FI81804B - Process for preparing therapeutically utilizable spiro/1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine/- 2,2'-,5'-triones - Google Patents

Description

81804

The process for the preparation of therapeutically useful spiro- [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2,5-triones - Förfarande för framställning av terapeutiskt användbara spiro [1,2,3,4 The present invention relates to a process for the preparation of therapeutically useful spiro [1,2,3,4-tetrahydroquinazoline-4,4'-thione] 4,4'-imidazolidine] -2,2 '-, 5'-trioner. imidazo-1idine] -2,2 ', 5'-trione compounds of the formula

IS H

R2 1 I

, HN I

! I) TT .1

R5 R

wherein R is a hydrogen atom or lower alkyl, R 1 is lower alkyl, R 2 and R 5 are the same or different and each represent a hydrogen atom or a halogen atom, and R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl or a salt thereof These new compounds are useful in the prophylaxis and treatment of various diabetic conditions.

Oiabetic complications are known to include diabetic neurosis, cataracts, microvascular disease such as diabetic retinopathy and diabetic kidney disease, and the like.

Accumulation of polyols, such as sorbitol, which are converted to hexose, etc. by aldose reductase in vivo, is known to induce these diabetic complications. [Cf. The New England Journal of Medicine, Vol. 288, 831-836 (1973)]. To prevent and treat diabetic complications, 2 81,804 different inhibitors of ladose reductase have been proposed to date, which can prevent the accumulation of polyols in the body, for example compounds with a chroman core [cf. Japanese Patent Publications (Firts) no. 53653/1978 and 45185/1982 and U.S. Patent 4,117,230], compounds having a thiazolidine core [cf. Japanese Patent Publication (First) no. 104876/1981] and compounds having a phthalazine core [cf. Japanese Patent Publication (Firts) no. 95582/1979].

In addition, some quinazolinone compounds are known, for example 3,1'-dimethyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4-imidazolidine] -2,2 ', 5'-trione [cf. Chemie Berichte, Vol. 103, 2394 (1970)] and 3,1 ', 3'-trimethyl-spiro [1,2,3,4-tetrahydro-quinazoline-4/4-imidazolidine] -2 / 2', 5'-trione [ cf.. Chemie Beriche, Vol. 110, 3849)], but these quinazolinone compounds have never been known to have any pharmacological activity.

The inventors of the present invention have extensively studied various [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] compounds and their pharmacological activities, and it has surprisingly been found that the compounds of formula (I) having no substituent at the 1 'and 3' positions of the known spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] compounds has excellent aldose reductase inhibitory activity.

It is an object of the invention to provide a process for the preparation of novel quinazoline compounds which have excellent aldose reductase inhibitory activity and which are therefore useful in the prophylaxis and treatment of diabetic complications. This and other objects and advantages of the invention will be apparent to those skilled in the art from the following description.

81804 3

The compounds obtained according to the invention have the above-mentioned formula (I).

Substituents of formula (1) mean the following groups.

The term "lower alkyl" is a straight-chain or branched alkyl of 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl, isopentyl, etc. "lower alkoxy" means a straight-chain or branched alkoxy of 1 to 5 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, etc. halogen atom "means fluorine, chlorine or bromine.

The compounds (I) of the invention have an asymmetric carbon in the molecule and can thus contain two optical isomers. The present invention encompasses these optical isomers and a racemic mixture thereof.

According to the present invention, compounds (I) in which R is a hydrogen atom, i.e. a compound of formula (I-a)

, HN I

T | 1 Ua)

i H

wherein R 1, R 2, R 4, R 4 and R 5 are as defined above, or a salt thereof, is prepared in the step of: (A) cyclizing a compound of formula 4 81804 S-R 6 -Z 1

R2 I R2 II

j HO .'CONH-C-NH I HO ^. CONHC-HH2 RS ^ r I '- *'

Γ 11 l or I 11 i R

gll ^ S / ^ N'O R1 | xliV ^ 'N' ^ Ö

I H I H

r5 R5

(II) (HD

wherein R 1 is lower alkyl, Z 1 is an oxygen atom or a sulfur atom, and R 1 / R 2 f r s, r 4 and R * are as defined above; (B) a compound of formula (IV) R 2 R 3 x x 2 COCONHCONHp | II (IV) NHCOOR 7 R5 wherein R7 is lower alkyl, and R2, R *, R4 and R * are as defined above, is reacted with an amine compound of formula (V) r1-nh2 (V) wherein R1 is as defined above, or with its salt; or (C) hydrolyzing a compound of formula (VI) 81804 5 Z2 κ * ι — r I HN 1 κ3ν ^ γ> <Ν-Β ’(VI)

1 * H

wherein Z2 is a sulfur atom or an imino group, R1 ·, R2, R *, R4 and R5 are as defined above, and optionally the product obtained is converted into a salt.

The cyclization of the compound (II) or the compound (III) can be carried out in a suitable solvent. The cyclization of compound (II) is best carried out either in the presence of an acid or in the presence of an alkaline substance and / or an oxidizing agent. Acids include hydrochloric acid, hydrobromic acid, formic acid and the like. Terminal agents include alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., potassium carbonate, etc.), and the like. The oxidant includes 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 best carried out at a temperature of 20 to 100 ° C, preferably 60 to 90 ° C.

The cyclization of the compound (III) in which Z1 is an oxygen atom [hereinafter referred to as (III-a)] is best performed at a temperature of 150 ° C to 250 ° C, preferably 180 ° C to 200 ° C. Solvents include 1,2-dichlorobenzene, nitrobenzene, naphthalene, biphenyl and the like.

The cyclization of the compound (III) in which Z * · is a sulfur atom [hereinafter referred to as the compound (III-b)] is best carried out in the presence of an alkaline substance and / or an oxidant.

6 81804

Terminal agents include alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.) / alkali metal carbonate (e.g., potassium carbonate, etc.) 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 best carried out at a temperature of 0 to 80 ° C.

The reaction of the compound (IV) and the compound (V) or a salt thereof can be carried out in a suitable solvent. Compound (IV) is preferably a compound of formula (IV) wherein R 7 is lower alkyl such as methyl, ethyl, propyl, butyl, etc. Salts of compound (V) include, for example, mineral acid salts such as hydrochloride, sulfate, etc. Solvents include, for example, dichlorobenzene. , toluene, methanol, ethanol, tetrahydrofuran or mixtures thereof. The reaction is usually carried out at atmospheric pressure or under pressure at a temperature ranging from room temperature to 200 ° C, preferably at 50 to 160 ° C. When the reaction is carried out under relatively mild conditions, the intermediate can sometimes be isolated as a crystal, and the intermediate can then be reacted with the compound (V) to give the desired compound (I-a).

The hydrolysis of the compound (VI) can be carried out in a suitable solvent. The hydrolysis of the compound (VI) in which Z2 is a sulfur atom [hereinafter referred to as the compound (VI-a)] is best performed in the presence of an alkaline substance and an oxidizing agent.

The hydrolysis of the compound (VI) in which Z2 is an imino group [hereinafter referred to as the compound (VI-b)] is best performed in the presence of a nitrosating agent. Temporal agents and oxidizing agents include those mentioned in connection with the cyclization of compound (III-a). Nitrosating agents include alkali metal nitriles, alkyl nitriles, nitrosyl chloride, nitrogen dioxide, and the like. Solvents include water, acetic acid, sulfuric acid and the like. The reaction is best carried out at a temperature of 0 to 80 ° C.

Alternatively, compounds of formula (I-b) may be used

% NH

HN 1 (I ~ b) BU1

R51 R

wherein R 31 is a halogen tower, 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, or a salt thereof is prepared by treating a compound of formula (I-c) with a halogenating agent.

-N H

HN 1 (I-o) Π i

R

wherein R, R1 and R41 are as defined above, or a salt thereof, and optionally converting the product obtained into a salt.

The starting compound (I-c) can be used in the reaction as a free base or a salt thereof, for example, an alkali metal salt (for example, a sodium salt, a potassium salt).

The treatment of the compound (I-c) with a halogenating agent can be carried out in a suitable solvent. Halogenating agents 81 804 8 include sulfuryl chloride, chlorine, bromine, iodobenzene dichloride, n-romosuccinimide and the like. Solvents include acetic acid, tetrahydrofuran, dioxane, water, or a mixture thereof. The reaction is best carried out at a temperature of 0 to 100 ° C, preferably 20 to 70 ° C.

In addition, compounds of formula (I-d)

° λ - NH

R2 1 I

| HN L

R3 JL> <"j ^ R1 (I-d)

bX-XNA

R5 R 'wherein R' is lower alkyl, R1, R2, r », r <and R» have the same meaning as above, or a salt thereof can be prepared by reacting a compound of formula (VII) 20 <jN-X1 (VII) IT i .

T H

wherein X 1 and X 2 represent a protecting group, and R 1, R a, R 3, R 4 and R 5 are as defined above, to react with an alkylating agent such as a lower alkyl halide and deprotect, followed by optionally converting the resulting product to a salt.

In the starting compound (VII), the protecting groups X1 and X2 include any conventional protecting groups suitable for protecting an amino or imino group, for example, acetyl, benzyl-oxymethyl, benzoyl, benzyloxycarbonyl, tetrahydrofuranyl and the like.

Alkylation of the compound (VII) with a lower alkyl halide is best 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 best carried out at -20 to 200 ° C.

Deprotection can be carried out by a conventional method suitable for deprotection of each grade, for example, hydrolysis, electrolytic reduction, treatment with a base, treatment with acid, catalytic reduction, oxidation and the like. Conversion of the free base to the salt can be performed by a conventional method.

The starting compound of formula (VII) can be prepared by reacting a compound of formula

% _N H

^ VkX0--11 '

TV. jT J. d-e)

l H

wherein R 1, R 2, R®, R * and R® are as defined above, to react with a compound of formula

X-Y

81804 10 wherein X1 is a protecting group and Y is a reactive group to form a compound of formula »* Y ~ v '

, I hn. JL

R (XVIII) n "ς 11 R5 wherein R1, R2, R3, R4, R5 and X1 are as defined above and by reacting the compound (XVIII) thus obtained with a compound of the formula:

X2-Y

wherein X2 is a protecting group and Y is the same as above.

When the compounds (I) are obtained as a racemic mixture, they can be separated into the optical isomers by a conventional method. For example, optical separation can be performed by reacting a racemic mixture of compounds (I) with a resolving agent in a suitable solvent, isolating the sparingly soluble diastereomeric salt as crystals, and then isolating the soluble diastereomeric salt from the mother liquor using the solubility difference between the two diastereomeric salts. Resolving agents include, for example, products of natural origin such as brucine, quinine, cinchonidine, N-n-octylglucamine, dehydroabietylamine, etc., and optically active compounds such as α-methylbenzylamine, lysine, phenylalanine amide, tyrosine hydrazide and the like. Solvents include methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water, or mixtures thereof. The diastereomeric salt thus prepared can be converted into the desired optically active compound (I), for example, by treatment with an acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, etc.). The starting materials (II) and (lii) used in the reaction are also novel compounds. . Compound (II) can be prepared, for example, by reacting a compound of formula (VIII) R2 r3 i Q (VIII)

R5 H

wherein R 2, R 3, R 4 and R 5 are as defined above, or a salt thereof (e.g. sodium salt, potassium salt, etc.) to react with a compound of formula (IX) R 1 NC * O (IX) wherein R 1 is as defined above, in a solvent with a base (e.g. triethylamine, etc.) in the presence of -20 to 50 ° C to give a compound of formula (X) R 2 ySr-T 00 R 5 CONHR 1 wherein R 1, R 2, R 3, R 4 and R 10 are as defined above, followed by the compound obtained above ( X) reacting a compound of formula (XI) with 8180412 H2N-C = NH (XI) SR «wherein R6 is as defined above, or a salt thereof in a solvent in the presence of a base (e.g. triethylamine, etc.) at a temperature of 0 to 100 ° C .

Compound (III) can be prepared by reacting compound (X) or a salt thereof with a compound of formula (XII) Z1 H2N-C-NH2 (XII) wherein Z1 has the same meaning as above, in a solvent of a base (e.g. 1,8-diazabicyclo [5.4. O] -7-undecene, triethylamine, etc.) in the presence of 0 to 100 ° C.

Compound (II) can be further prepared by reacting compound (III-b) with a compound of formula (XIII) R «-X (XIII) wherein X is a halogen atom and R * is as defined above, in a solvent in the presence of a base (e.g. sodium hydride, etc.) At a temperature of 0 to 50 ° C.

Compound (IV) can be prepared by reacting compound (VIII) or a salt thereof with a compound of formula (XIV) R70COX (XIV) wherein R7 is lower alkyl and X is as defined above, in a solvent in the presence of a base (e.g. triethylamine, etc.) 0 to 80 ° C to give a compound of formula (XV) 81804 13 R5 COOR7 wherein R2, R3, R *, R5 and R7 are as defined above, after which the compound (XI) is reacted with urea in a solvent at 50-120 ° C .

Compound (VI-a) can be prepared by heating compound (III-b) in a solvent at 100 to 180 ° C, and then treating the obtained product with an acid (e.g., hydrochloric acid, etc.) at 20 to 100 ° C.

Compound (VI-b) can be prepared by reacting compound (X) with guanidine or a salt thereof in a solvent in the presence or absence of a base (e.g., sodium hydroxide, etc.) at a temperature of 20 to 100 ° C. In this reaction, a compound of formula (XVI) 2 * ί H2 R2!

I H0L ^ COMHC-NH

ΤΪΓΤΒ '

Hv U * R5 wherein R1, R2, R3, R * and R5 have the same meaning as above. This by-product (XV) is treated with an acid (e.g. hydrochloric acid, etc.) to give compound (VI-b).

,. 81804 14

The compounds (I) of the invention can be used as a medicament as a free base or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include, for example, sodium salt, potassium salt, calcium salt, ethylenediamine salt, diethanolamine salt and the like. These salts can be easily prepared by treating the free base of the compounds (I) with a base by a conventional method.

The compounds (I) and their salts have excellent aldose reductase inhibitory activity and are thus useful in the treatment of various chronic symptoms associated with diabetes, i. in the prophylaxis and treatment of diabetic complications in warm-blooded animals, for example in the treatment of diabetic neurosis, diabetic cataracts and diabetic microvascular disease such as diabetic retinopathy or diabetic kidney disease.

The compounds (I) of the invention and their salts further have the advantages of low toxicity and lower neurotoxic side effects (e.g., walking disorder, non-reflectivity, inability to stand, drooping eyelids, etc.).

The compounds (I) of the invention and their salts can be administered orally or parenterally. They can be administered in conventional pharmaceutical preparations, for example, tablets, granules, hay granules, powders, capsules, injections, ophthalmic drugs (e.g., eye wash, eye cream, etc.) and the like. These preparations may be prepared by mixing the active compound (I) or a salt thereof with conventional pharmaceutically acceptable carriers or diluents. Pharmaceutically acceptable carriers or diluents include excipients (e.g., sucrose, starches, mannitol, glucose, cellulose, talc, calcium phosphate, etc.), binders (e.g., methylcellulose, gelatin, is 81804 gum arabic, polyethylene glycol (e.g., disintegrant), etc.). , sodium hydrogen carbonate, calcium phosphate, etc.), lubricants (e.g., magnesium stearate, talc, sodium lauryl sulfate, etc.), preservatives (e.g., citric acid, sodium citrate, etc.) and the like.

the dosage of the compounds (I) and their pharmaceutically acceptable salts may vary depending on the routes of administration, the age, weight and condition of the patients, the severity of the diseases and the like, but is usually from about 0.01 to 200 mg / kg / day, preferably from 0.1 to 50 mg / kg / day.

The following experiments illustrate the pharmacological activities of the compounds (I) and their salts.

KMJ

Aldose reductase inhibitory activity:

Mejiitelmä:

In J. Biol. Chem., Vol. 240, 877-882 (1965), aldose reductase was obtained from the lens of a canine rabbit (weight 2.5-3.5 kg). The aldose reductase inhibitory activity of the tested compounds was measured in the publication

Biochim. Biophys. Acta., Vol. 128, 474-482 (1966). The aldose reductase inhibitory activity of the test compounds is given at the concentration of the test compounds required to inhibit aldose reductase activity by 50% (i.e., 50% inhibitory concentration: IC50).

81 804 16

Compounds tested

Well. Name of the compound (Compounds prepared according to the invention) 1. 6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 2. d -6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 3,6-chloro-3-methyl-spiro [ 1,2,3,4-Tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 4. d-6-fluoro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline] -4,4'-imidazolidine] -2 / 2 ', 5'-trione 5. 6-chloro-3,7-dimethyl-spiro [1,2,3,4-tetrahydroquinazoline-4 / 4'-imidazolidine ] -2,2 ', 5'-trione 6. 6-Bromo-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2', 5'-trione 7. 6 # 7-Dichloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 8. 6,8-dichloro -3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 9. 6-fluoro-3-methyl-spiro [1, 2,3,4-Tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 10. 1-Isobutyl-6-chloro-3-methyl-spiro [1,2,3,4- Tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 81 804 17 11. 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] - 2,2 ', 5'-trione 12. 6,8-dichloro-7-methoxy-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,21 3,5'-trione 13. 3,7-Dimethyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 14. 7-chloro-3- methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 15. 8-fluoro-3-methyl-spiro [1,2,3,4 -tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione 16. 6-chloro-7-methoxy-3-methyl-spiro [1,2,3,4-tetrahydro-quinazolidine-4, 4, -imidazolidine] -2,2 ', 5'-trione (Reference compounds) 'trione [disclosed in Chem. Ber., 103, 2394 (1970)] 18. 3,1 ', 3'-trimethyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2 / 2', 5'- trione [disclosed in Ber., 110. 3849 (1977)]

The structures of compounds 1-18 are as follows:

O j NH

3 .vMsA, 3

Is! 18 81 804 R2

Compound r3

R

“-A 2 _S _" _ 3 _H __ "_ _r-Qc 5" C ”3 ~ 0 ^: __- Q:

7 "Cl ^ 10Q

:; . · “TS

Cl

9 "PO

81804 19 10 Isobutyl cl ~ C *

n h ®C

l2

Cl 13 "CH ~ 14" Cl-Cjl: »- 9 16" CHjO ^ O "

0 * 1-NH

17. I I

CH -N J-0 ÖQCH3

B

18- 0 * j-N-CH3 CH3-N> °

OfYcH3

B

81804 20

Score:

The results are shown in Table 1.

Aldose reductase inhibitory activity

Tested compound no. _ICso (M) _

A compound of the invention; 1 5.6 x 10-e 2 2.2 x 10-e 3 2.9 x 10-e 4 6.4 x 10-e 5 3.0 x 10-e 6 5.2 x 10-e 7 7 .4 x 10-e 8 3.7 x 10-e 9 1.0 x 10-7 10 2.7 x 10-7 11 2.8 x 10-7 12 7.2 x 10-e 13 2.2 x 10-7 14 9.4 x 10-e 15 4.2 x 10-e 16 5.9 x 10-e

Reference Compounds 17 1.0 x 10- * 18> 5 x 10-e

Test 2

Anti-accumulative activity of polyols:

Method:

Slc: Male Wistar rats (3-4 weeks old, one group: 3 rats) were fed (i) a diet supplemented with 20% 21 81804 galactose and containing 20 mg of test compound (i.e., 20 mg of test compound per 100 g): (test compound group), (ii) diet supplemented with 20% galactose (galactose control group) and (iii) normal diet (non-galactose) (normal control group) for 6 days. After the feed, the animals were killed by cutting the carotid under anesthesia with ether and immediately taken on each side of the sciatic nerves was measured and acetyl-acetone method. [Science, Vol. 182, 1146-1148 (1973) the amount of polyols accumulated in the hip nerves. The humanization of polyol accumulation was calculated by the following expression.

Inhibition of polyol accumulation (%) s S N *

Number of polyols (average Polyol (average) test compound - chimer) in normal tery group in control group = 1 - - x 100

✓ I

The amount of polyol (average) The amount of polyols (average) in the normal galactose chimera

[in the control group in the control group J

: k ^

Tv Lakasi ·.

Table 2

Compound Inhibition of polyol accumulation _ (%) _ 1 68.4 2 100 3 86.9 4 61.0 5 58.0 6 74.7 7 52.9 '8 63.1 9 58.7 10 72.3 17 7 , 3 18 10.4 81804 22

Test 3

Acute toxicity and symptom monitoring:

A suspension of the test compound in 0.5% carboxymethylcellulose was administered orally to ddY male mice (weight about 25 g, one group: 3 mice) and the general behavior and symptoms of the mice were monitored for 14 days. As a result, mice given the following compounds of the invention were administered; d- and dl-6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione, in doses of 10 g / kg , no mice died and no abnormal symptoms such as gait disturbance, non-reflective disability, incapacitation, addiction, dyspnoea, reddening of the skin, tearing, etc. were observed.

The following Preparation Examples A to P and Examples illustrate the compounds (I) of the invention and their salts and their preparation.

Preparation Example A

A mixture of 5-fluoroisatin (9.9 g), triethylamine (1 ml) and dimethylformamide (30 ml) is stirred under ice-cooling, and methyl isocyanate (3 g) is added dropwise thereto at the same temperature. The mixture was stirred at room temperature for 30 minutes and the precipitate was collected by filtration to give 5-fluoro-1-methylcarbamoyl-isatin (8.7 g), m.p. 230-232 ° C.

Preparation Example B - P

The corresponding starting materials are treated as described in Preparative Example A to give the compounds listed in Table 5.

81 804 23

Ta.ulviit.kp 5.

R2 R2

r3 i R1 NC-0 (IX) r3 I

rlrt * Vy-ΐ L H e I 1 R5 R5 CONH-R1 (VIII) (X) ΓΙ1 (R3 · = CHs. Rs = H) _

Mfr. Compound (X) no._R2_E3_E4_Physical properties

B * I H H H Sp. 154-156oC

C H Cl H Sp. 234-236 ° C

MS (m / e): 238 (M &lt; + &gt;)

D Cl H H Sp. 158-160 ° C

MS (m / e); 238 (M +)

E H H Cl Sp. 220-222 ° C

MS (m / e): 238 (M &lt; + &gt;)

F H CHsO H Sp. 205-208 ° C

G H CHs H Sp. 228 - 230®C

H H Cl Cl Sp. 220-221 ° C

MS (m / e): 272 (M &lt; + &gt;)

I H Cl CHs Sp. 217-219 ° C

J H H CHsO Sp. 217-219 ° C

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

dll (R1 = CHa, R2 = H) __

Mfr. Compound (VII) OS.! _ El_Ei_E * _Physical properties

K H H CHs Sp. 192-195 ° C

L F F F Sp. 169-171 ° C

-M H H F Sp. 145-146 ° C

ΓΙΙΙ1 (R1 = CH5, RS = H) _

Mfr. Compound (VII) no._Εϋ_E? _No_Physical properties

N H Br H Sp. 222-229 ° C

O H Cl CHsO Sp. 202-205 ° C

MS (m / e): 211 (M +) 81804 24 Evil (R2 - RS = H) -

Valin. Compound (VII) QSL · _No_Physical properties_

P CH3 (CH2) a- M.p. 97-99 ° C

Example 1 5-Chloro-1-methylcarbamoyl-isatin (4.0 g) is dissolved in tetrahydrofuran (40 ml) and 2-ethyl-isothiourea hydrobromide (4.0 g) and triethylamine (3.0 ml) are added and the mixture is stirred. at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure to remove the solvent. 10% hydrochloric acid (50 ml) is added to the residue [i.e. 6-chloro-3-methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline] and the mixture is stirred for 3 hours at 70-80 ° C. After cooling, the precipitate is collected by filtration to give 6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (2.5 g, yield 53.1%).

Sp. > 280 ° C

IR ν max (cm -1): 3300, 1780, 1740, 1718 max MS (m / e); 280 (M +) NMR (DMSO-d 6) δ: 2.80 (3H, s), 6.92 (1H, d, J = 9Hx), 7.06 (1H, d, J = 2Ht), 7.40 (1H, d, d, J = 9H5, J-2Hz), 9.11 (1H, s), 10.07 (1H, s), 11.40 (1H, s)

Examples 2 to 14

The corresponding starting compounds obtained according to the above Preparation Examples are treated as described in Example 1 to give the compounds given in Table 2.

25 81 804 on o λ o ^ oo co »- e) ie n • rt * · t— * o α \ ov · en * - · N r-» - K 32 X · 32 .¾ * t- ·> * - o cr »* - r- ✓> vx» -n in en

B w B S · I

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28 81 804 (1) 1-Methylcarbamoylsatin (8.16 g) was dissolved in tetrahydrofuran (100 ml), and 2-ethylisothiourea hydrobromide (7.4 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. The precipitate was filtered off, washed with water and dried to give 3-methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (8.0 g). ).

Sp. > 280 ° C.

(2) 3-Methyl-4-hydroxy-4- (2-ethylisothioureidocarbonyl) -2-oxo-1,2,3,4-tetrahydroquinazoline (2.0 g) is suspended

In 10% hydrochloric acid (20 ml) and the mixture is stirred for 3 hours at 70-80 ° C. After cooling, the precipitate is collected by filtration and recrystallized from dimethyl sulfoxide to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2, ', 5'-trione ( 1.2 g). Sp. > 280 ° C

IR ν max (cm-1): 3300, 3210, 2080, 1781, 1735, 1680, 1615 (λα MS (m / e): 246 (M +) NMR (DMSO-d 6) δ: 2.80 ( 3H, s), 6.70 - 7.50 (4H, m), 9.05 (1H, s), 9.91 (1H, s), 11.31 (1, s)

Eairosrkkl 16 (1) 5,6-Dichloro-1-methylcarbamoyl-isatin (9.6 g) is suspended in tetrahydrofuran (100 ml) and thiourea (3.0 g) and triethylamine (5.6 ml) are added thereto, and the mixture is stirred at room temperature. at 5 hours. The resulting precipitate was collected by filtration to give 6,7-dichloro-3-methyl-4-hydroxytioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (4.1 g), m.p. 225-228 ° C.

29 81 804 (2) 6,7-Dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (2.8 g) is dissolved in dimethylformamide (30 ml) and to this is added sodium hydride (60% oil suspension) (0.32 g) and the mixture is stirred at room temperature for 30 minutes. Ethyl bromide (2 ml) is added to the mixture, and the mixture is further stirred for 30 minutes, after which the solvent is distilled off under reduced pressure. To the residue [i.e. 6,7-Dichloro-3-methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline] is added 10% hydrochloric acid (30 ml ) and the mixture is stirred at 70 ° C for 4 hours. After cooling, the precipitate is collected by filtration, washed with 10% aqueous sodium hydrogencarbonate solution and then recrystallized from dimethylformamide-water to give 6,7-dichloro-3-methyl-spiroCl2S-tetrahydroquinazoline-4'-imidazolidine] -2.2 ', 5'-trione (1.4 g).

1 H-NMR (cm-1): 3250, 1770, 1720, 1615, 121597 δ131 NMR (DMSO-d 6) δ: 2.78 (3H, s), 7.09 (1H, s), 7.29 (1H, s), 9.12 (1H, s), 10.18 (1H, s), 11.41 (1H, s)

Example 17 (1) 1-Methylcarbamoylsatin (10.2 g) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.3 g) were dissolved in tetrahydrofuran (100 ml), and urea (4, 5 g), and the mixture was refluxed for 10 hours. After cooling, the precipitate was collected by filtration, washed with water and methanol, and recrystallized from a mixture of dimethyl sulfoxide and ethanol to give 3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-

1,2,3,4-tetrahydroquinazoline. Sp. > 280 ° C

MS (m / e): 246 (M + -18) (2) 3-methyl-4-hydroxy-4-ureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (1.5 g) is added. 2-dichlorobenzene 81804

to the fungus (30 ml) and the mixture is refluxed with stirring for 1.5 hours. After cooling, the precipitate is collected by filtration and crystallized from dimethyl sulfoxide to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (0.8 g). ). Sp. > 280®C

IR δ new (cm -1): 3300, 3120, 3080, 1781, 1735, 1680, 1615 max MS (m / e): 246 (M +) NMR (DMSO-d 6) δ: 2.80 (3H, s), 6.70-7.50 (4H, m), 9.05 (1H, s), 9.91 (1H, s), 11.31 (1H, s)

Example 18 d-3-Methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (17.24 g) is suspended in acetic acid ( 170 ml) and sulfuryl chloride (8.54 ml) is added dropwise to the suspension. 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 insoluble matter is separated by filtration. The filtrate is treated with activated carbon and then the solvent is distilled off under reduced pressure. Water is added to the residue and the precipitate is collected by filtration, washed with water and dried. The procedure is repeated once more to give d-6-chloro-3-methyl-spiro- [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione monohydrate ( this product has the R-configuration at the 4-position of the quinazolinone backbone) (14 g, yield: 71.3%).

IR ν max (cm -1): 3650, 3450, 3300, 3220, 3100, 1765, 1730, max 1660, 1600 NMR (in DMSO) δ: 2.80 (3H, s), 6.92 (1H, d, J = 9 H *), 7.06 (1H, d, J = 2 H *), 7.40 (1H, d, d, J = 9 Hz, J * 2 Hz), 9.11 (1H , s), 10.07 (1H, s), 11.40 (1H, s) [α] D + 32.9® (c, 1, ethanol) 31 81804

Examples 19-21

The corresponding starting materials are treated as described in Example 18 to give the compounds listed in Table 4.

Table 4

° r — NH _NH

hn 1 so n r31 HN

X ^ O I SO2C12 R v ^ X ^ O!

H ςί H

R51 (I-c) (I-b)

Eg Compound (I-b) _

Well. ... R1__Β1Ξ__FYgjfc & aUsgt <winftisw <tet> etc-

Yield: 76.5%; Sp. 169-173 ° C; 19 * 1 CH 3 Cl H H_ [a] 20-33.7 <> (c «1, ethanol) _

Yield: 71.4%; Sp. > 280 ° C; 20 "" "" IR λ max (cm-1): 3300, 1780, ___1740. 1718

Sp. > 280 ° C; 21 * 2 "" CH 3 O "HS (m / e): 334 (M +): IR nujo1 (cm-1): 3200, 1800, ___1715. 1645 * 1): This compound is a levorotatory isomer.

* 2): NMR spectral values of this compound: NMR (DMSO-d 6) Si 2.79 (3H, s), 3.82 (3H, s), 7.15 (1H, s), 9.10 (1H , s), 9.55 (1H, s), 11.38 (1H, s) 32 81 804

Example 22 3-Methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 *, 5'-trione (1.23 g) is dissolved in acetic acid (50 ml) and to this are added iodine and sulfuryl chloride (4.0 ml). The mixture is stirred 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 insoluble matter is separated by filtration. The filtrate is neutralized with 10% hydrochloric acid and the precipitate is collected by filtration, washed with water and dried to give

6,8-dichloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (1.35 g, 85.4% yield) ). Sp. > 280 ° C

IR Vnujo1 (cm-1): 3220, 1799, 1722, 1640 max NS (m / e): 314 (M1), 316 (M + 1), 318 (M + 3) NMR (in DMSO) 6- 2 , 77 (3H, s), 7.06 (1H, d, J-3 Hz), 7.59 (1H, d, J = 3 Hz), 9.10 (1H, s), 9.53 (1H , s), 11-11.7 (1H, br)

Example 23 6-Chloro-3-methyl-spiro [1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (1.4 g) is dissolved in 10.86% (w / w) to aqueous sodium hydroxide and the solution is treated with activated carbon and then concentrated under reduced pressure. The residue is crystallized from ethanol and collected by filtration. The crystals thus obtained are washed with ethanol and isopropyl ether and dried to give 6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'- trione-1 * sodium salt (1.17 g, 77.3% yield). IR ν max (cm-1): 3330, 3180, 1703, 1648 IQ9a 81 804 33 NMR (DMSO-d 6): 2.62 (3H, s), 6.6-6.9 (2H, m), δ, 70 - 7.5 (2 H, m), 9.3 - 9.8 (1H, br)

Example 24

The corresponding starting material is treated as described in Example 23 to give the following compound: d-6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5' -trione-1'-sodium salt (yield: 84.6%).

Sp. > 280 ° C, [α] D + 48.7 ° (cal, water) IR (cm -1): 3620, 3300, 1708, 1683, 1600 NMR (DMSO-d 6): 2.63 (3H, s ), 6.72 (1H, d, J = 10 Hz), 6.76 (1H, d, J = 3 Hs), 7.13 (1H, d, d, J = 10 Hz, J 3 Hs), 7.34 (1H, s), 9.57 (1H, s)

Example 25

Isatin (294.3 g) is suspended in tetrahydrofuran (3 liters) and triethylamine (279 ml) and methyl isocyanate (129.8 ml) are added thereto at 15 ° C with stirring. The mixture is stirred at 20-25 ° C for 2.5 hours (1-methylcarbamoyl-isatin is formed in the mixture). 2-Stylisothiourea hydrobromide (444.2 g) and triethylamine (55.8 ml) are added to the reaction mixture, and the mixture is refluxed for 2 hours. After cooling, the solvent is distilled off under reduced pressure. To the residue [i.e. 3-Methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline] is added 10% hydrochloric acid (4 liters) and the mixture is stirred for 4 hours at 70 ° C. After cooling, the precipitate is collected by filtration, washed with water, methanol (1 liter) and chloroform (1 liter) in this order and then dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4, 4, -imidazolidine] -2,2 ', 5'-trione (369.2 g) yield 75%.

The physicochemical properties of this product are the same as those of the product prepared in Example 15.

Example 25 (1) dl-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] .2,2 ', 5'-trione (12.3 g) and brucine dihydrogen - the brate (21.5 g) is dissolved in a mixture of methanol and water (265 ml) (3: 2 by volume) with heating. After allowing the solution to cool, the precipitate is collected by filtration [the filtrate is called "filtrate (I)"]. The crystals thus obtained are recrystallized from a mixture of methanol and water (3: 2) to give d-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione * brucine salt (7.8 g).

20 [α] β -67.0 ° (c = 1, dimethylformamide)

The salt obtained above (7.8 g) is dissolved in water (20 ml) and concentrated hydrochloric acid (2 ml) is added thereto. The precipitate is collected by filtration and recrystallized from a mixture of methanol and water to give d-3-methyl-spiro [1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine] -2,2 ', 5'- trionia (2.3 g)

Sp. 174-176 ° C

90 [α] D + 34.7 ° (c = 1, ethanol) (2) The filtrate (1) obtained in (I) above is concentrated to dryness under reduced pressure, and the residue is 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 to remove the solvent under reduced pressure, and the precipitate is collected by filtration. The crystals are recrystallized from methanol and water

II

81804 from a mixture of 1-3-methyl-spiro- [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (2.1 g ).

Sp. 174-176 ° C, [α] D 18 -34.7 ° (c = 1, ethanol)

Example 27 (1) dl-6-fluoro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (8.1 g) and quinine (prepared using (16.0 g of quinine hydrochloride) is dissolved in a mixture of methanol and water (2: 1 by volume) by heating (450 ml). After allowing the solution to cool, the precipitate is collected by filtration [the filtrate is hereinafter referred to as "filtrate (II)"] to give d-6-fluoro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5 * -trione- quinine salt (4.0 g).

20 [α] β -20.8 ° (c = 1, dimethylformamide)

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

Sp. 267 ° C 90 [α] D + 37.6 ° (c * 1, ethanol) (2) The filtrate (II) obtained in (1) above is adjusted to pH 2 with 10% hydrochloric acid and the precipitate is collected by filtration. The filtrate is neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract is distilled under reduced pressure to remove the solvent, and the residue is neutralized with 2% hydrochloric acid. The precipitate is collected by filtration and recrystallized from a mixture of methanol and water to give 1-fluoro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-36,8804 imidazolidine] -2,2 ', 5'-trione (0.7 g).

Sp. 276 ° C

[α] D 0 -39.6 ° (c = 1, ethanol)

Example 28 (1) 3-Methyl-spiro [1,2,3,4-tetrahydroquinoazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (7.38 g) is dissolved in dimethylformamide (60 ml), and sodium hydride (60%) (1.2 g) was added at 15 ° C, and the mixture was stirred at room temperature for 30 minutes. Benzyloxymethyl chloride (4.71 g) was added to the mixture at room temperature, and the mixture was further stirred at room temperature for 30 minutes. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from dimethylformamide and water to give 1'-benzyloxymethyl-3-methyl-spiro- [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (10 , 4 g).

Sp. 226-227 ° C

IR («η-1): 3200, 3050, 1800, 1735, 1660

IuclX

(2) The product obtained above and acetyl chloride were treated as described above (except that isopropanol-isopropyl ether was used as the crystallization solvent) to give 3 * -acetyl-1'-benzyloxy-methyl-3-methyl-spiro- [1,2 , 3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (yield: 70%).

Sp. 209-211 ° C.

(3) S'-acetyl-1'-benzyloxymethyl-S-methyl-spiro- [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (3, 06 g) is dissolved in dimethylformamide (20 ml) and methyl iodide (1 ml) and further sodium hydride (60%) (0.3 g) are added portionwise under ice-cooling. Mixture 37 81804 is stirred at room temperature for 30 minutes. 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 is purified by flash chromatography on silica gel (solvent: chloroform) to give 3'-acetyl-1'-benzyloxymethyl-1,3-dimethyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] - 2.2 ', 5'-trione (3 g, yield: 94.5%) as an oily substance.

IR Vmiv01 (cm-1): 1800, 1720, 1640, 1600

lilcl X

(4) The product obtained above (3.0 g) is dissolved in ethanol (20 ml) and palladium black (0.2 g) is added thereto, and the mixture is reduced from catalytic for 5 hours under hydrogen gas (pressure 2-3 atmospheres). The catalyst is filtered off and the solvent is distilled off. The residue is dissolved in 10% aqueous sodium carbonate and heated at 60-80 ° C for 30 minutes. The reaction mixture is neutralized with 10% hydrochloric acid and the precipitate is collected by filtration and recrystallized from dimethylformamide-water to give 3'-acetyl-1,3-dimethyl-spiro [1,2,3,4-tetrahydroquinazoline]. N-imidazolidine] -N, 5'-trione (0.85 g).

Sp. 261-263 ° C

MS (m / e): 302 (M +) NMR (OMSO-d 6) δ; 2.40 (3H, s), 2.80 (3H, s), 3.36 (3H, s), 3.00 - 4.00 (1H, 1br), 6.90 - 7.60 (4H, m) (5) The product obtained above (1.0 g) is added to a solution of sodium ethylate (prepared from sodium metal (161 mg) and ethanol (20 ml)] and the mixture is stirred for 3 hours at room temperature. The solvent is distilled off, then the residue is neutralized with 10- with hydrochloric acid and recrystallized from dimethylformamide-water to give 1,3-dimethyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (500 mg). as colorless prisms.

Sp. 223 - 225®C

3g 81804 IR ν max (cm-1): 3300, 3200, 1782. 1730, 1630 max NMR in DMSO) δ: 2.86 (3H, a), 3.33 (3H, a), 7.00 - 7 , 63 (4H, m), 9.10 (1H, a), 11.40 (1H, br)

Example 29_

3'-Acetyl-1'-benzyloxymethyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 'is treated as described in Example 28- (3). 5'-trione and isobutyl iodide to give 3'-acetyl-1'-benzyloxymethyl-1-isobutyl-5-methyl-spirot-1,3,4-tetrahydroquinazoline-4,4'-imidazolidine] - 2,2 ', 5'-trione and isobutyl iodide to give 3'-acetyl-1'-benzyloxymethyl-1-isobutyl-3-methyl-spiroCl, 2,3,4-tetrahydroquinazoline-4,4'-imidazolidine ] -2.2 ', 5 * -trione.

Sp. 70-72 ° C MS (m / e): 464 M +) NMR (in DMSO): 0.9-1.3 (6H, m), 1.9-2.3 (1H, m), 2 , 45 (3H, s), a, 284 (3H, a), 3.5-4.1 (2H, m), 4.68 (2H, s), 5.16 (2H, s), 6, 6-7.1 (3H, m), 7.1-7.5 (4H, m)

The product obtained above is treated as described in Example 28- (4), (5) to give 1-isobutyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine) -2.2 ', 5'-trione.

Sp. 270 ° C

MS (m / e): 302 (M +) IR ν max (cm-1): 1790, 1723, 1645, 1608

ΓΠ <31 X

NMR (DMSO-d 6) 0.90 (6H, d, J = 7Hx), 1.8-2.3 (1H, m), 2.79 (3H, 3a), 3.6-4.0 (2H , m), 6.9-7.6 (4H, m), 9.02 (1H, s), 11.19 (1H, s) 39 81804

Example 30

The 1-isobutyl-3-methyl-spiro- [1,2,3 / 4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (0.76 g) prepared in Example 29 was suspended in acetic acid ( 15 ml) and to this are added sulfuryl chloride (0.3 liters) and a small amount of iodine and the mixture is stirred at room temperature for 19 hours. The reaction mixture is poured into ice water, and the precipitate is collected by filtration, and the crystals are dissolved in 10% aqueous sodium hydroxide. The insoluble matter is filtered off and the filtrate is neutralized with 10% hydrochloric acid and the precipitate is collected by filtration (this dissolution and mixing are repeated). The precipitate is collected by filtration and dried to give 6-chloro-1-isobutyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5' -trione (0.45 g).

Sp. 118 ° C

MS (m / e): 338 (M + +1), 336 (M + -1) IR (cm-1): 1790, 1735, 1645, 1602 {δολλ NMR (DMSO-d 6): 0.90 (6H, d, J = 7 Hz), 1.7-2.4 (1H, m), 2.79 (3H, s), 3.6-4.0 (3H, m), 7.03 (1H, d) , J * 3 Hz), 7.10 (1H, d, J = 10 Hz), 7.40 (1H, dd, J * 10 Hz, J = 3 Hz), 9.09 (1H, s), 11 .26 (1H, s)

Example 31 (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 to the mixture with stirring, 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 filtered off, washed with water, isopropanol and diisopropyl ether and then dried to give 1-ethoxycarbonylisatin (39.4 g).

Sp. 113-116 ° C (decomposes).

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

. 81804 40 (2) The above product (2.79 g) is added to tetrahydrofuran (30 ml), and urea (1.15 g) is added thereto. The mixture is refluxed for 15 hours and the solvent is removed by distillation. The residue is extracted with ethyl acetate. The extracts are distilled to remove the solvent, and the residue is subjected to silica gel column chromatography (solvent, chloroform: methanol = 9: 1). The fractions containing the title compound are collected and distilled to remove the solvent, and chloroform is added to the residue. The precipitated crystals are filtered off and dried to give (2-ethoxycarbonylaminophenyl) oxalyl urea (2.42 g). Sp. 169-170 ° C.

(3) A mixture of (2-ethoxycarbamoylphenyl) oxalylurea (8.37 g), 10% methylamine-ethanol solution (21.5 g) and 2,3-dichlorobenzene (200 ml) was stirred in a pressure vessel at 150 ° C for 2 hours. After cooling, the reaction mixture is extracted with 1N sodium hydroxide solution and the aqueous layer is neutralized with 10% hydrochloric acid. The precipitated crystals are filtered off, washed successively with water and ethanol and then dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione. (2.6 g).

The physical properties of this product are the same as those of the product obtained in Example 15.

Example 32 (1) 5-Chloroisatin (18.16 g) was treated in the same manner as in Example 31- (1) to give 5-chloro-1-ethoxycarbonylisatin (23.3 g). Sp. 169-172 ° C (decomposes).

41 81804 (2) The above product (15.2 g) was treated in the same manner as in Example 31- (2) to give (5-chloro-2-ethoxycarbonylaminophenyl) oxalylurea (16.74 g).

Sp. 189-190 ° C (decomposes).

(3) A mixture of (5-chloro-2-ethoxycarbonylaminophenyl) oxalylurea (9.41 g), 40% methylamine-methanoyl solution (5.11 g), toluene (200 ml) and ethanol (20 ml) is stirred in a pressure vessel at 120 ° C. at 4 hours. After cooling, the precipitated crystals are filtered off, washed successively with toluene and methanol and dried to give 6-chloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (2.33 g).

Example 33 (1) Isatin (14.7 g) is added to tetrahydrofuran (150 ml) and triethylamine (13.9 ml) is added dropwise. Methoxycarbonyl chloride (7.7 ml) is added dropwise to the mixture, and the mixture is stirred at room temperature for one hour. Triethylamine (2.78 ml) and methoxycarbonyl chloride (1.54 ml) are added to the mixture, and the mixture is stirred for 10 minutes. Ethyl acetate and water are further added to the mixture, and the mixture is stirred. The precipitated crystals were filtered off, washed with water and ethyl acetate, and then dried to give 1-methoxycarbonylisatin (16.2 g).

Sp. 178-182 ° C (dec.).

(2) The above product (14.36 g) was treated in the same manner as in Example 31- (2) to give (2-methoxycarbonylamino-phenyl) oxalylurea (7.79 g).

Sp. 192 ° C (decomposes).

(3) A mixture of (2-methoxycarbamoylaminophenyl) oxalylurea (2.65 g), 10% methylamine-ethanol solution (12 g) and 81804 toluene (60 ml) is stirred in a pressure vessel at 110 ° C for 4 hours. The reaction mixture is treated as described in Example 40 to give 3-methyl-spiro [1,2,3,4-tetrahydro-quinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (0.51 g). .

The physical properties of this product are the same as those of the product obtained in Example 15.

Example 34 (1) (2-Ethoxycarbonylaminophenyl) oxalylurea (27.9 g) is dissolved in a mixture of 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 filtered off, washed with toluene and then dried to give a crystalline product (29 g), m.p. 130-133 ° C.

(2) A mixture of the crystalline product (2.51 g) obtained above, a 20% solution of methylamine-ethanol (6.1 g), toluene (60 ml) and ethanol (6 ml) was stirred in a pressure vessel at 110 ° C for 4 hours. . After cooling, the precipitated crystals are filtered off and dried to give 3-methyl-spiro- [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione-methylamine salt (1, 06 g). Sp. > 280 ° C NMR (DMSO-d 6) δ: 2.28 (3H, s), 2.67 (3H, s), 6.4-7.3 (9H, m) MS (m / e): 246 (M + -31)

Example 35 (2-Ethoxycarbonylaminophenyl) oxalyl urea (139.5 g) is treated as described in Example 34- (1) and the precipitated crystals are filtered off. The crystals are added to a mixture of 40% methylamine-methanol solution (85.25 g), toluene 43 81 804 (3.3 liters) and ethanol (330 ml) and the mixture is refluxed for 15 minutes at about 75 ° C. A 40% methylamine-methanol solution (155 g) is added dropwise to the reaction mixture over an 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 is neutralized with 10% hydrochloric acid, and the precipitated crystals are filtered off, washed with ethanol and then dried to give 3-ethyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2.2. ', 5'-trione (43 g). The physical properties of this product are the same as those of the product obtained in Example 15.

Example 36 (1) 1-Methylcarbamoyl-isatin (4.08 g) is dissolved in tetrahydrofuran (50 ml). Triethylamine (2.22 g) and thiourea (1.7 g) are added to the solution, and the mixture is stirred at room temperature for 3 hours. The precipitated crystals are filtered off, washed with water and then dried to give 4-hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline (3.7 g), m.p. > 280 ° C (recrystallized from dimethylformamide-ethanol).

(2) The product obtained above (1.0 g) is dissolved in 10% aqueous sodium hydroxide (10 ml). To the mixture is added 30% hydrogen peroxide (2 ml), 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 are filtered off, washed and then dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] 2,2 ', 5'-trione (0.75 g). , yield 85.4%).

44 81 804 The physical properties of this product are the same as those of the product obtained in Example 15.

Example 37 5.6-Dichloro-1-methylcarbamoyl-isatin (9.6 g) is treated as described in Example 36- (1) above to give 6.7-dichloro-4-hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo- 1,2,3,4-tetrahydroquinazoline (4.1 g), m.p. 225-228 ° C. This product is treated as described in Example 36- (2) above to give 6,7-dichloro-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2.2 ', 5'-trione.

The physical properties of this product are the same as those of the product obtained in Example 16.

Foreplay 38 4-Hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline (1.0 g) is dissolved in 10% aqueous sodium hydroxide (20 ml) and the mixture is stirred at 40-50 °. At C for 1.5 hours. After cooling, the reaction mixture is acidified with 10% hydrochloric acid. The precipitated crystals are filtered off, washed and then dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (1 .3 g, yield 85.4%).

The physical properties of this product are the same as the product obtained in Example 15.

Example 39 (1) 4-Hydroxy-4-thioureidocarbonyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline (2.2 g) is dissolved in dichlorobenzene 45 81804 (30 ml) and the mixture is stirred at 200 ° C. at 2 hours. The precipitated crystals are filtered off and recrystallized from dimethyl sulfoxide water to give 2'-imino-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,5'-thiazoline] -2,4'-dione (1.3 g), Sp. > 280 ° C.

(2) The product obtained above (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 are filtered off and recrystallized from dimethylformamide water to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,5'-dione-2'-trione (1.1 g), Sp. > 280®C.

(3) The product obtained above (1.0 g) is dissolved in 10% aqueous sodium hydroxide (10 ml). To the mixture is added 30% hydrogen peroxide (2 ml), 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 are filtered off, 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 are the same as those of the product of Example 15.

Example 40 (1) Guanidine hydrochloride (0.57 g) is added to tetrahydrofuran (5 ml), and 10N sodium hydroxide (0.6 ml) is added thereto, 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, and then the solvent is distilled off.

46 81 804 10% Hydrochloric acid (10 ml) is added to the residue and the mixture is refluxed for 1 hour. After cooling, the precipitated crystals are filtered off and washed with water and ethanol to give 2'-imino-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,5'- dione (0.86 g)

Sp. 257-259 ° C.

(2) The product obtained above (0.123 g) is dissolved in a mixture of acetic acid (1 ml) and water (23 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 room temperature for 1 hour and the solvent is distilled off. The residue is purified by flash chromatography on silica gel (solvent, chloroform: methanol = 7.3) to give 3-methyl-spiro- [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5' -trionia (39 mg).

The physical properties of this product are the same as those of the product of Example 15.

Example 41 3-Methyl-4-hydroxy-4- (2-ethylisothioureido) carbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (1 g) is dissolved in 10% aqueous sodium hydroxide (10 ml). ). To the solution is added 30% vesty peroxide (2 ml) 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 are filtered off, washed with ethanol and then dried to give 3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione (0.6 g). , yield 75%).

The physical properties of this products are the same as in Example 15.

Claims (2)

1. O> 1 C where k, R, RJ, R * and R 3 are the same as above, in the presence of a nitrating reagent to form a compound of formula (Ia), (g) treating a compound of formula Q : NHΠ (ic) R where R R is a hydrogen atom or lower alkoxy, or its salt, with a halogenating agent to form a compound of the formula ° -NH HN I (Ib) R5 , R is a hydrogen atom or halogen-1 41 atom, and R, R and R are the same as above (h) (1), a compound of the formula _NH fHV ~) "3Tni * '(1'e) in * M where R 1, R 2 and R 2 are the same as above, with a compound of the formula: 57 81 804 X 1 - (XVII) where X 2 is a protecting group and Y is a reactive group forming a compound of formula n2 ° i-rxl HNxro r (XVIII) r1 <^ N 4. A ip 1 wherein Rx, R, R, R, R1 and Xx are the same as above, (2) a compound of formula (XVIII) is reacted with a compound whose formula is: X2-Y (XIX) 2 wherein X is a protecting group and Y is the same as above, to form a compound of the formula:, N-X 1 i I "3 JLi 'N ^ 0, (vii) R2 H 0 5. R5 η O * 3> 1 K Ί O wherein R, R 2, R, R, R 1, X and X 2 are the same as above, a highly obtained compound of formula 2 (VII) is reacted with an alkylating agent, and (4) the protective groups are removed from the product obtained to form a compound of the formula: - R 2 R 1 R 2 R 1 R 2 R 1 R 2 R 1 is lower alkyl, R R, R, R and R refer to the same as above, and optionally the product obtained is transferred to its site. Wherein R, R, R, R 'and R3 are the same as above, in the presence of an alkaline reagent and / or an oxidizing agent, to form a compound of formula (Ia) 55 81 804 (d) where R is lower alkyl # and R # R # R and R are the same as above # with an amine of formula r1-nh2 ( V) where R ^ is the same as above # or with these sites # to form a compound of formula (Ia), (e) a compound of formula S. ^-NH 2 R2 is hydrolyzed in HN Λ XX Λ R1 'JN 0 R 1 and R 3 are the same as above, in the presence of an alkaline reagent and oxidizing agent to form a compound of formula (Ia) # (f), a compound of formula% -NH is hydrolyzed R2> 1 HN L (VI-b) H 56 8 1 8 0 4 A process for the preparation of therapeutically useful spiro / 1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine / -2,2 1,5'-trionic compounds of the formula n wherein R is a hydrogen atom or lower alkyl, R 3 is lower alkyl, R 5 and R, which may be the same or different and each refer to a hydrogen atom or a halogen atom, and R and R which are the same or various, and each refers to a hydrogen atom, halogen atom, alkyl or their salts, characterized in that in process (a), a compound of the formula, S-R6 R 3. HON, CONH'C-NH4 H H5 where R6 is lower alkyl and R1, R2, R3, R4 and R5 are the same as above, with an acid or an alkaline reagent and / or in the vicinity. being an oxidizing agent to form a compound of formula 54 81804% -NH R2 IIHN JL · r3 J ^> <£ Lr1 d- «) where R, R / R, R and R is the same as above, (b) a compound of the formula "20 n II, 1 h ° s C0NHC-NH9 L II I * (m- ·)" is cyclized H 5 m R 1, R 2, R 3, R 4 refers to the same as above, in an 18-agent to form a compound of formula (Ia), (c) a compound of formula S π2 II is cyclized. Process according to Claim 1, characterized in that 6-chloro-3-methyl-spiro- / 1,2,3,4-tetrahydroquinazoline-4,4'-imadazolidine / -2,2 ', 5'- trion or; its sait. Process according to claim 1, characterized in that d-6-chloro-3-methyl-spiro / 1,2,3,4-2 tetrahydroquinazoline-4,4 'imidazolidine / -2,2', 5 'is prepared. -trion or 3 its sait.