CS211195B1 - 5- (3-Iodo-propargyloxy) -pyrimidine derivatives - Google Patents

Abstract

The invention relates to 5-(3-iodopropargyloxy)pyrimidine derivatives of the general formula I, ",Λ _^-°ch2-C5C-j R, (I) in which R, represents a halogen atom or an alkylthio group with 1 to 4 carbon atoms and R, represents a halogen atom, an alkoxy-, alkylthio- or alkylamino group with 1 to 4 carbon atoms or a morpholino group. These new substances have significant antifungal activity. They are prepared by iodination of 5-propargyloxypyrimidines, substituted analogously as in formula X, with elemental iodine in an alkaline medium.

Description

The present invention relates to 5- (3-iodopropargyloxy) pyrimidine derivatives of the general formula I, I-C = CJ _(I) in which R 1 represents a halogen atom or a C 1 -C 4 alkylthio group and R 8 represents a halogen atom, alkoxy-, alkylthio- or (C 1 -C 4) alkylamino or morpholino.

There are known 5- (3-iodopropargyloxy) pyrimidines substituted only in the 2-position of the pyrimidine core (cf. No. 158,984), which have good antimicrobial effects.

It has now been found that the antimycotic activity of these compounds can be further enhanced by a suitable substitution at the 4-position of the pyrimidine nucleus to give compounds of formula I having a broad spectrum of antifungal activity, covering pathogenic and saprophytic lower fungi.

The following table shows the efficacy of the following substances (expressed as minimum inhibitory concentration in µg / ml):

2-methylthio-4-chloro-5- (3-iodopropargyloxy) pyrimidine (A) ,,

2-methylthio-4-n-butylamino-5- (3-iodopropargyloxy) pyrimidine (B),

2-methylthio-4-morpholino-5- (3-iodopropargyloxy) pyrimidine (C),

2-chloro-4-methoxy-5- (3-iodopropargyloxy) pyrimidine (D).

Microorganism substance AND (B) C D Saccharomyces pasteurianus 0.3 1.5 3,1, 0.7 Trichophyton mentagrophytes 0.15 0.15 5.0 0.7 Aspergillus niger 0.15 3.1 3.1 0.15

According to the invention, the novel 5- (3-iodopropargyloxy) pyrimidines of the formula I can be prepared, for example, by reacting 5-propargyloxypyrimidine of the formula II-OCH ₂ -C _with CH (II) in which R 6 and R 8 denote the same as in formula I , iodinated with elemental iodine in a C 1 -C 3 alkanol, optionally in dioxane. Iodination can also be accomplished by treatment with an alkali metal iodide in the presence of an oxidizing agent.

The starting materials of the formula II are accessible on the one hand by the addition of 5-hydroxypyrimidine of the formula III,

N = i / y

N ~ *

OH (III) wherein R 1 and R 8 denote the same as in formula (I), alkylated with propargyl halide, preferably propargyl bromide, on the one hand, in 5-propargyloxypyprimidine of the general formula II in which R 6 denotes the same as in chlorine, this reactive atom does not replace the desired group, for example by reaction with an alkali metal alcoholate or mercaptide, optionally with an alkylamine or morpholine.

The reaction of the 5-hydroxypyprimidine of the formula III with a propargyl halide is conveniently carried out in an organic solvent such as acetone, dioxane, dimethylformamide, preferably dimethylsulfoxide and in the presence of a hydrogen halide binding agent, for example anhydrous carbonate or alkali metal hydroxide. For the alkylation of 5-hydroxypyrimidines, 3-iodopropargyl halide may also be used as the alkylating agent, but due to the poor availability of the compound, this reaction is not suitable for larger scale production.

Said substitution of the chlorine atom in the 4-position may be effected by an alkali metal alcoholate in excess of the corresponding C 1 -C 4 alcohol or by an alkali metal mercaptide of the C 1 -C 4 alkyl in a suitable organic solvent.

The reaction can also be carried out with a primary aliphatic amine of 1 to 4 carbon atoms or with morpholine, either in excess of the corresponding amine, or in the presence of an organic solvent, preferably dimethylformamide.

Compounds of formulas II and III wherein Sg is alkylthio may also be prepared by alkylation of the appropriate 4-mercaptopyrimidine with a suitable alkyl halide, preferably in a lower alkanol such as ethanol or dialkyl sulfate such as dimethyl sulfate or diethyl sulfate in an aqueous alkaline medium such as hydroxide solution. sodium.

Further details of the preparation process are given in the following examples, which are illustrative but not limiting.

Example

To a solution of 2-methylthio-4-chloro-5-hydroxypyprimidine (19.4 g) in dimethylsulfoxide (80 ml) was added 40% aqueous sodium hydroxide (7 ml) and propargyl bromide (13.6 g) was added dropwise with stirring. The reaction mixture was then heated at 50-60 ° C for 3 h. After cooling, the reaction mixture was poured into 800 ml of water with stirring and further stirred for 4 h at 5 ° C. The product was filtered off and washed with water. The obtained 2-methylthio-4-chloro-5-propargyloxypyrimidine has mp 67-72 ° C.

Example 2

To a solution of 1.88 g of 2,4-dimethylthio-5-hydroxypyrimidine in 10 ml of dimethyl sulfoxide was added 1 g of anhydrous potash and 1.35 g of propargyl bromide was added dropwise. The reaction mixture was stirred at 30 ° C for 1 h and then poured into 50 mL of water. The product was filtered off and recrystallized from dilute ethanol. The obtained 2,4-dimethylthio-5-propargyloxypyrimidine has a melting point of 96-98.5 ° C.

Example 3

To a solution of 0.5 sodium in 50 ml of ethanol was added 4.3 g of 2-methylthio-4-chloro-5-propargyloxypyrimidine and the reaction mixture was heated at 45 ° C for 1 h. After cooling, it is poured into 500 ml of water, the precipitated product is filtered off and washed with water. The obtained 2-methylthio-4-ethoxy-5-propargyloxypyrimidine has a melting point of 80-82 ° C.

Example 4

To a solution of 2.14 g of 2-methylthio-4-chloro-5-propargyloxypyrimidine in 25 ml of dimethylformamide was added 2 g of morpholine, the reaction mixture was heated at 50 ° C for 1 h and, after cooling, poured into 250 ml of water. The precipitated product is filtered off and washed with water. The obtained 2-methylthio-4-orpholino-5-propargyloxypyrimidine has a melting point of 72-74 ° C after crystallization from cyclohexane.

Example 5

To a solution of 0.4 g of sodium hydroxide in 25 ml of water is added 2.1 g of 2-methylthio-4-mercapto-5-propargyloxypyrimidine and, after dissolution, 1.5 g of methyl iodide are added dropwise. The reaction mixture was stirred at room temperature for 3 h and the precipitate was filtered off. The obtained 2,4-dimethylthio-5-propargyloxypyrimidine has a melting point of 96-98 ° C.

Examples

To a solution of 2.15 g of 2-methylthio-4-chloro-5-propargyloxypyrimidine in 60 ml of dioxane was added a solution of 1.4 g of sodium hydroxide in 20 ml of water and 5.3 g of iodine and the reaction mixture was heated to 70 ° C. It is then filtered with activated carbon, the filtrate is diluted with twice the volume of water and the precipitated product is filtered off. The obtained 2-methylthio-4-chloro-5- (3-iodopropargyloxy) pyrimidine has mp 167-172 ° C.

Example 7

To a solution of 2.15 g of 2-methylthio-4-chloro-5-propargyloxypyrimidine was added sequentially 3.5 g of a 40% sodium hydroxide solution, 3.5 g of potassium iodide and a solution of 1.6 g of sodium hypochlorite in 20 ml of water. The reaction mixture was heated at 70 ° C for 6 h and then worked up as in Example 6. The product obtained had mp 166-172 ° C.

Example 8

To a solution of 1.3 g of 2-methylthio-4-morpholino-5-propargyloxypyrimidine in 30 ml of methanol is added a solution of 0.9 g of sodium hydroxide in 0 ml of water and 1.7 g of iodine. The reaction mixture was heated at 40 ° C for 2 h, then cooled and the product was filtered off. Crystallization from ethanol gave 2-methylthio-4-morpholino-5- (3-iodopropargyloxy) pyrimidine, mp 149-151.5 ° C.

Example 9

To a solution of 1.9 g of 2,4-dichloro-5-propargyloxypyrimidine in 50 ml of methanol is added a solution of 0.8 g of sodium hydroxide in 10 ml of water, and after stirring for 15 minutes at room temperature, 3 g of iodine are added and stirring is continued. The precipitated product was filtered off and crystallized from ethanol to give 2-chloro-4-methoxy-5- (3-iodopropargyloxy) pyrimidine, mp 148-153 ° C.

Example 10

To a solution of 2.5 g of 2-methylthio-4-n-butylamino-5-propargyloxypyrimidine in 50 ml of methanol was added a solution of 1 g of sodium hydroxide in 10 ml of water and 3.5 g of iodine. The reaction mixture is stirred for 1 hour, the precipitated product is filtered off with suction and recrystallized from ethanol. There was obtained 2-methylthio-4-n-butylamino-5- (3-iodopropargyloxy) pyrimidine, m.p. 117-119 ° C.

Claims (2)

SUBJECT OF THE INVENTION 5- (3-iodopropargyloxy) pyrimidine derivatives of the general formula I-OCHg-C = CJR, (I) wherein R R represents a halogen atom or a Cth-C alkyl alkylthio group and Rg represents a halogen atom, an alkoxy-, an alkylthio- or (C 1 -C 4) alkylamino or morpholino. A process for the preparation of 5- (3-iodopropargyloxy) pyrimidine derivatives of the general formula I, wherein R ₁ and R 8 are as defined above, characterized in that 5-propargyloxypyrimidine of the general formula II OCH ₂ -CHCH (II) wherein R 1 and R 3 denote the same as in formula I, iodine with elemental iodine in a C 1 -C 3 alkanol, in the presence of an aqueous alkali metal hydroxide solution.