JPH0325425B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 5-phenyl-1,3,4,
This invention relates to 5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives. More specifically, the present invention provides novel optically active or racemic 5-phenyl-1,3,4,
This invention relates to 5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives. The invention further relates to pharmaceutical compositions containing the same compounds. Novel 5-phenyl-1,3,
The 4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivative has the following general formula ()
included in In the above formula (), R is hydrogen or carbamoyl. However, when R is hydrogen, the compound of formula () is an optically active compound. Pharmaceutically acceptable acid addition salts of compounds of general formula () are also included within the scope of this invention. As used herein, the term "halogen" refers to
Represents fluorine, chlorine, bromine or iodine. The compound represented by the general formula () of the present invention is 3
General formula with irregular center at position () Optically active or racemic dihydro-
The 1,4-benzodiazepin-2-one derivative is reduced; if desired, the resulting general formula ()
(wherein R is hydrogen) into their acid addition salts; or reacting the compounds with an alkali metal cyanate or phosgene;
Further, the obtained compound is reacted with ammonia; or a compound in which the methyl group at position 1 in the general formula () is changed to hydrogen is reacted with a methylating agent; if desired, the obtained general formula () is further reacted with a methylating agent;
(where R is hydrogen) into their pharmaceutically acceptable acid addition salts. Compounds of general formula () have useful oxygen-induced activity and are substantially free of the sedative effects of related compounds. The most closely related known tetrahydro-
1,4-Benzodiazepin-2-one is unsubstituted at the 4-position and contains a lower alkyl group at the 3-position. These preparation methods are disclosed, for example, in the following documents: DE 1199776 describes the catalytic hydrogenation of the corresponding dihydro derivatives, and according to US Pat. No. 3,522,289 the compounds is, 2
- prepared by intramolecular condensation of aminoacetic acid esters N-substituted by an -amino-benzhydryl group. Austrian Patent No. 283370 discloses a method for cleaving the protecting group of the corresponding 2-amino-benzhydrol derivative acylated with a protected amino acid by acidolysis. On the other hand, Austrian patent no.
According to No. 311356, the compounds are prepared by catalytic hydrogenation from the corresponding aminobenzophenone derivatives acylated with protected amino acids. Finally, Austrian Patent No. 309,439 discloses the resolution of racemic tetrahydro-1,4-benzodiazepin-2-ones with an asymmetric center in the 5-position by salt formation. The present inventors surprisingly found that by reducing a dihydro-1,4-benzodiazepin-2-one derivative containing an asymmetric center at the 3-position, It has been found that novel tetrahydro-1,4-benzodiazepin-2-ones can be prepared whose absolute configuration of the asymmetric center matches that of the asymmetric center at position 3, which is also present in the starting material. The above method for preparing the compounds of the invention is stereospecific. That is, 3S, 3R and 3SR of the general formula ()
Starting from the dihydro compound, the corresponding 3S,
5S; 3R, 5R and 3SR, 5SR tetrahydro compounds can be prepared without each division. The compounds of general formula () used as starting compounds can be prepared by the method described in Austrian Patent No. 281035. Compounds of general formula () can be reduced by reducing agents that can saturate the 4,5-double bond (azomethine group) but do not affect other parts of the molecule. This reduction can be carried out using, for example, metal hydride complexes such as sodium borohydride, combinations of metals and acids such as zinc and acetic acid, or nascent hydrogen, or supported on a support surface as a catalyst. It can also be carried out by catalytic hydrogenation, which can use any conventional metal (for example palladium on charcoal catalyst) or metal oxide (platinum oxide). The reduction of the compound of general formula () can be carried out using an inert organic compound such as an aliphatic alcohol having 1 to 6 carbon atoms (for example, methanol, ethanol) or an aliphatic carboxylic acid having 1 to 6 carbon atoms (for example, acetic acid). Carry out in a solvent. The reaction temperature can vary over a wide range, but is preferably from 0 to 150°C, more preferably about room temperature. The reaction time depends on the starting compounds and solvents used as well as on the reaction temperature and is generally about 1
The time period is from 24 hours to 24 hours, preferably from 0.5 to 8 hours. A compound of general formula () [wherein R is a hydrogen atom] can be converted into an acid addition salt by reacting with the corresponding acid. Preparation of the salt can also be used for the purification of the compound, and in some cases, after recrystallization, the compound of general formula () can be liberated from the resulting acid addition salt by a known method. can. For example, the following acids can be used for the preparation of salts: inorganic acids such as hydrogen halides (e.g. hydrochloric acid, hydrobromic acid), sulfuric acid, phosphoric acid, nitric acid or perhalic acids (perchloric acid); ; Organic carboxylic acids (e.g., formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, salicylic acid, lactic acid, cinnamic acid,
Benzoic acid, phenylacetic acid, p-aminobenzoic acid,
p-hydrobenzoic acid, p-aminosalicylic acid, etc.),
Alkyl sulfonic acids (e.g. methanesulfonic acid, ethanesulfonic acid, etc.), alicyclic sulfonic acids (e.g. cyclohexylsulfonic acid), arylsulfonic acids (e.g. p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, etc.),
Organic acids such as amino acids (eg, aspartic acid, glutamic acid, etc.). Acid addition salts can be prepared in any conventional inert organic solvent that is capable of dissolving the compound of general formula () used as a starting compound, but in which the acid addition salt of the compound is insoluble. In this case, the acid addition salt precipitated from the reaction mixture can be easily separated by conventional methods, for example by filtration. Alternatively, the preparation of acid addition salts can also be carried out in inert organic solvents in which not only the compounds of general formula () but also their acid addition salts are soluble. In this case, the acid addition salt can be precipitated with a nonpolar organic solvent, such as petroleum ether. The compound of general formula () in which R is a hydrogen atom,
Preference is given to reacting them in the form of their acid addition salts with alkali metal cyanates. Compounds of the corresponding general formula () (R ⁴ is hydrogen) are converted to their acid addition salts, preferably their hydrohalides, the resulting salts are separated and treated with an inorganic acid such as acetic acid. After suspending or dissolving in an active organic solvent, the alkali metal cyanate is added to the resulting suspension or solution. As the alkali metal cyanate, for example, potassium or sodium cyanate can be used. Although the reaction temperature can vary over a wide range, it is preferred to carry out the reaction at about room temperature.
Reaction times are generally 0.5 to 10 hours, depending on the starting compounds, solvent and temperature. The reaction of the compound of the general formula () (in which R represents hydrogen) with phosgene is carried out in an inert organic solvent such as an aromatic hydrocarbon (e.g. benzene).
Preferably it is carried out in the presence of an acid binder such as magnesium oxide or sodium bicarbonate. Compounds of general formula () in which R corresponds to a chlorocarbonyl group are treated with a concentrated aqueous ammonium hydroxide solution, or treated with ammonia containing 1 carbon atom.
The treatment is carried out with a solution of an aliphatic alcohol having 1 to 6 carbon atoms, preferably a methanol solution of ammonia, optionally in an inert organic solvent, for example an aliphatic alcohol having 1 to 6 carbon atoms. or,
An ammonia solution can also be added to the reaction mixture obtained when preparing compounds of general formula () in which R is a chlorocarbonyl group. That is, the compound of general formula () does not necessarily need to be isolated before the reaction with ammonia. A compound in which the methyl group at position 1 in the general formula () has been changed to hydrogen can be converted to the compound of the present invention by reacting with a methylating agent. As methylating agents, customary reactants such as methyl halides, preferably methyl iodide or dimethyl sulfate can be used. Before carrying out the methylation, the starting compound is preferably converted into its alkali metal derivative. In this case, the compound is dissolved in an inert organic solvent such as dioxane, dimethylformamide, benzene or toluene;
It is then reacted with an alkali metal, alkali metal hydride or alkali metal amide, preferably sodium, sodium hydride or sodium amide at 0 to 150°C. The alkali metal compound obtained is then reacted with the corresponding methylating agent. New compounds of general formula () can be prepared in good yields and in well-identifiable forms according to the above-described methods.
The results of the chemical analysis are in good agreement with the calculated values. The purity of the compound was controlled by thin layer chromatography. The retention factor (Rf) of the compounds listed in the examples is Stahl.
About GF254 (Merck) silica gel plate,
Measured with a 1:1 mixture of ether and dichloromethane. Detection was performed using 254 nm ultraviolet light. Melting points were determined in an apparatus according to dr. Tottoli (uncorrected values). For structural analysis,
IR, circular dichroism or NMR spectroscopy was used. Racemic or optically active 1,3,4,5-tetrahydro- according to the invention containing two asymmetric centers
The pharmacological properties of 2H-1,4-benzodiazepin-2-one derivatives, in particular their excellent enzyme-inducing activity, significantly reduced sedative effect and low toxicity, are illustrated by the following pharmacological tests. The biological activity and duration of activity of various endogenous and exogenous compounds has a multifunctional role in the liver.
The activity of the NADPH (nicotinamide-adenine dinucleotide phosphate)-dependent oxidase system has a significant influence. A large number of compounds with various pharmacological activities are known that are capable of increasing or inducing the activity of the multifunctional vicarious oxidase system of the liver (see, for example, Sher, S.
P.: Toxicol.appl.Pharmacol. 18 , 780 (1971); G.
J. Mannering: A. Barger's Selected Pharmacological Test Methods
Pharmacological Testing Methods), 51~
119S., Marcel Dekker Inc., New York (1968)
(see ). As is well known, phenobarbital exhibits inducing activity in human diseases caused by defects in the metabolic enzyme system of the liver. Therefore, although the induction activity of phenobarbital is not optimal due to its hypnotic-sedative effects, CzigIer-Najjar and
It can be used with good results in the treatment of Cilbert syndrome and neonatal hyperbilirubinemia [Vessel and JE Page: J.Clin.Invest.
48, 2202 (1969); JT Wilson:
Pediatrics 43 , 424 (1969)]. In order to screen for enzyme-inducing activity, changes in sleep time induced by hexobarbital were measured according to a conventional method. The inducing activity of compounds of general formula () was compared to the corresponding activity of phenobarbital and their sedative effects according to the following test method. Measurement of sleep duration induced by hexobarbital (measurement of enzyme-inducing activity) A) 1 hour and b) 24 hours after pretreatment with the test compound at a dose of 40 mg/Kg (oral administration), each group Hexobabital 60 mg/Kg (intravenous administration) was administered to test animals. Table 1 below shows the mean sleep duration (standard error) and the change (%) with respect to the control group. Measurement of enhanced activity of sodium-barbital (measurement of sedative activity) Since Na-barbital is not metabolized in the liver, enhanced activity of Na-barbital can be considered as a direct CNS effect. Tests carried out [S. Goldschmidt and
R. Wohr: Z.Physiol.Chem. 308 , 9
(1957); DV Parker: J.Pharm.
Pharmac. 27 , 729 (1975)], test animals were pretreated with a test compound at a dose of 20 mg/Kg (intraperitoneal administration) and 1 hour later treated with a test compound at a dose of 100 mg/Kg (intraperitoneal administration).
of Na-barbital was administered. Na-barbital at the administered dose (100 mg/Kg) still does not exhibit an anesthetic effect. The number (%) of animals that fell asleep is shown in Table 2. Acute Toxicity (Oral Administration) Test animals were administered orally the test compound at doses of 250 and 500 mg/Kg and the number of animal deaths was recorded for 14 days.
The results are shown in Table 3. Male CFLP mice weighing 8 to 22 g were used as test animals. [TABLE] [TABLE] [TABLE] [TABLE] Known compounds with oxygen-inducing activity generally exhibit a suppressive effect immediately after administration, resulting in a prolongation of sleep duration. From the data listed in Table 1, it is clear that in the case of the compounds according to the invention the sleep duration measured 1 hour after administration increases only slightly.
In this regard, the compounds of Examples 3, 4 and 5 have the most favorable properties. It can also be seen that phenobarbital increases sleep time by almost three times its original value. 24 hours after administration, the compound according to the present invention exhibits enzyme-inducing activity similar to that of phenobarbital, thus promoting the decomposition of hexobarbital in the body and shortening sleep time. Not only the degradation time of hexobarbital in the liver, but also the sleep duration induced by hexobarbital can be influenced by CNS activity. From Table 2 it can be concluded that the test compounds have a very low, almost negligible sedative effect compared to phenobarbital. Therefore, the main biological action of the compounds according to the invention is enzyme-inducing activity. The data in Table 3 clearly show that the compounds according to the invention are much less toxic than phenobarbital. In short, 24 hours after pretreatment, the novel compound of general formula () according to the present invention exhibits enzyme-inducing activity roughly similar to that of phenobarbital. However, the main advantage of these compounds is that they do not enhance the activity of hexobarbital appreciably or at all (see compounds of Examples 3 to 5) after 1 hour of pretreatment, i.e., they do not enhance the enzyme-inducing activity. There is virtually no unfavorable period of inhibition, which is a general feature of known compounds having the following properties. Another advantage of the compounds of the invention is that they have no sedative activity and are much less toxic than phenobarbital. The compounds of general formula () can be used therapeutically in the form of pharmaceutical compositions containing the compounds as active ingredients and combined with solid or liquid carriers and/or other additives. The compositions are prepared by methods of the pharmaceutical industry known per se. Pharmaceutical compositions can be formulated in a form suitable for parenteral or enteral administration. As carriers there can be used, for example, water, gelatin, lactose, milk sugar, starch, pectin, magnesium stearate, stearic acid, talc, and vegetable oils such as peanut oil or olive oil. The compositions can be solid, e.g., tablets, lozenges, dragees, capsules such as hard gelatin capsules, suppositories, etc., or liquid, e.g., oily or aqueous solutions, suspensions, etc.
It can be prepared into forms such as emulsions, syrups, soft gelatin capsules, oily or aqueous solutions or suspensions for injection. The amount of solid carrier can vary over a wide range, but is preferably between 25 mg and 1 g. The pharmaceutical compositions may also contain conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents, emulsifiers, osmotic salts, buffering agents, flavoring agents, fragrances, and the like.
Optionally further pharmaceutically active compounds can also be included in the formulations of the invention. Preferably, the pharmaceutical composition is formulated in unit doses depending on the desired route of administration. The pharmaceutical compositions are prepared according to conventional methods comprising, for example, sieving, mixing, granulating, pressing or dissolving the ingredients. The resulting composition can be further subjected to conventional methods in the pharmaceutical industry, such as sterilization. The present invention will be further explained with reference to the following examples, but the present invention is not limited to these examples in any way. Example 1 3S,5S-1,3-dimethyl-5-phenyl-
7-chloro-1,3,4,5-tetrahydro-
2H-1,4-benzodiazepin-2-one 3S-1,3-dimethyl-5-phenyl-7-
10 g of chloro-1,3-dichloro-2H-1,4-benzodiazepin-2-one was dissolved in 50 ml of acetic acid, and 5 g of sodium borohydride was added portionwise to the resulting solution while cooling and stirring. Stirring was continued for an additional 30 minutes, after which time the mixture was neutralized with an 8% aqueous sodium hydrogen carbonate solution under ice cooling. The slowly solidifying product was separated, washed with water and then dried. As a result, 9.5 g of the target compound was obtained. Melting point: 102-103°C (after recrystallization from ethanol). Yield: 95.65%. [α] ²⁵ _D = +318.9 (C = 1.03 in chloroform). Analysis Calculated values [for C ₁₇ H ₁₇ N ₂ OCll (molecular weight: 300.79)]: C = 67.88%, H = 5.69%, N = 9.31%; Actual values: C = 67.72%, H = 7.05%, N = 9.47 %. Example 2 3R,5R-1,3-dimethyl-5-phenyl-
7-chloro-1,3,4,5-tetrahydro-
2H-1,4-benzodiazepin-2-one 3R-1,3-dimethyl-5-phenyl-7-
Dissolve 5 g of chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 50 ml of acetic acid and add 5 g of zinc powder to this stirred solution while cooling with water.
g was added. Continue stirring for an additional hour, then
The mixture of zinc and zinc salt was separated, and the acetic acid in the solution was neutralized with an 8% aqueous sodium hydrogen carbonate solution under ice cooling. The slowly solidifying product was separated, washed with water and dried. As a result, 4.28 g of the target compound was obtained. Melting point: 102-104°C (after recrystallization from ethanol). Yield: 86.29%. [α] ²⁵ _D = -322.6 (c = 1.015 in chloroform). Rf=0.58. Analysis Calculated values [as C ₁₇ H ₁₇ N ₂ OCl (molecular weight: 300.79)]: Actual values: C = 67.75%, H = 6.95%, N = 9.35%. Example 3 3S,5S-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,
5-tetrahydro-2H-1,4-benzodiazepin-2-one 3S,5S-1,3-dimethyl-5-phenyl-
7-chloro-1,3,4,5-tetrahydro-
2H-1,4-benzodiazepine-2-one 1.5g
(4.97 mmol) in 10 ml of ethanol and 2 ether
ml and anhydrous hydrochloric acid gas was introduced into this solution. After cooling on ice for 10 minutes, the precipitated hydrochloride was separated and suspended in 10 ml of acetic acid without drying beforehand. 0.5 g (6.16 mmol) of potassium cyanate was added little by little to this suspension while cooling on ice.
The mixture was stirred for 4 hours. Thereafter, 50 g of ice chips were added to the mixture, and the mixture was neutralized with a concentrated aqueous ammonium hydroxide solution. The product solidified by cooling was separated, washed with water and dried. As a result, 1.4 g of the target compound was obtained. Melting point: 208-209°C (after recrystallization from ethanol). Yield: 81.87%. [α] ²⁵ _D = -552.9 (C = 0.897, chloroform). R _f =0.06. Analysis Calculated values [C ₁₈ H ₁₈ N ₃ O ₂ Cl (molecular weight: 343.82)]: C = 62.88%, H = 5.28%, N = 12.22%; Actual values: C = 62.65%, H = 6.68%, N = 12.07%. Example 4 3R,5R-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,
5-tetrahydro-2H-1,4-benzodiazepin-2-one 3R,5R-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5- as starting compound
The procedure described in Example 3 was followed except that 1.5 g of tetrahydro-2H-1,4-benzodiazepin-2-one was used. As a result, the target compound was obtained. Melting point: 207-208℃. [α] ²⁵ _D = +550.4 (c = 1.19 in chloroform). R _f =0.06. Example 5 3RS,5RS-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,
4,5-tetrahydro-2H-1,4-benzodiazepin-2-one 3RS,5RS-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5 as starting compound
The method described in Example 3 was followed except that -tetrahydro-2H-1,4-benzodiazepin-2-one was used to obtain the target compound. Melting point: 241-242℃. R _f =0.06.

Claims (1)

[Claims] 1. Optically active or racemic 5 of the general formula () in which the asymmetric centers at the 3rd and 5th positions have the same absolute configuration
-phenyl-1,3,4,5-tetrahydro-
2H-1,4-Benzodiazepin-2-one derivatives and pharmaceutically acceptable acid addition salts thereof: [In the above formula (), R is hydrogen or carbamoyl. However, when R is hydrogen, the compound of formula () is an optically active compound. ] 2 3RS, 5RS-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,
Compounds according to claim 1 which are 4,5-tetrahydro-2H-1,4-benzodiazepin-2-ones and pharmaceutically acceptable acid addition salts thereof. 3 3R,5R-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,
Compounds according to claim 1 which are 5-tetrahydro-2H-1,4-benzodiazepin-2-ones and pharmaceutically acceptable acid addition salts thereof. 4 3S,5S-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,
Compounds according to claim 1 which are 5-tetrahydro-2H-1,4-benzodiazepin-2-ones and pharmaceutically acceptable acid addition salts thereof. 5 3R,5R-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-
2. Compounds according to claim 1 which are 2H-1,4-benzodiazepin-2-ones and their pharmaceutically acceptable acid addition salts. 6 3S,5S-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-
2. Compounds according to claim 1 which are 2H-1,4-benzodiazepin-2-ones and their pharmaceutically acceptable acid addition salts. 7 Optically active or racemic 5 of the general formula () in which the asymmetric centers at the 3rd and 5th positions have the same absolute configuration
-phenyl-1,3,4,5-tetrahydro-
2H-1,4-Benzodiazepin-2-one derivatives and pharmaceutically acceptable acid addition salts thereof: [In the above formula (), R is hydrogen or carbamoyl. However, when R is hydrogen, the compound of formula () is an optically active compound. ] A pharmaceutical composition for activating a drug-metabolizing enzyme system in the liver, comprising at least one of the above as an active ingredient and an inert solid or liquid pharmaceutical carrier. 8 3RS, 5RS-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1, as active ingredient
A pharmaceutical composition according to claim 7, comprising 4-benzodiazepin-2-one. 9 3R,5R-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4 as active ingredient
- The pharmaceutical composition according to claim 7, comprising a benzodiazepine-2-one. 10 3S,5S-1,3-dimethyl-4-carbamoyl-5-phenyl-5-chloro-1,3,4,5-tetrahydro-2H-1, as active ingredient
A pharmaceutical composition according to claim 7, comprising 4-benzodiazepin-2-one. [In the above formula (), R ¹ represents hydrogen, halogen, trifluoromethyl, or nitro group, R ² represents hydrogen or alkyl having 1 to 6 carbon atoms, and R ³ represents a known optically active or α-amino acid. represents a group, preferably a substituted or unsubstituted lower alkyl group, which ^is normally bonded to the -CH( _NH2 )-COOH group of Methyl, but when R ⁴ represents hydrogen in a racemic compound, R ³ is a group other than alkyl having 1 to 6 carbon atoms. General formula () [In the above formula (), R ¹ , R ² , R ³ and X
is as described above] racemic or optically active 5-phenyl-1,3
-dihydro-2H-1,4-diazepin-2-one derivative and; if desired, the resulting general formula () in which the asymmetric centers in the 3- and 5-positions have the same absolute configuration
(wherein R ⁴ is hydrogen, R ¹ , R ² , R ³ and X are as described above) or optically active 5
-phenyl-1,3,4,5-tetrahydro-
converting the 2H-1,4-benzodiazepin-2-one derivatives into their acid addition salts and/or reacting the same with alkali metal cyanates or phosgene; and, if desired, by reaction with phosgene. The resulting racemic or optically active compound of the general formula () (in which R ⁴ represents a chlorocarbonyl group and R ¹ , R ² , R ³ and X are as described above) is reacted with ammonia, and /or; if desired, the general formula ( ) (wherein R ² represents hydrogen and R ¹ , R ³ , R ⁴ and X are as described above)
with an alkylating agent, and/or; if desired, the asymmetric centers in the 3- and 5-positions have the same configuration (), where R ⁴ is hydrogen; (R ¹ , R ² , R ³ and X are as described above)
racemic or optically active 5-phenyl-1,3,4,5-tetrahydro-2H-1,4 comprising converting the racemic or optically active compounds of
- Process for producing benzodiazepine-2-one derivatives and pharmaceutically acceptable acid addition salts thereof. 12 5-phenyl-1,3 of the general formula ()
-dihydro-2H-1,4-benzodiazepine-
12. The method of claim 11, wherein the reduction of 2-one is carried out using a metal hydride complex, a combination of metal and an acid, or catalytically activated hydrogen. 13. The manufacturing method according to claim 12, wherein sodium borohydride is used as the reducing agent. 14 General formula () (in the formula, R ⁴ is hydrogen,
12. The manufacturing method according to claim 11, wherein the reaction of the compound (R ¹ , R ² , R ³ and X are as described above) with phosgene is carried out in the presence of an acid binder. 15 Reacting the compound of general formula () (in which R ⁴ is a chlorocarbonyl group, R ¹ , R ² , R ³ and X are as described above) with ammonia in an inert organic solvent. , optionally carried out in the reaction mixture obtained during the preparation of the starting compound, and using ammonia as a concentrated aqueous ammonium hydroxide solution or a solution of ammonia in an aliphatic alcohol having 1 to 6 carbon atoms. Manufacturing method described in section.