JPH0312068B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to quinazolinone derivatives. (Prior art) Diabetic complications include, for example, diabetic neuropathy, diabetic cataract, diabetic retinopathy, diabetic nephropathy,
Diabetic cardiovascular disorders are known. These complications are said to be caused by aldose reductase in the body, and as aldose reductase inhibitors for preventing and treating such diabetic complications, for example, chroman compounds (Japanese Unexamined Patent Publication No. 1989-1989-1) have been used as aldose reductase inhibitors. No. 53653, No. 57-45185, U.S. Pat.
No. 104876) and fratazine compounds (JP-A No. 104876)
95582) etc. are known. On the other hand, Chemie Berichte (Chem.Ber). , No.
Volume 103, page 2934 (1970) describes 3,1'-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione. , also Hemi Berichte. , Volume 110, 3849
(1977) describes 3,1',3'-trimethyl-spiro[1,2,3,4-tetrahydroquinazoline-
4,4'-imidazolidine]-2,2',5'-trione is described. However, to date, nothing is known about the pharmacological effects of these quinazolinone derivatives. (Object of the Invention) An object of the present invention is to provide a quinazolinone derivative having an excellent aldose reductase inhibitory effect. (Structure and effects of the present invention) The present invention relates to a quinazolinone derivative or a salt thereof represented by the following general formula. (However, R ¹ is a hydrogen atom or a lower alkyl group,
R ⁴ represents a hydrogen atom, a halogen atom, a nitro group, a cyclic imino group, or a disubstituted amino group, and when R ¹ is a hydrogen atom and R ⁴ is a hydrogen atom or a halogen atom, R ² , R ³ and R ⁵ is at least 1
When one is a nitro group or an amino group and the other represents a hydrogen atom or a halogen atom, R ¹ is a hydrogen atom and R ⁴ is a nitro group,
R ² , R ³ and R ⁵ represent a hydrogen atom or a halogen atom, and when R ¹ is a hydrogen atom and R ⁴ is a cyclic imino group or a di-substituted amino group, R ² , R ³ and R ⁵ represent at least 1 One is a nitro group, the other represents a hydrogen atom or a halogen atom, and when R ¹ is a lower alkyl group, R ² , R ⁴ and R ⁵ are a hydrogen atom, and R ³ is a hydrogen atom or a halogen atom. ) The object compound () of the present invention is obtained by removing substituents from the 1' and 3' positions of the spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] derivative, which is a known compound. However, it has an excellent aldose reductase inhibitory effect and is effective in preventing and preventing various diabetic complications.
It is a pharmaceutical compound useful as a therapeutic agent. In the target compound (), the lower alkyl group is a straight chain or branched alkyl group having 1 to 5 carbon atoms,
For example, methyl group, ethyl group, propyl group, butyl group, pentyl group, etc. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom, etc. Furthermore, a cyclic imino group is a general term for a nitrogen-containing heterocyclic group that is substituted on an imidazolidine skeleton at a nitrogen atom site, and examples of such a cyclic imino group include a morpholino group, 4-methylpiperazine, etc. Examples include a metal group and a piperidino group. Furthermore, examples of the di-substituted amino group include di-lower alkyl-substituted amino groups (eg, diethylamino group, dimethylamino group, etc.). Among the target compounds () of the present invention, preferred compounds include R ¹ as a hydrogen atom, R ² as a hydrogen atom or a halogen atom, and one or both of R ³ and R ⁵ as a nitro group or an amino group. and
The remaining one is a hydrogen atom or a halogen atom,
Is R ⁴ a hydrogen atom or a halogen atom: or
R ¹ , R ² , R ³ and R ⁵ are hydrogen atoms, and R ⁴ is a nitro group; or R ¹ is a hydrogen atom, and at least one of R ² , R ³ and R ⁵ is a nitro group; and R ⁴ is a morpholino group or a 4-methylpiperazinyl group; or R ¹ is a methyl or butyl group; R ² , R ⁴ and R ⁵ are hydrogen; Examples include compounds in which the atom R ³ is a hydrogen atom or a halogen atom. More preferred compounds include compounds in which R ¹ , R ² and R ⁴ are hydrogen atoms, R ³ is chlorine atoms, R ⁵ is nitro group or amino group, and R ¹ is isobutyl group, R ² , R ⁴ and R ⁵ are hydrogen atoms, and R ³ is a hydrogen atom or a halogen atom. Since the target compound () has an asymmetric carbon atom in its molecule, two types of optical isomers may exist, and the present invention includes both of these optical isomers and mixtures thereof. Among the target compounds (), the general formula (However, R ⁴¹ represents a hydrogen atom, a halogen atom, a nitro group, a cyclic imino group, or a di-substituted amino group, and when R ⁴¹ is a hydrogen atom or a halogen atom, R ²¹
At least one of R ³¹ and R ⁵¹ is a nitro group or an amino group, and the other represents a hydrogen atom or a halogen atom, and when R ⁴¹ is a nitro group, R ²¹ , R ³¹ and R ⁵¹ are a hydrogen atom or a halogen atom. represents an atom, and when R ⁴¹ is a cyclic imino group or a di-substituted amino group, at least one of R ²¹ , R ³¹ and R ⁵¹ is a nitro group, and the others represent a hydrogen atom or a halogen atom. ) The compound represented by, for example, (1-a) general formula or (However, R ⁴³ represents a hydrogen atom, a halogen atom or a nitro group, R ⁶ represents a lower alkyl group, and when R ⁴³ is a hydrogen atom or a halogen atom,
Either one or both of R ³³ and R ⁵³ is a hydrogen atom or a nitro group, and R ²³ represents a hydrogen atom, a halogen atom, or a nitro group, and when R ⁴³ is a nitro group, R ²³ , R ³³ and R ⁵³ represent a hydrogen atom or a halogen atom. ) is subjected to a ring-closing reaction to form the general formula (However, R ²³ , R ³³ , R ⁴³ and R ⁵³ have the same meanings as above.) Prepare the compound shown in (1-b) where one or both of R ³³ and R ⁵³ is a hydrogen atom. (1-c) If desired, the nitro group of the product of steps (1-a) and (1-b) above is reduced and aminated, and (1 -d) In the product of the above steps (1-a) and (1-b), if the substituent R ⁴³ on the benzene ring is a halogen atom, it is optionally reacted with a cyclic imine or a disubstituted amine, and ( 1-e) The product thus obtained can be produced by converting it into a salt, if desired.On the other hand, among the target compounds (), those with the general formula (However, R ¹ is a lower alkyl group, R ²² , R ⁴² and
R ⁵² represents a hydrogen atom, and R ³² represents a hydrogen atom or a halogen atom. ) The compound represented by, for example, (2-a) general formula (However, >N-X ¹ and >N-X ² represent protected imino groups.) After reacting the compound represented by halogenated lower alkyl, (2-b) optionally, the product (2-c) Also, before or after the halogenation step, the protecting group of the imino group is removed, and (2-d) the product thus obtained is optionally converted into a salt thereof. can be manufactured. Among the above raw material compounds, compounds () and ()
can be easily prepared, for example, by reacting the corresponding 1-methylcarbamoylisatin derivative with urea or lower alkyl-substituted isothiourea according to the method described in Japanese Patent Application No. 60-124008. can. The intramolecular ring-closing reaction (step 1-a) of the starting compounds () and () is preferably carried out in a suitable solvent. For example, the ring-closing reaction of the starting compound () is preferably carried out in the presence of an acid, and for example, hydrochloric acid, hydrobromic acid, formic acid, etc. can be appropriately used for this purpose. Suitable solvents include, for example:
It is preferable to use water, methanol, ethanol, dimethylformamide, 1,2-dichlorobenzene, etc. Further, the ring-closing reaction of the starting compound () can be carried out simply by heating it in an appropriate solvent. Examples of the solvent in this case include 1,2-dichlorobenzene, nitrobenzene, naphthalene,
Examples include biphenyl. The ring-closing reaction of the starting compound () is carried out at 20 to 100°C, especially at 60 to 90°C, and
The ring-closing reaction of the starting compound () is preferably carried out at 150-250°C, especially at 180-200°C. The nitration reaction (step 1-b) can be carried out according to a conventional method, for example, by reacting with a nitration agent in a suitable solvent or without a solvent. As a nitrating agent, sulfuric acid-nitric acid, sulfuric acid-sodium nitrite,
Nitric acid and the like can be used as appropriate, and examples of the solvent include acetic acid, acetic anhydride, acetone, and carbon tetrachloride. The reaction is preferably carried out at -20 to 100°C. Further, the reduction reaction of the nitro group (step 1-c) can also be carried out according to a conventional method. For example, by catalytic reduction in a suitable solvent (e.g., water, ethanol) in the presence of a catalyst (e.g., palladium black) under a hydrogen gas atmosphere, or by reaction with iron-hydrochloric acid, stannous chloride-hydrochloric acid, etc. However, it can be implemented as appropriate. Furthermore, in the product of the above steps (1-a) and/or (1-b), the reaction of the compound whose substituent R ⁴³ is a halogen atom with a cyclic imine or a disubstituted amine (step 1-d) This can be carried out by treating the raw material compound at 50 to 150°C. On the other hand, the protecting group in the above raw material compound ()
As X ¹ and X ² , any group generally used as a protecting group for an amino group or an imino group can be used, and such protecting groups include, for example,
Examples include acetyl group, benzyloxymethyl group, benzoyl group, benzyloxycarbonyl group, and tetrahydrofuranyl group. The reaction between the raw material compound () and the alkyl halide (step 2-a) is preferably carried out, for example, in a suitable solvent in the presence of a deoxidizing agent. As a deoxidizing agent, sodium hydride, sodium hydroxide,
Potassium hydroxide, potassium carbonate, etc. can be used as appropriate, and dimethylformamide, tetrahydrofuran, acetone, dimethyl sulfoxide, etc. are preferably used as the solvent. This reaction is −
Preferably it is carried out at 20-100°C. The subsequent halogenation reaction (Step 2-b) can be suitably carried out according to a conventional method, for example, by treating with a halogenating agent in a suitable solvent. Examples of the halogenating agent include sulfuryl chloride, chlorine,
Bromine, iodine, benzene chloride, N-bromosuccinimide, etc. can be used. Examples of suitable solvents include acetic acid, tetrahydrofuran, dioxane, water, and mixed solvents thereof. This reaction is carried out at 0 to 100℃, especially at 20℃.
Preferably, it is carried out at ~70°C. Also, removal of the protecting group after the reaction (step 2-c)
For example, according to the conventional method, depending on the type of protecting group,
This can be carried out using means such as hydrolysis, electrolytic reduction, base treatment, acid treatment, catalytic reduction, and oxidation reaction. The optically active form of the target compound () can be obtained according to a conventional method. For example, the expression It can be obtained by optically resolving the racemic form of the compound represented by to obtain an optically active form of the same compound, and introducing a substituent thereto according to the method described in the present invention. Optical resolution is performed by reacting a racemic compound () with an optical resolving agent (e.g., brucine, quinine) in a suitable solvent (e.g., methanol) according to a conventional method, and determining the solubility of the resulting diastereomeric salt. After splitting using the difference, for example, by decomposing with an acid (hydrochloric acid, etc.), an optically active form of the compound () can be obtained. The object compound () of the present invention can be used as a medicine either in its free form or in its salt form. When the target compound () is used for pharmaceutical purposes, it is preferably used as a pharmacologically acceptable salt, and examples of such salts include sodium salts, potassium salts, calcium salts, lysine salts, ethylenediamine salts, diethanolamine salts, etc. can give. These salts contain the free target compound ()
can be easily obtained by treating with a base in a conventional manner. The object compound of the present invention () or a pharmacologically acceptable salt thereof exhibits an excellent aldose reductase inhibitory effect and is useful as a prophylactic/therapeutic agent for various chronic symptoms associated with diabetes (i.e., diabetic complications). . For example, it can be used to prevent or treat diabetic neuropathy, diabetic cataracts, diabetic retinopathy, diabetic nephropathy, circulatory disorders caused by diabetes, and the like. The object compound () of the present invention or a salt thereof can be administered either orally or parenterally. Examples of dosage forms include tablets, granules, powders,
Capsules, injections, ophthalmic drugs (e.g. eye drops),
It can be used in any form of preparations such as ointments, and in preparing these preparations, pharmaceutically acceptable carriers (for example, excipients, binders, disintegrants, lubricants, etc.) Both can be used as appropriate. The dosage of the object compound () of the present invention or a pharmacologically acceptable salt thereof varies depending on the administration method, patient's age, body weight, condition, and type of disease, but is usually about 0.01 to 100% per day. It is preferably about 200 mg/Kg, especially about 0.1 to 50 mg/Kg. Examples (Experimental Methods) Aldose reductase inhibitory effect The Journal of Biological Chemistry (J.Biol.Chem). , Volume 240, No. 877−
882 pages (1965) According to the description method, Aldose
Reductase was prepared, and the inhibitory activity of the sample against the aldose reductase was determined using Biochimica E.
Biochim.Biophys.
Acta). , Vol. 128, pp. 474-482 (1966). The aldose reductase inhibitory effect of the sample is determined by the concentration required to inhibit aldose reductase activity by 50% (i.e., 50%
It was determined as the inhibitory concentration) (IC ₅₀ ). Polyol accumulation inhibitory effect SIc: Wistar male rats (3-4 weeks old; 1
Group: 3 animals) were fed a 20% galactose-added diet containing 20 mg% of the specimen (i.e., 20 mg of the specimen in 100 g of feed) (sample administration group), a 20% galactose-added diet (galactose control group), or no additive. The mice were fed normal feed (normal control group) for 6 days. After the rearing period, the rats were killed by cutting the carotid artery under ether anesthesia, the sciatic nerves on both sides were immediately removed, and the amount of polyol in the sciatic nerves was determined by Science. , Vol. 182, pp. 1146-1148 (1973)
It was measured by the acetylacetone method according to the method described in . The polyol accumulation inhibition rate was calculated from the following formula. Polyol accumulation inhibition rate (%) = [1-Amount of polyol in sample administration group (average value) - Amount of polyol in normal control group (average amount)/Amount of polyol in galactose control group (average value) - Amount of polyol in normal control group (Average value)] × 100 (Sample used) Specimen No. Chemical name (compound of the present invention) 1 1-iso-butyl-3-methyl-spiro (1,
2,3,4)-tetrahydroquinazoline-4,
4'-imidazolidine]-2,2',5'-trione2 1-iso-butyl-6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazo lysine]-2,2′,
5'-trione 3 6-chloro-3-methyl-8-nitro-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione 4 8 -Amino-6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (control compound) 5 3,1 '-dimethyl-spiro[1,2,3,4
-Tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (Chem.Ber.,
103, 2394 (1970)) 6 3,1',3'-trimethyl-spiro [1,2,
3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (Chem.
Ber., 110 , 3849 (1970)) (Experimental results) The results are shown in Table 1 below. [Table] Example 1 6-nitro-3-methyl- obtained in Production Example 1 described later
4-Hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo. 1, 2, 3, 4
- 5.5 g of tetrahydroquinazoline and 140 ml of 10% hydrochloric acid
Add and stir at 70-80℃ for 3 hours. 20℃ after reaction
6-nitro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5' - Obtain 1.9 g of trion. Mp＞280℃ IRν ^nujol _nal (cm ^-1 ) 3300, 1790, 1735, 1603 Mass (m/e): 291 (M ⁺ ) NMR (DMSO−d ₆ , δ): 2.88 (3H, s), 3.51
(2H, s), 7.10 (1H, d, J=9Hz), 7.89
(1H, d, J=2Hz), 8.14 (1H, dd,
J=9Hz, J=2Hz), 9.30 (1H, s), 10.70
(1H, s), 11.57 (1H, s) Example 2 6-nitro-3-methyl- obtained in Production Example 2 below
4-hydroxy-4-ureidocarbonyl-2-
Add 2.0 g of oxo-1,2,3,4-tetrahydroquinazoline to 50 ml of 1,2-dichlorobenzene,
Heat to reflux for 2 hours while stirring. After cooling, the precipitated crystals were collected by filtration and recrystallized from dimethylformamide-water to give 6-nitro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-
4,4′-imidazolidine]-2,2′,5′-trione
Get 1.1g. The physicochemical properties of this product were consistent with those of the specimen obtained in Example 1. Example 3 7-nitro-3-methyl- obtained in Production Example 3 described later
4-Hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo-1,2,3,4
-Tetrahydroquinazoline was treated in the same manner as in Example 1 to produce 7-nitro-3-methyl-spiro[1,
2,3,4-tetrahydroquinazoline-4,4'-
imidazolidine]-2,2',5'-trione is obtained. Mp＞280℃ NMR (DMSO-d ₆ , δ): 2.80 (3H, s), 7.37
(1H, d, J=8Hz), 7.6−8.0 (2H, m),
9.17 (1H, s), 10.27 (1H, s), 11.40 (1H,
s) Example 4 (1) 6-chloro-3-methyl-4-hydroxy-4-(2-ethylisothioureido)carbonyl-2-oxo-1,2, obtained in Production Example 4 below
3,4-tetrahydroquinazoline was treated in the same manner as in Example 1 to give 6-chloro-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2' , 5'-trion is obtained. Mp＞280℃ IRν ^nujol _nax (cm ^-1 ): 3300, 1780, 1740, 1718 Mass (m/e): 280 (M ⁺ ) (2) Dissolve 2.8 g of the above product in 15 ml of concentrated sulfuric acid,
Add sodium sulfite while stirring while cooling to 5°C.
Add 0.85g. After stirring overnight at room temperature, the reaction solution was poured into ice water, and the precipitated crystals were filtered and washed with water to give 6-chloro-8-nitro-3-methyl-spiro[1,
2,3,4-tetrahydroquinazoline-4,
4′-imidazolidine]-2,2′,5′trione 3.2g
get. Yield 99% Mp 280°C Mass (m/e): 325 (M ⁺ ) NMR (DMSO-d ₆ , δ): 2.80 (3H, s), 7.58
(1H, d, J=2Hz), 8.17 (1H, d), J=
2Hz), 8.22 (1H, s), 8.47 (1H, s),
11.45 (1H, s) Examples 5 to 8 Compounds listed in Table 2 below were obtained by treating the corresponding raw material compounds obtained in Production Examples 5 to 8 below in the same manner as in Example 4-(1) and (2). obtain. [Table] [Table] Example 9 6-nitro-3-methyl-spiro(1,2,3,4-tetrahydroquinazoline-
4,4′-imidazolidine]-2,2′,5′-trione
Dissolve 2.91g in 50ml of potassium carbonate (1.38g) aqueous solution, add 0.1g of palladium black, and pressurize with hydrogen gas (2~
Catalytic reduction is carried out under (3 atm). The catalyst is filtered off, the filtrate is neutralized with 10% hydrochloric acid, and then concentrated. Filter the precipitated greenish-brown crystals, dissolve in 10% hydrochloric acid, add activated carbon, and filter. The filtrate was neutralized with sodium carbonate, and the precipitated crystals were collected by filtration to give 6-amino-3-methyl-
1.0 g of spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione is obtained. Mp＞280℃ IRν ^nujol _nax (cm ^-1 ): 3400, 3350, 3300, 1780,
1725 Mass (m/e): 261 (M ⁺ ) NMR (DMSO-d ₆ , δ): 2.76 (3H, s), 3.1
−6.0 (2H, br), 6.33 (1H, s), 7.60 (2H,
s), 8.93 (1H, s), 9.43 (1H, s), 11.20
(1H, br) Example 10 6-chloro-8-nitro-3- obtained in Example 4
Methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',
5'-trione was treated as in Example 9 to give 8-amino-6-chloro-3-methyl-spiro[1,
2,3,4-tetrahydroquinazoline-4,4'-
imidazolidine]-2,2',5'-trione is obtained. Yield 85% Mp＞280℃ IRν ^nujol _nax (cm ^-1 ): 3410, 3350, 3220, 3050,
1790, 1720 Mass (m/e): 295 (M ⁺ ) NMR (DMSO-d ₆ , δ): 2.75 (3H, s), 5.55
(2H, s), 6.16 (1H, d, J=2Hz), 6.62
(1H, d, J=2Hz), 8.96 (1H, s), 9.05
(1H, s), 11.17 (1H, s) Example 11 7-chloro-6-nitro-3- obtained in Example 5
Methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',
Mix 0.2 g of 5′-trione with 2 ml of morpholine,
Heat and stir at ~100°C for 1 hour. Unreacted morpholine is distilled off under reduced pressure, and 10% hydrochloric acid is added to the residue to neutralize it. The precipitated crystals were collected by filtration and dried to give 7-morpholino-
6-nitro-3-methyl-spiro[1,2,3,
0.19 g of 4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione is obtained. Yield 82.2% Mp＞280℃ Mass (m/e): 376 (M ⁺ ) NMR (DMSO-d ₆ , δ): 2.78 (3H, s), 3.00
(4H, br), 3.70 (4H, br), 6.57 (1H, s),
7.60 (1H, s), 9.05 (1H, s), 10.28 (1H,
s), 11.00 (1H, br) Examples 12 to 13 The compounds obtained in Examples 5 and 8 were mixed with N-methylpiperazine, respectively, and treated in the same manner as in Example 11 to form a compound at the 7-position on the benzene ring. Compounds shown in Table 3 below into which an N-methylpiperazinyl group has been introduced are obtained. [Table] Example 14 (1) 3'-acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,
2,3,4-tetrahydroquinazoline-4,
4′-imidazolidine]-2,2′,5′-trione
Dissolve 3.06g in 20ml of dimethylformamide,
Add 1 ml of methyl iodide, add 0.3 g of sodium hydride (60%) little by little under ice cooling, and stir at room temperature for 30 minutes. Add water to the reaction solution and extract with ethyl acetate. The extract is dried and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform).
3'-acetyl-1'-benzyloxymethyl-
1,3-dimethyl-spiro[1,2,3,4-
3 g of tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione are obtained as an oil. Yield 94.5% IRν ^nujol _nax (cm ^-1 ): 1800, 1720, 1640, 1600 (2) Dissolve 3.0 g of the above product in 20 ml of ethanol,
Add 0.2 g of palladium black and catalytically reduce the mixture under hydrogen gas pressure (2 to 3 atm) for 5 hours. The catalyst is filtered off and the solvent is distilled off. Dissolve the residue in a 10% aqueous sodium carbonate solution, heat at 60 to 80°C for 30 minutes, neutralize the solution with 10% hydrochloric acid, and collect the precipitated crystals by filtration. Recrystallization from dimethylformamide-water gives 3'-acetyl-1,3-dimethyl-spiro[1,2,
0.85 g of 3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione is obtained. Mp261-263℃ Mass (m/e): 302 (M ⁺ ) IRν ^nujol _nax (cm ^-1 ): 1800, 1760, 1715, 1640 NMR (DMSO−d ₆ , δ): 2.40 (3H, s), 2.80
(3H, s), 3.36 (3H, s), 3.00−4.00 (1H,
br), 6.90-7.60 (4H, m) (3) Add 1.0 g of the above product to a sodium ethylate solution (prepared from 161 g of sodium metal and 20 ml of ethanol) and stir at room temperature for 3 hours. After distilling off the solvent, the residue was neutralized with 10% hydrochloric acid and left for 1 hour. The precipitated crystals were collected by filtration and dimethylformamide
Recrystallized from water to give 1,3-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-
500 mg of 4,4'-imidazolidine]-2,2',5'-trione is obtained as colorless prismatic crystals. Mp223-225℃ IRν ^nujol _nax (cm ^-1 ): 3300, 3200, 1782, 1730, 1630 NMR (DMSO-d ₆ , δ): 2.86 (3H, s), 3.33
(3H, s), 7.00−7.63 (4H, m), 9.10 (1H,
s), 11.40 (1H, br) Example 15 3'-acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,
3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione and isobutyl iodide were treated in the same manner as in Example 14-(1) to give 3'-
Acetyl-1'-benzyloxymethyl-1-isobutyl-3-methyl-spiro[1,2,3,4-
Tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione is obtained. Mp70-72℃ Mass (m/e): 464 (M ⁺ ) NMR (DMSO-d ₆ , δ): 0.9-1.3 (6H, m), 1.9
−2.3 (1H, m), 2.45 (3H, s), 2.84 (3H,
s), 3.5−4.1 (2H, m), 4.68 (2H, s),
5.16 (2H, s), 6.6-7.1 (3H, m), 7.1-7.5
(6H, m) The above product was treated in the same manner as in Example 14-(2) and (3) to produce 1-isobutyl-3-methyl-spiro[1,
2,3,4-tetrahydroquinazoline-4,4'-
imidazolidine]-2,2',5'-trione is obtained. Mp270℃ Mass (m/e): 302 (M ⁺ ) IRν ^nujol _nax (cm ^-1 ): 1790, 1723, 1645, 1608 NMR (DMSO−d ₆ , δ): 0.90 (6H, d, J=
7Hz), 1.8-2.3 (1H, m), 2.79 (3H, s),
3.6-4.0 (2H, m), 6.9-7.6 (4H, m), 9.02
(1H, s), 11.19 (1H, s) Example 16 1-isobutyl-3-methyl- obtained in Example 15
Suspend 0.76 g of spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione in 15 ml of acetic acid, and add 0.3 ml of sulfuryl chloride and a trace amount of iodine. , stir at room temperature for 19 hours. Pour the reaction solution into ice water, collect the precipitated crystals by filtration, dissolve in a 10% aqueous sodium hydroxide solution, filter off insoluble materials, neutralize the filtrate with 10% hydrochloric acid, and collect the precipitated crystals by filtration. (Repeat this dissolution/precipitation operation). Next, filter the crystals and dry them.
-Chloro-1-isobutyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,
4′-imidazolidine]-2,2′,5′-trione
Get 0.45g. Mp118℃ Mass (m/e): 338 (M ⁺ +1), 338 (M ⁺ -1)
IRνIRν ^nujol _nax (cm ^-1 ): 1790, 1735, 1645, 1602 NMR (DMSO-d ₆ , δ): 0.90 (6H, d, J=7
Hz), 1.7-2.4 (1H, m), 2.79 (3H, s), 3.6
-4.0 (2H, m), 7.03 (1H, d, J = 3Hz),
7.10 (1H, d, J = 10Hz), 7.40 (1H, d-
d, J=10Hz, J=3Hz), 9.09 (1H, s),
11.26 (1H, s) Production Example 1 (1) A mixture of 19.2 g of 5-nitroisatin, 2 ml of triethylamine and 60 ml of dimethylformamide is stirred under cooling, and 6.85 g of methyl isocyanate is added dropwise to the mixture at the same temperature. By stirring the mixture at room temperature and filtering the precipitated crystals,
5-nitro-1-methylcarbamoylisatin
Get 16.5g. Yield 66.3% Mp168℃ (decomposition) (2) Dissolve 6.3g of the above product in 60ml of tetrahydrofuran, add 6.0g of 2-ethylisothiourea hydrobromide and 4.57ml of triethylamine, and stir at room temperature for 3 hours. Stir. Collect the precipitated crystals by filtration to obtain 6-nitro-3-methyl-hydroxy-4
-(2-ethylisothioureido)carbonyl-2-oxo. 5.5 g of 1,2,3,4-tetrahydroquinazoline crude product is obtained. Production example 2 5-nitro-1-methylcarbamoylisatin
3.1g and 1,8-diazabicyclo[5,4,0]
-7-Undecene 0.1g in tetrahydrofuran 50ml
Add 1.2 g of urea to the solution and heat under reflux for 1.6 hours. After cooling, the precipitated crystals were collected by filtration, washed with water and methanol, and recrystallized from a mixture of dimethyl sulfoxide and ethanol to obtain 6-nitro-3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo. -0.8 g of 1,2,3,4-tetrahydroquinazoline is obtained. Pp>280°C Production Examples 3 to 8 The corresponding raw material compounds were treated in the same manner as in Production Example 1-(1) and (2) to obtain the compounds listed in Table 4 below. Incidentally, this product was used as a raw material compound in Examples without any purification. [Table] Production Example 9 (1) Add 7.38 g of 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione to 60 ml of dimethylformamide. Add 1.2 g of sodium hydride (60%) at 15°C, and stir at room temperature for 30 minutes. Then, 4.71 g of benzyloxymethyl chloride was added at room temperature, and the mixture was further stirred at room temperature for 30 minutes. Add water to the reaction solution and extract with ethyl acetate. The organic layer is washed with water, dried, and the solvent is distilled off. Dimethylformamide - crystallized from water
10.4 g of 1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione are obtained. Mp226〜227℃ IRν ^nujol _nax (cm ^-1 ): 3200, 3050, 1800, 1735,
1660, (2) The above product and acetyl chloride were treated in the same manner as in (1) above (however, isopropanol-isopropyl ether was used as the crystallization solvent) to obtain 3'-acetyl-1'-benzyloxymethyl. -3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',
We get 5′-trion. Yield 70% Mp 209-211℃ [Claims] 1 Formula A novel 9-nitrocamptothecin represented by 2. A method for producing 9-nitrocamptothecin, which comprises treating camptothecin with a small excess of concentrated nitric acid in concentrated sulfuric acid.

Claims (1)

vinegar. ) Quinazolinone derivatives or salts thereof.