4-morpholinyl-1H-indoles, pharmaceutical compositions and use

Novel racemic mixtures and optical isomers of 4-morpholinyl-1H-indoles of the formula: ##STR1## wherein R and R.sub.1 are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms and R.sub.2 is selected from the group consisting of hydroxymethyl, alkylthiomethyl of 1 to 3 alkyl carbons, cyanomethyl and carboxy optionally esterified with an aliphatic alcohol of 1 to 5 carbon atoms or optionally amidified with an amine of the formula ##STR2## R.sub.3 is alkyl of 1 to 4 carbon atoms and R.sub.4 is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having the ability to activate neurons and to protect the same against ischemic or anoxic aggressions.

STATE OF THE ART 
French Pat. No. 2,501,208 and No. 2,512,817 and U.S. Pat. No. 4,313,944, 
No. 4,493,836 and No. 3,901,384 describe various indoles Clark in Journal 
of Heterocyclic Chemistry (Vol. 20, 1983), pages 1393-1395 describes the 
preparation of 4-(4-alkyl-2-morpholinyl)-indoles. 
OBJECTS OF THE INVENTION 
It is an object of the invention to provide the novel 
4-morpholinyl-1H-indoles of Formula I and their non-toxic, 
pharmaceutically acceptable acid addition salts and a process and 
intermediates for their preparation. 
It is another object of the invention to provide novel compositions to 
combat hypoxia and cerebral ischemia and to a novel method of treating 
said conditions. 
These and other objects and advantages of the invention will become obvious 
from the following detailed description. 
THE INVENTION 
The novel compounds of the invention are selected from the group consisting 
of racemic mixtures and optical isomers of 4-morpholinyl-1H-indoles of the 
formula: 
##STR3## 
wherein R and R.sub.1 are individually selected from the group consisting 
of hydrogen and alkyl of 1 to 4 carbon atoms and R.sub.2 is selected from 
the group consisting of hydroxymethyl, alkylthiomethyl of 1 to 3 alkyl 
carbons, cyanomethyl and carboxy optionally esterified with an aliphatic 
alcohol of 1 to 5 carbon atoms or optionally amidified with an amine of 
the formula 
##STR4## 
R.sub.3 is alkyl of 1 to 4 carbon atoms and R.sub.4 is selected from the 
group consisting of hydrogen and alkyl of 1 to 4 carbon atoms and their 
non-toxic, pharmaceutically acceptable acid addition salts. 
Examples of alkyl in the compounds of Formula I are methyl, ethyl, propyl 
and isopropyl and examples of the aliphatic alcohols of 1 to 5 carbon 
atoms are methanol, ethanol, propanol and isopropanol. Examples of alkyl 
thiomethyls are n-propylthiomethyl, ethylthiomethyl and preferably 
methylthiomethyl. 
Examples of suitable acids for the preparation of the non-toxic, 
pharmaceutically acceptable acid addition salts are mineral acids such as 
hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and 
phosphoric acid and organic acids such as formic acid, acetic acid, 
propionic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, 
citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkane sulfonic 
acids such as methane sulfonic acid and ethane sulfonic acid, arylsulfonic 
acids such as benzene sulfonic acid and p-toluene sulfonic acid and 
arylcarboxylic acids such as benzoic acid. 
Among the preferred compounds of Formula I are those wherein R is hydrogen 
and those wherein R.sub.2 is hydroxymethyl, alkylthiomethyl, cyanomethyl, 
carboxy and 
##STR5## 
wherein R.sub.4 and R.sub.5 are linear alkyl of 1 to 4 carbon atoms and 
their non-toxic, pharmaceutically acceptable acid addition salts. 
Especially preferred are compounds of Formula I wherein R.sub.2 is 
alkylthiomethyl and a specific compound is 
4-[(2R-cis)-4-methyl-6-methylthiomethyl-2-morpholinyl]-1H-indole and its 
acid addition salts. 
The novel process of the invention for the preparation of the compounds of 
Formula I comprises submitting a compound of the formula 
##STR6## 
wherein Alk is an alkyl of 1 to 4 carbon atoms to dehydrogenation to 
obtain a compound of the formula 
##STR7## 
which may be isolated and optionally salified or dimethylated to obtain a 
compound of the formula 
##STR8## 
which may be isolated and optionally salified or reacted with an 
alkylation agent to obtain a compound of the formula 
##STR9## 
wherein R'.sub.2 is R.sub.2 other than hydrogen which may be isolated and 
optionally salified or reacted with an alkali metal amide and then an 
alkyl halide R'-Hal wherein R' is alkyl of 1 to 4 carbon atoms and Hal is 
chlorine, bromine or iodine to obtain a compound of the formula 
##STR10## 
which may be isolated and optionally salified or is subjected to 
saponification to obtain a compound of the formula 
##STR11## 
which may be isolated and optionally salified or reacted with an amine of 
the formula 
##STR12## 
wherein R.sub.4 and R.sub.5 have the above definitions to obtain a 
compound of the formula 
##STR13## 
wherein R'.sub.3 is 
##STR14## 
which may be isolated and optionally salified or the compound of Formula 
I.sub.A may be reduced to form a compound of the formula 
##STR15## 
which may be isolated and optionally salified or reacted with methane 
sulfonyl chloride on p-toluene sulfonyl chloride to obtain a compound of 
the formula 
##STR16## 
wherein K is methyl or p-tolyl and reacting the latter with an alkali 
metal cyanide or alkylmercaptan to obtain a compound of the formula 
##STR17## 
wherein R".sub.3 is cyanomethyl or alkylthiomethyl which may be isolated 
and optionally salified and optionally submitting the compounds of 
Formulae I.sub.E, I.sub.F, I.sub.G and I.sub.H to one or more of the 
reactions the compounds of Formula I.sub.A were submitted to and 
optionally salifying the corresponding compounds of Formula I. 
In a preferred mode of the process of the invention, the compound of 
Formula II is dehydrogenated with manganese dioxide or with oxygen in the 
presence of a metal such as palladium or selenium. The demethylation of 
the product of Formula I.sub.A is effected preferably by reaction with 
cyanogen bromide followed by a reduction such as by the action of zinc in 
acetic acid. The alkylation of the compound of Formula I.sub.B is effected 
preferably with an alkyl halide, particularly an alkyl iodide, in the 
presence of a condensation agent such as an alkali metal carbonate. 
The halide of Formula IV can be a chloride or a bromide, but preferably an 
iodide and is reacted after action, particularly in ammonia, of an alkali 
metal amide, preferably sodium amide, on the product of Formula I.sub.C. 
The saponification of the compound of Formula I.sub.A is effected 
preferably by the action of a strong base such as 2N sodium hydroxide or 
preferably an alkali metal alcoholate such as sodium methylate; a 
hydrolysis in an acid medium can also be carried out, for example by the 
action of a mineral acid such as dilute hydrochloric acid in a solvent 
such as an alkanol of 1 to 5 carbon atoms, in particular ethanol. 
The reaction of the compound of Formula I.sub.E with the amine of Formula V 
to form the compound of Formula I.sub.F is effected preferably after 
activation of the carboxylic acid function by formation of a mixed 
anhydride, for example, by the action of trifluoroacetic anhydride or an 
alkyl haloformate such as isobutyl chloroformate. The reduction of the 
compound of Formula I.sub.A is effected preferably by the action of sodium 
borohydride at reflux of a solvent such as dioxane or a dioxane-methanol 
or dioxane-ethanol mixture; other reducing agents such as sodium 
cyano-borohydride can also be used. 
The reaction of the compound of Formula I.sub.G with methane sulfonyl 
chloride or p-toluene sulfonyl chloride is effected preferably in pyridine 
at ambient temperature. The reaction of the compound of Formula VI with 
alkylmercaptan is effected preferably at ambient temperature in a solvent 
such as dimethylacetamide in the presence of sodium hydride and the 
alkylmercaptan is preferably methylmercaptan. The alkali metal cyanide 
which is reacted with the compound of Formula VI is preferably sodium or 
potassium cyanide and the operation is advantageously effected in a 
solvent such as dimethylformamide. 
The compounds of Formula I, with the exception of compounds wherein R.sub.2 
is free carboxy, show a basic character and the addition salts of 
compounds of Formula I can advantageously be prepared by reaction with a 
mineral or organic acid, preferably stoichiometric proportions, with the 
said compounds of Formula I. The salts can be prepared without isolating 
the corresponding bases. 
The starting compounds of Formula II can be prepared, for example, by 
reacting a compound of the formula 
##STR18## 
with a methyl haloformate wherein the halogen is bromine or preferably, 
chlorine, to obtain a compound of the formula 
##STR19## 
which is reduced, preferably with boranetrimethylamine complex to obtain a 
compound of the formula 
##STR20## 
which is reacted with a halide, preferably benzyl chloride, to obtain a 
compound of the formula 
##STR21## 
which is reduced, preferably with aluminium-lithium hydride, to obtain a 
compound of the formula 
##STR22## 
which is reacted with an alkyl glycidate of the formula 
##STR23## 
wherein Alk has the above definition to obtain a compound of the formula 
##STR24## 
in which Alk has the significance already indicated, which is cyclized, 
for example by the action of N-chloro-diisopropylamine in the presence of 
hexamethylphosphoramine or, preferably, of trisdimethylaminophosphine, to 
obtain a product of the formula 
##STR25## 
in which Alk has the significance already indicated which is debenzylated, 
for example, by catalytic hydrogenation, to obtain the product sought of 
Formula II. 
The novel antihypoxia and anticerebral ischemia compositions of the 
invention are comprised of an antihypoxially and anticerbral ischemically 
effective amount of at least one compound of Formula I and their 
non-toxic, pharmaceutically acceptable acid addition salts and an inert 
pharmaceutical carrier or excipient. The compositions may be in the form 
of tablets, dragees, capsules, granules, suppositories or injectable 
solutions or suspensions. 
Examples of suitable excipients are talc, arabic gum, lactose, starch, 
magnesium stearate, cocoa butter, aqueous and non-aqueous vehicles, fatty 
substances of animal and vegetable origin, paraffin derivatives, glycols, 
various wetting, dispersing or emulsifying agents and preservatives. 
The compositions of the invention protect neurons against ischemic or 
anoxic aggressions and ensure their activation and they improve the 
cognitive processes. They are useful in the treatment of essential 
arterial hypertension, of hypertension of fifty-year olds, of menopause, 
of the diabetic, of obese and plethoric, as well as in the treatment of 
arterial hypertension of old people or people affected with 
arteriosclerosis and in the treatment of hypertension originating in the 
kidneys. They can also be used in the treatment of cerebral degeneration 
and senescence or manifestations connected with cerebral hypoxia. 
The novel method of the invention of treating cerebral hypoxia and ischemia 
in warm-blooded animals, including humans, comprises administering to 
warm-blooded animals an amount of at least one compound of Formula I and 
their non-toxic, pharmaceutically acceptable acid addition salts 
sufficient to combat cerebral hypoxia and ischemia. The compounds may be 
administered orally, rectally or parenterally and the usual daily dose is 
0.07 to 2.8 mg/kg depending on the condition treated, the specific 
compound and the method of administration. For example, the compound of 
example 3 may be administered at 0.07 to 0.7 mg/kg for treating cerebral 
senescene. 
The novel intermediates of the invention are the compounds of the formula 
##STR26## 
wherein Alk is alkyl of 1 to 4 carbon atoms.

In the following examples there are described several preferred embodiments 
to illustrate the invention. However, it should be understood that the 
invention is not intended to be limited to the specific embodiments. 
EXAMPLE 1 
Ethyl (2RS, 6RS)6-(1H-indole-4-yl)-4-methyl-2-morpholine carboxylate 
Step A: Methyl N-[2-(1H-indol-4-yl)-2-hydroxyethyl]carbamate 
A solution of 94 ml of methyl chloroformate in 285 ml of ethyl acetate was 
added dropwise with stirring to a suspension of 285 g of 
.alpha.-(aminoethyl)-1H-indole-4-methanol fumarate and 270 g of sodium 
bicarbonate in 2,850 ml of water and 2,850 ml of ethyl acetate. After 
stirring for 1 hour, the decanted aqueous phase was extracted with ethyl 
acetate. The combined organic phases were washed with a saturated aqueous 
solution of sodium chloride, dried and evaporated to dryness. The residue 
was dissolved in methylene chloride, evaporated to dryness and the residue 
was dissolved in 500 ml of hot methanol. The solution was cooled and 
isopropyl ether was added. The insoluble matter was filtered off and the 
filtrate was evaporated to obtain 202 g of methyl 
N-[2-(1H-indole-4-yl)-2-hydroxyethyl]carbamate. 
Step B: Methyl N-[2-(2,3-dihydro-1H-indol-4-yl)-2-hydroxyethyl]carbamate 
35.5 g of borane-trimethylamine complex and then, slowly and while cooling 
to 10.degree. C., 40.55 ml of 12N hydrochloric acid aqueous solution were 
added to a solution of 22.8 g of the product of Step A in 570 ml of 
dioxane and the mixture was stirred for 16 hours at ambient temperature. 
It was poured into 1,500 ml of water, washed with ethyl acetate, made 
alkaline with 48 ml of concentrated ammonia and was extracted with ethyl 
acetate. The organic phases were dried, filtered and evaporated to dryness 
to obtain 22.6 g of methyl 
N-[2-(2,3-dihydro-1H-indol-4-yl)-2-hydroxyethyl]carbamate which was 
crystallized from methanol to obtain 13.125 g of the product melting at 
.perspectiveto.174.degree. C. 
Step C: Methyl 
N-[2-(1-benzoyl-2,3-dihydro-1-H-indol-4-yl)-2-hydroxyethyl]carbamate 
66.6 ml of benzoyl chloride were dropwise with stirring under an inert 
atmosphere over 10 minutes to an emulsion of 90.3 g of product of Step B 
in 2,000 ml of chloroform and 573 ml of N sodium hydroxide. After 2 hours 
30 minutes of stirring, the mixture was diluted with 1 liter of water. The 
decanted aqueous phase was extracted with chloroform and the organic phase 
was washed with water, dried, evaporated to dryness under reduced pressure 
and crystallized from ethyl acetate to obtain 113.5 g ofm 
ethylN-[2-(1-benzoyl-2,3-dihydro-1H-indol-4-yl)-2-hydroxyethyl]carbamate 
melting at 143.degree. C. 
Step D: 
2,3-dihydro-.alpha.-[(methylamino)-methyl]-1-benzyl-1H-indol-4-methanol 
A solution of 113 g of the compound of Step C in 1,130 ml of dioxane was 
added slowly with stirring under an inert atmosphere to a suspension of 
110 g of aluminium-lithium hydride and 55 g of aluminium chloride in 1,700 
ml of dioxane. After 1 hour of stirring betweeen 80.degree. C. and 
50.degree. C. and cooling to 10.degree. C., the excess hydride was 
destroyed with an ammonium chloride-dioxane-water mixture. The resulting 
mixture was diluted with water, filtered, and the filtrate was 
concentrated by eliminating about 1,000 ml of solvent. After adding water 
and extracting with methylene chloride, the extracts were washed with 
water saturated with sodium chloride, dried and evaporated to dryness to 
obtain 95 g of crude product. The crude product was refluxed with stirring 
in 1 liter of ethyl acetate and 8.5 g of insoluble matter corresponding to 
the hydrochloride of the expected product were filtered off and melted at 
.perspectiveto.179.degree. C. The filtrate was concentrated hot to 400 ml, 
left to crystallize to obtain 55.19 g of 
2,3-dihydro-.alpha.-[(methylamino)-methyl]-1-benzyl-1H-indol-4-methanol 
melting at .perspectiveto.112.degree. C. 
Step E: ethyl 
3-[[2-[2,3-dihydro-1-benzyl-1H-indol-4-yl]-2-hydroxy-ethyl]methylamino]-2- 
hydroxy propanoate 
51.1 g of the product of Step D were refluxed for 4 hours with stirring 
under an inert atmosphere with 511 ml of 100% ethanol and 39 ml of ethyl 
glycidate and after evaporating at 40.degree. C. under reduced pressure 
(20 mm, then 0.5 mm Hg), 81.2 g of impure ethyl 
3-[[2-[2,3-dihydro-1-benzyl-1H-indol-4-yl]-2-hydroxy-ethyl]methylamino]-2- 
hydroxy propanoate which was used as is in the following stages. 
Step F: ethyl (2RS, 6RS) 
6-[2,3-dihydro-1-(benzyl)-1H-indol-4-yl]-4-methyl-2-morpholine carboxylate 
8.03 g of the compound of Step E were dissolved in 70 ml of methylene 
chloride and then cooled to -40.degree. C. 9.13 ml of 
N-chloro-diisopropylamine were added under an inert atmosphere and then 
slowly, 11 ml of trisdimethylaminophosphine were added. After stirring for 
15 minutes at -40.degree. C., the temperature was allowed to rise. The 
mixture was diluted with 70 ml of methylene chloride, washed with water, 
then washed with water saturated with sodium chloride, dried and 
evaporated to dryness, chromatographed over silica (eluant: benzene-ethyl 
acetate 7-3 with 0.5% triethylamine) to obtain 4.706 g of ethyl (2RS, 6RS) 
6-[2,3-dihydro-1-(benzyl)-1H-4-yl]-4-methyl-2-morpholine carboxylate with 
an Rf-0.12. 
Step G: ethyl (2RS, 6RS) 
6-(2,3-dihydro-1H-indol-4-yl)-4-methyl-2-morpholine carboxylate 
4.7 g of the compound of Step F were dissolved in 235 ml of acetic acid and 
1.18 g of palladium at 10% on charcoal were added. Hydrogen was passed for 
1 hour, followed by filtering, evaporating to dryness, taking up in 200 ml 
of water, and alkalizing to pH 9 with concentrated ammonia. Extraction was 
with methylene chloride and the extracts were dried and evaporated to 
dryness to obtain 2.683 g of ethyl (2RS, 6RS) 
6-(2,3-dihydro-1H-indole-4-yl)-4-methyl-2-morpholine carboxylate which 
after crystallization from isopropyl ether melted at 
.perspectiveto.92.degree. C. 
Step H: ethyl (2RS, 6RS) 6-(1H-indol-4-yl)-4-methyl-2-morpholine 
carboxylate 
3.45 g of ethyl (2RS, 6RS) 
6-(2,3-dihydro-1H-indol-4-yl)-4-methyl-2-morpholine carboxylate were 
dissolved in 345 ml of methylene chloride and 13.8 g of active manganese 
dioxide were added. The mixture was stirred for 30 minutes, filtered and 
washed with methylene chloride. The organic phase was evaporated to 
dryness under reduced pressure to obtain 3.185 g of ethyl (2RS, 6RS) 
6-(1H-indole-4-yl)-4-methyl-2-morpholine carboxylate. 
EXAMPLE 2 
N,N-diethyl 6-(1H-indol-4-yl)-4-methyl-2-morpholine carboxamide and its 
mesylate 
A mixture of 4.5 g of ethyl (2RS, 6RS) 
6-(1H-indol-4-yl)-4-methyl-2-morpholine carboxylate in 45 ml of methanol 
was stirred for 65 hours under inert atmosphere with 31.21 ml of a 
solution of 0.5M of sodium methylate in methanol and was then evaporated 
to dryness to obtain 4.33 g of the sodium salt of the acid which was used 
as is for the next stage. The 4.33 g of product were added with stirring 
under inert atmosphere to 75 ml of dioxane and 90 ml of dimethylformamide 
and 5.48 ml of tributylamine were added at 10.degree. C. Then, 3 ml of 
isobutyl chloroformate were added dropwise and after stirring for 90 
minutes, 7.93 ml of diethylamine were added dropwise. The mixture was 
stirred for 4 hours and 30 minutes and evaporated to dryness under reduced 
pressure. The dry residue was dissolved in water and the solution was 
extracted with chloroform. The extracts were washed with water, dried and 
evaporated to dryness and the residue was chromatographed over silica 
(eluant: methylene chloride/isopropanol 9/1), treated with activated 
charcoal and chromatographed over silica (eluant: methylene 
chloride-isopropanol 85-15) to obtain 0.888 g of the desired carboxamide. 
The said product was dissolved in isopropanol and 2.82 ml of a solution of 
1M/l of methane sulfonic acid in isopropanol were added. The mixture was 
slightly concentrated and 8 ml of isopropyl ether were added to obtain 
1.107 mg of the expected mesylate melting at 
.perspectiveto.110.degree.-115.degree. C. 
Analysis: C.sub.19 H.sub.29 N.sub.3 O.sub.5 S; molecular weight=411.52. 
______________________________________ 
Calculated: 
C % 55.46 H % 7.10 N % 10.21 
S % 7.79 
Found: 55.5 7.6 9.4 6.7 
______________________________________ 
EXAMPLE 3 
(2RS, 6RS) 6-(1H-indol-4-yl)-4-methyl-2-morpholine methanol and its neutral 
fumarate 
3.185 g of sodium borohydride were added to a solution of 3.185 g of the 
carbonamide product of Example 2 in 40 ml of methanol and 20 ml of dioxane 
and the mixture was reluxed with stirring for 1 hour and was then cooled 
and diluted with 400 ml of water. After extraction with methylene 
chloride, the extracts were dried and evaporated to dryness under reduced 
pressure and chromatographed over silica (eluant: methylene 
chloride-methanol 88-12) to obtain 2.105 g of the desired methanol 
product. 
The said product was dissolved in methanol and a solution of fumaric acid 
in methanol was added to obtain 2.238 g of the neutral fumarate melting at 
.perspectiveto.263.degree. C. with decomposition. 
EXAMPLE 4 
4-[(2R-cis) 4-methyl-6-[(methylthio)methyl]-2-morpholinyl]-1H-indole (dl) 
and its neutral fumarate 
Step A: (2RS, 6RS) 6-(1H-indole-4-yl)-4-methyl-2-morpholine p-toluene 
sulfonate methanol 
A solution of 8.58 g of tosyl chloride in 43 ml of pyridine was added 
dropwise at 10.degree. C. with stirring under an inert atmosphere to a 
solution of 5.542 g of the base of Example 3 in 55 ml of pyridine and the 
mixture was stirred for 3 hours at 10.degree. C. and left to rest at 
5.degree. C. for about 65 hours. It was then poured into 500 ml of iced 
water, and after extraction with methylene chloride, the extracts were 
washed with an aqueous solution of sodium bicarbonate, dried, evaporated 
to dryness under reduced pressure and chromatographed over silica (eluant: 
methylene chloride-acetone 1-1) to obtain 7.7 g of (2RS, 6RS) 
6-(1H-indole-4-yl)-4-methyl-2-morpholine p-toluene sulfonate methanol. 
Step B: 4-[(2R-cis) 
4-methyl-6-[(methylthio)methyl]-2-morpholinyl]-1H-indole (dl) and its 
neutral fumarate 
25 ml of dimethylacetamide were added to 9 ml of methyl mercaptan at 
0.degree. C. with stirring under an inert atmosphere and then 1.8 g of 
sodium hydride at 55% in oil were slowly added. After stirring for 90 
minutes, 2.5 g of the product of Step A in 15 ml of dimethylacetamide were 
added and the mixture was stirred for another 2 hours at ambient 
temperature. It was then poured into 400 ml of iced water and extracted 
with ethyl acetate. The extracts were washed with water and with a 
saturated aqueous solution of sodium chloride, dried and evaporated to 
dryness, chromatographed over silica (eluant: methylene 
chloride-isopropanol 95-5) to obtain 1.165 g of the expected indole 
product which after crystallization from isopropanol melted at 156.degree. 
C. 
By addition of a solution of fumaric acid in methanol to a solution of 
1.105 g of the said product dissolved in isopropanol, 1.124 g of the 
expected fumarate melting at 130.degree. C. and then 220.degree. C. were 
obtained. 
EXAMPLE 5 
(2SR, 6RS) 6-(1H-indol-4-yl)-4-methyl-2-morpholine acetonitrile and its 
neutral fumarate 
5 g of sodium cyanide were added to a solution of 2 g of the product of 
Step A of Example 4 in 20 ml of dimethyl sulfoxide and 5 ml of water and 
the mixture was heated to 60.degree. C. for 18 hours. The reaction mixture 
was poured into water and extracted with methylene chloride. The extracts 
were washed with water, dried and evaporated to dryness. The residue was 
chromatographed over silica (elutant: methylene chloride/methanol 95/5) to 
obtain 1.24 g of (2RS, 6RS) 6-(1H-indole-4-yl)-4-methyl-2-morpholine 
acetonitrile. 
A solution of 332 mg of fumaric acid in 10 ml of methanol was added to 5 ml 
of a methanol solution of 1.32 g of the said product and the mixture was 
evaporated to dryness. The product was crystallized from ethanol at 
95.degree. C. to obtain 1.40 g of the fumarate melting at 
.perspectiveto.206.degree. C. 
UV spectrum in 0.1N hydrochloric ethanol. 
______________________________________ 
Max. 213-220 nm E.sub.1.sup.1 = 1,355 
.epsilon. = 42,500 
Infl. 249 nm E.sub.1.sup.1 = 68 
Infl. 273 nm E.sub.1.sup.1 = 244 
Max. 280 nm E.sub.1.sup.1 = 267 
.epsilon. = 8,350 
Max. 288 nm E.sub.1.sup.1 = 245 
.epsilon. = 7,650 
______________________________________ 
EXAMPLE 6 
Tablets were prepared containing 10 mg of the neutral fumarate of 4-[(2R, 
cis)-4-methyl-6-(methylthiomethyl)-2-morpholinyl]-1H-indole (dl) and 
sufficient excipient of starch, lactose, magnesium stearate and talc for a 
final weight of 100 mg. 
PHARMACOLOGICAL DATA 
A: Test of labyrinth in T after partial lesion of the septo hippocampic 
route 
By means of an electrolytic partial lesion of neurons of the 
septo-hippocampic route, a disfunction of the cognitive faculty was 
provoked in male rats having acquired an apprenticeship in a labyrinth in 
the form of a T and then the speed of recovery of the disturbed memory 
faculties was measured. The animals got accustomed to their new 
environment on days -9 to -6 and rested on days -5 and -4. Their 
apprenticeship was carried out on days -3 to 0. At this time, the response 
of the rats was positive at 75-80%. On day 0, the lesion was carried out 
and the animals rested on days +1 to +3. The animals were tested on day +4 
and at this time, only 50% of the responses were positive. From day +5 to 
+8, the rats were tested after being treated orally with the products 
under test 1 hour earlier. On day +11, the rats were tested without 
treatment. The percentage of positive responses of the treated animals 
were compared in relation to the untreated animals. The product of Example 
4 significantly improved the recovery of the memory functions at a dose of 
20 mg/kg and therefore, it improved the cognitive processes. 
B: Test for enolase 
Injured cerebral cells release enolase .gamma..gamma. which is a specific 
indicator of neuron lesions. The lesions were brought about in mice by 
sub-cutaneous injection of 35 mg/kg of kainic acid. The test product was 
administered intraperitoneally at a dose of 1 mg/kg one hour before the 
injection of the neurotoxin, kainic acid. A protector of the cerebral 
cells in the injured area decreases the serous concentration of enolase. 
The product of Example 4 at a dose of 1 mg/kg decreased the serous 
concentration of enolase .gamma..gamma. by 34% and is therefore, a 
protector of neuron cells. 
C: Test for neuron activation 
Neuron activation causes an increase in the corresponding metabolism which 
is shown by an increase in the consumption of glucose, a proof of energy 
consumption. This increase was evaluated by measuring the accumulation in 
the neuron cells of 2deoxyglucose-6-phosphate stemming from the conversion 
by hexokinase of 2-deoxyglucose .sup.14 C, an analogue of glucose, 
administered as a tracer dose, which used the same route of entry into the 
cell as glucose. It was observed that the product of Example 4 caused an 
increase in the accumulation of 2-deoxyglucose 6-P in the hippocampus of 
the rat and it therefore, activated selectively the metabolism of certain 
mesolimbic structures. 
D: Acute toxicity study 
The lethal doses LD.sub.O of the different compounds tested were evaluated 
after oral administration to mice. The maximum dose which does not cause 
mortality in 8 days was called the LD.sub.O and the results obtained are 
in the following Table. 
______________________________________ 
Product of 
LD.sub.O 
example in mg/kg 
______________________________________ 
2 .gtoreq.200 
3 .gtoreq.400 
4 200 
5 .gtoreq.200 
______________________________________ 
Various modifications of the products and method of the invention may be 
made without departing from the spirit or scope thereof and it is to be 
understood that the invention is intended to be limited only as defined in 
appended claims.