JPH0142272B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel thiazolo[3,2-a]pyrimidines and methods for their production. More specifically, the present invention relates to novel thiazolo[3,2-a]pyrimidines in which the 6-position is substituted with an oxygen atom or a sulfur atom, and a method for producing them. Conventionally, thiazolopyrimidines have the following formula obtained from 2-aminothiazoline and diethyl malonate. [Here, R is a hydrogen atom or an ethyl group, and when R is a hydrogen atom, R ¹ is a methyl group, ethyl group, iso-propyl group, phenyl group, or benzyl group, and when R is an ethyl group, In case, ethyl group,
isopropyl group, n-butyl group, phenyl group or benzyl group. ] 6-mono- or 6,6-disubstituted- represented by
5H-2,3,6,7-tetrahydro-5,7-
Dioxothiazolo[3,2-a]pyrimidine is known (Journal of American Chemical
Society, Vol64, 1942, pages2709−2712). This document states that the above-mentioned thiazolopyrimidines are expected to have hypnotic or anesthetic effects. Also, in Japanese Patent Application Laid-open No. 55-64591, the following formula [Wherein, R represents a substituted or unsubstituted alicyclic group, a substituted phenyl group, a substituted aralkyl group, or an unsubstituted alkyl group having 8 or more carbon atoms. ] A thiazolo[3,2-a]pyrimidine derivative represented by is described. Furthermore, in Japanese Patent Application Laid-open No. 55-66592, the following formula [In the formula, R ₁ is a substituted or unsubstituted alicyclic group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl group.
aralthyl, R ₂ represents a lower alkyl group, and the dotted line cooperates with the solid line to represent a single bond or a double bond. ] 7-alkoxythiazolo[3,2-
a] Pyrimidine derivatives are described. Furthermore, in Japanese Patent Application Laid-Open No. 57-130988, the following formula [Wherein, R ¹ is a hydrogen atom, a substituted or unsubstituted chain alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alicyclic group having 3 to 10 carbon atoms, a substituted or unsubstituted phenyl group, Alternatively, it represents a substituted or unsubstituted aralkyl group. R ² represents an alkyl group having 1 to 10 carbon atoms, and only when R ¹ is a hydrogen atom or a substituted or unsubstituted chain alkyl group having 1 to 10 carbon atoms, R ² also represents an acyl group. ] A thiazolo[3,2-a]pyrimidine-1-oxide derivative represented by is described. Also, in Japanese Patent Application Laid-open No. 57-67585, the following formula [Here, R represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkyloxy group. ] A thiazolo[3,2-a]pyrimidine derivative represented by is described. The above four publications disclose that the above-mentioned thiazolo[3,2-a]pyrimidine derivatives have immunomodulatory properties, especially immunostimulatory properties, as evaluated by delayed allergy tests. There is. The present inventor has determined that the atom bonded to the carbon atom corresponding to the 6-position of the skeleton of the thiazolo[3,2-a]pyrimidine derivatives represented by the above four general formulas can be changed from a carbon atom or a nitrogen atom to an oxygen atom. Or, by changing to a sulfur atom, a completely new thiazolo[3,2-
a] After synthesizing pyrimidine derivatives and examining their pharmacological effects, we found that these compounds have the ability to stimulate and activate the immune system, and are therefore extremely useful for the treatment of autoimmune diseases or malignant tumors, or for the defense against infection. The present invention was achieved by discovering that. That is, the present invention is based on the following formula [] [Here, A represents an oxygen atom or a sulfur atom, and R ₁ is a halogen atom-substituted or unsubstituted aryl group, a halogen atom, or C ₁ -
_C4 alkoxy substituted or unsubstituted aralkyl group, C1 to C6 alkyl group substituted or unsubstituted _C1 to _C3 alkoxy group, or C3 to C8 unsubstituted cycloalkyl group The bond in the moiety that represents a group and includes a dotted line represents a single bond or a double bond. ] Thiazolo[3,2-a]pyrimidines selected from thiazolo[3,2-a]pyrimidines represented by these and their enol derivatives, and a method for producing the same. In the above formula [], R ¹ is an aryl group substituted or unsubstituted with a halogen atom, an aralkyl group substituted or unsubstituted with a halogen atom or a C ₁ -C ₄ alkoxy group, or an aralkyl group having 1 to 1 carbon atoms.
represents an unsubstituted or unsubstituted alkyl group having 6 _C1 to _C3 alkoxy groups or an unsubstituted cycloalkyl group having 3 to 8 carbon atoms. Preferred examples of the aryl group substituted with a halogen atom or unsubstituted include, for example, a phenyl group or a naphthyl group substituted with a halogen atom such as fluorine, chlorine, or bromine. Particularly preferred are halogen-substituted or unsubstituted phenyl groups or naphthyl groups. Examples of the aralkyl group of the aralkyl group substituted or unsubstituted with a halogen atom or a _C1 - _C4 alkoxy group include a benzyl group, a phenethyl group, a phenylpropyl group, and the like. Examples of the halogen atom include fluorine, chlorine, and bromine, and examples of the _C1 to _C4 alkoxy group include methoxy, ethoxy, n-propoxy, and n-butoxy. Particularly preferred is a benzyl group substituted or unsubstituted with a halogen atom or a _C1 - _C4 alkoxy group. Examples of the alkyl group of the alkyl group substituted or unsubstituted with a _C1 - _C3 alkoxy group having 1 to 6 carbon atoms include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, t-
Butyl, n-pentyl, n-hexyl and the like can be mentioned. As the C ₁ to C ₃ alkoxy group,
Methoxy, ethoxy, n-propoxy, iso-propoxy and the like can be mentioned. Especially C ₁ ~
An ethyl group or an iso-propyl group substituted or unsubstituted with a C ₃ alkoxy group is preferred. The above unsubstituted cycloalkyl group having 3 to 8 carbon atoms may be either saturated or unsaturated, and includes cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, etc. be able to. Among these, _C5 - _C6 cycloalkyl groups, particularly cyclopentyl and cyclohexyl, are preferred. In the above formula [], A represents an oxygen atom or a sulfur atom. Further, the bond in the portion including the dotted line represents a single bond or a double bond. Preferred specific examples of the thiazolo[3,2-a]pyrimidines of the above formula [] include the following. (100), 5H-2,3,6,7-tetrahydro-
5,7-dioxo-6-phenoxythiazolo[3,2-a]pyrimidine (102), 6-p-chlorophenoxy-5H-2,
3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (104), 5H-2,3,6,7-tetrahydro-
6-β-naphthyloxy-5,7-dioxothiazolo[3,2-a]pyrimidine (106), 6-benzyloxy-5H-2,3,6,
7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (108), 5H-2,3,6,7-tetrahydro-
6-p-methoxybenzyloxy-5,7-dioxothiazolo[3,2-a]pyrimidine (110), 6-sec-butyloxy-5H-2,3,
6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (112), 6-cyclohexyloxy-5H-2,
3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (114), 6-(2-ethoxyethyloxy)-5H
-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (116), 6-p-chlorophenylthio-5H-2,
3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (118), 5H-6,7-dihydro-5,7-dioxo-6-phenoxythiazolo[3,2- a]
Pyrimidine According to the present invention, the thiazolo[3,2-a]pyrimidines represented by the above general formula [] are represented by the following general formula: [Here, the definitions of A and R ¹ are the same as in the above formula [], R ³ and R ⁴ are the same or different, and C ₁
~ _C4 alkyl group. ] A malonic acid derivative represented by is subjected to a condensation cyclization reaction with 2-aminothiazoline or 2-aminothiazole (a) under heating, or (b) a condensation reaction in the presence of an alkali metal alkoxide; It can be produced by neutralizing an alkali metal salt of an enol with an acid. The definitions of A and R ¹ in the above formula [] are the same as in the formula []. R ³ and R ⁴ are the same or different and are a C ₁ to C ₄ alkyl group,
Examples include methyl, ethyl, n-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. Among these, it is preferable that R ³ and R ⁴ are both methyl or ethyl. Such malonic acid derivatives [ ] can be obtained by heating the corresponding halogenated malonic acid diester, preferably brommalonic diester or chloromalonic acid diester, and (a) the corresponding alcohol or thiol in an organic solvent such as acetone in the presence of a base such as potassium carbonate. or (b) a heated reaction with the corresponding alcohol or alkali metal salt of a thiol in a polar solvent, such as ethanol. Separately, (c) the corresponding alkali metal salt of an alcohol or thiol and a halogenated acetic acid are reacted by heating in an organic solvent such as benzene or toluene, the resulting product is then esterified, and the substituted acetic acid is further esterified. It can also be produced by reacting an ester with a chloroformate in the presence of a base such as lithium diisopropylamine, sodium hydride, potassium hydride, etc. This manufacturing method has been published in the Journal of Organie, for example.
Described in Chemistry Vol. 39, 2115 (1974). As the other starting material, the following formula 2-aminothiazoline represented by and the following formula 2-aminothiazole represented by is used. The method of the present invention uses the above malonic acid derivative [] and 2-
This is carried out by subjecting aminothiazoline or 2-aminothiazole to a condensation cyclization reaction.
The condensation cyclization reaction is an equimolar reaction of a malonic acid derivative and 2-aminothiazoline or 2-aminothiazole. According to the method of the invention, preferably about 0.8 to 1.2 moles of 2-
Aminothiazoline or 2-aminothiazole is used. The condensation cyclization reaction (a) can be carried out under heating,
It can also be carried out in the presence of (b) an alkali metal alkoxide. It is preferably carried out under heating. When the reaction is carried out in the presence of an alkali metal alkoxide, the condensation cyclization reaction product is obtained as an alkali metal salt of an enol, and therefore it is necessary to neutralize it with an acid. The condensation cyclization reaction carried out under heating is preferably carried out in the presence of an inert organic solvent. As inert organic solvents it is advantageous to use aprotic inert organic solvents. Such inert organic solvents include, for example, aprotic solvents such as benzene, toluene, xylene, cumene, cymene, tetralin, decalin, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, diphenyl ether, dimethyl sulfoxide, dimethylformamide, nitrobenzene. C ₁ -C ₄ inert organic solvent such as ethanol or butanol
lower alcohols, etc. Such an inert organic solvent is suitable for the malonic acid derivative [] and 2-aminothiazoline or 2-aminothiazoline used.
- It is preferably used in an amount of about 1 to about 50 times by weight, particularly about 2 to about 20 times by weight, based on the total amount of aminothiazole. The reaction temperature and reaction time vary depending on the type of starting materials used, whether or not a solvent is used, and the type of solvent used. It is usually carried out preferably at 80 to 320°C for 1 minute to 48 hours, particularly at 100 to 300°C for 10 minutes to 24 hours. The reaction can be carried out under normal pressure to increased pressure. When using a lower alcohol as a reaction solvent,
Preferably, the reaction is carried out under pressure to increase the reaction temperature. The reaction products produced by the condensation cyclization reaction according to the above procedure are thiazolo[3,2-a]pyrimidines represented by the above formula []. Isolation and purification of this reaction product from the reaction mixture can be easily carried out by conventional methods such as recrystallization, chromatography, extraction and separation. On the other hand, when the condensation cyclization reaction is carried out in the presence of an alkali metal alkoxide as a catalyst, the reaction can be carried out at a relatively low temperature. As the alkali metal alkoxide, C ₁ -C ₄ alkoxide of lithium, sodium or potassium is preferably used. Examples of such alkali metal alkoxides include lithium methoxide, lithium ethoxide, lithium propoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, sodium sec-butoxide,
Examples include sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium t-butoxide, and the like. In particular, sodium methoxide, sodium ethoxide, etc. are preferably used. Such alkali metal alkoxide can be used in an amount of 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the commonly used malonic acid derivative. When carrying out the condensation cyclization reaction in the presence of such an alkali metal alkoxide, a C ₁ -C ₄ lower alcohol is preferably used as the reaction solvent. Examples of such lower alcohol include methanol, ethanol, propanol, isopropanol, Examples include lower alcohols such as butanol, isobutanol, sec-butanol, and t-butanol. In addition to this, a mixture of a C ₁ to C ₄ lower alcohol and another inert organic solvent (for example, the above-mentioned aprotic inert solvent) can also be used as the reaction solvent. The reaction solvent is generally used in an amount of 1 to 50 times, preferably 2 to 10 times, the total amount of the malonic acid derivative and 2-aminothiazoline or 2-aminothiazole used. The reaction time and temperature vary depending on the starting materials, the solvent used, the type of alkali metal alkoxide used, etc., but the reaction is usually carried out at 40 to 150°C.
It is carried out for 30 minutes to 72 hours, more preferably at 60 to 120°C for 1 hour to 8 hours. The reaction can be carried out under normal pressure to increased pressure. The procedure for actually carrying out the reaction is to add an alkali metal such as sodium to the above lower alcohols to prepare a lower alcohol solution of the alkali metal alkoxide, and then add the malonic acid derivative of the above formula [] and 2 It is preferred to carry out the condensation cyclization reaction by adding -aminothiazoline or 2-aminothiazole. The reaction product produced by the above condensation reaction using an alkali metal alkoxide is an alkali metal salt of an enol. This enol salt is then neutralized with an acid to give thiazolo[3,2-a]pyrimidines represented by the above formula []. Such a neutralization reaction can be carried out by adding a predetermined amount of acid required for the neutralization reaction into the reaction mixture obtained by the condensation reaction, or by isolating the alkali metal salt of the enol form from the reaction mixture, and then adding it to the reaction mixture, for example, in water. This can also be carried out by adding a predetermined amount of acid. As acids, various inorganic acids, organic sulfonic acids,
Organic carboxylic acids can be used. Preferably inorganic acids, such as hydrochloric acid, hydrobromic acid, etc.
Organic carboxylic acids such as acetic acid are used. The product thus obtained is isolated and purified by conventional means such as recrystallization, chromatography, extraction and separation. EXAMPLES Next, Examples will be described to explain the present invention in more detail, but the present invention is not limited thereto. Example 1 (i) Synthesis of diethyl phenoxymalonate 7.1 g of phenol, diethyl brommalonate
20.6 g of potassium carbonate, 10.4 g of potassium carbonate, and 75 ml of acetone were mixed, and the mixture was stirred and heated under reflux for 16 hours. After cooling, solids were removed by filtration, and the liquid was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography to obtain 7.4 g (yield: 39%) of diethyl phenoxymalonate in the eluate with a benzene-n-hexane (2:1) mixed solvent.
The physical properties of this product were as follows. NMR (δ ^CCl4 _TMS ); 1.23 (6H, t, J = 8Hz), 4.20 (4H, q,
J=8Hz), 5.05 (1H, s), 6.7~7.4 (5H,
m) (ii) 5H-2,3,6,7-tetrahydro-5,
7-Dioxo-6-phenoxythiazolo[3,
2-a] Synthesis of pyrimidine (100) 0.35 g of metallic sodium and 10 ml of absolute ethanol
diethyl phenoxymalonate dissolved in
1.9 g and then 0.77 g of 2-aminothiazoline were added, and the mixture was heated under reflux for 3 hours while stirring. After evaporating the solvent under reduced pressure, dissolve the residue in water and add dilute hydrochloric acid to adjust the pH to around 4. The precipitated solid was filtered, thoroughly washed with water, and then recrystallized using ethanol as a solvent to obtain 5H-2,3,
6,7-tetrahydro-5,7-dioxo-6
-Phenoxythiazolo[3,2-a]pyrimidine (100) 0.80 g (yield: 40%) was obtained.
The physical properties of this product were as follows. Melting point (mp); 250.0-252.8℃ IR (ν ^KBr _nax ) cm ^-1 ; 3470 (br), 3200-2150 (enol), 1650,
1570, 1522, 1390 NMR (δ ^DMSO-D6 _TMS ) ppm; 36.0 (2H, t, J = 7Hz), 4.36 (2H, t,
J=7Hz), 6.8~7.5 (5H, m), 10.5~12.0
(Disappeared with 1H, br, _D2O ) Example 2 (1) Synthesis of diethyl p-chlorophenoxymalonate Using 3.86 g of p-chlorophenol, 7.92 g of diethyl brommalonate, 4.15 g of potassium carbonate, and 30 ml of acetone, Reaction similar to (i) of Example 1,
After post-treatment and purification, 2.40 g (yield: 27.9%) of diethyl p-chlorophenoxymalonate was obtained. The physical properties of this product were as follows. NMR (δ ^CDCl3 _TMS ); 1.25 (6H, t, J = 8Hz), 4.25 (4H, q,
J=8Hz), 5.03 (1H, s), 6.8~7.5 (4H,
m) (2) 6-p-chlorophenoxy-5H-2,3,
Synthesis of 6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (102) 1.61 g of sodium metal, 10.1 g of diethyl p-chlorophenoxymalonate, 3.60 g of 2-aminothiazoline, 100 ml of absolute ethanol When the same operation as in Example 1 (2) was performed using 6-p
-Chlorphenoxy-5H-2,3,6,7-
3.31 g (yield: 30%) of tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (102) was obtained. The physical properties of this product were as follows. Melting point (mp); 241.0-243.8℃ IR (ν ^KBr _nax ) cm ^-1 ; 3450 (br), 3100-2100 (enol), 1642,
1573, 1522 NMR (δ ^DMSO-D6 _TMS ) ppm; 3.60 (2H, t, J = 7Hz), 4.45 (2H, t,
J=7Hz), 6.8~7.5 (4H, m), 10.5~12.0
(Disappeared with 1H, br, D ₂ O) Example 3 (1) Synthesis of diethyl β-naphthyloxymalonate 7.65 g of β-naphthol, 14.0 g of diethyl brommalonate, 7.33 g of potassium carbonate, 50 g of acetone
The same operation as in Example 1(1) was carried out using ml. When the obtained residue was purified by silica gel column chromatography, 7.1% of diethyl β-naphthyloxymalonate was found in the benzene eluate.
g (yield: 44%) was obtained. The physical properties of this product were as follows. NMR (δ ^CDCl3 _TMS ); 1.22 (6H, t, J=7Hz), 4.20 (4H, t,
J=7Hz), 5.18 (1H, s), 6.9~7.8 (7H,
m) (2) 5H-2,3,6,7-tetrahydro-6-
Synthesis of β-naphthyloxy-5,7-dioxothiazolo[3,2-a]pyrimidine (104) Using 0.47 g of sodium metal, 3.96 g of diethyl β-naphthyloxymalonate, 1.48 g of 2-aminothiazoline, and 70 ml of absolute ethanol. , The same operation as in Example 1 (2) was performed. The resulting residue was purified by silica gel column chromatography to yield chloroform-methanol (19:
In the mixed solvent elution part of 1), 5H-2, 3, 6,
7-tetrahydro-6-β-naphthyloxy-
0.89 g (yield: 20%) of 5,7-dioxothiazolo[3,2-a]pyrimidine (104) was obtained.
The physical properties of this product were as follows. Melting point (mp); 220℃ (decomposition) IR (ν ^KBr _nax ) cm ^-1 ; 3450 (br), 3100-2000 (enol), 1640,
1565, 1520 NMR (δ ^DDCl3 _TMS ) ppm; 3.50 (2H, t, J=7Hz), 4.41 (2H, t,
J=7Hz), 7.0~8.0 (7H, m), 10.5~12.0
(Disappears with 1H, br, D ₂ O) Example 4 (1) Synthesis of diethyl benzyloxymalonate (1-a) Synthesis of benzyloxyacetic acid 5.00 g of sodium metal, 33.3 g of benzyl alcohol, and 85 ml of anhydrous benzene were mixed. The mixture was stirred for 2 hours and heated to reflux. Chloroacetic acid here
9.45 g was added, and the mixture was further stirred and heated under reflux for 1 hour. The reaction solution was allowed to cool, 50 ml of water was added, and then neutralized with 19 ml of concentrated hydrochloric acid. The benzene layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 7.16 g (yield: 43%) of benzyloxyacetic acid. Distillation conditions: pressure 0.75Torr, boiling point 128-132℃ (1-b) Synthesis of benzyloxyethyl acetate 7.16g benzyloxyacetic acid, 30% ethanol
ml and 2 drops of concentrated sulfuric acid were mixed and heated under reflux for 6 hours with stirring. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and then with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 7.19 g of benzyloxyethyl acetate (yield: 85.9%). (1-c) Synthesis of diethyl benzyloxymalonate 10 ml of anhydrous tetrahydrofuran was cooled to 0°C, and a solution of 1.01 g of diisopropylamine in 3 ml of anhydrous tetrahydrofuran was added thereto, then n
-Add 0.01mol equivalent of butyllithium to 0
The mixture was stirred at ℃ for 15 minutes. This was cooled to -70℃, and 1.94 g of benzyloxyethyl acetate was added.
A solution of anhydrous tetrahydrofuran was added and stirred for 10 minutes. Here is 1.09g of ethyl chlorocarbonate.
Add 3 ml of anhydrous tetrahydrofuran solution of
Stirred at -70°C for 25 minutes. The reaction was stopped with a saturated aqueous ammonium chloride solution and extracted with ether. When the obtained residue was purified by silica gel column chromatography, 0.71 g of diethyl benzyloxymalonate was added to the eluate of a mixed solvent of n-hexane-ethyl acetate (12:1).
(yield: 26.7%). The physical properties of this product were as follows. NMR (δ ^CDCl3 _TMS ) ppm; 1.24 (6H, t, J=7Hz), 4.21 (4H,
q, J=7Hz), 4.53 (1H, s), 4.70 (2H,
s), 7.33 (5H, br, s) (2) 6-benzyloxy-5H-2,3,6,7
-Synthesis of tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (106) Sodium metal 90 mg, diethyl benzyloxymalonate 0.71 g, 2-aminothiazoline 0.33
6-benzyloxy-5H-2, in the same manner as in Example 1 (2) using 5 ml of absolute ethanol.
3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyridine (106) 0.33
g (yield: 44%) was obtained. The physical properties of this product were as follows. NMR (δ ^{CDCl3-DMSO-D6} _TMS ) ppm; 3.45 (2H, t, J = 7Hz), 4.40 (2H, t,
J=7Hz), 4.75 (2H, s), ~7.40 (5H, br,
s), 10.5-12.0 (disappeared with 1H, br, _D2O ) Example 5 (1) Diethyl p-methoxybenzylmalonate Starting materials: 5.1 g of sodium metal, 40.1 g of p-methoxybenzyl alcohol, and 9.5 g of chloroacetic acid. Perform the same operation as in Example 4 (1) as
Diethyl p-methoxybenzylmalonate 0.63g
(yield: 27%). The physical properties of this product are as follows. NMR (δ ^CDCl3 _TMS ) ppm; 1.25 (6H, t, J=7Hz), 3.75 (3H, s),
4.20 (4H, q, J=7Hz), 4.45 (1H, s),
4.60 (2H, s), 6.73-7.33 (4H, m) (2) 5H-2,3,6,7-tetrahydro-6-
p-Methoxybenzyloxy-5,7-dioxothiazolo[3,2-a]pyrimidine (108)
Synthesis of 5H-2,3,6.
7-tetrahydro-6-p-methoxybenzyloxy-5,7-dioxothiazolo[3,2-
a] Pyrimidine (108) 0.07g (yield: 10%)
I got it. The physical properties of this product are as follows. NMR (δ ^{CDCl3-DMSO-D6} _TMS ) ppm; 3.40 (3H, t, J = 7Hz), 3.80 (3H, s),
4.45 (3H, t, J=7Hz), 4.63 (2H, s),
6.75~7.40 (4H, m), 10.5~12.0 (1H, br,
Example ₆ (1) Synthesis of diethyl sec-butyloxymalonate 8.4 g of sodium metal, 180 g of sec-butanol
The same operation as in Example 4(1) was carried out using 15.7 g of chloroacetic acid to obtain 5.8 g of diethyl sec-butyloxymalonate (yield: 27%). The physical properties of this product were as follows. Boiling point: 115-120℃ NMR (δ ^CDCl3 _TMS ) ppm: 0.91 (6H, d, J=6Hz), 1.25 (6H, t,
J=8Hz), 1.5-2.2 (1H, m), 3.33 (2H,
d, J=6Hz), 4.24 (4H, q, J=7Hz),
4.33 (1H, s) (2) 6-sec-butyloxy-5H-2,3,6,
Synthesis of 7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (110) Performed using 0.69 g of sodium metal, 5.49 g of diethyl sec-butyloxymalonate, 2.12 g of 2-aminothiazoline and 25 ml of absolute ethanol The same operation as in Example 1 (2) was carried out to obtain 1.35 g of 6-sec-butyloxy-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (110) (yield: :28%).
The physical properties of this product were as follows. Melting point (mp); 181.5-183.5℃ IR (ν ^KBr _nax ) cm ^-1 ; 3450 (br), 3300-2100 (enol), 1640
(shoulder), 1605, 1535, 1407, 1295 NMR (δ ^CDCl3 _TMS ) ppm; 0.97 (6H, d, J = 6Hz), 1.6-2.3 (1H,
m), 3.48 (2H, t, J=8Hz), 3.77 (2H,
d, J=6Hz), 4.42 (2H, t, J=8Hz),
10.5-12.0 (disappeared with 1H, br, _D2O ) Example 7 (1) Synthesis of diethyl cyclohexyloxymalonate 5.06 g of sodium metal and cyclohexanol
The same operation as in Example 4 (1) was carried out using 69.0 g of chloroacetic acid and 9.45 g of chloroacetic acid as starting materials to obtain 1.25 g of diethyl cyclohexyloxymalonate (yield: 32
%) was obtained. The physical properties of this product are as follows. NMR (δ ^CDCl3 _TMS ) ppm; 1.24 (6H, t, J = 7Hz), 0.9-2.3 (10H,
m), 3.2-3.6 (1H, br), 4.23 (4H, q, J
=7Hz), 4.53 (1H, s) (2) 6-cyclohexyloxy-5H-2,3,
Synthesis of 6,7-dioxothiazolo[3,2-a]pyrimidine (112) Example 1 (2) ), 6-cyclohexyloxy-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-
a] Pyrimidine (112) 0.11g (yield: 9%)
I got it. The physical properties of this product were as follows. Melting point (mp); 231.5-233.5℃ IR (ν ^KBr _nax ) cm ^-1 ; 3450 (br), 3100-2050 (enol), 1670,
1625, 1535, 1448, 1435, 1400 NMR (δ ^CDCl3 _TMS ) ^+DMSO-D6 _ppn ; 0.85-2.1 (10H, m), 3.47 (2H, t, J=
7Hz), 3.7-4.1 (1H, m), 4.35 (2H, t,
J=7Hz), 10.5-12.0 (1H, br, disappeared with _D2O ) Example 8 (1) Synthesis of diethyl 2-ethoxyethyloxymalonate 6.6g of sodium hydride was suspended in 80ml of benzene, and 27.9 g of ethyl cellosolve was slowly added. Next, 1.19 g of chloroacetic acid was added dropwise, and the mixture was heated under reflux for 3 hours. It was neutralized by adding 100 ml of water and concentrated hydrochloric acid, and the benzene layer was separated. This was washed with water, dried, and concentrated to obtain 3.4 g of 2-ethoxyethyloxyacetic acid (yield: 45%). Using this 2-ethoxyethyloxyacetic acid, the same operations as in Example 4 (1-b) and (1-c) were carried out,
Diethyl 2-ethoxyethyloxymalonate
1.2 g (overall yield: 7%) was obtained. The physical properties of this product were as follows. NMR (δ ^CDCl3 _TMS ) ppm; 1.30 (6H, t, J=8Hz), 1.60 (3H, t,
J=8Hz), 3.3-4.0 (6H, m), 4 4.30
(4H, q, J=8Hz), 4.65 (1H, s) (2) 6-(2-ethoxyethyloxy)-5H-2,
Synthesis of 3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (114) 0.14 g of sodium metal, 1.22 g of diethyl 2-ethoxyethyloxymalonate, 0.63 g of 2-aminothiazoline and anhydrous Perform the same operation as in Example 1 (2) using 4 ml of ethanol to obtain 6-
(2-ethoxyethyloxy)-5H-2,3,
6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (114) 0.55g
(yield: 43%). The physical properties of this product were as follows. NMR (δ ^CDCl3 _TMS ) ppm; 1.30 (3H, t, J = 7Hz), 3.50 (2H, t,
J=7Hz), 3.4-4.3 (6H, m), 4.47 (2H,
t, J = 7 Hz), 8.70 (1H, s) Example 9 (1) Synthesis of diethyl p-chlorophenylthiomalonate 1.75 g of sodium metal was dissolved in 100 ml of ethanol, and p-chlorothiophenol was dissolved therein.
11.0 g was added and heated under reflux for 1.5 hours. After cooling, add 15.0 g of diethyl chlormalonate and heat to 25℃ for 12 hours.
Stir for hours. The reaction solution was extracted with ethyl acetate,
It was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 10.7 g (yield: 47%) of diethyl p-chlorophenylthiomalonate. The physical properties of this product were as follows. Boiling point: 140-155℃ (0.7mmHg) NMR (δ ^CDCl3 _TMS ) ppm: 1.23 (6H, t, J = 7Hz), 4.20 (4H, q,
J=7Hz), 4.50 (1H, s), 7.15~7.6 (4H,
dd) (2) 6-p-chlorophenylthio-5H-2,3,
Synthesis of 6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (116) Mix 0.52 g of 2-aminothiazoline, 1.52 g of diethyl p-chlorophenylthiomalonate, and 2 ml of phenyl ether. 180℃ under nitrogen gas atmosphere
The mixture was stirred for 1 hour. Thereafter, the reaction solution was purified by silica gel column chromatography, and 6-p-chlorophenylthio-5H-
2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine (116)
46 mg (yield: 2.9%) was obtained. The physical properties of this product are as follows. IR (ν ^KBr _nax ) cm ^-1 ; 3700-2100, 1660, 1645, 1580, 1540,
1475, 1443 NMR (δ ^{CDCl3-DMSO-D6} _TMS ) ppm; 3.67 (2H, t, J = 7Hz), 4.45 (2H, t,
J = 7Hz), 7.33 (4H, q, J _AB = 11Hz, J _AA ′
or J _BB ′=7Hz), 10.5~12.0 (1H, br,
Example ₁₀ 5H-6,7-dihydro-5,7-dioxo-
Synthesis of 6-phenoxythiazolo[3,2-a]pyrimidine (118) 4.11 g of diethyl phenoxymalonate, 1.73 g of 2-aminothiazole and 5 ml of phenyl ether
were mixed and heated at 180°C for 2 hours under a nitrogen gas atmosphere. The reaction solution was purified by silica gel column chromatography, and 5H-6,7-dihydro-5,7-dioxo-6-phenoxythiazolo[ 3,2-a]pyrimidine 0.54g (yield: 13
%) was obtained. The physical properties of this product were as follows. NMR (δ ^{CDCl3-DMSO-D6} _TMS ) ppm; 7.10 (1H, d, J = 4Hz), 7.0-7.6 (5H,
m), 7.50 (1H, d, J=4Hz), 10.5-12.0
(Disappears after 1H, br, D ₂ O) Reference example 1 Delayed allergy measurement Group of 5 C ₃ H/He male mice (7 weeks old)
The cells were sensitized by intravenously injecting 5×10 ⁵ sheep red blood cells. A suspension of the test drug in a 5% gum arabic solution was orally administered immediately after sensitization, and 1, 2, and 3 days after sensitization. Then, 4 days after sensitization, 1×10 ⁸ sheep red blood cells were injected into the right hind foot pad to induce an allergic reaction. 24 hours after allergy induction, the thickening of the feet was measured with a micrometer, and based on this value, sheep red blood cells 1×
10 Subtract the value before ⁸ cell injection foot pat reaction
Delayed allergy was measured at (0.1 mm). The results are shown in Table 1.

[Table] Reference Example 2 Tablets each having the following composition were manufactured. Active ingredient (6-p-chlorophenyloxy-5H
-2,3,6,7-tetrahydro-5,7-dioxo[3,2-a]pyrimidine) 200mg Lactose 250mg Diagaimo starch 70mg Polyvinylpyrrolidone 11mg Magnesium stearate 5mg Mix active ingredients, lactose and diagaimo starch This was then evenly moistened with a 20% ethanol solution of polyvinylpyrrolidone, passed through a 2.0 mm mesh sieve, dried at 45°C, and then recirculated to a 1.5 mm mesh.
I passed it through the mesh sieve. The granules thus obtained were mixed with magnesium stearate and compressed into tablets. As an active ingredient, 6-p-chlorophenyloxy-5H-2,3,6,7-tetrahydro-5,
7-dioxo[3,2-a]pyrimidine was used. Reference Example 3 Hard gelatin capsules were produced, each capsule containing the following composition. Active ingredient (6-p-chlorophenyloxy-5H
-2,3,6,7-tetrahydro-5,7-dioxo[3,2-a]pyrimidine) 200 mg Microcrystalline cellulose 185 mg Amorphous silicic acid 5 mg Active ingredient in finely powdered form, microcrystalline cellulose and unpressed Amorphous silicic acid was thoroughly mixed and packed into hard gelatin capsules.

Claims (1)

[Claims] 1. The following formula [] [In the formula, A represents an oxygen atom or a sulfur atom,
R ¹ is an aryl group substituted or unsubstituted with a halogen atom, an aralkyl group substituted or unsubstituted with a halogen atom or a C ₁ -C ₄ alkoxy group, a C ₁ -C ₃ alkoxy group having 1 to 6 carbon atoms represents a substituted or unsubstituted alkyl group or an unsubstituted cycloalkyl group having 3 to 8 carbon atoms, and the bond in the portion containing the dotted line represents a single bond or a double bond. ] Thiazolo[3,2-a]pyrimidines represented by: 2 In the above formula [], the aryl group is a phenyl group or a naphthyl group, Claim 1
The thiazolo[3,2-a]pyrimidines described in . 3. Thiazolo[3,2-a]pyrimidines according to claim 1, wherein in the above formula [], the aralkyl group is a benzyl group. 4. Thiazolo[3,2-a]pyrimidines according to claim 1, wherein in the above formula [], the alkyl group is an ethyl group or an iso-propyl group. 5 General formula below [] [In the formula, A represents an oxygen atom or a sulfur atom,
R ¹ is an aryl group substituted or unsubstituted with a halogen atom, an aralkyl group substituted or unsubstituted with a halogen atom or a C ₁ -C ₄ alkoxy group, a C ₁ -C ₃ alkoxy group having 1 to 6 carbon atoms represents a substituted or unsubstituted alkyl group or an unsubstituted cycloalkyl group having 3 to 8 carbon atoms, and R ³ and R ⁴ are the same or different;
~4 alkyl group. ] A malonic acid derivative represented by 2-aminothiazoline or 2-aminothiazole is subjected to (a) a condensation and cyclization reaction under heating, or (b) a condensation and cyclization reaction in the presence of an alkali metal alkoxide. The following general formula [] is characterized in that the alkali metal salt of the enol obtained is neutralized with an acid. [Here, the definitions of A and R ¹ are the same as in the above formula [], and the bond in the portion including the dotted line represents a single bond or a double bond. ] A method for producing thiazolo[3,2-a]pyrimidines represented by: 6. The method for producing thiazolo[3,2-a]pyrimidines according to claim 5, wherein the cyclocondensation reaction under heating is carried out in the presence of an inert organic solvent. 7. The method for producing thiazolo[3,2-a]pyrimidines according to claim 5 or 6, wherein the condensation cyclization reaction under heating is carried out at a temperature of about 80 to 320°C.