CH420165A - Process for the preparation of new heterocyclic compounds - Google Patents

Description

  

  
 



  Process for the preparation of new heterocyclic compounds
The present invention relates to a process for the preparation of new 4-aza-thioxanthene derivatives of the formula I,
EMI1.1
 wherein R1 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom, a halogen atom or a lower alkyl group and R2 is a lower alkyl group.



   According to the invention, the new compounds of general formula I are obtained by adding 4-aza-thioxanthene derivatives of formula II,
EMI1.2
 where R1, R2 and R3 have the above meanings, oxidized.



   In the starting substances of the formula II, R1 can be a hydrogen atom or a lower alkyl radical, such as. B. denote the methyl, ethyl, propyl or isopropyl radical, R2 can represent a hydrogen, chlorine or bromine atom or for a lower alkyl radical, such as for the methyl, ethyl, propyl or isopropyl radical and R3 for the methyl, ethyl, propyl, isopropyl or butyl radical.



   The sulfur atom can be oxidized with suitable oxidizing agents, such as. B. with hydrogen peroxide, organic peracids, inorganic peracids or their salts, e.g. B. Alkali Metaperiodata.



   The execution of the method is designed, for example, in such a way that the acetic acid solution of the starting substance, such as. B. 9- [1-methyl-piperidylidene- (4)] -4-aza-thioxanthene, (one mole) mixed with one mole of a dilute aqueous sodium metaperiodate solution for 3 to 5 hours at room temperature. To complete the reaction, the mixture is left to stand at room temperature for a further 4 to 5 days. After removing the precipitated sodium iodate and making it alkaline with ammonia or an alkali metal hydroxide, the end product is extracted with an inert organic solvent, preferably with methylene chloride, isolated therefrom by known methods and purified.



   Instead of using an aqueous sodium metaperiodate solution, the oxidation can also be carried out with organic peracids, e.g. B. with perbenzoic acid or with hydrogen peroxide at room temperature or slightly elevated Tem temperature, one mole of the oxidizing agent is used.



   The new 4-azathioxanthene derivatives of the formula I prepared according to the invention are basic compounds which crystallize at room temperature and which form stable salts which crystallize at room temperature with organic and inorganic acids.



  Such salts are, for example, the hydrochloride, hydrobromide, sulfate, fumarate, maleate, malate, acetate, tartrate.



   The new 4-azathioxanthene derivatives prepared according to the invention have a wide variety of therapeutically utilizable pharmacodynamic properties. They are characterized by a pronounced histamine-surrounding, narcosis-potentiating, adrenolytic, sedative and acetylcholine-inhibiting effect. The new compounds are therefore intended to be used as antihistamines in therapy, especially in allergic rhinitis, bronchial asthma and in a wide variety of allergic diseases.



   The compounds or their water-soluble, physiologically tolerable acid addition salts, alone or in appropriate medicinal forms for enteral or parenteral administration, can be used as medicaments. In order to produce suitable pharmaceutical forms, the active ingredients are processed as inorganic or organic, pharmacologically indifferent auxiliary substances; one uses z. B. for tablets and dragees: lactose, starch, talc, stearic acid etc., for injection preparations: water, alcohols, glycerine, vegetable oils and the like, for suppositories: natural or hardened oils and waxes and others.



   In addition, the preparations can contain suitable preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colorants, flavorings, etc.



   Starting substances in which R1 is hydrogen and R2 is halogen can be prepared from 7-halo-4-aza-thioxanthones and 1-alkyl-4-halo-piperidines by a Grignard reaction, hydrolysis and subsequent elimination of water. The 7-halo-4-aza-thioxanthones, in turn, are obtained by condensation of 2-chloro-nicotinic acid with a 4-halo-thiophenol and subsequent cyclization of the resulting carboxy-piperidyl- (2) -phenylsulfide derivative with polyphosphoric acid.



   In the following examples, which illustrate the implementation of the process but are not intended to restrict the invention in any way, all temperatures are given in degrees Celsius and are uncorrected.



   Example 1 9- [1 -Methyl-piperidylidene- (4)] -
4-aza-thioxanthene-1 O-oxide
It is added to a solution of 8.82 g of 9- [1-methyl-piperidylidene- (4)] -4-aza-thioxanthene (melting point 166-1670 from acetone) in 30 cm3 of water and 2.0 cm8 of glacial acetic acid The solution of 7.06 g of sodium metaperiodate in 80 cm3 of water is added dropwise over a period of 4 hours with thorough stirring and the reaction mixture is then stirred for a further 5 days at room temperature. The precipitated sodium iodate is filtered off, the filtrate is made alkaline with potassium hydroxide solution and extracted several times with methylene chloride. After the combined extracts have been dried over magnesium sulfate and the solvent has been evaporated off, the residue is recrystallized three times from ethanol.

   The 9- [1-methyl-piperidylidene- (4)] -4-aza-thioxanthene-10-oxide melts at 226-2280 (dec.).



   Example 2 7-chloro-9- [1 methyl-piperidylidene- (4)] -
4-aza-thioxanthene-1 O-oxide
The suspension of 3.29 g of 7-chloro-9- [1-methyl-piperidylidene- (4)] -4-aza-thioxanthene (melting point 150 to 1520) in 50 cm3 of water and 0.68 cm3 of glacial acetic acid becomes The solution of 2.46 g of sodium metaperiodate in 20 cm3 of water was added with thorough stirring at room temperature over the course of 80 minutes and the clear solution which had gradually formed was then stirred for a further 24 hours at room temperature. After making it alkaline with 7.5 cm3 of 2N sodium hydroxide solution, the precipitated crude product is extracted with methylene chloride and the extract is dried over sodium sulfate.

   After evaporation of the solvent, the residue is taken up in acetone and the acetone is removed by evaporation. The 7-chloro-9- [1-methyl-piperidylidene- (4)] -4-aza-thioxanthene-10 oxide is recrystallized twice from ethanol. M.p. 225-2260 (dec.).



   The 7-chloro 9 - [1 - methyl-piperidylidene - (4)] -4-aza-thioxanthene used as the starting substance is prepared as follows:
7-chloro-4-aza-thioxanthone
78 g (0.5 mol) of 2-chloro-nicotinic acid and 145 g (1 mol) of p-chlorothiophenol are on for 3 hours
Heated in 1700. It is then cooled and the crystalline reaction product is stirred with 500 cm3 of ether and 1000 cm3 of saturated sodium hydrogen carbonate solution until everything has dissolved. The ether layer is then separated off and extracted again with sodium hydrogen carbonate solution. The combined aqueous extracts are adjusted to pH 5 with acetic acid.

   The precipitated substance, 3-carboxypyridyl- (2) -p-chlorophenyl sulfide, is filtered off, dried and recrystallized from methanol. M.p. 216 to 2170.



   35 g of 3-carboxy-pyridyl- (2) -p-chlorophenyl sulfide are mixed with 350 g of polyphosphoric acid for 1 hour
1500, then heated to 1800 for 2 hours. After cooling to about 1000, the reaction mixture is allowed to flow into 1500 cm3 of water with thorough stirring. The precipitated substance is filtered off, then with
200 cm3 10 per. Sodium hydroxide solution stirred for 10 minutes, like that filtered off, washed well with water, dried and recrystallized from ice-cream.



   The 7-chloro -4-aza-thioxanthone melts at 194-195.



   7-chloro-9- [1 -methyl-piperidyl- (4)] -
4-aza-thioxanthydrol
2.43 g of magnesium shavings activated with iodine are covered with a layer of 10 cm3 of tetrahydrofuran and 0.3 cm8 of ethylene bromide is added to start the reaction. The solution of 14.7 g (0.11 mol) of 1-methyl-4-chloropiperidine in 25 cm3 of abs. Add tetrahydrofuran dropwise at such a rate that the reaction mixture boils continuously. The mixture is then heated for another 1-2 hours until most of the magnesium has dissolved, cooled and 12.4 g (0.05 mol) of 7-chloro-4-aza-thioxanthone are added in portions at 20-25 times. After stirring for 20 minutes at room temperature, the reaction mixture is poured into 300 cm3 of 10pro.



  Ammonium chloride solution and extracted with methylene chloride. After drying over magnesium sulfate and evaporation of the solvent, the residue is recrystallized from acetone. M.p. 225-226.



      7-chloro-9- [1-methyl-piperidylidene- (4)] -
4-aza-thioxanthene
10 g of 7-chloro -9- [1-methyl-piperidyl- (4)] - 4-aza- thioxanthydrol are concentrated with a mixture of 25 cm3 of water and 75 cm3. Sulfuric acid heated to 1400 for 20 min. Then you pour 500 cc of ice water, the solution is 50 percent.



  Sodium hydroxide solution is alkaline and extracted with methylene chloride. After drying over potassium carbonate and evaporation of the solvent, the residue is recrystallized from acetone. M.p. 150-152.



   Example 3 3-Methyl-9- [1 -methyl-piperidylidene- (4)]
4-aza-thioxanthene-1 O-oxide
The solution of 4.58 g of 3-methyl-9- [1-methylpiperidylidene- (4)] -4-aza-thioxanthene (melting point 195 to 1960) in 75 cm3 of water and 1.02 cm3 of glacial acetic acid is added with thorough stirring A solution of 3.70 g of sodium metaperiodate in 35 cm3 of water was added to room temperature within 70 minutes. After stirring for 20 hours at room temperature, the reaction mixture is made with conc. Ammonium hydroxide solution is alkaline and extracted several times with methylene chloride. After the combined extracts have been dried over sodium sulfate and the solvent has been evaporated off, the residue is recrystallized from acetone.

   The 3-methyl-9- [1-methyl-piperidylidene- (4)] -4-aza-thioxanthene-10-oxide melts at 195-196 (dec.).

 

Claims (1)

PATENT CLAIM Process for the preparation of new 4-azathioxanthene derivatives of the formula I, EMI3.1 wherein R1 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen, a halogen atom or a lower alkyl group and R8 is a lower alkyl group, characterized in that 4-aza-thioxanthene derivatives of the formula II, EMI3.2 oxidized. SUBCLAIMS 1. The method according to claim, characterized in that the 4-aza-thioxanthene derivatives of the formula II are oxidized with the corresponding molar amount of an alkali metal iodate, an organic peracid or hydrogen peroxide in an acidic medium. 2. The method according to claim, characterized in that the end products are converted into their acid addition salts.