JPH0140838B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention provides formula (1) (In the formula, R ¹ is a 1 or 2H-tetrazol-5-yl group, carboxyl group or lower alkoxycarbonyl group, R ² is an alkyl group having 4 or more carbon atoms,
It means a cycloalkyl group or an alkylthio group, or an aryl group or a heteroaryl group which may have a substituent. As the substituent for the aryl group or heteroaryl group, an alkyl group, an alkoxy group, an alkylenedioxy group, a halogen group, a hydroxy group, a nitro group, or an amino group is selected. ) and a bioacceptable salt thereof. Hitherto, several types of thiadiazolopyrimidine derivatives having chemical structures similar to the compounds of the present invention have been known. However, these known thiadiazolopyrimidine derivatives are either related to agricultural chemicals [Agr.Biol.Chem., 37 , 1197-1201 (1973)] or antitumor agents [[Agr.Biol. .Chem.，
41, 2047-2053 (1977)], there is nothing that mentions the relationship between thiadiazolopyrimidine derivatives and antiallergic effects. As a result of extensive research into compounds having anti-allergic effects, the present inventors have discovered that a novel thiadiazolopyrimidine derivative represented by formula () has excellent anti-allergic effects, and have completed the present invention. In particular, the compound of the present invention is characterized in that it is an antiallergic agent that suppresses the release of chemical mediators caused by antigen-antibody reactions, and that its action is effectively observed when administered orally. Sodium cromoglycate has conventionally been known as a typical drug having the above-mentioned mechanism of action, but this drug has not been found to be effective when administered orally and has been used by powder inhalation administration. However, the inhalation administration method has disadvantages such as difficulty in administering it to infants properly and difficulty in applying it to patients who are sensitive to powder irritation, so it has been difficult to develop superior drugs that can be administered orally. It has been requested. Therefore, the present invention also relates to the provision of a compound exhibiting a new type of anti-allergic effect, and its excellent anti-allergic effect can be used to treat bronchial asthma, allergic gastrointestinal disorders, allergic rhinitis, hay fever, ginsin, etc. It is effective for the treatment or prevention of. The compound of the present invention represented by formula () is produced according to the following reaction formula. In the above formula, R ¹ and R ² are the same as above. R ³ is a lower alkyl group, R ⁴ is a group that can be converted to R ² by reduction, halogenation, or alkylation, and R ⁵ is a lower alkoxycarbonyl group or 2-tert-butyl-2H
-Tetrazol-5-yl group. That is, the compound of the present invention can be produced by any of the production methods A to D above. Each manufacturing method will be explained in detail below. Manufacturing method A; When substituent R ⁵ is a 2-tertiary butyl-2H-tetrazol-5-yl group (manufacturing method A-1) and when it is a lower alkoxycarbonyl group (manufacturing method A-
2) will be explained separately. To produce the target compound according to Production Method A-1, the compound of formula () may be heated with an acid at about 70 to 180°C for about 30 minutes to about 10 hours in the presence or absence of a solvent. Solvents that can be used include water or Dowsum A,
Examples include high-boiling organic solvents such as sulfolane, tertiary butylbenzene, and toluene, and examples of acids include inorganic acids such as sulfuric acid, organic acids such as para-toluenesulfonic acid and trifluoroacetic acid, and Lewis solvents such as boron trifluoride etherate. Acids can be used. To produce the desired product according to Production Method A-2, the compound of formula () may be subjected to a hydrolysis reaction at room temperature to about 130°C for about 1 to 24 hours in the presence of an acid or alkali. Examples of acids that can be used include inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, organic acids such as acetic acid and trifluoroacetic acid, mixtures thereof, and Lewis acids such as aluminum halides. Typically, sodium hydroxide, potassium hydroxide, etc. can be used. Furthermore, when the substituent R ⁵ is a methoxycarbonyl group, aluminum halide-dimethyl sulfide can also be used. Production method B: To produce the target compound according to this production method, the compound of formula () may be subjected to a reduction, halogenation or alkylation reaction, and these reactions can be carried out by conventional means. For example, when the substituent R ⁴ contains a nitro group and is intended to be reduced, iron powder-acetic acid or the like can be used as the reducing agent. During the halogenation reaction,
Direct reaction with bromine, chlorine, etc. or other frequently used halogenating agents such as NBS or NCS can be used. Typical alkylation reaction reagents include dialkyl sulfuric acid, alkyl halide, and the like. Production method C: To produce the target compound according to this production method, the compound of formula () is heated to 100 to 100% in the presence or absence of a solvent.
It may be heated to 260°C or heated with boron trifluoride etherate in a solvent to 100 to 250°C for about 10 minutes to about 2 hours. Solvents that can be used for the reaction include Dowsum A,
Examples include sulfolane and other high boiling point organic solvents such as toluene, xylene, and tertiary butylbenzene. Production method D: To produce the target compound according to this method, the compound of formula () is heated with lower alkoxymethylene malonic acid di-lower alkyl ester at about 70 to 200°C for about 1 to 2 hours in the presence or absence of a solvent. and then heated to about 120-260°C in the presence or absence of a solvent, or heated to about 100-200°C with boron trifluoride etherate in a solvent for about 10 minutes to 2 hours.
The same solvent as in Production Method C can be used. Note that among the raw material compounds used in Manufacturing Methods A to D, those of formulas (), (), and () are new compounds. Moreover, a part of formula () also contains a new compound. These new substances can be produced by the method described below. The method for producing the raw material compound will be briefly explained below. Among the compounds of formula (), the new substance can be produced according to the known production method of thiadiazole derivatives. The compound of formula () is prepared by combining the compound of formula () and lower alkoxymethylene malonic acid di-lower alkyl ester in the presence or absence of a solvent.
It may be heated at 100-150°C for about 15 minutes to 4 hours. The compound represented by formula () is a compound represented by formula () and 2-(2-tert-butyl-2H-tetrazole-
5-yl)-3-dimethylaminoacrylic acid ethyl ester in acetic acid or propionic acid from about 8 to 25
Either the compound of formula () and the lower alkoxymethylene malonic acid di-lower alkyl ester may be reacted under the reaction conditions of Production Method D. Compounds of formula () may be prepared by similar means to compounds of formula (). In addition, when R ¹ in the compound of formula () is 1 or 2H-tetrazol-5-yl group or carboxyl group, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium, or ammonia, tris(hydroxy Addition salts with amines such as methyl)-aminomethane and N-methylglucamine can be formed. The excellent antiallergic activity of the compound of the present invention thus prepared was confirmed by measuring the inhibition rate of passive skin hypersensitivity reaction (PCA reaction) in homologous rats using rat serum containing reagin-like antibodies against egg albumin. . As a result, it was found that the compound of the present invention is effective not only for intravenous administration but also for oral administration.
It was found that it significantly suppressed the PCA reaction and had a strong anti-allergic effect. Note that sodium cromoglycate, which is well known as a chemical mediator inhibitor (antiallergic drug), hardly inhibits the above-mentioned PCA reaction when administered orally. The present invention will be explained by the following reference examples and examples. Reference example 1: 2-(2-tert-butyl-2H-tetrazol-5-yl)-3-dimethylaminoacrylic acid ethyl ester (2-tert-butyl-2H-tetrazol-5
-yl) A mixture of 58.7 g of acetic acid ethyl ester and 59.7 g of dimethylformamide diethyl acetal.
Heat and stir at 100°C for 8 hours. After cooling, it is recrystallized from ether-petroleum ether to give 2.
-(2-tertiary butyl-2H-tetrazole-5
-yl)-3-dimethylaminoacrylic acid ethyl ester (50.7 g) is obtained. Elemental analysis value (%) As C ₁₂ H ₂₁ N ₅ O ₂ Calculated value C 53.92, H 7.92, N 26.20 Actual value C 53.83, H 7.85, N 26.55 Reference example 2: 2-amino-5-(2,3- dimethoxyphenyl)-1,3,4-thiadiazole thiosemicarbazide 25.0g and sodium acetate 10.0g
2,3-dimethoxybenzaldehyde was added thereto, and the mixture was heated under reflux for 2 hours. After cooling, the precipitate was collected by filtration and the melting point
34.5 g of 2,3-dimethoxybenzaldehyde thiosemicarbazone at 234-236°C is obtained. This thiosemicarbazone 34.5g, acetic anhydride 100g
ml and 0.1 ml of pyridine are gently refluxed for 1.5 hours. After cooling, the precipitate was collected by filtration and washed with ether to give 2-acetamino-4- with a melting point of 236-237°C.
Acetyl-5-(2,3-dimethoxyphenyl)
44.6 g of -4,5-dihydro-1,3,4-thiadiazole is obtained. 44.6 g of this dihydrothiadiazole was added to 1 acetic acid.
Suspend the mixture in water and add 35.0 g of potassium permanganate while keeping the temperature below 20°C. After 2.5 hours, pour into 500ml of water and treat with 30% hydrogen peroxide. The precipitate was collected by filtration, washed with water, and dried to give 2-acetamino-5-(2,3-dimethoxyphenyl)- with a melting point of 291 to 293°C.
32.1 g of 1,3,4-thiazizole are obtained. A mixture of 32.1 g of this acetamino compound and 200 ml of 85% hydrazine hydrate was heated and stirred at 80° C. for 2 hours. After cooling, add water, filter out insoluble matter, wash with water, dry, and obtain 2-amino-5- with a melting point of 202-205°C
(2,3-dimethoxyphenyl)-1,3,4-
27.3 g of thiadiazole are obtained. Elemental analysis value (%) As C ₁₀ H ₁₁ N ₃ O ₂ S Calculated value C 50.62, H 4.67, N 17.71 Actual value C 50.28, H 4.76, N 17.72 In the same manner as Reference Example 2, the following formula () is calculated. A raw material compound was produced. [Table] Reference example 22: 2-tert-butyl-6-(2-tert-butyl-2H-tetrazolzol-5-yl)
―5H― [1, 3, 4] Chiadiazoro [3, 2
-a] Pyrimidin-5-one 2-amino-5-tertiary butyl-1,3,4-
Add 1.90 g of thiadiazole and 3.20 g of 2-(2-tert-butyl-2H-tetrazol-5-yl)-3-dimethylaminoacrylic acid ethyl ester to 10 ml of acetic acid, and heat and reflux at 130-140°C for 20 hours. Acetic acid was distilled off under reduced pressure, water was added to the residue, and the mixture was made slightly alkaline with an aqueous sodium hydrogen carbonate solution.
The precipitate was collected by filtration and recrystallized from isopropanol to give 2-tert-butyl-6-(2-
tertiary butyl-2H-tetrazol-5-yl)
―5H― [1, 3, 4] Chiadiazoro [3, 2-
a] Obtain 2.90 g of pyrimidin-5-one. Elemental analysis value (%) C ₁₄ H ₁₉ N ₇ As OS Calculated value C 50.43, H 5.74, N 29.41 Actual value C 50.39, H 5.70, N 29.28 In the same manner as Reference Example 22, the raw material compound of formula () below (However, R ⁵ is 2-tertiary butyl-2H-
tetrazol-5-yl group) was produced. [Table] [Table] Reference example 66: 2-(5-bromo-2-thienyl)-
6-(2-tert-butyl-2H-tetrazol-5-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 2-(2-thienyl)-6 -(2-tertiary butyl-2H-tetrazol-5-yl) -5H-
[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 3.13g, sodium acetate 5.00g
Add 2.0 ml of bromine to a mixture of 50 ml of acetic acid and reflux gently for 4 hours. After cooling, add water and neutralize with sodium carbonate. The precipitate was collected by filtration and recrystallized from ethanol to give 2-(5-
Bromo-2-thienyl)-6-(2-tert-butyl-2H-tetrazol-5-yl)-5H-
2.67 g of [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one is obtained. Reference example 67: 2-(4-aminophenyl)-6-
(2-tertiary butyl-2H-tetrazole-5-
yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 2-(4-nitrophenyl)-6-(2-tert-butyl-2H-tetrazol-5-yl )--5H
- Dissolve 2.0 g of [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one in 100 ml of acetic acid,
Add 3.0g of iron powder while maintaining the temperature at 90-100℃. Thereafter, after stirring at the same temperature for 1 hour, insoluble matter was filtered off.
The filtrate was concentrated under reduced pressure, poured into water, and the precipitate was collected by filtration.
Chloroform-recrystallized with ethanol, melting point 269~
2-(4-aminophenyl)-6-(2
-tertiary butyl-2H-tetrazol-5-yl)
―5H― [1, 3, 4] Chiadiazoro [3, 2-
a] Obtain 1.30 g of pyrimidin-5-one. Reference example 68: [5-(2-chlorophenyl)-1,
3,4-thiadiazol-2-yl]aminomethylenemalonic acid diethyl ester 2-amino-5-(2-chlorophenyl)-
A mixture of 6.28 g of 1,3,4-thiadiazole and 8.64 g of ethoxymethylene malonic acid diethyl ester is heated and stirred at 140° C. for 2.5 hours. After cooling, it is recrystallized from ethanol to give [5-(2
6.20 g of chlorophenyl)-1,3,4-thiadiazol-2-yl]aminomethylenemalonic acid diethyl ester are obtained. Elemental analysis value (%) As C ₁₆ H ₁₆ ClN ₃ O ₄ S Calculated value C 50.33, H 4.22, N 11.00 Actual value C 49.91, H 4.07, N 11.11 The following shown by formula () in the same manner as Reference Example 68 A raw material compound was produced. [Table] [Table] Example 1: 2-tertiary butyl-6-(1 or 2H
-tetrazol-5-yl)-5H-[1,3,
4] Thiadiazolo[3,2-a]pyrimidine-
5-one 2-tert-butyl-6-(2-tert-butyl-
2H-tetrazol-5-yl)-5H- [1,
Dissolve 0.50 g of 3,4]thiadiazolo[3,2-a]pyrimidin-5-one in 2 ml of sulfolane, add 0.10 g of para-toluenesulfonic acid, and dissolve 160
Heat and stir at ~170°C for 2 hours. After cooling, add water, collect the precipitate by filtration, and recrystallize from dimethylformamide to obtain 2-tert-butyl-6 with a melting point of 290°C or higher.
-(1 or 2H-tetrazol-5-yl) -5H
- Obtain 0.31 g of [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one. Elemental analysis value (%) C ₁₀ H ₁₁ N ₇ As OS Calculated value C 43.31, H 4.00, N 35.36 Actual value C 43.35, H 3.94, N 35.28 In the same manner as in Example 1, the target compound of the following formula () (wherein R ¹ is 1 or 2H-tetrazol-5-yl group) was produced. [Table] [Table] [Table] Example 33: 2-(3,4-dichlorophenyl)-
6-(1 or 2H-tetrazol-5-yl)
―5H― [1, 3, 4] Chiadiazoro [3, 2
-a] Pyrimidin-5-one 2-(3,4-dichlorophenyl)-6-(2
-tertiary butyl-2H-tetrazol-5-yl)
―5H― [1, 3, 4] Chiadiazoro [3, 2-
a] 3.10 g of pyrimidine-5-one in 7.5 ml of concentrated sulfuric acid
, and heat and stir at 100 to 110°C for 3 hours. After cooling, add ice water, collect the precipitate by filtration, and recrystallize from dimethylformamide to obtain 2-
(3,4-dichlorophenyl)-6-(1 or 2H
-tetrazol-5-yl)-5H-[1,3,
4] Thiadiazolo[3,2-a]pyrimidine-5
- Obtain 1.70g of on. Elemental analysis value (%) C ₁₂ H ₅ Cl ₂ N ₇ As OS Calculated value C 39.36, H 1.38, N 26.78 Actual value C 39.54, H 1.64, N 26.83 In the same manner as in Example 33, the compound of formula () However, R ¹ was 1 or 2H-tetrazol-5-yl group). [Table] [Table] Example 45: 2-(2-thienyl)-6-(1 or
2H-tetrazol-5-yl)-5H-[1,
3,4]thiadiazolo[3,2-a]pyrimidin-5-one 2-(2-thienyl)-6-(2-tert-butyl-2H-tetrazol-5-yl)-5H-
A mixture of 2.00 g of [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, 20 ml of Dowsum A, and 1 ml of boron trifluoride etherate was heated at 170°C.
Heat and stir for 30 minutes. After cooling, the precipitate was collected by filtration and recrystallized from dimethylformamide to a melting point of 300.
2-(2-thienyl)-6-(1 or
2H-tetrazol-5-yl)-5H-[1,
1.03 g of 3,4]thiadiazolo[3,2-a]pyrimidin-5-one is obtained. Elemental analysis value (%) C ₁₀ H ₅ N ₇ Calculated value as OS ₂ C 39.59, H 1.66, N 32.33 Actual value C 39.83, H 2.10, N 32.22 Example 46: 2-(3-fluoro-4-methoxyph) enyl)-6-(1 or 2H-tetrazole-
5-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 2-(3-fluoro-4-methoxyphenyl)
-6-(2-tert-butyl-2H-tetrazol-5-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one 0.50 g
Add to 10 ml of 50% trifluoroacetic acid and heat under reflux for 5 hours. Trifluoroacetic acid is distilled off under reduced pressure. Insoluble matter was filtered and recrystallized from dimethylformamide to obtain 2-(3-fluoro-4-methoxyphenyl)-6-(1 or 2H-) with a melting point of 298-300°C (decomposition).
Tetrazol-5-yl)-5H-[1,3,4]
0.26 g of thiadiazolo[3,2-a]pyrimidin-5-one is obtained. Elemental analysis value (%) As C ₁₃ H ₈ FN ₇ O ₂ S Calculated value C 45.21, H 2.34, N 28.39 Actual value C 45.34, H 2.83, N 28.06 Example 47: 2-(5-methyl-2-thienyl )―
5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 2-amino-5-(5-methyl-2-thienyl)-1,3,4 -2.96g of thiadiazole and 3.23g of ethoxymethylene malonic acid diethyl ester
Heat and stir the mixture at 120-130°C for 1.5 hours.
Add 10 ml of Dowsome A to this, keep it at 120°C, add 1.5 ml of boron trifluoride etherate, and keep at the same temperature for 1 hour. After cooling, ethanol was added, the precipitate was collected by filtration, and recrystallized from chloroform-ethanol to give 2-(5-methyl-2-thienyl)-5-oxo-5H-[1,3, 4] Obtain 2.50 g of thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester. Elemental analysis value (%) As C ₁₃ H ₁₁ N ₃ O ₃ S ₂ Calculated value C 48.58, H 3.45, N 13.08 Actual value C 48.58, H 3.47, N 13.01 Similarly to Example 47, the following formula () is calculated. The target compound (R ¹ =COOR ³ ) was produced. [Table] [Table] Example 63: 2-(2,3-dimethoxyphenyl)
-5-oxo-5H-(1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 2-amino-5-(2,3-dimethoxyphenyl)-1,3, 4.74 g of 4-thiadiazole and 4.50 g of ethoxymethylene malonic acid diethyl ester
Add to 2ml of Dowsome A and heat to 130℃ for 2 hours. Add 4 ml of Dowsome A to this, heat to 120°C, add 5 ml of boron trifluoride etherate, and further heat at the same temperature for 1 hour. Add ethanol,
After cooling, the precipitate was collected by filtration and recrystallized from chloroform-ethanol to give 2-(2,3
-dimethoxyphenyl)-5-oxo-5H-
6.10 g of [1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester is obtained. Elemental analysis value (%) As C ₁₆ H ₁₅ N ₃ O ₅ S Calculated value C 53.18, H 4.18, N 11.63 Actual value C 52.99, H 4.15, N 11.61 Purpose of the following formula () in the same manner as Example 63 A compound (where R ¹ =-COOR ³ ) was prepared. [Table] [Table] Example 80: 2-tertiary butyl-5-oxo-5H
-[1,3,4] Thiadiazoro [3,2-a]
Pyrimidine-6-carboxylic acid methyl ester 2-amino-5-tertiary butyl-1,3,4-
A mixture of 2.20 g of thiadiazole and 2.40 g of methoxymethylene malonic acid dimethyl ester was heated to 110-120 g.
℃ for 1 hour, and then further heated to 170-180℃ for 1.5 hours. After cooling, recrystallization from isopropanol yields 2-tert-butyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-] with a melting point of 136-137°C.
a] Pyrimidine-6-carboxylic acid methyl ester
Obtain 2.60g. Elemental analysis value (%) C ₁₁ H ₁₃ N ₃ O ₃ S Calculated value C 49.42, H 4.90, N 15.72 Actual value C 49.22, H 4.69, N 15.53 Example 81 Same as Example 80, R ¹ is methoxy A compound of formula () was prepared in which R ² is a carbonyl group and R 2 is a cyclohexyl group. Melting point 157-159℃. Elemental analysis value (%) As C ₁₃ H ₁₅ N ₃ O ₃ S Calculated value C 53.22, H 5.15, N 14.32 Actual value C 53.14, H 5.32, N 14.33 Example 82: 2-(6-methyl-2-pyridinyl )
-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl ester 2-amino-5-(6-methyl-2-pyridinyl)-1,3, 1.92 g of 4-thiadiazole and 1.74 g of methoxymethylene malonic acid dimethyl ester
Add to 10 ml of Dowsome A, heat to 120-140°C for 1 hour, and then further heat to 220-240°C for 15 minutes. After adding ethanol and cooling, the precipitate was collected by filtration and recrystallized from chloroform-ethanol.
-(6-methyl-2-pyridinyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-
a] Pyrimidine-6-carboxylic acid methyl ester
Obtain 2.04g. Elemental analysis value (%) As C ₁₃ H ₁₀ N ₄ O ₃ S Calculated value C 51.65, H 3.33, N 18.53 Actual value C 51.89, H 3.48, N 18.48 Example 83 Same as Example 82, R ¹ is ethoxy A compound of formula () in which R ² is a carbonyl group and 6-methyl-2-pyridinyl group was prepared. Melting point 219-221℃. Elemental analysis value (%) As C ₁₄ H ₁₂ N ₄ O ₃ S Calculated value C 53.15, H 3.83, N 17.71 Actual value C 52.89, H 3.83, N 17.64 Example 84: 2-(2-pyridinyl)-5- Oxo-5H-[1,3,4] Thiadiazolo[3,2
-a] Pyrimidine-6-carboxylic acid ethyl ester 2-amino-5-(2-pyridinyl)-1,
2.67 g of 3,4-thiadiazole and 3.24 g of ethoxymethylene malonic acid diethyl ester are added to 0.5 ml of sulfolane and heated to 120° C. for 1 hour. Next, add 15 ml of Dowsome A and heat under reflux for 15 minutes. After cooling, the precipitate was collected by filtration and recrystallized from chloroform-ethanol to give 2-(2
-pyridinyl)-5-oxo-5H-[1,3,
4] Thiadiazolo[3,2-a]pyrimidine-6
- Obtain 3.28 g of carboxylic acid ethyl ester. Elemental analysis value (%) As C ₁₃ H ₁₀ N ₄ O ₃ S Calculated value C 51.65, H 3.33, N 18.53 Actual value C 51.45, H 3.48, N 18.55 Example 85 Same as Example 84, R ¹ is methoxy Formula () in which R ² is a carbonyl group and 2-pyridinyl group
The compound was prepared. Melting point 228-230℃. Elemental analysis value (%) As C ₁₂ H ₈ N ₄ O ₃ S Calculated value C 49.99, H 2.80, N 19.44 Actual value C 49.90, H 2.99, N 19.26 Example 86: 2-(2-thienyl)-5- Oxo
5H- [1, 3, 4] Chiadiazoro [3, 2-
a] Pyrimidine-6-carboxylic acid ethyl ester 2-amino-5-(2-thienyl)-1,3,
Add 4.76 g of ethoxymethylene malonic acid diethyl ester to 3.66 g of 4-thiadiazole,
Heat at ℃ for 1 hour. Next, add 60 ml of Dowsome A and heat under reflux for 10 minutes. After cooling, ether was added, the precipitate was collected by filtration, and recrystallized from chloroform-ethanol to obtain 2-(2-thienyl)-5-oxo-5H-[1,3,4]thiadiazolo[ with a melting point of 170-172°C]. 5.02 g of 3,2-a]pyrimidine-6-carboxylic acid ethyl ester is obtained. Elemental analysis value (%) As C ₁₂ H ₉ N ₃ O ₃ S ₂ Calculated value C 46.89, H 2.95, N 13.67 Actual value C 47.05, H 3.08, N 13.76 Example 87: 2-(2-chlorophenyl)-5 -Oxo-5H- [1,3,4] Thiadiazolo [3,
2-a] Pyrimidine-6-carboxylic acid ethyl ester [5-(2-chlorophenyl)-1,3,4-
Add 6.00 g of thiadiazol-2-yl]aminomethylenemalonic acid diethyl ester to 30 ml of Dowsum A heated to reflux, and heat to reflux for 2 hours. After cooling, add hexane, collect the precipitate by filtration, and recrystallize from ethanol to obtain 2-(2-chlorophenyl)-5-oxo-5H-[1,3,4] with a melting point of 160-163°C.
3.85 g of thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester are obtained. Elemental analysis value (%) As C ₁₄ H ₁₀ ClN ₃ O ₃ S Calculated value C 50.08, H 3.00, N 12.51 Actual value C 50.15, H 3.23, N 12.68 In the same manner as Example 87, the following formula () The target compound (R ¹ =COOR ³ ) was produced. [Table] [Table] [Table] Example 120: 2-(4-fluorophenyl)-5
-Oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl ester [5-(4-fluorophenyl]-1,3,4
-Thiadiazol-2-yl] 0.92 g of aminomethylene malonic acid dimethyl ester in Dowsome A 10 ml
and heat to 100°. Add 0.5 ml of boron trifluoride etherate to this and heat to the same temperature for 0.5 hour. Add ethanol, cool, collect the precipitate by filtration, and recrystallize from dimethylformamide to a melting point of 258.
2-(4-fluorophenyl)-5- at ~260℃
Oxo-5H-[1,3,4] Thiadiazolo[3,
2-a] 0.73 g of pyrimidine-6-carboxylic acid methyl ester is obtained. Elemental analysis value (%) As C ₁₃ H ₈ FN ₃ O ₃ S Calculated value C 51.14, H 2.64, N 13.76 Theoretical value C 51.13, H 2.76, N 13.89 Compound of formula () shown below in the same manner as Example 120 (However, R ¹ =COOR ³ ) was produced. [Table] Example 127: 2-(3,4-dimethoxyphenyl)
-5-oxo-5H-[1,3,4]thiadiazolo[3,2,-a]pyrimidine-6-carboxylic acid ethyl ester [5-(3,4-dimethoxyphenyl)-1,
3.70g of 3,4-thiadiazol-2-yl]aminomethylenemalonic acid diethyl ester at 180-190g
Heat for 2.5 hours at °C. After cooling, recrystallize from dimethylformamide-ethanol to a melting point of 209-210℃.
2-(3,4-dimethoxyphenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,
2-a] Obtain 2.50 g of pyrimidine-6-carboxylic acid ethyl ester. Elemental analysis value (%) As C ₁₆ H ₁₅ N ₃ O ₅ S Calculated value C 53.18, H 4.18, N 11.63 Actual value C 52.96, H 4.26, N 11.60 Compound of formula () shown below in the same manner as Example 127 (However, R ¹ =COOR ³ ) was produced. [Table] Example 130: 2-(4-aminophenyl)-5-
Oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 2-(4-nitrophenyl)-5H-5-oxo-[1,3,4]thiadiazolo[ 3,2-a]
Pyrimidine-6-carboxylic acid ethyl ester 2.00
g is suspended in 100 ml of acetic acid and heated to 90-100°C.
Next, after adding 3.00 g of iron powder, the mixture was heated to the same temperature for 1 hour. After filtering off insoluble matter, the filtrate is concentrated under reduced pressure.
The residue was poured into water, the precipitate was collected by filtration, and recrystallized from dimethylformamide to give 2-
(4-aminophenyl)-5-oxo-5H-
1.46 g of [1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester is obtained. Elemental analysis value (%) As C ₁₄ H ₁₂ N ₄ O ₃ S Calculated value C 53.15, H 3.83, N 17.71 Actual value C 52.77, H 3.96, N 17.58 Example 131: 2-(5-bromo-2-thienyl )
-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 2-(2-thienyl)-5H-5-oxo-
[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 3.00g,
Add bromine to a mixture of 5.00 g of sodium acetate and 50 ml of acetic acid.
Add 2.0 ml and gently reflux for 4 hours. After cooling, add water and stir at room temperature for 30 minutes. The precipitate was collected by filtration and recrystallized from dimethylformamide.
2.48 g of 2-(5-bromo-2-thienyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester with a melting point of 261 to 262°C. obtain. Elemental analysis value (%) As C ₁₂ H ₈ BrN ₃ O ₃ S ₂ Calculated value C 37.41, H 2.09, N 10.91 Actual value C 37.76, H 2.11, N 10.82 Example 132: 2-(2-chlorophenyl)-5 ―
Oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid 2-(2-chlorophenyl)-5H-5-oxo-[1,3,4]thiadiazolo[3, 2-a]
Pyrimidine-6-carboxylic acid ethyl ester 2.70
g to 5.5 ml of concentrated sulfuric acid and heated to 110-120°C for 1.5 hours. After cooling, pour into ice water, collect the precipitate by filtration, and recrystallize from dimethylformamide to obtain a melting point of 249.
2-(2-chlorophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,
2-a] Obtain 1.90 g of pyrimidine-6-carboxylic acid. Elemental analysis value (%) as C ₁₂ H ₆ ClN ₃ O ₃ S Calculated value C 46.84, H 1.97, N 13.66 Actual value C 46.78, H 2.06, N 13.82 Compound of formula () shown below in the same manner as Example 132 (However, R ¹ =-COOH) was produced. [Table] [Table] Example 143: 2-(2-furyl)-5-oxo-
5H- [1, 3, 4] Chiadiazoro [3, 2-
a] Pyrimidine-6-carboxylic acid 2-(2-furyl)-5-oxo-5H-[1,
A mixture of 1.50 g of 3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester, 10 ml of trifluoroacetic acid, and 10 ml of 47% hydrobromic acid is heated and stirred at 100°C for 2 hours. Trifluoroacetic acid is distilled off under reduced pressure, and water is added to the residue. The precipitate was collected by filtration and recrystallized from dimethylformamide to determine the melting point.
2-(2-Frill)-5-oxo at 290-293℃
5H-[1,3,4] Thiadiazoro [3,2-a]
0.59 g of pyrimidine-6-carboxylic acid is obtained. Elemental analysis value (%) As C ₁₀ H ₅ N ₃ O ₄ S Calculated value C 45.63, H 2.13, N 15.96 Actual value C 45.53, H 2.12, N 16.06 In the same manner as in Example 143, the following formula () is calculated. A compound (R ¹ =-COOH) was prepared. [Table] Example 154: 2-cyclohexyl-5-oxo-
5H- [1, 3, 4] Chiadiazoro [3, 2-
a] Pyrimidine-6-carboxylic acid 2-cyclohexyl-5-oxo-5H-[1,
3.10 g of 3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester was added to 0.2
Add to 55ml of normal sodium hydroxide solution and add 1.5ml at room temperature.
Stir for an hour. Insoluble materials are removed by filtration, and the filtrate is made acidic with dilute hydrochloric acid. The precipitate was collected by filtration and recrystallized from isopropanol to obtain 2-cyclohexyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid with a melting point of 164-166°C.
Obtain 2.00g. Elemental analysis value (%) As C ₁₂ H ₁₃ N ₃ O ₃ S Calculated value C 51.60, H 4.69, N 15.04 Actual value C 51.77, H 4.94, N 14.80 In the same manner as in Example 154, the following formula () A compound (R ¹ =-COOH) was prepared. [Table] Example 160: 2-(3,4-methylenedioxyphenyl)5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid 2-( 3,4-methylenedioxyphenyl)5
-Oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester 1.00g was mixed with concentrated hydrochloric acid-90% acetic acid (1:11)
Add to 20 ml of the mixed solution and heat to 80-90°C for 4 hours.
After cooling, ethanol was added, the precipitate was collected by filtration, and recrystallized from dimethylformamide-ethanol to give 2-(3,4-methylenedioxyphenyl)5-oxo-5H- with a melting point of 287-290°C (decomposition). [1, 3,
4] Thiadiazolo[3,2-a]pyrimidine-6
- Obtain 0.39 g of carboxylic acid. Elemental analysis value (%) As C ₁₃ H ₇ N ₃ O ₅ S Calculated value C 49.21, H 2.22, N 13.25 Actual value C 49.45, H 2.26, N 13.33 In the same manner as in Example 160, the following formula () is calculated. A compound (R ¹ =-COOH) was prepared. [Table] Example 165: 2-phenyl 5-oxo-5H-
[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid 2-phenyl-5-oxo-5H-[1,3,
4] Thiadiazolo[3,2-a]pyrimidine-6
-Add 40 ml of a mixture of acetic acid and concentrated hydrochloric acid (9:1) to 2.40 g of carboxylic acid ethyl ester and heat to 100°C for 1.5 hours. After cooling, add water and collect the precipitate by filtration.
Recrystallized from dimethylformamide, melting point 271-274
2-phenyl 5-oxo-5H-[1,3,
4] Thiadiazolo[3,2-a]pyrimidine-6
- Obtain 0.95 g of carboxylic acid. Elemental analysis value (%) As C ₁₂ H ₇ N ₃ O ₃ S Calculated value C 52.74, H 2.58, N 15.38 Actual value C 52.95, H 2.64, N 15.46 Example 166 Same as Example 165, R ² is 2 -Chloro-6-
A compound of formula () in which R ¹ is a carboxyl group and has a fluorophenyl group was prepared. Melting point 266-270
℃. Elemental analysis value (%) As C ₁₂ H ₅ ClFN ₃ O ₃ S Calculated value C 44.25, H 1.55, N 12.90 Actual value C 43.62, H 1.75, N 12.94 Example 167: 2-(4-methylphenyl)-5-
Oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid 2-(4-methylphenyl)5-oxo-5H
-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid methyl ester 0.90g
Dissolve in 10 ml of dichloromethane. Under ice cooling, 1.00 g of aluminum chloride and 1 part of dimethyl sulfide
ml and stir overnight at room temperature. Low-boiling substances are distilled off under reduced pressure, and dilute hydrochloric acid is added to the residue. The precipitate was collected by filtration and recrystallized from dimethylformamide-ethanol to give 2-(4-methylphenyl) with a melting point of 280°C.
5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid 0.65
get g. Elemental analysis value (%) As C ₁₃ H ₉ N ₃ O ₃ S Calculated value C 54.35, H 3.16, N 14.63 Actual value C 54.32, H 3.40, N 14.56 Example 168 Same as Example 167, R ² is 4 -Formula () in which R ¹ is a carboxyl group in a tertiary butylphenyl group
The compound was prepared. Melting point 205℃. Elemental analysis value (%) As C ₁₆ H ₁₅ N ₃ O ₃ S Calculated value C 58.34, H 4.59, N 12.76 Actual value C 58.18, H 4.73, N 12.62 Example 169: 2-(2-fluorophenyl) 5 ―
Oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid 2-(2-fluorophenyl)-5H-5-oxo-[1,3,4]thiadiazolo[ 3,2-
a] Pyrimidine-6-carboxylic acid ethyl ester
Add 1.50 g to a mixture of 10 ml of acetic acid and 2.5 ml of 48% hydrobromic acid and heat to 120° C. for 4 hours. After cooling, the precipitate was collected by filtration and recrystallized from dimethylformamide to give 2-(2-fluorophenyl) 5 with a melting point of 310°C.
-Oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid 0.47
get g. Elemental analysis value (%) As C ₁₂ H ₆ FN ₃ O ₃ S Calculated value C 49.48, H 2.08, N 14.43 Actual value C 49.17, H 2.28, N 14.48 Example 170: PCA reaction test The PCA test was performed as follows. I went. Weight 170-220
male Sprague-Dawley rat (CD-SD)
0.05 ml of antiserum diluted 4 times with physiological saline was injected intradermally into the dorsal region of a dog (Charles River, Japan). 48 hours later, 0.5 mg containing egg albumin
A PCA reaction was induced by intravenously administering 1 ml of % Evans blue saline solution. Thirty minutes after the challenge, the rats were decapitated and exsanguinated, the back skin was peeled off, and the area of blue staining spots (dye leakage spots) was measured from the back surface. For the drug administration group, the test compound was suspended in 0.5% CMC solution and administered orally to each rat at a dose of 50 mg/kg body weight 30 minutes before challenge injection. On the other hand, only 0.5% CMC solution was administered to the control group. The PCA reaction inhibition rate of the drug administration group was calculated using the following formula. Inhibition rate of PCA reaction (%) = Average value of blue staining spot area in control group - Average value of blue staining spot area in drug administration group / Average value of blue staining spot area in control group x 100 The antiserum containing similar antibodies is prepared by dissolving 1 mg of ovalbumin per rat in physiological saline and intramuscularly administering the solution to CD-SD male rats weighing 300 to 350 g, and administering the solution intramuscularly to CD-SD male rats weighing 300 to 350 g.
10 ¹⁰ Bordetella pertussis (Bordetella
pertussis) were suspended in physiological saline and administered intraperitoneally, and 12 to 14 days later, blood was collected and separated.
The antibody titer of this antiserum is 128 when viewed at the maximum dilution factor that can induce blue staining spots (dye leakage spots) with a diameter of 5 mm or more when 0.05 ml is used for intradermal sensitization 48 to 72 hours before antigen injection. It was twice as hot. The table below shows the PCA reaction inhibition rates of the test compounds, that is, the compounds of the present invention and sodium cromoglycate. [Table] [Table] [Table] [Table]

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a 1 or 2H-tetrazol-5-yl group, carboxyl group or lower alkoxycarbonyl group, R ² is an alkyl group having 4 or more carbon atoms,
It means a cycloalkyl group or an alkylthio group, or an aryl group or a heteroaryl group which may have a substituent, and substituents for the aryl group or heteroaryl group include an alkyl group, an alkoxy group, an alkylenedioxy group, and a halogen group. basis,
Hydroxy, nitro or amino groups are selected. ) and its biologically acceptable salts. 2 In the formula, substituent R ¹ is 1 or 2H-tetrazole-
5-yl group, and the substituent R ² is an alkyl group or cycloalkyl group having 4 or more carbon atoms, or an alkyl group, an alkoxy group, an alkylenedioxy group,
The compound according to claim 1, which is an aryl group or a heteroaryl group which may have a halogen group or a hydroxy group, and a bioacceptable salt thereof.