JPH0441151B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel pyridopyrimidine derivatives having antibacterial activity. For more details, see the general formula (1) below. [In the formula, A represents alkylene having 1 to 5 carbon atoms. The alkylene may contain an unsaturated bond in the middle, and the alkylene may have as a substituent,
Lower alkyl, hydroxy, substituted or unsubstituted phenyl, alkoxy, substituted or unsubstituted phenoxy, alkylthio, substituted or unsubstituted phenylthio, halogen, halogen-substituted alkyl, amino-substituted alkyl, alkoxycarbonyl-substituted alkyl, carboxy-substituted alkyl, alkoxy substituted alkyl, alkylthio substituted alkyl,
May have hydroxy-substituted alkyl, acyloxy-substituted alkyl, furkylamino, substituted or unsubstituted phenylamino, carboxy, nitro, or cyano, and may have carbonyl, thiocarbonyl, or imino in the chain . As the most common,

【formula】 【formula】

【formula】

[Formula] etc. can be mentioned. R ¹ represents alkylthio or a heterocyclic compound residue containing 1 to 3 of 1 to 2 of O, N, or S. R ² represents hydrogen, lithium, sodium, potassium, calcium, methyl, ethyl, bivaloyloxysimethyl, or phthalidyl. ] The present invention relates to the compounds shown in (1) or their pharmacologically acceptable salts, their production methods, and antibacterial agents containing them as main ingredients. Currently, nalidixic acid, pyromidic acid, and pipemidic acid are widely used as synthetic antibacterial agents to treat infections caused by Gram-negative bacteria. However, these agents do not show satisfactory effects on the treatment of Pseudomonas aeruginosa infections and Gram-positive bacterial infections, which have been increasing in recent years and are intractable diseases. To improve this point, various compounds have been synthesized and their antibacterial activity against various bacteria has been investigated. As an improved version of existing synthetic antibacterial agents, 6-halogeno-1-substituted-7-(4-substituted piperazino)-4-oxo-1,
4-dihydroquinoline-3-carboxylic acid derivatives (JP-A-53-65887, JP-A-53-141286, JP-A-54-66686, JP-A-55-47658), 6 -Fluoro-1,8-naphthyridine derivatives (JP-A-55-83785) and the like are already known. Among the known synthetic antibacterial agents, quinoline carboxylic acid derivatives having a substituent at the 2-position, 1,8
- Naphthyridine derivatives, pyridopyrimidine derivatives are not included. Journal of Medicinal Chemistry vol. 20, 791 (1977), vol. 21,
485 (1978), and Journal of Heterocyclic Chemistry Vol. 17, 1729 (1980).
There are descriptions of compounds having a methyl group or hydroxyl group at the 2-position, and compounds in which nitrogen atoms at the 2- and 1-positions are fused, but none of them have any noteworthy antibacterial activity. In order to find a compound with antibacterial activity among these compounds having a substituent at the 2-position, the present inventors developed a compound (1) with an unknown and completely new skeleton.
Fortunately, when we synthesized and examined its antibacterial activity, we found that
We discovered that these compounds have excellent antibacterial activity not found in known synthetic antibacterial agents, and based on this we completed the present invention. Compound (1) according to the present invention has a strong antibacterial effect not seen in previous literature against both Gram-negative bacteria and Gram-positive bacteria, as well as Pseudomonas aeruginosa. The compound according to the present invention is
Also available as an oral agent for the prevention and treatment of infectious diseases.
It can also be safely administered to humans as an injection. These can also be safely administered to a wide range of animals. An example of the method for producing the compound of the present invention will be explained using a reaction formula. 5-, which is a very important intermediate in the present invention
Hydroxy-7-thioxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester derivative (7) can be synthesized, for example, by the following reaction route. That is, substituted pyrimidine-5-carboxylic acid (2)
(In the formula, R ₃ represents lower alkyl) When the magnesium salt of diethyl malonate is reacted with the mixed acid anhydride, compound (3) (in the formula, R ³ and R ⁴ represent lower alkyl) is obtained. be able to. This reaction is generally carried out using a suitable inert solvent (e.g. tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ether, benzene, toluene, xylene).
In the presence of a suitable base catalyst (for example, triethylamine and various other amines, or various alkalis such as sodium carbonate and potassium carbonate), a slight excess of alkyl chlorocarbonate was added under cold conditions (from -20 to
0°C, preferably -10 to -5°C) to form a mixed acid anhydride of compound (2), and then reacted with magnesium salt of diethyl malonate at 0°C to room temperature for several hours. Bye. The obtained compound (3) can be easily isolated and purified by known processing means (eg, extraction, concentration, recrystallization, chromatography). Then, by ring-closing compound (3), pyridopyrimidine-derived pair (4) (wherein R ³ and R ⁴ are the same as above) can be obtained. This reaction is generally carried out using a suitable base catalyst (e.g. hydrogen 0 to 200 using 2 equivalents of various alkalis such as sodium chloride, sodium amide, etc.
C. for 1 to 10 hours. The obtained compound (4) can be isolated and purified by the above-mentioned known methods. Compound (4)
is then treated with a reagent represented by the general formula R ⁶ -Y (wherein R ⁶ represents lower alkyl, benzyl, or benzhydrin, and Y represents halogen),
This leads to compound (5) (in the formula, R ³ , R ⁴ , and R ⁶ are the same as above). This reaction is generally carried out in a suitable solvent (e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, dioxane, glyme, acetone).
In the presence of a suitable base catalyst (for example, various alkalis such as sodium carbonate and potassium carbonate), the above halide is used in an equimolar amount to a large excess amount, preferably 2 to 5 times the amount of compound (4). , room temperature ~200
The reaction may be carried out by reacting at a temperature of 1 to 10 hours. The obtained compound (5) can be isolated and purified by the above-mentioned known methods. If compound (5) is then treated with phosphorus pentasulfide, thione compound (6) (wherein R ³ , R ⁴ and R ⁶ are the same as above) can be obtained. In general, this reaction is carried out by heating under reflux for several hours in a suitable inert solvent (e.g. benzene, toluene, xylene) and adding phosphorus pentasulfide in an equimolar amount to a large excess amount, preferably 1 molar amount to compound (5). It may be carried out using ~1.5 times the amount. The obtained compound (6) can be isolated and purified by the above-mentioned known methods, but it may also be used in its crude form as a raw material for the next reaction. Compound (6) is then dealkylated to yield the very important intermediate of interest, compound (7) (in the formula R ³
and R ⁴ are the same as above) can be obtained. This reaction is generally carried out at -70 to -10°C, preferably -
At 15 to -40°C, add an appropriate acidic substance (for example, trifluoromethanesulfonic acid, trifluoroacetic acid, methanesulfonic acid, or a mixture thereof) to compound (6) in an amount of 1 to 100 times, preferably 30
It may be carried out using ~50 times the amount. The obtained compound (7) can be isolated and purified by the above-mentioned known methods. If compound (7), which is an important intermediate, is reacted with a dihalide represented by general formula (12) (in the formula, Y represents a halogen and B represents a methylene chain which may have a substituent), , tricyclic compound (8)
(wherein R ³ and R ⁴ are the same as above) can be obtained. The reaction is generally carried out using a suitable base catalyst (e.g.,
In the presence of various alkalis such as sodium carbonate and potassium carbonate, or various amines such as triethylamine, the dihalide is added in an equimolar amount to several times the amount of compound (7), preferably 1.5 to several times, at room temperature to 200°C for several hours. It may be carried out using three times the amount. The obtained compound (8) can be isolated and purified by the above-mentioned known method. Compound (9) (wherein R ³ is the same as above) is then obtained by hydrolyzing compound (8). This reaction is generally carried out using an appropriate acid (e.g., sulfuric acid, hydrochloric acid, nitric acid) or an appropriate base (e.g., various alkalis such as sodium hydroxide, potassium hydroxide, etc.) for several hours to several tens of hours. It may be carried out by a method of processing at a temperature of 150°C to 150°C. The obtained compound (9) can be isolated and purified by the above-mentioned known method. On the other hand, compound (7) has general formula (13) (wherein R ⁵
is hydrogen, lower alkyl, halogen-substituted alkyl,
Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxy, substituted or unsubstituted phenoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted phenylthio, or other items such as tetrazole or thiazole It represents a thio compound having a ring, Z represents oxygen or alkoxy, and Y represents halogen. ), the compound (10) (in the formula,
R ³ , R ⁴ and R ⁵ are the same as above. ) can be obtained. The reaction is generally carried out using a suitable base catalyst (e.g.,
In the presence of various alkalis such as sodium carbonate and potassium carbonate, or various amines such as triethylamine) at 0°C to 200°C for 2 to 500 hours, the halide is added in an equimolar amount to 10 times the amount of compound (7), preferably. may be carried out using 1.2 to 3.0 times the amount. The obtained compound (10) is isolated by the above-mentioned known method,
Can be purified. Next, by ring-closing compound (10), compound (11) having an unsaturated bond in the third ring (in the formula R ³ , R ⁵
is the same as above. ) can be obtained. This reaction is
Generally, the treatment may be carried out using a suitable acid (for example, sulfuric acid, hydrochloric acid, nitric acid) at 0°C to 200°C for several minutes to several hours. The obtained compound (11) can be isolated and purified by the above-mentioned known methods. Rather, it is also possible to lead to compound (11) from compound (5) without passing through compound (7). That is, a crude compound (6) obtained by reacting compound (5) with phosphorus pentasulfide (in the formula, R ³ ,
R ⁴ and R ⁶ are the same as above. ) to compound (13) (wherein,
R ⁵ , Z, and Y are the same as above. ) is reacted to obtain compound (14) (wherein R ⁴ , R ⁵ and R ⁶ are the same as above). This reaction is generally carried out using a suitable base catalyst (for example, various alkalis such as sodium carbonate, potassium carbonate, or various amines such as triethylamine) at room temperature to 200°C for several hours.
Equimolar amount of halide to compound (6) ~
It may be carried out using 10 times the amount, preferably 1.2 to 3.0 times the amount. The obtained compound (14) can be isolated and purified by the above-mentioned known methods. If this compound (14) is then treated with a mineral acid, compound (11) (in the formula
R ³ and R ⁴ are the same as above. ) is obtained. This reaction is
Generally, the treatment may be carried out using a suitable acid (for example, sulfuric acid, hydrochloric acid, nitric acid) at 0°C to 200°C for several minutes to several hours. Compounds (9) and (11) (very general formula (15)
It is expressed as R ³ and A in the formula are the same as above. ) to monocyclic amines (e.g. morpholine, thiomorpholine, N'-substituted piperazine, N'-protected piperazine)
Compound (16) can be obtained by reacting with This reaction is generally carried out using a suitable inert solvent (e.g. dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile).
The reaction may be carried out at 0° C. to 250° C. using an excess amount of monocyclic amine, or in the absence of a solvent, for several minutes to several hours. Among the compounds obtained, N'-protected piperazinyl derivatives, such as N'-ethoxycarbonylpiperazinyl derivatives, can be prepared by known methods (for example, in acetic acid,
The desired piperazinyl derivative can be obtained by treatment with hydrobromic acid or with an alkali such as sodium hydroxide or potassium hydroxide.
The resulting compound (16) (wherein R ¹ is the same as above)
can be isolated and purified by the above-mentioned known methods. Furthermore, compound (16) can be converted into a suitable ester or a pharmacologically acceptable salt by a known method to form a compound of the general formula (1) (wherein R ¹ ,
R ² and A are the same as above. ) can lead to the compound shown in (Compound (1) contains compound (16).) The compound represented by the general formula (1) thus obtained is oxidized by a known method to obtain
This can lead to the corresponding sulfoxides and sulfones. Furthermore, the corresponding sulfylimine or sulfoximine can be derived by a known method. As described above, the compound represented by the general formula (1) and its salt can be produced with high yield and at low cost. Examples of the compounds of the present invention produced by the method described above include the following compounds. 8-Methylthio-5-oxo-1,2-dihydro-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid, 8
-(4-methyl-1-piperazinyl)-5-oxo-1,2-dihydro-5H-thiazolo[3',2'-
1,2]pyrido[2,3-d]pyrimidine-4-
Carboxylic acid, 8-methylthio-5-oxo-5H
-thiazolo[3′,2′-1,2]pyrido[2,3D]
Pyrimidine-4-carboxylic acid, 8-(1-piperazinyl)-5-oxo-5H-thiazolo[3,'2',
-1,2]pyrido[2,3-d]pyrimidine-4
-carboxylic acid, 8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3',2',-
1,2]pyrido[2,3-d]pyrimidine-4-
Carboxylic acid, 1-methyl-8-methylthio-5-
Oxo-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid, 1
-Methyl-8-(1-piperazinyl)-5-oxo-5H-thiazolo[3',2'-1,2]pyrido[2,
3-d]Pyrimidine-4-carboxylic acid, 1-methyl-8-(4-methyl-1-piperazinyl)-5-
Oxo-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid, 1
-Methyl-8-morpholino-5-oxo-5H-
Thiazolo[3′,2′-1,2]pyrido[2,3-
d] Pyrimidine-4-carboxylic acid, 1-methyl-
8-Thiomorpholino-5-oxo-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid. The biological properties of the compound of the present invention are as shown below. Antibacterial spectrum of compounds of the present invention Compound of Example 7, Compound of Example 8, Examples
The antibacterial test of 12 compounds, the compound of Example 13, was conducted using the method of the Japanese Society of Chemotherapy (Journal of the Japanese Society of Chemotherapy, 29
Vol., No. 1, 76-79 Mitsugu (1981)) The results are shown in Table 1. As is clear from the table, the compounds of the present invention exhibit extremely strong antibacterial activity against Gram-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa.

[Table] The comparison is pipemidic acid. The compounds of the present invention and their salts are usually obtained as crystalline powders or powders, and have low toxicity and excellent hydrophilicity and lipophilicity, so when used as antibacterial agents,
It can be safely administered parenterally or orally as a pharmaceutical composition in various dosage forms (eg, injections, tablets, capsules, liquids, suppositories, ointments). Formulation of injections, drips, injections, etc. is carried out in accordance with conventional methods using, for example, physiological saline or an aqueous solution containing glucose and other adjuvants. Tablets, capsules, etc. can also be prepared according to conventional methods. For example, by mixing it with a suitable solid carrier (diluent, bulking agent, etc.) or adsorbing it onto it,
If necessary, suitable additives such as emulsifiers, dispersants, suspending agents, spreading agents, penetrating agents,
By adding wetting agents, mucilages, stabilizers, etc., it is possible to prepare solutions, granules, emulsions, suspensions, ointments, powders, etc.
It can be in the form of a spray, a paste, a splash, or the like. These dosage forms can be administered in dosage unit form depending on the purpose of administration, for example, in the case of injections, intravenous, subcutaneous, parenteral administration such as direct administration to the affected area, tablets, etc.
In the case of capsules, etc., it can be used by a suitable administration route such as oral administration. The dosage for humans is generally about 0.1-150mg/
Kg/day, preferably about 5 to 20 mg/Kg/day, and can be appropriately determined depending on the symptoms, route of administration, etc. The number of administrations is usually once a day.
This is a continuous administration of about 4 times. Although the amount of the active ingredient of the antibacterial agent should not be limited, it is usually about 0.01 to 70% by weight, more preferably about 0.1 to 5% by weight of the compound of the present invention, based on the entire preparation. Antifungal agents are administered according to conventional methods.
It is applied by coating, spraying, etc. on the affected area once to several times a day. The acute toxicity of oral administration of the compounds of the present invention will be described below. A test was conducted by oral administration of the compounds of the present invention using ddy male mice (body weight 20±1 g) in groups of 10 mice, and all of the example compounds
No toxicity was observed when 2000mg/Kg was administered. Hereinafter, the present invention will be explained in more detail by showing Reference Examples related to the production of the raw material compound according to the present invention and Examples related to the production of the compound of the present invention. Reference example 1 Ethyl 3-(4-amino-2-methylthio-
5-pyrimidyl)-2-ethoxycarbonyl-
3-oxopropionate 1.11 4-amino-2-methylthio-5-pyridiminecarboxylic acid in dry tetrahydrofuran
After suspending 56.5 g (0.305 mol) and adding 33.9 g (0.336 mol) of triethylamine and stirring at room temperature for about 30 minutes, the system is immersed in an ice bath. To this, 36.6 g (0.336 mol) of ethyl chlorocarbonate was added dropwise over about 10 minutes, and after further stirring for 1 hour at -10 to -5°C, a solution of 0.336 mol of ethylmagnesium bromide dissolved in 112 ml of dry ether and diethyl malonate were added.
53.7g (0.336 mol) dry tetrahydrofuran 370
After adding an anionic solution of diethyl malonate prepared from a solution dissolved in 1 ml at 0℃ or below, the temperature of the reaction mixture was allowed to rise to room temperature naturally, and after stirring for another 2 hours, 2N-hydrochloric acid was added to the reaction mixture. neutralize,
Extract with 1.5 ml of ethyl acetate. The extract is washed with saturated brine, dried over MgSO ₄ and the solvent is distilled off under reduced pressure. The remaining crystalline material is washed with n-hexane and then dried to obtain the title compound. Melting point 112-113℃ Elemental analysis value (as C ₁₃ H ₁₇ N ₃ O ₅ S) Theoretical value (%) C: 47.70 H: 5.23 N: 12.84 Actual value (%) C: 48.03 H: 5.44 N: 12.56 Infrared absorption Spectrum (KBr, cm _-1 ) 3430, 3280, 3005, 1740, 1630, 1575, 1400,
1315, 1180 Nuclear magnetic resonance spectrum δ (CDCl ₃ ) 1.27 (6H, t, J = 7.0), 2.50 (3H, s), 4.23 (4H, q, J = 7.0), 5.08 (1H, s), 8.37 ( 1H, s) Reference example 2 Ethyl 5-hydroxy-2-methylthio-
7-oxo-7,8-dihydropyrido [2,3
-d]Pyrimidine-6-carboxylate ethyl 3-(4-amino-2-methylthio-
5-pyrimidyl)-2-ethoxycarbonyl-3
- 89.3 g (0.273 mol) of oxopropionate are dissolved in 1.75 g (0.567 mol) of sodium hydride (50%) in dry tetrahydrofuran.
was added under ice-cooling, allowed to rise to room temperature naturally, and further stirred at a bath temperature of 50°C for 7 hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 600 ml of water. This aqueous solution is passed through Celite to remove insoluble materials, and then neutralized with dilute hydrochloric acid. The resulting precipitate was collected by filtration and diluted with water.
Wash twice with ethanol and dry. melting point
The title compound is obtained as crystals at 242-243°C. Elemental analysis value (as C ₁₁ H ₁₁ N ₃ O ₄ S) Theoretical value (%) C: 46.97 H: 3.94 N: 14.94 Actual value (%) C: 47.25 H: 3.98 N: 14.85 Infrared absorption spectrum (KBr, cm _-1 ) 2990, 1680, 1590, 1385, 1350, 1190, 1135,
820, Nuclear magnetic resonance spectrum δ (CF ₃ CO ₂ D) 1.48 (3H, t, J = 7.0), 2.84 (3H, s), 4.54 (2H, q, J = 7.0), 9.14 (1H, s) Reference Example 3 Ethyl 5-isoproboxy-2-methylthio-7-oxo-7,8-dihydropyrido [2,
3-d]Pyrimidine-6-carboxylate ethyl 5-hydroxy-2-methylthio-
7-oxo-7,8-dihydropyrido [2,3-
d] Pyrimidine-6-carboxylate 25.0g
(0.089 mol) was suspended in 500 ml of DMF, 12.8 g (0.093 mol) of potassium carbonate was added, and the mixture was heated to 80°C to dissolve. Add 45.4g of isopropyl iodide to this solution.
(0.267 mol) and stirred at 80°C for 3 hours. The reaction mixture is then concentrated to about 100 ml, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The extract is washed with saturated brine, dried over magnesium sulfate, and then ethyl acetate is distilled off. Dissolve the residue in bezene and remove impurities. When the benzene solution is distilled off and the remaining crystalline material is washed with n-hexane, the title compound is obtained. Melting point 192-193℃ Elemental analysis value (as C ₁₄ H ₁₇ N ₃ O ₄ S) Theoretical value (%) C: 52.00 H: 5.30 N: 12.99 Actual value (%) C: 51.90 H: 5.24 N: 12.71 Infrared absorption Spectrum (KBr, cm _-1 ) 1725, 1655, 1605, 1380, 1310, 1255, 1190,
1095, Nuclear magnetic resonance spectrum δ (CdCl ₃ ) 1.40 (6H, J = 6.0), 1.40 (3H, t, J = 7.5) 2.56 (3H, s), 4.36 (2H, q, J = 7.5), 4.77 ( 1H, q, J = 6.0) 8.79 (1H, b, s), 10.29 (1H, b, s) Reference example 4 Ethyl 5-hydroxy-2-methylthio-
7-thioxo-7,8-dihydropyride [2,
3-d] Ethyl pyrimidine-6-carboxylate 5-isopropoxy-2-methylthio-
7-oxo-7,8-dihydropyrido [2,3-
d] Pyrimidine-6-carboxylate 8.44g
(0.0261 mol) in 450 ml of toluene, P ₂ S ₅
Add 6.09 g (0.0274 mol) and heat under reflux for 1 hour. Insoluble materials in the reaction mixture are removed by filtration, and the filtrate is concentrated under reduced pressure. -20~ for residual oily substances
70 g (0.614 mol) of trifluoroacetic acid are added while cooling to -30°C, then the suspension is cooled to -40 to -30°C and 32 g (0.213 mol) of trifluoromethanesulfonic acid is added dropwise with stirring. . The reaction mixture was left at -15°C overnight, poured into ice, and the resulting precipitate was collected by filtration. After washing with water, this solid is dissolved in ethanol, the initially formed crystalline material is removed by filtration, and the filtrate is concentrated under reduced pressure. Washing the remaining crystalline material with ethyl acetate provides the pure title compound. Melting point: 193℃ (decomposition). Elemental analysis value (as C ₁₁ H ₁₁ N ₃ O3S ₂ ) Theoretical value (%) C: 44.43 H: 3.73 N: 14.13 Actual value (%) C: 44.18 H: 3.59 N: 14.14 Infrared absorption spectrum (KBr, cm _{- 1} ) 1600, 1380, Nuclear magnetic resonance spectrum δ (CF ₃ CO ₂ D) 1.58 (3H, t, J = 8.0), 2.84 (3H, s), 4.63 (2H, q, J = 8.0), 9.33 (1H ,s) Example 1 Ethyl 8-methylthio-5-oxo-1,2
-dihydro-5H-thiazolo[3',2'-1,2]
Pyrido[2,3-d]pyrimidine-4-carboxylate ethyl 5-hydroxy-2-methylthio-
7-thioxo-7,8-dihydropyrido [2,3
-d] Pyrimidine-6-carboxylate 21.56g
was dissolved in 500 ml of dimethylformamide, and 31.46 g of dibromoethane and 49.6 g of potassium carbonate were added to this solution.
and stir at 50°C for 6 hours. After cooling, the reaction mixture is poured into water, made weakly acidic by adding dilute hydrochloric acid, and extracted with chloroform. The extract is washed with saturated brine, dried over magnesium sulfate, and then the solvent is distilled off. The residue is purified by silica gel chromatography to give the title compound. Melting point 235-236°C (decomposition). Elemental analysis value (as C ₁₃ H ₁₃ N ₃ O ₃ S ₂ ) Theoretical value (%) C: 48.28 H: 4.05 N: 12.99 Actual value (%) C: 48.36 H: 3.96 N: 12.94 Infrared absorption spectrum (KBr, cm _-1 ) 1720, 1620, 1590, 1360, Nuclear magnetic resonance spectrum δ (CF ₃ CO ₂ D) 1.59 (3H, t, J = 7.5), 2.82 (3H, s), 3.89 (2H, t, J = 8.0), 4.71 (2H, q, J = 7.5) 5.30 (2H, t, J = 8.0), 9,55 (1H, s) Example 2 8-Methylthio-5-oxo-1,2-dihydro-5 -H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid ethyl 8-methylthio-5-oxo-1,2
-Dihydro-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylate (1.21 g (3.74 mmol)) was dissolved in 10 ml of concentrated sulfuric acid and heated at 85°C for 12 hours. Warm up. After cooling, the reaction mixture is poured into 100 ml of cold water, and the precipitated crystals are collected by filtration. The crystals are recrystallized from acetonitrile to give the pure title compound. Melting point 285-287°C (decomposed). Elemental analysis value (as C ₁₁ H ₉ H ₃ O ₃ S ₂ ) Theoretical value (%) C: 44.74 H: 3.07 N: 14.23 Actual value (%) C: 45.03 H: 3.02 N: 14.33 Infrared absorption spectrum (KBr, cm _-1 ) 1705, 1585, 1480, 1460, 1380, 1360, Nuclear magnetic resonance spectrum δ (CF ₃ CO ₂ D) 2.94 (3H, s), 3.75 (2H, t, J = 8.0), 5.11 (2H, t, J=8.0), 9.56 (1H, s) Example 3 8-(4-methyl-1-piperazinyl)-5-oxo-1,2-dihydro-5H-thiazolo[3',
2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid 8-methylthio-5-oxo-1,2-dihydro-5H-thiazolo[3',2'-1,2]pyrido [2,3-d]pyrimidine-4-carboxylic acid 0.20g
and N-methylpiperazine on an oil bath at bath temperature.
After heating at 140° C. for 2 hours, the reaction mixture is concentrated under reduced pressure. The residue is crystallized from ethanol to give the title compound. Melting point 292-293°C (decomposition). Elemental analysis value (as C ₁₅ H ₁₇ N ₅ O ₃ S) Theoretical value (%) C: 51.86 H: 4.93 N: 20.16 Actual value (%) C: 51.70 H: 4.99 N: 19.99 Infrared absorption spectrum (KBr, cm _-1 ) 1710, 1610, 1500, 1460, 1445, 1365, Nuclear magnetic resonance spectrum δ ( _CDCl3 ) 2.36 (3H, s), 2.42-2.68 (4H, m), 3.42 (2H, t, J=8.0) , 3.86-4.20 (4H, m), 4.69 (3H, t, J = 8.0), 9.12 (1H, s) Example 4 Ethyl 5-isopropoxy-2-methylthio-7-(2-diethoxyethyl)thiopyride [2,3-d]pyrimidine-6-carboxylate ethyl 5-isopropoxy-2-methylthio-7-oxo-7,8-dihydropyrido [2,3
-d] Pyrimidine-6-carboxylate 2.00g
(6.19 mmol), 1.44 g (6.51 mmol) of phosphorus pentasulfide, and 110 ml of toluene are heated under reflux for 1 hour. The reaction mixture is poured into water and extracted with benzene. The extract is washed with saturated brine, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure.
Dissolve the residue in 50 ml of dimethylformamide and add promoacetaldehyde diethyl acetal to this.
1.81g (9.20mmol) and potassium carbonate 0.86g
(9.20 mmol) and heat at 75°C for 7.5 hours. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The extract is treated with activated carbon, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. If the residue is purified by silica gel chromatography,
The title compound is obtained as a pure oil. Elemental analysis value (as C ₁₉ H ₂₇ N ₃ O ₄ S ₂ ) Theoretical value (%) C: 51.68 H: 6.16 N: 9.52 Actual value (%) C: 2.20 H: 6.48 N: 9.00 Infrared absorption spectrum (liquid film , cm _-1 ) 2990, 1720, 1575, 1225 Nuclear magnetic resonance spectrum δ (CDCl ₃ ) 1.20-1.70 (15H, m), 2.65 (3H, s), 3.60-4.00 (6H, m), 4.40-4.80 ( 4H, m), 9.15 (1H, s) Example 5 8-Methylthio-5-oxo-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid Ethyl 5-isopropoxy-2-methylthio-7-(2-diethoxyethyl)pyrido [2,3
-d] Pyrimidine-6-carboxylate 0.485g
Dissolve in 5 ml of concentrated sulfuric acid and heat in an oil bath at a temperature of 100°C for 5 hours. After cooling, the reaction mixture is poured into water, and the resulting precipitate is collected by filtration, washed with water, ethanol, and ether, and dried to obtain the title compound. Melting point 305℃ (decomposition). Elemental analysis value (as C ₁₁ H ₇ N ₃ O ₃ S ₂ ) Theoretical value (%) C: 45.04 H: 2.41 N: 14.33 Actual value (%) C: 44.91 H: 2.30 N: 13.77 Infrared absorption spectrum (KBr, cm _-1 ) 3150, 1700, 1600, 1490, 1370, 1145, Nuclear magnetic resonance spectrum δ (CF ₃ COOD) 2.94 (3H, s), 7.97 (1H, bs) 9.10 (1H, bS), 9.88 (1H, s) Example 6 8-(4-ethoxycarbonyl-1-piperazinyl)-5-oxo-5H-thiazolo[3',2'-
1,2]pyrido[2,3-d]pyrimidine-4
-Carboxylic acid A mixture of 0.201 g of 8-methylthio-5-oxo-5H-thiazolo[3',2'-1,2]pyrido[2.3-d]pyrimidine-4-carboxylic acid and N-ethoxycarbonylpiperazine was added in an oil bath. Heat and stir at an upper bath temperature of 140°C for 30 minutes.
After cooling, the resulting precipitate is collected by filtration, washed with ethanol and ether, and dried to obtain the title compound. Elemental analysis value (as C ₁₇ H ₁₇ N ₅ O ₅ S) Theoretical value (%) C: 50.62 H: 4.25 N: 17.36 Actual value (%) C: 50.46 H: 4.10 N: 17.31 Infrared absorption spectrum (KBr, cm _-1 ) 1700, 1615, 1450, 1435, 1240, 1225, Nuclear magnetic resonance spectrum δ ( _CDCl3 ) 1.30 (3H, t, J=8.0), 3.50-3.74 (4H, m), 3.88-4.08 (4H, m), 4.20 (2H, q, J = 8.0), 7.16 (1H, d, J = 5.5), 8.42 (1H, d, J =
5.5), 9.38 (1H, s) Example 7 8-(1-piperazinyl)-5-oxo-5H-
Thiazolo[3′,2′-1,2]pyrido[2,3-
d] Pyrimidine-4-carboxylic acid 8-(4-ethoxycarbonyl-1-piperazinyl)-5-oxo-5H-thiazolo[3',2'-1,
2] Dissolve 0.062 g of pyrido[2,3-d]pyrimidine-4-carboxylic acid in 1N hydrobromic acid/acetic acid and heat for 2 hours at an oil bath temperature of 120°C. After cooling, the resulting precipitate is collected by filtration, washed with ethanol and ether, and dried to obtain the title compound. Melting point: 312°C (decomposition). Elemental analysis value (as C ₁₄ H ₁₃ N ₅ O ₃ S・HBr) Theoretical value (%) C: 40.79 H: 3.42 N: 16.99 Actual value (%) C: 37.91 H: 3.21 N: 15.20 Infrared absorption spectrum (KBr , cm _-1 ) 1695, 1625, 1500, 1450, 1370 Nuclear magnetic resonance spectrum δ (CF ₃ CO0D) 3.78 (4H, b, s), 4.68 (4H, b, s), 7.94 (1H, b, s) , 9.08 (1H, b, s), 9.69, (1H, b, s) Example 8 8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3',2'-1, 2] Pyrido[2,3-d]pyrimidine-4-carboxylic acid 8-methylthio-5-oxo-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4- A mixture of carboxylic acid and N-methylpiperazine is heated and stirred at an oil bath temperature of 130°C for 30 minutes, then concentrated under reduced pressure, and the residue is purified by syringel chromatography to obtain the title compound as crystals. Melting point 297-298 (decomposition). Elemental analysis value (as C ₁₅ H ₁₅ N ₅ O ₃ S) Theoretical value (%) C: 52.17 H: 4.38 N: 20.28 Actual value (%) C: 52.16 H: 4.29 N: 19.93 Infrared absorption spectrum (KBr, cm _-1 ) 2800, 1700, 1615, 1490, 1460, 1385, 1360, Nuclear magnetic resonance spectrum δ ( _CDCl3 ) 2.37 (3H, s), 2.48-2.64 (4H, m), 3.90-4.24 (4H, m) , 7.14 (1H, d, J = 5.0) 8.41 (1H, d, J = 5.0), 9,36 (1H, s) Example 9 Ethyl 2-methylthio-7-(2-oxopropylthio)-5- Hydroxypyrid [2,3
-d]Pyrimidine-6-carboxylate ethyl 5-hydroxy-2-methylthio-
7-thioxo-7,8-dihydropyrido [2,3
-d] Pyrimidine-6-carboxylate 0.516g
(1.737 mmol) was dissolved in a solution of 44 mg of sodium in 10 ml of ethanol, and 0.178 g (1.913 mmol) of chloroacetone was dissolved in 5 ml of ethanol.
Add the solution dissolved in and stir overnight at room temperature. The resulting precipitate was collected by filtration and diluted twice with water and twice with ethanol.
After washing twice with ether and drying, the title compound is obtained as crystals. Melting point 213-214°C (decomposition). Elemental analysis value (as C ₁₄ H ₁₅ N ₃ O ₄ S ₂ ) Theoretical value (%) C: 47.58 H: 4.28 N: 11.89 Actual value (%) C: 47.64 H: 4.29 N: 11.84 Infrared absorption spectrum (KBr, cm _-1 ) 1680, 1615, 1585, 1375, 1340, Nuclear magnetic resonance spectrum δ (CDCl ₃ ) 1.42 (3H, t, J = 8.0), 2.01 (3H, s), 2.64 (3H, s), 2.23 ( 1H, d, J = 12.0) 2.56 (1H, d, J = 12.0), 4.40 (2H, q, J =
8.0) 6.65 (1H, b, s), 9.29 (1H, s) Example 10 1-Methyl-8-methylthio-5-oxo-
5H-thiazolo[3′,2′-1,2]pyrido[2,
3-d] Pyrimidine-4-carboxylate a Ethyl 2-methylthio-7-(2-oxopropylthio)-5-oxo-5,8-dihydropyrido [2,3-d] Pyrimidine-6-carboxylate 0.394 g Dissolve in 3 ml of concentrated sulfuric acid and heat in an oil bath at 90°C for 10 hours. After cooling, the reaction mixture was poured into ice water, and the resulting precipitate was collected by filtration.
Wash with water, ethanol and ether and dry.
The title compound is obtained by recrystallizing the obtained crystals from ethanol. Melting point 270-271℃ (decomposition). Elemental analysis value (%) (as C ₁₂ H ₉ N ₃ O ₃ S ₂ ) Theoretical value (%) C: 46.90 H: 2.95 N: 13.67 Actual value (%) C: 46.61 H: 2.86 N: 13.39 Infrared absorption spectrum (KBr, cm _-1 ) 1690, 1580, 1480, 1380, Nuclear magnetic resonance spectrum δ (CF ₃ COOD) 2.94 (3H, s), 3.97 (3H, s), 7.57 (1H, s), 9.95 (1H, s) b Ethyl 5-isopropoxy-2-methylthio-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate 2.0 g (6.19 mmol), phosphorus pentasulfide 1.44 g
(6.50 mmol) and 110 ml of toluene was heated under reflux at an oil bath temperature of 120°C for 1 hour. After cooling, the reaction mixture is poured into a suspension of water and benzene. The organic layer was washed twice with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was then dissolved in 50 ml of DMF, and 0.68 g (4.92 mmol) of potassium carbonate and chloroacetone were added.
Add 0.46 g (4.92 mmol) and stir at room temperature for 18 hours. Pour the reaction mixture into dilute aqueous hydrochloric acid solution,
Extract with benzene. The extract is washed with aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography. The obtained crystals are dissolved in 15 ml of concentrated sulfuric acid and heated at an oil bath temperature of 90°C for 4.5 hours. After cooling, the reaction mixture was poured into ice water,
The resulting precipitate is collected by filtration, washed with water, ethanol and ether, and dried to obtain the title compound as crystals. This product was identified by comparison with the standard product using infrared spectrum. Example 11 8-(4-ethoxycarbonyl-1-piperazinyl)-1-methyl-5-oxo-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4- Carboxylic acid 1-methyl-8-methylthio-5-oxo-
5H-thiazolo[3′,2′-1,2]pyrido[2,3
-d]pyrimidine-4-carboxylic acid 0.524g
(1.71 mmol) and 20 ml of N-ethoxycarbonylpiperazine was stirred in an oil bath at a bath temperature of 140°C for 30 minutes. After cooling, the resulting precipitate is collected by filtration, washed with water, ethanol and ether, and dried to obtain the title compound as crystals. Melting point 295℃ (decomposition). Infrared absorption spectrum (KBr, cm _-1 ) 1690, 1625, 1605, 1560, 1490, 1415, 1385,
1365, 1250, 1000, 805, Nuclear magnetic resonance spectrum δ (CDCl ₃ + CF ₃ COOD) 1.35 (3H, t, J = 8.0) 3.14 (3H, s), 3.58-3.92 (4H, m), 3.92-4.40 ( 4H, m), 4.26 (2H, q, J = 8.0), 7.18 (1H, s), 9.48 (1H, s) Example 12 1-Methyl-8-(1-piperazinyl)-5oxo-5H-thiazolo [3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid 8-(4-ethoxycarbonyl-1-piperazinyl)-1-methyl-5-oxo-5H-thiazolo[ 3′,2′-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid. 0.531g (1.27 mmol)
was dissolved in 6 ml of 1N hydrobromic acid/acetic acid and heated at an oil bath temperature of 120°C for 6 hours. After cooling, the resulting precipitate is collected by filtration, washed with water and ethanol, and dried to obtain the hydrobromide salt of the title compound as crystals. Melting point: 323°C (decomposition). Elemental analysis value (as C ₁₅ H ₁₅ N ₅ O ₃ S・HBr) Theoretical value (%) C: 42.26 H: 3.78 N: 16.43 Actual value (%) C: 38.27 H: 3.88 N: 14.09 Infrared absorption spectrum (KBr , cm _-1 ) 1685, 1620, 1600, 1550, 1360, 805, Nuclear magnetic resonance spectrum δ (CF ₃ COOD) 3.29 (3H, s), 3.82 (4H, bs), 4.64 (4H, bs), 7.50 ( 1H,s), 9.72 (1H,s) Example 13 1-Methyl-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo[3',2'-
1,2]pyrido[2,3-d]pyrimidine-4
-Carboxylic acid 1-methyl-8-methylthio-5-oxo-
5H-thiazolo[3′,2′-1,2]pyrido[2,3
-d] pyrimidine-4-carboxylic acid 0.10g (0.326
(mmol) and N-methylpiperazine is heated in an oil bath at a bath temperature of 140°C for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel chromatography to give the title compound as crystals. Melting point 281-282°C (decomposition). Elemental analysis value (as C ₁₆ H ₁₇ N ₅ O ₃ S) Theoretical value (%) C: 53.47 H: 4.77 N: 19.49 Actual value (%) C: 53.21 H: 4.68 N: 19.21 Infrared absorption spectrum (KBr, cm _-1 ) 1695, 1620, 1605, 1555, 1490, 1440, 1360, Nuclear magnetic resonance spectrum δ (CDCl ₃ ) 2.38 (3H, s), 2.55 (4H, t, J=5.0) 3.04 (3H, s), 3.82-4.08 (4H, m), 6.74 (1H, s), 9.42 (1H, s) Example 14 1-Methyl-8-(4-morpholino)-5-oxo-5H-thiazolo[3', 2' -1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid 1-methyl-8-methylthio-5-oxo-
5H-thiazolo[3′,2′-1,2]pyrido[2,3
-d] pyrimidine-4-carboxylic acid 0.112g (0.365
(mmol) and morpholine (2 ml) was heated in an oil bath at a bath temperature of 120°C for 30 minutes. After cooling, the resulting precipitate was collected by filtration and purified by silica gel chromatography.
The title compound is obtained as crystals. Melting point: 313°C (decomposition). Elemental analysis value (as C ₁₅ H ₁₄ N ₄ O ₄ S) Theoretical value (%) C: 52.02 H: 4.07 N: 16.18 Actual value (%) C: 51.77 H: 4.03 N: 15.97 Infrared absorption spectrum (KBr, cm _-1 ) 1710, 1620, 1490, 1455, 1450, 1360, Nuclear magnetic resonance spectrum δ ( _CDCl3 ) 3.02 (3H, s), 3.78-4.14 (8H, m), 6.72 (1H, s), 9.36 (1H ,s) 15.23(1H,b,s.) Example 15 1-Methyl-8-(4-thiomorpholino)-5-
Oxo-5H-thiazolo[3',2'-1,2]pyrido[2,3-d]pyrimidine-4-carboxylic acid 1-methyl-8-methylthio-5-oxo-
5H-thiazolo[3′,2′-1,2]pyrido[2,3
-d] pyrimidine-4-carboxylic acid 0.10g (0.326
Heat a mixture of 1.5 ml of thiomorpholine and 1.5 ml of thiomorpholine on an oil bath for 40 minutes at a bath temperature of 130°C. After cooling, the resulting precipitate is collected by filtration and purified by silica gel chromatography to obtain the title compound as crystals. Melting point: 317°C (decomposition). Elemental analysis value (as C ₁₅ H ₁₄ N ₄ O ₃ S ₂ ) Theoretical value (%) C: 49.71 H: 3.89 N: 15.46 Actual value (%) C: 49.66 H: 3.78 N: 15.19 Infrared absorption spectrum (KBr, cm _-1 ) 2930, 1695, 1625, 1550, 1455, Nuclear magnetic resonance spectrum δ (CDCl ₃ ) 2.67-2.82 (4H, m), 3.00 (3H, s), 4.15-4.46 (4H, m), 6.74 ( 1H, s), 9.40 (1H, s)

Claims (1)

[Claims] First-order general formula [In the formula, A represents alkylene having 1 to 5 carbon atoms. The alkylene may contain an unsaturated bond in the middle, and the alkylene may have as a substituent,
Lower alkyrel, hydroxy, substituted or unsubstituted phenyl, alkoxy, substituted or unsubstituted phenoxy, alkylthio, substituted or unsubstituted phenylthio, halogen, halogen-substituted alkyl, amino-substituted alkyl, alkoxycarbonyl-substituted alkyl, carboxy-substituted alkyl, alkoxy Substituted alkyl, alkylthio substituted alkyl, hydroxy substituted alkyl, acyloxy substituted alkyl, alkylamino, substituted or unsubstituted phenylamino, carboxy, nitro, or
It may have cyano, and carbonyl,
It may have thiocarbonyl or imino. R ¹ represents alkylthio or a heterocyclic compound residue containing 1 to 3 of 1 to 2 of O, N, or S. R ² represents hydrogen, lithium, sodium, potassium, calcium, methyl, ethyl, pivaloyloxymethyl, or phthalidyl. ] or a pharmacologically acceptable salt thereof.