LV10616B - Substituted cyclopropylamino-1,3,5-triazines - Google Patents

Abstract

The substituted cyclopropylamino-1,3,5-triazines corresponding to the common formula<IMAGE>where:R<1> - C1-3-alkyl, C3-5-cycloalkyl group, which is either unsubstituted or substituted with the C1-3-alkyl group;R<2> - bis(2-hydroxyethyl)amino-, 3-hydroxy-1-azethidinyl-, 3-methoxy -1-azethidinyl-, 3-oxy-1-azethidinyl-, morpholine-, 3,3,5,5-tetramethylmorpholine-, 4-oxypiperedine-, thiomorpholine-, S-oxy-thiomorpholine-, S-dioxy-thiomorpholine-, 3-tiazolidinyl-, S-oxy-3-tiazolidinyl-, S-dioxy-3-tiazolidinyl-, S or 8-oxy-3-azabicyclo(3,2,1)oct-3-yl group or salts of these compounds with non-toxic pharmaceutically compatible acids. Methods of obtaining these compounds and their application for therapeutic purposes are described.

Description

LV 10616

SUBSTITUTED CYCLOPROPYLAMINO-1.3.5-TRIAZINES

DESCRIPTION

The present invention relates to new substituted cyclopropylamino-l,3,5-triazines, to their pharmaceutically acceptable non-toxic acid addition salts and to processes for their preperation. It also relates to therapeutic compositions containing the said compounds. 2-trifluoromethyl-l,3,5-triazines carrying, inter alia, an alkyl, a substituted or unsubstituted alkylamino, a dialkylamino, a cycloalkylamino, a morpholino or a 4-alkyl-l-piperazinyl substituent radical in the 4 position, and any one of these substituent radicals, except alkyl, in the 6 position are known ffom Japanese Patent Application 25786/78. According to this patent application, these compounds have tranquillizing and anticonvulsive properties. K.WAKABAYASHI KO et ai: (Yuki Gosei Kagaku Kyokai Shi. 28, (1970), 252-260; Chem. Abstr., 72, (1970), 100653v) have furthermore synthesized 2-alkyl-4,6-bis-(alkylamino)-l,3,5-triazines in which the 2-alkyl radical contains 1 to 17 carbon atoms and is optionally a trichloromethyl, tribromomethyl or 2-chloroethyl group, and the radicals in the 4 and 6 positions are identical and can be substituted by a hydroxyl group, or be a nitrogen-containing heterocyclic radical, such as piperidino or morpholino radical. A representative compound of this family is 2-methyl-4,6-dimorpholino-l,3,5-triazine. These compounds were investigated for herbicidal activity and for an ability to inhibit conversion of ammonia into nitrate. However, no mention is made of any pharmacological properties. I· 2

Finally, British Patent No. 1,053,113 describes l,2-dihydro-l-hydroxy-l,3,5-triazines which carry an imino substituent radical, optionally substituted by an alkyl, alkenyl, cyc!oalkyl, phenyl or naphthyl (optionally substituted by an alkyl radical) radical, in the 2 position, a dia!kylamino, dialkenylamino, N-alkyl-alkenylamino, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl, heptamethyleneimino, octamethyleneimino or morpholino substituent radical in the 4 position (each of said heterocyclic radicals being possibly substituted by 1 to 3 alkyl radicals), and a hydrogen atom or an alkyl, alkenyl alkoxyalkyl, cycloalkyl, phenyl or naphthyl substituent radical, optionally substituted by an alkyl, aralkyl, alkylaralkyl, alkoxyaralkyl or halogenoaralkyl radical, in the 6 position. According to this patent, these compounds are antihypertensive aģents which can be used for the treatment of hypertension and shock; they are also described as secretion inhibitors and centra! nervous system depresants. These compounds ara prepared by oxidation of the corresponding 1,3,5-triazines carrying the same substituents in positions 2, 4 and 6. However, there is no suggestion in this patent that the intermediate 1,3,5-triazines could have any pharmacological activity. Moreover, this patent does not describe any 1,3,5-triazines having a cyclopropylamino substituent radical.

As a result of research work in this field, the applicant has now found new cyclopropylamino substituted 1,3,5-triazines which have useful pharmaceutical properties. In particular, the new compounds can promote learning and ameliorate the amnesic effect resulting from cholinergic hypofunctioning induced by a cholinergic antagonist such as, for example, scopolamine. The cholinergic system is widely involved in memomry and learning phenomena. Thus, for example, administration of an anticholinergic aģent such as scopolamine to young subjects gives rise to memory deficiencies similar to those observed in elderly subjects. Conversely, cholinergic aģents, such as physostigmine, are capable of combating the amnesia resulting from administration of anticholinergic aģents (S.D. GLICK et al., Behavioural Biology, 7, (1972), 245-254; and U. SCHINDLER et al., Drug Develop. Res. 4, (1984), 567-576). For this reason, compounds according to the invention can be used for the treatment of cognitive and behavioural disturbances associated with age and with dementia syndromes. In particular, they find a use in the treatment of disturbances associated with Alzheimer's disease, with senile dementias of the Alzheimer type and with any evolutive cognitive pathology (C.G. GOTTFRIES, Psychopharmacology, 86, (1985), 245-252; and C.G. GOTTFRIES, Neurobiology of Ageing, 4, (1983), 261-271). The compounds according to the present invention also have a Central serotonergic activity, demonstrated by the power vvhich they have of causing a particular stereotypy in rats usually known as LV 10616 &quot;wet dog shake&quot; (A.R. GREEN and D.J. HEAL in &quot;Neuropharmacology of Serotonin&quot;, Ed. A.R. GREEN, Oxford Univ. press, 1985, Chapter 12, pages 326 to 365). It is known that serotonin plays an important role in regulation of the neuroendocrine fiinction, which may be disturbed in pathologies such as depression, anxiety and mood disturbances. A reduction in serotonergic activity is associated with numerous changes in mood and somatic fiinctions occuring in depressed patients (Η.Υ. MELTZER and M.T. LOWY in &quot;Psychopharmacology: The Third Generation of Progress&quot;, Ed. Η.Υ. MELTZER, Raven Press, New York, 1987, Chapter 52, pages 513 to 520). The compounds according to the invention can thus be used for the treatment of these various pathologies associated with a slowing down in serotonergic activity.

In addition, at the peripheral Ievel, compounds according to the invention also have a bronchospasmolytic activity and an inhibiting activity on the release of mastocyte mediators during an anaphylactic attack. Compounds according to the invention moreover potentiate the muscle-relaxing effect of β-adrenergic agonists (for example isoprenaline) on a smooth muscle contracted by histamine, and also have an anti-inflammatory and anti-oedematous action. For this reason, compounds according to the invention can also be used in the treatment of bronchial asthma, in particular as an alternative to treatment with theophylline or even in association with bronchodilatory aģents such as P-sympathomimetic aģents, which are known .to cause, during prolonged administration, desensitization of the β-adrenergic receptors in the bronchi, to the extent of rendering the bronchospasm of chronic asthmatics insensitive to and irreversible under the action of these aģents.

More particularly, the present invention relates to new substituted cyclopropylamino-1,3,5-triazines corresponding to the general formula R2-

N: (I) īs

N

Ri in which Rļ represents an alkyl radical, having 1-3 carbon atoms, or a cycloalkyl radical, having 3-5 carbon atoms, which is unsubstituted or carries an alkyl radical substituent having 1-3 carbon atoms, and R2 represents a bis(2-hydroxyethyl)amino, 3-hydroxy-l-azetidinyl, 3-methoxy-l-azetidinyl, 3-oxo-l-azetidinyl, morpholino, 3,3,5,5- 4 tetramethylmorpholino, 4-hydroxy-piperidino, thiomorpholino, thiomorpholino S-oxide, thiomorpholino S, S-dioxide, 3-thiazolidinyl, 3-thiazolidinyl S-oxide, 3-thiazolidinyl S, S-dioxide or 8-oxa-3-azabicyclo(3,2,l)oct-3-yl radical, and to their pharmaceutically acceptable non-toxic acid addition salts.

The preferred compounds according to the present invention are the cyclopropylamino-1,3,5-triazines corresponding to the general formula I, in which R2 represents a morpholino or thiomorpholino radical, and their pharmaceutically acceptable non-toxic acid addition salts.

The particularly preferred compounds according to the invention are: -2-cyclopropylamino-4-morpholino-6-n-propyl-l,3,5-triazine, -2-cyclopropyl-4-cyclopropylamino-6-morpholino-l,3,5-triazinehydrochloride, -2-cyclobutyl-4-cyclopropylamino-6-morpholino-1,3,5-triazine and -2-cyclopropyl-4-cyclopropylamino-6-thiomorpholino-1,3,5-triazine.

The present invention also relates to the pharmaceutically acceptable non-toxic acid addition salts of the substituted cyclopropylamino-l,3,5-triazines of the formula I. Examples of acids which may be used to provide such salts include mineral acids, such as hydrochloric, hydrobromic, sulphuric, nitric, phosphoric acid etc., and organic acids, such as acetic, citric, tartaric, benzoic, salicylic, maleic acid etc.

If the molecule contains one or more centres of asymmetry, the compounds of formula I may be either in the form of a racemic mixture or in the form of one or other of the enantiomers. These various forms also fall within the scope of the present invention.

The substituted cyclopropylamino-l,3,5-triazines according to the present invention can be prepared by one of the following processes: (a) A chloro-cyclopropylamino-l,3,5-triazine of the formula II is reacted with an amine of the formula R2H (III) in accordance with the equation

R (II) (III) LV 10616

In these formulae, Rj and R2 have the meanings given above; (b) A chloro-l,3,5-triazine of the formula IV is reacted with cyclopropylamine of the formula V in accordance with the equation

* (Ο I·

In these formulae, Rj and R2 have the meanings given above.

Processes (a) and (b) above are carried out by heating at elevated temperature for several hours in an inert solvent, preferably dioxane or isopropyl alcohol; in general, they are carried out by heating at the boiling point of the solvent used and in the presence of a base. The base, which is used to trap the hydrochloric acid liberated in the course of the reaction, can be either the amine which itself is used in the reaction or another organic base (for example triethylamine) or an inorganic base (for example potassium carbonate).

The starting compounds of the formula II are prepared by conventional methods, by reacting a 2,4-dichloro-6-Rļ-l,3,5-triazine of the formula VI with cyclopropylamine in accordance with the equation

In these formulae, Rļ has the meaning given above.

This reaction is generally carried out at a temperature ofbetween -10°C and room temperature in an inert solvent, such as chloroform, and in the presence of an inorganic or organic base, such as, for example, potassium carbonate, to trap the hydrochloric acid liberated during the reaction. 6

The starting compounds of the formula IV are also prepared by conventional methods, by reacting a 2,4-dichloro-6-Rļ-l,3,5-triazine of the formula VI with an amine of the formula R2H (III) in accordance with the equation 6 Cl-

N N%-a

+ R2H

Ri (VI) . (ΠΙ) R2-ļ^NN-ClN^N Ri (IV)

In these formulae, R2 has the meaning given above.

This reaction is generally carried out at a temperature of between 0°C and 20°C in an inert solvent, such as chloroform, and in the presence of a base, for example potassium carbonate.

The 2,4-dichloro-6-Rj-l,3,5-triazines of the formula VI used as starting substances can be prepared by the process of R. HIRT et al. (Helv. Chim. Acta 33, (1950), 1365-1369), which comprises reacting cyanuric chloride with a suitable organomagnesium compound of the formula RļMgX, in which Rļ has the meaning given above and X represents a halogen atom, preferably an iodine or bromine atom. (c) An N-cyclopropylbiguanide of the formula VII is reacted with an alkyl ester of the formula VIII by heating under reflux for several hours in an aliphatic alcohol in the presence of an alkali mētai alcoholate in accordance with the equation

Γ^&gt;-ΝΗ NH R2 + R, -COOAlk

Π Π NH NH (VII) (VIII)

In these formulae, Rļ and R2 have the meaning given above and Alk represents an alkyl radical having 1 to 4 carbon atoms, preferably the ethyl radical.

The starting compounds of the formula VII are prepared by a two-stage process: (1) reaction of cyclopropylamine of the formula V with the sodium salt of cyanoguanidine of the formula IX to give N-cyano-N'-cyclopropylguanidine of the formula X in accordance with the equation LV 10616 &gt;

NaN(CN)2 NH NH- CN Π

NH (V) (IX) (X) (2) heating the N-cyano-N'-cyclopropylguanidine of the formula X with an amine of the formula R2H (III) at a temperature of about 160°C for several hours under an inert atmosphere to give the N-cyclopropylbiguanide of the formula VII in accordance with the equation [VnH NH-CN + R^H —* Γ&gt;-ΝΗ NH R2 ^ π π π

NH NH NH (X) (ΙΠ) (VH) t·

In these formulae, R2 has the meaning given above.

The pharmaceutically acceptable non-toxic acid addition salts can be prepared from the substitued cyclopropylamino-l,3,5-triazines of the formula I by methods which are known per se.

The examples which follow iilustrate the present invention, without limiting it. Example 1. Preparation of the startine 2.4-dichloro-6-Rl-1.3.5-triazines of the formula VI. 2.4.-Dichloro-6-ethvl-1.3.5-triazine. 1.5 equivalents of ethylmagnesium bromide dissolved in diethyl ether (prepared by reacting magnesium with ethyl bromide) are added dropwise to a suspension of one equivalent of cyanuric chloride in toluene, while keeping the temperature of the reaction mixture between 10 and 15°C. After the addition, this mixture is ķept at room temperature for one hour. An aqueous solution containing 1.5 equivalents of hydrochloric acid is then added. The two phases are separated, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The 2,4-dichloro-6-ethyl-l,3,5-triazine is purified by distillation under reduced pressure.

Yield: 63%. B.p.: 83°C/17mbar.

The compounds summarized in Table I are prepared in the same manner. 8

Table I 2,4-dichloro-6-Rļ-l,3,5-triazines R1 Solvent (1) Solvent (2) B.p.°C/mbar Yield (in %) methyl (3) Et20 toluene 80-82/16 40 n-propyl Et20 toluene 110/25 60 isopropyl Et20 toluene 87/20 29 cyclopropyl Et20 benzene -(4) - cyclobutyl THF toluene -(4) - cyclopentyl Et20 benzene 135/13 25

Et20: diethyl ether; THF: tetrahydrofbran. (1) : solvent used to prepare the organomagnesium compound, (2) : aromatic solvent used for the cyanuric chloride dispersion. (3) : organomagnesium compound prepared from methyl iodide, (4) : the reaction product is not isolated by distillation: after addition of the organomagnesium compound, the reaction mixture is concentrated and the residue is taken up in anhydrous diethyl ether. The mixture is filtered over neutral Dicalite, the filtrate is evaporated and the residue is used as such in the following stage.

Example2. Preparation of the cvclopropvlamino-1.3.5-triazines of the formula I bv process Tai

A, Preparation of the starting chloro-cvclopropvlamino-1,3.5-triazines of the formula IL 2-Chloro-4-cyclopropylamino-6-methyl-l,3,5-triazine (new compound). 1 mol cyclopropylamine dissolved in chloroform is added to a molar solution of 2,4-dichloro-6-methyl-l,3,5-triazine in chloroform, previously cooled to -10°C. After the addition, the mixture is allowed to retum to room temperature. The mixture is then cooled again to 0°C and an aqueous solution containing 1 mol potassium carbonate is added. Stirring is continued for 1 to 2 hours at room temperature. The organic phase is separated off and dried over sodium sulphate, and the solvent is evoparated off under reduced pressure. The residue is reciystallized from hexane. 2-Chloro-4-cyclopropylamino-6-methyl-l,3,5-triazine is thus obtained.

Yield: 75%. M.p.: 117-119°C.

The follovving new compounds are prepared in the same manner: LV 10616 2-Chloro-4-cyclopropylamino-6-ethyl-l,3,5-triazine, the residue obtained after evaporation of the solvent (crude yield: 100 %) is used as such in the following stage; 2-Chloro-4-cyclopropylamino-6-n-propyl-1,3,5-triazine.

Yield: 100%. B.p.: 12570.4 mbar.; 2-Chloro-4-cyclopropylamino-6-isopropyl-l,3,5-triazine, the compound is recrystallized from hexane,

Yield: 74%. M.p.: 79-80°C.; 2-Chloro-4-cyclopropyl-6-cyclopropylamino-l,3,5-triazine, this compound is recrystallized from hexane,

Yield (calculated on the basis of the cyanuric chloride): 71.5 % . M.p.: 66-67°C.; 2-Chloro-4-cyclobutyl-6-cyclopropylamino-l,3,5-triazine,

Crude yield (calculated on the basis of the cyanuric chloride): 23%; the product is used as such, without other purification, in the following stage and; 2-Chloro-4-cyclopentyl-6-cyclopropylamino-1,3,5-triazine Yield (crude): 100%; the crude product is used as such in the following stage. B. Preparation of the cyclopropylamino-1.3.5-triazines of the formula I. 1. 2-Cvclopropvlamino-4-morpholino-6-n-propvl-1.3.5-triazine ('compound IV 45 ml (0.45 mol) morpholine dissolved in 200 ml dioxane are added to a solution containing 43 g (0.163 mol) 2-chloro-4-cyclopropylamino-6-n-propyl-l,3,5-triazine in 300 ml dioxane, while maintaining the mixture at room temperature. After the addition, the mixture is heated under reflux for one to two hours. The reaction mixture is then allowed to retum to room temperature and the precipitate is filtered off. The filtrate is concentrated and the residue is redissolved in methylene chloride. The solution is washed with water. The organic phase is separated off and dried over sodium sulphate. The solvent is evaporated off under reduced pressure. The recidue is purified by chromatography on silica (eluant: 98.5 : 1.5 (v/v) methylene chloride-ethanol) and the product is finally recrystallized from diethyl ether. 36.2 g 2-cyclopropylamino-4-morpholino-6-n-propyl-l,3,5-triazine are obtained.

Yield: 85%. M.p.: 104°C.

Analysis for C13H21N5O in % : calculated: C 59.29 H8.04 N 26.59 found: 59.20 8.15 26.43

The compounds summarized in Table II are prepared in the same manner. 10

R,

Table II

Compound R1 r2 Y.(%) M.p.(°C) Analyses calculated% found % 2 ethyl morpholino 61 152(1) C 50.44 50.00 H 7.05 7.06 N 24.51 24.10 cr 12.40 12.50 3 cyclopropyl morpholino 67.4 183(1) c 52.44 52.77 H 6.72 6.80 N 23.53 22.16 cr 11.93 11.92 4. cyclobutyl morpholino 80.7 119 c 61.09 61.68 H 7.64 7.67 N 25.82 25.35 5 n-propy! 4-hydroxy- 63.9 102 C 60.65 60.98 piperidino H 8.30 8.46 N 25.27 24.04 6 n-propyl N(CH2CH2OH)2 68 124(1) C 49.13 49.54 H 7.56 7.48 N 22.05 22.85 cr 11.18 11.18 7 cyclopropyl N(CH2CH2OH)2 30.8 94 c 55.91 55.90 H 7.53 7.53 N 25.09 24.78 8 cyclopentyl morphilino 40 152(1) C 55.30 55.64 H 7.33 7.44 N 21.50 21.31 cr 10.90 10.84 (1) Hydrochloride: Prepared by addition of one equivalent of hydrochloric acid in diethyl ether to one equivalent of the free base dissolved in diethyl ether. LV 10616

2. 2-Cvclopropvlamino-4-methvl-6-('8-oxa-3-azabicvclo[3.2.11oct-3-vl')-1.3.5-triazine (compound 9Y 2 equivalents of triethylamine dissolved in dioxane are added to one equivalent of 8-oxa-3-azabicyclo[3,2,l] octane hydrochloride suspended in the same solvent. 1 equivalent of 2-chloro-4-cyclopropylamino-6-methyl-l,3,5-triazine dissolved in dioxane is then added. The mixture is heated under reflux for some hours. It is cooled to room temperature and the precipitate which has formed is filtered off. The filtrate is evaporated under reduced pressure and the residue is redissolved in methylene chloride. The solution is washed with water. The organic phase is separated off and dried over sodium sulphate, and the solvent is then evaporated off under reduced pressure. The residue thus obtained is purified by chromatography on silica (eluant: 98:2 (v/v) methylene chlorideethanol). 2-Cyclopropylamino-4-methyl-6-(oxa-3-azabicyclo[3,2,l]-oct-3-yl)-l,3,5-triazine hydrochloride is prepared by addition of one equivalent of hydrochloric acid to the free base in diethyl ether.

Yield: 63%. M.p.: 220-223°C.

Analysis for C13H19N5O.HCI in % : calculated: C 52.44 H6.77 N 23.52 CF 11.92 found: 52.40 6.74 23.43 11.84

The 8-oxa-3-azabicyclo[3,2,l]octane used as the starting substance in this example is a known compound; it was prepared by the method of F.H. NEWS et al, (J. Chem. Soc. 1948, 115-158).

The compounds summarized in Table III are prepared in the same manner.

12

Table III

Compound Rļ R2 Y.(%) M.p.(°C) Analyses calculated % found % 10 ethyl OABCO (2) 74 156-159 C 53.93 53.81 (0 H 7.11 7.14 N 22.46 22.22 cr 11.37 11.49 11 n-propyl OABCO 72 129-133 c 55.29 54.97 0) H 7.42 7.40 N 21.49 20.98 cr 10.88 10.86 12 isopropyl OABCO 59 149-153 c 55.29 55.10 0) H 7.42 7.39 N 21.49 21.25 cr 10.88 10.92 13 cyclopropyl 3-HO-azet-idinyl 30.4 111 c 58.30 58.42 H 6.88 6.84 N 28.34 28.20 14 cyclopropyl 3-CH30-azet- 47.3 64 C 59.77 60.05 idinyl H 7.28 7.30 N 26.82 26.50 15 n-propyl 3-HO-azet-idinyl 46.4 76 C 57.83 57.64 H 7.63 7.66 N 28.11 27.99 16 cyclopropyl OABCO 35 177 C 55.64 55.59 H 6.80 6.84 N 21.64 21.40 17 cyclopropyl 3-oxo-azet-idinyl 17.1 192-194 C 51.15 50.36 (1) H 5.68 5.74 N 24.87 24.30 (1) HydrochIoride

(2) OABCO = 8-oxa-3-azabicyclo[3,2,l]oct-3-yI LV 10616

The 3-oxo-azetidine hydrochloride used as the starting substance for the synthesis of compound 17 is known; it was prepared by the method of H. BAUMANN et al. (Helv. Chim.Acta,7L (1988), 1035)

3, at 2-Cvclopropvl-4-cvclopropvlamino-6-thiomorpholino-1.3.5-triazine (compound 18T 12.2 g 2-chloro-4-cyclopropyl-6-cyclopropylamino-l,3,5-triazine (0.057 mol), 5.97 g thiomorpholine (0.057 mol) and 8 g potassium carbonate (0.057 mol) are mixed in 100 ml isopropyl alcohol and the mixture is heated at 75 - 80°C for 2 hours. It is cooled, the salts are filtered off and the filtrate is evaporated to dryness. The residue is taken up in 200 ml methylene chloride, the solution is washed with water and dried over sodium sulphate and the solvent is evaporated off. The product obtained is crystallized from a 1 : 2 (v/v) mixture of ethyl acetate-hexane to give 13.18 g 2-cyclopropyl-4-cyclopropylamino-6-thiomorpholino-1,3,5-triazine.

Yield: 83.5%. M.p.: 133 - 134°C Analysis for C13H19N5S in % : calculated: C 56.32 H6.86 N 25.27 S 11.55 found: 56.06 6.83 24.90 11.40

The following compounds are prepared in the same manner: . b) 2-Cyclopropyl-4-cyclopropylamino-6-thiomorpholino-l,3,5-triazine S-oxide (compound 19).

Yield: 23%. M.p.: 167-168°C.

Analysis for 013Η19Ν508 in % : calculated: C 53.24 H6.48 N 23.89 S 10.92 found: 53.10 6.52 23.46 10.62 c) 2-Cyclopropyl-4-cyclopropylamino-6-thiomorphoIino-1,3,5-triazine S,S-dioxide (compound 20).

Yield: 17%. M.p.: 178-179°C.

Analysis for C^H^NsC^S in % : calculated: C 50.49 H6.15 N 22.65 S 10.36 found: 50.72 6.18 22.56 10.35 14

Example 3, Preparation of the cvclopropvlamino-1.3.5-triazines of the formula I bv process fb\ A. Preparation of the starting chloro-l,3.5-triazines of the formula IV. 2-Chloro-4-cvclopropyl-6-morpholino-1.3.5-triazine. A solution of 2.61 g (0.03 mol) morpholine in 20 ml chloroform is added to a solution of 5.7 g (0.03 mol) 2,4-dichloro-6-cyclopropyl-l,3,5-triazine in 50 ml chloroform, cooled to between 3 and 5°C, in the course of 30 minūtes. The temperature of the mixture is allovved to retum to about 10°C, and the mixture is then cooled again to 5°C and a solution of 4.14 g (0.03 mol) potassium carbonate in 15 ml water is added dropwise. The mixture is then stirred at room temperature for two hours. 30 ml water are added and the organic phase is separated off. The solution is washed with water and dried over sodium sulphate, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on silica (eluant: 96.5 :3.5 (v/v) methylene chloride-ethyl acetate) and then recrystallized from hexane. 5.5 g 2-chloro-4-cyclopropyl-6-morpholino-1,3,5-triazine are thus obtained.

Yield: 76.2%. M.p.: 99-100°C.

Analysis for C10H13CIN4O in %: calculated: C 49.89 H5.41 N 23.28 C114.76 found: 49.91 5.44 23.06 14.46 B. Preparation of the cvclopropvlamino-1.3.5-triazines of formula I. 2-Cvclopropvl-4-cvclopropvlamino-6-morpholino-1.3.5-triazine. 2.85 g (0.050 mol) cyclopropylamine dissolved in 20 ml dioxane are added to a solution of 5.1 g (0.021 mol) 2-chloro-4-cyclopropyl-6-morpholino-l,3,5-triazine in 50 ml dioxane at room temperature. The mixture is heated under reflux for 5 hours. The solvent is then evaporated off under reduced pressure and the residue is dissolved in 50 ml methylene chloride and 50 ml water. The organic phase is separated off and dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The residue crystallizes from cold hexane and 5.22 g product are obtained. This product forms a hydrochloride in an ethanol-diethyl ether mixture. 5.1 g 2-cyclopropyl-4-cyclopropylamino-6-morpholino-l,3,5-triazine hydrochloride, which is identical to compound 3 prepared in example 2.B.I., are obtained.

Yield; 81.7%. M.p.: 183-184°C (acetonitrile).

Analysis for C23H19N5O.HCI in %. calculated: C 52.44 H6.72 N 23.53 C1 ~11.93 found: 52.46 6.73 23.44 11.89 LV 10616

Example4. Preparation of the cvclopropvlamino-1.3.5-triazines of the formula I bv process(cY A. N-Cvano-N'-cvclopropvlguanidine. 9.36 g (0.1 mol) cyclopropyIamine hydrochloride and 8.9 g (0.1 mol) of the sodium salt of cyanoguanidine are suspended in 100 ml n-butanol and 8 ml water. The mixture is heated under reflux for 2 hours. The suspension is filtered and the residue is washed over a filter using 100 ml n-butanol. The filtrate is evaporated under reduced pressure. The residual oil is taken up in 300 ml acetonitrile. The mixture is brought to the reflux and filtered hot and the residue on the filter is vvashed with acetonitrile. The filtrate is evaporated and the oil obtained crystallizes slowly. 7.7 g N-cyano-N'-cyclopropylguanidine are obtained.

Yield: 62%. M.p.: 106°C (isopropyl alcohol/diethyI ether).

Analysis for C5H8N4 in %: calculated: C 48.37 H6.49 N45.13 found: 48.40 6.50 45.15

B. Preparation of the starting N-cvclopropvlbiguanides of the formula VIL N-rimino('cvclopropvlamino’)methylļ-4-morpholinocarboximide-amide fhvdrochlorideV A mixture of 4.0 g (32.3 mmol) N-cyano-N'-cyclopropylguanidine and 3.98 g (32.3 mmol) morpholine hydrochloride is heated at 160°C under a nitrogen atmosphere for 2 and a half hours. The solid mass obtained is dissolved in 200 ml of boiling isopropyl alcohol. The mixture is filtered hot and the filtrate is concentrated until a suspension of a solid appears. The mixture is then cooled to room temperature and 200 ml diethyl ether are added. The reaction products crystallizes. The mixture is filtered and the product is washed with diethyl ether and dried. 6.8 g N-[imino(cyclopropilamino)methyl]-4-morpholinecarboximide-amide hydrochloride are obtained.

Yield: 85%. M.p.: 195-196°C.

Analysis for C9H17N5O.HCI in %: calculated: C 43.63 H7.32 N 28.27 Cl&quot; 14.21 found: 43.60 7.35 27.93 14.18

C. Preparation of the cvclopropvlamino-1,3.5-triazines of the formula I. 2-Cyclopropvlamino-4-n-methvlcvclopropvn-6-morpholino-1.3.5-triazine fcompound 2IV 0.48 g (20 mmol) sodium is dissolved in 20 ml anhydrous ethanol. This solution is added to an ethanol solution containing 2.48 g (10 mmol) N-[imino(cyclopropylamino)methyl]-4-morpholinecarboximide-amide hydrochloride, 16 and 2.82 g (22 mmol) ethyl l-methylcyclopropane-carboxylate are then also added to the mixture. The mixture is then heated under reflux under nitrogen for 88 hours. It is cooled, the alcohol is evaporated off under reduced pressure and the residue is redissolved in 50 ml water and 200 ml methylene chloride. The aqueous phase is separated off and the organic phase is washed twiče with 50 ml water and dried over magnesium sulphate. The solvent is evaporated off under reduced pressure and the residue is recrystallized irom a 1 : 1 (v/v) mixture of Petroleum ether-methylene chloride. 0.49 g 2-cyclopropylamino-4-(l-methylcyclopropyl)-6-morpholino-l,3,5-triazine are obtained.

Yield: 17%. M.p.: 94-95°C.

Analysis for C14H21N5O in %: calculated: C 61.06 H7.69 N 25.44 found: 61.15 7.66 25.56

As indicated above, the substituted cyclopropylamino-l,3,5-triazines of the formula I and their pharmaceutically acceptable non-toxic acid addition salts have the property of correcting the effects of hypofunctioning of the cholinergic system and consequently have a favourable activity on memory processes. In addition, they have a Central serotonergic and a bronchospasmolytic activity; they oppose the release of mastocyte mediators, have an antiinflammatory and anti-oedematous activity and potentiate the effect of a β-adrenergic agonist on muscle relaxation.

The pharmacological studies described below demonstrate these various advantageous properties. 1. Activitv on memorv processes.

The compounds according to the present invention were studied with the aim of demonstrating on the one hand their property of promoting leaming, expressed by the reduction in the number of tests needed to achieve a predetermined criterion, and on the other hand their property of opposing the amnesia caused by administration of scopolamine.

The method of passive avoidance in multiple tests was used to this effect. This method is well-known for evaluation of the effects which a product has on memory and leaming (A. FINE et al., Proc. Nati. Acad. Sci. USA, 82, (1985), 5227-5230).

The tēst is carried out on male Sprague-Dawley rats (160 - 200 g), which are ķept in standart cages during the experiment.

The apparatus used is a transparent square cage with sides of 35 cm and a height of 25 cm, fitted with a grid floor which can be electrified. A rubber insulating mat (10 χ 17 cm) is placed on the base in one of the corners of the cage. LV 10616

To evaluate whether a compound can promote leaming, the following tēst is carried out.

Each animal is placed on the rubber mat and the time which the animal takes to decide to leave this position to explore the cage is recorded. After 20 seconds of exploration, the animal receives an electric shock (3 seconds duration) in the paws, causing an escape reaction. The rat is immediately removed from the apparatus and replaced in its original cage. This experiment is repeated until the animal stays on the rubber mat for at least 180 seconds to avoid the electric shock. The learning is expressed by the average number of tests needed to achieve a time of staying on the mat of 180 seconds. A time of staying on the rubber mat of 180 seconds is regarded as being the maximum perfomance to be realized by the animal to avoid the electric shock. The rats which remain on the mat for this time have acquired the avoidance reflex and are replaced in their original cage without receiving an electric shock.

To evaluate vvhether a compound can promote memory retention in the course of time, the follovving experiment is carried out. Each animal is subjected to four tests at times 0, 4, 24 and 28 hours. In the first tēst (time 0), the animal is placed on the rubber mat and the time which it takes to decide to leave this position to explore the cage is recorded. After 20 seconds of exploration, the rat receives an electric shock (3 seconds duration) in the paws, causing an escape reaction. The rat is immediately removed from the apparatus and replaced in its original cage. In the course of the three subsequent tests (times: 4, 24 and 48 hours), the animal is replaced on the rubber mat and the time taken to leave this position is recorded. As soon as the four paws of the animal rest on the grid, it receives an electric shock and is removed immediately from the apparatus. At the start of the experiment, the rats are divided into 4 homogeneous groups of 15 animals. Thirty minūtes before eash tēst, each group of animals is subjected to a specific treatment: - group 1 receives an intraperitoneal injection of physiological serum; - group 2 receives an intraperitoneal injection of the compound to be tested; - group 3 receives an intraperitoneal injection of 0.5 mg scopolamine and - group 4 receives an intraperitoneal injection of 0.5 mg scopolamine and, simultaneously, an intraperitoneal injection of the compound to be tested.

Groups 1 and 2 are used in the first experiment (leaming) and groups 3 and 4 in the second experiment (memory retention).

The results obtained in this tēst with the compounds according to the invention are summarized in Table IV. This table shows the compound subjected to the tēst 18 (column 1) and the dose administered intraperitoneally, expressed in mg/kg (column 2).

The results obtained in the tēst used to evaluate leaming are given in columns 3 and 4. The figurēs indicate the average number of tests needed for a control animal (group 1) or an animal treated with the compound (group 2) to learn to stay on the rubber mat for 180 seconds to avoid the electric shock. The results were analysed by the Student tēst.

The results obtained in the experiment used to evaluate memoiy retention are given in columns 5 to 12. In columns 5 to 8, the figurēs represent average time of staying on the mat observed respectively at times 0, 4, 24 and 28 hours for the animals of group 3, treated only with scopolamine, and in columns 9 to 12 the corresponding figurēs are found for the animals of group 4, treated simultaneously with scopolamine and with the compound studied (at the dose indicated in the second column).

The favourable influence of a compound in opposing the amnesia caused by scopolamine is demonstrated by the increase in the time of staying on the mat at each observation. The differences found are analysed statistically by the Mann-Whitney method. ω co *aco u ω ΙΑ 01c &gt;

H

Compound Dose _Leaming 0&gt; O u. ω 6 a a&gt; Oli &lt;3 &lt;N o 3 0 &gt;_ 01 o, 3 01 00 &quot;Sb 8 LV 10616

sr o 3 0 V-* 01 cn P, 3 0 ll 01 vo o VO cn o CN o CN cn o rH r-H oc vd r-H vd cn od cn cn CN cn sf ov Ov CN r-H CN cn CN o t&quot;- CN cn VO sT Ov Ov Ov cn © r-H r-H r-H rH r-H r-H r^ CN cn © un Ov 00 O r—r OV vo H cn Ov cn un sf st- cn r-H Ov st· ^r oo oo od t“H CN cn sr od CN 1&gt; CN o Ov cn CN OV cn t&quot; cn cn OV r-- OV rH r—' rH 00 OV m un CN C^ un cn cn ST o cn cn cn rH sl- CN od cn sT ,—r l&gt; o ,—ί od cn vd OV un sf cn cn ^H cn r-H CN CN --1 cn cn .-”™&lt; cn CN ov &gt;n cn cn cn 00 VO t&quot; vo t&quot;; 00 cn O ov VO CN st-' un Ov cn cn d cn d r*H OV rH r-H r-H rH cn &gt;n »n cn © rH Ό vo cn cn r-H OV t&quot; t&quot; cn 00 sr sr t&quot;-' r-H T-H CN OV OV CN o t-H st OV CN cn rH r-H VO CN r-H un vo cn rH st en vo cn cn t&quot; CN Γ&quot; Ov VO un st vo cn VO r- m rH st ov t—H o&quot; © oo vd od en t-· un © Ov rH CN Ov CN r-H CN CN cn CN CN sr rH CN CN CN r—t cn c-~ r-H Ov un un t&quot;; r-H cn OV Ov r-H cn St&quot; oo f-' vd cn r~·' un od sr sf t&gt; o oo t&gt; CN o 1—1 hH r-H CN CN ^H cn VO un r-H r-H o- CN t&gt; CN CN © cn rH CN o cn cn&quot; cn un cn cn cn CN cn cn cn un vd sr t&gt; ov o\ cn un OV ov sf 00 Γ&quot; H cn OV CN r—i CN r-H r—ί CN CN H CN rH rH rH CN r—i r—ī CN r-~ cn o Ov cn sr o oo t&gt; &gt;—&lt; vo cn cn cn &gt;n cn cn cn cn cn cn cn esi cn cn&quot; cn cn &lt;N cn cn © © O oo oo CN 00 © cn © ir. vo cn cn &gt;-&lt; t-η cn cN cn CN μ M co ^ N oi CN ^

rtNM'iviOr'ON cn cn

sf Ό VO rH rH rH physostigmine 0.4 2.6 2.3 1.7 1.4 6.9 21.3 1.9 17.8 56.2 53.4 20

From this table, it is found that: - the compounds according to the invention promote leaming of the avoidance reflex: the average number of tests needed to reach the predetermined criterion (maximum time of staying on the mat of 180 seconds) is less for the treated animals (column 4) than for the control animals (column 3); - the amnesic effect of scopolamine is very pronounced: it is seen that the staying times of the animals of group 3 (columns 5 to 8) are clearly less than the 180 seconds realized by the Controls after an average number of tests (column 3); and, under these conditions, the favourable influence of the compounds according to the invention in opposing the amnesic effect of scopolamine is very clear: the animals of group 4, treated simultaneously with scopolamine and with a compound according to the invention, have staying times, at each observation, which are considerably higher than the animals of group 3, treated with scopolamine alone (compare the results of column 5 with those of column 9, 6 vvith 10, etc.); - physostigmine has a favourable effect against the amnesic effect of scopolamine, similar to that of the compounds according to the invention, but at a dose which causes secondary effects and is very close to the toxic dose, which is not the case for the compounds according to the invention. 2. Serotonergic activitv. A reduction in serotonergic activity has been correlated with the occurence of emotional disorders, such as depression and anxiety. Injections of rats vvith serotonin or 5-hydroxytryptophan (5-HPT), a serotonin antagonist, inducēs paroxysmal tremors of the head, neck and trunk in this animal, similar to the shuddering of a wet dog shaking itself. This behaviour is called &quot;wet dog shake&quot; (WDS) and is used as a modei to demonstrate the aminergic and in particular serotonergic properties found in antidepressants (P. BEDARD and C.J. PYCOCK, Neuropharmacology 16, (1977), 633-670).

The tēst is carried out in the morning on male Sprague-Dawley rats (±180g), divided the previous day into groups of 8 animals in residence cages. The cage used for the tests is a transparent enclosure of 12 χ 24 x 30 cm in height, the base of which is covered with a layer of sand.

The compounds to be tested, dissolved either in physiological serum or in a citrate buffer of pH 5, are administered intraperitoneally in a different dose for each group treated. The control groups receive an intraperitoneal injection of the same vehicle (either physiological serum or citrate buffer). LV 19616

After administration of the product, the animals are immediately placed in the tēst cage in groups of four at a time, and after a habituation period of 10 minūtes duration the number of shakes (WDS) which occur over a period of 30 minūtes is counted.

The mean values of the results are calculated and analysed statistically by the Mann-Whitney method.

The mean values of the number of shakes obtained for the compounds according to the invention administered intraperitoneally in the doses indicated (in mg/kg) are shown in Table V below. 22

Compound Table V &quot;Wet dog shake&quot; behaviour Dose (mg/kg) Average number of shakes 1 1.0 7.8 ±1.6 2 1.0 10.0±3.5 3 0.3 5.1 ±1.0 1.0 11.9 ±2.7 4 2.8 10.6 ±4.3 5 2.8 8.4 ±1.6 6 1.0 1.9 ±0.5 3.2 3.6± 1.1 7 2.8 7.9 ±1.8 10 3.1 16.3 ±3.8 11 1.1 4.3 ±1.4 12 3.2 16.3 ±4.2 13 2.5 5.6 ±1.8 14 0.8 2.1 ±0.7 16 1.0 10.6 ± 1.8 5-HTP/carbidopa (1) 100.0 4.7 ± 1.5 200.0 19.6 ±3.0 (1) The animals are pretreated with the peripheral decarboxylase inhibitor a-methyldopahydrazine or carbidopa (25 mg/kg, i.p., 30 minūtes before the 5-HTP); the measurements are made 90 to 120 minūtes after the intraperitoneal injection of 5-HTP.

This table demonstrates that the compounds according to the invention cause a &quot;wet dog shake&quot; behaviour in rats comparable to that caused by injections of a serotonergic agonist such as 5-HTP in the presence of carbidopa, but at doses which are clearly lovver. 3. Bronchospasmolvtic activitv.

This activity was measured on a Dunkin-Hartley guinea-pig by the method of Η, KONZETT and R. ROESSLER (Naunyn Schmiedebergs Arch. exp. Path. Pharmacol., 195. (1940), 71-74) and compared with that of theophylline. LV 10616

The anaesthetized (urethane) and curarized (gallamine) guinea-pig is placed under assisted respiration. The endotracheal pressure is recorded. Repeated bronchial spasms are induced by successive intravenous injections (every 5 minūtes) of serotonin, histamine or acetylcholine respectively at a dose which is capable of causing an increase in the endotracheal pressure of 20 to 50 cm water.

The compound to be tested is also administered intravenously two minūtes before the administration of the spasmogen and then in 3 to 4 cumulative doses in increasing amounts at intervāls of 15 minūtes. 6 animals per compound to be tested and per spasmogen are used. Table VI below shows the doses of products (ID50 in pmol/kg) which inhibit by 50 %, on average over ali the animals, the bronchospasms induced.

Table VI

Bronchospasmolytic activity

Compound Doses (ED50 in pmol/kg)

Serotonin Histamine Acetylcholine 1 0.01 0.01 0.1 2 0.5 0.3 0.5 3 0.1 0.03 0.07 4 0.03 0.004 0.03 5 0.1 0.06 0.1 6 0.1 0.1 0.3 7 0.4 0.2 0.7 S 0.3 0.1 0.2 9 1.0 0.4 2.1 10 0.3 0.1 0.5 11 0.1 0.1 0.09 12 0.06 0.04 0.2 13 0.6 0.1 1.3 14 0.2 0.09 0.5 15 0.2 0.08 0.3 16 0.009 0.009 0.05 17 0.2 0.1 0.2 18 - 0.003 - theophylline 4.6 5.6 10.0 24

It can be seen from this table that the compounds according to the invention have a remarkable bronchospasmolytic activity with respect to bronchospasms induced by, respectively, serotonin, histamine or acetylcholine. 4, Antiinflammatorv and anti-oedematous activitv.

The reaction between a soluble antigen and antibodies in the organism may lead to an acute inflammatory reaction accomponied by release of histamine, modification of vascular permeability and formation of a localized oedema.

The aim of the &quot;reverse passive Arthus&quot; (RPA) tēst is to demonstrate the antiinflammatory properties of a compound on the plantar oedema caused experimantally by immune complexes in the Sprague-Dawley rat (P.J. BAILEY and A. STURM, Biochem. Pharmacol., 32, (1983), 475). To this effect, the Arthus reaction is caused by subplantar administration of 0.1 ml heterologous antiovalbumin antibody serum into the right hind paw and by simultaneous intravenous injection of 1 ml/kg ovalbumin (25 mg/ml).

The compound to be tested is administered intravenously 30 seconds before induction of the Arthus reaction in at least 3 different doses. A group of 6 rats is used per dose of compound to be tested.

The volume of the paw is measured by plethysmometry before the Arthus reaction and 3 to 5 hours after induction of the Arthus reaction, both on the control animals and on the treated animals.

The effect of a compound on the reduction in the oedema for each dose and at each measurement time (3 hours and 5 hours) is expressed in % of the oedema observed in the control animals.

The doses of products (ID30 in μηιοΐ/kg) which inhibit by 30 %, on average over ali the animals, the volume of the oedema observed in the control animals are given in Table VII below. 1· LV 10616

Table VII

Antiinflammatory and anti-oedematous activity Compound Dose (ED30) in μηιοΐ/kg) 3 hours 5 hours 1 2.0 2.0 2 2.3 0.7 3 0.8 0.4 4 9.0 10.0 5 3.1 27.0 6 12.0 9.0 7 7.7 11.0 8 4.0 4.0 9 3.4 4.4 11 0.5 0.4 12 2.5 3.0 13 9.0 4.0 14 16.0 12.0 15 39.0 4.0 16 1.5 2.0 17 1.0 1.0 18 1.0 1.0 19 0.02 0.02 20 1.0 0.5 theophylline 18.0 10.0

This table shows that the compounds according to the invention have an antiinflammatory and anti-oedematous activity which is clearly superior to that of theophylline. 5, Inhibition of the anaphvlactic release of histamine.

This tēst has two aims: one the one hand to evaluate the &quot;in vitro&quot; inhibitory activity of a substance on the anaphylactic release of histamine caused by degranulation of mastocytes in the guinea-pig lung, and on the other hand to demonstrate a possible potentiation effect (synergism) on the inhibitory activity of a β-adrenergic agonist, for example isoprenaline, on this same release of histamine. (E.S.K. ASSEM and H.O. SCHILD, Int. Arch. Allergy, 40, (1971), 576-589). 26

Dunkin-Hartley guinea-pigs which are first sensitized passively by an intravenous injection of 1 ml of isologous antiovalbumin serum are used.

Twenty-four hours after the injection, the lungs are then perfused with a Tyrode buffer to evacuate the blood, and then removed and cut into sections of 1 mm. These sections are divided up into tēst tubes (3 sections per tube) to give 10 experimental groups of sections of lungs per guinea-pig. A &quot;positive&quot; control group of lung sections is stimulated by addition of an ovalbumin solution (0.1 mg/ml) to trigger off the anaphylactic release of histamine and serves to determine the maximum amount of histamine (100 %) which can be released. A &quot;negative&quot; control group which is not stimulated by ovalbumin serves to determine the amount of histamine released naturally (spontaneous release).

In three other groups, the lung sections are incubated at 37°C for 30 minūtes in the ovalbumin solution in the presence of three different doses of the compound to be tested (one dose per group).

To detect a potentiation effect of a compound according to the invention on the inhibition of histamine release by isoprenaline, three other groups of lung sections are treated in the same manner as above, but the incubation medium also contains isoprenaline in a dose of 10'7 mol per litre. At this dose, isoprenaline inhibits the release of histamine by 30 to 40 %, which is verified on a control group which is treated only with isoprenaline alone at this dose.

In addition, a supplementary control group which is not stimulated by ovalbumin is used to detect a possible spontaneous release of histamine by the highest dose of the compound studied.

In each group, the histamine released in the incubation medium is analysed by spectrofluorometry (D.P. EVANS et al., Life Sci. 12, (1973), 327-336).

The results obtained enable a minimum inhibitory dose (MED) (actual effect) to be determined for each compound, that is to say the dose of the compound at which the amount of histamine released is lower than that of the &quot;positive&quot; control group and at which this difference is statistically significant, and a minimum potentiating dose (MPD), which is the dose of compound which causes an inhibition greater n than that of isoprenaline in a dose of 10 mol per litre.

The minimum inhibitory doses (MID) and the minimum potentiating doses (MPD), expressed in mol/1, obtained in this tēst with the compounds according to the invention and with theophylIine as the reference substance are given in Table VIII below. LV 10616

TableVni

Inhibition of the anaphvlactic release of histamine Compound Minimum inhibitory Minimum potentiating dose dose (in μmol/l) (in pmol/l) 1 0.1 0.32 2 1.0 3.2 3 0.032 0.32 4 0.32 0.1 5 0.32 3.2 6 1.0 1.0 7 0.32 1.0 8 1.0 10.0 9 3.2 3.2 10 3.2 0.32 11 1.0 0.32 12 0.1 0.1 13 1.0 1.0 14 1.0 0.32 15 10.0 3.2 16 0.1 0.032 17 3.2 1.0 18 0.1 1.0 19 1.0 0.1 20 1.0 0.32 theophylline 100.0 1000.0

It can be seen from this table that the compounds according to the invention are much more active than theophylline in inhibiting the anaphylactic release of histamine (actual effect) and at the same time have, at low doses, a potentiating n effect on the inhibiting effect of isoprenaline obtained at a dose of 10 mol per litre. 28 6. Potentiation of the mvorelaxing effect of isoprenaline on the ileum of guinea-pig. (cf. R.A. TURNER, &quot;Screening Methods in Pharmacology&quot;, Ed. Acad. Press, San Diego, 1965, chapter IV, pages 43-47).

Fragments of the longitudinal muscles of the ileum of Dunkin-Hartley guinea-pigs (250 to 500 g) attached to an isometric force indicator are immersed in a Tyrode solution (37 ± 1°C, pH 7.6 ; 5.6 mmol/1 glucose), oxygenated by passing through a streem of gas (mixture of 95 % O2 - 5 % CO2) and stretched with a force of 1 g. After stabilization of the tension, successive cycles of histarriine injection (histamine dihydrochloride at a dose of 3.2 pmol/l) are eflfected by means of a periusion pump of the Braun type. Each injection cycle comprises the 6 following successive phases: a rest phase (duration: 25 seconds), a histamine injection phase (duration: 6 seconds), a period of muscular contraction (duration: 24 seconds), a first lavage with water (duration: 25 seconds), a period of stabilization, during which the muscle retums to the starting tension (duration: 35 seconds), followed by a second lavage with water (duration: 25 seconds).

Inhibition cycle: When the successive contractions induced by the histamine injections have become reproducible, the compound to be tested is injected immediately after the second lavage. The contraction induced by the follovving injection of histamine is measured and compared with the mean of the three preceding contractions caused by repeated injections of histamine (control contractions). From the result obtained, the percentage inhibition of the contraction is calculated. Several cycles of histamine injection are then performed again, until the contractions of the muscle become reproducible again; the muscle is then ready for testing of another compound.

The potentiating effect of a compound is measured in the course of a so-called &quot;potentiation&quot; cycle, which comprises three successive inhibition cycles, In the first inhibition cycle, the percentage inhibition of the contraction obtained by injection of isoprenaline alone in a dose of 10 mol/1 is determined. At this dose, the percentage inhibition of the contraction is usually between 10 and 25 %. In the course of the second inhibition cycle, the percentage inhibition of the contraction obtained with the compound to be tested, injected alone at a given dose, is determined. In the third inhibition cycle, isoprenaline and the compound to be tested are injected simultaneously, and the percentage inhibition of the contraction is calculated for the dose used of the compound studied. The same experiments are repeated for each of the doses of the compound studied.

From the results obtained, the minimum potentiating dose (MPD) is determined for each compound tested, this corresponding to the dose of product at which the LV 10616 inhibition obtained with the mixture of compound + isoprenaline is significantly greater (p &lt; 0.05) than the sum of each of the inhibitions recorded when the compound and isoprenaline are injected in isolation.

The minimum dose, expressed in μπιοΐ/ΐ, which potentiates the myorelaxing eifect n of isoprenaline administered in a dose of 10 mol/1 is given for the compounds according to the invention, in comparision with theophylline, in Table IX below.

Table IX

Potentiation of the mvorelaxing effect of isoprenaline on the euinea-pig ileum Compound Minimum dose (in μηιοΐ/l) ι· 1 0.032 2 1.0 3 0.032 4 0.032 5 1.0 6 1.0 7 0.32 9 10.0 10 1.0 11 0.032 12 0.01 13 1.0 14 1.0 15 3.2 16 0.032 17 0.032 18 0.1 19 0.32 20 0.1 theophylline 1000.0

This table shows that the compounds according to the invention are much more active than theophylline in potentiating the myorelaxing effect of isoprenaline. 30 7, Effect on polvmorphonuclear neutrophilic granulocvtes.

Polymorphonuclear neutrophilic granulocytes (PMN) are celis which are mobilized during inflammatory phenomena and which can be stimulated by various substances, such as, for example, formylmethionyl-leucyl-phenylalanine (FMLP) or prostaglandins E (PGEļ). The PMN granulocytes respond to these extracellular stimuli with an activation of oxygen metabolism with release of toxic oxygenated metabolites. An excessive response of PMN granulocytes may be the cause of a painful inflammation and is also accompanied by a reduction in the Ievel of cyclic adenosine monophosphate (cAMP) in these granulocytes. Consequently, the compounds which inhibit the respiratory reflex of PMN granulocytes or which increase the Ievel of cAMP can be regarded as veiy important in the treatment of arthritis and asthma.

The aim of the pharmacological tēst described below is to demonstrate that the compounds according to the invention have a double character: on the one hand i they inhibit the stimulation of PMN granulocytes, and on the other hand they increase the Ievel of cAMP in these celis. - Inhibition of the stimulation of PMN granulocvtes.

The stimulation of PMN granulocytes is demonstrated by the chemiluminescence which accompanies the activation of oxygen metabolism vvhen these celis are are stimulated in the presence of luminol (5-amino-2,3,-dihydro-l,4-phthalazinedione).

Rat PMN granulocytes (5 χ 106/ml) are preincubated in a phosphate buffer (150 pmol/litre, pH 7.4), containing luminol in a concentration of 10'5 mol per litre, for 15 minūtes at 37°C and then for 5 minūtes in the presence of the compound to be tested in a concentration of 10*6 mol/litre.

The reaction of PMN granulocyte stimulation is initiated by the addition of FMLP n to the medium m a final concentration of 3.2 χ 10 mol/litre. The luminescence which results from the stimulation is measured by means of an LKB 1251 luminometer in accordance with the method of C. DAHLGREN and O. STENDAHL (Infection and Immunology, 37, (1982), 34 to 39). An experimental cycle lāsts 38 seconds. The reaction is repeated 9 times for each compound studied and the mean of the results obtained is calculated.

The mean percentage of residual chemiluminescence calculated with respect to a control tēst, in the course of which the PMN granulocytes are incubated and stimulated by FMLP in the absence of the compound to be tested (100% chemiluminescence), is given for the compounds according to the invention and for theophylline (reference compound) in Table X below. LV 10616

Table X

Inhibition of the stimulation of PMN granulocvtes Compound Residual chemiluminescence (10·6 mol/1) (in %) 1 47 2 68 3 39 4 45 5 74 6 55 7 54 9 82 10 56 11 44 12 36 13 79 I· 14 51 15 70 16 42 theophylline 100

The table shows that the concentration of 10'6 mol/1, the concentration at which ali the compounds according to the invention are tested, theophylline is completely inactive. In contrast, it is seen that at this concentration the compounds according to the invention cause a significant reduction in the chemiluminescence and thus cause a significant inhibition of the stimulation of PMN granulocytes.

It has also been found that a concentration 100 times higher (10'4 mol/1) is needed to obtain a comparable effect with theophylline (residual chemiluminescence of 65 %). - Increase in the Ievel of cAMP,

Rat PMN granulocytes (107 in 200 μΐ) are incubated in a phosphate buffer (150 pmol/litre, pH 7.4) at 37°C for 3 minūtes in the presence of the compound to be tested in a concentration of 3.2 χ 10'6 mol per litre, and of PGEļ in a concentration of 10'6 mol/litre. The reaction is then stopped by addition of 1 ml propanol. After centrifugation at 15,000 g for 3 minūtes, the supernatant is 32 recovered and evaporated and the amount of cAMP in the residue is determined by radioimmunological assay in accordance with the process recommended by the supplier of the reaģent used for this purpose (Amersham). A control tēst is carried out under the same conditions, but in the absence of the compound to be tested.

The amounts of cAMP (expressed in picomol) obtained in the course of these tests, in comparision with theophylline, which is also used in a concentration of 3.2 χ 10&quot;6 mol/Iitre, are given in Table XI below.

Table XI

Compound Amount of cAMP produced (in picomol per 107 celis) 1 21.0 3 23.2 4 17.7 5 11.6 6 14.6 7 15.8 11 16.2 12 16.8 theophylline 5.0 control 4.3

This table shows that the compounds according to the invention are more active than theophylline and considerably increase the Ievel of cAMP in PMN granulocytes stimulated by PGEļ. 8. Toxicitv.

The toxicity of the compounds according to the invention was determined on the male NMRI mouse by means of the Irwin tēst (S. IRWIN, Psychopharmacologia, 13, (1968), 222-257).

Progressive doses of the compound to be tested are administered intraperitoneally to groups of three mice until the the fatal dose is reached (dose which causes the death of two animals out of three within 48 hours). LV 10616

The fatal dose found for the compounds according to the invention is given in Table XII belovv. This table shows that the compounds according to the invention have a very low toxicity, in contrast to physostigmine.

Table XII

Compound Fatal dose (in mg/kg) 1 898 2 285 3 297.8 4 165 5 277.4 6 635.6 7 279.3 8 326 9 297.8 10 311.8 11 325.8 12 325.8 13 247.3 14 156.8 15 498 16 194 17 281.5 18 277 19 175.6 20 185 physostigmine 0.82 9. Dosage and administration.

Pharmaceutical compositions containing the compounds according to the invention can be administered orally, parenterally or rectally. The pharmaceutical compositions which can be used for oral administration can be solid or liquid, for example in the form of tablets (coated or non-coated), pilis, dragees, gelatine capsules, Solutions, syrups etc. The compositions which can be used for parenteral administration more over are the forms known pharmaceutically for 34 this type of administration, for example Solutions, suspensions or aqueous or oily emulsions. For rectal administration, the compositions containing the compounds according to the invention are generally in the form of suppositories. The pharmaceutical forms, such as injectable Solutions, injectable suspensions, tablets, drops, suppositories etc., are prepared by the methods currently used by pharmacists. The pharmaceutical forms also comprise compositions which enable the active product to be delivered in a progressive manner. The compounds according to the invention are mixed with a pharmaceutically acceptable, non-toxic solid or liquid vehicle, and if appropriate with a dispersing aģent, a disintegrating aģent, a stabilizing aģent etc. If appropriate, sweetening aģents, colouring aģents etc. may be added. The percentage of active product in the pharmaceutical compositions can vary within veiy wide limits, depending on the patient and the mode of administration, and in particular depending on the frequency of administration. As regards the daily dose, this may vary within a wide range of unit doses, for example from 0.05 to 0.5 g of active product, depending on the mode of administration. Thus, for example, it can be from 0.1 to 0.5 g, preferably 0.1 g, one to several times daily if the compound is administered in tablet form. A formulation for tablets is mentioned by way of a non-limitative example of a composition containing a compound of the formula I which can be administered orally:

Compound 1 50 mg Methylcellulose (Methocel K4M) 200 mg Dried lactose 154 mg Aerosil 5 mg Citric anhydride 60 mg Talc 11 mg Magnesium stearate 20 mg LV 106X6

CLA1MS 1. A substituted cyclopropylamino-l,3,5-triazine of the general formula

Ri in which Rļ represents an alkyl radical, having 1-3 carbon atoms, or a cycloalkyl radical, having 3-5 carbon atoms, which is unsubstituted or carries an alkyl radical substituent having 1-3 carbon atoms, and R2 represents a bis(2-hydroxyethyl)amino, 3-hydroxy-l-azetidinyl, 3-methoxy-l-azetidinyl, 3-oxo-l-azetidinyl, morpholino, 3,3,5,5-tetramethylmOrpholino, 4-hydroxypiperidino, thiomorpholino, thiomorpholino S-oxide, thiomorpholino S,S-dioxide, 3-thiazolidinyl, 3-thiazolidinyl S-oxide, 3-thiazolidinyl S,S-dioxide or 8-oxa-3-azabicyclo(3,2,l)oct-3-yl radical or a pharmaceutically acceptable non-toxic acid addition salt thereof. 2. A substituted cyclopropylamino-l,3,5-triazine, or acid addition salt, as claimed in claim 1 in the form of an optically active enantiomer or a racemic mixture of enantiomers. 3. A cyclopropylamino-l,3,5-triazine, or acid addition salt, as claimed in claim 1 or claim 2, wherein R2 represents a morpholino or tiomorpholino radical. 4. 2-Cyclopropylamino-4-morpholino-6-n-propyl-l,3,5-triazine or a pharma-ceutically acceptable non-toxic acid addition salt thereof. 5. 2-Cyclopropyl-4-cyclopropylamino-6-morpholino-l,3,5-triazine or a pharma-ceutically acceptable non-toxic acid addition salt thereof. 6. 2-Cyclobutyl-4-cyclopropylamino-6-morpholino-l,3,5-triazine or a pharma-ceutically acceptable non-toxic acid addition salt thereof. 7. 2-Cyclopropyl-4-cyclopropylamino-6-thiomorpholino-1,3,5-triazine. 36 8. A process for the preparation of a substituted cyclopropylamino-l,3,5-triazine or an acid addition salt thereof, as defined in claim 1, characterized in that a) a chloro-cyclopropylamino-l,3,5-triazine of the formula

in which Rļ has the meaning given in claim 1, is reacted with an amine of the formula R2H (III), in which R2 has the meaning given in claim 1, or a chloro-1,3,5-triazine of the formula R 2

-C1 (IV)

N

R1 in which Rj and R2 have the meaning given in claim 1, is reacted with cyclopropylamine of the formula H2N-&lt;j (V), or b) an N-cyclopropylbiguanide of the formula [&gt;ΝΗ^ΝΗ R, (VII)

NH NH in which R2 has the meaning given in claim 1, is reacted with an alkyl ester of the formula Rļ-COOAlk (VIII), in which Rļ has the meaning given in claim 1 and Alk represents an alkyl radical having 1 to 4 carbon atoms, and c) in that, if appropriate, the cyclopropyIamino-l,3,5-triazine of the formula I thus obtained is converted into a pharmaceutically acceptable non-toxic acid addition salt thereof. 9. A cyclopropylamino-l,3,5-triazine according to any one of claims 1 to 7 and/or a pharmaceutically acceptable non-toxic acid addition salt thereof, for use in the LV 10616 treatment of memory and learning disturbances, pathologies such as depression, anxiety and mood disturbances, or in the treatment of arthritis and asthma. 10. A therapeutic composition containing a therapeutically effective amount of a cyclopropylamino-l,3,5-triazine according to any one of claims 1 to 7 or a pharmaceutically acceptable non-toxic acid addition salt thereof, in combination with at least one solid or liquid pharmaceutical excipient. 11. The use of a cyclopropylamino-l,3,5-triazine, or an acid addition salt, as claimed in any of claims 1-7 for use in the manufacture of a medicament for the treatment of memory and learning disturbances, pathologies such as depression anxiety and mood disturbances, or the treatment of arthritis and astma. 12. A substituted cyclopropylamino-l,3,5-triazine, or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described as being in accordance with the present invention. 13. A process for the preparation of a cyclopropylamino-l,3,5-triazine, or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described as being in accordance with the present invention or as set out in any of examples 1-4.

Claims (9)

Claims 1. Patented cyclopropylamino-1,3,5-triazine corresponding to the general formula CD wherein: R 1 is an alkyl radical of 1-3 carbon atoms »or a cycloalkyl radical of 3-5 carbon atoms which is unsubstituted or substituted with an alkyl radical of 1 to 3 carbon atoms and R 2 is bis (2-hydroxyethyl) amino, 3- hydroxy-1-azetidinyl, 3-methoxy-1-azetidinyl, 3-oxo-1-azetidinyl, morpholine-3,3,5,5-tetramethylmorpholine, 4-hydroxypiperidine, thiomorpholine, S-oxythiomorpholine -, S-dioxo-thiomorpholine, 3-thiazolidinyl, S-oxy-3-thiazolidinyl, S-dioxo-3-thiazolidinyl S or 3-oxa-3-azabicyclo (3.2.1) oct-3 il radical or salts of these compounds with non-toxic pharmaceutically acceptable acids. 2. Substituted cyclopropylamino-1. 3,5-Triazine or its salts with acids according to l.p. an optically active enantiomer or a racemic mixture of enantiomers. Cyclopropylamino-1,3,5-triazine or its salts with acids according to claim 1 or 2, wherein R 2 is morpholine or thiomorpholine-radical. 4. 2-Cyclopropylamino-4-morpholin-5-n-propyl-1,3,5-triazine or a salt thereof with non-toxic pharmaceutically acceptable acids. 5. 2-Cyclopropyl-4-cyclopropylamino-6-morpholine-1,3,5-triazine or its salts with non-toxic pharmaceutically acceptable acids. δ. 2-Cyclobutyl-4-cyclopropylamino-6-morpholine-1,3,5-triazine or a salt thereof with non-toxic pharmaceutically acceptable acids. 2. 7-Cyclopropyl-4-cyclopropyl Lamino-6-thiomorpholine-1,5-triazine. Process for the preparation of substituted cyclopropylamino-1,3,5-triazine or its salts with acids as indicated in claim 1, characterized in that: a) a reaction is carried out with chloro-cyclopropylamino-1,3,5-triazine of the formula: (II) wherein R 1 is as shown in I.p. and the amine of formula R 2 H (III), wherein is as defined in I.p. or the reaction is carried out between chloro-1,3,5-triazine of formula (IV) and cyclopropylamine with (Y) wherein R 1 and R 2 are as given in l.p. the reaction of the formula H2N- &lt; J or b) is carried out between N-cyclopropylbiguanide of formula J NE NH R_ (VII) • V NH NH where R 2 is as given in Ip, and alkyl esters of formula R 1 -COOAlk (ΥΙΙ) wherein R ^ is as given in lp and Alk is an alkyl radical of 1 to 4 carbon atoms, and c) by converting cyclopropylamino-1,3,5-triazine of formula I, if necessary, into salts with non-toxic pharmaceutically acceptable acids . 3. LV 10616 9. Cyclopropylamino-1,3,5-triazine according to any one of claims 1 to 7 and / or a salt thereof with non-toxic pharmaceutically acceptable acids, for the treatment of memory, for the treatment of training disorders, for the treatment of pathologies such as depression, restlessness and mood disorders. or arthritis and asthma. A therapeutic composition comprising a therapeutically effective dose of cyclopropylamino-1,3,5-triazine according to any one of claims 1-7. or a salt thereof with non-toxic pharmaceutically acceptable acids together with at least one solid or liquid pharmaceutical filler. Cyclopropylamino-1,3,5-triazine or a salt thereof with acids according to any one of claims 1-7. use in the manufacture of medicaments for the treatment of memory, for the treatment of training disorders, for the treatment of pathologies such as depression, restlessness and mood disorders, or for arthritis and asthma. A substituted cyclopropylamino-1,3,5-triazine or a salt thereof with pharmaceutically acceptable acids, essentially as pre-written according to the present invention. A process for the preparation of cyclopropylamino-1,3,5-triazine or a salt thereof with pharmaceutically acceptable acids, essentially as described above in accordance with the present invention, or set forth in any of Examples 1-4.