CA2098291A1 - 1-(4-acylaminophenyl)-7,8-methylenedioxy-5h-2,3-benzo- diazepine derivatives and acid addition salts thereof, pharmaceutical compositions containing them and process for preparingsame - Google Patents

Abstract

The invention relates to novel compounds of general formula (I), wherein R stands for hydrogen or a C1-4 alkyl group optionally substituted by a carboxyl or C2-5 alkoxycarbonyl group; and R1 means an aliphatic C1-6 acyl, benzoyl or phenylacetyl group, and the stereoisomers as well as acid-addition salts of these compounds. The invention also relates to pharmaceutical compositions containing the above compounds as well as to a process for the preparation of the novel compounds of general formula (I). The compounds of the invention possess central nervous system effects, more particularly antidepressive and antiparkinsonian action. They are non-mutagenic in the Ames test. Thus, they can be useful for the treatment of depressive illnesses and parkinsonism.

Description

2098~
~092/11262 PCT/HU91/000~3 1-(4-ACYLAMINOPHENYL)-7,8-METHYLENEDIOxy-5H-2,3-~ENZO-DIAZEPINE DERIVATIVES AND ACID ADDITION SALTS THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND P~OCESS FOR
PREPARING SAME

This invention relates to novel 1-(4-acylaminophenyl)--7,8-methylenedioxy-5H-2,3-benzodiazepine derivatives of the general formula (I), H2C~ ~, H~,N--R

I (I) NH-R

wherein R stands for hydrogen or a Cl_4 alkyl group optionally substituted by a carboxyl or C2_5 alkoxycarbonyl group;

and R1 means an aliphatic Cl_6 acyl, benzoyl or phenylacetyl group, as well as their acid-addition salts and pharmaceutical 5 compositions containing these compounds.
Due to the asymmetric C-4 carbon atom, the compounds of the general formula (I) can exist in the form of optically active enantiomers. The invention also relates to the race-' ..:'' ' W092/]1262 PCT/HU9l/000~ `
20~82~1 mates, pure individual enantiomers and any mixture thereof.
According to an other asp~ct of the invention, there is provided a process for the preparation of the new compounds of general formula (I) and acid addition salts thereof.
The aim of the present invention is to provide novel 5H-2,3-benzodiazepine derivatives possessing valuable central nervous system (CNS) effects, namely antidepressive and/or antiparkinsonian action, i.e. showing CNS-stimulating character and more advantageous properties than the 1-(4--aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3--benzodiazepine (see United States patent specification No.
4,835,152), the single 5H-2,3-benzodiazepine derivative known in this therapeutic area.
Now it has been found that the compounds of general formula (I) and their acid-addition salts entirely satisfy the above demands since their effectivity reaches that o~ the known compound mentioned above and, in opposition to the above compound, they proved to be non-mutagenic in the Ames-test.
According to the invention, the novel compounds of general formula (I) are prepared by al) trans~orming a compound o~ the general formula (III) ,~ ~'. . .

~092/11262 2 0 9 8 2 ~J 1 ~CT/HU91/00053 ~CH3 O ~CH2--Cy H2C~ ~ ,N ( III) wherein R is as defined above, to a compound of the general formula (II), H C/~ ~NHR
~O C~ N
1 X ~ (II) NH~
wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, by using an organic or inorganic acid, then acylating the product obtained, optionally without separating it, with a Cl_6 aliphatic carboxylic acid, benzoic or phenylacetic acid or a reactive derivative of these acids; or a2) acylating a compound of the general formula (II), W092/]1262 PCT/HV91/00~--^
20982~1 - 4 -wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, with a Cl_6 aliphatic carboxylic, benzoic or phenylacetic acid or a reactive derivative of these acids; or 5 b) reducing a compound of the general formula (IV), o H C/ ~C - N (IV) NH-R

wherein Rl is as defined above, by using an inorganic or inorganic-organic complex metal hydride in a suitable solvent, to obtain compounds of the general formula (I), wherein Rl is as defined above and R means hydrogen;
and, if desired, alkylating a compound of the general formula (I), wherein Rl is as defined above and R stands for hydro-gen, prepared by using any of the above processes al), a2) or b), with a Cl_4 alkyl halide optionally substituted by a C2_5 alkoxycarbonyl group or with a C2_g dialkyl sulfate in a suitable solvent, in the presence of an acid-binding agent and/or, if desired, hydrolyzing and then treating with an acid a compound of the general formula (I), wherein Rl is as defined above and R stands for a Cl_4 alkyl group substituted \ .
.

j'`'092/112~2 2 Q ~ ~ 2 9 ~ PCT/H~91/000~

by a C2_5 alkoxycarbonyl group, to obtain a compound of the general formula (I), wherein R stands for Cl_4 alkyl substi-tuted by a carboxyl group and/or, if desired, converting a compound of the general formula (I) thus obtained to an 5 acid-addition salt or, conversely, transforming a salt ob-tained to the corresponding free base.
According to a preferred embodiment of the process of the invention, a compound of the general formula (III), wherein R is as defined above, is transformed to a salt by using an organic or inorganic acid and then the salt of the general formula (II) thus obtained, wherein R is as defined above and X represents an inorganic or organic anion, prefer-ably chloride, bromide, hemisulfate or methanesulfonate anion, optionally without separation, is acylated with a Cl_6 aliphatic carboxylic, benzoic or phenylacetic acid or a reac-tive derivative of these acids.
In the salts of general formula (II), the quaternary nitrogen is present in the 7-membered cycle, therefore the aromatic primary amino group is free and can relatively readily be acylated. The acylation can be performed in a suitable solvent or in an excess of the acylating agent. It is particularly preferable to carry out the acylation in an excess of the carboxylic acid anhydride at a temperature between lO C and 50 C. This reaction lasts in general l to 5 hours.
A preferred embodiment of preparing compounds of the general formula (I), wherein Rl is as defined above and R
means hydrogen, comprises reducing a compound of the general ' W092/1]262 pCT/HU91/00~--20~2~ 6 -formula (IV), wherein Rl is as defined above, by using an inorganic or inorganic-organic complex metal hydride in a suitable solvent. For this selective reduction e.g. lithium aluminum hydride, sodium borohydride, potassium borohydride, 5 ~sodium borohydride-aluminum chloride, sodium cyanoboro--hydride, sodium dihydro-bis(2-methoxyethoxy)-aluminate, lithium trimethoxyaluminum hydride or sodium borohydride-triethyloxonium fluoborate may be used as complex metal hydrides. It is suitable to carry out the reduction in water, ethers, alcohols, aromatic hydrocarbons, pyridine or a mix-ture thereof. The use of solvents or solvent mixtures is defined by the reducing agent used in the given case: it should be chosen in such a way that it reacts with the reducing agent very slowly if at all.
According to a particularly advantageous embodiment of the process of the invention, sodium borohydride is used as complex metal hydride, pyridine is employed as solvent and the reduction is suitably carried out at a temperature between 50 C and 115 C.
According to the invention, compounds of the general formula (Ij, wherein R stands for C1_4 alkyl unsubstituted or substituted by a C2_5 alkoxycarbonyl group and R1 is as defined above, can preferably be prepared also by alkylating a compound of the general formula ~I), wherein R1 is as defined above and R represents hydrogen, with a C1_4 alkylhalide optionally substituted by a C2_s alkoxycarbonyl group, or with a C2_g dialkyl sulfate in a suitable solvent, prefer-ably dimethylformamide or dimethylacetamide, in the presence ~092/11262 2 ~ ~ 8 2 ~1 PCT/H~91tO005~

of an acid-binding agent such as e.g. an anhydrous alkali metal carbonate or hydrogen carbonate.
Free carboxylic acids can be obtained by the hydrolysis of esters, preferably by using an alkali metal hydroxide in 5 hot 50 % ethanol and liberating the carboxylic acid from its alkali metal salt thus obtained by using an acid, preferably acetic acid.
The transformation of bases of the general formula (I) to their acid-addition salts, suitably to pharmaceutically acceptable acid-addition salts, is carried out in a known way, e.g. by dissolving or suspending the base in an appro-priate solvent and adding the corresponding acid or its solu-tion prepared in a suitable solvent. The salts are separated either directly by filtration or after evaporating the sol-lS vent; if desired, the product obtained is suspended or re-crystallized and/or dried under reduced pressure.
The preparation of the compounds of general formulae (II) and (III) (wherein R is hydrogen) used as starting substances in the process according to the invention is published in the United States patent specification No.
4,835,lS2. The compounds of general formula (IV), wherein Rl is as defined above, are new, and are desribed hereinafter in the Examples.
As mentioned in the introduction, the novel compounds of general formula (I) prepared by the process according to the invention possess significant central nervous system effects.
The pharmacological activity of the compounds will W092/11262 PCT/HU91/000~-20~82~1 - 8 -hereinafter be illustrated by results achieved in animal tests carried out by using mainly the compound of Example 1.
In the comparative investigations 1-(4-amino-phenyl)-4--methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 5 (hereinafter: reference compound; see the United states patent specification No. 4,835,152) was used as reference substance which exerts similar effects but it has proven to be positive in the Ames-test on the TA-98 Salmonella strain after activation.
1. The behavioural effects of the compounds according to the invention were evaluated on male CFLP mice with an average body weight of 20 g (see Table 1) after oral or intraperitoneal treatment, respectively, by using Irwin's method ~Psychopharmacologia, 13, 222 (1968)].
Table 1 Behavioural effects in mice Compound Doses (mg/kg) (Exam~le No.) 100 i.D. 200 ~.o.

20 Reference compound SMA~ SMA ~
stereotypy stereotypy SMA t~ SMA
stereotypy stereotypy

2 transitory SMA

The number of animals was 5 in each group.

SMA: spontaneous motor activity;

''- ' ' ' ' ' .

2~
W092/11262 PCT/HU91/000~3 means increase; ~ means decrease ~: no symptom was observed Based on the above results, behavioural effects being similar to those of the reference compound could be elicited 5 by using the compound of Example 1.
2. The effect of the compound of Example 1 on the _otilitY in mice was more precisely analysed by means of a motimeter functioning on the basis of the capacitive re-sistance principle. The measurement was immediately commenced after the treatment and lasted for 2 hours. The number of animals was at least 12 in each group. The percentage changes determined from the total counts during 2 hours in relation to the vehicle as control are shown in Table 2. The signifi-cance was calculated from the number of counts by using 15 Duncan's test.
Table 2 Effect on the motility in mice ?reatment Doses (mg/kq) i.P. Change % Sianificance Reference compound 3 +2.8 N.S.
+90.6 p<0.01 +318.7 p<0.01 Compound of Example 1 S +8.0 N.S.
+57.8 p<0.05 +69.3 p~0.05 +317.3 p<0.02 N.S.: not significant It is obvious from the data of Table 2 that the moti-lity of mice was similarly increased both by the reference compound and the compound of Example 1.

W092/11262 2 ~ 9 ~ 2 9 1 - lo - -PCT/HU91/OOo~

3. Investi~ation into the antidepre~ive effect in rodents 3.l. Antaqonization of reserDine ~pothermia in mice These examinations were performed in male CFLP mice by 5 using an Ellab thermometer (measurement of the rectal temperature) by the method of AsXew [Life Sci. 2, 725 (1963)]~
The effects of the reference compound and the compound of Example l are shown in Table 3. The measurement was commenced after the treatment by the test substances.
Table 3 Antagonization of reserpine hypothermia in mice Treatment Doses Dlfference in the body temperature in relation to the (mg/kg) reserpine control ~oc) p,o. after _ 0 1 2 3 4 5 6 hours Vehicle - +5.0 +7.7 +6.7 +5.9 +4.9 +4.6 +4.7 Reference25 -0.3 +3.5 +3.7 +3.1 +2.2 +1.7 +1.4 20compound S0 -0.2 +5.5~^ +4.9~ +4.0 +2.9~ +2.6~ +2.3 _ _ _ _ Vehicle - +5.4 +5.3 +3.5 +2.9 +3.0 +2.5 +1.9 Compound 25 -0.3 -0.9 ~1.3 +2.0~ +1.7~ +0.9 +0.8 of 50 -l.S 0 +1.1 +2.5 +1.8~ +1.5~ +0.5 25Example 1 100 -1.8~ +0.5 +2.6~ +4.0~ +4.1~ +2.3~ +1.2 *: p ~ 0.05 **: p ~ 0.01.
The hypothermic effect of reserpine was significantly antagonized by both molecules.

-- .
" '': ` ''. '' ~

W092/11262 ~ n q~ 2~1 PCT/HU91tO00~8 3.2. Porsolt~ te~t in rat~
The escape-directed fight-strengthening effects of the reference compound and the compound of Example l in a state of despair were investigated in male OFA rats by using 5 Porsolt's method [Eur. J. Pharmacol. 47, 379 (1978)]. The pre-selected animals were orally treated 3 times (24, 5 and 2 hours, respectively, before the measurement) with the compounds (see Table 4).
~able 4 Antidepressive effect in rat~ (Porsolt' 9 test) Treatment Dose Increase in the Significance*
(mg/kg) fighting time p . o .
15 Vehicle - - -Reference lO 61.6 % p ~ 0.05 compound 30 lS9.5 % p < O.Ol Vehicle Compound of 3 40.3 % p < 0.05 20 Example l lO 66.8 % p < 0.05 llO.2 % P < O.Ol *: Calculated from the fighting time by using Duncan's test (R.G.D. Steel and J.H. Tonie: Principles and Procedures of Statistics, 2nd Edition, p. 187, McGraw-Hill Book Co.) The compound of Example l exerted in this test an anti-depressive effect being similar to that of the reference compound: it resulted in a significant escape-directed fight-strengthening effect even in an oral dose of 3 mg/kg.

WO9~11262 PCT/HU91/000-~
2 ~ ~ ~ 2 '9 ~

4. Anti-parkinsonian effect in mice [inhibition of the neurotoxicity of N-methyl-4-phenyltetrahydrOpyridine (abbreviated: MPTP)]
These examinations were carried out in male C57 mice

5 with an average bod~ weight of 25 g by using the method of Mayer et al. [J. Neurochem. 47, 1073 (1986)~.
This measurement is based on the fact that MPTP, more particularly the MPP+ ion arising from MPTP through an enzymatic way catalyzed by MAO-B and getting into the neuron via the dopamine-upta~e system, leads to the destruction of dopaminergic cells. Thus, a status being similar to the Parkinson's disease can experimentally be established. This process can be prevented by compounds showing an anti-par-kinsonian action.
The effect of the reference compound and compound of Example l are summarized in Table 5.
Tabl~ 5 Inhibition of the MPTP neurotoxicity in mice 20 Time of administration Reference Compound of of compounds in relation compound Example 1 to the treatment with RelativeN Relative N
MPTP (hour) effect (%) effect (%) X + S.E. X + S.E.
-4 -8 + 2.6 9 1 + 4.2 6 -2 18 + 16 4 8 + 3.5 6 -1 28 + 12 3 20 _ 4* 6 -0.5 32 + 6* 12 37 + 2.8* 12 +0.5 61 + 4* 11 55 + 6* 6 +1 61 + 4* 11 42 + 4.2* 10 +2 43 + 5* 12 25 + 5.2* 4 +4 l9 + 4* 17 ll + 3.4 ll +6 6 + 1.8 12 1 + 1.3 6 . . . _ w092~262 209~2~1 *: Significant difference in relation to the MPTP control N: number of animals Doses: 2 x 30 mg/kg i.p.

r)A _evel (MpTPtcompound) (MP~P) Rslative ef~ect (9~) = x 100 100 - DA level (MPTP) DA: dopamine According to the data of Table 5 both the reference compound and the compound of Example 1 significantly reduce the dopamine-level decrease induced by the treatment with MPTP. This effect of both compounds appear under the effect of treatments both before and after administration of MPTP.
Biochemical investigations were carried out in order to elucidate the action mechanism functioning ln the anti-depressive and anti-parkinsonian as well as stimulatory effects of the compound of Example 1 and appearing in the pharmacological investigations.
The direct dopamine receptor-binding studies gave negative results.
5. nhibition of the do~amine and MPP+ u~take These examinations were carried out on a raw synaptosome preparation from the striatal tissue of the rat brain according to Schacht and Hepter [Biochem. Pharmacol 12, 3412 (1974)] or Javitch and Snyder [Eur. J. Pharmacol~lo6 455 (1985)], respectively. The results are summarized in Table 6.

WO92/11262 2 0 9 ~ 2 9 ~ PCT/H~91/OOo-~

Table 6 The in vitro inhibition of dopamine and MPP+ uptake Compound IC50 (M) Dopamine MPP+

Reference compound 7.6 x 10-6 2.8 x 10-6 Compound of Example 1 8.3 x 10-6 8.8 x 10-6 _ _ _ The reference compound and the compound of Example 1 inhibit the dopamine and MPP+ upake into the neuron with the same effectivity. The pharmacological activity can be e~plained by this biochemical effect.

6. Other central nervous sv~tem eff~cts These measurements were performed in male CFLP mice with a body weight of 20 g.
For the examination of the narcosis-potentiating effect, the animals were orally treated with the test substances and 30 minutes later they received an intravenous dose of 50 mg/kg of hexobarbital inducing narcosis. The pro-longation of the duration of narcosis was measured in relation to the vehicle conrol group.
For investigation of the anticonvulsive effect, a tonic-clonic seizure was induced by electric current (10 mA, 2 sec, 0.4 msec) after 1-hour oral pretreatment. The ceasing of tonic extension of the hind legs was evaluated as an anti-convulsive effect [Swinyard: J. Pharm. Exp. Ther. 106, 319 20~
WO92/11262 ~ 15 - PCT/HU9l/0005 (1952)]. The results are summarized in Table 7.
T~ble 7 Other central nervous ~ystem effects on mic~
Compound Anticonvulsive Narcosis-potentiating effect (ES)effect after an oral oral ED50* dose of 50 mg/kg (mq/kg) Reference compound52 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 %
> 100 152 %

*: Calculated by using probit analysis ES: electric seizure (electroshock) None of the tested molecules reached the anticonvulsive and narcosis-potentiating effect of the reference compound;
however, the compounds of Examples 1 and 2 showed a consider-able activity in the anticonvulsive test.

7. Acute toxicitY in mice The approximating LDso values of the compound of Example 1 (after a single treatment with an observation period of 14 days) are as follows:
oral LD50: > 500 mg/kg Intraperitoneal LDso: ~ 150 mg/kg Summing up, it can be stated that, among the compounds according to the invention, the compound of Example 1 shows WO92/11262 PC~/HU91/000~
209~2~ - 16 -in rodents an antidepressive and anti-parkinsonian effect of the same order as the reference compound. The mechanism of action of both molecules is the same: they selectively inhibit the dopamine uptake (and simultaneously the MPP+) 5 system.
Considering that cerebral depaminergic systems play an actual and essential role in the motivated behaviour, it may be hoped that molecules acting on this system would show a considerable antidepressive effect in man. This supposition is supported by several drug candidates possessing a similar biochemical mechanism of action with a positive effect in man, such as e.g. bupropion [chemically (+)-2-tert-butyl-amino-3'-chloropropiophenone hydrochloride] or amineptine ~chemically 7-tl0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5--yl)aminoheptenoic acid hydrochloride].
On the other hand, the advantageous effect in the MPTP
model of the compound of Example 1, which is similar to that of the reference compound (MPTP induces Parkinson's disease in man, too), indicates the possibility of a human anti-par-kinsonian effectivity.
On the basis of the above pharmacological results, thecompounds of the invention can be used for treating depress-ive conditions and parkinsonism.
For therapeutical use, an indicated oral daily dose is in the range from about 0.05 mg/kg to about 20 mg/kg, prefer-abl~ from 0.1 mg/kg to 10 mg/kg, more preferably 1 mg/kg.
For therapeutical use, the active compounds of the invention are suitably formulated to pharmaceutical composi-2~38291 ~092~11262 - 17 - PCT/HU91/00053 tions by mixing them with nontoxic, inert solid or liquid carriers and/or additives, which are suitable for enteral or parenteral administration and are commonly used in the pharmaceutical industry. Suitable carriers are e.g. water, 5 gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc and vegetable oils. As additives preservatives, wetting (surface-active), emulsifying or dispersing, buffering and aromatizing agents may be used.
By using the above carriers and additives, the active compounds of the invention may be formulated to the usual pharmaceutical compositions, e.g. solid forms (such as mainly tablets, dragées and capsules) as well as to injectable solutions, suspensions and emulsions.
The invention also relates to pharmaceutical compositions containing a compound o~ the general formula (I) or a pharmaceutically acceptable acid-addition salt thereof as active ingredient as well as to a process for preparing these compositions.
The compositions according to the invention can be prepared by commonly known methods.
The invention also relates to a method for treating depressive illnesses and Parkinson's disease. This method comprises administering a therapeutically effective amount o~
an active ingredient of the general formula (I) to the patient in need of such treatment.
The identification of compounds of the invention was performed by element~ry analysis; their purity and structure were proven by thin-layer chromatography (TLC) as well as by WO92/11262 2 0 9 ~ 2 91 PCT/HU91/000~-their IR, lH-NMR and mass spectra. The date of analysis were in accordance with the empirical formula within the limits of error.
The invention is further illustrated by the following 5 non-limiting Exa~ples.
Example 1 1-~4-Acetylaminophenyl)-4-methyl-7,8-methylenedioxy--3,4-dihydro-sH-2,3-benzodiazepine Method A) To a solution containing 6.0 g (20 mmol) of 1-(4-amino-phenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo-diazepine (see United States patent specification No.
4,835,152) in 30 ml of ethyl acetate 1.38 ml (21 mmol) of methanesulfonic acid were added. The crystalline precipitate was filtered and washed with 5 x 5 ml of ethyl acetate. The dry weight oS the product was 7.37 g, m.p.: it sintered above 190 C and weakly decomposed at 210-212 C. The thus-obtained methanesulfonate salt of the starting substance could be acetylated as follows:
7.37 g of the powdered salt were suspended in 110 ml of acetic anhydride, the suspension was stirred at room tempera-ture for 2 hours, then the crystalline precipitate was filtered, washed with 5 x 10 ml of ethyl acetate and dried to give 6.54 g of methanesulfonate salt of the target compound, m.p. 240-241 C (with decomposition).
The base could be liberated from the methanesulfonate salt of the target compound e.g. in the following way: 6.54 g of salt were dissolved in 90 ml of water, the solution was .

~ .
: . .. , .. ,:

2 ~ 9 ~
`'092/11262 PCT/HU91/00053 clarified by charcoal, then 3.6 g of sodium hydrogen car-bonate were portionwise added to the clear solution. The precipitate was filtered, washed with 5 x 10 ml of water and dried to obtain 5.54 g of crude product. After recrystalliza-5 tion from 130 ml of isopropanol, 3.11 g (yield 46 %) ofproduct were obtained, m.p.: 221-223 DC (weak decomposition), the melting point of which was increased to 223-225 C after digesting with 15 ml of hot benzene.

Cl9H19N33 = 337.385 The hydrochloride salt decomposed at 262-264 C.
Method B) After dissolving 15.0 g (44.7 mmol) of 1-(4-acetyl-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-diazepine in 150 ml of pyridine under mild heating, 10.2 g (0.269 mol) of sodium borohydride were added and the mixture was stirred on an oil bath of 100 C temperature for S hours.
Then the reaction mixture was cooled to about 25 C, 150 ml of water were dropwise added under continuous stirring during 20 minutes, thereafter a mixture containing 180 ml of con-centrated hydrochloric acid and 265 ml of water was addedwhile cooling by ice-water. A yellowish suspension was formed. The precipitate was filtered, washed with 5 x 20 ml of water and dried to yield 15.2 g of salt, m.p. above 250 C. In order to liberate the base, this salt was suspended in 150 ml of 50 $ ethanol, 5.7 g of sodium hydrogen carbonate were portionwise added while stirring, then the suspension was filtered after 30 minutes, washed successively with 3 x 10 ml of 50 % ethanol, with 5 x 20 ml of water, finally WO92/11262 PCT/HU91/000,:

2 O~ 20 -with 20 ml of 50 % ethanol and dried to obtain lO.9S g of a crude product, m.p.: 218-220 oc (weak decomposition). After digesting this crude product with 50 ml of hot isopropanol and then with 100 ml of hot 99.5 % ethanol, 8.63 g (57.2 ~) 5 of the aimed compound were obtained, m.p.: 220-222 oc (weak decomposition).
The starting substance was prepared as follows.
10 g (34 mmol) of 1-(4-aminophenyl)-q-methyl-7,8--methylenedioxy-5H-2,3-benzodiazepine were stirred for 3 hours with 100 ml of acetic anhydride. The crystals formed were filtered, washed with SxlO ml of anhydrous ethanol and dried, to yield 9.2 g of raw product, m.p.: 252-254 C
~decomposition). This product was treated with 45 ml of hot 99.5 % ethanol. After cooling the crystals were filtered, washed with 3xlO ml of ethanol and dried to obtain 8.68 g (76.1 %) of 1-(4-acetylaminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine, m.p.: 256-258 C.

Cl9H17N33 = 335-369 Example 2 1-~4-Propionylaminophenyl)-4-methyl-7,8-methylenedioxy--3,4-dihydro-SR-2,3-benzodiazepine Method A) After adding 1.70 g (4.3 mmol) of powdered 1-(4-amino-phenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo-diazepine methanesulfonate to lO ml of propionic acid anhydride, the reaction mixture was stirred at 20 C for 2.5 hours. The precipitated salt was washed with 4 x 5 ml of ethyl acetate and dried to give 1.86 g of product, m.p.:

; :.
.

`'092/11262 - 21 - PCT/HU91/0005 246-248 oc (decomposition). The base was liberated as described in Method A) of Example 1 to obtain 1.36 g of product, m.p.: 226-233 C (weak decomposition). The melting point of this product was increased to 237-239 oc after re-5 crystallization from 40 ml of 99.5 ~ ethanol to give theaimed compound in a yield of 1.8 g (71.5 %).

C20H21N33 = 351-412 The same product was obtained with a yield of 65 ~ by adding first 2.15 mmol of concentrated sulfuric acid, then 4.3 mmol of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy--3,4-dihydro-5H-2,3-benzodiazepine base to the propionic acid anhydride and otherwise working as described above.
Method 3) When starting from 1.65 g (4.72 mmol) of 1-(4--propionylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3--benzodiazepine and otherwise following Method B) of Example 1 (except that alkalinization was carried out by using 40 %
aqueous sodium hydroxide solution and the extraction was per-formed by using benzene) and recrystallizing the crude product from ethanol, 1.2 g (72.3 %) of the aimed product were obtained, m.p.: 235-236 C (weak decomposition).
1-(4-Propionylaminophenyl)-4-methyl-7,8-methylenedioxy--5H-2,3-benzodiazepine used as starting substance was pre-pared in the same way as described above for the 4-acetyl-amino analogue, except that propionic acid anhydride was usedinstead of acetic acid anhydride, m.p.: 228-230 C (decompo-sition).

C20Hl9N33 = 349.396.

WO92/11262 PCT/HU91/~OOQ
2~98231 Examples 3 to 5 The compounds of Examples 3 to 5 were also prepared as described in Method B) of Example 1.
EX ample 3 1-(4-~enzoylaminophenyl)-4-methyl-7,s-methylenedioxy--3,4-dihydro-5X-2,3-benzodiazepine C24H21N33 = 399-456; it decomposes at 247-248 C.
The 1-(4-benzoylaminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine used as starting substance was obtained as follows.
1.0 ml ~15 mmol) of benzoyl chloride and 2.1 ml (15 mmol) of triethylamine were added to a solution of 4 g (13.6 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H--2,3-benzodiazepine in dichloromethane and the reaction mixture was stirred at 25 C for 24 hours. The solution was extracted with 3x30 ml of water, 3x20 ml of a 4 % aqueous sodium hydroxide solution and finally with 2x30 ml of distilled water. The organic layer was dried, evaporated at reduced pressure, then the crystalline residue was treated with 20 ml of hot ethanol to yield 3.97 g of raw product, m.p.: 242-243 C. This raw product was repeatedly treated with 20 ml of hot ethanol, next day it was filtered at 0-5 C, washed with 3x3 ml of ethanol and dried at 100 C to obtain 3.85 g (71.3~) of a pure product, m.p.: 246-247 C
(decomposition).

C24Hl9N33 = 397.40 .

WO92/11262 2 ~ 9 8 2 91 PCT/HU9l/00053 Example 4 4-Methyl-7,8-methylenedioxy-1-(4-phenylacetylamino--phenyl)-3,4-dihydro-5H-2,3-benzodiazepine C25H23N3O3 = 413.483; it decomposes at 213-215 C.
The 4-methyl-7,8-methylenedioxy-1-(4-phenylacetylamino-phenyl)-5H-2,3-benzodiazepine used as starting substance was prepared in the following way.
After adding 0.7 g (3.4 mmol) of DCC and 0.46 g (3.4 mmol) of phenylacetic acid to the solution of 0.5 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H--2,3-benzodiazepine in 30 ml of anhydrous methylene chloride, the mixture was stirred at 25 C for 48 hours and filtered.
The precipitate was combined with the evaporation residue of the filtrate and purified by chromatography on silica gel, by using a 4:1 mixture of ethyl acetate-methanol as eluent. The fractions containing the aimed product were evaporated, the residue was boiled with 5 ml of ethanol, cooled down and filtered to obtain 0.60 g (87.72 %) of the aimed product, m.p.: 245-247 C (decomposition).
Example 5 4-Methyl-7,8-methylenedioxy-1-(4-pivaloylaminophenyl)--3,4-dihydro-5H-2,3-benzodiazepine C22H2sN303 = 379.466; it decomposes at 134-136 C.
The 4-methyl-7,8-methylenedioxy-1-(4-pivaloylamino-phenyl)-5H-2,3-benzodiazepine used as starting substance was prepared in the following manner.
1.56 ml (11.2 mmol) of triethylamine and 1.38 ml (11.2 mmol) of pivaloyl chloride were added to a solution of 3 g WO92/l1262 2 ~ 9 ~ ~ 91 PCT/HU91/ooo}~

(10.2 mmol) of 1-(4-aminophenyl)-4-methyl-t,8-methylenedioxy--5H-2,3-benzodiazepine in 160 ml of dichloromethane and the reaction mixture was stirred at 25 C for one hour. The precipitate formed was filtered, washed with 3x5 ml of di-5 chloromethane, then wi.h 3x20 ml of water and dried to give1.59 g of the pure product, m.p. 225-227 oc (decomposition).
The other portion of the product was isolated from the organic phase. The filtrate was extracted with 3x20 ml of water, then with 3x15 ml of 4 % aqueous sodium hydroxide solution, finally with 2x30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressure.
The crystalline residue was combined with the former 1.59 g of the product and suspended in 20 ml of hot ethanol. The product was filtered after cooling, washed with 3x3 ml of 15 ethanol and dried to obtain 3.38 g (87.8 %) of the pure product, m.p.: 225-227 C.

C22H23N33 = 377 450 Example 6 1-~4-Acetylaminophenyl)-3-ethoxycarbonylmethyl-4-methyl-7,8-methylenedioxy-3,~-dihydro-5~-2,3--benzodiazepine 1.26 g (3.7 mmol) of the target compound of Example 1 were dissolved in 5 ml of pure dimethylformamide, then 0.51 g (3.7 mmol) of potassium carbonate (anhydrized by heating) and 25 0.42 ml (3.7 mmol) of ethyl bromoacetate were added while stirring. The reaction mixture was stirred at room tempera-ture for 6 hours. Next day the crude product was precipitated by adding 50 ml of water. After filtration, washing with WO92/11262 2 ~ n ,, ,~J ~ 1 PCT/HU91/000~3 5 x 4 ml of water and drying, the crude product weighed 1.36 g. This product was purified by column chromatography on Kieselgel GO by using a 4:1 ethyl acetate/benzene mixture for elution. Ater recrystallization from 10 ml of 50 % ethanol, 5 1.05 g (67 %) of the aimed product were obtained, m.p.:
156-157 C.

C23H25N35 = 423.477.
Example 7 1-~4-Acetylaminophenyl)-3,4-dimethyl-7,8-methylene-dioxy-3,4-dihydro-SH-2,3-benzodiazepine The process described in Example 6 was followed, except that methyl iodide was used instead of ethyl bromoacetate, the column chromatography was omitted and the crude product was recrystallized first from 50 % and then from 99.5 %
15 ethanol to give the pure aimed compound, m.p.: 207-209 C.

C20H21N33 = 351.412.
Example 8 1-(4-Acetylaminophenyl)-3-ethyl-4-methyl-7,8-methylene-dioxy-3,4-dihydro-5H-2,3-benzodiazepine The process described in Example 7 was followed, except that ethyl iodide was used instead of methyl iodide and the recrystallization was carried out with 50 % ethanol.

C21H23N33 = 365.439; m.p.: 185-187 C.

Example 9 1-(4-Acetylaminophenyl)-3-carboxymethyl-4-methyl-7,8--methylenedioxy-3,4-dihydro-SH-2,3-benzodiazepine 0.59 g (1.4 mmol) of the compound of Example 6 was boiled with 15 ml of 50 % ethanol and 0.10 g (1.8 mmol) of W092/11262 209g2V ~ - 26 - PCr/HU91/0005~

potassium hydroxide under reflux for 30 to 40 minutes. After cooling 0.15 ml (2.5 mmol) of acetic acid was added to the ~iltered, clear solution to liberate the free carboxylic acid which was then separated by filtration after cooling. The 5 acid was washed with 4 x 2 ml of 50 % ethanol and then with 3 x 3 ml of water and dried to obtain 0.45 g (81.3 %) of the aimed product which sintered from 162 C and weakly decomposed at 164-166 C.

C21H21N35 = 395.423.
Example 10 Preparation of pharmaceutical compositions a) Divided (grooved) tablets containing 25 mg of 1-(4--acetylaminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro--5H-2,3-benzodiazepine (compound o~ Example 1) Ingredients of one tablet:
Active ingredient 25.0 mg Magnesium stearate 0.5 mg Stearin 0.5 mg Talc 1.0 mg Gelatin 1.7 mg Microcrystalline cellulose 5.0 mg Maize starch 10.3 mg Lactose 46.0 mg.
b) Dragées containing 12.5 mg o~ 1-(4-acetylamino-phenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo-diazepine W092/11262 2 0 9 ~ 2 ~1 PCT/HU91/000~

Ingredients of one dragée-core:
Active ingredient 12.5 mg Magnesium stearate l.O mg Polyvinylpyrrolidone 5.0 mg Mai7e starch 16.0 mg Lactose 38.0 mg.
The dragée-core was coated with sugar and talc in the usual way and then polished by using bee-wax. Each dragée weighed about lOO mg.

Claims (11)

WO 92/11262 PCT/HU91/0005?

Claims

1. 1-(4-Acylaminophenyl)-7,8-methylenedioxy-5H-2,3--benzodiazepine derivatives of the general formula (I), (I) wherein R stands for hydrogen or a C1-4 alkyl group optionally substituted by a carboxyl or C2-5 alkoxycarbonyl group;
and R1 means an aliphatic C1-6 acyl, benzoyl or phenylacetyl group, and their stereoisomers and acid-addition salts.

2. 1-(4-Acetylaminophenyl)-4-methyl-7,8-methylenedioxy--3,4-dihydro-5H-2,3-benzodiazepine.

3. A pharmaceutical composition, which comprises as active ingredient a novel 1-(4-acylaminophenyl)-7,8--methylenedioxy-5H-2,3-benzodiazepine derivative of the general formula (I), wherein R and R1 are as defined in claim 1, or a pharmaceutically acceptable acid-addition salt thereof in admixture with carriers and/or additives commonly WO 92/11262 PCT/HU91/000??

used in the pharmaceutical industry.

4. A process for the preparation of novel 1-(4--acylamino-phenyl)-7,8-methylenedioxy-5H-2,3-benzodiazepine derivatives of the general formula (I), (I) wherein R stands for hydrogen or a C1-4 alkyl group optionally substituted by a carboxyl or C2-5 alkoxycarbonyl group;
and R1 means an aliphatic C1-6 acyl, benzoyl or phenylacetyl group, and their stereoisomers as well as acid-addition salts, which comprises a1) transforming a compound of the general formula (III) WO 92/11262 PCT/HU91/0005?

(III) wherein R is as defined above, to a compound of the general formula (II), (II) wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, by using an organic or inorganic acid, then acylating the product obtained, optionally without separating it, with a C1-6 aliphatic carboxylic acid, benzoic or phenylacetic acid or a reactive derivative of these acids; or a2) acylating a compound of the general formula (II), WO 92/11262 PCT/HU91/000??

wherein R is as defined above and X means chloride, bromide, hemisulfate or methanesulfonate anion, with a C1-6 aliphatic carboxylic, benzoic or phenylacetic acid or a reactive derivative of these acids; or b) reducing a compound of the general formula (IV), (IV) wherein R1 is as defined above, by using an inorganic or inorganic-organic complex metal hydride in a suitable solvent, to obtain compounds of the general formula (I), wherein R1 is as defined above and R means hydrogen;
and, if desired, alkylating a compound of the general formula (I), wherein R1 is as defined above and R stands for hydro-gen, prepared by using any of the above processes a1), a2) or b), with a C1-4 alkyl halide optionally substituted by a C2-5 alkoxycarbonyl group or with a C2-8 dialkyl sulfate in a suitable solvent, in the presence of an acid-binding agent and/or, if desired, hydrolyzing and then treating with an acid a compound of the general formula (I), wherein R1 is as defined above and R stands for a C1-4 alkyl group substituted WO 92/11262 PCT/HU91/000??

by a C2-5 alkoxycarbonyl group, to obtain a compound of the general formula (I), wherein R stands for C1-4 alkyl substi-tuted by a carboxyl group and/or, if desired, converting a compound of the general formula (I) thus obtained to an acid-addition salt or, conversely, transforming a salt obtained to the corresponding free base.

5. A process as claimed in claim 4, process a1) or a2), which comprises carrying out the acylation with the corresponding carboxylic acid anhydride, preferably in an excess of the carboxylic acid anhydride, at a temperature between 10 °C and 50 °C during 1 to 5 hours.

6. A process as claimed in claim 4, process b), which comprises using lithium aluminum hydride, sodium borohydride, potassium borohydride, sodium borohydride/aluminum chloride, sodium cyanoborohydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium trimethoxyaluminum hydride or sodium boro-hydride/triethyloxonium fluoborate and carrying out the re-duction in a solvent or solvent mixture which is non-reacting or slowly reacting to the complex metal hydride employed.

7. A process as claimed in claim 6, which comprises carrying out the reduction with sodium borohydride in pyridine.

8. A process as claimed in claim 4, which comprises carrying out the alkylation in dimethylformamide, in the presence of an anhydrous alkali metal hydrogen carbonate or carbonate as acid-binding agent.

9. A process as claimed in claim 4, which comprises carrying out the selective hydrolysis of compounds of the general formula (I), containing as R a C1-4 alkyl group substituted by a C2-5 alkoxycarbonyl group, by using an alkali metal hydroxide in hot 50 % ethanol and liberating the free carboxylic acid derivative by acetic acid.

10. A process for the preparation of a pharmaceutical preparation, which comprises mixing as active ingredient a novel 1-(4-acylaminophenyl)-7,8-methylenedioxy-5H-2,3-benzo-diazepine derivative of the general formula (I), wherein R
and R1 are as defined in claim 1, or a pharmaceutically acceptable acid-additon salt thereof, prepared by using any of processes a1) to b) claimed in claim 4, with carriers and/or additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.

11. Method for treating mammals (including man) suffering from a depressive illness or Parkinson's disease, which comprises administering a therapeutically effective amount of an 1-(4-acylaminophenyl)-7,8-methylenedioxy-5H-2,3-benzodiazepine derivative of the general formula (I), wherein R and R1 are as defined in claim 1, or a pharmaceutically acceptable acid-addition salt thereof, to a subject in need of such treatment.