Process for the alleviation of depression by administration of non-addicting meperidine analogues

A process is provided for the alleviation of depression by administration of meperidine analogues corresponding to the formula: ##STR1## in which R.sub.1 and R.sub.2 are each lower alkyl or allyl.

Depression is a very common condition characterized by symptoms such as 
depressed mood, loss of interest, loss of pleasure, loss of appetite and 
sexual desire, lack of energy, sleeplessness, and suicidal tendencies. 
Mild forms of the condition often occur in response to a personal loss, 
such as the death of a loved one. The condition is often transitory, but 
while it exists it can nonetheless be a severe problem, particularly in 
the case of a suicidal tendency, which may be consummated before the 
condition works itself out. In the more serious forms of the condition, 
sometimes also referred to as endogenous depression, a primary physical 
disturbance of the amine metabolism of the brain is suspected, as at least 
a contributory if not a causal factor. 
It is sometimes very important to be able to alleviate the condition 
promptly. In the case of a suicidal tendency, for example, tragic 
consequences may ensue if the condition cannot somehow be rapidly 
counteracted or controlled. However, up to the present time no wholly 
effective or even satisfactory treatment of serious depressive states has 
been available. 
The most effective treatment in widespread use is application of electric 
currents to the head to produce an electroconvulsive seizure. A number of 
electric shock treatments are usually required for a sufficient effect. 
Electric shock treatments can, however, have quite unfortunate 
consequences and side effects, as a result of which many physicians are 
reluctant to administer them. They may cause fractures and other physical 
injuries to the patient. Not infrequently, they result in partial loss of 
memory, or varying degrees of mental deterioration, which may last for a 
long time, if indeed they are not permanent. 
Chemical treatment has been less effective, however, as a result of which 
electric shock treatments must be resorted to in serious cases, where 
prompt alleviation is a prerequisite. 
The so-called tricyclic antidepressant agents, introduced in the late 
1950's, are effective only in a proportion of patients, and are quite slow 
to show a noticeable effect, frequently evidencing alleviation of the 
condition only after the patient has been taking them for two or three 
weeks. This is too long a time to wait for an alleviation in the case of a 
patient having a suicidal tendency, for example. 
The monoamine oxidase class of antidepressant agents is used only in 
patients which are refractory to other treatments, because of their 
toxicity and unpredictable effectiveness and side effects. 
Meperidine hydrochloride is an analgesic widely used for the relief of 
severe pain, and has the structure: 
##STR2## 
It has been sold in many countries under the trade names Demerol, Dolantin, 
Pethidine and others. It is among the classes of compounds disclosed and 
claimed in U.S. Pat. No. 2,167,351 issued to Eisleb on July 25, 1939; see 
column 1, page 2, lines 18 to 22, and claim 8. However, meperidine 
hydrochloride may be rapid and powerful in its addicting tendency. 
In accordance with the invention, it has been determined that meperidine 
hydrochloride and certain meperidine analogues, closely similar to 
merperidine in structure, and even homologous thereto, having a lower 
alkyl or allyl substituent attached both to the nitrogen of the piperidine 
nucleus and to the carboxylic group attached to the piperidine nucleus as 
a side chain, are quite effective in alleviating depression. Meperidine 
hydrochloride is quite effective in alleviating depression, and the effect 
of the chemical is usually noticeable within a few hours. However, it 
cannot of course be employed in the treatment of depression, because of 
its narcotic and habit-forming or addictive qualities. The difficulty is 
that depression, particularly in its more serious forms, is a recurrent 
condition, that may require treatment for protracted periods of time, and 
may recur even after it has apparently been completely cured. For these 
reasons, it is neither appropriate nor advisable to treat depressive 
conditions with any drugs possessing a marked addictive or habit-forming 
potential. Surprisingly, however, the meperidine analogues are 
substantially nonaddictive and non-habit-forming in the amounts effective 
to alleviate depression. The amounts required for addiction are well in 
excess of these amounts. As a result, these compounds of the invention can 
safely be used in treatment of depression without addiction consequences. 
The nonaddictive compounds of the invention are believed to be new as 
pharmaceuticals, and are defined by the formula: 
##STR3## 
In the above formula, R.sub.1 is lower alkyl having from one to four carbon 
atoms or allyl and R.sub.2 is alkyl having from one to two carbon atoms; 
but if R.sub.1 is methyl or ethyl, R.sub.2 is other than ethyl. 
Accordingly, these compounds differ from meperidine in that R.sub.1 can be 
alkyl higher than methyl, or allyl, and R.sub.2 can be methyl. 
The phenyl ring attached as a side chain to the 4-carbon atom of the 
piperidine ring and also bearing the carboxylic acid ester group can have 
inert substituents without material effect on antidepressive activity. 
Such inert substituents include, for example, halogen, such as fluorine, 
chlorine and bromine; lower alkyl, such as methyl, ethyl and propyl; and 
haloalkyl, such as trifluoromethyl. 
These compounds are known compounds, and can be synthesized by known 
procedures. There can be used, for instance, the general procedure used 
for the preparation of meperidine. This procedure, as described by Eisleb, 
Ber. 74 1433 (1941), involves the condensation of the corresponding phenyl 
acetonitrile with the corresponding bis-.beta.-chloroethylalkyl amine to 
give 4-phenyl-1-alkyl-piperidine-4-nitrile, which is then converted into 
the corresponding ethyl ester. The procedure can be outlined as follows: 
##STR4## 
Another synthesis has been proposed by Walton and Green, Journal of the 
Chemical Society 1945 315, which avoids the use of the vesicant 
bis-.beta.-chloroethylalkyl amine, employing 
4-cyano-4-phenylpentamethylene oxide, which is converted into .alpha. 
,.alpha.-bis-.beta.'-bromoethylphenyl acetic acid, and this is then 
treated as the ethyl ester with the corresponding alkyl amine. See also 
Bergel, Morrison and Rinderknecht Journal of the Chemical Society, 1944 
267. Using this procedure, Walton and Green were able to prepare 
ethyl-4-phenyl-1-ethyl-piperidine-4 -carboxylate; 
ethyl-4-phenyl-1-n-propyl-piperidine-4-carboxylate; and 
ethyl-4-phenyl-1-n-butyl-piperidine-4-carboxylate. 
Another procedure is described in a later paper by Thorpe and Walton, 
Journal of the Chemical Society 1947 559, by alkylation of norpethidine: 
##STR5## 
Using this procedure these workers were able to prepare the N-ethyl, 
N-n-propyl, N-isopropyl, N-n-butyl, N-secondary-butyl, N-n-amyl, 
N-1'-methylbutyl and N-allyl derivatives of meperidine. 
Thorpe and Walton studied the toxicity and analgesic activity of these 
compounds as compared to pethidine (meperidine) and found them slightly 
more effective as analgesics then pethidine, but not sufficiently 
different from or more potent than pethidine to prove of greater value. 
The toxicity increased slightly with the length of the alkyl chain, but 
the toxicity data reported shows no serious toxicity for any of them. 
The compounds can be prepared and used in the form of the free amine or as 
a pharmaceutically acceptable salt including acid addition salts. 
The acid addition salts include the pharmaceutically acceptable non-toxic 
addition salts with inorganic acids, for example, hydrochloric, 
hydrobromic, nitric, sulphuric or phosphoric acids, and with organic 
acids, for example acetic, glycollic, maleic, tartaric, citric, 
acetyloxy-benzoic, nicotinic or isonicotinic acids, methane sulphonic, 
ethane sulphonic, 2-hydroxyethane sulphonic, p-toluene sulphonic or 
naphthalene-2-sulphonic acids.

The following Examples illustrate preferred embodiments of the invention: 
EXAMPLES 1 to 4 
The antidepressant activity of the compounds in accordance with the 
invention has been evaluated in the Dopa response potentiation test 
described by G. M. Everett in "Antidepressant Drugs", Excerpta Medica 
Foundation, Amsterdam and New York 1967, pp. 164-167. This test is widely 
used in screening compounds for antidepressant activity, and is generally 
recognized in the field of psychopharmacology as being one of the best 
available tests for this purpose. 
The test is based on the observation that the behavioral response to Dopa 
(3,4-dihydroxyphenyl)-L-alanine), the precursor of the neurotransmitters 
dopamine and norepinephrine, is modified by antidepressants in the 
presence of monoamineoxidase inhibition. Under these conditions, 
antidepressants given prior to Dopa potentiate the behavioral response 
usually seen after administration of Dopa. 
The following Examples illustrate the activity of the compounds: 
In this test, mice are pretreated with pargyline (1% solution pargyline 
HCl, 40 mg/kg) orally, 16 hours prior to the test. The test drug is 
injected one hour prior to the intraperitoneal administration of L-Dopa 
(1% solution). The intensity of the L-Dopa syndrome is recorded on a scale 
from 1 to 3, maximal response being 3+: 
1+ Piloerection, slight salivation, slight increased motor activity. 
2+ Piloerection, salivation, marked increased activity & irritability. 
3+ Piloerection, profuse salivation, marked increased irritability & 
reactivity, jumping, squeaking and aggressive fighting. 
Table I lists the compounds in accordance with the invention that have been 
tested in the Dopa response potentiation test, and compares them with 
similar compounds in the meperidine series. The smallest dose of the 
compounds producing maximum response in the test is also given in the 
Table. For comparison, the results obtained with the standard 
antidepressant drug Imipramine are also given, as are the results obtained 
in control animals that have not been treated with any drug. 
TABLE I 
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##STR6## 
Rating 
Dose Dopa 
Compound R.sub.1 R.sub.2 mg/kg syndrome 
______________________________________ 
Control -- -- -- 1+ 
Imipramine -- -- 10 3+ 
Meperidine methyl ethyl 10 3+ 
Normeperidine 
H ethyl 25 2+ 
Example 1 n-propyl ethyl 25 2+ 
Example 2 allyl ethyl 25 3+ 
Example 3 n-butyl ethyl 25 3+ 
Example 4 methyl methyl 25 3+ 
______________________________________ 
The test results given in Table I show that maximum response in the Dopa 
test can be obtained with imipramine, meperidine, and the compounds of 
Examples 2, 3, and 4. The results indicate that these compounds possess 
strong antidepressant properties. Normeperidine and the compound of 
Example 1 gave a weaker response in the test, and are likely to have a 
weaker antidepressant action, but they are nonetheless sufficiently 
effective to be of interest. 
The addictive tendency of the compounds of the invention was also 
evaluated, as compared to meperidine and normeperidine, using the morphine 
withdrawal test described by Leong Way, Loh and Hsiung in the Journal of 
Pharmacology and Experimental Therapeutics 167 1- 8 (1969). 
This test involves priming mice with morphine injections prior to the 
implantation of a 75 mg. morphine pellet subcutaneously. Removal of the 
pellet after 3 days results in a time-dependent withdrawal syndrome, which 
is characterized strikingly by a non-controllable urge to jump. This 
response can be selectively suppressed by morphine, and other agents 
possessing similar addictive properties, such as meperidine. Thus, the 
jumping response can be used as an index for estimating the degree of 
physical dependence or addiction. With abrupt withdrawal, the incidence of 
withdrawal jumping is time-dependent, the response being maximal 6 to 8 
hours after removal of the morphine pellet. Abrupt abstinence is 
quantified by placing the animals on a circular platform, 35 centimeters 
in diameter and 70 centimeters high, and recording the percentage of 
animals that leap off within 15 minutes. 
In the test, all compounds were given at a dose of 50 mg/kg, and the 
percent antagonism of withdrawal jumping determined. Complete or 100 
percent antagonism means that the compound possessing this effect could 
completely replace morphine, and for this reason is as habit-forming or 
addictive as morphine. The lower the antagonism percent figure, the lower 
the addictive tendency of the compound. 
Table II gives the results of the test for compounds in accordance with the 
invention and near homologues thereof, including meperidine and 
normeperidine. 
TABLE II 
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##STR7## 
Percent antagonism of 
Compound R.sub.1 R.sub.2 withdrawal jumping 
______________________________________ 
meperidine 
methyl ethyl 100 
normeperidine 
H ethyl 75 
Example 1 n-propyl ethyl 25 
Example 2 allyl ethyl 25 
Example 3 n-butyl ethyl 25 
Example 4 methyl methyl 50 
A methyl n-propyl 75 
B methyl n-butyl 100 
C ethyl n-propyl 75 
D ethyl iso-propyl 
100 
E ethyl ethyl 75 
F n-pentyl ethyl 75 
G benzyl ethyl 75 
______________________________________ 
It is apparent from the results that the compounds in accordance with the 
invention are only one-third to one-fourth as addictive or habit forming 
as meperidine, and considerably superior to its near homologue, 
normeperidine. It is thus shown that R.sub.1 should have three or four 
carbon atoms, to avoid the addictive tendency of meperidine and 
normeperidine, if R.sub.2 is ethyl. Surprisingly, if R.sub.1 and R.sub.2 
are each methyl, the compound is relatively nonaddictive, even though the 
compound is addictive when R.sub.1 and R.sub.2 are each ethyl (E). The 
results show addictive tendency is not correlated with antidepressant 
effectiveness, and that it is possible for a compound to possess the 
latter and very little of the former, unlike what would be expected from 
the relative performance of meperidine and normeperidine, where relative 
addictiveness and antidepressant effectiveness are closely associated. 
Meperidine is more effective and also more addictive than normeperidine, 
whereas the compounds of the invention are as effective as meperidine, and 
relatively nonaddictive. 
The compositions can be administered orally, parenterally or rectally in 
the form of, for example, tablets, capsules, suppositories, solutions or 
suspensions. One or a mixture of compounds can be administered together or 
in sequence. A series of doses of different compounds can be more 
effective than repeated doses of the same compound. The dose administered 
is sufficient to obtain an antidepressant effect, and can be from 50 to 
800 mg. This can be by any mode of administration, such as by injection 
intra-muscularly or subcutaneously or by oral administration. A suitable 
daily dose in as many portions as desired is from 50 to 5000 mg. 
The compound is suitably administered in dosage unit form. The term "dosage 
unit form" refers to single units each containing a dose of the active 
compound, generally in admixture with a pharmaceutical diluent therefor or 
otherwise in association with a pharmaceutical carrier. The amount of 
compound can be such that one or more units is required for a single dose. 
In the case of severable units, such as scored tablets, at least one 
fraction such as a half or quarter of a severable unit is required for 
single therapeutic administration. A dosage unit may contain, for example, 
from 50 to 800 mg. of compound or compounds. 
A pharmaceutical carrier or diluent can be a solid, semi-solid or liquid 
material which serves as a vehicle, or medium for the active compound or 
compounds. Examples of diluents are water, alone or with varying 
proportions of ethanol, propylene glycol, polyethylene glycol 400, or 
similar solvents, and examples of solid carriers are lactose, dextrose, 
sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, liquid 
paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatine, 
syrup B.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, and 
methyl- and propyl-hydroxyl-benzoate. 
In the case of tablets, a lubricant may be incorporated to prevent sticking 
and binding of the powdered ingredients in the dies and on the punch of 
the tabletting machine. For such purpose, there may be employed for 
instance talc, aluminum, magnesium or calcium stearate or mineral oil. 
The following are Examples of compositions for dosage units or other 
application forms in accordance with the invention: 
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Tablet formulation 
Parts/tablet 
______________________________________ 
Active compound 15 
Lactose 86 
Corn starch (dried) 
45.5 
Gelatin 2.5 
Magnesium stearate 1.0 
______________________________________ 
The compound was powdered and passed through a sieve, and well mixed with 
the lactose and 30 mg. of the corn starch. 
The mixed powders were combined with a warm gelatin solution prepared by 
stirring the gelatin in water and heating to form a 10% w./w. solution, 
granulated by passing through a B.S. No. 12 sieve, and the moist granules 
dried at 40.degree. C. 
The dried granules were re-granulated and the balance of the starch and the 
magnesium stearate were added and thoroughly mixed. 
The granules were compressed to produce tablets each weighing 150 mg. 
______________________________________ 
Tablet formulation 
Parts/tablet 
______________________________________ 
Active compound 100 
Lactose 39 
Corn starch (dried) 
80 
Gelatin 4.0 
Magnesium stearate 2.0 
______________________________________ 
The method of preparation is identical with that of the preceding, except 
that 60 parts of starch is used in the granulation process and 20 parts 
during tableting. 
______________________________________ 
Capsule formulation 
Parts/capsule 
______________________________________ 
Active compound 250 
Lactose 150 
______________________________________ 
The compound and lactose were passed through a sieve and the powders well 
mixed together before filling into hard gelatin capsules of suitable size, 
so that each capsule contained 400 mg. 
______________________________________ 
Suppositories 
Parts/suppository 
______________________________________ 
Active compound 50 
Cocoa butter 950 
______________________________________ 
The compound was powdered and passed through a sieve and triturated with 
molten cocoa butter at 45.degree. C. to form a smooth suspension. 
The mixture was well stirred and poured into moulds, each of nominal 1 g. 
capacity, to produce suppositories. 
______________________________________ 
Cachets 
Parts/cachet 
______________________________________ 
Active compound 100 
Lactose 400 
______________________________________ 
The compound was passed through a sieve, mixed with lactose previously 
sieved and filled into cachets of suitable size so that each contained 500 
mg. 
______________________________________ 
Intramuscular injection (suspension in aqueous vehicle) 
Parts 
______________________________________ 
Compound 10 
Sodium citrate 5.7 
Sodium carboxymethylcellulose (low 
viscosity grade) 2.0 
Methyl para-hydroxybenzoate 
1.5 
Propyl para-hydroxybenzoate 
0.2 
Water for injection to 1.0 ml. 
______________________________________ 
The sodium citrate and sodium carboxymethylcellulose were mixed with 
sufficient water for injection at 80.degree. C. The mixture was cooled to 
50.degree. C. and the methyl and propyl para-hydroxybenzoates added 
followed by the medicament previously milled and sieved 300 mesh. When 
cooled the injection was made up to volume and sterilized by heating in an 
autoclave.