Method of suppressing appetite by administration of tetrahydro-beta-carboline derivatives

DESCRIPTION 
1. Technical Field 
This invention relates to pharmacologic control of appetite More 
specifically, this invention relates to methods for suppressing feeding 
behavior and modifying macronutrient preference, and compounds useful 
therefore. 
2. Background of the Invention 
The high prevalence of obesity in the United States attests to the general 
failure of existing medical treatments to adequately manage the problem. 
The limited efficacy of existing anorectic agents when measured against 
possible risk factors inherent in their use currently precludes them as 
treatments of choice for the management of obesity However, there is a 
growing awareness among both patients and the medical community that 
obesity is a disease that requires aggressive medical intervention. Thus, 
new anti-obesity agents with significantly improved performance 
characteristics are likely to be well-received in the future. 
Although the nosology of obesity and related eating disorders is not 
currently well defined, with its development and broadening acceptance 
grows the need to design safe and effective pharmacotherapies. The most 
commonly used weight control agents available without prescription are 
generally adrenergic stimulants such as phenylpropanolamine and 
phenethylamine derivatives. Although effective appetite inhibitors, 
adrenergic agents produce numerous untoward side effects, such as 
nervousness, irritability, insomnia, dizziness, tachycardia, palpitations, 
hypertension, and the like. These side effects may be severe enough to 
require cessation of treatment. Kopf, DE 3,430,389, disclosed 
weight-reduction by administering a combination of an adrenergic agent 
with a benzodiazepine sedative. The actual safety of such adrenergic 
agents is questionable, particularly in view of the 20-30% of the U.S. 
population suffering from hypertension. Although the non-stimulant 
anorectic agent fenfluramine is devoid of the psychomotor stimulant 
properties and abuse potential seen with stimulant-like compounds (e.g., 
amphetamine), it often has an inadequate clinical efficacy, and patients 
receiving the drug often complain of drowsiness and headache. Thus, it is 
apparent that none of the current anti-obesity pharmacotherapies available 
are particularly satisfactory. 
The present invention relates to a novel use for certain derivatives of 
1,2,3,4-tetrahydro-beta-carboline 
(1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole). The compound possesses the 
following structural formula: 
##STR2## 
Tetrahydro-beta-carboline (THBC) has a variety of pharmacological actions 
and has been variously evaluated as a cholinesterase inhibitor, 
sedative/hypnotic, analgesic, and psychotomimetic. It competes with low 
affinity for brain tryptamine, imipramine, 5-hydroxytryptamine (5-HT), and 
spiperone binding sites, enhances depolarization-induced 5-HT efflux from 
brain slices, and weakly inhibits 5-HT uptake in brain synaptosomes and 
5-HT oxidative deamination. It occurs naturally in mammalian brain tissue 
When THBC is administered parenterally to laboratory animals, it 
suppresses locomotion, exploratory activity, and conflict behavior, 
impairs performance on operantly conditioned learning and memory tasks, 
reduces seizure susceptibility, prolongs barbiturate sedation, and 
antagonizes specific drug-induced stereotypies. When given in high doses, 
THBC induces a characteristic behavioral syndrome characterized by 
hyperactivity, forepaw treading, body weaving, and circling (Airaksinen et 
al, Med Biol (1981) 59:190-211). Paradoxically, THBC has been reported to 
reduce motor activity, induce apparent anxiety, and increase voluntary 
ethanol consumption when administered intraventricularly to rats (P. 
Huttunen et al, Pharmacol Biochem & Behav (1986) 24:1733-38). Atkinson, GB 
1,183,219 disclosed its use as an analgesic. 
Physiological actions of THBC include effects on endocrine secretory 
patterns and body temperature. Systemic administration in rodents produces 
a dose-dependent elevation of plasma prolactin levels, decreased serum 
luteinizing hormone levels, and elevated plasma corticosterone. THBC 
elicits significant hypothermia when administered to rats parenterally in 
doses of 6.25 mg/Kg or greater (H. Rommelspacher et al, 
Naunyn-Schmiedeberg's Arch Pharmacol (1977) 298:83-91). 
It is also known that daily oral administration of THBC produces temporary 
dose-related decrements in food and fluid intake in rats Animals that 
receive average daily amounts of THBC in excess of 49 mg/Kg show 
significant reductions in food intake after two consecutive days of 
treatment; tolerance develops, and food consumption returns to normal by 
the twelfth treatment day. Smaller daily doses (less than 30 mg/Kg) do not 
significantly alter appetite (Rommelspacher; 
Airaksinen et al, Med Biol (1981) 59:190-211). It is noteworthy that in 
Rommelspacher,s report, 6 out of the 24 animals receiving 49 mg/Kg/day or 
greater died. 
Payne et al, U.S. Pat. No. 4,336,260 disclosed the use of 
1-aryl-3-carboxylic acid THBC derivatives as antidepressants. 
S. Cooper, Eur J Pharmacol (1986) 120:257-65 disclosed that three 
fully-unsaturated beta-carboline derivatives exhibit hyperphagic activity, 
while another beta-carboline derivative exhibits anorectic activity. The 
hyperphagic derivatives were ethyl 
6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate, ethyl 
5-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate, and ethyl 
5-isopropoxy-4-methyl-beta-carboline-3-carboxylate. The anorectic 
derivative was betacarboline-3-carboxylic acid methyl amide (FG 7142). 
When injected intraperitoneally at 10.0 mg/Kg, FG 7142 reduced food 
consumption by partially sated rats to 30% of control. 
P. Skolnick et al, in "Beta-Carbolines and Tetrahydroisoquinolines" (Alan 
R. Liss, 1982, N.Y.) pp. 233-52 disclosed that certain carboxy-ester 
beta-carboline derivatives bind with high affinity to benzodiazepine 
receptors. This binding may account for the ability of these compounds to 
antagonize the anticonvulsant, anxiolytic, and sedative properties of 
benzodiazepine drugs. However, saturated derivatives such as 
3-carbomethoxy-1,2,3,4-tetrahydro-beta-carboline bind with very low 
affinity (Skolnick, supra; H. A. Robertson et al, Eur J Pharmacol (1981) 
76:281-84). 
DISCLOSURE OF THE INVENTION 
We have now found that certain derivatives of THBC when administered to 
warm-blooded animals partially or fully suppress feeding behavior. The 
compounds of the invention are effective at doses lower than those 
required by other THBC analogs, and exhibit fewer and less severe side 
effects. These compounds are also useful for altering macronutrient 
preferences (e.g., by reducing appetite for carbohydrates), and for 
treatment of substance abuse. Compounds of the invention exhibit very low 
affinity for 5-HT receptors, 5-HT uptake sites, and benzodiazepine 
receptors. Thus, we currently believe that the compounds of the invention 
act by a mechanism different from that of related unsaturated compounds. 
One aspect of the invention is the method of suppressing feeding behavior 
in a mammal by administering an effective amount of a compound of formula 
I: 
##STR3## 
where R.sub.1 and R.sub.3 are each independently H, hydroxy-alkyl, 
alpha-cyanoalkyl, SO.sub.3 H, SO.sub.2 NH.sub.2, or C(O)R, where R is OH, 
NH.sub.2, lower alkoxy, benzyloxy, or aliphatic amino acyl; R.sub.2 and 
R.sub.9 are each independently H, lower alkyl, benzyl, succinyl, or 
C(O)R.sub.4, where R.sub.4 is H, lower alkyl, hydrocarboxy-lower alkylene, 
or lower alkoxycarboxy-lower alkylene; and R.sub.5, R.sub.6, R.sub.7, and 
R.sub.8 are each independently H, halo, lower alkyl, hydroxy, lower 
alkoxy, or two adjacent radicals form methylenedioxy or ethylenedioxy; 
with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, 
R.sub.7, R.sub.8, and R.sub.9 are not simultaneously H. 
Presently preferred compounds are those wherein either R.sub.1 or R.sub.3 
is C(O)R and R is OH, alkoxy or benzyloxy, particularly where R is 
benzyloxy. Another presently preferred compound is that wherein R.sub.2 is 
C(O)R.sub.4 and R.sub.4 is methyl, and R.sub.1 and R.sub.3 are each H. 
Another aspect of the invention is a composition useful for suppression of 
feeding behavior in a mammal, which comprises a pharmaceutically 
acceptable excipient in combination with an effective amount of a compound 
of formula I. 
Another aspect of the invention is a method for partially suppressing 
appetite in a mammal, by administering a compound of formula I in which 
R.sub.5-9 are all H to a mammal in need thereof Another aspect of the 
invention is a composition for partially suppressing appetite in a mammal. 
Another aspect of the invention is a method and composition for altering 
macronutrient preference in a mammal by administering a compound of 
formula I. 
Another aspect of the invention is a method and composition for suppressing 
substance cravings in a mammal by administering a compound of formula I. 
Another aspect of the invention is a method and composition for suppressing 
obsessive-compulsive behavior in a mammal by administering a compound of 
formula I.

MODES OF CARRYING OUT THE INVENTION 
A. Definitions 
The phrase "compound of formula I" as used herein refers to compounds 
having the following structural formula, and their pharmaceutically 
acceptable salts: 
##STR4## 
where R.sub.1 and R.sub.3 are each independently H, hydroxy-alkyl, 
alpha-cyanoalkyl, SO.sub.3 H, SO.sub.3 NH.sub.2, or C(O)R, where R is OH, 
NH.sub.2, lower alkoxy, benzyloxy, or aliphatic amino acyl; R.sub.2 and 
R.sub.9 are each independently H, lower alkyl, benzyl, succinyl, or 
C(O)R.sub.4, where R.sub.4 is H, lower alkyl, hydrocarboxy-lower alkylene, 
or lower alkoxycarboxy.-lower alkylene; and R.sub.5, R.sub.6, R.sub.7, and 
R.sub.8 are each independently H, halo, lower alkyl, hydroxy, lower 
alkoxy, or two adjacent radicals form methylenedioxy or ethylenedioxy; 
with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6, 
R.sub.7, R.sub.8, and R.sub.9 are not simultaneously H. 
The term "lower alkyl" as used herein refers to saturated monovalent 
hydrocarbon radicals having from 1 to 6 carbon atoms, for example, methyl, 
ethyl, propyl, isopropyl, butyl, hexyl, and the like. 
The term "lower alkoxy" refers to radicals of the form -OR, where R is 
lower alkyl as defined above. Suitable lower alkoxy radicals include 
methoxy, ethoxy, propoxy, and the like. 
The term "hydroxy-alkyl" refers to a lower alkyl group wherein one hydrogen 
atom is replaced with a hydroxy radical, for example, hydroxymethyl, 
2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-methyl-2-hydroxypropyl, 
and the like. 
The term "alpha-cyanoalkyl" refers to a radical of the form -CH(CN)R, where 
R is lower alkyl as defined above. Exemplary alpha-cyanoalkyl radicals 
include without limitation cyanomethyl, 1-cyanoethyl, 1-cyanopropyl, 
1-cyano-3-methylbutyl, 1-cyanohexyl, and the like. 
The term "halo" means fluoro, chloro, bromo, or iodo. 
The terms "methylenedioxy" and "ethylenedioxy" refer to divalent radicals 
of the formula --O--CH--O-- and --O--CH.sub.2 CH.sub.2 O--, respectively. 
When two adjacent radicals are methylenedioxy or ethylenedioxy, a five or 
six-membered ring is formed. "Two adjacent radicals" means R.sub.5 and 
R.sub.6, R.sub.6 and R.sub.7, or R.sub.7 and R.sub.8. 
The term "aliphatic amino acyl" refers to radicals derived from 
commonly-available amino acids which are fully saturated. Specifically, 
aliphatic amino acyl refers to glycyl, alanyl, leucyl, isoleucyl, valyl, 
and norleucyl. 
The term "hydrocarboxy-lower alkylene" refers to radicals of the form 
--(CH.sub.2).sub.n COOH, where n is an integer from 0 to 6. Thus, where 
R.sub.2 is C(O)R.sub.4 and R.sub.4 is hydrocarboxy-lower alkylene, 
suitable radicals will include oxalyl, malonyl, succinyl, glutaryl, and 
adipoyl. 
The term "alkoxycarboxy-lower alkylene" refers to radicals of the form 
--(CH.sub.2).sub.n COOR, where n is an integer from 0 to 6 and R is lower 
alkyl as defined above. Thus, where R.sub.2 is C(O)R.sub.4 and R.sub.4 is 
alkoxycarboxy-lower alkylene, suitable radicals will include methyloxalyl, 
methylmalonyl, ethylmalonyl, propylsuccinyl, and the like. 
The term "feeding behavior" as used herein refers to food intake and 
associated behavior. "Partial suppression" of feeding behavior refers to 
reduction of feeding behavior to a level between about 20% and about 70% 
of control behavior. 
The term "effective amount" refers to the amount of a selected compound of 
formula I which is necessary to cause suppression of feeding behavior. The 
precise amount required will vary depending upon the particular compound 
selected, the age and weight of the subject, route of administration, and 
so forth, but may easily be determined by routine experimentation. 
Suitable experiments are described in the Examples. In general, however, 
an effective amount will range from about 1 mg/Kg to about 100 mg/Kg, 
preferably about 2 mg/Kg to about 30 mg/Kg, more preferably about 4-12 
mg/Kg. Partial suppression of feeding behavior is effected by 
administration of similar amounts of the appropriate compounds of formula 
I (generally compounds of formula I in which R.sub.5-9 are all H). 
The term "appetite-altering amount" refers to the dosage of compound 
required to alter the appetite for carbohydrates experienced by the 
subject animal, i.e., to alter the subjects macronutrient preferences. The 
term "appetite-altering amount" also applies to the quantity required to 
effect a change in chemical dependency; in other words, a therapeutic 
amount in the treatment of e.g., alcohol, tobacco, narcotic or opiate 
addiction. The precise appetite-altering amount required will vary with 
the particular compounds employed, the species, age and condition of the 
subject to be treated. However, the amount may be determined by one of 
ordinary skill in the art with only routine experimentation, following 
methods known in the art, and disclosed below. In general, an 
appetite-altering amount will be roughly one half to one tenth the 
effective amount described above. Thus, the appetite-altering amount will 
range from about 0.01 to about 10 mg/Kg body weight, preferably about 
0.5-5 mg/Kg, and most preferably about 1 mg/Kg. 
The term "drugs of abuse" refers to those compounds other than alcohol and 
tobacco which present the potential for addiction and chemical dependency, 
such as opiates (e.g., heroin, morphine, etc.), alkaloids (e.g., cocaine), 
marijuana, peyote, and the like. 
The term "obsessive-compulsive behavior" refers to actions and/or thoughts 
which a mammal experiences on a frequent or repetitive basis with little 
or no volitional control. "Habits" are a very mild, subclinical form of 
such behavior, but are generally not considered obsessive-compulsive 
behavior until they become socially debilitating. Subjects exhibiting 
obsessive-compulsive behaviors are generally aware of their behavior and 
its abnormality, but are unable to consciously modify their behavior. 
Examples of obsessive-compulsive behavior include compulsive hand-washing, 
washing, obsessive counting, continual hand-wringing, and the like. A 
"behavior modifying amount" refers to the amount of a compound of formula 
I which is necessary to assist a subject in regaining volitional control, 
so that an obsessive-compulsive behavior may be consciously suppressed. 
The behavior modifying amount will generally be similar to the amount 
needed for appetite suppression. 
The term "pharmaceutically acceptable" refers to a compound, salt, or 
excipient which is not unacceptably toxic to the subject to which it is 
administered. Pharmaceutically acceptable salts include inorganic anions 
such as chloride, bromide, iodide, sulfate, sulfite, nitrate, nitrite, 
phosphate, and the like, and organic anions such as acetate, malonate, 
pyruvate, propionate, cinnamate, tosylate, and the like. Pharmaceutically 
acceptable excipients are described at length by E. W. Martin, in 
"Remington's Pharmaceutical Sciences" (Mack Pub. Co.). 
B. General Method 
Compounds of the invention may be prepared by a variety of methods known to 
those of ordinary skill in the art (M. Cain et al, J Med Chem (1982) 
25:1081-91). Three exemplary methods are presented below as Schemes I-III. 
In Scheme I, a substituted tryptamine is cyclized by reaction with an 
appropriate aldehyde under acid catalysis to form a 
tetrahydro-beta-carboline derivative of formula I (where R.sub.2 is H). 
This product may be N.sup.2 -acylated in pyridine, with or without a 
co-solvent, to provide compounds of formula I wherein R.sub.2 is other 
than hydrogen. 
In Scheme II, tryptamine or a substituted tryptamine is cyclized by 
reaction with an appropriate ketoacid under acid catalysis to form a 
tricyclic carboxy product. This product may then be decarboxylated under 
acid catalysis to provide a tetrahydro-beta-carboline derivative of 
formula I (where R.sub.2 is H). This product may be N.sup.2 -acylated in 
pyridine, with or without a co-solvent, to provide compounds of formula I 
wherein R.sub.2 is other than hydrogen. 
In Scheme III, the N.sup.2 -acylated product of Scheme I or II above is 
alkylated at the N.sup.9 position in the presence of sodium hydride in 
dimethyl formamide to provide compounds of formula I in which R.sub.9 is 
other than hydrogen. These N.sup.2 -acyl-N.sup.9 -alkyl derivatives may be 
deacylated by refluxing with alkali to provide compounds of formula I in 
which R.sub.9 is other than H and R.sub.2 is H. 
##STR5## 
Pharmaceutical compositions containing compounds of formula I, preferably 
as acid addition salts, may contain one or more pharmaceutical carriers. 
When the carrier serves as a diluent, it may be solid, semisolid, or 
liquid material acting as a vehicle, excipient, or medium for the active 
ingredient. Pharmaceutical unit dosage forms may be prepared for 
administration by any of several routes including, but not limited to, 
oral and parenteral (especially by intramuscular and intravenous 
injection, or by subcutaneous implant or transdermal administration). 
Representative of such forms are tablets, soft and hard gelatin capsules, 
powders, lozenges, chewing gums, emulsions, suspensions, syrups, 
solutions, sterile injectable solutions, and sterile packaged powders. 
Compositions containing compounds of formula I may be formulated by 
procedures known in the art so as to provide rapid, sustained, or delayed 
release of any or all of the compounds after administration. 
Solid pharmaceutical excipients such as magnesium stearate, calcium 
carbonate, silica, starch, sugar, talc, and the like may be used with 
other conventional pharmaceutical adjuvants including fillers, lubricants, 
wetting agents, preserving agents, disintegrating agents, flavoring 
agents, and binders such as gelatin, gum arabic, cellulose, 
methylcellulose, and the like, to form admixtures which may be used as 
such or may be tabulated, encapsulated, or prepared in other suitable 
forms as noted above. The preferred liquid diluent is physiologically 
normal saline. A general description of formulation is given in 
"Remington's Pharmaceutical Sciences" (Mack Pub. Co.). 
Compounds of formula I produce significant, long-lasting reduction in 
feeding behavior when administered to mammals within 8 hours prior to meal 
presentation. Administration is preferably by oral dosage, but may be by 
transdermal application, intranasal spray, bronchial inhalation, 
suppository, parenteral injection (e.g., intramuscular or intravenous 
injection), and the like. At other doses, compounds of formula I are 
useful for suppressing obsessive-compulsive behavior, for altering 
macronutrient preferences, and for reducing craving of substances, 
particularly substances of abuse such as alcohol, tobacco, opiates and 
other narcotics. 
Compounds of formula I wherein R.sub.5-9 are all H are particularly useful 
for partial appetite suppression. These compounds provide partial 
suppression (where food intake is 20-70% of control) over a wide dose 
range, in contrast to full anorectic agents which provide large 
suppression (.ltoreq.80%) at effective dosages, and provide partial 
suppression over a very narrow range. As it is impractical to titrate the 
dosage of a full anorectic agent for each patient to achieve a particular 
partial appetite suppression, the method of the invention for partial 
appetite suppression is distinct and advantageous. 
C. Examples 
The examples presented below are provided as a further guide to the 
practitioner of ordinary skill in the art, and are not to be construed as 
limiting the invention in any way. 
EXAMPLE 1 
(Preparation of Compounds) 
(A) L-1-Carboxy-1,2,3,4-tetrahydro-beta-carboline hydrochloride was 
prepared as follows: 
L-Tryptophan benzyl ester hydrochloride (3.308 g, 10 mmol, obtained from 
Bachem) was suspended in 0.05 N H.sub.2 SO.sub.4 (18.8 mL) with stirring, 
and 37% formaldehyde (0.938 mL) was added. The reaction mixture cleared, 
followed by crystallization of the product. Stirring was continued for 24 
hours, and the product filtered off, and dried over P.sub.2 O.sub.5 One 
gram of crude material was crystallized from ethanol:water, by dissolving 
in 20 mL EtOH with gentle warming, adding 30 mL water, and evaporating the 
mixture to 2/3 volume. The precipitated material was filtered off and 
discarded. The mother liquor was further evaporated to 1/4 volume, and was 
refrigerated overnight. The product crystals were filtered and dried over 
P.sub.2 O.sub.5. 
Calculated for C.sub.19 H.sub.18 O.sub.2 N.sub.2 (%): C-66.57; H-5.59; 
N-8.08; 0-9.33; Cl-10.34. Found: C-66.45; H-5.45; N-8.08; 0-9.67; 
Cl-10.18. 
(B) D,L-1-Carboxy-1,2,3,4-tetrahydro-beta-carboline was prepared as 
follows: 
A solution of 110 mmol glyoxylic acid monohydrate (10.1 g, obtained from 
Sigma) in 23 mL water was added to 100 mmol tryptamine HCl (19.7 g, 
obtained from Sigma) in 310 mL water. The stirred mixture was brought to 
pH 4 with 10 N NaOH and maintained at ambient temperature for 1 hr. The 
precipitated solid was filtered, washed with 100 mL water, and 
recrystallized from EtOH/H.sub.2 O to provide 
D,L-1-carboxy-1,2,3,4-tetrahydro-beta-carboline (R.sub.1 =COOH; R.sub.2-9 
=H). 
Calculated for C.sub.12 H.sub.12 N.sub.2 O.sub.2 (%): C-66.65; H-5.59; 
N-12.95; 0-14.80. Found: C-66.51; H-5.58; N-12.88; O-15.01. 
(C) 2-Acetyl-1,2,3,4-tetrahydro-beta-carboline was prepared as follows: 
A solution of 10 mmol D,L-1,2,3,4-tetrahydrobeta-carboline-1-carboxylic 
acid (2.16 g) in 30 mL 2.5 N hydrochloric acid was boiled for 1 hr to 
provide 1,2,3,4-tetrahydro-beta-carboline. The product precipitated on 
cooling, and was filtered, washed with 5 mL water, and dried under vacuum. 
One gram of the product was dissolved in a minimum amount of water and 
brought to pH 12 with 10 N NaOH. The precipitated free base was 
centrifuged, washed with water (2.times.30 mL) and dried under vacuum. The 
product was then dissolved in a minimum of ethyl acetate, and pyridine (3 
mL, 37 mmol) and acetic anhydride (1.5 mL, 16 mmol) were added. After 30 
minutes, the mixture was dried, and the resulting 
2-acetyl-1,2,3,4-tetrahydro-beta-carboline was crystallized from acetone 
(R.sub.1 =R.sub.3-9 =H; R.sub.2 =COMe). 
Calculated for C.sub.13 H.sub.14 N.sub.2 O (%): C-72.87; H-6.59; N-13.07; 
0-7.47. Found: C-72.88; H-6.47; N-12.94; 0-7.75. 
(D) 9-(1-pentyl)-1,2,3,4-tetrahydro-beta-carboline hydrochloride was 
prepared as follows: 
Under a nitrogen atmosphere, 8.0 mmol 
2-acetyl-1,2,3,4-tetrahydro-beta-carboline (1.71 g) was dissolved in 40 mL 
dry dimethylformamide (DMF). The solution was stirred over ice, and NaH (2 
g) was added under N.sub.2. The suspension was stirred for 1 hour, and 
then 1-bromopentane (9.2 mmol, 1.14 mL, 1.39 g) was added slowly to the 
cooled suspension. After a further 2 hours of stirring at ambient 
temperature, the mixture was filtered and the filtrate added to 320 mL 0.1 
N HCl. Crude 2-acetyl-9-(1-pentyl)-1,2,3,4-tetrahydro-beta-carboline 
separated as an oil. The oil was collected by centrifugation, washed with 
water, and dried over anhydrous MgSO.sub.4. (R.sub.1 =R.sub.3-8 =H; 
R.sub.2 =Ac; R.sub.9 =C.sub.5 H.sub.11) 
A portion of the crude 
2-acetyl-9-(1-pentyl)-1,2,3,4-tetrahydro-beta-carboline (1.7 g) was heated 
at reflux for 4.5 hours in 2 N NaOH (50 mL) in methanol:water (2:3, v/v). 
The methanol was removed by evaporation under vacuum, and the crude 
9-(1-pentyl)-1,2,3,4-tetrahydro-beta-carboline free base was extracted 
into chloroform. This extract was dried over anhydrous MgS.sub.4, 
filtered, and the filtrate evaporated under vacuum. The hydrochloride salt 
was prepared by passing dry HCl through a solution of the crude free base 
in diethyl ether. The resulting precipitate was filtered and 
recrystallized from acetonitrile to yield 
pure 9-(1-pentyl)-1,2,3,4-tetrahydro-beta-carboline (R.sub.1-8 =H; R.sub.9 
=C.sub.5 H.sub.11). 
Calculated for (%): C.sub.16 H.sub.28 N.sub.2 Cl (%): C-68.92; H-8.32; 
N-10.05; Cl-12.72. Found: C-69.20; H-8.51; N-9.95; Cl-12.58. 
(E) 5-Methyl-1,2,3,4-tetrahydro-betacarboline hydrochloride was prepared as 
follows: 
A suspension of 4-methyltryptophan (1.14 g, 5.2 mmol, Sigma) in 
diphenylmethane (45 mL) was heated at reflux until complete solution was 
obtained. The solution was then mixed with 45 mL water and 45 mL ethyl 
acetate, and the pH brought to 1 or lower with concentrated HCl. The 
mixture was vortexed vigorously for 30 seconds, and centrifuged to provide 
three layers. The middle (aqueous) layer was washed with ethyl acetate, 
and adjusted to pH 10 or higher with 10 N NaOH. The resulting white 
precipitate was extracted into ethyl acetate, and the extract evaporated 
to dryness under vacuum, to yield crude 4-methyltryptamine base. The crude 
base was dissolved and acidified in 50 mL EtOH containing 6 mmol 6 N HCl, 
and the resulting 4-methyltryptamine hydrochloride was crystallized from 
solution. 
5-Methyl-1,2,3,4-tetrahydro-beta-carboline hydrochloride was prepared 
following the procedure described in parts B and C above, substituting 
4-methyltryptamine hydrochloride for tryptamine hydrochloride. The product 
was recrystallized from EtOH. 
Calculated for C.sub.12 H.sub.15 N.sub.2 Cl (%): C-64.72; H-6.79; N-12.58; 
Cl-15.92. Found: C-64.48; H-6.81; N-12.33; Cl-15.55. 
(F) 6-Methyl-1,2,3,4-tetrahydro-betacarboline hydrochloride was prepared as 
follows: 
5-Methyltryptamine hydrochloride (Sigma) was condensed with glyoxylic acid 
as described in part B above, and decarboxylated according to the 
procedure described in part C. The product, 
6-methyl-1,2,3,4-tetrahydro-beta-carboline hydrochloride was 
recrystallized from ethanol:water (R.sub.1-5 =R.sub.7-9 =H; R.sub.6 =Me). 
Calculated for C.sub.12 H.sub.15 N.sub.2 Cl (%): C-64.72; H-6.79; N-12.58; 
Cl-15.92. Found: C-64.51; H-6.76; N-12.42; Cl-15.79. 
(G) 7-Fluoro-1,2,3,4-tetrahydro-beta-carboline hydrochloride was prepared 
as follows: 
6-Fluorotryptamine hydrochloride (Sigma) was condensed with glyoxylic acid 
as described in part B, and decarboxylated according to part C. The 
product, 7-fluoro-1,2,3,4-tetrahydro-beta-carboline hydrochloride was 
recrystallized from ethanol:water (R.sub.1-6 =R.sub.8-9 =H; R.sub.7 32 F). 
Calculated for C.sub.11 H.sub.12 N.sub.2 FCl (%): C-58.28; H-5.34; N-12.36; 
F-8.38; Cl-15.64. Found: C-58.50; H-5.29; N-12.43; F-8.11; Cl-15.35. 
(H) 8-Methyl-1,2,3,4-tetrahydro-betacarboline hydrochloride was prepared as 
follows: 
7-Methyltryptamine (free base, Sigma) was dissolved in aqueous hydrochloric 
acid and condensed with glyoxylic acid as described in part B. The product 
was decarboxylated according to part C to yield 
8-methyl-1,2,3,4-tetrahydro-beta-carboline hydrochloride, which was 
recrystallized from ethanol:water R.sub.1-7 =R.sub.9 =H; R.sub.8 =Me). 
Calculated for C.sub.12 H.sub.15 N.sub.2 Cl(%): C-64.72; H-6.79; N-12.58; 
Cl-15.92. Found: C-64.61; H-6.86; N-12.61; Cl-15.48. 
EXAMPLE 2 
(Reduction of Food Intake) Dose ranging studies showed that compounds of 
formula I significantly reduced food intake when administered parenterally 
to rats in amounts appreciably lower than 25 mg/Kg. 
Adult male rats weighing between 250 and 300 g were acclimated to 
laboratory conditions for a period of 4-5 days, during which they were 
allowed unrestricted access to food (Ralston-Purina #5001M) and water. All 
animals were housed in individual cages. The animal facility was 
maintained on a 12:12 hr light-dark schedule at 22.degree. C. 
Fasted animals were sorted into groups of 10-12 each by weight and baseline 
food intake. Each was then given saline containing 0-32 mg/Kg of a 
compound of the invention (or THBC) by intraperitoneal injection. After 20 
minutes, animals were allowed access to food and water. Cumulative food 
intake was measured at 1 hour post-injection. Doses as low as 4 mg/Kg 
significantly reduced food consumption (Table I). 
In the examples herein, compounds were administered parenterally. In 
clinical usage as an anorectic agent in mammals, particularly humans, the 
oral, intranasal, or transdermal routes of administration would be 
preferred. In the case of intraperitoneal administration in rodents, 
amounts as low as about 1.5 mg/Kg of body weight have been shown to 
achieve effective significant appetite suppression. 
TABLE I 
______________________________________ 
(Reduction of Food Intake) 
Dose 1 Hr Food Intake 
Compound (mg/Kg) (g, mean + sem) 
p 
______________________________________ 
THBC 0 5.13 .+-. 0.51 
NA 
(HCl) 5.0 4.44 .+-. 0.36 
&lt;0.14 
10.0 3.70 .+-. 0.18 
&lt;0.01 
15.0 2.63 .+-. 0.21 
&lt;0.00021 
25.0 1.10 .+-. 0.12 
&lt;2.9 .times. 10.sup.-6 
R.sub.6 = OMe 
0 5.88 .+-. 0.56 
NA 
(HCl) 5.0 5.08 .+-. 0.33 
&lt;0.12 
10.0 4.45 .+-. 0.20 
&lt;0.015 
15.0 2.88 .+-. 0.31 
&lt;0.0001 
25.0 1.74 .+-. 0.26 
&lt;3.4 .times. 10.sup.-6 
R.sub.6 = F 
0 5.53 .+-. 0.49 
NA 
(HCl) 5.0 4.20 .+-. 0.27 
&lt;0.015 
10.0 2.29 .+-. 0.21 
&lt;1.0 .times. 10.sup.-5 
15.0 1.89 .+-. 0.14 
&lt;3.5 .times. 10.sup.-6 
25.0 0.73 .+-. 0.15 
&lt;1.8 .times. 10.sup.-7 
R.sub.7 = F 
0 4.99 .+-. 0.40 
NA 
(HCl) 5.0 3.99 .+-. 0.57 
&lt;0.083 
10.0 2.78 .+-. 0.27 
&lt;9.1 .times. 10.sup.-5 
25.0 0.50 .+-. 0.12 
&lt;7.4 .times. 10.sup.-8 
R.sub.1 = Me 
0 5.33 .+-. 0.39 
NA 
(HCl) 5.0 5.16 .+-. 0.51 
&lt;0.39 
10.0 3.95 .+-. 0.26 
&lt;0.0038 
25.0 2.36 .+-. 0.20 
&lt;2.3 .times. 10.sup.-6 
R.sub.6 = Cl 
0 4.12 .+-. 0.44 
NA 
5.0 3.75 .+-. 0.39 
&lt;0.27 
10.0 2.42 .+-. 0.24 
&lt;0.0016 
25.0 0.58 .+-. 0.22 
&lt;9.3 .times. 10.sup.-7 
R.sub.6 = Cl 
0 5.85 .+-. 0.41 
NA 
(HCl) 4.0 3.68 .+-. 0.42 
&lt;0.00076 
8.0 2.69 .+-. 0.17 
&lt;5.4 .times. 10.sup.-6 
16.0 2.22 .+-. 0.22 
&lt;8.5 .times. 10.sup.-7 
32.0 0.29 .+-. 0.14 
&lt;2.6 .times. 10.sup.-8 
R.sub.2 = Me 
0 4.69 .+-. 0.54 
NA 
(HCl) 5.0 4.66 .+-. 0.33 
&lt;0.48 
10.0 3.73 .+-. 0.29 
&lt;0.068 
25.0 2.27 .+-. 0.24 
&lt;0.00046 
R.sub.8 = Me 
0 5.28 .+-. 0.66 
NA 
(HCl) 5.0 4.42 .+-. 0.42 
&lt;0.14 
10.0 3.30 .+-. 0.23 
&lt;0.0075 
25.0 0.56 .+-. 0.33 
&lt;6.0 .times. 10.sup.-6 
R.sub.6 = Me 
0 4.50 .+-. 0.42 
NA 
(HCl) 5.0 2.69 .+-. 0.22 
&lt;0.00073 
10.0 1.53 .+-. 0.24 
&lt;4.5 .times. 10.sup.-6 
25.0 0.08 .+-. 0.02 
&lt;2.3 .times. 10.sup.-7 
R.sub.3 = Et 
0 4.86 .+-. 0.52 
NA 
(HCl) 5.0 5.42 .+-. 0.56 
&lt;0.24 
10.0 3.66 .+-. 0.40 
&lt;0.041 
25.0 1.47 .+-. 0.21 
&lt;1.2 .times. 10.sup.-5 
R.sub.3 = COOH 
0 6.47 .+-. 0.33 
NA 
(HCl) 4 4.72 .+-. 0.45 
&lt;0.0029 
8 2.57 .+-. 0.32 
&lt;5.4 .times. 10.sup.-8 
16 2.31 .+-. 0.23 
&lt;3.0 .times. 10.sup.-9 
32 2.11 .+-. 0.25 
&lt;2.2 .times. 10.sup.-9 
R.sub.3 = COOH, 
0 5.18 .+-. 0.44 
NA 
R.sub.6 = OH 
4.0 6.00 .+-. 0.31 
&lt;0.074 
8.0 4.89 .+-. 0.38 
&lt;0.31 
16.0 3.12 .+-. 0.48 
&lt;0.0027 
32.0 1.57 .+-. 0.31 
&lt;1.5 .times. 10.sup.-6 
R.sub.2 = Ac 
0 7.19 .+-. 0.44 
NA 
4.0 5.21 .+-. 0.33 
&lt;0.0011 
8.0 3.27 .+-. 0.34 
&lt;7.1 .times. 10.sup.-7 
16.0 2.85 .+-. 0.19 
&lt;5.4 .times. 10.sup.-7 
32.0 2.80 .+-. 0.20 
&lt;3.0 .times. 10.sup.-7 
R.sub.5 = Me 
0 6.78 .+-. 0.50 
NA 
(HCl) 4.0 3.76 .+-. 0.32 
&lt;3.8 .times. 10.sup.-5 
8.0 3.22 .+-. 0.42 
&lt;1.6 .times. 10.sup.-5 
16.0 2.22 .+-. 0.22 
&lt;1.2 .times. 10.sup.-6 
32.0 0.10 .+-. 0.05 
&lt;1.6 .times. 10.sup.-7 
R.sub.9 = CHO 
0 4.44 .+-. 0.42 
NA 
4.0 4.35 .+-. 0.41 
&lt;0.44 
8.0 3.96 .+-. 0.14 
&lt;0.15 
16.0 3.23 .+-. 0.25 
&lt;0.012 
32.0 1.03 .+-. 0.35 
&lt;3.6 .times. 10.sup.-6 
R.sub.9 = Bz 
0 5.91 .+-. 0.33 
NA 
(HCl) 4.0 4.34 .+-. 0.53 
&lt;0.011 
8.0 2.36 .+-. 0.18 
&lt;8.2 .times. 10.sup.-8 
16.0 0.51 .+-. 0.18 
&lt;3.9 .times. 10.sup.-10 
32.0 0.10 .+-. 0.02 
&lt;1.3 .times. 10.sup.-8 
R.sub.9 = Et 
0 6.02 .+-. 0.46 
NA 
(HCl) 4.0 4.01 .+-. 0.37 
&lt;0.0015 
8.0 3.03 .+-. 0.26 
&lt;2.8 .times. 10.sup.-5 
16.0 2.65 .+-. 0.23 
&lt;9.1 .times. 10.sup.-6 
32.0 0.13 .+-. 0.07 
&lt;2.4 .times. 10.sup.-7 
R.sub.6 = Me, 
0 6.34 .+-. 0.44 
NA 
R.sub.9 = Pent 
4.0 3.72 .+-. 0.22 
&lt;6.5 .times. 10.sup.-5 
(HCl) 8.0 2.46 .+-. 0.11 
&lt;3.1 .times. 10.sup.-6 
16.0 0.64 .+-. 0.14 
&lt;4.3 .times. 10.sup.-8 
32.0 0.26 .+-. 0.03 
&lt; 1.1 .times. 10.sup.-7 
R.sub.9 = Pent 
0 5.18 .+-. 0.44 
NA 
(HCl) 4.0 2.89 .+-. 0.37 
&lt;0.00045 
8.0 2.27 .+-. 0.17 
&lt;2.4 .times. 10.sup.-5 
16.0 0.93 .+-. 0.21 
&lt;4.4 .times. 10.sup.-7 
32.0 0.01 .+-. 0.01 
&lt;4.5 .times. 10.sup.-6 
R.sub.3 = COOBz 
0 5.74 .+-. 0.46 
NA 
(HCl) 4.0 5.06 .+-. 0.49 
&lt;0.16 
8.0 3.81 .+-. 0.45 
&lt;0.004 
16.0 2.55 .+-. 0.21 
&lt;2.0 .times. 10.sup.-5 
32.0 2.86 .+-. 0.27 
&lt;2.2 .times. 10.sup.-5 
R.sub.1 = Me 
0 4.99 .+-. 0.59 
NA 
R.sub.3 = COOH 
4.0 4.41 .+-. 0.44 
&lt;0.23 
R.sub.9 = Me 
8.0 2.94 .+-. 0.22 
&lt;0.0039 
16.0 3.13 .+-. 0.41 
&lt;0.0092 
32.0 2.69 .+-. 0.45 
&lt;0.0031 
R.sub.1 = COOH 
0 4.84 .+-. 0.53 
NA 
4.0 3.74 .+-. 0.25 
&lt;0.042 
8.0 3.21 .+-. 0.30 
&lt;0.0075 
16.0 2.89 .+-. 0.13 
&lt;0.0025 
32.0 1.83 .+-. 0.14 
&lt;0.00013 
R.sub.2 = Ac 
0 4.82 .+-. 0.56 
NA 
R.sub.9 = Bz 
4.0 4.00 .+-. 0.56 
&lt;0.16 
8.0 3.18 .+-. 0.28 
&lt;0.01 
16.0 2.04 .+-. 0.19 
&lt;0.00032 
32.0 0.82 .+-. 0.14 
&lt;2.0 .times. 10.sup.-5 
R.sub.3 = COOH 
0 5.50 .+-. 0.43 
NA 
(D isomer) 
4.0 5.48 .+-. 0.29 
&lt;0.48 
8.0 5.99 .+-. 0.30 
&lt;0.18 
16.0 4.58 .+-. 0.66 
&lt;0.13 
32.0 2.34 .+-. 0.40 
&lt;2.8 .times. 10.sup.-5 
R.sub.1 = COOH 
0 6.64 .+-. 0.33 
NA 
R.sub.3 = COOMe 
4.0 5.50 .+-. 0.65 
&lt;0.072 
(HCl) 8.0 5.90 .+-. 0.61 
&lt;0.15 
16.0 4.53 .+-. 0.53 
&lt;0.0016 
32.0 4.22 .+-. 0.27 
&lt;1.2 .times. 10.sup.-5 
R.sub.2 = Suc 
0 5.05 .+-. 0.45 
NA 
4.0 5.65 .+-. 0.37 
&lt;0.16 
8.0 5.80 .+-. 0.47 
&lt;0.13 
16.0 5.85 .+-. 0.45 
&lt;0.11 
32.0 2.45 .+-. 0.29 
&lt;6.8 .times. 10.sup.-5 
______________________________________ 
R.sub.1-9 = H unless otherwise specified. Me = methyl; Et = ethyl; Ac = 
acetyl; Bz = benzyl; Pent = pentyl; Suc = succinyl. All compounds are 
racemic unless otherwise specified. p values were computed by twotailed 
Students ttest. 
EXAMPLE 3 
(Dose Response Characteristics) 
A number of compounds of the invention exhibit dose-response 
characteristics which are qualitatively different from those of THBC. 
Unlike THBC, several compounds of formula I will not depress feeding 
behavior to zero over a comparatively large concentration range. This 
feature is termed "partial suppression" of feeding behavior, and greatly 
increases the margin of safety, as overuse of the compounds will not 
result in fatal anorexia. 
Reduction in food intake over one hour was measured versus dose per unit 
body weight for THBC, and for 2-acetyl-THBC (R.sub.2 =C(O)CH.sub.3), 
D,L-3-carboxy-THBC (R.sub.3 =COOH), D,L-1-carboxy-THBC (R.sub.1 =COOH), 
and D,L-3-carbobenzyloxy-THBC (R.sub.3 =COOCH.sub.2 C.sub.6 H.sub.5). 
The results are shown in FIGS. 1-4. FIG. 1 compares D,L-3-carboxy-THBC 
(R.sub.3 =COOH) with THBC. FIG. 2 compares D,L-3-carbobenzyloxy-THBC 
(R.sub.3 =COOCH.sub.2 C.sub.6 H.sub.5) with THBC. FIG. 3 compares 
2-acetyl-THBC (R.sub.2 =C(O)CH.sub.3) with THBC. FIG. 4 compares 
D,L-1-carboxy-THBC carboxy-THBC (R.sub.1 =COOH) with THBC. (Note that the 
scales vary from figure to figure.) The results demonstrated that THBC 
effected little feeding depression at low dosage, but relatively complete 
feeding depression at higher dosage, with a comparatively narrow range of 
concentration in the transition region. In contrast, each of the compounds 
tested demonstrated moderate feeding depression over a broad dosage range, 
beginning at dosages lower than required for THBC, and extending past 
dosages at which THBC caused complete feeding cessation. 
EXAMPLE 4 
(Alteration of Macronutrient Preference) 
This Example demonstrates alteration of macronutrient preference in rats. 
Sixty adult male rats (Sprague-Dawley, 225-300 g) are acclimated to 
laboratory conditions for a period of 10 days, during which they are 
allowed unrestricted access to food (Ralston-Purina #5001M) and water. All 
subjects are housed in individual cages, and the animal facility is 
maintained on a 12:12 hour light:dark cycle at 24.degree.-27.degree. C. 
Animals are assigned to 6 groups (10 per group), then allowed to consume, 
ad libitum, one of two iso-nitrogenous test diets containing either 75% or 
25% carbohydrate. After 3 days, food jars are removed. After an additional 
24 hours, rats are administered either saline or a compound of formula I 
(1.5 or 3.0 mg/Kg body weight), then given immediate access to the test 
diets. The cumulative amount in grams (mean.+-.SEM) of each diet consumed 
by the experimental and control groups during the subsequent 2-hour period 
is recorded. 
The results indicate that animals receiving a compound of the invention 
consume significantly less of the high carbohydrate diet than do controls, 
but consume equivalent quantities of the low carbohydrate diet. Thus, 
compounds of the invention selectively suppress carbohydrate cravings when 
administered at doses lower than the dosage effective for global reduction 
in appetite. This demonstrates the utility of the present invention as a 
method for reducing substance cravings per se, insofar as food cravings 
model clinical syndromes in which there is excessive preoccupation with, 
or urges for, specific habituating substances (Glassman et al., Science 
(1984) 226:864). Accordingly, this Example may be taken as evidencing 
efficacy in the treatment of alcohol, tobacco, or drug (particularly 
opiate) addiction. 
EXAMPLE 5 
(Formulations) 
(A) A representative capsule formulation is prepared as follows: 
______________________________________ 
Compound 50.0 mg 
starch 3.0 mg 
magnesium stearate 
3.0 mg 
lactose 110.0 mg 
polyvinylpyrrolidone 
3.0 mg 
______________________________________ 
The compound of formula I, starch, magnesium stearate, lactose, and 
polyvinylpyrrolidone are granulated in methanol, dried, and loaded into 
capsules. Alternatively, the mixture may be tableted by standard methods. 
(B) An oral suspension is prepared as follows: 
______________________________________ 
Compound 60.0 mg 
fumaric acid 0.5 g 
NaCl 2.0 g 
methyl paraben 0.1 g 
granulated sugar 25.5 2 
sorbitol (70% aq) 
12.85 g 
Veegum K 1.0 g 
flavorings 0.035 mL 
colorings 0.5 mg 
distilled water qs 
100.0 mL 
______________________________________ 
The components are mixed together and stored in a sealed vessel. 
(D) A formulation suitable for parenteral administration is prepared as 
follows: 
______________________________________ 
Compound 40.0 mg 
KH.sub.2 PO.sub.4 buffer (0.4M) 
2.0 mL 
KOH (1N) qs pH 7.0 
water qs 20.0 mL 
______________________________________ 
The components are mixed together and stored under sterile conditions. 
The foregoing is offered primarily for purposes of illustration. It will be 
readily apparent to those skilled in the art that numerous variations, 
modifications and substituents, in the materials and methods described 
herein may be made without departing from the spirit and scope of the 
invention.