WO 2007/030589 PCTAJS2006/034813
PHARMACEUTICAL DOSAGE FORMS AND COMPOSITIONS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Application No. 60/715,417, filed
September 9, 2005, the entire disclosure of which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates, for example, to novel formulations and' methods for the
delivery of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally
related compounds, and/or metabolites; as well as to use of these formulations and methods
for treating disease.
BACKGROUND OF THE INVENTION
[0003] Recent data has suggested that the 5-HTIA receptor is involved in cognitive
processing. See, for example, Schechter, L. E., et al, "Lecozotan (SRA-333): A Selective
Serotonin 1A Receptor Antagonist That Enhances the Stimulated Release of Glutamate and
Acetylcholine in the Hippocampus and Possesses Cognitive-Enhancing Properties," JPET
314:1274-1289, 2005. The 5-HTiA receptor antagonist, 4-cyano-N- [(2R)-[4-(2,3-
dihydrobenzo [1,4] dioxin-5-yl) piperazin-1-yl] propyl]-N-pyridm-2-yl-benzamide
hydrochloride (lecozotan) has been characterized in multiple in vitro and in vivo
pharmacologic assays as a drug to treat cognitive dysfunction. In vitro binding and intrinsic
activity determinations demonstrated that lecozotan is a potent and selective 5-HTIA receptor
antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg sc) antagonized the decrease in
hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg sc) of 8 OH-DPAT
and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the
potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of
the hippocampus. Chronic administration of lecozotan did not induce 5-HTIA receptor
tolerance or desensitization in a behavioral model indicative of 5-HT]A receptor function. In
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T / ii f R m iK / 3 4- El ;i 3
'dfugdis'cnnHnafion studies, lecozotan (0.01-1 tng/kg im) did not substitute for 8-OH-DFAT
and produced a dose-related blockade of the 5-HTu agonist discriminative stimulus cue. In
aged rhesus monkeys, lecozotan produced a significant improvement in task performance
efficiency at an optimal dose (1 mg/kg po). Learning deficits induced by the glutamatergic
antagonist MK-801 (assessed by perceptually complex and visual spatial discrimination) and
by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination)
were reversed by lecozotan (2 mg/kg im) in marmosets. The heterosynaptic nature of the
effects of lecozotan imbues this compound with a novel mechanism of action directed at the
biochemical pathologies underlying cognitive loss in Alzheimer's disease.
[0004] Since 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide (lecozotan) and its pharmaceutically acceptable salts,
structurally related compounds, metabolites, and combinations thereof are important in the
treatment of Alzheimer's Disease, it is important to provide formulations of these active
ingredients that provide optimum bioavailability and efficacy. The invention is directed to
these, as well as other, important needs.
SUMMARY OF THE INVENTION
[0005] The present invention provides, inter alia, formulations comprising 4-cyano-N-
{(2R)-2-[4-(2,3-dmydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-
benzamide, also referred to as lecozotan, pharmaceutically acceptable salts thereof,
structurally related compounds, metabolites, and combinations thereof.
[0006] Compounds provided by the present invention include:
4-cyano-N-{(2R)-2-[4-(2,3-dmydro-berizo[l,4]dioxin-5-yI)-piperazin-l-yl]-propyl}-
N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof (e.g., 4-{(2R)-
2-[4-(2,3-dmydro-benzo[l,4]dioxin-5-yl)-piperazm-l-yl]-propyl}-N-pyridm-2-yI-benzamide
hydrochloride salt) and structurally related compounds and metabolites thereof, including, but
not limited to:
{(2R)-2-[4-(2,3-dmydro-benzo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyJ}-N-pyridin-2-
yl-amine or a pharmaceutically acceptable salt thereof; 4-cyano-N-{(2S)-2-[4-(2,3-dihydro-
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Den2o[l'3T3ioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-beazamide cr a
pharmaceutically acceptable salt thereof;
4-cyano-iV-(2-piperazin-l-yl-propyl)-iV"-pyridin-2-yl-benzainide or a pharmaceutically
acceptable salt thereof; iV"-(5-cHoro-pyridin-2-yl)-4-cyano-iV'-[2-(4-hydroxy-piperazin-l-yl)-
propyl]-benzamide or a pharmaceutically acceptable salt thereof;
A^-(5-cUoro-pyridin-2-yl)-4-cyano-A''-{2-[4-(2,3-dihydro-beiizo[l ,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-ben2amide or a pharmaceutically acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(8-hydroxy-2,3-dihydro-benzo[l54]dioxin-5-yl)-piperazin-l-
yl]-propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(3-hydroxy-23-dihydro-benzo[l54]dioxiri-5-yl)-piperazin-l-
yl}-propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(2-hydroxy-23-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-
yl]-propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof;
4-cyano-N^2R-2-piperazin-l-yl-propyl)-N-pyridm-2-yl-benzarhide or a
pharmaceutically acceptable salt thereof;
4-cyano-N-{(2R)-2-[4<8-{l-[8-(4-{(lS)-2-[(4-cyanobenzoyl)(pyridme-2-yl)amino]-
1 -methylethyl}piperazin-1 -yl)-2,3-dihydro~ 1,4-benzodioxin-5-yl]-2-methylpropyl}-2,3 -
dihydro-1,4-benzodioxin-5-yl)piperazin-1 -yljpropyl} -N-pyridm-2-ylbenzarnide or a
pharmaceutically acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(8-{ 1 -[8-(4-{(l S)-2-[(4-cyanobenzoyl)(pyridine-2-yl)amino]-
l-memylemyl}piperazm-l-yl)-2,3-dmydVo-l,4-benzodioxin-5-yl]butyl}-2,3-dihydro-l,4-
benzodioxin-5-yl)piperazin-l-yI]propyl}-N-pyridin-2-ylbenzamide or a pharmaceutically
acceptable salt thereof;
4-cyano-N-{(2R)-244-(8-{148<4-{(lS)-2-[(4-cyanobenzoyl)(pyridirie-2-yl)amino]-
1 -methylethyl}piperazin-1 -yl)-2,3-dihydro-1,4-benzodioxin-5-ylJhexyl}-2,3-dihydro-l, 4-
berrzodioxm-5-yl)piperazm-l-yl]propyl}-N-pyridin-2-ylberi2amide or a pharmaceutically
acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(8-{[8-(4-{(l S)-2-[(4-cyanober^oyl)(pyriajne-2-yl)amino]-l - .
methyIemyl}piperazin-l-yl)-23-dihydro-l,4-benzodioxin-5-yl]methyl}-2,3-dihydro-l,4-
benzodioxin-5-yl)pipefazin-l -yljpropyl} -N-pyridin-2-ylbenzamide or a pharmaceutically
acceptable salt thereof;
4-cyano-N-{(2R)-2-[4<8-{l<8<4-{(lS)-2-[(4-cyanobenzoyl)(pyricune-2-yl)amino]-
1 -methylethyl}piperazin-l -yl)-2,3-diliydro-1,4-benzodioxin-5-yl]ethyl}-2,3-dihydro-1,4-
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be^ljdioxino-ytypiperazm-l-y^ or a pharmaceutically
acceptable salt thereof; and
4-cyano-N-[2(R)-(4-cyano-benzamido)-propyl]-N-pyridin-2-yl-berizamide or a
pharmaceutically acceptable salt thereof.
[0007J In one embodiment, the compounds are in the form of particles. In one aspect, the
particles have a mean diameter of no more than about 20 microns. In another aspect, the
particles have a mean diameter of from about 0.75 to about 10 microns. In another aspect,
the particles have a mean diameter of from about 2 to about 8 microns.
[0008] Compositions of the present invention comprise 4-cyano-N-{(2R)-2-[4-(2,3-
dihydro-benzo[l ,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide or a
pharmaceutically acceptable salt form thereof (e.g., 4-{(2R)-[4-(2,3-dihydro-
benzo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-pyridm-2-yl-benzamide hydrochloride
salt), structurally related compounds or metabolites thereof as described herein. In some
embodiments, compositions of the present invention comprise 4-cyano-N-{(2R)-2-[4-(2,3-
dihydro-benzo[l ,4]aMoxm-5-yl)-piperazm-l-yl]-propyl}-N-pyridin-2-yl-benzamide or a
pharmaceutically acceptable salt form thereof and one or more structurally related
compounds and/or metabolites. In some embodiments, 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l ,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-ben2amide or a
pharmaceutically acceptable salt form thereof and its structurally related compounds and/or
metabolites are present in the composition in the form of particles. In one aspect, the
particles have a mean diameter of no more than about 20 microns. In another aspect, the
particles have a mean diameter of from about 0.75 to about 10 microns. In another aspect,
the particles have a mean diameter of from about 2 to about 8 microns. In some
embodiments, the structurally related compounds and/or metabolites, when provided in a
composition with 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-
yl]-propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof
{e.g., 4-{(2R)-2-[4-(2,3-dihydro-ben2»[l,4]dioxin-5-yl)-piperazm-l-yl]-propyl}-N-pyridin-2-
yl-benzamide hydrochloride salt) are in an amount of less than about 0.1 weight percent each.
In some embodiments, compositions of the present invention further comprise a
pharmaceutically acceptable carrier.
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WO 2007/030589 PCT/US2006/034813
"' [0009] /TrTsorne* embodiments, compositions and dosage forms of the present'invention "
comprising 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof are
substantially free of one or more dimers of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzarnide. "Substantially
free," as used in this context, means that the dimers will be present in the compositions in an
amount of less than about 0.5% each, by weight, preferably in an amount of less than about
0.3% each, by weight, more preferably in an amount of less than about 0.2% each, by weight,
and even more preferably in an amount of less than about 0.1% each, by weight, based on the
total weight of the composition, and in the dosage forms in an amount of less than about
0.5% each, by weight, preferably in an amount of less than about 0.3% each, by weight, more
preferably in an amount of less than about 0.2% each, by weight, and even more preferably in
an amount of less than about 0.1% each, by weight, based on the weight of the active
ingredient in the dosage form. Accordingly, the present invention provides formulations
comprising 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l ,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof that are
substantially free of dimers of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide and/or other structurally related
compounds of 4-cyano-N-{(2R)-2-[4-(2,3-dmydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide. Representative dimers of 4-cyano-N-{(2R)-2-[4-(2,3-
dihydro-benzo[l ,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzarnide are as
shown in formulas 7 and 8.
[0010] Dosage forms of the present invention comprise 4-cyano-N-{(2R)-2-[4-(2,3-
dmyclro-benzo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-pyridm-2-yl-benzamide or a
pharmaceutically acceptable salt form thereof {e.g., 4-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yI-benzamide hydrochloride
salt), structurally related compounds or metabolites as described herein. In some
embodiments, dosage forms of the present invention will comprise 4-cyano-N-{(2R)-2-[4-
(2,3-dmydro-ben2X)[l,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-berizamide or a
pharmaceutically acceptable salt form thereof and one or more structurally related
compounds and/or metabolites. In some embodiments, 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-pyridin-2-yl-benzamide or a
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WO 2007/030589 PCT/US2006/034813
' pliarffialieuticmly acceptable salt form thereof and its structurally related .compounds and/or
metabolites are present in the dosage form in the form of particles. In one aspect, the
particles have a mean diameter of no more than about 20 microns. In another aspect, the
particles have a mean diameter of from 0.75 to about 10 microns. In another aspect, the
particles have a mean diameter of from about 2 to about 8 microns. In some embodiments,
the structurally related compounds and/or metabolites when provided in a dosage form with
4-cyano-N-{(2R)-2-[4-(2,3-dmydrcHbenzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-
pyridin-2-yl-benzamide or a pharmaceutically acceptable salt form thereof (e.g., 4-{(2R)-2-
[4-(2,3-dmyo^o-benzo[l,4]dioxin-5-yl)-piperaiii-l-yl]-propyl}-N-pyridin-2-yl-benzamide
hydrochloride salt) is in an amount of less than about 0.1%, by weight, based on the total
weight of the dosage form.
[0011] The term active ingredient refers to 4-cyano-N-{(2R)-2-[4-(2s3-dihydro-
benzo[l,4]dioxin-'5-yl)-piperazin-l-yl]-propyl} -N-pyridin-2-yl-benzamide or a
pharmaceutically acceptable salt form thereof (e.g., 4-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride
salt), structurally related compounds or metabolites (as shown herein) and, their'
pharmaceutically acceptable salts.
[0012] In some embodiments, pharmaceutical compositions and/or dosage forms comprise
in addition to the active ingredient (e.g., 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l ,4]dioxin-5-yl)-piperazin-l-yl]-propyl} -N-pyridin-2-yl-benzamide or a
pharmaceutically acceptable salt form thereof) at least one rate controlling polymer and at
least one organic acid. In some embodiments, the organic acid is citric acid anyhydrate, citric
acid monohydrate, ascorbic acid, aspartic acid, glutamic acid, fumaric acid, malic acid or
tartaric acid. In some embodiments, the organic acid is citric acid or a polyfunctional organic
acid. In some embodiments, the at least one release rate controlling polymer is a
methylcellulose. In some embodiments, the polymer is a hydroxypropyl methylcellulose,
hydroxypropyl cellulose, hydroxyethyl cellulose or hydroxypropyl methylcellulose phthalate.
In some embodiments, the hydroxypropyl methylcellulose is hypromellose 2208 or 2910
(e.g., Methocel™ K4M, Methocel™ KI5M, Methocel™ KI00M, Methocel™ E10M, Methocel™
E4M , Methocel™ K100LV, Methocel™ E50LV, Methocel™ E5, Methocel™ E6, or
Methocel E15LV. In some embodiments, the organic acid is citric acid and the rate
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WO 2007/030589 PCT/US2006/034813
r T /11 K n «=i •'•" 1 <* a i 3
m controlling" polymer is . hypromellose 2208, (e.g., Methocel K4M premium CR and/or
Methocel™ K100M Premium CR).
[0013] In some embodiments, pharmaceutical compositions and/or dosage forms further
comprise at least one filler. In some embodiments, the filler is microcrystalline cellulose,
lactose, calcium carbonate, calcium phosphate, maltodextrin, dextrose, fructose, maltose,
mannitol, starch, or sucrose. In some embodiments, the microcrystalline cellulose is silicified
microcrystalline cellulose and the lactose is lactose monohydrate. In some embodiments,
pharmaceutical compositions and/or dosage forms further comprise at least one lubricant. In
some embodiments, the lubricant is magnesium stearate, talc, stearic acid, or colloidal silicon
dioxide. Accordingly in some embodiments, pharmaceutical compositions and/or dosage-
forms of the present invention comprise, in addition to the active, ingredient or ingredients, at
least one rate controlling polymer, at least one organic acid, at least one filler, and at least one
lubricant.
[0014] In some embodiments, pharmaceutical compositions and/or dosage forms of the
present invention comprise about 2 to about 45 or 46 parts of a release rate controlling
polymer and about 1 to about 5 parts of an organic acid per part of active ingredient. In some
embodiments, the pharmaceutical compositions and/or dosage forms comprise about 0.4 to
about 10 mg of active ingredient. In some embodiments, the pharmaceutical compositions
and/or dosage forms of the present invention comprise about 50 to about 150 mg of rate
controlling polymer(s), about 5 to about 50 mg of organic acid(s), about 85 to about 179 mg
of filler(s) and about 1 mg of lubricant. In some embodiments, there is from about 2 to about
50 mg of organic acid(s).
[0015] In some embodiments, pharmaceutical compositions and/or dosage forms of the
present invention comprise in addition to the active ingredient (e.g., 4-cyano-N-{(2R)-[4-
(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-1 -yl]-propyl}-N-pyridin-2-yl-benzamide or a
pharmaceutically acceptable salt form thereof), at least one filler and at least one lubricant.
In some embodiments, the filler is microcrystalline cellulose, lactose, calcium carbonate,
calcium phosphate, maltodextrin, dextrose, fructose, maltose, mannitol, starch, sucrose or a
blend thereof. In some embodiments, the filler is microcrystalline cellulose, lactose, or a
blend thereof. In some embodiments, pharmaceutical compositions and/or dosage forms
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WO 2007/030589 PCT7US2006/034813
CT/:USQ6/31L|'S13 , u. T , ,. , , , . .
" iurther comprise at least one lubricant. In. some embodiments, the lubricant is magnesiuiu
stearate, talc, stearic acid, or colloidal silicon dioxide. In some embodiments, the lubricant is
magnesium stearate.
[0016] In some embodiments, pharmaceutical compositions and/or dosage forms comprise
about 15 to about 300 parts of filler and about 0.1 to about 3 parts of lubricant per part of
active ingredient In some embodiments, the pharmaceutical compositions and/or dosage
forms comprise about 0.1 to about 5 mg of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-pyrid^-2-yl-benzamide or a
pharmaceutically acceptable salt form thereof. In some embodiments, the pharmaceutical
compositions and/or dosage forms comprise about 80 to about 150 mg of one or more filler(s)-
and at least about 0.75 mg of one or more lubricant(s).
I
[0017] In some embodiments, the dosage forms of the present invention are in the form of
tablets. In one aspect, the tablets are film coated.
[0018] In some embodiments, the compositions or dosage forms of the present invention
are in the form of a dry blend.
[0019] The present invention provides processes of providing the compositions and dosage
forms of the present invention. In some embodiments, the compositions are compressed for a
time and under conditions effective to form a tablet thereof. In some embodiments, the
tablets are farther film coated.
[0020] The present invention also provides processes comprising mixing the active
ingredient, at least one rate controlling polymer and at least one organic acid thereby forming
a blend thereof. In some embodiments, the process further comprises compressing the blend
for a time and under conditions effective to form a tablet thereof. In some embodiments, the
tablets are farther film coated.
[0021] The present invention also provides processes comprising mixing the active
ingredient, at least one filler and at least lubricant thereby forming a blend thereof. In some
embodiments, the process further comprises compressing the blend for a time and under
8

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p*-T/|lf5Qfi/3,+aj.3 ,
"*' cotiditions-effective to form a tablet thereof. In some embodiments^ the tablets are finther
film coated.
[0022] In some embodiments, the dosage forms of the present invention are free of base.
[0023] In some embodiments, the present invention provides methods and processes of
administering a dosage form, compound or composition of the present invention to a
mammal, e.g., to a human. In some embodiments, the dosage forms, compounds, or
compositions are orally administered. In one aspect, they are orally administered once every
12 or 24 hours. In another aspect, they are orally administered once every 48 hours. In some
particularly preferred embodiments, the dosage forms, compounds, or compositions are
administered to treat Alzheimer's Disease.
[0024] In certain aspects, the present invention provides methods of administering to a
patient an oral dosage form that comprises lecozotan and a pharmaceutically acceptable
carrier. In some embodiments, the methods comprise administering to a patient an oral
dosage form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves
a maximum plasma concentration (Cmsx) in a patient and a 24 hour plasma concentration
(C24) in a patient, wherein a mean ratio of Cmax/C24 in a patient population is from about 5:1
to about 1.1:1. In certain embodiments, the mean ratio of Cmax/C24 is from about 3:1 to about
1.1:1, from about 2.8:1 to about 1.1:1, or from about 2.3:1 to about 1.1:1. In certain aspects,
the Cmax and C24 values are measured after administration of a single dose of the oral dosage
form to a patient. In some embodiments, the oral dosage form comprises about 5 mg of
lecozotan. In certain aspects, the mean tmax in the patient population is about 3.5 hours or
greater or about 5 hours or greater. In certain aspects, the mean Cmax in the patient population
is about 100 ng/ml or lower. In some embodiments, administration of these dosage forms
minimizes an adverse side effect associated with the administration of lecozotan to a patient.
In some embodiments, these methods include a step of identifying a patient at risk of an
adverse side effect through administration of lecozotan; and subsequently administering the
oral dosage form to the patient. In certain aspects, the adverse side effect is headache,
dizziness, paresthesia, abnormal vison, tinnitus, or a combination thereof.
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[0025]' '"" lii some embodiments, the methods or- administering lecozotan and a •■
pharmaceutically acceptable carrier comprise administering to a patient an oral dosage form
that comprises lecozotan and a pharmaceutically acceptable carrier and achieves a maximum
plasma concentration (Cmax) in a patient and a 24 hour plasma concentration (C24) in a
patient, wherein a mean ratio of Cmax/ C24 in a patient population is from about 2.4:1 to about
1.1:1. In certain embodiments, the mean ratio of Cmax/C24 is from about 2.3:1 to about 1.1:1,
from about 2:1 to about 1.1:1, from about 1.9:1 to about 1.1:1 or from about 1.5:1 to about
1.1:1. In certain aspects, the Cmax and C24 values are measured at steady state in a fasting
population. In some embodiments, about 10 mg of lecozotan is provided daily to the patient.
In certain aspects, the mean Cmax in the patient population is about 350 ng/ml. In some
, embodiments, administration of these dosage forms minimizes an adverse side effect
associated' with, the administration of lecozotan to a patient. In some embodiments, these
methods include a step of identifying a patient at risk of an adverse side effect through
administration of lecozotan; and subsequently administering the oral dosage form to the
patient. In certain aspects, the adverse side effect is headache, dizziness, paresthesia,
abnormal vison, tinnitus, or a combination thereof.
[0026] The present invention also provides methods comprising administering to a patient
an oral dosage form that comprises lecozotan and a pharmaceutically acceptable carrier and
achieves a mean maximum plasma concentration (Cmax) in a patient population and a mean
24 hour plasma concentration (C24) in a patient population, wherein a ratio of mean
Cmax/mean C24 is from about 5:1 to about 0.5:1. In certain aspects the ratio of mean
Cmax/mean C24 is from about 2.8:1 to about 1.1:1, from about 2:1 to about 1.1:1, or from about
1.5:1 to about 1.1:1. In certain aspects, the Cmax and C24 values are measured after
administration of a single dose of the oral dosage form to a patient In other aspects, the Cmax
and C24 values are measured at steady state in a fasting population. In some embodiments,
the oral dosage form comprises about 5 mg of lecozotan. In some embodiments,
administration of these dosage forms minimizes an adverse side effect associated with the
administration of lecozotan to a patient. In some embodiments, these methods include a step
of identifying a patient at risk of an adverse side effect through administration of lecozotan;
and subsequently administering the oral dosage form to the patient. In certain aspects, the
adverse side effect is headache, dizziness, paresthesia, abnormal vison, tinnitus, or a
combination thereof.
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[0027] The present invention also provides methods comprising administering to a patient
an oral dosage form that comprises Iecozotan and a pharrnaceuticaHy acceptable carrier and
achieves a mean maximum plasma concentration (Cmax) in a patient population and a mean
12 hour plasma concentration (Cn) in a patient population, wherein a ratio of mean
Cmax/mean C24 is from about 3:1 to about 0.5:1. In certain embodiments, the ratio of mean
Cmax/mean Cn is from about 2:1 to about 1.1:1 or from about 1.5:1 to about 1.1:1. In some
embodiments, administration of these dosage forms minimizes an adverse side effect
associated with the administration of Iecozotan to a patient. In some embodiments, these
methods include a step of identifying a patient at risk of an adverse side effect through
administration of Iecozotan; and subsequently administering the oral dosage form to the
patient. In certain aspects, the adverse side effect is headache, dizziness, paresthesia,
abnormal vison, tinnitus, or a combination thereof.
[0028] In some embodiments, the present invention provides methods for administering
Iecozotan to a patient comprising administering to the patient an oral dosage form that
comprises Iecozotan and a pharrnaceuticaHy acceptable carrier, wherein the dosage form
exhibits an in vitro dissolution profile when measured in a USP type II dissolution apparatus
at 50 rpm, in 900 ml of USP pH 6.8 phosphate buffer at 37°C and a sinker is used for each
dosage form, wherein no more than 40% of Iecozotan is released at about 2 hours of
measurement in said apparatus; and from about 50% to about 85% of Iecozotan is released at
about twelve hours of measurement in said apparatus.
[0029] In some embodiments, the present invention provides methods for administering
Iecozotan to a patient comprising administering an oral dosage form that comprises Iecozotan
and a pharrnaceuticaHy acceptable carrier to a patient and (i) achieves a mean Cmax in a
patient population that is less than the mean Cmax obtained from administering an equivalent
dose of Iecozotan from an immediate release formulation to the patient population; (ii)
achieves a mean tmax in a patient population that is greater than the tmax obtained from
administering an equivalent dose of Iecozotan from an immediate release formulation to the
patient population; and (iii) achieves a curve of concentration of Iecozotan over time, the
curve having an area under the curve (AUC) in a patient population that is substantially the
same as the AUC obtained from administering an equivalent dose of Iecozotan from an
11

WO 2007/030589 PCT/US2006/034813
, ""immediate release dosage form to the patient population. In certain embodiments, the oral
dosage form achieves a mean Umax of about 100 ng/ml or less and/or a mean tmax of from
about 4 hours to about 8 hours and/or a mean AUC that is from about 2000 to about 2500 ng
h/mL. In one aspect, these measurements are measured after administration of a single dose
of the oral dosage form, for example, a single dose of 5 mg of lecozotan. In certain
embodiments, the oral dosage form achieves a mean Craax of less than 400 ng/mL, for
example a mean Cmax of about 350 ng/mL, and/or a mean tmax of from about 4 hours to about
8 hours and/or a mean AUC that is from about 5500 to about 6300 ng h/mL. In certain
aspects, these measurements are measured at steady state in a fasting population. In certain
aspects, 10 mg of lecozotan is administered daily to the patient. In some embodiments,
administration of these dosage forms minimizes an adverse side effect associated with the
administration of lecozotan to a patient In some embodiments, these methods include a step
of identifying a patient at risk of an adverse side effect through administration of lecozotan;
and subsequently administering the oral dosage form to the patient. In certain aspects, the
adverse side effect is headache, dizziness, paresthesia, abnormal vison, tinnitus, or a
combination thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIGURE 1 presents a graph showing mean lecozotan concentration over time for
three sustained release formulations and one immediate release formulation after a single
dose of 5 mg of lecozotan.
[0031] FIGURE 2 presents a graph showing mean lecozotan plasma concentration versus
time profiles in Alzheimer's patients receiving multiple oral doses of immediate release (5
mg twice daily) and sustained release (10 mg once daily) formulations.
[0032] FIGURE 3 presents a graph showing lecozotan plasma concentration vs time
profile in Alzheimer's patients receiving single and multiple oral doses (QD) doses of 10 mg
lecozotan sustained release formulation as described in part 2 of example 8. The data for Day
1 shows from 0 to 24 hours. The data for Day 28 shows 0 to 72 hours.
12

WO 2007/030589 PCT/US2006/034813
~ f 0033]""" ^FTGTIR'F" 4 presents a graph-showing a comparison of lecozotan mean plasma
concentrations vs. time profiles in Alzheimer's patients receiving multiple oral doses of IR (5
mg) and SR (10 mg QD) formulations.
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention provides, inter alia, formulations comprising 4-cyano-N-
{(2R)-2-[4-(233-dmydro-benzo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-p3mdin-2-yl-
benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, and/or
metabolites. As used herein, the term "formulations" refers to compounds, compositions, and
dosage forms, such as, for example, immediate release and sustained release dosage forms.
[0035] The present invention also provides processes for making the formulations and
methods of administering them to a mammal.
[0036] Preferred formulations for use in the present invention are those that act as
serotonergic agents and have 5-HTIA binding activity. In particular, preferred compounds act
as 5-HTIA antagonists. See, for example, US-B-6,784,294, US-B-6,713,626, US-B- US-B-
6,469,007, US-B-6,586,436, US-A-5,710,149, and US-A-6,127,357, and WO 97/03982, the
disclosures, of which are incorporated herein by reference in their entirety for all purposes.
Compounds of the present invention, as well as compositions comprising more than one
compound of the present invention, can be prepared by those skilled in the art of organic
synthesis employing known methods that utilize readily available reagents and starting
materials, see, for example, EP-B-0512755, WO \ 97/03982, US-B-6,127,357, US-B-
6,469,007, US-B-6,713,626, and US-B-6,784,294, and US-A-20030208075A1, the
disclosures of which are incorporated herein by reference in their entirety for all purposes.
[0037] Such methods include alkylating l-(2,3:dihydro-l,4-benzodioxin-5-yl)piperazine
hydrochloride with sulfamate 4,5-dihydro-5S-methyl-3-(2-pyridinyl)-3H[1.2.3]oxathiazole-
2,2-dioxide to give a sulfamic acid intermediate which is hydrolyzed to{(2R)-2-[4-(2,3-
dmydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yI]-propyl}pyridin-2-yl-amine and then treating
{(2R)-2-[4-(2,3-dmydro-berizo[l,4]dioxin-5-yl)-piperazm-l-yl]-propyl}pyridin-2-yl-amine
with 4-cyanobenzoyl chloride to give 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-
13

WO 2007/030589 PCT/US2006/034813
.**. 5-$d)Ppipe7az^^ base. Treatment of 4-cyari'o""-N-"
{(2R)-2-[4-(23-dihydro-benzo[l,4]dioxin-5-yl)-pipera2dn-l-yl]-propyl}-N-pyridin-2-yl-
benzamide base with hydrochloric acid gives its hydrochloride salt.
[0038] In some embodiments of the present invention, preparations comprising 4-cyano-N-
{(2R)-2-[4-(2,3-d&ydro-benzo[l,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-
benzamide and its pharmaceutically acceptable salts are further processed and purified. For
example, in one embodiment, a preparation comprising p4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzofl ,4]dioxin-5-yl)-piperazin-l-yl]-propyl} -N-pyridin-2-yl-benzamide prepared by
methods disclosed herein is dissolved in organic solvent, treated with silica gel, and filtered
in order to remove structurally related compounds, e.g., dimers represented by Formulas 7
and 8. The remaining product can then be concentrated and re-crystallized in order to
provide, e.g., 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide hydrochloride salt.
[0039] Preferred formulations of the present invention can be used to modulate, e.g.,
antagonize or agonize, 5-HTIA receptor activity and are useful in the treatment of diseases
such as CNS disorders, including, but not limited to, schizophrenia, (and other psychotic
disorders such as paranoia and mano-depressive illness), Parkinson's disease and other motor
disorders, anxiety (e.g., generalized anxiety disorders, panic attacks, and obsessive
compulsive disorders), depression (such as by the potentiation of serotonin reuptake
inhibitors and serotonin norepinephrine reuptake inhibitors), Alzheimer's disease, Tourette's
syndrome, migraine, autism, attention deficit disorders and hyperactivity disorders. Preferred
formulations • are useful for the treatment of sleep disorders, social phobias, pain,
thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm, stroke,
eating disorders such as for example obesity, anorexia and bulimia, sexual dysfunction, and
the treatment of alcohol, drug and nicotine withdrawal.
[0040] Preferred formulations of the present invention are also useful for the treatment of
cognitive dysfunction including but not limited to cognitive dysfunction associated with mild
cognitive impairment (MCI), Alzheimer's disease and other dementias including Lewy Body,
vascular, and post stroke dementias. Cognitive dysfunction associated with surgical
procedures, traumatic brain injury or stroke can also be treated in accordance with the present
14

WO 2007/030589 PCT/US2006/034813
; if! T /1 IK p & / 3! HM X 3
~r"mv~enu"orI"Turther;plefeireoS formulations are useful for the treatment of diseases in which
cognitive dysfunction is a co-morbidity such as, for example, Parkinson's disease, autism and
attention deficit disorders.
[0041] Despite its high solubility in water (about 51 mg/ml at 25°C), 4-cyano-N-{(2R)-2-
[4-(2,3-dmydro-benzo[l,4]dioxin-5-yl)-piperazm-l-yl]-propyl}-N-pyridm-2-yl-benzamide
and its salts are preferably provided in micronized form. As such, the present invention
provides formulations comprising 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-
yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts
thereof, structurally related compounds, or metabolites in micronized and in non-micronized
form. For purposes of the present invention, a compound in micronized form is in the form
of particles having a mean diameter of no more than about 20 microns. It is understood that
compounds of the present invention can be in the form of particles having a mean diameter of
greater than about 20 microns, for example in the form of particles having a mean diameter
from about 20 microns to about 300 or about 500 microns. Preferably, the particles have a
mean diameter of about 10 microns, more preferably a mean diameter from about 0.75 to
about 10 microns, even more preferably from about 2 to about 8 microns. Methods of
micronization or particle size reduction are known and are thus not described herein in detail.
[0042] As will be recognized, 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide is represented by the following formula:

[0043] Within the present invention, the compounds of formula 1 can be prepared in the
form of pharmaceutically acceptable salts. As used herein, the term "pharmaceutically
15

WO 2007/030589 PCT/US2006/0348I3
if" ~a~ ^ if !i lci" O IK -■''" 31 ""i"'l;;i!i "K .3!
■■-?" ^ecs^aHc™3Sl,t3,^'refers" to" salts prepared from pharmaceutically acceptable non toxic acids,
including inorganic salts, and organic salts. Suitable non-organic salts include, for example,
inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,
ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,
succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most preferably is the
hydrochloride salt.
[0044] In certain embodiments, formulations comprising 4-cyano-N-{(2R)-2-[4-(2,3-
dmydro-ber^o[l,4]dioxm-5-yl)-piperazm-l-yl]-propyI}-N-pyridin-2-yl-benzamide or
pharmaceutically acceptable salts thereof will also comprise one or more structurally related
compounds that can be detected and quantified using known methods. Examples of such
structurally related compounds include, but are not limited to, those compounds represented
by Formulas 2-9 and pharmaceutically acceptable salts thereof, including, for example:
{(2R)-2-[4^(2,3-dmycb:o-benzo[l,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-
yl-amine or a pharmaceutically acceptable salt thereof;
4-cyano-N-{(2S)-2-[4-(2,3-dihydro-benzo[l,4]dioxhi-5-yl)-piperazin-l-yl]-propyl}-
N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof;
4-cyano-AT-(2-piperazin-l-yl-propyl)-A''-pyridin-2-yl-benzamide or a pharmaceutically
acceptable salt thereof;
4-cyanQ-A^-[(2R)-2-piperazin-l-yl-propyl]-A''-pyridin-2-yl-benzamide or a
pharmaceutically acceptable salt thereof;
A^(5-chloro-pyridin-2-yl)-4-cyano-iV-[2-(4-hydroxy-piperazin-l-yl)-propyl]-
benzamide or a pharmaceutically acceptable salt thereof;
AT-(5-cmoro-pyridin-2-yl)-4-cyano-A'-[(2R)-2-(4-hydroxy-piperazin-l-yl)-propyl]-
benzamide or a pharmaceutically acceptable salt thereof;
Ar-(5-chloro-pyridin-2-yl)-4-cyano-A'-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-benzamide or a pharmaceutically acceptable salt thereof;
iV-(5-cMoro-pyridm-2-yl)-4-cyano-7y''-{(2R)-2-[4-(2,3-dihydro-l,4-benzodioxin-5-yl)-
piperazin-l-yl]-propyl}benzamide or a pharmaceutically acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(8-{ 1 -[8-(4-{(l S)-2-[(4-cyanobenzoyl)(pyridine-2-yl)amino]-
1 -methylethyl} piperazin-1 -yI)-2,3-dihydro-1,4-benzodioxin-5-y l]-2-methyIpropyI} -2,3-
16

WO 2007/030589 PCT/US2006/034813
■"T/iicjrsfi/ "»;ii «•■«- R J3
"*' ^ihyar6"-P3^5enzddibxui 5 -yl)piperazin 1 yljpropjd-} N-pjnridin 2 ylbenzamide ■ - or a
pharmaceutically acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(8-{l-[8-(4-{(lS)-2-[(4-cyanoberczoyl)(pyridine-2-yl)amino]-
l-methylethyl}piperazin-l-yl)-23-dihydxo-l,4-benzodioxin-5-yl]butyl}-23-dihydro-l,4-
berizodioxin-5-yl)piperazin-l-yl]propyl}-N-pyridin-2-ylbenzarnide or a pharmaceutically
acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(8^1-[8-(4-{(lS)-2-[(4-cyanober^oyl)(pyridine-2-yl)amino]-
l-methylethyl}piperazin-l-yl)-23-dihydro-l,4-benzodioxin-5-yl]hexyl}-2,3-dihydro-l3 4-
benzodioxin-5-yl)piperazin-l-yl]propyl}-N-pyridiii-2-ylbenzamide or a pharmaceutically
acceptable salt thereof;
4-cyano-N-{(2R)-2-[4<8-{[8-(4-{(lS)-2-[(4-cyanobenzoyl)(pyridine-2-yl)amino]-l-
methylethyllpiperazin-l-y^^^-dmydro-l^-benzodioxin-S-yljmethyll^^-dihydro-l, 4-
benzodioxm-5-yl)piperazm-l-yl]propyl}-N-pyridin-2-ylbenzamide or a pharmaceutically
acceptable salt thereof;
4-cyano-N-{(2R)-2-[4-(8-{ 1 -[8-(4-{(l S)-2-[(4-cyanobenzoyl)(pyridine-2-yl)amino]-
l-methylethyl}piperazm-l-yl)-23-dmyaxo-l,4-benzodioxin-5-yl]ethyl}-2,3-dihydro-l,4-
benzodioxin-5-yl)piperazm-l-yl]propyl}-N-pyridin-2-ylbenzamide or a pharmaceutically
acceptable salt thereof; and
17
4-cyano-N-[2(R)-(4-cyano-benzamido)-propyl]-N-pyridin-2-yl-benzamide or a
.pharmaceutically acceptable salt thereof.


WO 2007/030589 PCT/US2006/034813


19
WO 2007/030589 PCTVUS2006/034813


WO 2007/030589 PCT/US2006/034813
[0045] *" '■ In some embodiments, the present invention provides formulations comprising one
or more compounds represented by Formulas 2, 3, 4, 5, 6, 7, 8 or 9 or a pharmaceutically
acceptable salt thereof. In some aspects of the present invention, the formulations will
comprise 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof and one or
more compounds of Formula 2, 3, 4, 5, 6, 7, 8 or 9 or a pharmaceutically acceptable salt
thereof. In some embodiments, for example, formulations of the present invention can
comprise 4-cyano-N-{(2R)-2-[4-(2,3-dmydro-berizo[l,4]dioxin--5-yl)-piperazin-l-yl]-
propyl}-N-pyridm~2-yl-benzarnide or a pharmaceutically acceptable salt thereof, {(2R)-2-[4-
(2,3-dmyc!ro-benzo[l,4]dioxm-5-yl)-pipera2dn-l-yl]-propyl}-N-pyric%-2-yl-ariakie or a
pharmaceutically acceptable salt thereof, and 4-cyano-N-{(2S)-2-[4-(2,3-dihydro-
benzofl ,4]dioxin-5-yl)-piperazin-1 -yl]-propy!} -N-p3Tidin-2-yl-benzamide or a
pharmaceutically acceptable salt thereof. Accordingly, the present invention provides
formulations comprising 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride salt, {(2R)-2-[4-(2,3-
dihydro-beiizo[l,4]dioxm-5-yl)-pipera2in-l-yl]-propyl}-N-pyridin-2-yl-amine, and 4-cyano-
N-{(2S)-2-[4-(2,3-dmydro-benzo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-pyridin-2-yl-
benzamide hydrochloride salt. When the structurally related compounds described above are
present in combination with 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable salt
thereof, the former preferably predominates and the latter preferably are present in the
composition in amount of less than about 10%, more preferably present in amount of less
than about 5% and even more preferably in amounts of less than about 1% or 0.1%, for
example, in amounts from between about 0.08% and about 0.27%.
[0046] 4-Cyano-N-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yI]-propyl}-N-
pyridin-2-yl-benzamide contains one chiral center and is used predominately as the R-isomer.
The formulations, e.g., compounds, compositions, or dosage forms, of the present invention
can include both R and S isomers, and are not limited to a single enantiomer or particular
enantiomeric mixture.
[0047] The present invention also provides formulations comprising metabolites of 4-
cyano-N-{(2R)-2-[4-(2,3-dmydro-berizo[l,4]dioxm-5-yl)-pipera2in-l-yl]-propyl}-N-pyridin-
20

WO 2007/030589 PCT/US2006/034813
v 2-tl-Benzamrae. ""MeFabontes include, but are not limited to, 4-cyann-N-{(?R)-?-[4-(8-
hydroxy-2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-
benzamide or a pharmaceutically acceptable salt thereof, 4-cyano-N-{(2R)-2-[4-(3-hydroxy-
2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide or a
pharmaceutically acceptable salt thereof, 4-Cyano-N-{(2R)-2-[4-(2-hydroxy-2,3-dihydro-
berizo[l34]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide or a
21
pharmaceutically acceptable salt thereof, and 4-cyano-N-(2R-2-piperazin-l-yl-propyl)-N-
pyridin-2-yl-benzamide or a pharmaceutically acceptable salt thereof. As is recognized, these
metabolites are represented by Formulas 10-13. It will be recognized that these metabolites
can be employed as pharmaceutically active compounds and in pharmaceutical dosage forms
in their own right, alone or in combination with other pharmaceutically active compounds.



WO 2007/030589 PCT/US2006/034813
[0048] The present invention provides immediate release and sustained release dosage
forms comprising one or more active ingredients, e.g., 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically
acceptable salts thereof, structurally related compounds and metabolites thereof that have 5-
HTIA binding activity.
[0049] A drug "release rate" refers to the quantity of drug released from a dosage form per
unit time, e.g., milligrams of drug released per hour (mg/hr). Drug release rates can be
calculated, for example, under in vitro dosage form dissolution testing conditions known in
the art. As used herein, a drug release rate obtained at a specified time "following
administration" refers to the in vitro drug release rate obtained at the specified time following
implementation of an appropriate dissolution test. Methods of performing dissolution tests or
release rate assays are known in the art. The time at which a specified percentage of the drug
within a dosage form has been released can be referenced as the "Tx" value, where "x" is the
percent of drug that has been released. A commonly used reference measurement for
22

WO 2007/030589 PCT/US2006/034813
kT/llfiQK/3WSJ:*3 . ,
"evaluating drug release from .oral dosage forms ts the rime at which 70% or 90% of drug-
within a dosage form has been released. This measurement is referred to as "T70" or "T90" for
the dosage form.
[0050] For purposes of this invention, the terms "immediate release formulation" refer to
formulations that provide a relatively rapid and non-gradual release of active compound from
the formulation; e.g., formulations that contain active compound and a rapidly dissolving
carrier that does not retard the release of the active compound from the formulation. Such
immediate release formulation are either devoid of release rate controlling polymers or other
species that retard the release of the active compound from the formulation, or contain such
polymers or species in amounts that are sufficiently small such that the release of the active
compound from the formulation is not retarded relative to an otherwise identical formulation
lacking such polymers or species. One example of such an immediate release formulation is
the active ingredient, e.g., 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salt thereof,
structurally related compounds, or metabolites, blended in microcrystalline cellulose, such as
Avicel® brand from FMC corporation, which results in greater than 75% dissolution of the
active ingredient in less than 0.25 hours in a 0.1 N HC1 solution.
[0051] As used herein, the terms "sustained release", "sustained release formulation,"
"sustained release dosage formulation" and the like refer to formulations that contain
materials that retard the release of active compound from the formulation relative to an
"immediate release" formulation as described above, e.g., relative to an otherwise identical
formulation lacking the release rate controlling polymer or other release-retarding materials.
Thus, the term "sustained release" can apply to any number of extended release forms and is
considered substantially synonymous with delayed release, time release, prolonged release,
time programmed release, time released, time coated release, sustained release, slow acting,
long acting, delayed acting, spaced release, time spaced release, extended acting, extended
- action, and the like.
[0052] The terms "slow release," "medium release," and "fast release" are intended to refer
to sustained release formulations as described herein that release active compound at a rate that is
slow, medium or fast rate relative to each other.
23

WO 2007/030589 PCT/US2006/034813
[0053] It is appreciated that sustained release formulations can result in a release of active
compound from the dosage form at a rate effective to increase the time it takes to reach
maximum therapeutic concentration as compared to an immediate release formulation, for
example and not limitation, by a period of 50% or more, 100% or more, 150% or more, or
200% or more as compared to an immediate release formulation; e.g., as compared to an
otherwise identical formulation lacking the release rate controlling polymer or other release-
retarding materials. Sustained release formulations can also result in release of active
compound from the dosage form at a rate effective to decrease the maximal therapeutic
concentration of said compound compared to an immediate release formulation, for example and
not limitation, by at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, or at least
50% compared to an immediate release formulation. Sustained release formulations can also
result in release of active compound from the dosage form at a rate effective to increase the
amount of time a pharmaceutically effective concentration of the active compound is
maintained relative to an immediate release formulation, for example and not limitation, by at
least 25%, at least 50%, at least 75%, at least 100%, or at least 125% the amount of time a
pharmaceutically effective concentration of active compound is maintained relative to an
immediate release formulation. Satisfaction of any of the preceding criteria is sufficient to make
a formulation a "sustained release" formulation.
[0054] The present invention provides methods for sustained release of the active ingredient
comprising adrninistering to a subject the disclosed dosage forms. In one aspect, the release
rate of the active compound from the dosage forms is zero order. In another aspect, the
release rate of the active ingredient from the dosage forms is ascending.
[0055] As used herein, the term "release rate controlling polymer" is intended to denote any
polymer material suitable for pharmaceutical dosage forms that retards the release of drug
substances from such dosage forms. The release rate-controlling polymer will preferably
inhibit the release of the drug in the stomach. Preferably, the release rate-controlling polymer
is a hydrogel that imbibes and/or absorbs fluid thereby preventing the release of the drug in
the stomach. Examples of suitable release rate controlling polymers can be found in
Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton,
PA, 1990.
24

WO 2007/030589 PCT/US2006/034813
[0056] Some preferred release rate-controlling polymers suitable for use in the present
invention include, without limitation, hydroxypropyl celluloses, methylcelluloses,
polymethacrylates, methacrylic acid-methacrylic acid ester copolymers, cellulose acetate
phthalate, ethyl celluloses, ' hydroxyethyl celluloses, hydroxymethyl celluloses,
hydroxypropylethyl celluloses, polyvinyl acetate-phthalate, hydroxypropylmethylcellulose
phthalate, poly(ethylene) oxides, hydroxypropyl methyl celluloses such as, for example,
hypromellose 2208 and 2910 and combinations of two or more thereof. Suitable release rate
controlling polymers are available from commercial sources, such as Methocel K4M,
Methocel™ K15M, Methocel™ K100M, Methocel™ E4M, Methocel™ K100LV, Methocel™
E50LV, Methocel E5, Methocel E6, Methocel E15LV , and Surelease available from
Colorcon and Eudragit™, RS Eudragit RL available from Rohm GmbH & Co. In some
embodiments, the formulations of the present invention will comprise high-density matrix-
forming hydroxypropyl methylcellulose, low-density matrix-forming hydroxypropyl •
methylcellulose, or combinations thereof.
[0057] The sustained release formulations of the present invention comprise at least one
release rate controlling polymer. The range of release rate controlling polymer in the
formulation is preferably from about 10% to about 75% by weight, more preferably from about
20% to about 60% by weight. In one embodiment of the present invention, the amount of
release rate controlling polymer in a 250 mg dosage form is from about 50 to about 150 mg. In
some embodiments, the release rate controlling polymer is a cellulose ether, such as, for
example, matrix-forming hydroxypropyl methylcellulose, hydroxypropyl cellulose, or
hydroxyethyl cellulose, e.g., Methocel K4M Premium CR or Methocel K100M Premium
CR.
[0058] In addition to comprising at least one release rate controlling polymer, sustained release
dosage forms of the present invention generally comprise at least one agent to improve the
release rate in the intestine, e.g., an organic acid. For uses herein, the term "organic acid"
encompasses any acid that can be safely ingested by a mammal. While not wishing to be bound
by any particular theory, the acid is believed to improve the release of the drug product in the
intestine. Examples of organic acids suitable for use in the present invention include, but are not
limited to, tartaric acid, malic acid, furnaric acid, aspartic acid, glutamic acid, glycine
25

WO 2007/030589 PCT/US2006/034813
hydrocmdride, adipic acid, succinic acid, ascorbic acid, oleic acid or citric acid. Preferred
organic acids are citric acid or polyfunctional organic acid. The range of organic acid in the
formulation is preferably from about 1% to about 30%, more preferably from about 2% to
about 10% by weight. In one embodiment of the present invention, the amount of organic acid
in a 250 mg dosage form is from about 5 to about 50 mg, preferably from about 5 to about 25
mg. In some embodiments, the amount of organic acid is from about 2 to about 50 mg.
[0059] Preferably, the sustained release formulations is substantially free of base. For use
herein, a formulation, dosage form, or composition that is substantially of base refers to a
formulation, dosage form, or composition that has less than about 10% base, preferably less
than about 5% base, and more preferably less than about 1% or 0.1% base. As used herein,
the term "base" refers to a chemical compound that functions as a proton acceptor.
[0060] In addition to the active compound and release rate controlling polymer, the
formulations of the invention can comprise any of a variety of additional materials that
confer beneficial properties to the formulation. Such materials include, for example,
solubility modifiers such as surfactants such as, for example, sodium lauryl sulfate, acidic
compounds, antioxidants, pH modifiers, chelating agents, fillers, disintegrants, binders,
lubricants, stabilizers, excipients including water soluble excipients such as sugars and water
dispersing excipients such as, for example, microcrystalline cellulose, colloidal silicon dioxide,
silicified microcrystalline cellulose and starch. In some embodiments, the formulation is
provided at a pH of about 6 or lower, for example at a pH of from about 1 to about 6.
[0061] Nonlimiting examples of water-soluble excipients or water dispersing excipients
include lactose, mannitol, sucrose, and the like. The water-soluble excipients can be present in
a range on weight percentages depending upon the particular therapeutic objective required. For
use in the present invention, percentages and parts are expressed as part by weight or
percentage by weight, unless otherwise noted. In general, the range of water soluble
excipients can be, for example, from about 0% to about 50% or to about 99%, or from about
2% to about 25%. Examples of water dispersible excipients include microcrystalline
cellulose, colloidal silicone dioxide, silicified microcrystalline cellulose (Prosolv™), starches,
croscarmelose sodium and the like.
26

WO 2007/030589 PCT/US2006/034813
* [0062] "" Nonlimiting examples of stabilizers mclude. .antioxidants such as BHA, BHT,
ascorbic acids, tocopherols, and the like. Nonlimiting examples of suitable metal chelators
include EDTA, citric acid and the like. Nonlimiting examples of pH modifiers include citric
acid, fumaric acid, and the like. Nonlimiting examples of binders include starches, PVP
(polyvinylpyrrolidone), HPMC (hydroxy/propyl methyl celluloses), HPC (hydroxypropyl
cellulose) and the like. Nonlimiting examples of flow aids include magnesium stearate and
the like. Nonlimiting examples of solubility modifiers include surfactants like sodium lauryl
sulfate or polysorbate (e.g., Tween 80), and the like.
[0063] In a preferred embodiment, the sustained release formulations of the present
invention comprise the active ingredient, at least one release rate controlling polymer, an
organic acid, at least one filler and at least one lubricant
[0064] Examples of lubricants include, but are not limited to, stearic acid, magnesium
stearate, glyceryl behenate, talc, mineral oil (in PEG), colloidal silicon dioxide and. the like.
It is appreciated however that any lubricant known in the art can be used in the formulations
described herein. The range of lubricant can be, for example, from about 0.2% to about 5%, by
weight. In one embodiment of the present invention, the amount of lubricant in a 250 mg
dosage form is about 1 mg.
[0065] Examples of fillers include, but are not limited to, silicified microcrystalline
cellulose, microcrystalline cellulose, cellulose acetate, cellulose diacetate, cellulose triacetate,
lactose monohydrate, lactose anhydrous, calcium carbonate, calcium phosphate (e.g., dibasic
anhydrous), maltodextrin, dextrose, fi-uctose, maltose, mannitol, starch, starch (e.g.,
pregelatinized), sucrose, and lactose. It is appreciated, however, that any filler known in the
art can be used in the formulations described herein. The range of filler can be, for example,
from about 25% to about 75%, or to about 99% by weight. In one embodiment of the present
invention (e.g., for exemplary sustained release formulations), the amount of filler present in a
250 mg dosage form is from about 85 to about 179 mg.
[0066] The sustained release dosage forms of the present invention can comprise the active
compound in any convenient percentage and part in relation to the other ingredients.
Typically, the formulation comprises active ingredient in percentage of from about 0.3% to
27

WO 2007/030589 PCT/US2006/034813
'"if "'' H ^ '»^* iHt \& >?' *"$ 8»K» li"'ii "II '""('
ayW?f5%r^reierSTy"¥6m. about-0.3% to about 15%. In some embodiments, the
formulation will comprise active ingredient in percentage of from about 1% to about 25%,
preferably from about 2% to about 15%.
[0067] In a preferred embodiment, sustained release formulations will comprise from about
2 to about 46 parts of release relate controlling polymer and about 0.4 to about 10 parts of an
agent to improve release rate in the intestine per part active ingredient. More preferably from
about 10 to about 46 parts release rate controlling polymer and about 1 to about 5 parts of an
agent to improve release rate in the intestine per part active ingredient.
[0068] For example, in one embodiment, fast sustained release formulations comprise about
10 parts of release rate controlling polymer, and about 5 parts of organic acid per part of
active ingredient, e.g., 4-cyano-N-{(2R)-2-[4-(2,3-dmydro-benzo[l,4]dioxin-5-yl)-piperazin-
l-yl]-propyl}-N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
[0069] In another embodiment, medium sustained release formulations comprise about 25
parts of release rate controlling polymer, and about 5 parts of organic acid per part of active
• ingredient, e.g., 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
[0070] In another embodiment, slow sustained release formulations comprise about 30 parts
of release rate controlling polymer, and about 1 part of organic acid per part of active
ingredient, e.g., 4-cyano-N- {(2R)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1 -yl]-
propyl}-N-pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
[0071] In another embodiment, sustained release formulations comprise about 18 parts of
release rate controlling polymer, and about 1 part of organic acid per part- of active ingredient,
e.g., 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-
pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
[0072] In another embodiment, sustained release formulations comprise about 46 parts of
release rate controlling polymer, and about 1 part of organic acid per part of active ingredient,
28

WO 2007/030589 PCT/US2006/034813
T / if s "^ O f. -■•"' "~i: H-M "li "^
e.g.*,""3"cyMb"N^((2K^^^^^ -
pyridin-2-yl-benzamide or pharmaceutically acceptable salt thereof.
[0073] In some embodiments, sustained release formulations comprise about 5 mg of active
ingredient, from about 50 to 150 mg of release rate controlling polymer, from about 5 to
about 50 mg of organic acid, from about 85 to about 179 mg of filler and about 1 mg of
lubricant.
[0074] In some embodiments, sustained release formulations comprise about 2 mg of active
ingredient, from about 50 to 150 mg of release rate controlling polymer, from about 2 to
about 50 mg of organic acid, from about 85 to about 179 mg of filler and about 1 mg of
lubricant.
[0075] In some embodiments, exemplary sustained release formulations comprise, in a 250
mg tablet, about 5 mg of active ingredient and about 50 mg of release rate controlling
polymer. Such an exemplary formulation can further comprise, for example, about 169 mg
of filler, about 25 mg of organic acid (or other agent to improve release rate in the intestine)
and about 1 rng of lubricant.
[0076] In some embodiments, exemplary sustained release formulations comprise, in a 250
mg tablet, about 5 mg of active ingredient and about 125 mg of release rate controlling
polymer. Such an exemplary formulation can further comprise, for example, about 94 mg of
filler, about 25 mg of organic acid (or other agent to improve release rate in the intestine) and
about 1 mg of lubricant.
[0077] In some embodiments, exemplary sustained release formulations comprise, in a 250
mg tablet, about 5 mg of active ingredient and about 150 mg of release rate controlling
polymer. Such an exemplary formulation can further comprise, for example, about 89 mg of
filler, about 5 mg of organic acid (or other agent to improve release rate in the intestine) and
about 1 mg of lubricant.
[0078] In some embodiments, exemplary sustained release formulations comprise, in a 250
mg tablet, about 5 mg of active ingredient and about 92 mg of release rate controlling
29

WO 2007/030589 PCT/US2006/034813
T .<*' 11H n 6 ••■•' "3 LS-S :i 3
pdlymerl~Such ah exemplary formulation can further comprise, for example, about 150 mg
of filler, about 5 mg of organic acid (or other agent to improve release rate in the intestine)
and about 1 mg of lubricant.
[0079] In some embodiments, exemplary sustained release formulations comprise, in a 250
mg tablet, about 2 mg of active ingredient and about 92 mg of release rate controlling
polymer. Such an exemplary formulation can further comprise, for example, about 150 mg
of filler, about 2 mg of organic acid (or other agent to improve release rate in the intestine)
and about 1 mg of lubricant.
[0080] The sustained release formulations contemplated by the present invention can be in
any form suitable for administration to a mammal and are not limited to the examples
presented herein.
[0081] In some embodiments, the formulations of the invention are in the form of coated
pellets or spheres. One nonlimiting example of such a formulation is a sphere containing a
core of active compound in an inert matrix, coated with a release rate-controlling polymer
as disclosed herein. Nonlimiting examples of suitable release rate controlling polymers are pH
dependent or independent polymers described herein, such as polymethacrylates, Eudragit
IVS, Eudragit™ RS/RL, cellulose acetate phthalate, ethyl celluloses, hydroxypropyl methyl
celluloses, hydroxypropyl celluloses, hydroxypropyl ethyl celluloses and the like.
[0082] In some embodiments, the formulations of the invention are in the form of pellets.
Examples of such formulations include those containing pellets that contain a layer of active
compound on top of an inert core, for example, a sugar sphere, and a surface coating
containing one or more release rate controlling polymers. In other embodiments, the
formulations are in the form of capsules, e.g., hard or soft gelatin capsules and/or powder.
[0083] In some embodiments, the formulations of the invention are in the form of tablets. The
percentage by weight of active compound in the representative formulations of this type is from
about 0.3% to about 25%, preferably from about 0.3% to about 15%. In some embodiments,
the percentage by weight of active compound in the representative formulations of this type are
30

WO 2007/030589 PCT/US2006/034813
•abbuFi'^ld'alDOut 25%,~pfeierably from about 2% to about 15%. Nonlimiting examples of
such tablets are co-compressed tablets , e.g., "tablet-in-tablet" and matrix tablets.
[0084] The co-compressed tablet can include a core and-an-outer compressed coat. Either or
both of the core and the outer compressed coat can contain active compound and/or one or more
release rate controlling polymers. In some embodiments, the dosage form is a co-compressed
tablet wherein both the core and the outer compressed coat contain active compound, and at
least one release rate-controlling polymer, one of which is preferably a hydroxypropyl methyl
cellulose. Preferred matrix forming polymers include a hydroxypropyl: methylcellulose
selected from Methocel™ K4M, Methocel™ K15M, Methocel™ KI00M, Methocel™ E10M,
Methocel™ E10M, Methocel™ E4M, Methocel K4M, Methocel™ K100LV, Methocel™
E50LV, Methocel™ E5, Methocel™ E6, Methocel™ E15LV or a combination of two or more
thereof.
[0085] In some embodiments, the tablet is a matrix tablet. The matrix forming composition
can contain waxes, gums, polyethylene oxides, carbapols, hydroxypropyl methylcelluloses,
' hydroxypropyl celluloses, hydroxyethyl celluloses, polymethacrylates or other release
rate controlling polymers as described herein. In some embodiments, such matrix tablets are
prepared by blending the active compound and the matrix-forming polymer together, and
compressing the blend.
[0086] In some embodiments, the tablet is a matrix tablet that includes a wax matrix. Such
tablets can be prepared, for example, by melting a wax such as carnauba wax, cetostearyl
alcohol or fatty acids, or combinations thereof, and adding active compound along with a
filler, such as microcrystalline cellulose as well as other excipients, fillers, lubricants and the
like, and allowing the mixture to cool. The formulations prepared can be pptionally coated
with or contain one or more water-soluble or release rate controlling control release
polymers. The wax can be present in the formulation in a total amount by weight of, for
example, from about 10% to about 60%, preferably from about 20% to about 40%. A wide variety
of suitable waxes is amenable to the present invention. Nonlimiting examples of such waxes
include carnauba wax, cetostearyl alcohol, fatty acids, or a rnixture or two or more thereof. The
matrix tablet also can contain one or more release rate-controlling polymers as described herein.
31

WO 2007/030589 PCT/US2006/034813
t / U S O fk /'"! "4 P A 3
[0087]"'"'' "Ijri"some emboajuitents, the matrix tablet is a tablet that includes a polyethylene oxide
matrix, for example and not limitation, polyethylene oxide resins such as SENTRY POLYOX
(Union Carbide Corporation) or equivalents. Suitable POLYOX's include POLYOX™ WSRN-10,
N-60 K, WSR-1105N, or WSR 303. The POLYOX™ can have a molecular weight in the range of,
for example, 100,000 to 7,000,000, or 900,000 to 5,000,000. The polyethylene oxide can be. present
in the formulation in a total amount by weight of, for example, from about 5% or about 10% to
about 40%, or about 75% preferably from about 5% to about 40% or from about 10% to about 20%
of the formulation. The matrix tablet also can contain one or more release rate-controlling
polymers as described herein.
[0088] In some embodiments, the matrix tablet is a tablet that includes one or more release rate
controlling polymers as described herein as the matrix forming polymer. In some embodiments,
such tablets include one or more matrix forming hydroxypropyl methyl celluloses as described
herein as the matrix forming polymer. In some preferred embodiments, it is advantageous to use a
high viscosity hydroxypropyl methylcellulose such as Methocel K4M at an amount by weight of,
for example, from about 15% to about 70%, preferably from about 18% to about 50%. Other high
. viscosity polymers can also be used such as, for example, Methocel™ Kl 5M, Methocel™ Kl OOM,
or Methocel™ E4M and the like. In some embodiments, a low viscosity hydroxypropyl
methylcellulose can be used, such as Methocel E50LV, Methocel™ E5, Methocel™ E6, or
Methocel E15LV or combinations thereof and the like. In certain embodiments, both a high
viscosity and a low viscosity hydroxypropyl methylcellulose can be used in the matrix. In some
embodiments, when the low density hydroxypropyl methylcelluloses is present in a range of from
about 15% to about 70%, preferably from about 25% to about 50%, the high density
hydroxypropyl methylcellulose is present in an amount by weight of from about 20% to about 50%.
[0089] In general, the active compound or ingredient can be contained within any layer of a
dosage form of the invention, and sustained release of the active compound can be achieved by
the use of a release rate controlling polymer either contained within the layer containing the
active compound, or in any layer encompassing the layer containing the active compound, for
example an enteric coating. Such an enteric coating can also be applied to pellets, beads or
spheroids containing active compound, or the active compound can be contained within the
enteric coating itself.
32

WO 2007/030589 PCT/US2006/034813
iH'-T /J 8 iCi i[1 P- •''"^^•l-lR! "B ""I
"•* [0090]' "''Irrsome'embdmWients'Oi'te tablet formulations of the invention, fee active '""' '
compound is present in an amount by weight of from about 0.02% to about 16%, preferably
from about 0.02% to about 4%.
[0091] Tablets of the invention can be coated with water-soluble film coat(s), coloring
agents, or coated with pH dependent or pH independent polymers to further control the rate
of release of active compound. In some embodiments, the tablets are coated with a subcoat, an
enteric coating or an overcoating, or any combination thereof. In some preferred embodiments,
the tablets of the formulations of the invention are coated with film.
[0092] The present inventions provides methods and/or processes for preparing sustained-
release formulations comprising 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof,
structurally related compounds, and/or metabolites. In one embodiment, a composition
comprising the active ingredient with at least one rate controlling polymer and at least one
organic acid is compressed for a time and under conditions effective for forming a tablet
thereof. In some embodiments, the tablet is further coated, e.g., with film.
[0093] In another embodiment, the active ingredient is mixed with at least one release rate
controlling polymer and a least one organic acid thereby forming a blend. The blend can be
further compressed for a time and under conditions to form a tablet. In some embodiments,
the tablet is further coated, e.g., with film. In a preferred embodiment, the blend is a dry
blend."
[0094] In some embodiments, the formulations are prepared by roller compaction. For
example, tablets can be prepared by granulation followed by milling. In some embodiments,
the active ingredient, filler (e.g., microcrystalline cellulose) and polymer (e.g.,
hydroxypropylmethylcellulose) are granulated and then milled. The milled granules are then
mixed with additional excipients, such as, for example, citric acid and magnesium stearate.
[0095] Also included in accordance with the present invention are any of the numerous
technologies that exist for attaining sustained release oral formulations including those
described above, as well as micro and macroencapsulation, fibers, matrices both polymeric
33

WO 2007/030589 PCT/US2006/034813
-"" (high density ana low density) and non-polymenc, foams, iiposomesj micelles, gels,
physically dispersed drug in polymeric, porous, slightly porous or non-porous matrices,
adsorption onto ion exchange resins, mixing with or adsorption onto chemically or
biologically degradable matrices and the like. The active compound can be formulated in such
a way that the drug achieves a single maximal concentration or can be formulated so that the
drug is pulsed in two or more peaks. Oral delivery can be via way of liquid or solid dosage
form. Liquid dosage forms include syrups, suspensions, emulsions, elixirs, and the like. The
liquid carrier can include an organic or aqueous base and can be further modified with suitable
pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives,
sweeteners, flavoring agents, suspending agents, thickening agents, colorants, viscosity
regulators, stabilizers or osmoregulators, or combinations thereof. The aqueous carrier can
also contain, for example, polymeric substances or oils.
[0096] The present invention also provides immediate release dosage forms. Immediate
release dosage forms of the present invention can comprise the active ingredient, for
example, 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally
related compounds, or metabolites. As in the sustained release formulations, in some
embodiments, the active ingredient is micronized. Preferably, the immediate release
formulations are substantially free of base.
[0097] In a preferred embodiment, the immediate release formulation comprises the active
ingredient, at least one filler and at least one lubricant. The formulations of the invention
additionally can include any of a variety of materials that confer beneficial properties to the
formulation. Such materials include, for example, solubility modifiers such as surfactants
such as, for example, sodium lauryl sulfate, acidic compounds, fillers, lubricants, antioxidants,
pH modifiers, chelating agents, disintegrants, binders, stabilizers, excipients including water
soluble excipients such as sugars, and water dispersing excipients such as macrocrystalline
cellulose, colloidal silicone dioxide, silicified microcrystalline cellulose and starch. The range
of lubricant is typically from about, for example, 0.2% to about 5% by weight. In one
embodiment of the present invention, the amount of lubricant in a 150 mg dosage form is from
about 0.5 to about 1 mg. The range of filler can be, for example, from about 70% to about 99%,
34

WO 2007/030589 PCT/US2006/034813
by Welgnt: Si one empoainientqf the present invention, the amount of filler in a 150 mg dosage
form is from about 80 to about 149 mg.
[0098] The immediate release dosage forms of the present invention can contain the active
compound in any convenient percentage and part in relation to the other ingredients.
Typically, the formulation comprises active ingredient in percentage of from about 0.05% to
about 10%.
[0099] For example, in one embodiment, immediate release formulations comprise about
297 parts of filler, and about 1.5 parts of lubricant per part of active ingredient, e.g., 4-cyano-
N-{(2R)-2-[4-(2,3-dmydro-benzo[l,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-
benzamide or pharmaceutically acceptable salt thereof.
[0100] Ixi another embodiment, immediate release formulations comprise about 29 parts of
filler, and about 0.15 parts of lubricant per part of active ingredient, e.g., 4-cyano-N-{(2R)-2-
[4-(2,3-dihydro-berizo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-pyridm-2-yl-ber^annde or
pharmaceutically acceptable salt thereof.
[0101] In another embodiment, immediate release formulations comprise about 148 parts of
filler, and about 0.75 parts of lubricant per part of active ingredient, e.g., 4-cyano-N-{(2R)-2-
[4-(2,3-dihydro-benzo[l,4]a^oxm-5-yl)-piperazm-l-yl]-propyl}-N-pyridm-2-yl-ben2amide or
pharmaceutically acceptable salt thereof.
[0102] In another embodiment, immediate release formulations comprise about 58 parts of
filler, and about 0.3 parts of lubricant per part of active ingredient, e.g., 4-cyano-N-{(2R)-2-
[4-(2,3-dmydro-berizo[l,4]dioxm-5-yl)-piperazm-l-yl]-propyl}-N-pyria%-2-yl-berizamide or
pharmaceutically acceptable salt thereof.
[0103] The immediate release formulations contemplated by the present invention can be in
any form suitable for administration to a mammal and are not limited to the examples
presented herein.
35

WO 2007/030589 PCT/US2006/034813
[0104]' ^Ine'plres"ent invention provides methods and/or processes for preparing immediate
release formulations comprising 4-cyano-N-{(2R)-2-[4-(233-dihydro-benzo[l,4]dioxin-5-yl)-
piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof,
and/or metabolites thereof. In one embodiment, a composition comprising the active
ingredient with at least one filler and at least one lubricant is compressed for a time and under
conditions effective to form a tablet thereof. In some embodiments, the tablet is further
coated, e.g., with film.
[0105] In some embodiments, the active ingredient is mixed with at least filler and a least
one lubricant thereby forming a blend. The blend can be further compressed for a time and
under conditions to form a tablet. In some embodiments, the tablet is further coated, e.g.,
with film.
[0106] In some embodiments, the formulations are prepared by roller compaction.
[0107] The immediate release dosage forms like the sustained release dosage forms can be,
for example, in the form of coated pellets, spheres, capsules, powder, or tablets.
[0108] Thus, in accordance with the present invention there are provided sustained release and
immediate release dosage forms, including oral and non-oral sustained release dosage
formulations. Accordingly, the present invention includes each of the numerous technologies
that exist for immediate release non-oral dosage formulations. Delivery of active compound in
accordance with the present invention can be via mucosal, vaginal, rectal, ocular, transdermal,
intrauterine, routes and the like.
[0109] The present invention therefore provides, inter alia, dosage forms for 4-cyano-N-
{(2R)-2-[4-(2,3-dmya^o-benzo[l,4]d^oxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-
benzamide, pharmaceutically acceptable salts thereof, structurally related compounds, and/or
metabolites, methods for immediate delivery of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
berizo[l,4]d^oxin-5-yl)-piperazm-l-yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically
acceptable salts thereof, structurally related compounds, and/or metabolites, and methods for
sustained delivery of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-
yl]-propyl}-N-pyridin-2-yl-benzamide, pharmaceutically acceptable salts thereof, structurally
36

WO 2007/030589 PCT/US2006/034813
feiatea'"'coftipounds,' and/or metabolites over an cxtcndta" period of time. In seme
embodiments, administration of the dosage form is once every 24 hours, once every 12 hours,
or once every 6 hours.
[0110] The dosage forms described herein facilitate the immediate or sustained release of
active compounds in a mammal through many routes, including oral administration. In some
preferred embodiments, the dosage forms include the compound 4-cyano-N-{(2R)-2-[4-(2,3-
dmydro-benzo[l,4]dioxm-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide,
preferably the hydrochloride salt thereof, commonly referred to as lecozotan.
[0111] In preferred embodiments of the present invention, oral sustained release dosage
forms comprising the drug lecozotan and a pharmaceutically acceptable carrier are provided.
In one aspect, sustained release dosage forms comprising lecozotan, such as those described
herein, possess improved pharmacokinetic profiles as compared to immediate release dosage
forms. When administered to a patient population, oral dosage forms comprising lecozotan
achieve a mean maximum (e.g., peak) plasma concentration (Cmax) of lecozotan in the patient
■ population and a mean minimum plasma concentration (Cmjn) of lecozotan in the patient
population. Preferred sustained release dosage forms of the present invention will minimize ,
the variance between the Cmax and Cm;n plasma levels in the patient population. In particular,
preferred sustained release dosage forms of the present invention will minimize the variance
between the maximum and trough plasma levels in the patient population.
[0112] As used herein peak or maximum concentration (Cmax) of an active ingredient, such
as lecozotan, in blood plasma, area under concentration vs. time curve (AUC) of an active
ingredient, such as lecozotan, in blood plasma, and time to maximal plasma concentration
(tmax) of an active ingredient, such as lecozotan, in blood plasma are pharmacokinetic
parameters known to one skilled in the art. (Applied Biopharmaceutics and
PharmacokiJtetics, Chapter 7; Scargle and Yu, 4th edition, 1999). Unless otherwise
indicated, the pharmacokinetic parameters are measured at steady state in a fasting
population. The concentration vs. time curve measures the concentration of active ingredient
in blood serum of a subject verses time after oral administration of a dosage form. "Cmax" is
the maximum concentration of active ingredient in the blood serum of a subject after
administration of the dosage form to the subject, "tmax" is the time to reach maximum
37

WO 2007/030589 PCT/US2006/034813
T / 8 .8 'lR O B / "^ ILI-li:;;|i 1 3
ebhcenfct'ioifdf ffitivfelngrdcKcntin the blood serum of a subject following administration of ■•*
the dosage form to a subject. The plasma drug concentration at any time following drug
administration is referenced as Ctime, as in Cph or C24h.. "Ctr0Ugh" refers to the plasma drug
concentration at the end of the dosing interval. The "plasma drug concentration" or "plasma
concentration" is, generally expressed as mass per unit volume, typically nanograms per
milliliter.
[0113] Persons of skill in the art appreciate that plasma drug concentrations obtained in
individual subjects will vary due to interpatient variability in the many parameters affecting
drug absorption, distribution, metabolism and excretion. For this reason, unless otherwise
indicated, mean values obtained from groups of patients ("patient populations.") are used
herein.
[0114] As used herein, the area under concentration vs. time curve (AUC) of active
ingredient, e.g., lecozotan, in blood plasma is calculated according to the linear up / log down
trapezoidal rule. The "delivery rate" or "rate of absorption" is estimated by comparison of
the time (W) to reach the maximum concentration (Cmax). Both Cmax and tmax are analyzed
using non-parametric methods. Comparisons of the pharmacokinetics of immediate and
sustained release formulations are performed by analysis of variance (ANOVA). P <0.05 is
considered significant. Results are given as mean values +/- SEM. Equivalence of a
pharmacokinetic parameter generally refers to the 90 % confidence interval of the ratio of the
central values of the pharmacokinetic parameter of the test formulation to the reference
formulation being contained within about 0.8 to about 1.25.
[0115] In one aspect of the present invention, the sustained release formulations will
achieve a Cmax in a patient and a C24 in a patient wherein the mean ratio of Cmax/C24 in a
patient population is from about 5:1 to about 1.1:1. In some preferred embodiments, the
mean ratio of Cmax/C24 in a patient population is from about 3:1 to about 1.1:1, from about
2.8:1 to about 1.1:1, from about 2.5 to about 1.1:1, from about 2.3:1 to about 1.1:1 or even
from about 2:1 to about 1.1:1 or from about 1.5:1 to about 1.1:1. Accordingly, in certain
embodiments, the mean ratio of Cmax/C24 in a patient population is about 5. In other
embodiments, the mean ratio of Cmax/C24 in a patient population is about 3, about 2.8, about
2.5 or even about 2.3, about 2, or about 1.5. In certain embodiments, these Cmax and C24
38

WO 2007/030589 PCT/US2006/034813
"v/*** jf ti ft if"*1' 'Vfy. it'"1 i.*' """U fl It II""!' "}[ "'"(l
^yaluerafe'imeasuted. after aSministration of a single'dose Of the drug to a. patient. In some
embodiments, a 5 mg single dose of the drug is administered. In other embodiments, these
Cmax and C24 values are measured at steady state in a fasting population.
[0116] In one aspect of the present invention, the sustained release formulations will
achieve a Cmax in a patient and a C24 in a patient wherein the mean ratio of Cmax/C24 in a
patient population is from about 2.4:1 to about 1.1:1, from about 2.3:1 to about 1.1:1, from
about 2:1 to about 1.1:1, from about 1.9 to about 1,1:1, from about 1.5:1 to about 1.1:1 or
from about 1.25:1 to about 1.1:1. Accordingly, in certain embodiments, the mean ratio of
Cmax/C24 in a patient population is about 2.3. In other embodiments, the mean ratio of
Cmax/C24 in a patient population is about 2, about 1.9, about 1.5 or even about 1.25. In one
aspect, these Cmax and C24 values are measured at steady state in a fasting population, e.g.,
after 28 daily doses of the drug to a patient. In some embodiments, the drug is administered
at a daily dose of 10 mg. In other embodiments, these Cmax and C24 values are measured after
administration of a single dose of the drug to a patient.
[0117] In some embodiments, the variation between Cmax and Cn or C24 in a patient
population can be characterized as a percent variation. For example, in certain aspects, the
mean ratio of Cmax/C24 or Cmax/Ci2 in a patient population that has been administered
lecozotan will vary no more than about 250%. In other embodiments, the mean ratio of
Cmax/C24 or Cmax/Ci2 in a patient population will vary no more than about 100%, about 50%,
about 30%, or even about 25%. In some embodiments, the Cmax and C12 or C24 are measured
at steady state. In other embodiments, the Cmax and Cmjn are measured after administration of
a single dose of the drug to a patient.
[0118] In certain aspects of the present invention, the sustained release formulations will
achieve a mean Cmax in a patient population and a mean C24 in a patient population wherein
the ratio of mean Cmax/mean C24 is from about 5:1 to about 1.1:1. In some preferred
embodiments, the ratio of mean Cmax/mean C24 is from about 2.8:1 to about 1.1:1, from about
2:4 to about 1.1:1, from about 2.3 to about 1.1:1, from about 2:1 to about 1.1:1, from about
1.5:1 to about 1.1:1 or even from about 1.25:1 to about-1.1:1. Accordingly, in certain
embodiments, the ratio of mean Cmax/mean C24 is about 5, about 2.8, about 2.4, about 2.3,
about 2, about 1.5, or even about 1.25. In one aspect, these Cmax and C24 values are measured
39

WO 2007/030589 PCT/US2006/034813
X / S l!«? JR !H ••''■ "^ l!+ H "* ";;;|1
after atmnmstfalion of a single dose of the drug to a patient. In some embodiments, a 5 mg
single dose of the drug is administered. In one aspect, these Cm^ and C24 values are
measured at steady state in a fasting population, e.g., after 28 daily doses of the drug to a
patient.
[0119] In one aspect of the present invention, the sustained release formulations will
achieve a mean Cmax in a patient population and a mean Cn in a patient population wherein
the ratio of mean Cmax/mean C\2 is from about 3:1 to about 1.1:1. In some preferred
embodiments, the ratio of mean Cmax/mean Cn is from about 2.3:1 to about 1.1:1, from about
2:1 to about 1.1:1, from about 1.9 to about 1.1:1, from about 1.5:1 to about 1.1:1 or from
about 1.25:1 to about 1.1:1. Accordingly, in certain embodiments, the ratio of mean
Cmax/mean C12 is about 2.3. In other embodiments, the ratio of mean Cmax/mean Ci2 is about
2, about 1.9, about 1.75 or even about 1.5, about 1.4, about 1.3, about 1.25, about 1.2, or
about. 1.1. In some embodiments, the Cmax and C]2 are measured at steady state. In other
embodiments, the Cmax and C12 are measured after administration of a single dose of the drug
to a patient. In some embodiments, the drug is administered at a dosage of 5 mg.
[0120] Certain preferred sustained release formulations maintain therapeutic levels of
lecozotan over a 24 hour dosing period, thus providing for once daily dosing. Preferred
sustained release formulations also reduce the incidence or severity of side effects associated
with lecozotan therapy. The adverse side effects include headache, dizziness, paresthesia,
abnormal vision, tinnitus, or a combination thereof.
[0121] A decreased incidence of side effects refers to a reduced incidence of side effects in
a patient population, and not to a total absence of side effects, when measured in a
comparable population consuming an immediate release formulation of lecozotan.
[0122] Preferably, the sustained release formulations that have an improved
pharmacokinetic profile have a dissolution profile wherein no more than about 40% of
lecozotan is released at about 2 hours of measurement, and from about 50 to 85% of
lecozotan is released at about 12 hours of measurement.
40

WO 2007/030589 PCT/US2006/034813
[01237 ^TneTifssolutidn 61 the sustained release tablets or oral dosage forms is determined as
directed in the USP, using Apparatus II (paddles), at 50 rpm, in 900 milliliters of USP pH 6.8
phosphate buffer at 37°C. A sinker is used for each tablet or dosage form. A filtered sample
of the dissolution medium is taken at the time(s) specified. The amount of active ingredient
dissolved is determined by chromatographing the sample, along with a standard of known
concentration, on a reverse-phase high performance liquid chromatography column. The
concentration of active ingredient in each sample is determined by comparing the peak
responses of the sample chromatogram with the peak responses of the standard
chromatograms obtained concomitantly.
[0124] Certain sustained release formulations preferably reduce peak plasma levels of
lecozotan without have a substantial impact on either Cmin (e.g., trough) levels of lecozotan or
the extent of lecozotan absorption in the patient. Preferably, sustained release formulations
achieve certain pharmacokinetic parameters when compared to an immediate release dosage
form. One example of such an immediate release formulation is lecozotan, blended in
. microcrystalline cellulose, such as Avicel® brand from FMC Corporation, lactose
monohydrate and magnesium stearate that results in greater than 75% dissolution of the active
ingredient in less than 0.25 hours in a 0.1 N HC1 solution.
[0125] Certain sustained release formulations of the present invention preferably achieve a
mean Cmax in a patient population that is lower than the mean Cmax achieved in a patient
population administered an immediate release dosage form. Preferably, mean peak plasma
levels are reduced by at least about 10%, more preferably at least about 20%. In some
embodiments, mean peak plasma levels are reduced by at least about 30% or more. In some
embodiments, mean peak plasma levels are reduced by greater than 50%. Preferably, a single
dose of a 5 mg oral dosage formulation achieves a mean Cmax in a patient population that is
about 100 ng/ml or lower. In another aspect of the present invention, multiple daily doses of
10 mg of lecozotan achieve a mean Cmax in a patient population that is about 350 ng/ml. In
some embodiments, the Cmax is measured at steady state. In other embodiments, the Cmax is
measured after administration of a single dose of the drug to a patient.
[0126] Certain sustained release formulations of the present invention preferably achieve a.
mean tmax in a patient population that is greater than the mean tmax achieved in a patient
41

WO 2007/030589 PCT/US2006/034813
T /18 *% ill fi ■■'"' '"I! 4- R J "™l!
plopumlfHn^Mmirustered an immediate release, dosage,form Preferably, tmaA is doubled,
tripled, or even quadrupled. In certain embodiments of the present invention, the mean W
achieved in a patient population administered a sustained release dosage form of lecozotan is
from about 4 to about 8 hours.
[0127] Sustained release formulations of the present invention preferably achieve a mean
Qrough in a patient population that is substantially equivalent to the Ctr0Ugh achieved in a
patient population administered an immediate release dosage form. Maintaining comparable
trough levels to those obtained with immediate release dosage forms maintains the
therapeutic efficacy of the active ingredient. A mean Chough of at least 80% should be
achieved with the preferred sustained release formulations of the present invention over a 24-
hour interval when compared to immediate release dosage form over a 12-hour interval. In
some embodiments, the mean Chough is at least about 90% or at least about 95% when
compared to immediate release dosage form.
[0128] In order to maintain the therapeutic efficacy, it is also preferred that the total amount
of lecozotan absorbed from the sustained release dosage form (AUC) is. substantially
equivalent to the total amount of lecozotan absorbed from an immediate release formulation
over a 24 hour dosing interval. Accordingly, in preferred embodiments, the sustained release
dosage forms achieve a mean AUC in a patient population that is substantially equivalent to
the mean AUC achieved in a patient population administered an immediate release dosage
form. For example, a mean AUC of at least about 80% should be achieved with the preferred
sustained release formulations of the present invention when compared to immediate release
dosage form over a 24 hour interval. In some embodiments, the mean AUC is at least about
90% or at least 95% when compared to immediate release dosage form over a 24-hour
interval. The AUC should be no more than about 125% of the AUC of an immediate release
formulation.
[0129] The present invention provides methods comprising administering the sustained
release dosage forms to a patient. In certain embodiments, the sustained release dosage forms
are administered to treat Alzheimer's disease in a patient. In some embodiments, the
methods of adrninistering sustained release dosage forms also include a step of identifying a
patient at risk at adverse side effects through administration of lecozotan. In an exemplary
42

WO 2007/030589 PCT/US2006/034813
•'embodiment oittieTpfeseftt' invention, to identify subject patients for treatment according to
the methods of the invention, accepted screening methods can be employed to determine the
status of Alzheimer's disease in a subject In certain aspects, a routine medical history can be
taken to determine whether the patient already suffers from or is prone to suffer from one or
more of the side effects" associated with administration of immediate release dosage forms of
lecozotan. A patient that already suffers from one or more of these side effects or is prone to
suffer from one or more of these side effects can be classified as a patient at risk of adverse
effects through administration of lecozotan. In other aspects, an electrocardiogram can be
performed to determine if the patient has any cardiac abnormalities, e.g., slow heart rate, that
may indicate that he or she will be better treated with a formulation that has a reduced p^ax-
These and other routine methods allow the clinician to identify patients in need of therapy
using the methods and formulations of the invention.
[0130] Preferred sustained release formulations of the present invention achieve certain mean
pharmacokinetic parameters in a patient population. The patient population is selected in
accordance with standard procedures for performing randomized studies. The patient population
comprises at least 12 people selected without prior knowledge of the manner in which drugs of ■
this class would be metabolized in them.
43

WO 2007/030589 PCT/US2006/034813
iX^IJS CM / 3. s+ S JL 3
Example 1: Identification of metabolites of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxin-5-yI)-piperazin-l-yIJ-propyl}-N-pyridin-2-yI-benzamide
[0131] Four metabolites referred to as M8, Ml 1, M12, and M13 were isolated by solvent
(ethyl acetate containing 10% methanol) extraction followed by semi-preparative HPLC. The
semi-preparative HPLC separation was conducted on a xTerra CI8 column (7.8 x 300 mm,
10 \im), and a gradient of acetonitrile/water containing 10 mM ammonium acetate (pH=4.5)
was used as the mobile phase.
[0132] . The structures of the metabolites were determined based on NMR and mass spectra
data. For NMR, all samples were dissolved in CD3CN. For sample Mil, about 10% D20
was added to increase solubility. Proton and COSY data were acquired on all samples. For
the samples containing Mil and Ml2, FISQC and HMBC data were also acquired to
determine the structures.
[0133] Mil, M12 and Ml3 metabolites were formed through hydroxylation at the
dihydrobenzo-[l, 4]dioxin-piperazine moiety. The NMR studies were conducted to
determine the locations of the hydroxylation in these metabolites and to confirm the structure
ofM8.
[0134] Mil: ID proton spectrum of Ml 1 showed two aromatic protons of the 2,3-dihydro-
benzo[l,4] dixon moiety instead of 3 as in the parent compound, indicating the hydroxylation
occurred on the benzene ring. The two proton signals are doublets suggesting the
hydroxylation occurred either on C6 or Cg positions. To distinguish the two regio isomers, a
ID NOE experiment was carried out, since relatively strong NOE correlations between the
benzene proton H6 and the piperazine protons are expected for Cg hydroxylation, but not for
Cg hydroxylation. Such NOE correlations were indeed observed in the ID NOE experiment.
Therefore the structure of Ml 1 is as shown below where the hydroxyl group is on Cg of the
2,3-dihydro-benzo[l .4] dixon moiety.
44

WO 2007/030589 PCT/US2006/034813

[0135] M12: ID proton spectrum of M12 was more complicated than expected for the
metabolite. ' A careful analysis of the spectrum however, suggested the sample contained
. isomers. Comparison of the proton spectrum of the Ml2 metabolite with that of the parent
compound indicated that the aromatic moieties and the piperazine moiety are intact in Ml 2.
The protons of the 1,4-dioxin ring however, are quite different Three methine signals are
observed at 5.5, 5.15 sand 5.1 ppm. These methine protons integrated into one equivalent
proton for the sample. The HSQC data showed that the carbon shifts of these methine groups
are between 80 to 88 ppm, suggesting the hydroxylation on one of the dioxin methylenes.
COSY spectrum showed that the down-filed methine proton correlates to the methylene
protons of the dioxane ring, confirming the hydroxylation on the dioxane ring. The fact that
more than two sets of signals were observed indicates chiral isomers existed in the sample.
Whether the chiral isomers were generated by the enzymes or through racemization in the
sample purification steps is not clear. Based on the NMR results the structure of Ml 2 is as
shown below:

[0136] M13: Comparison of the proton spectrum of M13 with that of M12 suggests M12
and Ml 3 are very similar. All aromatic protons observed in the parent compound were
observed in Ml 3 suggesting that the aromatic moieties are intact in the metabolite. It
45

WO 2007/030589 PCT/US2006/034813
appeared that in MB, trie hydroxyiation also occuired on the dioxin ring. Similar to Mi 2,
M13 contained isomers as indicated by four methine protons observed at 5.5, 5.19, 5.10 and
4.86 ppm. It was noted that over time the intensity of these four methine signals changed,
suggesting the ratio of the isomers have changed. Similar changes were observed in Ml 2.
Combined with the results from Ml 2 analysis, it appeared that the observed NMR spectra of
Ml 2 and Ml 3 might not represent the original components. The NMR analysis indicated
that Ml 2 and Ml 3 were produced by hydroxyiation on the dioxane ring, corresponding to 2
and 3 positions, respectively. Ml 2 and Ml 3 can rearrange, and both can be racemized.

[0137] M8: Proton and COSY spectra of M8 were acquired for this sample. The data are
consistent with the proposed structure for M8 based on MS/MS analysis performed by DSM.
The pyridine moiety, the piperazine moiety and the cyano-propyl benzamide moieties are all
intact. Compared with the parent compound, the only group missing is the 2,3-dihydro-
benzo[ 1,4] dioxin moiety.

Example 2: Identification of compounds structurally related to 4-cyano-N-{(2R)-2-[4-
(2,3-dihydro-benzo[l,4]dioxin-5-yI)-piperazin-l-yl]-propyI}-N-pyridin-2-yl-benzamide
[0138] Structurally related compounds represented by Formulas 2-9 were identified. The
structurally related compounds were isolated from a preparation comprising 4-cyano-N-
{(2R)-2-[4-(2,3-dmyoio-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-
benzamide by preparative chromatography in the amounts of about 1 mg with the purity of
46

WO 2007/030589 PCT/US2006/034813
were established by nuclear magnetic resonance spectroscopy..
electrospray ionization mass spectrometry and determination of the number of exchangeable
protons.
[0139] A preparation comprising 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-
yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl--benzamide hydrochloride salt was further
processed as follows. The starting material was converted to base by treatment with aqueous
sodium hydroxide and ethyl acetate. The resulting ethyl acetate solution was dried
azeotropically, diluted with heptane to give a 3:1 ethyl acetate heptane mixture and treated
with silica gel. The resulting mixture was filtered and concentrated repeatedly to remove
heptane. -The base was treated in ethyl acetate solution with 1.0 equivalent of hydrogen
chloride in ethyl acetate. The product was dissolved in hot denatured ethanol. The mixture
was filtered and concentrated. The product was crystallized by cooling and isolated by
filtration. The final wet cake was dried. This process reduced the levels of dimeric
impurities of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-
propyl} -N-pyridin-2-yl-benzamide.
47

WO 2007/030589 PCT/US2006/034813

Example 3: Representative sustained release formulations of the present invention.
Ingredient Function of
Ingredient Amount per Tablet (mg)
Fast Medium Slow
Active Core:
4-cyano-N-{(2R)-
2-[4-(2,3-dihydro-
benzo [ 1,4] dioxin-
5-yl)-piperazin-l-
yl]-propyl}-N-
pyridin-2-yl-
benzamide
hydrochloride* Active 5.0 5.0 5.0
Silicified
microcrystalline,
cellulose
(ProSolv®KD90) Filler 169.0 94.0 88.75
HPMC
(MethocerK4M
Premium CR) Polymer 50.0 125.0 37.5
HPMC
(MethocefKlOOM
Premium CR) Polymer 112.75
MgStearateNF Lubricant 1.0 1.0 1.0
Citric Acid,
Anhydrous To improve .
release
rate in intestine' 25.0 25.0 5.0
Weight of Core
(mg) 250 250 250
Film Coating:
Opadry White
(YS-1-
18202A) White Film 7.5 7.5 7.5
Opadry Clear (YS-
1-
19025A) Clear Film 1.25 1.25 1.25
Total Tablet
Weight(mg) 258.75 258.75 258.75
a: The amount of active ingredient may need to be adjusted according to its release
potency. ....'..
48

WO 2007/030589 PCT/US2006/034813

Exanfplfe^:"Rfepfeseriiaftve'sustaine.d release formulations of the present inveiiiiuc.
Ingredient Function of
Ingredient Amount per Tablet (mg)
4-cyano-N-{(2R>
2-[4-(2,3-dihydro-
benzo[l ,4]dioxin-
5-yl)-piperazin-l-
yl]-propyl}-N-
pyridin-2-yl-
benzamide
hydrochloride3 Active 5.0 2.0
Microcrystalline
cellulose
(Avicel®PH112) Filler 46.5 52.5
Fast-Flow Lactose Filler 100.00 100.00
HPMC
(Methocel™K4M
Premium CR) Polymer 55.00 55.00
HPMC™
(Methocel™
K100LV Premium
CRLH) Polymer 37.50 37.50
Mg Stearate NF Lubricant 1.0 1.0
Citric Acid,
Anhydrous To improve
release
Rate in intestine 5.00 2.00
Weight of Core
(mg) 250 250
Opadry White
(YS-1-
18202A) White Film 7.5 7.5
Opadry Clear
(YS-1-
19025A) Clear Film 1.25 1.25
Total Tablet Wt
(mg) 258.75 258.75
a: The amount of active ingredient may need to be adjusted according to its release
potency.
49

WO 2007/030589 PCT/US2006/034813
•"r/lflf'Rin!R./3»4.ai.3. ... . . . . . •
JB/xampie D: jR.epreseui.auve IUUJUICU
i»ie release j. uimuiauuus ui me pieseui luveuuuu.
0.5 mg Tablets
Claim % Input
Ingredient (TOR) Wt/Wt (me/tablet)
Active ingredients micronized % 0.5 0.33 0.50
Lactose Monohydrate, NFb 79.17 118.75
Microcrystalline cellulose, NF 20.00 30.00
Magnesium stearate, NF .50 0.75
Total 100.0 150.00
The active ingredient is 4-(^ano-N-{(2R)-2-[4-(2,3-d2hydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-
pyridin-2-yl-benzamide hydrochloride

a: The active moiety portion (free base) is theoretically 93% of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride drug
substance. Actual amounts added are based on the potency of the hydrochloride drug substance.
Inputs listed in the table above are based on the weight of the active ingredient

b: If the hydrochloride drug substance is not at 100% potency, adjustment to the drug substance input
must be made with corresponding adjustment to the lactose monohydrate input.

c: - Includes an excess quantity. Theoretical quantity is 0.075 Kg. 1.0 mg Tablets,

Claim % Input
Ingredient (mg) Wt/Wt (mg/tablef)
Active ingredients micronized % b 1.0 0.67 1.0
Lactose Monohydrate, NFb 78.83 118.25
Microcrystalline cellulose, NF 20.00 30.00
Magnesium stearate, NF 0.50 0.75
Total 100.0 150.00
The active ingredient is 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-
pyridin-2-ykbenzamide hydrochloride

a: The active moiety portion (free base) is theoretically 93% of 4-cyano-N-{(2R)-2-[4-(2,3-dihydrc~
benzo[l,4]dioxin-5-yl)-piperazin- l-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride drug
substance. Actual amounts added are based on the potency of the hydrochloride drug substance.
Inputs listed in the table above are based on the weight of the active ingredient

b: If the hydrochloride drug substance is not at 100% potency, adjustment to the drug substance input
must be made with corresponding adjustment to the lactose monohydrate input

c: fecludes an excess quantity. Theoretical quantity is 0.075 kg
50

WO 2007/030589 PCT/US2006/034813

2.5 mg Tablets
Claim % Input
Ingredient (me) Wt/Wt fme/tablef)
Active ingredients micronized *■ b 2.5 1.67 2.50
Lactose Monohydrate, NFb 77.83 116.75
Microcrystalline cellulose, NF 20.00 30.00
Magnesium stearate, NF .50 0.75
Total 100.0 150.00
The active ingredient is 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-
pyridin-2-yl-benzamide hydrochloride

a: The active moiety portion (free base) is theoretically 93% of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxin-5-yl)-piperazm-l-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride drug
substance. Actual amounts added are based on the potency of the hydrochloride drug substance.
Inputs listed in the table above are based on the weight of the active ingredient

b: If the hydrochloride drug substance is not at 100% potency,-adjustment to the drug substance input
must be made with corresponding adjustment to the lactose monohydrate input

c: Includes an excess quantity. Theoretical quantity is 0.075 kg

5.0 mg Tablets
Claim % Input
Ingredient (mg) Wt/Wt (mg/tablet)
Active ingredients micronized ^ 5.0 3.33 5.0
Lactose Monohydrate, NFb 76.17 114.25
Microcrystalline cellulose, NF 20.00 30.00
Magnesium stearate, NF .50 0.75
Total 100.0 150.00
The active ingredient is 4-cyano-N-{(2R)-2-[4-(23-dmydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]-propyl}-N-
pyridin-2-yl-benzamide hydrochloride

a: The active moiety portion (free base) is theoretically 93% of 4-cyano-N-{(2R)-2-[4-(2,3-dihydro-
benzo[l,4]dioxm-5-yl)-pipera2m-l-yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride drug
substance. Actual amounts added are based on the potency of the hydrochloride drug substance.
Inputs listed in the table above are based on the weight of the active ingredient

b: If the hydrochloride drug substance is not at 100% potency, adjustment to the drug substance input
must be made with corresponding adjustment to the lactose monohydrate input

c: Includes an excess quantity. Theoretical quantity is 0.075 kg
Example 6: Representative manufacturing directions for representative immediate
release tablets
1. Dispense the lactose monohydrate and microcrystalline cellulose into suitable
containers.
2. Dispense the 4-cyano-N-{(2R)-[4-(2)3-dihydro-benzo[l,4]dioxin-5-yl)-piperazui-l-
yl]-propyl}-N-pyridin-2-yl-benzamide hydrochloride into a suitably sized tumbler
mixing bowl. Add a small portion of the dispensed lactose monohydrate and mix into
a tumbling mixer.
51

WO 2007/030589 PCT/US2006/034813
. ■ -ir s y ej ip,| IR y "^ 54.;F| II "SB
■ 3\ * Fa§'s ffie pre-brena'fifom step 2, followed by the microcrystalline cellulcse, through a
500 |im screen into a suitably sized tumbler mixer bowl. Mix.
4. Transfer the pre-blend from step 3 into a suitably sized tumbler mixer bowl. Pass the
remaining lactose monohydrate through a 500 urn screen into the mixing bowl. Mix.
5. Weigh the blend and calculate the amount of magnesium stearate required for the
batch. Dispense the magnesium stearate into a suitable container, and mix with a
portion of the blend from step 4.
6. Pass this pre-mix through a 500 urn screen and into the remaining blend in the mixing
bowl. Mix the final blend.
7. Compress the blend from step 6 using a suitable compression machine fitted with
appropriate tooling, to produce tablets with the required weight and hardness.
8. De-dust,, weight check, and visually inspect the finished tablets.
Example 7: Single dose study between three sustained release formulations and an
immediate release formulation of lecozotan
[0140] This study was a single-dose, randomized, 4-period, crossover, bioequivalence study
between three modified release formulations and an immediate release formulation of
lecozotan in healthy subjects. Doses were administered orally after an overnight fast of at
least 10 hours. Formulations used in this study were 5 mg of an immediate release (IR), 5 mg
of a modified fast-release formulation (MR (fast)), 5 mg of a modified medium-release
formulation (MR (medium)), and 5 mg of a modified slow-release formulation (MR (slow)).
These-formulations are provided in Example 3. Blood samples for lecozotan analysis were
obtained within 2 hours of test article administration and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12,
16,24,30, 36 and 48 hours after test article administration.
[0141] Plasma concentration data and PEL parameters of lecozotan were compared between
the four formulations using an analysis of variance for a four-period crossover study.
Additionally, the geometric mean (log-transformed) relative bioavailability of the maximum
observed concentration (Cmax) of lecozotan, area under the concentration-time curve (AUC)
and AUC up to the time of the last quantifiable concentration (AUGr) and their 90%
confidence limits were estimated to determine the magnitude of difference in these
parameters between the 4 formulations. The lecozotan immediate release tablet was used as
the reference treatment. The 90% confidence limits for parameter estimates were constructed
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WO 2007/030589 PCT/US2006/034813
'on-;th64r6g scile using1,the 2 1-sided tests procedure. The 4 treatments (formulations) were
judged to be bioequivalent if the 90% confidence limits fell within the interval (0.80,1.25).
[0142] A total of 20 subjects contributed pharmacokinetic data for this analysis. Figure 1
provides mean concentrations of lecozotan versus time for the four formulations. As shown
by Figure 1, the mean Cmax for the IR formulation is 278.5 ng/mL. The mean values for the
modified release formulations are below 100 ng/mL. The MR (fast) and MR (medium)
formulations have Cmax values of 99.7 and 95.1 ng/mL, respectively. The MR (slow)
formulation has a Cmax value of 58.4 ng/mL. The Tmax for the IR formulation occurs at 0.88
hours. Tmax values for the MR (fast), MR (medium) and MR (slow) occur at 5.63, 8.83 and
7.90 hours, respectively.
[0143] AUC values for the IR, MR (fast) and MR (medium) formulations range from
2058.8 to 2246.8 ng h/mL. The AUC value for the MR (slow) formulation is 1565.0 ng
h/mL. The mean AUC ratio of MR to the IR formulations is above 100% for the MR (fast)
and MR (medium). The mean ratio of AUC for MR (slow) to IR is 79.3%. The mean ratio
of Cmax lecozotan concentrations at 24 hours (Cmax/C24 h ratio) ranges from 23 for the IR
formulation to values of 2.8, 2.3 and 3.5 for the MR (fast), MR (medium), MR (slow)
formulations, respectively.
Example 8: Multiple dose study between three sustained release formulations and an
immediate release formulation of lecozotan
[0144] This study was a randomized, double-blind, placebo-controlled study to assess
safety, tolerability, pharmacokinetic and pharmacodynamic study of 1) ascending multiple-"
doses of 0.5,1,2.5 and 5 mg lecozotan administered orally as a twice daily regimen (ql2h) to
patients with mild to moderate Alzheimer's disease (AD; age range = 53 to 80 yrs) using the
immediate-release (TR) formulation and 2) multiple doses of 10 mg administered orally as
once-daily regimen (QD) to patients with mild to moderate Alzheimer's disease using the
sustained-release (SR) formulation.
PART 1: TR FORMULATION
53

WO 2007/030589 PCT/US2006/034813
°[0l45f* L>IX subjects received lecozotan and 2 received placebo in the 0.5, 1 and 2.5 mg dose
groups (cohorts 1- 3) whereas 12 subjects received lecozotan and 4 received placebo in the 5
mg dose group (cohort 4). Blood samples for lecozotan analysis were obtained on days 1 and
28 within 2 hours of test article administration and at 0.5,1,1.5, 2, 4, 8, 24 (day 1 only) and
28 (day 28 only) hours after test article administration.
PART 2: SR FORMULATION
[0146] In this part of the study, 12 subjects received lecozotan (10 mg QD of SR
formulation) and 4 received placebo. Blood samples for lecozotan analysis were obtained at
predose (within 2 hours of test article administration), 0.5, 1, 1,5, 2, 4, 8, 24 hours post dose
on day 1 and at predose, 1,2, 4, 8,24, 48 and 72 hours post dose on day 28.
[0147] A total of 11 AD patients (age range =52 to 90 yrs) contributed pharmacokinetic data
for this analysis. After both single and multiple dose adrninistration of the SR formulation, a
plateau-like concentration vs. time profile was seen for all subjects up to a period of 24 hours,
with peak/trough fluctuation (i.e. Cmax/Cmin) = 1.9 at steady-state. Lecozotan concentrations
were seen to start declining after 24 hours. In part 1, mean tmax for lecozotan with the IR
formulation was seen to range from 1 — 1.5 hours after both single and multiple dose
administration. In comparison, lecozotan mean tmax values with the SR formulation after
single and multiple dosing were 8 and 4 hrs, respectively. The dose dependent
pharmacokinetic parameters Cmax and AUC0-24 after single dose adrninistration of the SR
formulation at a dose of 5 mg and 10 mg is as follows: 5 mg SR single dose: Cmax = 99.7
ng/mL, AUCo-24 = 1845 ng hr/mL; 10 mg SR single dose: Cmax = 210.4 ng/mL, AUC0-24 =
3738.3 ng hr/mL).
[0148] Based on pharmacokinetic modeling of single dose plasma concentration data
obtained with 5 mg SR formulation, it was predicted that at steady state, a QD regimen of the
SR formulation is predicted to achieve similar exposure (AUCo-24), a lower Cmax and a similar
Cmj„ in comparison to the ql2h regimen with the IR formulation. In agreement with these
predictions, the mean lecozotan steady-state total daily exposure (AUCo-24) was 5788
ng*hr/mL after administration of 5 mg ql2h IR formulation and 6111 ng*hr/mL after
adrninistration of 10 mg QD SR formulation in AD patients. Mean lecozotan steady-state Craax
54

WO 2007/030589 PCT/US2006/034813
rWaS 45Vn|riffiTm6derpfe"dicted = 425 ng/mL) with 5 mg ql2h IR regimen in comparison to
the mean steady-state Cmax of 353 ng/mL (model-predicted = 319 ng/mL) with 10 mg QD SR
formulation. Trough concentrations at the end of the dosing interval are 180 ng/mL and 184
ng/mL for 5 mg ql2h of IR and 10 mg QD of SR formulations, respectively. Mean Cmax/Cmjn
ratio at steady-state for 10 mg QD SR formulation was 1.91. Mean Cmax/Cmjn ratio at steady-
state for 5 mg ql2h of IR was 2.4. Mean tmax with the 5 mg ql2h IR regimen was 0.8 while
mean tmax with 10 mg QD SR formulation was 4.2.
Example 9: Adverse Effects.
[0149] The following table demonstrates that the incidence of side effects was reduced
following treatment with sustained release formulations of lecozotan as compared to the
immediate release formulation of lecozotan.

Treatment of Emergent Adverse Events (TEAEs)
Immediate Release (IR) vs. Sustained Release Formulation
TEAE Lecozotan 5 mg
IR Lecozotan 5 mg
SR- fast Lecozotan 5 mg
SR- medium
Headache 1 0 0
Dizziness 9 0 1
Paresthesia 1 0 0
Abnormal Vision 2 0 0
Tinnitus 1 0 0
Total 14 0 1
[0150] Although the foregoing invention has been described in detail by way of example
for purposes of clarity of understanding, it will be apparent to the artisan that certain changes
and modifications are comprehended by the disclosure and can be practiced without undue
experimentation within the scope of the appended claims, which are presented by way of
illustration not limitation.
[0151] All publications and patent documents cited above are hereby incorporated by
reference in their entirety for all purposes to the same extent as if each were so individually
denoted.
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WO 2007/030589 PCT/US2006/034813
whatTs"claimea:
1. A method comprising administering to a patient.an oral dosage form that comprises
lecozotan and a pharmaceutically acceptable carrier and achieves a maximum plasma
concentration (Cmax) in a patient and a 24 hour plasma concentration (C24) in a
patient, wherein a mean ratio of Cmax/ C24 in a patient population is from about 5:1 to
about 1.1:1.
2. The method of claim 1, wherein the Cmax and C24 values are measured after
administration of a single dose of the oral dosage form to a patient.
3. The method -of claim 2, wherein the oral dosage form comprises about 5 mg of
lecozotan.
4. The method of claim 2, wherein the mean Cmax in the patient population is about 100
ng/ml or lower.
5. The method of claim 1, wherein the mean ratio of Cmsx/ C24 in the patient population
is from about 3:1 to about 1.1:1.
6. The method of claim 5, wherein the Cmax and C24 values are measured after
administration of a single dose of the oral dosage form to a patient.

7. The method of claim 1, wherein the mean ratio of Cmax/ C24 in the patient population
is from about 2.8:1 to about 1.1:1.
8. The method of claim 1, wherein the mean ratio of Cmax/ C24 in the patient population
is from about 2.3:1 to about. 1.1:1.
9. The method of claim 1, wherein the mean tmax in the patient population is about 3.5
hours or greater.
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WO 2007/030589 PCT/US2006/034813
T / 8 ft "3,11 H /' ""•!! HM113
10. * Tab metKod of claim 1, wherein the mean tmax in the patient population is'about 5
hours or greater.
11. A method comprising administering to a patient an oral dosage form that comprises
lecozotan and a pharmaceutically acceptable carrier and achieves a maximum plasma
concentration (Cmax) in a patient and a 24 hour plasma concentration (C24) in a patient,
wherein a mean ratio of Cmax/C24 in a patient population is from about 2.4:1 to about
1.1:1.
12. The method of claim 11, wherein the Cmax and C24 values are measured at steady state
in a fasting population.
13. The method of claim 12, wherein about 10 mg of lecozotan is provided daily to the
patient.
14. The method of claim 12, wherein the mean Cmax is about 350 ng/ml.
15. The method of claim 11, wherein the mean ratio of Cmax/C24 in the patient population
is from about 2.3:1 to about 1.1:1.
16. The method of claim 11, wherein the mean ratio of Cmax/C24 in the patient population
is from about 2:1 to about 1.1:1.
17. The method of claim 11, wherein the mean ratio of Cmax/C24 in the patient population
is from about 1.9:1 to about 1.1:1.
18. The method of claim 11, wherein the mean ratio of Cmax/C24 in the patient population
is from about 1.5:1 to about 1.1:1.
-... 19, ^ A method comprising adrninistering to a patient an oral dosage form that comprises
lecozotan and a pharmaceutically acceptable carrier and achieves a mean maximum
plasma concentration (Cmax) in a patient population and a mean 24 hour plasma
57

WO 2007/030589 PCT/US2006/034813
USOS/3HBi3 +. ,■ ■ . .. , . , - n , r .
"concentration (C24) in a patient population, wherein a ratio 01 mean Cmax/mean C24 is
from about 5:1 to about 0.5:1.
20. The method of claim 19, wherein the Cmax and C24 values are measured after
administration of a single dose of the oral dosage form to a patient.
21. The method of claim 20, wherein the oral dosage form comprises about 5 mg of
lecozotan.
22. The method of claim 19, wherein the ratio of mean Cmax/mean C24 is from about 2.8:1
to about 1.1:1.
23. The method of claim 19, wherein the ratio of mean Craax/mean C24 is from about 2:1 to
about 1.1:1.
24. The method of claim 19, wherein the ratio of Cmax/mean C24 is from about 1.5:1 to
about 1.1:1.
25. A method comprising administering to a patient an oral dosage form that comprises
lecozotan and a pharmaceutically acceptable carrier and achieves a mean maximum
plasma concentration (Cmax) in a patient population and a mean 12 hour plasma
concentration (Cn) in a patient population, wherein a ratio of mean Cmax/mean Cn is
from about 3:1 to about 0.5:1.

26. The method of claim 18, wherein the ratio of mean Craax/mean C12 is from about 2:1 to
about 1.1:1.
27. The method of claim 18, wherein the ratio of mean Cmax/mean C12 is from about 1.5:1
to about 1.1:1.
28. A method for minimizing an adverse side effect associated with the administration of
lecozotan to a patient, comprising administering to a patient an oral dosage form that
comprises lecozotan and a pharmaceutically acceptable carrier and achieves a
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WO 2007/030589 PCT/US2006/034813
" nTaxiffi-iim' • plasma concentration (Cmax) in a patient and a 24 hour plasma
concentration (C24) in a patient, wherein a mean ratio of Cmax/ C24 in a patient
population is from about 5:1 to about 1.1:1.
29. The method of claim 28, wherein the Cmax and C24 values are measured after
administration of a single dose of the oral dosage form to a patient.
30. A method for minimizing an adverse side effect associated with the administration of
lecozotan to a patient, comprising administering to a patient an oral dosage form that
comprises lecozotan and a pharmaceutically acceptable carrier and achieves a
maximum plasma concentration (Cmax) in a patient and a 24 hour plasma
concentration (C24) in a patient, wherein a mean ratio of Cmax/ C24 in a patient
population is from about 2.4:1 to about 1.1:1.
31. The method of claim 30, wherein the Cmax and C24 values are measured at steady state
in a fasting population.
32. A method for rninirnizing an adverse side effect associated with the administration of
lecozotan to a patient, comprising
identifying a patient at risk of an adverse side effect through administration of
lecozotan; and
administering to a patient an oral dosage form that comprises lecozotan and a
pharmaceutically acceptable carrier and achieves a maximum plasma concentration
(Cmax) in a patient and a 24 hour plasma concentration (C24) in a patient, wherein a
mean ratio of Cmax/ C24 in a patient population is from about 5:1 to about 1.1:1.
33. The method of claim 32,. wherein the Cmax and C24 values are measured after
administration of a single dose of the oral dosage form to a patient.
34. The method of claim 32, wherein the adverse side effect is headache, dizziness,
paresthesia, abnormal vison, tinnitus, or a combination thereof.
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WO 2007/030589 PCT/US2006/034813
-35.- Trie method of clatm 323 wherein the incidences of the adverse side effects are
reduced.
36. A method for minimizing an adverse side effect associated with the administration of
lecozotan to a patient, comprising
identifying a patient at risk of an adverse side effect through administration of
lecozotan; and
administering to a patient an oral dosage form that comprises lecozotan and a
pharmaceutically acceptable carrier and achieves a maximum plasma concentration
(Cmax) in a patient and a 24 hour plasma concentration (C24) in a patient, wherein a
mean ratio of Cmsx/C24 in a patient population is from about 2.4:1 to about 1.1:1.
37. The method of claim 36, wherein the Cmax and C24 values are measured at steady state
in a fasting population.
38. The method of claim 36, wherein the adverse side effect is headache, dizziness,
paresthesia, abnormal vison, tinnitus, or a combination thereof.
39. The method of claim 36, wherein the incidences of the adverse side effects are
reduced.
40. A method for acbninistering lecozotan to a patient, the method comprising
administering to the patient an oral dosage form that comprises lecozotan and a
pharmaceutically acceptable carrier, wherein the dosage form exhibits an in vitro
dissolution profile when measured in a USP type II dissolution apparatus at 50 rpm, in
900 ml of USP pH 6.8 phosphate buffer at 37°C and a sinker is used for each dosage
form, wherein:
no more than 40 % of lecozotan is released at about 2 hours of measurement in
said apparatus; and
from about 50 % to about 85 % of lecozotan is released at about .twelve hours
of measurement in said apparatus.
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WO 2007/030589 PCT/US2006/034813
~41r A method for administering lecozotan to a patient, the method comprises
administering an oral dosage form that comprises lecozotan and a pharmaceutically
acceptable carrier to a patient and
(i) achieves a mean Cmax in a patient population that is less than the mean Cmax
obtained from administering an equivalent dose of lecozotan from an
immediate release formulation to the patient population;
(ii) achieves a mean tmax in a patient population that is greater than the tmax
obtained from administering an equivalent dose of lecozotan from an
immediate release formulation to the patient population; and
(iii) achieves a curve of concentration of lecozotan over time, the curve having an
area under the curve (AUC) in a patient population that is substantially the
same as the AUC obtained from administering an equivalent dose of lecozotan
from an immediate release dosage form to the patient population.
42. The method of claim 41, wherein the oral dosage form achieves a mean Cmax of about
lOOng/mlorless.
43. The method of claim 42, wherein when the Cmax is measured after administration of a
single dose of the oral dosage form.
44. The method of claim 43, wherein the oral dosage form comprises about 5 mg of '
lecozotan.
45. The method of claim 41, wherein the oral dosage form achieves a mean tmax of from
about 4 hours to about 8 hours.
46. The method of claim 41, wherein the oral dosage form achieves a mean AUC that is
from about 2000 to about 2500 ng h/mL.
47. The method of claim 46, wherein when the mean AUC is measured after
administration of a single dose of the oral dosage form.
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WO 2007/030589 PCT/US2006/034813
^/USQ6-^3NUS;!.3 ,-■.-.,. * .
48. The method of claim 4/, wherein the oral dosage form comprises about 5 uag of
lecozotan.
49. The method of claim 41, wherein the oral dosage form achieves a mean Cmax of less
than 400 ng/mL.
50. The method of claim 49, wherein the oral dosage form achieves a mean Cmax of about
350 ng/mL
51. The method of claim 49, wherein when the Cmax is measured at steady state in a
fasting population.
52. The method of claim 51, wherein 10 mg of lecozotan is administered daily to the
patient.
53. The method of claim 41, wherein the oral dosage form achieves a mean tmax of from
about 4 hours to about 8 hours.
54. The method of claim 41, wherein the oral dosage form achieves a mean AUC that is
from about 5500 to about 6300 ngh/mL.
55. A method for nnnimizing an adverse side effect associated with the administration of
lecozotan to a patient, the method comprises administering an oral dosage form that
comprises lecozotan and a pharmaceutically acceptable carrier to a patient and
(i) achieves a mean Cmax hi & patient population that is less than the mean Cmax
obtained from administering an equivalent dose of lecozotan from an
immediate release formulation to the patient population;
(ii) achieves a mean tmax in a patient population that is greater than the tmax
obtained from administering an equivalent dose of lecozotan from an
immediate release formulation to the patient population; and
(hi) achieves a curve of concentration of lecozotan over time, the curve having an
area under the curve (AUC) in a patient population that is substantially the
62

WO 2007/030589 PCT/US2006/034813
samlTas the'ATJC obtained from administering an equivalent dose of lecozotan
from an immediate release dosage form to the patient population.
56. A method for minimizing an adverse side effect associated with the administration of
lecozotan to a patient, comprising
identifying a patient at risk of an adverse side effect through administration of
lecozotan; and
administering to the patient an oral dosage form that comprises lecozotan and
a pharmaceutically acceptable carrier to the patient and
(i) achieves a mean Cmax in a patient population that is less than the mean Cmax
obtained from administering an equivalent dose of lecozotan from an
immediate release formulation to the patient population;
• (ii) achieves a mean tmax in a patient population that is greater than the mean tmax
obtained from administering an equivalent dose of lecozotan from an
immediate release formulation to the patient population; and
(iii) achieves a curve of concentration of lecozotan over time, the curve having an
area under the curve (AUC) in a patient population that is substantially the
same as the AUC obtained from administering an equivalent dose of lecozotan
from an immediate release dosage form to the patient population.
57. A method of treating Alzheimer's disease in a patient comprising administering a
sustained release formulation of lecozotan to the patient.
58. Use of lecozotan in the preparation of a medicament in the form of an oral dosage
form that comprises and a pharmaceutically acceptable carrier and achieves a
maximum plasma concentration (Cmax) in a patient and a 24 hour plasma
concentration (C24) in a patient, wherein a mean ratio of Cmax/ C24 in a patient
population is from about 5:1 to about 1.1:1.
59. Use of lecozotan in the preparation of a medicament in the form of an oral dosage
form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves
a maximum plasma concentration (Cmax) in a patient and a 24 hour plasma
63

WO 2007/030589 PCT/US2006/034813
61R fl R /" "1llii-pi! "lf "^
'wbbncenfrati6n (C24) Ufa patient, wherein a mean ratio of Cmax/C24 in a patient
population is from about 2.4:1 to about 1.1:1.
60. Use of lecozotan in the preparation of a medicament in the form of an oral dosage
form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves
a mean maximum plasma concentration (Craax) in a patient population and a mean 24
hour plasma concentration (C24) in a patient population, wherein a ratio of mean
Cmax/mean C24 is from about 5:1 to about 0.5:1.
61. Use of lecozotan in the preparation of a medicament in the form of an oral dosage
form that comprises lecozotan and a pharmaceutically acceptable carrier and achieves
a mean maximum plasma concentration (Cmax) in a patient population and a mean 12
hour plasma concentration (C12) in a patient population, wherein a ratio of mean
Cmax/mean Q2 is from about 3:1 to about 0.5:1.
62. Use of lecozotan in the preparation of a medicament in the form of an oral dosage
form for mimmizing an adverse side effect associated with the administration of
lecozotan to a patient, wherein the oral dosage form comprises lecozotan and a
pharmaceutically acceptable carrier and achieves a maximum plasma concentration
(Cmax) in a patient and a 24 hour plasma concentration (C24) in a patient, wherein a
mean ratio of Cmax/ C24 in a patient population is from about 5:1 to about 1.1:1.

63. Use of lecozotan in the preparation of a medicament in the form of an oral dosage
form for minimizing an adverse side effect associated with the administration of
lecozotan to a patient, wherein the oral dosage form comprises lecozotan and a
pharmaceutically acceptable carrier and achieves a maximum plasma concentration
(Cmax) in a patient and a 24 hour plasma concentration (C24) in a patient, wherein a
mean ratio of Cmax/ C24 in a patient population is from about 2.4:1 to about 1.1:1.
64. Use of lecozotan in the preparation of a -medicament in the form of an oral dosage
form that comprises lecozotan and a pharmaceutically acceptable carrier, wherein the
dosage form exhibits an in vitro dissolution profile when measured in a USP type II
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WO 2007/030589 PCT/US2006/034813
I