CA1300623C - Process for the preparation of quinazolinone compounds - Google Patents

Abstract

Abstract:
The present invention is directed to processes for preparing novel quinazolinone compounds of the formula:

(I)

Description

062;3 PROCESS FOR THE PREPARATION OF QUINAZOLINONE COMPOUNDS

This invention relates to a process for preparing novel quinazolinone compounds and salts thereof. More particularly, it relates to a process for preparing novel quinazolinone compounds of the formula:

HN L
R3 ~ A ~o Rl (I) wherein Rl is a lower alkyl, a substituted or unsubstituted phenyl or an aralkyl, and R2, R3, R4 and R5 are the same or different and are each a hydrogenatom, a halogen atom, a lower alkyl, a lower alkoxy, a lower alkoxycarbonyl or a lower alkoxycarbonyl-lower alkenyl, or two adjacent groups of R2, R3, R4 and R5 when taken together form methylenedioxy and the other two are hydrogen atoms, and salts thereof, which are u~eful for the prophylaxis and treatment of various diabetic complications.

It is known that diabetic complications include diabetic neurosis, diabetic cataract, diabetic micro-angiopathy e.g., diabetic retinopathy and diabetic nephrosis, and the like and that these diabetic compli-13(~6~:3 cations are induced by the accumulation of polyols e.g.,sorbitol which are converted from hexose etc. by aldose reductase in vivo [cf. The new England Journal of Medicine, Vol. 288, 831 - 836 (1973)]. In order to prevent and treat the diabetic complications, there have hitherto been proposed various aldose reductase inhibitors which can inhibit the accumulation of polyols within the body, for instance, compounds having a chromane nucleus (cf. Japanese Patent First Publication Nos. 53653/1978 and 45185/1982, and U.S. Patent No. 4,117,230), compounds having a thiazolidine nucleus (cf. Japanese Patent First Publication No.104876/1981), and compounds having a phthalizine nucleu, (cf. Japanese Patent First Publication No. 95582/1979).
Besides, there have been known some quinazolinone compounds, for instance, 3,1' -dimethyl-spiro[1,2 3,4,-tetra-hydroqinazoline-4,4'-imidazolidine]-2,2',5l-trione [cf.
Chemie Berichte, Vol. 103, 2394 (1970)] and 3,1',3'-tri-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazoli-dine]-2,2',5'-trione [cf. Chemie Berichte, Vol. 110, 3849 (1977)], but there has never been known any pharmacologica]
activity of these quinazolinone compounds.
The present inventors have extensively studied various spiro[l,2,3,4-tetrahydroquinazoline~,4'-imidazol-idine]compounds and pharmacological activities thereof and it has unexpectedly been found that the compounds of the C16~3 formula (I) which have no substituent at the 1'- and 3'-positions of known spiro[l,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] compounds have excellent aldose reductase inhibitory activity.
An object of the invention is to provide processes for the preparation of novel qunazolinone compounds having excellent aldose reductase inhibitory activity and hence being useful for the prophylaxis and treatment of diabetic complications. This and other objects and advantages of the invention will be apparent to persons skilled in the art from the following description.

The compounds of the invention have the formula (I) as mentioned hereinbefore.
The substituents on the formula (I) denote the following groups.
The term "lower alkyl" denotes a straight chain or branched chain alkyl having 1 to 5 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.--butyl, tert.-butyl, or n-pentyl, isopentyl, etc. The term "lower alkoxy" denotes a straight chain or branched chain alkoxy having 1 to 5 carbon atoms, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, etc. The term "substituted or unsubstituted phenyl" denotes a phenyl or a phenyl substituted by a member selected from the group 130(~623 consisting of a lower alkyl and a halogen atom, e.g., an alkylphenyl having 1 to 5 carbon atoms in the alkyl moiety (e.g. methylphenyl, ethylphenyl, n-propylphenyl, isopropyl-phenyl, n-butylphenyl, n-pentylphenyl, etc.) and a halogeno-phenyl (e.g. chlorophenyl, fluorophenyl, bromophenyl). Theterm "aralkyl" denotes a phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety, e.g., benzyl, phenethyl, etc.
The term "halogen atom" denotes fluorine, chlorine, or bromine. The term "lower alkoxycarbonyl" denotes a straight chain or branched chain alkoxycarbonyl having 2 to 6 carbon atoms, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxy-carbonyl, isopropoxycarbonyl, n-butoxycarbonyl, n-pentyloxy-carbonyl, etc. The term "lower alkoxycarbonyl-lower alkenyl" denotes a straight chain or branched chain alkenyl having 2 to 6 carbon atoms which is substituted by the lower alkoxycarbonyl as set forth above, e.g., methoxycarbonyl-vinyl, ethoxycarbonylvinyl, n-propoxycarbonylvinyl, iso-propoxycarbonylvinyl, n-butoxycarbonylvinyl, n-pentyloxy-carbonylvinyl, etc.
Preferred groups for the substituents in the formula (I) include Cl 4alkyl, phenyl, Cl_4 alkyl-phenyl, halogenophenyl and phenyl-Cl_2 alkyl for Rl; and hydrogen, halogen, Cl_4 alkyl, C2_5 alkoxycarbonyl, and C2_5 alkoxy-carbonyl-Cl~4 alkenyl for each R2, R3, R4 and R5, or methylenedioxy formed by two adjacent groups of R2, R3, R4 and R5.

~3(~V6Z3 Preferred compounds of the invention are compounds of the formula (I) wherein Rl is Cl_4 alkyl, phenyl, Cl_4 alkyl-phenyl, halogenophenyl, or phenyl-Cl_2 alkyl; and R2, R3, R4 and R5 are the same or different and are each hydrogen, halogen, Cl_4 alkyl, C2_5 alkoxycarbonyl, or C2_5 alkoxycarbonyl-C2_4 alkenyl, or two adjacent groups of R2, R3, R4 and R5 when taken together form methylenedioxy and the other two are hydrogen.
Further preferred compounds of the invention are compounds of the formula (I) wherein Rl is Cl_4 alkyl, phenyl, Cl_4 alkyl-phenyl, halogenophenyl, or phenyl-Cl_2 alkyl; R2 is hydrogen, halogen or Cl_4 alkyl; R3 and R4 are the same or different and are each hydrogen, halogen, Cl_4 alkyl, Cl_4 alkoxy, C2_5 alkoxycarbonyl, or C2_5 alkoxy-carbonyl-C2_4 alkenyl, or R3 and R4 when taken together form methylenedioxy; and R5 is hydrogen or halogen.
Still further preferred compounds of the invention are compounds of the formula (I) wherein Rl is methyl, n-butyl, phenyl, methylphenyl, chlorophenyl, or benæyl; R2 is hydrogen, chlorine or methyl; R3 and R4 are the same or different and are each hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxycarbonyl, or ethoxycarbonyl-vinyl, or R3 and R4 when taken together form methylenedioxy;
and R5 is hydrogen, fluorine or chlorine.
Particularly preferred compounds of the invention are compounds of the formula (I) wherein Rl is methyl, n-~3~6Z3 butyl, phenyl, methylphenyl, chlorophenyl, or benzyl; R
is hydrogen or methyl; R3 is hydrogen, fluorine, chlorine, bromine, methyl or ethoxycarbonyl; R4 is hydrogen, fluorine, chlorine, methyl or methoxy, or R3 and R4 when taken together form methylenedioxy; and R5 is hydrogen, fluorine or chlorine.
In an other preferred embodiment, Rl is Cl 4 alkyl;
R2 is hydrogen; R3 is halogen; R4 is hydrogen, halogen or Cl 4alkyl; and R5 is hydrogen or halogen. Particularly, R
is hydrogen or isobutyl; Rl is methyl; R2 is hydrogen; R3 is fluorine, chlorine or bromine; R4 is hydrogen, chlorine or methyl; and R5 is hydrogen or chlorine.
The compounds of formula (I) of the present invention have an asymmetric carbon in the molecule and hence may include two optical isomers. The present invention includes these optical isomers and racemic mixtures thereof.
According to the present invention, the compounds of formula (I) or salts thereof can be prepared by:
(A) subjecting a compound of the formula:
S
R2Ho CONH-C-NH
R3 ~ ~- Rl (II) wherein Rl, R2, R3, R4 and R5 are the same as above, to a cyclization reaction; or 130~6Z3 (B) reacting a compound of the formula:
~ NH

~ ~ HR6 (III) wherein R6 is a lower alkyl, and R2, R3, R4 and R5 are the same as above, with an amine compound of the formula:
Rl-NH2 (IV) wherein Rl is the same as defined above, or a salt thereof;

or (C) hydrolyzing a compound of the formula:

~ NH

~4 ~ ~ Rl (V) wherein Z is a sulfur atom or an imino group, and Rl, R2, R3, R4 and R5 are the same as above, and optionally converting the resulting product into a salt thereof.
The cyclization reaction of the compound of formula (II) can be carried out in an appropriate solvent. The cyclization is preferably carried out in the presence of an alkali agent and/or an oxidizing agent. The alkali agent in--cludes alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, ~, , .

` ~30~623 etc.), alkali metal carbonate (e.g. potassium carbonate, etc.), and the like. The oxidizing agent includes hydrogen peroxide, m-chloroperoxybenzoic acid, ozone, nickel peroxide, and the like. The solvent includes water, methanc,l, acetone, acetic acid, or a mixture thereof. The reaction is preferably carried out at a temperature of 0 to 80C.
The reaction of the compound of formula (III) and the compound of formula (IV) or a salt thereof can be carried out in an appropriate solvent. The compound of formula (III) includes preferably a compound of the formula (III) wherein R6 is a lower alkyl e.g., methyl, ethyl, propyl, butyl, etc.
The salt of the compound of formula (IV) includes, for example, mineral acid salts e.g., hydrochloride, sulfate, etc. The solvent includes, for example, dichlorobenzene, toluene, methanol, ethanol, tetrahydrofuran, or a mixture thereof.
The reaction is usually carried out under atmospheric pressure or under pressure at a temperature of room temperature to 200C, preferably S0 to 160C. When the reaction is carried out under comparatively mild conditions, an intermediate may occasionally be isolated in the form of a crystal, and then the intermediate can react with the compound of formula (IV) to give the desired compound of formula (I).
The hydrolysis of the compound of formula (V) can be carried out in an appropriate solvent. The hydrolysis of the compound of formula (V) in which Z is a sulfur atom [herein--after referred to as the compound of formula (V-a)]
is preferably carried out in the presence of an alkali agent:

6~3 g and an oxidizing agent, and the hydrolysis of the compound of formula (V) in which Z is an imino group [hereinafter referred to as the compound of formula (V-b)] is prefer-ably carried out in the presence of a nitrososation agent.
The alkali agent and oxidizing agent include the agents which are mentioned for the cyclization of the compound of formula (II). The nitrososation agent includes alkali metal nitrites, alkyl nitrites, nitrosyl chloride, nitrogen dioxide, and the like. The solvent includes water, acetic acid, sulfuric acid, and the like. The reaction is prefer-ably carried out at a temperature of 0 to 80C.
When the compounds of formula (I) are obtained in the form of a racemic mixture, they can be resolved into each optical isomer by any conventional method. For instance, the optical resolution can be carried out by reacting the racemic mixture of the compounds of formula (I) with a resolving agent in an appropriate solvent, isolating a hardly soluble diastereomeric salt in the form of a crystal and then isolating the soluble diastereomeric salt from the mother liquid by utilizing the difference in the solubility of the two diastereomeric salts. The resolving agent includes, for example, natural origin products e.g., brucine, quinine r cinchonidine, N-n-octylglucamine, dehydroabietylamine, etc., and optically active compounds e.g., ~-methylbenzylamine, lysine, phenylalaninamide, tyrosine hydrazide, etc. The solvent includes methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water, or mixtures thereof. The diastereomeric salts thus prepared S310~6Z3 can be converted to the desired optically active compounds of formula (I), for example, by treating with an acid (e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, etc.).
The starting compounds of formulae (II), (III) and (V) used in the above reactions are also novel compounds.
The compound of formula (II) can be prepared, for example, by reacting a compound of the formula:

~ H (VI) wherein R2, R3, R4 and R5 are the same as above, or a salt thereof (e.g. sodium salt, potassium salt, etc.) with a compound of the formula:
Rl-N=C=O (VII) wherein Rl is the same as above, in a solvent in the presence of a base (e.g. triethylamine, etc.) at a temperature of -20 to 50C to give a compound of the formula:

R4 ~ N O (VIII) R5 CONHRl wherein Rl, R2, R3, R4 and R5 are the same as defined above, ~3~062;~

and then reacting the compound of formula (VIII) obtained above with thiourea in a solvent in the presence of a base (e.g. triethylamine, etc.) at a temperature of 0 to 100C.
The compound of formula (III) can be prepared by reacting the compound of formula (VI) or a salt thereof with a compound of the formula:
~ OCOX (IX) wherein R6 is the same as defined above and X is a halogen atom in a solvent in the presence of a base (e.g. triethyl--amine, etc.) at a temperature of 0 to 80C to give acompound of the formula:

R 4~C~o ( x ) wherein R , R , R , R and R are the same as defined above, and then reacting the compound of formula (X) with urea in a solvent at 50 to 120C.
The compound of formula (V-a) can be prepared by heating the compound of formula (II) in a solvent at a temperature of 100 to 180C, followed by treating the resulting product with an acid (e.g. hydrochloric acid, etc.) at a temperature of 20 to 100C.
The compound of formula (V-b) can be prepared by reacting the compound of formula (VIII) with guanidine or a salt thereof in a solvent in the presence or absence l;~W623 of a base (e.g. sodium hydroxide, etc.) at a temperature of 20 to 100C. In this reaction, a compound of the formula:

2 ~H2 R4 ~ H ~O Rl (XI) wherein Rl, R2, R3, R4 and R5 are the same as defined above, is obtained as the by-product. This by-product of formula ~XI) is treated with an acid ~e.g. hydrochloric acid, etc.) to give the compound of formula (V-b).
The compounds of formula (I) of the invention can be used as medicaments in the form of a free base or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include, for example, sodium salt, potassium salt, calcium salt, lysine salt, ethylenediamine salt, diethanolamine salt, and the like. These salts can easily be prepared by treating the free base of the compounds of formula (I) with a base by a conventional method.
The compounds of formula (I) and salts thereof have excellent aldose reductase inhibitory activity and hence are useful for the prophylaxis and treatment of various chronic symptoms associated with diabetes, i.e. diabetic compli-cations, in warm-blooded animals, for example, diabetic neurosis, diabetic cataract, and diabetic microangiopathy e.g., diabetic retinopathy and diabetic nephrosis. The compounds of formula (I) and salts thereof of the invention also have the advantages that they have low toxicity and less neurotoxic side effects (e.g. dysbasia, areflexia, astasia, blepharoptosis, etc.).
The compounds of formula (I) and salts thereof of the invention can be administered orally or parenterally.
They can be administered in conventional pharmaceutical prepar-ations, for example, tablets, granules, fine granules, powders, capsules, injèctions, eye drugs (e.g. eyewash, eye ointment, etc. ?, and the like. These preparations can be prepared by admixing the active compound of formula (I) or a salt thereof with conventional pharmaceutically acceptable carriers or diluents. The pharmaceutically acceptable carriers or diluents include excipients (e.g. sucrose, starches, lS manitol, glucose, cellulose, talc, calcium phosphate, etc. ?, binding agents (e.g. methylcellulose, gelatin, gum arabic, polyethylene glycol, etc. ?, disintegrators (e.g.
starches, carbo~ymethyl cellulose, sodium hydrogen carbonate, calciurn phosphate, etc.), lubricants (e.g.
magnesium stearate, talc, sodium laurylsulfate, etc), preservatives (e.g. sodium benzoate, sodium hydrogen sulfide, etc.), stabilizers (e.g. citric acid, sodium citrate, etc.), and the like.
The dose of the compounds of formula (I) and the pharmaceutically acceptable salts thereof may vary depending on the administration routes, ages, weight and states of the patients, severity of diseases, and the like, but is usually 13~t623 in the range of about 0.01 to 200 mg/kg/day, perferably 0.1 to 50 mg/kg/day.
The pharmacological activities of the compounds of formula (I) and the salts thereof are illustrated by the following experiments.

Experiment 1 Aldose reductase inhibitory activity:
Method:
Aldose reductase was obtained from the lens of a male ra~bit (weighing 2.~ - 3.5 kg) in the same manner as described in J. Biol. Chem., Vol. 240, 877 - 882 (1965).
The inhibitory activity of the test compounds against the aldose reductase was measured in the same manner as described in Biochim. Biophys. Acta., Vol. 128, 474 - 482 (1966). The aldose reductase inhibitory activity of the test compounds was shown by a concentration of the test compounds which was required for 50 % inhibition of aldose reductase activity (i.e. 50 % inhibitory concentration:

IC50 ) -Test compounds:
No. Compound name (Compounds of the invention) 1. 6-Chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione 2. 6-Chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione-1'-sodium salt .

~ :~L3(~16~3 3. 6-Chloro-3,7-dimethyl-spiro[1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine]-2,2',5'-trione 4. 6-Bromo-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione 5. 6,7-Dichloro-3-methyl-spiro[1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine]-2,2',5'-trione 6. 6,8-Dichloro-3-methyl-spiro[1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine]-2,2',5'--trione 7. 6-Fluoro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-irnidazolidine]-2,2',5'-trione (~eference compounds) 8. 3,1'-Dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione [disclosed in Chem. Ber., 103, 2394 ~1970)]

9. 3,1',3'-Trimethyl-spiro[1,2,3,4-tetrahyclroquinazoline-4,4'-imidazolidine]-2,2',5'-trione [disclosed in Chem.
Ber., 110, 3849 (1977)]
Results:
The results are shown in Table 1.

:13~623 Table 1 Test Compd. No. Aldose reductase inhibitory activity IC50 (M) .. ._ Compounds of the invention: 5.6 x 10 8 2 2.9 x 10-8 3 3.0 x 10-8 4 5.2 x 10-8 7.4 x 10-8 6 3.7 x 10-8 .0 x 10-7 ~eference compounds 8 1.0 x 10-5 9 > 5 x 10-5 ~ . .

Experiment 2 Inhibitory activity of accumulation oE polyols:

~ethod:
Slc:Wistar male rats (3-4 weeks old, one group: 3 rats) were fed with (i) a 20 % galactose-added diet containing 20 mg ~ of a test compound (i.e. the test compound being contained in an amount of 20 mg per 100 g of the diet) (test compound-administered group), (ii) a 20 %
galactose added diet (galactose control group), and (iii) a normal diet (no galactose) (normal control group) for 6 days. After the feeding, the rats were killed by cutting ,!

. 13~623 the carotid artery under ether anesthesia, and immediately, the sciatic nerves at both sides were taken out, and the amount of polyols accumulated in the sciatic nerves was measured by an acetyl-acetone method as described in S Science, Vol. 182, 11~6 - 1148 (1973). The polyol accumu-lation inhibition rate was calculated by the following equation.
Polyol accumulation inhibition rate (%) rPolyol amount (aver-~ rPolyol amount (aver-age) in test compd.-l - lage) in normal 1 - ~administd. group J lcontrol group x 100 -Polyol amount (aver-~ Polyol amount (aver-`
age) in galactose I - age) in normal control group ~ control group Results:
As a result, the compounds of the invention used in Experiment 1 ~i.e. Test Compound Nos. 1-7) showed all more than 50 ~ of polyol accumulation inhibition rate.
Experiment 3 Acute toxicity and observation of symptoms:
A suspension of the test compound in 0.5 ~ carb-oxymethyl cellulose was orally administered to ddY male mice (weighing about 25 g, one group: 3 mice), and gross behavior and symptoms of the mice were observed for 14 days. As a result, in the mice administered with the compounds of the invention: d- and dl-6-chloro-3-methyl-spiro[1,2,3,4-tetra-hydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione at a dose of 10 g/kg, respectively, no mice died, and no ~30~6Z3 abnormal symptoms e.g., dysbasia, areflexia, astasia, blep-haroptosis, dyspnea, skin flush, lacrimation, etc. were observed.
The compounds of formula (I) and their salts of the invention and prepaxation thereof are illustrated by the following Examples and Preparations.
Example 1 A mixtureOf s~5-chloro-2-ethoxycarbonylamino-phenyl) -5-hydroxyimidazolidine-2,4-dione (9.41 g), 40% methylamine-methanol solution (5.11 g), toluene (200 ml) and ethanol (20 ml) was stirred in a pressure vessel at 120C for 4 hours. After cooling, the preclpitated crystals were separated by filtration, washed successively with toluene and methanol and dried to give 6-chloro-3-methyl-spiro[1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine]-2,2',5'-trione (2.33 g).

M.p. >280C
IR ~nu~ol (cm 1): 3300, 1780, 1740, 1718 MS (m/e): 280 (M+) NMR (DMSO-d6) ~: 2.80 (3H, s), 6.92 (lH, d, J=9 Hz), 7.06 (lH, d, J=2 Hz), 7.40 (lH, d, d, J=9 Hz, J=2 Hz), 9.11 (1~, s), 10.07 (lH, s), 11.40 (lH, s) Sodium salt IR ~nu~ol (cm 1): 3330, 3180, 1703, 1648 NMR (DMSO-d6) ~: 2.62 (3H, s), 6.6-6.9 (2H, m), 7.0-7.5 (2H, m), 9.3-9.8 (lH, br) , ^~;`h - 13C~623 Example 2 A mixture of5~2-ethoxycarbamoylaminophenyl)-5-hydroxy-imidazolidine-2,4-dione (8.37 g), 10% methylamine-et~anol solution (21.5 g) and 2,3-dichlorobenzene (200 ml)was stirred in a pressure vessel at 150C for 2 hours. After cooling, the reaction mixture was extracted with lN NaOH solution, and the aqueous layer wasneutralized with 10 ~ hydrochloric acid. The precipitated crystals were separated by filtration, washed successively with water and ethanol and then dried to give l-methyl-spiro[1,2,3,q-tetrahydroquinazoline-4,4'-imidazol-idine]-2,2',5'-trione t2.6 g).
M.p. >280C

IR ~nujol (cm 1): 3300, 3120, 3080, 1781, 1735, 1680, 161S
max MS (m/e): 246 ~M+) NM~ (DMSO-d6) ~: 2.80 (3H, s), 6.70-7.50 ~4H, m), 9.05 (lE~, 5), 9.91 (lH, s), 11.31 (lH, s) Example 3 A mixture of 5-( 2 _methoxycarbamoylaminophenyl)-5-hydroxyimidazolidine-2,4-dione ~2.65 g), 10% methylamine-ethanol solul:ion (12 g) and toluene (60 ml)was stirred in a pressure vessel at 110C for 4 hours. The reaction mixture wastreated in the same manner as described in Example 2 to give 3-methyl-spiro[l,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (0.51 g).
The physical properties of this productwere the same as those of the product obtained in Example 2.

..

~L3L)~i23 _ample 4 (1) 5-(2-Ethoxycarbonylaminophenyl)-5-hydroxyimidazo:Li-dine-2,4-d;one (27.9 g) was dissolved in a mixture of 40% methylamine-ethanol solution (17 g), toluene (600 ml) and methanol (600 ml), and the mixture wasstirred at room temperature for one hour.
The precipitated crystalswere separated by filtration, washed with toluene and then dried to give a crystalline product (29 g), m.p. 130 - 133C.
(2) A mixture of the crystalline product obtained above (2.51 g), 20 % methylamine-ethanol solution (6.1 9), toluene (60 ml) and ethanol (6 ml) was stirred in a pressure vessel at 110C for ~ hours. After cooling, the precipi-tated crystals were separated by iltration and dried to give 3-methyl-spiro[1,2,3,4-tetrahydroquinazoline~4,4'-imidazol--idine]-2,2',5'-trione methylamine salt (1.06 g).
M.p. >280C
NMR (DMSO-d6) ~: 2.28 (3H, s), 2.67 (3H, s), 6.4-7.3 (9H, m) MS (m/e): 246 (M~ -31) Example 5 5-(2-Ethoxycarbonylaminophenyl)-5-hydroxyimidazolidine 2,4-dione ~139.5 g) was treated in the same manner as described in Example 4 ~1), and the precipitated crystals were separated by filtration.
The crystals were added to a mixture of 40 % methylamine-methanol solution (85.25 g), toluene (3.3 liters) and ethanol (330 ml), and the mixturewas refluxed at about 75C
for 15 minutes. To the reaction mixturewas added dropwise ~3~6Z3 " ~. ~

40 % methylamine-methanol solution (155 g) during one hour, and the mixture was further refluxed for 2.5 hours. The precipitated crystals were separated by filtration and then dissolved in water. The aqueous solution was neutral-ized with 10 % hydrochloric acid, and the precipitatedcrystals were separated by filtration, washed with ethanol and then dried to give 3-methyl-spiro[1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine]-2,2',5'-trione (43 g).
The physical properties of this product were the same as those of the product obtained in Example 2.
Example 6 (1) l-Methylcarbamoylisatin (4.08 g) was dissolved in tetrahydrofuran (50 ml). Triethylamine (2.22 g) and thiourea (1.7 g) were added to the solution, and the mixture was stirred at room temperature for 3 hours. The precipi-tated crystals were separated by filtration, washed with water and then dried to ~ive 4-hydroxy-4-thioureidocarbonyl--3-methyl-2-oxo-1,2,3,4-tetrahydroqu.inazoline (3.7 g), m.p.
>280C (recrystallized from dimethylformamide-ethanol).
(2) The product obtained above (1.0 g) was dissolved in 10 ~ aqueous sodium hydroxide (10 ml). To the mixture was added 30 % hydrogen peroxide (2 ml), and the mixture was stirred at room temperature for one hour. After completion of the reaction, the reaction mixture was acidi-fied with 10 % hydrochloric acid. The precipitated crystals were separated by filtration, washed and then dried to give 3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazol-~ 13~6Z3 idine]-2,2',5'-trione (0.75 g, yield 85.4 %).
The physical properties of this product were the same as those of the product obtained in Example 2.
Example 7 5,6-Dichloro-l-methylcarbamoylisatin (9.6 g) was treated in the same manner as described in the above Example 6-(1) to give 6,7-dichloro-4-hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline (4.1 g), m.p. 225 - 228C. This product was treated in the sarne manner as described in the above Example 6-(2) to give 6,7-dichloro~3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazol-idine]-2,2',5'-trione.
IR ~nujol (cm 1): 3250, 1770, 1720, 1615, 1597 max NMR (DMSO-d6) ~: 2.78 (3H, s), 7.09 (lH, s), 7.29 (lH, s), 9.12 ~lH, s), 10.18 (lH, s), 11.41 (lH, s) Example 8 4-Hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline (1.0 g)was dissolved in 10 ~
aqueous sodium hydroxide (20 ml), and the mixture wasstirred at 40 - 50C for 1.5 hour. After cooling, the reaction mixture wasacidified with 10 % hydrochloric acid. The precipitated crystals were separated by filtration, washed and then dried to give 3-methyl-spiro[1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine]-2,2',5'-trione (1.3 g, yield 85.4 %).
The physical properties of this product were the same as those of the product obtained in Example 2.

.

.

~ 13(~623 Example 9 (1) 4-~ydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline (2.2 g)was dissolved in dichlorobenzene (30 ml), and the mixture wasstirred at 200C
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-tetrahydroquinazol-ine-4,5'-thiazoline]-2,4'-dione (1.3 g), m.p. >280C.
(2) The above product (1.3 g) was dissolved in 10 % hydrochloric acid (20 ml), and the mixture was stirred at 80C for 3 hours. The precipitated crystals were separated by filtration and recrystallized from dimethylformamide-water to give 3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,~'-imidazolidine]-2,5'-dione-2'-thione ~1.1 g), m.p.
>280C.
(3) The above product (1.0 g)was dissolved in 10 % aqueous sodium hydroxide (10 ml). To the mixturewas added 30 % hydrogen peroxide (2 ml), and the mixturewas stirred at room temperature for one hour. After the reaction, the reaction mixture was acidified with 10 % hydrochloric acid.
The precipitated crystals were separated by filtration, washed and then dried to give 3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (0.85 g, yield 90.8 %).
The physical properties of this product were the same as those of the product obtained in Example 2.

.. . .

Example 10 tl) Guanidine hydrochloride (0.57 g) was added to tetrahydrofuran (5 ml) and thereto was added 10N NaOH (0.6 ml?, and the mixture was stirred at room temperature for 5 minutes. Tetrahydrofuran (15 ml) and l-methylcarbamoylisatin (1.02 g) were added to the mixture, the mixture was stirred at room temperature for 4 hours, and the solvent was distilled off. To the residue was added 10 ~ hydrochloric acid (10 ml?, and the mixture was reflu~ed for one hour. After cooling, the precipitated crystals were separated by filtration and washed with water and ethanol to give 2'-amino-3-methyl-spiro[l,2,3,4-tetrahydroq~linazoline-4,4'-imidazolidine]-2,5'-ione (0.86 g?, m.p. 257 ~ 259C.
(2) The above product (0.123 g) was dissolved in a mixture of acetic acid (1 ml) and water (2 ml). To the solution was added dropwise a solution of sodium nitrite (0.052 ~) in water ~1 ml) at room temperature. The mixture was stirred at room temperature for one hour and the solvent was 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-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (39 mg).
The physical properties of this product were the same as those of the product obtained in Example 2.
Examples 11 to 35 -In the same manner as described in Examples 6 to 10, the corresponding starting compounds were treated to give the compounds as shown in Table 2.

3~623 _ _ ~ o~ o_ o~ o u~
.C ~$ ~$ ~
O ~- ê O E~o m O _,~
.. ~ " r~

E~ r ~ a ~ ~ ` O ` ~ ` O

t~ ~ ~ $`_ $`~ t.
--U~

V~ _ O ~-- ~ _ ~ _ O
.~ I~ Q ~lo o`O 0`0 ~ 1~ .
~ _ ~ a~ O~ 0`0 0~
~ X O ~ a~ o o~
~ ~ ~ a~ x ~ ~ 1 ~ l ~, o 1~ ~
7 ~_~ 3 r u ~ u ~J
~ m ~ w w ~ ¦
P; o ~ u ~ $

H ~ _ I:G ~ U ~ ~ ,f . . ~ ~ ~ ~r X O
Z

130C~6;~3 .
,_ o ~ o ~ m u~ O ~
~, `O ~ ~~, . ~, ~O .
-- N ~1 `l` trl^-- --O-- N ~
~: m I N r~:C ' $
O O~ ,_1 o ~ ~ o t~l o a~ ~1 0 `
~ O~ O m . Il ~. ~, ~U~. _. Il ~ .
N ~ ~` N ~r ~m ~N ` :C` `` ~m ,1 ~ m ^~
~ O
.. $ ^ ~ ` $ P~ $ o ^
.0 t~ ~ ~ tn ~ ~ ~ ~1 ~ ~ ~ u~ ~ ` ` u -- ~
_~ ,~
m ~ O
m ,~ O U~ m l . ,~ ,~ _. ~, . . ~ . ~ _. ~ ,, _ . ,~
O ~ ~ _ N -- U~ -- N _ cJ~ o a~ . o ~ ` ~D CO O` ~ ^ ~ O ` O ^
~ ~ o ~ ~m ~ o ~a~ u~
_ ~n ~ . o u~ . o u~ .
~ ` N ` tI ` ` ` ` N ` m . ~: m m ~ m :~ ~ m o ~m ~ m ~ ~
~ Z ~ ~ ,~ I~~ r-l ~~ ~ ~ ~ _ _ J _ ~ N 111-- ~ ~ ~ N ul -- E~
a) 1l m Oa~ ~_ Il m If~
o t~ ~o ~ N~ 11~ O ~ O ~ r-l ~ C~ N I ~ I m U~ ~ 11 ~, ~ ~ ~ . ~r~ . ~ 11 r~ . ~ r~
~ ~ ~ ~--~--~~ ~D ~~ U~--~ ~ I~-- `I--r~
.. ~ _ ~
V
~ ~ 0 00 00 0 Q~r1 N1~ 0:)CO O t~') 1~ I I~ O
O ~ r~~ r~ r~
_ O OO Lr)O O O ~
r~ O r~0~ r~O ~D CO O
~ O C~ ~r~ t~r~
U
r~
U~

';' O OO a~ NO O O O
.C O L~O CO ~ U~
PlPC ~ ~D~ r~ ~ ~ I~ ~ ~s ~I ~_1 ~ r~1 rl r~ 1 r~
.~ _ ~ .
~ ~_ +~ +~ +~ +~ +X +~
~O ~
u~ ~ tn ~ u~ o o~r D O
N ;~ l~3 1~
_ ~I N N N N ~I
~ _ l $ U U U U U C.) . I O O O I O O
lR~ o ~I o o o o N O
. r~ I` ~oo~ co ~ l` c~
Ltl :E t'~ lN ~N N
P~ A ~
_ O
~q ~ ~ I
U H P~ ~: $ O $ m m _ ~ C~ C~ U
Il ~ _ o ~
o r~
P~ :~ ~ ~ ~ I U
_ o C~ C~

~ U P~ = ::C = = = =
.. .~ _, , . . ~ u~ o X O ~1 ~ ~1 ~ ~ ~
~ Z _ _ _ .

- 13(~C~623 U~ ~ ~^ `~ `~
X
a~
I ~ 1 N U) ~1 ` ~
u, ~.a^
u~ o~ r 1l ~ 1~ u~
,~ ~ ,1 ~ ~1` O ~ '- ;~
--o ~ o ~
.. ~ r~ 1 ~ X
~o r~ ~_ _ o --I ~ I ~ ~ N I C~
~ r~ m 'O O~ ~ o ~ o . o~
l . - . - . ~ . ~ ~ .
O I~
~n u~ o ~ ~ ~o ~ ^ 3 _ ~n o ~n o In ~ a~
~ ~ ~ $ m p: o r~ Z
JJ
o ~ o ~
` m ~ ~--~ - o o o o ~ u~
~ ~ ~ u~ ~ ~ ~ ~
~, l o o r~
O E~
~ _ o o o o o 1~ a~ o ~1 u~ ~ o u~ o O ~I r~ ~ I` ~` ~n 1- co . ~ X
~i O O O O o Ln o o o U~
u~ o o o u~ r o ~r P~ ~ ~ co ~ a~
H ~) ~1 ~) ~1 ~ ~I t') ~1 ~) r-l _ I
~ '~' + :~

r~ u~ ~r ~ Ei _ . U U U U
o o o o . o o o o ~; ~ Cl~
~ A /~ A
$ _ O ~ In ~ r1 H P~ ~ C U U
ll ro-- O
P~ C ~r ~ U X U~

H O ~1 H ~ ~ I
U p:; ~ ) t,) U
_, ~ ~n X O ~ ~ ~ ~ ~
_. I

- ~30~6~:3 _ _ ~ m ^~ I~
N ~ ` a~ Ul 'a ~ U~ ~ ~( `
~ O ~ u m com ~ mmo~ mm^

11 ~1 ~ O -- t~l ~ O ` t~ ~I N ` `
~,--m ~ m ----m~m ~1 ~
Cl~ O ~ a~ ~--U~ CT~ ~ t~ ~ 11 ~
~ m ~ ~O ~0 _0 .. m -- :c-- m ~
~o ,~ o _ _ o --m --~ ^ ^ m ,~
~ N ` 1~ O N N N N N ` -~D r~;C^- o~ mm--~ mmmr~ ~^
N ~1 0 I CO ~1: - ^ ~1 ^
O ~O 11 ~ . ~ _ ,~ 11 11 . Il 11 u~
~ I m CO m m a _ u~ m~
~C ~ ~ o ~ O IJ~) ~: ~c ~ m ,~ m ~ m ~ m P~ ~ m ~
. z ~ ~ -- ~ m ^ ~ ^ ,, ~ N ^ t~) N N O~ ~
----co --N U~ -- ---- N O ----m co ,, . 11 a~ -- ~ ~ r~ I
a~ O ~ O t~ In ~ ~ ~ I ~ a~
I~ ~1 ~/ o ~ N ~ ` N ~ ~1 ~ ^ -~ ` O ~ ~1 Il ~ Il N O
u) N 1` ~ ~N 1`-- ~`I --a~ ~1 ~ 1~ U~ ~1 ~ ~ 1` ;I: ~1 al ~_ _ .,~
,_ U) oN N O a~ ~
Ll ~1 1` 0 ~ ~1 , ~) 1` 0 ~ l I` ~O l` ~O 1~ ~O ~D
0~ E~
_ O O O O Ul D O ~
r-l O 1/~ N ~0 a~ r r 1 -1 ~
a~1-7 X ~ ~IN -1 ~1 ~I rl ~l U
~1 U~ ;~ o o o o o o 11') a~
:~ u~ ~1 o t~
.C ~ ~ 7 1` N ~0 t--P~ ~_/ ~
_ +-- +'` -t^ +

U~ ~ ~ O O ~
~ E~ t~l ~o : _ N

m u u u c~ c~
. O O O O O
Il ~ O O O O O
. co a~ OD
~; N N t~l N N
t~; _ A
~ __ _ .
m ~r u ~ ~ ~ = m I l H U
_ ~1 1 In m mm ~; ~: N U
_ ~ ~ ~ ~ C~ 11 C.) o ~ m m c~ o ~ o H O O U O
H U ~N X
~_ ~ ~ ~ m =
. . ~ r~ coa) o X O ~ r~
Z

1;~0~23 _ a~ ~ $
, . _ I 0~ N
^ Cl~ ` ` ` O
__ ~_ ~ _ r~ _ ` U~ ~1 0 ~ U~

~ 0 m~m mU~ om m --~
CO ~ ~ ~ ~D
. _O ,~ ~ ~O
.. r~) _~1 --N ~1~:C t~l -- `
~oI Lr) U~
t-- OC~ O~ u~ N o _. . ~ m, ~D~m ~ O ~ .
ro ,, --o ~1--m ~,~o ,, _ _ _ ~ 11 U~
~n ~: ,~ m-- cr ~
m a~ m u _ r~
---- O I ~ O ~ ~ O P~ `
. ~: ~ m ~ ,I m o ,1 v za~ ~ ~ . _~ . ~ ~ . _ ~ ~ _ J~ U~ I` --I~ ^ --r~ -- -r~ ~ o I I ` ~ O O 1~ ~ O O o r~
I` $ ~D In CO ` r~) C~ 00 ~ .
~ . .~ .o . m .o .~,, O ~ -- ~D ~1 ~ ~D r~N ~O ~1 ~ ~ ~1 O ~ U~ O r~ O
r-l I~
~ 4 l I~
O E~
~ _ L17 o o o o ~ O
~( ~1 Ct:) ~O Ul ~D Ill ~`I~r ~r ~ O t- ~ O ~D O 1~ r~
U n X ~1~1 ~ .~ ~ ,1 ,1 ,~
.,, tn ;~ ~ o In o coo a:) o co oo o o r~ o ~ ~
P~ I:r; ~ r~ ~r r~~ r~ I` ~o 1` ~o H ~ r l ~ H ~7 -1r1 ~1 ~1 ~
. _ _ _ _ ~ _ _ ~ + + + +
,_ ~
a~ u~ ~ oo 0 N :~ ~ CO O ~
_~ ~ ~ t`~ ~ ~1 __ . .. .
U ~_) . I o o U C~
~ ~'1 ~ O I o o _ . ~ ~ O
m ~: ~
Il A
_ U~
._ H _ _ I I r~
~ ~ $ m ^ ~ 1 ~; ~ ~( ~ ~ ~ _,~
_ ~ L ~ I I Z ~ ~ z ~
o ~ ~ ~ ~ ou '11 Ou ,_ P. _ ~, I ~ I C~ ~ ~ U
> ~ $~ ~ ~ ,~ m~
C~ t~
. . _ . . ~ ~ r~
X O r~
r" ~
~_ _. .

~L30a623 , The preparation of the starting materials is illustrated below.
Preparation 1 A mixture of 5-fluoroisatin (9.9 g), triethylamine (1 ml) and dimethylformamide (30 ml)was stirred under ice-cooling, and thereto wasadded dropwise methyl isocyanate (3 g) at the same temperature. The mixturewas stirred at room temperature for 30 minutes, and the precipitates were taken by filtration to give 5-fluoro-1-methylcarbamoylisatin (8.7 g). M.p. 230 - 232C
Preparations 2 to 22 In the same manner as described .in Preparation 1, the corresponding starting materials were treated to give the compounds as shown in Table 3.

l3~a6z3 Table 3 R3 ` Rl-N=C=O (VII) R3 R4 ~ \ ~; R4 ~

(VI~ (VIII) [I] (Rl = CH3, R5 = H) Prepn. Compound (X) Physical properties No. R2 R3 R4 _ 2*1 H H H M.p. 154 - 156C
3 ,l Cl O M.p. 234 - 236C
MS (m/e): 238 (M+) 4 Cl H ll M.p. 158 - 160C
. MS (m/e): 238 (M+) H .~ Cl M.p. 220 - 222C
MS (m/e): 238 (M+) 6 ,l CH30 H M.p. 205 - 208C
7 ll CH3 ll M.p. 228 - 230C
8 ll -OCH2O- M.p. 235 - 240C
9 ll Cl Cl M.p. 220 - 221C
MS (m/e): 272 (M+) ll CH3 M.p. 217 - 219C
11 H CH3O M.p. 217 - 219C

*l) This compound is the same as the compound disclosed in Ann. Chem., 1974, page 2003.

~3c~a623 -[II] (Rl = CH3, R2 = H) Prepn. Compound (VII) Physical properties No. R3 R4 R5 12 H H CH3 M.p. 192 - 195C

13 F F F M.p. 169 - 171C

14 H H F M.p. 145 - 146C

[III] (Rl = CH3, R5 = H) Prepn. Compound (VII) Physical properties No. R2 R3 R4 . _ H Br H M.p. 222 - 229C
16 CH3 H ll NMR (DMSO-d6) ~: 2.52 (3H, s), 2.87 (3H, d, J=5 Hz), 7.10 . (lH, d, J=9 Hz), 7.57 (lH, t, . J=9 Hz), 8.03 (lH, d, J=9 Hz), 8.0-8.4 (lH, m) 17 H Cl CH O M p 202 - 205C
3 MS (m/e): 211 (M+) 18 ll COOC2H5 H IR ~nujol (cm~l) 3360, 1748, max 1720, 1703, 19 ,l -CEI=CH- n IR ~nujol (cm~l) 3360, 1757 COOC2H5 max 1738, 1705, _ 1640, 1617 ~3~ i2~3 [VI] (R2 _ RS = H) Prepn. Compound (VII) Physical properties No Rl CH3(CH2)3~ M.p. 97 - 99C

21 CH3 ~ M.p. 189 - 190C

22 ~ CH2- IR ~nujol (cm~l) 3300, 1755, max 1740, 1708 Preparation 23 _ _ _ (1) Isatin (29.4 g) was added to tetrahydrofuran (200 ml) and there-to was added triethylamine (30.7 ml).
Ethoxycarbonyl chloride (20~9 ml) was added dropwise with stirring to the mixture, and the mixture was stirred at room temperature for 5 minutes. The solvent was distilled off, and water was added to the residue. The precipitated crystals were separated by filtration, washed with water, isopropanol and diisopropyl ether and then dried to give 1-ethoxycarbonylisatin t39.4 g?, m.p. 113 - 116C (decomp.).

This p~oduct was identical with the compound as disclosed in Journal fur Praktische Chemie, Band 315, 1973, pages 339-344.
(2) The above product (2.79 g) was added to tetra-hydrofuran (30 ml), and thereto was added urea (1.15 g). The mixture was refluxed for 15 hours and then the solvent was distilled off. The residue was extracted with ethyl acetate.

~.30~:?623 The extract was distilled to remove the solvent, and the residue was subjected to silica gel column chromatography (solvent, chloroform : methanol = 9 : 1). The fractions containing the object compound were collected and distilled to remove the solvent, and to the residue was added chloroform. The precipitated crystals were separated by filtration and dried to giveS~2-ethoxycarbonylamino-phenyl)-5- -hydroxyimida~olidine-2,4-dione (2.42 g), m.p. 169 - 170C.

Preparation 24 (1) 5-Chloroisatin (18.16 g) was treated in the same manner as described in Preparation 23-(1) to give S-chloro-l-ethoxycarbonylisatin (23.3 g), m.p. 169 - 172C
(decomp.).
(2) The above product (15.2 g) was treated in the same manner as described in Preparation 23-(2) to giveS~S-chloro-2-ethoxycarbonylaminophenyl)-5-hydroxyimidazolidine-2~4 dione ~16.74 g), m.p. 189 - 190C (decomp.).
Preparation 25 (1) Isatin (14.7 g) was added to tetrahydrofuran (150 ml) and thereto was added dropwise triethylamine (13.9 ml). Methoxycarbonyl chloride (7.7 ml) was added dropwise to the mixture, and the mixture was stirred atroom temperature for one hour. Triethylamine (2.78 ml) and methoxycarbonyl chloride (1.54 ml) were added to the mixture, and the mlxture was stirred for 10 minutes. Ethyl acetate and water were further added to the mixture, and the mixture was stirred.
The precipitated crystals were separated by filtration, ~.
~.~

O~iZ3 washed with water and ethyl acetate, and then dried to give l-methoxycarbonylisatin (16.2 g), m.p. 178 - 181C
(decomp.) (2) The above product (14.36 g) was treated in the same manner as described in Preparation 23-(2) to give5-(2-methoxycarbonylaminophenyl)-5-hydroxyimidazolidine-2,4-dione (7.79 g), m.p. 192C (decomp.).

., ~' ~i~
.L ~'.~

Claims (7)

1. A process for preparing a quinazolinone compound of the formula:

wherein R1 is a lower alkyl, phenyl, a lower alkyl-phenyl, a halogeno-phenyl or a phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety, and R2, R3, R4, and R5 are the same or different and are each a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a lower alkoxycarbonyl or a lower alkoxycarbonyl-lower alkenyl, or two adjacent groups of R2, R3, R4 and R5 when taken together form methylenedioxy and the other two are hydrogen atom, or a salt thereof, which comprises:
(A) subjecting a compound of the formula:

wherein R1, R2, R3, R4 and R5 are the same as above, to a cyclization reaction in the presence of an alkali agent and/or oxidizing agent at a temperature from about 0°C to about 80°C in an appropriate solvent: or (B) reacting a compound of the formula:

wherein R6 is a lower alkyl, and R2, R3, R4 and R5 are the same as above, with an amine compound of the formula:

wherein R1 is the same as above, or a salt thereof, in an appropriate solvent under atmospheric pressure or under pressure at a temperature of room temperature to 200°C; or (C) hydrolyzing a compound of the formula:

wherein Z is sulfur atom or imino group, and R1, R2, R3, R4, and R5 are the same as above, in an appropriate solvent and when z is a sulfur atom, in the presence of an alkali agent, and when z is an imino group, in the presence of a nitrososation agent, at a temperature of 0 to 80°C, and (D) if required converting the resulting product:
into a salt thereof.

2. The process according to claim 1, wherein R1 is C1-4 alkyl, phenyl, C1-4 alkyl-phenyl, halogenophenyl, or phenyl-C1-2alkyl; and R2, R3, R4 and R5 are the same or dif-ferent and are each hydrogen, halogen, C1-4 alkyl, C2-5 alkoxycarbonyl, or C2-5 alkoxycarbonyl-C2-4 alkenyl, or two adjacent groups of R2, R3, R4 and R5 when taken together form methylenedioxy and the other two are hydrogen.

3. The process according to claim 2, wherein R1 is C1-4 alkyl, phenyl, C1-4 alkyl-phenyl, halogenophenyl, or phenyl-C1-2 alkyl; R2 is hydrogen, halogen or C1-4 alkyl; R3 and R4 is the same or different and are each hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C2-5 alkoxycarbonyl, or C2-5 alkoxycarbonyl-C2-4 alkenyl, or R3 and R4 when taken together form methylenedioxy; and R5 is hydrogen or halogen.

4. The process according to claim 3, wherein is methyl, n-butyl, phenyl, methylphenyl, chlorophenyl, or benzyl; R2 is hydrogen, chlorine or methyl; R3 and R4 are the same or different and are each hydrogen, fluorine, chlorine, bromine, methyl, methoxy, ethoxycarbonyl, or ethoxycarbonylvinyl, or R3 and R4 when taken together form methylenedioxy; and R5 is hydrogen, fluorine or chlorine.

5. The process according to claim 3, wherein R1 is methyl, n-butyl, phenyl, methylphenyl, chlorophenyl, or benzyl; R2 is hydrogen or methyl; R3 is hydrogen, fluorine, chlorine, bromine, methyl or ethoxycarbonyl; R4 is hydrogen, fluorine, chlorine, methyl or methoxy, or R3 and R4 when taken together form methylenedioxy; and R5 is hydrogen, fluorine or chlorine.

6. The process according to claim 3, wherein is C1-4 alkyl; R2 is hydrogen; R3 is halogen; R4 is hydrogen, halogen or C1-4 alkyl; and R5 is hydrogen or halogen.

7 . The process according to claim 6, wherein R1 is methyl; R2 is hydrogen; R3 is fluorine, chlorine or bromine; R4 is hydrogen, chlorine or methyl; and R5 is hydrogen or chlorine.