Derivatives of 1,3,4-thiadiazole, a method of obtaining them and pharmaceutical compositions containing them

The present invention relates to thiadiazole derivatives having the formula: ##STR1## in which: R.sub.1 represents a phenyl group, non-substituted or substitued 1 to 3 times by a halogen atom, preferably chlorine or fluorine, or by a C.sub.1 -C.sub.4 alkyl group, preferably the methyl group, or by a C.sub.1 -C.sub.4 alkoxy group, preferably the methoxy group, or by a hydroxy group or by a trifluoromethyl group or a phenyl group substituted simultaneously by 1 to 3 halogen atoms and by 1 or 2 methyl groupings; PA1 R.sub.2 represents hydrogen or a C.sub.1 -C.sub.4 alkyl group, PA1 R.sub.3 represents an alkylamino group or a heterocyclic group, Application: Drugs for treatment of notably senile dementia.

The invention relates to novel thiadiazole derivatives, the method of 
preparing them, and the use thereof in therapy. 
Some thiadiazole derivatives are known in the prior art. European patent 
application 183 577 describes derivatives of 2-(2-morpholino ethylamino) 
thiadiazole having the formula: 
##STR2## 
in which R represents an alkyl or cycloalkyl or biphenyl or naphthyl or 
phenyl group (substituted if required). 
These compounds have antidepressant and dopaminomimetic properties. 
Also an article in the Journal of Pharmaceutical Sciences, 1975, 65, No. 7, 
1250-1252 describes derivatives of 2-amino thiadiazole having the 
formulae: 
##STR3## 
in which: R' represents methyl, trifluoromethyl or monosubstituted phenyl 
and 
R" represents methyl or ethyl. 
These compounds have antihistamine and anticholinergic properties. 
Accordingly, European patent application 183 577 and the aforementioned 
article from J. Pharm. Sci. describe 1,3,4-thiadiazole derivatives 
substituted by a phenyl grouping in position 5 and by an amine grouping in 
position 2. 
In both cases the amine grouping has the form: 
##STR4## 
in which X is a straight-chain carbon group or included in a ring system 
comprising two carbon atoms. 
In the invention, we have found novel 1,3,4-thiadiazole derivatives 
carrying a phenyl grouping, substituted if required, in position 5 and an 
amine grouping having the form 
##STR5## 
in position 2, where the grouping A between the two nitrogen atoms 
comprises three or four carbon atoms, the grouping being either 
straight-chain, i.e. trimethylene or tetramethylene, or included in a ring 
containing either of the nitrogen atoms. 
In completely surprising manner, it has been found that these compounds are 
agonists of the cholinergic muscarinic system whereas on the contrary the 
prior-art compounds where the grouping X contains only two carbon atoms 
have no effect on the cholinergic muscarinic system. 
According to a first feature, the invention relates, as novel products, to 
thiadiazole derivatives having the general formula: 
##STR6## 
in which: R.sub.1 represents a phenyl group, non-substituted or substitued 
1 to 3 times by a halogen atom, preferably chlorine or fluorine, or by a 
C.sub.1 -C.sub.4 alkyl group, preferably the methyl group, or by a C.sub.1 
-C.sub.4 alkoxy group, preferably the methoxy group, or by a hydroxy group 
or by a trifluoromethyl group or a phenyl group substituted simultaneously 
by 1 to 3 halogen atoms and by 1 or 2 methyl groupings; 
R.sub.2 represents hydrogen or a C.sub.1 -C.sub.4 alkyl group, 
R.sub.3 represents: 
##STR7## 
in which A.sub.1 denotes a straight chain C.sub.3 -C.sub.4 alkyl group, 
R.sub.4 and R.sub.5 considered independently represent hydrogen or a 
C.sub.1 -C.sub.4 alkyl group, or R.sub.4 and R.sub.5 considered with the 
nitrogen atom bonded thereto constitute a heterocyclic ring system made up 
of 5 or 6 links and if required containing a second heteroatom, inter alia 
one of the following rings: pyrrolidine, imidazole, piperidine, 
morpholine, piperazine or N-alkylpiperazine; or 
##STR8## 
where the methylene group substitutes the pyridine ring in position 3 or 
4; 
##STR9## 
where the ethylene group substitutes the pyridine ring in position 2 or 
3; 
##STR10## 
where R.sub.6 denotes a methyl or ethyl group and A.sub.2 denotes a 
(CH.sub.2).sub.m group where m=1 or 2, the A.sub.2 group being in position 
3 or 4 of the piperidine ring when m=1 and in position 2 or 3 thereof when 
m=2, 
##STR11## 
or alternatively the substituent 
##STR12## 
represents a group 
##STR13## 
where R.sub.6 is as indicated hereinbefore and salts of addition thereof 
with mineral or organic acids. 
The invention also relates to a method of obtaining compounds of formula 
(I), the method being characterized in that a corresponding 2-halogeno 
1,3,4-thiadiazole having the formula: 
##STR14## 
in which X represents chlorine or bromine and R.sub.1 is as above defined 
is reacted with a compound having the formula: 
EQU --HN R'.sub.2 R'.sub.3 (III) 
in which R'.sub.2 and R'.sub.3 have the same meanings as R.sub.2 and 
R.sub.3 defined hereinbefore R'.sub.2 is a protective group when hydrogen 
and, if required, the product thus obtained is converted into one of its 
pharmaceutically acceptable salts. 
the substitution reaction (II)+(III) is brought about in the presence 
either of a reagent which fixes the hydracid XH formed during the 
reaction, or an excess of amine (III) at a temperature between 40.degree. 
C. and 130.degree. C. The reaction is carried out in a polar solvent such 
as alkanol e.g. ethanol, n-butanol or isopropanol or in a non-polar 
solvent such as benzene. It is preferable to operate in a nitrogen 
atmosphere to avoid carbonation of the amine (I) formed. 
The resulting product is isolated by conventional methods, e.g. by 
evaporating the solvent and chromotographing the residue, or by 
evaporating the solvent and isolating the base, after recrystallization if 
required, or by evaporating the solvent and isolating the product in the 
form of one of its salts by treating the residue, consisting of the crude 
free base, with a solution of an acid, e.g. in an alcohol. 
When the final product is isolated in salt form, the free base can be 
released by neutralization. 
When R.sub.1 denotes the hydroxyphenyl or polyhydroxyphenyl group, the 
compounds according to the invention are obtained by demethylation of 
compounds (I) in which R.sub.1 represents a methoxyphenyl or 
polymethoxyphenyl group, using a known method, e.g. heating in an acid 
medium. 
The halogenated starting products (II) are known or can be prepared by 
known methods. For example, products (II) can be obtained from the 
following amino compounds: 
##STR15## 
Diazotation is carried out, followed by decomposition of the diazonium 
salt, in the presence of hydracid XH, by the methods described in 
Chemische Berichte, 1956, 89, 1534-1543 and Tetrahedron, 1968, 24 
3209-3217. 
Amino thiadiazoles (IV) are known or can be prepared by known methods, 
consisting in converting the acid R.sub.1 COOH or the acid chloride 
R.sub.1 OCL into the corresponding thiosemicarbazide and in conversion 
thereof to cyclic form, using a dehydration agent by the methods described 
in J. Pharm. Soc. Japan, 1952, 72, 373-375; J. Chem. Soc., 1949, 1163-1167 
and Can. J. Chem., 1959, 37, 1121-1123. The dehydration agent can be 
polyphosphoric acid or methane sulphonic acid or sulphuric acid when 
R.sub.1 represents a phenyl grouping. 
Compounds HN R.sub.2 R.sub.3 (III) are known or are prepared by known 
methods. 
When R.sub.3 represents a group A.sub.1 --NR.sub.4 R.sub.5 in which A.sub.1 
is tetramethylene, either the diamine 
EQU R.sub.2 NH--(CH.sub.2).sub.4 --N R.sub.4 R.sub.5 (III) 
can be prepared by known methods, or it can be reacted with the thiadiazole 
derivative (II) or the compound (I) according to the invention can be 
obtained by catalytic hydrogenation of the corresponding acetylene 
derivative of thiadiazole (V), in accordance with the following reaction 
diagram: 
##STR16## 
Compound (V) can be obtained by substitution of thiadiazole (II) by 
2-butyne 1,4-diamine (VI): 
##STR17## 
The reaction is carried out under conditions similar to those described for 
substitution of (II) by the derivative HN R.sub.2 R.sub.3 (III). 
Compounds (VI) can be prepared by various known methods depending on the 
values of the substituents R.sub.2, R.sub.4 and R.sub.5. 
For example, a symmetrical compound (VI) in which R.sub.2 =R.sub.4 =alkyl 
and R.sub.5 =H is prepared from 2-butyne 1,4-diol by action of excess 
thionyl chloride in pyridine followed by action of the amine NH.sub.2 
R.sub.2 on the resulting dichlorinated derivative, in accordance with the 
following reaction diagram described in J. Chem. Soc., 1946, 1007-1014: 
##STR18## 
Also, derivatives (VI) in which R.sub.2 represents hydrogen can be 
synthesized form N-propargyl phthalimide, which is subjected to a Mannich 
reaction to form the N(4-amino 2-butynyl) phthalimide by the method 
described in Eur. J. Med. Chem.--Chim. Ther., 1982, 17, 85-88. 
##STR19## 
Finally, derivatives (VI) in which R.sub.2 represents an alkyl can 
alternatively be synthesized by the methods described in Can. J. Chem., 
1980, 58, 2183-2188; by aminomethylation of an N-alkyl 
N-propargylphosphoramide followed by acid hydrolysis of the product 
obtained, in accordance with the following reaction diagram: 
##STR20## 
In the special case where R.sub.3 represents a group: 
##STR21## 
in which at least one of the substituents R.sub.4 and R.sub.5 is hydrogen, 
the amino derivatives (III) must be protected. They can be prepared from 
the aminonitrile R.sub.4 NH--A'.sub.1 --CN. This substance, when reacted 
with the anhydride (Boc).sub.2 O, leads to the aminonitrile 
##STR22## 
which, by reduction leads to the corresponding primary amine 
##STR23## 
where A'.sub.1, deprived of a methylene group and Boc represent the 
tertiobutyloxycarbonyl grouping. 
When R.sub.2 is different from H, a known method is then used to prepare 
the appropriate diamine: 
##STR24## 
The substitution reaction of thiadiazole (II) with diamine (VII) or (VIII) 
is carried out under the usual conditions. Finally, the resulting compound 
is deprotected in an acid medium to prepare the compound (I) according to 
the invention.

The following examples illustrate the invention without limiting it. In 
these examples, the term Boc denotes the tertiobutyloxycarbonyl grouping. 
EXAMPLE 1 
2-(3-dimethylamino propylamino)-5-(2,4,6-trimethylphenyl)-1,3,4 thiadiazole 
dihydrochloride: SR 45 341 A 
A) 2,4,6-trimethyl benzoyl thiosemicarbazide 
37.25 g of thiosemicarbazide was dissolved in 400 ml dimethylformamide and 
32.05 g of pyridine, after which 74 g of 2,4,6-trimethylbenzoyl chloride 
was added at 0.degree. C. in 20 minutes. The reaction mixture was heated 
at 80.degree. C. for 2 hours and then concentrated to three-quarters in 
vacuo and the remaining mixture was poured into 1500 ml of cold water. The 
resulting white precipitate was filtered, washed in water and dried. 
78 g was obtained 
Yield: 81% 
Melting-point above 260.degree. C. 
B) 2-amino 5-(2,4,6-trimethylphenyl)-1,3,4-thiadiazole 
60 g of 2,4,6-trimethylbenzoyl thiosemicarbazide previously obtained was 
mixed with 1250 g of polyphosphoric acid. The mixture was heated at 
130.degree. C. with agitation for 18 hours, then poured into 20 liters of 
cold water. The resulting precipitate was filtered, washed in ethyl 
acetate and in isopropyl ether and dried. 
Weight obtained: 22.9 g 
Yield: 41% 
Melting-point: about 280.degree. C. 
C) 2-chloro 6-(2,4,6-trimethylphenyl)-1,3,4-thiadiazole 
24.5 g of 2-amino 5-(2,4,6-trimethylphenyl) 1,3,4-thiadiazole and 122.5 g 
of sodium nitrite were mixed in a mortar. The mixture was added in 
portions at -10.degree. C. and for two and a half hours to a solution 
containing 302 ml of hydrochloric acid concentrated to 37% (d=1.19) and 5 
g copper. Next, the reaction mixture was slowly heated to 0.degree. C. 
after 30 minutes and +15.degree. C. after an hour. The mixture was left 
overnight at ambient temperature, then 1 liter of water was added. It was 
extracted twice with 700 ml of ethylacetate, and then washed with 500 ml 
of 2-N soda and 200 ml of water saturated with sodium chloride. It was 
dried over sodium sulphate, concentrated and the residue was 
chromatographed on silica gel. The impurities at the top were eliminated 
by a mixture of methylene chloride and hexane (60/40), after which the 
expected product was eluted with methylene chloride. 
Weight obtained: 17.3 g 
Melting-point: 90-92.degree. C. 
Yield: 65% 
D) SR 45 341 A 
3.6 g of dimethylamino propylamine was added to 2.8 g of 2-chloro 
5-(2,4,6-trimethylphenyl) 1,3,4-thiadiazole dissolved in 60 ml butanol and 
reflux-heated in a nitrogen atmosphere for 18 hours. The mixture was 
concentrated then dissolved in 200 ml ethyl acetate and extracted with 
twice 50 ml of 4 N hydrochloric acid. The medium was made basic by adding 
concentrated soda and cooling in ice, then extracted with twice 150 of 
ethyl acetate, dried on sodium sulphate and concentrated. After 
chromatography on alumina, using ethyl acetate as an eluent, the 
impurities at the top were eliminated and the expected product was eluted 
in base form by a mixture of ethyl acetate and methanol (50/50). 
Weight obtained: 2.7 g 
Melting-point: 102.degree.-104.degree. C. 
Yield: 76% 
The mixture was dissolved in 150 ml ethanol and 2.26 ml of concentrated 
hydrochloric acid was added. The mixture was left to crystallize and then 
filtered to obtain the expected product. 
Weight obtained: 2.9 g 
Yield: 65% 
Melting-point: 216-218.degree. C. 
EXAMPLE 2 
2-(3-dimethylamino propylamino) 5-(3,5-dibromo-2,4,6-trimethylphenyl) 
1,3,4-thiadiazole: SR 45 639 A 
A) 2-bromo 5-(5-bromo-2,4,6-trimethylphenyl)-1,3,4-thiadiazole and 2-bromo 
5-(3,5-dibromo-2,4,6-trimethylphenyl)-1,3,4-tiadiazole 
24.5 g of 2-amino 5-(2,4,6-trimethylphenyl) thiadiazole obtained previously 
was mixed with 122.5 g of sodium nitride in a mortar. The composition was 
added in portions at -30.degree. C. to a solution comprising 402 ml of 47% 
hydrobromic acid and 5 g copper. The mixture was slowly and gradually 
heated to a temperature of -20.degree. C. after 1 hour and +10.degree. C. 
after 2 hours, then heated to 35.degree. C. for 2 hours. 1 liter of cold 
water is added, followed by extraction twice with 700 ml of ethylacetate. 
The mixture was washed with 500 ml of 2 N soda then with 200 ml of water 
saturated with sodium chloride. It was dried on sodium sulphate and 
concentrated. The residue was chromatographed on silica gel and eluted 
with methylene chloride. 
The first eluted compound was 2-bromo 
5-(3,5-dibromo-2,4,6-trimethylphenyl)-1,3,4-thiadiazole. 
Weight obtained: 6.2 g 
Melting-point: 131-132.degree. C. 
the second eluted compound was 2-bromo 
5-(5-bromo-2,4,6-trimethylphenyl)-1,3,4-thiadiazole. 
Weight obtained: 19.3 g 
Melting-point: 91.degree. C. 
B) SR 45 639 A 
a solution of 2.2 g of the dibromo derivative and 2.04 g of dimethylamino 
propylamine was reflux-heated with agitation and in a nitrogen atmosphere 
overnight in 20 ml of n-butanol. The mixture was concentrated then 
dissolved in 200 ml of ethyl acetate. It was extracted twice with 100 ml 
of 4 N hydrochloric acid. It was decanted then washed with 50 ml ethyl 
acetate. The mixture was made alkaline by adding 120 ml of concentrated 
soda and cooling. It was extracted with ethylacetate and then dried on 
sodium sulphate and concentrated. 1.9 g of the expected product was 
obtained in base form. 
Yield: 82% 
Melting-point: 162-164.degree. C. 
The base was dissolved in 200 ml of absolute alcohol, 1.6 ml of 
concentrated hydrochloric acid was added, and the mixture was filtered 
while hot, concentrated to 100 ml. crystallized and then centrifuge-dried. 
1.8 g of the expected product was obtained. 
Melting-point: 234-236.degree. C. 
Yield: 65% 
EXAMPLE 3 
Dihydrochloride of 2-(4-diethylamino 
butylamino)-5-phenyl-1,3,4-thiadiazole: SR 45 339 A 
A) 2-[(4-diethylamino butyn-2-yl) amino]-5-phenyl-1,3,4-thiadiazole hydrate 
4 g of 2-bromo 5-phenyl-1,3,4-thiadiazole prepared as indicated in 
Tetrahedron, 1968, 24, 3214 was mixed with 6.98 g of 4-diethylamino 
butyn-2-yl amine prepared as indicated in Eur. J. Med. Chem. Chim. Ther., 
1982, 17, 85-88. The mixture was reflux-heated in 100 ml of ethanol for 48 
hours. The ethanol was concentrated in vacuo, and the residue was 
dissolved in a 4 N soda solution. It was extracted with ethyl acetate, 
then the organic phase was washed with water, dried on sodium sulphate and 
the residual oil was chromatographed on silica gel, using ethylacetate as 
the eluent. 
The pure fractions were concentrated in vacuo. Recrystallization from a 
mixture of hexane and isopropyl ether (50/50). 
The product crystallized with 1 molecule of water. 
Weight: 0.26 g 
Melting-point: 55.degree. C. 
B) SR 45 339 A 
Hydrogenation at atmospheric pressure was carried out for 20 hours on 1.75 
g of the compound prepared in the previous step and dissolved in 100 ml 
ethanol and 1 ml of concentrated hydrochloric acid, in the presence of 
platinum prepared in situ from 0.34 g of platinum oxide. 
The mixture was flushed out with nitrogen and the catalyst was filtered. 
The filtrate was concentrated, dissolved in ethyl acetate, and extracted 
with twice 50 ml of 4 N hydrochloric acid. Dilute soda was added to obtain 
a basic pH (pH=10-11). The mixture was extracted with ethylacetate, dried 
and concentrated. 
Weight obtained: 1.4 g 
Yield: 80% 
The base was dissolved in 70 ml ethanol and, after adding 1.1 of 
concentrated hydrochloric acid, was left to crystallize. It was 
centrifuge-dried then washed in isopropyl ether. 
Weight obtained: 0.85 g 
Total yield: 39% 
Melting-point: 158-160.degree. C. 
EXAMPLE 4 
2-(4-dimethylamino butylamino)-5-(2,4,6-trimethylphenyl)-1,3,4-thiadiazole 
dihydrochloride: SR 45 641 A 
4-dimethylamino butylamine was prepared by the method reported in 
Beilstein, Volume 4, Supplement 3, 573-574. 
4.28 g of 4-dimethylamino butylamine and 2.2 g 
2-chloro-5-(2,4,6-trimethylphenyl)-thiadiazole prepared as in Example 1, 
stage C, was added to 60 ml of normal butanol. 
The mixture was refluxed in a nitrogen atmosphere for 1 week, after which 
2.14 g of 4-dimethylamino butylamine was added and heating was continued 
for 1 week. After the mixture has been concentrated, the residue was 
dissolved in ethyl acetate, extracted twice with 50 ml of 4 N hydrochloric 
acid, then washed with ethyl acetate. The mixture was made alkaline with 
concentrated soda and cooled, then extracted with ethyl acetate, dried on 
sodium sulphate and concentrated. The residue was chromatographed on 
alumina; the impurities at the top were eliminated by elution with ethyl 
acetate, after which the expected product was eluted with a mixture of 
ethyl acetate and methanol (80/20). After concentration, an oil formed and 
coagulated and the expected product was obtained in base form. 
Weight obtained: 1.25 g 
Yield: 39% 
The product was dissolve din 100 ml of absolute alcohol, 10 ml of 
concentrated hydrochloric acid was added and the mixture was filtered 
while hot to remove impurities, then concentrated to a volume of 30 ml 
left to crystallize and then centrifuge-dried to obtain the expected salt. 
Weight: 0.8 g 
Melting-point: 216-218.degree. C. 
Total yield: 22% 
EXAMPLE 5 
2-(3-methylamino propylamino) 5-(2,4,6-trimethylphenyl) 1,3,4-thiadiazole 
dihydrochloride: SR 45 418 A 
A) N-phenyl N-Boc 3-amino propylamine 
34 g of N-3-methylamino-propionitrile was poured into 100 ml 
dichloromethane. 88 g of (Boc).sub.2 O was added with agitation and left 
for 18 hours with agitation at ambient temperature. The product after 
concentration was 77 g of N-methyl N-Boc 3-amino propionitrile, which was 
used as such. 
The product obtained was mixed with 800 ml water, 400 ml ethanol and 80 ml 
ammonia, followed by catalytic hydrogenation on activated Raney nickel for 
10 minutes. The volume of hydrogen absorbed was 16.7 liters. The mixture 
was concentrated, then dissolved in methylene chloride, decanted, dried on 
sodium sulphate and calcium chloride, and concentrated. An oil was 
obtained and used as such in the next step. 
B) SR 45 418 A 
A mixture containing 2.2 g of 2-chloro 5-(2,4,6-trimethylphenyl 
1,3,4-thiadiazole and 8.67 g of N-methyl N-Boc 3-amino propylamine was 
reflux-heated for 72 hours under nitrogen and with agitation in 60 ml of 
normal butanol. The mixture was concentrated then dissolved in 200 ml 
water and extracted twice with 200 ml of methylene chloride. It was washed 
in water, dried on sodium sulphate and concentrated. It was 
chromatographed on silica gel. The expected product was eluted with ethyl 
acetate. After concentration the residual oil crystallized form isopropyl 
ether. The product was in the form of a base in which the terminal 
nitrogen carried a Boc grouping. The substance was 2-(N-methyl N-Boc 
3-amino propylamino) 5-(2,4,6-trimethylphenyl)-1,3,4-thiadiazole. 
Weight obtained: 2.2 g 
Melting-point: 113-115.degree. C. 
Yield: 65% 
The base was dissolved in 150 ml of absolute alcohol followed by addition 
of 2.9 ml of concentrated hydrochloric acid. The mixture was concentrated 
to a volume of 100 ml, left to crystallize and filtered. 1.8 g of the 
expected product was obtained. 
Melting-point: 256-258.degree. C. 
Total yield: 54% 
EXAMPLE 6 
2-(4-methylamino piperidino)-5-phenyl-1,3,4-thiadiazole dihydrochloride: SR 
44 825 A 
2.4 g of 2-bromo 5-phenyl-1,3,4-thiadiazole was dissolved in 25 ml of 
normal butanol, 3.85 g of 4methylamino-1-methyl-piperidine were added and 
the mixture was reflux-heated in a nitrogen atmosphere. It was cooled, the 
precipitate was filtered and the filtrate was concentrated in vacuo. The 
residue was dissolve din 100 ml of ethyl acetate then extracted twice with 
50 ml of 3 N hydrochloric acid. It was made alkaline with 50 ml of 
concentrated soda with cooling. It was extracted with twice 100 ml of 
ethyl acetate, dried on sodium sulphate and concentrated. The residue was 
recrystallized form a mixture of methylene chloride and isopropyl ether. 
The product described was obtained in the form of a base. 
Weight: 0.83 g 
Melting-point: 96.degree. C. 
Yield: 29% 
The base was dissolved in 50 ml of absolute ethanol. 0.74 ml of 
concentrated hydrochloric acid were added, filtered when hot then 
concentrated to three-quarters on a water bath and left to crystallize. 
Weight: 0.9 g 
Total yield: 25% 
Melting-point&gt;260.degree. C. 
The RMN spectrum of SR 44 825 A was recorded in the DMSO at 250 MHz. 
In order to interpret the spectrum, the following abbreviations have been 
used: 
D=doublet, T=triplet, Q=quartet, M=multiplet, J.ltoreq.coupling constant, 
a=axial, e=equatorial. 
______________________________________ 
##STR25## 
RMN SPECTRUM 
Delta Aspect Protons Attribution 
______________________________________ 
1,7 Q D 2 H H.beta.a 
J = 4Hz 
J = 14Hz 
2,15 D of Q 2 H H.beta.e 
J = 4Hz 
J = 14Hz 
2,5 T 3 H CH.sub.3 
3,25 T of D 2 H H.alpha.a 
J = 14Hz 
J = 4Hz 
4 D of T 2 H H.alpha.e 
J = 14Hz 
J = 4Hz 
7,5 M 3 H H 3,4 and 5 
7,75 M 2 H H 2 and 6 
______________________________________ 
EXAMPLE 7 
Dihydrochloride and hydrate of 2-[N-methyl N-(1-methyl 4-piperidyl) amino 
-5-phenyl-1,3,4-thiadiazole: SR 44828 A 
2.4 g of 2-bromo 5-phenyl-1,3,4-thiadiazole was dissolved in 25 ml of 
normal butanol. 3.85 g of 4-methylamino-1-methyl-piperidine were added and 
reflux-heated overnight in a nitrogen atmosphere. The mixture was cooled, 
the resulting precipitate was filtered and dissolved in 20 ml of 2 N soda. 
The mixture was extracted with 100 ml of methylene chloride, dried on 
sodium sulphate and concentrated, followed by chromatography on silica gel 
and eluting with a mixture of methylene chloride and methanol (60/40). 
0.77 g of the expected product was obtained in base form. 
Melting-point: 74.degree.-76.degree. C. 
Yield: 27% 
The base was dissolved in 50 ml of absolute ethanol, 0.62 ml of concentrate 
hydrochloric acid was added, insoluble substance was filtered when hot and 
concentrated to three-quarters in the water bath and left to crystallize. 
Weight obtained: 0.65 g 
Yield: 19% 
Melting-point: 276.degree.-278.degree. C. 
EXAMPLE 8 
Dihydrochloride and hydrate of (4-pyridyl)-2-methylamino 
5-(2,4,6-trimethylphenyl) 1,3,4-thiadiazole: SR 45 638 A 
2.2 g of 2-chloro 5-(2,4,6-trimethylphenyl)-1,3,4-thiadiazole and 4.98 g of 
4-aminomethyl-pyridine were mixed in 20 ml of normal butanol. The mixture 
was reflux-heated for 48 hours in a nitrogen atmosphere. The reaction 
mixture was concentrated then dissolved in 30 ml water and extracted twice 
with 50 ml of methylene chloride, dried on sodium sulphate and 
concentrated. The residue was chromatographed on alumina nd eluted with 
ethyl acetate. After the impurities of the first fraction had been 
eliminated, the subsequent fractions were concentrated and the residual 
oil was crystallized. 
1.6 g of the expected product was obtained in base form. 
Melting-point: 136.degree.-138.degree. C. 
Yield: 56% 
The base was dissolve din 100 ml of absolute ethanol and 1.3 ml of 
concentrated hydrochloric acid was added. The insoluble substance was 
filtered and the filtrate was concentrated to a total volume of 30 ml. It 
was left to crystallize, then centrifuge-dried to obtain the expected 
product. 
Weight: 1.5 g 
Melting-point: 200-202.degree.C. 
Total yield: 41% 
EXAMPLE 9 
2-(3-dimethylamino propylamino)-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole 
dihydrochloride: SR 45 642 A 
A mixture comprising 4 g of 
2-chloro-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole and 6.36 g of 
3-dimethylamino propylene was reflux-heated overnight in 30 ml normal 
butanol in a nitrogen atmosphere. The mixture was concentrated then 
dissolve din 100 ml ethyl acetate and extracted twice with 70 ml of 4 N 
hydrochloric acid. 90 ml of concentrated soda was added with cooling, and 
the resulting precipitate was filtered and washed with water. The 
precipitate was dissolved in methylene chloride, then dried on sodium 
sulphate and concentrated. 
The extracted product was obtained in base form. 
Weight: 4 g 
Yield: 80% 
Melting-point 147.degree.-149.degree. C. 
2.25 g of the base was dissolved in 100 ml absolute ethanol and 1.787 ml of 
concentrated hydrochloric acid was added. The impurities were filtered 
when hot The filtrate was concentrated to a volume of 30 ml, then left to 
crystallize and filtered to obtain the expected salt. 
Weight: 2.4 g 
Melting-point: 210.degree.-212.degree. C. 
Yield: 66% 
EXAMPLE 10 
Dihydrobromide, hydrate of 2-(dimethyl-3-amino 
propylamino)-5-(3,4-dihydroxyphenyl) 1,3,4-thiadazole: SR 45 643 A 
A mixture containing 1.7 g of SR 45 642 in base form and 25 ml of 47% 
hydrobromic acid was reflux-heated for 7 hours. The mixture was 
concentrated in vacuo and then dissolved in 150 ml of hot absolute 
ethanol. It was filtered then concentrated to a volume of 50 ml. It was 
left to crystallize then filtered to obtain the expected product. 
Weight: 2.45 g 
Yield: 95% 
Melting-point: 172.degree.-174.degree. C. 
EXAMPLE 11 
2-[(N-methyl 3-piperidyl) methylamino]-5-(4-chlorophenyl)-1,3,4-thiadiazole 
dihydrochloride: SR 45 491 
A) N-methyl-3-aminomethyl-piperidine 
This compound was prepared from 3-aminomethyl-pyridine by the method 
described in Biochem. J., 1971, 122, 557-567. 
B) 2-chloro-5-(4-chlorophenyl)-1,3,4-thiadiazole 
Preparation of this compound is described in U.S. Pat. No. 4,454,147. 
Melting-point: 122.degree. C. 
C) SR 45 491 A 
This compound is obtained from the products obtained in step A and step B, 
by the method described in the preceding Examples. 
The hydrochloride is formed in the ethyl ether and 2-propanol solvent 
mixture. 
Melting-point: 178.degree. C. 
Other compounds (I) according to the invention were prepared by methods of 
operation similar to those described hereinbefore. They are describe in 
Table 1 hereinafter and characterized by their melting point (Fc). 
TABLE 1 
______________________________________ 
##STR26## (I) 
N.degree. 
N.degree. Fc .degree.C. 
Product Example R.sub.1 R.sub.3 (solvent) 
______________________________________ 
SR 44824 A 
12 phenyl 3-dimethyl- 
230-232 
2HCl amino EtOH 
propyl 
SR 45340 A 
13 5-bromo 3-dimethyl- 
218-220 
2HCl, H.sub.2 O 2,4,6-tri- 
amino EtOH 
methyl- propyl 
phenyl 
SR 45352 A 
14 2,4,6- 3-diethyl- 
188-190 
2HCl trimethyl 
amino EtOH 
phenyl propyl 
SR 45417 A 
15 2,4,6- 3-pyridyl 
190-192 
2HCl trimethyl 
methyl EtOH 
phenyl 
SR 45421 A 
16 4-fluoro 3-dimethyl- 
233-235 
2HCl phenyl amino iPrOHEt.sub.2 O 
propyl 
SR 45422 A 
17 2,4- 3-dimethyl- 
230-231 
2HCl dichloro amino Et.sub.2 O 
phenyl propyl 
SR 45447 A 
18 4-fluoro 3-pyridyl 
183-184 
2HCl phenyl methyl iPrOHEt.sub.2 O 
0,5 H.sub.2 O 
SR 45458 A 
19 2,4- 3-pyrrolidino 
230 
2HCl dichloro propyl iPrOH 
phenyl 
SR 45459 A 
20 2,4- 3-pyridyl 
228 
2HCl dichloro methyl iPrOH 
phenyl 
SR 45460 A 
21 2,4- 4-pyridyl 
246 
HCl dichloro methyl iPrOH 
phenyl 
SR 45479 A 
22 2,4- 3-methyl- 
237 
2HCl dichloro amino iPrHO 
phenyl propyl 
SR 45480 A 
23 4-chloro 3-dimethyl- 
238 
2HCl phenyl amino iPrOH 
propyl 
SR 45481 A 
24 2,4- 3-diethyl- 
122 
2HCl dichloro amino iPrOH 
phenyl propyl 
SR 45482 A 
25 4-fluoro 4-pyridyl 
222-224 
HCl phenyl methyl iPrOHEt.sub.2 O 
SR 45483 A 
26 4-fluoro 3-dimethyl- 
180-182 
2HCl phenyl amino iPrOHEt.sub.2 O 
1,5 H.sub.2 O* propyl 
SR 45488 A 
27 4-chloro 3-pyridyl 
208 
phenyl methyl Et.sub.2 O 
SR 45489 A 
28 4-chloro 3-(4-methyl 
256-257 
3 HCl phenyl 1-piperazinyl) 
iPrOH 
propyl 
SR 45490 A 
29 2,4- 2-(1-methyl 
228 
2HCl dichloro 2-pyrro- iPrOH 
0,5 H.sub.2 O phenyl lidinyl) 
ethyl 
SR 45492 A 
30 2,4- 2-(2-pyridyl) 
212 
2HCl dichloro ethyl iPrOH 
phenyl 
SR 45504 
31 2,4- 3-(1-imi- 
258 
2HCl dichloro dazolyl) iPrOH 
phenyl propyl 
SR 45520 A 
32 4-chloro 3-morpholino 
242 
2HCl, H.sub.2 O phenyl propyl iPrOH 
SR 45530 A 
33 4-fluoro 3-pyridyl 
254 
2HCl* phenyl methyl iPrOH 
SR 45544 A 
34 4-chloro 4-pyridyl 
244 
HCl phenyl methyl iPrOH 
0,5 H.sub.2 O 
SR 45640 A 
35 4-tri- 3-dimethyl- 
220-222 
2HCl fluoro- amino EtOH 
methyl propyl 
phenyl 
SR 45716 A 
36 3-tri- 3-dimethyl- 
198-200 
2HCl fluoro- amino EtOH 
methyl propyl 
phenyl 
SR 45717 
37 2-chloro 3-dimethyl- 
244-246 
2HCl phenyl amino EtOH 
propyl 
SR 45718 
38 3-chloro 3-dimethyl- 
215-217 
2HCl phenyl amino 
propyl 
______________________________________ 
*The radical R.sub.2 represents hydrogen except for the following 
compounds: 
SR 45483 A where R.sub.2 denotes ethyl and 
SR 45530 A where R.sub.2 denotes methyl 
The following abbreviations have been used for the recrystallization 
solvents: EtOH=ethanol, iPrOH=isopropanol, Et.sub.2 O=ethyl ether. 
The melting point (Fc) of certain compounds in base form was measured after 
they had been purified by chromatography: 
______________________________________ 
Example No 
______________________________________ 
12 Fc = 66-68.degree. C. 
14 Fc = 62-64.degree. C. 
15 Fc = 130-132.degree. C. 
35 Fc = 148-150.degree. C. 
36 Fc = 79-81.degree. C. 
37 Fc = 62-64.degree. C. 
38 Fc = 76-78.degree. C. 
______________________________________ 
The products according to the invention were studied with regard to their 
pharmacological properties, more particularly their affinity for 
cholinergic muscarinic receptors. 
They were studied by biochemical tests in vitro and also by pharmacological 
tests in the animal. 
BIOCHEMICAL STUDY IN VITRO 
Two sub-classes of cholinergic muscarinic receptors exist in mammals: 
receptors M.sub.1 and M.sub.2. 
M.sub.1 type receptors are concentrated in certain zones of the brain such 
as the hippocampus, the cerebral cortex, the corpus striatum and the 
sympathetic ganglia. These connection sites can be selectively tagged with 
tritiated pirenzepine (.sup.3 H--PZ). Type M.sub.2 receptors predominate 
in the heart and the ileum and can be tagged with tritiated 
N-methylscopolamine (.sup.3 H--NMS). In order to determine the selectivity 
of the products according to the invention, with regard to sites M.sub.1 
and M.sub.2, a study was made of their interaction in vitro, with 
high-affinity tagging with .sup.3 H--PZ and .sup.3 H--NMS, on rat 
hippocampus membranes and smooth muscle from guinea-pig ileum 
respectively. 
Procedure 
a) Search for an affinity for the type M.sub.1 muscarinic cholinergic 
receptor 
The interaction of molecules with type M.sub.1 muscarinic receptors was 
studied in vitro on homogenized rat hippocampus, by studying the 
displacement of tritiated pirenzepine form its specific tagging sites. 10 
.mu.l portions of homogenized rat hippocampus (5% w/v) in an Na.sub.2 
HPO.sub.4 buffer (50 mM, pH 7.40) were incubated at 4.degree. C. for 2 
hours in the presence of .sup.3 H--Pz (76 Ci/mmol/l nM final), with 
increasing concentrations of the product under study. The final volume was 
2 ml. The reaction was stopped by centrifuging for 10 minutes at 50 000 g. 
After decantation and washing of the bottoms, the tagged radioactivity was 
counted by liquid scintillation. Non-specific tagging was determined in 
the presence of 10 .mu.M of atropine sulphate. The 50 inhibiting 
concentration (IC.sub.50) was determined graphically. 
(Ref: J. D. Watson, W. R. Roeskoe and H. I. Yamamura, Life Sci., 1982, 31, 
2019-2029). 
b) Search for an affinity for the type M.sub.2 muscarinic cholinergic 
receptor 
Interaction with type M.sub.2 muscarinic receptors was studies in vitro on 
homogenized smooth muscle of guinea-pig ileum by measuring the 
displacement of tritiated N-methyl-scopolamine from its specific tagging 
sites. 50 .mu.l portions of homogenized smooth muscle form guinea-pig 
ileum (0.625% w/v) in 20 mM of HEPES buffer: 2-((2-hydroxy 4-ethyl) 
piperazin-1-yl) ethanesulphonic acid containing NaCl (100 mM) and Mg 
Cl.sub.2 (10 mM) (final pH=7.5) were incubated at 30.degree. C. for 20 
minutes int eh presence of .sup.3 H--NMS (85 Ci/mmol/0.3 nM final) with 
increasing concentrations of the products under test. The final volume was 
1 ml. The reaction was stopped by centrifuging for 5 minutes at 15000 g. 
Non-specific tagging was determined in the presence of 10 mM of atropine 
sulphate. 
(Ref: R. Hammer et al., Nature, 1980, 283, 90-92; E. C. Hulme et al., Mol. 
Pharmacol., 1978, 14, 737-750). 
Results 
Table 2 shows the affinities of the products according to the invention for 
M.sub.1 and M.sub.2 receptors. The results are expressed as 50% inhibiting 
concentrations (IC.sub.50), i.e. the concentration (in .mu.M) which 
induces a 50% displacement of the tritiated ligand fixed to the membrane 
receptors. The IC.sub.50 displacement of .sup.3 H--PZ represents affinity 
for the M.sub.1 receptor, and 
The IC.sub.50 displacement of .sup.3 H--NMS represents affinity for the 
M.sub.2 receptor. 
In the next column of the Table we show the ratio R between the IC.sub.50 
for receptors M.sub.1 and M.sub.2, which expresses the selectivity of the 
products relative to one type of receptor. 
TABLE 2 
______________________________________ 
No.Product 
IC.sub.50 .mu.M.sup.3 H-PZ(M.sub.1) 
IC.sub.50 .mu.M.sup.3 H-NMS(M.sub.2) 
##STR27## 
______________________________________ 
SR 44824 A 
3 &gt;100 &gt;30 
SR 44825 A 
2.5 80 32 
SR 44828 A 
9 -- -- 
SR 45339 A 
5 34 7 
SR 45340 A 
3.5 27 6 
SR 45341 A 
0.45 72 160 
SR 45352 A 
5.5 30 5 
SR 45418 A 
20 &gt;100 &gt;5 
SR 45422 A 
0.70 26 37 
SR 45458 A 
0.8 12 15 
SR 45479 A 
14 70 5 
SR 45480 A 
4.5 50 11 
SR 45483 A 
2.4 20 8 
SR 45489 A 
3.6 26 7 
SR 45504 A 
3 40 13 
SR 45520 A 
4.5 80 17 
______________________________________ 
The results show that the compounds according to the invention have strong 
affinity for muscarinic cholinergic receptors, with a marked specificity 
for type M.sub.1 central receptors. 
PHARMACOLOGICAL STUDY IN VIVO 
Pirenzepine (PZ) is a specific antagonist of the M.sub.1 central muscarinic 
cholinergic receptors. Intrastriatal injection of PZ into the mouse 
induces rotatory behaviour. Antagonism to this behaviour by the products 
according to the invention was studied. 
The products according to the invention were administered in doses of 0.3 
or 3 mg/kg orally after being solubilized in distilled water or suspended 
in a 5% solution of gum arabic. The controls were given pure solvent under 
the same conditions. 
The animals used were female mice (Swiss, CD 1, Charles River, France), 
body weight between 25 and 30 grams. 
Pirenzepine was dissolved in a phosphate buffer, the pH of the solution 
being 6. 
The products under study or solvents thereof were orally administered, 
using a probang, in a volume of 0.4 ml per 20 g body weight. 
Administration occurred 4 hours before direct injection of pirenzepine, in 
a dose of 1 .mu.g in 1 .mu.l of solvent, into the right corpus striatum of 
the mouse, by the method described by P. WORMS at al in 
Psychopharmacology, 1987, 93, 489-492. 
The number of contralateral rotations (in the opposite direction to the 
side of the injection) was counted for three 2-minute periods after 
injection of pirenzepine (minutes 2-4, 8-10 and 13-15) and was then 
totalled for each animal. Each treatment comprised three to four doses and 
ten animals per dose. For each treatment, the total number of rotations 
and the percentage inhibition relative to the control batch (solvent) was 
calculated. 
The results are given in Table 3. 
By way of comparison, results are given for certain products known in the 
prior art. 
TABLE 3 
______________________________________ 
Product % inhibition 
n.degree. 0,3 mg/kg p.o. 
3 mg/kg p.o. 
______________________________________ 
SR 44824 A -7 -27** 
SR 44828 A -3 -26** 
SR 45339 A -49** -77** 
SR 45340 A -58** -95** 
SR 45341 A -31** -74** 
SR 45352 A -6 -32** 
SR 45417 A -7 -43** 
SR 45418 A -31** -77** 
SR 45421 A -10 -38** 
SR 45422 - -7 
-50** 
SR 45447 A -36** -62** 
SR 45458 A 0 -28** 
SR 45459 A -11 -29** 
SR 45480 A -35** -54** 
SR 45481 A -31** -67** 
SR 45482 A -23* -53** 
SR 45483 - 0 
-20* 
SR 45488 A -19 -49** 
SR 45489 A 0 -29** 
SR 45490 A -47** -73** 
SR 45491 A -6 -57** 
SR 45492 A -12 -50** 
SR - A -27* -60** 
SR 45520 A -34** -75** 
SR 45530 A -6 -41** 
A -8 -8 
B Inactive Inactive 
C -6 -12 
______________________________________ 
*p &lt; 0.05 in Student's test 
**p &lt; 0.01 in Student's test. 
##STR28## 
##STR29## 
? 
##STR30## 
? 
The results in table 3 show that the compounds according to the invention 
stimulate central cholinergic transmission and are therefore capable of 
use as agonists of the muscarinic receptors. 
It has been found that the comparison products do not affect the central 
cholinergic transmission. 
The products according to the invention do not show any sign of toxicity at 
the doses at which they are effective. 
The acute toxicity was determined for one product according to the 
invention: SR 45341 A. The product was orally administered in increasing 
doses to a batch of 10 female mice (Swiss, CD 1, Charles River, France), 
body weight 20 g. 
The death rate caused by the product under study was noted during the 24 
hours after administration of the product. The 50% lethal dose (DL.sub.50) 
was determined, i.e. the dose which killed 50% of the animals. 
This dose was above 300 mg/kg. 
Compounds (I) can therefore be used as drugs. 
In view of the aforementioned results, the products according to the 
invention may be of use in the treatment of degenerative syndromes 
associated with ageing, inter alia disturbances of memory and senile 
dementia. 
The invention therefore also relates to pharmaceutical compositions 
containing at least one of the formula (I) compounds or a salt thereof as 
the active ingredient. 
In pharmaceutical compositions according to the invention for oral or 
sublingual or transdermic or rectal administration, the active ingredients 
of formula (I) hereinbefore can be administered in unit forms of 
administration, mixed with conventional pharmaceutical excipients. The 
appropriate unit forms of administration comprise oral forms, such as 
pills, capsules, powders, granulates and oral solutions or suspensions; 
sublingual and buccal forms, subcutaneous forms, intramuscular or 
intravenous forms and rectal forms. 
In order to obtain the desired effect, the dose of active principle may 
vary between 20 and 500 mg per day. 
Each unit dose can contain 5 to 200 mg of active ingredient in combination 
with a pharmaceutical excipient. The unit dose can be administered 1 to 4 
times per day. 
when a solid composition is prepared in the form of pills, the main active 
ingredient is mixed with a pharmaceutical vehicle such as gelatine, 
starch, lactose, magnesium stearate, talcum, gum arabic or the like. Pills 
can be coated with saccharose or other suitable substances or can be 
treated to give them prolonged or delayed activity and so that they 
continuously release a given quantity of active principle. 
A preparation in capsules can be obtained by mixing the active ingredient 
with a diluent and pouring the resulting mixture into soft or hard 
capsules. 
Water-dispersible powders or granulates can contain the active ingredient 
mixed with dispersion agent or wetting agents or suspension agents such as 
polyvinyl pyrrolidone, or with sweeteners or taste adjusters. 
Rectal administration is via suppositories prepared with binders melting at 
the rectal temperature, e.g. cocoa butter or polyethylene glycols. 
Parenteral administration is via aqueous suspensions, isotonic saline 
solutions or sterile injectable solutions containing pharmacologically 
compatible dispersion agents and/or wetting agents, e.g. propylene glycol 
or butylene glycol. 
Alternatively the active principle can be formulated in microcapsules, with 
one or more excipients or additives if required. 
As an example of a galenic preparation, capsules containing 
SR 45341 A: 0.010 g 
Lactose: 0.050 g 
Magnesium stearate: 0.005 g 
can be prepared by intimately mixing the aforementioned ingredients and 
pouring the mixture into hard gelatine capsules.