Antiasthmatic Agents 1
Antiasthmatic Agents
Hans Michael Jennewein, Boehringer Ingelheim Pharma KG, Ingelheim/Rhein, Federal Republic of
Germany
Jorge Casals-Stenzel, Gauting-Königswiesen, Federal Republic of Germany
Kurt Schromm, Boehringer Ingelheim Pharma KG, Ingelheim/Rhein, Federal Republic of Germany
1. Introduction . . . . . . . . . . . .
2. Bronchodilators (Relievers) . .
2.1. Adrenoceptor Agonists . . . . .
2.1.1. Aminocatechol Derivatives . . . .
2.1.2. Resorcinol Derivatives . . . . . .
2.1.3. Saligenin Derivatives . . . . . . .
2.1.4. Further Arylalkylamines . . . . .
2.2. Xanthine Derivatives . . . . . . .
1. Introduction
Asthma therapy is based on the complex patho-
physiology of this disease. Because of the vari-
ety of stimuli and the multiple factors that are
involved in the induction and development of
asthma, its treatment involves a multiplicity of
therapeutic approaches and drugs [1], [2].
Bronchial asthma is generally understood to
be a chronic inflammatory pulmonary disease
characterized by recurrent episodes of wheezy
labored breathing with prolonged expiration ac-
companied by dry coughing and tough mucus.
These symptoms are the clinical expression of
a narrowing of the bronchi (bronchoconstric-
tion), a bronchial mucosal thickening (edema,
eosinophilic bronchial infiltration), bronchial
wall remodeling, and an excessive mucus pro-
duction with plugging of the conducting airways
in the lungs. This more or less generalized air-
way changes result in an increased irritability or
sensitivity of the bronchi (bronchial hyperreac-
tivity) to a wide variety of stimuli (irritants), al-
lergic and nonallergic. The obstruction is usually
reversible, either spontaneously or in response to
appropriate therapy.
Depending on its dynamics bronchial asthma
is clinically categorized into acute (attacks, sta-
tus asthmaticus) and chronic (persistent) asthma.
It is further subdivided into extrinsic and intrin-
sic asthma depending on the nature of its causes.

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10.1002/14356007.a02 453
. . . 1 2.3. Anticholinergic Drugs . . . . . . . . . 16
. . . 3 3. Antiinflammatory Drugs or Con-
. . . 3 trollers (Glucocorticosteroids) . . . . 17
. . . 3 4. Antiallergic Therapy . . . . . . . . . . 18
. . . 6
5. Antileukotrienes . . . . . . . . . . . . . 19
. . . 8
. . . 9 6. Newer Concepts in Asthma Therapy 20
. . . 13 7. References . . . . . . . . . . . . . . . . . 20
Extrinsic or allergic asthma (50 % of cases)
generally occurs in childhood or young adult-
hood (under the age of 40) and relates to such
extrinsic factors as common allergens (pollens,
house dust, animal dander, inhalants, and some
foods and drugs) or occupationally encountered
dust (sawdust, flour). The house dust mite Der-
matophagoides pteronyssinus is often involved.
Extrinsic asthma can be controlled effectively
with drug therapy.
Intrinsic or nonallergic asthma generally
occurs in middle-aged patients who have no
family history of allergies and exhibit negative
allergy tests. It relates to intrinsic factors that are
not well understood, e.g., respiratory tract in-
fections, exercise, emotional stress, changes in
weather and temperature, cold air, and inhalation
of such air pollutants as sulfur dioxide and other
chemicals, e.g., diisocyanates, poly(vinyl chlo-
ride), phthalic anhydride, or ethylenediamine.
Patients with intrinsic asthma do not respond
well to drug therapy and may progressively de-
velop a chronic form of asthma.
Bronchial hyperreactivity, the fundamental
feature of asthma, has been attributed to a
pathophysiologic mechanism, which involves
dysfunction of sympathetic nerves mediated
by β-adrenergic receptors, hyperfunction of
the parasympathetic nerves (efferent fibers of
the vagus nerves), and altered intracellular cy-
clic adenosine monophosphate (cAMP) – cyclic
2 Antiasthmatic Agents
guanosine monophosphate (cGMP) ratios in
bronchial smooth muscles (effector cells) or
in mast cells [3–5]. Immunologic mechanisms
(antigen – antibody reactions) also are involved.
Remodeling of the bronchial wall due to the
chronic inflammatory event may also contribute
to airway hyperreactivity.
The smooth muscle of the airway is con-
trolled by the autonomic nervous system and
bronchoactive chemical mediators. The air-
ways are supplied with both sympathetic and
parasympathetic nerve fibers from the auto-
nomic nervous system. At the bronchial smooth
muscle preferentially β2 -adrenoreceptors medi-
ate relaxation of the muscle, i.e., dilation of
the bronchi. Stimulation of the parasympathetic
nerve fibers (Nervus vagus) or the administration
of acetylcholine causes bronchoconstriction.
The bronchial smooth muscle also responds
to bronchoactive chemical mediators, includ-
ing such bronchoconstrictors as histamine, sero-
tonin, neurokinins, and prostaglandins (PG),
e.g., PGF2a . The leukotrienes C4 , D4 , and E4 , are
also included in this group. Bronchodilating me-
diators are, e.g., PGE1 and PGI2 . All these me-
diators act via specific receptors on the bronchial
smooth muscle. The chemical mediators capable
of causing bronchoconstriction generally are re-
leased by precursors stored either in static cells
fixed within tissue (the mast cells) or in mobile
blood cells (the eosinophilic leukocytes) infil-
trating the bronchial mucosa. The classic exam-
ple of such a mediator release is the allergic chal-
lenge in allergic or extrinsic asthma, in which the
allergen interacts with a specific immunoglobin
E (IgE) antibody (antigen – antibody reaction,
type I allergic reaction) fixed to the surface of
mast cells. It is also possible that mediators are
released by other nonallergic stimuli in nonal-
lergic or intrinsic asthma.
The binding of the mediators histamine,
leukotriene, PG, etc., or of β-adrenoceptor
agonists to the corresponding receptors on
the smooth muscle cells triggers intracellu-
lar changes in the concentrations of cAMP or
cGMP. There is an optimal ratio of cAMP to
cGMP. An increase in cAMP concentration or a
fall in that of cGMP, triggered by β2 -adrenergic
sympathomimetics, PGE1 , or phosphodiester-
ase inhibitors, such as theophylline, induces re-
laxation of smooth muscle. Conversely, a fall in
cAMP concentration or a rise in that of cGMP
triggered by vagal stimulation, cholinergic ag-
onists, histamine, β-adrenergic antagonists, or
PGF2α , causes contraction. Calcium plays an
important role in the mast cell, where it in-
teracts with cAMP in the regulation of gran-
ule release. The release of mediators (e.g., his-
tamine and leukotrienes) is stimulated by a flow
of calcium into the cell, possibly initiated by the
IgE – antigen reaction at the cell surface.
Eosinophilic bronchial infiltration is one of
the hallmarks of asthma. This infiltration is obvi-
ously caused by a dominant T lymphocyte helper
cell subpopulation (so called TH2 cells → Blood,
Chap. 2.1.3.), which, via secretion of various cy-
tokines (i.e., IL-5), facilitates this eosinophilic
inflammation. Eosinophils are thought to be the
most important inflammatory cells in asthma.
Taking into consideration the pathophysiol-
ogy of bronchial asthma, the therapy of this
disease can be directed to several sites along
the trigger-to-target organ response pathway. A
causal therapy would include the prevention of
exposure to precipitating factors, on the one
hand, and the prevention of mast cell stimula-
tion by hyposensitization or desensitization pro-
cedures (immunotherapy) on the other. Causal
therapy is uncertain and difficult to accom-
plish. Current antiasthmatic therapy is therefore
to a great extent symptomatic and its princi-
pal aim is to keep airway patency at the opti-
mal level for each particular patient. The symp-
tomatic therapy of asthma consists of bron-
chodilation by modification of the end-organ re-
sponse, i.e., the smooth muscle response or by
blockage of the cholinergic reflex pathways (va-
gal reflex) and of antiallergic therapy, includ-
ing anti-inflammatory treatment, inhibition of
antibody formation (immunosuppression), and
prevention of mast cell degranulation or media-
tor antagonism. These symptomatic therapeutic
measures are achieved by five main groups of
substances: sympathomimetic agents, methylx-
anthines, anticholinergic drugs, corticosteroids,
and disodium cromoglycate and related drugs. In
the last few years new types of possible antiasth-
matic agents have been proposed: leukotriene
antagonists or inhibitors of leukotriene synthe-
sis [6], [7].

2. Bronchodilators (Relievers)
This type of antiasthmatic drug acts on the
bronchial smooth muscle and induces a relax-
ation of the airway muscle which leads to desired
bronchodilation thus relieving the most promi-
nent symptom of asthma. The term bronchodila-
tor drug might be expected to cover any drug
that causes dilation of the bronchi, but by com-
mon usage it is restricted to drugs with a fairly
rapid action. Because this sort of therapy causes
a more of less immediate relieve, therapy with
bronchodilators is also known under the term
reliever therapy.
2.1. Adrenoceptor Agonists
β-Receptor stimulation produces bronchodila-
tion. This can be achieved by a wide variety
of agents including those which release ami-
nocatechols producing α and β effects (e.g.,
ephedrine), direct β stimulants which stimu-
late both β1 and β2 receptors (e.g. isoprenaline
and adrenaline, which also has α effects), and
drugs that are more selective in their stimula-
tion of β2 receptors (e.g., fenoterol, clenbuterol,
and salbutamol) [8]. The development of rel-
atively specific agents for β2 stimulation left
little place for ephedrine or other nonselective
drugs that stimulate both β1 and β2 receptors
and have adverse effects on the heart caused
by β1 stimulation (tachycardia, palpitations).
The β2 -adrenoceptor agonistic bronchodilators
can be used by inhalation, by oral, or by intra-
venous administration. In clinical practice the
main problem in their use lies in the cardiovas-
cular side effects and the skeletal muscle tremor
caused by overdosage. Nevertheless, they are the
drugs of choice in the treatment of acute bron-
chospasm. Long-acting β2 -adrenoceptor ago-
nists have been introduced. They are especially
useful in the treatment of nocturnal asthma at-
tacks.
The parent compound of the sympath-
omimetic agents is 2-phenylethylamine. Substi-
tutions on the benzene ring, on the α- and β-
carbon atoms, or on the terminal amino group
yield a wide range of compounds with sym-
pathomimetic activity. They can be classified
into aminocatechols, resorcinol derivatives, and
saligenin derivatives depending on their chemi-
Antiasthmatic Agents 3
cal structure. Further substitutions on the benz-
ene ring lead to other very active compounds,
e.g., the long-acting clenbuterol, procaterol, or
bitolterol.
Aminocatechols are largely eliminated by
neuronal and extraneuronal uptake mechanisms
at the sympathomimetic nerve terminals. Non-
aminocatechols are resistant to both uptake
mechanisms. The aminocatechols (adrenaline,
isoprenaline, isoetharine, and rimiterol) contain-
ing a 3,4-benzenediol ring are also metabolized
by the enzyme catechol-O-methyltransferase
(COMT) to relatively inert 3-methoxy metabo-
lites. Non-aminocatechols (resorcinol and sali-
genin derivatives) are not metabolized by this
enzyme and thus their half-lifes are prolonged.
Another widely distributed enzyme, monoamine
oxidase (MAO), cleaves the aminocatechol be-
tween the α-carbon and the amino group. The re-
moval of one or both of the hydroxyl groups from
the benzene ring prevents the action of COMT,
and substitution of the α-carbon atom and the
amino group blocks oxidation by MAO.
2.1.1. Aminocatechol Derivatives
Epinephrine [51-43-4], adrenaline, 1-(3,4-
dihydroxyphenyl)-2-(methylamino)etha-
nol, free base, C9 H13 NO3 , M r 183.21,
mp 211 – 212 ◦ C (l-form); hydrochloride
[51-42-3], C9 H13 NO3 · HCl, M r 219.67,
mp 147 – 154 ◦ C (l-form); for pharmacology,
see [9].
A naturally occurring hormone, l-epi-
nephrine is produced by the medulla of the
adrenal gland and released when the body is
under stress (→ Hormones). It is the model for
all other sympathomimetic drugs, but its clinical
use has been largely supplanted.
Synthesis [10], [11]: see next page.
Trade names: Suprarenin (Hoechst, Ger-
many), Medihaler Epi (Riker, United Kingdom,
USA), Adrenalin (Parke-Davis, USA).
4 Antiasthmatic Agents

Isoproterenol [149-53-1], isoprenaline, 1-

(3,4-dihydroxyphenyl)-2-(isopropylamino)eth-
anol, free base, C11 H17 NO3 , M r 211.26,
mp 155.5 ◦ C (racemic form); hydrochloride
[949-36-0], C11 H17 NO3 · HCl, M r 247.72,
mp 170 – 171 ◦ C (racemic form); sulfate di-
hydrate [6078-56-4], C11 H17 NO3 · 1/2 H2 SO4
· 2 H2 O, M r 296.33, mp128 ◦ C (racemic form,
some decomp.); for pharmacology, see [12].
Clinical use has been all but abandoned in Eu-
rope because isoproterenol is not selective for β2
receptors.
Synthesis [13]: see right column, above.
Alternative synthesis [14]: see right column,
centre.
Trade names: Aludrin (Boehringer Ingel-
heim, FRG), Aleudrin (Lewis, United King-
dom), Isomenyl (Kaken, Japan), Isuprel
(Winthrop, USA).

Isoetharine [530-08-5], 1-(3,4-dihydroxy-

phenyl)-2-(isopropylamino)butanol, free base,
C13 H21 NO3 , M r 239.32, hydrochloride
[50-96-4], C13 H21 NO3 · HCl, M r 275.78, mp
212 – 213 ◦ C (decomp.); for pharmacology, see
[15].
The clinical use of isoetharine is declining
because of its low β2 specificity, but it is still
used in combinations.
Synthesis [16]: see right column, below.
Trade names: Asthmalitan (Kettelhack-
Riker, FRG), Numotac (Riker, United King-
dom), Bronkosol (Breon, USA).

Protokylol [136-70-9], 1-(3,4-dihydroxy-
phenyl)-2-(α-methyl-3,4-methylenedioxyphen-
ethylamino)ethanol, free base, C18 H21 NO5 ,
M r 331.37, mp 163 ◦ C; hydrochloride
[136-69-6], C18 H21 NO5 · HCl, M r 367.83,
mp 126 – 127 ◦ C; for pharmacology, see [17]:
Synthesis [18]:
Trade names: Caytine (Chugai, Japan), Ven-
taire (Marion, USA).
Rimiterol [32953-89-2], 1-(3,4-dihydroxy-
phenyl)-1-(2-piperidinyl)methanol, free base,
C12 H17 NO3 , M r 223.27, mp 203 – 204 ◦ C;
hydrobromide [31842-61-2], C12 H17 NO3
· HBr, M r 304.19, mp 220 ◦ C (decomp.); for
pharmacology, see [19].
Rimiterol is not in wide-spread clinical use.
Synthesis [20]:
Antiasthmatic Agents 5
Trade name: Pulmadil (Riker, United King-
dom).
Trimethoquinol [30418-38-3], tetroquinol,
(−)-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetra-
hydro-6,7-isoquinolinediol, free base,
C19 H21 NO5 , M r 343.38, mp 125 – 126 ◦ C; hy-
drochloride [18559-59-6], C19 H21 NO5 · HCl,
M r 379.84; for pharmacology, see [21].
Trimethoquinol is a β-sympathomimetic
agent that inhibits the aggregation of platelets.
Synthesis of d,l-trimethoquinol [22]:
The racemic mixture is resolved using (+)-
tartaric acid to yield l-trimethoquinol.
Trade names: Inolin (Tanabe, Japan), Vems
(ISF, Italy).
Hexoprenaline [3215-70-1], N,N -bis[2-
(3,4-dihydroxyphenyl)-2-hydroxyethyl]hexa-
methylenediamine, free base, C22 H32 N2 O6 ,
M r 420.51, mp 162 – 165 ◦ C; dihydrochlo-
ride [4323-43-7], C22 H32 N2 O6 · 2 HCl,
M r 493.43, mp 197.5 – 198 ◦ C; sulfate
[32266-10-7], C22 H32 N2 O6 · H2 SO4 ,
M r 518.59, mp 222 – 228 ◦ C; for pharmacol-
ogy, see [23].
Synthesis [24]: see next page.
Trade names: Etoscol (Byk Gulden, Ger-
many), Etoscol (Morishita, Japan).
6 Antiasthmatic Agents

Alternative synthesis [27]:

2.1.2. Resorcinol Derivatives

Metaproterenol [586-06-1], orciprenaline,

1-(3,5-dihydroxyphenyl)-2-(isopropylamino)-
ethanol, free base, C11 H17 NO3 , M r 211.26,
mp 100 ◦ C (racemic form); hydro-
chloride [7104-40-7], C11 H17 NO3 · HCl,
M r 247.72, mp 147 ◦ C (racemic form); sul-
fate [31023-56-0], C11 H17 NO3 · 1/2 H2 SO4 ,
M r 260.30, mp 202 – 203 ◦ C (racemic form);
for pharmacology, see [25].
Metaproterenol was the first β-
sympathomimetic drug with metabolic stability
to achieve wide clinical use. Trade names: Alupent (Boehringer Ingel-
Synthesis [26]: heim, Germany, France, United Kingdom,
USA), Alotec (Boehringer-Tanabe, Japan).

Terbutaline [23031-25-6], 1-(3,5-dihydro-

xyphenyl)-2-(tert-butylamino)ethanol, free
base, C12 H19 NO3 , M r 225.29; sulfate
[23031-32-5], C12 H19 NO3 · 1/2 H2 SO4 ,
M r 274.33, mp 246 – 248 ◦ C; for pharmacol-
ogy, see [28].
Terbutaline is a specific β2 -sympathomimetic
agent in wide clinical use.
Synthesis [29]: see next page.
Trade names: Bricanyl (Astra, Germany,
United Kingdom, USA), Bricanyl (Astra-
Injisawa, Japan), Terbasmin (Erba, Italy).

Fenoterol [13392-18-2], 1-(3,5-dihydroxy-
phenyl)-2-(4-hydroxy-α-methylphenethylami-
no)ethanol, free base, C17 H21 NO4 , M r 303.36;
hydrobromide [1944-12-3], C17 H21 NO4 · HBr,
M r 384.28, mp 232 – 233 ◦ C; for pharmacology,
see [30].
Fenoterol is a selective β2 -sympathomimetic
agent that is in wide clinical use in Europe.
Synthesis [31]:
Antiasthmatic Agents 7
Trade names: Berotec (Boehringer Ingel-
heim, Germany, Switzerland, Sweden, the
Netherlands, Canada), Berotec (Warner-
Lambert, United Kingdom, Ireland), Respilac
(Angeli, Italy).
Reproterol [54063-54-6], 7-[-3-[[2-(3,5-
dihydroxyphenyl)-2-hydroxyethyl]amino]pro-
pyl]-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-
dione, free base, C18 H23 N5 O5 , M r 389.41;
hydrochloride [13055-82-8], C18 H23 N5 O5
· HCl, M r 425.88, mp 249 – 250 ◦ C; for phar-
macology, see [32].
Reproterol is structurally a combination of
a β-sympathomimetic compound and theo-
phylline, but it shows only sympathomimetic ac-
tivity.
Synthesis [33]:
8 Antiasthmatic Agents

Trade names: Bronchospasmin (Chemiew-

erke Homburg, Germany), Bronchospasmin Alternative synthesis [36]:
(Farmades, Japan), Bronchodil (Keymer, United
Kingdom).

2.1.3. Saligenin Derivatives

Salbutamol [18559-94-9], albuterol,

2-(tert-butylamino)-1-(4-hydroxy-3-hydroxy-
methylphenyl)ethanol, free base, C13 H21 NO3 ,
M r 239.32, mp 151 ◦ C; sulfate [51022-70-9],
C13 H21 NO3 · 1/2 H2 SO4 , M r 288.36; for phar-
macology, see [34].
Salbutamol is a specific β 2 -stimulant in wide
clinical use in Europe and Japan.
Synthesis [35]:
 Antiasthmatic Agents 9

C12 H20 N2 O3 · 2HCl, M r 312.2, mp 182 ◦ C

(decomp.), acetate [65652-44-0], for pharma-
cology see [93]. Pirbuterol is a β2 -agonist in the
management of disorders with reversible air-
ways obstruction. It is given by inhalation and
orally. Synthesis [94]:

Trade names: Sultanol (Glaxo, Germany,

Japan), Ventolin (Glaxo, France; Allen & Han-
burys, United Kingdom; Sankyo, Japan), Bron-
covaleas (Valeas, Italy).

Salmeterol [89365-50-4], (±)-4-hydroxy-

α1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-
1,3-benzenedimethanol, 1-hydroxy-2-naphtho-
ic acid salt [94749-08-3], C25 H37 NO4 C11 H8 O3 ,
M r 603.75, mp 137 – 138 ◦ C, for pharmacology
see [90], [91]. Salmeterol is a long-acting β2 -
agonist for patients with chronic asthma, useful
also in controlling persistent nocturnal asthma.
Synthesis [92]:

Trade names: Exirec, Spirolair, Noxair,

Zeisin (3M Medical).

2.1.4. Further Arylalkylamines

Trade name: Serevent (Glaxo Wellcome).
Pirbuterol [38677-81-5], α6 -[(tert-butyl-
amino)methyl]-3-hydroxy-2,6-pyridinedimeth-
anol, dihydrochloride [38029-10-6],
Modern β2 -specific sympathomimetics with dif-
ferent substituents on the aromatic ring are de-
scribed in this group along with ephedrine and
thiadrine.
10 Antiasthmatic Agents

Ephedrine [299-42-3], 2-methylamino- free base, C12 H18 Cl2 N2 O, M r 277.20,

1-phenylpropanol, free base, C10 H15 NO, mp 109.1 ◦ C; hydrochloride [21898-19-1],
M r 165.24, mp 79 ◦ C (racemic form); C12 H18 Cl2 N2 O · HCl, Mr 313.66,
hydrochloride [50-98-6], C10 H15 NO · HCl, mp 174.0 – 175.5 ◦ C; for pharmacology, see
M r 201.70, mp 187 – 188 ◦ C; sulfate [134-72-5], [41].
C10 H15 NO · 1/2 H2 SO4 , M r 214.28, mp 247 ◦ C; Clenbuterol is a long-acting, potent, and spe-
for pharmacology, see [37]. cific β2 stimulator that is used orally.
Ephedrine is a naturally occurring alkaloid Synthesis [42]:
drug (→ Alkaloids) derived from Ephedra equi-
stina and Ephedra vulgaris. It can be prepared
synthetically. It is used mainly in combination
with other agents.
Synthesis of l-(−)-ephedrine [38]:

Trade names: Ephetonin (E. Merck, Ger-

many), Ephedrin (Knoll, Germany), Spaneph
(Smith Kline & French, United Kingdom),
Ephedrine “Nagai” (Dainippon, Japan), Cal-
cidrine (Abbott, USA).
Alternative synthesis [43]:
Thiadrine [14007-67-1], 3,4-dimethyl-2-
imino-5-phenylthiazolidine, free base,
C11 H14 N2 S, Mr 206.31; thiocyanate,
C11 H14 N2 S · HSCN, M r 265.40, mp 190 – 192 ◦ C;
for pharmacology, see [39].
Thiadrine is not in wide-spread clinical use
as a bronchodilator.
Synthesis [40]:

Trade name: Priatan (Chem. Werke Minden,

Germany).

Clenbuterol [37148-27-9], 1-(4-amino-3,5-

dichlorophenyl)-2-(tert-butylamino)ethanol,
 Antiasthmatic Agents 11

C12 H18 ClNO · HCl, M r 264.20, mp 165 – 170 ◦ C;

for pharmacology, see [46].
Synthesis [47]:

Trade name: Spiropent (Dr. Karl Thomae,

Germany).
Trade names: Berachin (Toyo Tanabe,
Japan), Hokunalin (Hokuriku Senjaku, Japan).
Mabuterol [56341-08-3], 1-(4-amino-3-
chloro-5-trifluoromethylphenyl)-2-(tert-butyl-
amino)ethanol, hydrochloride [54240-36-7], Carbuterol [34866-47-2], 1-(5-[2-(tert-
C13 H18 ClF3 N2 O · HCl, M r 347.21 for phar- butylamino)-1-hydroxyethyl]-2-hydroxy-
macology see [44]. Mabuterol is an orally active phenyl)urea, free base, C13 H21 N3 O3 ,
β2 -adrenergic agonist related to Clenbuterol. M r 267.33, mp 205 – 207 ◦ C; hydrochloride
Synthesis [45]: [34866-46-1], C13 H21 N3 O3 · HCl, M r 303.79,
mp 209 – 210 ◦ C; for pharmacology, see [48].
Synthesis [49]:

Trade name: Broncholin (Kaken Pharmaceu-

tical).

Tulobuterol [41570-61-0], 2-(tert-

butylamino)-1-(2-chlorophenyl)ethanol,
free base, C12 H18 ClNO, M r 227.74,
mp 89 – 91 ◦ C; hydrochloride [56776-01-3],
12 Antiasthmatic Agents

Trade names: Bronsecur (Smith

Kline & French, Belgium, the Netherlands,
South Africa), Pirem (Gödecke/ Sasse, FRG).

Formoterol [73573-87-2], (RR,SS)-(±)-N-

[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-
phenyl)-1-methylethyl]amino]ethyl]phenyl]-
formamide, semifumarate [43229-80-7],
C21 H26 N2 O6 , M r 402.21, for pharmacology
see [50], [51]. Formoterol is a potent bronchos-
elective β-agonist with long duration of action
given by inhalation. Trade names: Foradil (Novartis Pharma),
Synthesis [52]: Atock (Rhône Poulenc), Oxis (Astra/pharma
stern.)

Procaterol [72332-33-3], 8-hydroxy-5-[1-

hydroxy-2-(isopropylamino)butyl]-2(1H)-
quinolinone, C16 H22 N2 O3 , M r 290.37,
mp 141 – 142 ◦ C; hydrochloride [62929-91-3],
C16 H22 N2 O3 · HCl ·1/2 H2 O, M r 335.83,
mp 193 – 197 ◦ C (decomp.); for pharmacology,
see [53].
Synthesis [54]: see left column of next page,
above.
Trade name: Meptin (Otsuka, Japan).

Bitolterol [30392-40-6], 4-[2-(tert-butyl-

amino)-1-hydroxyethyl]-1,2-phenylene-bis(p-
toluate), free base, C28 H31 NO5 , M r 461.56,
mp 80 – 84 ◦ C; mesylate [30392-41-7],
C28 H31 NO5 · CH4 O3 S, M r 557.67,
mp 170 – 172 ◦ C; for pharmacology, see [55].
Synthesis [56]: see left column of next page,
below.
Trade names: Effectin (Shionogi, Japan), Tor-
nalate (Sterling Drug, USA).

Bambuterol [81732-65-2], (±)5-[2-(tert-
butylamino)-1-hydroxyethyl]-m-phenylene-
bis-
(dimethylcarbamate), C18 H29 N3 O5 , M r 367.45,
Antiasthmatic Agents 13
hydrochloride [81732-46-9], C18 H29 N3 O5
· HCl, M r 403.9, for pharmacology see [57],
[58]. Bambuterol is an inactive prodrug of terbu-
taline (see page 6). It has a prolonged duration
of action when administered orally.
Synthesis [59]:
Trade name: Bambec (Astra/pharma stern,
Germany).
2.2. Xanthine Derivatives
This group includes the familiar compounds
present in the stimulant beverages, i.e., caffeine
(coffee, tea, cola), theobromine (cocoa), and
theophylline (tea) [60–62]. All are methylated
derivatives of the natural metabolite xanthine, a
14 Antiasthmatic Agents

precursor of uric acid. Apart from their stimulat-

ing effects, methylxanthines possess a number
of properties that are clinically useful (diuretic
effect, increase in cardiac output, vasodilation).
Most xanthines have bronchodilator activity, but
only some are employed therapeutically for this
purpose.
The following processes contribute to the
mechanism of action of theophylline. Phospho-
diesterase inhibition enhances monophosphate
(cAMP). The intracellular metabolism and con-
centration of calcium in bronchial smooth mus-
cle (bronchodilation) and in the mast cells (in-
hibition of mediator release) change consecu-
tively. Adenosine receptor antagonism also may
contribute to the relaxation of bronchial smooth
muscle and to the inhibition of histamine release
from mast cells; adenosine is known to increase
this release. Theophylline also influences pros-
taglandin synthesis. (Rona, United Kingdom), Theophyllol (Sankyo,
Theophylline preparations can be adminis- Japan), Broncodyl (Breon, USA), Blixophyllin
tered intravenously, orally, or rectally. They (Berlex, USA).
would be ineffective and irritating if admin-
istered as aerosols. The major pharmacologi- Theophylline ethylenediamine [317-34-0]
cal problem with these agents is the enormous is a salt of theophylline with ethylenediamine.
individual variability in their rates of absorp-
tion and metabolism. The unpredictability of
its levels in plasma after oral administration
and the low therapeutic index of theophylline
make it difficult to handle, and careful moni-
toring of plasma levels may be required. Theo-
phylline must be used in different preparations
because its solubility in water is poor (about
1 %). Therefore, theophylline itself is not suit- Trade names: Aminophylline (Promonta,
able for intravenous use, but is sufficiently sol- Germany), Aminophylline (ICN; Searle; Wyeth;
uble for oral administration. Theophylline is USA), Euphyllin (Byk Gulden, Germany), Car-
prepared as a soluble salt of ethylenediamine dophylin (Fisons, United Kingdom), Neophyllin
or of choline (choline theophyllinate) for intra- (Eisai, Japan).
venous use. True theophylline derivatives are
7-substituted compounds, e.g., dihydroxypro- Etofylline [519-37-9], 3,7-dihydro-7-(2-hy-
pyltheophylline (proxyphylline). These are less droxyethyl)-1,3-dimethyl-1H-purine-2,6-dione,
potent bronchodilators than theophylline, but C9 H12 N4 O3 , M r 224.22, mp 158 ◦ C; for phar-
they cause less intestinal irritation than theo- macology, see [65].
phylline or its salts and are much used in Europe. Synthesis [66], [67]: see next page.
Trade names: Cordalin (Chemiewerke
Theophylline [58-55-9], 3,7-dihydro-1,3- Homburg, Germany), Oxyphylline (Amido,
dimethyl-1H-purine-2,6-dione, C7 H8 N4 O2 , France), Oxyphylline (Sankyo, Japan), Mesotin
M r 180.17, mp 270 – 274 ◦ C. (Malescil, Italy).
Synthesis [63], [64]: see next column, above.
Trade names: Solosin (Cassella-Riedel, Ger-
many), Neulin (Riker, United Kingdom), Phyllin
 Antiasthmatic Agents 15

Trade names: Asthmolysin (Kade, Ger-

many), Neutraphylline (Houdé, France), Neu-
traphylline (Cox-Continental, United King-
dom), Dihydrophylline (Tokyo Hosei, Japan),
Neothylline (Lemmon, USA).

Acephylline piperazine [18833-13-1],

acepifylline, piperazine salt of 1,2,3,6-tetra-
hydro-1,3-dimethyl-2,6-dioxo-7-purineacetic
acid, C9 H10 N4 O4 C2 H5 N, M r 281.27.
Synthesis [71]: The compound is synthesized
by reacting theophylline with chloroacetic acid.

Proxyphylline [603-00-9], 3,7-dihydro-7-

(2-hydroxypropyl)-1,3-dimethyl-1H-purine-
2,6-dione, C10 H14 N4 O3 , Mr 238.25,
mp 135 – 136 ◦ C; for pharmacology, see [68].
Synthesis [69]:

Trade name: Etaphydel (Delalande, Ger-

many).

Bamifylline [2016-63-9], 3,7-dihydro-7-[N-

ethyl-2-(hydroxyethylamino)ethyl]-8-benzyl-
1,3-dimethyl-1H-purine-2,6-dione, free base,
C20 H27 N5 O3 , M r 385.47, mp 80 – 85.5 ◦ C;
hydrochloride [20684-06-4], C20 H27 N5 O3
· HCl, M r 421.93, mp 185 – 186 ◦ C; for phar-
macology, see [72].
Trade names: Spantin (Pharmacia, Ger- Synthesis [73]:
many), Spasmolysin (Kade, Germany), Brontyl
(Reckitt & Colman, United Kingdom), Mono-
phylline (Yoshitomi, Japan).

Diprophylline [479-18-5], dyphylline,

7-(2,3-dihydroxypropyl)-3,7-dihydro-1,3-di-
methyl-1H-purine-2,6-dione, C10 H14 N4 O4 ,
M r 254.25, mp 158 ◦ C.
Synthesis [67], [70]:
16 Antiasthmatic Agents

Trade name: Trentadil (Sedaph, France), Trade names: Bronchovycrin (Endopharm,

Trentadil (Armour, United Kingdom). Germany), Perasthman Inhalat (Bissantz, Ger-
many).

2.3. Anticholinergic Drugs Ipratropium bromide [22254-24-6],

(8r)-3α-hydroxy-8-isopropyl-1αH,5αH-tro-
The rationale for using anticholinergic drugs panium bromide (±)-tropate, C20 H30 BrNO3 ,
in the treatment of asthma is based on an M r 412.38, mp 230 – 232 ◦ C; for pharmacology,
irritant – bronchoconstrictor vagal reflex [74]. see [75], [77].
The allergen combines with antibodies on the Synthesis [78]:
surface of the mast cells releasing mediators
that act on nervous receptors in the epithelium
and elicit a reflex bronchoconstriction via the
vagus nerves (parasympathetic nerves). Com-
pounds, such as atropine (→ Alkaloids), which
block transmission at parasympathetic neuroef-
fector junctions, inhibit vagally induced smooth
muscle contraction and secretory activity. The
clinical use of atropine has been discouraged
because of fears of side effects (an increase in
the sputum viscosity and a possible decrease in
the ciliary activity). However, the clinical use of
this type of compound has been reassessed in
response to the introduction of ipratropium bro-
mide [75] and oxitropium bromide. These drugs
are inhaled. A long acting anticholinergic drug Trade name: Atrovent (Boehringer Ingel-
is tiotropiumbromide, which is in an advanced heim, Austria, Belgium, Germany, United King-
phase of development. dom, Italy, Mexico, the Netherlands, Spain).

Atropine [51-55-8], d,l-hyoscyamine, Oxitropium bromide [30286-75-0], 7(S)-

1αH,5αH-tropan-3α-ol (±)-tropate, endo-(±)-
α-(hydroxymethyl)phenylacetic acid 8-methyl-
8-azabicyclo[3.2.1]oct-3-yl ester, free base,
C17 H23 NO3 , M r 289.38, mp 114 – 116 ◦ C;
sulfate [55-48-1], C17 H23 NO3 · 1/2 H2 SO4 ,
M r 338.42, mp 190 – 194 ◦ C; methylnitrate
[52-88-0], C17 H23 NO3 · CH3 NO3 , M r 366.42,
mp 163 ◦ C; for pharmacology, see [9].
(1α,2β,4β,5α,7β)-9-ethyl-7-(3-hydroxy-1-oxo-
2phenylpropoxy)-9-methyl-3-oxa-9-azoniatri-
cyclo[3.3.1.02,4 ]nonane bromide, C19 H26 BrNO4 ,
M r 412.33, mp about 198 ◦ C.
Synthesis [79]:

Atropine is an alkaloid drug (→ Alkaloids)

found in the plants Atropa belladona, Datura
stramonium, and Hyoscyamus niger. l-
Hyoscyamine is obtained by extraction from
these plants and then transformed into the Trade name: Ventilat (Dieckmann, Ger-
racemic form using an alkaline ethanol solu- many), Tersigat (Laboratoires Francais de
tion [76]. Thérapeutique, France).

Tiotropium bromide [136310-93-5]
[7(S)-(1α,2β,4β,5α,7β]-7-[2-hydroxy-2,2-
di(2-thienyl)acetoxy]-9,9-dimethyl-3-oxa-9-
azoniatricyclo[3.3.1.02.4 ]nonane bromide,
C19 H22 BrNO4 S2 , M r 472.41, mp 226 – 227 ◦ C
(decomp.), bromide hydrate [139404-48-1], for
pharmacology, see [80]
Synthesis [81]:
3. Antiinflammatory Drugs or
Controllers (Glucocorticosteroids)
Glucocorticosteroids are the most potent agents
available for the treatment of asthma [82]. When
given orally, these substances cause adrenal sup-
pression, metabolic side effects like obesity, os-
teoporosis, hyperglycemia, glycosuria, and dis-
turbance of growth. However, when admin-
istered topically via inhalation glucocorticoid
therapy can avoid these systemic side effect to a
great extent. Therefore glucocorticoids given by
inhalation have become the primary treatment
of asthma. The mechanism of action of this type
of compound is not fully understood, but it in-
cludes interaction with an intracellular glucocor-
ticoid receptor [83]. The glucocorticoid receptor
binds the steroid at its C-terminal part. After nu-
clear translocation the middle part of the recep-
tor, which forms so-called “zinc fingers”, inter-
acts with DNA. An N -terminal domain then in-
duces transcriptional transactivation of genes. In
its inactivated form the glucocorticoid receptor
is bound to a protein complex that includes heat
shock proteins, immunophilline proteins, and
others. The binding site of the DNA is termed
glucocorticoid response elements (GRE). The
interaction of the steroid receptor complex with
GREs change the rate of transcription of steroid
Antiasthmatic Agents 17
responsive genes resulting in either induction or
repression of genes. Thereby production of in-
flammatory cytokines, enzymes, antiinflamma-
tory proteins, receptors and adhesion molecules
may be influenced. So for example β2 -receptors
are upregulated which improves the efficacy of
β-receptor agonists. This is known as the per-
missive effect of glucocorticoids.
Oral corticosteroid therapy suffers from a ma-
jor drawback. The high dosage of steroids used
to control inflammatory and immunologic reac-
tions leads inevitably to unwanted, disturbing
influences on metabolism; moreover withdrawal
symptoms occur after long-term administration.
Every effort should be made to avoid such long-
term oral use. However, in severe case this can-
not always be avoided. For intravenous adminis-
tration during severe acute asthma (attacks), hy-
drocortisone (→ Hormones) is the preparation
of choice, among other drugs. For oral corti-
costeroid therapy, prednisolone is preferred. For
topical or inhalative treatment, aerosol prepa-
rations of beclomethasone dipropionate, be-
tamethasone valerate, flunisolide, budenoside,
and triamcinolone acetonide (→ Hormones) are
available. In some countries fluticasone has al-
ready been introduced. Inhalative administration
minimizes the metabolic side effects of the glu-
cocorticoids. Side effects, like candidiasis of the
mouth and hoarseness of the throat are usually
mild and can be tolerated.
Beclomethasone [4419-39-0], 9α-chloro-
11β,17α,21-trihydroxy-16β-methylpregna-
1,4-diene-3,20-dione; 17,21-dipropionate
[5534-09-8], C28 H27 ClO7 , M r 510.97, mp
117 – 120 ◦ C. Beclomethasone dipropionate is
claimed to exert a topical effect on the lungs
without significant systemic activity. It is used
by inhalation, generally from a metered aerosol,
for the prophylaxis of the symptoms of asthma
[84], [85]. Chemical structure:
18 Antiasthmatic Agents
Trade names: Sanasthmax, Sanasthmyl
(Glaxo, UK).
Flunisolide [3385-03-3], 6α-fluoro-11β,21-
dihydroxy-16α,17α-isopropyldioxypregna-
1,4-diene-3,20-dione, C24 H31 FO6 , M r 434.5,
hemihydrate [77326-96-6]. Flunisolide hemi-
hydrate is administered by inhalation from me-
tered aerosol and used in the management of
asthma. Chemical structure:
Trade name: Inhacort (Boehringer Ingel-
heim, Germany).
Budesonide [51333-22-3], an epimeric mix-
ture of α- and β-propylforms of 16α,17α-
butylidendioxy-11β-21dihydroxy-pregna-1,4-
diene, C25 H34 O6 , M r 430.54. Comparative in-
vestigations of the clinical efficacy/safety of
budesonide and beclomethasone dipropionate
administered by inhalation in patients with
chronic bronchial asthma showed no differences
[86], [87]. Nebulized budenoside was effec-
tive in severe childhood asthma [88]. Chemical
structure:
Trade name: Pulmicort (Astra/Pharma stern,
Germany).
Fluticasone propionate [80474-14-2], S-
fluoromethyl-6α,9α-difluoro-11β-hydroxy-
16α-methyl-17α-propionyloxy-3-oxoandrosta-
1,4-diene-17β-carbothioate, C25 H31 F3 O5 S, M r
500.58, mp 272 – 273 ◦ C (decomp.). Flutica-
sone propionate is claimed to exert a topical
effect on the lungs without significant systemic
effects, due to its low systemic bioavailability
[89]. Chemical structure:
Trade name: Flutide (Glaxo Wellcome).
4. Antiallergic Therapy
Antiallergic therapy, including the use of cor-
ticosteroids, is an alternative to bronchodila-
tor therapy in the treatment of asthma. The
objectives of antiallergic therapy are the in-
hibition of mediator release, e.g., by dis-
odium cromoglycate or related compounds
(→ Antiallergic Agents, Chap. 3.) or by corti-
costeroids (→ Hormones, Chap. 4.), and the an-
tagonism of mediators, e.g., by antihistamines
or by the inhibition of either the activity or the
synthesis of leukotrienes. The classical antihis-
tamines are irrelevant to asthma therapy, pre-
sumably because of the presence and impor-
tance of other strong mediators. Newer antihis-
taminic agents, such as ketotifen [34580-13-7],
have been employed in the treatment of asthma
(→ Antiallergic Agents, Chap. 2.1.7.). Antago-
nists of cysteinyl-leukotrienes (i.e., leukotriene
D4 antagonists, zafirlukast, montelukast) or in-
hibitors of the enzyme 5-lipoxygenase are close
to registration or already on the market (zileu-
ton).
Disodium cromoglycate [15826-37-6] dis-
odium 4,4’-dioxo-5,5’-(2-hydroxytrimethy-
lenedioxy)di-14H-chromene-2-carboxylate,
C23 H14 Na2 O11 , M r 512.3, free acid
[16110-51-3] is a relatively nontoxic agent used
for the long-term prevention of many types of
asthma [95]. It has no bronchodilator proper-
ties and is used in the prophylaxis of asthma.

It does not play a role in the treatment of acute
asthmatic attacks including severe asthma [96],
[97]. Chemical structure:
Disodium cromoglycate was developed from
khellin, a natural substance that has been used
for centuries to alleviate colic pains. It is a
highly soluble powder that must be inhaled di-
rectly into the lung to be effective. Less than
1 % is absorbed when it is administered orally.
Trade name: Intal (Fisons).
Nedocromil sodium [69049-74-7], di-
sodium 9-ethyl-6,9-dihydro-4,6-dioxo-10-pro-
pyl-4H-pyrano[3,2-g]quinoline-2,8-dicarbox-
ylate, C19 H15 Na2 O7 , M r 415.3; free acid
[69049-73-6]. Nedocromil sodium has simi-
lar properties to sodium cromoglycate and can
inhibit asthmatic responses provoked by aller-
gen challenge and attenuate allergen-induced
bronchial hyperresponsivness. It is rapidly ab-
sorbed from the lungs following inhalation and
poorly absorbed from the gastrointestinal tract
[98]. Chemical structure:
Trade name: Tilade (Fisons).
5. Antileukotrienes
It has been shown that leukotrienes
(→ Prostaglandins, Chap. 2.) play a funda-
mental role in asthma. Especially the cystenyl
leukotrienes are thought to be involved in the
pathophysiology of asthma. The leukotriene an-
tagonists montelukast and zafirlukast are the
most prominent antileukotrienes which are reg-
istered or close to registration. Another possi-
bility is to inhibit the synthesis of leukotrienes.
The key enzyme is 5-lipoxygenase which, when
inhibited, blocks the formation of leukotriene
Antiasthmatic Agents 19
C4 , D4 , E4 and of leukotriene B4 . Zileuton is the
most advanced 5-lipoxygenase inhibitor, which
has been introduced into the therapy of asthma
in some countries.
Zafirlukast [107753-78-6], N-[4-[5-cy-
clopentyloxycarbonylamino)-1-methylindol-
3-ylmethyl]-3-methoxybenzoyl]-2-methylben-
zenesulfonamide, C31 H33 N3 O6 S, M r 575.68.
Chemical structure:
Zafirlukast is a potent LTC4 -, LTD4 - and
LTD4 -antagonist and is clinically effective in pa-
tients with mild to moderate asthma [99], [100].
Trade name: Accolate (Zeneca).
Montelukast sodium [151767-02-1],
sodium 2-[1-[1(R)-[3-[2(E)-(7-chloroquinolin-
2-yl)vinyl]-phenyl]-3-[2-(1-hydroxy-1-methyl-
ethyl)phenyl]propylsulfanylmethyl]cyclopro-
pyl]acetate, C35 H35 ClNNaO3 S, M r 608.17, free
acid [158966-92-8]. Chemical structure:
Montelukast sodium is a potent, selective
competitive antagonist for cysteinyl leukotriene
receptors such as LTD4 . It is orally active and
shows therapeutic effects in patients with asthma
[101].
Trade name: Singulair (Merck Frosst).
Zileuton [111406-87-2], (±)-N-(1-benzo-
[b]thien-2-ylethyl)-N-hydroxyurea, C11 H12 N2 O2 S,
M r 236.29. Chemical structure:
20 Antiasthmatic Agents
Zileuton is a potent and selective orally ac-
tive 5-lipoxygenase inhibitor. It inhibited LTB4
synthesis and was active in some inflammation
models. Clinically it shows effects after acute
and chronic administration in mild to moderate
asthma [102], [103].
Trade name: Zyflo (Abbott).
6. Newer Concepts in Asthma
Therapy
Various new and old approaches have been tried
in the therapy of asthma. Calcium antagonists
have no place in the routine management of
asthma [7]. A substantial portion of ongoing
research concentrates on phosphodiesterase in-
hibitors of type IV. The isoenzyme phospho-
diesterase is located in inflammatory cells like
the eosinophils which are important in asthma.
There are also trials going on using human-
ized monoclonal antibodies against IgE, IL-5,
IL-4, tumor necrosis factor α (TNFα) or ad-
hesion molecules. Search for inhibitors of in-
ducible NO synthetase is also continuing. Ef-
forts are made to influence various transcription
factors (i.e., NFK B) or to find inhibitors of phos-
pholipase A2 and antagonists for neurokinin re-
ceptors. Endothelin receptor antagonists are in
development. Also potassium channel openers
are still under evaluation. Time will show which
of those various approaches will lead to novel
therapies of asthma.
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Antiasthmatic Agents 21
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Antiatherosclerotic Agents → Cardiovascular Drugs

Antibacterial Chemotherapeutics → Chemotherapeutics