1-[2-(4-BENZYL-4-HYDROXY-PIPERIDIN-1-YL)-ETHYL]-3-(2-METHYL-QUINOLIN-4-YL)-UREA SALT

SEL DE 1-[2-(4-BENZYL-4-HYDROXYPIPERIDIN-1-YL)ETHYL]-3-(2-METHYLQUINOLIN-4-YL) UREE

English Abstract

The invention relates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-
methyl-
quinolin-4-yl)-urea as a crystalline salt or a non defined salt hydrate
thereof and a
process for its preparation. Further, the present invention relates to the use
of said
1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)urea
as a
crystalline salt alone or in combination with other compounds or formulations
of
said 1-(2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-
yl)-urea
as a crystalline salt in the preparation of pharmaceutical compositions. The
invention also relates to the use of such salts in formulations as
neurohormonal
antagonists.

Claims

15
CLAIMS
1. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-
urea of formula I as crystalline salt or non defined crystalline salt hydrate.
2. 1-[2-(4-Benzyl-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-
urea according to claim 1, as a sulfate or a non-defined sulfate hydrate.
<IMG>
3. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinolin-4-yl)-
urea according to claim 1, as a malate or a non defined malate hydrate.
<IMG>
4. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-
urea according to claim 1, as a citrate or a non defined citrate hydrate.
<IMG>
5. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinolin-4-yl)-
urea of formula I as sulfate salt according to claim 1 and 2 having a
corresponding X-ray powder diffraction pattern as depicted in Figure 1.
6. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-
urea of formula I as sulfate salt according to claim 1 and 2 which shows the

16
peaks at the diffraction (2-theta) angles shown in the following table in its
X-ray powder diffraction pattern.
<IMG>

<IMG>

18
7. The process for the preparation of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-
ethyl-3-(2-methyl-quinolin-4-yl)-urea of formula I as a salt according to any
one of claims 1 to 6 which process comprises
a. mixing 1-[2-(4-benzyl-4-hydroxy piperidin-1-yl)-ethyl]-3-(2-methyl-
quinolin-4-yl)-urea of formula I with an organic solvent and adding an
acid, a solution of an acid in water, a solution of an acid in an organic
solvent, or s solution of an acid in a mixture of water with an organic
solvent, and stirring the mixture; or
b. mixing 1-[2-(4-benzyl-4-hydroxy-piperidin-1-ylmethyl]-3-(2-methyl-
quinolin-4-yl-urea of formula I with a mixtures of an organic solvent
with water and adding an acid, a solution of an acid in water, a
solution of an acid in an organic solvent, or a solution of an acid in a
mixture of water with an organic solvent, and stirring the mixture; or
c. adding 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-9-(2-methyl-
quinolin-4-yl)-urea of formula 1 as a solid, or dissolved in a mixture of
an organic solvent with water to an acid, to a solution of an add in
water, to a solution of an acid in an organic solvent, or to a solution
of an acid in a mixture of water with an organic solvent, and stirring
the mixture; or
d. adding 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl-ethyl]-3-(2-methyl-
quinolin-4-yl)-urea of formula I as a solid, or dissolved in an organic
solvent to an acid, to a solution of an acid in water, to a solution of an
acid in an organic solvent, or to a solution of an acid in a mixture of
water with an organic solvent, and stirring the mixture.
8. 1-[2-(4-Benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-
urea of formula I as a salt obtainable by the process according to claim 7.
9. Compositions comprising 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-
(2-methyl-quinolin-4-yl)-urea of formula I as a salt according to any one of
claims 1 to 6 or 8 and inert carrier material.

19
10. Pharmaceutical compositions containing a Compound of any one of claims
1 to 8 or 8 and usual inert carrier material and adjuvants for the treatment
of
disorders which are associated with a dysregulation of urotensin II or
urotensin II receptors, or disorders associated with vascular or myocardial
dysfunction, comprising hypertension, atherosclerosis, angina or myocardial
ischemia, congestive heart failure, cardiac insufficiency, cardiac
arrhythmias, renal ischemia, chronic kidney disease, renal failure, stroke,
cerebral vasospasm, cerebral ischemia, dementia, migraine,
subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, diabetic
nephropathy, connective tissue diseases, cirrhosis, asthma, chronic
obstructive pulmonary disease, high-altitude pulmonary edema, Raynaud's
syndrome, portal hypertension, thyroid dysfunction, pulmonary edema,
pulmonary hypertension, or pulmonary fibrosis.
11. Pharmaceutical compositions containing a compound of any one of claims
1 to 6 or 8 and usual inert carrier material and adjuvants for the treatment
of
disorders comprising restenosis after balloon or stent angioplasty, for
treatment of cancer, prostatic hypertrophy, erectile dysfunction, hearing
loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia,
shock, sickle cell anemia, sickle cell acute chest syndrome,
glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of
diabetic complications, complications of vascular or cardiac surgery or after
organ transplantation, complications of cyclosporin treatment, pain,
addictions, schizophrenia, Alzheimer's disease, anxiety, obsessive-
compulsive behavior, epileptic seizures, stress, depression, demential,
neuromuscular disorders, or neurodegenerative diseases.
12. The use of one or more compounds of any one of claims 1 to 6 or 8 to 9 in
combination with other pharmacologically active compounds for the
treatment of hypertension, atheroaclerosis, angina or myocardial ischemia,
congestive heart failure, cardiac insufficiency, cardiac arrhythmias, renal
ischemia, chronic kidney disease, renal failure, stroke, cerebral vasospasm,
cerebral ischemia, dementia, migraine, subarchnoidal hemorrhage,
diabetes, diabetic arteriopathy, diabetic nephropathy, connective tissue

20
diseases, cirrhosis, asthma, chronic obstructive pulmonary disease, high-
altitude pulmonary edema, Raynaud's syndrome, portal hypertension,
thyroid dysfunction, pulmonary edema, pulmonary hypertension, pulmonary
fibrosis, restenosis after balloon or stent angioplasty, cancer, prostatic
hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic
bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia,
sickle cell acute chest syndrome, glomerulonephritis, renal colic, glaucoma,
therapy and prophylaxis of diabetic complications, complications of vascular
or cardiac surgery or after organ transplantation, complications of
cyclosporin treatment, pain, addiction, schizophrenia, Alzheimer's disease,
anxiety, obsessive-compulsive behavior, epileptic seizures, stress,
depression, dementias, neuromuscular disorders, or neurodegenerative
diseases.
13. The use of one or more compounds of any one of claims 1 to 6 or 8 to 9 in
combination with other pharmacologically active compounds comprising
ACE inhibitors, angiotensin II receptor antagonists endothelin receptor
antagonists, vasopressin antagonists, beta-adrenergic antagonists, alpha-
adrenergic antagonists, vasopressin antagonists, TNFalpha antagonists, or
peroxisome proliferator activator receptor modulators.
14. The method of treating a patient suffering from a disorder given in any
one
of claims 10 to 12 by administering a pharmaceutical composition according
to any one of claims 9 to 11.
15. Compositions containing crystalline parts of 1-[2-(4-benzyl-4-hydroxy-
piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a salt
according to any one of claims 1 to 6 and amorphous parts of 1-[2-(4-
benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of
formula I as a salt according to any one of claims 1 to 6, to sum up to
100%,
16. The invention as hereinbefore described.

Description

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Actelion 73IU8
i-[2-(4-BENZYL-4-HYDROXY-PIPERIDIN-1-YL~ETHYL]-3-(2-METHYL
QUINOLIN-4-YL)-UREA SALT
The prosent Invention rotates to 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-
ethyl]-3-
(2-methyl-quinolin-4-yl)-urea as a crystalline salt or a non defined salt
hydrate
thereof and a process for its preparation. Further, the present Invention
rotates to
the use of said 1-[2-(4-benryl~-hydroxy-piperidin-1-yl)-ethyl)-3-(2-methyl-
quinolin-
4-yl)-urea as a crystalline salt alone or In combination with other compounds.
The
present invention also relates to compositions containing said 1-[Z-(4-benryl-
4-
hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa as a
crystalline sah
and inert carrier material which are useful as urotensln-li antagonist.
1-[2-(4-Benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-qulnolin-4-yl~urea
of
formula I as well as the process for its preparation as free base is known
from
WO-2004026838. 1-[2-(4-Benzyl~-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-
quinolin-4-yl)-urea of formula I has been shown to be a potent urotensin II
receptor
antagonist [Marline Clozel et al. in J. Pharmcol. Exp. Ther. 2004, 311, 204-
212].
I HO
O
Nw/''.N~N w
H H .4 I
,', .
1-[2-(4-i3enryi-4-hydroxy-piperidln-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-
urea of
formula I as free base has the disadvantages that it is hygroscopic, its
colour
chang~s at higher temperature and higher humidity, and it agglomerates to a
substance cake under these conditions. 1-[2-(d-Benzyl-4-hydroxy-piperidin-1-
yl)-
ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as free base is slightly
soluble in
water at pH 7 {comparo F~cample 9). The said compound of formula I as free
base
was shown to have a low bioavailabillty after oral dosing in the rat (comparo
Example 10). 'Therefore, the said compound of formula I as free base Is not
suitable as a pharmaceutical product since it is not easy to handle in
pharmaceutical proparations. In addition, large scale production and storage
of the

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2
said compound of formula I causes problems due to the properties mentioned
above.
The subject of the prosent invention is to provide 1-[2-(4-benzyl-4-hydroxy-
piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin~4-yl)-urea of formula I in
crystalline forms
which show improved properties suitable for a pharmaceutical product,
pharmaceutical prepatations, production In large scale, and atorape.
The present invention relates to 1-[2-(4-benZyi-4-hydroxy-piperidin-1-yl)-
ethyl]-3-
(2-methyl-quinolin-4-yl)-uroa of formula I as a sulfate or non defined sulfate
hydrate. A sulfate sail of 1-[2-(4-benryl-4-hydroxy-piperldin-1-yl)-ethylr3-(2-
methyl-quinolin-4-yl~-urea of formula I is described by [Martins Clozei et.
al., J
Pharmacol i:xp Ther. X004; 001:10.11241jpet.104.088320] but no procedure for
its
preparation has been disolosed.
The present invention in addition also relates to 1-[2-(4-benryl-4-hydroxy-
piperldin-
1-yl)-ethylJ-3-(2-methyl-quinolin-4-yl)-unsa of formula 1 as a malate or non
defined
malate hydrate.
Further the present invention also relates to 1-[2-(4-benzyl-~4-hydroxy-
piperidin-1-
yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I as a citrate or non
defined
citrate hydrate.
The present invention also rotates to a process for preparing the above
mentioned
salts of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-
4-yl)-
urea which process comprises
a) mixing 1-[2-(4-benzyl-4-hydroxy-plperidin-1-yl)-ethyl]-3-(2-methyl-quinoiin-
4-
yl)-urea of formula I with an organic solvent and adding an acid, a solution
of an acid in water, a solution of an acid in an organic solvent, or a
solution
of an acid in a mixture of water and an organic solvent, and st(rring the
mixture; or
b) mixing 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)~thyl]-3-(2-methyl-quinolin~-
yl)-urea of tormuta I wfth a mixture of an organic solvent and water and
adding an acid, a solution of an acid in water, a solution of an acid in an

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3
organic solvent, or a solution of an acid in a mixture of water and an organic
solvent, and stiMng the mixturo; or
c) adding 1-[2-(4-benryl~4-hydroxy-piperldin-1-yl)-ethyl]-3-(2-methyl-quinoiin-
4-yl)-urea of formula I as s solid, or dissolved in a mixture of an organic
solvent and water to an acid, to a solution of an acid in water, to a solution
of an acid in an organic solvent, or to a solution of an acid in a mixture of
water with an organic solvent, and stirring the mixture; or
d) adding 1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-amyl]-3-(2-methyl-quinoiin-
~-yl)-urea of formula 1 as a solid, or dissolved in an organic solvent to an
acid, to a solution of an acid in water, to a solution of an acid in eon
organic
solvent, or to a solution of an acid in a mixturo of water with an organic
solvent, and stirring the mixture.
The acids used in the above process are sulfuric acid, malic acid, and citric
acid
(compare also Facamples 1 to B).
16 Further, the present invention rotates to 1-[2-(4~benzyl-4-hydraxy-
piperidin-1-yi)~
ethylJ-3-(2-methyl-quinolin-4-yl)-uroa salts obtainable by the process
mentioned
above.
Further, the present invent'ron rotates to pharmaceutical compositions
comprising
1-[2-(4-benryl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-qulnolin-4-yl)-
urea salts
as mentioned above and inert carrier material.
Further, the present invention relates to 1-[2-(4-benzyl-4-hydroxy-plperidln-1-
yi)-
ethyl]-3-(2-methyl~uinolin-4-yl)-urea salts as mentioned above end their use
as
medicaments,
Because of their ability to inhibit the actions of urotensin II, 1-[2-(4-
benryl-4-
hydroxy-piperidin-1-yl)-ethyl]-3-{2-methyl-quinolln~i-yl)-urea salts as
described
above can be used for treatment of diseases which are associated with an
incroase in vasoconstriction, proliferation or other disease states associated
with
the actions of urotensin II. F~camples of such diseases aro hypertension,
atherosclerosis, ang)na or myocardial ischemia, congestive heart (allure,
cardiac
insufficiency, cardiac arrhythmias, ronat Ischemia, chronic kidney disease,
renal

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4
failure, stroke, cerebral vasospasm, cerebral ischemia, dementia, migraine,
subarachnoidal hemorrhage, diabetes, diabetic arteriopathy, diabetic
nephropathy,
connective tissue diseases, cirrhosis, asthma, chronic obstructive pulmonary
disease, high-altitude pulmonary edema, Raynaud's syndrome, portal
hypertension, thyroid dysfunction, pulmonary edema, pulmonary hypertension, or
pulmonary fibrosis. They can also be used for prevention of restenosis after
balloon or stent angioplasty, for the treatment of cancer, prastatic
hypertrophy,
en3ctile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma,
gram
negative septicemia, shock, sidle cell anemia, sickle cell acute chest
syndrome,
glomerulonaphrttis, renal oolic, glaucoma, therapy and prophylaxie of diabetic
Complications, complications of vascular or cardiac surgery or after organ
transplantat'ron, complications of cyclosporin treatment, pain, addic~tiona,
schizophrenia, Alzheimer's disease, anxiety, obsessive-compulsive behavior,
epileptic seizures, stress, depression, demsntlas, neuromuscular disorders,
neurodegenerative diseases, as well as other diseases related to a
dyeregulation
of urotensin II or urootensin II receptors.
These oompositlons may be adminiaten3d in enteral or oral form e.g. as
tablets,
dragees, gelatine capsules, emulsions, sofutlons or suspensions, In nasal form
ltke
sprays and aerosols, or rectally in form of suppositories. 1-[2-(4-Benryl~-
hydroxy-
piperidin-1-yl)-ethylJ-3-(2-methyl-quinolin-4-yl)-uroa salts as mentioned
above may
also be administered in intramuscular, parenteral or intravenous form, e.a. in
torte
of in)ectable solutions.
These pharmaceutical compositions may contain 1-[2-(4-benzyM~-hydroxy-
piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea salts as mentioned
above in
combination with inorganic andlor organic exapients, which are usual in the
pharmaceutical industry, like lactose, maize or derivatives thereof, talcum,
stearic
acid or salts of these matcrlals,
For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid
polyols etc.
may be used. For the proparatlon of solutions and slrups e.g. water, polyols,
sacchaross, glucose stc. ere used. Injectables are prepared by using e.g.
water,
pvlyols, alcohols, glycerin, vegetable oils, lecithin, lipoaomes stc.
Suppositories

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are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats
), liquid
or half-liquki polyols etc.
The compositions may contain in addition preservatives, stabilisation
improving
substances, viscosity improving or r~equlating substances, solubility
improving
5 substances, sweeteners, dyes, taste improving compounds, salts to change the
osmotic pressure, buffer, anti-oxidants etc.
1-j2-(4-6enzyl-4-hydroxy-piperidin-1-yl)ethyl]-3-(2-methyl-quinoiin-4-yl)-urea
salts
as mantioned above may also be used in combination with one or more other
therapeutically useful substances e.g. with a- and ~i-bk~ckers like
phen6olamine,
phenoxybenzamine, atenolot, propranolol, timolol, metoprolol, car~olal,
carvedilol,
etc.; with vasodilators Ilke hydralazlne, minoxidil, diszoxide, flosequlnan,
stc.; with
calcium-antagonists like diltiazem, nicardipine, nimodlpfne, verapamil,
nifedipine,
etc.; with angiotensin converting enzyme-inhibkora like cllazapril, captopril,
enalapril, Ilsinopril etc.; with potassium channel activators like plnacidll,
chromakalim, etc.; with angiotensin receptor antagonists like losartan,
valsarten,
candeaartan, irbesartan, eprosartan, teimisartan, and tasosartan, etc.; with
diuretics like hydrochlorothiazide, chlorothiazlde, acetolamide, bumetanide,
furosemide, metolazone, chlortalidone, etc.; with syrnpatholytics like
methyldopa,
clonidine, guanabenz, reserpine, etc.; with endothelin roceptor antagonists
like
bosentan, tezosentan, clazosentan, darusentan, atrasentan, enrasentan, or
sitaxser~tan, etc.; with anti-hyperlipidemic agents like lovastatln,
pravastatin,
tluvastatin, atorvastatin, cerivaatatin, simvaatatin, etc.; and other
th4rapeutics
which serve to treat high blood pressure, vascular disease or other disorders
listed
above.
The dosage may vary within wide limits but should be adapted to the apee~tc
situation. In general the dosage given daily in oral form should be between
about
3 mg and about 3 g, preferably between about 5 mg and about 1 g, especially
preferred between 10 mg and 300 mg, per adult with a body weight of about 70
kg.
The dosage should be administered preferably in 1 to 3 doses of equal weigh
per
day. As usual children should receive lower doses which are adapted to body
weight and age.

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6
The present invention also relates to compositions containing amorphous
parts of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-
4-
yl)-urea salts as mentioned above.
The term "crystallinity" or "crystalline" is used to describe the part of
crystalline
material compared to amorphous material and is estimated e.g. by the line
shape and the background intensity in X-ray diffraction patterns.
According to these methods, a crystallinity of 90% to 100% is estimated. In a
more preferred embodiment the crystallinity is within the range of 92% to
100%. In the most preferred embodiment the crystallinity is within the range
of 95% to 100%.
The term "non-defined crystalline salt hydrate" is used to describe salts that
contain variable amounts of water. A part of all of the water molecules can be
bound to the crystal lattice. The term "non-defined crystalline salt hydrate"
also describes salts that contain water that is not bound to the crystal
lattice.
The amount of water contained in a "non-defined crystalline salt hydrate" is
within a range of 0 to 20%, preferably within a range of 0 to 10%.
The term "non-defined sulfate hydrate" is used to describe 1-[2-(4-benzyl-4-
hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salts
that
contain variable amounts of water as described above.
The term "non-defined malate hydrate" is used to describe 1-[2-(4-benzyl-4-
hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea malate salts
that
contain variable amounts of water as described above.
The term "non-defined citrate hydrate" is used to describe 1-[2-(4-benzyl-4-
hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea citrate salts
that
contain variable amounts of water as described above.

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6a
The term "acid", as used with4rt the present anve~on, means acids, such as
sulfuric add, malic acid, and dtric acid. Matic acid like all optically active
acids can
be used as a racemate, as optically pure enantiomer, and mixtures of
enantiomers. Especlatly preferred acids are sulfuric acid, and malic add. Most
prefen~ed acid is sulfuric acid. The acid may be used without solvent or
dissolved
either in organic solvents, mixtures of organic solvents and water, or water:
Pn~ferably, the acid is dissolved In mixtures of organic solvents and water,
or In
water.
The term 'organic solvents", as used within the present Invention, means
solvents
or mixtures of solvents, such as C~.,-alkanol (CH30H, CsHsOH, n-CaHzOH, i-
C~H~OH, n-C~HoOH, i-C4H~OH, t-C,H90H), ketoses (acetone, ethylmethylketone,
methylisobuiylketone), ethers (diethylether, tetrahydrofurane, 1,4~ioxane,
methyl_
tart. butylether) or acatonttrile. Preferred "organic solvents" are CH'OH,
CZH~OH,
n-C3H~OH, i-CsHrOH and acetone. Most preferred "organic solvents" are CH30H,
C2H30H, i-C~H~OH and acetone.
The term "solution of an acid" as used within the present invention, means
solutions of an acid as described before, preferably aqueous solutions. Acid
solutions are tn the concentration range of 0.01 to 10 moUl., more preferred
in the
concentration range of 0.1 to 5 moUL, most preferred in the concentration
range of
0.6 to 2 moIIL.

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7
The foregoing general description of the invention will now be further
illustrated
with a number of non-limiting examples.
El(AAIIPLES OF THE INVENTION
lis~r of ABeaevanoNa:
aq. aqueous
AUC area under the curve
DM80 dimethylsulfoxide
HV high vacuum conditions
J coupling constant in NMR
min minutes
MHz megahertz
MP melting point
NMR nuclear magnetic resonance
ppm part per million
RH relative humidity
r.t. room temperature
XRD X-ray powder diffraction
NMR spectra
were roc~rded
on a Varian
Mercury 300VX
NMR Spectrometer.
The
spectra are
referenced
to tetramethylsilane
as external
standard.
X-ray diffraction
patterns (XRD) were recorded on a Bruker D5000, using
a Cu-K,,ph~ (1.6418 A)
source, a
40kV - 30mA
generator,
in a range
of 3 et 40
(2theta).
Stress test
studies were
done by exposing
samples In
open and
dosed glass
bottles to
the
following conditions: 60CI80 % RH (8 weeks) and 80CIRH
not controlled (48 h).

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8
1-I2-(4-Benzvl-4-hvdroxv-niuoridin-1-YIL~thvll~3-(~ mr~ui~l~olin-4.v11-urea
suH(~
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-y!)-ethyl]-3-(2-methyl-
quinolin-4-yirurea of formula 1 (9.70 g, 0.22$ mol) In CH~OH (260 mL, 0.9 M
solution of compound I) is added aqueous HzSO4 (11.4 mL, 2 M, 0.228 rnol). The
clear solution Is stirrod at 4°C for 15 h. The formed preclpit8te Is
filtered, washed
with CH3OH (2 x 10 mL) and dried in HV to provide the title compound as white
crystalline powder in 83 % yield.
AnalytlCs
MP: 239-242 °C (deGOmpositlon).
Ha0 oontent:1.41 %,
Elemental Analysis for CZeHszN40sS (0.41 H20): % found (calculated):
C: 57.20 (57.30); H 8.37 (8,31); N 10.73 (10.89); S 6.14 (6.12).
'H-NMR (d8-DMSO): 8.28 (d, J = 8.5, 1 H); 8.09 (s, 1 H); 7.83 (d, J ~ 8.2, 1
H): 7.70
(t, J = 7.8, 1 H); 7,51 (t, J = 7.8, 1 H); 7.43 (br. s, 1 H); 7.27-7.15 (m,
5H); 4.77 (br. s,
1 H); 3.54-3.53 (m, 2H); 3.36-3.31 (m, 2H); 3.20-3.08 (m, 5H); 2.70 (s, 2H);
2,58 (s,
3H); 1.83-1.75 (m, 2H); 1.69-1.54 (m, 2H).
~'~. 20 if2d4~Benzvl.4-hYdroxv-olnerldin-9-vl)-eth 11.3-(2~ethvl-
auinolin~vl~na
su~,f,8to.
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-
quinolin-4-ylrurea of formula I (4.3 kg) In CH3OH (88 L) is added aqueous
HzS04
(8.5 L, 9.91%) durin0 15 min. The solution is cooled to -8°C and
stirred at this
temperature for 1 h. The formed precipitate is filtered, washed with cooled
CH30H
(-5°C, 2 X 9 L) and dried under a stream of nitrogen to provide the
title compound
as white crystalline powder in i38% yield.
Analytlcs
MP: ca. 200°C (decomposition).
Hz0 content: 0.38 %.

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Examo~e 3~
9
1-fZ-l4-Benzvl~4~hyyoxv-oiosridin-1-yll.ethv11~8-IZ.~thvl.aui~olin~.i f11~
sulfate.
To a suspension of 1-(2-(4-benzyl-4-hydroxy-piperidin-1-ylrethylj-3~2-methyl-
qulnolln-4-yl)-urea of formula I {21.38 kg) in GH30H (178 L) is added aqueous
H2S0,, (8 L, 9.91 °~) during 10 min. The clear solution i8 filtered and
further
aqueous IizS04 (33.A L, 1.07 M) is added during 45 min. The aolutlon is cooled
to
-2°C during 1.5 h and stirnsd at -5 to~9'C for 1 h. The fanned
precipitate is
filtered, washed with cooled CNaOH (- 5'C, 54 L) and dried under a stream of
nitrogen to provide the title compound as white crystalline powder in 84
°~ yield.
AnalytJcs
Hx0 content: 0.84 %.
Eautmols 4~
1-I2-t4-Benzvl~~hvdroxv~py~rldin~1 ~vll.ethvll.3-IZ-methvl~auinoll_n-4-vlHrrsa
isu fate.
To a suspension of 1-(2-(4-t~er~zyl-4-hydroxy-piperidn-1-yl)-etr,yl]-3-(2-
methyt-
quin0lin-4-yl~urea of formula I (68.29 mol) in CH30H (285 L, 0.24 M solution
of
compound I) is added aqueous HzS04 (11 L, 9.91 %) during i0 min. The clear
solution is hl~red and further aqucous HzS04 (39.5 L, 9.91 %, 1.07 M) Is added
_ 20 during 30 min. Ths solution Is cooled to -7°C during 2 h and
stirred at this
temperature for 1 h. The formed precipitate is filtered, washed with cooled
CH90H
{- 4°C, 41 L) and dried under a stream of nitrogen to provide the title
compound as
white crystalline powder in 83 % yield.
Analytics
26 Hz0 content: o.5a %.
'H-NMR (DSO): 7.97 {d, J = 8.5, 1 H); 7,75 (s, 1 H); 7.65 (t, J = 7.4, 1 H);
7.53 (d, J =
8.2, 1 H); 7.45 (t, J ~ 7.7, 1 H); 7.21-7.07 (m, 5H); 3.82 (t, ~ 5.7, 2H);
3.41-3.45 (m,
2H); 3.27 (t, J a 5.7, 2H); 3.08-3.18 (m, 2H); 2.88 (s, 2H); 2.54 (s, 3H);
1.88-1.93
(m, 2H); 1.87-1.71 (m, 2H).

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-(4-Beipnl.4-hvdroxv-oloarld_in-~.y11-ethvll-3-(2-methpvl-auinalin-4-v11-uroa
malate.
A suspension of 1-[2-(4-benzyi-4-hydroxy-piperldin-1-yl)-ethyl]-3-{2-methyl-
5 qulnolin-4-ylrurea of formula I (2,09 g, 0.005 mol) In acetone (50 mL) is
heated at
50'C arM an aqueous solution of L-(-~mallc acid (738 mg in 10 mL) is added.
The
clear solution is cooled at 4°C for 15 h, The formed precipitate is
filtered, washed
with acetone (20 mL) and dried In HV at 50'C to provide the title compound as
white crystalline powder in 71 % yield.
10 Analytic:
MP: 143-148°C (decomposition).
H20 oorltent: 1.92 96.
Elemental Analysis for CzAH~sN40~ (0.80 H20): % found (calculated):
C: 81.53 (81.82); H 8.80 (8.85); N 9.87 (9,94).
'N-NMR (d8-DMSO): 9.12 (br, s, 1 H); 8.12 (d, J = 8.3, 1 H); 8.07 (s, 1 H);
7.82 (d, J
= 8.8, 1 H); 7.85 (t, J - 7.2, 1 H); 7.49 (t, J = 7.1, 1 H); 7.27-7.15 (m,
5H); 7.08 (br. t,
J = 4.8, 1 H); 4.49 (br. s, 1 H); 4.05 (dd, J = 5.9, 7.3, 1 H); 3.38 {m, 2H);
2.96 (m,
2N); 2.81 (m, 2H); 2.70 (m, 4H); 2.55 (dd, J = 7.5, 15.5, 1 H); 2.54 (s, 3H);
2.36 (dd,
J = 5.9, 15.8, 1 H); 1.89-1.81 (m, 2H); 1.61-1.47 (m, 2H).
nl~ B.
i t2.f4-Benzvl-4-hvdroxv-niosridin-1 vl1-tthvll-3.(Z-mdhvl-auinolin-4 v11-urea
A solution of citric acid (1.05 ~) in C2HeOH {400 mL) is heated at 85°C
and 1~[2-(4-
benxyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-uroa of
formula I
(2.09 g, 0.006 mol) is added portion wise as a solid. The mixture is stirred
at 4°C
for 15 h. The formed precipitate is fliterod and dried in HV at 50°C to
provide the
tide compound as white crystalline powder in 72 % yield.
Analytics
MP: 152-15T°C (decomposition).

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11
Hz0 content; 1.08 %.
Elemental Analysis for C3~H3aNa~~ (0.37 H20): % found {calculated):
C: 80.51 (60.31 ); H 8.31 (d,33); N 8.97 (9,08).
'H-NMR (CD~OD): 8.48 (d, 8.5, 1 H); 8.18 (s, 1 H); 7.83 (d, J ~ 7,9, 1 H);
7.72 (t, J
7.4, 1 H); 7.57 (t, J ' 7,3, 1 H); 7.28-7.15 {m, 5H); 3.88 (m, 2H); 3.48 (m,
2H); 3.31
(m, 2H); 3.17 (m, 2H); 2.87 (d, J = 15.2, 2H), 2.80 (s, 2H); 2.70 (d, J ~
15.5, 2H),
2.87 (s, 3H); 2,07 (m, 2H); 1.8B (m, 2H).
The following examples serve to aid the understanding of the present
invention.
Figure 1 shows the XRD-diffraction pattern of the compound described in
Example
2. Table 1 summarizes the peaks and their intensity. It has to be understood
that
due to small changes in the experimental details, small deviations in the 2-
Theta
values of the characteristic peaks in the X-ray powder diffraction patterns
may
occur.
Figuro 1: X-ray dH'fradion pattern (XRD) of the compound da:crlbed in Example
2
,a 90 ~0
Z-Theta - Scab

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12
Facampla 2 Type : 2ThlTh locked - Stwt : 3.000' - End : 40.000- - Slep :
0,020' - Step time : 1 s -
Temp. : 30~G - Tlme Started : 3 s - 2-Theta : 3.00
DIF-Y:87.92%dxby:l.WL:1.5403l3-0-
Table 1: 2-Theta Andes and them intensities of the X-ray diffraction pattern
(XRD)
of the compound described In Example 2
Z Theta Angled valve ht~nslty tnbnslty
C1 fM4~~1 tCount] . I%1
7.988 11.062 21125 12.8
9.016 9.8 15544 9.4
9.46 9.341 88555 41.6
~' ~~.-
9.749 9.085 72939 44.3
9.974 8.881 184812 100
10. i 98 8.887 128740 ~ 78.2
10.838 8.158 25110 15.3
-
11.236 7.888 150862 91.5
12.582 7.041 18342 9.9
12.738 8.945 31888 19.4
13.217 8.893 5979 3.8
13.43 8.587 12358 7.5
14.339 8.172 8568 5,8
14.541 8.087 30690 18.8
15.538 5.898 19530 11.9
18.012 5.53 21922 13.3
18.289 5.437 32286 19.6
18.541 5.355 45039 2~.4
18.979 5.218 41452 25.2
17.18 5.183 86491 62.6
17.874 5.014 45438 27.8
... 17.807 4.977 24313 14.8
-_ -
-
18.8A7 4.744 75729 48
19.037 4.858 158840 95.2
19.429 4.565 85388 39.7
19.983 4.44 43445 28,4
21.284 4.171 31487 19.1
-
22.431 3.98 ~ 48828 z9.s
22.641 3.924 124'764 73.8
23.121 3.844 39080 23.7
23.812 3.734 19132 11.8
23.946 3.713 33082 20.1
~
25.033 3.564 38283 23.2
25.209 3.53 29893 18.2
25.841 3.471 44242 28.9

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13
25.804 3,46 72541 44.1
26.081 3.414 62213 31.7
27.27 3.268 19132 ~ 11.6
28.438 3.136 10762 8.5
28.758 3.102 21125 12,8
~
29.023 3.074 18342 9.8
30.028 2,973 7174 4.4
30.824 2.898 10363 8.3
31.509 2.837 17537 10.7
33.925 2.84 13153 8
34.236 2,817 7673 4.6
34.803 2.578 9984 6.1
35.838 2.517 111 fi0 8.8
36.094 2.488 7174 4.4
36.825 2.452 7174 4.4
37.882 2.373 __ 3.8
6979
39.827 2.272 13652 8.2
Ny~rosoopicity was evaluated using the stag method acconiing to European
Pharmacoposla Technical 4uide. Welght increase of the compound was observed
when stored In a humidfty cabinet at RT I 79% RH for 24 h. The rosults are
shown
6 in Table 2.
Table 2. Increase in webht ( M1) after exposure to 79% Rhl for 24 h
f:xampk em [Xl
Compound I 8
os ire beep
2 4
s 6
s 2
Example 9: Solubillhr In water and at nH 7
Solubility was measured in water and aqueous phosphate buffer
(pH = 7, 100 mM). Results aro exprossed as mg dissolved compound per mL
solvent. The results are summarized in Tablo 3.

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14
Table 3: Solubility in water and phosphate buffer
Sxampls Solubhity Bufhr pH 7
wabr (phosphstr.100 mM)
(mp I mL) (mp I mL)
Compound 0.8 0.31
1
Z 11.3 27
8 ~ 101 -
6 17.8 -
Examols 10; Pl~amm~t>at(c usnsmant of 1-f2-(4-banzvl-4-hvdroxv-
niooridin-1-vl[~pthy~~~0p~,i~nolin~ vli-unaa compounds
The pharmaookinedc parameter8 after oral (pavage) administration of 10 mg per
kg of 1-[2-(4-benzyl-4-hydroxy-plperldin-1-yl~ethylj-3-(2-methyl-quinolin-4-
yl)-uroa
given as free base or sulfate salt have been determined in male Wlstar rata.
Blood
samples were taken over a time period of 24 h after dosing and analysed wlth a
spaclflc and sensklve Ilquld chromatogwaphy-mass-spectrometry (LC-MSIMS)
methad. Phannacokinetic parameters were calculated using a non-compartmental
method. The mean exposure of 1-[2-(4-benzyl-4-hydroxy-pipetidin-1-ylrethyQ-3-
(2-methyl-quinolin-4-yl}~urea, expressed as area under the curve (AUCo-~ ),
after
administration of compound I as froe base was 194 ng"hlmL. The mean exposuro
of 1-[2-(4-benzyl-4-hydroxy-piporidin-1-yl~.ethyl]-3-(2-methyl-puinolin~l-
yl~urea
expressed as area under the curve (AUCo-,~,,), after administration of the
compound described in Example 1 was 396 ng~hlmL.