DE1470268A1 - New 1-aza-thioxanthene derivatives and processes for their preparation - Google Patents

Description

SANDOZ AG, ' Case 17? Jl · '

Basel / Sohwei * Patent Attorney '· Dr.W. Schalk PU 70 268.2

Wih

Dipl.lng. DipU-lng. G. Dannenberg Dr. V. Schmied-Kowarzik

Dr. P. Wcinhoid

6Franifurt a.Main

Size Eschenheimer sir. 39 New 1-aza-thioxanthene derivatives and processes for their Manufacturing

The present invention relates to new 1-aza-thioxanthene derivatives of the general formula I (see formula sheet) and their acid addition salts, wherein R, a hydrogen or a halogen atom, R _? denotes a lower alkyl group and χ denotes the value 1 or 2, as well as a process for the preparation of these new 1-aza-thioxanthene derivatives and their acid addition salts.

According to the invention one arrives at the new compounds of general formula I by adding a 1-aza-thioxanthene derivative of the general formula II (see formula sheet), in which R, and Rp have the above meaning, in a manner known per se a) with the corresponding molar amount of an alkali metal iodate to give a compound of the formula I in which χ is 1, or b) with twice the molar amount of an alkali metal iodate, an organic peracid or hydrogen peroxide in the presence of a strong mineral acid to a compound of the formula I in which χ 2 is oxidized and the compounds obtained are optionally converted into their acid addition salts.

In the starting substances of the formula II, R 1 can be a hydrogen, a chlorine or a bromine atom, and Rp can for the methyl, ethyl, propyl, isopropyl or butyl group stand.

909822/1317

New document 1 (Art; $ I Para. 2 No. 1 Sau 3 des Ärxterungagu. V. 4. U

- 2 - 1774

The execution of the method is designed for example. as follows:

End products of the formula I, in which χ stands for 1, are obtained by adding the acetic acid solution of the starting substance (1 mol) such as 9-tl'-methyl-piperidylidene- ^ ¹ ) 3-1-aza-thioxanthene, one mole of a dilute aqueous sodium metaperiodate solution is added for 5 to 5 hours at room temperature. To complete the reaction, the mixture is left to stand at room temperature for a further three days. After removing the precipitated sodium iodate and making it alkaline with ammonia or an alkali hydroxide, the end product is extracted with an inert organic solvent, preferably with methylene chloride, isolated therefrom by known methods, purified and, if desired, converted into an acid addition salt.

End products of the formula I, where ---:

rin χ is 2, are obtained, for example, by adding one mole of the starting product of the formula II in the presence of Glacial acetic acid and a strong mineral acid, e.g. concentrated sulfuric acid, at room or elevated temperature with two Moles of hydrogen peroxide treated. The oxidation can, however just as well with two moles of an organic peracid, e.g. perbenzoic acid or peracetic acid. After a reaction time of several hours, the mixture is concentrated and the residue taken up in water, desolate with ammonia ^ '- with an alkali lye mixed up to the alkaline reaction, the precipitated base in an inert organic solvent, preferably with methylene chloride, added, and after Washed out with water, the solvent evaporated again: The bases can be crystallized directly and / or with organic

9 0982 2/1317 ^ -

- 5 - 1774

see or inorganic acids converted into a suitable salt will.

The new 1-aza-thioxanthene derivatives prepared according to the invention of formula I are basic, crystallized at room temperature compounds with organic and inorganic Acids form stable, crystallized salts. Such salts are, for example, the hydrochlorides, hydrobromides, Sulphates, pumarates, maleinates, malates, acetates, tartrates.

Starting substances in which FL is halogen and R_ is a lower alkyl group mean, can according to the process described in Belgian patent specification 601 668 from 6-halo-l-azathioxanthones and l-alkyl-4-halopiperidines Grignard reaction and subsequent elimination of water are produced.

The new 1-aza-thioxanthene derivatives prepared according to the invention have a variety of therapeutically utilizable pharmacodynamic properties. So they stand out at good tolerance due to pronounced and specific histamine-inhibiting, or anti-allergic effect. In addition to their anti-clinergic properties, they also have a special one pronounced brincholytic effect which does not affect a sympathomimetic Effect is due, as with the previously used broncholytic and anti-asthmatic drugs. Even anti-cough properties are inherent in the preparations.

Unwanted side effects, such as sedative effects that occur with known antihistamines or antiallergic drugs occur are reduced to a minimum with the new process products. The new connections should therefore be saved as Antihistamines, antiallergics, as well as antiasthmatics and antitussives, e.g. for allergic rhinitis, bronchial asthma

909822/1317

-τ 4 - 1774

or status asthmaticus, bronchitis etc. in therapy use Find. As a result of their anticholinergic properties, they can also be used to dampen vagotcner diseases used as antispasmodics.

The 9-tl'-methyl-piperidylidene- (4 ¹ ) 3-l-aza-thioxanthene-10,10-dioxide (Example 3) prepared according to the invention was compared with the 9- known from Belgian patent 601 668 with regard to broncholytic effect and toxicity. compared tl'-methylpiperidylidene- (4 ') 3-l-aza-thioxanthene.

By irritating the peripheral vagus stump in anesthetized guinea pigs and vagotomized on both sides, a bronchial spasm is produced and the degree of opening of the bronchi is determined according to the method of H. Konzett and R. Rössler [Arch.exp.Patho] .- Pharmakol. 195 , 71 (1960); Viennese clin. Wschr. 6] _, 306 (1955) 3. Before the irritation, the test substance is administered intravenously and _{the dose defined as ED, - 0, is} that which inhibits bronchial spasm by 50 %.

Test substance Broncholysis; ED _C _
50 Toxicity (mouse) j IA50 connection of
Example 3
Comparison substance 0.0005 mg / kg iv
0.005 mg / kg iv 30 mg / kg iv
23 mg / kg iv

The product of the process is thus 10 times more effective in broncholytic activity, but 1.3 times less toxic than the comparison substance.

The compounds can be used as medicaments alone or in corresponding medicament forms for enteral or parenteral administration. For the purpose of producing suitable dosage forms, these are mixed with inorganic or organic,

909822/1317

processed pharmacologically indifferent auxiliaries. as Auxiliaries are used e.g.

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, among other things

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

In the following examples showing the execution of the procedure explain, but are not intended to restrict the invention in any way, all temperatures are given in degrees Celsius and are uncorrected.

909322/13 17

1774

II

909822/1317

- 7 - 1774

Example Ii 9; Ul; Methyl-piperidylidene- (V) jl-aza-thioxanthene-10-oxide

A solution of 5.88 g of 9-U ^f -methyl-piperidylidene- (V) 3-laza-thioxanthene (melting point 154-156 ° from acetone) in 20 ecm of water and 1.2 ecm of glacial acetic acid is left with thorough stirring 45 cctn 0.5 molar sodium metaperiodate solution is added dropwise over 4 hours and then stirred for 5 days at room temperature. The precipitated sodium iodate is then filtered off, the filtrate is made alkaline with potassium hydroxide solution and extracted several times with methylene chloride. After drying the combined extracts over magnesium sulfate and evaporating the solvent, the residue is dissolved in acetone, whereupon the 9- [l'-methyl-piperidylidene- (4 ')] - i-aza-thioxanthene-10-oxide crystallizes. After recrystallizing twice from acetone, it melts at 146-147 °.

Example 2; 6-chloro-9- [l'-methyl-piperidylidene- (4 ¹ )] - l-azathioxanthene-10-oxide

The solution of 2.7 g of 6-chloro-9- [l ^t -methyl-piperidylidene- (4 ^l )] -1-aza-thioxanthene in 40 ecm of water and 0.56 ecm of glacial acetic acid is stirred well at room temperature within 75 min. With a solution of 2.03 g of sodium metaperiodate in 20 ecm of water. After 128 hours of stirring at room temperature and 4 hours of stirring at 50 °, 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 twice from ethanol / acetone (approx. 1: 2). The 6-chloro-9- [l-methyl-piperidyliden- (4 ')] - l-aza-thioxanthene-10-oxide melting at 178-I80 ⁰ under low decomposition.

The 6-chloro-9- [l'-methyl-piperidylidene- (4 ')] - l-aza-thioxanthene used as starting material is made as follows:

909822/1317

- 8 - 1774

2 , h ~ 5 g magnesium shavings activated with iodine are treated with 10 ecm abs. Tetrahydrofuran covered and mixed with 0.2 ecm of ethylene bromide. As soon as the reaction starts, the solution of 14.7 g of 1-methyl-4-chloro-piperidine in 25 ecm abs. Add dropwise tetrahydrofuran, the reaction mixture boiling continuously. The mixture is then refluxed for about 2 hours until most of the magnesium has dissolved. After cooling to 20 °, 12.4 g of finely ground 6-chloro-1-aza-thioxanthone are added to the mixture in portions and the mixture is stirred for another 50 minutes at room temperature. The reaction mixture is then in ^ OOccm 10 percent. Poured ammonium chloride solution and extracted three times with methylene chloride. The combined extracts, dried over potassium carbonate, are evaporated and the residue is dissolved in acetone, from which the 6-chloro-9-Ll'-methyl-piperidyl- (4 ')] -1-aza-thioxanthydrol crystallizes. Mp. 166-167 ⁰ after recrystallization twice from ethanol.

3 * 75 g of the compound obtained are concentrated with a mixture of 22.5 ecm. Sulfuric acid and 7.5 ecm of water heated to 140 ° for 15 minutes. The reaction mixture is then poured into ice water and the solution, which has been made alkaline with sodium hydroxide solution, is extracted with methylene chloride. After the methylene chloride extract has been dried over potassium carbonate and the solvent has been evaporated off, the residue is crystallized from acetone. 6-Chloro-9- [1'-methy1-piperidylidene- (4 ^f )] -1-aza-thioxanthene melts at 110-112 °.

Example 3: 9 ->[1'-methyl-piperidylidene- (4 ')] - 1-aza-thioxanthene-10,10-dioxide

The mixture of 9> 5 g of 9- [l'-methyl-piperidylidene- (4 ')] - l-azathioxanthene (M.p. 154-156 ° after sintering from 152 °), l40 ecm glacial acetic acid and 58 ecm conc. Sulfuric acid is heated to 60 ° and while stirring dropwise with the solution of 17.1 ecm 58.5 percent.

909822/1317

aqueous hydrogen peroxide solution in 17 ecm glacial acetic acid. After stirring at 60 ° for 16 hours, the reaction mixture is concentrated under a pressure of 15 mm Hg. The residue is then dissolved in water, the aqueous solution is made with conc. Ammonium hydroxide solution is alkaline and extracted several times with methylene chloride. The combined extracts are washed neutral with water, dried over sodium sulfate and evaporated to dryness under a pressure of 15 mm Hg. After recrystallizing twice from methanol, the 9-U'-methyl-piperidylidene- (V) 3-1-aza-thioxanthene-10,10-dioxide melts at 188-189 ⁰ (decomp.).

909822/1317

Claims (3)

Claims 1. New 1-aza-thioxanthene derivatives of the general formula I (see formula sheet) and their acid addition salts, in which R _{1 is} a hydrogen or halogen atom, R _{p is} a lower alkyl group and χ is 1 or 2. 2. Process for the preparation of new 1-aza-thioxanthene derivatives of the general formula I, in which R ,, R ₂ and χ have the above meaning, characterized in that a 1-aza-thioxanthene derivative of the general formula II (see Formula sheet), in which R ₁ and R 2 also have the above meaning, in a manner known per se a) with the corresponding molar amount of an alkali metal iodate to give a compound of the general formula I, in which χ 1 means, or b) with twice the amount of an organic peracid, an alkali metal iodate or hydrogen peroxide in the presence a strong mineral acid to a compound of the general formula I in which χ is 2, oxidized and the compounds obtained are optionally converted into their acid addition salts. 3) Medicinal product, characterized in that it consists wholly or partially of the new 1-aza-thioxanthene derivative of the general formula I, in which R ,, R ₂ and χ have the above meaning. 37 / SR / EST. amCXKXIXXXXXXXXHX The patent attorney: 909822/1317 New documents (Art. 7, Paragraph 1, Paragraph 2, No. 1, Clause 3 of the Amendment Act of 4. ··