Title of Invention

A PROCESS FOR PREPARING THE FORM 1 SUCCINATE SALT OF BIPHENY-2-YLCARBAMIC ACID 1-[2-(2-CHLORO-4-{[(R)-2-(8-HYDROXY-2-(8-HYDROXY-2-OXO-1,2-DIHYDROQUINOLIN-5-YL)ETHYLAMINO]METHYL}-5-METHOXYPHENYLCARBOMOYL)ETHYL]PIPERIDIN-4-YL ESTER

Abstract A succinic acid salt of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2- (8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyIcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof for use in treating pulmonary disorders.
Full Text SUCCINIC ACID SALT OF BIPHENYL-2-YLCARBAMIC ACID
1-[2-(2-CHLORO-4-{[(R)-2-HYDROXY-2-(8-HYDROXY-2-OXO-1,2-DIHYDROQUINOLIN-5-YL)
ETHYLAMINO]METHYL]}-5-METHOXYPHENYLCARBAMOYL)ETHYL]PIPERIDIN-4-YL
ESTER AND ITS USE FOR THE TREATMENT OF PULMONARY DISORDERS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a novel succinic acid salt of a biphenyl
compound, in particular crystalline solid state forms of the succinic acid salt. The
biphenyl compound is expected to be useful as a therapeutic agent for treating pulmonary
disorders. This invention also relates to pharmaceutical compositions comprising the salt
or prepared from this salt, processes and intermediates for preparing the salt and methods
of using the salt to treat a pulmonary disorder.
State of the Art
International Patent application no PCT/US2004/004449, publication no.WO
2004/074246 A2 (Theravance Inc, South San Francisco, California, US) discloses novel
biphenyl compounds that arc useful as therapeutic agents for treating pulmonary
disorders, such as chronic obstructive pulmonary disease (COPD) and asthma. In
particular, the compound biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-
2-(8-hydroxy-2-oxo-l ,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester is specifically disclosed in these
applications as possessing both muscarinic antagonist and 02 adrencrgic receptor agonist
activity. The chemical structure of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-
h.ydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin.-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester is represented by formula T:


Therapeutic agents useful for treating pulmonary disorders are advantageously
administered directly into the respiratory tract by inhalation. In this regard, several types
of pharmaceutical inhalation devices have been developed for administering therapeutic
agents by inhalation, including dry powder inhalers (DPI), metercd-dose inhalers (MDI)
and nebulizer inhalers. When preparing pharmaceutical compositions and formulations
for use in such devices, it is highly desirable to have a crystalline form of the therapeutic
agent that is neither hygroscopic nor deliquescent and which has a relatively high melting
point (i.e. greater than about 150°C), thereby allowing the material to be micronized
without significant decomposition or loss of erystallinity.
International Patent application no PCT/US2004/004449, publication no. WO
2004/074246 A2 (Theravance Inc, South San Francisco, California, US), at page 135, as
Example 35, describes the preparation of the compound of formula I, as the di-
trifluoroacetate salt, in a lyophilised form.
International Patent application no PCT/US2005/029013, publication no. WO
2006/023454 , filed 15 Aug 2005, (Theravance Inc, South San Francisco, California, US)
describes crystalline 1,2-ethanedisulfonic acid salts of the compound of formula I.
There remains the need to identify further stable, non-deliquescent, crystalline salt
forms of the compound of formula I which have an acceptable level of hygroscopicity and
a relatively high melting point.
SUMMARY OF THE INVENTION
The present invention provides a succinic acid salt of biphcnyl-2-ylcarbamic acid
l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-
yl)ethylammo]methyl}-5-methoxyphenylcarbamoyl)ethyI]piperidin-4-yl ester, in
particular a crystalline solid state form thereof, or a solvate thereof
In one embodiment, a crystalline form of the salt of the present invention,
hereinafter referred to as Form 1, has a melting point greater than about 170 °C and has
been found not to be deliquescent, even when exposed to atmospheric moisture. Further
crystalline salt forms, hereinafter referred to as Form 2 and 3, have also been identified.
Among other uses, a succinic acid salt of the compound of formula I is useful for
preparing pharmaceutical compositions which are expected to be useful for treating
pulmonary disorders. Accordingly, in a further embodiment, the present invention
provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier

and a succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-
2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)elhylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester, in particular a crystalline solid slate
form thereof, or a solvatc thereof.
In a particular embodiment, the pharmaceutical composition of this invention
further comprises a steroidal anti-inflammatory agent, such as a cortecosteroid; a
muscarinic antagonist or a phosphodiesterase-4 inhibitor; or a combination thereof.
In another embodiment, this invention provides a pharmaceutical composition
comprising an aqueous isotonic saline solution comprising a succinic acid salt of
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-
yl ester, wherein the solution has a pH in the range of from about 4 to about 6.
In yet another embodiment, this invention provides a combination comprising:
(a) a succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-
2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl} -5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester, in particular a crystalline solid state
form thereof, or a solvate thereof; and
(b) a steroidal anti-inflammatory agent.
The compound of formula I has both muscarinic antagonist and β2 adrenergic
receptor agonist activity. Accordingly, a succinic acid salt of this invention is expected to
be useful as a therapeutic agent for treating pulmonary disorders, such as asthma and
chronic obstructive pulmonary disease.
Accordingly, in one of its method aspects, this invention provides a method for
treating a pulmonary disorder, the method comprising administering to a patient in need
of treatment a therapeutically effective amount of a succinic acid salt of biphenyl-2-
ylcarbamic acid 1 -[2-(2-ch]oro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-5-mcthoxyphenylcarbamoyl)ethyl]piperidin-4-
yl ester or a solvate thereof.
Additionally, in another of its method aspects, this invention provides a method of
producing bronchodilation in a patient, the method comprising administering by
inhalation to the patient a bronchodilation-producing amount of a succinic acid salt of
biphcnyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-

dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-pipcridin-
4-yl ester or a solvate thereof.
This invention also provides a method of treating chronic obstructive pulmonary
disease or asthma, the method comprising administering to a patient in need of treatment
a therapeutically effective amount of a succinic acid salt of biphenyl-2-ylcarbamic acid 1-
[2-(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroqumolin-5-
yl)ethylamino]methyl}-5-methoxyphenylcarbamoyi)ethyl]piperidin-4-yl ester or a solvate
thereof.
This invention is also directed to processes for preparing a succinic acid salt of the
compound of formula 1, in particular a crystalline form thereof.
Accordingly, this invention provides a process for preparing a succinic acid salt of
biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-
yl ester or a solvate thereof; the process comprising contacting biphenyl-2-ylcarbamic
acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroqumolin-5-
yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester with
succinic acid.
This salt formation step may be conveniently carried out using the corresponding
free base prepared from the corresponding tri-aLkyl silyloxy-protected precursor, without
the need for full isolation of the free base intermediate.
This invention is also directed to a succinic acid salt of biphenyl-2-ylcarbamic
acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydiroquinolin-5-
yl)ethylamino]methyr}-5-mcthoxyphenylcarbamoyl)ethyl]pipcridin-4-yl ester, or a
crystalline solid state form thereof, or a solvate thereof, for use in therapy or as a
medicament.
Additionally, this invention is directed to the use of a succinic acid salt of
biphenyl-2-ylcarbamic acid 1 -[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino Jmethyl} -5 -methoxypheny lcarbamoyl)ethyl]pipcridin-4-
yl ester, or a crystalline solid state form thereof, or a solvate thereof for the manufacture
of a medicament; especially for the manufacture of a medicament for the treatment of a
pulmonary disorder.
This invention is also directed to the use of:

(a) a succinic acid salt of biphenyl-2-ylcarbamic acid 1 -[2-(2-chloro-4-{[(R)-
2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester, or a crystalline solid state form
thereof, or a solvatc thereof; and
(b) a steroidal anti-inflammatory agent;
in themanufacture of a medicament for the treatment of a pulmonary disorder.
This invention is also directed to a succinic acid salt of biphenyl-2-ylcarbamic
acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-
yl)ethylamino]mcthyl}-5-methoxyphenylcarbamoyl)ethyl]pipcridin-4-yl ester, or a
crystalline solid state form thereof, or a solvate thereof, in micronized. form; and to
pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a
succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]-piperidin-4-yl ester, or a crystalline solid state form
thereof, or a solvate thereof, in micronized form.
BRIEF DESCRIPTION OF THE DRAWINGS
Various aspects of the present invention are illustrated by reference to the
accompanying drawings.
Figure 1 shows a differential scanning calorimetry (DSC) trace for a sample of a
first crystalline solid state form of a succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-
(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin- 5 -
yl)cthylamino]mcthyl} -5-mcthoxyphcnylcarbarnoyl)ethyl]piperidin-4-yl ester of this
invention, hereinafter referred to as Form 1.
Figure 2 shows a differential scanning calorimetry (DSC) trace for a sample of a
second crystalline solid state form of a succinic acid salt of biphenyl-2-ylcarbamic acid 1-
[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-
yl)ethylamino]methyl} -5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester of this
invention, hereinafter referred to as Form 2.
Figure 3 shows a differential scanning calorimetry (DSC) trace for a sample of a
third crystalline solid state form of a succinic acid salt of biphenyl-2-ylcarbamic acid 1-
[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-

yl)ethylaminoJmethyl} -5-methoxyphenylcarbamoyl)ethyI]piperidin-4-yl ester of this
invention, hereinafter referred to as Form 3.
Figure 4 shows a x-ray powder diffraction (XRPD) pattern of a sample of
crystalline 1,2-succinic acid salt of biphcnyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-
hydroxy-2-(8-hydroxy-2-oxo-l ,2-dihydroquinolm-5-yl)cthylamino]mcthyi} -5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester (Form 1).
Figure 5 shows a x-ray powder diffraction (XRPD) pattern of a sample of
crystalline 1,2-succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-
hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyi} -5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester (Form 2).
Figure 6 shows a x-ray powder diffraction (XRPD) pattern of a sample of
crystalline 1,2-succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-
hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methy1 }-5-
methoxyphenylcarbamoyl)erhyl]piperidin-4-yl ester (Form 3).
Figure 7 shows an infrared (1R) absorption spectra of a sample of crystalline 1,2-
succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
mcthoxyphenylcarbamoyl)ethyl] piperidin-4-yl ester (Form 1).
Figure 8 shows an infrared (IR) absorption spectra of a sample of crystalline 1,2-
succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl} -5-
mcthoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester (Form 2).
Figure 9 shows an infrared (IR) absorption spectra of a sample of crystalline 1,2-
succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methy 1} -5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester (Form 3).
Figure 10 shows a Dynamic Vapour Sorption profile of a sample of the crystalline
succinate salt (Form 1).
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-
chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-

yl)ethylamino]methyl}-5-raethoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester, in
particular crystalline solid state forms (polymorphs) thereof and including solvates
thereof. The crystalline succinic acid salt of the present invention may be present as one
or more different distinct crystalline solid state forms. The present invention
encompasses all such solid state forms.
In one embodiment, the present invention provides a first crystalline solid state
form of the succinic acid salt of the compound of formula I: Form 1 thereof.
In a further embodiment, the present invention provides a second crystalline solid
state form of the succinic acid salt of the compound of formula I: Form 2 thereof.
In a further embodiment, the present invention provides a third crystalline solid
state form of the succinic acid salt of the compound of formula I: Form 3 thereof.
The active therapeutic agent in these salts (i.e., the compound of formula 1)
contains one chiral center having the (R) configuration. However, it will be understood
by those skilled in the art that minor amounts of the (S) stereoisomer may be present in
the compositions of this invention unless otherwise indicated, provided that any utility of
the composition as a whole is not eliminated by the presence of such an isomer.
The compound of formula I has been named using the commercially-available
AutoNom software (MDL, San Lcandro, California).
Definitions
When describing the compounds, compositions, methods and processes of this
invention, the following terms have the following meanings unless otherwise indicated.
The term "melting point" as used herein means the melting onset temperature as
observed by differential scanning calorimetry.
The term "micronized form" means a form of particles in which at least about
90% of the particles have a diameter of less than about 10 urn.
The term "solvate" means a complex or aggregate formed by one or more
molecules of a solute, i.e. a succinic acid salt of the compound of formula I, and one or
more molecules of a solvent. Such solvates typically have a substantially fixed molar
ratio of solute and solvent. This term also includes clathrates, including clathrales with
water. Representative solvents include, by way of example, water, methanol, ethatvol,
isopropanol, acetic acid and the like. When the solvent is water, the solvate formed is a
hvdrate.

The term "therapeutically effective amount" means an amount sufficient to effect
treatment when administered to a patient in need of treatment.
The term "treating" or "treatment" as used herein means the treating or treatment
of a disease or medical condition (such as COPD) in a patient, such as a mammal
(particularly a human) that includes:
(a) preventing the disease or medical condition from occurring, i.e.,
prophylactic treatment of a patient;
(b) ameliorating the disease or medical condition, i.e., eliminating or causing
regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing or arresting the
development of the disease or medical condition in a patient; or
(d) alleviating the symptoms of the disease or medical condition in a patient.
The term "unit dosage form" refers to a physically discrete unit suitable for dosing
a patient, i.e., each unit containing a predetermined quantity of a salt of the invention
calculated to produce the desired therapeutic effect either alone or in combination with
one or more additional units. For example, such unit dosage forms may be dry powder
inhaler capsules or blister strips, a metered dose from a metered dose inhaler, capsules,
tablets, pills, and the like.
Succinic Acid Salts of the Invention
A succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(i?)-2-
hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl} -5-
mcthoxyphenylcarbamoyl)cthyl]piperidin-4-yl ester of this invention can be prepared
from biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-
l,2-dihydroquinDlin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]
piperidvn-4-yl ester and succinic acid.
A succinic acid salt of this invention typically contains between about 0.90 and
about 1.10 molar equivalents of succinic acid per molar equivalent of the compound of
formula I; including between about 0.95 and about 1.05 molar equivalents of succinic
acid per molar equivalent of the compound of formula I. In a particular embodiment, the
succinic acid salt of this invention contains about 1 molar equivalent of succinic acid per
molar equivalent of the compound of formula I.

The molar ratio of succinic acid to biphenyI-2-ylcarbamic acid l-[2-(2-chloro-4-
{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyI}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-y! ester can be readily determined by various
methods available to those skilled in the art. For example, such molar ratios can be
readily determined by 1H NMR. Alternatively, elemental analysis can be used to
determine the molar ratio.
Biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-
oxo-l,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-
pipcridin-4-yl ester may be conveniently prepared from, the corresponding
2-rm-(Butyldimethylsilanyloxy)-protected precursor. This precursor may be deprotected
using a source of fluoride ion such as cesium fluoride, with acetic acid, in a solvent such
as methanol. The preparation of the tert-(Butyldimethylsilanyloxy)-protected precursor is
described in International Patent application no PCT/US2004/004449, publication no. WO
2004/074246 A2, at page 135, Preparation 98.
Succinic acid is commercially available from, for example, Sigma-Aldrch Co.
Ltd., Gillingham, UK. In one embodiment, the succinic acid has a purity greater than or
equal to 99% (as determined by HPLC).
A crystalline salt of this invention may be prepared by contacting biphenyl-2-
ylcarbamic acid 1 -[2-(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-
yl ester with about 0.75 to about 1.3 molar equivalents of succinic acid. Generally, this
reaction is conducted in an inert diluent at a temperature ranging from about 0oC to about
60oC; including about 20oC to about 55oC, such as about 25 oC to about 55oC.
Suitable inert diluents for this reaction include, but are not limited to, methanol, ethanol,
isopropanol, isobutanol, ethyl acetate, telrahydrofuran, dichloromethane and the like, or a
mixture thereof, optionally containing water.
In one embodiment, the succinic acid may be added as a solution, in a solvent
such as ethanol or isopropanol, to a solution of biphenyl-2-ylcarbarmc acid l-[2-(2-
chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-
yl)ethylamino]methyl} -5-methoxyphenylcarbamoyl)ethyl]piperidin-4-y 1 ester. The
solution of the thus formed salt is then allowed to cool over a period of lime, optionally
with seeding at an intermediate temperature, and optionally with stirring, to allow
crystalline product to form.

In a further embodiment, a solution of succinic acid in ethanol is added to a
solution of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-
2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyI]pipcridin-4-yl ester in a similar volume of
tctrahydrofuran, at a temperature of about 55oC, this solution is then cooled to about
45oC, seeded, then further cooled to about 20oC and left stirring over an extended period,
for instance about 48 h, as crystalline product is formed.
In a a further embodiment, a solution of succinic acid in isopropanol may be
added to a solution of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ei:hylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester in about three times the volume of
tetrahydrofuran, at a temperature of about 37oC, this solution is then seeded and then held
at this temperature for about four hours, then further cooled to about 15oC over a period
of several hours, for example about 4 hours, and then left at this temperature, as
crystalline product is formed. This process was found to provide predominantly Form 3.
In a further embodiment, a crystalline succinic acid salt may be prepared from the
compound of formula I by adding a solution of succinic acid in ethanol portionwise to a
solution of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-
2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester in ethanol, at a temperature of about
50eC, over a period of about 4 h, followed by the addition of water (about 10 to 15% by
volume, and then temperature cycling for instance over the range 0 to 40 aC, over a
period of several days, for instance 2 to 5 days, typically about 3 days. This process was
found to provide predominantly Form 1.
In a further embodiment, a crystalline succinic acid salt may be prepared from the
compound of formula T by adding a solution of succinic acid portionwise over a period of
hours, for instance 3 to 7 h, typically about 5 h, to a suspension of the compound of
formula 1 in an inert liquid such as methanol or tetrahydrofuran, at an elevated
temperature, for instance in the range 40 to 60oC, typically about 50oC, and then
subjecting the resultant slurry to temperature cycling, for instance over the range 0 to 40
oC, over a period of several days, for instance 3 to 7 days, typically about 5 days. This
process was found to provide predominantly Form 2 (solvent = methanol) or
predominantly Form 3 (solvent = THF), depending on the solvent used.

In the foregoing processes, the product from the deprotection of the silyl-protected
derivative of the compound of formula 1 may be contacted with succinic acid without the
need for full isolation or purification of the intermediate product.
It will be appreciated that the purity of the initially prepared crystalline salt may
be improved by recrystallisation. Furthermore, recrystallisation conditions may be
selected which determine which Form of the salt is obtained.
Thus, it has been found that Form 1 may be conveniently prepared by anti-solvent
recrystallisation of initially prepared crystalline salt from aqueous THF using a lower
alcohol such as cthanol or isopropanol as anti-solvent. The % of water is found to be
important, as too little results in incomplete dissolution whilst too much leads to
incomplete recrystallisation and degradation. It is also found beneficial to limit the upper
temperature used, to avoid unwanted product degradation. It was found desirable to
allow recystallisation to occur slowly, over a period of hours, to improve the quality of
the crystals thus formed. In contrast, the solubility characteristics and difference in
solubility between higher and lower temperatures in a range of single solvents appeared
to preclude solvent recrystallisation.
Accordingly, in a further embodiment, the present invention provides a process
for preparing the Form 1 succinatc salt which process comprises the steps:
dissolving the succinate salt in aqueous THF (10-18%, for example 10-16%), at a
temperature in the range 18 to 23°C, for example about 20°C;
adding a first volume of a lower alcohol as an antisolvent, for example elhanol or
isopropanol, in particular isopropanol, and warming to 32-40°C, typically 36 ±3 °C;
optionally seeding with Form 1;
adding a second volume of the lower alcohol, for example over several hours, preferably
about 12 h;
cooling to a temperature in the range 18 to 23°C, for example about 20 °C; and
collecting the crystalline product.
In particular embodiment, a crystalline succinic acid salt, for example the Form 3
salt, is dissolved in tetrahydrofuran containing 14% water, at a temperature of about 20
oC, to which a similar volume of isopropanol may then be added. The solution is warmed
to about 36 oC, and seed crystals then added. Typically, the ratio of the weight of seed
crystals to the weight of crystalline salt in the solution is about 1:400. The solution is
then stirred at this temperature for a short time, for example about 1 hour, after which

further isopropanol is added over a period of hours, for example about 12 hours, during
which time crystallization occurs. After a further short period, for example about 1 hour,
the thus formed suspension is cooled to a temperature of about 20oC and left for a further
short period, for example 1 hour, before crystalline product, for instance the Form 1 salt,
is collected by filtration.
It has been found useful to prepare the crystalline succinic acid salt with a level of
purity suitable for use as an active pharmaceutical ingredient (API) by a two step process,
involving the initial preparation of an intermediate grade of the salt, followed by the
rccrystallisation of this intermediate grade product, in a controlled manner and with
seeding, to obtain the desired Form, having the desired crystal quality. In one
embodiment, the intermediate grade is isolated as essentially the Form 3, as a
consequence of the conditions used, and this is then converted to the desired Form 1 form
by anti-solvent recrystallisation.
High throughput polymorph screening techniques, by variation in crystallization
conditions, for instance, solvent, temperature, are now being developed and becoming
available to the skilled man or being offered by commercial suppliers such as Avantium
Technologies. Further crystalline solid state forms may be identified using such high
through put techniques.
In a further aspect of the present invention, it has been found that a grade of
biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-bydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-
yl ester suitable for use in a subsequent succinic acid salt forming reaction (so-called
Intermediate Grade compound, the initial product of stage 3) may be conveniently
prepared from l-(3-{[2-chloro-4-(hydroxymethyl)-5-methoxyphenyl]amino}-3-
oxopropyl)piperidin-4-yl biphenyl-2-ylcarbamate (International Patent application no
PCT/US2004/004449, publication no. WO 2004/074246 A2, at page 134, Preparation 96)
in a three step process, without the need for full isolation and purification of the
intermediates, from stages 1 and 2, according to scheme 1:


5 Solid state forms
In a further embodiment, the present invention provides three distinct crystalline
solid state forms of the succinic acid salt of biphcnyl-2-ylcarbamic acid l-[2-(2-chloro-4-

{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester, forms 1, 2 and 3, that have been
identified by differential scanning calorimetry (DSC). The preferred solid slate form,
designated as Form 1, is characterized by a high melting point, as evidenced by a
differential scanning calorimetry (DSC) trace, at about 174 oC. The remaining solid state .
forms, Forms 2 and 3, are characterized by melting points, as evidenced by differential
scanning calorimetry (DSC) traces, at about 161 oC and 150 oC respectively.
Furthermore, Form 1 is characterized by an x-ray powder diffraction (XRPD)
pattern having significant diffraction peaks at 28 values of 5.0 ±0.3, and 10.0±0.3.
Furthermore, Form 2 is characterized by an x-ray powder diffraction (XRPD)
pattern having significant diffraction peaks at 26 values of 5.0 ±0.3, and 9.9±0.3.
Furthermore, Form 3 is characterized by an x-ray powder diffraction (XRPD)
pattern having a significant diffraction peaks at 20 values of 5.0 ±0.3.
In addition, Form 1 is characterized by its infrared (IR) absorption spectrum
which shows significant absorption bands at about: 3265,2832, 1735, 1718, 1679, 1669,
1591, 1540, 1518, 1493, 1439, 1405, 1339, 1302, 1283, 1239, 1202, 1163, 1144, 1107,
1095, 1039, 1009, 973, 921, 885, 868, 838, 773, 751, and 707 cm"1.
In addition, Form 2 is characterized by its infrared (IR) absorption spectrum
which shows significant absorption bands at about: 3317, 2947, 1728, 1678, 1667, 1591,
1537, 1494, 1453, 1439, 1403, 1339, 1302, 1284, 1213, 1172, 1111, 1058, 1046, 999,
975, 885, 839, and 750 cm1.
In addition. Form 3 is characterized by its infrared (IR) absorption spectrum
which shows significant absorption bands at about: 3335, 2949, 1745, 1715, 1678, 1641,
1592, 1542, 1493, 1464, 1439, 1405, 1338, 1303, 1283, 1247, 1211, 1170, 1109, 1093,
1053, 1041,997,974,919,889,842,774,766,751 and 721 cm"1.
Form 1 has been demonstrated to have a reversible sorption/desorption profile
with a good level of hygroscopicity (i.e. less than about 2.0 % weight gain in the
humidity range of 30 % relative humidity to 90 % relative humidity), as shown by its
Dynamic Vapour Sorption profile.
These properties of the salts of this invention are further illustrated in the
Examples below.
Pharmaceutical Compositions and Formulations

The succinic acid salt of the compound of formula I may typically be administered
lo a patient in the form of a pharmaceutical composition or formulation. Such
pharmaceutical compositions may be administered to the patient by any acceptable route
of administration including, but not limited to, inhaled, oral, nasal, topical (including
transdcrmal) and parcnteral modes of administration, in particular inhaled administration.
However, it will be understood by those skilled in the art that, once the crystalline salt of
this invention has been formulated, it may no longer be in a crystalline form, i.e., the salt
may be dissolved in a suitable carrier, or the original crystalline form.
Accordingly, in one of its compositions aspects, this invention is directed to a
pharmaceutical composition comprising a pharmaceutically acceptable carrier or
excipient and a succinic acid salt of biphenyl1-2-ylcarbamic acid 1 -[2-(2-chloro-4-{[(R)-2-
hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof. Optionally,
such pharmaceutical compositions may contain other therapeutic and/or formulating
agents if desired.
The pharmaceutical compositions of this invention typically contain a
therapeutically effective amount of a succinic acid salt of biphenyl-2-ylcarbamic acid 1-
[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-
yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate
thereof. Typically, such pharmaceutical compositions will contain from about 0.01 to
about 95% by weight of the active agent; including, from about 0.01 to about 30% by
weight; such as from about 0.01 to about 10% by weight of the active agent.
Any conventional carrier or excipient may be used in the pharmaceutical
compositions of this invention. The choice of a particular carrier or excipient, or
combinations of carriers or excipients, will depend on the mode of administration being
used to treat a particular patient or type of medical condition or disease state. In this
regard, the preparation of a suitable pharmaceutical composition for a particular mode of
administration is well within the scope of those skilled in the pharmaceutical arts.
Additionally, the ingredients for such compositions are commercially available from, for
example, Sigma, P.O. Box 14508, St. Louis, MO 63178. By way of further illustration,
conventional formulation techniques are described in Remington: The Science and
Practice of Pharmacy, 20th Edition, Lippincott Williams & White, Baltimore, Maryland

(2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,
7 Edition, Lippincott Williams & White, Baltimore, Maryland (1999).
Representative examples of materials which can serve as pharmaceutically
acceptable carriers include, but arc not limited to, the following: (1) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3)
cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and
cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,
such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflowcr oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene
glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents,
such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-
free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate
buffer solutions; (21) compressed propellant gases, such as chlorofluorocarbons and
hydrofluorocarbons; and (22) other non-toxic compatible substances employed in
pharmaceutical compositions.
The pharmaceutical compositions of this invention are typically prepared by
thoroughly and intimately mixing or blending a salt of the invention with a
pharmaceutically acceptable carrier and one or more optional ingredients. If necessary or
desired, the resulting uniformly blended mixture can then be shaped or loaded into
tablets, capsules, pills, canisters, cartridges, dispensers and the like using conventional
procedures and equipment.
In one embodiment, the pharmaceutical compositions of this invention are suitable
for inhaled administration. Suitable pharmaceutical compositions for inhaled
administration will typically be in the form of an aerosol or a powder. Such compositions
are generally administered using well-known delivery devices, such as a nebulizer
inhaler, a metered-dose inhaler (MD1), a dry powder inhaler (DPI) or a similar delivery
device.
In a specific embodiment of this invention, the pharmaceutical composition
comprising the active agent is administered by inhalation using a nebulizer inhaler. Such
nebulizer devices typically produce a stream of high velocity air that causes the
pharmaceutical composition comprising the active agent to spray as a mist that is carried
into the patient's respiratory tract. Accordingly, when formulated for use in a nebulizer

inhaler, the active agent is typically dissolved in a suitable carrier to form a solution.
Suitable nebulizer devices are provided commercially, for example, by PARI GmbH
(Starnberg, German). Other nebulizer devices include Respimat (Boehringer Ingelheim)
and those disclosed, for example, in U.S. Patent No. 6,123,068 and WO 97/12687.
A representative pharmaceutical composition for use in a nebulizer inhaler
comprises an aqueous solution comprising from about 0.05 µg/mL to about 10 mg/mL of
a succinic acid salt of compound of formula I or a solvate thereof. In one embodiment,
the aqueous nebulizer formulation is isotonic. In one embodiment, the aqueous nebulizer
formulation has a pH in the range of from about 4 to about 6. In a particular embodiment,
the aqueous nebulizer formulation is buffered with citrate buffer to a pH of about 5. In
another particular embodiment, the aqueous nebulizer formulation contains from about
0.1 mg/mL to about 1.0 mg/mL free base equivalents of biphenyl-2-ylcarbamic acid l-[2-
(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-
yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester.
In another specific embodiment of this invention, the pharmaceutical composition
comprising the active agent is administered by inhalation using a dry powder inhaler.
Such dry powder inhalers typically administer the active agent as a free-flowing powder
that is dispersed in a patient's air-stream during inspiration. In order to achieve a free
flowing powder, the active agent is typically formulated with a suitable excipient such as
lactose, starch, mannitol, dextrose, polylactic acid (PLA), polylactide-co-glycolide
(PLGA) or combinations thereof. Typically, the active agent is micronized and combined
with a suitable carrier to form a blend of micronized particles of respirable size, where
"micronized particles" or "micronized form" means at least about 90% of the particles
have a diameter of less than about 10 urn. The dry powder composition may further
comprise a ternaiy agent such as magnesium stearate, presenting from 0.1-2%w/w, to
stabilize the composition.
A representative pharmaceutical composition for use in a dry powder inhaler
comprises lactose having a particle size between about 1 µm and about 100 µm and
micronized particles of a succinic acid salt of compound of formula 1, or a solvate thereof.
Such a dry powder composition can be made, for example, by combining the
lactose with the active agent and then dry blending the components. Alternatively, if
desired, the active agent can be formulated without an excipient. The pharmaceutical

composition is then typically loaded into a dry powder dispenser, or into inhalation blister
strips, cartridges or capsules for use with a dry powder delivery device.
Examples of dry powder inhaler delivery devices include Diskhaler (GlaxoSmithKline,
Research Triangle Park, NC) (see, e.g., U.S. Patent No. 5,035,237); Diskus
(GlaxoSmithKline) (sec, e.g., U.S. Patent No. 6,378,519; Turbuhalcr. (AstraZcneca,
Wilmington, DE) (see, e.g., U.S. Patent No. 4,524,769); Rotahaler (GlaxoSmithKline)
(see, e.g., U.S. Patent No. 4,353,365) and Handihaler (Boehringer Ingelheim). Further
examples of suitable DPI devices are described in U.S. Patent Nos. 5,415,162, 5,239,993,
and 5,715,810, WO-A-2006/018261, and WO-A-03/061743, and references cited therein.
In yet another specific embodiment of this invention, the pharmaceutical
composition comprising the active agent is administered by inhalation using a metered-
dose inhaler. Such metered-dose inhalers typically discharge a measured amount of the
active agent or a pharmaceutically acceptable salt thereof using compressed propel lant
gas. Accordingly, pharmaceutical compositions administered using a metered-dose
inhaler typically comprise a solution or suspension of the active agent in a liquefied
propellant. Any suitable liquefied propellant may be employed including
chlorofluorocarbons, such as CCl3F, and hydrofluoroalkanes (HFAs), such as 1,1,1,2-
tetrafluoroethanc (HFA 134a) and 1,1,1,2,3,3,3-heptafluoro-n-propane, (HFA227). Due
to concerns about chlorofluorocarbons affecting the ozone layer, formulations containing
HFAs are generally preferred. Additional optional components of HFA formulations
include co-solvents, such as ethanol or pentane, and surfactants, such as sorbitan trioleate,
oleic acid, lecithin, and glycerin. See, for example, U.S. Patent No. 5,225,183,
EP 0717987 A2, and WO 92/22286.
A representative pharmaceutical composition for use in a metered-dose inhaler
comprises from about 0.01 % to about 5 % by weight of a succinic acid salt of compound
of formula I, or a solvate thereof; from about 0 % to about 20 % by weight ethanol; and
from about 0 % to about 5 % by weight surfactant; with the remainder being an HFA
propellant.
Such compositions are typically prepared by adding chilled or pressurized
hydrofluoroalkane to a suitable container containing the active agent, ethanol (if present)
and the surfactant (if present). To prepare a suspension, the active agent is micronized
and then combined with the propellant. The formulation is then loaded into an aerosol
canister, which forms a portion of a metered-dose inhaler device. Examples of metered-

dose inhaler devices developed specifically for use with HFA propellants are provided in
U.S. Patent Nos. 6,006,745 and 6,143,277. Alternatively, a suspension formulation can
be prepared by spray drying a coating of surfactant on micronized particles of the active
agent. See, for example, WO 99/53901 and WO 00/61108.
For additional examples of processes of preparing respirablc particles, and
formulations and devices suitable for inhalation dosing see U.S. Patent Nos. 6,268,533,
5,983,956, 5,874,063, and 6,221,398, and WO 99/55319 and WO 00/30614.
The pharmaceutical compositions of this invention may also contain other
therapeutic agents that are co-administered with a succinic acid salt of compound of
formula I or solvate thereof. For example, the pharmaceutical compositions of this
invention may further comprise one or more therapeutic agents selected from anti-
inflammatory agents (e.g. steroidal anti-inflammatory agents, such as corticosteroids; and
non-steroidal anti-inflammatory agents (NSAlDs), phosphodiesterase IV inhibitors, anti-
infective agents (e.g. antibiotics or antivirals), antihistamines, β2 adrenergic receptor
agonists, muscarinic receptor antagonistst (i.e., anticholinergic agents) and the like, in
particular a steroidal anti-inflammatory agent or a muscarinic receptor antagonistst. The
other therapeutic agents can be used in the form of pharmaceutically acceptable salts or
solvates. Additionally, if appropriate, the other therapeutic agents can be used as
optically pure stereoisomers.
If desired, the salts of this invention can also be administered in combination with
another therapeutic agent or agents, such those described herein. In this embodiment, the
components are not physically mixed together but are administered simultaneously or
sequentially as separate compositions. For example, a salt of this invention can be
administered by inhalation simultaneously or sequentially with a steroidal anti-
inflammatory agent, such as a corticosteroid, using an inhalation delivery device that
employs separate compartments (e.g. blister packs) for each therapeutic agent.
Alternatively, the combination may be administered from multiple delivery devices, i.e.,
one delivery device for each therapeutic agent.
Representative steroidal anti-inflammatory agents that can be used with the
compounds of this invention include, but are not limited to, methyl prednisolone,
prednisolone, dexamcthasonc, fluticasone propionatc, 6,9-difluoro-17 -[(2-
furanylcarbonyl)oxy]-11 -hydroxy-16-mcthyl-3-oxoandrosta-1,4-dicne-17-carbothioic
acid S-fluoromethyl ester, 6,9-difluoro-l l-hydroxy-16 -methyl-3-oxo-17 -propionyloxy-

androsta-1,4-diene-17-carbothioic acid S-(2-oxotetrahydrofuran-3S-yl) ester,
beclomethasone esters (e.g. the 17-propionale ester or the 17,21-dipropionate ester),
budesonide, flunisohde, mometasone esters (e.g. the furoate ester), triamcinolone
acetonide, rofleponide, ciclesonidc, butixocort propionatc, RPR-106541, ST-126 and the
like, or pharmaceutically-accetable salts thereof. In a particular embodiment, the
steroida! anti-inflammatory agent is 6a,9a-difluoro-17a -[(2-furanyk;arbonyl)oxy]-l} £-
hydroxy-16a-methyl-3-oxoandrosta-l,4-diene-17p-carbothioic acid S-fluoromethyl ester
or a pharmaceutically acceptable salt or solvate thereof. When employed, the steroidal
anti-inflammatory agent will be present in the pharmaceutical composition in a
theraputically effective amount. Typically, the steroidal anti-inflammatory agent will be
present in an amount sufficient to provide from about 0.05 ug to about 500 µg per dose.
Representative muscarinic antagonists (i.e., anticholinergic agents) that can be
used with the compounds of this invention include, but arc not limited to, atropine,
atropine sulfate, atropine oxide, methylatropine nitrate, homatropine hydrobromide,
hyoscyamine (d, f) hydrobromide, scopolamine hydrobromide, ipratropium bromide,
oxitropium bromide, tiotropium bromide, methantheline, propantheline bromide,
anisotropine methyl bromide, clidinium bromide, copyrrolate (Robinul), isopropamidc
iodide, mepcnzolatc bromide, tridihexethyl chloride (Pathilone), hexocyclium
methylsulfate, cyclopentolate hydrochloride, tropicamide, trihexyphenidyl hydrochloride,
pirenzepine, telenzepine, AP-DX 116 and methoctramine and the like, or a
pharmaceutically acceptable salt thereof; or, for those compounds listed as a salt,
alternate pharmaceutically acceptable salt thereof.
Representative antihistamines, phosphodiesterase-4 (PDE4) inhibitors or mixed
PDE3/PDE4 inhibitors and J32 adrenergic receptor agonists that can be used with the
compounds of this invention are described in International Patent application no
PCT/US2004/004449, publication no.WO 2004/074246 A2.
Other therapeutic agents which may be used with compounds of the present
invention include, for example, other anti-inflammatory agents, e.g., NSAIDs (such as
sodium cromoglycate; nedocromil sodium; leukotriene antagonists (e.g. monteleukast);
inhibitors of leukotriene synthesis; iNOS inhibitors; protease inhibitors, such as tryptase
and clastase inhibitors; bcta-2 intcgrin antagonists and adenosinc receptor agonists or
antagonists (e.g. adenosine 2a agonists); cytokine antagonists (e.g. chemokine antagonists

such as, an interleukin antibody (IL antibody), specifically, an IL-4 therapy, an IL-13
therapy, or a combination thereof); or inhibitors of cytokine synthesis. Suitable doses for
the other therapeutic agents administered with a compound of the invention are in the
range of about 0.05 mg/day to about 100 mg/day.
The following formulations illustrate representative pharmaceutical compositions
of the present invention:

Formulation Example A
A dry powder for administration by inhalation is prepared as follows:
Ingredients Amount
Salt of the invention 0.2 mg
Lactose 25 mg
Representative Procedure: The compound of the invention is micronized and then
blended with lactose. This blended mixture is then loaded into a gelatin inhalation
cartridge. The contents of the cartridge are administered using a powder inhaler.
Formulation Example B
A dry powder formulation for use in a dry powder inhalation device is prepared as
follows:
Representative Procedure: A pharmaceutical composition is prepared having a
bulk formulation ratio of micronized salt of the invention to lactose of 1:200. The
composition is packed into a dry powder inhalation device capable of delivering between
about 10 ug and about 100 ug of the compound of the invention per dose.
Formulation Example C
A dry powder for administration by inhalation in a metered dose inhaler is
prepared as follows:
Representative Procedure: A suspension containing 5 wt. % of a salt of the
invention and 0.1 wt. % lecithin is prepared by dispersing 10 g of the compound of the
invention as micronized particles with mean size less than 10 urn in a solution formed
from 0.2 g of lecithin dissolved in 200 mL of demineralized water. The suspension is
spray dried and the resulting material is micronized to particles having a mean diameter
less than 1.5 um. The particles are loaded into cartridges with pressurized 1,1,1,2-
tetrafluoroethane.
Formulation Example D
A pharmaceutical composition for use in a metered dose inhaler is prepared as
follows:

Representative Procedure: A suspension containing 5 % salt of the invention,
0.5 % lecithin, and 0.5 % trehalose is prepared by dispersing 5 g of active ingredient as
micronized particles with mean size less than 10 m in a colloidal solution formed from
0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 mL of dcmincralized water. The
suspension is spray dried and the resulting material is micronized to particles having a
mean diameter less than 1.5 urn. The particles are loaded into canisters with pressurized
1,1,1,2-tetrafluoroethane.
Formulation Example E
A pharmaceutical composition for use in a nebulizer inhaler is prepared as
follows:
Representative Procedure: An aqueous aerosol formulation for use in a nebulizer
is prepared by dissolving 0.5 mg of the salt of the invention in 1 mL of a 0.9 % sodium
chloride solution acidified with citric acid. The mixture is stirred and sonicated until the
active ingredient is dissolved. The pH of the solution is adjusted to a value of about 5 by
the slow addition of NaOH.
Formulation Example F
Bulk formulations were prepared comprising 0.8%, 1.6% and 4% w/w of succinate salt
(Form 1, micronised to give a median size of approx 2microns) in lactose monohydrate
(having a mass median size of 70-90 microns ), to provide 100,200 and 500ug of free
base (Biphenyl-2-ylcarbamic Acid l-[2-(2-Chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-
oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl} -5-methoxyphenylcarbamoyl)-
ethyl]piperidin-4-yl Ester) per blister, for use in a D1SKUS™ dry powder inhalation
device.
Formulations as above were also prepared but also comprising magnesium stcaratc as a
stabiliser, at levels from 0.2-l%w/w.
Utility
The compound of formula I possesses both β2 adrenergic receptor agonist and
muscarinic receptor antagonist activity and, therefore, a succinic acid salt of the

compound of formula I of the present invention is expected to be useful as a therapeutic
agent for treating medical conditions mediated by β2 adrenergic receptors or muscarinic
receptors, i.e., medical conditions thai are ameliorated by treatment with a β2 adrenergic
receptor agonist or a muscarinic receptor antagonist. Such medical conditions include, by
way of example, pulmonary disorders or diseases including those associated with
reversible airway obstruction, such as chronic obstructive pulmonary disease (e.g.,
chronic and whee2y bronchitis and emphysema), asthma, pulmonary fibrosis, allergic
rhinitis, rhinorrhea, and the like. Other conditions which may be treated include
premature labor, depression, congestive heart failure, skin diseases (e.g., inflammatory,
allergic, psoriatic and proliferative skin diseases, conditions where lowering peptic
acidity is desirable (e.g., peptic and gastric ulceration) and muscle wasting disease.
Accordingly, in one embodiment, this invention is directed to a method for
treating a pulmonary disorder, the method comprising administering to a patient in need
of treatment a therapeutically effective amount of a succinic acid salt of biphenyl-2-
ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5 -y l)ethylamino]methyl} -5 -methoxyphenylcarbamoy l)ethyl]piperidin-4-
yl ester or a solvate thereof. When used to treat a pulmonary disorder, the salt of this
invention will typically be administered by inhalation in multiple doses per day, in a
single daily dose or a single weekly dose. Generally, the dose for treating a pulmonary
disorder will range from about 10 µg/day to about 200 ug/day.
When administered by inhalation, the compounds of this invention typically have
the effect of providing bronchodilation. Accordingly, in another of its method aspects,
this invention is directed to a method of providing bronchodilation in a patient in need of
bronchodilation, the method comprising administering to the patient a bronchodilation-
producing amount of a succinic acid salt of biphenyl-2-ylcarbamic acid 1-[2-(2-chlovo-4-
{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)cthyl]piperidin-4-yl ester or a solvate thereof. Generally, the
dose for providing brochodilation will range from about 10 ug/day to about 2.00 ug/day.
In one embodiment, this invention is directed to a method of treating chronic
obstructive pulmonary disease or asthma, the method comprising administering to a
patient in need of treatment a therapeutically effective amount of a succinic acid salt of
biphcnyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethy[]-piperidin-

4-yl ester or a solvate thereof. When used to treat a COPD or asthma, the salt of this
invention will typically be administered by inhalation in multiple doses per day or in a
single daily dose. Generally, the dose for treating COPD or asthma will range from about
10 ug/day to about 200 µg/day. As used herein, COPD includes chronic obstructive
bronchitis and emphysema (sec, for example, Barnes, Chronic Obstructive Pulmonary
Disease, N Engl J Med 2000: 343:269-78).
When used to treat a pulmonary disorder, the salt of this invention is optionally
administered in combination with other therapeutic agents. Accordingly, in a particular
embodiment, the pharmaceutical compositions and methods of this invention further
comprise a therapeutically effective amount of a steroidal anti-inflammatory agent.
The properties and utility of succinic acid salts of this invention can be demonstrated
using various in vitro and in vivo assays well-known to those skilled in the art. For
example, representative assays are described in International Patent application no
PCT/US2004/004449, publication no. WO 2004/074246 A2 (Theravance Inc, South San
Francisco, California, US)..

EXAMPLES
The following Preparations and Examples are provided to illustrate specific embodiments
of this invention. These specific embodiments, however, are not intended to limit the
scope of this invention in any way unless specifically indicated.
Unless noted otherwise, reagents, starting materials and solvents were purchased from
commercial suppliers (such as Sigma-Aldrich, Fluka and the like) and were used without
further purification.
1 -(3- {[2-chIoro-4-(hydroxymethyl)-5-methoxyphenyl]amino} -3-oxopropyl)piperidin-4-yl
biphenyl-2-ylcarbamate may be prepared according to the description provided in
International Patent application no PCT/US2004/004449, publication no.WO
2004/074246 A2, at page 134, Preparation 96.
Biphenyl-2-ylcarbamic Acid 1 -[2-(4- {[(R)-2-(tert-Butyldimethy lsilanyloxy)-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-chloro-5-
mcthoxyphenyicarbamoyl)-ethyl]piperidin-4-yl Ester may be prepared according to the
description provided in International Patent application no PCT/US2004/004449,
1 publication no. WO 2004/074246 A2, at page 135, Preparation 98.
Example 1: Biphenyl-2-ylcarbamic Acid l-[2-(2-Chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yI)ethylamino | methyl}-5-
methoxyphenylcarbamoyi)-ethyl]piperidin-4-yl Ester Succinic acid Salt
l-(3-{[2-chloro-4-(hydroxymethyl)-5-methoxyphenyl]amino}-3-oxopropyl)piperidin-4-yl
biphenyl-2-ylcarbamate (69g) was suspended in toluene (480 mL) at -65 °C. Manganese
dioxide (48g) was added and the resulting mixture stirred at -65 °C for about 6 hours.
The mixture was then diluted with toluene (300mL), and Celite (24 g) added. The
resulting mixture was filtered and washed with toluene (180 ml), to remove manganese
residues. The resulting solution was concentrated to about half the original volume (540
ml), cooled to -20 °C, and diluted with methanol (240ml.). 5-((1R)-2-amino-1-{[tert-
butyl(dimethyl)silyl]oxy}ethyl)-8-hydroxyquinolin-2(1H)-one acetate (48.4g) was added
and the mixture stirred at -65 °C until dissolution was complete. The solution was cooled

to ~ -2 °C and sodium borohydride (2.12g) was added in 4 portions over 1 h. Upon
complete addition the reaction was quenched by the addition of water (300mL). The
mixture was stirred thoroughly and then the layers were separated, at- 20°C. Methanol
(540mL) was added to the organic layer and this was then concentrated to about a third of
the original volume. Additional methanol (600mL) was added to the residue which was
then concentrated to about half the original volume. The solution was cooled to -17 "C
and cesium fluoride (54. lg) and acetic acid (9.2g) were added. The resulting mixture was
stirred at ~] 7 °C for about 13 hours. Upon complete reaction, 2-methyltetrahydrofuran
(605mL) and water (275mL) were added. The mixture was stirred thoroughly and the
layers then separated. The organic layer was washed with aqueous saturated sodium
hydrogen carbonate solution (275mL) and then water (220mL). The organic layer was
then concentrated to about half the original volume by vacuum distillation before being
diluted with THF (500mL)*. The solution was warmed to -37 °C and a solution of
succinic acid (1 l.Og) in isopropanol (250ml) was added. The solution was then seeded
(with Form 1), held at -37 °C for about 4 hours, cooled to ~15 °C over about 4 hours
before being held at -15 °C for 84 hours. The resulting solid was isolated by filtration,
washed with THF:isopropanol:water mixture (50:50:3, 300mL) and TBME (300mL)
before being dried in vacuo at -45 °C to provide the title compound as a white powder
which was almost exclusively (~ 98%) Form 3 (55,0g).
1H NMR (500 MHz, DMSO-d6: 5(ppm): 10.27 (s, 1H), 8.67 (s,lH), 8.11 (d, 1H, J =
9.5), 7.79 (s, 1H), 7.33 (m, 10H), 7.07 (d, 1H, J = 8.0), 6.93 (d, 1H, J = 8.5), 6.49 (d, 1H,
J = 10.0), 5.10 (m, 1H), 4.50 (m, 1H), 3.80 (s, 2H), 3.73 (s, 3H), 2.74 (m, 4H), 2.62 (m,
2H), 2.55 (m, 2H), 2.38 (s, 4H), 2.24 (m, 2H), 1.77 (m, 2H), 1.51 (m, 2H);
m/z: [M+H+] calculated for C40H42C1N5O7, 740.29; found 740.24
* the organic layer may be evaporated to dryness to provide biphenyl-2-ylcarbamic acid
l-[2-(2-Chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoIin-5-
yl)ethylamino]methyl} -5-methoxyphenylcarbamoyl)-ethyl]piperidin-4-yl ester, for
subsequent conversion to succinate salt.
Preparation 1: Bipheny]-2-ylcarbamic Acid l-I2-(2-Chloro-4-{I(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethytamino\methyl}-5-
methoxyphenylcarbamoyl)-ethyllpiperidin-4-yl Ester

l-(3-{[2-chloro-4-(hydroxymethyl)-5-methoxyphenyl]amino}-3-oxopropyl)piperidin-4-yl
biphenyl-2-ylcarbamale (12.5g) and manganese dioxide (8g) were healed together in
toluene (94 mL) at ~60 °C for 5 h. The manganese dioxide (8g) was then removed by
filtration through Celite (2 g), with washing with toluene (2 x 3ml). The resulting
solution was concentrated (to about 100 ml) and then warmed to -60 °C. 5-((1R)-2-
amino-1 -{[tert-butyl(dimethyl)silyl]oxy} ethyl)-8-hydroxyqumolin-2(1H)-one acetate
(8g) and methanol (19 ml) were added and the mixture stirred until dissolution was
complete. The solution was cooled to ~ -5 °C, sodium borohydride (0.28g) was added
and the mixture then stirred for 2h.. Water (50 ml) was then added, to quench the
reaction and the mixture stirred vigorously at 20 °C for 30 min. The layers were
separated and the aqueous discarded. The organic layer was then solvent switched into
methanol (75 ml).Cesium fluoride (11.4g) and acetic acid (1.7g) were added and the
resulting mixture was stirred at 20 °C for about 22 hours. The mixture was reduced in
volume (to approximately 60ml) and methyltetrahydrofuran (100ml) and water (50ml)
added, to enable a phase separation. The aqueous layer was discarded and the organic
layer evaporated to dryness to provide the title compound as a solid (12.0g. 70%).
Example 2: Biphenyl-2-ykarbamic Acid H2-(2-Chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)-ethyllpiperidin-4-yl Ester Succinic acid Salt (Form 1)
Ethanol (14 ml) was added to Biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-
hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl} -5-
methoxyphenylcarbamoyl)-ethyl]piperidin-4-yl ester (1.5g) and heated at -70 °C for 1 h.
The temperature was then lowered to 50 °C and succinic acid (251.25mg, 1.05 equiv) in
ethanol (2 ml) was added portionwise over approximately 4 hours. After all the acid was
added, water (2.25 ml) was added, followed by a further 30 min at 50 °C. The reaction
was then temperature cycled between 0 °C and 40 °C over 3 days. The resulting white
solid was isolated by filtration, washed with ethanol and dired in a vacuum oven at
ambient temperature, to provide the title compound as a crystalline solid (727mg).
Example 3: Biphenyl-2-ylcarbamic Acid l-(2-(2-Chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylaminolmethyl}-5-
methoxyphenylcarbamoyl)-ethyl]piperidin-4-yI Ester Succinic acid Salt (Form 2)

Biphenyl-2-ylcarbaraic acid 1-[2-(2-chioro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)etbylamino]methyl}-5-methoxyphenylcarbamoyl)-ethyl]piperidin-
4-yI ester (prepared as in Preparation 3) (200mg) was; suspended in melhano] (1.5ml) at
-70 °C. A first portion (100µl) of succinic acid in mcthanol was added, from a total of
succinic acid (67mg7 2.1 cquiv) in methanol (0.5 ml), and the temperature reduced to
50°C. The remaining succinic acid in methanol was added in four further portions
(100 µl) over approximately 5 hours, with further methanol (1 ml) added after 3 h, to
replace lost solvent. After a further 30 min, The resulting slurry was temperature cycled
between 0 °C and 40 °C over 5 days. The resulting solid was isolated by filtration,
washed with THF, dried on filter paper and then in a vacuum oven, to provide the title
compound as a crystalline solid (148mg).
Example 4: Biphenyl-2-ylcarbamic Acid H2-(2-Chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyIaminoJmethyl}-5-
methoxyphenylcarbamoyl)-ethyl]piperidin-4-yl Ester Succinic acid Salt (Form 2)
Biphenyl-2-ylcarbamic acid 1 -[2-(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethy[amino]methyl}-5-methoxyphenylcarbamoyI)-ethyl]piperidin-
4-yl ester (2g) was dissolved in methanol (16ml) at -70 °C, over a period of 1 h. After a
further 1 h, succinic acid (335mg) in methanol (4 ml) was added and this was left to
temperature cycle between 0 °C and 40 °C over 2 days. The resulting solid was isolated
by filtration, washed with methanol, dried on filter paper and then dried at 40 °C in a
vacuum oven overnight, to provide the title compound as a crystalline solid (979mg).
This was confirmed by DSC to be Form 2.
Example 5: Biphenyl-2-ylcarbamic Acid l-l2-(2-Chloro-4-{[(R)-2 hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylaminolmethyl}-5-
methoxyphenyIcarbamoyl)-ethyJ]piperidin-4-yl Ester Succinic acid Salt (Form 3)
Biphenyl-2-ylcarbamic acid 1 -[2-(2-chloro-4- {[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dibydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbatnoy()-ethyl]piperidin-
4-yl ester (200mg) was suspended in tetrahydrofuran (1.5ml) at -70 °C. A first portion
(lOOul) of succinic acid in methanol was added, from a total of succinic acid (33.5mg,
1.05 equiv) in THF (0.5ml) and the temperature reduced to 50°C. The remaining
succinic acid in methanol was added in four further portions over approximately 5 hours,

with further THF (1ml) added after lh, to replace lost solvent. After a further 30 min, the
resulting slurry was temperature cycled between 0 °C and 40 °C over 5 days. The
resulting solid was isolated by filtration, washed with melhanoi, dried on filter paper
overnight and then in a vacuum oven, to provide the title compound as a crystalline solid
(140mg).
Example 6: Biphenyl-2-ylcarbamic Acid l-[2-(2-Chloro-4-{[(R)-2-hydroxy-2-(8-
hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethy]amino]tnethyl}-5-
methoxyphenylcarbamoyl)-ethyIlpiperidin-4-yl Ester Succinic acid Salt (Form 1)
Biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-
dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)-ethyI]piperidin-
4-yl ester succinic acid salt, prepared as in Example 1 (363.6g) was dissolved in 14%
water in tetrahydrofuran (2906mL) at -20 °C and stirred for 1.5 hours until a solution was
formed. Isopropanol (635mL) was added to the clear solution which was then warmed to
36 ±3 °C. Seed (0.9 lg) was added and the solution was stirred at -36 ±3 °C for about 1
hour. Isopropanol (6080mL) was then added to the mixture over about 12 hours. The
suspension was then held at 36 ±3 °C for about 1 hour before being cooled to -20 °C and
held at this temperature for at least a further hour. The resulting precipitate was isolated
by filtration, washed with. THE isopropanol:water (70:25:5, 3636ml,) and then TBME
(3636mL) and dried in vacuo at -60 °C to provide the title compound as a crystalline
solid.
Example 7 - Thermal Analysis
DSC thcrmograms of the solid state forms Form 1, 2 and 3 were obtained using a TA
Instruments Q1000 calorimeter number: 970001.901, and serial number: 1000-0126. The
sample was weighed into an aluminium pan, a pan lid placed on top and lightly crimped
without scaling the pan. The experiments were conducted using a heating rate of 10°C
min-1.
A representative DSC thermogram for a sample of each of the Form 1, 2 and 3 succinic
acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-
2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]
piperidin-4-yl ester, as prepared by the method described in Examples 2, 3 and 5, is
shown in Figure 1 to 3.

Example 8 - X-Ray Powder Diffraction
The X-ray powder diffraction (XRPD) data of the solid state forms Form 1, 2 and 3 were
acquired on a PANalytical X.Pert Pro powder diffractometer, model PW3040/60, using
an XCelcrator detector. The acquisition conditions were: radiation: Cu Ka, generator
tension: 40 kV, generator current: 45 mA, start angle: 2.0° 29 , end angle: 40.0° 2 6, step
size: 0.0167° 26, time per step: 31.75 seconds. The sample was prepared by mounting a
few milligrams of sample on a Silicon wafer (zero background) plates, resulting in a thin
layer of powder. Characteristic XRPD angles and d-spacings are recorded in Table 1 for
a sample of each of Forms Form 1, 2 and 3, as prepared by the method described in
Examples 2, 3, and 5.


Characteristic peak positions and calculated d-spacings are summarised in Table 1.
These were calculated from the raw data using Highscore software. Peaks marked with a
* distinguish that form from the others. Other peaks (underscored and in bold) also
distinguish the forms, however, there arc shoulders or low intensity peaks of another form
in close proximity that make these peaks less specific than those with a shaded
background.
The XRPD data are illustrated in Figures 4 to 6, respectively.

Example 9 - FT-IR
The FT-IR spectrum of the solid forms, Forms 1, 2 and 3, was recorded using a Nicolet
Avatar 360 FT-IR spectrometer, fitted with a Diamond/ZnSe ATR Accessory at 4 cnr*
resolution, over the frequency range 4000 to 700 cm"1.
Form 1 bands were observed at: 3265,2832, 1735, 1718, 1679, 1669, 1591, 1540, 1518,
1493, 1439, 1405, 1339, 1302, 1283, 1239, 1202, 1163,1144, 1107, 1095, 1039, 1009,
973, 921, 885, 868, 838, 773, 751, and 707 cm1.
Form 2 bands were observed at: 3317, 2947, 1728, 1678, 1667, 1591, 1537, 1494, 1453,
1439,1403, 1339, 1302, 1284,1213, 1172, 1111, 1058, 1046, 999, 975, 885, 839, and
750 cm-1.
Form 3 bands were observed at: 3335, 2949, 1745, 1715, 1678, 1641, 1592, 1542, 1493,
1464, 1439, 1405, 1338, 1303, 1283, 1247, 1211, 1170,1109, 1093, 1053,1041,997,
974, 919, 889, 842, 774, 766, 751 and 721 cm'1.
The data for a representative sample of each of Forms 1,2 and 3 is shown in Figures 7 io
9, respectively.
Example 10 - Dynamic Vapour Sorption Assessment
A Dynamic Vapour Sorption (DVS) profile of Form 1 was obtained using an SMS DVS-1
with water as a reagent at 25°C. 20-30mg of sample were placed in a glass bulb and
equilibrated at 30%RH. The %RH was increased to 90% in 10% steps. The %RH was
then decreased to 0% in 10% steps, and finally increased to 30%RH, again in 10% steps.
The results of two sorption/desorption cycles are shown in Figure 10
The DVS profile shows that the succinate salt, Form 1, has a reversible
sorption/desorption profile with a good level of hygroscopicity (less than about 2.0 %
weight gain in the humidity range of 30 % relative humidity to 90 % relative humidity).
The reversible moisture sorption/desorption profile demonstrates that the Form 1
succiante salt of the present invention possesses an acceptable hygroscopicity and is not
deliquescent, thereby making it suitable for pharmaceutical development.

Claims
1. A succinic acid salt of biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-
2-hydroxy-2-(84iydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvatc thereof.
2. The compound of Claim 1 which is a crystalline solid state form.
3. The compound of Claim 2 which is the Form 1 crystalline solid state form.
4. The compound of Claim 3, wherein the compound is characterized by a
differential scanning calorimetry trace which shows a melting point in the range of about
170 °C to about 180°C.
5. The compound of Claim 3, wherein the compound is characterized by an
x-ray powder diffraction pattern having diffraction peaks at 28 values of 5,0±0.3 and
10.0±0.3.
6. The compound of Claim 3, wherein the compound is characterized by an
x-ray powder diffraction pattern in which the peak positions are substantially in
accordance with the peak positions of the pattern shown in Figure 4.
7. The compound of Claim 3, wherein the compound has infrared absorption
spectrum with significant absorption bands at about 3265, 2832, 1735, 1718, 1679, 1669,
1591, 1540,1518, 1493, 1439, 1405, 1339,1302, 1283,1239,1202, 1163, 1144, 1107,
1095, 1039, 1009, 973, 921, 885, 868, 838, 773, 751, and 707 cm"1.
8. The compound of Claim 3, wherein the compound is characterized by an
infrared absorption spectrum substantially in accordance with that shown in Figure 7.
9. The compound of Claim 2 which is the Form 2 or the Form 3 crystalline
solid state form.

10. The compound of any one of claims Claim 1 to 9 which is in micronized
form.
11. A pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of any one of Claims 1 to 10.
12. The pharmaceutical composition of Claim 11, wherein the composition
further comprises a steroidal anti-inflammatory agent.
13. The pharmaceutical composition of Claim 12, wherein the steroidal anti-
inflammatory agent is 6α,9α-difluoro-17α -[(2-furanylcarbonyl)oxy]-l 1 p-hydroxy-16α-
methyl-3-oxoandrosta-l,4-diene-17β-carbothioic acid 5-fiuoromethyl ester or a solvate
thereof.
14. The pharmaceutical composition of Claim 11, wherein the composition is
formulated for administration by inhalation.
15. The pharmaceutical composition of Claim 11, in micronized form.
16. The pharmaceutical composition of Claim 14, wherein the carrier is
lactose, starch, mannitol, dextrose, polylactic acid, polylactide-co-glycolide or a
combination thereof.
17. A combination comprising:

(a) a compound of any one of Claims 1 to 9; and
(b) a steroidal anti-inflammatory agent.
18. The combination of Claim 17, wherein the steroidal anti-inflammatory
agent is 6a,9a-difluoro-17α -[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-
oxoandrosta-l,4-diene-17P-carbolhioic acid 5-fluoromethyl ester or a solvate thereof.

19. A method for treating a pulmonary disorder, the method comprising
administering to a patient in need of treatment a therapeutically effective amount of a
compound of any one of Claims 1 to 10.
20. A method of producing bronchodilation in a patient, the method
comprising administering by inhalation to the patient bronchodilation-producing amount
of a compound of any one of Claims 1 to 10.
21. A method of treating chronic obstructive pulmonary disease or asthma, the
method comprising administering to a patient in need of treatment a therapeutically
effective amount of a compound of any one of Claims 1 to 10.
22. A succinic acid salt of biphenyl-2-ylcarbamic acid 1 -[2-(2-chloro-4- {[(R)-
2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino ]methyl} -5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof for use in therapy
or as a medicament.
23. Use of a succinic acid salt of biphcnyl-2-ylcarbamic acid l-[2-(2-chloro-4-
{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyLamino]methyl}-5-
methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof for the
manufacture of a medicament.
24. The use of Claim 23, wherein the medicament is for treating a pulmonary
disorder.
25. The use of Claim 23, wherein the pulmonary disorder is chronic
obstructive pulmonary disease or asthma.
26. Use of:

(a) a succinic acid salt of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-
2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl)-5-
mcthoxyphcnylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof; and
(b) a steroidal anti-inflammatory agent;

in the manufacture of a medicament for the treatment of a pulmonary disorder.
27. The use of Claim 26, wherein the steroidal anti-inflammatory agent is
6a,9a-difluoro-17a -[(2-furanylcarbonyl)oxy]-11 p-hydroxy-16a-methyl-3-oxoandrosta-
1,4-diene-l 7£-carbothioic acid S-fiuoromethyl ester or a solvate thereof.
28. A process for preparing a compound of Claim 1, the process comprising
contacting biphenyl-2-ylcarbamic acid l-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-
oxo-1,2-dihydroquinolin-5-yI)ethylamino]methyl} -5-methoxyphenylcarbamoyl)ethyl]-
piperidin-4-yl ester with succinic acid.
29. A process for preparing the Form 1 succinate salt which process comprises
the steps:
dissolving the succinate salt in aqueous THF (10-18%, for example 10-16%), at a
temperature in the range 18 to 23°C, for example about 20°C;
adding a first volume of a lower alcohol for example ethanol or isopropanol, in particular
isopropanol, and warming to 32-40°C;
optionally seeding with Form 1;
adding a second volume of the lower alcohol, for example over several hours, preferably
about 12 h;
cooling to temperature in the range 18 to 23°C, for example about 20 °C; and
collecting the crystalline product.

A succinic acid salt of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihy-
droquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a solvate thereof for use in treating
pulmonary disorders.

Documents:

3210-KOLNP-2008-(20-04-2012)-CORRESPONDENCE.pdf

3210-KOLNP-2008-(29-02-2012)-ABSTRACT.pdf

3210-KOLNP-2008-(29-02-2012)-AMANDED CLAIMS.pdf

3210-KOLNP-2008-(29-02-2012)-DESCRIPTION (COMPLETE).pdf

3210-KOLNP-2008-(29-02-2012)-DRAWINGS.pdf

3210-KOLNP-2008-(29-02-2012)-EXAMINATION REPORT REPLY RECEIVED.pdf

3210-KOLNP-2008-(29-02-2012)-FORM-1.pdf

3210-KOLNP-2008-(29-02-2012)-FORM-13.pdf

3210-KOLNP-2008-(29-02-2012)-FORM-2.pdf

3210-KOLNP-2008-(29-02-2012)-FORM-3.pdf

3210-KOLNP-2008-(29-02-2012)-FORM-5.pdf

3210-KOLNP-2008-(29-02-2012)-OTHERS.pdf

3210-KOLNP-2008-(29-02-2012)-PETITION UNDER RULE 137.pdf

3210-kolnp-2008-abstract.pdf

3210-KOLNP-2008-ASSIGNMENT 1.1.pdf

3210-KOLNP-2008-ASSIGNMENT.pdf

3210-KOLNP-2008-CANCELLED PAGES.pdf

3210-kolnp-2008-claims.pdf

3210-KOLNP-2008-CORRESPONDENCE 1.2.pdf

3210-KOLNP-2008-CORRESPONDENCE-1.1.pdf

3210-kolnp-2008-correspondence.pdf

3210-kolnp-2008-description (complete).pdf

3210-kolnp-2008-drawings.pdf

3210-KOLNP-2008-EXAMINATION REPORT.pdf

3210-kolnp-2008-form 1.pdf

3210-KOLNP-2008-FORM 13.pdf

3210-KOLNP-2008-FORM 18 1.1.pdf

3210-KOLNP-2008-FORM 18.pdf

3210-KOLNP-2008-FORM 3 1.1.pdf

3210-kolnp-2008-form 3.pdf

3210-KOLNP-2008-FORM 5 1.1.pdf

3210-kolnp-2008-form 5.pdf

3210-kolnp-2008-gpa.pdf

3210-KOLNP-2008-GRANTED-ABSTRACT.pdf

3210-KOLNP-2008-GRANTED-CLAIMS.pdf

3210-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE).pdf

3210-KOLNP-2008-GRANTED-DRAWINGS.pdf

3210-KOLNP-2008-GRANTED-FORM 1.pdf

3210-KOLNP-2008-GRANTED-FORM 2.pdf

3210-KOLNP-2008-GRANTED-FORM 3.pdf

3210-KOLNP-2008-GRANTED-FORM 5.pdf

3210-KOLNP-2008-GRANTED-LETTER PATENT.pdf

3210-KOLNP-2008-GRANTED-SPECIFICATION-COMPLETE.pdf

3210-kolnp-2008-international publication.pdf

3210-KOLNP-2008-INTERNATIONAL SEARCH REPORT & OTHERS.pdf

3210-kolnp-2008-international search report.pdf

3210-KOLNP-2008-OTHERS.pdf

3210-kolnp-2008-pct priority document notification.pdf

3210-kolnp-2008-pct request form.pdf

3210-KOLNP-2008-PETITION UNDER RULE 137.pdf

3210-KOLNP-2008-REPLY TO EXAMINATION REPORT.pdf

3210-kolnp-2008-specification.pdf


Patent Number 256599
Indian Patent Application Number 3210/KOLNP/2008
PG Journal Number 28/2013
Publication Date 12-Jul-2013
Grant Date 05-Jul-2013
Date of Filing 06-Aug-2008
Name of Patentee GLAXO GROUP LIMITED
Applicant Address GLAXO WELLCOME HOUSE, BERKELEY AVENUE GREENFORD, MIDDLESEX UB6 0NN
Inventors:
# Inventor's Name Inventor's Address
1 CHUDASAMA, RESHMA GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE HERTFORDSHIRE SG1 2NY
2 KINDON, LEANDA, JANE GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE HERTFORDSHIRE SG1 2NY
3 MALLET, FRANCK, PATRICK GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE HERTFORDSHIRE SG1 2NY
4 KENNEDY, ANDREW GLAXOSMITHKLINE, GUNNELS WOOD ROAD, STEVENAGE HERTFORDSHIRE SG1 2NY
PCT International Classification Number C07D 401/12
PCT International Application Number PCT/EP2007/051196
PCT International Filing date 2007-02-08
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0602778.3 2006-02-10 U.K.