JPS6233236B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel compound, thiazolo[3,2-a]
The present invention relates to pyrimidine derivatives, methods for producing the same, and drugs containing the same. More specifically, the present invention provides novel compounds that have anti-inflammatory effects such as anti-inflammatory effects, antipyretic effects, and analgesic effects, and are also useful as compounds that have immunomodulatory effects.
The present invention relates to thiazolo[3,2-a]pyrimidine derivatives, methods for producing the same, and drugs containing the same. Conventionally, many nonsteroidal anti-inflammatory agents have been developed as drugs for various types of inflammation including arthritis, and many have been used clinically. However, despite the fact that many of these drugs have been introduced to the world in response to a wide variety of inflammations, the side effects and toxicity of these drugs are still not fully satisfactory, and further improvements are desired. . In addition, in recent years, immunomodulatory therapy has been attempted for autoimmune diseases such as rheumatism, systemic ectomatosis, and malignant tumors, and various drugs have been developed, but many of these drugs lack specificity and cannot be used for long periods of time. However, there are problems such as serious side effects or development of drug resistance, and there is currently no satisfactory therapeutic agent. On the other hand, the literature “Journal of American
Chemical Society Vol. 64, pp. 2709-2712 (1942), describes the production of barbituric acid derivatives from 2-aminothiazoline and diethyl malonate.
It has been described that such compounds can have hypnotic and anesthetic effects. There is no mention of any medicinal effects other than hypnotic and anesthetic effects. Therefore, the present inventors developed a novel thiazolo[3,2-
a] As a result of producing pyrimidine derivatives and conducting detailed studies on the medicinal effects of these new compounds on various disease models in animals, it was surprisingly found that these compounds have extremely superior pharmacological effects that are completely different from hypnotic and anesthetic effects. The inventors have discovered that the present invention is a compound that has an anti-inflammatory effect and can also have an immunomodulatory effect, and is extremely useful as a drug having anti-inflammatory and immunomodulatory effects. That is, the present invention provides the following formula [] In the formula, R is an alicyclic group substituted or unsubstituted by an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. It represents a substituted phenyl group, or an aralkyl group substituted or unsubstituted with any one of a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, and an amide group. Thiazolo[3,2-a]pyrimidine derivatives represented by and the following formula [] In the formula, R is an alicyclic group substituted or unsubstituted by an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. It represents a substituted phenyl group, or an aralkyl group substituted or unsubstituted with any one of a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, and an amide group. The following formula [] is characterized by subjecting a compound represented by to a heating cyclization reaction. [The definition of R in the formula is the same as in the above formula []. The present invention provides a method for producing a thiazolo[3,2-a]pyrimidine derivative represented by the above formula [], and an antiinflammatory agent containing the thiazolo[3,2-a]pyrimidine derivative represented by the above formula [] as an antiinflammatory active ingredient. In the present invention, R of the thiazolo[3,2-a]pyrimidine derivative represented by the above formula [] is an alicyclic group substituted or unsubstituted with an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group,
A phenyl group substituted or unsubstituted with an alkyloxy group, a nitro group, a hydroxyl group, or an amide group, or a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. Represents a substituted or unsubstituted aralkyl group. Examples of substituted or unsubstituted alicyclic groups include cyclopropyl, cyclobutyl, cyclopentyl,
Examples include cyclohexyl, cycloheptyl, 2-methylcyclopropyl and the like. Substituted or unsubstituted phenyl groups include, for example, phenyl groups or P-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-bromphenyl, m-bromphenyl. , a phenyl group having a halogen atom as a substituent such as o-bromphenyl, a phenyl group having an alkyl group as a substituent such as p-tolyl, o-tolyl, o-ethylphenyl, m-isopropylphenyl, p-butylphenyl, etc. Phenyl groups having an alkanoyloxy group as a substituent such as o-formyloxyphenyl, o-acetoxyphenyl, m-propanoyloxyphenyl, o-methoxyphenyl, p-ethoxyphenyl, m-propoxyphenyl A phenyl group having an alkyloxy group as a substituent, p-nitrophenyl group, p-hydroxyphenyl group, p-formamidophenyl group, o-acetamidophenyl group, and the like. Examples of the substituted or unsubstituted aralkyl group include benzyl group, p-chlorobenzyl, o-
A benzyl group having a halogen atom as a substituent such as chlorobenzyl, m-chlorobenzyl, p-fluorobenzyl, o-fluorobenzyl, m-fluorobenzyl, p-bromobenzyl, m-bromobenzyl, o-bromobenzyl, p -A benzyl group having an alkyl group such as methylbenzyl, o-ethylbenzyl, m-isopropylbenzyl as a substituent, or an alkanoyloxy group such as o-formyloxybenzyl, o-acetoxybenzyl, m-propanoyloxybenzyl as a substituent a benzyl group having as a substituent an alkyloxy group such as o-methoxybenzyl, p-ethoxybenzyl, m-propoxybenzyl, or a p-nitrobenzyl group, p-hydroxybenzyl group, p-formamidobenzyl group ,o
-acetamidobenzyl group or phenethyl group,
Alternatively, phenethyl groups having a halogen atom as a substituent such as p-chlorophenethyl, o-chlorophenethyl, p-fluorophenethyl, o-fluorophenethyl, p-bromphenethyl, m-bromphenethyl, etc. can be mentioned. Among these, preferred as R are phenyl group, benzyl group, or p-chlorophenyl,
o-chlorphenyl, m-chlorphenyl, p-
Chlorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-fluorobenzyl, o-fluorobenzyl, m-fluorobenzyl, p-bromphenyl, Phenyl group or benzyl group having a halogen atom as a substituent such as m-bromphenyl, o-bromphenyl, p-bromobenzyl, m-bromobenzyl, o-bromobenzyl, phenethyl group, p-chromephenethyl, o-chlorophenethyl, p- A phenethyl group such as fluorophenethyl, o-fluorophenethyl, p-bromphenethyl, m-bromphenethyl, a phenethyl group having a halogen atom as a substituent, or a cyclohexyl group. In particular, phenyl groups, benzyl groups, or p-chlorophenyl, o-chlorophenyl, p-chlorobenzyl, o-chlorobenzyl, p-fluorophenyl, m-fluorophenyl, p-fluorobenzyl, m-fluorobenzyl, p- A phenyl group or a benzyl group having a halogen atom as a substituent such as bromphenyl or p-bromobenzyl is preferable, and a phenyl group, a benzyl group, or a p-bromobenzyl group is preferable.
Chlorphenyl or chlorobenzyl groups such as -chlorophenyl, o-chlorophenyl, p-chlorobenzyl, a-chlorobenzyl, etc. are particularly preferred. Specific examples of such preferable compounds include the following. That is, for example, 6-phenyl-5H-6,7-dihydro-5,
7-Dioxothiazolo[3,2-a]pyrimidine, 6-p-chlorophenyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]
Pyrimidine, 6-o-chlorophenyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]
Pyrimidine, 6-m-chlorophenyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]
Pyrimidine, 6-benzyl-5H-6,7-dihydro-5,
7-dioxothiazolo[3,2-a]pyrimidine, 6-p-chlorobenzyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]
Pyrimidine, 6-o-chlorobenzyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]
Pyrimidine, 6-m-chlorobenzyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]
Such as pyrimidine. Note that such thiazolo[3,2-a]pyrimidine derivatives may be in the enol form, and even in the enol form, they have similar pharmacological effects. As mentioned above, the thiazolo[3,2-a]pyrimidine derivative has the following formula [] In the formula, R is an alicyclic group substituted or unsubstituted by an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. It represents a substituted phenyl group, or an aralkyl group substituted or unsubstituted with any one of a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, and an amide group. It is produced by subjecting the compound represented by to a heating cyclization reaction. Here, R in the above formula [] is the same as R in the above formula [] as described above. R ¹ is a halogen atom such as bromine, iodine, chlorine,
Alternatively, it represents a lower alkyloxy group such as methyloxy, ethyloxy, propyloxy, etc., with methyloxy and ethyloxy being particularly preferred. When heating and cyclizing the compound represented by the above formula [], a solvent may be used or the reaction may be carried out without a solvent. When using a solvent, any solvent may be used as long as it does not react with the compound represented by the above formula [], and examples of such solvents include toluene, xylene, cumene, cymene, tetralin, decalin, Examples include diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, diphenyl ether, dimethyl sulfoxide, dimethyl formamide, nitrobenzene, and the like. The amount of the solvent used is usually in the range of 1 to 1000 times the mole of the raw material. Reaction temperature and reaction time depend on starting materials, presence or absence of solvent,
Depends on the solvent used, but usually 80-320℃
By reacting for 1 minute to 48 hours, the desired thiazolo[3,2-a]pyrimidine derivative can be obtained. In particular, the reaction temperature and reaction time are 100~
A range of 10 minutes to 24 hours at 300°C is preferred. Further, the compound represented by the above formula [] may be obtained by any method, and such a compound may be, for example, the compound represented by the following formula [] 2-aminothiazole represented by and the following formula [] In the formula, R is an alicyclic group substituted or unsubstituted by an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. It represents a substituted phenyl group, or an aralkyl group substituted or unsubstituted with any one of a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, and an amide group. It can be easily obtained by carrying out a heating reaction with a compound represented by Here, R in the above formula [] is the same as R in the above formula [], and R ¹ is the above formula []
is similar to R ¹ . Further, such heating reaction may be carried out using a solvent or without a solvent. When using a solvent, the same solvent and the same amount can be used as the solvent used in the heating cyclization reaction of the compound represented by the formula [] described above. The reaction time and reaction temperature are also selected to be approximately the same as in the case of obtaining the above formula []. In addition, in order to obtain the thiazolo[3,2-a]pyrimidine derivative of the present invention, the compound represented by the above formula [] is heated to react with the compound represented by the above formula [] to obtain the compound represented by the above formula []. The thiazolo[3,2-a]pyrimidine derivative of the present invention can also be produced by subsequently subjecting the compound represented by the formula [] to a heating reaction without isolating it. Thus, according to the present invention, the following formula [] [In the formula, the definition of R is the same as in the above formula []. ] A novel thiazolo[3,2-a]pyrimidine derivative represented by the formula is obtained, and such a compound has an extremely excellent anti-inflammatory effect and may also have an immunomodulatory effect, making it extremely useful as a drug. It is a compound. The thiazolo [3,2-
a] The anti-inflammatory action of the pyrimidine derivatives was measured using the carrageenan edema method. That is, using SD male rats, 5% of the thiazolo[3,2-a]pyrimidine derivative of the present invention was used.
The gum arabic suspension was orally administered to the SD male rats, and 1 hour later, 0.1 ml of 1% carrageenan was injected into the epidermis of the rat's right paw to induce inflammation. , the edema rate was determined, and the control group, ie, thiazolo[3,2-
a] Calculate the edema suppression rate compared to the case of a 5% gum arabic suspension containing no pyrimidine derivative,
The anti-inflammatory action of thiazolo[3,2-a]pyrimidine derivatives was measured. The effective amount of the thiazolo[3,2-a]pyrimidine derivative varies depending on the administration method, but is preferably
The range is 0.1 to 50 mg/Kg, more preferably 1 to 20 mg. The dosage form may be oral dosage forms such as tablets, capsules, powders, or granules, or suppositories, liquids, ointments, or injections such as intravenous injections or intramuscular injections, depending on the pathology and site of manifestation. Selected appropriately. Among these, oral dosage forms are particularly preferred from the viewpoint of ease of use and safety. When preparing these dosage forms, for example, in the case of injections, distilled water for injection, buffer solution, etc. may be added and sterilized, and in the case of tablets, binders, kneading agents, etc. Each dosage form can be prepared according to general formulation methods such as granulation and tabletting operations. A drug containing the thiazolo[3,2-a]pyrimidine derivative prepared in this manner is extremely useful as a drug having anti-inflammatory effects such as anti-inflammatory, antipyretic, and analgesic effects, and also has immunomodulatory effects. The present invention will be explained in more detail below using Examples. Example 1 Ethyl α-(thiazol-2-ylcarbamoyl)phenyl acetate (2.40 g) was added without solvent under a nitrogen stream.
Heated to 180°C for 1.5 hours. After cooling the reaction product to room temperature, the resulting solid was suspended in ether and the precipitated crystals were collected to obtain the desired 5H-6,7.
-dihydro-5,7-dioxo-6-phenyl-
0.98 g (yield: 49%) of thiazolo[3,2-a]pyrimidine was obtained. The physical properties of this material are as follows. Melting point (mp); 255℃ ~ 256.5℃ IR (KBr) cm ^-1 ; 3100 ~ 2300 (enol),
1651, 1524, 1417, 1350, 1152, 715, 697 S from NMR (DMSO-d ₆ ) TMS; 7.5 (7H, m) 7.98 (1H, d, J = 5
Hz) Example 2 A mixture of 2-aminothiazole (1.0 g) and diethyl microhexylmalonate (2.42 g) was reacted by heating at 180° C. for 1 hour under a nitrogen stream. After the reaction, the solid product obtained by cooling to room temperature was subjected to silica gel column chromatography and eluted with ethyl acetate-benzene (1:9). 1.25 g (yield: 42%) of ethyl (carbamoyl)acetate was obtained. The physical properties of this material are as follows. Melting point (mp) 141-142℃ IR (KBr) cm ^-1 ; 2860, 1718, 1690, 1570,
1241, 1175, 1022 S from NMR (CDCl ₃ ) TMS; 1.26 (3H t J = 7Hz) 1.3-1.8
(11H, m), 3.30 (1Hd, J=9Hz), 4.25
(2H, tJ=7Hz), 7.06 (1H, d, J=4
Hz, 7.63 (1H, d, J = 4Hz, 8.5 (1H,
br) Above, α-cyclohexyl-α-(thiazo-2
-ylcarbamoyl)ethyl acetate (1.25g),
The mixture was added to diphenyl ether (6 ml) which had been heated to reflux in advance, and the reaction was further heated for 10 minutes.
The resulting reaction product was allowed to cool to room temperature, and the precipitated crystals were collected and washed with hexane to obtain the desired 6
-Cyclohexyl-5H-6.7-dihydro-5.7-dioxothiazolo[3,2-α]pyrimidine 0.88g
I got it. The physical properties of this material are as follows. Melting point (mp); 243-245℃ IR (KBr) cm ^-1 ; 3200-2500 (enol)
1660, 1520, 1431, 1308, 710 S from NMR (DMSO- _d6 ) TMS; 1.2-2.0 (10H, m) 2.7 (1H, m),
7.30 (1H, d, J=5Hz) 7.95 (1H,
d, J = 5 Hz) 10.3 (disappeared with 1H, brS, D ₂ O) Example 3 A mixture of 2-aminothiazole (1.0 g) and diethyl p-chlorophenylmalonate (3.0 g) was heated to 180°C. The reaction was heated for 40 minutes. After cooling the resulting reaction product to room temperature, ether (30 ml) was added, the precipitated crystals were collected, and the desired 6
1.7 g (yield: 64%) of -p-chlorophenyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]pyrimidine was obtained. The physical properties of this material are as follows. Melting point (mp); 280-282℃ IR (KBr) cm ^-1 ; 3100-2300 (enol),
1650, 1585, 1550, 1523, 1430, 1393,
1352, 1153, 1046, 721 S from NMR (DMSO-d ₆ ) TMS; 7, 40
(1H, d, J=4Hz) 7.50 (4H, m),
8.00 (1H, d, J=4Hz) 11.00 (1H,
br) Example 4 A mixture of 2-aminothiazole (1.0 g) and diethyl p-chlorobenzylmalonate (3.0 g) was reacted by heating at 180° C. for 1.5 hours under a nitrogen stream. The resulting reaction product was subjected to silica gel column chromatography, eluted with chloroform, and α-
(p-chlorobenzyl)-α-(thiazol-2-ylcarbamoyl)ethyl acetate 1.86 g (yield: 48
%) was obtained. The physical properties of this material are as follows. Melting point (mp); 95.5-96℃ IR (KBr) cm ^-1 ; 3170, 1730, 1680, 1570,
1240, 1170, 805 NMR (CDCl ₃ ) S from TMS; 1.13 (3H,
t, J = 7Hz) 3.30 (1H, d, J = 9
Hz) 3.30 (1H, d, J=7Hz) 3.76
(1H, dd, J=7Hz, 4.15 (2H, g, J=
7Hz) 7.02 (1H, d, J=4Hz) 7.18
(4H, m) 7.50 (1H, d, J=4Hz)
7.7 (1H, br, N-H) Above, α-(p-chlorobenzyl)-α-(thiazol-2-ylcarbamoyl)ethyl acetate (1.7
Diphenyl ether (7 ml) was added to g), and the mixture was reacted by heating at 210 to 220°C for 1 hour under a nitrogen stream. The resulting reaction product was subjected to silica gel column chromatography and chloroform-methanol (98:2)
The target is elution. 0.98 g (yield: 65%) of 6-(p-chlorobenzyl)-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]pyrimidine was obtained. The physical properties of this material are as follows. Melting point (mp); 261-262.8℃ IR (KBr) cm ^-1 ; 3200-2300 (enol)
1665, 1600, 1528, 1445, 1350, 1300,
1210, 1090 NMR (DMSO-d ₆ ) S from TMS; 3.67
(2H, S) 7.29 (4H, S) 7.40 (1H,
d, J=5Hz) 7.93(1H, d, J=5
Hz) 11.9 (disappeared by 1H, br, D ₂ O) Example 5 A mixture of 2-aminothiazole (1.0 g) and diethyl O-chlorobenzylmalonate (3 g) was heated to 180°C under a nitrogen stream for 1.5 hours. I forced it. The resulting oily product was dissolved in diphenyl ether (8 ml).
In addition, the reaction mixture was further heated at 220° C. for 2 hours under a nitrogen stream. After cooling the resulting reaction product to room temperature, it was subjected to silica gel column chromatography and eluted with chloroform-methanol (96:4) to obtain the desired 6-(O-chlorobenzyl)-5H-6,
7-dihydro-5,7-dioxothiazolo[3,
2-a] 0.69 mg (yield: 20%) of pyrimidine was obtained. The physical properties of this material are as follows. Melting point (mp); 2435-246℃ IR (KBr) cm ^-1 ; 3200-2300 (enol)
1660, 1602, 1518, 1445, 1351, 1298,
1213, 1098, 758 NMR (DMSO-d ₆ ) S from TMS; 3.80
(2H, S) 7.25 (4H, m) 7.49 (1H,
d, J=5Hz) 8.01 (1H, d, J=5
Hz) Example 6 A mixture of 2-aminothiazole (1.0 g) and diethyl phenethylmalonate (3.0 g) was reacted by heating at 170° C. for 1.5 hours under a nitrogen stream. The resulting reaction product was subjected to silica gel column chromatography and eluted with chloroform-methanol (98:2) to obtain 1.51 g of ethyl α-phenethyl-α-(thiazo-2-ylcarbamoyl)acetate (yield: 47
%) was obtained. The physical properties of this material are as follows. Melting point (mp); 86-88.5℃ IR (KBr) cm ^-1 ; 1725, 1682, 1565, 1350,
1260, 1230, 1171, 1157, 1030, 712 S from NMR (CDCl ₃ ) TMS; 1.16 (3H,
t, J=7Hz) 2.5 (4H, m) 3.45
(1H, t, J = 7Hz) 4.13 (2H, d, J
=7Hz) 6.90 (1H, d, J = 4Hz)
7.13 (6H, S) 7.19 (1H, d, J=4
Hz) The above α-phenethyl-α-(thiazol-2-ylcarbamoyl)ethyl acetate (1.5 g) was dissolved in diphenyl ether (8 ml) and heated at 220°C under a nitrogen stream.
The mixture was heated and reacted for 2 hours. The resulting reaction product was subjected to silica gel column chromatography and eluted with chloroform-methanol (96:4) to obtain the desired 5H-6,7-dihydro-5,7-dioxo-6-phenethyl-thiazolo [ 0.80 g (yield: 62%) of 3,2-a]pyrimidine was obtained. The physical properties of this material are as follows. Melting point (mp); 260-261.5℃ IR (KBr) cm ^-1 ; 3200-2300 (enol)
1640, 1610, 1565, 1501, 1490, 1414,
1300, 1160, 1090, 700 NMR (DMSO-d ₆ ) S from TMS; 2.67
(4H, S) 7.24 (5H, br, S) 7.38
(1H, d, J = 5Hz) 7.92 (1H, d, J
= 5 Hz) Example 7 Using SD male rats (5 weeks old), 4 rats per group, the compounds listed in Table 1 were used as test drugs,
A drug prepared by dissolving 25 mg of the test drug in 5 ml of a 5% aqueous gum arabic solution was prepared using the above SD.
A dose of 25 mg/Kg was orally administered to male rats, and 1 hour later, 0.1 ml of 1% carrageenan was injected into the right footpad of the rats to induce inflammation. The edema rate was determined, and the edema suppression rate was calculated in comparison with a control group, that is, a 5% gum arabic suspension containing no test drug. The results are shown in Table 1.

[Manufacture of tablets]

Tablets suitable for enteral administration containing the following ingredients were manufactured in a conventional manner. Ingredients Weight 6-phenyl-5H-6,7-dihydro-5,
7-Dioxothiazolo[3,2-a]pyrimidine 30mg Lactose 69.05mg Corn starch 14mg Polyvinylpyrrolidone 5mg Magnesium stearate 0.7mg Talc 1.2mg Coloring agent 0.05/120mg Example 9 [Manufacture of capsules] The following suitable for enteral administration Hard gelatin capsules containing the following ingredients were prepared in a conventional manner. Ingredient Weight 6-p-chlorobenzyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-
a] Pyrimidine 30 mg Lactose 78 mg Corn starch 20 mg Talc 4.5 mg Magnesium stearate 1.5 mg Coloring agent if necessary Sufficient amount/135 mg Example 10 [Manufacturing of suppositories] Suppositories containing the following ingredients were manufactured in the usual manner. did. Ingredients Weight 6-benzyl-5H-6,7-dihydro-5,
7-dioxothiazolo[3,2-a]pyrimidine 30mg Cocoa butter Sufficient amount/1.5g Example 11 [Manufacture of intra-articular injection] An intra-articular injection containing the following ingredients was manufactured in a conventional manner. Ingredients Weight 6-phenyl-5H-6,7-dihydro-5,
7-dioxothiazolo[3,2-a]pyrimidine 10 mg Buffer to adjust PH to desired stability Sufficient water Water Enough for 1.5 ml for injection Example 12 2-Aminothiazole (1.0 g) and p-methyl After heating the mixture with diethyl benzylmalonate (2.6 g) at 180°C under a nitrogen stream for 1.5 hours, phenyl ether (10 ml) was added, and the heating reaction was continued for an additional 1.5 hours at 220°C under a nitrogen stream. Ta. The reaction product was subjected to silica gel chromatography and eluted with chloroform-methanol (98:2) to obtain the desired 5H-6,7-dihydro-6-
p-Methylbenzyl-5,7-thiazolo [3.2-
a] 0.8 g (yield 29%) of pyrimidine was obtained. The physical properties of this material are as follows. Melting point (mp); 268-269℃ IR (ν ^KBr _nax ); 3400-2600 (enol type),
1653, 1595, 1550, 1515, 1445, 1345,
1293, 1208, 1090, 777, 758, 741,
721cm ^-1 NMR (δ ^DMSO-d6 _TMS ); 2.25 (3H, S), 3.75 (2H, S), 7.0 to 7.4
(4H, m), 7.51 (1H, d, J=5Hz),
8.08 (1H, d, J = 5Hz), 11.3 (1H,
br) Example 13 In the same manner as in Example 12, 5H-6,7-dihydro-6-P-methoxybenzyl-5,7-dioxothiazolo[3,2-a]pyrimidine was obtained. Yield: 19% Melting point (mp): 243-244°C IR (ν ^KBr _nax ): 3430-2650 (enol type),
1653, 1600, 1500, 1450, 1350, 1290,
1240, 1208, 1120, 1088, 1037, 748,
728cm ^-1 NMR (δ ^DMSO-d6 _TMS ); 3.70 (2H, S), 386 (3H, S), 6.6-7.2
(4H, m), 7.45 (1H, d, J=5Hz),
7.98 (1H, d, J=5Hz), 11.4~12.0
(Disappeared with 1H, br, D ₂ O) Example 14 5H-6,7-dihydro-6-P-methoxybenzyl-5,7-dioxothiazolo[3,2-a] Pyrimidine was obtained. Yield: 47% Melting point (mp): 258-260°C IR (ν ^KBr _nax ): 3400-2650 (enol type),
1645, 1592, 1517, 1504, 1440, 1345,
1294, 1240, 1112, 1088, 1020, 800,
720cm ^-1 NMR (δ ^DMSO-d6 _TMS ); 3.59 (2H, S), 3.66 (3H, S), 6.74
(2H, d, J = 9Hz), 7.18 (2H, d, J
= 9Hz), 7.38 (1H, d, J = 5Hz), 7.92
(1H, d, J=5Hz), 11.8 (1H, br,
Example 15 In the same manner as in Example ₁₂ , 6-p-fluorobenzyl-5H-6,7-dihydro-5,7-dioxothiazolo[3,2-a]pyrimidine was obtained. Yield: 17% Melting point [mp]: 259.5-261.5°C IR (ν ^KBr _nax ): 3400 (enol type), 1652,
1597, 1520, 1503, 1450, 1212, 1097,
785, 720 cm ^-1 NMR (δ ^DMSO-d6 _TMS ); 3.54 (2H, S), 6.7-7.3 (4H, m), 7.32
(1H, d, J = 5Hz), 7.86 (1H, d, J
= 5 Hz), 11.8 (disappeared with 1H, br, D ₂ O) Example 16 In the same manner as in Example 12, 5H-6,7-dihydro-6-P-methoxyphenyl-5,7-dioxothiazolo[ 3,2-a]pyrimidine was obtained. Yield: 11% Melting point (mp): 269.5-271.5°C IR (ν ^KBr _nax ): 3350-2900 (enol type),
1648, 1580, 1506, 1422, 1402, 1346,
1245, 1020, 822, 810, 745, 728 cm ^-1 NMR (δ ^DMSO-d6 _TMS ); 3.82 (2H, S), 6.99 (2H, d, J = 9
Hz), 7.3-7.7 (3H, m), 8.08 (1H, d,
J=5Hz), 11-12 (disappeared with 1H, br, _D2O ) Example 17 In the same manner as in Example 12, 5H-6,7-dihydro-6-O-methoxyphenyl-5,7 -Dioxothiazolo[3,2-a]pyrimidine was obtained. Yield: 43% Melting point (mp): 248-249°C IR (ν ^KBr _nax ): 3400-2630 (enol type),
1650, 1590, 1546, 1511, 1423, 1345,
1240, 1198, 1152, 1033, 743, 728,
712cm ^-1 NMR (δ ^DMSO-d6 _TMS ); 3.75 (3H, S), 6.9-7.5 (4H, m), 7.53
(1H, d, J = 5Hz), 8.09 (1H, d, J
= 5Hz), 11.6 (disappeared with 1H, S, D ₂ O)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R is substituted with an alicyclic group substituted or unsubstituted with an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. or an unsubstituted phenyl group, or an aralkyl group substituted or unsubstituted with any one of a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, and an amide group. ] A thiazolo[3,2-a]pyrimidine derivative represented by: 2. The thiazolo[3,2- a] Pyrimidine derivative. 3. The thiazolo[3,2-a]pyrimidine derivative according to claim 1, wherein in the above formula [], R is a phenyl group, a chlorphenyl group, a benzyl group, or a chlorobenzyl group. 4 The following formula [] [In the formula, R is substituted with an alicyclic group substituted or unsubstituted with an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. or an unsubstituted phenyl group, or an aralkyl group substituted or unsubstituted with any of a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, and an amide group, and R ¹ is a halogen Represents an atom or a lower alkyloxy group. ] The following formula [] is characterized by subjecting a compound represented by to a heating cyclization reaction. A method for producing a thiazolo[3,2-a]pyrimidine derivative represented by [wherein the definition of R is the same as in the above formula]. 5. The method for producing a thiazolo[3,2-a]pyrimidine derivative according to claim 4, wherein R ¹ in the above formula [] is a lower alkyloxy group. 6 The thiazolo[3,2] according to claim 4, wherein R in the above formula [] is a phenyl group, a benzyl group, a phenyl group having a halogen atom as a substituent, a benzyl group, a phenethyl group, or a cyclohexyl group. -a] Method for producing a pyridine derivative. 7. The method for producing a thiazolo[32-a]pyrimidine derivative according to claim 4, wherein R in the above formula [] is a phenyl group, a chlorphenyl group, a benzyl group, or a chlorobenzyl group. 8 The following formula [] [In the formula, R is substituted with an alicyclic group substituted or unsubstituted with an alkyl group, a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, or an amide group. or an unsubstituted phenyl group, or an aralkyl group substituted or unsubstituted with any one of a halogen atom, an alkyl group, an alkanoyloxy group, an alkyloxy group, a nitro group, a hydroxyl group, and an amide group. ] An anti-inflammatory agent containing a thiazolo[32-a]pyrimidine derivative represented by the following as an anti-inflammatory active ingredient.