Anti-Obecity Drugs 1
Anti-Obecity Drugs
William J. Houlihan, Sandoz Research Institute, East Hanover, New Jersey 07936, United States
1. Introduction . . . . . . . . . . . . . . . .
2. Animal and Human Test Procedures
3. Mechanism of Action . . . . . . . . . .
4. Clinical Side Effects . . . . . . . . . . .
5. Phenethylamine Derivatives . . . . .
5.1. β-Phenylisopropylamines . . . . . . .
1. Introduction
Anorexiants are substances that depress the de-
sire for food. They are also referred to as anorec-
tic agents, anorexigenics, and appetite suppres-
sants. Because the main therapeutic use of these
substances is to control weight, they are also
called antiobesity agents. This term, however,
is too broad when only the suppression of the
desire for food is meant, for antiobesity drugs in-
clude not only anorexiants but also metabolism
and biosynthesis modifiers [1].
The control of weight or obesity by drug ther-
apy rather than dieting alone remains controver-
sial because of the potential health risks and the
limited efficacy of most of the available drugs.
However, because many people find dieting dif-
ficult and seek some supportive measure, the
use of drugs in a reducing program as an ad-
junct to diet modification and exercise is well
established. A report on obesity in the United
Kingdom [2] documents the adverse effects of
obesity when coupled with such medical prob-
lems as coronary heart disease, hypertension, di-
abetes, gall bladder disease, respiratory disease,
varicose veins, and certain forms of cancer.
2. Animal and Human Test
Procedures
The main techniques used to search for anorexi-
ants in animal models are the free feeding and
operant behavioral methods [3]. Both measure
the effectiveness of a compound at reducing food
consumption in animals made hungry by dietary
restrictions.

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10.1002/14356007.a02 313
. 1 5.2. β-Phenyl-tert-butylamines . . . . . . . 4
. 1 5.3. β-Phenyl-β-oxyisopropylamines . . . 4
. 1 5.4. 1-Methyl-2-phenylmorpholines . . . . 5
. 2 6. Other Compounds . . . . . . . . . . . . . 6
. 2 7. Economic Aspects . . . . . . . . . . . . . 7
. 3 8. References . . . . . . . . . . . . . . . . . . 7
In the free feeding procedure the food in-
take is measured over a period of time. The an-
imals then are given a drug and the effect on
food intake is determined. Agents that reduce
intake are potential anorexiants. Because this
technique cannot distinguish true anorectic ef-
fects from conflicting pharmacologic properties,
more refined models involving measurement of
operant behavior have been designed. Animals
are trained to respond to a food presentation by
lever pressing, runway performance, and various
shock schedules [4]. These methods have veri-
fied anorectic efficacy in a number of phenethyl-
amine derivatives but are less successful in defin-
ing unique compounds with confirmed activity
in humans [5].
Human testing of potential anorexiants in-
volves measuring weight loss after drug therapy
has been initiated. In addition the measurement
of the thickness of the underarm skin-fold and
subjective reports from the patient regarding de-
sire for food also are used frequently. Despite
many clinical references on anorectic agents, a
standard testing procedure has not yet been de-
signed [6].
3. Mechanism of Action
The regions of the brain that are involved in cen-
tral control of appetite are thought to be mainly
in the hypothalamus. Control of food intake is
considered to involve a feeding center and a sati-
ety center. Electrical stimulation of the ventro-
lateral hypothalamus causes feeding in sated an-
imals; whereas stimulation of the ventromedial
hypothalamus inhibits ongoing feeding [7], [8].
2 Anti-Obecity Drugs
At the molecular level a multiplicity of neu-
rotransmitters are involved in the control of
appetite. These substances can be classified
broadly as neuropeptides and monoamines, with
the latter class being investigated the most. The
satiety and feeding centers appear to be con-
trolled mainly by norepinephrine [51-41-2] and
serotonin [50-67-9].
Commercial anorectic agents all appear to
operate through a mechanism that involves
the control of reuptake or release of these
monoamines from the appropriate area of the
hypothalamus [8], [9].
4. Clinical Side Effects
The drugs used to control appetite are taken
orally one to three times daily, usually before
meals. Medical practice in the United States calls
for a maximum usage of twelve weeks; the ma-
jority of drugs appear to lose effectiveness af-
ter this time [10]. Because the neurotransmitters
that control appetite also are involved in other
biochemical pathways, drugs that affect them
give rise to a variety of side effects. These side ef-
fects can be grouped into four major categories:
– Central nervous system (CNS)
– Cardiovascular
– Gastrointestinal
– Abuse and/or dependence
All the anorectic drugs except fenfluramine
excite the central nervous system and give rise
to restlessness, insomnia, tremor, euphoria, and
headache. Cardiovascular problems include el-
evated blood pressure, palpitations, and rapid
heart action (tachycardia). Gastrointestinal ir-
ritation can cause nausea, vomiting, dry mouth,
unpleasant taste, diarrhea, and constipation.
Abuse and dependence of a physiologic or
psychological origin are a particular problem
with those compounds closely related to amphet-
amine. Symptoms of chronic abuse include pro-
longed insomnia, severe skin diseases, baldness,
and dramatic personality changes resulting in
schizophrenia-like behavior. Withdrawal by ad-
dicted patients is characterized by profound fa-
tigue and mental depression. The seriousness of
the abuse and dependency with these drugs has
led various United States regulatory agencies to
control them under the Bureau of Narcotics and
Dangerous Drugs (BNDD). To assist the physi-
cian the drugs have been classified under BNDD
Schedules I – IV, with Schedule IV substances
being the least prone to cause abuse and depen-
dency problems [11].
5. Phenethylamine Derivatives
The β-phenethylamine framework is found in all
but one of the clinically useful anorectic drugs.
This same unit is also found in the neurotrans-
mitter
norepinephrine (see Chap. 3). Modification of
the molecule by introducing one or two me-
thyl groups in the α position has led to the
β-phenylisopropylamines (Section 5.1) and β-
phenyl-tert-butylamines (Section 5.2). Addi-
tional modification at the β position with a
hydroxyl or ketone group gives the β-phenyl-
β-oxyisopropylamines (Section 5.3), and cy-
clization of the oxygen and nitrogen atoms by
a two-carbon bridge results in the 1-methyl-2-
phenylmorpholines (Section 5.4). The (+) iso-
mer of those compounds containing a chiral α
carbon atom is the more active anorectic agent.
Extensive studies have demonstrated that a Cl
or CF3 group in the ring or a group on the ni-
trogen atom that can be metabolized to the NH2
derivative gives rise to clinically useful drugs
[12].
The first phenethylamine derivative to be
used as an anorexiant was (±)-amphetamine
[13]. Subsequently, studies showed that the (+)
isomer, dextroamphetamine, has fewer side ef-
fects and it has become used more widely. Com-
binations of phenethylamines with sedatives and
tranquilizers have been prescribed in an attempt
to alleviate the undesirable stimulant effects.
Slow-release and resin-bound forms also have
been marketed to overcome the same problem.

5.1. β -Phenylisopropylamines
Drugs containing β-phenylisopropylamine or its
structural framework constitute the largest group
of anorexiants on the market.
The general procedure for preparing these
compounds involves reaction of a phenylacetone
with hydroxylamine followed by catalytic hy-
drogenation, or reaction of the ketone with form-
amide (Leuckart-Wallach reaction) and subse-
quent acid hydrolysis (Eq. 1).
The N-alkyl derivatives are made by reduc-
tive aminoalkylation of phenylacetone by cat-
alytic hydrogenation (Eq. 2). The optically ac-
tive forms can be obtained by resolution with an
optically active acid or by starting with (+)- or
(-)-ephedrine, conversion to a chloroamine, and
then catalytic hydrogenation (Eq. 3).
Amphetamine [300-62-9], benzedrine, (±)-
α-methlybenzeneethanamine, R1 = R2 = H,
C9 H13 N, M r 135.21, is a colorless liquid, bp
200 – 201 ◦ C; hydrochloride, mp 148 – 149 ◦ C.
Amphetamine is prepared by treating pheny-
lacetone with formic acid and ammonia under
the Leuckart-Wallach conditions (Eq. 1) [14].
Trade names: Benzedrine (SKF), Obetrol-10
and Obetrol-20 (combined with dextroamphet-
amine; Schein), Biphetamine (resin combined
with dextroamphetamine, Pennwalt), all United
States; Adiparthrol (Medial, Switzerland).
Recommended adult dosage is 10 – 30 mg/d;
BNDD Schedule II (United States).
Dextroamphetamine [51-64-9], (+)-α-me-
thylbenzeneethanamine, R1 = R2 = H, C9 H13 N,
Anti-Obecity Drugs 3
M r 135.21, is a colorless liquid, bp 80 ◦ C
(1.6 kPa), [α]15 ◦
D + 35.6 (neat); 0.5 sulfate, mp
> 300 ◦ C, [α]20
D + 21.8 to 24 ◦ (c = 5 g/100 mL
H2 O).
The compound can be prepared by optical
resolution of amphetamine (see above) or di-
rectly from (-)-norephedrine by conversion to
the (+)-chloroamine followed by catalytic hy-
drogenation (Eq. 3) [14].
Trade names: Dexedrine (SKF, United
States, Federal Republic of Germany, Switzer-
land), Obetrol-10 and Obetrol-20 (combined
with amphetamine; Schein, United States).
Recommended adult dosage is 10 – 30 mg/d;
BNDD Schedule II (United States). Dextroam-
phetamine also is approved for use in narcolepsy
and for control of hyperkinetic children [15].
Methamphetamine [537-46-2], desoxy-
ephedrine, S-( + )-N, α-dimethlybenzeneethan-
amine, R1 = H, R2 = CH3 , C10 H15 N, M r 149.24;
hydrochloride, mp 171 – 175 ◦ C, [α]20
D + 16.0 to
19.2 ◦ (c = 5 g/100 mL H2 O) is prepared from
phenylacetone and methlyamine (Eq. 2) or from
(-)-ephedrine (Eq. 3) [16].
Trade names: Desoxyn (Abbott), Obedrin
(Beecham-Massengill), both United States;
Pervitin (Temmler-Werke, Federal Republic of
Germany).
Recommended adult dosage is 7.5 – 15 mg/d;
BNDD Schedule II (United States).
Benzphetamine [156-08-1], (+)-N,α-di-
methyl-N-(phenylmethyl)benzeneethanamine,
R1 = CH3 , R2 = C6 H5 CH2 , C17 H21 N, has
M r 239.35, bp 127 ◦ C (3.5 Pa); hydro-
chloride, mp 129 – 130 ◦ C, [α]20 ◦
D + 22 to 26
(c = 5 mg/100 mL H2 O).
Benzphetamine can be prepared by treating
methamphetamine (see above) with a benzyl-
halide in the presence of a base [17].
Trade names: Didrex (Upjohn, United
States, United Kingdom), Inapetyl (Upjohn,
France).
Recommended adult dosage is
25 – 150 mg/d; BNDD Schedule III (United
States).
Fenfluramine [458-24-2], N-ethyl-α-me-
thyl-3-(trifluoromethyl)benzeneethanamine,
R1 = H, R2 = C2 H5 , 3-CF3 , C12 H16 F3 N, has
4 Anti-Obecity Drugs
M r 231.27, bp 108 ◦ C (1.7 kPa); hydrochloride,
mp 166 ◦ C.
Fenfluramine is prepared by reductive alkyl-
ation of norfenfluramine with acetaldehyde [18].
The nor compound is obtained by catalytic
hydrogenation of the oxime made from 3-tri-
fluoromethlyphenyl acetone (Eq. 2).
Trade names: Pondomin (Robbins, United
States), Ponderal (Servier, France), Ponderax
(Boehringer Ingelheim, Federal Republic of
Germany).
Recommended adult dosage is 60 mg/d;
BNDD Schedule IV (United States).
Fenfluramine is the only marketed anorectic
agent that exerts its appetite depressant effect
via a serotoninrgic mechanism (see Chap. 3). Its
major metabolite, norfenfluramine, is believed
to be the main active form in humans [19].
Propylhexedrine [101-40-6], cy-
clexedrine, N,αdimethlycyclohexaneethan-
amine, C10 H21 N, has M r 155.28, bp 92 – 93 ◦ C
(2.7 kPa); (-)-hydrochloride, mp 138 – 140 ◦ C,
[α]20
D −14.2
◦
(H2 O); (±)-hydrochloride, mp
127 – 128 ◦ C.
Propylhexedrine is prepared by catalytic hy-
drogenation of (±)- or (-)-ephedrine in a strong
mineral acid [20].
Trade names: Eventin [(-) isomer, Chemi-
sche Werke Minden]; Eggobasin, [(±) isomer,
Fahlberg-List]; both Federal Republic of Ger-
many.
The compound is marketed in the United
States as an inhalant for nasal congestion and
not as an anorectic agent.
5.2. β -Phenyl-tert-butylamines
The β-phenyl-tert-butylamines appear to of-
fer no advantages over the β-phenylisopro-
pylamines (Section 5.1). These tert-butylamines
are known to induce pulmonary hypertension
and their use in medical practice is declining.
Phentermine [122-09-8], α,α-dimethly-
benzeneethanamine, C10 H15 N, M r 149.23, is
a colorless liquid, bp 100 ◦ C (0.36 kPa); hydro-
chloride, mp 198 ◦ C.
Phentermine is prepared by converting the
condensation product of benzaldehyde and
nitropropane to the corresponding aminoalcohol
followed by transformation to the chloroamine
and then catalytic hydrogenation (as in Eq. 3)
[21].
Trade names: Ionamin (resin; Pennwalt),
Fastin (Beecham), Adipex (Lemmon), Oby-
Trim (Obetrol), Teramine (Legere), Phenter-
mine (Schein, Rugby), all United States.
Recommended adult dosage is 20 – 40 mg/d;
BNDD Schedule IV (United States).
Phentermine has not been marketed in the
Federal Republic of Germany since 1968 be-
cause of suspected pulmonary hypertension.
Phenpentermine [434-43-5], pentorex, α,
α,β-trimethlybenzeneethanamine, C11 H17 N,
has M r 161.35; hydrochloride, mp 164 – 166 ◦ C;
hydrogen tartrate [22876-60-4], mp
160 – 162 ◦ C, [α]20D + 13.4 ◦
(c = 0.8 g/100 mL
H2 O).
Phenpentermine is prepared by N-
formylating the alcohol obtained from 3-phenyl-
2-butanone and methlymagnesium bromide; the
intermediate is hydrolyzed in acid [22].
Trade name: Modatrop (Nordmark Werke,
Federal Republic of Germany).
5.3. β -Phenyl-β -oxyisopropylamines
These drugs are the safest and most widely used
anorexiants on the market.

Ephedrine [299-42-3], (-) isomer, [R-(R∗,
S∗)]-α-[1-(methlyamino)ethyl]benzenemetha-
nol, A = HCOH, R1 = H, R2 = CH3 , C10 H15 NO,
has M r 165.23, mp 33 – 39 ◦ C; hydrochloride
[50-98-6], mp 217 – 220 ◦ C, [α]20
D −34.0 to
−35.0 ◦ (c = 5 g/100 mL H2 O).
(-)-Ephedrine is obtained by the catalytic
hydrogenation of (-)-1-phenyl-2-methlyami-
nopropan-1-one. The latter substance is pre-
pared by the optical resolution of the (±)-
ketoamine [23].
Trade name: Alfabet (Zeppenfeldt, Federal
Republic of Germany).
Norephedrine [14838-15-4], phenyl-
propanolamine (PPA), (R∗,S∗)-( ± )-α-(1-
aminoethyl)benzenemethanol, A = HCOH,
R1 = R2 = H, C9 H13 NO, has M r 151.18; hydro-
chloride [154-41-6], mp 190 – 194 ◦ C.
Phenylpropanolamine is prepared by con-
verting propiophenone to the α-oximino deriva-
tive with an alkyl nitrite, followed by catalytic
hydrogenation, using a Pd or Pt catalyst [24].
Phenylpropanolamine is the only FDA ap-
proved (1978) appetite suppressant that is sold
without a prescription on the United States mar-
ket. In 1983, there were 35 brands of PPA avail-
able as a single drug entity (100 – 150 mg) or
mixed with the central nervous system stimulant
caffeine (50 – 200 mg), with the local anesthetic
benzocaine, or with such bulk products as me-
thyl or carboxymethlycellulose. Because PPA
is so widely available, it has been abused, ne-
cessitating tighter controls on availability [25].
Anti-Obecity Drugs 5
Phenylpropanolamine also has been used med-
ically since the 1950s, primarily as a nasal de-
congestant and ingredient in cold remedies.
Norpseudoephedrine [492-39-7],
[36393-56-3], cathine, (+) isomer, [R-
(R∗,R∗)]-α-(1-aminoethyl)benzenemethanol,
A = HCOH, R1 = R2 = H, C9 H13 NO, has
M r 151.18, mp 77 – 79 ◦ C; hydrochloride
mp 180 – 182 ◦ C, [α]20 + 42.5 to 44.0 ◦
D
(c = 5 mg/100 mL H2 O).
(+)-Norpseudoephedrine can be obtained by
resolving the (±) form with d-mandelic acid or
by isomerization of (-)-norephedrine [26].
Trade names: Adiposetten (Reiss), Boxoget-
ten (Boxberger), both Federal Republic of Ger-
many; Minusin (Doetsch-Grether, Switzerland).
Diethylpropion [90-84-6], amfepranon, α-
(diethylamino)-phenyl-1-propanone, A = CO,
R1 = R2 = C2 H5 , C13 H19 NO, has M r 205.30, bp
140 ◦ C (0.1 kPa); hydrochloride [134-80-5], mp
172 – 176 ◦ C.
Diethylpropion is prepared by α-bromination
of propiophenone followed by reaction with di-
ethylamine [27].
Diethylpropion is the anorectic prescription
drug of choice in the United States. It possesses
central nervous system stimulant effects that are
considerably weaker than those of amphetamine
and its close analogs. Drug abuse and depen-
dence is also low with diethylpropion.
Trade names: Tenuate (Merrell Dow, United
States, Federal Republic of Germany, United
Kingdom), Regenon (Temmler Werke, Fed-
eral Republic of Germany), diethylpropion HCl
(Schein, Rugby, United States), Tepanil (Riker,
United States).
Recommended adult dosage is 75 mg/d;
BNDD Schedule IV (United States).
5.4. 1-Methyl-2-phenylmorpholines
The clinical side effects and efficacy of the 1-me-
thyl-2-phenylmorpholines are similar to those of
the amphetamines, and the probability of drug
abuse is quite high.
All of these anorectics exist as threo isomers.
6 Anti-Obecity Drugs
Phenmetrazine [134-49-6], trans-3-me-
thyl-2-phenylmorpholine, R = H, C11 H15 NO,
has M r 177.50, bp 138 – 140 ◦ C (0.04 kPa);
hydrochloride [1707-14-8], mp182 ◦ C.
Phenmetrazine is prepared by reacting
α-bromopropiophenone with N-benzyletha-
nolamine, catalytic reduction of the intermedi-
ate ketone to N-hydroxyethyl norephedrine or
norpseudoephedrine, and then cyclization with
concentrated sulfuric acid [28].
Trade names: Preludin (Boehringer-
Ingelheim, United States), Cafilon [in combi-
nation with 8-chlorotheophyllinate and phen-
butrazate (see below), Ravensberg, Federal Re-
public of Germany].
Recommended adult dosage is 50 – 75 mg/d;
BNDD Schedule II (United States).
Phendimetrazine [634-03-7], L-(+)−3R-
trans-3,4-dimethyl-2-phenylmorpholine,
R = CH3 , C12 H17 NO, has M r 191.26, bp
134 – 135 ◦ C (0.21 kPa); hydrochloride, mp
208 ◦ C, [α]20 ◦
D + 35.7 (H2 O); hydrogen tartrate
[50-58-8].
The compound can be prepared by the same
procedure used to prepare phenmetrazineexcept
that N-methlyethanolamine is reacted with α-
bromopropiophenone [29].
Trade names: Plegine (Ayerst), Prelu-2
(Boehringer-Ingelheim), Bontril (Carnrick),
Melfiat (Reid-Provident), all United States.
Recommended adult dosage is 30 mg/d;
BNDD Schedule III (United States).
Phenbutrazate [4378-36-3], α-ethyl-2-
(3-methyl-2-phenyl-4-morpholinyl)ethyl es-
ter benzeneacetic acid, R = CH2 CH2 OCOCH-
(C2 H5 )C6 H5 , C23 H29 NO3 , has M r 367.47;
hydrochloride [6474-85-7], mp 154 ◦ C.
Phenbutrazate is prepared by condensing N-
hydroxyethylphenmetrazine (R = CH2 CH2 OH)
with 2-phenylbutyric acid. The N-hydroxyethyl
compound is obtained in the same manner as
phendimetrazine [30].
Trade name: Cafilon [in combination with
8-chlorotheophyllinate and phenmetrazine (see
above), Ravensberg, Federal Republic of Ger-
many].
6. Other Compounds
A variety of compounds that do not possess the
phenethylamine framework has been studied as
anorectic agents; to date, however, only mazin-
dol has reached the marketplace [12].
Mazindol [22232-71-9], 5-(4-chlo-
rophenyl)-2,5-dihydro-3H-imidazo[2,1-
a]isoindol-5-ol, C16 H13 ClN2 O, has M r 284.74,
mp 198 – 199 ◦ C.
Mazindol is prepared by treating the dilithio
reagent, obtained from 2-phenylimidazoline,
with methyl 4-chlorobenzoate [31].
Although mazindol is unrelated structurally
to the phenethylamine anorectic agents, it pos-
sesses a similar medical profile in humans. The
most common side effects observed are dry
mouth, tachycardia, constipation, nervousness,
and insomnia. The mechanism responsible for
the anorectic effects of mazindol differs from
that for amphetamine and probably involves ef-
fects on both norepinephrine and serotonin [32].
Trade names: Sanorex (Sandoz), Mazanor
(Wyeth), both United States; Teronac (Wander,
Federal Republic of Germany).
Recommended adult dosage is 2 – 3 mg/d;
BNDD Schedule IV (United States).
 Anti-Obecity Drugs 7
Table 1. Sales of prescription anorexiants on the United States market between October 1983 and October 1984

Anorexiant (BNDD schedule) Trade name(s) Sales, % of

$ × 103 Market

Phentermine (IV) Ionamin, Fastin, Adipex-P, generic 27868 36.7

Diethylpropion (IV) Tenuate, Tepanil, generic 17970 23.7
Benzphetamine (III) Didrex 7282 9.6
Phendimetrazine (III) Prelu-2, Melfiat, Plegine, Bontril, generic 4899 6.5
Phenmetrazine (III) Preludin 3977 5.3
Methamphetamine (II) Desoxyn 3681 4.9
Mazindol (IV) Sanorex, Mazanor 2928 3.9
Dextroamphetamine and amphetamine (II) Biphetamine 2919 3.9
Dextroamphetamine (II) Dexedrine 2858 3.9
Fenfluramine (IV) Pondimin 393 0.4

7. Economic Aspects 9. S. Garattini, R. Samanin (eds.): Central

The total sales of prescription anorexiants in the
United States between October 1983 and Octo-
ber 1984 were $ 76 188 000. Products contain-
ing anorexiants classified as BNDD Schedule III
or IV accounted for 82.3 % of the sales, while
the more restricted drugs of Schedule II totaled
17.7 %. Table 1 gives United States sales figures
for individual prescription anorexiants [33].
8. References
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Rep. Med. Chem. 15 (1980) 1972.
2. “Obesity: A Report of the Royal College of
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(1983) 6 – 65.
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Evaluating Anorexigenic Agents,” in J. H.
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5. R. P. Maickel, J. E. Zabik, Life Sci. 21 (1977)
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8. J. A. Morley, A. S. Levine, Lancet 1983, 398.
Mechanisms of Anorectic Drugs, Raven Press,
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10. A. C. Sullivan, K. Comai, Int. J. Obes. 2
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Stimulants: Chemical, Biological and
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Fla., 1980.
12. W. J. Houlihan, R. G. Babington:
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Medicinal Chemistry, Part 3, J. Wiley & Sons,
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14. W. B. Hartung, J. C. Munch, J. Am. Chem. Soc.
53 (1931) 1875.
15. Physicians Desk Reference, 37th ed., Medical
Economics Co., Litton Industries, Oradell, N.
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17. Upjohn Co., US 2789138, 1957 (R. V.
Heinzelman, B. D. Aspergren).
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T. M. Speight, G. S. Avery, Drugs 10 (1975)
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Bruce, J. Seifter).
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26. C. I. Jarowski, W. H. Hartung, J. Org. Chem. 8
(1943) 564.
8 Anti-Obecity Drugs
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