Method of making the disubstituted or trisubstituted xanthines

The invention relates to a process for the preparation of novel, pharmacologically active disubstituted or tri substituted xanthines and their physiologically acceptable salts.

Xanthines are known for their central nervous system stimulant effect. Examples include caffeine or theophylline.

Some xanthines are known for their spasmolytic activity, for example from German Patent Application Publication No. 2,713,389 or European Patent Application Publication No. 7735. '

It has now been found that the novel xanthines substituted at the 1,3 and 1,3,8 positions, unlike the psychosiculating xanthines used in therapy, are largely characterized by sedative or anxiolytic efficacy, with no side effects observed at doses effective for neuroleptic efficacy (ED? q).

In addition, some of these compounds exhibit diuretic, antiallergic, bronchodilatory or antihistamine activity at the minimum effective doses, i.e. eliciting a significant response at baseline, significantly higher at the effective doses (ED ^ q) for the neuroleptic effect, i.e. this side effect does not in any way reduce the value of neuroleptic efficacy.

The compounds produced by the process of the invention can be represented by the general formula I wherein

<img file="CS221829B2_D0001.tif" />

^R3 (AND)

R represents a (C 2 -C 4) -alkyl radical as well as a (C 4 -C 4) -alkyl radical, CH₂- a (C 2 -C 3) alkenyl radical or a C 3 -C 3 isoalkenyl radical,

R3 represents a (C3-C5) alkyl radical, a (C3-C5) isoalkyl radical, a CH3-C2-C4 alkenyl radical or CH₂a (C 3 -C 4) isoalkenyl radical, and

R 8 is hydrogen, methyl or ethyl, wherein 1. when R 8 is hydrogen, R 6 is allyl, and

2. Κϊ and Rj do not simultaneously have a butyl or allyl residue.

The compounds of formula (I) are ex^hO^dare those where R¹ tedious allylic^, R 4 is an isobutyl radical, R 1 is a propyl, butyl or even sutyl group and R 8 is a methyl radical, with particularly preferred compounds of the formula I being 1-α-3-yl-3-utyl-4- (4-methyl-ethyl) -thiamine 1,1-propyl-1-butyl-4-methylyanthine, 1-allyl-Soobutyl-1-ethylxanthine, 1,1-diisobutyl-8-ethylxanthine, 1,1-dipropyl-8-ethylxanthine, 1-propyl-- -isobutyl-8-methylxanthine and 1-ally-1-poopy-1-ethyl-xanthine. '

Compounds of formula I wherein R 1 is an allyl radical, R 3 is a butyl or isobutyl radical and R 8 is hydrogen are also a preferred group of these compounds.

Physiologically acceptable salts of the compounds of formula (I) are those which form these compounds with pharmaceutically acceptable bases: those salts whose cations are harmless to the living organism and do not have a salt thereof. at therapeutic doses, it has its own effects. Examples include alkali metal salts such as sodium or potassium, ammonium salts and salts of pharmaceutically acceptable amines. These salts may be prepared by heating a compound of formula I with or without the appropriate base in the presence of a solvent, preferably followed by recrystallization.

The process according to the invention for the preparation of the compounds of the formula (I) is characterized in that the derivative of the curing agent of the formula (Id) is used

<img file="CS221829B2_D0002.tif" />

(II_AND) where ^R3 ^R8 has the meaning as ^R^ except ^and.soprop^ylové^hand is as defined above, reacted with an alkylating agent of the formula

R - X where

R 'is as R except for the isopropyl radical a

X represents a halogen or a eotinphate or disulfate or p-toluenesulfonate residue.

and the resulting compound of formula III_AND The compound of formula (I) wherein at least one of R 1 and R 1 is alkenyl or isoalkenyl as defined above is hydrogenated.

The alkylation reaction is carried out in a solvent in which both reactants are dissolved, such as dimethylformamide, dirneethysulfoxide or hexamethylformamide, at a temperature in the range of 20 to 40 ° C and at a temperature of between 20 and 40 ° C.^with% solid alkali metal hydroxide such as sodium hydroxide. Accordingly, this rea^toThe reaction is carried out in dimethylamide at temperatures ²⁰ ° C and can be represented by the reaction scheme:

<img file="CS221829B2_D0003.tif" />

The alkali metal compound is then cyclized according to the reaction scheme

III_AND in boiling hydroxide solution

<img file="CS221829B2_D0004.tif" />

&lt;^J_AND)

Although it is possible to isolate the compound of formula III_AND, it is preferable to carry out the cyclization directly without isolating or purifying the compound of formula Шд. To this end, the reaction medium is refluxed and the solvent is evaporated, the residue is dissolved in an alkali metal hydroxide solution and the resulting solution is heated to reflux.

The process according to the invention can advantageously be used for the preparation of 1-alkyl-3-succyl-8-methylxanthine of the formula

CH₂= CH-CH_2X AND _NHo ^ n \ A_CH3(СН₂) з-СН₃ or physiologically acceptable salts thereof.

The process consists of: 1-butyl-5-mlyl-propylcarbonylamino-6-aminosilane of the formula

<img file="CS221829B2_D0005.tif" />

NH-C-CH 3 O. I í^(CH₂)³-^CH³ is reacted with an alkylating agent of the formula

CH₂ = CH - CH 2 X, where

X represents a halogen or a non-sulphate or disulphate or p-toluenesulphonate residue, after which the resulting 1-butyl-3-allyl-5-alkylcarbonylamino-6-aminouracil is cyclized.

The starting compound of formula (II) may be prepared by known methods, for example Traube &amp; apos; s death (Chem. Ber. 33, p. 371 and 3055, 1900) by reaction of the mooophins of formula (II).

R 1 -NH-C-NH 11 with cyanoacetic acid in acetic anhydride, evaporation of acetic anhydride and treatment with sodium hydroxide to give 1-alkyl-6-aminouracil, which is then converted to the compound of formula II_AND according to the reaction scheme

1) n »no₂/ ch₃cooh

2) N.₂WITH₂O₄/ NH₃

ΊΜ 3) RgCPOH / zl ₀AA_Nh₂^R3 O

<img file="CS221829B2_D0006.tif" />

nh ^_C/ R₈ nh₂⁰ (II_AND)

In order to prepare compounds of formula I wherein R 1 and R 2 are alkyl or isoalkyl radicals, the resulting compound of formula I wherein at least one of H, and R 6 is alkenyl or isoalkenyl may be hydrogenated. This process has been found to be advantageous in cases where a compound of formula (I) is to be prepared wherein R 1 is a propyl, butyl or isobutyl radical and is an alkyl radical other than R 1, particularly since of formula III_(B)will achieve very good yields with an alkylating agent of the type / OC-CHg-X, wherein X is as defined above.

Catalytic hydrogenation of one or both of the alkenyl or isoalkenyl residues is carried out in a xanthine solvent such as methanol, ethanol or ethyl acetate in the presence of a hydrogenation catalyst such as Raney nickel, palladium on activated carbon (Pd / C) or platinum oxide. As a rule, it is preferable to use ethanol and palladium-on-carbon catalyst. While it is possible to work under pressure and with heating, it is preferable to work under normal conditions, e.g. at room temperature and at atmospheric pressure.

The present invention also provides a pharmaceutical composition comprising a compound of Formula I in an amount effective for a neuroleptic effect, in combination with an inert, pharmaceutically acceptable carrier.

The composition may take a variety of pharmaceutical forms, such as tablets, capsules, suppositories, solutions and suspensions, containing conventional therapeutically inactive ingredients or carriers, and may be administered orally, sublingually, rectally, subcutaneously, intramuscularly, intravenously or by inhalation at 0.0004 doses. up to 0.04 g per day.

The invention is illustrated by the following examples in which amounts are given in weight units unless otherwise indicated.

Example 1

Synthesis of 1-allyl-3-butyl-8-methylxanthine

1. 1-Butyl-6-aminouracil

115 g (1 mol) of butyl urea and 94 g (1.1 mol) of cyanoacetic acid are heated in 200 ml of acetic anhydride for 2 hours at a temperature in the range of 75 to 80 ° C. The reaction mixture was cooled and ether (500 ml) was added. The precipitate formed is filtered off, washed with ether and dried.

The product thus obtained is suspended in a mixture of 300 ml of water with 150 ml of ethanol. Heat the suspension to 85 ° C and slowly add 75 ml of 10¾ aqueous sodium hydroxide solution. The solid fraction of the suspension dissolves and in a short time it begins to precipitate. After the addition was complete, the mixture was allowed to react for a further 30 minutes. It is then acidified to pH 5 with hydrochloric acid, allowed to cool and the precipitate formed is filtered off and washed with ice-water to give 100 g of colorless powder crystals.

2. 1-butyl-5-nitro-6-aminouracil

In a reactor equipped with a magnetic stirrer, 91.5 g (0.5 mole) of 1-butyl-6-aminouracil is suspended in 1 liter of water. To the resulting slurry was added a solution of 38 g of ODE in 250 mL of water. Acetic acid (65 m) was added dropwise from the stirring, and stirring was continued at room temperature for 18 hours. The reaction mixture was then cooled in an ice bath and the precipitate formed was filtered off. 90 g of violet-colored crystals are obtained.

3. 1-butyl-5,6-diaminoacetyl

In 440 m. Of a 50% aqueous ammonium hydroxide solution was suspended 84.8 g (0.4 mole) of 1-but^y1- 5-eiroooo-6-amyguacil. The resulting suspension was warmed to temperature⁸⁰ ° C, ecCe^of 88 g (0.48 mol) of sodium dithioliate were added portionwise with stirring over 30 minutes. Stirring was then continued for 30 minutes at 80 ° C, then overnight at room temperature. The reaction mixture was cooled in an ice bath, the precipitate was filtered off and washed with a small amount of ice water. 62 g of very fine crystals are obtained.

4. 1-Butyl-5-actt^yaarin-6-ominated

In a reactor equipped with a condenser, 59.4 g (0.3 mol) of 1-butyl-5,6-dicmino-anacil in 240 ml of acetic acid are heated to the boiling temperature of the reaction mixture for 2 hours with stirring. The acetic acid was evaporated and the residue dissolved in a small amount of ethanol, which was then evaporated. This process is repeated several times until a semicrystalline residue is obtained, which is triturated in ether until it solidifies. The solid thus obtained was filtered and washed with ether to give 72 g of yellowish fine crystals.

5. 1'Cllyl-Zbutyl88methylxaethie

13.2 g (0.055 mol) of 1-butyl-5-amino-6-acetylaminate are dissolved in 110 ml of dimethylformamide. 0.06 mol) of the amide. The reaction is allowed to proceed at room temperature for 30 to 60 minutes.

The reaction mixture was then neutralized to pH 5 with a concentrated hydrochloric acid solution and the dimethyl amide was discarded. The oily residue is dissolved in 40 ml of 10% sodium hydroxide solution. and the solution was heated under reflux for 2 hours. It is then cooled to room temperature, washed twice with 10 ml of dichloromethane and the pH is adjusted to 5 by addition of concentrated hydrochloric acid solution. The resulting precipitate is extracted three times with 20 ml of dichloromethane each time, then this solution is dried and the waste is discarded. 6.5 g of colored crystals are obtained.

These crystals are then degrade in boiling ethanol by treatment with activated carbon for 1 hour. The product is then recrystallized from a 1: 1 mixture of ethanol and water. Get colorless Or^ystood^y in likeness^E vat^y temperature^E melting in the range ¹⁷⁰ to ¹⁷¹ Deň: 32 ° C.

The Nuclear Carbon Resonance Spectrum of Carbon (C-NMR) is shown in Table II.

Example 2 to 10

Using the procedure described in Example 1, the compounds of Table I were prepared using the appropriate starting materials containing R @ 2._p R and Rg) i.e. monosubstituted moiety in step 1, Ocrbox^yThe compounds of step 4 and the reagent of step 5 as shown in Table I are listed in Table I. Table II lists the solvent, the melting points and the nuclear molecular values ​​of the carbon spectrum.

Table I

<td>Example number</td><td>Compound</td><td>Urea (level 1)</td><td>Acid (level 4)</td><td>Alkylation products dl o (Grade 5)</td>

<td> 2</td><td>18tlly8з8-butylxtetie</td><td>butylurea</td><td>ant</td><td>tllyObsolid</td>

<td> 3</td><td>18tlly8з8iioobutylxtetíie</td><td>i sobutylurea</td><td>ant</td><td>^^ b ^ omid</td>

<td> 4</td><td>1-Any-isobutyl-8-methylthio</td><td>i sobutylurea</td><td>acetic</td><td>allybbomide</td>

<td> 5</td><td>18tl·ly-зЗ-butyl-8-ethylxtetium</td><td>butylurea</td><td>propionsvá</td><td>allybboomide</td>

<td> 6</td><td>18tlly8з8-tccpy ---- methyltetium</td><td>prspylurea</td><td>acetic</td><td>allybbomide</td>

<td> 7</td><td>1-a-lyl- ^ li ^ ρβ ^^ - δ-ββ ^lanthin</td><td>i sopeenylmovina</td><td>acetic</td><td>allybboolid</td>

<td> 8</td><td>18-Ethyl-3-butyl-8-methyl-ethoxy</td><td>butylurea</td><td>acetic</td><td>diethylsulfate</td>

<td> 9</td><td>1,8-diethyl-3-O-butyltetyl</td><td>butylurea</td><td>propisnová</td><td>diethylsulfate</td>

<td> 10</td><td>180utyl838tlly888ímttylxtetíie.</td><td>aHylurea</td><td>acetic</td><td>butyl ester of p-1 olenesulfonic acid</td>

He did!

Synthesis of 1-propyl-3-butyl-8-methylxanthine

A solution of 5 g of 1-allyl-3-Uuyyl-8-methylxanthine (from Example 1) in 100 ml of eyanol was added to the hydrogenation apparatus and 500 mg of an activated carbon catalyst containing 10% palladium were added. The hydrogenation was allowed to proceed at room temperature until hydrogen uptake ceased (approximately 1 hour). Heat the reaction mixture. the precipitate was washed with ethanol and the solvent was evaporated. 5 g of colorless crystals are obtained, which, after recrystallization, are obtained^ystalov^andfrom methanol melted in the range 174 ^{to 175} Deň: 32 ° C. Nuld-eami magnn^Eic^toFor resonance spectrum of carbon see Table II.

Examples 12 and 13

Using the procedure described in Example 11, 1-propyl-3-isobutyl-8-methylxanthine was prepared from 1-ayl-1-isouutyl-8-methylxanthine (from Example 4), and 1-butyl-3-propyl-8-methyl-xanthine. from 1-butyl-3-allyl-8-methylxanthine (from Example 10).

The melting point, the solvent, and the nuclear maggee resonance spectrum of the carbon of these compounds are shown in Table II.

Table II

Example Temperature. Recrystallization Values ​​of Nuclear Magnetic Eesonance Spectrum⁰C Carbon Solvent (CDCl 4 * 5 ppm)

КопПгоЫ tttrtmeetlsilte

<td> 1</td><td> 170</td><td>to</td><td> 171</td><td>ethanol / water 1:</td><td> 1 13,8;</td><td> 14,8; 20,0; 30,2; 43,8;</td><td> 43,8; 106,7; 117,3;</td>

<td></td><td></td><td></td><td></td><td></td><td> 132,4;</td><td>i 149.7; 150.7; 152.4; 1</td><td> 55,6;</td>

<td> 2</td><td> 149</td><td>to</td><td> 150</td><td>mmtanol</td><td> 13,8;</td><td> 20,0; 30,2; 43,7; 43,9;</td><td> 107,0; 117,5; 132,2;</td>

<td></td><td></td><td></td><td></td><td></td><td> 140,6;</td><td>i 149.0; 157.7; 155.9;</td><td></td>

<td> 3</td><td> 194</td><td>to</td><td> 195</td><td>ethanol / water 1</td><td> :1 20,0;</td><td> 20,0; 27,4; 43,8; 51,0;</td><td> 106,9; 11’7,5; 132,2;</td>

140,5; 149,4, 151,0; 1«56,1;

continued table

<td rowspan="2">Example number</td><td colspan="2">Temperature</td><td rowspan="2">Re-start the solvent</td><td rowspan="2">Nuclear Maagneic Yielding Carbon Spectrum Values ​​(CDCl3: 8 ppm) TetrammtySíilcc</td>

<td>tánn, '</td><td>Deň: 32 ° C</td>

<td> 4</td><td>226 ai</td><td> 227</td><td>ethanol / water 1: 1</td><td> 14,8; 19,9; 19,9; 27,2; 43,7; 50,8; 106,5; 117,2; 1.324; 150,1; 152,3; 155,6;</td>

<td> 5</td><td>153 to</td><td> 154</td><td>ethanol / water 1: 1</td><td> 12,6; 13,8; 20,0; 22,7; 30',2; 43,7; 43,7; 106,7; 117,2; 132,5; 149,6; 150,8; 155,5; 157,4;</td>

<td> 6</td><td>186 ai</td><td> 187</td><td>meeanol</td><td> 1,1; 14,8; 21,4; 43,7; 45,4; 106,6; 117,'3; 132,4; 149,7; 150,7; 152,3; 155&gt;6;</td>

<td> 7</td><td>171 ai</td><td> 172</td><td>mmeanol</td><td> 14,8; 22,5? 22,5; 26,1; 36,8; 42,6; 43,7; 106,7; 117,3; 1:»,4; 149,7; 150,6; 152,4; 165,6;</td>

<td> 8</td><td>214 ai</td><td> 215</td><td>ethanol / water 1: 1</td><td> 13,3; 13,8; 14,7; 20,0; 30,2; 36,9; 43,7; 106,8; 149,5; 150,7; 152,1; 155,7;</td>

<td> 9</td><td>153 ai</td><td> 154</td><td>ethanol / water 1: 1</td><td> 12,5; 13,3; 13,8; 20,0; 22,7; 30,3; 36,9; 43,7; . 106,9; 149,4; 150,9; 155,7; 15 7,1;</td>

<td> 10</td><td>196 ai</td><td> 197</td><td>mmtanol</td><td>13.8; 14.7; 20.3; 30.2; 41.7; 45.7; 106.8; 117.8; 131.6; 149.2; 150.7; 152.2; 155.8;</td>

<td> 1 1</td><td>174 ai</td><td> 175</td><td>mmeanol</td><td> 1,4; 13,8; 14,74 20,0; 21,5; 30,2; 43,3; ' 43,8; 106,8; 149,5; 151,0; 152,1; 155,9;</td>

<td> 12</td><td>230 ai</td><td> 231</td><td>methanol</td><td> 11,4; 14,7; 19,9; 19,9; 21,4; 27,3; 43,3; 50,8; 106,7; 149,9; 151,2; 152,04 155,9;</td>

<td> 13</td><td>189 ai</td><td> 190</td><td>ethanol / water 1: 1</td><td> 11,1; 13,8; 14,7; 20,3; 21,4; 30,2; 41,6; 45,4; 106,8; 149,6; 150,9; 152,1; 155,9;</td>

Example 14

The xanthines from the previous examples were used in rats' behavioral tests based on anxiety caused by the new environment. For the cover te anxiety manifests erection on the hind paws, while its running over is an expression of movement activity.

Method

Induction of anxiety is performed in male naive Sprague-Dawley rats (Ifaa-Credo, France), at about 40 ° C. 260 and 300 g by placing them in a new environment consisting of 30 x 25 cm Macrolon cages, which are placed in. acoustically izooovemé and air conditioned room (at temperature²² ° C and 50% relative humidity).

The determination of the number of erections and deflections takes place autommaically with the use of electrical photocells with a bleached radiation, which emit electrical impulses only during movements of the animal, such as erection or overrunning, and not in static movements such as head movements. tail, for reasons of repsdužkovtelncsti. These electric photocells divide the cages at two different levels so that they can differentiate the ricks from overruns. The number of ups and downs is matched to these two rows of electric batons, stored and reproduced by a printing device according to a specified program.

An oesophageal solution is administered orally to a solution of the test compound in the form of its sodium salt; control animals receive 6 ml / kg of distilled water. Application is carried out 30 minutes before the animals are placed in the cages. The number of ups and downs is reduced for 15 minutes after the animals are transferred to the cage and compared to the effect induced in the control animals.

Processing results .

From the course of the effects of the test compounds on the number of deflections and eruptions depending on the applied progressive densities, which is expressed as a percentage of the number of deflections and eruptions of control animals, the effective ED50 (expressed in mm / kg), i.e. needed to induce 50% of the movement amount compared to the control animals.

The data are based on the method described by Saubrie in PJ Pharmmcol, (PaCiz), 2, (1971), pp. 457-472. These regression lines correspond to the mean value (expressed in%) of the control animals in relation to the dose rheumatism generated by 10 (only dosages which are more than 75% physically active are considered).

Comparison of the regression lines with respect to the deflections and the eruptions is performed by plotting the value of the straight line of the deflections per line segment (d) into the set of orthogonal coordinates and the value of the straight line c of the ordinate line (r). These values ​​result in an effect / effect relationship for the compound.

Similarly, the ratio of the waveform srnmroice to the slope of the erection curve is determined, which allows to shift the tpesOfiioott effect of the test compound to and narrowly.

The results obtained are shown in Table III.

Table III

<td>Compound · from Example #</td><td>^W50 (mg / k)</td><td>Line straight line simulation / 0 (d)</td><td>Rising Line Simulation / 0 (r)</td><td>Ratio d / y</td><td>Effect</td>

<td> 1</td><td> 0,14</td><td>P &lt;0.001</td><td>P &amp; lt; 0.01</td><td>ns</td><td>SN</td>

<td> 2</td><td> 1 ,60</td><td>p &lt;0.00i</td><td>p &lt;0.001</td><td>&lt;1; P &lt;0.001</td><td>SA</td>

<td> 3</td><td> 0,98</td><td>P &lt;0.001</td><td>p &lt;0.001</td><td>&lt;1; P &lt;0O01</td><td>SA</td>

<td> 4</td><td> 0,25</td><td>P &lt;0.001</td><td>P &amp; lt; 0.01</td><td>o. S.</td><td>SN</td>

<td> 5</td><td> 6,24</td><td>P &lt;001</td><td>P &lt;0.001</td><td>&lt;1; P &lt;0.001</td><td>SA</td>

<td> 6</td><td> 0,27</td><td>p &lt;0.001</td><td>p &lt;0.001</td><td>&lt;1; P &amp; lt; 0.01</td><td>SA</td>

<td> 7</td><td> 1 ,03</td><td>p &lt;0.001</td><td>p &lt;0.01</td><td> &lt;1^; · P &lt;001</td><td>SA</td>

<td> 8</td><td> 1 ,02</td><td>P &lt;0.05</td><td>p &lt;0.01</td><td>&lt;1; P &lt;0.05</td><td>SA</td>

<td> 9</td><td> 2,38</td><td>P &lt;0.001</td><td>P &lt;0.001</td><td>&lt;1; P &lt;0.00 ^ 1</td><td>SA</td>

<td> 10</td><td> 3,95</td><td>P &amp; lt; 0.01</td><td>P &amp; lt; 0.01</td><td>pers</td><td>SN</td>

<td> 1 1</td><td> 0,35</td><td>P &lt;0.001</td><td>p &lt;0.001</td><td>&lt;1; P &lt;0.001</td><td>SA</td>

<td> 12</td><td> 0,25</td><td>P &amp; lt; 0.01</td><td>P &amp; lt; 0.01</td><td>&lt;1; P &lt;0.001</td><td>SA</td>

<td> 1 3</td><td> 1 ,05</td><td>p &lt;0.01</td><td>P &amp; lt; 0.01</td><td>&lt;1; P &lt;0.05</td><td>SA</td>

<td>ohlsrpromazine</td><td> 21</td><td>P &lt;0.05</td><td>p &lt;0.05</td><td>pers</td><td>SN</td>

<td>halsperidol</td><td> 1</td><td>P &amp; lt; 0.01</td><td>P &amp; lt; 0.01</td><td>o.</td><td>SN</td>

<td>chlorine! cepoxide</td><td> 12</td><td>P &amp; lt; 0.01</td><td>P &amp; lt; 0.01</td><td>&lt;i; p &lt;o, oi</td><td>SA</td>

<td>teof ^ llo</td><td> -</td><td>P &lt;0.001</td><td>pers</td><td>&lt;1; P &lt;0.001</td><td>P.</td>

NOTES: - Comparison is performed using the probability test

P &lt;0.05, P &lt;0.01 c P &lt;0.001

- the axes that the simulation is statistically insignificantly differentiated from 0 or that the slope ratio of the overrun lines c is statistically insignificantly differentiated from 1.

It is noted that the compound has an opioid-high theliogenic effect

SA denotes a sedentary effect with a crocislyl character;

- P. zocmenIn psychostimulatory effect.

Conclusions

The effect of the test substance results from its position in relation to the line d = r and slope = 1. Substances lying on this line have a similar effect on erection and overrun, being non-specific sedatives (S.N). For these compounds, the ED50 value corresponds to the mean value derived from both regression lines.

Substances whose absolute value of the slope of the straight line is significantly higher than the absolute value of the straight line of the overhangs have a specific effect on anxiety. They are sedatives with anKiolytsky character (SA). In this case, the ED50 value is calculated from the regression straight line.

Table III shows that:

- the compounds of Examples 1, 4 and 10 have pro-efficacy similar to chloropnomazine and halopeeidol,

- the compounds of Examples 2,3,5 to 9 and 11 to 13 exhibit efficacy similar to that of chloraiazcpoxia,

Theooylin is a psychostimulant and has no effect on the subset.

Example 15

The compounds of Examples 1, 2, 4, 11 and 12 were subjected to toxicology testing:

(a) The acute toxicity of LDg in male and female mice was determined by administering the test compound dissolved in ethyl stiloxide by administering dimmeylsulfoxide alone to control animals, according to the method of JT Litchfield and F. Wilcoxone. , described in Jour. m., IL of Pharmacology and Experimental Medicine, Vol. 96, pp. 99-113, (1949).

(b) The acute toxicity of LD5Q in male and female rats is determined by administering the test compound dissolved in alppCyltulfoxiau (control animals receive only aimiCylSu.foxia) according to CS Veda and GJ Wrght, Intra- and inter laboratory commaartive evalúation of single oral test, as described in Toxicology and applied pharmmcology, Vol. 11, p.

378 to 388, (1967).

The compounds of Examples 1, 2, 3, 4, 5, 9 and 11 are basically:

c) a diuretic in a male rat, according to WL LLps®, J. Hdiadia A. Kerposcrc, JPET, Vol. 79, pp. 97-100 (1943);

d) In the male and female rats, according to J. Goose and AMJN В1с1гс, ^ шрпп! -, Vol. 16, pp. 749-760 (1969);

e) bronchodilatory in vitro, according to F. p. Luduen et al., Arch. int. alhcгmmaaoon ,, sv. 111, pp. 392-400, (1957);

f) in vitro, by R. Magnus, Arch. fd, ges. plhsto0., Vol. 102,. pp. 123-15, (1904).

The results of these tests are shown in Table IV.

Table

TV

<td>Example compound</td><td>^ld5° in mg / kg p male</td><td>.o., female mouse</td><td>b^LD5⁰in mg / kg p</td><td>o. female rat</td><td colspan="2">CD The minimum effective dose in mg / kg, which produces a significant response</td><td colspan="2">ě f A minus effective concentration in (α / ml) elicits a significant response</td>

<td> 1</td><td> 72</td><td> 62</td><td> 35</td><td> 24</td><td> 5</td><td> 2,5</td><td> 100</td><td> 100</td>

<td> 2</td><td> -</td><td> -</td><td> 200</td><td> 200</td><td> 10</td><td> 10</td><td> 25</td><td> 100</td>

<td> 3</td><td> -</td><td> -</td><td> -</td><td> -</td><td> 5</td><td>without effect</td><td>without effect</td><td> 200 .</td>

<td> 4</td><td> 79</td><td> 49</td><td> 23</td><td> 17</td><td> 20</td><td> 5°</td><td>without effect</td><td>without effect</td>

<td> 5</td><td> -</td><td> -</td><td> - ‘</td><td> -</td><td> 2,5</td><td>without effect</td><td> 5</td><td> 100</td>

<td> 9</td><td> - -</td><td> -</td><td> -</td><td> -</td><td> 5</td><td>without effect</td><td> 25</td><td> 5°</td>

<td> 11</td><td> 91</td><td> 151</td><td> 25</td><td> 15</td><td> 0,25</td><td>without effect</td><td> 10</td><td> 50</td>

<td> 12</td><td> -</td><td> -</td><td> 28</td><td> 19</td><td> -</td><td> -</td><td> -</td><td> -</td>

Note: indicates not tested

The compounds of Examples 1, 4, 11, and 12 were subjected to behavioral testing according to Poedictability and Specificity of Behavioral Screening Tests for Nevueptics, by B. Worms and KG Lloyd, published in Phabomabclogy, Teratology, Vol. 5, pp. 445-450. , (1979), which included:

- catalepsy induced by ha: 1 ^ opeoj ^ (^ oeii in mice:

Р ^ 1 ^ &lt;^ г ^ с ^ Сь: 1: ^ з ^ ь ^ ср at 1 mg / kg po

pentobarbite-induced anaagepsis UOS: potential for 0.5 mg / kg po

- cliobing behhaiour (climbing cage walls) induced by apomorphine In myya: inhibition at 1 mg / kg po

apomorphineo induced stereotyped behavior in rat: no antagonism up to 8 mg / kg po

- rectal temperature of the skin:

hypoteroid effect at 2 mg / kg po

h / pperolite induced by amphetamine in rat:.

antagonism at 0.5 mg / kg po

These effects are typical of neuroleptics, except that, unlike nemeleppics, such as halopeidol or chloroproazine, the above compounds do not have an effect on the stereotypical behavior in rats induced by atomorOfineo.