'CH
H3C~ 3
CH3
CA 02497333 2005-02-22
WO 2004/029042 PCT/IB2003/004158
29
tert-Butyl-dimethyl-silyl chloride (2.4 g, 16.1 mmol) was added to a solution
of the
alcohol of preparation 7 (4.0 g, 13.4 mmol) in N,N-dimethylformamide (20 ml)
and triethylamine (5.6 ml, 40.3 mmol). The mixture was stirred at room
temperature under a nitrogen atmosphere for 3 hours and then was partitioned
between ethyl acetate and water. The organic layer was washed with brine
(2x100 ml) dried over magnesium sulphate and evaporated under reduced
pressure. The residue was purified by chromatography on silica gel using
dichloromethane as eluant to give the title compound (3.6 g).
M.p.203.5-204.5°C
APCI MS m/z 413 [M+H]+
Preparation 10
5-[1-f2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-ethyl-5- pyridin-2-yloxy)-1
H
pyrazol-4-yloxyl-isophthalonitrile
H3C
~~ CH3
HsC Si,CH
H C
CH3
A mixture of the pyrazole of preparation 9 (150 mg, 0.36 mmol) and 2-
chloropyridine (54 mg, 0.47 mmol) was heated to 150°C for 2 hours and
then
was partitioned between ethyl acetate and water. The organic layer was
evaporated under reduced pressure and the residue was purified by
chromatography on silica gel using methanol in dichloromethane as eluant
(2:98)
to give the title compound (32 mg).
LCMS: m/z ES+ 512 [M+Na]+
