JPH06506442A - 1-(4-acylaminophenyl)-7,8-methylenedioxy-5H-2,3-benzo-diazepine derivatives and acid addition salts thereof, pharmaceutical compositions containing the same, and methods for producing the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 1-(4-acylaminophenyl)-7,8-methylenedioxy-5H-2,3 - benzodiazepine derivatives and acid addition salts thereof, pharmaceutical compositions containing them and Its manufacturing method.

1. Ofuqiu Field The present invention provides novel 1-(4-acylaminophenyl)-7, 8-Methylenedioxy-5H-2,3-benzo-diazepine derivatives.

In the formula, R is hydrogen or optionally carboxyl or C8-alkoxycar is a C1-6 alkyl group substituted with a bonyl group; and R1 is an aliphatic C3 -6 Means an acyl group, benzoyl group or phenylacetyl group. And that and pharmaceutical compositions containing these compounds.

Due to the asymmetric C-4 carbon atom, the compound of general formula (1) is an optically active enantiomer. can exist in the form of The present invention relates to racemates, pure individual enantiomers and their Concerning mixtures.

According to another aspect of the present invention, the preparation of novel compounds of general formula (1) and acid addition salts thereof Provides a method of construction.

It is an object of the present invention to have a valuable central nervous system (CNS) effect, i.e. an anti-depressant have antiparkinsonian and/or antiparkinsonian effects, i.e. have CN5-stimulating properties and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5 H-3,4-dihydro-5H-2,3-benzodiazepine (U.S. Pat. No. 4.83 5,152) and also the single 5H-2 known in this therapeutic area. , a novel 5H-2, which has more advantageous properties compared to 3-benzodiazepines. It provides a 3-benzodiazepine derivative.

Now, the compound of general formula (1) and its acid addition salt satisfy all the above requirements, This is because its effectiveness reaches that of the above-mentioned known compounds, and the above-mentioned compounds On the contrary, the Amesu test showed that the finding was non-mutagenic. It was done.

According to the present invention, the novel compound of general formula (1) has al) an organic acid or an inorganic acid. to form a compound of general formula (111) [wherein R is as described above]. ] Converting into a compound of general formula (II); [wherein R is as described above, and X is chloride, bromide, hemisulfate or means methanesulfonic acid anion] Next, the obtained product is optionally Separation step may be required, C3-6 aliphatic carboxylic acid, benzoic acid or phenylacetic acid or acylated with reactive derivatives of those acids, or C2) general formula (11 ) [wherein R is as above, and X is chloride, bromide, hemisulfate] or methanesulfonic acid anion], aliphatic C1-, carboxylic acid , acylated with benzoic acid or phenylacetic acid or reactive derivatives of these acids; Or, b) Using an inorganic or inorganic-organic composite metal hydride in a suitable solvent, A compound of formula (IV).

[wherein R1 is as above] is reduced, and the above step al), C2) or b) of the general formula (1) (wherein R' is as above and R is water to obtain the compound (which is elementary).

If desired, the general formula (I) [wherein R1 is as described above and R is water] of CI-1 in the presence of an acid binder in a suitable solvent. C1-alkyl halide optionally substituted with a koxycarbonyl group, or is alkylated with CI-a dialkyl sulfate. and/or desired to hydrolyze the compound of general formula (1) (wherein R1 is the above, R is It is a C2-4 alkyl group substituted with an alkoxycarbonyl group of Ct-I) is treated with an acid to form a compound of formula (1) (wherein R is substituted with a carboxyl group). and/or optionally The compound of general formula (I) thus obtained is converted into an acid-addition salt, and conversely, the obtained salt is is prepared by converting the corresponding free base into the corresponding free base.

According to a preferred specific example of the production method of the present invention, general formula (III) (wherein R is the above using an organic or inorganic acid, and then the thus obtained General formula (II) [R is as above, X is an inorganic or organic anion Preferably, chloride, bromide, hemisulfate or methanesulfonic acid C1-, aliphatic carboxylic acid, benzoic acid, without optional separation. Acylation with acid, phenylacetic acid or reactive derivatives of these acids.

In the salts of the general formula (I), the quaternary nitrogen is present in the 7-membered ring and therefore the aromatic The primary amine group is liberated and can be acylated relatively easily. This acylation is Acylation is carried out at temperatures between 10°C and 50°C in a suitable solvent or in an excess of acyl. It is preferable that the This reaction is generally continued for 1 to 5 hours.

-a Formula (■) [wherein R' is as above and R is hydrogen, to produce a compound of l] A preferred specific example is a compound of general formula (IV) [R' is as described above], by using inorganic or inorganic-organic complexes, metal hydrides in appropriate solvents. It is to give back.

For this selective reduction, lithium, aluminum hydride, sodium Mu borohydride, potassium borohydride, sodium borohydride Ride - aluminum chloride, sodium cyanoborohydride, sodium Mu dihydro-bis(2-methoxyethoxy)-aluminate, lithium tri Methoxyaluminum hydride or sodium borohydride Ethyloxonium fluoroborate is used as a composite metal nohydride It can be done. Water, ethers, alcohols, aromatic hydrocarbons, pyridines or It is appropriate to carry out the reduction in a mixture thereof. solvent or solvent mixture The use of a product is determined by the reducing agent used in a given case: it is It should be chosen so that it reacts with the reducing agent very slowly and very slowly.

According to a particularly advantageous embodiment of the process according to the invention, sodium borohydride is used as a composite metal hydride, pyridine is used as a solvent, and Thus, the reduction reaction was suitably carried out at temperatures between 50°C and 115°C.

According to the present invention, general formula (I) [R is an unsubstituted C1-, alkyl group or C is a C+-a alkyl group substituted with 1-5 alkoxycarbonyl group, R1 is as above] Compounds of general formula (1) [R' is as above, R is hydrogen] optionally substituted with an alkoxycarbonyl group of Ct-s. C1-1 alkyl halide or Cm-s dialkyl sulfate Preferably, dimethyl 7-olamide or dimethyl acetate is added in a suitable solvent. In the toamide, for example, acids such as anhydrous alkali metal carbonates or hydrogen carbonates are added. It can be suitably produced by alkylation in the presence of a binder.

The free carboxylic acid is obtained by hydrolysis of the ester, preferably 50% using an alkali metal hydroxide in warm ethanol, and the resulting alkali The carboxylic acid is liberated from the metal salt by using an acid, preferably acetic acid. It can be obtained by

converting the base of general formula (1) into its acid-addition salt, suitably for pharmaceutical use; The base can be converted into a usable acid-addition salt by known methods, e.g. , dissolved or suspended in a suitable solvent and the corresponding acid or its prepared This is done by adding the solution into a suitable solvent. The salt is - optionally, directly or after evaporation of the solvent. The resulting product is suspended or recrystallized and/or dried under reduced pressure. Ru.

General formulas (II) and (Ill) used as starting materials in the process according to the invention (wherein R is hydrogen) as described in U.S. Pat. No. 4,835,152 There is. The compound of general formula (IV) [wherein R1 is as above] is novel. The details are explained below in the examples.

As explained above, the novel compound of general formula (1) produced according to the present invention is , has significant central nervous system effects.

The pharmaceutical activity of the compound will be explained below mainly based on the results of the experiments carried out using the compound of Example 1. This can be demonstrated by the results obtained in physical experiments. In a comparative study, 1-(4-amino phenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H -2,3-benzodiazepine (hereinafter referred to as reference compound; U.S. Patent No. 4.835,15) (see No. 2) was used as a reference compound, but it has a similar effect but has no activity. Ameste on TA-98 Salmonella (Salmonel la) strain after sexualization Test (Ames-test) proved positive.

1. The behavioral effects of the compounds of the present invention are: After oral or intraperitoneal treatment, respectively, the method of Irwin [ Psychopharmacologia, 13.222 (1968)] was evaluated on male CFLP mice with an average body weight of 20 g (see Table 1).

Compound dosage (mg/kg) (Example number) 100 i, p, 200 p, o.

Reference compound SMAf SMA↑ stereotypy thunder syndrome I 5 MAt SMA↑ stereotypy thunder syndrome 2 Transient SMA↓φ 5 φ φ The number of animals was 5 in each group.

SMA: spontaneous motor activity; ↑ means increase. ↓ indicates a decrease.

φ indicates that no symptoms are observed.

Based on the above results, it is true that the behavioral effect is the same as that of the reference compound. The compound of Example 1 is used to elicit.

2. The resistance of the compound of Example 1 to the 9th Imperial Order I Award is based on the capacitive resistance principle. was analyzed more precisely using a functional method based on The measurement is performed after the procedure. It started immediately and continued for 2 hours. Number of animals in each group is at least 612 It is. during 2 hours, corresponding to excipient (vehicle) as a control. , the rate of change calculated from the total number is shown in Table 2. Its salience is due to Duncan (D. It was calculated from the counted numbers using the Uncan test.

Todoroki Mata Effect on mouse movement Treatment rIiL-Administration Togoku νk) i9. Change % Significant reference compound 3 +2. 8 N, S.

10+90. 6 p<0.01 30+318. 7 p<0.01 Example 1 (7) 5 +8. ON, S-Compound 10 +57. 8 p<0. 0520+69. 3 p<0.05 From the data in Table 2, it can be seen that the mobility of mice was significantly lower for both the reference compound and the compound of Example 1. It is clear that there has been an increase as well.

These studies were conducted in male CFPL mice using an Elab body temperature needle (measuring rectal temperature). By being present, Askew (Life Sci, 2.725 (1963)) It was done by the method.

The effects of the reference compound and the compound of Example 1 are shown in Table 3.

The measurements were started after being treated with the test substance.

Boiling Treatment of reserpine hyperthermia in mice, dosage, and reserpine control Difference in body temperature (℃) (mg/kg) after hours p・0・ 0 1 2 3 4 5 6 (hours) Excipient -15.0 +7.7 +687 ◆5.9 +4.9 +4.6 ◆ 4,7 Reference 25 -0.3 +3.5"÷3.7"+3.1"+2.2"41 ．． 7° + 1.4” Compound 50 -0.2 + 5.5° 44.9” 44.0” + 2.9° + 2.6" + 2.3" Excipient - + 5.4 + 5.3 ◆ 3.5 ◆ 2 ．． 9 +3.0 +2.5 +1.9 Example 25 -0.3 -0.9 +1 ．． 3 + 2.0” + 1.7” + 0.9 + 0.81 50-1.5” O÷1 ．． 1 ◆2.5”÷1.8”41.5”40.5 Compound 100-1°8” +0.5 +2.6”+4.0°’44.1°”+2.3°+1.2 Reserpine The hypothermia effect of was significantly antagonized by both molecules.

3.2. Test of Polsolt in rats Reference compound and the compound of Example 1; The effect of reinforcement of the deviant one-way struggle car in the desired state was investigated in male OFA rats. LeSolt's method [Eur, J. Pharmacol, 47.379 (19 78)]. Pre-selected animals were tested 3 times (24 each before measurement). The compound was administered orally (see Table 4).

boiled Treatment Dose Fighting time Salience 9 Reference 10 61.6Z p<0.05 Compound 30 +59.5zp<o, 01 Example 1 3 40.3Z p<o, os's 1 0 66.8Z p(0 ,05 Compound 30 110.22 9<0.01" is determined by Duncan's test (R , G., D., 5teel and J.H., Tonie: Pr1nciplesan. d 5tatisLics, 2nd Edition, p, 187. Mc Using Graw-Hill Book Co.), 1 was calculated from the fighting time. It is.

In this test, the compound of Example 1 showed an antidepressant effect similar to that of the reference compound. As a result, even with two orally administered doses of 3 mg/kg, deviations were significantly reduced. The effect of strengthening the opponent's fighting car was remarkable.

4. Handling ticks in mice! [N-methyl-4-phenyltetrahydro Neurotoxic inhibitory properties of pyridine (abbreviated as M　P　TP　P)] These tests were performed by Mayer et al. [J, Neurochem, 47.1073 (19 86)] on male C57 mice with an average body weight of 25 g.

This assay shows that MPTP is transmitted through an enzyme specifically activated by MAO-B. MPP"4-on, which originates from MPTP and enters the nerves through the dopamine uptake system, - Based on the fact that it causes the destruction of pamine-producing cells. Therefore, parkinsonism A similar situation can occur in the laboratory. This process is an anti-Parkinsonian Symptomatic effects can be prevented by certain compounds.

The effects of the reference compound and the compound of Example 1 are shown in Table 5.

[Table 51 Reference compounds for MPTP treatment by MPTP nerves in mice Example 1 Compound Compound administration time Comparative effect (χ) N Comparative effect (Z) N (Time) Xis, E, X Sats, E, --114 -8±2.6 9 1±4 ．． 26-2 18±16 4 8±3.56 -1 28±12 3 20±416 -〇、5 32±6" 12 37±2.8" 12+0.5 61±4° 1 1 55±6116+1 61±46 11 42±4.2° 1°+2 43 ±5” 12 25±5.23 4+4 19±49 17 11±3.4” 11N: Number of animals Dose: 2X30mg/kg i, I).

Comparative effect (%) = IDA level 4 (MPTP + compound) - DA level s (MPTP )l/[100-D^Shuku4 (MPTP)]X 1 0 0 DA = Dopamine According to the data in Table 5, both the reference compound and the compound of Example 1 were treated with MPTP. significantly reduces the decrease in dopamine levels induced by exposure. horny compound This effect appears as a result of treatment both before and after administration of MPTP.

Biochemical investigations have also shown that the compound of Example 1 has anti-depressant and anti-parkinsonian properties. In order to elucidate the activation mechanism that acts due to the stimulatory effect of substances, pharmacological research has also been conducted. It was carried out in order to clarify what is happening.

Studies of direct dopamine receptor binding have yielded negative results.

5. Suppression of dopamine and MPP+ intake These tests were conducted in shaft and hep ( Schacht and Hepter's method (Biochem, Phar macol 12.3411 (1974)] or Javitt and Snyder (J avitch and 5nyder [Eur, J, PharlIlac ol., 106.455 (1985)]. was carried out on rat Cinnabuttum preparations from body tissues. The results are summarized in Table 6. Omitted.

[Table 6 In vitro inhibitory compound of dopamine and MPP” uptake IC, (M) Reference compound 7,6X10-' 2.8X10-' Compound of Example 1 8,3X 10-@8.8X10-' The reference compound and the compound of Example 1 were injected into the nerve. Dopamine and MPP' taken up are suppressed with the same efficiency. Pharmacological activity is This may be explained by biochemical effects.

6. Kame 0 Dojokasa Enjo Yoshu These measurements were performed in male CFLP mice weighing 20 g.

For testing the anesthetic-capacity effect, animals were treated orally with the test substance for 30 min. Later, 50 mg/kg of hexobarbicur-induced anesthesia was administered intravenously. anesthesia Duration prolongation was determined relative to the vehicle control group.

Antispasmodic! To investigate the clinical effect, tonic-clonic AM seizures were observed 1 hour after pretreatment. was induced by an electrical current (10 mA, 2 seconds, 0.4 milliseconds). hind leg tension The cessation of tension extension has been evaluated as an antispasmodic effect [Swinyard et al. yard): J, Pharm, Exp, Ther, 106.319 (1 952)]. The results are summarized in Table 7.

Todoroki Other nervous system effects on mice Compound antispasmodic effect (ES) ED after oral administration of 50 mg/kg. .

(m/k) Orin! Go-bai first-law! -1 reference compound 52 479% (39,7-68,1) 1 195 68% (159.8-237.9) 2 98 159% (77.8~123.5) 3 >100 232% 4 >100 159% 5 >100 152% ES: Electroepileptic seizure (electroshock) All molecules tested are reference Antispasmodic and anesthetic potency effects have not been achieved with the compound. However, Example 1 and Compound 2 showed considerable activity in the antispasticity test.

7. Etatetamadosu 1 exploding dust Approximate LD of the compound of Example 1. The values (after a single treatment with an observation period of 14 days) are: It seems like.

Oral LDis: >500mg/kg Intraperitoneal LDs*”Fl 50r ng/kg Generally speaking, among the compounds according to the invention, the compound of Example 1 The anti-depressant and anti-Birkinsonian effects were shown to be similar to those of the reference compound in dentists. have the same order. The mechanism of action for both molecules is the same and is responsible for dopamine uptake (and At the same time, it selectively inhibits the MPP'') system.

The brain's dopaminergic system plays a real and essential role in motivated behavior With consideration given to achieving the It is expected to exhibit depressant effects. This assumption applies, for example, to bupropion [chemical Specifically, (±)-2-tertiary butyl T minnow 3-chloropropiophenone hydrochloride] or aminebutine [chemically, 7-(10,11-dihydro-5H -dibenzo] a, dl cyclohebuten-5-yl) aminohebutenoic hydrochloride ], which have similar biochemical mechanisms of action that have positive effects in humans. It is supported by several drug candidates.

On the other hand, the beneficial effect of the compound of Example 1 on the MPTP model is similar to that of the reference compound. (MPTP induces Parkinsonism in humans) and (MPTP induces Parkinsonism in humans). It shows the IIF potential of antiparkinsonism effect.

Based on the pharmacological results described in -1-, the compounds of the present invention can It can be used in the treatment of Nson's disease.

For therapeutic use, the indicated daily dosage is approximately 0.05 mg/k g - in the range of about zomg/kg, preferably Q, 1 mg/kg - 10 mg/kg kg, more preferably 1 mg/kg.

For therapeutic use, the active compounds of the invention can be prepared in non-toxic, inert solid or liquid form. suitable for pharmaceutical formulations by mixing with body carriers and/or excipients. Prescribed. They are suitable for parenteral or parenteral administration and usually include Used in the pharmaceutical industry. Suitable carriers include, for example, water, gelatin, lactose. , starch, pectin, magnesium stearate, stearic acid, talc and It is vegetable oil. Additive preservatives include wetting agents (surface active), suspending or dispersing agents, Buffers and pulverizing agents can be used.

By using the excipients and additives mentioned above, the active compounds of the invention can be incorporated into conventional pharmaceutical compositions. For example, in solid form (mainly tablets, dragees and capsules), as well as injectables. It can be incorporated into injection solutions, suspensions, and emulsions.

The present invention provides a compound of general formula (I) or its pharmaceutical use as an active ingredient. pharmaceutical compositions containing acid-addition salts that can Regarding the manufacturing method.

The composition according to the invention can be manufactured by commonly known methods.

The present invention also provides 91 symptoms for depression and Parkinsonism. :5! Regarding the method. this The method comprises administering a therapeutically effective amount of an active ingredient of general formula (I) to such treatment. by administering it to a patient who needs it.

Identification of the compounds of the present invention is carried out by elemental analysis, and purity and structure are confirmed in a thin layer. chromatography (TLC), and its IR1'H-NMR and mass spectra. Proved by Kutle. The data of the analysis were obtained according to the empirical formula within the error limits. It was done.

The invention is further illustrated by the following non-limiting examples.

Example l- 1-(4-acet and 1maZヱgokushi and 4-Tomoe Shi27.8-, /fl-hi?2oki 30 ml of C-3,4-dihydro-5H-2,3-benzodiazepine (Method A) 6. in ethyl acetate. 1-(4-aminophenyl)-4-methylof Og. 8- Methylenedioxy-3,4-dihydro-5H-2゜3-benzodiazepine (U.S. Patent No. 4,835,152) was added to 1°38 ml (21 mmol) of methanesulfate. Added to fonic acid. The crystalline precipitate was filtered and dissolved in 5×5 ml of ethyl acetate. Washed with water. The dry weight of the product was 7.37 g, and the melting point was determined to be above 190°C. It was sintered above and slightly decomposed at 7.210-212°C. Starting material thus obtained The methanesulfonate of could be acetylated as follows.

7.37 g of the powdered salt were suspended in ]110 m acetic anhydride.

The suspension was stirred at room temperature for 2 hours. The crystalline precipitate was then filtered and 5X10 m After washing with 1 liter of ethyl acetate and drying, 6.54 g of methanesulfate of the target compound was obtained. phonate was obtained. Melting point: 240-241°C (decomposed).

The base can be released from the methanesulfonate of target compound a by the following method. Ta. That is, 6.54 g of salt was dissolved in 90 ml of water. Add the solution to charcoal Then, 3.6 g of sodium bicarbonate was added dropwise to the clear liquid. . The precipitate was filtered, washed with 5×10 ml of water and dried to yield 5.54 g of crude A product was obtained. Recrystallize from 130 ml of in-proper tool, 3. l1g (Yield 46%) product was obtained. Melting point: 221-223℃ (weakly decomposes) , after evaporation with 15 ml of hot benzene, its melting point increases to 223-225 °C. It was.

C+JLJmO+=337. 385 Its hydrogen chloride salt is Disassembled.

Method B) In 150 ml of pyridine, 15. Og (44.7 mmol) of 1-(4-a cetylaminophenyl)-4-methyl-7,8-methylenedioxy-5T(-2 , 3-benzodiazepine was dissolved by gentle heating, then 10.2 g (0 , 269 mmol) of sodium borohydride is added and the mixture is heated to The mixture was stirred in an oil bath at 100°C for 5 hours. The reaction mixture is then cooled to about 25°C. 150 ml of water was added dropwise under continuous stirring during 20 minutes, then 180 ml of A mixture of ml of concentrated hydrochloric acid and 265 ml of water was added while cooling with ice water. yellow A colored suspension formed. Filter the precipitate, wash with 5 x 20 ml water and dry. , 15.2 g of salt was obtained. Melting point: 250°C or higher. free the base To do this, this salt was suspended in 150 tnl of 50% ethanol and 5.7 g of sodium bicarbonate was added in portions with stirring and the suspension was dissolved after 30 minutes at - filtered, followed by successive washes with 3 x 10 ml of 50% ethanol, and 5 x 20 ml of 50% ethanol. of water, and finally with 20 ml of 50% ethanol, dried, and 10. 95 g of crude product was obtained. Melting point: 218-220°C (slightly decomposed).

This crude product was mixed with 50 ml of hot improvator tool and 100 ml of hot 99.5% ethanol. After digestion with tanol, 8.63 g (57.2%) of the target compound was obtained. . Melting point: 220-222°C (slightly decomposes).

The starting material was prepared as follows.

10 g (34 mmol) of 1-(4-aminophenyl)-4-methyl-7,8- Methylenedioxy-5H-2,3-benzodiazepine was stirred with acetate anhydride for 3 hours. Stirred. The crystals formed were filtered and washed with 5 x 10 ml of absolute ethanol. After drying, 9.2 g of crude product was obtained. Melting point: 252-254℃ ( decomposition). This product was treated with 45ml of hot 99.5% ethanol. Ta. After cooling, filter the crystals, wash with 3 x 10 ml of ethanol and dry. and 8.68 g (76.1%) of 1-(4-acetylaminophenyl)-4- Methyl-7,8-methylenedioxy-5I (-2,3-benzodiazepine was obtained) It was. Melting point: 256-258°C.

C+eH+-N*O+=335.369 Example 2 l-(4-propionylaminophenyl)-4-methyl-7,8-methylenedio xy-3,4-dihydro-5H-2,3-benzodiazepine 1, 70g (4 , 3 mmol) powder of 1-(4-aminophenyl)-4-methyl-7,8-methy Dioxy-3,4-dihydro-5H-2゜3-benzodiazepine methane After adding the sulfonate salt into 10 ml of propionic anhydride, the reaction mixture was The mixture was stirred at 20° C. for 2.5 hours. Wash the precipitated salts with 4 x 5 ml of ethyl acetate. After cleaning and drying, 1.86 g of product was obtained. Melting point: 246-248℃ ( decomposition). The base is liberated as described in Example 1, Method A) and 1 , 369 g of product were obtained. Melting point: 226-233°C (decomposed). this life The melting point of the product is: 1.8 g (7 After the desired compound was obtained with a yield of 1,5%), the temperature was increased to 237-239 °C. .

C2゜Ht+N*Os=351, 412 The same product was first 1 mol of concentrated sulfuric acid is added, then 4.3 mmol of 1-(4-aminophenyl )-4-Methyl-7゜8-methylenedioxy-3,4-dihydro-5H-2,3 - Add benzodiazepine base to propionic anhydride (others as above) was obtained in a yield of 65%.

Method B) First, 1.65 g (4.72 mmol) of 1-(4-propionylaminophene) Nyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiaze The alkalization was carried out according to method B) of Example 1, but starting from the pins (the alkalization was 0% aqueous sodium hydroxide and extraction with benzene. ), and the crude product was recrystallized from ethanol to yield 1.2 g (72,3 %) of the target compound was obtained. Melting point: 235-236°C (slightly decomposed) .

1-(4-propionylaminophenyl)-4-methyl- used as starting material 7,8-methylenedioxy-5H-2,3-benzodiazepine is the same as above. , 4-acetylamino analogs. That is, propionic anhydride, It was used in place of acetic anhydride.

Melting point: 228-230°C (decomposed).

C1゜H+*N5Os=349.396 Examples 3-5 The compounds of Examples 3-5 were also prepared as described in Example 1, Method B). .

cold nose handstand 1-(4-Benzoylaminophenyl)-4-methyl-7,8-methylene dioxy C-3,4-dihydro-5H-2,3-benzodiazepine Cm<Ht+N5Os =399.456; Decomposes at 247-248°C.

1-(4-Benzoylaminophenyl)-4-methyl-7 used as starting material ,8-methylenedioxy-5H-2,3-benzodiazepine was obtained as follows. It was.

1.0 ml (15 mmol) of benzoyl chloride and 2.1 ml (15 mmol) ) of triethylamine in dichloromethane (4 g (13.6 mmol) of 1- (4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2, 3-Benzodiazepine solution and the reaction mixture was stirred at 25°C for 24 hours. did. Solution with 3 x 30 ml of water and 3 x 30 ml of 4% aqueous Extracted with sodium hydroxide solution and 2×30 ml of distilled water. organic layer Dry, evaporate under reduced pressure and then pour the crystallized residue into 20 ml of hot ethanol. 3.97 g of crude product was obtained. Melting point: 242-243°C . This crude product was treated with 20 ml of hot ethanol. The next day, 0-5 ℃, washed with 3×3 ml of ethanol, dried at 100℃, 3.85 g (71.3%) of pure product were obtained. Melting point: 246-247℃ (Disassembly). C□H+*Nm0s=397. It was 40.

Ken AΔ4 4-Methyl-7,8-methylenedioxy-1-(4-phenylacetylaminophenyl) phenyl)-3,4-dihydro-5H-2,3-penzodiazepine Cm5HssN sO*=413.483i Decomposes at 213-215°C.

4-Methyl-7,8-methylenedioxy-1-(4-phenylenedioxy) used as starting material Nylacetylamine phenyl)-5H-2,3-penzdiazepine is prepared by the following method Manufactured in

0.7 g (3.4 mmol) of DCC and 0.7 g (3.4 mmol) of DCC. 46g (3.4 mmol) 0.5 g (1.7 mmol) of phenylacetic acid in 30 ml of anhydrous methylene chloride. 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy- After addition to the solution of 5H-2,3-benzodiazepine, the mixture was heated at 25°C for 4 hours. Stir for 8 hours and filter. The precipitate is combined with the evaporated residue of the P solution to form a silica gel. Chromatography on a 4:l ethyl acetate-methane column as eluent Purification was performed using a mixture of Evaporate the part containing the desired product The residue was boiled with 5 ml of ethanol, cooled and filtered to 0.5 ml.　60g (87.72%) of the desired product was obtained. Melting point: 245-247℃ (decomposition) Met.

C**H*-NsOs=379,466; decomposes at 134-136°C.

4-Methyl-7,8-methylenedioxy-1-(4-piva) used as starting material roylaminophenyl)-5H-2,3-benzodiazepine is manufactured as follows. It was done.

1.56 ml (11.2 mmol) of triethylamine and 1°38 ml (1 1.2 mmol) of pivaloyl chloride in 160 ml of dichloromethane 3 g (10,2 mmol) of 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzodiazepine solution. reaction The mixture was stirred at 25°C for 1 hour. Pass through the formed precipitate and apply 3X Wash with 5 ml of dichloromethane, then 3 x 20 ml of water. After cleaning and drying, 1.59 g of pure product was obtained. Melting point: 225-227℃ (decomposition). The other part of the product was isolated from the organic phase. -The excess liquid is 3 x 20 ml water, extracted 3 x 10 ml 4% aqueous sodium hydroxide solution and finally with 2 x 30 ml of water. The organic layers are sequentially dried. and evaporated under reduced pressure. The crystalline residue was combined with the previous 1.59 g of product. , suspended in 20 ml of hot ethanol. After cooling, the product is filtered and 3 Washed with 3ml of ethanol, dried, and weighed 3.38g (87.8% ) was obtained. The melting point was 1225-227°C. Cm*H**N5 Os=377. 450 cold nose 6 1.26 g (3.7 mmol) of the target compound of Example 1 was added to 5 ml of pure dimethyl 0.51 g (3.7 mmol) of potassium carbonate. (dehydrated by heating) and 0.42 ml (3.7 mmol) of bromoacetic acid ester. The chill was added with stirring. The reaction mixture was stirred at room temperature for 6 hours. the next day , the crude product was precipitated by adding 50 ml of water. r last, 5 x 4 Washed with ml of water and dried, the crude product weighed 1.36 g. This product is , for column chromatography on Kieselgel Go. It was purified using an ethyl acetate/benzene mixture of 41 as an eluent.

By recrystallization from 10 ml of 50% ethanol, 1.05 g (67%) of The desired product was obtained. Melting point: 156-157°C.

C! IH11NIOI=423. 477 left A down 1-(4-acetylaminophenyl)-3,4-dihydro-7,8-methylenedi Oxy-3,4-dihydro-2,3-benzodiazepine The method of Example 6 was repeated using Column chromatography using methyl in place of ethyl bromide acetate The crude product was first recrystallized from 50% ethanol and then 99% ．． The purified target compound was obtained by recrystallization from 5% ethanol. Melting point; 20 At 7-209°C, C8°8118m01 = 351.412.

cold nose l The method of Example 7 was carried out using ethyl bromide in place of methyl bromide. Re Crystallization was carried out in 50% ethanol. Cm+H,,NIO,=365.4 39, and the melting point was 185-187°C.

cold weather calendar 1-(4-acetylaminophenyl)-3-carboxymethyl-4-methy Example 0.59 g (1.4 mmol) of compound 6 was mixed with 15 ml of 50% ethanol. 0. Boil with 10g (1.8 mmol) of calcium hydroxide, Refluxed for minutes. After cooling, 0°15 ml (2.5 mmol) of acetic acid was added to the The free carboxylic acid is recovered by adding it to the clean solution obtained, and then passing through after cooling. and separated. The acid was washed with 4×2 ml of 50% ethanol and then 3× Washing with 3 ml of water and drying yielded 0.45 g (81.3%) of the desired compound. Ta. It was sintered from 162°C and slightly decomposed at 164-166°C.

Ct+)lt+N5Os=395.423.

Example 10 Manufacture of pharmaceutical compositions a) 25 mg of 1-(4-acetylaminophenyl)-4-methyl-7°8-methyl Tyledioxy-3,4-dihydro-5H-2,3-benzodiazepine (Example A split (slotted) tablet containing compound No. 1).

Ingredients of 1 tablet: Active ingredient 25.0mg Magnesium stearate 0.5mg Stearin 0.　5mg Talc 1.0mg Gelatin 1. 7mg Microcrystalline Cellulose 5.0mg Maize Corn Starch 1 0.3mg lactose 46. Omg b) 12.5 mg of 1-(4-acetylaminophenyl)-4-methyl-7,8 -Methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine sugar coating agent.

l Sugar coating - core components: Active ingredient 12.5mg Magnesium stearate 1.0mg Polyvinylpyrrolidone 5.0mg Maize Corn Starch 16.0mg Lactose 38.0mg Dragee - The kernels are coated with sugar and talc in the usual way, then coated with beeswax. Used and polished. Each dragee weighed approximately 100 mg.

international search report 1. , l-1, ^- Urn book - + lj, PCT/Hυ91100 → ;) 534 hJ HAhJ C14hJ NE X AhJ hJ E X IE front page Continuation of Ji (72) Inventor Bocca, Peter Hungary Bar-1033 Budapest Harler Pe Uzza 18 (72) Inventor Golditz Midone, Holvearts Power Tarin Hungary Bar-1118 Budapest Arcó Hedi Uzza 28 (72) Inventor: Barmoly, Tamash Hungary Bar-1031 Budapest Tomfiteartrum Uzza 27 (72) Inventor Koeroesi, Ieno Hungary Bar-1013 Budapest Attila Uzza 27 (72) Inventor Moravczyk, Imre Hungary Bar-1095 Buda Pestomeshtel Uzza 38 (72) Inventor: Siraki, István Hungary Bar-1054 Buda Pesto Batholi Uzza 12

Claims (11)

[Claims] 1. 1-(4-acylaminophenyl)-7,8-methylenediode of general formula (I) xy-5H-2,3-benzodiazepine derivatives and their stereoisomers and their Acid addition salts. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R is hydrogen or optionally a carbon C1-4 alkoxycarbonyl group substituted with carboxyl or C2-5 alkoxycarbonyl group alkyl group, and R1 is an aliphatic C1-6 acyl group, a benzoyl group, or (means phenylacetyl group) 2.1-(4-acetylaminophenyl)-4-methyl-7,8-methylenedio xy-3,4-dihydro-5H-2,3-benzodiazepine. 3. As active ingredient, a novel 1-(4-acylaminophenyl) of general formula (I) -7,8-methylenedioxy-5H-2,3-benzodiazepine derivative (in the formula, R and R1 are as defined in claim 1) or the pharmaceutically available acid thereof Pharmaceutical preparations in which addition salts are mixed with carriers and/or adducts commonly used in the pharmaceutical industry. composition. 4. a1), using an organic or inorganic acid, general formula (III) ▲ mathematical formula, chemical formula, table etc.▼(III) (wherein, R is hydrogen or optionally carboxyl or is a C1-4 alkyl group substituted with a C2-5 alkoxycarbonyl group ), the compound of general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R is as above, X is an anion of chloride, bromide, hemisulfate or methanesulfonic acid ), and then the resulting product optionally without separation, C1-6 aliphatic carboxylic acid, benzoic acid or phenylacetic acid or those acids acylated with a reactive derivative; or a2) of the general formula (II) (wherein R is As above, X is chloride, bromide, hemisulfate or methanesulfate. (means an anion of phonic acid), C1-6 aliphatic carboxylic acid, benzoic acid or is acylated with phenylacetic acid or reactive derivatives of these acids; or b), general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R1 is as above) compound using an inorganic or inorganic-organic composite metal hydride in an appropriate solvent. and reduction to form the general formula (I) (R1 is as above and R is hydrogen). and, if necessary, the above treatment steps a1), a2) or b1). General formula (I) (wherein R1 is as described above, R is hydrogen) in a suitable solvent in the presence of an acid-binding agent. by a C1-4 alkyl halide optionally substituted with an alkoxycarbonyl group of or alkylated with a C2-5 dialkyl sulfate, and and/or optionally, general formula (I) (wherein R1 is as above) , R is a C1-4 alkyl group substituted with a C2-5 alkoxycarbonyl group A compound of general formula (I) (wherein R is carbon) is hydrolyzed and treated with acid. is a C1-4 alkyl group substituted with a ruboxy group, and /Alternatively, the compound of general formula (I) thus obtained may be subjected to acid-addition. salt or, conversely, the resulting salt into the corresponding free base. Characteristic general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R is , hydrogen or optionally carboxyl or C2-5 alkoxycarbonyl group is a substituted C1-4 alkyl group, R1 is an aliphatic C1-6 acyl group, ben A novel 1-(4-acyl amide) of zoyl group or phenylacetyl group. nophenyl)-7,8-methylenedioxy-5H-2,3-benzodiazepine derivative Methods for producing conductors, stereoisomers thereof, and acid addition salts thereof. 5. In treatment step a1) or a2), the corresponding carboxylic acid anhydride, preferably for 1 to 5 hours at a temperature of 10°C to 50°C in an excess of the carboxylic acid anhydride. 5. The manufacturing method according to claim 4, further comprising performing an acylation treatment. 6. In treatment step b), lithium aluminum hydride, sodium Mu borohydride, potassium borohydride, sodium borohydride Ride/aluminum chloride, sodium cyanoborohydride, sodium Mubis(2-methoxyethoxy)aluminum hydride, lithium Rimethoxyaluminum hydride or sodium borohydride. Using triethyloxonium fluoroborate, non-reactive or non-reactive The reaction takes place in a solvent or solvent mixture that reacts slowly with the composite metal hydride. 5. The manufacturing method according to claim 4, wherein: 7. The reaction is carried out with sodium polyhydride in pyridine. The manufacturing method according to claim 6, characterized in that: 8. Anhydrous alkali metal carbonate as acid-binding agent in dimethylformamide Claim 4, characterized in that the alkylation is carried out in the presence of a salt or a carbonate. Manufacturing method described. 9. R is C1-4 alkyl substituted with a C2-5 alkoxycarbonyl group A compound of general formula (I) containing a group is added to an alkyl metal aqueous solution in hot 50% ethanol. By dissociating the free carboxylic acid derivative with acetic acid using an oxide, The manufacturing method according to claim 4, characterized in that selective hydrolysis is carried out. . 10. As active ingredient, general formula (I) prepared using the treatment method according to claim 4 Novel 1-(4-acylaminophenyl)-7,8-methylenedioxy-5H -2,3-benzodiazepine derivative (wherein R and R1 are as described in claim 1) ) or its pharmaceutically used acid addition salts, which are commonly used in the pharmaceutical industry. and then converting them into a pharmaceutical composition. A method for producing a pharmaceutical composition, characterized in that: 11. 1-(4-acylaminophenyl)-7,8-methylenedi of general formula (I) Oxy-5H-2,3-benzodiazepine derivative (wherein R and R1 are (as described in ) or its pharmaceutically usable acid addition salts as therapeutically effective to treat depressive symptoms or hyperactivity, which is characterized by A method for treating mammals (including humans) suffering from Nsonosis.