JPS6346756B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyrimidine derivatives having vasodilating, hypotensive, platelet aggregation-inhibiting and cholesterol-lowering effects.

Circulatory system diseases such as ischemic heart disease, cerebrovascular disorders, arteriosclerosis, and hypertension account for a large proportion of the causes of death in Japan, along with malignant tumors, and are extremely important diseases. Among these circulatory system diseases, ischemic heart disease and cerebral and peripheral circulation failure are caused by insufficient blood flow due to arterial thrombosis and arteriosclerosis, which causes malnutrition and oxygen deficiency in the ischemic area. It is believed that. Therefore, drugs that improve blood flow based on vasodilation in ischemic regions such as coronary arteries are effective for these diseases. Furthermore, drugs that suppress platelet aggregation, which is one of the causes of arterial thrombosis, and drugs that lower cholesterol, which causes arteriosclerosis, are considered useful in preventing the onset of these diseases.

On the other hand, among drugs that have a vasodilatory effect, there are some that have a hypotensive effect, such as hydralazine, and are frequently used in the treatment of hypertension. Recently, attempts have been made to use vasodilators in the treatment of heart failure, and Takashi Ito et al. [Japan Clinical (1978)
36, No. 11, p. 51] and Shinobu Matsui et al. [Japanese Circulation Society (1979) 43rd Annual General Meeting Lecture 165].

Based on the above findings, the present inventors believe that the above-mentioned circulatory system diseases are mutually related, and that the optimal treatment is one that comprehensively improves the circulatory system disorders. As a result of many years of research to find a compound that satisfies the following, it is expressed by the general formula (). The present invention has been completed by discovering that a new pyridine derivative has vasodilatory, antihypertensive, platelet aggregation-inhibiting, and cholesterol-lowering effects.

The compound of the present invention has the general formula () (In the formula, X represents a nitrogen atom substituted with an oxygen atom, a sulfur atom, an alkyl or w-carboxyalkyl group.) It is a novel pyrimidine derivative, and can generally be produced as follows. .

That is, 4-diethylamino-6-hydroxy-
2-methyl-5-nitropyrimidine, 4-diethylamino-6-mercapto-2-methyl-5-nitropyrimidine or 4-diethylamino-2
-Methyl-5-nitro-6-(alkylamino or w-carboxyalkylamino)pyrimidine is reduced according to a known method to convert the 5-position nitro group to an amino group. Either reacting the aminopyrimidine derivative obtained in this way with formic acid and directly ring-closing it, or
Alternatively, after formylating the amino group with formic acid, the ring is closed using phosphorus oxychloride, phosphorus trichloride, thionyl chloride, etc. to obtain an oxazolopyrimidine, thiazolopyrimidine or imidazopyrimidine derivative.

The compound represented by the general formula () thus obtained can be made into a pharmacologically acceptable salt form. Pharmaceutically acceptable salt forms include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or acetic acid, maleic acid, citric acid, tartaric acid, oxalic acid, succinic acid, etc. Mention may be made of acid addition salts with organic acids such as acids.

All of the novel pyrimidine derivatives of the present invention have strong vasodilation, antihypertensive, platelet aggregation inhibiting and cholesterol-lowering effects, and are soluble in water, making them compounds with excellent properties as pharmaceuticals. The compounds of the invention as well as their acid addition salts can therefore be used alone or together with other pharmaceutically active compounds and, if desired, with binders, fillers, flavorants, etc. used in the pharmaceutical industry. It can be converted into a medically usable product by conditioning it in any of the following ways.

The following examples illustrate methods for producing the compounds of the present invention.

Example 1 7-diethylamino-5-methyloxazolo[5,4-d]pyrimidine 6-chloro-4-hydroxy-2-methyl5-
6 g of nitropyrimidine and 33 ml of diethylamine were dissolved in 150 ml of tetrahydrofuran and stirred at room temperature for 2 hours. After the reaction is complete, remove the precipitate,
After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 6.1 g of 4-diethylamino-6-hydroxy-2-methyl-5-nitropyrimidine. (Melting point 179.4-181.9℃) 4-diethylamino-6-hydroxy-2-methyl-5-nitropyrimidine 6.0g and metal tin 8.6g
50 ml of concentrated hydrochloric acid was gradually added dropwise to the mixture while cooling and stirring. After the dropwise addition was completed, stirring was further continued for 1 hour at room temperature to complete the reaction. While cooling the reaction solution with ice water, the pH was adjusted to 8-9 with 3N sodium hydroxide solution, and the resulting oil was extracted with 200 ml of ethyl acetate. The organic layer was dehydrated over anhydrous magnesium sulfate and then evaporated under reduced pressure to obtain 4.0 g of 5-amino-4-diethylamino-6-hydroxy-2-methylpyrimidine.

4.0 g of 5-amino-4-diethylamino-6-hydroxy-2-methylpyrimidine was added to 90% formic acid.
The solution was dissolved in 50 ml and heated under reflux for 2 hours. After the reaction was completed, formic acid was distilled off under reduced pressure, 70 ml of water was added, and the mixture was neutralized with aqueous ammonia. Add 300% of this aqueous solution to ethyl acetate.
After dehydrating the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and 4-diethylamino-
2.3 g of 5-formamino-6-hydroxy-2-methylpyrimidine was obtained. (Melting point 248.6-249.8℃) 4-diethylamino-5-formamino-6-
2.1 g of hydroxy-2-methylpyrimidine was dissolved in 35 ml of phosphorus oxychloride and heated under reflux for 4.5 hours.
After the reaction is complete, excess phosphorus oxychloride is distilled off under reduced pressure.
50 ml of water was added to the residue, and the pH was adjusted to 8-9 with aqueous ammonia. Extract this aqueous solution with 300ml of ethyl acetate,
The organic layer was dehydrated with anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.3 g of 7-diethylamino-5-methyloxazolo[5,4-d]pyrimidine.

Melting point 124-126℃ Mass spectrometry value M ⁺ 206 Elemental analysis value C ₁₀ H ₁₄ N ₄ O Theoretical value C: 58.22%, H: 6.85%, N: 27.17% Actual value C: 58.20%, H: 6.85 %, N: 27.07% NMR spectrum (δppm, CDCl ₃ ) 7.80 1H s, 3.5 4H m, 2.47 3H s, 1.22
6H t Example 2 7-diethylamino-5-methylthiazolo[5,4-d]pyrimidine 7.3 g of 4-chloro-6-diethylamino-2-methyl-5-nitropyrimidine was added to 100 ml of a mixed solvent of methanol and water in a ratio of 9:1. 4.7 g of 70% sodium bisulfide was gradually added. After stirring the reaction solution at room temperature for 30 minutes, the solvent was distilled off under reduced pressure and the residue was
The pH was adjusted to 5-6 by adding 5N hydrochloric acid. The precipitated yellow crystals were collected and recrystallized from a mixed solvent of chloroform and n-hexane to obtain 5.2 g of 4-diethylamino-6-mercapto-2-methyl-5-nitropyrimidine. (Melting point 181.3-183.3℃) 5g of 4-diethylamino-6-mercapto-2-methyl-5-nitropyrimidine and 7.0g of metal tin
50 ml of concentrated hydrochloric acid was gradually added dropwise to the mixture while cooling and stirring. After the dropwise addition was completed, the reaction solution was continued to be stirred at room temperature for 3 hours to complete the reaction. The reaction solution was cooled with ice water and adjusted to pH 8-9 with 3N sodium hydroxide solution, and the resulting oil was dissolved in ethyl acetate.
Extracted with 200ml. After dehydrating the organic layer with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform-n-hexane.
3.9 g of 5-amino-4-diethylamino-6-mercapto-2-methylpyrimidine was obtained.

3 g of 5-amino-4-diethylamino-6-mercapto-2-methylpyrimidine and 50 ml of 90% formic acid.
The mixture was dissolved in water and heated under reflux for 2 hours. After the reaction was completed, formic acid was distilled off under reduced pressure, 30 ml of water was added to the residue, and the mixture was neutralized with aqueous ammonia. This aqueous solution was extracted with 200 ml of ethyl acetate, and the organic layer was dehydrated with anhydrous magnesium sulfate.
The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.6 g of 7-diethylamino-5-methylthiazolo[5,4-d]pyrimidine.

Melting point 41.6-43℃ Mass spectrometry value M ⁺ 222 Elemental analysis value C ₁₀ H ₁₄ N ₄ For S Theoretical value C: 54.05%, H: 6.37%, N: 25.23% Actual value C: 54.11%, H: 6.32 %, N: 25.29% NMR spectrum (δppm, CDCl ₃ ) 8.48 1H s, 3.91 4H q (7Hz), 2.49 3H s,
1.36 6H t (7Hz) Example 3 6-diethylamino-2-methyl-9-n-heptylimidazo[4,5-d]pyrimidine 4 g of 4-chloro-6-diethylamino-2-methyl-5-nitropyrimidine was dissolved in tetrahydrofuran. Dissolve in 50 ml and add 2.3 ml of n-heptylamine.
g and 2.0 g of triethylamine were added thereto, and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.6 g of 4-diethylamino-6-n-heptylamino-2-methyl-5-nitropyrimidine.

Concentrated hydrochloric acid was added to a mixture of 4 g of 4-diethylamino-6-n-heptylamino-2-methyl-5-nitropyrimidine and 4.8 g of metal tin while cooling and stirring.
30 ml was gradually added dropwise. After the dropwise addition was completed, the reaction solution was continued to be stirred at room temperature for 2 hours to complete the reaction. The reaction solution was cooled with ice water and adjusted to pH 8-9 with 3N sodium hydroxide solution. The aqueous solution is ethyl acetate.
After extraction with 200 ml, the organic layer was dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 5-
3.5 g of amino-4-diethylamino-6-n-heptylamino-2-methylpyrimidine was obtained.

3.0 g of 5-amino-4-diethylamino-6-n-heptylamino-2-methylpyrimidine was dissolved in 20 ml of formic acid and heated under reflux for 3 hours. After the reaction was completed, formic acid was distilled off under reduced pressure, 20 ml of water was added to the residue, and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate. This aqueous solution was extracted with 150 ml of ethyl acetate, the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography,
1.3 g of 6-diethylamino-2-methyl-9-n-heptylimidazo[4,5-d]pyrimidine was obtained.

Melting point Oily substance amount analysis value M ⁺ 303 Elemental analysis value C ₁₇ H ₂₉ N For ₅ Theoretical value C: 67.33%, H: 9.67%, N: 23.12% Actual value C: 67.25%, H: 9.60%, N :23.22% NMR spectrum (δppm, CDCl ₃ ) 7.38 1H s, 3.82 4H q (7Hz), 2.44 3H s,
1.73 2H t (8Hz), 1.4~1.1 16Hm, 0.83 3H
t (7Hz) Example 4 9-w-carboxy-n-hexyl-6-diethylamino-2-methylimidazo [4.5-d]
Pyrimidine 3.4 g of 4-chloro-6-diethylamino-2-methyl-5-nitropyrimidine was dissolved in 70 ml of tetrahydrofuran, 1.8 g of 7-aminoheptanoic acid methyl ester and 1.6 g of triethylamine were added thereto, and the mixture was heated under reflux for 3 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-w-carboxy-n.
2.5 g of -hexylamino-6-diethylamino-2-methyl-5-nitropyrimidine was obtained.

4-w-carboxy-n-hexylamino-6
2.0 g of -diethylamino-2-methyl-5-nitropyrimidine and 2.0 g of metal tin were thoroughly mixed, and 25 ml of concentrated hydrochloric acid was gradually added dropwise to the mixture while cooling and stirring. After the dropwise addition was completed, stirring was further continued for 3 hours at room temperature to complete the reaction. 3N while cooling the reaction solution with ice water.
After neutralization with sodium hydroxide solution, the aqueous solution was extracted with 300 ml of ethyl acetate. After dehydrating the organic layer with anhydrous magnesium sulfate, the solvent was removed under reduced pressure and 5-amino-4-w-carboxy-n-hexylamino-6-diethylamino-2-methylpyrimidine was added.
1.6g was obtained.

1.5 g of 5-amino-4-w-carboxy-n-hexylamino-6-diethylamino-2-methylpyrimidine was dissolved in 30 ml of 90% formic acid and heated under reflux for 2 hours. After the reaction was completed, formic acid was distilled off under reduced pressure, 30 ml of water was added to the residue, and the mixture was neutralized with aqueous ammonia. This aqueous solution was extracted with 200 ml of ethyl acetate, the organic layer was dehydrated with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of 9-w-carboxy-n-hexyl-6-diethylamino-2-methylimidazo[4,5-d]pyrimidine.

Melting point 122-122.5℃ Mass spectrometry value M ⁺ 333 Elemental analysis value C ₁₇ H ₂₇ N ₅ O ₂ Theoretical value C: 61.26%, H: 8.19%, N: 21.02% Actual value C: 61.19%, H: 8.11%, N: 21.08% NMR spectrum (δppm, CDCl ₃ ) 9.33 1H bs, 7.62 1H s, 4.00 4H q (7Hz)
2.48 3H s, 2.25 2H q (7Hz) 2.17~1.26
10H m1.18 6H t (7Hz)

Claims (1)

[Claims] 1 General formula () A novel pyridine derivative represented by the formula (wherein X represents a nitrogen atom substituted with an oxygen atom, a sulfur atom, an alkyl or w-carboxyalkyl group).