KR810000560B1 - Process for the preparation of 2-disubstituted phenyl-3,4-dihydro-4-oxo-quinazolines - Google Patents

Abstract

Antiallergic quinazolines(I; R = ester or carboxyl; R' = C1-4 alkyl or C3-4 alkenyl; R2 = H, methyl or C1-2 alkoxy; R3 = H, C1-6 alkoxy, C2-4 alkyl or C3-4 alkenyloxy) were prepd. by cyclization of II, or by oxidation of III. Thus, 5 g dimethyl-4-amino-isophthalate was treated with 2-ethoxy-3-methoxy-benzoyl chloride, the acid products cyclized with Ac2O, and the benzoxazine treated with 32 % NH4OH for 4 hr to give I.

Description

2-2 Preparation of Substituted Phenyl-3,4-dihydro-4-oxo-quinazolin-Derivative

The present invention relates to a process for the preparation of 2-2 substituted phenyl-3,4-dihydro-4-oxo-quinazoline derivatives of formula (I) having antiallergic action.

Wherein R is an esterified carboxy group or a carboxy group and R ₁ is a) C ₁ -C ₄ alkyl which may be substituted with C ₁ -C ₂ alkoxy.

b) C ₃ -C ₄ alkenyl; R ₂ is hydrogen, methyl or C ₁ -C ₂ alkoxy, R ₃ is a ') hydrogen and b') C ₁ -C ₆ alkoxy which may be substituted by C ₁ -C ₂ alkoxy. c ') C ₂ -C ₄ alkyl and d') C ₃ -C ₄ alkenyloxy.

In the above, one of R ₂ and R ₃ is hydrogen and the other is not hydrogen. And R ₃ is not unsubstituted methoxy when R ₁ is methyl and R ₂ is hydrogen.

The compounds of the invention as defined above include all possible isomers, stereoisomers and mixtures thereof.

Alkyl, alkenyl, alkoxy and alkenyloxy groups are straight or branched chains.

그룹으로 치환될 수도 있고 치환되지 않을 수도 있다. 여기서 R₄와 R₅는 각각 수소 및 C₁-C₄알킬 특히 C₁-C₂알킬이고 혹은 R₄와 R₅는 함께 질소원자와 N-피롤리딜, 피페리디노 및 모르포리노기를 형성한다.When R is an esterified carboxy group, it is preferred that it is a C ₂ -C ₁₂ carboalkoxy group, in particular a C ₂ -C ₇ carboalkoxy group, which is

It may or may not be substituted with a group. Wherein R ₄ and R ₅ are hydrogen and C ₁ -C ₄ alkyl, in particular C ₁ -C ₂ alkyl, or R ₄ and R ₅ together form a nitrogen atom and N-pyrrolidyl, piperidino and morpholino groups do.

When R ₃ is C ₂ -C ₄ alkyl, preferred is ethyl; Preferred when R ₃ is C ₁ -C ₆ alkoxy is C ₁ -C ₃ alkoxy. When R ₃ is C ₃ -C ₄ alkenyloxy, aryloxy is preferred.

R is a free carboxy group or 2- (N, N-diethyl-amino) -ethoxy-carbonyl group or 2- (N, N-dimethyl-amino) -ethoxy-carbonyl group or 2- (1- It is preferred to be a pyrrolidinyl) -ethoxy-carbonyl group or a carboxy group of salts. Particularly preferred are compounds of formula (I) which are compounds of the invention wherein R is a free carboxy group, 2- (N, N-diethylamino) -ethoxy-carbonyl group, 2- (N, N-dimethyl-amino)- Ethoxy-carbonyl group, 2- (1-pyrrolidinyl) -ethoxy-carbonyl group or a carboxy group consisting of a salt and R ₁ is C ₁ -C ₄ alkyl, preferably C ₁ -C ₂ alkyl and R ₂ is C ₁ -C ₂ alkoxy, with methoxy being preferred and R ₃ being hydrogen.

Pharmaceutically nontoxic salts are formed with inorganic or organic bases, which include sodium hydroxide, calcium hydroxide, calcium hydroxide and aluminum hydroxide, and organic bases with lysine, triethanolamine, triethylamine, dibenzylamine, procaine, di Ethanolamine, N, N'-dibenzylethylenediamine, N-methyl-N-benzylamine, N, N-di (2-ethyl-hexyl) -amine, N-ethylpiperidine, N-ethylmorpholine, Piperidine, N, N-diethylaminoethylamine, β-phenethylamine, N-benzyl-β-phenethylamine, N-benzyl-N, N-dimethylamine and other nontoxic organic amines.

In addition, salts are also formed with inorganic or organic acids, which include hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids include citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, methanesulfonic acid and ethanesulfonic acid.

Preferred in this free carboxy group are hydrochlorides of sodium or potassium salts of the compound of formula (I) with 2- (N, N-diethylamino) -ethyl ester and 2- (N, N-dimethylamino) -ethyl ester. Chloride.

Particularly preferred compounds of the invention are as follows:

And pharmaceutically toxic sodium salts, and hydrochlorides of base esters, in particular 2- (N, N-diethylamino) -ethanol, 2- (N, N-dimethylamino) -ethanol, 2- (1- Pyrrolidinyl) -ethanol and hydrochloride of ethyl ester, isopropyl ester, t-butyl ester, hexyl ester.

The compound of the present invention is prepared by the following method.

a) Cyclizing the compound of formula II.

Wherein R, R ₁ , R ₂ , R ₃ are as defined above or a salt thereof.

b) Oxidizing the compound of formula III.

Wherein R, R ₁ , R ₂ , R ₃ are as defined above or a salt thereof.

And optionally convert the compound of formula (I) to another compound of formula (I) in a known manner, or optionally convert the compound of formula (I) to a pharmaceutically toxic salt or The salts are converted into free compounds or, in some cases, mixed isomers are broken down into single isomers.

When the compound of formula (II) is to be cyclized, the tetrahydrofuran dioxane, dimethylporamide and mixtures thereof are treated with ammonium hydroxide, sodium hydroxide and potassium hydroxide between 200 ° C and 200 ° C at room temperature. In addition, the cyclization of the compound of formula (II) is carried out by dehydrogenating agents such as acetic anhydride, PCl ₃ , POCl ₃ , polyphosphoric acid, dicyclohexylcarbodiimide, with or without solvents, between 0 ° and 200 ° C. Treat it with Solvents to be used include benzene, toluene, xylene, pyridine, tetrahydrofuran, dioxane, acetic acid and dimethyl foramide. Oxidation of the compound of formula III occurs when treated with carrimanganate in acetone at 0 ° to 30 ° C. or with chromium trioxide in acetic acid. In the above, the compound of formula (I) is converted to another compound of formula (I) by known methods. For example, when R is an esterified carboxy group, the compound of formula (I) undergoes base hydrolysis with sodium or potassium hydroxide in a solvent such as water or a lower alicyclic alcohol at 150 ° C. in Ceylon, where R is carboxy. (I) can be converted into a compound. The same reaction is carried out by treatment with lithium bromide in dimethylporamide at 50 ° C. or higher.

The compound of formula (I), wherein R is carboxylate, esterifies the alkali salts with a suitable alkyl halide in an inert solvent such as acetone, dioxane, dimethylporamide, hexamethylphosphprotriamide, between 0 ° and 100 ° C. Is converted to a compound of formula (I) wherein R is an esterified carboxy group, ie a carbalkoxy group.

It is also possible to salt the compound of formula (I) or to convert the salt into a free compound by conventional methods and to decompose the mixed isomer into a single isomer.

The preparation method of the compound of formula (II) is as follows.

a ') The compound of formula IV is reacted with ammonium hydroxide.

Wherein R, R ₁ , R ₂ and R ₃ are as described above and the reaction is carried out between room temperature and 200 ° C. when inert organic solvents such as lower alicyclic alcohols, dioxane and dimethylporamide are present or in the absence of solvent. do.

b ') The compound of formula (V) is reacted with a compound of formula (VI).

Wherein R ₁ , R ₂ and R ₃ are as described above and Z is chlorine or bromine.

The reaction is carried out using sodium bicarbonate, sodium carbonate, pyridine, triethylamine as acid acceptors in the presence or absence of solvents such as benzene, toluene, xylene, pyridine, dioxane, dimethylporamide, between room temperature and 150 ° C. Is performed.

The compound of formula (III) is prepared by reacting aldehyde of formula (V) with aldehyde of formula (VII).

Wherein R ₁ , R ₂ , R ₃ are as described above and are inert solvents such as benzene, toluene, xylene, dioxane, ethanol, dimethoxyethane, bis- (2-methoxyethyl) ether, dimethylporamide It is carried out at room temperature to 150 ° C. using a base or acid catalyst such as ferridine, hydrochloric acid, silperinic acid P-toluenesylperrinic acid.

The compound of formula (IV) is then prepared by heating the compound of formula (VIII) in acetic anhydride between room temperature and reflux.

In the above formula, R, R ₁ , R ₂ are as described above.

Wherein R is as defined above and R ₆ is alkyl, in particular C ₁ -C ₄ alkyl.

The compound of formula (VIII) is a compound of formula (IX) and compound (VI) in benzene, toluene, dioxane, pyridine solvents at room temperature and 150 ° C or as an acid acceptor in the absence of solvent, sodium bicarbonate, sodium carbonate, pyridine, Triethylamine is used to hydrolyze ester groups with sodium or potassium hydroxide when R 6 is alkyl, between 10 ° C. and 100 ° C., in solvents such as water, lower alicyclic alcohols, in particular ethanol, dioxane and mixtures thereof. .

In which R is as described above.

Structural (V) compounds may be used to reduce the corresponding nitro-derivatives or organic compounds such as methanol, ethanol, dioxane, dimethylporamide, tetrahydrofuran or It can manufacture by making it react in a solvent.

Structural formula (VI) compounds are known and can be prepared by conventional methods. Next, the compound of formula (X) can be prepared from the compound of formula (X) wherein R ₆ is hydrogen by one of the following methods.

(aiii) React with phosgene in an acidic solution at room temperature.

(biii) between 50 ° C. and 120 ° C. in the presence or absence of a solvent such as dioxane, benzene, toluene or xylene, followed by reaction with ethyl chloroformate to obtain the corresponding N-carbethoxy derivative. It is cyclized using ethyl chloroformate. Or between 50 ° C. and 150 ° C. with acetyl chloride and PBr 3. The compound of formula (IX) is known and can be prepared by reducing the corresponding nitro derivative in a conventional manner.

In addition, the compound of formula (VII) is known.

The compound of the present invention has anti-allergic activity, and it can be seen that GOOSE Y. and Blair A.M.Y.N are active in passive skin sensitivity (PCA) experiments in rats (Immunology, 1969, 16: 749). Therefore it is used for the prevention and treatment of bronchial asthma, high fever, gallbladder, and skin diseases. An important property of the compounds of the present invention, when orally administered, shows high anti-allergic effects as potency ratios of various compounds, as shown in the following table, which is the active quinacase described in P 26 54 215,4. 6-carboxy-2- (2'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazoline (K11695) and 6-carboxy-2- (2'-methoxy which are sleepy derivatives It is reported compared with -5'-methyl-phenyl) -3,4-dihydro-4-oxo- quinazoline (K11963).

Anti-allergic action of compound K11695 is indicated by the value 1. Inventive compounds in the diagrams are represented by the following symbols.

[table]

Anti-allergic activity is described by Goose J. and Blair A.M.J.N (loc.cit) in Mota I., Immunology. 7, 681, (1964) can be used to determine the inhibition of IgE-indirect PCA using a cell-compatible antibody obtained in rats. The test compound is administered orally 15 minutes prior to antigen administration with at least 6 of each being used for all doses. The potency ratio is Finney. D.J. (1952), Statistical Method in Biological Assay, C. Griffin, London ,. Compounds of the invention can be evaluated for acute toxicity appearing 7 days after oral administration.

For example, LD 50 is as follows.

The compound of the present invention is administered by a conventional method, wherein the daily dose for oral and parenteral administration is preferably 0.5 to 15 mg / kg, and the daily dose for inhalation is preferably 0.5 to 100 mg, particularly 0.5 to 25 mg, May be administered.

Pharmaceutical compositions containing the compounds of the present invention and pharmaceutically toxic carriers or excipients vary depending on the dosage form. The composition may be formulated in conventional manner and components. For example, it can be topically administered as an aqueous solution, an oily solution, a suspension, an aerosol, an industrial powder, a tablet, a pill, a gelatin capsule, a granule, a cream, and a lotion agent.

For oral administration, preference is given to tablets, pills and gelatin capsules which contain the active and excipients, lubricants, binders, disintegrants, boiling mixtures, colorants, sweeteners, wetting agents and nontoxic inerts used in pharmaceutical formulations. . The excipients used are lactose, dextrose, sucrose, mannitol, sorbitol and cellulose. The lubricants include silica, talc, stearic acid, magnesium stearate, calcium stearate and polyethylene glycol. The binders are starch, gelatin, methylcellulose. Rose, carboxymethylcellulose, gum arabic, tragacanth and polyvinylpyrrolidone; disintegrants include starch, arginine acid, alginate and sodium starch glycolate; wetting agents include lecithin, polyzobate and la There is us sulphate. In pharmaceutical preparations, the processes of mixing, granulation, tableting, sugar coating or membrane coating are performed.

Administration may be by inhalation to treat allergic asthma, using conventional nebulizers as suspensions or solutions with the sodium salt of the active substance. The composition is also administered in a pressurized container, such as an aerosol, as a suspension or solution of the active substance in dichlorofluoromethane and dichlorotetrafluoroethane, which are conventional liquefied jets.

When the chemical component is poorly soluble in the jet liquid, nonionic surfactant lecithin is commonly used for this purpose to disperse the chemical component by adding ethanol, dipropylene glycol, isopropyl myristate and a surfactant.

The compound of the present invention can be administered in an air inhalation container suitable as a powder, in which case the active ingredient microparticles are mixed with the excipient lactose.

Furthermore, the compound of the invention can be intradermal or intravenous and can be administered as a suppository. In addition to in vivo administration, skin treatments may be topically administered as creams, lotions and pastas, with the actives being mixed with oily ointments and emulsions.

The following examples do not limit the invention to be viewed.

Example 1

50 ml of dioxane and dimethyl-4-amino-isophthalate (5 g) in 10 ml of anhydrous pyridine are treated overnight at room temperature with 7.5 g of 2-ethoxy-3-methoxy-benzoyl chloride. Dilute with water, collect precipitates, dissolve in ethyl acetate and wash with 5% sodium bicarbonate and water. Crystallization in isopropyl ether after evaporation to dryness in vacuo afforded dimethyl-4- (2'-ethoxy-3'-methoxy-benzoylamino) -isophthalate (9 g; melting point 113-115 ° C.), which is dioxane Dissolve in 80 ml and treat with 70 ml of 1N sodium hydroxide for 4 hours at room temperature. The precipitate formed by acidification with diluted hydrochloric acid is collected in vacuo and washed with water until neutral. 7.4 g of 4- (2-ethoxy-3'-methoxy-benzoylamino) -isophthalic acid having a melting point of 244 to 246 ° C. are treated with 10 ml of anhydrous acetic acid for 10 minutes at reflux. After cooling, it is diluted with 60 ml of isopropyl ether and filtered. 5 g of 6-carboxy-2- (2'-ethoxy-3'-methoxy-phenyl) -4H-3,1-benzoxazin-4-one having a melting point of 175 to 177 ° C. are obtained, which is the first at room temperature. The reaction was reacted with 70 ml of 32% ammonium hydroxide for 4 hours, followed by overnight reaction with 2N sodium hydroxide. The precipitate resulting from acidification with 4N hydrochloric acid was filtered and determined in ethanol to give 6-carboxy-2- (2'-ethoxy-3'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin ( 3 g, melting point 228 to 229 ° C.) is obtained.

In the same way the following compounds can be obtained:

Example 2

The starting material is 2-alkoxy-3-ethoxy-benzoyl-chloride and following the same preparation as in Example 1, the following compounds are prepared:

6-carboxy-2- (2'-methoxy-3'-ethoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin melting point 272-273 ° C.

6-carboxy-2- (2 ', 3'-diethoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin melting point 233-234 ° C

Example 3

The starting material is 2-alkoxy-5-ethoxy-benzoyl-chloride and the following compounds are prepared by the same preparation method as in Example 1:

Example 4

17 g of 4-amino-isophthalic acid is refluxed for 18 hours in 800 ml of methanol and 39 ml of etherate. After concentration in vacuo, dilution with water, filtration and the resulting precipitate are partitioned between 250 ml of ethyl acetate and 250 ml of 5% sodium bicarbonate. The precipitates formed by separating and acidifying the aqueous phase are filtered off and washed with water until neutral. 12 g of 2-amino-5-carbomethoxybenzoic acid are obtained, which are reacted under reflux for 20 hours with 60 ml of ethyl chlorocarbonate in 80 ml of dioxane. 48 ml of acetyl chloride are added and refluxed for 72 hours. The suspension obtained is concentrated in vacuo, diluted with ethyl ether and filtered. 10 g of 5-carbomethoxy-isotoanhydride having a melting point of 275 to 278 ° C. are obtained, which is treated with 25 ml of 32% ammonium hydroxide in 25 ml of dimethylporamide for 30 minutes at room temperature. The precipitate formed after dilution with water is filtered and washed until neutral. 8.1 g of 2-amino-5-carbomethoxybenzamide is obtained, which is dissolved in 10 ml of 80 mldh pyridine in dioxane and reacted with 14 g of 2-ethoxy-3-methyl-benzoyl-chloride for 16 hours at room temperature. After dilution with water, the precipitate is filtered off and washed until neutral. Crystallization in ethanol yields 9.4 g of 2- (2'-ethoxy-3'-methyl-benzoylamino) -5-carbomethoxybenzamide which is treated with 45 ml of 2N sodium hydroxide in 45 ml of dioxane for 8 hours at room temperature. do. After dilution with water and acidification, the precipitate is filtered and washed with hot ethanol to give 6-carboxy-2- (2'-ethoxy-3'-methyl-phenyl) -3,4-dihydro-4-oxo-quina 7.4 g of sleepy are obtained. Melting point 240-241 ° C. Similarly the following compounds are obtained

6-carboxy-2- (2'-methoxy-3'-methyl-phenyl) -3,4-dihydro-4-oxo-quinazolin melting point 252 to 253 ° C

Example 5

The starting material is 2,5-dialkoxy-benzoyl-chloride and according to the preparation method of Example 1 the following compounds are obtained.

Example 6

The starting material is 2-ethoxy-5-alkyl-benzoyl-chloride and according to the preparation method of Example 1, the following compounds can be obtained.

Example 7

2-amino-5-carbomethoxy-benzamide (4 g) obtained in Example 4 was reacted with 4.5 g of 2-ethoxy-3-methoxy-benzaldehyde when 0.2 ml of piperidine and 150 ml of xylene were present. Reflux for time. After cooling, the resulting precipitate is filtered off and washed with benzene.

Obtain 3.9 g of 6-carbomethoxy-2- (2'-ethoxy-3'-methoxy phenyl) -1,2,3,4-tetrahydro-4-oxo-quinazolin, which is 250 ml of acetone Dissolved in a fine powder of potassium permanganate was slowly added and oxidized at 0? 5 占 폚 for 3 hours. After 1 hour of excess sodium sulfite was added, the inorganic precipitate was filtered off, and the acetone solution was evaporated to dryness, leaving a residue. When recrystallized from ethanol, 6-carboxymethoxy-2- (2'-ethoxy having a melting point of 165 to 167 ° C. 2. 6 g of -3'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazoline are obtained. This is treated with 12 ml of 1N sodium hydroxide in 25 ml of dioxane for 16 hours at room temperature. Dilution with water and acidification gave 6-carboxy-2- (2'-ethoxy-3'-methoxy phenyl) -3,4dihydro-4-oxo-quinazolin (2.1 g; melting point 228-229 ° C). Obtained.

Similarly, the following compounds are obtained.

Example 8

Thionyl chloride excess of 6-carboxy-2- (2'-ethoxy-3'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin 5.8 obtained in Example 1 in dioxane (2 mols / mol) at reflux for 4 hours. After cooling and concentrated to dryness under reduced pressure, the residue was reacted with excess anhydrous ethanol at 50 ° C. for 2 hours. After cooling, the precipitate is filtered off and washed with ethanol and water. 5.1 g of 6-carb ethoxy-2- (2'-ethoxy-3'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin having a melting point of 168 to 169 ° C are obtained. Similarly the following compounds are obtained:

Example 9

3.6 g of 6-carboxy-2- (2 ', 3'-dimethoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin is treated with 800 mg of sodium bicarbonate with hot water. After cooling, the solution is filtered, concentrated to a small amount and diluted to 4 volumes of acetone. The precipitate is filtered off and washed with acetone

Example 10

Preparation with an alicyclic alcohol suitable according to example 8 yields isopropyl ester tert-butyl ester, octyl ester, hexyl ester, undecyl ester of the following compounds.

Example 11

6.1 g of 6-chlorocarbonyl-2- (2'-ethoxy-3'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin obtained in Example 8 was added to 60 ml of dioxane. Suspension and treat as 4.2 ml of 2- (N, N-diethylamino) -ethanol and 1 ml of triethyleneamine for 18 hours at room temperature. After dilution with water and alkalinization with potassium carbonate, the precipitate is filtered and washed to neutrality and crystallized from ethanol.

2- (N, N-diethylamino) -ethyl ester of 6-carboxy-2- (2'-ethoxy-3'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin 5.5 g are obtained. Melting Point 93-94 ° C

Similarly, 2- (N, N-diethylamino) -ethyl ester of the following compound is obtained.

Example 13

A 150 mg tablet containing 50 mg of active substance is prepared as follows.

6-carboxy-2- (2'-ethoxy-3'-methoxy-phenyl) -3,4-dihydro-4-oxo-quinazolin,

양을 혼합한다; 혼합물을 구경 0.5mm인 체를 통과시킨다. 옥수수전분 18g을 온수 180ml에서 현탁시켜서 생기는 죽상을 약품분말을 과립화하는데 사용한다. 과립을 건조시켜 구경 1.4mm의 체를 통과시키고 나머지 전분, 탈크 및 마그네슘 스테아레이트를 가하고, 잘 혼합한 후 직경 8mm인 펀취로 제정한다.Lactose and Corn Starch

Mix the amounts; The mixture is passed through a sieve with a diameter of 0.5 mm. The porridge produced by suspending 18 g of corn starch in 180 ml of hot water is used to granulate the pharmaceutical powder. The granules are dried and passed through a sieve of 1.4 mm in diameter and the remaining starch, talc and magnesium stearate are added, mixed well and entrained in a punch of 8 mm in diameter.

Example 14

[Aerosol Composition]

Claims (1)

A method of preparing a compound of formula (I) by cyclizing the compound of formula (II) with a base or dehydrogenating agent or oxidizing the compound of formula (III).

Wherein R is ester and carboxy or free carboxy, R ₁ is a) C ₁ -C ₄ alkyl which may be optionally substituted with C ₁ -C ₂ alkoxy, b) C ₃ -C ₄ alkenyl, R ₂ is hydrogen, methyl or C ₁ -C ₂ alkoxy and R ₃ is a ′) hydrogen; b ') C ₁ -C ₆ alkoxy, optionally substituted with C ₁ -C ₂ alkoxy, c') C ₂ -C ₄ alkyl; d ') C ₃ -C ₄ alkenyloxy. only; One of R ₂ and R ₃ is hydrogen and the other is not hydrogen. When R ₁ is methyl and R ₂ is hydrogen, R ₃ is not unsubstituted methoxy.