WO 2006/090177 PCT/GB2006/000684
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USE OF 2-(2-NITRO-4-TRIFLUOROMETHYLBENZOYL)-l,3-
CYCLOHEXANEDIONE IN THE TREATMENT OF PARKINSON'S DISEASE
The present invention relates to, inter alia, the use of a 4-hydroxyphenylpyruvate
dioxygenase (HPPD) inhibitor in the treatment of neurodegenerative disease. More
specifically, the invention relates to the use of a HPPD inhibitor in an amount which is
effective to treat Parkinson's disease. In a particular embodiment the HPPD inhibitor is
2-(2-Nitro-4-Trifluoromethylbenzoyl)-1,3-Cyclohexanedione (compound 2).
Neurodegenerative diseases affect millions of people worldwide. In particular,
Parkinson's disease is increasing in prevalence due to increasing lifespan. The disease is
not very well understood, though a key aspect is oxidative damage, resulting in the loss
of dopaminergic neurones in the substantia nigra region of the brain and consequential
reductions in striatal dopamine. Once striatal dopamine levels have been depleted by
approximately 80%, symptoms of Parkinson's become apparent. Such symptoms
increase in severity as more neurones are lost. There are numerous publications which
provide an overview of the disease. More recent publications provide an overview of
treatments for patients suffering from Parkinson's disease.
Virtually all symptomatic treatment of the disease involves increasing the brain
supply of dopamine or by systemic administration of dopamine agonists. Dopamine
itself cannot cross the blood-brain barrier (BBB), and the dominant drug used is
levodopa, the immediate precursor for dopamine, which can readily cross the BBB.
Levodopa treatment has to be supplemented with other drugs (e.g. carbidopa) that inhibit
the metabolism of levodopa in other parts of the body — this reduces adverse side-effects
and increases and extends the levodopa concentration in plasma. Slow-release
formulations of levodopa are also used, but the kinetics of levodopa remain far from
optimal. After a few years of levodopa therapy, during which time more neurones have
been lost in the patient, the effectiveness of levodopa is reduced (referred to clinically as
"wearing off') and the therapeutic margin reduces or disappears. Patients experience
Parkinsonian symptoms before their next dose is due ("off periods"), yet the dose cannot
be increased without causing side-effects, primarily dyskinesia. These side-effects are to
a significant extent believed to be the result of the fast kinetics of levodopa, and the
pulsatile dopaminergic stimulation that this causes. Dopamine receptor agonists are
available in the art and more are being developed, but their potency is limited. Such

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agonists seem to be of use, primarily, in the early stages of treatment or as adjuncts to
levodopa treatment. Other adjunct therapies to levodopa treatment are also used and more
are being developed.
More recent research into treatments is aimed at identifying ways to detect the
disease before it becomes symptomatic, and to treat it with "neuroprotectants". If
completely effective, these would prevent further loss of neurones and so halt disease
progression. However pre-symptomatic detection is proving to be extremely difficult.
For patients who already have symptoms, any treatment with neuroprotectants would
supplement rather than replace drugs for treating the symptoms. Also, at present,
neuroprotectants so far only result in, at best, a modest delay in disease progression,
rather than halting the disease.
It would therefore be desirable to provide a pharmaceutical which would produce
a constant elevation of brain dopamine levels in Parkinson's disease patients. This
concept is known as continuous dopaminergic stimulation. Then, treatment would be
more effective than systemic levodopa or dopamine agonists and such treatment could
maintain its effectiveness for longer, with fewer side-effects.
The present invention therefore seeks to provide, inter alia, a pharmaceutical for
use in the treatment of Parkinson's disease which pharmaceutical overcomes and/or
ameliorates the problems mentioned above.
Accordingly the present invention provides, amongst other things, compositions
and methods for their use to inhibit 4-hydroxyphenylpyruvate dioxygenase in animals
such that an increase in levodopa and/or dopamine synthesis is achieved.
According to the present invention there is provided the use of 2-(2-Nitro-4-
Trifluoromethylbenzoyl)-1,3-Cyclohexanedione (compound 2), or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a
neurodegenerative disease.
The present invention further provides the use as described above wherein' said
disease is Parkinson's disease.
It will be appreciated that 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-
Cyclohexanedione may exist in one or more tautomeric forms, one of which is shown in
formula (II) (i.e. compound 2) : and which forms are readily inter-convertible by keto-
enol tautomerism.

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It is to be understood that the invention includes the use of 2-(2-Nitro-4-
Trifluoromethylbenzoyl)-1,3-Cyclohexanedione in any of such tautomeric forms or as a
mixture thereof.
2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-Cyclohexanedione is acidic and readily
forms salts with a wide variety of bases.
Particularly suitable salts of 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-
Cyclohexanedione suitable for use as active ingredients in pharmaceutical compositions
according to the invention include, for example, pharmaceutically acceptable base-
addition salts, for example, alkali metal (such as potassium or sodium), alkaline earth
metal (such as calcium or magnesium) and ammonium salts, and salts with organic bases
giving physiologically acceptable cations (such as salts with methylamine,
dimethylamine, trimethylamine, piperidine and morpholine).
2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-Cyclohexanedione may be obtained by
conventional procedures of organic chemistry already known for the production of
structurally analogous materials.
Thus, for example, 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-Cyclohexanedione
may be conveniently obtained by reaction of 2-rutro-4-trifluoromethylbenzoyl chloride
with cyclohexane-l,3-dione in the presence of acetone cyanhydrin and a suitable base
such as triethylamine.
The starting 2-nitro-4-trifluoromethylbenzoyl chloride may itself be obtained
from the corresponding benzoic acid, for example by reaction with thionyl chloride or
oxalyl chloride as is described in Reagents for Organic Synthesis, (J Wiley and Sons,
1967; editors: Fieser L. F. and Fieser M.; Vol 1, pp. 767-769) and is generally used
without special purification.

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Similarly, 2-Bitro-4-trifluroromethylbenzoic acid may be obtained, for example,
as described by Haupstein et al. in J. Amer. Chem. Soc, 1954,76,1051, or by one of the
general methods well known to the skilled person.
The present invention still further provides the use as described above wherein
the medicament comprises compound 2 or a pharmaceutically acceptable salt thereof and
a further compound which is also capable of inhibiting 4-hydroxyphenylpyruvate
dioxygenase (HPPD) in an animal.
The present invention still further provides the use as described above wherein
said medicament comprises a dopamine agonist.
The present invention still further provides the use as described above wherein
said medicament comprises levodopa and a decarboxylase inhibitor.
In a further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of compound 2 or a pharmaceutically acceptable salt
thereof and a pharmaceutically effective amount of a dopamine agonist and a means for
the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of compound 2 or a pharmaceutically acceptable salt
thereof and a pharmaceutically effective amount of levodopa and a means for the
delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of compound 2 or a pharmaceutically acceptable salt
thereof and a pharmaceutically effective amount of levodopa and a decarboxylase
inhibitor and a means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of compound 2 or a pharmaceutically acceptable salt
thereof and a pharmaceutically effective amount of a catechol-O-methyl transferase
inhibitor and a means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of compound 2 or a pharmaceutically acceptable salt
thereof and a pharmaceutically effective amount of a monoamine oxidase inhibitor and a
means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of compound 2 or a pharmaceutically acceptable salt

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thereof and a pharmaceutically effective amount of a further compound which is also
capable of inhibiting HPPD in an animal and a means for the delivery thereof to an
animal.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising as an active ingredient compound 2 or a pharmaceutically
acceptable salt thereof and a pharmaceutically effective amount of a further compound
which is also capable of inhibiting HPPD in an animal optionally together with a
pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a
dopamine agonist optionally together with a pharmaceutically acceptable diluent or
carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of
levodopa optionally together with a pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of
levodopa and a decarboxylase inhibitor optionally together with a pharmaceutically
acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a
catechol-O-methyl transferase inhibitor optionally together with a pharmaceutically
acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a
monoamine oxidase inhibitor optionally together with a pharmaceutically acceptable
diluent or carrier.

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In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a
decarboxylase inhibitor optionally together with a pharmaceutically acceptable diluent or
carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of a
neuroprotectant optionally together with a pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of an
adenosine (A2a) receptor antagonist optionally together with a pharmaceutically
acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount of
istradefylline optionally together with a pharmaceutically acceptable diluent or carrier.
The invention still further provides a pharmaceutical composition as described
above which is in a form suitable for oral or parenteral administration.
In a particular embodiment, said pharmaceutical composition is in palatable form
suitable for oral administration selected from the group consisting of: tablets; lozenges;
hard capsules; aqueous suspensions; oily suspensions; emulsions; dispersible powders;
dispersible granules; syrups and elixirs.
In a further embodiment said pharmaceutical composition is intended for oral use
and is in the form of hard or soft gelatin capsules.
In a still further embodiment said pharmaceutical composition is in a form
suitable for parenteral administration.
In a still further aspect of the invention there is provided a method of treating
and/or preventing a neurodegenerative disease comprising administering to an animal a
pharmaceutically effective amount of compound 2 or a composition as described above.
The invention further provides a method as described above wherein said disease
is treated.

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The invention still further provides a method as described above wherein said
animal is a human being.
The invention still further provides a method as described above wherein said
neurodegenerative disease is Parkinson's disease.
In a further aspect of the invention there is provided the use of a compound
capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase (HPPD) in an animal in the
manufacture of a medicament for use in the treatment and/or prevention of a
neurodegenerative disease.
In a further aspect of the invention there is provided the use of a precursor
compound in the manufacture of a medicament for use in the treatment and/or prevention
of a neurodegenerative disease. In a particular embodiment said disease is Parkinson's
disease.
HPPD inhibitors that are applicable to the present invention include compounds
of formula I (the term formula I may be interchanged with compound 1):

wherein;
TisTi
Wherein:
G is C or N wherein when G is N then only one of E and R2 are present;
D is hydrogen or R3;
E is hydrogen or R4; or
D and E together are C2-C3alkylene which can be mono- or poly-substituted by R6;
A is C1 -C2alkylene which can be mono- or poly-substituted by R5; or A may additionally
be carbonyl, oxygen or -N-R7- when D and E are other than C2-C3alkylene;

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R1, R2, R3, R4, R5 and R6 are each independently of the others hydrogen, C1-C4alkyl,
phenyl, C1-C4alkoxy, halogen, hydroxy, cyano, hydroxycarbonyl or C1-
C4alkoxycarbonyl;
or R2 and R4 together form a C2-C4alkylene chain which can be interrupted by oxygen
and/or carbonyl and/or sulfur, with the proviso that the oxygen and sulfur atoms are
separated by at least one methylene group;
R7 is C1-C4alkyl, alkoxycarbonyl or C1-C4alkylcarbonyl;
R036 is hydroxy, OM+, wherein M+ is an alkali metal cation or ammonium cation,
halogen, C1-C12alkylsulfonyloxy, amino, C1-C4alkylthio, C1-C12alkylsulfinyl, C1-
C12alkylsulfonyl, C1-C12aloalkylthio, C1-C12haloalkylsulfinyl, C1-C12haloalkylsulfonyl,
C1-C6alkoxy-C1-C6alkylthio, C1-C6alkoxy-C1-C6alkylsulfmyl, C1-C6alkoxy-C1-
C6alkylsulfonyl, C3-C12alkenylthio, C3-C12alkenylsulfinyl, C3-C12alkenylsulfonyl, C3-
C12alkynylthio, C3-C12alkynylsulfiriyl, C3-C12alkynylsulfonyl, C1-C4alkoxycarbonyl-C1-
C4alkylthio, C1-C4alkoxycarbonyl-C1-C4alkylsulfinyl, C1-C4alkoxycarbonyl-C1-
C4alkylsulfonyl, (C1-C4alkoxy)2P(O)O, C1-C4alkyl-(C1-C4alkoxy)P(O)0, H(C,-
C4alkoxy)P(O)O, R037R038N, R039R040NNH, R4041R042NC(0)0-, R043R044NC(O)NH-, C1-
C18alkylcarbonyloxy, C2-C18alkenylcarbonyloxy, C2-C18alkynylcarbonyloxy, C3-
C6cycloalkylcarbonyloxy, C1-C12alkoxycarbonyloxy, C1-C12alkylthiocarbonyloxy or
C1-C12alkylthiocarbamoyl, wherein the alkyl, alkenyl and alkynyl groups can be sub-
stituted by halogen, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl
or by cyano; or
R036 is phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonylamino,
phenylsulfonyloxy, benzoyloxy or benzoyl-C1-C6alkoxy, wherein the phenyl groups can
in turn be substituted one or more times by halogen, nitro, cyano, C1-C6alkyl, C1-
C4haloalkyl, C1-C4alkoxy and/or C1-C4haloalkoxy,
or R036 is a group Het07-thio, Het08-sulfinyl, Het09-sulfonyl, Het010-(CO)O or Het011-
N(R047); wherein
Het07, Het08, Het09, Het010 and Heton are each independently of the others a five- to ten-
membered monocyclic or annellated bicyclic ring system which may be aromatic or
partially saturated and may contain from 1 to 4 hetero atoms selected from nitrogen,
oxygen and sulfur, and each ring system may contain not more than two oxygen atoms
and not more than two sulfur atoms, and the ring system itself can be substituted by C1-
C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylthio,.C1-

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C6alkylsulfinyl, C1-C6alkylsulfonyL, di(C1-C4alkyl)ammosulfonyl, di(C1-C4alkyl)amino,
halogen, cyano, nitro or by phenyl, and the substituents on the nitrogen atom in the
heterocyclic ring are other than halogen;
R037, R038, R039, R040, R041, R042, R043, R044 and R047 are each independently of the others
hydrogen or C1-C6alkyl; or
R037 and R038 together or R039 and R040 together or R041 and R042 together or R043 and R044
together are pyrrolidino, piperidino, morpholino or thiomorpholino, which can be mono-
or poly-substituted by methyl groups;
or T is T2

wherein
R34 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, C2-C4alkenyl, C2-
C4alkynyl or benzyl, it being possible for the phenyl group to be substituted one or more
times by C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, halogen, cyano,
hydroxy and/or nitro;
R35 is hydrogen, C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, C3-C4alkenyl, C3-
C4alkynyl or benzyl, it being possible for the phenyl group to be substituted one or more
times by C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, halogen, cyano,
hydroxy and/or nitro;
R36 is hydroxy, O'M+, wherein M+ is an alkali metal cation or ammonium cation,
halogen, C1-C12alkylsulfonyloxy, amino, C1-C4alkylthio, C1-C12alkylsulfinyl, C1-
C12alkylsulfonyl, C1-C12haloalkylthio, C1-C12haloalkylsulfinyl, C1-C12haloalkylsulfonyl,
C1-C6alkoxy-C1-C6alkylthio, C1-C6alkoxy-C1-C6alkylsulfinyl, C1-C6alkoxy-C1-
C6alkylsulfonyl, C3-C12alkenylthio, C3-C12alkenylsulfinyl, C3-C12alkenylsulfonyl, C3-
C12alkynylthio, C3-C12alkynylsulfinyl, C3-C12alkynylsulfonyl, C1-C4alkoxycarbonyl-C1-
C4alkylthio, C1-C4alkoxycarbonyl-C1-C4alkylsulfinyl, C1-C4alkoxycarbonyl-C1-
C4alkylsulfonyl, (C1-C4alkoxy)2P(O)O, C1-C4alkyl-(Cl-C4aIkoxy)P(O)O, H(C1-

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C4alkoxy)P(O)O, R37R38N, R39R40NNH, R41R42NC(O)O-, R43R44NC(O)NH-,
C1-C18alkylcarbonyloxy, C2-C18alkenylcarbonyloxy, C2-C18alkynylcarbonyloxy, C3-C6-
cycloalkylcarbonyloxy, C1-C12alkoxycarbonyloxy, C1-C12alkylthiocarbonyloxy or C1-
C12alkylthiocarbamoyl, wherein the alkyl, alkenyl and alkynyl groups can be substituted
by halogen, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl or by
cyano; or
R36 is phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylsulfonylamino,
phenylsulfonyloxy, benzoyloxy or benzoyl-C1-C6alkoxy, it being possible for the phenyl
groups in turn to be substituted one or more times by halogen, nitro, cyano, C1-C4alkyl,
C1-C4haloalkyl, C1-C4alkoxy and/or C1-C4aloalkoxy,
or R36 is a group Het7-thio, Het8-sulfinyl, Het9-sulfonyl, Het10-(CO)O or Het11-N(R47);
wherein
Het7, Het8, Het9, Het10 and Het11 are each independently of the others a five- to ten-
membered monocyclic or annellated bicyclic ring system which may be aromatic or
partially saturated and may contain from 1 to 4 hetero atoms selected from nitrogen,
oxygen and sulfur, and each ring system may contain not more than two oxygen atoms
and not more than two sulfur atoms, and the ring system itself can be substituted by C1-
C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkyltbio, C1-
C6alkylsulfinyl, C1-C6alkylsulfonyl, di(C1-C4alkyl)aminosulfonyl, di(C1-C4alkyl)amino,
halogen, cyano, nitro or by phenyl, and the substituents on the nitrogen atom in the
heterocyclic ring are other than halogen;
R37, R38, R39, R40, R41, R42, R43, R44 and R47 are each independently of the others
hydrogen or C1-C6alkyl; or
R37 and R38 together or R39 and R40 together or R41 and R42 together or R43 and R44
together are pyrrolidino, piperidino, morpholino or thiomorpholino, which can be mono-
or poly-substituted by methyl groups;
or T is T3


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wherein
R49 is C1-C4alkyl, C1-C4aloalkyl, C3-C6cycloalkyl or halo-substituted C3-C6cycloalkyl;
Z01 is a chemical bond, S, SO or SO2; or -CO2-
R50 is hydrogen or C1-C3alkylene which can be substituted by the following substituents:
halogen, hydroxy, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C1-
C6alkoxy-C1-C6alkoxy, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkoxy, (3-oxetanyl)-oxy, C1-
C6alkyl-substituted (3-oxetanyl)-oxy, benzylthio, benzylsulfinyl, benzylsulfonyl, phenyl,
phenoxy, phenylthio, phenylsulfinyl or phenylsulfonyl, it being possible for the phenyl-
and benzyl-containing groups in turn to be substituted by one or more C1-C6alkyl, C1-
C6haloalkyl, C1-C4alkoxy, C1-C6haloalkoxy, halogen, cyano, hydroxy and/or nitro
groups;
or R50 is phenyl, it being possible for the phenyl-containing group in turn to be
substituted by one or more C1-C6salkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy,
halogen, cyano, hydroxy and/or nitro groups,
or R50 is C3-C6cycloalkyl, C1-C6alkoxy- or C1-C6alkyl-substituted C3-C6cycloalkyl, 3-
oxetanyl or C1-C6alkyl-substituted 3-oxetanyl;
or T is T4
wherein
R045 is C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl or halo-substituted C3-C6cycloalkyl;
and their pharmaceutically acceptable salts, isomers and enantiomers.
The compounds of formula I also include the salts which such compounds are
able to form with amines, alkali metal and alkaline earth metal bases or quaternary
ammonium bases. Among the alkali metal and alkaline earth metal hydroxides as salt
formers, special mention should be made of the hydroxides of lithium, sodium,
potassium, magnesium and calcium, but especially the hydroxides of sodium and
potassium.
Examples of amines suitable for ammonium salt formation include ammonia as
well as primary, secondary and tertiary C1-C18alkylamines, C1-C4hydroxyalkylamines

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and C2-C4alkoxyalkylamines, for example methylamine, ethylamine, n-propylamine,
isopropylamine, the four butylamine isomers, n-amylamine, isoamylamine, hexylamine,
heptylamine, octylamine, nonylamine, decylaraine, pentadecylamine, hexadecylamine,
heptadecylamine, octadecylamine, methylethylamine, metfaylisopropylamine,
methylhexylamitie, methylnonylamine, methylpentadecylamine, methyloctadecylamine,
ethylbutylamine, ethylheptylamine, ethyloctylamine, hexylheptylamine,
hexyloctylamine, dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-
n-butylamine, di-n-amylamine, diisoamylamine, dihexylamine, diheptylamine,
dioctylamine, ethanolamine, n-propanolamine, isopropanolamine, N,N-diethanolamine,
N-ethylpropanolamine, N-butylethanolamine, allylamine, n-butenyl-2-amine, n-pentenyl-
2-amine, 2,3-dimethylbutenyl-2-amine, dibutenyl-2-amine, n-hexenyl-2-amine,
propylenediamine, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine,
tri-n-butylamine, triisobutylamine, tri-sec-butylamine, tri-n-amylamine,
methoxyethylamine and ethoxyethylamine; heterocyclic amines, for example pyridine,
quinoline, isoquinoline, morpholine, piperidine, pyrrolidine, indoline, quinuclidine and
azepine; primary arylamines, for example anilines, methoxyanilines, ethoxyanilines, o-5
m- and p-toluidines, phenylenedtamines, benzidines, naphthylamines and o-, m- and p-
chloroanilines; but especially triethylamine, isopropylamine and diisopropylamine.
Because the compounds of formula I wherein T is T1 are preferably in enolised
forms or in the form of salts, formula I also includes the enolised forms of formulae la,
Ib, Ic and Id wherein M is hydrogen or a metal ion or an ammonium ion.

Since compounds of formula I may also contain asymmetric carbon atoms, for
example in the case of the carbon atom carrying R1, D and A, all stereoisomeric forms
are also included.
The organic substituent Q may be an inert substituent of any desired structure,
provided that the compounds of formula I retain their action as HPPD inhibitors in

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animals. Such tests of these compounds may be carried out in accordance with the
experimental methods described herein.
Q is preferably a mono- or poly-substituted phenyl, pyridyl or heteroaryl group,
especially 2-benzoyl, 2-isonicotinoyl and 2-nicotinoyl derivatives, the substitution
pattern of those groups being freely selectable provided that the compounds of formula I
retain their action as HPPD inhibitors in animals.
In a particular embodiment said HPPD inhibitors are compounds of formula I
wherein
Q is Q1
wherein
A1 or A2 are independently selected from methine, C(Ra1) or N(O)P; (wherein preferably
at least one of A1 or A2 is methine
p is 0 or 1;
Ra1 is hydrogen, C1-C6alkyl, hydroxy, C1-C4alkoxy, C1-C6haloalkoxy, C3-C6alkenyloxy,
C3-C6haloalkenyloxy, C3-C6alkynyloxy, C1-C4alkylcarbonyloxy, C1-C4alkylsulfonyloxy;.
tosyloxy, C1-C4alkylthio, C1-C4alkylsulfinyl, C1-C4alkylsulfonyl, C1-C4alkylamino, di-
C1-C4alkylamino, C1-C4alkoxycarbonyl, C1-C4haloalkyl, formyl, cyano, halogen, phenyl
or phenoxy; it being possible for phenyl in turn to be substituted by C1-C3alkyl, C1-
C4haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro;
or Ra1 is a three- to ten-membered monocyclic ring system or, together with Ra2 or Ra5,
annellated mono- or bi-cyclic ring system which may be interrupted by oxygen, sulfur,
SO, SO2, NRa6, carbonyl and/or by =NORa7, the ring system, unless it is annellated,
being bonded to the carbon atom of the substituent A1 directly or by way of a C1-
C4alkylene, -CH=CH-, -OC-, -CH2O-, -CH2N(C1-C4alkyl)-, -CH2S-, -CH2SO- or -
CH2SO2- group, and the ring system may contain not more than two oxygen atoms and
not more than two sulfur atoms, and the ring system can itself be mono-, di- or tri-
substituted by C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-
C6alkynyl, C2-C6haloalkynyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6alkenyloxy, C3-

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C6alkynyloxy, C1-C6alkylthio, C1-C6haloalkylthio, C3-C6alkenylthio, C3-C6halo-
alkenylthio, C3-C6alkynylthio, C1-C4alkoxy-C1-C2alkylthio, C1-C4alkylcarbonyl-
C1-C2alkylthio, C1-C4alkoxycarbonyl-C1-C2alkylthio, cyano-C1-C6alkylthio, C1-
C6alkylsulfinyl, C1-C6haloalkylsulfmyl, C1-C6alkylsulfonyl, C1-C6haloalkylsulfonyl,
aminosulfonyl, C1-C2alkylaminosulfonyl, di(C1-C2alkyl)aminosulfonyl, di(C1-
C4alkyl)amino, halogen, cyano, nitro, phenyl and/or benzylthio, it being possible for
phenyl and benzyltliio in turn to be substituted on the phenyl ring by C1-C3alkyl, C1-
C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, and substituents
on the nitrogen atom in the heterocyclic ring are other than halogen;
or Ra1 is the group -X5-X7 or the group -X6-X5-X7; wherein
X6 is a C1-C6alkylene, C3-C6alkenylene or C3-C6alkynylene chain which can be mono- or
poly-substituted by halogen and/or by X8, the unsaturated bonds of the chain not being
bonded directly to the substituent X5;
X8 is hydroxy, C1-C6alkoxy, C3-C6cycloalkyloxy, C1-C6alkoxy-C1-C6alkoxy, C1-
C6alkoxy-C1-C6alkoxy-C1-C6alkoxy or C1-C2alkylsulfonyloxy;
X5 is oxygen, -O(CO)-, -(CO)O-, -O(CO)O-, -N(C1-C4alkyl)-O-, -O-N(C1-C4alkyl)-,
thio, sulfinyl, sulfonyl, -SO2N(C1-C4alkyl)-, -N(C1-C4aIkoxy)SO2-, -N(C1-C4aIkyl)SO2-,
-N(C1-C2alkoxy-C1-C2alkyl)SO2- or -N(C1-C4alkyl)-;
Ra6 is hydrogen, C1-C4alkyl, C1-C4alkylthio-C1-C4carbonyl, C1-C6alkylsulfinyl-C1-
C4carbonyl, C1-C4alkylsulfonyl-C1-C4carbonyl, C1-C4alkoxycarbonyl, C1-
C4alkylcarbonyl, phenylcarbonyl or phenyl, it being possible for the phenyl groups in
turn to be substituted by C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-
C4alkylcarbonyl, C1-C4alkoxycarbonyl, C1-C4alkylamino, di-C1-C4alkylamino, C1-
C4alkyl-S-, C1-C4alkyl-SO-, C1-C4alkyl-SO2, C1-C4alkyl-S(O)2O, C1-C4haloalkyl-S-, C1-
C4haloalkyl-SO, C1-C4haloalkyl-SO2, C1-C4haloalkyl-S(O)2,O C1-C4alkyl-S(O)2NH, C1-
C4alkyl-S(O)2N(C1-C4alkyl), halogen, nitro or by cyano;
Ra7 is C1-C4alkyl;
Ra2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, vinyl
substituted by C1-C2alkoxycarbonyl or by phenyl, C2-C6alkynyl, C2-C6haloalkynyl,
ethynyl substituted by trimethylsilyl, hydroxy, C1-C2alkoxy, C1-C2alkoxycarbonyl or by
phenyl, C3-C6allenyl, C3-C6cycloalkyl, halo-substituted C3-C6cycloalkyl, C1-C6alkoxy,
C3-C6alkenylpxy, C3-C6alkynyloxy, C1-C6haloalkoxy, C3-C6haloalkenyloxy, cyano-C1-
C4alkoxy, C1-C4alkoxy-C1-C4alkoxy, C1-C4alkylthio-C1-C4alkoxy, C1-C4alkylsulfmyl-

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C1-C4alkoxy, C1-C4alkylsulfonyl-C1-C4alkoxy, C1-C4alkoxycarbonyl-C1-C4alkoxy, C1-
C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6haloalkylthio, C1-
C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl, C1-C6alkoxycarbonyl-C1-C4alkylthio, C1-
C4alkoxycarbonyl-C1-C4alkylsulfinyl, C1-C4alkoxycarbonyl-C1-C4alkylsulfonyl, benzyl-
s', benzyl-SO, benzyl-SO2-, C1-C6alkylamino, di-C2-C6alkylamino, C1-C6alkylamino-
sulfonyl, di(C1-C6alkylamino)sulfonyl, benzyloxy, benzyl, phenyl, phenoxy, phenylthio,
phenylsulfinyl or phenylsulfonyl, it being possible for the phenyl-containing groups in
turn to be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy,
halogen, cyano or by nitro, or Ra2 is OS-C1-C4alkyl, OSO-C1-C4alkyl, OSO2-C1-C4alkyl,
OS-C1-C4aloalkyl, OSO-C1-C4haloalkyl, OSO2-C1-C3haloalkyl, N(C1-C3aIkyl)-S-C1-
C4alkyl, N(C1-C4alkyl)-SO-C1-C4alkyl, N(C1-C4alkyl)-SO2-C1-C4alkyl, cyano,
carbamoyl, C1-C4alkoxycarbonyl, formyl, halogen, rhodano, amino, hydroxy-C1-C4aIkyl,
C1-C4alkoxy-C1-C4alkyl, C1-C4alkyl-S-C1-C4alkyl, C1-C4alkyl-SO-C1-C4alkyl, C1-
C4alkyl-SO2-C1-C4alkyl, cyano-C1-C4alkyl, C1-C6alkylcarbonyloxy-C1-C4alkyl, C1-
C4alkoxycarbonyl-C1-C4alkyl, C1-C4alkoxycarboriyloxy-C1-C4alkyl, C1-C4rhodano-C1-
C4alkyl, benzoyloxy-C1-C4alkyl, C2-C6oxiranyl, C1-C4alkylamino-C1-C4alkyl, di(C1-
C4alkyl)amino-C1-C4alkyl, C1-C12alkylthiocarbonyl-C1-C4alkyl or formyl-C1-C4alkyl, or
Ra2 is a five- to ten-membered monocyclic or annellated bicyclic ring system which may
be aromatic or partially saturated and may contain from 1 to 4 hetero atoms selected from
nitrogen, oxygen and sulfur, the ring system being bonded to the pyridine ring by way of
a C1-C4allcylene, -CH=CH-, -OC-, -CH20-, -CH2N(C1-C4alkyl)-, -CH2SO- or -CH2SO2-
group, and each ring system may contain not more than two oxygen atoms and not more
than two sulfur atoms, and the ring system itself can be mono-, di- or tri-substituted by
C1-C6alkyl, C1-C6haloalkyl, C3-C6alkenyl, C3-C6haloalkenyl, C3-C6alkynyl, C3-
C6haloalkynyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6alkenyloxy, C3-C6alkynyloxy,
mercapto, C1-C6alkylthio, C1-C6haloalkylthio, C3-C6alkenylthio, C3-C6haloalkenylthio.
C3-C6alkynylthio, C2-C5alkoxyalkylthio, C3-C5acetylalkylthio, C3-
C6alkoxycarbonylalkylthio, C2-C4cyanoalkylthio, C1-C6alkylsulfinyl, C1-C6-
haloalkylsulfmyl, C1-C6alkylsulfonyl, C1-C6haloalkylsulfonyl, aminosulfonyl,
C1-C2alkylaminosulfonyl, di(C1-C2alkyl)aminosulfonyl, di(C1-C4alkyl)amino, halogen,
cyano, nitro, phenyl and/or by benzylthio, it being possible for phenyl and benzylthio in
turn to be substituted on the phenyl ring by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-

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C3haloalkoxy, halogen, cyano or by nitro, and substituents on the nitrogen atom in the
heterocyclic ring are other than halogen;
or Ra2 is the group -X1-X3 or the group -X2-X1-X3; wherein
X2 is a C1-C6alkylene, C3-C6alkenylene or C3-C6alkynylene chain which can be mono- or
poly-substituted by halogen or by X4, the unsaturated bonds of the chain not being
bonded directly to the substituent X1;
X4 is hydroxy, C1-C6alkoxy, C3-C6cycloalkyloxy, C1-C6alkoxy-C1-C6alkoxy, C1-
C6alkoxy-C1-C6alkoxy-C1-C6alkoxy or C1-C2alkylsulfonyloxy;
X1 is oxygen, -O(CO)-, -(CO)O-, -O(CO)O-, -N(C1-C4alkyl)-O-, -O-N(C1-C4alkyl)-,
thio, sulfmyl, sulfonyl, -SO2N(C1-C4alkyl)-, -N(C1-C4alkyl)SO2-, -N(C1-C2alkoxy-C1-
C2alkyl)SO2- or-N(C1-C4alkyl)-;
X3 and X7 are each independently of the other a C1-C8alkyl, C3-C6alkenyl or C3-
C6alkynyl group which is mono- or poly-substituted by the following substituents:
halogen, hydroxy, amino, formyl, nitro, cyano, mercapto, carbamoyl, C1-C6alkoxy, C1-
C6alkoxycarbonyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C3-
C6cycloalkyl, halo-substituted C1-C6cycloalkyl, C3-C6alkenyloxy, C3-C6alkynyloxy, C1-
C6haloalkoxy, C3-C6haloalkenyloxy, cyano-C1-C6alkoxy, C1-C6alkoxy-C1-C6alkoxy, C1-
C6alkoxy-C1-C6alkoxy-C1-C6alkoxy, C1-C6alkylthio-C1-C6alkoxy, C1-C6alkylsulfniyl-C1-
C6alkoxy, C1-C6alkylsulfonyl-C1-C6alkoxy, C1-C6alkoxycarbonyl-C1-C6alkoxy, C1-
C6alkoxycarbonyl, C1-C6alkylcarbonyl, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6-
alkylsulfonyl, C1-C6haloalkylthio, C1-C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl,
oxiranyl, which can in turn be substituted by C1-C6alkyl, (3-oxetanyl)-oxy, which can in
turn be substituted by C1-C6alkyl, benzylthio, benzylsulfinyl, benzylsulfonyl, C1-C6alkyl-
amino, di(C1-C6alkyl)araino, C1-C4alkyl-S(O)2O, C1-C4alkyl-N(C1-C4alkyl)SO2-,
rhodano, phenyl, phenoxy, phenylthio, phenylsulfinyi and/or phenylsulfonyl;
it being possible for the phenyl- or benzyl-containing groups in turn to be substituted by
one or more C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, halogen, cyano,
hydroxy and/or nitro groups, or
X3 and X7 are each independently of the other phenyl which can be substituted one or
more times by C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, halogen,
cyano, hydroxy and/or nitro; or
X3 and X7 are each independently of the other C3-C6cycloalkyl, C3-C6alkoxy- or C1-C6
C6alkyl-substituted C3-C6cycloalkyl, 3-oxetanyl or C1-C6alkyl-substituted 3-oxetanyl;

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or X3 and X7 are each independently of the other a five- to ten-membered monocyclic or
annellated bicyclic ring system which may be aromatic or saturated or partially saturated
and may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur, the
ring system being bonded to the substituent X1 or X5 directly or by way of a C1-
C4alkylene, C2-C4alkenyl-C1-C4alkylene, C2-C4alkynyl-C1-C4alkylene, -N(C1-C4alkyl)-
C1-C4alkyiene, -SO-C1-C4alkylene or -SO2-C1-C4alkylene group, and each ring system
may contain not more than two oxygen atoms and not more than two sulfur atoms, and
the ring system can itself be mono-, di- or tri-substituted by C1-C6alkyl, C1-C6haloalkyl,
C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C1-C6alkoxy, hydroxy,
C1-C6haloalkoxy, C3-C6alkenyloxy, C3-C6alkynyloxy, mercapto, C1-C6alkylthio, C2-
C6haloalkylthio, C3-C6alkenylthio, C3-C6haloalkenylthio, C3-C6alkynylthio, C2-
C5alkoxyalkylthio, C3-C5acetylalkylthio, C3-C6alkoxycarbonylalkylthio, C2-C4-
cyanoalkylthio, C1-C6alkylsulfinyl, C1-C6haloalkylsulfinyl, C1-C6alkylsulfonyl, C1-
C6haloalkylsulfonyl, aminosulfonyl, C1-C2alkylaminosulfonyl, di(C1-C2alkyl)-
aminosulfonyl, di(C1-C4alkyl)amino, halogen, cyano, nitro, phenyl and/or by benzylthio,
it being possible for phenyl and benzylthio in turn to be substituted on the phenyl ring by
C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro,
and the substituents on the nitrogen atom in the heterocyclic ring are other than halogen;
Ra3 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-
C6alkynyl, C2-C6haloalkynyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-
C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, C1-C6haloalkyltbio, C1
C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl, C1-C6alkylamino, di-C2-C6alkylamino, C1-
C6alkylaminosulfonyl, di-C2-C6alkylaminosulfonyl, phenyl, phenylthio, phenylsulfinyl,
phenylsulfonyl or phenoxy, it being possible for phenyl in turn to be substituted by C1-
C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, or
Ra3 is -N(C1-C4alkyl)-S-C1-C6alkyl, -N(C1-C6alkyl)-SO-C1-C4alkyl, -N(C1-C6alkyl)-SO2-
C1-C4alkyl, cyano, halogen, ammo, C1-C4alkoxy-C1-C4alkyl, C1-C4alkyl-S-C1-C4alkyl,
C1-C4alkyl-SO-C1-C4alkyl or C1-C4aIkyl-SO2-C1-C4alkyl;
Ra4 is hydrogen, C1-C6alkyl, hydroxy, C1-C4alkoxy, C1-C4haloalkoxy, C3-C6alkenyloxy,
C3-C6haloalkenyloxy, C3-C6alkynyloxy, C1-C4alkylcarbonyloxy, C1-C4alkylsulfonyloxy,
tosyloxy, C1-C4alkylthio, C1-C4alkylsulfinyl, C1-C4alkylsulfonyl, C1-C4alkylamino, di-
C1-C4alkylamino, C1-C4alkoxycarbonyl, C1-C4haloalkyl, formyl, cyano, halogen, phenyl

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or phenoxy, it being possible for phenyl in turn to be substituted by C1-C4alkyl, C1-
C4haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro;
or Ra4 is a five- to ten-membered monocyclic ring system or, with Ra3, annellated
bicyclic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen,
oxygen and sulfur, the ring system, unless it is annellated, being bonded to the ring
containing the substituent A directly or by way of a C1-C4alkylene, -CH=CH-, -CsC-, -
CH2O-, -CH2N(C1-C4alkyl)-, -CH2S-, -CH2SO- or -CH2SO2- group, and the ring system
may contain not more than two oxygen atoms and not more than two sulfur atoms, and
the ring system can itself be mono-, di- or tri-substituted by C1-C6alkyl, C1-C6haloalkyl,
C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C1-C6alkoxy, C1-C6
C6haloalkoxy, C3-C6alkenyloxy, C3-C6alkynyloxy, C1-C6alkylthio, C1-C6haloalkylthio,
C3-C6alkenylthio, C3-C6haloalkenylthio, C3-C6alkynylthio, C1-C4alkoxy-C1-C2alkylthio,
C1-C4alkylcarbonyl-C1-C2alkylthio, C1-C4alkoxycarbonyl-C1-C2alkylthio, cyano-C1-
C4alkylthio, C1-C6alkylsulfinyl, C1-C6haloalkylsulfmyl, C1-C6alkyisulfonyl, C1-C6
C6haloalkylsulfonyl, aminosulfonyl, C1-C6alkylaminosulfonyl, di(C1-
C2alkyl)aminosulfonyl, di(C1-C4alkyl)amino, halogen, cyano, nitro, phenyl and/or by
benzylthio, it being possible for phenyl and benzyltbio in turn to be substituted on the
phenyl ring by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen,
cyano or by nitro, and substituents on the nitrogen atom in the heterocyclic ring are other
than halogen;
Ra5 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-
C6alkynyl, C2-C6haloalkynyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-
C6alkylthio, C1-C6alkylsumnyl, C1-C6alkylsulfonyl, C1-C6haloalkylthio, C1-
C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl, C1-C6alkylamino, di-C2-C6alkylamino, C1-
C6alkylaminosulfonyl, di-C2-C6alkylaminosulfonyl, phenyl, phenylthio, phenylsulfinyl,
phenylsulfonyl or phenoxy, it being possible for phenyl in turn to be substituted by C1-
C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, or
Ra5 is -N(C1-C4alkyl)-S-C1-C4alkyl, -N(C1-C4alkyl)-SO-C1-C4alkyl, -N(C1-C4alkyl)-SO2-
C1-C4alkyl, cyano, halogen, amino, C1-C4alkoxy-C1-C4alkyl, C1-C4alkyl-S-C1-C4alkyl,
C1-C4alkyl-SO-C1-C4alkyl or C1-C4alkyi-SO2-C1-C4alkyl, and pharmaceutically
acceptable salts/N-oxides/isomers/enantiomers of those compounds.
The alkyl groups appearing in the above substituent definitions may be straight-
chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-

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butyi, isobutyl or tert-butyl. Alkoxy, alkenyl and alkynyl radicals are derived from the
mentioned alkyl radicals. The alkenyl and alkynyl groups may be mono- or poly-
unsaturated. Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
isobutoxy, sec-butoxy or tert-butoxy. Alkoxycarbonyl is, for example, methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, iso-
butoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; preferably methoxycarbonyl
or ethoxycarbonyl.
Halogen is generally fluorine, chlorine, bromine or iodine. The same is also true
of halogen in conjunction with other meanings, such as haloalkyl or halophenyl.
Haloalkyl groups having a chain length of from 1 to 6 carbon atoms are, for
example, fiuoromethyl, difiuoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2-fiuoroethyl, 2-chloroethyl, 2-
fluoroprop-2-yl, pentafiuoroethyl, l,l-difiuoro-2,232-trichloroethyl, 2,2,3,3-
tetrafluoroethyl and 2,2,2-trichloroethyl, pentafiuoroethyl, heptafluoro-n-propyl and
perfiuoro-n-hexyl.
Alkenyl and alkynyl groups can be mono- or poly-unsaturated, so that alkyl,
alkenyl and alkynyl chains having one or more double or triple bonds are also included.
Alkenyl is, for example, vinyl, allyl, isobuten-3-yl, CH2=CH-CH2-CH=CH-, CH2=CH-
CH2-CH2-CH=CH- or CH3-CH=CH-CH2-CH=CH-. A preferred alkynyl is, for example,
propargyl, and a preferred allenyl is CH2=C=CH2-.
An alkylene chain can also be substituted by one or more C1-C3alkyl groups,
especially by methyl groups. Such alkylene chains and alkylene groups are preferably
unsubstituted. The same applies also to all groups containing C3-C6cycloalkyl, C3-
C5oxacycloalkyl, C3-C5thiacycloalkyl, C3-C4dioxacycloalkyl, C3-C4dithiacycloalkyl or
C3-C4oxathiacycloalkyl which occur, for example, also as part of oxygen- and sulfur-
containing heterocyclic ring systems of the radicals Ra1 and Ra2.
A C1-C4alkylene, C1-C4alkenylene or C2-C4alkynylene bridge which may be
interrupted by oxygen, -N(C1-C4alkyl)-, sulfur, sulfinyl and/or sulfonyl, or in X2 or X6 in
the meaning of a C1-C6alkylene, C3-C6alkenylene or C3-C6alkynylene chain which can be
mono- or poly-substituted by halogen and/or by X4 or X8, and wherein the unsaturated
bonds of the chain are not bonded directly to the substituent X1 or X5, is to be understood
as being, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)-,
-CH2CH(CH3)-, -CH2CH(CH3)CH2-, -CH2CH(C1)CH2-, -CH2CH(OCH3)CH2-,-CH2O-, -

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OCH2-, -CH2OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -CH2OCH2CH2-, -
CH2OCH(CH3)CH2, -SCH2-, -SCH2CH2-, -SCH2CH2CH2-, -CH2S-, -CH2SCH2-, -
CH2S(O)CH2-, -CH2SO2CH2-, -CH2SCH2CH2-, -CH2S(O)CH2CH2-, -CH2SO2CH2CH2-,
-CH2SO2NH-,-CH2N(CH3)SO2CH2CH2,-N(SO2Me)CH2CH2,-, -CH2C(O)NH- or-
CH2NHC(O)CH2-. A C2-C4alkenylene chain which may be uninterrupted or interrupted
by oxygen is accordingly to be understood as being, for example, -CH=CH-CH2-, —
CH=CH-CH2CH2- or -CH=CHCH2OCH2-, and a C2-C4alkynylene chain which may be
uninterrupted or interrupted by oxygen is to be understood as being, for example, -C=C-,
-C=CCH2-, -C=CCH2O-, -C=CH2OCH2- or -OC=CCH2-.
A three- to ten-membered mono- or bi-cyclic ring system Ra1 or Ra2, which may
be interrupted once or up to three times selected from oxygen, sulfur, S(O), SO2, N(Ra6),
carbonyl and C(=NORa7) and which is bonded to the carbon atom of the substituent A1
or to the group Q1 or Q2 either directly or by way of a C1-C4alkylene, C1-C4alkenylene or
C2-C4alkynylene bridge which may be interrupted by oxygen, -N(C1-C4alkyl)-, sulfur,
sulfinyl and/or sulfonyl, is to be understood as being, for example, 1-methyl-lH-pyrazol-
3-yl, l-ethyl-lH-pyrazol-3-yl, l-propyl-lH-pyrazol-3-yl, lH-pyrazol-3-yl, 1,5-dimethyl-
lH-pyrazol-3-yl, 4-chloro-l-methyl-lH-pyrazol-3-yl, lH-pyrazol-1-yl, 3-methyl-lH-
pyrazol-1-yl, 3,5-dimethyl-lH-pyrazol-l-yl, 3-isoxazolyl, 5-methyl-3-isoxazolyl, 3-
methyl-5-isoxazolyl, 5-isoxazolyl, lH-pyrrol-2-yl, l-methyl-lH-pyrrol-2-yl, lH-pyrrol-
1-yl, l-methyl-lH-pyrrol-3-yl, 2-furanyl, 5-methyl-2-furanyl, 3-furanyl, 5-methyl-2-
thienyl, 2-thienyl, 3-thienyl, l-methyl-lH-imidazol-2-yl, lH-imidazol-2-yl, 1-methyl-
lH-imidazol-4-yl, l-methyl-lH-imidazol-5-yl, 4-methyl-2-oxazolyl, 5-methyl-2-
oxazolyl, 2-oxazolyl, 2-methyl-5-oxazolyl, 2-methyl-4-oxazolyl, 4-methyl-2-thiazolyl, 5-
methyl-2-thiazolyl, 2-thiazolyl, 2-methyl-5-tliiazolyl, 2-methyl-4-thiazolyl, 3-methyl-4-
isothiazolyl, 3-methyl-5-isothiazolyl, 5-methyl-3-isothiazolyl, 1 -methyl- 1H-1,2,3-triazol-
4-yl, 2-methyl-2H-l,2,3-triazol-4-yl, 4-methyl-2H-l,2,3-triazol-2-yl, l-methyl-lH-1,2,4-
triazol-3-yl, l,5-dimethyl-lH-l,2,4-triazol-3-yl, 3-methyl-lH-l,2,4-triazol-l-yl, 5-
methyl-lH-l,2,4-triazoH-yl,4,5-dimethyl-4H-l,2,4-triazol-3-yl, 4-methyl-4H-1,2,4-
triazol-3-yl, 4H-l,2,4-triazol-4-yl, 5-methyl-l,2,3-oxadiazol-4-yl, l,2,3-oxadiazol-4-yl,
3-methyl-l,2,4-oxadiazol-5-yl, 5-methyl-l,2,4-oxadiazol-3-yl, 4-methyl-3-furazanyl, 3-
furazanyl, 5-methyl-l,2,4-oxadiazol-2-yl, 5-methyl-l,2,3-thiadiazol-4-yl, 1,2,3-
thiadiazol-4-yl, 3-methyl-l,2,4-thiadiazol-5-yl, 5-methyl-l,2,4-thiadiazol-3-yl, 4-methyl-
l,2,5-thiadiazol-3-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 1-methyl-lH-tetrazol-5-yl, 1H-

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tetrazol-5-yl, 5-methyl-lH-tetrazol-l-yl, 2-methyl-2H-tetrazol-5-yl, 2-ethyl-2H-tetrazol-
5-yl, 5-methyl-2H-tetrazol-2-yI, 2H-tetrazol-2-yl, 2-pyridinyl, 6-methyl-2-pyridinyl, 4-
pyridinyl, 3-pyridinyl, 6-methyl-3-pyridazinyl, 5-methyl-3-pyridazinyl, 3-pyridazinyl,
4,6-dimemyl-2-pyrimidinyl, 4-methyl-2-pyrimidinyl, 2-pyrimidinyl, 2-methyl-4-
pyrimidinyl, 2-chloro-4-pyrimidmyl, 2,6-dimethyl-4-pyrimidinyl, 4-pyrimidinyl, 2-
methyl-5-pyrimidinyl, 6-methyl-2-pyrazinyl, 2-pyrazinyl, 4J6-dimethyl-l,3>5-triazin-2-yl,
4,6-dichloro-l,3,5-triazin-2-yl, l53,5-triazin-2-yl, 4-methyl-l,3,5-triazin-2-yl, 3-methyI-
1,2,4-triazin-5-yl, 3-methyl-1,2,4-triazin-6-yl,
wherein each R26 is methyl, each R27 independently
is hydrogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylthio or trifluoromethyl, and X9 is
oxygen or sulfur.
A further annellated (fused-on), monocyclic or bicyclic ring system which is
formed, for example, by two adjacent substituents Ra1 and Ra2 or Ra1 and Ra5 and which
is uninterrupted or interrupted once or up to three times selected from oxygen, sulfur,
S(O), SO2, -N(Ra6)-, carbonyl and C(=NORa7) and which may be additionally
substituted by one or more substituents is to be understood as being, for example, an

WO 2006/090177 PCT/GB2006/000684
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annellated, bidentate ring system of formula
, wherein especially
R46 is hydrogen, halogen, C1-C4alkyl, C1-C4aloalkyl, C1-C4alkoxy or C1-C4alkylthio;
R47 is hydrogen, halogen, C1-C4alkyl or C1-C4alkoxy; and R50, R51, R52, R53, R54, R55,
R56, R57, R58 and R59 are hydrogen or C1-C4alkyl; and X10 is oxygen or NOR59.
A number of HPPD inhibitors of formula I are described within the art.
In a particular embodiment of the invention the HPPD inhibitor comprises the
compound of formula I wherein:
T is Ti;
R1 and R2 are hydrogen;
A is C1-C2alkylene;
D and E together are C2-C3alkylene;
Q is Q1 , wherein
A1 is methine, CRa1 or =N-(O)P, but preferably =N-(O)P;
p is 0;
Ra1 is hydrogen, C1-C6alkyl, hydroxy, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6alkenyloxy,
C3-C6haloalkenyloxy, C3-C6alkynyloxy, C1-C4alkylcarbonyloxy, C1-C4alkylsulfonyloxy,
tosyloxy, C1-C4alkylthio, C1-C4alkylsulfinyl, C1-C4alkylsulfonyl, C1-C4alkylamino, di-
C1-C4alkylamino, C1-C4alkoxycarbonyl, C1-C4haloalkyl, formyl, cyano, halogen, phenyl
or phenoxy; it being possible for phenyl in turn to be substituted by C1-C3alkyl, C1-
C3haloalkyl, C1-C3alkoxy, C1-C3shaloalkoxy, halogen, cyano or by nitro;
Ra2 is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, vinyl
substituted by C1-C2alkoxycarbonyl or by phenyl, C2-C6alkynyl, C2-C6haloalkynyl,
ethynyl substituted by trimethylsilyl, hydroxy, C1-C2alkoxy, C1-C2alkoxycarbonyl or by
phenyl, C3-C6allenyl, C3-C6cycloalkyl, halo-substituted C3-C6cycloalkyl, C1-C6alkoxy,
C3-C6alkenyloxy, C3-C6alkynyloxy, C1-C6haloalkoxy, C3-C6haloalkenyloxy, cyano-C1-

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C4alkoxy, C1-C4alkoxy-C1-C4alkoxy, C1-C4alkylthio-C1-C4alkoxy, C1-C4alkylsulfinyl-
C1-C4alkoxy, C1-C4alkylsulfonyl-C1-C4alkoxy, C1-C4alkoxycarbonyl-C1-C4alkoxy, C1-
C4alkylthio, C1-C6alkylsuliinyl, C1-C6alkylsulfonyl, C1-C6haloalkylthio, C1-
C6haloalkylsulfinyl, C1-C6haloalkylsulfonyl, C1-C4alkoxycarbonyl-C1-C4alkylthio, C1-
C6alkoxycarbonyl-C1-C6alkylsulfinyl,C1-C4alkoxycarbonyl-C1-C4alkylsulfonyl, benzyl-
s', benzyl-SO-, benzyl-SO2, C1-C6alkylamino, di-C2-C6salkylamino, C1-
C6alkylarainosulfonyl, di(C1-C6alkylatnino)sulfonyl, benzyloxy, benzyl, phenyl,
phenoxy, phenylthio, phenylsulfinyl or phenylsulfonyl, it being possible for the phenyl-
containing groups in turn to be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy,
C1-C3haloalkoxy, halogen, cyano or by nitro, or Ra2 is OS-C1-C4alkyl, OSO-C1-C4alkyl,
OSO2-C1-C4alkyl, OS-C1-C4haloalkyl, OSO-C1-C4haloalkyl, OSO2-C1-C4haloalkyl,
N(C1-C4aIkyl)-S-C1-C4alkyl,N(C1-C4alkyI)-SO-C1-C4alkyI,N(C1-C4alkyI)-SO2-C1-
C4alkyl, cyano, carbambyl, C1-C4alkoxycarbonyl, forinyl, halogen, rhodano, amino,
hydroxy-C1-C4alkyl, C1-C4alkoxy-C1-C4alkyl, C1-C4alkyl-S-C1-C4alkyl, C1-C4alkyl-SO-
C1-C4alkyl, C1-C3alkyl-SO2-C1-C4alkyl, cyano-C1-C4alkyl3 C1-C3alkylcarbonyloxy-C1-
C4alkyl, C1-C4alkoxycarbonyl-C1-C4alkyl, C1-C4alkoxycarbonyloxy-C1-C4alkyl, C1-C4-
rhodano-C1-C4alkyl, benzoyloxy-C1-C4aIkyl, C2-C6oxiranyl, C1-C4alkylamino-C1-
C4alkyl, di(C1-C4alkyl)amnio-C1-C4alkyl, C1-C12alkylthiocarbonyl-C1-C4alkyl or formyl-
C1-C4alkyl, or Ra2 is the group —X1-X3 or the group -X2-X1-X3; wherein X1, X2 and X3
are as defined above;
Ra3 and Ra4 are hydrogen and Ra5 is as defined above.
In a still further embodiment the invention the HPPD inhibitor comprises a
compound of formula I wherein:
T is T1 ;
R1 and R2 are hydrogen, A is methylene, D and E together are ethylene, A1 is =N-(O)P;
wherein p is 0;
Q is Q1, Ra3 and Ra4 are hydrogen, Ra5 is C1-C3haloalkyl, especially trifluoromethyl, and
Ra2 is C1-C4alkoxy-C1-C4alkoxy-C1-C4alkyl, especially methoxyethoxymethyl.
HPPD inhibiting compounds are well known in the art and there are numerous
tests that can be employed to identify the capacity of a test compound to inhibit HPPD.
For example, in vitro screening assays as described in the examples of the present
application may be use or alternative in vitro screening methods can be employed such as

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the method described in example 11 of WO02/46387 wherein a known HPPD enzyme is
selected and a test inhibitor compound is applied.
In a still further embodiment of the invention the HPPD inhibitor or precursor is a
compound having the structure depicted in Table A below.
Table A.
!
i

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WO 2006/090177 PCT/GB2006/000684
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WO 2006/090177 PCT/GB2006/000684
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WO 2006/090177 PCT/GB2006/000684
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In addition to the compounds described herein, it is also possible to use a
compound which is a precursor to an HPPD inhibiting compound.
A "precursor" is a compound which itself is not an HPPD inhibitor but is
metabolised to produce an HPPD inhibitor for use in accordance with the present
invention. For example the compound depicted as compound No. 3.01 in Table A above
is a precursor to the compound depicted as compound No. 3.15.
Thus, throughout this specification, "HPPD inhibitor" includes those compounds
which are capable of inhibiting HPPD in animals and any precursor compound thereof
which is capable of being metabolised in the animal to produce the HPPD inhibiting
compound.
It will also be appreciated that alternative steps in the tyrosine catabolism
pathway may be inhibited in addition to or as an alternative to the inhibition of HPPD.

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For example, inhibitors of enzymes/compounds that are "upstream" of HPPD in said
pathway such as tyrosine aminotransferase, may be used and/or likewise inhibitors of
enzymes/compounds "downstream" of HPPD in said pathway such as homogentisic acid
oxidase may also be used.
The present invention further provides the use as described above wherein said
disease is treated. In a particular embodiment said treatment includes retarding the
progression of said disease. In a further embodiment said treatment ameliorates the
symptoms of said disease.
The present invention still further provides the use as described above wherein
said disease is prevented.
The present invention still further provides the use as described above wherein
said animal is a human being.
The present invention still further provides the use as described above wherein
said animal or said human being is suffering from a neurodegenerative disease.
The present invention still further provides the use as described above wherein
said disease is Parkinson's disease.
The term "Parkinson's disease" throughout this specification includes: idiopathic
Parkinson's disease; early-onset Parkinson's disease; post-encephalitic parkinsonism;
drug-induced Parkinson's disease; toxin-induced Parkinson's disease; post-traumatic
parkinsonism; dopa-responsive dystonia; Machado Joseph disease (also referred to as
spinocerebellar ataxia Type 3); multiple system atrophy (which includes
olivopontocerebellar atrophy, striatonigral disease and Shy-Drager syndrome);
progressive subnuclear palsy; and vascular parkinsonism. In a particular embodiment of
the invention the term "Parkinson's disease" means idiopathic Parkinson's disease.
In a further aspect of the invention there is provided the use of a compound of
formula 1 or a pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for use in the treatment of a neurodegenerative disease. In a particular
embodiment of the invention said neurodegenerative disease is Parkinson's disease.
In a still further aspect of the invention there is provided the use of any one of
compounds depicted as 2, 3.01, 3.11, 3.12, 3.13, 3.15, 3.18, 3.20, 3.21, 3.22, 3.23, 3.24,
3.25 and 3.26 or a pharmaceutically acceptable salt thereof, in the manufacture of a
medicament for use in the treatment of a neurodegenerative disease. In a particular
embodiment said compound is any one of compounds depicted as 2, 3.01, 3.11, 3.12,

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3.15, 3.18, 3.20,3.23 and 3.24. In a particular embodiment of the invention said
neurodegenerative disease is Parkinson's disease.
In a further aspect of the invention there is provided the use of a precursor to any
one of compounds depicted as 2, 3.01, 3.11, 3.12, 3.13, 3.15, 3.18, 3.20, 3.21, 3.22, 3.23,
3.24, 3.25 and 3.26 in the manufacture of a medicament for use in the treatment of a
neurodegenerative disease. In a particular embodiment of the invention said
neurodegenerative disease is Parkinson's disease.
The present invention still further provides the use as described above wherein
said medicament is administered in combination with an anti-inflammatory agent.
The present invention still further provides the use as described above wherein
said medicament comprises an anti-inflammatory agent.
The present invention still further provides the use as described above wherein
said medicament comprises a first HPPD inhibitor and a further HPPD inhibitor and
wherein said first inhibitor is different from said further inhibitor. In a particular
embodiment said first and further HPPD inhibitor is selected from an inhibitor described
above. In a still further embodiment said first inhibitor is any one of compounds
depicted as 2, 3.01,3.11, 3.12, 3.13, 3.15, 3.18,3.20, 3.21, 3.22, 3.23, 3.24,3.25 and
3.26 or a pharmaceutically acceptable salt thereof. In a still further embodiment said first
inhibitor is any one of the compounds depicted as 2, 3.01, 3.11, 3.12, 3.15, 3.18,3.20,
3.23 and 3.24 or a pharmaceutically acceptable salt thereof.
In a still further embodiment said first and/or second compound comprises a
precursor compound.
The present invention still further provides the use as described above wherein
said medicament comprises a dopamine agonist. In a particular embodiment said agonist
comprises a compound selected from the group consisting of: Pramipexole; Cabergoline;
Pergolide; and Ropinirole. In a particular embodiment said agonist may be administered
separately to the medicament comprising said HPPD inhibitor.
The present invention still further provides the use as described above wherein
said medicament comprises levodopa. In a particular embodiment said levodopa may be
administered separately to the medicament comprising said HPPD inhibitor.

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The present invention still further provides the use as described above wherein
said medicament comprises levodopa and a decarboxylase inhibitor. In a particular
embodiment said levodopa and a decarboxylase inhibitor combination comprises
Carbidopa and Levodopa. In a still further embodiment said levodopa and a
decarboxylase inhibitor combination comprises Levodopa and Benserazide. In a
particular embodiment said levodopa and a decarboxylase inhibitor may be administered
separately to the medicament comprising said HPPD inhibitor.
The present invention still further provides the use as described above wherein
said medicament comprises Entacapone. In a particular embodiment said medicament
comprises Carbidopa, Levodopa and Entacapone. In a particular embodiment said
Entacapone or said Carbidopa, Levodopa and Entacapone may be administered
separately to the medicament comprising said HPPD inhibitor.
The present invention still further provides the use as described above wherein
said medicament comprises a catechol-O-methyl transferase (COMT) inhibitor. In a
particular embodiment said COMT inhibitor comprises Tolcapone. In a particular
embodiment said COMT inhibitor may be administered separately to the medicament
comprising said HPPD inhibitor.
The present invention still further provides the use as described above wherein
said medicament comprises a monoamine oxidase (MAO) inhibitor. In a particular
embodiment said MAO inhibitor may be administered separately to the medicament
comprising said HPPD inhibitor.
The present invention still further provides the use as described above wherein
said medicament comprises an anti-dyskinesia agent In a particular embodiment said
anti-dyskinesia agent may be administered separately to the medicament comprising said
HPPD inhibitor.
The present invention still further provides the use as described above wherein
said medicament comprises a decarboxylase inhibitor.
The present invention still further provides the use as described above wherein
said medicament comprises a neuroprotectant.
The present invention still further provides the use as described above wherein
said medicament comprises an adenosine (A2a) receptor antagonist, hi a particular
embodiment said antagonist comprises istradefylline.

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The present invention still farther provides the use as described above wherein
said medicament comprises a HPPD inhibitor (or a precursor thereof) and at least one of
the following: (a) a dopamine agonist; (b) levodopa; (c) levodopa and a decarboxylase
inhibitor; (d) levodopa and a decarboxylase inhibitor and Entacapone; (e) a catechol-O-
methyl transferase inhibitor; (f) a monoamine oxidase inhibitor; (g) an anti-dyskinesia
agent; (h) an anti-inflammatory agent; (i) a further HPPD inhibitor (or a precursor
thereof); (j) a decarboxylase inhibitor; (k) a neuroprotectant; (1) an adenosine (A2a)
receptor antagonist; (m) istradefylline.
In a still further aspect of the invention there is provided the compound depicted
as 3.01, 3.11, 3.12, 3.13, 3.15,3.18, 3.20, 3.21,3.22, 3.23, 3.24,3.25 and 3.26 or a
pharmaceutically acceptable salt thereof for use as pharmaceutical agent.
In a further embodiment there is provided the use of a precursor of the compound
depicted as 3.01, 3.11, 3:12, 3.15, 3.18, 3.20, 3.23 and 3.24 for use as a pharmaceutical
agent.
In a still further aspect of the invention there is provided the compound depicted
as 3.01 to 3.26 inclusive or a pharmaceutically acceptable salt thereof, for use as an
inhibitor of the catalytic activity of 4-hydroxyphenyIpyruvate dioxygenase in animals.
In a still further aspect of the invention there is provided the compound depicted
as 3.01,3.11, 3.12, 3.13, 3.15,3.18, 3.20, 3.21,3.22, 3.23, 3.24, 3.25 and 3.26 or a
pharmaceutically acceptable salt thereof, for use as an inhibitor of the catalytic activity of
4-hydroxyphenylpyruvate dioxygenase in animals.
In a particular embodiment of the invention there is provided the compound
depicted as 3.01, 3.11, 3.12, 3.13, 3.15,3.18, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25 and 3.26
or a pharmaceutically acceptable salt thereof, for use as an inhibitor of the catalytic
activity of 4-hydroxyphenylpyruvate dioxygenase in human beings.
In a still further aspect of the invention there is provided the compound depicted as 3.01,
3.11, 3.12, 3.13, 3.15, 3.18, 3.20, 3.21,3.22, 323, 3.24, 3.25 and 3.26 or a
pharmaceutically acceptable salt thereof, for use as an inhibitor of the catalytic activity of
4-hydroxyphenylpyruvate dioxygenase in a patient suffering from Parkinson's disease.
In a still further aspect of the invention there is provided a compound depicted as
compound depicted as 3.01 to 3.26 inclusive or a pharmaceutically acceptable salt
thereof, for use as a medicament.

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In a particular embodiment there is provided a compound depicted as 3.01, 3.02,
3.03, 3.04, 3.05, 3.06, 3.07, 3.08, 3.09, 3.10, 3.11, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, .
3.19, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25, 3.26 or a pharmaceutically acceptable salt thereof;
for use as a medicament
In a particular embodiment of the invention there is provided a compound
depicted as 3.01, 3.11, 3.12, 3.13, 3.15, 3.18, 3.20, 3.21, 3.22, 3.23,3.24, 3.25 and 3.26
or a pharmaceutically acceptable salt thereof, for use as a medicament.
In a further embodiment there is provided the use of a precursor of the compound
3.01 to 3.26 inclusive for use as a medicament.
In a further embodiment there is provided the use of a precursor of the compound
depicted as 3.01, 3.11, 3.12, 3.13, 3.15, 3.18, 3.20, 3.21, 3.22,3.23,3.24, 3.25 and 3.26
for use as a medicament
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor other than 2-(2-Nitro-4-
Trifluoromethylbenzoyl)-1,3-Cyclohexanedione and a means for the delivery thereof to
an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and an anti-inflammatory agent
and a means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a first HPPD inhibitor and a further HPPD inhibitor
and wherein said first inhibitor is different from said further inhibitor. In a particular
embodiment said first and further HPPD inhibitor is selected from an inhibitor described
above. In a still further embodiment said first inhibitor comprises 2-(2-Nitro-4-
Trifluoromethylbenzoyl)-1,3-Cyclohexanedione (compound 2). In a still further
embodiment said first inhibitor comprises the depicted as 3.01, 3.11, 3.12, 3.13, 3.15,
3.18, 3.20, 3.21, 3.22, 3.23,3.24, 3.25 and 3.26 as described above.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of a dopamine agonist and a means for the delivery thereof to an animal.

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In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of aHPPD inhibitor and a pharmaceutically effective
amount of levodopa and a means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of levodopa and a decarboxylase inhibitor and a means for the delivery thereof to
an animal.
hi a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of levodopa and a decarboxylase inhibitor and Entacapone and a means for the
delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of aHPPD inhibitor and apharmaceutically effective
amount of a catechol-O-methyl transferase inhibitor and a means for the delivery thereof
to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective .
amount of a monoarnine oxidase inhibitor and a means for the delivery thereof to an
animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of and an anti-dyskinesia agent and a means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of a decarboxylase inhibitor and a means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of a neuroprotectant and a means for the delivery thereof to an animal.

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In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of an adenosine (A2a) receptor antagonist and a means for the delivery thereof to
an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of istradefylline and a means for the delivery thereof to an animal.
In a still further aspect of the invention there is provided a kit comprising a
pharmaceutically effective amount of a HPPD inhibitor and a pharmaceutically effective
amount of at least one of the following: (a) a dopamine agonist; (b) levodopa; (c )
levodopa and a decarboxylase inhibitor; (d) levodopa and a decarboxylase inhibitor and
Entacapone; (e) a catechol-O-methyl transferase inhibitor; (f) a monoamine oxidase
inhibitor; (g) an anti-dyskinesia agent; (h) an anti-inflammatory agent; (i) a further HPPD
inhibitor (or a precursor thereof); (j) a decarboxylase inhibitor; (k) a neuroprotectant; (1)
an adenosine (A2a) receptor antagonist; (m) istradefylline; and, a means for the delivery
thereof to an animal.
In a particular embodiment there is provided a kit as described above wherein
said animal is a human being. As described above, said HPPD inhibitor may comprise a
precursor compound.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising as an active ingredient any one of the compounds depicted as
compound 3.01 to 3.26 inclusive or a pharmaceutically acceptable salt thereof, together
with a pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising as an active ingredient any one of the compounds depicted as
compound 3.01, 3.11, 3.12, 3.13, 3.15, 3.18, 3.20, 3.21, 3.22, 3.23, 3.24,3.25 and 3.26 or
a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable
diluent or carrier. In a particular embodiment said pharmaceutical composition comprises
as an active ingredient any one of the compounds depicted as compound 3.01, 3.11, 3.12,
3.15, 3.18,3.20, 3.23 and 3.24 or a pharmaceutically acceptable salt thereof, together
with a pharmaceutically acceptable diluent or carrier.

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In a further aspect of the invention said composition comprises a precursor
compound.
In a particular embodiment of the invention said pharmaceutical composition is in
a form suitable for oral or parenteral administration. In a further embodiment of the
invention said composition is in palatable form suitable for oral administration selected
from the group consisting of: tablets; lozenges; hard capsules; aqueous suspensions; oily
suspensions; emulsions; dispersible powders; dispersible granules; syrups and elixirs.
In a still further embodiment of the invention said composition is intended for
oral use and is in the form of hard or soft gelatin capsules.
In a still further embodiment of the invention said composition is in a form
suitable for parenteral administration.
In a still further embodiment of the invention there is provided a pharmaceutical
which comprises a composition as described above in combination with a further HPPD
inhibitor which is different from the compound depicted as compound 3.01, 3.11, 3.12,
3.13, 3.15, 3.18, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25 and 3.26.
In a still further embodiment of the invention there is provided a pharmaceutical
which comprises a composition as described above in combination with a further HPPD
inhibitor which further inhibitor is selected from the compounds depicted as compound
3.01,3.11,3.12,3.13,3.15,3.18, 3.20, 3.21, 3.22, 3.23, 3.24,3.25 and 3.26.
In a still further embodiment of the invention there is provided a pharmaceutical
which comprises compound 2 and a further HPPD inhibitor. In a still further embodiment
said further inhibitor is a compound depicted as compound 3.01, 3.11, 3.1Z, 3.13, 3.15,
3.18, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25 and 3.26.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of a dopamine agonist optionally together with a
pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of levodopa optionally together with a
pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a

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pharmaceutically effective amount of levodopa and a decarboxylase inhibitor optionally
together with a pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of a catechol-O-methyl transferase inhibitor
optionally together with a pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of a monoamine oxidase inhibitor optionally together
with a pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a first HPPD inhibitor
and a pharmaceutically effective amount of a further HPPD inhibitor wherein said first
inhibitor is different from said further inhibitor optionally together with a
pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of a decarboxylase inhibitor optionally together with a
pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of a neuroprotectant optionally together with a
pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of an adenosine (A2a) receptor antagonist optionally
together with a pharmaceutically acceptable diluent or carrier.
In a still further aspect of the invention there is provided a pharmaceutical
composition comprising a pharmaceutically effective amount of a HPPD inhibitor and a
pharmaceutically effective amount of istradefylline optionally together with a
pharmaceutically acceptable diluent or carrier.
In a particular embodiment of the invention there is provided a pharmaceutical
composition as described above wherein said HPPD inhibitor comprises pharmaceutical

WO 2006/090177 PCT/GB2006/000684
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composition comprising as an active ingredient any one of the compounds depicted as
compound 3.01, 3.11,3.12, 3.13, 3.15, 3.18, 3.20, 3.21, 3.22, 3.23, 3.24, 3.25 and 3.26 or
a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically
acceptable diluent or carrier.
The compositions of such HPPD inhibitors for use in the invention may be in
various conventional forms well know in the pharmaceutical art and which are especially
adapted for pharmaceutical purposes that is for administration to man and other warm-
blooded animals.
Thus, they may be in a palatable form suitable for oral use (for example as tablets,
lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible
powders or granules, syrups or elixirs), or for parenteral administration (for example as a
sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or
intravascular dosing).
The compositions of the invention may be obtained by conventional procedures
using conventional pharmaceutical excipients, well known in the art.
Thus, compositions intended for oral use will normally contain, for example, at
least one or more colouring, sweetening, flavouring and/or preservative agents and may
be in the form of hard gelatin capsules in which the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin,
Compositions for oral use may also be in the form of soft gelatin capsules in which the
active ingredient is mixed with water or an oil such as arachis oil, liquid paraffin or olive
oil.
Suitable pharmaceutically acceptable excipients for use in tablet formulations
include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate
or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic
acid; binding agents such as gelatin or starch; lubricating agents such as magnesium
stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-
hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
Tablet formulations may be uncoated or coated either to modify their
disintegration and the subsequent absorption of the active ingredient within the

WO 2006/090177 PCT/GB2006/000684
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gastrointestinal tract, or to improve their stability and/or appearance, in either case, using
conventional coating agents and procedures well known in the art.
Aqueous suspensions will generally contain the active ingredient in finely
powdered form together with one or more pharmaceutically acceptable suspending
agents, such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth
and gum acacia; dispersing or wetting agents such as lecithin or condensation products of
an alkylene oxide with fatty acids (for example polyoxyethylene stearate), or
condensation products of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial
esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
monooleate, or condensation products of ethylene oxide with partial esters derived from
fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono-oleate.
Aqueous suspensions will also typically contain one or more preservatives (such
as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring
agents, normally together with a flavouring and/or sweetening agent (such as sucrose,
saccharin or aspartame).
Oily suspensions may be formulated by suspending the active ingredient in a
vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil
(such as liquid paraffin).
The oily suspensions may also contain a thickening agent such as beeswax, hard
paraffin or cetyl alcohol.
Sweetening agents such as those set but above, and flavouring agents may be
added to provide a palatable oral preparation.
These compositions may be preserved by the addition of an anti-oxidant such as
ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water generally contain the active ingredient together with
a dispersing or wetting agent, suspending agent and one or more preservatives.

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Suitable dispersing or wetting agents and suspending agents are exemplified by
those already mentioned above.
Additional pharmaceutically acceptable excipients such as sweetening, flavouring
and colouring agents, will generally also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-
in-water emulsions.
The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral
oil, such as for example liquid paraffin or a mixture of any of these.
Suitable emulsifying agents may be, for example, naturally-occurring gums such
as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean,
lecithin, or esters or partial esters derived from fatty acids and hexitol anhydrides (for
example sorbitan monooleate) and condensation products of the said partial esters with
ethylene oxide such as polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening, flavouring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol,
propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent,
preservative, flavouring and/or colouring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable
aqueous or oily suspension, which may be formulated according to known procedures
using one or more of the appropriate dispersing or wetting agents and suspending agents,
which have been mentioned above.
A sterile injectable preparation may also be a sterile injectable solution or
suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a
solution in 1,3-butanediol.
Dosage
The amount of active ingredient that is combined with one or more excipients to
produce a single dosage form will necessarily vary depending upon the host treated and
the particular route of administration.

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Generally, a formulation intended for oral administration to humans will
generally contain for example from 0.0lmg to l0mg of active agent per Kg of
bodyweight combined with an appropriate and convenient amount of excipients.
Dosage unit forms will generally contain about 0.1 mg to about 500 mg of an
active ingredient.
More specifically, a formulation comprising compound 2, for example, intended
for oral administration to humans will generally contain for example from 0.0lmg to
lmg of active agent per Kg of bodyweight combined with an appropriate and convenient
amount of excipients.
Dosage unit forms for a formulation comprising compound 2 will generally
contain about 0.1 mg to about 100 mg of an active ingredient.
However, it will be readily understood that it may be necessary to vary the dose
of the active ingredient administered in accordance with well known medical practice in
order to take account of the nature and severity of the condition or disease under
treatment, any concurrent therapy, and of the age, weight, genotype and sex of the patient
receiving treatment.
Generally, in therapeutic use, it is envisaged that a composition according to the
invention would be administered so that a dose of the HPPD inhibitor (or of an
equivalent amount of a pharmaceutically acceptable salt thereof) is received which is
generally in the range 0.00002 to 10 mg/kg/day, or 0.001 to 500 mg/day more
specifically, 0.05-10mg/day and 0.1-5mg/day or 0.01 to 10 mg of active agent per Kg of
bodyweight daily given if necessary in divided doses.
More specifically, for a composition comprising compound 2, in therapeutic use,
it is envisaged that a composition according to the invention would,be administered so
that a dose of the HPPD inhibitor (or of an equivalent amount of a pharmaceutically
acceptable salt thereof) is received which is generally in the range 0.0002 to 1
mg/kg/day, or. 0.01 to 100 mg/day. More specifically, from between 0.05 to lOmg/day
and 0.1 to 5mg/day or 0.01 to lmg of active agent per Kg of bodyweight daily given if
necessary in divided doses. All ranges throughout this specification are inclusive. For
example from 0.01 to 100 includes the values 0.01 and 100.

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Mennittent dosing of the HPPD inhibitor (or of a pharmaceutically acceptable
salt thereof) may also be desirable.
In addition to assessment of the overall condition of the patient, the effects of
administration of the HPPD inhibitor thereof may be monitored by standard clinical
chemical and blood assays.
In a still further aspect of the invention there is provided a method of treating
and/or preventing a neurodegenerative disease comprising administering to ah animal a
pharmaceutically effective amount of a HPPD inhibitor.
hi a still further aspect of the invention there is provided a method of treating
and/or preventing a neurodegenerative disease comprising administering to an animal a
pharmaceutically effective amount of a precursor compound,
hi a particular embodiment of the invention said disease is treated. In a still further
embodiment of the invention said animal is a human being. In a still further embodiment
of the invention said neurodegenerative disease is Parkinson's disease. In a still further
embodiment of the invention said HPPD inhibitor is as described above, hi a particular
embodiment said inhibitor comprises the compound depicted as compound 2, 3.01, 3.11,
3.12, 3.13,3.15, 3.18, 3.20, 3.21,3.22, 3.23, 3.24, 3.25 and 3.26 or a pharmaceutically
acceptable salt thereof.
hi a further aspect of the present invention there is provided a method for
increasing levodopa availability and/or dopamine synthesis, in the brain, comprising
administering to an animal an amount of a compound depicted as 3.01, 3.11, 3.12, 3.13,
3.15, 3.18,3.20, 3.21, 3.22, 3.23,3.24, 3.25 and 3.26 in said animal.
hi a further aspect of the present invention there is provided a method for
increasing levodopa availability and/or dopamine synthesis, in the brain, comprising
administering to an animal an amount of a precursor compound to a compound depicted
as 3.01, 3.11, 3.12,3.13, 3.15, 3.18, 3.20, 3.21,3.22, 3.23, 3.24, 3.25 and 3.26.
hi a particular embodiment of the invention, dopamine synthesis in the brain is
increased, hi a particular embodiment of the invention, levodopa availability in the brain
is increased.
The invention will now be described by way of the following non-limiting
examples and Figures of which:

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Figure 1 is a representation of part of a pathway indicating the metabolism of
tyrosine.
Figures 2 to 4 ilustrate the mean catalepsy descent latency data from tables 1.4,
1.5 and 1.6 respectively.
EXAMPLES
EXAMPLE 1
Determination of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) enzyme activity in
vitro
The method used to determine the inhibitory effect of test compounds on HPPD
activity was based on the method by Ellis et al 1996 (Ellis, M.K., Whitfield, A.C.,
Gowans, L.A., Auton, T.R., Provan, W.M., Lock, E.A., Lee, D.L., Smith, L.L. (1996)
Characterization of the interaction of 2-[2-nitro-4-(trifluoromethyl)benzoyl]-4,4,6,6-
tetramethyl-cyclohexane-l,3,5-trione with rat hepatic 4-hydroxyphenylpyruvate
dioxygenase. Chemical Research Toxicology, 9, 24-27).
The principle of the assay is that 4-hydroxyphenyl pyruvate dioxygenase (HPPD),
an enzyme that participates in the catabolism of tyrosine, catalyses the oxidative
decarboxylation and rearrangement of 4-hydroxyphenylpyruvate (HPPA) to
homogentisate, with the incorporation of both atoms of molecular oxygen into the
product.

Rat liver was homogenised in buffer of the following composition; 0.25 M
Sucrose, 5.4 mM EDTA, 20 mM Tris base, pH 7.4, (25% homogenate) using 6 passes of
a Potter type homogehiser. The homogenate was then centrifuged at 1,800 g for 10
minutes at 4°C, the pellet was discarded and the supernatant centrifuged at 17,000 g for a
further 15 minutes at 4°C. The pellet was then discarded and the supernatant centrifuged
at 110,000 g for 80 minutes at 4°C. The supernatant containing the HPPD enzyme from
this 110,000 g spin was collected and stored frozen at -70°C and used in the assays of the
test compounds (see below).

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The effect of the test compound or vehicle (0.04% DMSO) on the formation of
homogentisate from HPPA (i.e. HPPD activity), was determined by incubating at 37°C a
reaction mixture containing 0.2 M sodium phosphate buffer (pH 7.2), 7.1 M ascorbate,
0.2 mM HPPA, rat liver cytosol (2.7 mg of protein/ml incubate) and test compound (0 -
300 nM) in a total volume of 4 ml, and measuring the rate of oxygen consumption. Prior
to the start of the enzymatic reaction by the addition of HPPA substrate, the enzyme and
test compound (inhibitor) were incubated together for 3 minutes. In the absence of
inhibitor, the rate of oxygen consumption was 0.96 ± 0.113 l oxygen/min/mg protein
(n=10). The vehicle alone had no effect on HPPD activity.
The rate of oxygen consumption in the presence of the HPPD inhibitor test compound
was expressed as a percentage of the rate of oxygen consumption in the absence of the
. inhibitor, to give a value as a % of the control. In cases where the effects of several
concentrations of an inhibitor were investigated, an IC50 value (the half-maximal
inhibitory concentration of test compound) was determined by plotting the data using a
non-linear regression curve-fitting program using a GraphPad Prism™ software package.
The data in Table 1 show the percentage inhibition of HPPD activity at two
concentrations of 100 and 300 nM. In addition, IC50 values for compound 2 and
compound 3.13 are indicated. Data are expressed as mean values from two experiments
except where indicated. Where appropriate the values are expressed as the mean ±
standard deviation.
Table 1


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EXAMPLE 2
Plasma tyrosine concentration kinetic profiles in the rat following single oral doses of
HPPD inhibitors
The plasma tyrosine concentration kinetic profile in the rat was determined for
each of the HPPD inhibitor test compounds by administering a single oral dose to 10-12
week old male Sprague Dawley rats. Compounds 3.20, 3.13 and 3.26 were dosed at 2
mg/kg in 1% carboxymethylcellulose (1% CMC) vehicle, whilst compounds 3.22,3.12,
3.15, 3.18, 3.23, 3.21, 3.11, 3.01, 3.24 and 3.25 were administered at 10 mg/kg in 1%
CMC.
Blood samples to determine plasma tyrosine concentration were obtained at
frequent intervals during the first 24 hours post-dose, and at 48 hours post-dose. These
samples were either compared with blood samples obtained from control rats which only
received an equivalent volume of the vehicle, 1% CMC, or by comparison with control
samples obtained from the rats 1 hour prior to dosing with test the compound. Prior to the
analysis of the samples for plasma tyrosine concentration, the blood samples were
centrifuged at 1800 g for 10 minutes at 4°C. The plasma was collected and then filtered
through a centrifugal micro partition device at 1500 g for 30 minutes at 4°C. The filtered
plasma was then divided into two aliquots and stored frozen at -70°C for subsequent
gradient reverse phase high performance liquid chromatographic (HPLC) analysis of
plasma tyrosine. Aliquots of plasma were analysed by HPLC using a 250 x 4.6 mm
Hichrom S5ODS2 column at 30°C, eluted with a mobile phase of water / acetonitrile /
trifluoroacetic acid (950:50:2 v/v/v) at a flow rate of 1 ml/min. Detection was by a diode
array detector at 274 nm. Appropriate tyrosine standards were run alongside the samples
for calibration purposes.

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The plasma tyrosine concentration kinetic profile for the test compounds 3.20,
3.13 and 3.26 are shown at the time points 1,2,4, 6,12,24 and 48 hours post-dose in
Table 1.1. The data shown are the mean ± standard deviation (n=4), except for the 6 hour
time point where the data were obtained from n=3 rats for the control and 3.26 groups.

Table 1.1
Time
point
(hours) Plasma tyrosine (nmol/ml)

Control Compound 3.13
2.0mg/kg Compound 3.26
2.0 mg/kg Compound 3.20
2.0 mg/kg
1 84 ±3.3 158 ± 6.4 173 ± 9.6 169 ±13.6
2 78 ± 5.3 209 ±14.8 241 ± 24.0 231 ± 30.2
4 72 ±8.1 324 ±50.2 337 ±53.5 353 ± 50.9
6 68 ±3.8 461 ± 52.2 504 ±72.7 479 ±40.0
12 66 ±8.8 801 ±24.8 897 ±140.8 796 ± 44.3
24 86 ± 14.6 1281 ± 90.0 1987 ±.50.0 745 ±171.8
48 91 ± 6.9 115 ±3.0 2449 ±156.8 96 ±1.7
The plasma tyrosine concentration kinetic profile for the test compounds 3.22,
3.12, 3.15, 3.18,3.23, 3.21, 3.11, 3.01, 3.24 and 3.25 are shown at the time points -1 hour
(pre-dose control), 1, 3, 6,12, 24 and 48 hours post-dose, in Tables 1.2 and 1.3. The data
shown are the mean ± standard deviation (n=3), except for the -1 hour time point with
compound 3.23, where n=2 (Table 1.2), and for the 3 and 6 hour time points with
compound 3.21, where n=2 (Table 1.3).

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Tablel.2

Time Plasma Tyrosine Concentration (nmol/ml)
(hours) Compound
3.22 Compound
3.12 Compound
3.15 Compound
3.18 Compound
3.23
-1 99 ± 0.8 92 ±3.0 100±15.1 101 ±5.1 118
1 179 ±18.5 168 ±20.1 177 ±21.7 177 ±3.5 173 ± 22.0
3 319 ±43.5 289 ±35.6 299 ±18.8 303 ± 3.9 307 ±28.0
6 507 ± 86.4 451 ±72.7 458 ±29.4 504 ± 29.4 502 ± 37.5
12 1011 ±
134.8 969 ±65.2 671 ±119.7 1027 ± 62.7 1041 ± 88.5
24 2067 ± 36.6 1543 ±91.1 228 ± 76.6 1987 ±
133.0 1835 ±
444.1
48 2377 ±
518.5 114±8.0 117±11.3 313±216.6 299 ±202.8

Table 1.3
Time Plasma Tyrosine Concentration (nmol/ml)
(hours) Compound
3.21 Compound
3.11 Compound
3.01 Compound
3.24 Compound
3.25
-1 88 ±1.6 96 ±7.1 89 ±15.2 98 ± 6.5 105 ± 7.9
1 177 ±17.8 193 ± 22.9 160 ±7.4 184 ±27.8 . 162 ±17.7
3 300 338 ± 48.9 276 ±12.9 313 ±49.9 267 ±19.4
6 472 551 ± 80.7 445 ± 32.9 548 ±83.9 370 ±60.8
12 555 ±39.0 1041 ±
106.0 666 ±16.1 1008 ±85.2 415 ±152.8
24 181 ±23.6 2125 ±65.8 264 ±23.5 2110±
111.1 136 ±31.2
48 100 ±6.4 993 ± 260.6 110 ±23.9 2571 ±
167.7 100 ±13.5

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EXAMPLE 3
The efficacy of compound 2 and other HPPD inhibitors in the AMPT rat model of
Parkinson's disease.
The efficacy of compound 2 and other HPPD inhibitor test compounds in the rat oc-
methyl-p-tyrosine (AMPT) model of Parkinson's disease was determined by
administration of a single oral dose of the test compound to AMPT treated rats. AMPT is
a competitive inhibitor of tyrosine hydroxylase. Rats dosed with >150 mg/kg AMPT
develop parkinsonian-like behavior and locomotor deficits (e.g. catalepsy and reduced
rearing activity) within hours owing to the depletion of striatal dopamine concentration
as a consequence of the reduced flux through the dopamine synthetic pathway.
Dopamine replacement anti-Parkinson drugs, such as L-3,4-dihydroxyphenylalanine (L-
dopa), are effective at restoring normal activity function in this rodent model (Ahlenius,
S., Anden, N.E., and Engel, J. (1973). Restoration of locomotor activity in mice by low
L-DOPA doses after suppression by alpha-methyltyrosine but not reserpine. Brain Res.
62,189-199. Ahlenius, S. (1974). Reversal by L-dopa of the suppression of locomotor
activity induced by inhibition of tyrosine-hydroxylase and DA-beta-hydroxylase in mice.
Brain Res. 69, 57-65. Singh, A., Naidu, P.S., and Kulkarni, S.K. (2003). FK5O6 as
effective adjunct to L-dopa in reserpine-induced catalepsy in rats. Indian J. Exp. Biol. 41,
1264-1268).
Test compound induced reversal of the behavioral deficits induced by AMPT
demonstrate efficacy in this animal model for Parkinson's disease.
Male Sprague-Dawley rats (300-350 g) were administered a single i.p. dose of
225 mg/kg AMPT and a single oral dose of 2 mg/kg compound 2. Compound 2 was
administered either 16 hours prior to AMPT administration or 4 hours post AMPT dose
in order to examine the effects of a large tyrosinaemia (>2000 nmol/mL) and a smaller,
sub-maximal tyrosinaemia (<1000 nmol/mL). Behavioral assessment (catalepsy and
centre rearing counts) was conducted 8 hours post AMPT administration, this being a
time point when the AMPT treated rats were clearly cataleptic. The effect was compared
with appropriate vehicle control groups (oral vehicle was 1% carboxymethylcellulose;
CMC) and a group that received a 150 mg/kg i.p. dose of L-dopa.
Eight hours after AMPT (or vehicle) administration rats were assessed for
catalepsy and centre rearing activity. During the catalepsy test, the front paws of the rat

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were placed over a horizontal bar suspended 9 cm off the floor. The time taken for the rat
to get off the bar (descent latency) was measured with a maximum time of 3 minutes
being allowed. Centre rearing counts were determined over a 1 hour monitoring period
using an automated activity monitoring system (AM1053). This system used an array of
infrared beams to determine the activity and mobility of each animal. Each cage had 48
infrared beams, 24 on each of two levels arranged in an 8 x 16,1" (25.4 mm) pitch grid.
The lower grid measured horizontal x, y movement, whilst the upper grid measured
rearing movement. The activity detector operated by counting the number of times the
beams changed from unbroken to broken and then incrementing the relevant counters.
Centre rearing counts were incremented when an animal had broken a beam on the upper
level and none of the outer two beams were broken, thus detecting rearing when the rats
did not use the cage walls for support. The descent latency (seconds) and centre rearing
counts for the six treatment groups at 8 hr post AMPT administration are shown in Table
1.4.
Table 1.4

Group
Number Treatment Group Mean Catalepsy
Descent Latency
(s) Mean Centre
Rearing Counts
1 AMPT vehicle + compound 2
vehicle 2±0.1 277 ±61
2 AMPT vehicle + compound 2 (+4
hours) 12 ±4.3 485 ±108
3 AMPT + compound 2 vehicle 78±11.1++ 13 ±8++
4 AMPT + compound 2 (-16 hours) 27 ± 5.4++ 364 ±74++
5 AMPT + compound 2 (+4 hours) 27 ± 6.7++ 298 ±574+
6 AMPT + L-dopa (+6.5 hours) 25 ± 6.9++ . 258±71+
Data represent the mean ± standard error of the mean for n=12.
* p<0.05, ** p<0.01 statistical significance compared to the AMPT vehicle + compound
2 vehicle group (1); +p<0.05, ++ p<0.01 statistical significance compared to the AMPT

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treated + compound 2 vehicle group (3); one-way ANOVA followed by Dunnett's
multiple comparison test.
Treatment groups were as follows: a vehicle control group (1) was administered
AMPT vehicle (saline i.p.) + compound 2 vehicle (1% CMC oral); a compound 2 group
(2) was administered AMPT vehicle (saline i.p.) + 2 mg/kg compound 2 oral; an AMPT
group (3) was administered 225 mg/kg AMPT i.p. + compound 2 vehicle (1% CMC
oral); two groups (4 & 5) were administered a single i.p. dose of 225 mg/kg AMPT and a
single oral dose of 2 mg/kg compound 2. In one of these groups (4), compound 2 was
administered 16 hour prior to AMPT administration, and in the other group (5), it was
administered 4 hour post AMPT dosing. These groups were compared to a positive
control group (6) dosed with 225 mg/kg AMPT i.p. + 150 mg/kg L-dopa i.p. 6.5 hour
post AMPT dose. L-dopa was administered with a peripheral dopa decarboxylase
inhibitor (benserazide), at 100 mg/kg i.p.
Compound 2 substantially reversed the AMPT induced catalepsy and was as
effective as 150 mg/kg L-dopa in this respect. Both compound 2 dosing regimens were
equally effective, indicating that a sub-maximal tyrosinaemia is sufficient to reverse the
effect of AMPT. Compound 2 also reversed the AMPT induced deficits in centre rearing
counts as effectively as L-dopa.
Analysis of plasma tyrosine concentration from samples obtained immediately
following behavioral assessment confirmed a substantial tyrosinaemia (mean = 2205 ±
238 nmol/mL) in those rats administered compound 2 16 hours prior to AMPT, and a
sub-maximal tyrosinaemia (mean = 345 ± 45 nmol/mL) in those rats which received
compound 2,4 hours post AMPT dose.
In conclusion a single oral dose of 2 mg/kg compound 2 is effective in reversing
the AMPT induced catalepsy and centre rearing deficits in the AMPT rat model of
Parkinson's disease. These effects occur at time points post dosing when plasma tyrosine
concentrations are elevated to >345 nmol/mL. Compound 2 is as effective as L-dopa in
this animal model of the disease.
In a second and third series of experiments, the efficacy of eight other HPPD
inhibitor test compounds were assessed in the AMPT rat model of Parkinson's disease
(Tables 1.5 & 1.6). Male Sprague-Dawley rats (300-350 g) were administered a single
i.p. dose of 225 mg/kg AMPT and a single oral dose of 10 mg/kg of the HPPD inhibitor

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test compound was administered either 1 or 16 hours prior to (-16 or -1 hours) AMPT
administration. Behavioral assessment (catalepsy and centre rearing counts) was
conducted 8 hours post AMPT administration. The effect was compared with a vehicle
control group and a group receiving AMPT alone.
5 Table 1.5

Group
Number Treatment Group Mean Catalepsy
Descent Latency
(s) Mean Centre
Rearing Counts
1 Vehicle Control (saline + 1%
CMC) 2 ±0.2 417 ±120
2 AMPT+1% CMC 86 ±18.5*** 76 ± 25*
3 AMPT + compound 3.23 (-16
hours) 10±3.0+++ 273 ± 63
4 AMPT + compound 3.18 (-16
hours) 12±4.6++ 359 ±116+
5 AMPT + compound 3.24 (-16
hours) 15 ± 8.9+++ 189 ±36
6 AMPT + compound 3.11 (-16
hours) 9 ± 2.7+++ 303 ± 53
Data represent the mean ± standard error of the me.an for n=12.
* p<0.05, *** p<0.001 statistical significance compared to the vehicle control group (1);
+p<0.05, ^pO.001 statistical significance compared to the AMPT + 1% CMC group
(2); one-way ANOVA followed by Dunnett's multiple comparison test.
Test compounds 3.23,3.18,3.24 and 3.11 substantially reversed the AMPT
induced catalepsy. The AMPT induced deficits in the mean centre rearing counts were
also partially reversed by all the test compounds, although this only reached statistical
significance with test compound 3.18. The data demonstrate efficacy of these compounds
in this animal model for Parkinson's disease.

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Tablel.6

Group
Number Treatment Group Mean Catalepsy
Descent Latency
(s) Mean Centre
Rearing Counts
1 Vehicle Control (saline + 1%
CMC) 2 ±0.3 529 ±71
2 AMPT+1%CMC 131 ±16.1*** 48 ±13***
3 AMPT + compound 3.12 (-16
hours) 16±4.2+++ 211 ±65
4 AMPT + compound 3.20 (-16
hours) 8±1.8+++ 409 ± 50+++
5 • AMPT + compound 3.01 (-1 hour) l1±3.0+++ 88 ±26
6 AMPT + compound 3.15 (-1 hour) 23 ± 8.0+++ 199 ± 54
Data represent the mean ± standard error of the mean for n=12.
*** p<0.001 statistical significance compared to the vehicle control group (1);
+++p<0.00l statistical significance compared to the AMPT + 1% CMC group (2); one-
way ANOVA followed by Dunnett's multiple comparison test.
Test compounds 3.12, 3.20, 3.01 and 3.15 substantially reversed the AMPT
induced catalepsy. The AMPT induced deficits in the mean centre rearing counts were
also partially reversed by all the test compounds, although this only reached statistical
significance with test compound 3.20. The data demonstrate efficacy of these compounds
in this animal model for Parkinson's disease.
In conclusion, a single oral dose of 10 mg/kg of any of the eight HPPD inhibitor test
compounds (3.23,3.18,3.24,3.11,3.12, 3.20,3.01 and 3.15) is effective in reversing the
AMPT induced catalepsy, and either partially or completely reversing the centre rearing
deficits inthe AMPT rat model of Parkinson's disease. These effects occur at time points
when plasma tyrosine concentrations are elevated.

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CLAIMS
1. The use of 2-(2-Nitro-4-Trifluoromethylbenzoyl)-l,3-Cyclohexariedione
(compound 2), or a pharmaceutically acceptable salt thereof, in the manufacture
of a medicament for use in the treatment of a neurodegenerative disease.
2. The use according to claim 1 wherein said disease is Parkinson's disease.
3. The use according to claim 1 or claim 2 wherein the medicament comprises
compound 2 or a pharmaceutically acceptable salt thereof and a further compound
which is also capable of inhibiting 4-hydroxyphenylpyruvate dioxygenase
(HPPD) in an animal.
4. The use according to any one of the previous claims wherein said medicament
comprises a dopamine agonist.
5. The use according to any one of the previous claims wherein said medicament
comprises levodopa and a decarboxylase inhibitor.
6. A kit comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount
of a dopamine agonist and a means for the delivery thereof to an animal.
7. A kit comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount
of levodopa and a means for the delivery thereof to an animal.
8. A kit comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount
of levodopa and a decarboxylase inhibitor and a means for the delivery thereof to
an animal.

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9. A kit comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount
of a catechol-O-methyl transferase inhibitor and a means for the delivery thereof
to an animal.
10. A kit comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount
of a monoamine oxidase inhibitor and a means for the delivery thereof to an
animal.
11. A kit comprising a pharmaceutically effective amount of compound 2 or a
pharmaceutically acceptable salt thereof and a pharmaceutically effective amount
of a further compound which is also capable of inhibiting HPPD in an animal and
a means for the delivery thereof to an animal.
12. A pharmaceutical composition comprising as an active ingredient compound 2 or
a pharmaceutically acceptable salt thereof and a pharmaceutically effective
amount of a further compound which is also capable of inhibiting HPPD in an
animal together with a pharmaceutically acceptable diluent or carrier.
13. A pharmaceutical composition comprising a pharmaceutically effective amount
of compound 2 or a pharmaceutically acceptable salt thereof and a
pharmaceutically effective amount of a dopamine agonist together with a
pharmaceutically acceptable diluent or carrier.
14. A pharmaceutical composition comprising a pharmaceutically effective amount
of compound 2 or a pharmaceutically acceptable salt thereof and a
pharmaceutically effective amount of levodopa together with a pharmaceutically
acceptable diluent or carrier.
15. A pharmaceutical composition comprising a pharmaceutically effective amount
of compound 2 or a pharmaceutically acceptable salt thereof and a

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pharmaceutically effective amount of levodopa and a decarboxylase inhibitor
together with a pharmaceutically acceptable diluent or carrier.
16. A pharmaceutical composition comprising a pharmaceutically effective amount
of compound 2 or a pharmaceutically acceptable salt thereof and a
pharmaceutically effective amount of a catechol-O-methyl transferase inhibitor
together with a pharmaceutically acceptable diluent or carrier.
17. A pharmaceutical composition comprising a pharmaceutically effective amount
of a HPPD inhibitor and a pharmaceutically effective amount of amonoamine
oxidase inhibitor and a means for the delivery thereof to an animal.
18. A pharmaceutical composition according to any one of claims 12 to 17 which is
in a form suitable for oral or parenteral administration.
19. A pharmaceutical composition according to claim 18 which is in palatable form
suitable for oral administration selected from the group consisting of: tablets;
lozenges; hard capsules; aqueous suspensions; oily suspensions; emulsions;
dispersible powders; dispersible granules; syrups and elixirs.
20. A pharmaceutical composition according to claim 18 which is intended for oral
use and is in the form of hard or soft gelatin capsules.
21. A pharmaceutical composition as claimed in claim 18 which is in a form suitable
for parenteral administration.
22. A method of treating and/or preventing a neurodegenerative disease comprising
administering to an animal a pharmaceutically effective amount of compound 2 or
a composition according to any one of claims 12 to 21.
23. A method according to claim 22 wherein said disease is treated.

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24. A method according to claim 22 or claim 23 wherein said animal is a human
being.
25. A method according to any one of claims 22 to 24 wherein said
neurodegenerative disease is Parkinson's disease.

The present invention relates to, inter alia, the use of 2-(2-Nitro-4- Trifluoromethylbenzoyl)-1,3-Cyclohexanedione
(compound 2) in the treatment of a neurodegenerative disease, such as Parkinson's disease. The invention also relates to the use of
the compound depicted as compound 2 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in
the treatment of a neurodegenerative disease such as Parkinson's disease.