HU200182B - Process for producing new spiroquinazoline imidazolidine derivatives and pharmaceutical compositions comprising same - Google Patents

Abstract

Spiro(1,2,3,4-tetrahydroquinazoline -4,4'-imidazolidine) derivs. of formula (I) and their salts are new. In (I), R = H or 1-5C alkyl; R1 = 1-5C alkyl, opt. substd. Ph or aralkyl; R2-R5 = H, halogen, 1-5C alkyl, 1-5C alkoxy, (2-6C)alkoxycarbonyl or (2-6C)alkoxycarbonyl (2-6C)alkenyl; or 2 adjacent substituents R2-R5 = OCH2O; and the other 2 substituents = H. - Intermediates of formula (II) are new. X = CONH2 or C(=NH)SR6; R6 = 1-5C alkyl.

Description

The present invention relates to novel spiro-quinazoline-imidazolidine derivatives, more particularly to compounds of formula I, wherein

R is hydrogen or 1-4 carbon atoms

R is C 1-4 alkyl, phenyl optionally substituted with halo or C 1-4 alkyl, or unsubstituted phenyl (C 1-4) alkyl, and

R, R, R and R have the same or different mean hydrogen or halogen or C 1-4 -alkyl or C 1-4 -alkoxy; R ^{3 is} also C 1-5 -carbalkoxy or (C 1-5 -alkyl) alkoxy; or two adjacent groups of R, R ³ , R ⁴ and R ⁵ together represent a methylenedioxy group and the other two are hydrogen atoms - and their pharmaceutically acceptable salts, for the preparation of a medicament for the prevention and treatment of various diabetic symptoms.

Symptoms of diabetes mellitus are known to include, for example, diabetic neurosis, diabetic cataract, diabetic capillary disease (such as diabetic reticulum), and diabetic nephrosis, and these diabetic symptoms are caused by the accumulation of polyols such as sorbitol. For example, these polyols are formed in vivo from hexose by the action of aldose reductase (The New England Journal of Medicine, 228: 831-836 (1973)). To date, a variety of aldose reductase inhibitors have been suggested for the prevention and treatment of diabetic symptoms. They are capable of preventing the accumulation of polyols in the body. Such known inhibitors include chroman nucleus compounds (Japanese Patent Laid-open Nos. 53653/1978 and 45185/1982 and U.S. Patent 4,117,230), thiazolidine nucleus compounds (Japanese Patent Publication 104876/1981). and compounds containing a phthalazine core (Japanese Patent Publication No. 95582/1979).

Certain quinazolinone derivatives are also known, such as 3, 1'-dimethylspiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2,5,5'-trione / Chemie Berichte, 1, 12394 (1970 and 3, 1,3'-trimethyl-spiro [1, 3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione / Chemie Berichte, 110, 3849 (1977)). However, no therapeutic effects of these quinazolinone compounds have been known.

The various spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] derivatives and their pharmacological activity have been extensively studied and surprisingly found that the known spiro [1,2,3,4- tetrahydroquinazoline-4,4'-imidazolidine] compounds of formula (I) which do not carry a substituent at the Γ and 3 'positions have excellent aldose reductase inhibitory activity.

Returning to the substituents of formula (I), "alkyl having 1 to 4 carbon atoms" means straight or branched chain groups such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, sec- butyl or tert-butyl. "C 1-4 -alkoxy" refers to straight or branched chain groups such as methoxy, ethoxy, n-propoxy, η-butoxy, isobutoxy, sec-butoxy or tert-butoxy. Examples of phenyl groups optionally substituted with C 1-4 alkyl or halogen include methylphenyl, η-propylphenyl, isopropylphenyl or n-butylphenyl, and chlorophenyl, fluorophenyl or bromine. -phenyl. Examples of phenylalkyl groups having 1 to 4 carbon atoms in the alkyl moiety include, for example, benzyl or phenethyl. By "halogen" is meant fluorine, chlorine or bromine.

Preferred compounds of formula (I) are those wherein R is hydrogen or C 1-4 alkyl, R ¹ is C 1-4 alkyl, phenyl, (C 1-4) alkylphenyl, halo. phenyl or super (C 1 or C 2) alkyl; R ² is hydrogen or halo or C 1 -C 4 alkyl; R ³ and R 4 are the same or different hydrogen or halo or C 1 -C 4 alkyl-; or an alkoxy group containing from 1 to 4 carbon atoms; or IC and R ⁴ together form a methylenedioxy group and R ⁵ is hydrogen or halogen.

Even more preferred are those of formula (I)! compounds in which R is hydrogen or methyl or isobutyl, R ¹ is methyl, n-butyl, | enyl, methylphenyl, chlorophenyl or or methyl, R and R are the same or different and each represents a hydrogen ', represents a fluorine, chlorine or bromine atom or a methyl or methoxy group, or R ³ and R * together form a methylene oxide salt and R ⁵ represents a hydrogen, fluorine or chlorine atom.

Particularly preferred among the latter compounds are those compounds of formula I wherein R is hydrogen or isobutyl, R is methyl, η-butyl, phenyl, methylphenyl, chlorophenyl or benzyl; ^z is hydrogen or methyl, R ³ is hydrogen, fluoro, chloro, bromo or methyl, R ⁴ is hydrogen, fluoro or kho, or methyl or methoxy, or R ³ and R ⁴ together form a methylenedioxy group and R ⁷ is hydrogen, fluorine or chlorine.

A further preferred group of compounds of formula I are those wherein R is hydrogen or C 1-4 alkyl, R ¹ is C 1-4 alkyl, R ² is hydrogen, R ³ is halogen, R ⁴ is hydrogen or halo or C 1-4 alkyl and R ⁵ is hydrogen or halogen. Of these, compounds wherein R is hydrogen are particularly preferred

R is hydrogen, R is fluoro, chloro or bromo, R ⁴ is hydrogen, chloro or methyl, and R ⁵ is hydrogen, and chloro is desired.

The compounds of formula I contain asymmetric carbon atoms in their molecules and thus exist in the form of two optical isomers. It is understood that the invention encompasses the two isomers

-2EN 200182 Β and their racemic mixture.

According to the present invention, compounds of formula (I) and salts thereof, wherein R is hydrogen, i.e. compounds of formula (Ia) and salts thereof, can be prepared by (a) reacting a compound of formula (Π) or (ΙΠ) ⁶ is C 1 -C 4 alkyl, Z ^{1 is} oxygen or sulfur, while R ¹ , R, R, R * and R ³ are as defined above — cyclizing. or (b) a compound of formula IV prepared from a compound of formula XV wherein R ⁷ is C 1 -C 4 alkyl, and R, R, R ⁴ and R ³ are as previously defined; of the formula with an amine, wherein ^R1 is akorúbban defined or a salt thereof is reacted, or (c) (VI) vegyületet- formula wherein Z ² is S or NH and R ^1, R, R, R ⁴ and R ³ is as defined above and is hydrolyzed as described above in any one of processes (a) to (c). converting the compound of formula Ia thus obtained into a salt.

Process (a) may be carried out in a suitable solvent. The cyclization of the compounds of formula (Π) is preferably carried out in the presence of an acid or a basic agent and / or an oxidizing agent. Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid or formic acid. Suitable basic agents for this purpose are, for example, hydrochloric acid, hydrobromic acid or formic acid. Alkali metal hydroxides (such as sodium hydroxide or potassium hydroxide) or alkali metal carbonates (such as potassium carbonate) may be used as basic agents for this purpose. Suitable oxidizing agents are, for example, hydrogen peroxide, 3-chloroperbenzoic acid, ozone or nickel peroxide. Suitable solvents for this purpose include, for example, water, methanol, ethanol, dimethylformamide or 12-dichlorobenzene. The reaction is preferably carried out at 20-100 'C, particularly preferably 60-90' C.

The cyclization of the compounds of formula (ΠΙ) wherein Z * is sulfur, hereinafter referred to as (ΙΠ-a), is preferably carried out at 150-250 ° C, particularly preferably at 180-200 ° C. Suitable solvents for this purpose are, for example, 12-dichlorobenzene, nitrobenzene, naphthalene or biphenyl.

The compounds of formula ¹ is S (ΙΠ) general - hereinafter referred to as (ΙΠ-b) Compounds A - cyclization is preferably an alkaline agent and / or carried out in the presence of an oxidant. Suitable basic agents for this purpose include, for example, alkali metal hydroxides (such as sodium hydroxide or potassium hydroxide) and alkali metal carbonates (such as potassium carbonate). Suitable oxidizing agents are, for example, hydrogen peroxide, 3-chloroperoxybenzoic acid, ozone or nickel peroxide. Suitable solvents include, for example, water, methanol, acetone, acetic acid or mixtures. The reaction is preferably carried out at 0-80 ° C.

Process (b), that is, the reaction of the compounds of formula (IV) with the compounds of formula (V) or salts thereof, may be carried out in a suitable solvent. Salts of compounds of formula V include, for example, salts with mineral acids such as hydrochlorides or sulfates. Suitable solvents are, for example, dichlorobenzene, toluene, methanol, ethanol, tetrahydrofuran or mixtures thereof. The reaction is usually carried out at atmospheric pressure or under pressure at room temperature. If the reaction is carried out under relatively mild conditions, an intermediate may sometimes be isolated in a ton of crystals when this intermediate is reacted with a compound of formula (V) to produce a compound of formula (I-a).

Process (c), i.e. hydrolysis of compounds of formula (VI), is carried out in a suitable solvent. The hydrolysis of compounds of formula (VI) wherein Z is ² , hereinafter referred to as VI (a), is preferably carried out in the presence of a basic agent and an oxidizing agent. The hydrolysis of compounds of formula (VI) wherein Z is ² , hereinafter referred to as (VIb), is preferably carried out in the presence of a nitrosating agent. The alkali agents and oxidizing agents used in the labeling of compounds of formula (ΙΠ-a) may be, for example, alkali metal nitrites, aryl nitrite, nitrosyl chloride or nitrogen dioxide. Suitable solvents for this purpose include, for example, water, acetic acid or sulfuric acid. The reaction is preferably carried out at a temperature between 0 ° C and 80 ° C.

Compounds of formula (Ia) forming a narrower group of compounds of formula (Ia) from compounds of formula (Ia) (VII) obtained by any of processes (a) to (c) - wherein R 'is an alkyl group containing 1 to 4 carbon atoms, mfg. R ¹ , R ² , R, R ⁴ and R ⁵ as defined above and salts thereof may be prepared by reacting a compound of formula (ΫΠ) - wherein X ⁷ »and X ² are protecting groups, while R ¹ , R ² , R , R ⁴ and R ⁵ are as previously described — an alkylating agent such as an alkyl halide (C 1 -C 4) and deprotecting, and if desired, converting the resulting product of formula (Id) to a salt.

In the compounds of formula (VH), X ¹ and

The protecting group X ² may be any protecting group commonly used to protect amino or imino groups, such as acetyl, benzyloxymethyl, benzoyl, benzyloxycarbonyl or tetrahydrofuranyl.

Alkylation of compounds of formula (VII) with (C 1 -C 4) alkyl halides is preferably carried out in a suitable solvent in the presence of a base such as sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate. Examples of the solvent used include dimethylformamide, tetrahydrofuran, acetone or dimethylsulfoxide. The reaction is preferably carried out at a temperature of -20 ° C to 101 ° C.

Removal of the protecting groups is left to this purpose3

-382 200182 by any of the well known methods such as hydrolysis, electrolytic reduction, base treatment, acid treatment, catalytic reduction or oxidation. Conversion of the free base to a salt may also be carried out in a conventional manner.

Compounds narrower group of the formula (I) comprises Ω-b) formula was vegyületeket- R ^J1 is a halogen atom, R ⁴¹ represents a hydrogen atom or an alkoxy group having 1-5 carbon atoms, Lock-hydrogen or halogen atom, and R and R ¹ are as and their salts may be prepared by reacting a compound of formula (1-c) - wherein R, R * and R ⁴¹ are as defined above - or a salt thereof with a halogenating agent and, if desired, converting the resulting product into a salt.

The compounds of formula (I-c) may be used in the form of the free base or in the form of their salts, for example, their alkali metal salts, such as their sodium or potassium salts.

The halogenation of the compounds of formula (I-c) may be carried out in a suitable solvent. The halogenating agent used is, for example, sulfuryl chloride, elemental chlorine, elemental bio, iodobenzene dichloride or N-bromosuccinimide. Suitable solvents are, for example, acetic acid, tetrahydrofuran, dioxane, water or mixtures thereof. The agitation is preferably carried out at a temperature between 0 'C and 100 ° C, more preferably at a temperature between 20' C and 70 ° C.

When the compounds of formula (I) are obtained as a racemic mixture, these mixtures can be resolved by conventional methods for each optical isomer. For example, optical resolution may be accomplished by reacting a racemic mixture of compounds of Formula I with a resolution solvent in a suitable solvent, separating the poorly soluble diastereomeric salt, even in crystalline form, and recovering the soluble diastereomeric salt from the mother liquor, natural substances such as brucine, quinine, quinonidine, N- (n-octyl) glycylamine or dehydroabiethylamine; and optically active substances such as alpha-methylbenzylamine-lysine, phenylalanine amide or tyrosine; Suitable solvents for this purpose include methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, water and mixtures thereof. The diastereomeric salts thus prepared may be converted into the optically active compound of formula I to be prepared, for example, by treatment with an acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid or formic acid).

The starting compounds of formula (Π) and (ΙΠ) are also novel compounds. For example, a compound of formula (Π) may be prepared by reacting a compound of formula (ΫΙΠ) i - wherein R, R ³ , R ⁴ and R ⁵ are as previously defined - or a salt thereof (such as a sodium or potassium salt). (IX) formula was the compound: - wherein ^R1 is as defined above, in a solvent base (for example triethylamine) at -20 * C to 50 * at a temperature between, and a compound thus obtained (X) - wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above with a compound of formula QQ wherein R ⁶ is as hereinbefore defined or a salt thereof in the presence of a base such as triethylamine. , At temperatures between 0 'c and 100' C.

Compounds of formula (ΙΠ) may be prepared by reacting a compound of formula (X) or a salt thereof with a compound of formula (TOL) wherein Z * is as defined above, in a solvent such as 1,8-diazabicyclo ( 5.4.0] in the presence of undec-7-ene or triethylamine) at a temperature between 0 ° C and 100 ° C.

Compounds of formula (Π) may also be prepared by reacting a compound of formula (ΙΠ-b) with a compound of formula (XIH) wherein X is halogen and R ⁶ is as previously defined, such as sodium hydride. ) at 0 ° C to 50 ° C.

Compounds of formula (TV) may be prepared by reacting a compound of formula (VIII) or a salt thereof with a compound of formula (XIV) wherein R ⁷ is C 1 -C 4 alkyl and X is as defined above in a solvent base. (e.g. triethylamine) at a temperature between 0 ° C and 8 ° C, then the resulting compound of formula XV, wherein R, R ³ , R, R ⁵ and R ⁷ are as previously defined, with urea and in a solvent at a temperature between 50 ° C and 120 ° C.

Compounds of formula (VI-a) may be prepared by heating a compound of formula ΩΠ-b) in a solvent at a temperature between 100 ° C and 180 ° C and treating the resulting product with an acid such as hydrochloric acid at a temperature between 20 ° C and 100 ° C.

Compounds of formula (VI-b) may be prepared by reacting a compound of formula (X) with guanidine or a salt of the latter in a solvent, optionally in the presence of a base (e.g. sodium hydroxide) at a temperature between 20 ° C and 101 ° C. During the reaction, a by-product of the formula (XVn), wherein R ¹ , R, R ³ , R ⁴ and R ⁵ are as defined above, is formed. This by-product of formula (XVI) is treated with an acid, e.g. -b).

The compounds of formula (I) may be used for pharmaceutical purposes in the form of the free base or of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include, for example, the sodium salt, the potassium salt, the calcium salt, the lysine salt, the ethylenediamine salt, or the diethylamine salt. These salts are readily prepared by reacting a compound of formula (I) with a suitable base.

The compounds of the formula I and their salts have excellent aldose reductase inhibitory activity and are thus useful in the treatment of a variety of chronic diabetes-related symptoms, e.g. and treat. A further advantage of the compounds of the formula I and their salts is that they have a low a

H their toxicity and reduced neurotoxic side effects (such as gait, reflex, inability to work or blepharoptosis).

The compounds of formula (I) and their salts prepared according to the invention may be administered orally or parenterally. They can be administered in the form of conventional pharmaceutical preparations such as tablets, granules, fine granules, powders, capsules, injections and medications for eye treatment (eye lotion or ointment). These compositions may be prepared by mixing an active ingredient of formula (I) or a salt thereof with a carrier and / or excipient conventionally used in the manufacture of a medicament. These agents include, for example, sucrose, starches, mannitol, glucose, cellulose, talc or calcium phosphate, binders such as methylcellulose, gelatin, acacia or polyethylene glycol, and disintegrants such as starches, carboxylic acids, cellulose, sodium bicarbonate or calcium phosphate, lubricants such as magnesium stearate, talc or sodium lauryl sulfate, preservatives such as sodium benzoate or sodium hydrogen sulfide and stabilizers such as citric acid or sodium citrate.

The test compounds are as follows:

Compound Name of compound (compound of the invention)

1. 6-Chloro-3-methyl-spiro [133.4-tetrahydro-quinazoline-4,4'-imidazolidine] -23'3'-trione

2. D-6-Chloro-3-methyl-spiro [133,4-tetrahydro-indazolin-4,4'-imidazolidine] -2,2'3'-trione

3. Sodium salt of 6-chloro-3-methyl-spiro [133,4-tetrahydroquinazoline-4,4'-imidazolidine] -23'3'-trione-1'-

4. D-6-Fluoro-3-methyl-spiro [133.4'-tetrahydro-quinazoline-4,4'-imidazolidine] -23 ', 5'-trione

5. 6-Chloro-3,7-dimethyl-spiro [133,4-tetrahydro-1-quinazoline-4,4'-imidazolidine] -23'3'-trione

6. 6-Bromo-3-methyl-spiro [13,3,4-tetrahydro-quetoline-4,4'-imidazolidine] -23'3'-trione

7. 6,7-Dichloro-3-methyl-spiro [133.4-tetrahydro-quinazoline-4,4 * -imidazolidine] -23'3'-trione

8. 6,8-Dichloro-3-methyl-spiro {133,4-tetrahydro-quinazoline-4,4'-imidazolidine] -23'3'-trione

9. 6-Fluoro-3-methyl-4 H- [13,4-tetrahydroquinazoline-4,4'-imidazolidine] -23'3'-triOT0. 1-Isobutyl-6-chloro-3-methyl-spiro [13,3,4-tetrahydro-quinazoline-4,4'-imidazolidine] -23'3'-trione ^r '. Dimethyl-spiro [133,4-tetrahydro-ndazoline-4,4'-imidazolidine] -23'3'-trione / Chem. Payroll, DJ. 2394 (1970) / * 2. 3, l ', 3'-trimethyl-spiro- [133,4-tetrahydro-4,4'-imidazolidine] -23'3'-trione

The dosage of the compounds of formula (I) and their pharmaceutically acceptable salts may depend, among other things, on the route of administration, the age, weight and general condition of the subject being treated and the severity of the disease. Generally, this dose will be between 0.01 mg / kg and 200 mg / kg, preferably between 0.1 mg / kg and 50 mg / kg per day.

The pharmacological activity of the compounds of formula (I) and their salts prepared according to the invention is illustrated by the following examples.

1. Experimental Example

Aldose reductase inhibitory activity

KísUstijnódszet

Aldose reductase was isolated from the lens of male rabbits weighing 23-33 kg according to J. Bioi. Chem., 24Q 877-882 (1965). The inhibitory activity of the test compounds against aldose reductase is described in Biochim. Biophys. Acta 128.474-482 (1966). The aldose reductase inhibitory activity of the test compounds is expressed as the concentration of the test compounds required to inhibit the activity of the aldose reductase by 50%, i.e. the 50% inhibitory concentration (IC50).

/ Chem. Salary, UQ. 3849 (1977).

Results

The results are shown in Table 1 below.

Table 1

Compound Aldose Reductase Inhibitory Activity IC50 (M)

The compounds of the invention.

1. 5.6x10,

2. 2.2x10,

3. 2.9x10,

4. 6.4x10,

5. 3.0x10,

6. 53x10,

7. 7.4x10,

8. 3.7x10?

9. 1.0x10,

10. Comparative Compounds 2.7x10 ⁷ :

11, Ι, ΟχΙΟ ⁵

12. 5xxxl0 ⁵

ZJÜsédeiLpélda

Anti-accumulation effect of polyols

Experimental method

Three to three male rats of the Sic: Wistar breed, three to four weeks old, (i) were enriched with 20% galactose, 20 mg of the test compound (i.e., 20 mg of the test compound per 100 g of feed).

-5HU 200182 Β set) (group receiving test compound), (ii) 20% galactose-enriched diet (galactose control group) and (iii) normal diet (galactose-free) (normal control group) for 6 days we sit down, under ether anesthesia, cutting through the carotid artery. Immediately thereafter, the sciatic nerves are removed from both sides and the amount of polyols accumulated therein is determined by the so-called acetylacetone method described in Science, 182.1146-1148 (1973). The rate of inhibition of the accumulation of polyols is calculated from the following equation:

Polyol Accumulation Ratio (%) = = [(average amount of polyol in the group receiving the test compound) - (average amount of polyol in the normal control group) / (average amount of polyol in the galactose control group) - (average amount of polyol in the normal control group)] x 100

Results:

The compounds used in Experimental Example 1, i. Each compound has a rate of inhibiting the accumulation of polyols greater than 50%

2J ^ £ Serla íipálda

Observation of acute toxicity and symptoms

In groups of 3-3 individuals, the test compound was orally administered as a suspension of ddY male mice weighing approximately 25 g in 0.5% carboxymethylcellulose solution and observed for 14 days for general behavior and symptoms. In mice treated with -6-chloromethyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2'''-trione at a dose of 10 g / kg, no mortality was observed and we have not experienced abnormal symptoms such as gait, reflex, inability to stand, blepharoptosis (difficulty paralyzing the upper eyelid), difficulty breathing, reddening of the skin and tearing.

The following examples are intended to illustrate the invention.

Example 1

To a solution of 4.0 g of 5-chloro-1- (methylcarbamoyl) isatin in 40 ml of tetrahydrofuran was added 4.0 g of

S-ethylisothiourea hydrobromide and 3.0 ml triethylamine were added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to remove the solvent. The resulting 6-chloro-3-methyl-4-hydroxy-4 - [(2-ethylisothioureido) carbonyl] -2-oxo-1,2,3,4 To 10-tetrahydroquinazoline was added 50 ml of 10% hydrochloric acid, and the resulting mixture was framed at 70-80 ° C for 3 hours. After the reaction mixture has cooled, the precipitate formed is filtered off when

2.5 g (52.1%) of 6-chloro-3-methylspiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -23 'having a melting point higher than 280 ° C, We get a 5'-trion.,

IR ^(cm-1): 3300,1780,1740,1718

Mass Spectrum (MS) (m / e): 280 (M ⁴ )

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ: 2.80 (3H, s), 6.92 (1H, d, J = 9Hz), 7.06 (1H, d, J = 2Hz), 7.40 (1H, d, d, J = 9Hz, J-2Hz), 9.11 (1H, s), 10.07 (1H, s), 11.40 (1H, S).

2z22 ^ Eáldúk

The compounds listed in Tables 2 and 3 can be prepared from the appropriate starting materials as described in Example 1. The reactions leading to the preparation of the compounds are illustrated in Scheme A.

(Ia) (R * = CH 3, R ⁵ = H)

Table 2

Example number R ⁵ R ²

R ³

Physical characteristics

R ⁴ Yield MS IR υ ^η ιηΜ (cm -1: NMR spectrum (DMSO) delta:

and p.p. (M / e)

2. H F

3. Cl H

4. Η H

5. H CH 3 O

H 280'C 264 (M ⁴ ) 3280, 3190, 1783, 1735, 1657, 1610 H 280'C 280 (M ⁴ ) 3300, 2900, 1780, 1740, 1720, 1640 cl 75% 280 ° C 280 (M ⁴ ) 3200, 2900, 1770, 1740, 1725, 1670 H 270-272'C276 (M ⁴ )

2.78 (3H, s). 6.67-735 (3H, m), 9.03 (1H, s), 930 (1H, s), 1131 (1H, s)

2.82 (3H, s), 6.87-7.30 (3H, m), 9.00 (1H, s), 10.20 (1H.S), 11.40 (1H.S)

2.82 (3H, s), 6.90-7.30 (3H, m), 9.10 (1H, s), 10.08 (1H, s), 1130 (1H, s).

2.80 (3H3), 3.77 (3H, s), 6.50 (1H, d, J = 2Hz), 630 (1H, d, J2o) 6.67 (1H, d, d, J = 9Hz) , J = 2Hz),

7.08 (1H, d, J = 9Hz), 9.10 (1H, s), 10.00 (1H, s), 11.45 (1H, s).

-6HU 200182 Β

The number of the example r ⁵ r ² R ³ R ⁴ Yield éso.p. Physical characteristics; MS ^ujo1 itwx IR ^(cm-1): NMR (DMSO-d) (M / e) delta: 6th H CH3 H 57.4% 280C 260 (M ⁴ ) 3200, 1800, 1720, 1650, 1610 220 (3H, s), 2.79 (3H, s), 6.60-720 (3H, m), 8.94 (1H, s), 9.72 (1H, s), 1120 (1H, s). 7th H -OCH2C 1- 280'C 290 (M ⁴ ) 3400, 3180, 3070, 1789, 1715, 1680, 1642 2.76 (3H, s), 6.01 (2H, d, J = 2Hz), 6.45 (1H, s), 6.54 (1H, s), 634 (1H, s), 9.00 (1H, s), 9.74 (1H, s), 1130 (1H, s). 8th H the CH3 50.1% 280 'C 294 (M ⁴ ) 3250, 3001, 1780, 1730, 1660, 1600 230 (3H, s), 2.80 (3H, s) 6.93 (1H, s), 7.10 (1H, s), 9.20 (1H, s), 10.11 (1H, s), (1.49 (1H, s) 9th H H CH3 O 270-272-C276 * (M ⁴⁾ 2.80 (3H, s), 3.77 (3H, s), 6.50 (1H, d, J = 2Hz), 6.67 (1H, d, J = 9Hz, J = 2Hz), 7.08 (1H, d, J = 9Hz), 9.10 (1H, S), 10.00 (1H, S), 11.45 (1H, S). 10th H H CH3 65% 280'C 260 (M ⁴ ) 3270, 1780, 1730, 1660, 1604 231 (3H.S), 2.72 (3H, s), 6.60-7.00 (3H, m), 8.90 (1H, s), 9.76 (1H, s), 11.15 (1H, s). 11th F F F 553% 280'C 3250,3150,3020, 1800,1720 2.80 (3H, s), 7.07-7.40 (1H, m), 9.15-1720 (1H, s), 1035 (1H, s), 11.45 (1H, S). 12th F H H 503% 280'C 264 (M ⁴ ) 3300,3200,3050, 1800,1750,1710 2.80 (3H, s), 6.70-7.40 3H, m), 9.12 (1H, s), 10.00 (1H, s), 1138 (1H, s). 13th H Br H 50.4% 324 (M ⁴ ) 3250,3100,1775, 280'C 1730,1650,1600 2.79 (3H, s), 6.87 (1H, d, J = 8Hz), 7.15 (lH, d, J = 2Hz), 7.50 (lH, d, d, J = 8 Hz, J = 2Hz), 9.12 (1H, s), 10.09 (1H, S), 1130 (1H.hr). 11:50 (lH, br). 14th CH3 H 280'C 260 (M ⁴ ) 3300, 2720, 1742, 1720, 1660, 1612 2.17 (3H, s), 2.80 (3H, s), 6.6-7.0 (2H, m), 7.1-73 (1H, m), 8.98 (1H, s) ). 15th H the CH 3 O-55% .280'C 310 (M ⁴ ) 2.74 (3H, s), 3.80 (3H, s), 638 (1H, s), 6.98 (1H, s), 8.99 (1H, s), 9.90 (1H, s), 1120 (1H, s). : 6th H -COOC2C5 H 553% 280'C 318 (M ⁴ ) 3250, 1795, 1730, 1690, 1616 127 (3H, t, J = 7Hz), 2.78 (3H, s), 425 (2H, q, J = 7Hz), 6.93 (1H, d, J = 9Hz) 7.4-8.1 (2H, m), 9.09 (1H, s), 10.26 (1H, s), 11.33 (1H, s). 17th H CH = CH -COOC2H5 H 280'C 344 (M ⁴ ) 1795,1740,1678 1658,1615,1603 133 (3H, t, J = 7Hz), 2.76 (3H, s), 4.13 (2H, q, J = 7Hz), 6.4 L (1H, d, J = 17Hz), 6.84

-ΊHU 200182 Β

Continuation of Table 2

The number of the example is R ⁵ R ²

R ³

Physical characteristics

Yield R ⁴ MS IR ν ^{m, J 0} (cm ^-1 ): NMR spectrum (DMSO d 6) and δ (m / e) delta:

(1H, d, J = 9Hz), 73-7.9 (2H, m), 756 (1H, d, J = 17Hz), 8.96 (1H, s), 10.07 (1H, s), 10.9-115 (1H, br).

(Ia) (R ² -R ⁵ = H)

Physical characteristics

Example A R ¹ Yield MS IR u ^nujo, mM (cm ¹ ): NMR spectrum (DMSO-dode) delta:

number and op. (M / e)

18th CH3 (CH2) 3- 263-266'C 288 (M *) 3240,1782,1770. 1725,1665,1613 0.7-1.9 (7H, m), 2.7-33 (2H, tn), 6.7-7.4 (4H, m), 9.05 (1H, s), 9.77 1H , s), 11.14 (1H, s). 19th phenyl '308 (M *) 3400, 3050, 1785, 1738, 1660, 1610 6.64-750 (9H, m), 9.10 (1H, s), 10.05 (1H, s). 1030 (1H, br s). 20th benzyl 280'C 322 (M ⁴ ) 3240.3050.1782, 1738.1720 450 (2H, ABq, J = 24Hz, 16Hz), 6.87-750 (9H, m), 9.13 (1H, s),

9.97 (1H, s), 11.18 (1H, s).

Example 21

2.0 g of 3-methyl-4-hydroxy-4 - [(2-ethylisothioureaeidocarbonyl)] - 2-oxo-123.4-tetrahydroquinazoline are suspended in 20 ml of 10% hydrochloric acid and the resulting mixture is stirred for 70-80 minutes. Stir at C for 3 hours. After cooling the reaction mixture, the precipitate was filtered off and recrystallized from dimethyl sulfoxide. 12 g of 3-methylspiro [123.4-tetrahydroquinazoline-4,4'-imidazolidine] -22'5'-trione having a melting point above 280 DEG C. are obtained. > 40

IR (cm ^-1 ): 3300, 3120, 3080, 1781, 1735,

1680.1615

MS (m / e): 246 (M +).

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ: 2.80 (3H, s), 6.70-750 (4H, m), 9.05 (1H, s), 9.91 (1H, s), 1131-45 ( 1H, s).

22-23. Examples

The following kits can be prepared from the appropriate starting materials as described in Example 21.

(22) 3- (4-Methyl-phenyl) -spiro [12,3,4-tetrahydro-quinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione x 0.5 HCON (CH 3> 2, m.p. 213-215 ° C (after recrystallization from dimethylformamide / water 55);

IR u ^TOJ0l m «x (cm &^lt; ¹ >): 17680,1740,1670,1608.

MS (m / e): 322 (M +).

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ: 231 (3H, s),

230 (3H, d, J = 11Hz), 630-7.60 (8H, m), 920 (1H, 60

s), 10.08 (1H, s), 1036 (1H, s).

(23) 3- (4-Chloro-phenyl) -spiro [123,4-tetrahydro-quinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione x 0.5 HCON (CH 3) 2, yield 82.7%, mp> 280 ° C. 65

IR υ '^ ηβ (cm ^-1 ): 1788,1740,1662,1610.

MS (m / e): 342 (hf).

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ 230 (3H, d, J = 11Hz), 630-7.70 (8H, m), 9.60 (1H, s), 1020 (1H, s), 11.70 (lH, s).

Example 24 (1) To a suspension of 9.6 g of 55-dichloro-1- (methylcarbamoyl) -isatin in 100 ml of tetrahydrofuran was added 3.0 g of thiourea and 55 ml of triethylamine, and the resulting mixture was stirred at room temperature for 5 hours. the precipitate was filtered off to give 4.1 g of 6,7-diloro-3-methyl-4-hydroxy-thioureidocarbonyl-2-oxo-123.4-tetrahydroquinazoline, m.p. 225-228 ° C.

(2) To a solution of the compound obtained in Step (1) (2.8 g) in dimethylformamide (30 ml) was added 032 g of a 60% oily sodium hydride suspension and the resulting mixture was stirred at room temperature for 30 minutes. Subsequently, 2 ml of ethyl bromide were added to the reaction mixture, which was stirred for an additional 30 minutes and then the solvent was removed under reduced pressure. To the resulting 6,7-dichloro-3-methyl-4-hydroxy-4 - [(2-ethylisothioureido) carbonyl] -2-oxo-123.4-tetrahydroquinazoline was added 10 ml of 10% hydrochloric acid and the The resulting fly was stirred at 70 ° C for 4 hours. After cooling the reaction mixture, the crude precipitate was filtered off, washed with 10% aqueous sodium bicarbonate and recrystallized from dimethylformamide / water. Thus, 1.4 g of 6.7 diodo-γ-3-methylphenyl [123.4-tert-butylquinoline-4,4 * -imidazolidine] -22 * 5'-trione (q) are obtained.

IRu ^ mwtcm ¹ ): 3250,1770,1720,1615,1597.

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ 2.78 (3H, s),

-8HU 200182 Β

7.09 (IU s), 739 (1H, s), 9.12 (Here s), 10.18 (1H, s),

11.41 (Here s).

Example 25 To a solution of 13-dichlorobenzene in ml was added 1.5 g of 3-methyl-4-hydroxy-4- (ureido-methylbromo-2-ol-133.4-4et) loodro-quadmizine and the resulting mixture was stirred under reflux. After cooling the mixture, the precipitate was collected by filtration and recrystallized from dimethylsulfoxide to give 08 g of 3-methylspiro [133.4-tetrahydroquinaroline-4] m.p. , 4'-imidazoüdin] ^-23, 5'-trione is obtained.

IRv ^ moícm ' ¹ ): 3300.3120,3080.1781,1735, 15

1680; 1615th

MS (m / e): 246 (M +).

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) δ 280 (3tt s),

6.70-750 (4H, m), 9.05 (1H, s), 981 (Here s), 11.31 (ltts). 20

Example 26

To a suspension of 1734 g of D-3-methylspiro (133.4-tetrahydroquinazoline-4,4'-imidazolidine) -23'5''trion in 170 ml of acetic acid was added dropwise 854 ml of sulfuryl chloride, followed by dropwise addition to the suspension. The resulting reaction mixture was stirred at room temperature for 135 hours, then poured into 500 ml of ice water and the precipitate was filtered off, the crystals were dissolved in 1 liter of ethanol and the insoluble material was filtered off. The solvent was distilled off under reduced pressure, water was added to the residue, and the precipitate was collected, washed with water and dried.

This procedure was repeated once more with 14 g (713%) of D.64-dor-3-methyl-spiro [133.4-tetrahydro-quinazoline-4,4'-imidazolidine] -23'5'-trio-monohydrate. the product is in the R configuration at position 4 of the lonazolinone backbone).

IRn ^ maxfcm ' ¹ ): 3650,3450,3300,3220,3100, 1765,1730,1660,1600.

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) δ: 2 JSO (3H, s), 682 (Here d, J = 9Hz), 7.06 (H, d, J = 2Hz), 7.40 (1H, d, d, J = 9Hz, J = 2Hz), 9.11 (1H, s), 1007 (1H, s), 11.40 (1H, s) (alpha + 32.9 * (c = 1.ethanol).

27-29. Examples

A26. In accordance with Scheme B, the starting materials listed in Table 4 can be prepared from the appropriate starting materials.

The number of the example R ¹ R ⁵¹ Physical characteristics R ^JJ R 27. * ¹ CH3 the H H yield: 765%, 00; 169-173 ° C; ([alpha] D = -33.7 * (c = 1, ethanol) 28th CH3 the H H yield: 713%; mp: 28 ° C; IR Autoline ¹ ): 3300,1780,1740,1718. 29. * ² CH3Cl CH30- the Op.:280'C; MS (m / e): 334 (MH +); IR υΑ "χ (cm ^-1): 3200,1800,1715,1645.

a rotator isomer. NMR of the compound:

Nuclear Magnetic Resonance Spectrum (DMSO-drO delta: 2.79 (3H, s), 3.82 (3H, s), 7.15 (1H, s), 9.10 (1H, s), 955 (1H, s)). 1138 (Here s).

Example 30

To a solution of 3-methylspiro [133,4-tetrahydroquinazoline, 4,4 * -imidazolidine] -23'5'-trione (133 g) in acetic acid (50 ml) was added elemental iodine (40 ml) and sulfuryl chloride (40 ml) was added. 60 'Con for 90 hours. After cooling, 100 ml of water were added to the reaction mixture, which was stirred under ice-cooling. The precipitate was filtered off. The crystals thus obtained are dissolved in aqueous sodium hydroxide solution and the insoluble material is filtered off. The filtrate was neutralized with 10% hydrochloric acid and the precipitate was filtered off, washed with water and dried. There was thus obtained 6,8-dichloro-3-methyl-spiro (13,3,4-tetrahydroquinazoline-4,4'-imidazolidine) X 2'5'-trione, 135 g (85.4%), m.p. 280 ° C. greater than.

IR (cm ^-1): 3220,1799,1722,1640.

MS (m / e): 314 (?).

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ: 2.77 (3H, s), 7.06 (1H, d, J = 3Hz), 759 (Here d, J = 3Hz), 9.10 (Here

s) 953 (Here s), 11.1-11.7 (1H, broad).

Example 31

1.4 g of 6-chloro-3-methyl-spiro [133,4-tetrahydro-quinazoline-4,4'-imidazolidine] -23'5'-trion are dissolved in

1086% w / w aqueous sodium hydroxide, the resulting solution was treated with activated carbon and then concentrated under reduced pressure. The residue was crystallized from ethanol and filtered. The crystals thus obtained are washed with ethanol and diisopropyl ether and dried. 1.17 g (773%) of the sodium salt of 6-chloro-3-methyl-spiro [133,4-tetrahydro-quinazoline-4,4'-imidazolifin-23'5'-trione] are obtained.

Au IR (cm ^-1): 3330,3180,1703,1648.

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ 2.62 (3H, s),

-9HU 200182 Β

6.6-6.9 (2H, m), 7.0-73 (2H, m), 93-9.8 (1H, broad).

Example 32

In a similar manner to that described in Example 31, D-6-chloro-3-methyl-spiro [1,2,3,4-tetrahydro-quinazoline is obtained in a yield of 84.6% from the appropriate starting materials. 4,4'-imidazolidine] ^{23'3'-trip-l,} sodium salt was obtained.

(alphaTp + 48.7 * cm -1, water). 10

IRtf ^ nux (cm &^lt; -1 ^> ): 3620,3300,1708,1683,1645,

1600th

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) δ 2.63 (1H, s),

6.72 (1H, d, J = 10Hz), 6.76 (1H, d, J = 3Hz), 7.13 (1H, d, d, J = 10Hz, J = 3Hz), 734 (1H, s ), 9.57 (1H, s). 15

Example 33

To a suspension of 294.3 g of isatin in 3 liters of tetrahydrofuran is added 279 ml of triethylamine and 129.8 ml of methyl isocyanate with stirring at 15 ° C, and the resulting mixture is stirred at 20-25 ° C.

After stirring for 2.5 hours, 1- (methylcarbamoyl) isatin was prepared. To the reaction mixture was added 4443 g of 2-ethylisothiouriourea hydrobromide and 55.8 ml of triethylamine, and the resulting mixture was refluxed for 2 hours. After the reaction mixture was cooled, the solvent was distilled off under reduced pressure to give 3-methyl-4-hydroxy-4 - [(2-ethylisothioureido) carbonyl] -2-oxo-1,2,3,4-tetrahydroquinazoline. 10 liters of 10% hydrochloric acid are added. After cooling, the precipitate was filtered off, washed with water, 1 L of methanol and 1 L of chloroform in the same order and finally dried to give 3693 g (75%) of 3-35 methyl. -spirol 133.4-tetrahydroquinazoline-4,4'-imidazolidine] -23'3'-trione.

The physico-chemical properties of this product are the same as those of Example 21. 40 i

Example 34 (1) 123 g DL-3-methylspiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 ', 5'-trione and 21.5 g brucine dihydrate in methanol / water (3: 2) was cooled to room temperature with 625 mL of heating and the precipitate was filtered. (This filtrate will be referred to as "(I) filtrate.) The crystals thus obtained are recrystallized from methanol / water (3: 2) to give D-3-methylspiro [133.4-tetrahydroquinazoline (7.8 g)]. -4,4'-imidazolidine] -23'3 * -trionbrucine salt is obtained. (alpha / D -67,0 '(c = 1, dimethylformamide).

The resulting salt (7.8 g) was dissolved in water (20 ml) and concentrated hydrochloric acid (2 ml) was added. The precipitate was filtered off and recrystallized from methanol / water. Thus 23 g of the 174-176 ° C melting D3-methyl-spiro [133.4-tetrahydro-quinazolin-imidazolyl 60 4,4-oxazolidin] -23 * .5 * -trione is obtained (alpha) ²⁾ + 34 , 7 '(c = 1, ethanol).

(2) The filtrate (I) obtained as described in step (1) above is evaporated to dryness under reduced pressure and the residue is dissolved in 60 ml of water. The resulting solution 65 is then neutralized with 6 ml of concentrated hydrochloric acid and the precipitate is filtered off. The filtrate is evaporated under reduced pressure to remove solvent and the precipitate is filtered off. The crystals thus obtained were recrystallized from methanol-water to yield 2.1 g of L-3-methylspiro [133β, 4-tetrahydroquinazoline-4,4′-imidazolidine] 23′3 *-trione, m.p. 1741766C. (alpha ^ D -34.7 '(c = 1, ethanol).

Example 35 (1) 8.1 g of DL-6-fluoro-3-methylspiro [133.4-tetrahydroquinazoline-4,4'-imidazolidine] -23 ', 5'-trione and 16 µ g of quinine from quinine hydrochloride are dissolved. of methanol: water (2: 1) at 450 mi with heating. The resulting solution was allowed to cool and the precipitate was filtered off. (The filtrate thus obtained will be referred to as "(II) filtrate.") Thus, 4.0 g of D-6-fluoro-3-methyl-spiro [1,3,4-tetrahydro-quinazoline-4,4'-imidazolidine] ] -2,2'3'-trion quinine salt is obtained. (alpha-D -20,8 '(c = 1, dimethylformamide).

To the resulting 4.0 g of salt was added 2% hydrochloric acid, the precipitate was filtered off and finally recrystallized from methanol / water. Thus 1.1 g of the 'melting point of D-6-fluoro-3-methyl-spiro- 267 [133,4-tetrahydro-quinazoline-4,4' imidazolidine] ^-23, 5'-trione is obtained, (alpha) ² + 37.6 '(c = 1, ethanol).

(2) The filtrate (II) obtained in step (1) above was adjusted to pH 2 with 10% hydrochloric acid and the precipitate formed was filtered off. The filtrate was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was evaporated under reduced pressure to remove solvent and the residue was neutralized with 2% hydrochloric acid. The precipitate was filtered off. then recrystallized from methanol / water. 0.7 g of L-6-fluoro-3-methyl-spiro [133.4-tetrahydro-quetoline-4,4'-imidazolidine] -23 *, 5'-tricm, m.p. -39.6 '(c = 1, ethanol).

Example 36 (1) 3.06 g of 3'-acetyl-1- (benzyloxymethyl) -3-methylspiro [133,4-tetrahydroquinazoline-4,4'-imidazolidine] 23'3'-trione To a solution of 20 ml of dimethylformamide was added 1 ml of methyl iodide followed by small portions of 0.3 g of 60% sodium hydride in mineral oil under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes and then added with water and extracted with ethyl acetate. The extract was dried and the solvent was evaporated. as floating agent · using chloroform. Thus, 3 g (943%) of 3'-acetyl-1-benzyloxymethyl-13-diroethylspiro [133.4 * tetrahi (1H-quinazoline-4,4'-imidazolidine) as an oily substance. 2,2 ', 5'-trione is obtained.

IR (cm &^lt; ¹ >): 1800,1720,1640,1600.

(2) To a solution of the above product (3.0 g) in ethanol (20 ml) was added 03 g palladium on carbon and the resulting reaction mixture was subjected to catalytic reduction for 5 hours under a hydrogen atmosphere at 2 to 3 atmospheres. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in 10% aqueous sodium carbonate-10HU 200182 82 solution and the resulting solution was heated at 60-80 ° C for 30 minutes. The solution was then neutralized with 10% hydrochloric acid and the precipitate was filtered off and finally recrystallized from dimethylformamide / water. This gives 3'-acetyl-13-dimethyl-spiro [1,3,4,4-tetrahydro-quinazoline-4,4'-imidazolidine] -23 ', 5'-trione having a melting point of 266-263 ° C.

MS (m / Ti: 302 (M +) ·

IR υ ^ η ,, χ (cm ¹ ): 1800,1760,1715,1640. 10

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ 2.40 (3H, s),

2.80 (3H, s), 336 (3H, s), 3.00-4.00 (1H, broad), 6.90-7.60 (4H, m).

(3) 1.0 g of the above product is added to a solution of sodium sodium acetate 15 in ethanol 15 (161 mg) and ethanol (20 ml), and the reaction mixture is removed at room temperature for 3 hours. The solvent is distilled off and the residue is evaporated. The precipitate was collected by filtration, and then recrystallized from a mixture of dimethylformamide and water. and then dried to give 0.45 g of 6-chloro-1-isobutyl-3-methylethyl-spiro [1,2,3,4-tetrahydro-quinazoline-4,4'- m.p. imidazolidine] -2,2 ', 5'-trione is obtained.

MS (m / e): 338 (M + +1), 336 (M + -1).

IR (cm ^4): 1790,1735,1645,1602.

Nuclear Magnetic Resonance Spectrum (DMSO-d6) delta: 030 (6H, d,

J = 7Hz), 1.7-2.4 (1H,?), 2.79 (3H, s), 3.6-4.0 (2H, m), 7.03 (1H, d,?) 3Hz), 7.10 (1H, d, J = 10Hz), 7.40 (1H, dd, J = 10Hz, J = 3Hz). 9JD9 (1H, s), 1136 (1H, s).

13-dimethyl-spiro (133.4-tetrahydro-quinazoline-4,4 * -imidazolidine) -23,5,5-trione is obtained in the form of tanks, m.p. 223-225 ° C.

IRU ^nujor mM (cm ^4): 3300,3200,1782,1730,1630.

Nuclear Magnetic Resonance Spectrum (DMSO-d6) δ: 2.86 (3H, sd), 333 (3H, s), 7.00-7.63 (4H, m), 9.10 (1H, s), 11.40 (1H, broad).

3LKlda

3-Acetyl-1 '- (benzyloxymethyl) -3-methylspiro [1,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2, as described in Example 36, Part 1. 3'-trione and isobutyl iodide are reacted to give 3'-acetyl-1 '- (benzyloxymethyl) -1-isobutyl-3-methylspiro [1,3,3,4-tetrahydro] m.p. quinazoline-4,4'-imidazolidine] -23'3'-trione is obtained.

MS (m / e): 464 (M +).

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) δ 0.9-13 (6H, m), 1.9-23 (1H, m), 2.465 (3H, s), 2.84 (3H, s), 33-. 4.1 (2H, m), 4.68 (2H, s), 5.16 (2H, s), 6.6-7.1 (3H, m), 7.1-73 (4H, m) .

The above product was treated with isobutyl-3-methylspiro [1,3,4,4-tetrahydroquinazoline-4,4'-imidazolidine] -2,2 melting point 270 ° C as described in Example 36 (2) and (3). ', 5'-trion is obtained.

MS (m / e): 302 (M +).

IR (cm &^lt; ¹ >): 1790, 1723, 1645, 1608.

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) δ: 0.90 (6H, d, J = 7Hz), 1.8-23 (1H, m), 2.79 (3H,?), 3.6-4.0 ( 2H, m), 6.9-7.6 (4H, m), 9.02 (1H, s), 11.19 (1H, s).

Example 38

0.76 g of 1-isobutyl-3-methyl-spiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -23'3'-trione prepared in the same manner as in Example 37 is obtained. To a suspension of 15 ml of acetic acid was added 03 ml of sulfuryl chloride and a small amount of elemental iodine, and the resulting reaction mixture was stirred at room temperature for 19 60 U. The reaction mixture was poured into ice / water and the precipitated precipitate was filtered off and the crystals on the solution were dissolved in 10% aqueous sodium hydroxide. The insoluble matter was filtered off and the filtrate was diluted with 10% hydrochloric acid.

Example 39

9.41 g of 5- [5-chloro-2- (ethoxycarbylamino) phenyl] 5-hydroxyimidazolidine-2,4-dione, 5.11 g of 40% methanol in methylamine; After stirring for 4 hours at 120 DEG C., the reaction mixture was cooled and the precipitated crystals were collected by filtration, washed successively with toluene and methanol and finally dried. 233 g of 6-chloro-3-methylspiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] 23'3'-trione are obtained having the same physical characteristics as in Example 1. produced according to the proper characteristics.

Example 40

A mixture of 837 g of 5- [2- (ethoxycarbonylamino) phenyl] -5-hydroxyimidazolidine-2,4-dione, 213 g of a 10% solution of methylamine in ethanol and 200 ml of 23-dichloro-benzene under pressure After stirring at 150 DEG C. for 2 hours, the reaction mixture was cooled, and the reaction mixture was extracted with 1N sodium hydroxide solution. The stolen aqueous extract was neutralized with 10% hydrochloric acid, and the precipitated crystals were collected by filtration, washed successively with water and ethanol and finally dried. 2.6 g of 3-methylspiro [133.4-tetrahydroquinazoline-4,4'-imidazolidine] 23'3'-trione are obtained. The physical characteristics of the article are the same as those of the example 21 product.

Example 41

A mixture of 2.65 g of 5- [2- (methoxycarbonylamino) phenyl] -5-hydroxyimidazolidine-2,4-dione, 12 g of a 10% solution of methylamine in ethanol and 60 ml of toluene under pressure The reaction mixture was worked up as in Example 40 and stirred at 110 DEG C. for 4 hours. Thus, 031 g of 3-methylspiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] 23 * 3 * -trione having the same physical characteristics as the product of Example 21 is stolen.

Example 42 (1) In a mixture of 17 g of 40% methylamine in ethanol, 600 ml of toluene and 600 ml of methanol is dissolved 27 g of 5- [2- (ethoxycarbonylamino) phenyl] -5-hydroxyimidazolidine The 2,4-dione was then stirred at room temperature for 1 hour. The activated crystals were collected by filtration, washed with toluene and dried. This gives 29 g of 130-133 ° C

A crystalline product having a melting point of 200182 is obtained.

(2) A mixture of 2.51 g, 6.1 g of 20% ethanol methylamine in ethanol, 60 ml of toluene and 6 ml of ethanol is obtained in a pressurized vessel at 110 DEG C. for 4 hours from the crystalline product obtained in the previous step. stir. After cooling, the precipitated crystals were collected by filtration and dried to give 1.06 g of 3-methylspiro [133,4-tetrahydroquinazoline-4,4'-imidazolidine] 23'3'-trionomethyl, m.p.> 280 ° C. - we get amms salt.

Nuclear Magnetic Resonance Spectrum (DMSO-d 6) δ 2.28 (3H, s),

2.67 (3H, s), 6.4-7.3 (9H, m).

MS (m / e): 246 (M + - 31).

42 ^ Belden

A42. In the same manner as in Example 1 (1), 1395 g of 5- [2- (ethoxybenzylamino) phenyl) -5-hydroimidazolidine-2,4-dione was collected and the precipitated crystals were collected by filtration. The crystals were added with 85.25 g of 40% methanolic methanol solution,

Of toluene (330 L) and ethanol (330 mL), and the resulting mixture was refluxed for 15 minutes at about 75 ° C. Thereafter, 155 g of 40% methanolic methanol in methanol are added dropwise over 1 hour, and the reaction mixture is refluxed for a further 2 to 5 hours. The precipitated crystals are then collected by filtration and then dissolved in water. The resulting aqueous solution was neutralized with 10% hydrochloric acid and the precipitated crystals were collected by filtration, washed with ethanol and dried. 43 g of 3-methylspiro [13,3,4-tetrahydroquinazoline-4,4'-imidazolidine] 23'5'-trione are obtained. The product has the same physical characteristics as the product of Example 21.

Example 44 (1) To a solution of 4.08 g of 1- (methylcarbamoyl) isatin in 50 ml of tetrahydrofuran is 222 g of triethylamine and

Thiocarbamide (1.7 g) was added and the reaction mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration, washed with water and dried. 3.7 g of 4-hydroxy-4- (thioureido-quinonyl) -3-methyl-2-oxo-133.4-tetrahydroquinazoline are obtained, m.p.> 280 DEG C. after recrystallization from dimethylformamide / ethanol.

(2) To a solution of 1.0 g of 10 g of the above product in 10% aqueous sodium hydroxide solution is added 2 ml of 30% hydrogen peroxide solution and the resulting mixture is stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was acidified with 10% hydrochloric acid, and the precipitated crystals were collected by filtration, washed and dried. 0.75 g (85.4%) of 3-methyl-spiro [133,4-tetrahydro-quinazoline-4,4'-imidazolidine] -23 ', 5'-trione are obtained. The viscous properties of the article are those of the product of Example 21

45. Eflda

9.6 g of 5,6-dichloro-1- (methylcarbamoyl) -isatin were treated in the same manner as in Example 44, Step 1 with 4.1 g of 6,7-dichloro melting at 225-228 ° C.

4-Hydroxy-4- (thioureidocarbonyl) -3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline is obtained. This product was treated as described in Example 44, Step 2 to give 6,7-dichloro-3-methyl-spiro [133,4-tetrahydro-quinazoline-4,4 '-imidazolidine] -23'3'-trione. The product has the same physical characteristics as the product of Example 24.

Example 46

Dissolve 1.0 g of 4-hydroxy-4- (thioureido-quinonyl) -3-methyl-2-oxo-133.4-tetrahydroquinazoline in 20 ml of a 10% aqueous sodium hydroxide solution and add 40 Stir at 50 ° C for 1.5 hours. After cooling, the solution was acidified with 10% hydrochloric acid and the precipitated crystals were filtered off, washed and dried. 13 g (85.4%) of 3-methyl-spiro (133.4-tetrahydro-quinazoline-4,4'-imidazolidine) -23 ', 5'-trione are obtained with the same physical characteristics as in Example 21. characteristics.

(2) 23 g of 4-hydroxy-4- (thioureidocarbonyl) -3-methyl-2-oxo-13,3,4-tetrahydroquinazoline are dissolved in 30 ml of dichlorobenzene and the resulting solution is stirred at 200 'C for 2 hours. over them. The precipitated crystals were collected by filtration and then recrystallized from a mixture of dimethylstdfoxide and water. 13 g of 2'-imino-3-methyl-spiro [133,4-tetrahydroquinazoline-43'-imidazolidine] -2,4'-dione having a melting point above 280 'C are obtained.

(2) 13 g of the above product are dissolved in 20 ml of 10% hydrochloric acid and the resulting solution is stirred at 80 ° C for 3 hours. The activated crystals were collected by filtration and recrystallized from a mixture of dimethylformamide and water. 1.1 g of 3-methylspiro [133.4-tetrahydroquinazoline-4,4'-imidazolidine] 25'-dione-2'-trione having a melting point higher than 280 ° C are obtained.

(3) 1.0 g of the above product is dissolved in 10 ml of 10% aqueous sodium hydroxide solution and 2 ml of 30% hydrogen peroxide solution are added to the resulting solution and the reaction mixture is stirred at room temperature for 1 hour. agitated. After completion of the reaction, the reaction mixture was acidified with 10% hydrochloric acid, and the precipitated crystals were filtered off, washed and dried. This gives 0.85 g (903%) of 3-1,4,10,101,103,133.4- ^ 0 ^ 1010-10113201 ^ 1-4,4 ^ imidazolidine] -23'3'-trione. are identical to those of the product of Example 21.

Example 48 (1) To 5 ml of tetrahydrofuran is added 057 g of guanidine hydrochloride followed by 0.6 ml of 10 N sodium hydroxide solution and the resulting mixture is stirred at room temperature for 5 minutes. Thereafter, 15 ml of tetrahydrofuran and 1.02 g of 1- (methylcarbamoyl) isatin were added, and the resulting mixture was stirred at room temperature for 4 hours. The solvent was distilled off, and to the residue was added 10 ml of 10% hydrochloric acid. The resulting mixture was refluxed for 1 hour, cooled, and the precipitated crystals were collected by filtration and washed with water and ethanol.

This gives 0.86 g of 2'-imino-3-methyl-spiro [133,4-tetrahydro-quinazoline-4,4'-imidazolidine] -23'-dione, m.p. 257-259 'C.

(2) 0.123 g of the above product is dissolved in a mixture of 1 ml of acetic acid and 2 ml of water, and a solution of 0.052 g of sodium nitrite in 1 ml of water is added dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour and then the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with chloroform: methanol = 7: 3 (v / v). 39 mg of 3-methylspiro [1,2,3,4-tetrahydroquinazolyl] -4,4'imidazolidine] -2,2 '3 * -trione are obtained. The physical characteristics of the product are the same as those of the product of Example 21.

Example 49 3-Methyl-4-hydroxy-4 - [(2-ethylisothioureido) carbonyl] -2-oxo-1,2,3,4-tetrahydroquinazoline in 10 ml of 20% aqueous sodium -hydroxide solution, add 2 ml of 30% hydrogen peroxide solution, and the resulting reaction mixture is cooled to room temperature. stir in stool for 1 hour. After completion of the reaction, the reaction mixture was acidified with 10% hydrochloric acid, and the precipitated crystals were filtered off, washed with ethanol and dried. Thus, 0.6 g (75%) of 3-methylspiro [1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine] -23'3'-triontkq) is obtained. with the appropriate characteristics.

The following examples are used to prepare the starting compounds.

JLBsfiasaiciaíóMft

Under ice-cooling and under reduced pressure, 3 g of methyl isocyanate were added dropwise to a mixture of 9.9 g of 5-fluoroisatin, ml of triethylamine and 30 ml of dimethylfannamide, and the resulting mixture was stirred at room temperature for 30 minutes. The activated precipitate is filtered off to give 5-fluoro-1- (methylcarbamoyl) isatin (8.7 g, m.p. 230232 ° C).

2-2Q.Rcferenciapfld &

In the same manner as in Reference Example 1, the appropriate starting materials can be prepared from the appropriate starting materials as shown in Scheme C, and the compounds listed in Table 5 are obtained.

,, Table 5 (X) (R = CH 3, R = H)

Reference example number R ² R ³ R ⁴ Physical characteristics 2. " H H H mp / 154-156'C Third H cl H mp: 234-236'C MS (m / e): 238 (M +) 4th the H H 158-160 ° C MS (m / e): 23800 5th H H the m.p. 220-222C MS (m / e): 238 (M + ¹ ). 6th H CH 3 O H mp 205-208'C 7th H CH3 H ' mp 228-230 ° C 8th H -OCH2 - mp: 235-240'C 9th H the cl mp: 220-221'C MS (m / e): 272 (M +) 10th H H CH3 mp: 217-219'C 11th H H CH 3 O mp: 217-219 ° C

* ^]) The compound is the same as Ann. Chem., 1974, 2003.

(XXR CHa.R ^ ^ H)

Reference example number r ' R ⁴ R ⁵ Physical characteristics · * 12th H H CH3 m.p. 192-195 'C 13th F F F 169-171 ° C 14th H H ~ F mp 145-146'C.

1 ''

-13HU 200182 Β

25 Continuation of Table 5 26 (X) (R = CH 3, R = H) t Reference example number R ² R ³ R ⁴ Fizgaijdlemzők 15th H Br H mp 222-229'C 16th CH3 H H NMR (DMSO-d 6) delta: 232 (3H, s), 2.87 (3H, d, WH 2), 7.10 (1H, d, 737 (1H, t, J = 9Hz), 8.03 (1H, d, J = 9Hz) 8.0-83 (1H, m), 17th H α CH 3 O mp 202-205'C MS (m / e): 211 (M +) 18th H COOC 2 H 5 H IR (cm ⁴ ): 336.1748.1720, 1703.1619 19th H -CH = CH-H-COOC 2 H 5 IR ^(cm-1): 3360,1757,1738, 1705,1640,1617

(X) (R ² -R ⁵ «= H)

Reference example number R ¹ Physical characteristics 20th CH3 (CH2) 3- · m.p. 97-99'C 21st 4-methylphenyl mp 189-190 'C, 22nd benzyl IR (cm ^4): 3300,1755,1740,1708

23.RefeiBDCiapflda

To a solution of 8.16 g of 1- (methylcarbamoyl) -isatin in 100 ml of tetrahydrofuran is added 7.4 g of 2-ethylisothiourea hydrobromide, and the resulting mixture is stirred at room temperature for 3 hours.

The precipitate was filtered off, washed with water and dried. Thus, 8.0 g of 3-methyl-4-hydroxy-4 - [(2-ethylisothioureido) -carboxyl) -2-oxo-123.4-tetrahydro-m.p. quinazoline is obtained.

24-25. PREPARATION

The following compounds can be prepared from the appropriate starting materials as described in Reference Example 23:

(24) 3- (4-Methylphenyl) -4-hydroxy-4 - [(2-ethylisothioureido) carbonyl] -2-oxo-1,2,3,4-tetrahydroquinazoline, m.p. after recrystallization from a mixture of water, 215-218 ° C; 50 (25) 3- (4-Chlorophenyl) -4-hydroxy-4 - [(2-ethylisothioureido) carbonyl] -2-oxo-1,2,3,4-tetrahydroquinazoline, m.p. -224'C.

Reference Example 26

To a solution of 102 g of 1- (methylcarbamoyl) isatin and 03 g of 1,8-diazabicyclo [5.4.0] -7-undecene in 100 ml of tetrahydrofuran was added 43 g of urea and the resulting mixture was refluxed. Boil for 10 hours. After cooling the reaction mixture, the precipitate was filtered off, washed with water, washed with methanol and finally recrystallized from a mixture of dimethylsulfoxide and ethanol. 3-Methyl-4-hydroxy-4-ureido-carbonyl-2-oxo-123,4-tetrahydro-quinazoline 65 having a melting point above 280 ° C is obtained. MS (m / e): 246 (M + -18).

27.RefcgyqaPflda (1) To a solution of 15 'Con 738 g of 3-methylspiro (133.4-tetrahydroquinazolyl) -N'-imidazolidinyl] trione in 60 ml of dimethylformamide was added 12 g of 60% sodium hydroxide. After stirring for 30 minutes at room temperature, 4.71 g of benzyloxymethyl chloride are added and the reaction mixture is stirred at the same temperature for a further 30 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried and evaporated to give a residue which was crystallized from dinyl formaldamide / water (10.4 g), m.p. methyl-spiro (123.4-tetrahydroquinazoline-4,4'-imidazolidine] is obtained.

JRu '« ⁰ ^« (cm ⁴ ): 3200,3050,1800,1735,1660.

(2) The above product is treated with acetyl chloride as described above (but using a mixture of isopropanol and diisopropyl ether as the solvent for crystallization) to give 3'-acetyl-1- (benzyloxy) m.p. 209211C in 70% yield. methyl 3-methyl spiro (133.4-tetrahydroquinazoline-4,4'-imidazolyl) -22'3'-trione is obtained.

(1) 201 ml of tetrahydrofuran acetate 29.4 g of isatin are added, followed by 30.7 ml of triethylsmium, and 20.9 ml of ethoxymkmbeal chloride are added dropwise with stirring. The reaction mixture was then stirred at room temperature for 5 minutes and then the olive oil was added

-1 427

The mixture was distilled off and water was added to the residue. The precipitated crystals are filtered off, washed with water, isopropanol and diisopropyl ether and dried to give 39.4 g of 1- (ethoxycarbonyl) -isatin, m.p. 113-116 ° C.

The products are identical to the Journal für Praktishe Chemie,

215,339-344 (1973).

(2) 2.79 g of the above product are added to 30 ml of tetrahydrofuran and 1.15 g of urea are added. The reaction mixture was refluxed for 15 hours, then the solvent was distilled off. The residue was extracted with ethyl acetate and the extract was evaporated. The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol = 9: 1). The product-containing fractions were collected and the solvent was distilled off and chloroform was added to the residue. The precipitated crystals were collected by filtration and dried to give 2.42 g of 5- [2- (ethoxycarbonylamino) phenyl] -5-hydroxyimidazolidine-2,4-dione, m.p. 169-170 ° C.

(. 291 Refercnelia 25 (1) 18.16 g of 5-chloroisatin treated with the same procedure as in Reference Example 28, Step 1 (233 g), m.p. 169-172 ° C (decomposed) 5-chlorophenol-ethoxycarbonyl). -isatin (2) is obtained from 53 g of aphentene by treating as described in step 28 (2), 16.74 g of 5- [5-chloro-2- (ethoxycarbonyl) melting point 189-190 ° C. -amino) -phenyl] -5-hydroxyimidazolidine-2,4-dione is obtained

3Q.Forferential (1) Into 150 ml of tetrahydrofuran is added 14.7 g of isatin followed by dropwise addition of 13.9 ml of triethylamine. To the resulting mixture was added dropwise 7.7 ml of methoxycarbonyl chloride and the reaction mixture was treated with lorane at room temperature.

Triethylamine (2.78 mL) and methoxycarbonyl chloride (134 mL) were added and the mixture was stirred for 10 minutes. Ethyl acetate and water were added to the reaction mixture. The precipitated crystals were collected by filtration, dried to yield 163 g of m.p. 178-181 ° C (decomposed) i-methoxycarbonylisate (2). 1436 g of the above product, treated as described in Reference Example 21, Step 2, are 7.79 g. In 50 yields 5- [2- (methoxycarbonylamino) phenyl] -5-hydroxyimidazolidine-2,4-dione, m.p.

Claims (2)

Patent Claims 55 A process for the preparation of a new quinazolinone derivative of formula (I) - in the formula R is hydrogen or C 1-4: Mahnazoalkyl, 60 R ¹ is phenyl substituted with 1 to 4 carbon atoms, phenyl substituted with 1 to 4 carbon atoms, p 'o 6 oc < 6 > halogen or alkyl having 1 to 4 carbon atoms, and phenyl substituted with 1 to 4 carbon atoms; R ² , R ³ , R ⁴ and R ^{5 have the} same or different meanings for hydrogen, halogen, C 1-4 -alkyl or C 1-4 -alkoxy, R ^{3 is} also C 1-5 -carboxy or Or (C 1 -C 5) carbalkoxy vinyl, or two adjacent groups between R, R ³ , R ⁴ and R ⁵ together represent a methylenedioxysopone and the other two hydrogen atoms, and pharmaceutically acceptable salts thereof, wherein: To form a narrower group of compounds of Formula I, compounds of Formula I-4, wherein R ¹ , R ³ , R ⁴ and Statement are as hereinbefore defined, may be prepared by: (a) Compound of Formula (Π) or G9 in the formulas, R ⁶ is an alkyl group having 1 to 4 carbon atoms, Z ¹ is oxygen or sulfur, and R ¹ , R, R ³ , R ⁴ and R ³ are as previously defined - cyclized or (b) alkyl of prepared compound of formula (IV) compound-a: wherein R ⁷ is from 1 to 4 carbon atoms and R, R ^3, R ⁴ and R ^s are as defined above, (V) with an amine-aképletbenR formula ¹ is or reacting a salt thereof or (c) reacting a compound of formula (VI) wherein Z is sulfur or imino, while R ¹ , R, R, R ⁴ and R ⁵ are as defined above. The compound of formula (I) is reacted with a protecting group X and X - wherein X, X is as defined above - and then deprotected to give a compound of formula (Id) - wherein R * is 1-4 ^D , R, R, R ⁴ and R ³ are as defined above - and / or compounds of formula I are synthesized - wherein R ³¹ is halogen, R ⁴¹ is hydrogen or C 1-4 alkoxy, R ⁵¹ is hydrogen or halogen , while R and R ^r have the meanings given above - for the preparation of formula (I)! halogenating one of the compounds of formula Ic, wherein R, R ¹ and R ⁴¹ are as defined above, and optionally forming a compound of formula Ia, Id or Ib into a pharmaceutically acceptable salt thereof. or, if desired, drawing the resulting racemic mixture onto the appropriate pptypodes 2. A process for the preparation of a pharmaceutical composition comprising the compounds of formula I obtained by the process of claim 1 R is hydrogen or C 1-4 alkyl, R ¹ is C 1 -C 4 alkyl, optionally substituted phenyl or unsubstituted phenyl (C 1 -C 4) alkyl optionally substituted by halogen or C 1 -C 4 alkyl, and is a bridging group, and R ² R ³ R ^{4 and} R -15H 200182 Β represents a halogen atom or a halogen atom or a C 1-4 alkyl or C 1-4 alkoxy group, R ^{3 may} also mean a C 1-5 carbalkoxy or C 1-5 carboxyl group, or and two adjacent groups of R, R ³ , R ⁴ and R ⁵ together represent a methylene dicyloxy group and the other two represent a hydrogen atom - or a pharmaceutically acceptable salt thereof in admixture with a carrier and / or excipient conventionally used in pharmaceuticals to form a pharmaceutical composition.