Discovery of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24 h bronchodilatory efficacy

Article abstract of DOI:10.1016/j.bmcl.2009.12.087

Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human β₂-adrenoceptor with a high β₁/β₂-selectivity. A complete reversal of acetylcholine-induced bronchoconstrictio

Full text of DOI:10.1016/j.bmcl.2009.12.087

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1410–1414
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of olodaterol, a novel inhaled b2-adrenoceptor agonist with a 24 h
bronchodilatory efficacy
Thierry Bouyssou b, Christoph Hoenke a, Klaus Rudolf a, Philipp Lustenberger a, Sabine Pestel c, Peter Sieger c,
Ralf Lotz c, Claudia Heine a, Frank H. Büttner d, Andreas Schnapp b, Ingo Konetzki a,
*
a Department of Chemical Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
b Department of Pulmonary Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
c Department of Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
d Department of Lead Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of
the human b2-adrenoceptor with a high b1/b2-selectivity. A complete reversal of acetylcholine-induced
bronchoconstriction which lasted over the whole study period of 5 h was demonstrated for 4p in a guinea
pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching
100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy
over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which
was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did
not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also
known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved
safety profile.
Received 10 December 2009
Revised 23 December 2009
Accepted 24 December 2009
Available online 4 January 2010
Keywords:
Beta2
Adrenoceptor agonist
LABA
Bronchodilator
Bronchoprotection
Asthma
Ó 2010 Elsevier Ltd. All rights reserved.
COPD
Olodaterol
COPD and asthma are characterized by a reduced airflow on
expiration and difficulty in breathing. b2-Adrenoceptor agonists
are used for the treatment of both conditions due to their bron-
chodilatory effect mediated by a relaxation of the airway smooth
muscles through an increase of cAMP. The availability of once-daily
corticosteroids and the once-daily anticholinergic tiotropium, a
bronchodilator with a different mechanism of action, suggested
the development of b2-agonists suitable for a q.d. dosing regiment1
as potential combination partner. This requirement is not fulfilled
by the two marketed long-acting b2-agonists (LABAs) salmeterol
and formoterol 1 (Fig. 1) which are both exerting a duration of ac-
tion over 12 h only. Consequently, programs targeting towards the
identification of q.d. LABAs are ongoing in different laboratories2
and we herewith continue the disclosure of our efforts in this
area.3,4
substituents at the phenyl group of their amine moiety. The only
compound identified during this study displaying a high b1/b2-
selectivity was the carboxylic acid bearing example 2 (Fig. 1),
which, however, demonstrated an inferior safety margin compared
to formoterol 1 (Fig. 1) in an in vivo model of bronchodilation. In
our present work, we now show how a minor structural modifica-
tion of these 5-hydroxy-4H-benzo[1,4]oxazin-3-ones led to a series
of compounds with a considerably optimized profile.
It is documented in the literature that the b2-selectivity im-
proves if the phenolic hydroxyl group of the b2-agonist is shifted
from the para- to the meta-position with respect to the ethanol-
amine substituent.5,6 A prominent selective b2-agonist with a phe-
nolic hydroxyl group in the meta-position is for example
terbutaline 3 (Fig. 1). Driven by this hypothesis, a series of 6-hydro-
xy-4H-benzo[1,4]oxazin-3-ones
4 with different substituents
Recently, we described a series of potent b2-adrenoceptor ago-
nists consisting of a 5-hydroxy-4H-benzo[1,4]oxazin-3-one head
group and a phenethylamine residue.4 Unfortunately, the moder-
ate sub-type selectivity of these compounds could not be signifi-
cantly improved through the introduction of lipophilic
bound to the right hand side phenyl group was investigated. As
in our previous work, mainly lipophilic substituents were selected
due to reports stating that the duration of action increases with
lipophilicity.7,8
The synthetic route towards the 6-hydroxy-4H-benzo[1,4]oxa-
zin-3-ones 4 described in this study is outlined in Scheme 1. Selec-
tive alkylation of commercially available 2,5-dihydroxy
acetophenone 5 followed by nitration of the resulting benzyl ether
* Corresponding author. Tel./fax: +49 7351 5498716.
E-mail address: ingo.konetzki@boehringer-ingelheim.com (I. Konetzki).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.087

T. Bouyssou et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1410–1414
1411
OH
O
OH
O
OH
H
N
H
O
N
R
b
d
HO
O
OBn
OR
1
R = NO2
R = NH2
7
8
R = H
5
6
c
a
O
OH
O
O
R = Bn
H
HN
HO
N
OH
O
O
O
O
O
O
2
e
HN
HN
OR
OH
EC50 (hβ2-AR) = 2.9 nM, β1/β2 = 87
OH
H
OBn
OBn
HO
N
10 R = H
9
f
R = Et
11
OH
OH
3
O
H2N
O
O
H
O
OH
R
H
N
HN
HN
N
R
12
g, h, i
R
OH
OH
4
4
Figure 1. Structure of the b.i.d. LABA formoterol 1, the 5-hydroxy-4H-
benzo[1,4]oxazin-3-one 2, terbutaline 3, and the 6-hydroxy-4H-benzo[1,4]oxazin-
3-ones 4 from this study.
Scheme 1. Reagents and conditions: (a) 1 equiv BnBr, K2CO3, acetone, rt, 4 d, 64%;
(b) fuming HNO3, acetic acid, rt, 74%; (c) Rh/C, H2, MeOH, 89%; (d) chloro-acetyl
chloride, K2CO3, acetonitrile, 0 °C to rt, then 6 h reflux, 66%; (e) selenium dioxide,
dioxane, H2O, reflux; (f) EtOH, 2 h reflux, 63% over two steps; (g) 1 equiv of amine
12, THF, then LiBH4, 0 °C to rt; for 4d, e, h, j, q: 1 equiv of amine 12, EtOH, 50–80 °C,
then NaBH4, rt; (h) Pd/C, H2, MeOH; only for 4r: (i) concd H2SO4, tert-butyl nitrite,
MeOH; examples 4l, m, n and p were prepared from glyoxal hydrate 10 in an
analogous fashion.
afforded intermediate 7. Hydrogenation of the nitro group of 7 and
treatment with chloro-acetyl chloride yielded the 4H-
benzo[1,4]oxazin-3-one 9. The acetyl group of 9 was oxidized with
selenium dioxide to the corresponding glyoxal aldehyde which
was further converted into a hemi-acetal through heating in etha-
nol. The hemi-acetal 11 was then condensed with the phenethyl-
amines 12 in the presence of a reducing agent. A subsequent
debenzylation delivered the target compounds 4 as racemates.
Alternatively, the target compounds were obtained from the reac-
tion of the glyoxal aldehyde 10 with the phenethylamines 12.
The phenethylamines 12a–k were synthesized as previously de-
scribed.4 Compounds 12l–n were derived from commercial sources
and the preparation of the remaining amines 12o–r is detailed in
Scheme 2.
CF3
Br
e
NO2
a, b
O
R
Cl
13
14
16
c
The sub-type selectivity and agonistic activity of the target
compounds were assessed in functional cellular assays. In these as-
says, the rise of cAMP is measured in CHO cells expressing either
the human b1- or b2-adrenergic receptor. cAMP is generated from
H
H2N
N
d
R
R
O
ATP upon stimulation of the adenylyl cyclase by the G subunit
as
15
R = 2-CF3, 4-Cl 12o
which translocates from the b-adrenergic receptor on binding of
an agonist. The results from these tests including those for formo-
terol which was measured as comparator are summarized in
Table 1.
R = 3-NO2
12r
The majority of the racemic 6-hydroxy-4H-benzo[1,4]oxazin-3-
ones 4 display a considerable potency at the b2-adrenoceptor with
EC50 values ranging between 1 and 15 nM. The most potent exam-
ple 4b (R = 2-Me) has an EC50 of 0.7 nM which is comparable to for-
moterol in this assay. Modest EC50 values and intrinsic activities
(means efficacy; expressed in percentage of the maximal efficacy
of the full agonist isoprenaline) were only obtained for examples
4d, e and g with sterically more demanding groups in the para-po-
sition at the phenyl residue. Interestingly, the introduction of 4-
tert-butyl (example 4f) resulted in an inactive compound, whereas
a phenyl group (example 4g) was still tolerated at this position.
f, g, h
H2N
H2N
OR
OH
17
R = Me 12p
R = Et
12q
Scheme 2. Reagents and conditions: (a) Mg-Grignard preparation in Et2O, then
isobutyraldehyde; (b) p-toluenesulfonic acid monohydrate, toluene, reflux; (c)
NaCN, AcOH, concd H2SO4; (d) HCl, Et2O; (e) isopropyl triphenylphosphonium
iodide, n-BuLi, THF, Et2O; (f) 1 equiv ClCbz, DCM, H2O, Na2CO2; (g) alkyliodide,
K2CO3, DMF; (h) Pd/C, H2, MeOH.

1412
T. Bouyssou et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1410–1414
Table 1
Potency and intrinsic activity at the human b1- and b2-adrenoceptors for formoterol fumerate 1 and the 6-hydroxy-4H-benzo[1,4]oxazin-3-ones 4 from this study
Compounds
R
hb1 EC50 (nM)
hb1 IAa (%)
hb1 n
hb2 EC50 (nM)
hb2 IAa (%)
hb2 n
b1/b2
1
86 23
35.0 22.6
4.5 5.1
42.0
215.0
207.0
989.5 29.0
207.0
22
15
28
8
36
13
14
41
8
7
4
8
2
2
2
1
1
1
2
1
2
2
2
2
3
2
3
2
2
3
3
7
0.4 0.2
2.4 0.7
0.7 0.1
4.1 1.8
49.7
58.0
5167.0 6835.6
68.0
12.1 11.2
12.4 3.4
3.4 1.6
11.9 2.7
3.4 0.9
1.3 0.7
10.7 7.8
1.4 0.4
1.4 0.8
97.7 1.4
15.4 13.5
14.3 9.5
133 48
3
2
2
2
1
1
2
1
2
2
3
2
3
2
3
2
2
3
3
5
215
15
6
10
4
4
<1
3
>83
57
128
20
30
132
10
19
256
28
13
19
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
(S)-4p
4q
4r
H
57
64
48
29
23
2
2
6
8
2-Me
3-Me
4-Et
4-i-Pr
4-t-Bu
4-Ph
3,5-di-Fluor
4-CF3
3-CF3
4-OCF3
4-F
6
1
52
50 12
>1000.0
1
711.5 60.1
436.5 217.1
240.0 22.6
101.0 13.9
171.0 103.4
103.4 91.9
27.0 12.7
358.0 69.3
2725.0 620.8
200.0 112.7
278.4 288.6
17 5.7
40
44
0
2
13
24
18
30 11
20 12
19
7
17
3
3
7
50 17
65 10
55 35
64 19
4-Cl
4-Br
2-CF3
4-OMe
4-OMe
4-OEt
3-OMe
7
7
4
25
53
50
3
6
8
15 38
8
43 48
44 11
5
a
Recombinant human b1- and b2-adrenoceptors are expressed in CHO-K1 cell lines and the intracellular accumulation of cAMP after addition of various test compounds is
measured. The intrinsic activity (IA) is reported as percentage of the maximal effect of isoprenaline (=100%). The standard deviation is given.
Table 2
0.1 µg/kg
0.3 µg/kg
1 µg/kg
3 µg/kg
A
Results from the 5 h guinea pig model of acetylcholine-induced bronchoconstriction
(Konzett–Roessler model)
120
100
80
60
40
20
0
Compounds
Dosesa
(l
g/kg)
Dur >80%b (min)
FEDc
(
lg/kg)
TId
1
0.1, 0.3, 1, 3, 10
1, 3
3, 10, 30, 100
3, 10, 30
3, 10
3, 10, 30, 100
3, 10
3, 10
300
300
300
300
150
300
300
220
300
300
1
3
30
10
None
None
10
None
3
10
1
3
4a
4c
4h
4i
4j
4l
4m
4p
4q
3
<1
<1
1
<1
10
10
1, 3, 10, 30
1, 3, 10, 30
time [minutes]
3
a
b
c
Doses administered intratracheally.
Time period with >80% bronchoprotecton at the highest tested dose.
The fully effective dose (FED) corresponds to the first dose reaching a full
1 µg/kg
3 µg/kg
10 µg/kg
B
120
100
80
60
40
20
0
inhibition of the acetylcholine-induced bronchospasm (=100% bronchoprotection).
d
Therapeutic index (TI), ratio of the first dose producing an increase in heart rate
of >10% and the FED.
Fortunately, several compounds exert an excellent sub-type selec-
tivity based on the ratio of the EC50 values for the b1- and b2-recep-
tor which is for compound 4p9 even higher than for formoterol. In
this respect, it has to be considered that a decreased intrinsic activ-
ity at the b1-adrenoceptor is observed for all compounds from this
study which is in some cases even negligible, adding to the favor-
able overall profile of this class.
Only a weak b-adrenergic activity was determined for the dis-
tomer (S)-4p ((S)-enantiomer of compound 4p). These data are
strong evidence that the measured EC50s of the racemates are
mainly influenced by the eutomers and thereby justify the use of
racemates in this early stage of the test cascade. If the measured
residual activity of (S)-4p stems from the distomer itself or from
a contamination with its eutomer is unknown.
time [minutes]
Figure 2. Bronchoprotective effect of formoterol 1 (A) and example 4p (B) in the
Konzett-Roessler model. Bronchospams were induced in guinea pigs by iv injections
of acetylcholine every 10 min. Bronchoprotection is expressed as the percentage of
inhibition of the increase in pulmonary resistance induced by acetylcholine (N = 2
animals per dose). The 10
were omitted for clarity.
lg/kg dose for formoterol and the 30 lg/kg dose for 4p
the heart rate was recorded and used as an indicator for the sys-
temic availability of a test compound.12
Nine compounds from this study (examples 4a, c, h–j, l, m, p, q)
were selected for further profiling and tested in an in vivo model of
bronchodilation (Table 2).10 In this model, bronchospasms were in-
duced in anaesthetized guinea pigs by iv injections of acetylcho-
Cardiovascular effects which are observed for b2-agonists with
high sub-type selectivity can be attributed both to the residual
b1-acitivity and to the dominant b2-component of the compound.
One potential cause for an accelerated heart rate results from the
b2-adrenoceptor mediated vasodilation and concomitant reduced
blood flow which is counterbalanced through an increased cardiac
output. The b2-adrenoceptor can also directly act on the heart,
line.11 The test compound was administered via
a tracheal
cannula using a RespimatÒ soft mist inhaler and bronchodilation
was quantified over the entire study period of 5 h. In addition,

T. Bouyssou et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1410–1414
1413
or lactate at all doses tested. In contrast, formoterol showed at
an equally effective dose a decrease in serum potassium level
and a tachycardia (heart rate increase) was more pronounced
and longer lasting than for (R)-4p. None of the other 6-hydroxy-
4H-benzo[1,4]oxazin-3-ones from this study exhibited a compara-
ble profile in these tests (data not shown).
O
O
OH
O
O
O
c
b
HN
HN
Cl
R
OBn
OBn
In further studies, bronchodilatory efficacy over 24 h was dem-
onstrated in two species (dog and guinea pig) and similar experi-
mental settings for (R)-4p but not for formoterol.16 The results
from these experiments in connection with a measured log D value
of 1.2 (at pH 7.4) for compound (R)-4p are a clear disprove of the
hypothesis that lipophilicity is a prerequisite for an inhalatively
applied LABA exerting a long duration of action.
R = H
R = Cl
9
19
a
18
O
O
O
O
OH
d, e
H
O
HN
N
HN
The low systemic availability of (R)-4p suggested by the ab-
sence of undesired systemic pharmacodynamic effects was sup-
ported by data from pharmacokinetic studies. A low permeability
was determined for (R)-4p in an in vitro assay measuring the apical
to basolateral flux across a monolayer of CaCo-2 cells (Papp ap >
bas = 3.5 Â 10À7 cm/s, Papp bas > ap = 9.0 Â 10À6 cm/s). Further, a
medium metabolism was observed in hepatocytes from humans
(CL = 13 mL/min/kg) and rats (CL = 45 mL/min/kg). Consequently,
a low oral bioavailability of the swallowed fraction was concluded
from these in vitro data. This prediction was confirmed in vivo
where an oral bioavailability of 3 2% was found for (R)-4p after
po administration in rats.
A key requirement for the development of a q. d. LABA was the
identification of a salt form suitable for an inhalative application.
Fortunately, a crystalline hydrochloride salt of (R)-4p was identi-
fied with physico-chemical properties consistent with a formula-
tion in a dry power inhalation (DPI) device and as an aqueous
solution in the RespimatÒ soft mist inhaler. Based on these charac-
teristics, (R)-4p was selected to be the first clinical candidate from
our program aiming to identify a q. d. LABA. This compound desig-
nated BI 1744 CL or olodaterol is currently undergoing clinical
studies in man. The manuscript represents the first disclosure of
the name and structure of this compound (olodaterol).
R
OBn
OH
20
(R)-4
Scheme 3. Reagents and conditions: (a) Benzyltrimethylammonium-chloroiodate,
1,2-dichloroethane, acetic acid, H2O, 65 °C, 86%; (b) 1 mol % Cp RhCl[(S,S)-TsDPEN],
*
formic acid/triethylamine (5:2), DMF, À15 °C, 76%, 95.4% ee; (c) 2 M aqueous NaOH,
DMF, 0 °C, 96%; (d) amine 12, i-PrOH, 140 °C, microwave; (e) Pd/C, H2, MeOH.
although its occurence in this organ is less prevalent than that of
the b1-receptor.
All 6-hydroxy-4H-benzo[1,4]oxazin-3-ones 4 tested in the gui-
nea pig model showed a dose-dependent bronchodilation. A com-
plete reversal of the induced bronchospasms (=100%
bronchoprotection) was always observed with the exception of
4i, j and m, which already caused a significant increase in heart
rate (>10%) at a sub-maximal dose. Cardiovascular effects were
also accounted for compounds 4a and 4l at the first dose reaching
100% bronchoprotection resulting in a therapeutic index of 1, only.
In contrast, a therapeutic index of 10 was determined for the
examples 4p and 4q which is as good as for formoterol in this set-
ting (Fig. 2). All compounds producing a maximal bronchoprotec-
tion of 100% and with a therapeutic index >1 were moved to the
next stage in our screening cascade, a dog model of acetylcho-
line-induced bronchodilation.
In this model, only the eutomers ((R)-enantiomers) were stud-
ied to exclude pharmacodynamic effects associated with the dis-
tomer (including off-target effects). For this purpose, an
enantioselective route towards the 6-hydroxy-4H-benzo[1,4]oxa-
zin-3-ones 4 was developed (Scheme 3). The key step of the syn-
thesis is a transfer hydrogenation of the 2-chlororacetophenone
18. The reaction is catalyzed by a recently described rhodium com-
plex and provided the chlorohydrine 19 in good yield and excellent
enantiomeric excess.13 Conversion of the chlorohydrine 19 into the
styrene oxide 20, followed by coupling with the phenethylamines
12 and subsequent removal of the benzyl group delivered the
enantiomerically pure (R)-form of 4. This method gave ready ac-
cess towards the eutomers and was used to generate the amounts
required for the profiling of the compounds from this study.14
The bronchoprotective effect of the selected examples ((R)-4c,
(R)-4h, (R)-4p, (R)-4q) was studied in anaesthetized beagle dogs
over a time period of 3 h. Again, the test compound was adminis-
tered by inhalation using the RespimatÒ soft mist inhaler and bron-
choconstriction was induced by iv injections of acetylcholine. Since
beagle dogs are very sensitive to cardiovascular and metabolic ef-
fects (decrease in serum potassium, increase in serum glucose and
lactate) mediated by the stimulation of b-adrenoceptors,15 these
parameters were assessed during the experiment to monitor the
systemic availability of the test compound. Example (R)-4p dem-
onstrated a dose-dependent bronchoprotection in this model in
the absence of any changes in serum levels of potassium, glucose
In conclusion, several potent and selective b2-agonists have
been identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-
3-ones. One compound, (R)-4p demonstrated a duration of action
over 24 h in two preclinical in vivo models of bronchoprotection
and a superior safety margin compared to the marketed formoter-
ol. The encouraging pharmacodynamic profile and CMC character-
istics are supporting further clinical development of this
compound.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.12.087.
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3 mL isopropanol were stirred for 30 min at 140 °C under irradiation of
microwaves (Emrys Optimizer from Personal Chemistry). The mixture was
concentrated, filtered twice through a column of alumina (dichloromethane/
methanol = 50:1, then ethylacetate/methanol = 100:1 to 20:1) and then
crystallized from diethylether/diisopropylether to yield 1360 mg (68%) of the
benzyl-protected intermediate. 1340 mg (2.81 mmol) of this intermediate in
28 mL methanol were hydrogenated in the presence of 200 mg palladium on
carbon (10% wt) at 50 °C and a hydrogen pressure of 50 psi. The catalyst was
filtered off and the solvent removed in vacuo. The residue was dissolved in
methanol and 0.6 mL 5 M hydrogen chloride in isopropanol and then
precipitated through addition of ether. Yield: 1120 mg (94%; hydrogen
chloride; 94% ee by chiral HPLC).
9. Potency and intrinsic activity of compound 4p at the human b3-AR:
EC50 = 910 nM (n = 1), IA = 26% (n = 1).
10. The results from the anaesthetized guinea pig experiments are available in
Supplementary data.
11. Walland, A.; Palluk, R.; Burkard, S.; Hammer, R. Eur. J. Pharmacol. 1997, 330,
213.
12. Mazzanti, G.; Di Sotto, A.; Daniele, C.; Battinelli, L.; Brambilla, G.; Fiori, M.;
Loizzo, S.; Loizzo, A. Food Chem. Toxicol. 2007, 45, 1694.
Analytical data of compound (R)-4p: Mass spectroscopy: [M+H]+ = 387. 1H NMR
(400 MHz, DMSO-d6) d = 10.62 (s, 1H), 9.28 (s, 1H), 8.76 (m, 1H), 8.54 (m, 1H),
7.13 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 6.58 (d, 1H, J = 2.8 Hz), 6.37 (d,
1H, J = 2.8 Hz), 6.06 (d, 1H, J = 3.8 Hz), 5.12 (m, 1H), 4.58 (d, 1H, J = 15.0 Hz),
4.49 (d, 1H, J = 15.0 Hz), 3.74 (s, 3H), 3.17 (m, 1H), 2.90 (m, 3H), 1.19 (s, 6H). 13C
NMR (100 MHz, DMSO-d6) d = 165.3, 158.2, 152.5, 132.3, 131.6, 130.1, 127.8,
127.0, 113.6, 106.6, 102.2, 66.9, 63.5, 59.5, 55.0, 46.5, 41.5, 22.2, 20.2.
15. Greaves, P. Toxicol. Lett. 2000, 112–113, 547.
13. Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T. Org. Lett. 2002, 4, 4373.
16. Bouyssou, T.; Casarosa, P.; Naline, E.; Pestel, S.; Konetzki, I.; Devillier, A.;
Schnapp, A.; Pharmacological characterization of BI 1744 CL, a novel, inhaled
14. Synthesis protocol of
a representative example (compound (R)-4p): 750 mg
(2.52 mmol) 6-benzyloxy-(8R)-oxiranyl-4H-benzo[1,4]oxazin-3-one 20 and
900 mg (5.02 mmol) 2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamine 12p in
b2-adrenoceptor agonist exerting a 24 h duration of action in preclinical
models, in preparation.