Inhibition of indoleamine-N-methyl transferase by 2-iminopyridines

A method of inhibiting indoleamine-N-methyl transferase comprises the administration to a host of a therapeutically effective amount of 1-alkyl-2-iminopyrrolidines or 1-alkyl-2-iminopyridines or pharmaceutically acceptable salts thereof.

The present invention relates to novel and useful pharmaceutical 
compositions and a method of treatment. More specifically, it relates to 
compositions and a method for inhibiting indoleamine-N-methyl transferase 
by the administration of 1-alkyl-2-iminopyrrolidines or 
1-alkyl-2-iminopyridines or pharmaceutically acceptable salts thereof. 
N,N-dimethylindoleamines are generally psychotomimetic agents and some of 
these (e.g. dimethylserotonin and dimethyltryptamine) may be produced in 
excessive amounts by patients with mental aberrations (i.e. 
schizophrenia). Indoleamine-N-methyl transferase catalyzes the methylation 
steps in the biosynthesis of these compounds. Accordingly, inhibitors of 
this enzyme are of therapeutic value in the management of the body 
chemistry of patients having mental aberrations and in alleviating some 
symptoms of the disease. 
It is an object of the present invention to provide compositions which 
inhibit indoleamine-N-methyl transferase. Another object is to provide a 
method of inhibiting the transferase with the active compounds and novel 
compositions thereof. 
The compounds employed in the novel method of treatment have the following 
structural formula: 
##STR1## 
or a pharmaceutically acceptable salt thereof, wherein N IS 0 OR 1; 
R is lower alkyl, especially C.sub.1-3 alkyl; 
R.sup.1 is hydrogen or amino; and the dotted line represents saturation or 
unsaturation. 
Some of the compounds useful in the composition and method of treatment of 
this invention are known in the art, available commercially or may be 
prepared by well known prior art methods. For example, 
1-alkyl-2-iminopyrrolidines are described in J. Org. Chem., 32, 738 
(1967), and 1-alkyl-1H-2-iminodihydropyridine is described in Chem. Ber., 
54 B, 814 (1921). The compound, 
2-imino-1-methyl-1,2,5,6-tetrahydropyridine, is a new compound and forms 
another embodiment of this invention. 
The pharmaceutically acceptable salts coming within the purview of this 
invention are acid-addition salts prepared from other acid addition salts 
or the free bases by standard procedures. Acids useful for preparing these 
salts include, inter alia, inorganic acids, such as the hydrohalic acids 
(e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and 
phosphoric acid, and organic acids such as maleic, fumaric, tartaric, 
citric, acetic, benzoic, succinic, p-aminobenzoic, p-acetamidobenzoic, 
methanesulfonic, ethanedisulfonic, or isethionic acid. 
In general, the daily dose can be from about 0.10 mg./kg. to about 100 
mg./kg. per day and preferably from 1 mg./kg. to 10 mg./kg. per day, 
bearing in mind, of course, that in selecting the appropriate dosage in 
any specific case, consideration must be given to the patient's weight, 
general health, metabolism, age and other factors which influence response 
to the drug. 
Another embodiment of this invention is the provision of pharmaceutical 
compositions in unit dosage form which comprise from about 5 mg. to 500 
mg. of a compound of the above formula. 
The pharmaceutical compositions may be in a form suitable for oral use, for 
example, as tablets, solutions, aqueous or oily suspensions, dispersible 
powders or granules, emulsions, hard or soft capsules, or syrups or 
elixirs. Compositions intended for oral use may be prepared according to 
any method known to the art for the manufacture of pharmaceutical 
compositions and such compositions may contain one or more agents selected 
from the group consisting of sweetening agents, flavoring agents, coloring 
agents and preserving agents in order to provide a pharmaceutically 
elegant and palatable preparation. Tablets contain the active ingredient 
in admixture with non-toxic pharmaceutically acceptable excipients which 
are suitable for manufacture of tablets. These excipients may be, for 
example, inert diluents, for example calcium carbonate, sodium carbonate, 
lactose, calcium phosphate or sodium phosphate; granulating and 
disintegrating agents, for example, maize starch or alginic acid; binding 
agents, for example, starch, gelatin or acacia, and lubricating agents, 
for example, magnesium stearate, stearic acid or talc. The tablets may be 
uncoated or they may be coated by known techniques to delay disintegration 
and adsorption in the gastro-intestinal tract and thereby provide a 
sustained action over a longer period. 
Formulations for oral use may also be presented as hard gelatin capsules 
wherein the active ingredient is mixed with an inert solid diluent, for 
example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin 
capsules wherein the active ingredient is dissolved or mixed with an oil 
or aqueous medium, for example, arachis oil, liquid paraffin, olive oil or 
water. 
Aqueous suspensions or solution containing the active compound in admixture 
with excipients are suitable for the manufacture of aqueous suspensions. 
Such excipients are suspending agents, for example, sodium carboxymethyl 
cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, 
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting 
agents may be a naturally occurring phosphatide, for example lecithin, or 
condensation products of an alkylene oxide with fatty acids, for example 
polyoxyethylene stearate, or condensation products or ethylene oxide with 
long chain aliphatic alcohols, for example heptadecaethyleneoxy-cetanol, 
or condensation products of ethylene oxide with partial esters derived 
from fatty acids and a hexitol, for example polyoxyethylene sorbitol 
mono-oleate, or condensation products of ethylene oxide with partial 
esters derived from fatty acids and hexitol anhydrides, for example 
polyoxyethylene sorbitan mono-oleate. The said aqueous suspensions may 
also contain one or more preservatives, for example ethyl, or n-propyl 
p-hydroxybenzoate, one or more coloring agents, one or more flavoring 
agents and one or more sweetening agents, such as sucrose, saccharin, or 
sodium or calcium cyclamate. 
Oily suspensions may be formulated by suspending the active ingredient in a 
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut 
oil, or in a mineral oil such as liquid paraffin. The oil suspensions may 
contain a thickening agent, for example beeswax, hard paraffin or cetyl 
alcohol. Sweetening agents, such as those set forth above, and flavoring 
agents may be added to provide a palatable oral preparation. These 
compositions may be preserved by the addition of an anti-oxidant such as 
ascorbic acid. 
Dispersible powders and granules suitable for preparation of an aqueous 
suspension by the addition of water provide the active ingredient in 
admixture with a dispersing or wetting agent, suspending agent and one or 
more preservatives. Suitable dispersing or wetting agents and suspending 
agents are exemplified by those already mentioned above. Additional 
excipients, for example sweetening, flavoring and coloring agents, may 
also be present. 
The pharmaceutical compositions of the invention may also be in the form of 
oil-in-water emulsions. The oily phase may be a vegetable oil, for example 
olive oil or arachis oils, or a mineral oil, for example liquid paraffin 
or mixtures of these. Suitable emulsifying agents may be naturally 
occurring gums, for example gum acacia or gum tragacanth, naturally 
occurring phosphatides, for example soya bean lecithin, and esters of 
partial esters derived from fatty acids and hexitol anhydrides, for 
example sorbitan mono-oleate and condensation products of the said partial 
esters with ethylene oxide, for example polyoxyethylene sorbitan 
mono-oleate. The emulsions may also contain sweetening and flavoring 
agents. 
Syrups and elixirs may be formulated with sweetening agents, for example 
glycerol, sorbitol or sucrose. Such formulations may also contain a 
demulcent, a preservative and flavoring and coloring agents. The 
pharmaceutical compositions may be in the form of a sterile injectable 
preparation, for example as a sterile injectable aqueous solution or 
suspension. This aqueous medium may be formulated according to the known 
art using those suitable dispersing or wetting agents and suspending 
agents which have been mentioned above. The sterile injectable preparation 
may also be a sterile injectable solution or suspension in a non-toxic 
parenterally acceptable diluent or solvent, for example as a solution in 
1:3 butane diol. 
The pharmaceutical compositions may be tableted or otherwise formulated so 
that for every 100 parts by weight of the composition there are present 
between 5 and 95 parts by weight of the active ingredient and preferably 
between 25 and 85 parts by weight of the active ingredient. The dosage 
unit form will generally contain between about 0.10 mg. and about 500 mg. 
of the active ingredient of the formulae stated above. 
From the foregoing formulation discussion it is apparent that the 
compositions of this invention can be administered orally or parenterally. 
The term parenteral as used herein includes subcutaneous injection, 
intraveneous, intramuscular, or intrasternal injection or infusion 
techniques. In addition, the compounds can be given rectally as 
suppositories or topically with penetrants. 
The following examples are presented to further illustrate the invention.

EXAMPLE 1 
1-Ethyl-2-iminopyrrolidine 
2-Amino-1-pyrroline (1.26 g., 15 mmoles) and 4.68 g. (30 mmoles) of ethyl 
iodide were refluxed in 10 ml. of ethanol for 2 hours. The cooled mixture 
was diluted with ether and refrigerated overnight. The oil that 
precipitated was collected, dissolved in methanol and treated with excess 
potassium carbonate. The solvent was evaporated and the residue was 
extracted with chloroform, and the chloroform was concentrated to dryness. 
This residue was dissolved in alcohol and treated with 1 g. of oxalic 
acid. After heating to provide a clear solution, it was cooled and treated 
with ether to incipient cloudiness. The solid that separated was 
discarded, and the mother liquors were concentrated to dryness. The 
residue was dissolved in water and extracted with chloroform. The aqueous 
solution was basified with sodium hydroxide solution, and extracted with 
chloroform. Concentration of the chloroform to dryness provided 630 mg. of 
oily 1-ethyl-2-iminopyrrolidine which was converted to 680 mg. of the 
hydrogen oxalate salt, m.p. 68.degree.-75.degree. C. (as a hydrate). 
EXAMPLE 2 
2-Imino-1-methyl-1,2,5,6-tetrahydropyridine 
Step A: Preparation of 1-methyl-2-oxo-1,2,5,6-tetrahydropyridine 
A mixture of 20 g. of vinylacrylic acid, 400 ml. of methylamine solution 
(40% aqueous by weight) and 0.5 g. of hydroquinone was heated overnight at 
170.degree. C. in a stainless steel pressure vessel. After cooling, the 
mixture was concentrated to dryness and the residue was fractionally 
distilled. The fraction distillng at 125.degree.-130.degree. C. at 0.4-0.5 
mm. Hg. (12.5 g.) was shown by n.m.r. to be the desired 
1-methyl-2-oxo-1,2,5,6-tetrahydropyridine. 
Steps B: Preparation of 2-imino-1-methyl-1,2,5,6-tetrahydropyridine 
A mixture of 3.0 g. of 1-methyl-2-oxo-1,2,5,6-tetrahydropyridine from Step 
A, 50 ml. of methylene chloride, and 4.1 g. of trimethyl oxonium 
fluoborate was stirred at room temperature for 41/2 hours. The mixture was 
concentrated to dryness, and the residue was treated with 50 ml. of 
concentrated ammonium hydroxide, and sodium hydroxide solution. The 
strongly basic mixture was extracted 5 times withchloroform. The 
chloroform extract was extracted with dilute hydrochloric acid. The acid 
extract was made basic with sodium hydroxide solution and extracted 5 
times with chloroform. The chloroform extract was washed with water, dried 
(Na.sub.2 SO.sub.4) and concentrated to dryness to give 1.89 of oily 
2-imino-1-methyl-1,2,5,6-tetrahydropyridine. Conversion to the oxalate 
salt and recrystallization from ethanol/ether gave 1.23 g. of 
2-imino-1-methyl-1,2,5,6-tetrahydropyridine, hydrogen oxalate, m.p. 
110.degree.-112.degree. C. 
EXAMPLE 3 
6-Amino-2-imino-1-methyl-1,2-dihydropyridine 
Step A: Preparation of methyl 2,6-difluoropyridinium fluorosulfonate 
A mixture of 5 g. of 2,6-difluoropyridine and 15 g. of methyl 
fluorosulfonate was warmed at 70.degree.-100.degree. C. for 4 minutes. The 
solid mass was cooled, suspended in methylene chloride and collected on a 
filter to give 9.9 g. of methyl 2,6-difluoropyridinium fluorosulfonate. 
Step B: Preparation of 6-amino-2-imino-1-methyl-1,2-dihydropyridine 
Methyl 2,6-difluoropyridinium fluorosulfonate (2 g.) was added to excess 
concentrated ammonium hydroxide solution, and the mixture was evaporated 
to dryness. The residue was stirred in acetonitrile and filtered. The 
filtrate was concentrated to dryness. The residue was suspended in 
chloroform and collected on a filter to give 1.08 g. of 
6-amino-2-imino-1-methyl-1,2-dihydropyridine, fluorosulfonate. This 
material was dissolved in 50 ml. of ethanol and treated with 6 g. of solid 
potassium carbonate, stirred for 3 hours, and concentrated to dryness. The 
residue was stirred in isopropanol and filtered. The filtrate was treated 
with 1 g. of oxalic acid in isopropanol. The precipitate was collected, 
dissolved in hot ethanol, treated with decolorizing charcoal, for 5 
minutes, filtered and concentrated to dryness. The residue was suspended 
in isopropanol and collected on a filter to give 950 mg. of 
6-amino-2-imino-1-methyl-1,2-dihydropyridine, hydrogen oxalate, which 
after recrystallization from ethanol, had m.p. 166.degree.-168.degree. C. 
(dec.). 
EXAMPLE 4 
Pharmaceutical Compositions 
A typical tablet containing 150 mg. of 2-imino-1-methylpyrrolidine per 
tablet is prepared by mixing together with the active ingredient calcium 
phosphate, lactose and starch in the amounts shown in the table below. 
After these ingredients are thoroughly mixed, the dry mixture is blended 
for an additional three minutes. This mixture is then compressed into 
tablets. Similarly prepared are tablets containing 
2-imino-1-methyl-1,2,5,6-tetrahydropyridine or other compound within the 
scope of this invention. 
______________________________________ 
Tablet Formula 
Ingredient Mg. per tablet 
______________________________________ 
Active Ingredient 150 mg. 
Calcium phosphate 52 mg. 
Lactose 60 mg. 
Starch 10 mg. 
Magnesium stearate 1 mg. 
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