Note: Descriptions are shown in the official language in which they were submitted.
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USE OF 1H-QUINAZOLINE-2,4-DIONES FOR USE IN THE PREVENTION OR TREATMENT OF
PHOTOSENSITIVE EPILEPSY
Field of the invention
The present invention relates to pharmaceutical uses of 1H-quinazoline-2,4-
diones, their
pharmaceutically acceptable salts, and prodrugs thereof specifically for the
treatment of
photosensitive epilepsy (PSE).
Background of the invention
Epilepsy is one of the most common neurological disorders, with lifetime
prevalence in
excess of 1% of the world population. Despite the fact that there are about 20
antiepileptic
drugs (AEDs) on the market, there is still a high medical need for improved
treatments of
epilepsy since about 30-40% of patients are inadequately controlled or suffer
from drug side
effects.
Photosensitive epilepsy (PSE) is a rare form of reflex epilepsy in which
seizures are triggered
in photosensitive individuals by periodic visual stimuli such as flashing or
flickering lights or
regular patterns like stripes or checks. The patterns are usually high in
luminance contrast
(bright flashes of light alternating with darkness, or white bars against a
black background).
Both natural and artificial light may trigger seizures. Examples of flashing
lights or rapidly
changing or alternating images that may trigger the seizure in these patients
include
exposure to faulty lights or stroboscopic lights such as those in disco-clubs,
the light of
emergency vehicles, images in films or television programs (with an increased
risk of
seizures with closer proximity to the light source); driving at dawn or dusk
through an area in
which the sun is shining through a line of trees or through a sudden change in
light intensity
(such as coming out of a tunnel); exposure to the light pattern caused by sun
flickering on
water; looking out from the window of a fast moving vehicle; or observing
geometric patterns.
PSE is a type of reflex epilepsy and individuals with PSE may either have
seizures
exclusively in response to specific stimuli, not suffer spontaneous seizures
or, alternatively,
have reflex seizures coexisting with spontaneously occurring seizures. PSE is
mostly
associated with generalized epilepsies. The previously mentioned visual
stimuli may provoke
clinical photoconvulsive seizures or subclinical photoparoxysmal responses
(PPR) in PSE
patients. Photosensitive epilepsy is a generalized epileptic-form reaction on
intermittent
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photic stimulation (IPS) outlasting the stimulus sequence in about 5% of
epileptic patients.
Photosensitive epilepsy has a strong genetic component and a higher incidence
in females.
The triggering stimuli vary from one patient to another, as do the nature and
severity of the
resulting seizures (ranging from brief absence to full tonic clonic seizure).
Some patients are
more sensitive with their eyes closed; others are more sensitive with their
eyes open.
An effective treatment for PSE is avoidance of the provoking stimulus. However
this can be
difficult if the real trigger is not known. Therefore, the large majority of
patients with epilepsy
and photosensitivity need treatment with antiepileptic drugs. The drug of
choice is often
Valproate in monotherapy, if necessary Clobazam could be given as an
adjunctive treatment.
Lamotrigine, Topiramate and Levetiracetam are recommended as second choices.
Besides
the rather typical adverse effects like sedation, nausea and drowsiness
Valproate can cause
severe liver injury particularly in patients just starting the treatment.
Valproate can also cause
birth defects and should not be given during pregnancy, a major problem in
photosensitive
epilepsy since this is mainly diagnosed in young females. Several of the above
mentioned
drugs also cause induction of metabolizing enzymes which can cause drug-drug
interactions.
It would therefore be desirable to provide alternative or improved treatments
for PSE, for
example treatments not suffering from some or all of the above
disadvantages/limitations.
Summary of the invention
In accordance with a first aspect of the invention, there is provided a 1H-
quinazoline-2,4-
dione of formula (I)
0
HO
R1 CH3
0
R2 NO
(I),
wherein
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R1 is C1-C6alkyl substituted by one, two or three substituents selected from
hydroxy, C1-
C6alkoxy or C6-C6cycloalkoxy; or
R1 is
R3 R4 \rN
(11(
or
in
D1 D2
R3 is C1-C6alkyl, hydroxy or C1-C6alkoxy-C1-C6alkyl;
R4 is hydrogen or C1-C6alkyl;
n is 1 or 2;
R2 is C1-C3alkyl or C1-C3fluoroalkyl;
or a pharmaceutically acceptable salt or prodrug thereof;
for use in the treatment or prevention of photosensitive epilepsy.
A second aspect of the invention concerns a method for the treatment of
photosensitive
epilepsy in a subject in need of such treatment, which comprises administering
to said
subject a therapeutically effective amount of a 1H-quinazoline-2,4-dione of
formula (I) or a
pharmaceutically acceptable salt or prodrug thereof.
A third aspect of the invention relates to the use of a 1H-quinazoline-2,4-
dione of formula (I),
or a pharmaceutically acceptable salt or prodrug thereof, for the treatment or
prevention of
photosensitive epilepsy.
A fourth aspect of the invention relates to a 1 H-quinazoline-2,4-dione of
formula (I), or a
pharmaceutically acceptable salt or prodrug thereof, for the treatment or
prevention of
photosensitive epilepsy.
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A fifth aspect of the invention relates to a pharmaceutical composition
comprising a 1H-
quinazoline-2,4-dione of formula (I), or a pharmaceutically acceptable salt or
prodrug thereof,
in the treatment or prevention of photosensitive epilepsy.
A sixth aspect of the invention relates to the use of a 1H-quinazoline-2,4-
dione of formula (I),
or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture
of a
medicament for the treatment or prevention of photosensitive epilepsy.
A seventh aspect of the invention relates to a method for the treatment of
photosensitive
epilepsy in a subject in need of such treatment, which comprises administering
to said
subject a therapeutically effective amount of a 1H-quinazoline-2,4-dione of
formula (I) or a
pharmaceutically acceptable salt or prodrug thereof.
An eight aspect of the invention concerns a 1H-quinazoline-2,4-dione of
formula (I) or a
pharmaceutically acceptable salt or prodrug thereof in combination with one or
more
antiepileptic drugs (AEDs), preferably one or two antiepileptic drugs (AEDs),
for use in the
treatment or prevention of photosensitive epilepsy.
A ninth aspect of the invention relates to a formulation comprising a compound
of Formula (I)
e.g. Compound C7, or a pharmaceutically acceptable salt or prodrug thereof,
the compound
having an AUC2.0 greater than or equal to 5000 hrng/mL and/or Cm ax greater
than or equal
to 300ng/m1 e.g. such that the PPR is suppressed and/or the SPR is reduced,
e.g. by at least
3 steps, optionally for use in the treatment of PSE
Detailed description of the invention
The invention relates to a 1H-quinazoline-2,4-dione of formula (I)
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0
HO
R1 io N'9' CH3
o
.
R2 N 0
1-1 (I),
wherein
R1 is C1-C6alkyl substituted by one, two or three substituents selected from
hydroxy, C1-
C6alkoxy or C6-C6cycloalkoxy; C6-C6cycloalkyl substituted by one, two or three
substituents
selected from hydroxy, C1-C6alkoxy or C6-C6cycloalkoxy; or
R1 is
(N R3 R4 \rNN
/ N
¨
__c 0
)n .
,
*
D1 D2
R3 is C1-C6alkyl, hydroxy or C1-C6alkoxy-C1-C6alkyl;
R4 is hydrogen or C1-C6alkyl;
n is 1 or 2;
R2 is C1-C3alkyl or C1-C3fluoroalkyl;
their pharmaceutically acceptable salts, and their prodrugs thereof;
for use in a method for the treatment or prevention of photosensitive
epilepsy.
The compound of formula (I) is a competitive AMPA antagonist. It is well
understood that
allosteric (non-competitive) antagonists provide an insurmountable blockade of
AMPA
receptors, potentially preventing any AMPA receptor-mediated neurotransmission
at the
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synapse. In contrast, a high concentration of glutamate at the synapse can
still activate the
post-synaptic membrane in the presence of a competitive AMPA antagonist
(albeit with a
lower efficacy). Competitive AMPA antagonists may therefore exhibit an
improved safety
profile, as they will not fully block neurotransmission, but instead reduce
the exaggerated
glutamate signaling observed in some neurological disease, e.g. epilepsy.
Compounds of the formula (I) not only block AMPA-induced glutamate release
from activated
astrocytes but after oral dosing also suppress epilepsy seizures in epilepsy
or in Rasmussen
encephalitis.
The compound of the invention of formula (I) in addition to the advantage of
being a
competitive AMPA antagonist receptor inhibitor, presents also the advantage of
being a
selective competitive AMPA antagonist. Furthermore the compound of the
invention of
formula (I) is capable of penetrating the blood brain barrier and may be
formulated in an oral
dosage form.
In the present specification, the following definitions shall apply if no
specific other definition
is given:
Bonds with the asterisk (*) denote point of binding to the rest of the
molecule.
"C1-Cealkyl " represents a straight-chain or branched-chain alkyl group; for
example, methyl,
ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl, with
particular preference
given to methyl, ethyl, n-propyl and iso-propyl.
"C5-C6cycloalkyl" represents cyclopentyl or cyclohexyl; preferably
cyclopentyl.
Each alkyl/cycloalkyl-part of "alkoxy", "cycloalkoxy", "alkoxyalkyl" and
"fluoroalkyl" shall have
the same meaning as described in the above-mentioned definitions of
"alky1"/"cycloalkyl".
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"C1-C3fluoroalkyl" preferably represents trifluoromethyl, difluoromethyl or
fluoromethyl.
It will be understood that any discussion of methods or references to the
active ingredients
includes said active ingredient in free form and in form of a pharmaceutically
acceptable salt.
If the active ingredients have, for example, at least one acidic center (for
example COOH)
they can form salts with bases. The active ingredient or a pharmaceutically
acceptable salt
thereof may also be used in the form of a hydrate or may include other
solvents used for
crystallization.
A "pharmaceutically acceptable salt" is intended to mean a salt of a free
base/free acid of a
compound represented by formula (I) that is not toxic, biologically
intolerable, or otherwise
biologically undesirable. Preferred pharmaceutically acceptable salts are
those that are
pharmacologically effective and suitable for contact with the tissues of
patients without undue
toxicity, irritation, or allergic response. Such salts are known in the field
(e.g. S.M. Berge, et
al, "Pharmaceutical Salts", J. Pharm. Sd., 1977, 66:1-19; and "Handbook of
Pharmaceutical
Salts, Properties, Selection, and Use", Stahl, RH., Wermuth, C.G., Eds.; Wiley-
VCH and
VHCA: Zurich, 2002).
In one embodiment of the invention, the 1H-quinazoline-2,4-diones of formula
(I) is used in
free form.
The 1H-quinazoline-2,4-diones of formula (I), their manufacture and their use
as competitive
AMPA receptor antagonists are known from WO 2006/108591 or can be prepared
analogously to said reference. WO 2006/108591 is incorporated herein by
reference.
On account of asymmetrical carbon atom(s) that may be present in the 1H-
quinazoline-2,4-
diones of formula (I) and their pharmaceutically acceptable salts, the
compounds may exist
in optically active form or in form of mixtures of optical isomers, e.g. in
form of racemic
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mixtures or diastereomeric mixtures. All optical isomers and their mixtures,
including racemic
mixtures, are part of the present invention.
In one embodiment of the invention, the 1H-quinazoline-2,4-dione of formula
(I) is a
compound, wherein R1 is C1-C6alkyl substituted by one, two or three
substituents selected
from hydroxy, C1-C6alkoxy or C6-C6cycloalkow and R2 is C1-C3alkyl or C1-
C3fluoroalkyl.
In one embodiment of the invention, the 1H-quinazoline-2,4-dione of formula
(I) is a
compound, wherein Ri is
Cr(iR3
*
DI
R3 is C1-C6alkyl, hydroxy or C1-C6alkoxy-C1-C6alkyl; and R2 is C1-C3alkyl or
C1-C3fluoroalkyl.
In one embodiment of the invention, the 1H-quinazoline-2,4-dione of formula
(I) is a
compound, wherein R1 is
R4
0
D2 =
R4 is hydrogen or C1-C6alkyl; n is 1 or 2; and R2 is C1-C3alkyl or C1-
C3fluoroalkyl.
In one embodiment of the invention, the 1H-quinazoline-2,4-dione of formula
(I) is a
compound selected from the group consisting of
A-1: N46-(1-Hydroxy-ethyl)-2,4-dioxo-7-trifluoromethy1-1 ,4-dihydro-2H-
quinazolin-3-yll-
methanesulfonamide;
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A-2: N-[6-(1-Methoxy-ethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-311]-
methanesulfonamide;
A-3: N-16-(1-Hydroxy-propy1)-2,4-dioxo-7-trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-y11-
methanesulfonamide;
A-4: N-[6-(1-lsopropoxy-ethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-3-ylj-
methanesulfonamide;
A-5: N46-(1-Ethoxy-ethyl)-2,4-dioxo-7-trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-y11-
methanesulfonamide;
A-6: N(2,4-Dioxo-6-(I-propoxy-propy1)-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-3-yly
methanesulfonamide;
A-7: N46-(1-isopropoxy-propy1)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
A-8: N[7-Difluoromethy1-6-(I-ethoxy-ethyl)-2,4-dioxo-1 ,4-dihydro-2H-
quinazolin-311]-
methanesulfonamide;
A-9: N42,4-Dioxo-6-(1-propoxy-ethyl)-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
A-10: N-[6-(1-Butoxy-ethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
A-11: N46-(1-lsobutoxy-ethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-3-ylj-
methanesulfonamide;
A-12: N-[6-(1-methoxy-buty1)-2,4-dioxo-7-trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-y11-
methanesulfonamide;
A-13: N46-(1-Ethoxy-propy1)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
A-14: N-[6-(1-Cyclopentyloxy-ethyl)-2,4-dioxo-7-trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-
y1]-methanesulfonamide;
A-15: N-[6-(1-Hydroxy-buty1)-2,4-dioxo-7-trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
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A-16: N-[6-(1-Methoxy-2-methyl-propy1)-2,4-dioxo-7-trifluoromethy1-1,4-dihydro-
2H-
quinazolin-3-ylj-methanesulfonamide;
A-17: N46-(3-Hydroxy-propy1)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-
quinazo1in-3-y1]-
methanesulfonamide;
A-18: N-[6-(1-Hydroxy-3-methoxy-propy1)-2,4-dioxo-7-trifluoromethy1-1,4-
dihydro-2H-
quinazolin-3-ylj-methanesulfonamide;
A-19: N46-(1-Hydroxy-2-methyl-propy1)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-
2H-
quinazolin-3-y11-methanesulfonamide;
B-1: ,4-dihydro-2H-quinazolin-3-yI]-
B-2: N42,4-Dioxo-6-(tetrahydro-furan-2-y1)-7-trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-yll-
methanesulfonamide;
B-3: N42,4-Dioxo-6-(tetrahydro-furan-3-y1)-7-trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-ylj-
methanesulfonamide;
C-1: N-{7-lsopropy1-642-(2-methoxy-ethyl)-2H-pyrazol-3-y11-2,4-dioxo-1,4-
dihydro-2H-
quinazolin-3-y1}-methanesulfonamide,
C-2: N-(6-(2-Isopropyl-2H-pyrazol-3-y1)-2,4-dioxo-7-trif1uoromethyl-1,4-
dihydro-2H-quinazolin-
3-y1Fmethanesulfonamide;
C-3: N47-Fluoromethy1-6-(2-isopropyl-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-
3-y1Fmethanesulfonamide;
C-4: N-(642-(2-Methoxy-ethyl)-2H-pyrazol-3-y1]-2,4-dioxo-7-trifluoromethy1-1,4-
dihydro-2H-
quinazolin-3-y1}-methanesulfonamide;
C-5: N46-(2-Hydroxy-2H-pyrazol-3-y1)-2,4-dioxo-7-trifluoromethy1-1,4-dihydro-
2H-quinazolin-
3-y1Fmethanesuffonamide;
C-6: N-[7-Ethy1-6-(2-isopropyl-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
C-7: N47-1sopropyl-6-(2-methyl-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-y11-
methanesulfonamide;
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C-8: N47-Isopropyl-6-(2-isopropyl-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
C-9: N-17-Difluoromethy1-6-(2-methy1-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-
yli-methanesulfonamide;
C-10: N47-Difluoromethy1-6-(2-isopropy1-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-
2H-
quinazolin-3-y1J-methanesulfonamide;
C-11: N47-Ethy1-6-(2-methyl-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide;
C-12: ,4-dihydro-2H-quinazolin-3-ylJ-
C-13: N-[7-Fluoromethy1-6-(2-methy1-2H-pyrazol-3-y1)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-
y1]-methanesulfonamide;
C-14: N-[7-(1-fluoro-ethyl)-6-(2-methyl-2H-pyrazol-3-y1)-2,4-dioxo-1 ,4-
dihydro-2H-quinazolin-
3-M-methanesulfonamide;
C-15: N-[7-(1, 1-difluoro-ethyl)-6-(2-methy1-2H-pyrazol-3-y1)-2,4-dioxo-1,4-
dihydro-2H-
quinazolin-3-A-methanesulfonamide;
C-16: N47-(1,1-difluoro-ethyl)-6-(2-isopropy1-2H-pyrazol-3-y1)-2,4-dioxo-
1,4-dihydro-2H-
quinazolin-3-y11-methanesulfonamide;
C-17: N47-(1-fluoro-ethyl)-6-(2-isopropyl-2H-pyrazol-3-y1)-2,4-dioxo-1,4-
dihydro-2H-
quinazolin-3-y1Fmethanesulfonamide; and
C-18: N46-(2-Methy1-2H-pyrazol-3-y1)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-
2H-quinazolin-
3-ylj-methanesulfonamide.
The compounds of the invention, including the specific exemplified compounds,
may be
prepared by any suitable method, e.g. as described in WO 2006/108591.
In one embodiment of the invention, the 1H-quinazoline-2,4-dione of formula
(I) is a
compound selected from the group consisting of compound A-1, A-2, A-3, A-4, A-
5, A-6, A-7,
A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18 and A-19.
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In one embodiment of the invention, the 1H-quinazoline-2,4-dione of formula
(I) is a
compound selected from the group consisting of compound B-1, B-2 and B-3.
In one embodiment of the invention, the 1H-quinazoline-2,4-dione of formula
(I) is a
compound selected from the group consisting of compound C-1, C-2, C-3, C-4, C-
5, C-6, C-
7, C-8, C-9, C-10, C-11, C-12, C-13, C-14, C-15, C-16, C-17 and C-18.
Advantageous compounds of the invention, i.e., the 1H-quinazoline-2,4-diones
of formula (I),
should be well absorbed from the gastrointestinal tract, penetrate the blood
brain barrier, be
sufficiently metabolically stable and possess favorable pharmacokinetic
properties.
Preferred compounds, having superior bioavailibility are 1H-quinazoline-2,4-
dione of formula
(I) selected from the group consisting of compounds: A-1, A-2, A-3, A-4, A-5,
A-6, A-7, A-13,
A-14, A-15, A-18, B-2, B-3, C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8, C-9, C-10,
C-11, C-12, C-
15, C-16, C-17 and C-18.
More preferred compounds, having superior bioavailibility are 1H-quinazoline-
2,4-dione of
formula (I) selected from the group consisting of compounds: A-1, A-2, A-3, A-
4, A-5, A-7, A-
15, B-2, B-3, C-1, C-2, C-3, C-6, C-7, C-8, C-9, C-10, C-11, C-12, C-15, C-17
and C-18.
Further more preferred compounds, having superior bioavailibility are 1H-
quinazoline-2,4-
dione of formula (I) selected from the group consisting of compounds: A-2, A-
3, A-4, A-5 B-2,
C-2, C-3,C-7, C-9, C-10, C-11, C-15 and C-18.
Most preferred compounds, having superior bioavailibility are 1H-quinazoline-
2,4-dione of
formula (I) selected from the group consisting of compounds: A-2, A-5, B-2, C-
7, C-9 and C-
11, such as compound C-7.
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Compounds for use in the present invention are either obtained in the free
form, as a salt
thereof, or as prodrug derivatives thereof.
The term "prodrug" as used herein relates to a compound, which converts in
vivo into a
compound used in the present invention. A pro-drug is an active or inactive
compound that
is modified chemically through in vivo physiological action, such as
hydrolysis, metabolism
and the like, into a compound of this invention following administration of
the prodrug to a
subject. The suitability and techniques involved in making and using pro-drugs
are well
known by those skilled in the art. The term "prodrug," as used herein,
represents in
particular compounds which are transformed in vivo to the parent compound, for
example, by
hydrolysis in blood, for example as described in T. Higuchi and V. Stella, Pro-
drugs as Novel
Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche,
ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical Association and
Pergamon
Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier, 1985; and Judkins,
et al.
Synthetic Communications, 26(23), 4351-4367 (1996), and "The Organic Chemistry
of Drug
Design and Drug Action", 2nd Edition, R B Silverman (particularly Chapter 8,
pages 497 to
557), Elsevier Academic Press, 2004.
Prodrugs therefore include drugs having a functional group which has been
transformed into
a reversible derivative thereof. Typically, such prodrugs are transformed to
the active drug by
hydrolysis. As examples may be mentioned the following:
Functional Group Reversible derivative
Carboxylic acid Esters, including e.g. alkyl esters
Alcohol Esters, including e.g. sulfates and phosphates as
well
as carboxylic acid esters
Amine Amides, carbamates, imines, enamines,
Carbonyl (aldehyde, 'mines, oximes, acetals/ketals, enol esters,
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ketone) oxazolidines and thiazoxolidines
Prodrugs also include compounds convertible to the active drug by an oxidative
or reductive
reaction. As examples may be mentioned
Oxidative activation
N- and 0- dealkylation
Oxidative deamination
N-oxidation
Epoxidation
Reductive activation
Azo reduction
Sulfoxide reduction
Disulfide reduction
Bioreductive alkylation
Nitro reduction.
Each of the above described reactions and/or reaction steps can be used
individually or in
combination in a method to prepare a AMPA-inhibitor or a prodrug thereof.
Furthermore, the compounds of the present invention, including their salts,
can also be
obtained in the form of their hydrates, or include other solvents used for
their crystallization.
The compounds of the present invention may inherently or by design form
solvates with
pharmaceutically acceptable solvents (including water); therefore, it is
intended that the
invention embrace both solvated and unsolvated forms. The term "solvate"
refers to a
molecular complex of a compound of the present invention (including
pharmaceutically
acceptable salts thereof) with one or more solvent molecules. Such solvent
molecules are
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those commonly used in the pharmaceutical art, which are known to be innocuous
to the
recipient, e.g., water, ethanol, and the like.
The term "hydrate" refers to the complex where the solvent molecule is water.
The
compounds of the present invention, including salts, hydrates and solvates
thereof, may
inherently or by design form polymorphs.
Preferred prodrugs of the invention should be well absorbed from the
gastrointestinal tract,
be transformed into the parent compound (or active principle, being the
compound that in-
vivo acts as AMPA receptor antagonist), the parent compound should be
sufficiently
metabolically stable and possess favorable pharmacokinetic properties.
Further preferred prodrugs of the invention lead to an oral bioavailability of
the parent
compound which is comparable to the bioavailability when administered as a
drug.
Further preferred prodrugs of the invention exhibit increased oral
bioavailability compared to
the parent compound when administered as a drug. Oral bioavailability may
manifest itself in
different ways: (i) a biological effect may be achieved after oral
administration when the
parent compound is less effective upon oral administration, (ii) an earlier
onset of action upon
oral administration, (iii) a lower dose needed to achieve the same effect,
(iv) a higher effect
achieved by the same dose or (v) a prolonged action at the same dose.
Further preferred prodrugs of the invention are transformed into parent
compounds which in-
vivo bind potently to AMPA receptors whilst showing little affinity for other
receptors.
Some prodrugs of the invention are transformed into parent compounds which
also show
antagonistic activity at kainate receptors. Besides such dual activity,
showing little affinity for
other receptors is a preferred feature.
Further prodrugs of the invention - when the active principle is targeted
against receptors in
the central nervous system - are transformed into parent compounds that cross
the blood
brain barrier freely.
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Further prodrugs of the invention - when the active principle is targeted
selectively against
receptors in the peripheral nervous system - are transformed into parent
compounds that do
not cross the blood brain barrier.
Prodrugs, parent compounds and released pro-moieties should be non-toxic and
demonstrate few side-effects.
Furthermore, the ideal prodrug of the invention will be able to exist in a
physical form that is
stable, non-hygroscopic and easily formulated.
The higher oral bioavailability of the compounds for use in the invention may
give rise to the
following beneficial effects relating to less bioavailable compounds: (i) an
enhanced
biological effect may be achieved after oral administration; (ii) an earlier
onset of action may
be observed following oral administration; (iii) a lower dose may be needed to
achieve the
same effect; (iv) a higher effect may be achieved by the same dose or (v) a
prolonged action
may be observed at the same dose.
Preferably the compound for use in the invention when tested in-vivo potently
binds to AMPA
receptors whilst showing little affinity for other receptors.
The term "subject" as used herein typically refers to a mammal, e.g. a human,
especially to a
human patient diagnosed with photosensitive epilepsy (PSE).
The term "treatment" as used herein refers to any type of treatment that
imparts a benefit to a
subject affected with photosensitive epilepsy, e.g. a human patient diagnosed
with PSE,
including prevention or reduction in number and severity of seizures.
The term "therapeutically effective amount" as used herein typically refers to
a drug amount
which, when administered to a subject, is sufficient to provide a therapeutic
benefit, e.g. is
sufficient for treating or preventing the photosensitive epileptic seizure
(e.g. the amount
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provides an amelioration of symptoms, e.g. it leads to a reduction in number
and severity of
seizures).
For the above-mentioned indications (the conditions and disorders) the
appropriate dosage
will vary depending upon, for example, the compound employed, the host, the
mode of
administration and the nature and severity of the condition being treated.
However, in
general, satisfactory results in animals are indicated to be obtained at a
daily dosage of from
about 0.01 to about 100 mg/kg body weight, preferably from about 1 to about 30
mg/kg body
weight, e.g. 10 mg/kg. In larger mammals, for example humans, an indicated
daily dosage is
in the range from about 0.1 to about 1000 mg, preferably from about 1 to about
400 mg, most
preferably from about 10 to about 100 mg of a 1H-quinazoline-2,4-dione of
formula (I)
conveniently administered, for example, in divided doses up to four times a
day. In one
embodiment, about 100mg of a 1H-quinazoline-2,4-dione of formula (I) is
administered daily.
In a further embodiment, about 200mg of a 1H-quinazoline-2,4-dione of formula
(1) is
administered daily.
For use according to the invention, the 1H-quinazoline-2,4-diones of formula
(I) may be
administered as single active agent or in combination with one or more other
active agents,
in any usual manner, e.g. orally, for example in the form of tablets, capsules
or drinking
solutions; rectally, for example in the form of suppositories; intravenously,
for example in the
form of injection solutions or suspensions; or transdermally, for example in
the form of a
patch.
In one embodiment, the manner of administration is oral administration, for
example in the
form of a tablet, capsule or drinking solution. In one embodiment, the manner
of
administration is rectal administration, for example in the form of a
suppository. In one
embodiment, the manner of administration is transdermal administration, for
example in the
form of a patch. In one preferred embodiment, the manner of administration is
oral
administration.
Preferred pharmaceutical compositions comprise a 1H-quinazoline-2,4-dione of
formula (I) in
association with at least one pharmaceutical carrier or diluent. Such
compositions may be
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manufactured in conventional manner. Unit dosage forms may contain the
compound of
formula (I) e.g. compound C7 in an amount greater than or equal to 2.5mg, for
example
greater than or equal to 5mg, such as for example greater than or equal to
10mg or for
example greater than or equal to 15mg. Unit dosage forms may also contain the
compound
of formula (I) e.g. compound C7 in an amount of greater than or equal to 40mg,
50mg, 75mg
or 100mg or greater than or equal to 150mg or 200mg.
Unit dosage forms may contain the compound of formula (I) e.g. compound C7 in
an amount
less than or equal to 300mg, for example less than or equal to 200mg, such as
for example
less than or equal to 150 mg or for example less than or equal to 100mg.
Unit dosage forms may also contain the compound of formula (I) e.g. compound
C7 in an
amount in the range from 5-200mg, e.g. 10-150mg or 15-100mg such as 50-100mg.
The pharmaceutical compositions according to the invention are compositions
for enteral
administration, such as oral or rectal administration; or parenteral
administration, such as
intramuscular, intravenous, and nasal or transdermal administration, to warm-
blooded
animals (human beings and animals) that comprise an effective dose of the
pharmacological
active ingredient alone or together with a significant amount of a
pharmaceutically acceptable
carrier. The dose of the active ingredient depends on the species of warm-
blooded animal,
body weight, age and individual condition, individual pharmacokinetic data,
the disease to be
treated and the mode of administration.
The pharmaceutical compositions comprise from approximately 1% to
approximately 95%,
preferably from approximately 20% to approximately 90%, active ingredient.
Pharmaceutical
compositions according to the invention may be, for example, in unit dose
form, such as in
the form of ampoules, vials, suppositories, dragees, tablets or capsules.
The pharmaceutical compositions of the present invention may be prepared in a
manner
known per se, for example by means of conventional dissolving, lyophilizing,
mixing,
granulating or confectioning processes. Such processes are exemplified in WO
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2005/079802, WO 2003/047581, WO 2004/000316, WO 2005/044265, WO 2005/044266,
WO 2005/044267, WO 2006/114262 and WO 2007/071358.
The compound of formula (I) e.g. C7, which is comprised in the composition,
may give an
AUC24h or C. such that the PPR is suppressed and/or the SPR is reduced, e.g.
by at least 3
steps.
The compound of formula (I) e.g. C7, which is comprised in the composition,
may give an
AUC24h greater than or equal to 5000 hr*ng/mL, for example greater than or
equal to 8000
hr*ng/mL, such as greater than or equal to 10000 hr*ng/mL or greater than or
equal to 12000
hr*ng/mL or 15000 hr*ng/mL. The compound of formula (I) e.g. C7, which is
comprised in the
composition, may also give an AUC24h less than or equal to 25000 hr*ng/mL, for
example
less than or equal to 22000 hr*ng/mL, such as less than or equal to 20000
hr*ng/mL.
Alternatively or in addition, the compound of formula (I) e.g. compound C7
which is
comprised in the composition may give a Cmax of greater than or equal to
300ng/mL, such as
greater than or equal to 400ng/mL or greater than or equal to 50Ong/mL e.g
greater than or
equal to 750ng/mL, greater than or equal to 1000ng/mL, greater than or equal
to 1400ng/mL,
greater than or equal to 1800ng/mL or greater than or equal to 2400ng/mL such
as greater
than or equal to 2800ng/mL. The compound of formula (I) e.g. compound C7 which
is
comprised in the composition may also give a Cmax of less than or equal to
4000ng/mL, such
as less than or equal to 3500ng/mL or less than or equal to 3000ng/mL.
It will be understood that, for a given formulation, some variation in AUC24h
or Cmõ may be
observed from patient to patient. The skilled person would understand that in
this situation
AUC24h or C. is an aggregate value obtainable using a meaningful patient
sample size e.g.
as defined in EU or US clinical guidelines as in force at the filing date.
Compositions for transdermal administration are described in Remington's
Pharmaceutical
Sciences 16th Edition Mack; Sucker, Fuchs and Spieser, Pharmazeutische
Technologie, 1st
Edition, Springer.
1. Diagnosis of Photosensitive Epilepsy
Epilepsy is usually diagnosed by observing seizures occurring spontaneously. A
seizure is a
burst of abnormal electrical activity in the brain. Seizures can originate in
a single location
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and involve a relatively small area (partial seizures), or they may involve
the entire brain
(generalized seizures). Certain epilepsy syndromes require particular
precipitants or triggers
for seizures to occur. Such syndromes are termed reflex epilepsy. Diagnosis of
Photosensitive Epilepsy may be made by noting a correlation between the
exposure to
specific visual stimuli and seizure activity. This may be straightforward in
situations where the
seizures may impair the PSE subject's everyday life, e.g. by limiting his
ability to drive a car.
In other cases, patients suffering from PSE often are not recognized as
affected by PSE as it
is not always easy to identify that they are undergoing photosensitive
epileptic episodes.
Some seizures are so subtle that they can easily go unnoticed by the person
experiencing
them or by others. While the seizures themselves may not be noticed, the after-
effects may
include disabilities that linger for days: difficulties with mood, focus,
memory, learning, sleep,
sensory perception, and other functions.
Clinical methods for diagnosing photosensitive epilepsy are known.
Photosensitive epilepsy
is a reflex form of epilepsy, in which epileptiform electroencephalogram (EEG)
discharges
may be evoked at any time by intermittent photic stimulation (IPS). This EEG
response is
also called photoparoxysmal response (PPR).
Each patient displays a different photosensitivity range, which is the
difference between the
lower and upper sensitivity limit to the visual stimulation. This range is
related to liability of
seizures in daily life. The sensitivity range is specific for each patient and
can be modified or
abolished by using antiepileptic medicaments.
In patients with photosensitive epilepsy, a standardized photoparoxysmal
response range
(SPR) may be determined by performing the IPS with a standardized series of
flash
frequencies, for instance 14 frequencies from a range of 2 to 60 Hz. SPR is a
dimensionless
parameter and is defined as the number of frequencies (steps) between the
lowest and
highest frequencies, e.g. between 2 and 60 Hz, that consistently elicit a PPR.
If 14
frequencies are tested, the minimum and maximum possible SPR values are 0 and
14. Zero
means complete abolition of reactivity on any stimulation frequency, i.e.
complete
abolishment of the PPR. SPR is relatively stable for each patient and reflects
the liability for
seizures in daily life. The potential efficacy of an AED could be assessed by
measuring
hourly changes in the SPR after a single oral dose given to the PSE patients.
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The efficacy of the compounds of formula (I) in the treatment and prevention
of PSE is
confirmed by the following worked examples.
Examples
The compound C-7 used in the study described hereinafter is an orally active
compound of
general formula (I).
The study used the IPS/PPR paradigm. It was a multicenter, non-randomized,
single blind,
within-subject, placebo-controlled proof of concept study conducted to assess
the effect of
single oral doses of the compounded formula C-7 in suppressing the
photoparoxysmal
response (PPR) or reducing the standardized photoparoxysmal response range
(SPR) in
patients with PSE. Photosensitivity was detected using electroencephalography
(EEG)
measurements of subjects exposed to Intermittent Photic Stimulation (IPS).
This EEG
response was a photoparoxysmal response (PPR). For the purpose of the study,
provocation
of PPRs by IPS, not of seizures, was required. The SPR of each patient was the
number of
standard visual stimulation frequencies (in Hertz) that the patient was
sensitive to, between
the lower and upper thresholds. 14 frequencies were tested (from 2 to 60
Hertz). The time of
onset and the duration of response (PPR suppression or SPR reduction) to the
treatment
with Compound C-7 in patients with PSE and the maximal reduction in SPR in
patients with
PSE were also evaluated.
Moreover in this study the pharmacokinetic profile of Compound C-7 in patients
with PSE
was measured.
Study
1. Demographic and other baseline characteristics
The study included 6 patients in Cohort I, 4 patients in Cohort II and 3
patients in Cohort III.
Of these, 3 patients participated twice i.e. participated in two cohorts after
the 3-month
washout period; and therefore a total of 10 patients participated in the
entire study.
Table 1
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Demographic and Background Characteristics
Cohort I Cohort II Cohort III
C-7 50mg C-7 100mg C-7 15mg Total
1=6 N=4 N=3 N=13
Age (years) Mean (SD) 28.0 (10.94) 24.0 (2.31) 40.7
(21.13) 29.7 (12.96)
Median 23.5 24.0 38.0 25.0
Range (20, 48) (22, 26) (21, 63) (20, 63)
Gender - n Male 1 0 2 3
Female 5 4 1 10
Race - n Caucasian 6 4 3 13
Ethnicity - n Other 6 4 3 13
Weight (kg) Mean (SD) 73.08 (12.607) 73.30 (16.556) 77.07
(10.132) 74.07 (12.441)
Median 72.70 74.55 78.00 77.00
Range (57.0, 92.6) (52.0, 92.1) (66.5, 86.7)
(52.0, 92.6)
Height (cm) Mean (SD) 171.3 (7.06) 168.3 (7.89) 178.0
(16.52) 171.9 (9.78)
Median 172.5 165.0 177.0 172.0
Range (163, 180) (163, 180) (162, 195) (162, 195)
BMI (kg/m2) Mean (SD) 24.856 (3.7356) 25.748 (4.5592) 24.583
(4.5190) 25.067 (3.8275)
Median 23.848 27.454 22.801 25.895
Range (21.45, 29.73) (19.10, 28.98) (21.23,
29.72) (19.10, 29.73)
BMI = body mass index; SD = standard deviation; n = patients with non-missing
data points; and N = analysis set
total.
The selected patients had a documented diagnosis of epilepsy for at least 6
months prior to
initial dosing of compound C-7. The selected patients showed a consistent PPR
during EEG
evaluations prior to the first dosing indicating a diagnosis of photosensitive
epilepsy. Women
of child-bearing potential (VVOCBP) were asked to use acceptable methods of
contraception.
Patients with an SPR value of 3 or less at the screening and patients with no
consistent PPR
(less than 3 SPR steps difference between the two evaluations required) when
stimulated by
intermittent photic stimulation (IPS), as determined by comparison between
screening and
pre-dose Day 1, were excluded from the study. Furthermore subjects with
history of status
epilepticus and/or regular use of benzodiazepines as rescue medication,
subjects with
evidence or history of any medically significant cardiac, respiratory,
hepatic, gastrointestinal,
renal, hematologic, oncologic or progressive neurological disorder, requiring
current medical
intervention/therapy likely to have a significant impact on the outcome of
this study, were
also excluded.
There were three periods: a screening period for the assessment of patient's
eligibility for
participation in the study; a 3-day in hospital treatment period with single-
blind dosing with
placebo on days 1 and 3, and the compound of formula C-7 on day 2; and a study
completion period consisting of a follow-up call by the medical investigator
to the patient
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between day 10 and day 14 inclusive and a full study completion visit between
day 29 and
day 33 inclusive.
The dose of the compound of formula C-7 in Cohort studies I, 11 and III was
50, 100 and 15
mg respectively.
Some patients in Cohort I were treated with one concomitant AED from a pre-
selected list of
AEDs (valproate, lamotrigine, levetiracetam, clobazam, topiramate, pregabalin,
gabapentin,
zonisamide). Some patients in Cohort II and III were treated with a
combination of two
concomitant AEDs from a preselected list of AEDs devoid of interaction
potential with the
compound of formula C-7 (valproate, lamotrigine, levetiracetam, clobazam,
topiramate,
zonisamide). A stable dosing regimen was required for at least 4 weeks prior
to initial dosing,
and throughout the entire study.
With the exception of the study drug, only medication required to treat AEs
was permitted
from the start of screening until the end of all evaluations.
2. Antiepileptic Drugs (AEDs)
Some patients were treated with one or a combination of maximum two
concomitant AEDs
(cohorts 11 and III only), but had to be on stable dosing regimen for at least
4 weeks prior to
initial dosing, and throughout the entire study.
The allowed AEDs were: valproate, lamotrigine, levetiracetam, clobazam,
topiramate and
zonisamide
With the exception of two patients in Cohort I and one patient in Cohort III,
who did not take
AEDs, patients had pre-existing treatment with 1 AED (lamotrigine, valproate
or zonisamide)
or 2 AEDs (levetiracetam and topiramate for one patient in Cohort III). It was
noted that one
of the patients of Cohort 1 also participated in Cohort III, and therefore in
total only 2 patients
did not have prior concomitant AEDs in the study. Similar AEDs concentration-
time profiles
were observed on Days 1, 2 and 3 for each patient. Two of the patients in
Cohort I were also
enrolled in Cohort II. Their lamotrigine PK profiles were similar in the 2
treatment periods.
These observations confirm stable pre-existing treatment for all the patients.
The co-
administration of C-7 on Day 2 did not seem to affect the AED PK, since no
difference in the
PK profiles could be observed between Day 1 and Days 2 and 3.
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A list of patients with concomitant AEDs and their PD effect is presented in
Table2. Of the 9
patients who showed suppression of PPR, 5 patients received lamotrigine (3 in
C-7 50 mg
group, 2 in C-7 100 mg group), 2 patients did not receive any AED (1 each in C-
7 50 mg and
15 mg groups), and 1 patient each received valproate (C-7 100 mg group) and a
combination
of levetiracetam and topiramate (C-7 15 mg group). Moreover, all 13 patients,
either
receiving a concomitant AED or not, showed reduction of SPR (.3) in at least
one eye
condition after administration of C-7. Overall, it was noted that concomitant
treatment with
selected AEDs did not impact the PD effect of C-7.
Table 2 - List of patients with AEDs and their PD effect of Compound C7
Center/ Patient # Concomitant AEDs PD effect of C7d
Cohort I, C-7 50 mg
Patient Aa Lamotrigine 100 mg bid Suppression of PPR
Patient B Valproate 500 mg bid Reduction of SPR
(.3)
Patient C None Reduction of SPR
(.3)
Patient D Lamotrigine 400 mg Suppression of PPR
Patient Eb Lamotrigine 175; 150 mg Suppression of PPR
Patient Fc None Suppression of PPRe
Cohort II, C-7 100 mg
Patient Ga Lamotrigine 100 mg bid Suppression of PPR
Patient Hb Lamotrigine 175; 150 mg Suppression of PPR
Patient I Zonisamide 100 mg bid Reduction of SPR
(.3)
Patient L Valproate 300 mg bid Suppression of PPR
Cohort III, C-7 15 mg
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Patient M Levetiracetam 1000;1500 mg Suppression of PPRe
Topiramate 100 mg
Patient N Valproate 600 mg bid Reduction of SPR
(?..3)
Patient Cf None Suppression of PPR
a' c Patients enrolled in two cohorts.
d All patients showed the PD effect of reduction of SPR (3) in at least one
eye condition
after administration of C-7.
e Suppression of PPR was noted already at "0" hours of dosing on Day 2.
3. Pharmacokinetic and Pharmacodvnamic (PK/PD) measurements
Data sets for analysis were grouped by cohorts. All 13 patients enrolled in
the study were
included in PK, PD, and safety analysis sets
3.1 Pharmacokinetics (PK)
The C-7 PK parameters were determined in plasma using non-compartmental
methods using
WinNonlin Pro (Version 5.2), as detailed in Table 3.
Table 3¨ Compound C-7 PK parameters determined
AUCiaat The area under the concentration-time curve from time zero to
the last
measurable concentration sampling time [ng/mL.h]
AUCo.t The area under the plasma concentration-time curve from time
zero to
concentration sampling time (t) [ng/mL.h]
AUCinf The AUC from time zero to infinity [mass x time x volume-1]
Cmax The maximum (peak) observed drug concentration over a dosing
interval at
steady-state [ng/mL]
Tmax The time to reach maximum (peak) plasma drug concentration [h]
Tiag Lag-time [h]
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AUCIast The area under the concentration-time curve from time zero to
the last
measurable concentration sampling time [ng/mL.h]
AUC04 The area under the plasma concentration-time curve from time
zero to
concentration sampling time (t) [ng/mL.h]
AUCinf The AUC from time zero to infinity [mass x time x volume-1]
Tv2 The elimination half-life associated with the terminal slope
(Xz) of a semi
logarithmic concentration-time curve [time]. Use qualifier for other half-
lives
Biofluid concentrations were expressed in mass per volume units (ng/mL). All C-
7 and AEDs
concentrations below LLOQ were reported as zero in the concentration data
listings.
Concentrations below LLOQ were treated as zero in summary statistics of
concentration data
as well as for calculation of C-7 PK parameters. A geometric mean was not
reported
whenever at least one concentration was below the LLOQ (i.e. zero). Missing
data were
labeled as such and no imputation methods were used.
Terminal elimination rate constant (lambda_z) was calculated as the slope of
the linear
regression of the terminal phase of the logarithmic concentration-time profile
for each
individual dataset available. A minimum of three time points was used for
determining
lambda_z. Regression was performed without weighting, and a minimum value of
0.75 for
Rsq_adjusted was necessary for acceptance.
The different areas under the concentration-time curve were calculated using
the linear
trapezoidal summation (both ascending and descending phase).
Descriptive statistics of pharmacokinetic parameters included mean, SD, and
CV, minimum
and maximum. The geometric mean was identified when presented. A range of
values were
presented for selected variables. Since T. is generally evaluated by a
nonparametric
method, median values and ranges were provided.
AED concentrations were listed and summarized; analysis of level of exposure
of AED(s)
taken by the patient was performed on an ad-hoc basis as it depended on
specifics of the
AED.
3.2 Representation of PK/PD in relation to SPR
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The existence of an exposure-response relationship was investigated
graphically. A scatter
plot of the area under the effect curve (AUECt, SPR change from baseline)
versus area
under the C-7 plasma concentrations curve (AUCt) was produced. A similar plot
was
produced for AUECt versus Cmax.
3.3 Suppression of PPR or reduction of SPR
The SPR results for all eye conditions (i.e., eyes open, eyes closed or eyes
closure) in
Cohort I of the study are shown in Figure 1. Interim analysis results of the C-
7 50 mg dose
group (Cohort I) showed that treatment with C-7 resulted in complete
suppression of PPR in
3 of 6 patients and all 6 patients showed reductions of the SPR range by at
least 3 steps in at
least one eye condition on Day 2. In subsequent Cohorts, complete suppression
of PPR was
noted in 3 out of 4 patients in C-7 100 mg dose group (Cohort 11) and 1 out of
3 patients in C-
7 15mg dose group (Cohort III); and all 7 patients (of Cohorts II and III)
showed reductions of
the SPR range by at least 3 steps in at least one eye condition on Day 2. The
magnitude of
the post-treatment effect differed between doses. Magnitude of effect was
found dose
dependent. Compound C-7 15 mg dose group showed a numerically markedly lower
PD
effect when compared to Compound C-7 50 and 100 mg dose groups.
Compound C-7 15 mg dose group showed a numerically lower but still measurable
PD effect
compared to 50 and 100 mg dose groups.
3.4 Time of onset and duration of effect
The majority of patients had response onset within 1 to 2 hours of dosing.
Time to maximum
reduction of SPR was shorter in C-7 100 mg dose group compared to the other 2
dose
groups.
The duration of response was similar in C-7 50 and 100 mg dose groups, ranging
from 23 to
34 hours inclusive. Two patients in C-7 50 mg group and 1 patient in C-7 100
mg group
maintained SPR response (i.e., stayed in responding status at all time points
between first
and last response), i.e. 33 hours in both patients. In the C-7 15 mg dose
group, the response
was noted to be intermittent in all eye conditions and none of the patients
maintained the
SPR response.
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Suppression was observed in 7 of the 13 patients, with the onset ranging from
1 to 4 hours
after dosing and the duration ranging from 2 to 32 hours. Of these 7 patients,
4 patients
maintained suppression (i.e., stayed in suppression status at all time points
between first and
last suppression) that included 2 patients each in C-7 50 mg group and C-7 100
mg group,
i.e. 2 hours, 7 hours, 4 hours and 3 hours respectively. One patient in the C-
7 15 mg group
showed onset of suppression at 2 hours post dosing, however the effect was not
maintained
and was noted only in one eye condition (eye open).
Overall, in the C-7 15 mg group, neither the SPR response nor PPR suppression
was
maintained.
The proportion of subjects with suppression of PPR was numerically lower in C-
7 15 mg
dose group (33%) compared to the C-7 50 mg (50%) and 100 mg (75%) dose groups.
3.5 Maximal reduction in SPR
A summary of maximum reduction of SPR by eye condition and treatment is shown
in Table
4. The maximum reduction of SPR by eye condition and treatment was observed on
active
treatment Day 2 in patients who received the highest dose (Cohort II, C-7 100
mg), and it
was noted for eye closure condition.
Table 4¨ Summary of maximum standardized photoparoxysmal response range (SPR)
by eye and treatment conditions.
Treatment Eye condition
Overall reduction Reduction from predose Day 2
C-7 50mg Eyes open n 6 6
Mean (SD) 6.8 (2.99) 4.8 (3.43)
Median 7.5 6.5
Eye closed n 6 6
Mean (SD) 6.0 (2.37) 5.0 (2.00)
Median 6.0 5.0
Eye closure n 6 6
Mean (SD) 7.7 (3.01) 6.5 (2.95)
Median 8.5 7.5
C-7 100mg Eyes open n 4 4
Mean (SD) 8.8 (2.50) 7.0 (1.41)
Median 8.5 6.5
Eye closed n 4 4
Mean (SD) 7.5 (2.38) 6.5 (2.38)
Median 8.5 6.5
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Eye closure n 4 4
Mean (SD) 9.3 (2.22) 8.3 (1.50)
Median 10.0 9.0
C-7 15mg Eyes open n 3 3
Mean (SD) 4.0 (3.46) 3.0 (4.36)
Median 2.0 1.0
Eye closed n 3 3
Mean (SD) 6.7 (1.15) 5.0 (3.61)
Median 6.0 6.0
Eye closure n 3 3
Mean (SD) 8.0 (1.73) 7.3 (2.89)
Median 9.0 9.0
Note: Maximum reductions for each subject over all timepoints
3.6 Area under SPR curve
The summary of AUECt by eye condition, treatment and visit in the primary PD
analysis set
was measured. Statistical analysis of change from Day 1 in AUECt by eye
condition in the
primary PD analysis set was measured.
3.7 Pharmacokinetics results (PK results)
The arithmetic mean plasma concentration time profile of C-7 following a
single oral
administration of 15 (Cohort III), 50 (Cohort I) and 100 (Cohort II) mg to
male and female
patients with PSE is presented in Figure 2.
Table 5 summarizes the C-7 PK parameters after a single dose administration of
15, 50 and
100 mg to male and female patients with PSE.
The patients received the study medication in the morning between 8:00h and
9:00h, at least
30 minutes after a light breakfast had been completed.
In the single dose healthy volunteer study at same or similar dose levels of C-
7, C-7 was
measurable in the plasma as early as 0.25 h post-dose following single
administration of a
15, 50 or 100 mg dose to patients with PSE. The plasma concentration of C-7
peaked at
around 3 h post-dose (median) with minimum values of approximately 2h and
maximum
values of 4h in individual patients.
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The pharmacokinetic data of C-7 in the patients with PSE in all 3 cohorts
appeared to be
overlapping with those in male healthy subjects observed in healthy volunteer
study,
although mean exposure in patients with PSE tended to be slightly higher. A
comparison of
the means demonstrates that in patients mean Cm ax was about 10-20% and mean
AUCIast
was about 10-40% higher than in healthy male subjects.
The inter-subject variability in Cmax and AUClast was low to moderate with %CV
geometric
mean between 9% and 27% for Cm,, and between 13% and 36% for AUCs, as observed
at
the same or similar dose levels in the healthy volunteer study.
Table 5 - Main Compound C-7 plasma PK parameters following single oral
administration of 15, 50 and 100 mg of Compound C-7
PK parameters Cohortl Cohort II Cohort III
50 mg 100 mg 15 mg
n=6 n=4 n=3
Tiag (hr)1 0.00 (0.00-0.00) 0.00 (0.00-0.00) 0.00
(0.00-0.00)
Tmax (hr)1 2.96 (2.00-3.98) 2.94 (2.00-3.00) 2.98
(1.97-4.00)
Cmax (ng/mL)2 1987 [27] 2976 [26] 637 [9]
AUCiast (hr*ng/mL)2 10701 [25] 17011 [19] 3665 [21]
AUC0-24hr (hr*ng/mL)2 10628 [25] 16883 [19] 3638 [20]
AUC04hr (hr*ng/mL)2 6791 [21] 10186[36] 2130 [13]
'Median (min-max); 2Geometric mean [%CV geo mean]
4. Drug dose, drug concentration and relationships to response
4.1 PK-PD relationship:
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The mean SPR per eye condition and plasma PK concentrations of C-7 50, 100,
and 15 mg
dose groups is shown in Figure 3, Figure 4 and Figure 5, respectively. The SPR
and PK
concentration over time plots show a linear relationship between the SPR T.
and PK Tmax=
A PK-PD model was developed sequentially for the SPR data. Firstly a
pharmacokinetic
model was fitted using nonlinear mixed effects methodology in NONMEM version
VI to
describe the 13 patients with both PK and PD data. A 3 compartment disposition
model with
first order absorption and absorption lag time was selected to describe the
pharmacokinetic
time profile for each patient. The between patient variability was described
by exponential
random effects on each pharmacokinetic parameter, with all parameters assumed
to be
independent between individuals. The residual error model combined the
additive and
proportional error terms. The estimated pharmacokinetic parameters for each
patient were
used to generate each patient's PK profile as an input to the pharmacodynamic
model.
For the Pharmacodynamic response, SPR, an Emax model was fitted on the logit
transformed
scale:
SPR = 14/(1+exp(-{Base-EmaxxC/(EC50+C)}])
where Base is the baseline SPR on the logit scale, Emax is the maximum
reduction in SPR on
the logit scale, EC50 is the concentration at which the 50% of the maximum
reduction is
obtained and C is C-7 concentration. For each patient, the PD parameters for
the three eye
conditions, eyes closure, eyes closed and eyes open, were estimated separately
but with a
common additive residual variance on the logit scale. The PD parameter
estimates were
highly variable across the 13 patients, with the estimation having trouble
identifying E. and
EC50 (see Table 6 below). The mean (SD) EC50 for eyes open, eyes closed and
eyes
closures was 2964 ng/ml (4235 ng/ml), 3746 ng/ml (4475 ng/ml), 2252 ng/ml
(3505 ng/ml)
respectively. This wide variability was the result of either many patients
having either a low
estimated EC50 (5 ng/ml) or high estimated EC50 (9900 ng/ml). The mean (SD)
Emõ on the
logit scale for eyes open, eyes closed and eyes closures was 21.6 (23.5), 16.3
(21.7), 12.9
(19.6) respectively suggesting there was a substantial reduction in SPR in the
3 eye
conditions.
Table 6 - Pharmacodynamic model parameter estimates for each patient
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Eyes open Eyes closed Eyes
closure
Base Emax EC50 Base Emax EC50 Base Emax EC50
Patient A - 1.14 7.67
1410
Patient B -0.072 2.66 9900 0.406 0.487 5 0.425
0.05 5
Patient G 6.47 49.5 1880 6.38 49.5 2080 6.46
49.5 3080
Patient M -3.28 0.05 5 -0.21 49.5 9200 0.321 0.495 83.3
Patient C 0.674 1.14 1470 0.538 0.963 219 1.16
2.38 1690
Patient D -0.144 40.8 9900 -0.802 2.54 5 1.5 41.5
9900
Patient E 0.531 1.03 629 0.303 1.79 1170 0.164 0.571 320
Patient F -6.31 49.5 131 -8.37 2.47 310 7.53
49.5 788
Patient H 0.0576 14.5 9900 1.11 6.99 2040 1.15 3.25
1270
Patient! 0.876 1.29 5 0.494 0.58 229 2.56 2.39 5
Patient N 0.0687 0.05 5 0.0692 0.05 9900
0.487 0.05 9900
Patient 0 4.02 49.5 137 -4.57 30.9 9900 4.69 9.23
10
Patient L 6.16 49.5 1610 -4.23 49.5
9900 -5.45 1.31 814
Onset of PD effect was noted either an hour before or around the same time
when maximum
plasma concentrations were achieved. A list of patients with C-7 AUCo-24h,
Cmax, Tmax and
their PD effect is presented in Table 7. Across the three treatment groups,
the maximum and
minimum AUC0-24h between which suppression of PPR was noted to be maintained
was
21302 hrng/mL (patient H; C-7 100 mg group) and 10056 hrng/mL (patient A; C-7
50 mg
group), respectively. Similarly, the maximum and minimum AUCO-24h between
which
relevant reduction of SPR was noted to be maintained was 15334 hr*ng/rnL
(patient I; C-7
100 mg group) and 11624 hrng/mL (patient D; C-7 50 mg group), respectively
Similarly, across the three treatment groups, the Cmõ between which
suppression of PPR
was noted to be maintained was 3700 ng/mL (patient H, C-7 100 mg group) and
1530 ng/mL
(patient A; C-7 50 mg group), respectively; and the Cmax, between which
relevant reduction of
SPR was noted to be maintained was 2490 ng/mL (patient E, C-7 50 mg group) and
2070
ng/mL (patient 1; C-7 100 mg group), respectively.
Table 7 - List of patients with Compound C-7 Cmax, Tmax and their PD effect
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Center/ AUC 0-24h Cmax T max PD effectd Onset Effect
Patient # Time maintained
(heng/mL) (ng/mL) (hr)
(h)
Cohort I, C-7 50 mg
Patient Aa 10056 1530 3.87 Suppression of PPR 4 Yes
Reduction of SPR (.3) 2 No
Patient B 7043 1410 2.00 Reduction of SPR (3) 1 No
Patient C 9838 1910 3.00 Reduction of SPR (3) 2 No
Patient D 11624 2140 2.00 Suppression of PPR 2 No
Reduction of SPR (?.3) 1 Yes
Patient Eb 12564 2490 2.92 Suppression of PPR 3 Yes
Reduction of SPR (?..3) 1 Yes
Patient Fb 14162 2800 3.98 Suppression of PPR e - No
Reduction of SPR (3) - No
Cohort H, C-7 100 mg
Patient Ga 17924 3470 3.00 Suppression of PPR 2 Yes
Reduction of SPR (?.3) 1 No
Patient Hb 21302 3700 2.88 Suppression of PPR 3 Yes
Reduction of SPR (3) 2 No
Patient I 15334 2070 3.00 Reduction of SPR (3) 1 Yes
Patient L 13877 2950 2.00 Suppression of PPR 2 No
Reduction of SPR (3) 1 No
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Cohort III, C-7 15 mg
Patient M 4274 581 4.00 Suppression of
PPR* No
Reduction of SPR (3) No
Patient N 2906 634 1.97 Reduction of SPR
(3) 1 No
Patient Oc 3878 701 2.98 Suppression of
PPR 2 No
Reduction of SPR (3) 1 No
a' C Same patients enrolled in two cohorts.
d All patients showed the PD effect of reduction of SPR (3) in at least one
eye condition.
e Suppression of PPR was noted already at "0" hours of dosing on Day 2
4.2 Drug-drug and drug-disease interactions
The pharmacokinetic data of C-7 in the patients with photosensitive epilepsy
in all 3 cohorts
appeared to be similar to those in male healthy subjects observed in healthy
volunteer study;
although mean exposure in patients with photosensitive epilepsy tended to be
slightly higher
(patients mean Cmax was about 10-20% and mean AUCtaat about 10-40% higher than
in
healthy male subjects).
Concomitant treatment with AEDs did not appear to be causative for the
slightly higher
exposure since it is a patient without pre-existing AED treatment (patient F)
that showed the
highest exposure in Cohort I.
Since patients received the study medication at least 30 minutes after a light
breakfast had
been completed, versus fasted administration in healthy volunteer study, the
slightly higher
C-7 exposure observed in that study may be due to an increased C-7
bioavailability in the
presence of food.
The co-administration of C-7 on Day 2 did not seem to affect the PK of
selected AEDs
(preexisting treatment), since no difference in the PK profiles could be
observed between
Day land Days 2 and 3.
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Summary of pharmacodynamic and pharmacokinetic results
Pharmacodvnamic results:
= Treatment with compound C-7 resulted in complete suppression of PPR in 7
of 13
patients: 3 of 6 patients in C-7 50 mg group; 3 of 4 patients in compound C-7
100 mg
group; and 1 of 3 patients in compound C-7 15 mg group. All 13 patients showed
reductions of the SPR range by at least 3 steps in at least one eye condition
on Day 2,
i.e. all doses of compound C-7 showed some effect.
= The majority of patients had response onset within 1 to 2 hours of
dosing. Time to
maximum reduction of SPR was shorter in compound C-7 100 mg dose group
compared
to the other 2 dose groups.
= compound C-7 15 mg dose group showed a numerically lower PD effect
compared to
compound C-7 50 and 100 mg dose groups.
= A maximum reduction of mean SPR was noted in the compound C-7 100 mg dose
group,
and at time points 3, 4 and 6 hours post-dose.
= The SPR response and suppression of PPR was maintained in compound C-7 50
and
100 mg dose groups. The maximum duration of maintenance was 33 hours and 7
hours
for SPR response and suppression of PPR, respectively. In the compound C-7 15
mg
group, neither the SPR response nor suppression of PPR was maintained.
= Within the dose groups, magnitude (reduction of SPR vs suppression of
PPR) and
maintenance of PD effect appeared to be greater in patients with numerically
higher C...
= In compound C-7 50 mg and 100 mg dose groups, for all eye conditions,
significantly
lower AUECt was noted on Day 2 compared to Day 1.
= Treatment with selected concomitant AEDs did not appear to relevantly
impact the PD
effect of compound C-7, i.e. there was no sign for a relevant PD interaction
between C-7
and these AEDs.
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Pharmacokinetic results:
= The pharmacokinetic data of compound C-7 in the patients with
photosensitive epilepsy
in all 3 cohorts appeared to be overlapping with those in male healthy
subjects observed
in healthy volunteer study, although mean exposure in patients with
photosensitive
epilepsy tended to be slightly higher (10-20% for Cmax) 10-40% for AUCiast).
= With the exception of two patients in Cohort I (patients C and F) and one
patient in
Cohort III (patient 0), who did not take AEDs, patients had pre-existing
treatment with 1
AED (lamotrigine, valproate or zonisamide) or 2 AEDs (levetiracetam and
topiramate for
patient M in Cohort III). It was noted that patient C of Cohort I also
participated in Cohort
III (patient l), and therefore in total only 2 patients did not have prior
concomitant AEDs in
the study. Similar AEDs concentration-time profiles on Days 1, 2 and 3 for
each patient
confirmed stable pre-existing AED treatment. Co-administration of compound C-7
did not
appear to affect the AED PK.
PK-PD results
= SPR and PK concentration over time plots show a linear relationship between
SPR Tma),
and PK Tmax=
= The maximum and minimum AUCo-24h between which suppression of PPR was
noted to
be maintained was 21302 hr*ng/mL (patient H; C-7 100 mg group) and 10056
hr*ng/mL
(patient A; C-7 50 mg group), respectively. Similarly, the maximum and minimum
AUCO..20 between which relevant reduction of SPR 3 steps)
was noted to be
maintained was 15334 hr*ng/mL (patient I; C-7 100 mg group) and 11624 hr*ng/mL
(patient D; C-7 50 mg group), respectively
= The maximum and minimum Cmax between which suppression of PPR was noted
to be
maintained was 3700 ng/mL (patient H, C-7 100 mg group) and 1530 ng/mL
(patient A;
C-7 50 mg group), respectively. Similarly, the maximum and minimum Cm ax
between
which relevant reduction of SPR was noted to be maintained was 2490 ng/mL
(patient E,
C-7 50 mg group) and 2070 ng/mL (patient I; C-7 100 mg group), respectively.
Oral bioavailabilitv of the compounds of the invention
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Oral bioavailability of the compounds of the invention may be demonstrated
using any
generally known test in which the compound is administered orally and a
biological effect
observed.
Oral bioavailability of the compounds of the invention in the treatment of
photosensitive
epilepsy may be further quantified by the Maximal Electroshock test, which
demonstrates
that the compounds are orally bioavailable, penetrate the blood brain barrier
and bind to the
target receptor.
The oral bioavailability was tested using the audiogenic mouse test
(Audiogenic seizures,
R.L. Collins; Chapter 14, pages: 347-372. In: Experimental Models of Epilepsy;
By: Pupura,
Penry, Tower, Woodbury, Walter, Raven Press, New York, 1972. Standard Book
Number: 0-
911216-26-X) and/or the MES test. Where the MES test was used (as described
below), the
result is given in Table 8.
Table 8: In-vivo activity of parent compounds and prodruqs in the murine
Maximal
Electro Shock Test
Compounds of the invention were tested in OF1 mice using the maximal
electroshock test
(MES Test) described in detail by Schmutz et al., Naunyn-Schmiedeberg's Arch
Pharmacol
1990, 342, 61-66. Briefly, generalized tonic-clonic convulsions of the hind
extremities were
induced by passing electrical current through temporal electrodes (50 Hz, 18
mA, 0.2s). Mice
treated by vehicle showed mean seizure durations of 12-14s. 30 mg/kg
carbamazepine was
used as a positive control; mice were classified as protected by a compound if
the duration of
the seizure lasted only 3 second or less. Five mice were used for each
treatment condition
and the percentage of protected mice was used as readout (i.e. a compound
could give 0%,
20%, 40%, 60%, 80% or 100% protection). Compounds of the invention were given
at a dose
of 50 mg/kg, p.o., 1 hour prior to induction of convulsions (i.e. "pre-
treatment time -1h").
ED50 values (ED: effective dose) were calculated using GraphPad Prism, v4.02.
15 s after shock administration, mouse blood was collected for determination
of compounds'
blood exposure.
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The results are shown below in Table 8.
TABLE 8
MES-Test IUPAC name
In
Compou vivo
Structure (1h, po)
nd orally ED5O[mg/
active kg]
OH0 N-[6-(1-Hydroxy-ethyl)-2,4-dioxo-
0
7-trifluoromethy1-1,4-dihydro-2H-
A-1 ioJo
Yes 64
quinazolin-3-yI]-
F F
methanesulfonamide
0 N-[6-(1-Methoxy-ethyl)-2,4-dioxo-
H 0
e 7-trifluoromethy1-1,4-dihydro-2H-
t:Li oes Yes 6.0
A-2 ,
H0 quinazolin-3-yI]-
F
methanesulfonamide
N-[6-(1-Hydroxy-propyI)-2,4-dioxo-
OH 0
e 7-trifluoromethy1-1,4-dihydro-2H-
A-3 F 1-- Yes 19.6
N 0 quinazolin-3-y11-
methanesulfonamide
N- 6- 1-lso -2,4-
ro ox -ethyl
I P P Y )
o 0 dioxo-7-trifluoromethy1-1,4-
A-4 0 (.7e, Yes 15.6
dihydro-2H-quinazolin-3-yI]-
NO
F F methanesulfonamide
L N46-(I-Ethoxy-ethyl)-2,4-dioxo-7-
0 0
trifluoromethy1-1,4-dihydro-2H-
A-5 iii)1`,$/./:, Yes 8.8
quinazolin-3-y1]-
NO
methanesulfonamide
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- N-[2,4-Dioxo-6-(1-propoxy-
0 0 . propy1)-7-trifluoromethy1-1,4-
A-6 0 ,v0,1 Yes nt1
F dihydro-2H-quinazolin-3-ylj-
F 11
F methanesulfonamide
N-[6-(1-isopropoxy-propy1)-2,4-
-----0 .
dioxo-7-trifluoromethy1-1,4-
A-7 I Yes 24 7
0 ,,,L, /...., .
F dihydro-2H-quinazolin-3-y11-
F11
, methanesulfonamide
N-[7-Difluoromethy1-6-(1-ethoxy-
0 0
ii
ethyl)-2,4-dioxo-1,4-dihydro-2H-
A-8 ,
, 0 ; /õ,,, nt nt
quinazolin-3-y1F
NC.
H
F methanesulfonamide
N-[2,4-Dioxo-6-(1-propoxy-ethy1)-
0 . 7-trifluoromethy1-1,4-dihydro-2H-
A-914 1 nt nt
0 'C :"S' '
F quinazolin-3-y1F
N 0
F F H
methanesulfonamide
N-[6-(1-Butoxy-ethyl)-2,4-dioxo-7-
A-10 , (110 nt
.m. I' trifluoromethy1-1,4-dihydro-2H-
'Ll ot` nt
F H quinazolin-3-y1]-
methanesulfonamide
...,_.....- N-[6-(1-lsobutoxy-ethyl)-2,4-dioxo-
--. .
H 0 7-trifluoromethy1-1,4-dihydro-2H-
A-11 i. N/
nt nt
,quinazolin-3-y1F
4111111frilli N 0
F F H
methanesulfonamide
0 a
. 0 N46-(1-methoxy-buty1)-2,4-dioxo-
A.. I
A-12 10 N I ace-, nt nt
F 7-trifluoromethy1-1,4-dihydro-2H-
F
F
quinazolin-3-y1F
1 The term "nt÷ throughout the table means "not tested"
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methanesulfonamide
L N-[6-(1-Ethoxy-pro pyI)-2,4-d ioxo-
0
H
7-triflu oromethyl-1 ,4-d ihydro-2H-
A-13 e
(Nc-es, Yes nt
quinazolin-3-y1F
NO
F
methanesulfonamide
N-[6-(1-Cyclopentyloxy-eth yI)-2,4-
0 dioxo-7-trifluoromethy1-1 14-
A-14 ,11
F 7 yes nt
dihydro-2H-quinazolin-3-y1]-
methanesulfonamide
N-[6-(1-Hydroxy-buty1)-2,4-dioxo-
OH 0
O 7-trifluoromethy1-1 ,4-dihydro-2H-
A-15 F N,L01 ' Yes 35
quinazolin-3-y1]-
methanesulfonamide
N46-(1-Methoxy-2-methyl-propy1)-
0
H 0 2 ,4-d ioxo-7-trifluoromethy1-1 ,4-
A-16 nf 4, nt nt
No dihydro-2H-quinazolin-3-y1]-
methanesulfonamide
N46-(3-Hydroxy-propy1)-2,4-dioxo-
.
H 0
7-trifluoromethy1-1,4-dihydro-2H-
HO
A-17 :L09 nt nt
H .
quinazolin-3-A-
F
methanesulfonamide
N-[6-(1-Hyd roxy-3-methoxy-
00 0 propyI)-214-dioxo-7-
A-18Yes nt
trifluoromethy1-1,4-dihydro-2H-
quinazolin-3-y1]-
methanesulfonamide
N-[6-(1-Hydroxy-2-methyl-propy1)-
OH 0
H 0
2,4-dioxo-7-trifluoromethy1-114-
A-19 , nt
nt
dihydro-2H-quinazolin-3-yll-
methanesulfonamide
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-
N42,4-Dioxo-6-(tetrahydro-pyran-
)L #0 2-y1)-7-trifluoromethy1-1,4-
dihydro-
B-1 F =nt nt
2H-quinazolin-3-y1]-
F F
rnethanesulfonamide
N-[274-Dioxo-6-(tetrahydro-furan-
o 0
12.8 (R)2 2-y1)-7-trifluoromethy1-1,4-
dihydro-
B-2 _L Yes
F HO 33.2 (S)
2H-quinazolin-311}-
methanesulfonamide
N-[2,4-Dioxo-6-(tetrahydro-furan-
o= 3-y1)-7-trifluoromethy1-1,4-dihydro-
I Nis,
B-3 ro Yes 20%@253 2
N 0
H-quinazolin-3-y1]-
methanesulfonamide
0, N-{7-lsopropy1-6-[2-(2-methoxy-
C-1 yes 40%@25
,N--N 0
ethyl)-2H-pyrazol-3-y11-2,4-dioxo-
I.
1,4-dihydro-2H-quinazolin-3-y1}-
methanesulfonamide
0 N-[6-(2-lsopropyl-2H-pyrazol-3-
y1)-
0
2,4-dioxo-7-trifluoromethy1-1,4-
C-2
to 0 Yes 17.7
dihydro-2H-quinazolin-3-y11-
methanesulfonamide
N-[7-Fluoromethy1-6-(2-isopropyl-
C 3 0 0
2H-pyrazol-3-y1)-2,4-dioxo-1,4-
- NrO Yes 13.5
dihydro-2H-quinazolin-311]-
methanesulfonamide
2 (R) and (S) indicate the two enantiomers.
3 The term "20%@25"means 20% protection at 20 mg/kg.
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\c, N-{642-(2-Methoxy-ethyl)-2 H-
pyrazol-3-y1]-2,4-dioxo-7-
C-4 0 '3% y
Yes nt trifluoromethy1-1,4-dihydro-2H-
rH
methanesulfonamide
OH N4
N- 6-(2-
Hydroxy-2H-pyrazol-3-y1)-
-/ 0
H II
Yes nt
C-5 2,4-dioxo-7-trifluoromethy1-1,4-
LF g
14". dihydro-2H-quinazolin-3-A-
methanesulfonamide
N-[7-Ethyl-6-(2-isopropyl-2H-
O pyrazol-3-y1)-2,4-dioxo-1,4-
C-6 ,
rA\ yes 20%@50
40 ,L dihydro-2H-quinazolin-3-yl]-
N0
methanesulfonamide
/ N47-1sopropyl-6-(2-methy1-2H-
N--N
// pyrazol-3-y1)-2,4-dioxo-1,4-
C-7
R-P NYes 6.9
/ 0
dihydro-2H-quinazolin-3-y1]-
methanesulfonamide
N-[7-Isopropyl-6-(2-isopropyl-2H-
0
C-8 ,o yes 40%@50
pyrazol-3-y1)-2,4-dioxo-1,4-
r
NC) ui
dihydro-2H-quinazolin-3-yll-
methanesulfonamide
N-[7-Difluoromethy1-6-(2-methyl-
0 H
II
C-9 N Yes
2H-pyrazol-3-y1)-2,4-dioxo-1,4-
X 7.5
N 0 dihydro-2H-quinazolin-3-yI]-
methanesulfonamide
N-[7-Difluoromethy1-6-(2-
0
H isopropy1-2H-pyrazol-3-y1)-2,4-
C-10 F
NN-11 Yes 20.3
dioxo-1,4-dihydro-2H-quinazolin-
N 0
3-y1]-methanesulfonamide
CA 02846503 2014-02-25
WO 2013/036224 PCT/US2011/050687
-43-
N47-Ethyl-6-(2-methy1-2H-pyrazol-
z 0
/N
C-11 Yes 6.1 3-yI)-2,4-dioxo-1,4-dihydro-2H-
101 ?LA"
g quinazolin-3-y11-
N
0
methanesulfonamide
N-[7-Ethy1-6-(2-ethy1-2H-pyrazol-
N--/--- 0
C-12 Yes 42.8 3-yI)-2,4-dioxo-1,4-dihydro-2H-
quinazolin-3-yI]-
methanesulfonarnide
N-[7-Fluoromethy1-6-(2-methyl-2H-
N¨N/ 0 0
H
C-13 nt nt
pyrazol-3-y1)-2,4-dioxo-1,4-
N-S-
F.
0
dihydro-2H-quinazolin-3-yI]-
N
methanesulfonamide
0
N-[7-(1-fluoro-ethyl)-6-(2-methyl-
0
C-14 XIV' nt nt 2H-pyrazol-3-y1)-2,4-dioxo-1,4-
N 0 dihydro-2H-quinazolin-3-yI]-
methanesulfonamide
0
N-[7-(1,1-difluoro-ethyl)-6-(2-
_ z
N
methy1-2H-pyrazol-3-y1)-2,4-dioxo-
C-15 Yes 80%@20
1,4-dihydro-2H-quinazolin-3-y11-
methanesulfonamide
N-[7-(1,1-difluoro-ethyl)-6-(2-
C-16
N¨N
õ Yes nt isopropyl-2H-pyrazol-3-y1)-2,4-
x
0
F dioxo-1,4-dihydro-2H-quinazolin-
N
3-y1}-methanesulfonamide
0
N-[7-(1-fluoro-ethyl)-6-(2-
C-17
N----ry
isopropyl-2H-pyrazol-3-y1)-2,4-
p
110 Yes >20
0
N 0 dioxo-1,4-dihydro-2H-quinazolin-
3-y1]-methanesulfonamide
CA 02846503 2014-02-25
WO 2013/036224 PCT/US2011/050687
-44 -
N46-(2-Methy1-2H-pyrazol-3-y1)-
0 0
2,4-dioxo-7-trifluoromethy1-1 4-
C-IS N-N-1,
Yes 14.8
N 0 dihydro-2H-quinazolin-3-yI]-
methanesulfonamide
N-(6-(1-methy1-1H-1,2,3-triazol-5-
.,
.--N =
Comparati 4 H 0
yI)- 2,4-
dioxo-7-trifluoromethyl-
F it No 0%@50
ye 1,4-dihydro-2H-quinazolin-3-y11-
methanesulfonamide
This data shows that the compounds for use in the invention exhibit beneficial
oral
bioavailability relating to the comparative example (not in accordance with
the invention).
