KR820001216B1 - Process for preparing quina joline derivatives - Google Patents

Abstract

7-Methoxy-5-oxo-5H-thiazolo 2,3,-b quinazoline-2-carboxylic acid or its salts(I; R = H, lower alkyl; X = Cl, Br, I; R1 = formyl; R1 = lower alkyl), useful as hypoallergenic agent, were prepd. by condensation of anthranilic acid deriv. (II) and thiazole deriv.(III). The reaction of 6-methoxy-2-mercapto-4(3H)-quinazolinone(IV) and compd.(V), or hydrolysis of compd. (VI) also give compd. (I). Thus, 5-methoxyanthranilic acid 1.49 g, methyl-2-chlorothiazol-5-carboxylate 1.58 g, and KI 0.075 g was stirred at 160-165≰C for 80 min, treated with satd. NaHCO3 75 ml, extracted with chloroform, dried, condensed, and then crystallized to give compd(I) 0.86g.

Description

Method for preparing quinazoline derivatives

The present invention provides a method for preparing 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid of the following structural formula (I) as an antiallergic agent and pharmaceutically toxic salts thereof It is about.

The term "lower alkyl" as used herein is an alkyl group having 1 to 7 carbon atoms, in particular an alkyl group having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, butyl and the like.

7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazoline-2-carboxylic acids and their toxicly harmless salts according to the invention can be prepared as follows.

(a) The anthranilic acid derivative of formula (II) is condensed with a thiazole derivative of formula (III).

Wherein R is hydrogen or lower alkyl and X is chlorine, bromine or iodine.

(b) 6-methoxy-2-mercapto-4 (3H) -quinazolinone of the following formula (IV) is reacted with a compound of the following formula (V).

Where R 1 is formyl and X is as mentioned above.

(c) Hydrolyze the compound of formula (IA).

R 'in the above formula is lower alkyl.

(d) Where necessary, these obtained compounds are converted into pharmaceutically harmless salts.

The condensation reaction of the anthranilic acid derivative of formula (II) with the thiazole derivative of formula (III) is carried out at a temperature of 100 ° to 180 ° C. This condensation reaction can be carried out in the absence of a solvent without adding a suitable solvent, but a high boiling point polar solvent such as 2-methoxyethanol, triglyme, dimethylformamide or the like can also be used. Furthermore, the condensation reaction is carried out in the absence or presence of a catalyst, and examples of these ammonia include alkali metals such as sodium iodide, lithium iodide and potassium iodide, suitable acids such as iodide or formic acid, and Potassium hydride is good.

The reaction of 6-methoxy-2-mercapto-4 (3H) -quinazolinone with a compound of formula (V) is carried out at a temperature of about 80 ° to 150 ° C., isopropane, n-butanol or ethanol, etc. In a suitable solvent such as lower alkanol.

Furthermore, this reaction is carried out in the presence or absence of a catalyst such as an alkali metal iodide such as potassium iodide.

Hydrolysis of the compound of formula (IA) to obtain the desired acid of formula (I) is carried out at a temperature of 0 ° to 30 ° C in the presence of an excess of alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, in particular 25 ° C. React in

After hydrolysis, the mixture is refluxed with organic carboxylic acids such as acetic acid and propionic acid, and the desired 7-methoxy-5-oxo-5H-thiazolo [3,3-b] quinazolin-2 is subjected to a usual procedure such as recrystallization. Recover the carboxylic acid.

The compounds of the structural formulas (IA), (II), (III), (IV) and (V) as starting materials can be prepared according to known methods as known materials.

Compounds of formula (I) form pharmaceutically harmless salts with bases. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkaline earth metal hydroxides of calcium hydroxide and barium hydroxide; Alkali metal alkoxides such as ethanolate and potassium ethanolate; Organic bases such as piperidine, diethylamine, and N-methylglucamine.

Compounds of formula (I), i.e., 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid and their pharmaceutically harmless salts, can be used for skin hypersensitivity in rats. It is useful for preventing allergic reactions. For example, it is useful for the prophylaxis of bronchial asthma. The anti-hypersensitivity effect was demonstrated by passive skin sensitization assay (PCA test) in rats. This test involves passive localized hypersensitivity by injecting antiserum into the rat's blood and 5 minutes after intravenous injection of the antigen and Evans blue dye, followed by a 24-hour incubation period of 7-methoxy-5-oxo-. 5H-thiazole [2, 3-b] quinazoline-carboxylic acid is injected intraperitoneally. Local antibody-antigen response results are determined by measuring the size of the lesion on the skin. The effect of this compound on reducing the size of lesions compared to the control is considered to be the potency of this compound.

Intraperitoneal administration of 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid in an amount of 16 mg / kg resulted in a 100% reduction in lesion size.

Oral administration of 7-methoxy-5-oxy-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid in an amount of 0.07 mg / kg resulted in a 50% reduction in lesion size.

7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid and its pharmaceutically harmless salts can be used orally in an amount suitable for an individual's needs as a prophylactic agent for bronchial asthma. Or by injection. These can be administered orally or parenterally in therapeutic amounts in conventional forms (eg tablets, capsules, elixirs, suspensions, solutions, aerosols, etc.). These may be administered in combination with conventional pharmaceutical carriers or excipients such as corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose and the like. Furthermore, they can be administered with buffers, osmotic pressure regulators and pharmaceutical formulations can also be sterilized. As mentioned above, the dose may be adjusted to the needs of the individual. The formulation may also include another therapeutically useful substance.

The amount of active agent in the aforementioned formulations can vary in many ways, from 10 to 20 mg of 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid or an equivalent pharmaceutical amount. Tablets or capsules containing nontoxic salts are preferred.

The frequency of administration of such forms to warm-blooded animals may vary depending on the amount of effective agent present therein and the needs of the warm-blooded animals. In general, up to about 200 mg / kg of 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid may be administered multiple times daily. However, the doses presented here provide a range, not limitation.

The following examples illustrate the invention in more detail. All temperatures are in degrees Celsius.

Example 1

Preparation of Methyl 2-chlorothiazole-5-carboxylate

10 ml aqueous solution in which 3.7 g of sodium nitrite was dissolved was added dropwise over 15 minutes in 54 ml of 6N hydrochloric acid in which 5.0 g of methyl 2-aminothiazole-5-carboxylate was dispersed at -5 ° to 0 °. . The brown suspension is added in one portion in a suspension of 10.6 g copper sulfate and 10.6 g (cooled at 5 °) sodium chloride with stirring for 5 minutes. Remove the cold bath and stir for 30 minutes. 6N sodium hydroxide solution is added to pH7.3, and the green suspension is filtered through Celite, the solid is washed three times with ethyl acetate, and the ethyl acetate extract is collected. The extract is dehydrated over magnesium sulfate and concentrated in vacuo to give a brown solid. Four treatments with hot petroleum ether (35-60 °) separate the soluble product from some starting material. Concentration of the petroleum ether solution in vacuo yields 3.9 g of pure methyl-chloro-thiazole-5-carboxylate.

Melting Point: 41 to 46 °

Example 2

Preparation of methyl-7-methoxy-5-oxo-5H-thiazolo [2, 3-b] quinazolin-2-carboxylate

A mixture of 1.49 g 5-methoxy anthranilic acid, 1.58 g methyl-2-chlorothiazole-5-carboxylate and 0.075 g potassium iodide powder is stirred and 80 minutes in an oil bath at 160 to 165 ° C. Heat. The resulting dark solid is treated with 75 ml of saturated sodium bicarbonate solution and extracted three times with chloroform. The extracts were combined, dehydrated on magnesium sulfate, dried and concentrated in vacuo to yield a brown solid (1.59 g). Crystallization from methylene chloride / ether gives 0.86 g of methyl 7-methoxy-5-oxo-5H-thiazolo [2,3-d] quinazolin-2-carboxylate.

Melting Point: 186 ~ 192 °

Example 3

Preparation of methoxy 7-methoxy-5-oxo-5H-thiazolo [2, 3-b] quinazoline-2-carboxylic acid

0.86 g of methyl 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylate was stirred with 30 ml of 1N sodium hydroxide and 30 ml of methanol at room temperature for 16 hours. Hydrolysis. Filter, add acetic acid to the filtrate to pH5 and concentrate in vacuo. Water is added and filtered to remove solids. Base treatment results in the opening of the lactam ring, so the solid is refluxed in 75 ml of acetic acid for 1 hour, concentrated to 25 ml and cooled to crystallize and filtered to give 0.53 g of pure 7-methoxy-5-oxo-5H-thia Solo [2, 3, -b] quinazoline-2-carboxylic acid is obtained.

Melting Point: 247 to 247.5 °

Example 4

Preparation of 7-methoxy-5-oxo-5H-thiazole [2, 3-b] quinazolin-2-carboxylic acid

80 ml of 2-methoxyethanol (containing 0.88 moles of formic acid) containing 1.000 g (0.006 moles) of 5-methoxyanthranilic acid and 0.981 g (0.006 moles) of 2-chlorothiazole-5-carboxylic acid The solution is stirred at reflux for 3.5 h. Cool to room temperature, add 50 ml of ether, and filter the solid to afford 1.083 g of a yellow solid. Treatment of this solid with 25 ml of methanol and filtration gave 0.806 g of product, which was recrystallized from acetic acid and 0.601 g of 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin- 2-carboxylic acids are obtained.

Melting Point: 241 ~ 244 °

Example 5

Preparation of 7-methoxy-5-oxo-5H-thiazolo [2, 3-b] quinazoline-2-carboxylic acid

7 ml 2-methoxyethanol (containing 0.07 ml formic acid) solution containing 0.848 g (0.0047 mole) methyl 5-methoxy anthranilate and 0.766 g (0.0047 mole) 2-chlorothiazole-5-carboxylic acid Stir at reflux for 6.5 h. After cooling to room temperature the solid is filtered off. Recrystallization from acetic acid yields 0.495 g of a yellow solid. The solid is stirred rapidly with excess saturated sodium bicarbonate solution. Insoluble material is filtered off and the filtrate is acidified. Filtration of the obtained yellow solid yielded 0.260 g of 7-methoxy-5-oxo-5H-thiazolo [2, 3-b] quinazoline-2-carboxylic acid.

Melting Point: 246 ~ 249 °

Example 6

Preparation of Methyl 7-methoxy-5-oxo-5H-thiazole [2, 3-b] quinazoline-2-carboxylate

8 ml 2-methoxyethanol (0.1 ml formic acid) containing 0.905 g (0.005 mole) methyl 5-methoxy anthranilate and 0.888 g (0.005 mole) methyl 2-chlorothiazole-5-carboxylate The solution is stirred at reflux for 2.5 hours. Cool to room temperature and filter the yellow solid by adding 10 ml of ether. The solid is treated with excess saturated sodium bicarbonate solution and extracted with methylene chloride. Concentration of the extract in vacuo afforded a solid which was recrystallized from methylene chloride / ether to give 0.943 g of methyl 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylate. Obtained.

Melting Point: 190 ~ 193 °

Example 7

7-methoxy-5-oxo-5H-thiazolo [2, 3-b] quinazoline-2-carboxylic acid

0.943 g of methyl 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazoline-2-carboxylate was combined with 3.6 ml of 1.0N sodium hydroxide and 35 ml of methanol at room temperature for 17 hours. Hydrolyze by stirring. The solvent is removed in vacuo and the solid residue is dissolved in 50 ml of water and hydrochloric acid is added to pH2. After filtration, the yellow solid was recrystallized twice from acetic acid to give 0.661 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid.

Melting Point: 248 ~ 249 °

Example 8

Methyl 7-methoxy-5-oxo-5H-thiazolo [2, 3-b] quinazoline-2-carboxylate

Metal sodium (0.044 g, 1.92 mmol) is dissolved in 4 ml of anhydrous isopropyl alcohol and 0.400 g (1.92 mmol) 6-methoxy-2-mercapto-4 (3H) -quinazolinone is added. The mixture is heated and stirred for 15 minutes at reflux under argon gas. After cooling to room temperature, 0.262 g (1.92 mmol) of methyl formylchloro acetate are added. The reaction mixture was stirred at reflux for 16 hours, cooled to room temperature, filtered and washed with water to obtain methyl 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxyl. The rate is obtained.

Example A

process :

7-methoxy-5-oxo-5H-thiazolo [2,5-b] quinazolin-2-carboxylic acid, lactose and corn starch are mixed in a suitable mixer. Grind through a suitable mill and mix with magnesium stearate and talc and fill into capsules.

Example B

process :

7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid, lactose, microcrystalline cellulose, modified starch, corn starch in a suitable mixer for 1 to 15 minutes After mixing, magnesium stearate is added and mixed for 5 minutes. Tableting.

Example C

Process: 7-methoxy-5-oxo-5H-thiazolo [2,3-b] quinazolin-2-carboxylic acid-lactose, pregelatinized starch, corn starch are mixed in a suitable mixer and granulated with water . After milling through a mill, mixed with modified starch and magnesium stearate and tableted.

Claims (1)

Anthranilic acid derivative of the following formula (II) is condensed with a thiazole derivative of the following formula (III) or 6-methoxy-2-mercapto-4 (3H) -quinazolinone of the following formula (IV) By reacting with a compound of formula (V) or by hydrolyzing a compound of formula (IA), 7-methoxy-5-oxo-5H-thiazolo [2, 3-b] quinazoline of formula (I) 2-carboxylic acids and their pharmaceutically harmless salts.

Wherein R is hydrogen or lower alkyl, X is chlorine, bromine or iodide, R 'is formyl and R' is lower alkyl.