JPH0234356B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula Novel oxadiazolopyrimidine derivatives ^and
It relates to the salts of said compounds in which R ¹ represents the group -COOR. "Alkyl" as used herein refers to linear and branched saturated hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, either by itself or in combination with other groups; For example, methyl, ethyl,
It relates to n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.
"Alkoxy" refers to an alkyl ether group in which "alkyl" has the meaning given above. “Alkenyl refers to straight-chain and branched hydrocarbon groups having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, in which at least one carbon-carbon bond is unsaturated, such as allyl, butenyl, etc. "Alkynyl" likewise relates to straight-chain and branched hydrocarbon radicals of 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, in which at least one carbon-carbon triple bond is present. Among the compounds of the formula, those are preferred in which R ¹ denotes the group -COOR, in which R denotes alkyl or alkenyl. Particularly preferable ones include R being alkyl having 1 to 4 carbon atoms or R being 2 to 4 carbon atoms;
It is a compound of the formula meaning 3 alkenyls. Very particularly preferred are compounds of the formula in which R means butyl or allyl, ie butyl 7-[3,
6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-
c] Pyrimidine-5-carbamate and allyl 7
-[3,6-dihydro-1(2H)-pyridyl]-2
-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate. According to the present invention, compounds of the formula in which R ¹ represents a group -COOR and salts thereof are of the formula (a) 5-amino-7-[3,6-dihydro-1
(2H)pyridyl]-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidin-2-one with the general formula [wherein R is as defined above, and A is a group -CH=CH-,

or -N=CH-, where the nitrogen atom in the latter case is in the 2-position], and (b) optionally the resulting compound of the formula can be produced by converting a salt into a salt or by converting one salt into another salt. The reaction of a compound of formula a with an azole derivative of formula is carried out by known methods. For convenience,
The anion of the compound of formula a is reacted with an azole derivative of formula. The anion of the compound of formula a is advantageously prepared in that case by reaction with a base. Bases such as alkali metal hydrides (eg sodium hydride), alkali metal amides (eg sodium amide or potassium amide), lithium diisopropylamide, potassium t-butyrate, etc. are suitable for this purpose. The reaction is carried out in an inert solvent under the reaction conditions and at approximately −25
It is carried out at a temperature of 0.degree. to room temperature, preferably 0 to 15.degree. The solvent may be dimethylformamide, a saturated hydrocarbon (eg hexane), an aromatic hydrocarbon (eg benzene, toluene or xylene), an ether (eg diethyl ether, dioxane or tetrahydrofuran), and the like. The starting material of formula a can be, for example, of the general formula [In the formula, R has the same meaning as above] It can be produced by cyclizing the compound. Cyclization of compounds of formula can be carried out according to known methods to approximately
This is carried out by heating to a temperature of 50-200°C, preferably about 100-150°C. Cyclization can be carried out in the absence or presence of a solvent or solvent mixture. If the cyclization is carried out in a solvent or solvent mixture, the solvent includes aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as dibutyl ether, dioxane or diethylene glycol dimethyl ether, dimethyl formamide, etc. or mixtures thereof. It will be appreciated that in this case a solvent can be used whose boiling point is above the crystallization temperature or a solvent boiling at a boiling point within the above-mentioned temperature range can be used. Cyclization is preferably carried out using dimethylformamide or toluene as solvent. The time for cyclization is about 1/4 to 18 hours depending on the time to perform the cyclization. When the cyclization is carried out at a suitable temperature range of about 100 to 150°C, the cyclization time is about 1/4 to 12 hours, preferably 1/4 to 12 hours.
Equivalent to 2 hours. The compounds of formula and belong to the known class of compounds. They are therefore particularly those mentioned above;
Alternatively, it can be produced in the same manner as conventionally known compounds. Compounds of the formula in which R ¹ represents a group -COOR are:
For example, it can be converted to a salt by treatment with an inorganic base such as an alkali hydroxide (eg sodium hydroxide or potassium hydroxide) or an alkaline earth hydroxide (eg calcium hydroxide). R ¹ is the group −COOR
Salts of compounds of the formula can also be prepared by metathesis of suitable salts. Among the salts of compounds of formula, pharmaceutically useful salts are preferred. Compounds of the formula in which R ¹ represents the group -COOR and salts thereof have long-lasting vasodilatory and/or blood pressure lowering activity and are therefore useful in the treatment of hypertension caused by vascular conditions or in peripheral vascular blood supply disorders. It can also be used as a vasodilator in some cases. The hypotensive activity can be determined in conscious spontaneously hypertensive rats according to the following method: The systolic blood pressure and cardiac rate are measured twice before administration of the test substance. Then 2 times a day in the morning and afternoon
The test substance is administered twice using the esophageal probe. Both parameters are measured 1, 3, 6 and 24 hours after administration and the percentage change relative to the control value is calculated.
Cardiac systolic blood pressure was determined by the method of Gerold et al. (Helv.
Physiol, Acta 24 , 58-69, 1966;
Arzneimittelforschung 18 , 1285-1287, 1968)
was measured indirectly in the tail artery of rats. The results obtained are shown in the table below. In each case, the highest percentage deviation from the control value is indicated. Additionally, the following table shows the toxicity values.

【table】

[Table] Compounds of the formula in which R ¹ represents the radical -COOR and their pharmaceutically useful salts can be carried out, for example, by carrying them with pharmaceutical organic or inorganic carrier substances suitable for enteral or parenteral administration. For example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol,
It can be used as a medicament in the form of a pharmaceutical preparation containing it in combination with petrolatum and the like. Pharmaceutical preparations can be made in solid form (eg tablets, dragees, suppositories or capsules) or liquid form (eg solutions, suspensions or capsules). If necessary, the pharmaceutical preparation can be sterilized and/or contain auxiliary agents, such as preservatives, stabilizers,
It may also contain wetting or emulsifying agents, salts to modify osmotic pressure, or buffering agents. They may also contain other pharmaceutically useful substances. The daily dosage for oral administration is approximately 10-500mg
and about 1-50 mg for intravenous administration. However, it will be understood that these dosages are exemplary only and may vary depending on the severity of the condition being treated or at the discretion of the physician. The following examples illustrate the invention. All temperatures are given in Mr. Setsu. Melting points are uncorrected. Example 1 4.30 g of sodium hydride (55-60% oil suspension)
(98-108 mmol) was washed with hexane and suspended in 150 ml of dimethylformamide under argon. To this stirred and ice-cooled suspension was added 5-amino-7-[3,6-dihydro-1(2H)-pyridyl]
-2H-[1,2,4]oxadiazolo[2,3-
c] Pyrimidin-2-one 20.54 g (88 mmol)
was added dropwise within 10 minutes while maintaining the temperature at 14°. The ice bath was removed and the mixture was stirred for 30 minutes. A solution of 15.8 g (125 mmol) of 1-methoxycarbonyl-imidazole in 50 ml of dimethylformamide was then added quickly and the solution was stirred at 20-25° for 1 hour. Clear reddish-brown solution in 1.2 ml of water
The slightly cloudy solution was filtered through a Speedex filter bed and treated with 40 ml of glacial acetic acid with stirring. Separate the precipitate,
Thoroughly washed with 600 ml of water. The excess residue was soaked with 400 ml of methanol on absorbent paper and quickly aspirated. After drying (40°, 20mmHg), methyl 7
-[3,6-dihydro-1(2H)-pyridyl]-2
-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate
23.37 g (91%) were obtained as a white powder, melting point 213° (decomposition). 10.00 g of the crude product was dissolved in 500 ml of methanol and 25 ml of triethylamine under reflux and filtered. Mix this warm solution with 20 ml of glacial acetic acid in 50 ml of methanol for 30 min.
The suspension was stirred for a further 30 minutes at room temperature. Separate the crystals and add 200ml of methanol three times,
Thoroughly cleaned. Melting point after drying (40°, 20mmHg)
8.99 g of white crystals of 215° (decomposed) were obtained. 5-Amino-7-[3,
6-dihydro-1(2H)-pyridyl]-2H-[1,
2,4]oxadiazolo[2,3-c]pyrimidin-2-one could be produced as follows. Methyl 2-amino-6-[3,6-dihydro-
28.8 g (0.109 mol) of 1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide were treated with 350 ml of dimethylformamide and the mixture was dissolved in an oil bath.
Stir at 135° for 30 minutes. The brown solution was evaporated under reduced pressure. Pour the still wet residue into 350ml of ether.
The crystals were separated and washed with ether. After drying (40°, 20 mmHg), 23.4 g (92.5%) of an amber crystalline powder with a melting point of 228° (decomposed) was obtained. The 1-methoxycarbonyl-imidazole used as starting material could be prepared as follows: 34.05 g imidazole in 500 ml acetonitrile.
To a stirred solution of (0.50 mol) and 52.5 g (0.52 mol) of triethylamine, 47.2 g (0.50 g) of methyl chloroformate in 60 ml of ether was added dropwise at 10° within 40 minutes. This suspension was stirred at room temperature for 30 minutes. The precipitate was separated and washed with ether. The liquid was evaporated under reduced pressure and the residue was taken up in 500 ml of benzene and stirred for 10 minutes. The insoluble material was separated off again, the liquid was evaporated under reduced pressure, and the residual oil slowly solidified. This resulted in 61.7 g (98%) of a light yellow solid with a melting point of 35-40°. This could be used without further purification. Example 2 Following a method similar to that described in Example 1,
5-amino-7-[3,6-dihydro-1(2H)-
Pyridyl]-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidin-2-one was reacted with 1-isobutyroxycarbonyl-imidazole, melting point 197-198° (methylene chloride/methanol / diethyl ether) isobutyl 7-[3,6-dihydro-1(2H)-pyridyl]-
2-Oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, reacted with 1-(2-methoxyethyl)oxycarbonyl-imidazole to give a melting point of 203-204° ( (2-methoxyethyl)7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H from methylene chloride/methanol/diethyl ether)
-[1,2,4]oxadiazolo[2,3-c]
Pyrimidine-5-carbamate, reacted with 1-butyloxycarbonyl-imidazole to give butyl 7-[3,
6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-
c] Pyrimidine-5-carbamate, reacted with 1-ethoxycarbonyl-imidazole to give ethyl 7[3,6
-dihydro-1(2H)-pyridyl]-2-oxo-
2H-[1,2,4]oxadiazolo[2,3-
c]-pyrimidine-5-carbamate, reacted with 1-propyloxycarbonyl-imidazole to give propyl 7-carbamate, melting point 201-202° (from methylene chloride/methanol/diethyl ether).
[3,6-dihydro-1(2H)-pyridyl]-2-
Oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, reacted with 1-isopropyloxycarbonyl-imidazole, melting point 186-187° (methylene chloride/
isopropyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5- (from methanol/diethyl ether) Reaction with the carbamate 1-propargyloxycarbonyl-imidazole gives propargyl 7-[3,6-dihydro-1(2H)-pyridyl]- with a melting point of 211-213° (from methylene chloride/methanol/diethyl ether).
2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate,
and 1-allyloxycarbonyl-imidazole to form allyl 7-[3,
6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-
c] Pyrimidine-5-carbamate, was obtained. The above imidazole derivatives used as starting materials were prepared according to a method similar to that described in the last section of Example 1 by reacting imidazole with the corresponding chloroformate ester. Since these derivatives are not crystalline at room temperature, they were identified by spectroscopic methods. Example 3 5-amino- in 200 ml dimethylformamide
7-[3,6-dihydro-1(2H)-pyridyl]-
2H-[1,2,4]oxadiazolo[2,3-
c] pyrimidin-2-one 4.66 g (20 mmol)
1.2 g of sodium hydride in a solution cooled to 15°
was added in portions. This mixture was stirred vigorously for 30 minutes at room temperature. To this was then added 5.28 g of 1-methoxycarbonyl-benzimidazole in 50 ml of dimethylformamide. After 2 hours, the mixture was treated with ice-cold water and adjusted to PH5 with glacial acetic acid.
The resulting precipitate was recrystallized from methylene chloride/methanol to give methyl 7-[3,6
-dihydro-1(2H)-pyridyl]-2-oxo-
2H-[1,2,4]oxadiazolo[2,3-
c] Pyrimidine-5-carbamate was obtained. The 1-methoxycarbonyl-benzimidazole used as starting material could be prepared as follows: 11.8 g of benzimidazole in acetonitrile.
(100 mmol) of triethylamine
16.72ml was added dropwise. To this, ether 30
A solution of 7.68 ml of methyl chloroformate in ml
It was added at 10°. The precipitate was separated and the solution was evaporated under reduced pressure. 1-Methoxy- thus obtained
Carbonyl-benzimidazole was used without further purification. Example 4 13 g of methyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate was added to water. The mixture was stirred in 100 ml and treated with 44.7 ml (1.001 molar equivalent) of 1N aqueous sodium hydroxide. At this time, changes in PH were tracked until the PH became stable. As soon as the pH value stabilized, the resulting solution was filtered and freeze-dried. After repeated drying under vacuum at 50°, methyl 7-[3,6-dihydro-1
(2H)-pyridyl]-2-oxo-2H-[1,2,
4] Oxadiazolo[2,3-c]pyrimidine-
13.5 g of sodium salt of 5-carbamate, melting point
It was obtained in the form of a fine white powder of 192-198°. Butyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-
From 33 g of [1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate and 1.001 molar equivalent of 1N aqueous sodium hydroxide, melting point 158 ~
The corresponding sodium salt of 169° was obtained. Reference Example A Tablets containing the following ingredients were manufactured:

[Table] Phase ingredients were sifted and mixed.
This mixture was moistened with corn starch paste and kneaded. The wet mass was granulated and dried to the appropriate particle size. Phase was mixed. The resulting mixture was further briefly mixed with phase. This mixture was compressed into tablets weighing 100 mg with a diameter of 7 mm and cut lines. Reference Example B Tablets containing the following ingredients were manufactured:

【table】

[Table] Phase ingredients were sifted and mixed.
This mixture was moistened with corn starch paste and kneaded. The wet mass was granulated and dried to the appropriate particle size. Phase was mixed. The resulting mixture was further briefly mixed with phase. This mixture was compressed into tablets weighing 350 mg with a diameter of 11 mm and cut lines. Reference Example C A capsule containing the following ingredients was manufactured:

[Table] Phase ingredients were sifted and mixed.
This mixture was moistened with corn starch paste and kneaded. The wet mass was granulated and dried to the appropriate particle size. Phase was mixed. The resulting mixture was further briefly mixed with phase. This capsule mixture was filled into capsules (size 2) at 150 mg each. Reference Example D An aqueous drip suspension containing the following ingredients was prepared. Butyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-c]pyrimidine-5-carbamate (micronized) 0.1 g Sodium benzoate 0.035g Satucalin sodium 0.015g Acrylic acid polymer 0.1~1.0g Satucarose 3.5g Citric acid 0.025g Polyoxyethylene stearate 0.002~0.1g Sodium hydroxide Sufficient amount Flavor Taste Sufficient amount Food coloring agent Sufficient amount Ionized water Up to 10 ml Reference Example E Tablets, capsules and injectable preparations can be prepared by using the following similarly suitable compounds and their pharmaceutically acceptable salts according to the methods described in Reference Examples A to D. could be manufactured. Methyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, ethyl 7-[3 ,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, propyl7-[3,6-dihydro- 1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, isopropyl 7-[3,6-dihydro-1(2H)
-pyridyl]-2-oxo-2H-[1,2,4]
Oxadiazolo[2,3-c]pyrimidine-5-
Carbamate, isobutyl 7-[3,6-dihydro-1(2H)-
pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate, and allyl7-[3,6-dihydro-1(2H)-pyridyl]-2 -Oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate.

Claims (1)

[Claims] 1. General formula Novel oxadiazolopyrimidine derivatives ^and
Salts of said compounds in which R ¹ represents the group -COOR. 2. Compounds according to claim ¹ , in which R 1 denotes the radical -COOR, in which R denotes alkyl or alkoxyalkyl. 3. Compounds according to claim ¹ , in which R 1 denotes the group -COOR, in which R denotes alkyl or alkenyl. 4. The compound according to claim 3, wherein R is alkyl having 1 to 4 carbon atoms or alkenyl having 2 to 3 carbon atoms. 5 Methyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate A compound according to scope 1. 6 Ethyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate A compound according to scope 1. 7 Isobutyl 7-[3,6-dihydro-1(2H)
-pyridyl]-2-oxo-2H-[1,2,4]
Oxadiazolo[2,3-c]pyrimidine-5-
A compound according to claim 1 which is a carbamate. 8 Butyl 7-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate A compound according to scope 1. 9 Propyl 7-[3,6-dihydro-1(2H)-
pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate. 10 Isopropyl 7-[3,6-dihydro-1
(2H)-pyridyl]-2-oxo-2H-[1,2,
4] Oxadiazolo[2,3-c]pyrimidine-
A compound according to claim 1 which is a 5-carbamate. 11 Allyl 7-[3,6-dihydro-1(2H)-
pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidine-5-carbamate. 12. A salt of the compound according to any one of claims 5 to 11. 13 (a) Formula 5-amino-7-[3,6-dihydro-1
(2H)pyridyl]-2H-[1,2,4]oxadiazolo[2,3-c]pyrimidin-2-one with the general formula [wherein R means alkyl, alkenyl, alkynyl or alkoxyalkyl, and A
means one of the groups -CH=CH-, [formula] or -N=CH-, where the nitrogen atom in the latter case is located in the 2-position], and (b) A general formula characterized by converting the obtained compound into a salt or converting the salt into another salt, if desired. In the formula, R has the same meaning as above. A method for producing an oxadiazolopyrimidine derivative and a salt thereof. 14 General formula [wherein R means alkyl, alkenyl, alkynyl or alkoxyalkyl] An antihypertensive agent or vasodilator characterized by containing an oxadiazolopyrimidine derivative or a pharmaceutically useful salt thereof.