NO125850B - - Google Patents

Description

Analogy method for the preparation of anti-inflammatory active triazaspyrodecandiones.

The present invention relates to a method for the production of new triazaspyrodecandiones with the formula:

where R is lower alkyl and cycloalkyl, R 1 and R 2 are hydrogen and lower alkyl.

These compounds have very high anti-inflammatory activity and low toxicity.

The new compounds are prepared according to the invention by reacting essentially equimolar amounts of an N-substituted 4-piperidone with the formula:

where R has the same meaning as above, with an alkali metal cyanide, ammonium chloride and carbon disulphide at a temperature between room temperature

turn and the mixture's boiling temperature for a period of time varying from 2 - 24 hours. Although the reaction can be carried out in the absence of solvents,

then it is usually preferred to use an inert solvent.

In particular, lower alkanols have been found usable, e.g. ethanol alone or diluted with water. When no solvent is used, so

after cooling, the reaction mixture can be recrystallized from a suitable solvent. In other cases where a solvent has been used, the product can precipitate on cooling, if necessary

reverse after concentration of the mixture to a reduced volume. Optionally, the entire solvent can be removed and the residual

dual masses by recrystallization. This procedure gives triaza-

1 2

spirodecaneditioners where the substituents R and R in the above formula are hydrogen. When compounds where R 1 and R 2 are lower alkyl groups are desired, these can be introduced by commonly known methods. One of these methods, which is given by way of example only, is a treatment with diazomethane in a suitable solvent, such as methanol, diethyl ether and mixtures thereof.

In an assessment of the compounds' biological properties

a suitable amount of one or more of the compounds was added to animals in which an experimental inflammation had been produced.

In the known carrageenin edema test, performed according to the method described by CA. Winter et al. Pro. Soc. Exp. Biol.-Med. 111, 544 (1962), thus the compound 8-cyclohexy 1-1,3,8-triazaspyro[4,5]decan-2,4-dithio was administered per os to separate groups of rats in doses of 40' and 20 mg/ kg. The mean reduction of the experimentally induced edema was 30 and 21%, respectively. It was found that the LD^Q for the same compound in mice was 200 mg/kg per os. Using the same method, the compound 8-methyl-1,3»8-triazaspiro[4,5]decane-2,4-dithio, which has an LD^Q of 500 mg/kg, was administered to rats in doses of 100 and 50 mg/kg. The corresponding reduction was 40.3 and 21% respectively.

In another experiment where the granuloma pellet sample was used, as described by R. Meier et al. Experientia 6,494 (1950), the compound 8-isopropyl-1,3,8-triazaspiro[4,5]decane-2,4-dithio was thus administered to rats in doses of 200 and 100 mg/kg. The inhibition of said granuloma was 34 and 23% respectively. It was found that the LDj-q in this case was 1000 mg/kg per os in mice. Moreover, the compound showed remarkable activity when tested under these conditions in adrenalectomized rats. In this case, an inhibition of 17% was found at a dose of 200 mg/kg.

The following examples illustrate the invention.

Example 1 8-methyl-1,3,8-triazaspiro[4,5]decan-2,4-dithio

A solution of 113 g of 1-methyl-4-piperidone in 500 ml of aqueous ethanol was added to 55 g of ammonium chloride, 50 g of sodium cyanide and 77 g of carbon disulfide, and the mixture was kept at 50°-60°C for 15 hours with stirring. The solvent was then distilled off in vacuo until the mixture had gained approximately half its original volume, after which the mixture was cooled. A crystalline precipitate was formed which was collected and dried. Yield: 66 g, m.p. 280°C. Example 2 1,3>8-trimethyl-1,3,8-triazaspiro[4,5]decan-2,4-dithio

A solution of the compound from the aforementioned example ('21.5 g) in 200 ml of methanol was contacted at room temperature with 16.4 g of diazomethane and 300 ml of diethyl ether for 2 hours. The solvents were distilled off in vacuo, and the residue was dissolved in chloroform and chromatographed through a column of silica gel, using a mixture of methanol and chloroform for the elution. Yield: 13 g (53%), m.p. 102° - 104°C. Example 3 8-isopropyl-1,3,8-triazaspiro[4,5]decan-2,4-diition

A solution of 141 g of 1-isopropyl-4-piperidone in 500 ml of aqueous methanol was added with 55 g of ammonium chloride, 50 g of sodium cyanide and 77 g of carbon disulfide, and the mixture was kept at 60°-65°C for 10 hours. The solvent was evaporated until the solution had gained approx.

1/3 of its original volume, and upon cooling the product was precipitated which was then collected and dried. Yield: 58 g, m.p. 288° - 290°C.

Example 4 8- cyclohexy1- 1, 3, 8- triazaspiro[ 4, 5] decan- 2, 4- dition

A solution of 18.1 g of 1-cyclohexyl-4-piperidone, 5.5 g of ammonium chloride, 5 g of sodium cyanide and 7.7 g of carbon disulphide in 100 ml of aqueous ethanol was kept at approx. 70°C for 12 hours. The product precipitated on cooling, was then collected and dried. Yield: 14 g, m.p. 249°-251°C.

Claims (1)

Analogous process for the preparation of anti-inflammatory active triazaspyrodecandiones with the general formula: where R is lower alkyl and cycloalkyl, and R and R are hydrogen and lower alkyl, characterized in that in a period of 2 - 24 hours at a temperature between room temperature and boiling temperature, a mixture of essentially equimolar amounts of a l -substituted-4-piperidone with the formula: where R has the above meaning, an alkali metal cyanide, ammonium chloride and carbon disulphide, possibly in the presence of a solvent.