CH619219A5 - Process for the preparation of novel m-dioxane compounds - Google Patents

Abstract

The novel compounds of the formula I <IMAGE> in which R<1> represents benzyl or methyl, are prepared by methylating a corresponding monomethylamine or benzylamine with a methyl halide. The benzyl radical present in any case can then be removed by reductive debenzylation, compounds of the formula I where R<1> denotes a hydrogen atom being obtained. In the compounds of the formula I, one of the radicals R<2> and R<3> denotes a hydrogen atom, while the other represents hydrogen or methyl, and Ar is phenyl, halophenyl, methoxyphenyl, methylphenyl, trifluoromethylphenyl, acetoxyphenyl, benzyloxyphenyl or 3-pyridyl. The compounds of the formula I and their salts have very good analgesic activities combined with only a slight tendency for addictive symptoms in the patients treated therewith.

Description

The present invention relates to a process for the preparation of new m-dioxane derivatives, and their acid addition salts. The new compounds produced by the process according to the invention have strong analgesic properties.

3rd

619 219

The present invention relates to a process for the preparation of new compounds of the formula I.

</ CH3

N

Ar *

I CHa-O.

c-c; XHa i 1 CH-0

(I)

H

R ° l Rfi in which

Ri is a benzyl group or a methyl group, and one of the radicals R2 and R3 represents a hydrogen atom, while the other of the radicals R2 and R3 is either a hydrogen atom or a methyl group, and Ar a phenyl radical, a halophenyl radical, a methoxyphenyl radical, a methylphenyl radical is a trifluoromethylphenyl radical, an acetoxyphenyl radical, a benzyloxyphenyl radical or the 3-pyridyl radical,

or of salts of the compounds of formula I.

The process according to the invention for the preparation of the new compounds of the formula I is characterized in that a compound of the formula II

(IIa)

Hn / r1

N

Ar-

1 ^ CHa-O ^

C-Cv l! CH 'H Röla R

, /

CBa

(II)

in which

Ri, R2, R3 and Ar have the same meaning as in formula I,

methylated with a methyl halide.

The new compounds of the formula I prepared by the process according to the invention are to be used in particular as active ingredients with analgesic activity. Therefore, when the compounds of the formula I are prepared in the form of their salts, pharmaceutically acceptable acid addition salts should expediently be produced.

Those starting materials of formula II in which Ri is a benzyl radical can be obtained by using corresponding unsubstituted amines, i.e. thus compounds which correspond to the formula II, but the radical R 1 has the meaning of a hydrogen atom, reacted with benzaldehyde to form the corresponding Schiff base and then catalytically reduced it to the corresponding benzylamine of the formula II.

Another object of the present invention is therefore a process for the preparation of new M-dioxane compounds of the formula III

H CH *

V

I -CHa ~ 0. Ar-CH - (/ yCHa I CH — 0. R® I R ° *

(Iii)

in which one of the radicals R2 and R3 denotes a hydrogen atom, while the other of the radicals R2 and Rs is either a hydrogen atom or a methyl group, and Ar is a phenyl radical, a halophenyl radical, a methoxyphe-5-nyl radical, a methylphenyl radical, a trifluoromethylphenyl radical, is an acetoxyphenyl radical, a benzyloxyphenyl radical or the 3-pyridyl radical,

or of salts of the compounds of formula III, which is characterized in that a benzylamine of For-io mei IIa

H CHs0 N

i / —a

"TO

20 U

in which the radicals R2, R3 and Ar have the same meaning as in formula III with a methyl halide to form the corresponding 25 a-methyl-a-benzylamine and then subject this to reductive debenzylation, the compounds of formula III being obtained and these isolated in free form or in the form of their salts.

The new compounds of the formula I and III are to be used in particular as active ingredients for pain relief. When testing the new compounds of formula I for their analgesic activity, it was found that those compounds in which Ar is a halogenophenyl radical, a methoxyphenyl radical, a methyl-35 phenyl radical, a trifluoromethylphenyl radical, an acetoxyphenyl radical or a benzyloxyphenyl radical in which the corresponding substituents are located in the ortho division or para position of the phenyl nucleus, have a significantly better analgesic activity than those compounds of the formula I and III in which corresponding substituents on the phenyl radical can be found in the meta position. Accordingly, of the new compounds of the formula I and III with Ar in the meaning of the substituted phenyl radicals mentioned, preference is given to those in which the 45 substituents in question can be found exclusively in the ortho or para position of the phenyl nucleus.

In pain relief, morphine and the synthetic substitutes for them, when used in equianalgesic doses, have about the same dangers 50 of getting used to these substances and the same extent of undesirable side effects. Even so, there are patients who experience side effects with one of these drugs while lacking other drugs. For this reason, the 55 substitutes for morphine are valuable supplements in therapeutic treatment. If pain is likely to be short-lived, such as in diagnostic procedures, cystoscopy, and orthopedic surgery and similar treatments, then a medication that provides shorter-term pain relief 60 may be more beneficial than morphine or methadone.

Various compounds that contain a 1,3-dioxolane backbone in their chemical structure are described in the literature as compounds with analgesic activity 65. Dexoxadrol, d-2,2-diphenyl-4- (2-piperidyl) -l, 3 - dioxolane hydrochloride is a mild analgesic that has a high likelihood of psychotic side effects, such as that of Lasagna and

619 219

4th

Pearson in Proc. Soc. Exp. Biol. M. Y. 118,352 (1965). N, N, 2-trimethyl-1,3-dioxolane-4-methylamine is also a mild analgesic with cholinergic side effects, as described by McClure in Arch. Int. Pharmacodyn. 179, 154 (1969).

The amines produced by the process according to the invention are named according to the designation recommended in Chemical Abstracts, "The Naming and Indexing of Chemical Compounds", Section 259. Cyclic compounds in which the amino group is separated from the ring, namely the dioxane ring, by an aliphatic chain are named using a compound chemical name, as is the case for example with m-dioxane-5-methylamine. The Greek letter a is used to indicate the position closest to the amino group.

The term "halophenyl" is understood to mean phenyl radicals which are substituted by halogen atoms, such as, for. B. the 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl and 4-fluorophenyl. The term "methylphenyl" means phenyl radicals which have methyl groups as substituents, such as the 2-methylphenyl or 4-methylphenyl radicals. The term "trifluoromethyl-phenyl" means phenyl radicals which carry trifluoromethyl groups as substituents, such as the residues 2-trifluoromethyl-phenyl and 4-trifluoromethyl-phenyl.

The term "methoxyphenyl" refers to phenyl radicals which carry methoxy groups as substituents, e.g. the 4-methoxyphenyl radical.

The 4-acetoxyphenyl radical may be mentioned as an example of an acetoxyphenyl radical.

A preferred example of a benzyloxyphenyl radical is the 4-benzyloxyphenyl radical.

As already mentioned, the new compounds of the formula I prepared by the process according to the invention can also be used in the form of their pharmaceutically acceptable acid addition salts. The term “pharmaceutically acceptable acid addition salts” is understood to mean those salts which are formed with acids which do not increase the toxicity of the entire compound to warm-blooded animals. Otherwise, the type of salt-forming group is generally not critical, although in some cases a certain anion can lead to certain advantages, for example easy solubility of the compound, easy crystallizability of the compound and the like. Examples of suitable pharmaceutically acceptable acids are mineral acids such as e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and nitric acid, as well as carboxylic acids such as acetic acid, citric acid, maleic acid, tartaric acid and similar acids.

If, however, compounds of the formula II in which R 1 is a methyl radical are used as starting material in carrying out the process according to the invention, these can be converted into compounds of the formula I in which R is a methyl group by carrying out a corresponding methylation on the nitrogen atom Implementation with a methyl halide. This methylation reaction is illustrated by the following reaction scheme:

CH öv> CH a CHa

Compounds of the formula I in which R is a hydrogen atom are prepared as follows:

A corresponding starting material of formula II is used, in which Ri is a benzyl radical. This corresponding starting material of the formula II can be prepared by reacting correspondingly substituted 5-benzoyl-m-dioxanes with hydroxylamine on the aryl radical, the corresponding oximes being obtained. These oxime derivatives are then catalytically reduced, the a-aryl-m-dioxan-5-methylamines optionally substituted in the aryl radical being obtained accordingly. These a - aryl-m-dioxane-5-methylamines are then condensed with benzyldehyde, the corresponding Schiff bases of the methylamine derivatives mentioned being obtained. These Schiff bases are then catalytically reduced to give corresponding starting materials of the formula II in which R 1 is a benzyl radical. This preparation of the starting materials of the formula II is explained using the following reaction scheme:

0

Ar-C '

25th

NH ^ GH

/ h3

Ar

5p

The reaction with benzaldehyde and reduction of the 30 Schiff base then gives the following starting material of the formula II:

H CHztf H

35

Ar-

~ p

45

R "

The starting materials of the formula II thus produced are then alkylated using methyl halides on the nitrogen atom, the corresponding benzyl analogs of the compounds of the formula I being obtained, that is to say compounds which correspond to the formula I, but in which the radical Rx is not a methyl group but the benzyl group is. The benzyl group is then reductively split off from these, giving the following compounds of the formula III:

Ar-CH

CHX 5.

In these compounds, R necessarily has the meaning of a hydrogen atom, while R2 represents either a hydrogen atom or a methyl group.

If desired, the compounds of the formula III thus obtained can then be converted into compounds of the formula I in which R 1 is a methyl group by reaction with methyl halides.

5

619219

If, when carrying out the process according to the invention, those starting materials of the formula II are used in which Ri is a benzyl radical, then the products obtained after the methylation on the nitrogen atom, which correspond to the formula I, but R1 5 does not mean the meaning of a hydrogen atom but still has the meaning of a benzyl radical, as already explained above, subjected to a reductive debenecylation.

This reductive debenzylation of the methylbenzylamine analogs of the formula I is usually carried out (see R. B. Wagner and H. D. Zook, "Synthetic Organic Synthesis", John Wiley, New York, N.Y. 1965, page 665) in an amphiprotic solvent, e.g. in 95% alcohol under a hydrogen pressure of 1.05 to 4.22 atmospheres (15-60 psi) using a catalyst, for example palladium-on-carbon or platinum, whereby a compound of the formula HI is obtained in the R. Means hydrogen atom. The debenzylated compound thus obtained can then be methylated with a methyl halide of the formula CH3-X, giving compounds of the formula I in which the radical R1 is a methyl group.

It can be seen that the compounds of the formula I have at least one asymmetric carbon atom which is derived from methylamine. Accordingly, two different forms of each of these compounds are possible, which represent an enantiomeric pair, these two enantiomers being separated to give the corresponding dextro form and Levo form. If the substitution occurs at an asymmetrical position of the m-dioxane nucleus, for example the 4 position, then the compounds have two additional asymmetrical carbon atoms. In this case 8 different forms of each individual connection are possible. The optical separation of such mixtures then leads to analgesically active pure enantiomers. The optical separation of an analgesic compound that has 3 asymmetric centers is a difficult task that leads to the separation of 4 diastereoisomeric pairs. Although it is preferable to use pure isomeric forms for analgesic purposes, the racemic mixtures are nevertheless well suited for the purposes mentioned here, in accordance with the corresponding analgesic content. All compounds produced by the process according to the invention have an analgesic effect in the form of their racemic mixtures. It is clear to the person skilled in the art that in such mixtures the pharmacological activity is frequently to a large extent or even wholly due to one of the stereoisomeric forms contained in this mixture. 50

In a further preferred embodiment of the invention, the dl-N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine is redissolved in order to produce analgesically active 1-N, N-dimethyl-a-phenyl- to produce m-dioxane-5-methylamine by performing the separation using dibenzoyl-55 -1-tartaric acid monohydrate. The dl-N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine is dissolved in ethyl acetate and this solution is treated with half a molar equivalent of dibenzoyl-1-tartaric acid monohydrate, also dissolved in ethyl acetate. Salt 60 immediately precipitates out of the solution. The recrystallization is achieved by adding methanol and heating in a water bath. Allow to crystallize completely by standing overnight. The tartaric acid salt is then isolated and recrystallized from ethyl acetate using the least possible amount of methanol required to carry out the solution. The crystalline salt is isolated and recrystallized again in order to isolate the pure salt of the 1-N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine with the dibenzoyl-1-tartaric acid. This salt of 1-N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine of dibenzoyl-1 - tartaric acid is then suspended in distilled water and made alkaline by adding an ammonium hydroxide solution. The basic mixture is extracted with ether. The ethereal extract is washed and dried and finally evaporated to give a solid residue. The solid is the corresponding 1-amine and this is taken up in ether and treated with hydrogen chloride gas, after recrystallization from methanol / ethyl acetate, the IN, N-dimethyl-a-phenyl-m-dioxane-5- receives methylamine hydrochloride in pure form.

The analgesic activity of typical compounds produced by the method according to the invention was tested using two standardized animal test methods. The so-called test method of the curving mice was modified in such a way that the frequency of the curvatures [Hendershot and Sorsaith, J. Pharm. Exp. Ther. 125, 237 (1959)] after intraperitoneal administration of 0.6% acetic acid [Koster et al., Fed. Proc. Soc. Expt. Biol. 18, 412 (1959)] was observed. The mice were normal Cox males weighing 20 to 22 g. The number of curvatures (contortions) was determined for every 5 mice during a period of 5 to 15 minutes after the acetic acid treatment. The percentage decrease in responsiveness due to drug treatment was determined by comparing it to control mice.

The other analgesic test method was the rat tail twitch test, which was developed by Robbins, J. Amer. Pharm. Assoc. Be. Ed., 44, 497 (1955). The rats were Sprague-Dawley females weighing 70 to 90 g. The test can be briefly described as follows: The rat tail was held on a tail holder of known temperature in the vicinity of a nichrome resistance wire through which a current could flow. A switch was used to initiate the current flow and thus the development of heat in the wire, and at the same time a stopwatch was started. When the investigator found a tail twitch, the switch was opened again and the latent time of the physical response was recorded and named the "response time". The rats' tails were left near the hot wire stimulus for a maximum of 30 seconds. 20 rats were tested in groups at random. At least 5 rats were used for each treatment, and each rat was treated with the drug only once and tested only once.

The following Table 1 shows the results of typical compounds produced according to the invention in their action as analgesics, characterized by the above-mentioned methods.

The first four columns of Table 1 describe the compounds tested in detail. The next 8 columns give the mouse contortion results and rat tail twitch test results for both oral and subcutaneous administration. The columns with the heading PT (“Time of maximum analgesic effect”; “Peak analgesia time”) indicate the time in minutes which elapses after administration until the maximum analgesic effect on stimuli is measured. The columns with the heading «ED50 (mg / kg)» indicate the dosages (EDj0) in mg per kg body weight (mg / kg), which produce a significant, up to a maximum increasing analgesic effect in 50% of the test animals.

619 219 6

Table 1

In Vivo test the analgesic effectiveness of m-dioxane-5-methylamines

CH3 CHs

'N'

I.

nm /

Aj — CH— ^ x salt

-0

formula

Form Ar

Mouse Contour Subcutaneous Oral

Rat tail twitch subcutaneously oral

Salt p'p *

(min)

ED50 (mg / kg)

PT (min)

ED50 (mg / kg)

PT (min)

EDso (mg / kg)

PT (min)

ED50 (mg / kg)

dl c6h5

HCl

15

15

45

28

15

4.5

15

27th

1

cßhg

HCl

15

6

15

16

15

7.0

15 '

10 to 20

dl

4-cha-ceh4

Maleates

30th

20th

45

110

30th

8.0

45

60

dl

3-pyridyl

2hc1

30th

10th

30th

25th

15

7.0

15

7.0

: PT is the time that passes until the maximum analgesic effect.

Other compounds have comparable analgesic activity, although the dose required to achieve analgesic effects varies from compound to compound. In addition, the time for the maximum analgesic effect is somewhat dependent on the type of connection. Many of the compounds provided here are effective for a short time and this is an advantage when pain of short duration can be expected. The compounds described here are from relatively low toxicity to non-toxic in their analgesically effective doses, since they are low compared to the dosage at which toxic effects occur. With some of the connections, a habituation effect develops slowly and the physical dependency formation (addiction formation) is minimal.

Since the compounds provided by the method according to the invention are effective when administered orally, this type of administration is preferred. The compounds concerned here can be used at non-toxic doses between about 1 and 200 mg per kg of body weight in a single dose or in the form of repeated doses to the desired degree of the therapeutic result. When administered orally, the compound can be placed in sealable gelatin capsules either with or without conventional pharmaceutical carrier or excipient materials. The compounds can also be mixed in tablets with various carrier materials and pharmaceutical auxiliaries, binders and the like. In addition, it is also possible to administer the compounds orally in the form of an aqueous suspension of their acid addition salts.

Typical examples of the m-dioxane-5-methylamines which can be prepared by means of the process according to the invention are the following:

a- (4-acetoxyphenyl) -N, N-dimethyl-m-dioxane-5-methylamine, a- (4-benzyloxyphenyl) -N, N-dimethyl-m-dioxane 5-methylamine,

N, N-dimethyl-a- (4-chlorophenyl) -m-dioxane-5-methylamine, N, N-dimethyl-a- (2,4-dichlorophenyl) -m-dioxane-5-methylamine,

30 N, N-dimethyl-a- (4-trifluoromethylphenyl) -m-dioxan-5-methylamine,

N, N-dimethyl- <x- (4-fluorophenyl) -m-dioxane-5-methylamine, N, N-dimethyl-a- (3-methoxyphenyl) -m-dioxane-5-methylamine,

35 N-methyl-ot-phenyl-m-dioxane-5-methylamine, N-methyl-ot- (3-pyridyl) -m-dioxane-5-methylamine, N, N, 4-trimethyl-a- (3- pyridyl) -m-dioxane-5-methylamine, N, N, 5-trimethyl-oi- (3-pyridyl) -m-dioxane-5-methylamine,

and the pharmaceutically acceptable acid addition salts 40 thereof.

example 1

Preparation of N-methyl-5-methyl-a-phenyl-m-dioxane - 5-methyl-amine hydrochloride A) 5-benzoyl-5-methyl-m-dioxane: 45 9 g paraformaldehyde (0.30 mol) were dissolved in 100 ml of aceto-nitrile with heating and 13.4 g (0.10 mol) of propiophenone was added to the mixture. The mixture was then cooled in an ice bath and 15 g (0.10 mol) of boron trifluoride etherate were added dropwise at about 0 ° C. 50 The solution became cloudy. The cloudy mixture was clarified by boiling on the water bath for about 15 minutes. The boiled solution was stirred into a mixture of ice and saturated sodium bicarbonate solution. The amber-colored layer was separated from the aqueous melt 55 and extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 17 g of an oil. The oil was distilled and the fraction with a boiling point of 120 to 130 ° C (0.40 Torr) was collected-60 de. A redistilled fraction with a boiling point of 118 to 122 ° C (0.40 Torr) crystallized. The yield of 5-benzoyl-5-methyl-m-dioxane after recrystallization from acetone-hexane was 2.1 g and showed a melting point of 84 ° C.

65 Elemental analysis showed the following results: for C12H1403:

Calculated: C 69.88 H 6.84 Found: C 70.08 H 6.62

7

619 219

B) 5-benzoyl-5-methyl-m-dioxane oxime:

2 g of 5-benzoyl-5-methyl-m-dioxane and 2 g of hydroxylamine hydrochloride in 10 ml of ethanol and 10 ml of pyridine were heated under reflux for 3 hours. The mixture was then evaporated to dryness in vacuo and the residue was treated with 10 ml of water. The oxime was collected and recrystallized from aqueous ethanol to give 1.5 g of 5-benzoyl-5-methyl-m-dioxane-oxime, which had a melting point of about 144 ° C. The elementary analysis gave the following values: for C12H15N03:

calculated: C 65.14 H 6.83 found: C 65.36 H 6.93

C) 5-methyl-oi-phenyl-m-dioxane-5-methylamine:

1.37 g of lithium aluminum hydride (0.036 mol) were covered with 100 ml of dry tetrahydrofuran. 4.0 g of 5-benzoyl-5-methyl-m-dioxane-oxime (0.018 mol) was dissolved in 50 ml of tetrahydrofuran and added dropwise to the hydride suspension with stirring. The mixture was refluxed with stirring for about an hour and then cooled. The mixture was then decomposed with a saturated ammonium chloride solution and the aqueous phase was decanted. The residue was treated twice with ether. The ether was evaporated and the residue was taken up again with ether. The hydrochloride salt was prepared by treating the ethereal solution with gaseous hydrogen chloride. The salt was dissolved in water and the aqueous phase was extracted with ether. The ether extract was washed with water. The aqueous phase and the wash waters were combined and made basic with ammonium hydroxide. The basic solution was extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and finally treated with gaseous hydrogen chloride to obtain the salt of the product. The yield of 5-methyl-ot-phenyl-m-dioxane-5-methylamine hydrochloride was 2.26 g after recrystallization from a mixture of methanol and ethyl acetate and the product showed a melting point of about 235 ° C. The elementary analysis gave the following values: for C12H17N02 HCl:

Calculated: C 59.13 H 7.44 Found: C 59.07 H 7.56

D) Preparation of N-methyl-5-methyl-a-phenyl-m-dioxane - 5-methylamine hydrochloride:

The 5-methyl-oi-phenyl-m-dioxane-5-methylamine hydrochloride was converted into the free base by dissolving the salt in water, then basifying with ammonium hydroxide and extracting the basic solution with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to give the free base in the form of an oil. The oil was methylated with methyl chloride and the product obtained was isolated in the form of the salt with hydrochloric acid.

Example 2

Production of N, N, 5-trimethyl-a-phenyl-m-dioxane - 5-methylamine hydrochloride

The N-methyl-5-methyl-a-phenyl-m-dioxane-5-methylamine hydrochloride produced by the process according to Example 1 was converted into the corresponding free base by reaction with ammonium hydroxide and extraction.

This was then methylated with methyl chloride by the process described in Example 1, step D), and the product obtained was isolated in the form of the hydrochloride. The N, N, 5-trimethyl-a-phenyl-m-dioxane-5-methylamine hydrochloride thus prepared showed a melting point of about 195 ° C.

Elemental analysis showed the following results: for C14H21N02 HCl:

calculated: C 61.87 H 8.16 N 5.15 found: C 61.74 H 8.41 N 4.98

Example 3

Production of N-methyl-a-phenyl-m-dioxane - 5-methylamine hydrochloride

A) 5-benzyol-m-dioxane:

60 g (0.5 mol) of acetophenone and 150 g (5.0 mol) of paraformaldehyde were added to 500 ml of acetonitrile. 213 g of boron trifluoride etherate (1.5 mol) was added dropwise to the reaction mixture with stirring. The mixture reached the temperature at which reflux occurred, about half the boron trifluoride ether addition. The addition was completed and the reaction mixture was then heated under reflux for 2 hours. The cooled reaction mixture was then stirred into a mixture of ice, water and saturated sodium bicarbonate solution. The melt thus obtained was extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oil as a residue. The oil was distilled and the fraction which had a boiling point of 115 to 120 ° C at a pressure of 0.5 Torr was collected and a yield of 40 g of 5-benzoyl-m-dioxane was obtained. This compound was characterized by means of NMR spectroscopy.

B) 5-benzoyl-m-dioxane oxime:

The procedure described in Example 1B) was repeated, but instead of the 5-benzoyl-5-methyl-m-dioxane used there, the 5-benzoyl-m-dioxane obtained in step A) above was replaced with the hydroxylamine hydrochloride implemented.

C) a-phenyl-m-dioxane-5-methylamine:

The oxime obtained after step B) was reduced by the process described in Example 1 C) using lithium aluminum hydride, the product obtained being the a-phenyl-m-dioxane-5-methylamm.

D) Preparation of N-methyl-a-phenyl-m-dioxane-5-methyl-amine hydrochloride:

The amine obtained after step C) was methylated with methyl chloride by the process described in Example 1, step D), and the product was isolated in the form of the hydrochloride. The N-methyl-a-phenyl-m-dioxane-5-methylamine hydrochloride thus produced showed a melting point of 183 to 184 ° C. after recrystallization from a mixture of methanol and ethyl acetate.

The elementary analysis gave the following values: for C12H17N02 HCl:

calculated: C 59.13 H 7.44 N 5.75 found: C 58.90 H 7.51 N 5.64

Example 4

Production of N, N-dimethyl-a-phenyl-m-dioxane - 5-methylamine hydrochloride

The N-methyl-a-phenyl-m-dioxane-5-methylamine hydrochloride produced by the process according to Example 3 was converted into the corresponding free base by reaction with ammonium hydroxide, and this was treated with methyl chloride by the process according to Example 3, step D) methylated. The product obtained was isolated in the form of the hydrochloride salt. The N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine hydrochloride thus prepared had a melting point of 172 ° C. after recrystallization from methanol and ethyl acetate.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

619 219

The elemental analysis of this product gave the following values for C13H19N02 HCl:

calculated: C 60.58 H 7.82 N 5.43

found: C 60.83 H 7.90 N 5.58

Example 5

Separation of dl-N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine into the optical antipodes

A) Preparation of the dibenzoyl-l-tartrate of the amine:

1'106.5 g of dl-N, N-dimethyl-oi-phenyl-m-dioxane-5-methyl-amine (5.0 mol) were dissolved in 4 liters of ethyl acetate. 940.8 g (2.5 mol) of dibenzoyl-1-tartrate monohydrate were dissolved in 4 liters of ethyl acetate with heating. The warm tartaric acid solution was added to the amine solution and an oil immediately formed. Then 300 ml of methanol was added to the mixture and the oil crystallized when treated on the water bath. The crystallization was completed by standing overnight. The salt was then collected and recrystallized from 5 liters of ethyl acetate, adding a minimal amount of methanol necessary for the solution. The crystalline salt was collected and recrystallized again to give 548 g of IN, N-dimethyl-a-phenyl-m-dioxane-5-methylamine-di-benzoyl-1-tartaric acid salt, which had a melting point of 132 to 133 ° C and an optical rotation of [a] D25 + 61.40 ° (c = 1, ethanol).

B) l-N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine - hydrochloride:

543 g of l-N, N-dimethyl-ct-phenyl-m-dioxane-5-methylamine-dibenzoyl-1-tartrate were suspended in distilled water and it was made basic with ammonium hydroxide. The basic mixture was extracted with ether. The ether extract was washed with water and dried over anhydrous magnesium sulfate and finally evaporated to a solid residue. 210 g of the solid were taken up in ether and treated with gaseous hydrogen chloride. The salt was collected and recrystallized from a mixture of methanol and ethyl acetate to give a yield of 156 g IN, N-dimethyl-o-phenyl-m-dioxane-5-methylamine hydrochloride, which had a melting point of about 202 to 203 ° C and an optical rotation of [a] 27527 ° - 92.6 (c = 51.825 mg / 5 ml, water).

The elementary analysis gave the following values: for C13H19N02 HCl:

calculated: C 60.58 H 7.82 N 5.43 Cl 13.75 found: C 60.83 H 7.58 N 5.51 Cl 13.67 According to the examples described, further compounds of the formula I were prepared and these and the physical data of which are given below: N, N, 4-tri-methyl-a-phenyl-m-dioxane-5-methylamine hydrochloride:

After recrystallization from methanol + ethyl acetate, this compound had a melting point of approximately 213 ° C.

The elementary analysis gave the following results: for C14H2IN02 HCl:

calculated: C 61.87 H 8.16 N 5.15 found: C 61.63 H 8.13 N 5.25

A: N, N-Dimethyl-a- (3-pyridyl) -m-dioxane-5-methylamine - hydrochloride

After recrystallization from methanol and ethyl acetate, this compound had a melting point of 196 to 197 ° C.

The results of the elementary analysis were as follows:

for C12H20Cl2N2O2:

calculated: found:

C 48.82 C 48.73

11

6.83 6.67

N 9.46 N 9.33

5 B: N, N-Dimethyl-a- (2-chlorophenyl) -m-dioxane-5-methylamine hydrochloride

This product had a decomposition melting point of 220 ° C. The elementary analysis gave the following values: for C13H18C1N02 • HCl:

io calculated: C 53.44 N 6.55 N 4.79 found: C 53.62 H 6.79 N 4.97

C: N, N-Dimethyl-a ~ (4-chlorophenyl) -m-dioxane-5; methylamine hydrochloride i5 The product has a decomposition melting point of 219 ° C.

Elemental analysis for this compound gave the following values:

for C13H18C1N02 • HCl:

thus calculated: C 53.44 H 6.55 N 4.79 found: C 53.37 H 6.62 N 4.67

D: N, N-Dimethyl-a .- (2,4-dichlorophenyl) -m-dioxane-5-methylamine hydrochloride

The product has a decomposition melting point of 230 ° C.

The elemental analysis of this product gave the following values:

for C13H1TC1ZN02 • HCl:

calculated: C 47.95 H 5.26 N 4.30 Cl 32.66 found: C 48.05 H 5.49 N 4.16 Cl 32.42

E: N, N-dimethyl-a- (4-beta-phenyl) -m-dioxane-5-methyl-amine hydrochloride

3s The product had a melting point of 195 - 196 ° C. Elemental analysis of the product thus obtained gave the following values:

for C13H18FN02 • HCl:

calculated: C 56.62 H 6.95 N 5.08 40 found: C 56.75 H 7.22 N 5.30

F: N, N-Dimethyl-a- (4-methoxyphenyl) -m-dioxane-5-methylamine hydrochloride

This product had a melting point of 194-195 ° C. 45 The elementary analysis of the product thus produced gave the following values:

for C14H21NC> 3 ■ HCl:

calculated: C 58.43 H 7.71 N 4.87 found: C 58.55 H 7.69 N 4.73

50

G: N, N-Dimethyl-a .- (2-methylphenyl) -m-dioxane-5-methyl-amine hydrochloride

The product had a decomposition melting point of 230 ° C.

55 The product obtained in the elemental analysis gave the following values:

for C14H21N02 • HCl:

calculated: C 61.87 H 8.16 N 5.15 found: C 61.90 H 8.42 N 4.97

60

H: N, N-Dimethyl-a- (4-benzyloxyphenyl) -m-dioxane-5-methyl-amine hydrochloride

The product had a decomposition melting point of 210 ° C.

65 The elementary analysis gave the following values: for C20H2gNO3 • HCl:

calculated: C 66.02 H 7.20 N 3.85 found: C 66.07 H 7.12 N 3.81

9

619 219

J: N, N-Dimethyl-a- (4-acetoxyphenyl) -m-dioxane-5-methyl-amine hydrochloride

The product had a melting point of 182-183 ° C. The elemental analysis of this product gave the following values:

for C15H21N04 ■ HCl:

calculated: C 57.05 H 7.02 N 4.44

found: C 57.08 H 7.06 N 4.61

K: N, N-dimethyl-a- (4-methylphenyl) -m-dioxane-5-methyl-amine maleate

Elemental analysis of this product gave the following results:

for C14H21N02 • C4H404:

calculated: C 61.52 H 7.17 N 3.99 found: C 61.60 H 7.38 N 3.80 The compounds prepared according to the preceding examples were tested for their analgesic activity in an in vivo test. The compounds in question were administered subcutaneously and the test method of the curving mice described above, ie the mouse contortion test, was used.

TABLE 2

Connection with the label

ED5o, mg / kg

A

10th

B

47

C.

32

D

50

E

30th

F

50

G

39

TABLE 2 (continued)

Compound labeled EDgo, mg / kg

5 H 50

J 8

according to Example 3 23

10 K 20

Example 6

Production of N-methyl-a-phenyl-m-dioxane-5-15-ethylamine hydrochloride

Using this example, the reductive debenzylation of compounds of the formula I with R1 in the meaning of a benzyl group with formation of the corresponding compounds

2o bonds of formula III explained.

18 g of N-benzyl-N-methyl-a-phenyl-m-dioxane-5-methyl

amine were at 4.22 atm. (60 psi) hydrogenated in 80 ml ethanol,

by using 0.9 g of a catalyst consisting of 5% palladium on activated carbon and the hydrogenation conditions

25 were 35 ° C for 1 lA hours. The catalyst was removed

filtered and the filtrate was evaporated to give a

Oil received as a residue. The oil was taken up in ether and the ethereal solution became gaseous

Treated hydrogen chloride, whereby 3.7 g of N-methyl-a-

30 -phenyl-m-dioxane-5-methylamine hydrochloride was obtained, and the melting point was about 155 ° to 157 ° C after recrystallize from a mixture of methanol and acetic ether.

The elementary analysis showed the following values:

Molecular formula C12H17HC1:

35 calculated: C 59.13 H 7.44 N 5.75 Cl 14.55

found: C 58.91 H 7.43 N 5.82 Cl 14.82

In the same way, the N-methyl-a- (3-pyridyl) -

-m-dioxan-5-methylamine through a reductive debenzyl

tion of N-benzyl-N-methyl-a- (3-pyridyl) -m-dioxan-5-me-

40 thylamine produced.

Claims (16)

619 219 1 -methylamine produces. 2. The method according to claim 1, characterized in that the compounds of formula I are prepared in the form of pharmaceutically acceptable acid addition salts. 2nd PATENT CLAIMS 1. Process for the preparation of new compounds of formula I. N Arco I CHß-O. ■ C-C'yCHa I l CH-'0 H Röl Ra in which Ri is a benzyl group or a methyl group, and one of the radicals R2 and R3 represents a hydrogen atom, while the other of the radicals R2 and Rs is either a hydrogen atom or a methyl group, and Ar a phenyl radical, a halophenyl radical, a methoxyphenyl radical, a methylphenyl radical , a trifluoromethylphenyl radical, an acetoxyphenyl radical, a benzyloxyphenyl radical is the 3-pyridyl radical, or of salts of the compounds of formula I, characterized in that a compound of formula II N (II) 3. The method according to claim 1 or 2, characterized in that the compound of formula I is the N, N-dimethyl-a-phenyl-m-dioxane-5-methylamine. 4. The method according to claim 1 or 2, characterized in that the compound of formula I is the N, N-4-trimethyl- <x-phenyl-m-dioxane-5-methylamine. 5. The method according to claim 1 or 2, characterized in that the N, N-5-trimethyl-a-phenyl-m - dioxane-5-methylamine is prepared. 6. The method according to claim 1 or 2, characterized in that the N, N-dimethyl-a- (3-pyridyl) -m - dioxane-5-methylamine is prepared. 7. The method according to claim 1 or 2, characterized in that the N, N-dimethyl-a- (4-chlorophenyl) - m-dioxane-5-methylamine is prepared. 8. The method according to claim 1 or 2, characterized in that the N, N-dimethyl-a- (2,4-dichlorophenyl) -m-dioxane-5-methylamine is prepared. 9. The method according to claim 1 or 2, characterized in that the N, N-dimethyl-a- (4-fluorophenyl) - m-dioxane-5-methylamine is produced. 10. The method according to claim 1 or 2, characterized in that the N, N-dimethyl-a- (4-benzyloxy-phenyl) -m-dioxane-5-methylamine is prepared. 30th V I .CHa ~ 0. Ar-CH-C ^; CHa I CH-0. R I ROE. in which one of the radicals R2 and R3 denotes a hydrogen atom, while the other of the radicals R2 and R3 is either a hydrogen atom or a methyl group, and Ar a phenyl radical, a halophenyl radical, a methoxyphenyl radical, a methylphenyl radical, a trifluoromethylphenyl radical Is acetoxyphenyl radical, a benzyloxyphenyl radical or the 3-pyridyl radical, or of salts of the compounds of formula III, characterized in that a benzylamine of formula IIa 40 (IIa) in which the radicals R2, R3 and Ar have the same meaning as in formula Ia, methylated with a methyl halide to form the corresponding a-methyl-a-benzylamine and then subjected to reductive debenzylation to give the compounds of formula HI and isolating them in free form or in the form of their salts. 11. The method according to claim 1 or 2, characterized in that the N, N-dimethyl-oi- (4-acetoxyphe-nyl) -m-dioxane-5-methylamine is prepared. 12. The method according to claim 1 or 2, characterized in that the N, N-dimethyl-a- (4-methyl-phenyl) -m-dioxane-5-methylamine is prepared. 13. Process for the preparation of new m-dioxane compounds of the formula III H CH * (Hi) l CHa-Q. Ar— C-C. yCHa I I CH — Q H R ° let ■ R in which R1, R2, R3 and Ar have the same meaning as in Formula I, methylated with a methyl halide. 14. The method according to claim 13, characterized in that one produces the N-methyl-a-phenyl-m-dioxane-5-methylamine. 15. The method according to claim 13, characterized in that the N-methyl-a- (3-pyridyl) -m-dioxane-5- 16. The method according to claim 13, characterized in that the compound of formula III is prepared in the form of pharmaceutically acceptable acid addition salts.