KR910009940B1 - Process for the preparation of quinazoline compound - Google Patents

Abstract

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Description

Method for preparing quinazolinone derivatives

The present invention relates to a method for preparing a novel quinazolinone compound, and more particularly, to a method for preparing a new quinazolinone compound of the following general formula (I) and salts thereof useful for the prevention and treatment of various diabetic complications. It is about.

Wherein R is a hydrogen atom or lower alkyl, R ¹ is lower alkyl, substituted or unsubstituted phenyl, or aralkyl, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, Halogen atom, lower alkyl, lower alkoxy, lower alkoxycarbonyl or lower alkoxycarbonyl-low alkenyl, or two adjacent groups in R ² , R ³ , R ⁴ and R ⁵ may be bonded together to form methylene dioxy And the other two groups represent hydrogen.

The present invention also includes the novel quinazolinone compounds of formula (I) and pharmaceutical compositions containing these compounds as active ingredients.

Diabetic complications include diabetic neurosis, diabetic cataracts, diabetic microvascular disease, for example diabetic retinopathy and diabetic nephropathy, and the like. It is known to be caused by the accumulation of polyols, such as sorbitol converted from. The New England Journal of Medicine, Vol. 288, 831-836 (1973). For the prevention and treatment of diabetic complications, to date, various aldose reductase inhibitors capable of inhibiting polyol accumulation in the body, for example, compounds having a chroman nucleus [Japanese Patent Laid-Open No. 53653/1978 And 45185/1982, and US Pat. No. 4,177,230, compounds having a thiazolidine nucleus (see Japanese Patent Application Laid-open No. 104876/1981), and compounds having a phthalazine nucleus [Japan] Korean Patent Publication No. 95582/1979 has been proposed.

In addition, several quinazolinone compounds, for example 3,1'-dimethyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5 '-Trion [Chemie Berichte, Vol. 103, 2394 (1970)] and 3,1 ', 3'-trimethyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazoline] -2,2', 5 ' Trion [Chemie Berichte, Vol. 110, 3949 (1977), but no pharmacological activity is known for these quinazolinone compounds.

The inventors have conducted extensive studies on various spiro [1,2,3,4-tetrahydro-quinazolin-4,4′-imidazolidine] compounds and their pharmacological activity, and unexpectedly known spiro Aldose reductase excels in compounds of formula (I) without substituents at the 1'- and 3'- positions of [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] It was found to have inhibitory activity.

It is an object of the present invention to provide novel quinazolinone compounds which have excellent aldose reductase inhibitory activity and are therefore useful for the prevention and treatment of diabetic complications. Another object of the present invention is to provide a process for the preparation of the novel compounds mentioned. It is a further object of the present invention to provide novel intermediates useful for the preparation of the novel quinazolinone compounds mentioned above. Another object of the present invention is to provide a pharmaceutical composition suitable for the prevention and treatment of diabetic complications. The above and other objects and advantages of the present invention will become apparent to those skilled in the art from the following description.

The compound of the present invention has the structure of general formula (I) mentioned above.

Substituents in general formula (I) represent the following groups.

The term "lower alkyl" refers to one to five carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, n-pentyl or isopentyl, etc. It means having a straight chain or branched alkyl having. The term "lower alkoxy" means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secondary-butoxy, tert-butoxy, n-pentyloxy or isopentyloxy Straight or branched alkoxy having 1 to 5 carbon atoms such as the like. The term “substituted or unsubstituted phenyl” refers to phenyl or phenyl substituted by a substituent selected from the group consisting of lower alkyl and halogen atoms, for example alkylphenyl having 1 to 5 carbon atoms in the alkyl moiety (eg methylphenyl , Ethylphenyl, n-propylphenyl, isopropylphenyl, n-butylphenyl, n-pentylphenyl and the like) and halogenophenyl (eg chlorophenyl, fluorophenyl, bromophenyl). The term “aralkyl” refers to phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety, such as benzyl, phenethyl and the like. The term "halogen atom" denotes fluorine, chlorine or bromine. The term "lower alkoxycarbonyl" refers to carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, n-pentyloxycarbonyl, and the like. Straight or branched alkoxycarbonyl having 2 to 6 is shown. The term "lower alkoxycarbonyl-lower alkenyl" refers to a straight or branched chain alkenyl having 2 to 6 carbon atoms substituted by the aforementioned lower alkoxycarbonyl, for example methoxycarbonylvinyl, ethoxy Carbonylvinyl, n-propoxycarbonylvinyl, isopropoxycarbonylvinyl, n-butoxycarbonylvinyl, n-pentyloxycarbonylvinyl and the like.

Preferred groups for the substituents present in formula (I) are hydrogen and C _1-4 alkyl for R; For R ¹ are C _1-4 alkyl, phenyl, C _1-4 alkyl-phenyl, halogenophenyl and phenyl-C _1-2 alkyl; Each of R ² , R ³ , R ⁴ and R ⁵ is hydrogen, halogen, C _1-4 alkyl, C _2-5 alkoxycarbonyl and C _2-5 alkoxy carbonyl-C _1-4 alkenyl or R ² , Methylenedioxy formed by two adjacent groups of R ³ , R ⁴ and R ⁵ .

Preferred compounds of the invention are those wherein R is hydrogen or C _1-4 alkyl; R ¹ is C _1-4 alkyl, phenyl, C _1-4 alkyl-phenyl, halogenophenyl, or phenyl-C _1-2 alkyl; R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents hydrogen, halogen, C _1-4 alkyl, C _2-5 alkoxycarbonyl or C _2-5 alkoxycarbonyl-C _2-4 alkenyl Or two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ join together to form methylene dioxy and the other two groups are compounds of formula (I) representing hydrogen.

More preferred compounds of the invention are those wherein R is hydrogen or C _1-4 alkyl; R ¹ is C _1-4 alkyl, phenyl C _1-4 alkyl-phenyl, halogenophenyl, or phenyl-C _1-2 alkyl; R ² is hydrogen, halogen or C _1-4 alkyl, R ³ and R ⁴ are the same or different and each is hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl or C _2-5 alkoxycarbonyl-C _2-4 alkenyl or R ³ and R ⁴ join together to form methylenedioxy; R ⁵ is hydrogen or a halogen compound of formula (I).

Still more preferred compounds of the invention are those wherein R is hydrogen, methyl or isobutyl; R ¹ is methyl, n-butyl, phenyl, methylphenyl, chlorophenyl or benzyl; R ² is hydrogen, chlorine or methyl; R ³ and R ⁴ are the same or different and are each hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxycarbonyl or ethoxycarbonylvinyl, or R ³ and R ⁴ join together to form methylenedioxy To; R ⁵ is a compound of formula (I) which is hydrogen, fluorine or chlorine.

Particularly preferred compounds of the invention are those wherein R is hydrogen or isobutyl; R ₁ is methyl, n-butyl, phenyl, methylphenyl, chlorophenyl or benzyl; R ² is hydrogen or methyl; R ³ is hydrogen, fluorine, chlorine, bromine, methyl or ethoxycarbonyl and R ⁴ is hydrogen, fluorine, chlorine, methyl or ethoxy, or R ³ and R ⁴ join together to form methylene dioxy; R ⁵ is a compound of formula (I) which is hydrogen, fluorine or chlorine.

In the next preferred embodiment, R is hydrogen or C _1-4 alkyl; R ¹ is C _1-4 alkyl; R ² is hydrogen; R ³ is halogen; R ⁴ is hydrogen, halogen or C _1-4 alkyl; R ⁵ is hydrogen or halogen. In particular R is hydrogen or isobutyl; R ¹ is methyl; R ² is hydrogen; R ³ is fluorine, chlorine or bromine; R ⁴ is hydrogen, chlorine or methyl; R ⁵ is hydrogen or chlorine.

Compound (I) of the present invention has an asymmetric carbon in the molecule and may therefore comprise two optical isomers. The present invention includes these optical isomers and racemic mixtures thereof.

According to the present invention, the compound (I) wherein R is a hydrogen atom, i.e., a compound of the general formula (I-a) or a salt thereof, (A) ring-closes a compound of the following general formula (II) or (III); (B) reacting a compound of formula (IV) with an amine compound of formula (V) or a salt thereof; (C) can be prepared by the step of hydrolyzing the compound of formula (VI) and optionally converting the obtained product to its salt.

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above, R ⁶ is lower alkyl, Z ¹ is an oxygen atom or a sulfur atom, R ⁷ is a lower alkyl, Z ² is a sulfur atom Or imino group.

The ring closure of compound (II) or compound (III) can be carried out in a suitable solvent. The ring closure of compound (II) is preferably carried out in the presence of an acid or in the presence of alkaline reagents and / or oxidizing agents. Such acids include hydrochloric acid, hydrobromic acid, formic acid, and the like. Alkaline reagents include alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (e.g. potassium carbonate, etc.). Oxidizing agents include hydrogen peroxide, m-chloroperoxybenzoic acid, ozone, nickel peroxide and the like. Solvents include water, methanol, ethanol, dimethylformamide, 1,2-dichlorobenzene, and the like. The reaction is preferably carried out at a temperature of 20 to 100 ° C, more preferably at a temperature of 60 to 90 ° C.

The ring-closure reaction of compound (III) (hereinafter referred to as compound (III-a)) in which Z ¹ is an oxygen atom is preferably performed at a temperature of 150 to 250 ° C, more preferably at a temperature of 180 to 200 ° C. Solvents include 1,2-dichlorobenzene, nitrobenzene, naphthalene, biphenyl, and the like.

The ring closure of compound (III) (hereinafter referred to as compound (III-b)) in which Z ¹ is a sulfur atom is preferably carried out in the presence of an alkaline reagent and / or an oxidizing agent. Alkaline reagents include alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (such as potassium carbonate), and the like. Oxidizing agents include hydrogen peroxide, m-chloroperoxybenzoic acid, ozone, nickel peroxide and the like. Solvents include water, methanol, acetone, acetic acid or mixtures thereof. The reaction is preferably carried out at a temperature of 0 to 80 ° C.

The reaction of compound (IV) with compound (V) or a salt thereof can be carried out in a suitable solvent. Compound (IV) preferably comprises a compound of formula (IV) wherein R ⁷ is lower alkyl such as methyl, ethyl propyl, butyl and the like. Salts of compound (V) include, for example, inorganic acid salts such as hydrochloride salts, sulfate salts and the like. Solvents include, for example, dichlorobenzene, toluene, methanol, ethanol, tetrahydrofuran, or mixtures thereof. The reaction is generally carried out at a temperature of room temperature to 200 ° C., preferably at a temperature of 50 to 160 ° C., under atmospheric pressure or under pressure. If the reaction is carried out under relatively mild conditions, the intermediate can sometimes be separated in the form of crystals, after which the intermediate can be reacted with compound (V) to afford the desired compound (I-a).

The hydrolysis reaction of compound (VI) can be carried out in a suitable solvent. The hydrolysis reaction of compound (VI), in which Z ² is a sulfur atom (hereinafter referred to as compound (VI-a)), is preferably carried out in the presence of an alkaline reagent and an oxidizing agent, and Z ² is an imino group. The hydrolysis reaction of [hereinafter referred to as compound (VI-b)] is preferably carried out in the presence of a nitrosation agent. Alkaline reagents and oxidizing agents include those mentioned for the ring-closure reaction of the compound (III-a. Nitrogenating agents include alkali metal nitrites, alkylnitrites, nitrosyl chlorides, nitrogen dioxide, etc. Solvents include water, acetic acid, sulfuric acid Etc. The reaction is preferably carried out at a temperature of 0 to 80 ° C.

On the other hand, the compound of formula (I-b) or a salt thereof may be prepared by treating the compound of formula (I-c) or a salt thereof with a halogenating agent and optionally converting the obtained product into a salt thereof. .

Wherein R ³¹ is a halogen atom, R ⁴¹ is a hydrogen atom or lower alkoxy, R ⁵¹ is a hydrogen atom or a halogen atom, and R and R ¹ are as defined above.

The starting compounds (I-c) can be used for the reaction in the form of free bases or in the form of their salts, for example alkali metal salts such as sodium salts, potassium salts.

The reaction of treating compound (I-c) with a halogenating agent can be carried out in a suitable solvent. Halogenating agents include sulfyl chloride, chlorine, bromine, iodobenzene dichloride, N-boromosuccinimide and the like. Solvents include acetic acid, tetrahydrofuran, dioxane, water or mixtures thereof. The reaction is preferably carried out at a temperature of 0 to 100 ° C, more preferably 20 to 70 ° C.

In addition, compounds of formula (I-d) or salts thereof may be prepared by reacting compounds of formula (VII) with alkylating agents, such as lower alkyl halides, removing protective groups, and then optionally converting the obtained product to its salts. Can be.

Wherein R 'is lower alkyl, X ¹ and X ² are protecting groups and R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above.

In the starting compounds (iv), protecting groups X ¹ and X ² include any conventional protecting group suitable for the protection of amino or imino groups, for example acetyl, benzyloxymethyl, benzoyl, benzyloxycarbonyl, tetra Hydrofuranyl and the like.

The alkylation reaction of compound (VII) with lower alkyl halides is preferably carried out in a suitable solvent in the presence of a base such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate and the like. Solvents include dimethylformamide, tetrahydrofuran, acetone, dimethyl sulfoxide and the like. The reaction is preferably carried out at a temperature of -20 to 100 ° C.

Removal of the protecting group is carried out by conventional methods suitable for each type of protecting group, for example by hydrolysis, electrolytic reduction reaction, treatment with base, treatment with acid, catalytic reduction reaction, oxidation reaction and the like. can do. The conversion reaction of the free base to a salt can be carried out by conventional methods.

If compound (I) is obtained in the form of a racemic mixture, they can be divided into individual optical isomers by conventional methods. For example, the optical cleavage reaction involves reacting a racemic mixture of compound (I) with a resolving agent in an appropriate solvent, separating the sparingly soluble diastereomeric salts into crystalline form, and then solubility of the two diastereomeric salts. This can be done by separating the soluble diastereomeric salt from the mother liquor using tea. The splitting agents include, for example, natural products such as buruic acid, quinine, synconidine, Nn-octylglucamine, dehydroabiethylamine, and the like, and optically active such as α-methylbenzylamine, lysine, phenylalanine amide, tyrosine hydrazide, etc. Compound is included. Solvents include methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water or mixtures thereof. The diastereomeric salts thus prepared can be converted to the desired optically active compound (I), for example, by treatment with an acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, etc.).

Starting compounds (II) and (III) used in the reaction are also novel compounds. Compound (II) is, for example, the presence of a base (eg, triethylamine, etc.) of a compound of the general formula or a salt thereof (eg, sodium salt, potassium salt, etc.) at a temperature of -20 to 50 ° C. Under reaction with a compound of the formula (VII) in a solvent to give a compound of the formula (VII), which is then reacted with a base (e.g. triethylamine, etc.) at a temperature of from 0 to 100 ° C. It can be manufactured by reacting with a compound of the formula (XI) or a salt thereof in a solvent in the presence of.

Wherein R ¹ , R ² , R ⁴ , R ⁵ and R ⁶ are as defined above.

Compound (III) is obtained by the compound (iii) or a salt thereof in the presence of a base (eg, 1,8-diazabicyclo [5.4.0] -7-undecene, triethylamine, etc.) at a temperature of 0 to 100 ° C. It can manufacture by reacting with the compound of general formula (XII) in a solvent.

Wherein Z ¹ is as defined above.

In addition, compound (II) can also be prepared by reacting compound (III-b) with a compound of the general formula (XIII) in a solvent in the presence of a base (for example, sodium hydride) at a temperature of 0 to 50 ° C.

Wherein X is a halogen atom and R ⁶ is as defined above.

Compound (IV) is reacted with a compound of formula (XIV) by reacting compound (VIII) or a salt thereof in a solvent in the presence of a base (e.g. triethylamine or the like) at a temperature of 0 to 80 캜. After obtaining a compound of, the compound (XV) can be prepared by reacting with urea in a solvent at a temperature of 50 to 120 ℃.

Wherein R ⁷ is lower alkyl and R ² , R ³ , R ⁴ , R ⁵ and X are as defined above.

Compound (IV-a) is prepared by heating compound (III-b) in a solvent at a temperature of 100 to 180 ° C. and then treating the obtained product with an acid (such as hydrochloric acid) at a temperature of 20 to 100 ° C. can do.

Compound (VI-b) may be prepared by reacting compound (.VII) with guanidine or a salt thereof in a solvent at the temperature of 20 to 100 ° C. in the presence or absence of a base (such as sodium hydroxide). In this reaction, the compound of general formula (XIV) is obtained as a by-product.

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above. This by-product (VI) is treated with an acid (such as hydrochloric acid) to give compound (VI-b).

Compound (I) of the present invention can be used as a medicament in the form of a free base or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include, for example, sodium salts, potassium salts, calcium salts, lysine salts, ethylenediamine salts, diethanol amine salts, and the like. These salts can be easily prepared by treating the free base of compound (I) with a base by a conventional method.

Compound (I) and salts thereof have excellent aldose reductase inhibitory activity, and thus have various chronic syndromes associated with diabetes in warm-blooded animals, namely diabetic complications such as diabetic neurosis, diabetic cataracts, and diabetic retinopathy and It is useful for the prevention and treatment of diabetic microvascular lesions such as diabetic nephropathy. Compounds (I) and salts thereof of the present invention also have the advantage that they have low toxicity and small neurotoxic side effects (e.g., difficulty walking, no reflection, no stereotyping, emphysema).

Compound (I) and salts thereof of the present invention can be administered orally or parenterally. These are conventional pharmaceutical preparations and can be administered, for example, in tablets, granules, granules, powders, capsules, injections, eye drops (eg, eye washes, ointments, etc.). These formulations can be prepared by mixing the active compound (I) or salts thereof with a conventional, pharmaceutically acceptable carrier or diluent. Pharmaceutically acceptable carriers or diluents include excipients (e.g., sucrose, starch, mannitol, glucose, cellulose, talc, calcium phosphate, etc.), binders (e.g. methylcellulose, gelatin, gum arabic, polyethyleneglycol, etc.) Disintegrants (e.g. starch, carboxymethylcellulose, sodium bicarbonate, calcium phosphate, etc.), lubricants (e.g. magnesium stearate, talc, sodium lauryl sulfate, etc.), preservatives (e.g. sodium benzoate, sodium hydrogen sulfide) Etc.), stabilizers (e.g. citric acid, sodium citrate, etc.).

The dosage of Compound (I) and its pharmaceutically acceptable salts may vary depending on the route of administration, the age, weight and condition of the patient, the severity of the lesion, etc., but is typically about 0.01 to 200 mg / kg, preferably 0.1, per day. To 50 mg / kg.

The pharmacological activity of compound (I) and salts thereof is illustrated by the following experiment.

[Experiment 1]

Aldose Reductase Inhibitory Activity:

[Way]

The aldose reductase is obtained from the lens of a male rabbit (weight 2.5-3.5 kg) in the same manner as described in J. Biol. Chem. Vol. 240,877-882 (1965). The inhibitory activity of the test compound is determined by the same method as described in Biochem. Biophys. Acta., Vol. 128,474-482. The aldose reductase inhibitory activity of the test compound inhibits the aldose reductase activity by 50%. It is indicated by the concentration of test compound required to do so (ie 50% inhibitory concentration: IC ₅₀ ).

[Test Compound]

[result]

The results are shown in Table 1.

TABLE 1

[Exam 2]

Inhibitory activity on the accumulation of polyols:

[Way]

Slc: Wistar male rats (3 to 4 weeks old, one group: three rats) (iii) a 20% galactose-added diet containing 20 mg% of the test compound (i.e., test) Compound is contained in an amount of 20 mg per 100 g of diet) (test compound dosing group), (ii) 20% galactose-added diet (galactose control group) and (iii) normal diet (galactose) (Normal control) is fed for 6 days. After feeding, the rats were lethal by cutting the carotid artery under ether anesthesia, and then the amount of polyol accumulated in the sciatic nerve by extracting both sciatic nerves was described in Science, Vol. 182, 1146-1148 (1973), by the acetyl-acetone method. The inhibition rate of polyol accumulation is calculated by the following equation.

[result]

As a result of the experiment, the compounds of the present invention (ie Test Compound Nos. 1 to 10) used in Experiment 1 all exhibited 50% or more inhibition of polyol accumulation.

[Experiment 3]

Observation of severe toxicity and syndrome: A suspension of test compound in 0.5% carboxymethyl cellulose is orally administered to ddY male mice and all reactions and symptoms of the mice are observed for 14 hours. As a result, d- and dL-6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2, compounds of the present invention, None of the mice that received 2 ', 5'-trione at doses of 10 g / kg each died and had any abnormalities such as difficulty walking, anechoic reflexes, anarchy, scab, respiratory distress, skin redness, and uterus. No symptoms were observed. Compound (I) of the present invention and salts thereof and a method for preparing the same are illustrated by the following Examples and Preparation Examples.

Example 1

5-Chloro-1-methylcarbamoylisatin (4.0 g) was dissolved in tetrahydrofuran (40 ml), and 2-ethylisothiourea hydrobromide (4.0 g) and triethylamine (3.0 ml) were added thereto. Add and stir the mixture at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure to remove the solvent. To the residue [ie 6-chloro-3-methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazolin] 10% hydrochloric acid (50 ml) is added and the mixture is stirred at 70-80 for 3 hours. After cooling, the precipitate was taken up by filtration to give 6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2'-5 '-Trione [2.5 g, yield 53.1%) is obtained.

[Examples 2 to 22]

The corresponding starting compounds are treated in the same manner as described in Example 1 to give the compounds shown in Table 2.

TABLE 2

Example 21

3-Methyl-4-hydroxy-4- (2-ethylisothioureidocarbonyl) -2-oxo-1,2,3,4-tetrahydroquinazoline (2.0 g) in 10% hydrochloric acid (20 ml) Suspension and the mixture is stirred at 70 to 80 ° for 3 hours. After cooling, the precipitate was filtered off and recrystallized from dimethyl sulfoxide to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 '. , 5'-trione (1.2 g) is obtained.

[Examples 22 to 23]

Treatment of the corresponding starting material in the same manner as described in Example 21 yields the following mixture.

(22) 3- (4-methylphenyl) -spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione.1 / 2HCON (CH ₃ ) ₂

(23) 3- (4-chlorophenyl) -spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] 2,2 ', 5'-trione.1 / 2HCON (CH ₃ ) ₂

Example 24

(1) 5,6-dichloro-1-methylcarbamoylisatin (9.6 g) was suspended in tetrahydrofuran (100 ml), and thiourea (3.0 g) and triethylamine (5.6 ml) were added thereto. The mixture is stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration to give 6,7-dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydro at a melting point of 225 to 228 ° C. Obtain quinazoline (4.1 g).

(2) Dimethyl 6,7-dichloro-3-methyl-4-hydroxy-4-thioureido-carbonyl-2-oxo-1,2,3,4-tetrahydroquinazolin (2.8 g) Dissolve in formamide (30 ml) and add sodium hydride (0.32 g of 60% oily suspension) and stir the mixture for 30 minutes at room temperature. Ethyl bromide (2 ml) is added to the mixture, the mixture is stirred for an additional 30 minutes, and then the solvent is distilled off under reduced pressure. Residue [ie 6,7-dichloro-3-methyl-4-hydroxy-4- (2-ethylisothioureido) -carbonyl-2-oxo-1,2,3,4-tetrahydroquina 10% hydrochloric acid (30 ml) is added to Joline and the mixture is stirred at 70 ° C. for 4 hours. After cooling, the precipitate was filtered off and washed with 10% aqueous sodium hydrogen carbonate solution and then recrystallized from dimethylformamide-water [6,7-dichloro-3-methyl-spiro [1,2,3,4-tetra]. Hydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (1.4 g) is obtained.

Example 25

3-Methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazolin (1.5 g) was added to 1,2-dichlorobenzene (30 ml) and the mixture was Reflux with stirring for 1.5 hours. After cooling, the precipitate was filtered off and recrystallized from dimethyl sulfoxide to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 '. 5'-trione (0.8 g) is obtained.

Example 26

d-3-methyl-spiro [1,2,3,4-tetharidroquinazolin-4,4′-imidazolidine] -2,2 ′, 5′-trione (17.24 g) was diluted with acetic acid ( 170 ml), and the mixture is added dropwise to sulfuryl chloride (8.54 ml) and the mixture is stirred at room temperature for 1.25 hours. The reaction mixture is poured into ice water (500 ml) and the precipitate is collected by filtration. The crystals thus obtained are dissolved in ethanol (1 liter) and the undissolved material is filtered off. The filtrate is treated with activated carbon and then the solvent is distilled off under reduced pressure. Water is added to the residue, the precipitate is collected by filtration, washed with water and dried. The process was repeated one more time to obtain d-6-chloro-3-methyl-3spiro [1,2,3,4-tetrahydroquinazolin-4,4′-imidazolidine] -2,2 ′. , 5'-trione monohydrate, which product has an R-configuration at the 4-position of the quinazolinone nucleus (14 g, yield: 71.3%).

[Examples 27 to 29]

The corresponding starting materials were treated in the same manner as described in Example 26 to afford the compounds shown in Table 4.

TABLE 4

^* 1): This compound is a left-handed isomer.

^* 2) This compound has NMR spectral data:

Example 30

3-Methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (1.23 g) in acetic acid (50 ml) Dissolve and add iodine and sulfyl chloride (4.0 ml) and stir the mixture at 60 ° C. for 90 hours. After cooling, water (100 ml) is added to the mixture and the mixture is stirred under ice cooling. The precipitate is collected by filtration. The crystals thus obtained are dissolved in aqueous sodium hydroxide and the undissolved material is filtered off. The filtrate was triturated with 10% hydrochloric acid, the precipitate was collected by filtration, washed with water and dried to give 6,8-dichloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4′-imida Zolidine] -2,2 ', 5'-trione (1.35 g, yield: 85.4%) is obtained.

Example 31

6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (1.4 g) was added 10.86 Dissolve in% (w / w) aqueous sodium hydroxide and treat this solution with activated carbon and then concentrate under reduced pressure. The residue is crystallized from ethanol and then collected by filtration. The crystals thus obtained were washed with ethanol and isopropyl ether and dried to give 6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine]- 2,2 ', 5'-trione-1'-sodium salt (1.17 g, yield: 77.3%) is obtained.

Example 32

In the same manner as described in Example 31, the corresponding starting material is treated to give the following compound: (32) d-6-chloro-3-methyl-spiro [1,2,3,4-tetrahydro Quinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione-1'-sodium salt (yield 84.6%). Melting Point: ＞ 280 ℃

Example 33

Isatine (294.3 g) is suspended in tetrahydrofuran (3), to which triethylamine (279 ml) and methylisocyanate (129.8 ml) are added with stirring at 15 ° C. The mixture is stirred for 2.5 hours at 20-25 ° C. (1-methyl-carbamoylisatin is produced in the mixture). To the reaction mixture is added 2-ethylisothiourea hydrobromide (444.2 g) and triethylamine (55.8 ml) and the mixture is refluxed for 2 hours. After cooling, the solvent is distilled off under reduced pressure. 10% hydrochloric acid in the residue [ie 3-methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazolin] 4 liters) is added and the mixture is stirred at 70 ° C. for 4 hours. After cooling, the precipitate was collected by filtration, washed sequentially with water, methanol (1 liter) and chloroform (1 liter), followed by drying to afford 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4, 4'-imidazolidine] -2,2 ', 5'-trione (369.2 g, yield: 75%).

The physicochemical properties of this product are the same as the product prepared in Example 21.

Example 34

(1) dl-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (12.3 g) and Burucine dihydrate (21.5 g) is dissolved in a mixture (625 ml) of methanol and water (3: 2 volume ratio) while heating. After cooling the solution, the precipitate is collected by filtration (filtrate is called "filtrate (I)"). The crystals thus obtained were crystallized from a mixture of methanol and water (3: 2) to give d-3-methyl-spiro [1,2,3,4-tetrahydro-quinazolin-4,4′-imidazolidine ] -2,2 ', 5'-trione leucine salt (7.8 g) is obtained. [α] _D ²⁰ -67.0。 (c = 1, dimethylformamide)

The obtained salt is dissolved in water (20 ml), and concentrated hydrochloric acid (2 ml) is added thereto. The precipitate was collected by filtration and recrystallized from a mixture of methanol and water to give d-3-methyl-spiro [1,2,3,4-tetra hydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (2.3 g) is obtained. Melting Point: 174-176 ° C

[α] _D ²⁰ +34.7。 (c = 1, ethanol)

(2) The filtrate (I) obtained in (1) was concentrated to dryness under reduced pressure, and the residue was dissolved in water (60 ml). The solution is neutralized with concentrated hydrochloric acid (6 ml) and the precipitate is collected by filtration. The filtrate is distilled off under reduced pressure to remove the solvent, and the precipitate is collected by filtration. The crystals were recrystallized from a mixture of methanol and water to give l-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'- Trion (2,1 g) is obtained. Melting Point: 174-176 ° C

[α] _D ²⁰ -34.7。 (c = 1, ethanol)

Example 35

(1) dl-6-fluoro-3-methyl-spiro [1,2,3,4-tetra hydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (8.1 g) and quinine (prepared from 16.0 g of quinine hydrochloride) are dissolved in a mixture (450 ml) of methanol and water (2: 1 volume ratio) while heating. After cooling the solution, the precipitate is collected by filtration (filtrate is called "filtrate (II)"). Thus here d-6-fluoro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione Quinine salt (4.0 g) is obtained.

[α] _D ²⁰ -20.8。 (c = 1, dimethylformamide)

2% hydrochloric acid is added to the salt (4.0 g) obtained above. The precipitate was collected by filtration and recrystallized from a mixture of methanol and water to give d-6-fluoro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4′-imidazolidine]-. 2,2 ', 5'-trione (1.1 g) is obtained. Melting Point 267 ℃

[α] _D ²⁰ +37.6。 (c = 1, ethanol)

(2) The filtrate (II) obtained in (1) was adjusted to pH 2 with 10% hydrochloric acid, and the precipitate was collected by filtration. The filtrate is neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract is distilled off under reduced pressure to remove the solvent and the residue is neutralized with 2% hydrochloric acid. The precipitate was collected by filtration and recrystallized from a mixture of methanol and water to give l-6-fluoro-3-methyl-spiro [1,2,3,4-tetra hydroquinazolin-4,4'-imidazolidine]-. 2,2 ', 5'-trione (0.7 g) is obtained. Melting Point: 267 ℃

[α] _D ²⁰ -39.6。 (c = 1, ethanol)

Example 36

3'-acetyl-1'-benzyloxymethyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2'5'-tri Warm (3.06 g) is dissolved in dimethylformamide (20 ml), to which methyl iodide (1 ml) is added, followed by the addition of sodium hydride (60%) (0.3 g) gradually under ice-cooling and the mixture at room temperature for 30 minutes. Stir in Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The residue was purified by silica gel column chromatography (solvent: chloroform) to give 3'-acetyl-1'-benzyloxymethyl-1,3-dimethyl-spiro [1,2,3,4-detrahydroquinazolin-4 , 4′-imidazolidine] 2,2 ′, 5′-trione (3 g, yield: 94.5%) is obtained as an oily material.

(2) The product (3.0 g) was dissolved in ethanol (20 ml), 0.2 g of palladium black was added thereto, and the mixture was subjected to catalytic reduction under hydrogen gas pressure (2 to 3 atmospheres) for 5 hours. . The catalyst is filtered off and the solvent is distilled off.

The residue is dissolved in 10% aqueous sodium carbonate and the mixture is heated at 60-80 ° C. for 30 minutes. The reaction mixture was neutralized with 10% hydrochloric acid, the precipitate was collected by filtration and recrystallized from dimethylformamide-water to give 3'-acetyl-1,3-dimethyl-spiro [1,2,3,4-tetra hydroquinazolin-4 , 4'-imadazolidine] -2,2 ', 5'-trione (0.85 g) is obtained.

(3) The product (1.0 g) was added to a sodium ethylate solution (prepared from metal sodium (161 mg) and ethynal (20 ml)) and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent, the residue is neutralized with 10% hydrochloric acid and the mixture is left to stand. The precipitate was collected by filtration and recrystallized from dimethyl formamide-water to give 1,3-dimethyl-spiro [1,2,3,4-detrahydroquinazolin-4,4'-imidazolidine] -2,2 ′, 5′-trione (500 mg) is obtained as a colorless prismatic material. Melting Point: 223-225 ° C

Example 37

3′-acetyl-1′-benzyloxymethyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4 in the same manner as described in Example 36- (1) '-Imidazolidine] -2,2', 5'-trione and isobutyl iodide were reacted to react with 3'-acetyl-1'-benzyloxymethyl-1-isobutyl-3-methyl-spiro [ 1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione is obtained. Melting Point: 70-72 ℃

The product was treated in the same manner as described in Examples 36- (2), (3) to give 1-isobutyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4 ′. -Imidazolidine] -2,2 ', 5'-trione is obtained. Melting Point: 270 ℃

Example 38

1-isobutyl-3-methylspiro [1,2,3,4-tetrahydroquinazolin-4,4′-imidazolidine] -2,2 ′, 5′-trione prepared in Example 37 (0.76 g) is suspended in acetic acid (15 ml), to which furfuryl chloride (0.3 ml) and a small amount of iodine are added and the mixture is stirred at rt for 19 h. The reaction mixture is poured into ice water, the precipitate is collected by filtration and the crystals dissolved in 10% aqueous sodium hydroxide. The undissolved material is filtered off, the filtrate is neutralized with 10% hydrochloric acid, and the precipitate is collected by filtration (these dissolution and precipitation processes are repeated). The precipitate was collected by filtration and dried to give 6-chloro-1-isobutyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ' , 5'-trione (0.45 g) is obtained. Melting Point: 118 ℃

Example 39

5- (5-chloro-2-ethoxycarbonylaminophenyl) -5-hydroxy imidazolidine-2,4-dione (9.4 g), 40% methylamine-methanol solution (5.11 g), toluene ( 200 ml) and ethanol (20 ml) are stirred at 120 ° C. for 4 hours in a pressure vessel. After cooling, the precipitated crystals were separated by filtration, washed successively with toluene and methanol and dried to give 6-chloro-3-methyl-spiro [1,2,3,4-tetra hydroquinazolin-4,4′- Imidazolidine] -2,2 ', 5'-trione (2.33 g) is obtained. The physical properties of this product are the same as the physical properties of the product obtained in Example 1.

Example 40

5- (2-ethoxycarbamoylaminophenyl) -5-hydroxyimidazolidine-2,4-dione (8.37 g), 10% methylamine-ethanol solution (21.5 g) and 2,3-dichlorobenzene (200 ml) is stirred at 150 ° C. for 2 hours in a pressure vessel. After cooling, the reaction mixture is extracted with 1N NaOH solution and the aqueous layer is neutralized with 10% hydrochloric acid. The precipitated crystals were separated by filtration, washed successively with water and ethanol, and then dried to 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine]- 2,2 ', 5'-trione (2.6 g) is obtained. The physical properties of this product are the same as the physical properties of the product obtained in Example 21.

Example 41

A mixture of 5- (2-methoxycarbamoylaminophenyl) -5-hydroxyimidazolidine-2,4-dione (2.65 g), 10% methylamine-ethanol solution (12 g) and toluene (60 ml) Stir in a pressure vessel for 4 hours at 110 ℃. The reaction mixture was treated in the same manner as described in Example 40 to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ' , 5'-trione (0.51 g) is obtained.

The physical properties of this product are the same as the physical properties of the product obtained in Example 21.

Example 42

(1) 5- (2-ethoxycarbonylaminophenyl) -5-hydroxyimidazolidine-2,4-dione (27,9 g) in 40% methylamine-ethanol solution (17 g), toluene (600 ml ) And methanol (600 ml) and the mixture is stirred at room temperature for 1 hour. The precipitated crystals are separated by filtration, washed with toluene and dried to give crystalline product (29 g) with a melting point of 130 to 133 ° C.

(2) A mixture of crystalline product (2.51 g), 20% methylamine-ethanol solution (6.1 g), toluene (60 ml) and ethanol (6 ml) obtained above was stirred in a pressure vessel at 110 ° C. for 4 hours. . After cooling, the precipitated crystals were separated by filtration and dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5 Obtain tri-methylamine salt (1.06 g). Melting Point: ＞ 280 ℃

Example 43

5- (2-ethoxycarbonylaminophenyl) -5-hydroxyimidazolidine-2,4-dione (139.5 g) was treated in the same manner as described in Example 42- (1), The precipitated crystals are separated by filtration. The crystals are added to a mixture of 40% methylamine-methanol solution (95.25 g), toluene (3.3 liters) and ethanol (330 ml) and the mixture is refluxed at about 75 ° C. for 15 minutes. To the reaction mixture is added 40% methylamine-methanol solution (155 g) dropwise over 1 hour and the mixture is further refluxed for 2.5 hours. The precipitated crystals are separated by filtration and then dissolved in water. The aqueous solution was neutralized with 10% hydrochloric acid and the precipitated crystals were separated by filtration, washed with ethanol and dried to 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4′-imida Zolidine] -2,2 ', 5'-trione (43 g) is obtained.

The physical properties of this product are identical to the physical properties of the product obtained in Example 21.

Example 44

(1) 1-methylcarbamoylisatin (4.08 g) is dissolved in tetrahydrofuran (50 ml). Triethylamine (2.22 g) and thiourea (1.7 g) are added to this solution and the mixture is stirred at room temperature for 3 hours. The precipitated crystals were separated by filtration, washed with water and dried to obtain 4-hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo- with a melting point of> 280 ° C (recrystallized from dimethylformamide-ethanol). 1,2,3,4-tetrahydroquinazoline (3.7 g) is obtained.

(2) The product (1.0 g) obtained above was dissolved in 10% aqueous sodium hydroxide (10 ml). 30% hydrogen peroxide (2 ml) is added to the mixture and the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture is acidified with 10% hydrochloric acid. The precipitated crystals were separated by filtration, washed and dried to 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5 '-Trione (0.75 g, yield 85.4%) is obtained.

The physical properties of this product are the same as the physical properties of the product obtained in Example 21.

Example 45

5,6-Dichloro-1-methylcarbamoylisatin (9.6 g) was treated in the same manner as described in Example 44- (1) to give 6,7-dichloro-4- at a melting point of 225 to 228 ° C. Hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline (4.1 g) is obtained. This product was treated in the same manner as described in Example 44- (2) to give 6,7-dichloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4 ′ -Imidazolidine] -2,2 ', 5'-trione is obtained.

The physical properties of this product are identical to the physical properties of the product obtained in Example 24.

Example 46

4-hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin (1.0 g) is dissolved in 10% aqueous sodium hydroxide (20 ml) and the mixture is Stir at 40-50 ° C. for 1.5 h. After cooling, the reaction product is acidified with 10% hydrochloric acid. The precipitated crystals were separated by filtration, washed and dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4′-imidazolidine] -2,2 ′, 5 ′ Trion (1.3 g, yield: 85.4%) is obtained.

The physical properties of this product are the same as the physical properties of the product obtained in Example 21.

Example 47

(1) 4-hydroxy-4-4thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin (2.2 g) was dissolved in dichlorobenzene (30 ml) The mixture is stirred at 200 ° C. for 2 hours. The precipitated crystals were separated by filtration and recrystallized from dimethylsulfoxide-water to give 2'-imino-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,5'-thiazoline] -2,4'-dione (1.3 g, melting point> 280 DEG C) is obtained.

(2) The product (1.3 g) is dissolved in 10% hydrochloric acid (20 ml) and the mixture is stirred at 80 ° C. for 3 hours. The precipitated crystals were separated by filtration and recrystallized from dimethyl formamide-water to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,5 '-Dione-2'-thione (1.1 g, melting point> 280 占 폚) is obtained.

(3) The product (1.0 g) is dissolved in 10% aqueous sodium hydroxide (10 ml). 30% hydrogen peroxide (2 ml) is added to the mixture and the mixture is stirred at room temperature for 1 hour. After the reaction, the reaction mixture is acidified with 10% hydrochloric acid. The precipitated crystals were separated by filtration, washed and dried to 3-methyl-spiro [1,2,3,4-tetra hydroquinazolin-4,4'-imidazolidine] -2,2 ', 5' Trion (0.85 g, yield 90.8%) is obtained.

The physical properties of this product are the same as the physical properties of the product obtained in Example 21.

Example 48

(1) Guanidine hydrochloride (0.57 g) is added to tetrahydrofuran (5 ml), to which 10N NaOH (0.6 ml) is added and the mixture is stirred at room temperature for 5 minutes. Tetrahydrofuran (15 ml) and 1-methylcarbamoylisatin (1.02 g) are added to the mixture, and the mixture is stirred at room temperature for 4 hours, after which the solvent is distilled off. 10% hydrochloric acid (10 ml) is added to the residue and the mixture is refluxed for 1 hour. After cooling, the precipitated crystals were isolated by filtration and washed with water and ethanol to give 2'-imino-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imida Zolidine] -2,5'-dione (0.86 g, melting point 257-259 ° C.) is obtained.

(2) The product (0.123 g) is dissolved in a mixture of acetic acid (1 ml) and water (2 ml). To this solution is added dropwise a solution of sodium nitrite (0.052 g) in water (1 ml) at room temperature. The mixture is stirred at rt for 1 h and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent, chloroform: methanol = 7: 3) to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4′-imidazolidine] -2,2 ', 5'-trione (39 mg) is obtained.

The physical properties of this product are the same as the physical properties of the product obtained in Example 21.

Example 49

3-Methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (1 g) was added to 10% aqueous sodium hydroxide ( 10 ml). This solution 30% hydrogen peroxide (2 ml) is added and the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture is acidified with 10% hydrochloric acid. The precipitated crystals were separated by filtration, washed with ethanol and dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (0.6 g, yield: 75%) was obtained.

The physical properties of this product are the same as the physical properties of the product obtained in Example 21.

The preparation of starting materials is described below.

[Production Example 1]

A mixture of 5-fluoroisatin (9.9 g), triethylamine (1 ml) and dimethyl formamide (30 ml) is stirred under ice cooling, and methyl isocyanate (3 g) is added dropwise at the same temperature. The mixture is stirred at room temperature for 30 minutes and the precipitate is collected by filtration to give 5-fluoro-1-methylcarbamoylisatin (8.7 g) at a melting point of 230 to 232 ° C.

Production Example 2 to 20

In the same manner as described in Preparation Example 1, the corresponding starting materials are treated to give the compounds shown in Table 5.

TABLE 5

* 1) This compound is the same compound as that described in Ann, chem., 1974, page 2003.

[Manufacture example 23]

1-methylcarbamoylisatin (8.16 g) is dissolved in tetrahydrofuran (100 ml), to which 2-ethylisothioureahydro bromide (7.4 g) is added and the mixture is stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with water and dried to obtain 3-methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3 at a melting point of> 280 ° C. , 4-tetrahydroquinazoline (8.0 g) is obtained.

Preparation Examples 24 to 25

Treatment of the corresponding starting materials in the same manner as described in Preparation 23 yields the following compounds.

(24) 3- (4-methylphenyl) -4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo- with a melting point of 215 to 218 ° C (recrystallized from dimethylformamide-water) 1,2,3,4-tetrahydroquinazoline

(25) 3- (4-chlorophenyl) -4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4- at a melting point of 223 to 224 ° C. Tetrahydroquinazoline

Production Example 26

Dissolve 1-methylcarbamoylisatin (10.2 g) and 1.8-diazabicyclo [5.4.0] -7-undecene (0.3 g) in tetrahydrofuran (100 ml), where urea (4.5 g) is added. And the mixture is refluxed for 10 hours. After cooling, the precipitate was collected by filtration, washed with water methanol and recrystallized from a mixture of dimethylsulfoxide and ethanol to 3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3 , 4-tetrahydroquinazolin (melting point:> 280 ° C) is obtained.

MS (m / e): 246 (M ⁺ -18)

[Production Example 27]

(1) 3-Methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (7.38 g) in dimethylform Dissolve in amide (60 ml), add sodium hydride (60%) (1.2 g) at 15 ° C. and stir the mixture for 30 minutes at room temperature. Benzyloxymethyl chloride (4.71 g) is added to the mixture at room temperature and the mixture is further stirred at room temperature for 30 minutes. Water is added to this mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and distilled to remove the solvent. The residue was crystallized from dimethyl formamide-water to give 1'-benzyloxymethyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 Obtain 5'-trione (10.4 g).

Melting Point: 226-227 ° C

(2) The product and acetyl chloride obtained above were treated in the same manner as described above, except that isopropanol-isopropyl ether was used as a solvent for crystallization, and 3′-acetyl- at a melting point of 209 to 211 ° C. 1'-benzyloxymethyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazolin-4,4'-imidazolidine] -2,2 ', 5'-trione (yield: 70%).

Production Example 28

(1) Isatin (29.4 g) is added to tetrahydrofuran (200 ml), and triethylamine (30.7 ml) is added thereto. Ethoxycarbonyl chloride (20.9 ml) is added dropwise with stirring to the mixture and the mixture is stirred at room temperature for 5 minutes. The solvent is distilled off and water is added to the residue. The precipitated crystals are separated by filtration, washed with water, isopropanol and diisopropyl ether, and then dried to give 1-ethoxycarbonylisatin (39.4 g) having a melting point of 113 to 116 ° C (decomposition).

This product is identical to the compound described in Journal fur Parktische Chemie, Band 315, 1973, pages 339-344.

(2) The product (2.79 g) was added to tetrahydrofuran (30 ml), and urea (1.15 g) was added thereto. The mixture is refluxed for 15 hours and then the solvent is distilled off. The residue is extracted with ethyl acetate. The extract is distilled off to remove the solvent and the residue is subjected to silica gel column chromatography (solvent, chloroform: methanol = 9: 1). Fractions containing the desired compound are collected and distilled to remove the solvent, and chloroform is added to the residue. The precipitated crystals were separated by filtration and dried to give 5- (2-ethoxycarbonylaminophenyl) -5-hydroxyimidazolidine-2,4-dione (2,42 g) having a melting point of 169 to 170 ° C. do.

[Manufacture example 29]

(1) 5-Chloroisatin (18.16 g) was treated in the same manner as described in Preparation Example 28- (1) to give 5-chloro-1-ethoxycarbonylisatin having a melting point of 169 to 172 ° C (decomposition). (23.3 g) is obtained.

(2) The product (15.2 g) was treated in the same manner as described in Preparation Example 28- (2) to give 5- (5-chloro-2-ethoxycarbonylamino having a melting point of 189 to 190 ° C (decomposition). Phenyl) -5-hydroxyimidazolidine-2,4-dione (16.74 g) is obtained.

Production Example 30

(1) Isatin (14.7 g) is added to tetrahydrofuran (150 ml), and triethylamine (13.9 ml) is added dropwise thereto. To the mixture is added methoxy carbonyl chloride (7.7 ml) dropwise and the mixture is stirred at room temperature for 1 hour. Triethylamine (2.78 ml) and methoxycarbonyl chloride (1.54 ml) are added to the mixture and the mixture is stirred for 10 minutes. Further ethyl acetate and water are added to the mixture and the mixture is stirred. The precipitated crystals were separated by filtration, washed with water and ethyl acetate and dried to give 1-methoxycarbonylisatin (16.2 g) having a melting point of 178 to 181 ° C (decomposition).

(2) The product was treated in the same manner as described in Preparation Example 28- (2) to give 5- (2-methoxycarbonylaminophenyl) -5-hydroxyimidazoli having a melting point of 192 ° C (decomposition). Obtain Dean-2,4-dione (7.79 g).

Claims (5)

A method for producing a quinazolinone compound of the general formula (I-a) or a salt thereof, characterized by ring closure of the compound of the general formula (II) or (III).

Wherein R ¹ is lower alkyl, substituted or unsubstituted phenyl, or aralkyl, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, Lower alkoxycarbonyl or lower alkoxycarbonyl-lower alkenyl, or when two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ are bonded together to form methylenedioxy and the other two groups Hydrogen, R ⁶ is lower alkyl, and Z ¹ is an oxygen atom or a sulfur atom. A process for producing a quinazolinone compound of formula (I-d) or a salt thereof, characterized by alkylating a compound of formula (VII) or a salt thereof and removing the protecting group from the product obtained.

Wherein R 'is lower alkyl, R ¹ is lower alkyl, substituted or unsubstituted phenyl, or aralkyl, and R ² , R ³ , R ⁴ and R ⁵ are the same or different and each hydrogen atom, halogen atom Or lower alkyl, lower alkoxy, lower alkoxycarbonyl or lower alkoxycarbonyl-low alkenyl, or methylenedioxy when two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ are bonded together Two other groups represent hydrogen atoms, and X ¹ and X ² are protecting groups. A process for producing a quinazolinone compound of formula (I-b) or a salt thereof, characterized by halogenating a compound of formula (I-c) or a salt thereof.

Wherein R is a hydrogen atom or lower alkyl, R ¹ is lower alkyl, substituted or unsubstituted phenyl, or aralkyl, R ³¹ is a halogen atom, R ⁴¹ is a hydrogen atom or lower alkoxy, R ⁵¹ is It is a hydrogen atom or a halogen atom. A method of preparing a quinazolinone compound of the general formula (I-a) or a salt thereof, characterized by reacting a compound of the general formula (IV) with an amine compound of the general formula (V) or a reaction thereof.

Wherein R ¹ is lower alkyl, substituted or unsubstituted phenyl, or aralkyl, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, Lower alkoxycarbonyl or lower alkoxycarbonyl-lower alkenyl, or when two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ are bonded together to form methylenedioxy and the other two groups Hydrogen, and R ⁷ is lower alkyl. A method for producing a quinazolinone compound of the general formula (I-a) or a salt thereof, characterized by hydrolyzing the compound of the general formula (VI).

Wherein R ¹ is lower alkyl, substituted or unsubstituted phenyl, or aralkyl, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, Lower alkoxycarbonyl or lower alkoxycarbonyl-lower alkenyl, or when two adjacent groups of R ² , R ³ , R ⁴ and R ⁵ are bonded together to form methylenedioxy and the other two groups Hydrogen, and Z ² is a sulfur atom or an imino group.