Method of preparation of active derivatives of acétoxime.

The present invention relates, generally, to the method for preparing acetoxime endowed of pharmacological activities.

The pharmacologically active compounds, prepared by the method of the invention, may be represented by the general formula:

THE R.

1 vBE1

the I *

A DH

THE R/

ACTIVATED C-C-R..,

THE OH

I

wherein, the R ^ ^ and R, which may be the same or different, each represent a linear or branched alkyl radical, containing 1 to 4 carbon atoms, or R ^ of £and R, when taken together represent, together with the carbon atom to which they are attached, a cyclohexyl radical.

As is described in more detail subsequently, it has been found that the derivatives of acetoxime obtained by the process of the invention are endowed with pharmacological properties, including in particular activities tranquilising, thymoanaleptic, muscle relaxant, anticonvulsant and sedation of the central nervous system.

The compounds of formula I are either products mentioned namely in literature, either as those included within the scope of general formulas published previously.

In this connection, may retain the cc.r.acad. IBS. 1_76, 516 - 518 (1923) and the patent no. ee.u.a of 3,346 523.

However, any pharmacological property has not been described or even mentioned in these publications are subject to compounds of formula I.

The compounds of formula I can be prepared by heating, in a suitable solvent such as an alcohol, for example, 1' ethanol and in the presence of an acid acceptor such as for example pyridine, a ketone of general formula:

R

O

_D¹ ^ C-C-R,

R₂ the I ^³

^Z THE OH

THE II

wherein R ^, ^ ^ where R and R have the same values as in formula I, with the hydrochloride or hydroxylamine sulfate to obtain the desired oxime derivative.

The compound of formula II, wherein R ^ ^ and R, which are identical, each represent methyl, is a known product having been described in Berichte dd.ch. G, 16 September 1922 e. 2903. Similarly, the compounds of formula II wherein represents tert-butyl and R 00 represents methyl or R ^ and which are identical, each represents ethyl or n-propyl or R^00 and R, when taken together with the carbon atom to which they are attached, represent cyclohexyl and R ^ represents methyl, are also known products having been published in cc.r.acad. IBS ., jj76, 516 - 518 (1923). The other hydroxy ketones of formula II can be prepared by known methods, in particular by hydrolyzing the corresponding éthinylcarbinol derivatives in the presence of acid sulfate of mercury as described in the mentioned reference of the cc.r.acad. IBS. These derivatives can be éthinylcarbinol, themselves, or condensing obtained ketone derivatives with acetylenic derivatives of naphthalene and sodium as published in the Miniature bull. Share. Chem. French 1960, 2, 354 - 359. The acetylenic ketone derivatives and necessary thereby to prepare the compounds of formula II required, are all known products.

And far more foregoing, it has been found that the derivatives of acetoxime prepared according to the invention have excellent pharmacological properties which make them useful in human and veterinary medicine.

In particular, it has been found that the compounds according to 1¹ invention possess psychotropic extended, especially tranquilising thymoanaleptic properties and activities including anxiolytic and antidepressant and anticonvulsant activity, muscle relaxant and, high doses, a sedative action on the central nervous system.

Furthermore, the compounds of the invention are completely free from neuroleptic.

All of these pharmacological properties is capable of rendering the compounds obtained according to the invention useful for the treatment of disorders requiring mental functions or not mild sedative action

It is known that a patient, having a high negative pressure and undergoing treatment with antidepressants, can exhibit anxiety reactions when its vacuum evolves in a normal way and consciousness of the depressive state in which it is disposed.

This phenomenon is reported by KECH and MDORE in "summaries of psychopharmacology" 337 (1971) P when they say:

" Known suicide attempt during the initial stages of treatment with antidepressant drugs... when the patient begins to show objective signs of improvement. This phenomenon paradoxus occurring during treatment apparently effective has been explained as being from a psychomotor increasing energy so that the patient is able to grant a desire to commit suicide is but having always a substantial degree of depressive state ".

To prevent this reaction anxious during delivery of antidepressants, the practitioner uses a tranquilizer type anxyolytic it combines the antidepressant used.

In addition, retort all cases of depression are characterized by a certain degree of anxiety, any agent that decreases the voltage state of the patient should logically give it some relief.

For this reason, many drug cocktails combine both an antidepressant and a tranquilizer, since most of the antidepressants used at present do not have tranquilising properties.

The essential interest of the compounds according to the invention is of having, in one molecule minimally toxic, the dual property of being both antidepressant and tranquilizer type anxiolytic. This advantage therefore avoids the association, very frequently made, an antidepressant a tranquilizer in a same therapeutic composition, separate or prescription of an antidepressant and a tranquilizer by the practitioner.

The originality of the compounds according to the invention lies in the fact that neither their antidepressant properties nor tranquilising manifest themselves with the degree of intensity which is characterized, on the one hand, antidepressants and, on the other hand, the anxiolytic themselves.

The compounds made according to the invention commonalities two properties so that the antianxiety activity, acting gently, facilitates the antidepressant activity shown by these compounds and this due to interference of anxiety in the patient's depressive behavior as described above. In this way, it is achieved that the maximum benefits for the patient of the two properties. possessed by the compounds of the invention without exposing to undergo undesirable side-effects that accompany administration so often, in separate medicaments, antidepressants and tranquilizers conventional.

Among the antidepressant is a composite component tranquiliser, must include some tricyclic antidepressants. Only, these compounds cause, to some extent, side effects of anticholinergic order such as dry mouth, disorders of 1' accommodation, sweating, tachycardia.

These disadvantages can be avoided by means of compounds made according to the invention, the doses used for obtaining an effect of antidepressant manifest a tranquiliser.

In addition, when treated with tricyclic antidepressant in a patient suffering from epilepsy, it is usually necessary to increase the dose of anticonvulsant. The compounds of the invention do not have this problem because they have, at the doses tranquilising and antidepressant, anticonvulsant component a non-negligible.

The tranquillizing effect observed with the compounds of the invention allows their assembly, in general, the class of minor tranquilizers, it is to say among the psychoactive compounds having anticonvulsant activity, anxiolytic and myorelaxant and devoid of any cataleptic effect. In addition, these activities-dose that always give a ratio very favorably with the neurotoxic dose 50 discussed hereinafter. This would pull them benzodiazepine type products. In addition, the properties tranquilising appear already at non-sedative advantage when none sedation is not mandatory.

As pain, the different kinds of anxiety are numerous and constitute a most common headaches. Therefore, it is very difficult, for the practitioner, select, in the range of drugs tranquilising the client application, the anxiolytic that will at case to be treated. It is not uncommon that in the presence of a patient anxiety, the psychiatrist gropes attempting to successively multidrug tranquilising to eventually detect the drug satisfying.

In this regard, the compounds prepared according to the invention will constitute a precious addition to the armamentarium of agents which must be provided and the physician, to the stringency, will replace usefully the either agent has become ineffective for any reason, such as changes in status of a diseased or addiction.

The compounds of the invention have been found to be particularly useful, especially as tranquilizers, are 1 'oxime the éthyl-a 3 hydroxy 3 hexanone are-a 2, 1' oxime n-propyl 3 hydroxy 3 hexanone are and 2 and 1' oxime n-butyl 3 hydroxy 3 and heptanone-a 2.

Pharmacological tests have been undertaken to determine the toxicity of compounds made according to the invention as well as the presence of different properties that, taken as a whole, are capable of rendering the compounds of formula I useful as tranquilizers, thymoanaleptic, anticonvulsants, muscle relaxants and central nervous system sedative.

1. Determining acute toxicity

Acute toxicity was determined in mouse type the decisions to. To this end, administered to batches of five mouse, intraperitoneally, a dose of the test compound in solution in olive oil neutralized, so that each batch receives a dose higher than that administered to the previous batch. We thus determined the maximum tolerated dosage (D.M.T.) or last dose that makes no mortality in animals of the experiment.

The following results were attained with the compounds according to the invention listed hereafter:

The éthyl-a 3 - oxime-hydroxy 3 pentanone refrigerant-to-2 (compound a)

- Oxime methyl 3 hydroxy 3 hexanone are above 2 (compound bj is

The éthyl-a 3 - oxime-hydroxy 3 hexanone are above 2 (compound Q.

- Oxirae n-propyl 3 hydroxy 3 hexanone are-a 2

Oxime - n-butyl 3 hydroxy 3 and heptanone-a 2

- Oxime n-propylbiphenyl 5 hydroxy 5 octanone and 4

The acêtyl-a 1 - Qxime of the cyclohexanol-a 1

WITH

B

C

D

E

F

G

(Compound d)

(Compound e) (compound f)

(Compound grams)

D.M.T. in mg/kg.

600

400

600

500

600

700

600

2. Determining hypnotic properties

The hypnotic properties have been highlighted by studying the reflex posture.

Is distributed male mice of1 of 22 g to about in batches of ten animals. The pets are administered to each batch, intraperitoneally, the compound to be studied so that each batch of animals receives a dose higher than that administered to the previous batch.

By noting the number of subjects who lose the reflex thirty minutes after administration of the compound.

In this way, it is determined the DHj Q, it is to say the dose of the test compound which causes 50 VBE1 animals loss reflex posture.

The following results have been obtained with the compounds according to the invention:

Compound

WITH

B

C

D

E

F

G

A DH₅₀ in mg/kg.

250

350

240

250

350

300

500

3. Action on the behavior.

a) determining the dose 50 neurotoxic

The test employed is that of the rota ROST, according Boissier (therapy 1958, XIII., pp.1074-to-1118). Is worked to appreciate the ability of animals to coordinate their movements.

The test is performed on batches of ten mouse of 22 grams. Administered intraperitoneally to animals of each batch the test compound so that each batch receives a dose higher than that administered to the previous batch. Thirty minutes after administration, the mouse is placed for two minutes on a cylinder of wood of 4.8 cm diameter rotating at a speed of four revolutions/min. The cylinder has a rough surface for the animals do not slip.

By this method, the DNT ^ Q-determined, it is to say the dose of the compound for which half of the animals in a batch fails on the turning rod during the time taken as a reference.

This test is interesting for two reasons. Indeed, the Test failure begins to translate a very thin with impaired function neuromuscular indiscernible by other means. On the other hand, this test is useful as a basis for comparison for establishing indexes with the results of other pharmacological tests.

The following results have been obtained with the compounds according to the invention:

The DNT compound_S0 in mg/kg.

150 B.

120 C.

110 D.

I 180

150 F.

225 GRAMS

b) action on spontaneous motility

The purpose of this test is to see what are the doses of compounds prepared according to the invention that increase or decrease the movement activity, thus one of factors of animal behavior in the conventional.

The motor activity of the animals is measured using a double electromagnetic apparatus on which arranges, on one side, a cage containing a group of ten to twenty controls and, on the other, a cage containing the same number of animals treated intraperitoneally with the test compound is administered for each batch at a dose higher than that received by the previous batch.

The apparatus automatically records the sum of the displacements of the controls and the treated animals and the totals per time slot.

Under these conditions, it is determined the threshold dose giving a significant decrease displacements of treated animals, it is to say a decrease of at least 30% of motor function of treated animals compared to control animals. It is found that this significant dosage is reached thirty minutes after administration of the compound to be studied.

In the case of compounds c and d, for example, it is found that this significant dosage is 100 mg and 75 respectively/kg body weight.

4. Determining tranquilising properties

Antianxiety effect

We showed the antianxiety action of the compounds of the invention by means of the testing of the four plates according Boissier (Animal food Chem. 1968, _ 4, 145 - 151).

Mice is distributed in four identical groups of ten to twenty animals, two groups constituting the controls. The material used is an apparatus equipped with four metal plates. They are connected to a current source plates so that the plates fed alternately with positive and negative poles of the electric current. Thus, when the animal crosses the plates, it receives an electrical discharge.

It is then determined the number of crossings without current plates of each animal of a control groups and the number of crossings of the plates with current animals of the second control group.

After a phase exploratory, control animals of the second group disrupt very quickly the crossing plates by fear of punishment and they are then electrically an attitude characteristic: aliasing ball, pile whiskering, toilet movements, emotional defecation.

Is then administered to the animals of the third and fourth groups a dose, intraperitoneally, of the compound of interest. Noted in the number of crossings of the plates without current by each animal of the third group and the number of crossings of the plates with current by the animals in the fourth group. Under these conditions, the animals treated with a compound to overstep antianxiety effect much more plates-control animals, the compound reaction inhibiting anxious due to the fear of the electrical discharge.

Is calculated thereby, on batches of ten to twenty animals•, the number moyai plates crossed by the control and the treated at different increasing doses of the test product. Noted in the first dose which significantly increases the number of plates crossed with current without changing the number of crossings of the plates without current so as to dissociate the acticn anxiolytic of eventual spontaneous motility.

Under these conditions, it has been found that the effective dosage (of) of the compounds according to the invention is as follows:

100 HAS

150 B.

75 C.

50 D.

I>150

150 F.

150 GRAMS

By comparing the of obtained in this test with the D.M.T. reported previously, it is noted that this same D.M.T. is 2.5 to 10 times higher than the of anxiolytic in question.

Throughout this process thus providing an ample margin of safety between the of anxiolytic and dl ^, this last dose are obviously herself greater than the dd.m.t.

5. With possible neuroleptic

In rats, all tests catalepsy (crossing legs homolatérales, testing of the four plugs, testing parallel bars] practiced with the compounds of the invention were found to be negative.

Similarly, we investigated the inhibition potential toxicity of group to amphetamine by injecting, intraperitoneally, the compounds of the invention, the dose to 50 hypnotic, fifteen minutes prior to the injection, also intraperitoneally, of 20 mg/kg of amphetamine sulfate mice grouped by ten per cage.

It has been found that, even hypnotic doses, the compounds of the invention do not inhibit the toxicity of group to amphetamine, which confirms the absence of neuroleptic.

6. Activity using a thymoanaleptic (antidepressive]

Acting antiréserpine

The antidepressants/counteract or retard the sedative action of the reserpine evaluated as by the phenomenon of the ptosis and catatonia in rats.

A CTO delivers, intraperitoneally, 50 mg/kg of the test compound to batches of five male rats with CF ^ an average weight of 300 grams. Thirty minutes later, is injected in the same manner, 3 mg/kg of reserpine. Noting the ptosis and catatonia three hours after injection of reserpine. A test identical over control animals that received the reserpine but not the test compound.

For the ptotic, each result represents the average of ten measurements (five animals whose examined both eyes], the ptotic is evaluated on each eye, according to the following scale:

0 -: not closing eyelids

- 1: eyelids closed at 1/4

2 -: eyelids closed at half

3 -: eyelids closed at 3/4

4 -: fully closed eyelids.

In this manner if, for example, an animal with ptosis of 1 on an eye and 2 on the other, it is counted 1.5.

For catatonia, each result represents the average of five measurements at the fixed bar test.

To this end, placing the forelegs of the animal on a fixed bar located horizontal to fifteen cm from the floor. The animal is judged catatonic if it maintains this position for more than twenty seconds. It is quoted 0 if it does not maintain this position and 1 if it maintains it. The maximum score is therefore 5 per batch.

The following results were attained with the compounds according to the invention:

Ptotic Catatonia Witnesses 3.7 3 compound

2.1 HAS 0

3.2 1 B.

C. 3, - 0

D. 2.8 0

I 3, - 0

3 F., - 0

3 GRAMS, - 0

7. Determination of the anticonvulsant activity

a) action on the seizure pentetrazolic

This test is carried out on mice, for searching the compounds according to the invention, administered preventively, intraperitoneally, have the property, certain amounts, for protecting a portion of the animals against the seizure, which would be lethal to 100 % in the absence of the compound, for a sufficient amount of convulsions and previously experienced.

The test is performed on batches of ten mouse. The pets are administered to each batch, intraperitoneally, the compound to be studied so that each batch of animals receive a dose higher than that administered to the previous batch. Fifteen minutes after administration of the compound, animals receive, intraperitoneally, 125 mg/kg of convulsions. By noting the number of dead three hours after the injection of the product. We can calculate the ^ of the Q, it is to say the dose of the test compound that protects OS I of animals against death. In a test carried out with the compounds according to the invention, there is obtained the following results:

Compound

WITH

B

C

D

E

F

G

OF₅₀ in mg/kg.

50

80

60

60

100

90

150

An index was calculated by comparing the efficiency of ^ Q which is obtained in this test with the dose required to achieve a hypnotic effect in 50 % animals (DHj Q) previously determined.

The index of efficiency is designated by the fraction: ^ Q-dt

The indexes of efficiency obtained for the compounds according to the invention as well as for phenobarbital are as follows:

HAS 5, -

4.4 B.

C. 4, -

4.2 D.

I 3.5

3.3 F.

3.3 GRAMS

3.3 Phenobarbital

These results demonstrate that, in the case that sedation on the central nervous system is required, the compounds made according to the invention are at least as advantageous and, generally, more advantageous as the phenobarbital, as regards the safety margin between the dose anticonvulsant and hypnotic dose.

It is pointed out also that, unlike phenobarbital, the compounds according to the invention have antidepressant properties.

It was also establishing another activity index by comparing the DNTj Q and the DEj Q obtained in the above test, it is to say the dose required to attain an anticonvulsant effect in 50 % treated animals as compared to controls.

This pointer is indicated by the following fraction: DNT, Q

In the case of compounds studied above we found the following index:

1.9 B.

C. 2, -

D. 1.8 1.8 IS

1.7 F.

1.5 GRAMS

These numbers show that there is in this test a substantial headroom between lala.dose anticonvulsant and the dose reaching the neuromuscular functions.

b) action on the electrical seizure

This crisis is manifested in the mouse by an extension hind legs during 5 to 10 seconds, extent similar to that observed during seizures tonicocionic caused by a chemical convulsant pentêtrazol or strychnine-type.

This test is performed as follows: is subjected, the sleep test, batches of ten mouse to an electroshock anticonvulsant (30 volt, 50 periods during 0.4 second) for selecting the subjects sensitive. The following day, administered, intraperitoneally, animals thus selected, different doses of the compound to be studied so that each batch receives a dose higher than that administered to the previous batch. Fifteen minutes later, animals are subjected to a shock of 60 volt, 50 periods during 0.4 second. By noting the percentage of mouse protected against tonic extension of hind legs and calculating the of ^ Q-it is to say the dose of the test compound which protects 50 % animals tonic manifestations.

The following results were obtained with the compounds according to the invention:

Compound of_S0 in mg/kg.

250 HAS

270 B.

C200

200 D.

300 W

F> 200

200 GRAMS

8. Determining muscle relaxant properties

The highlight muscle relaxant properties of compounds of the invention was done using the tensile test according to Courvoisier-Attinger (Psychotropic drugs or, in Milan, 1957, pp.373 and 391) and checking the analgesic properties strychnine-of these same compounds of the invention.

a) tensile test

This test judges the functions of equilibration and tone to the muscle.

The test is performed on batches of ten male mouse d' ^ 22 grams. It involves suspending the animals by the forelegs to a wire stretched horizontally. First noted the time required for a group of control animals for restoration, it is to say for installing at least one hind legs on the wire. Then administered, intraperitoneally, to each lot of mouse to be treated, a dose of the compound to be studied so that each batch receives a dose higher than that administered to the previous batch. Which is then the number of subjects who lose traction reflex thirty minutes after administration of the compound, and computing the ^ ^ of, it is to say the dose of the test compound which causes a loss of the reflex in 50% of animals.

Under these conditions the of, -₀ compounds according to the invention is as follows:

Compound of_S0 in mg/kg.

130 HAS

B200

C.■100

110 D.

I 150

F200

250 GRAMS

To obtain an activity index, was compared the ratios between the DNTj Q and of [. Q using tensile test with regard to the compounds according to the invention and a muscle relaxant well known, namely the Mephenesin. This ratio is therefore represented by the fraction: ^~50

Compound Index finger

0.7 B.

1.2 C.

D1, -

I 1.2

0.7 F.

0.9 GM

. (=100) 0.4 Mephenesin

250

This test highlights for the compounds according to the invention, an activity index favorable with regard to the index of the muscle relaxant used for comparison purposes. Indeed, in the case of the compounds according to the invention, it appears that the dose myorelaxant is farther away from the neurotoxic dose than in the case of the Mephenesin.

b.) Antagonism with strychnine

Treated batches of ten male mouse intraperitoneally at 100 mg/kg of a compound of the invention. Fifteen minutes later, the infusion is begun, the tail vein, an aqueous solution of sulfate to 0.05 mg/ml to strychnine-the rate of 0.5 ml/min. Noted in the average time of occurrence of atonic which is expressed in seconds. The same test is carried out on control animals having received strychnine but not compound under study.

The following results were attained:

49.6 Controls

HAS 56.8

B. 57.8

55.2 C.

D. 54, -

I 56.4

51.2 F.

52 GRAMS, -

Therapeutic compositions containing one or more compounds made according to the present invention can be presented in any form suitable for administration in human or veterinary therapy. As regards administration units, these can take the form, for example, a sugar-coated tablet or not, capsule or suspension or syrup for oral administration.

The administration unit will in this case, for example, of 50

to 500 mg, preferably from 100 to 250 mg of active ingredient.

The therapeutic compositions herein may also êtfe presented as a suppository containing, for example, 50 to 500 mg of active ingredient per administration unit for rectal administration.

The daily area is preferably 200 to 1000 mg of an active ingredient to a human of 60 kg.

According to the route of administration, the therapeutic compositions may be prepared by combining at least one of the compounds according to the invention together with a suitable excipient, the latter can be constituted, for example, of at least one ingredient selected from the following substances: talcum, magnesium stearate, lactose-, sucrose, carboxymethylcellulose, starch or corn, kaoline, lévilite, cocoa butter.

The preparation of the compounds of formula I as well as the formulation of therapeutic compositions referred to above are illustrated by the following examples, non-limiting exemplary:

Example 1

Preparation of 1' oxime the éthyl-a 3 hydroxy 3 hexanone are-a 2

In a flask provided with a reflux condenser, is heated for two hours in a water bath, a mixture of 7.2 grams (0.05 moles) of éthyl-a 3 hydroxy 3 hexanone are and 2, 6.95 grams (0.1 moles) of hydroxylamine hydrochloride, 75 ml of ethanol and 7.5 ml of pyridine.

The alcohol is removed by evaporation under vacuum and added 75 ml of distilled water to the residue obtained. Cooling the aqueous solution and is then extracted with ether. The ether layer is dried over anhydrous sodium sulfate and evaporated. Is then purged by recrystallization from hot octane, 1' oxime that has crystallized out.

This gives 5.53 g of 1 'oxime the éthyl-a 3 hydroxy 3 hexanone are and 2 which represents a yield of 70% with respect to 1' hydroxyketone starting. The melting point is 59 °c.

By the same method as described above, but initially products suitable, the following compounds were prepared: