Alkaloid aminoester derivatives and medicinal compositions thereof

44 Pages·2013·2.82 MB·English

US008492548B2
(12) United States Patent (10) Patent N0.: US 8,492,548 B2
Amari et al. (45) Date of Patent: *Jul. 23, 2013
(54) ALKALOID AMINOESTER DERIVATIVES (56) References Cited
AND MEDICINAL COMPOSITIONS
THEREOF U.S. PATENT DOCUMENTS
2010/0035922 A1 2/2010 Amari et a1.
(75) Inventors: Gabriele Amari, Parma (IT); Mauro
2010/0173880 A1 7/2010 Caligiuri et al.
Riccaboni, Parma (IT); Stefano Bossolo,
2011/0308519 A1* 12/2011 Schiaretti ............... .. 128/20315
Parma (IT) 2011/0311461 A1* 12/2011 Amari et a1. .................. .. 424/45
(73) Assignee: Chiesi Farmaceutici S.p.A., Parma (IT) FOREIGN PATENT DOCUMENTS
WO 03/053966 7/2003
( * ) Notice: Subject to any disclaimer, the term of this W0 WO 2010/072338 * 7/2010
patent is extended or adjusted under 35
OTHER PUBLICATIONS
U.S.C. 154(b) by 0 days.
U.S. Appl. No. 13/165,936, ?led Jun. 22, 2011, Amari, et al.
This patent is subject to a terminal dis
claimer. US. Appl. No. 13/165,948, ?led Jun. 22, 2011, Amari, et a1.
European Search Report in Application No. 101669075, issued Dec.
(21) Appl. No.: 13/165,930 29, 2010.
US. Appl. No. 13/219,109, ?led Aug. 26, 2011, Amari, et al.
(22) Filed: Jun. 22, 2011 US. Appl. No. 13/232,415, Sep. 14, 2011, Amari, et al.
US. Appl. No. 13/303,413, Nov. 23, 2011, Amari, et al.
(65) Prior Publication Data US. Appl. No. 13/729,388, ?led Dec. 28, 2012, Amari, et al.
US 2011/0311458A1 Dec. 22, 2011 * cited by examiner
(30) Foreign Application Priority Data
Primary Examiner * John Mabry
(74) Attorney, Agent, or Firm * Oblon, Spivak,
Jun. 22, 2010 (EP) ................................... .. 10166907
McClelland, Maier & Neustadt, L.L.P.
(51) Int. Cl.
C07D 221/02 (2006.01) (57) ABSTRACT
A61K 31/44 (2006.01) The present invention relates to alkaloid aminoester com
(52) US. Cl. pounds Which act as muscarinic receptor antagonists, pro
USPC ......................................... .. 546/112; 514/299 cesses for their preparation, compositions comprising them,
(58) Field of Classi?cation Search and therapeutic uses thereof.
USPC ......................................... .. 514/299; 546/112
See application ?le for complete search history. 22 Claims, No Drawings
US 8,492,548 B2
1 2
ALKALOID AMINOESTER DERIVATIVES presence of a substituted oxoethyl group on the aZonia-bicy
AND MEDICINAL COMPOSITIONS clo[2.2.2]octane ring are endoWed With high plasma instabil
THEREOF ity and longer duration of action than the corresponding com
pounds devoid of such group.
CROSS REFERENCES TO RELATED Thus, the present invention provides alkaloid aminoester
APPLICATIONS derivatives of general formula (I) With a substituted oxoethyl
group on the aZonia-bicyclo[2.2.2]octane, acting as muscar
This application claims priority to European Patent Appli inic receptor antagonists.
cation No. 101669075, ?led on Jun. 22, 2010, Which is incor In another embodiment, the present invention provides
porated herein by reference in its entirety. processes for the preparation of such compounds.
In another embodiment, the present invention provides
BACKGROUND OF THE INVENTION
pharmaceutical compositions Which contain such a com
pound.
1. Field of the Invention In another embodiment, the present invention provides
The present invention relates to alkaloid aminoester deriva methods for the treatment of respiratory disorders.
tives Which act as muscarinic receptor antagonists, processes In another embodiment, the present invention provides
for their preparation, compositions comprising them and
combinations of the such a compound With other pharmaceu
therapeutic uses thereof. tical active ingredients among Which are, for instance, those
2. Discussion of the Background
currently used in the treatment of respiratory disorders, eg
Quaternary ammonium salts acting as muscarinic (M) 20 beta2-agonists, corticosteroids, P38 MAP kinase inhibitors,
receptor antagonist drugs are currently used in therapy to
IKK2, HNE inhibitors, PDE4 inhibitor, leukotriene modula
induce bronchodilation for the treatment of respiratory dis
tors, NSAIDs, and mucus regulators.
eases. Examples of Well knoWn M receptor antagonists are for The compounds of the present invention thus behave as
instance represented by ipratropium bromide and tiotropium
soft-drugs, since they are able to produce a more persistent
bromide. 25 bronchodilating effect in the lungs but are more consistently
Several chemical classes acting as selective M3 receptor and rapidly transformed into inactive metabolites after pass
antagonist drugs have been developed for the treatment of ing into human plasma. This behavior gives great advantages
in?ammatory or obstructive airWay diseases such as asthma in terms of safety.
and chronic obstructive pulmonary disease (COPD).
Quinuclidine carbamate derivatives and their use as M3 30 DETAILED DESCRIPTION OF THE PREFERRED
antagonists are for instance disclosed in WO 02/051841, WO EMBODIMENTS
03/053966 and WO 2008/012290, all of Which are incorpo
rated herein by reference in their entireties. In particular, the invention is directed to alkaloid ami
Said M and M3 receptor antagonists are currently admin noester derivatives of general formula (I):
istered through inhalation route in order to deliver the drug 35
directly at the site of action, thus limiting the systemic expo
sure and any undesirable side effect due to systemic absorp
tion. Therefore, it is highly desirable to provide M3 receptor R H (I)
l \ N /
antagonists able to act locally, While having high potency and
long duration of action. Said drugs, once adsorbed, are 40
H O
degraded to inactive compounds Which are deprived of any
systemic side effects typical of muscarinic antagonists. R2
The co-pending application WO 2010/072338, Which is O
N+
incorporated herein by reference in its entirety, describes
aZonia-bicyclo[2.2.2]octane compounds acting as muscar 45 A' W
inic receptor antagonists, further possessing the above thera
peutically desirable characteristics.
O
HoWever, there remains a need for muscarinic receptor
antagonists With even further improved properties.
50 wherein:
SUMMARY OF THE INVENTION R1 is aryl optionally substituted by one or more substitu
ents selected from the group consisting of halogen atoms,
Accordingly, it is one object of the present invention to 40H, iSH, iNOZ, 4CN, 4COOH, (Cl-C6)alkoxycar
provide novel compounds Which act as muscarinic receptor bonyl, (Cl-C6)alkylsulfanyl, (Cl-C6)alkylsul?nyl, (Cl-C6)
antagonists. alkylsulfonyl, (Cl-C6)alkyl, (Cl-C6)haloalkyl, (Cl-C6)
55
It is another object of the present invention to provide novel alkoxy, and (Cl-C6)haloalkoxy;
processes for producing such a compound. R2 is aryl optionally substituted by one or more substitu
It is another object of the present invention to provide novel ents selected from the group consisting of halogen atoms,
pharmaceutical compositions Which contain such a com 40H, iSH, iNOZ, 4CN, 4COOH, (Cl-C6)alkoxycar
pound. bonyl, (Cl-C6)alkylsulfanyl, (Cl-C6)alkylsul?nyl, (Cl-C6)
60
It is another object of the present invention to provide novel alkylsulfonyl, (Cl-C6)alkyl, (Cl-C6)haloalkyl, (Cl-C6)
methods of treating and/ or preventing certain diseases and alkoxy, and (Cl-C6)haloalkoxy;
conditions by administering an effective amount of such a W is selected from the group consisting of (Cl-C6)alkyl,
compound. aryl, iNH-heterocyclyl and heteroaryl, each of Which
These and other objects, Which Will become apparent dur 65 optionally substituted by one or more substituents, the same
ing the folloWing detailed description, have been achieved by or different, selected from the group consisting of halogen
the inventors’ discovery that compounds characterized by the atoms, oxo, iNOZ, iCN, (Cl-C6)alkyl, (Cl-C6)alkoxy,
US 8,492,548 B2
3 4
(Cl-C6)haloalkyl, (Cl-C6)haloalkoxy, (C3-C8)cycloalkyl, (benZothiophenyl), dihydrobenZo dioxin, dihydrobenZo
heterocyclyl, aryl, aryloxy, haloaryl, (Cl-C6)alkyl-NCOi dioxepin, dihydrobenZo oxaZin radicals, and the like.
(Cl-C6)alkyl, iOR3, iN(R3)2, iSR3, 4OSO2R3, Examples of suitable aryl or heteroaryl tricyclic systems
iCOR3, 4CO2R3, iOCOR3, 4CON(R3)2, iNHCOR3, include ?uorene (?uorenyl) radicals as well as benZocon
iNHCO2R3, iNHSO2R3, iNHCOi(Cl-C6)alkyl densed derivatives of the aforementioned heteroaryl bicyclic
COOH, iCO2i(Cl-C6)alkyl-N(R3)2 and ‘CO-heterocy systems.
clyl; The expression “aryloxy” refers to aryl-oxy groups.
R3 is H or is selected from the group consisting of (C 1-C6) Examples of said groups may thus comprise phenyloxy
alkyl and heteroaryl, optionally substituted by one or more and the like.
substituents selected from the group consisting of phenyl, The expression “haloaryl” refers to aryl groups wherein
halogen atoms, 40H, oxo, iSH, iNOZ, 4CN, iCONHZ one or more hydrogen atoms are replaced by halogen atoms.
and iCOOH; The expression “heterocyclyl” refers to a saturated, par
A“ is a physiologically acceptable anion; tially unsaturated or fully unsaturated 3 to 8 membered het
and pharrnaceutically acceptable salts thereof. erocyclic ring system in which at least one ring atom is a
In the present description, unless otherwise provided, the heteroatom or heteroaromatic group (eg N, NH, S or O).
term “halogen” includes ?uorine, chlorine, bromine and Examples include pyrrolidinyl, piperidinyl, pyridinyl,
iodine atoms. morpholinyl, furyl, and imidaZolyl, and the like.
The term “(Cl-C6)alkyl”, refers to straight or branched From the above, it is clear that when referring to a fully
chain alkyl groups wherein the number of carbon atoms is unsaturated heterocyclic ring, the above de?nition also
from 1 to 6. Examples of said groups are methyl, ethyl, 20 embraces the aforementioned heteroaryl-groups.
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Advantageously, the physiologically acceptable anions A‘
pentyl, hexyl and the like. include those selected from chloride, bromide, iodide, trif
The term “(C l -C6)alkoxy” refers to alkyl-oxy (e.g. alkoxy) luoroacetate, formate, sulfate, phosphate, methanesulfonate,
groups. Examples of said groups may thus comprise meth nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate,
oxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 25 succinate, benZoate, and p-toluenesulfonate, preferably chlo
sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like. ride, bromide and tri?uoroacetate.
Likewise, the expression “(Cl-C6)alkoxycarbonyl” refers Besides the presence of A“ anion, whenever further basic
to the above (C l -C6)alkoxy groups further bearing a carbonyl amino groups are present in the compounds of formula (1),
group among which is, for instance, acetoxy (e.g. acetyloxy additional physiological acceptable anions, among those for
carbonyl), tert-butoxycarbonyl and the like. 30 merly indicated, may be present. Likewise, in the presence of
The expressions “(Cl-C6)haloalkyl” and “(Cl-C6)ha acidic groups such as COOH groups, corresponding physi
loalkoxy”, refer to the above “(Cl-C6)alkyl” and “(Cl-C6) ological cation salts may be present as well, for instance
alkoxy” groups wherein one or more hydrogen atoms are including alkali or earth-alkali metal ions.
replaced by one or more halogen atoms, which can be the A ?rst preferred group of compounds of general formula
same or different from each other. Examples of said (C l-C6) 35 (I) is that wherein R1 and R2 are independently aryl groups
haloalkyl and (Cl-C6)haloalkoxy groups may thus include optionally substituted by one or more halogen atoms or
halogenated, poly-halogenated and fully halogenated alkyl ‘COOH groups; and W and A“ have the above reported
and alkoxy groups wherein one or more of the hydrogen meanings.
atoms are replaced by halogen atoms, e.g. tri?uoromethyl or Still more preferred, within this class, are the compounds
tri?uoromethoxyl groups. 40 of general formula (I) wherein R1 and R2 are independently
Likewise, the expression “(C 1 -C6)alkylsulfanyl”, “(C 1 -C6) phenyl groups optionally substituted by one or more halogen
alkylsul?nyl” or “(Cl-C6)alkylsulfonyl” refer, respectively, atoms or iCOOH groups.
to alkyl-Si, alkyl-SOi or alkyl-SO2i groups. Another preferred group of compounds of general formula
The expression “(C3-C8)cycloalkyl” refers to cyclic non (I) is that wherein W is aryl or heteroaryl, each of which being
aromatic hydrocarbon groups with from 3 to 8 carbon atoms. 45 optionally substituted by one or more substituents, the same
Examples include cyclopropyl, cyclobutyl, cyclopentyl, or different, selected from the group consisting of halogen
cyclohexyl, cycloheptyl, and the like. atoms, ‘0R3, oxo, iSR3, 4OSO2R3, iNOZ, 4COR3,
The expression “aryl” refers to mono or bi- or tri-cyclic 4CO2R3, 4OCOR3, 4CON(R3)2, 4CN, iN(R3)2,
ring systems which have 6 to 20 ring atoms, preferably from iNHCOR3, iNHCO2R3, iNHSO2R3, (Cl-C6)alkyl, (Cl
6 to 15 and wherein at least one ring is aromatic. 50 C6)haloalkyl, (Cl-C6)alkoxy, (Cl-C6)haloalkoxy (C3-C8)cy
The expression “heteroaryl” refers to mono, bi- or tri cloalkyl, (C3-C8)heterocyclyl, aryl, iNHCOi(Cl-C6)
cyclic ring systems with 5 to 20 ring atoms, preferably from alkyl-COOH, 4CO2i(Cl-C6)alkyl-N(R3)2, (Cl-C6)alkyl
5 to 15, in which at least one ring is aromatic and in which at NCOi(Cl-C6)alkyl and 4CO-heterocyclyl; and R1, R2 and
least one ring atom is a heteroatom or heteroaromatic group A‘ are as de?ned above.
(eg N, NH, S or O). 55 Even more preferred, within this class, are the compounds
Examples of suitable aryl or heteroaryl monocyclic sys of formula (I) wherein W is selected from the group consist
tems include, for instance, thiophene (thiophenyl), benZene ing of phenyl, thiophenyl, dihydrobenZo-dioxepin, dihy
(phenyl), pyrrole (pyrrolyl), pyraZole (pyraZolyl), imidaZole drobenZo-dioxin, dihydrobenZo-oxaZin, naphthalenyl, or
(imidaZolyl), isoxaZole (isoxaZolyl), oxaZole (oxaZolyl), pyrrolidinyl-phenyl, each of which being optionally substi
isothiaZole (iosthiaZolyl), thiaZole (thiaZolyl), pyridine (py 60 tuted as above indicated; and R1 and R2 andA' are as set forth
ridinyl), imidaZolidine (imidaZolidinyl), furan (furanyl) radi above.
cals and the like. Still more preferred, within this class, are the compounds
Examples of suitable aryl or heteroaryl bicyclic systems of formula (I) wherein W is phenyl optionally substituted by
include naphthalene (naphthyl), biphenyl (biphenylyl), one or more groups selected from halogen atoms, iCN,
purine (purinyl), pteridine (pteridinyl), benZotriaZole (benZo 65 iNO2, ‘C133, 4OCH3, 4OCF3, iOH, 4CONH2,
triaZolyl), quinoline (quinolinyl), isoquinoline (isoquinoli methyl, ethyl, ethoxy, phenoxy, ethoxycarbonyl, butoxycar
nyl), indole (indolyl), isoindole (isoindolyl), benZothiophene bonyl, iCOOH, iNHZ, iN(CH3)2, (Cl-C6)alkyl, aceta
US 8,492,548 B2
5 6
midopropyl, iSCH3, phenyl, ?uorophenyl, morpholinyl,
-continued
morpholinecarbonyl, isopropoxycarbonyl, dimethylamino
ethoxy, methylsulfonyloxy, acetoxy, butyramidyl, pivala Com
midyl, carboxypropanamidyl, methylsulfonamidyl and pyr pound Chemical Name
rolidinyl; and R1, R2, R3 and A‘ are as de?ned above. C40
Still more preferred are the compounds of formula (I)
Wherein W is selected from the group consisting of dihy
drobenZo-dioxepin, dihydrobenZo-dioXin, dihydrobenZo-oX
aZin, naphthalenyl or pyrrolidinyl-phenyl optionally substi
tuted by one or more groups selected from halogen atoms,
iCOOH and ethyl.
Another preferred group of compounds of formula (I) is
that Wherein W is iNH-heterocyclyl and R1, R2 and A‘ are
as de?ned above.
Still more preferred, Within this class, are the compounds
of formula (I) Wherein W is pyridin-2-ylamino and R1, R2, R3
C50
and A“ are as de?ned above.
According to speci?c embodiments of the invention, spe
20
ci?c examples of compounds of general formula (I) are
reported beloW:
25
30
35
C60
40
45
50
55
60
(phenylalnino)acetoxy)—l —azoniabicyclo [2.2.2]octane 2,2,2 65
tri?uoro acetate
US 8,492,548 B2
8
diseases, preferably asthma or chronic bronchitis or chronic
obstructive pulmonary disease (COPD).
In a further aspect, the invention provides the use of the
compounds of formula (I) for the manufacture of a medica
ment for the prevention and/ or treatment of broncho-ob struc
tive or in?ammatory diseases, preferably asthma or chronic
bronchitis or chronic obstructive pulmonary disease (COPD).
The present invention also provides methods for the pre
vention and/or treatment of broncho-obstructive or in?am
matory diseases, preferably asthma or chronic bronchitis or
chronic obstructive pulmonary disease (COPD), which com
prises administering to a subject in need thereof a therapeu
tically effective amount of a compound of formula (I).
The invention also refers to a device for the administration
of the above pharmaceutical composition, which may be a
single- or multi-dose dry powder inhaler, a metered dose
inhaler and a soft mist nebuliZer comprising the compounds
of formula (I).
20
The invention also refers to a kit comprising the above
pharmaceutical compositions in a suitable vial or container
and a device which may be a single- or multi-dose dry powder
hydroxyphenyl)—2—oxoethyl)— 1—aZoniabicyclo [2 .2. 2] octane 2 ,2 ,2 inhaler, a metered dose inhaler and a soft mist nebuliZer,
tri?uoro acetate 25 adapted to hold the above vial or container.
The compounds of formula (I) may be prepared according
The compounds of general formula (I) show at least two to known or conventional methods.
chiral centers, which are represented by the carbon atoms
The present invention is also directed to a process for the
with asterisks as set forth below:
30 preparation of the compounds of general formula (I), which
process comprises:
(a) the alkylation of a compound of general formula (III)
R H (I)
l \N/ wherein R1 is as de?ned above
35
H O
(111)
40
with a compound of general formula (II)
(11)
Further, depending on the meanings of R1, R2 and W, it will 45 4L.G
be clear that additional asymmetric centers may be present in
the compounds of formula (I). Therefore, the invention also
includes any of the optical stereoisomers, diastereomers and
mixtures thereof, in any proportion.
50
In one of the preferred embodiment, the chiral center on the
wherein R2 is as de?ned above, LG is a suitable leaving group
quinuclidine ring shows a R con?guration.
and K is a carboxyl group, either as such or in an optionally
In the present invention, since the ab solute con?guration of
protected form or an acyl halide group, to give a compound of
the diastereomers is not de?ned, they are indicated in the
general formula (IV)
examples as diastereomer 1, 2, or mixtures of them.
55
The invention also provides pharmaceutical compositions
comprising one or more compounds of formula (I), optionally
(1V)
in combination or in admixture with one or more pharmaceu
tically acceptable carriers and/or excipients.
The invention also provides pharmaceutical compositions 60
suitable for administration by inhalation such as, for instance,
inhalable powders, propellant-containing metering aerosols
or propellant-free inhalable formulations.
The invention also provides compounds of formula (I) for
(b) the optional removal of the protecting carboxyl group
use as a medicament.
The invention also provides compounds of formula (I) for from the compound of general formula (IV) and its coupling
use in the treatment of broncho-obstructive or in?ammatory with the compound of formula (V)
US 8,492,548 B2
10
(V) (VII)
HO
@ 5
N
to give a compound of general formula (V I)
in Which A is a suitable leaving group and W is as de?ned
above, so as to obtain a compound of general formula (I); and,
optionally
(d) the conversion of the compound of general formula (1)
into another compound of general formula (1) and/or into a
pharmaceutically acceptable salt thereof.
The operative conditions that may be used in the process of
the invention are described in more details beloW and are
further reported in the folloWing Scheme 1 . The starting mate
rials for the preparation of the compounds of formula (I), that
(c) the alkylation reaction of the compound of general 20 is the compounds of formula (II) and (III), as Well as any
formula (V I) With an alkylating agent of general formula reactant of the process, are knoWn or are easily prepared
(VII) according to knoWn procedures.
Scheme 1
HO\@
R1
R1 \ NH
\ NH N
(111)
H —> H I (V) H O
K Alkylati on
K Condensatl on R2
R2
R2 O
(11)
(W) N
(VI)
A
W
O
(VII)
Alkylation
R1 H
\ N /
H 0
R2
0
N+
W
A.
(I)
US 8,492,548 B2
11 12
Procedure for the preparation of compounds of formula (I). bonylimidaZole, in a suitable aprotic solvent (e.g. dichlo
According to step (a) of the process, the compounds of romethane, tetrahydrofuran), at about RT, to be then reacted
formula (IV) may be prepared through the alkylation of an With compound (V).
amine of formula (III) With a compound of formula (II), in In addition, compounds of formula (VI) may also be e?i
Which LG is a suitable leaving group (eg an halide such as ciently prepared by the condensation betWeen carboxylic
bromine) and K is a carboxyl group in an optionally protected acids (IV) alcohol (V) under typical Mitsunobu conditions
form. (see Kumara SWamy, K. C., Chem. Rev., 2009, 109, 2551
Typically, LG is a halide atom and, more preferably, it is a 2651, Which is incorporated herein by reference in its
bromine atom. K may be a carboxyl group either as such or in entirety). For example, acid (IV) and alcohol (V) are reacted
an optionally protected form, typically including carboxy in the presence of a suitable phosphine (e.g. triphenylphos
alkyl ester groups (eg K:COO(Cl-C6)alkyl), preferably phine) and an aZadicarboxylate ester (e.g. diethyl aZodicar
carboxymethyl (e.g. COOMe). boxylate or diisopropyl aZodicarboxylate) in an aprotic sol
The alkylation reaction may be promoted by the presence vent such as tetrahydrofuran. The reaction typically proceeds
of a base, for instance an amine selected from the group at temperature range from about 00 C. to about 100° C., for a
consisting of triethylamine, pyridine and 4-dimethylami time in the range of about 30 minutes to about 72 hours.
nopyridine, either neat or in a suitable solvent (e.g. acetoni In some embodiments of the present invention, the car
trile). This reaction is usually performed in a temperature boxylic acid (IV) Wherein K:COOH may be most conve
range from about 0° C. to about 130° C. over a period of about niently converted into the corresponding acyl halide (IV)
1 hour to about 74 hours. The reaction may be conducted Wherein K:COCl. This activation may be affected accord
under conventional heating (using an oil bath) or under 20 ing to one of the several standard procedures reported in the
microWave heating. The reaction may be carried out in an literature. They comprise, for instance, treatment of acid (IV)
open vessel or in a sealed tube. Wherein K:COOH With one or more equivalents of oxalyl
According to step (b) of the process, the compounds of chloride in the presence of a catalytic amount of dimethylfor
general formula (VI) may then be prepared by coupling the mamide (DMF) in a halocarbon solvent, such as dichlo
alcohol of formula (V) With a compound of formula (IV), as 25 romethane, at temperature ranging from about 0° C. to about
per step (a). The operative conditions are chosen on the basis 35° C.
of the reactivity of the compound (IV) over alcohol (V) and of Finally, the acyl chloride (IV) (K:COCl) is directly
the compatibility of other groups being present in both reac reacted With the alcohol (V), using knoWn or conventional
tants (for a general reference on the above reaction and opera methods. The reaction may be promoted by a base such as
tive conditions thereof, see, for instance, Carey, F. A. and 30 triethylamine, pyridine and 4-dimethylaminopyridine, and
Sundeberg, R. J. Advanced Organic Chemistry, Third Edition carried out in a suitable solvent (e.g. dichloromethane). This
(1990), Plenum Press, New York and London, pg 145, Which reaction is performed in a temperature range from about 0° C.
is incorporated herein by reference in its entirety). to about 130° C. over a period of about 1 hour to about 74
In particular, When K is a protecting carboxyl group, the hours. The reaction may be conducted under conventional
protecting group has to be ?rst removed before the coupling 35 heating (using an oil bath) or under microWave heating. The
reaction takes place. When K is a carboxyester moiety (e.g. reaction may be carried out in an open vessel or in a sealed
K:COOMe), removal of the protecting group is carried out tube.
under hydrolysis conditions, typically in the presence of any From all of the above, it is clear that alternative conven
suitable aqueous base selected from the group consisting of tional synthetic pathWays may be applied as Well for the
sodium, lithium and potassium hydroxide. The reaction is 40 preparation of the compounds of formula (VI) from reactants
performed in any suitable solvent, for instance in the presence (IV) and (V).
of tetrahydrofuran or dioxane, at room temperature (RT) and Inparticular, carboxylic derivatives of formula (IV) may be
over a period of about 1 hour to about 36 hours. conveniently converted, in situ, into the corresponding acyl
Alternatively, When starting from a compound of formula halides to be then reacted With alcohol (V). For example,
(IV) Wherein K is carboxyl, standard amidation and peptide 45 alcohols (V) are reacted With acids (IV) Wherein K:COOH
coupling conditions may be applied to obtain the compounds in the presence of triphenylphosphine and a halocarbon sol
of formula (VI). Said conditions include, for instance, acti vent such as carbon tetrachloride or dichloromethane, at
vating intermediate (IV) by means of one or more equivalents about RT, in a maximum period of time of 16 hours (see Lee,
of a commercially available condensing agent such as a car J. B]. Am. Chem. Soc, 1966, 88, 3440, Whichis incorporated
bodiimide (e.g., N,N'-dicyclohexylcarbodiimide (DCC) and 50 herein by reference in its entirety).
the like) in the presence of N-hydroxybenZotriaZole (HOBt). Once obtained, compounds of general formula (VI) can be
An organic base such as triethylamine may be also present in obtained either as single diastereomer or as a mixture of
the reaction mixture. The activated intermediate may be diastereomers. For instance, When alcohol (V) has the R
either isolated, or pre-formed or generated in situ, and then con?guration, the corresponding compounds of formula (VI)
properly reacted With the alcohol of formula (V). Suitable 55 can be obtained in both SiR con?guration or RiR con?gu
solvents for the coupling reaction include, but are not limited ration, as Well as a mixture of diastereomers (RiR and SiR
to, halocarbon solvents (e.g. dichloromethane), tetrahydrofu con?guration).
ran, dioxane and acetonitrile. The reaction proceeds at tem The mixture of diastereomers may be converted to com
perature ranging from about 0° C. to about 170° C., for a time pounds of formula (I) as per step (c) of the process or can be
period in the range of about 1 hour to about 72 hours. The 60 most conveniently resolved to give the tWo single diastere
reaction may be carried out under conventional heating (using omers Which, in turn, may be converted to compounds of
an oil bath) or under microWave irradiation. The reaction may formula (I). This separation can be accomplished by using
be conducted either in an open vessel or in a sealed tube. knoWn procedures. These procedures include, but are not
Alternatively, a compound of formula (IV) Wherein limited to, chromatography puri?cation, preparative HPLC
K:COOH may be ?rst activated With other commercially 65 puri?cation and crystallization. For example, the tWo diaste
available activating agents such as, for instance, bromotripyr reomers may be separated by ?ash chromatography on silica
rolidinopho sphonium hexa?uoropho sphate (PyBrOP) or car gel eluting With suitable solvents or With a mixture of solvents
US 8,492,548 B2
13 14
such as DCM (dichloromethane) and methanol and the like. LikeWise, subsequent deprotection of those same protected
In another process of the present invention, separation of groups may folloW upon completion of the said reactions.
diastereomers may be carried out by using a column ?lled In the present invention, unless otherWise indicated, the
With a chiral stationary phase, for example Chiralpack AY or term “protecting group”, designates a protective group
Chiralcel OD or Chiralcel OZ, and eluting, for example, With adapted to preserving the function of the group to Which it is
acetonitrile and/or With mixtures of acetonitrile and an alco bound. Speci?cally, protective groups are used to preserve
hol. Alternatively, the separation of diastereomers may be amino, hydroxyl or carboxyl functions.
most conveniently achieved by crystallization from an oppor Appropriate protective groups may thus include, for
tune solvent (e. g. ethyl ether), as a free base or after the example, benZyl, benZyloxycarbonyl, alkyl or benZyl esters,
formation of a suitable salt (eg (+)-tartaric acid)). 10 or other substituents commonly used for the protection of
According to step (c) of the process, the compounds of such functions, Which are all Well knoWn [see, for a general
formula (VI) are then alkylated With an agent of formula (VII) reference, T. W. Green; Protective Groups in Organic Synthe
to give compounds of formula (I). sis (Wiley, N.Y. 1981) Which is incorporated herein by refer
This kind of reaction is largely described in the literature ence in its entirety].
under several different conditions. For instance, the reaction The invention also provides pharmaceutical compositions
may be performed neat or in a suitable solvent selected from of compounds of formula (I) in admixture With one or more
the group consisting of acetonitrile, ethyl acetate, dimethyl pharmaceutically acceptable carriers, for example those
formamide (DMF), dimethyl sulfoxide (DMSO) and tetrahy described in Remington ’s Pharmaceutical Sciences Hand
drofuran (THF). The reaction typically proceeds at tempera book, XVII Ed., Mack Pub., N.Y., U.S.A., Which is incorpo
ture range from about 0° C. to about 170° C., for a time in the 20 rated herein by reference in its entirety.
range of feW minutes to about 72 hours. The reaction may be In the present invention, the terms active ingredient or
carried out under conventional heating (using an oil bath) or active or compound are to be considered synonyms to be used
under microWave irradiation. The reaction may be conducted interchangeably.
either in an open vessel or in a sealed tube. Administration of the compounds of the invention may be
According to step (d) of the process, the compounds of 25 accomplished according to patient needs, for example, orally,
formula (I) canbe either considered as ?nal products or canbe nasally, parenterally (subcutaneously, intravenously, intra
further reacted to prepare other compounds of general for muscularly, intrasternally and by infusion), by inhalation,
mula (I). Thus, any suitable moiety of R1, R2 or W group in rectally, vaginally, topically, locally, transdermally, and by
formula (I) could undergo a variety of reactions to afford ocular administration.
other ?nal compounds of formula (I). 30 Various solid oral dosage forms can be used for adminis
Likewise, the optional sali?cation of the compounds of tering the compounds of the invention including such solid
formula (I) may be carried out by properly converting any of forms as tablets, gelcaps, capsules, caplets, granules, loz
the free acidic groups (eg carboxylic) or free amino groups enges and bulk poWders. The compounds of the present
into the corresponding pharmaceutically acceptable salts. invention can be administered alone or combined With vari
In this case too, the operative conditions employed for the 35 ous pharmaceutically acceptable carriers, diluents (such as
optional sali?cation of the compounds of the invention are sucrose, mannitol, lactose, starches) and excipients knoWn in
conventional. the art, including but not limited to suspending agents, solu
As previously reported, the compounds of formula (II) and biliZers, buffering agents, binders, disintegrants, preserva
(III) are knoWn and, if not commercially available, may be tives, colorants, ?avorants, lubricants and the like. Time
readily prepared according to knoWn methods. 40 release capsules, tablets and gels are also advantageous in
In particular, compounds of formula (II) are commercially administering the compounds of the present invention.
available or may be conveniently prepared according to stan Various liquid oral dosage forms can also be used for
dard procedures extensively reported in literature. For administering compounds of the invention, including aque
instance, compounds of general formula (II) in Which LG is a ous and non-aqueous solutions, emulsions, suspensions, syr
halogen such as a bromine, may be prepared by halogenation 45 ups, and elixirs. Such dosage forms can also contain suitable
of the opportunely substituted phenyl acetic ester (for knoWn inert diluents such as Water and suitable excipients
example folloWing the procedure reported by Epstein, J. W. in such as preservatives, Wetting agents, sWeeteners, ?avorants,
J. Med. Chem, 1981, 24/5, 481, Which is incorporated herein as Well as agents for emulsifying and/ or suspending the com
by reference in its entirety). Alternatively, compounds of pounds of the invention. The compounds of the present inven
general formula (II) may be prepared starting from the appro 50 tion may be injected, for example, intravenously, in the form
priately substituted mandelic derivative, using knoWn proce of an isotonic sterile solution. Other compositions are also
dures (a survey of the suitable reactions is given by Larock, L. possible.
C., Comprehensive Organic Transformation, Second edition Suppositories for rectal administration of the compounds
(1999), John Wiley & Son Inc, pg 689-700, Which is incor of the present invention can be prepared by mixing the com
porated herein by reference in its entirety). 55 pound With a suitable excipient such as cocoa butter, salicy
From all of the above, it should be clear that the above lates and polyethylene glycols.
process, comprehensive of any variant thereof for the prepa Formulations for vaginal administration can be in the form
ration of suitable compounds of formula (I) of the invention, of cream, gel, paste, foam, or spray formula containing, in
may be conveniently modi?ed so as to adapt the reaction addition to the active ingredient, such suitable carriers as are
conditions to the speci?c needs, for instance by choosing 60 knoWn in the art.
appropriate condensing agents, solvents and protective For topical administration the pharmaceutical composition
groups. can be in the form of creams, ointments, liniments, lotions,
More in particular, functional groups present in any of the emulsions, suspensions, gels, solutions, pastes, poWders,
compounds of formula (II), (III) or (IV) and Which could give sprays, and drops suitable for administration to the skin, eye,
rise to unWanted side reactions and by-products, need to be 65 ear or nose. Topical administration may also involve trans
properly protected before the condensation reaction takes dermal administration via means such as transderrnal
place. patches.
US 8,492,548 B2
15 16
For the treatment of the diseases of the respiratory tract, the 351591, AN-6415, indus-82010, TP1-PD3, ELB-353,
compounds according to the invention are preferably admin CC-11050, GSK-256066, oglemilast, OX-914, tetomilast,
istered by inhalation. Inhalable compositions include inhal MEM-1414 and RPL-554.
able poWders, propellant-containing metering aerosols or
The invention also provides combinations of a compound
propellant-free inhalable formulations.
of formula (I) With a leukotriene modulator selected from the
For administration as a dry poWder, knoWn single- or multi
group consisting of montelukast, Za?rlukast and pranlukast.
dose inhalers may be utiliZed. In that case the poWder may be
The invention also provides combinations of a compound
?lled in gelatine, plastic or other capsules, cartridges or blis
of formula (I) With a NSAID selected from the group consist
ter packs or in a reservoir. ing of ibuprofen and ketoprofen.
A diluent or carrier, generally non-toxic and chemically
The invention also provides combinations of a compound
inert to the compounds of the invention, e.g. lactose or any
of formula (I) With a mucus regulator selected from the group
other additive suitable for improving the respirable fraction
consisting of INS-37217, diquafosol, sibenadet, CS-003, tal
may be added to the poWdered compounds of the invention.
netant, DNK-333, MSI-1956 and ge?tinib.
Inhalation aerosols containing propellant gas such as
The dosages of the compounds of the invention depend
hydro?uoroalkanes may contain the compounds of the inven
upon a variety of factors including the particular disease to be
tion either in solution or in dispersed form. The propellant
treated, the severity of the symptoms, the route of adminis
driven formulations may also contain other ingredients such
tration, the frequency of the dosage interval, the particular
as co-solvents, stabiliZers and optionally other excipients. 20 compound utiliZed, the ef?cacy, toxicology pro?le, and phar
The propellant-free inhalable formulations comprising the
macokinetic pro?le of the compound. Advantageously, the
compounds of the invention may be in form of solutions or
compounds of formula (I) canbe administered for example, at
suspensions in an aqueous, alcoholic or hydroalcoholic
a dosage of 0.001 to 1000 mg/day, preferably 0.1 to 500
medium and they may be delivered by jet or ultrasonic or
25 mg/day.
mesh vibrating nebuliZers or by soft-mist nebuliZers.
When the compounds of formula (I) are administered by
The compounds of the invention may be administered as
inhalation route, they are preferably given at a dosage of
the sole active agent or in combination With other pharma
0.001 to 500 mg/day, preferably 0.1 to 200 mg/day.
ceutical active ingredients including those currently used in
The compounds of formula (I) may be administered for the
the treatment of respiratory disorders, eg beta2-agonists, 30
prevention and/ or treatment of any disease Wherein M3
corticosteroids, mitogen-activated protein kinases (P38 MAP
antagonists are active. Said disease include: diseases involv
kinase) inhibitors, nuclear factor kappa-B kinase subunit beta
ing in?ammation such as asthma and COPD, acute rhinitis;
(IKK2) inhibitors, human neutrophil elastase (HNE) inhibi
diseases involving the gastrointestinal tract such as peptic
tors, phosphodiesterase 4 (PDE4) inhibitors, leukotriene 35 ulcer; diseases involving the cardiovascular system such as
modulators, non- steroidal anti-in?ammatory agents acute myocardial infarction; diseases involving the genitouri
(NSAIDs) and mucus regulators.
nary tract such as renal colic; anticholinesterase and mush
The invention also provides combinations of a compound
room poisoning; uses in anesthesia; uses in ophthalmology.
of formula (I) With a [32-agonist selected from the group They also include neurological and psychiatric disorders
40
consisting of GSK-642444, indacaterol, milveterol, arfor
such as Parkinsonism and motion sickness.
moterol, salbutamol, levalbuterol, terbutaline, AZD-3199, Preferably, the compounds of formula (I) may be admin
BI-1744-CL, LAS-100977, bambuterol, isoproterenol, pro istered for the prevention and/or treatment of respiratory dis
caterol, clenbuterol, reproterol, fenoterol and ASP-1020.
eases such as from mild to acute severe conditions of asthma
The invention also provides combinations of a compound 45 and COPD.
of formula (I) With a corticosteroid selected from the group Other respiratory diseases include bronchitis, bronchioli
consisting of propionate, ciclesonide, mometasone furoate
tis, bronchiectasis, acute nasopharyngitis, acute and chronic
and budesonide. sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngi
The invention also provides combinations of a compound
tis, tracheitis, epiglottitis, croup, chronic disease of tonsils
50
of formula (I) With a P38 inhibitor selected from the group and adenoids, hypertrophy of tonsils and adenoids, periton
consisting of semapimod, talmapimod, pirfenidone,
sillar abscess, rhinitis, abscess or ulcer and nose, pneumonia,
PH-797804, GSK-725, minokine and losmapimod. viral and bacterial pneumonia, bronchopneumonia, in?u
The invention also provides combinations of a compound
enZa, extrinsic allergic alveolitis, coal Workers’ pneumoco
of formula (I) With a IKK2 inhibitor. 55 niosis, asbestosis, pneumoconiosis, pneumonopathy, respira
The invention also provides combinations of a compound
tory conditions due to chemical fumes, vapors and other
of formula (I) With a HNE inhibitor selected from the group external agents, emphysema, pleurisy, pneumothorax,
consisting of AAT, ADC-7828, Aeriva, TAPI, AE-3763, abscess of lung and mediastinum, pulmonary congestion and
KRP-109, AX-9657, POL-6014, AER-002, AGTC-0106, hypostasis, postin?ammatory pulmonary ?brosis, other
respriva, AZD-9668, Zemaira, AAT IV, PGX-100, ela?n, 60 alveolar and parietoalveolar pneumonopathy, idiopathic
SPHD-400, prolastin C and prolastin inhaled. The invention ?brosing alveolitis, Hamman-Rich syndrome, atelectasis,
also provides combinations of a compound of formula (I) ARDS, acute respiratory failure, mediastinitis.
With a PDE4 inhibitor selected from the group consisting of Other features of the invention Will become apparent in the
AN-2728, AN-2898, CBS-3595, apremilast, ELB-353, 65 course of the folloWing descriptions of exemplary embodi
KIT-66490, K-34, LAS-37779, IBFB-211913,AWD-12-281, ments Which are given for illustration of the invention and are
cipamfylline, cilomilast, ro?umilast, BAY19-8004 and SCH not intended to be limiting thereof.
US 8,492,548 B2
17 1 8
EXAMPLES Preparation of 2-phenyl-2-(phenylamino)acetic acid
(11)
In the following examples:
IIintermediates ot-Bromophenylacetic acid (5.01 g, 23.2 mmol) Was dis
C:compounds. solved in aniline (25 ml, 274 mmol), and the mixture reacted
in a closed vessel under microWave irradiation at 1200 C. for
Example 1 5 minutes (U PLC-MS monitoring: complete conversion).
Dichloromethane (DCM) (100 ml) Was added to the reaction
Preparation of (R)-quinuclidin-3-yl 2-phenyl-2-(phe 10 mixture, and the resulting solid Was ?ltered; 2M NaZCO3 (50
nylamino)-acetate (Diastereomers 1 and 2 of 12)
ml) Was added to the solution, and the aqueous layer Was
Washed With DCM (3x100 ml). The aqueous layer Was acidi
?ed With 12N HCl (36 ml) and the title compound Was recov
15
Scheme 2 ered as racemic mixture by ?ltration (5.1 g, 97% yield).
Br
Preparation of (R)-quinuclidin-3-yl 2-phenyl-2-(phe
OH NH; 20
nylamino)-acetate (Diastereomers 1 and 2 of 12)
MW, 120° C.
To a solution of 2-phenyl-2-(phenylamino)acetic acid (11)
(3.40 g, 14.9 mmol) in THF (600 ml), Was added DCC (4.02
25
g, 19.4 mmol), HOBt (3.06 g, 19.44 mmol) and 3(R)-quinu
clidinol (3.80 g, 29.9 mmol). The resulting mixture Was
H010,’ stirred for 16 hours at room temperature (UPLC-MS moni
toring: complete conversion). The solvent Was evaporated,
the residue Was taken up With EtOAc and the insoluble Was
N
removed by ?ltration. The clear solution Was Washed With 1M
HOBt, DCC
KZCO3 and then With brine, Was dried over Na2SO4, ?ltered
OH THF
and evaporated to dryness. The resulting crude Was puri?ed
35
by ?ash chromatography (DCM/MeOH:95/ 5, 0.1% NH3
O (aq.)) recovering ?rst diastereomer 1 of 12 (1.13 g, 22.5%
yield, single diastereomer), and subsequently diastereomer 2
of 12 (0.69 g, 13.7% yield, single diastereomer).
40
Diastereomer 1 of 12:
1H NMR (300 MHZ, DMSO-d6) ppm: 7.48-7.59 (m, 2H),
45 7.26-7.46 (m, 3H), 7.02-7.14 (m, 2H), 6.67-6.79 (m, 2H),
6.51-6.64 (m, 1H), 6.27 (d, 1H), 5.26 (d, 1H), 4.61-4.78 (m,
1H), 2.96 (ddd, 1H), 2.55-2.67 (m, 3H), 2.16-2.37 (m, 1H),
2.06 (d, 1H), 1.79-1.94 (m, 1H), 1.59-1.76 (m, 1H), 1.35-1.59
(m, 2H), 1.20-1.34 (m, 1H);
50
LC-MS (ESI POS): 337.04 (MH+);
Diastereomer l of 12
[(X]D:—44.6 (6:025 MeOH).
55
Diastereomer 2 of 12:
1H NMR (300 MHZ, DMSO-d6) ppm: 7.48-7.60 (m, 2H),
7.24-7.43 (m, 3H), 6.97-7.14 (m, 2H), 6.66-6.78 (m, 2H),
60
6.51-6.66 (m, 1H), 6.26 (d, 1H), 5.24 (d, 1H), 4.62-4.81 (m,
1H), 3.08 (ddd, 1H), 2.54-2.70 (m, 5H), 1.64-1.79 (m, 1H),
1.32-1.64 (m, 2H), 1.16-1.32 (m, 1H), 0.93-1.16 (m, 1H);
Diastereomer 2 of 12 65
LC-MS (ESI POS): 337.04 (MH+);
[6]D:+27.6 (6:025 MeOH).