JPS6339596B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides general formulas useful as anticoccidial agents. [In the formula, R ¹ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ² is an alkyl group or an allyl group having 1 to 3 carbon atoms, and R ³ and R ⁴ are halogen atoms] The present invention relates to a method for producing a novel purine derivative. More specifically, the present invention relates to the general formula The compound represented by [wherein R ¹ and R ² have the same meanings as above] has the general formula [In the formula, R ³ and R ⁴ have the same meanings as above, and X represents a halogen atom] is reacted in the presence of a base to produce a purine derivative represented by the general formula () It's a method. In each of the above general formulas, the alkyl group having 1 to 3 carbon atoms represented by R ¹ and R ² includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, and the like. Examples of the halogen atoms represented by R ³ and R ⁴ include chlorine atoms and fluorine atoms, and these may be the same or different. Examples of the halogen atom represented by X include a chlorine atom and a bromine atom. Examples of the purine derivatives () include the compounds shown below. 9-(2-chloro-6-fluorobenzyl)-
6-Methylaminopurine 9-(2,6-dichlorobenzyl)-6-methylaminopurine 9-(2-chloro-6-fluorobenzyl)-
6-dimethylaminopurine 9-(2,6-dichlorobenzyl)-6-dimethylaminopurine 9-(2-chloro-6-fluorobenzyl)-
6-ethylaminopurine 9-(2,6-dichlorobenzyl)-6-ethylaminopurine 9-(2-chloro-6-fluorobenzyl)-
6-diethylaminopurine 9-(2,6-dichlorobenzyl)-6-diethylaminopurine 9-(2-chloro-6-fluorobenzyl)-
6-Propylaminopurine 6-allylamino-9-(2-chloro-6-fluorobenzyl)purine Among these purine derivatives (), R ¹
is a hydrogen atom or a methyl group, ^R2 is a methyl group or an ethyl group, ^R3 is a chlorine atom, and ^R4 is a chlorine atom or a fluorine atom.
R ¹ is a hydrogen atom, R ² is a methyl group, R ³ is a chlorine atom,
9-(2-chloro-6-) where R ⁴ is a fluorine atom
Fluorobenzyl)-6-methylaminopurine is preferred. The purine derivative () may be in the form of a salt,
Examples of such salts include acid addition salts such as hydrochloride and sulfate. The method of the present invention is carried out by reacting compound () with compound () in the presence of a base. Examples of the base used in this reaction include alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), tertiary amines (e.g.,
trimethylamine, triethylamine, tri-n
-propylamine), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, calicum tert-butoxy), sodium hydride, etc., and the amount used is the same as the compound ().
Amounts of about 1-4 moles per mole are convenient. By using such a base, this method succeeded in selectively reacting the compound () at the 9-position of the compound () in high yield for the first time, and when no base is used, the compound ()
The intended purpose is not achieved by replacing it in the 3rd position. This reaction is usually carried out using solvents that do not interfere with the reaction, such as N, N-
Reaction using dimethylformamide, N,N-dimethylacetamide, acetonitrile, nitromethane, alcohols (e.g. methanol, ethanol, tert-butanol) at room temperature - about 150°C, preferably about 50°C - about 110°C. It is done at temperature. The amount of compound () to be used is conveniently about 1 to 4 moles per 1 mole of compound (). The purine derivative () thus produced can be isolated from the reaction mixture by conventional separation and purification means (eg, concentration, filtration, recrystallization). Furthermore, the purine derivative (2) can also be isolated in the form of the above-mentioned acid addition salt by a conventional method. The novel purine derivative () and its salt produced by the method of the present invention have excellent anti-coccidial activity and extremely low toxicity, and are effective against coccidiosis in poultry, livestock (e.g., chickens, turkeys, cows), etc. It is useful as a prophylactic therapeutic agent. Such a coccidiosis preventive and therapeutic agent can be prepared by diluting the compound () and its salt with a solid or liquid diluent or without diluting it into powders, dusts, granules, tablets, liquids, capsules, etc. It is produced by adding directly or dispersed in a diluent to feed, drinking water, etc.
Any diluent may be used as long as it is physiologically harmless in itself, and it is more desirable to use a diluent that can be used as feed or a component of feed. Examples of solid carriers include barley flour, wheat flour, corn flour, soybean meal, soybean flour, rapeseed meal, rice husks, rice bran, defatted rice bran, cornstarch flour, potato flour, tofu cake, starch, lactose, sucrose, Examples include glucose, fructose, yeast, waste yeast, and fishmeal.
Examples of liquid carriers include water, physiological saline, physiologically harmless organic solvents, and the like.
Other appropriate auxiliary agents such as emulsifiers, dispersants, suspending agents, wetting agents, thickening agents, gelling agents, and solubilizing agents may be added as appropriate. Furthermore, preservatives, bactericidal agents, antibiotics, enzyme preparations, and lactic acid bacteria preparations may be added, and other anti-coccidial agents, sulfur agents, vitamin preparations, etc. may also be added to these compositions. The preventive and therapeutic agent for coccidiosis containing the purine derivative () or its salt produced by the present invention includes:
Prevention of coccidiosis in poultry and livestock as described above,
Since it exhibits excellent therapeutic effects and low toxicity, the dosage can be appropriately determined depending on, for example, the type of poultry, livestock, body weight, age, method of administration, purpose of administration, etc. For example, when the purpose is to prevent or treat coccidiosis in chickens, the compound () should be administered at a dose of about 0.4 to 100 mg/Kg/day, preferably about 0.8 to 30 mg/Kg/day. As a practical method, for example, 0.0004-
It is convenient to administer the compound in an amount of about 0.1% by weight, preferably about 0.0008-0.03% by weight. As shown in the following experimental examples, the coccidia disease prevention and treatment agent containing the compound () or its salt completely suppresses bleeding, death due to infection, and intestinal lesions, and reduces body weight even when administered at low concentrations. It has excellent effects, such as a remarkable increase. The following is an example of an experiment using chicken chicks to demonstrate the effectiveness of the above-mentioned coccidiosis preventive and therapeutic agent. As used below, "uninfected control" refers to "uninfected, unmedicated control," and "infected control" refers to "infected, unmedicated control."
represents. Experimental example Test materials and test methods (1) Test compound: 9-(2-chloro-6-fluorobenzyl)-6-methylaminopurine (2) Mixing ratio of test drug to feed: Anti-coccidial agent It was mixed into a compound feed for day-old chicks (see Table 2 for the composition) to a concentration of 0.009% by weight. (3) Test method: A group of three 9-day-old white Leghorn male chicks were fed with a basal diet containing the above test compound, and 24 hours after the start of drug administration, 50,000 chicks per bird were given.
Eimeria tenella mature oocysts were directly inoculated into chicken pouches. Separately, an infected control group was established in which three birds were raised as a group on a basal diet containing no drug and infected with coccidia at the same time as above. In addition, a non-infected control group was set up in which three birds were raised in groups with only basal feed containing no drugs, and no oocyst inoculation was performed. Judgment was based on the following method. (a) The chicks were examined for signs of bleeding on days 4, 5, 6, and 7 after infection, and determined by the number of drops. (b) Liveness and death were observed on days 5, 6, 7, and 8 after infection. (C) On the 7th day after infection, the weight gain ratio per group (test group weight gain/uninfected control group weight gain x 100) was measured.
(d) On the 8th day, the chicks were necropsied, the cecum was macroscopically observed, and the lesions were detected according to the method of Johnsson and Reed described in Experimental Paragitology, Vol. 28, p. 30 (1970). ) - ( ⁺⁺⁺⁺ ) 5-step method was used. The results are shown in Table-1.

【table】

[Table] Example 1 6-methylaminopurine. 45g, potassium carbonate
6.9g and 250ml N,N-dimethylacetamide
were mixed, 17.9 g of 2-chloro-6-fluorobenzyl chloride was added thereto, and the mixture was stirred at 110°C for 6 hours. After cooling, insoluble materials were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. Water was added to the residue, the crystals were collected by filtration, and recrystallized from ethanol to give 9-(2-chloro-6-
9.08 g (yield, 63%) of colorless needle-like crystals of (fluorobenzyl) 6-methylaminopurine were obtained. Melting point 188
-190℃. The nuclear magnetic resonance spectrum of this product is the same as that of a standard product synthesized by a different method (Japanese Patent Application No. 101349/1986). Example 2 6-methylaminopurine 1.49g, potassium carbonate
Colorless needle-like crystals of 9-(2,6-dichlorobenzyl)-6-methylaminopurine were prepared in the same manner as in Example 1 from 1.38 g of N,N-dimethylacetamide, 50 ml of 2,6-dichlorobenzyl chloride, and 3.92 g of 2,6-dichlorobenzyl chloride.
1.9 g (yield, 62%) was obtained. Melting point 219-220℃.
The nuclear magnetic resonance spectrum of this product was obtained using a different method (patent application 1973-
101349). Example 3 1.63 g of 6-dimethylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride
1.9 g (yield, 62%) of colorless needle-like crystals of 9-(2-chloro-6-fluorobenzyl)-6-dimethylaminopurine were obtained in the same manner as in Example 1.
Melting point 134-135℃. Elemental analysis C ₁₄ H ₁₃ ClFN ₅ Calculated value C55.00; H4.29; N22.91 Experimental value C54.91; H4.23; N22.86 Example 4 6-ethylaminopurine 1.63 g, potassium carbonate
1.38 g, 50 ml of N,N,-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride
1.04 g (yield, 34%) of colorless needle-like crystals of 9-(2-chloro-6-fluorobenzyl)-6-ethylaminopurine were obtained in the same manner as in Example 1.
Melting point 175-176℃ Elemental analysis C ₁₄ H ₁₃ ClFN ₅ Calculated value C55.00; H4.29; N22.91 Experimental value C54.66; H4.05; N22.90 Example 5 6-n-propylaminopurine 1.77 g, potassium carbonate 1.38 g, N,N-dimethylacetamide 50
ml and 3.58 g of 2-chloro-6-fluoro-benzyl chloride to prepare 9-(2-
1.89 g of colorless needles of chloro-6-fluorobenzyl)-6-n-propylaminopurine (yield, 59
%) was obtained. Melting point 166-167℃ Elemental analysis C ₁₅ H ₁₅ ClFN ₅ Calculated value C56.34; H4.73; N21.90 Experimental value C56.12; H4.59; N21.67 Example 6 6-allylaminopurine 1.75 g, potassium carbonate
1.38 g, N,N-dimethylacetamide 50 ml and 2-chloro-6-fluorobenzyl chloride 3.58 g
6-allylamino-
1.84 g (yield, 58%) of colorless needle-like crystals of 9-(2-chloro-6-fluorobenzyl)purine was obtained. Melting point 163-164℃ Elemental analysis C ₁₆ H ₁₃ ClFN ₅ Calculated value C56.70; H4.12; N22.04 Experimental value C56.43; H3.92; N22.09

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R ² represents an alkyl group or an allyl group having 1 to 3 carbon atoms]. [In the formula, R ³ , R ⁴ and X represent a halogen atom] A general formula characterized by reacting a compound represented by the following in the presence of a base: A method for producing a purine derivative represented by the formula [wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as above].