PT100191B - N-ACYL-2,3-BENZODIAZEPINIC DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESSES FOR THE PREPARATION OF DERIVATIVES AND COMPOSITION, LOCKOUT METHOD AND TREATMENT METHOD - Google Patents

Description

R means an aliphatic acyl group which is optionally substituted by a methoxy, cyano group. carboxyl, amino. alkylamino. Or by one or more halogens, or R 1 is a benzoyl, cyclopropanecarbonyl, alkylcarbamoyl, C 1-5 -alkyl or phenylcarbamoyl group, or R 3 is absent when there is a double bond between the N (3) and C (4) atoms; R 2 is hydrogen, or R 2 is absent when there is a double bond between the N (3) and C means a double bond between the N (3) and C (4) 3 4 atoms when both R 1 and R 2 are hydrogen.

The compounds of formula (I) have useful effects on the central nervous system, particularly muscle relaxant, anticonvulsive and neuroprotective action. Thus, they may be useful for the treatment of various diseases of the central nervous system. -4 *

This invention relates to novel N-acyl-2,3-benzodiazepine derivatives of general formula (I)

wherein R means a C1-6 aliphatic acyl group optionally substituted with. a methoxy, carboxy, amino, alkylamino group. , di (C1-4 alkyl) amino, pyrrolidino, phthalimido or phenyl, or by one or more halogens, or R is a benzoyl, cyclopropanecarbonyl, C1-6 alkylcarbamoyl or phenylcarbamoyl group, or R is absent when there is a double bond between the N (3) and C (4) atoms; R 1 ??? is hydrogen; or R is absent - when there is a double bond between the N (3) and C (4) atoms; R 2 denotes a C 1-3 alkyl group; or 1 ' R 2 and R 2 together signify a methylene group and there is no double bond present between the N (3) and the (4) - atoms. R3

means hydrogen or a C1-6 aliphatic group; R 4 represents hydrogen; an aliphatic acyl group Crg optionally substituted by a methoxy group. cyano. carboxyl. amino. alkylamino, pyridino, pyridino, phthalimido or phenyl, or by one or more halogen atoms as well as a benzoyl, palmitoyl, cyclopropanecarbonyl, C1-5 alkylcarbamoyl or phenylcarbamoyl group, and dashed lines represent valence bonds optionally present provided that there is no double bond between the N (3) and C (4) atoms when both R 3 and R 4 are hydrogen, and stereoisomers thereof, as well as acid addition salts (if possible), and pharmaceutical compositions containing such compounds.

The compounds of formula (I) according to the invention have an asymmetric molecular structure. The general formula (I) refers to all possible individual stereoisomers and their mixtures.

According to another aspect of the invention there is provided a process for the preparation of the novel compounds of formula (I) and their acid addition salts. The object of the present invention is to provide novel compounds of general formula (I) which have a useful activity in the central nervous system (CNS), particularly reiaxant. muscular and / or anticonvulsivahte,

Ip

effect is only known among the 2,3-benzodiazepines, namely 1- (4-aminophenyl) -4-methyl-7S-methylenedioxy-5H-2,3-benzodiazepine, No. 4, 6, 14, 740), also prepared by the present inventors. In the course of a detailed pharmacological screening, however, it was revealed that the above compound was positive in the Ames test, ie, mutagenic. Thus, it is a particular object of the present invention to find novel 2,3-benzodiazepine derivatives which retain their useful muscle relaxant and anticonvulsant activity, but which are negatively tested in the Ames test.

The novel compounds of formula (I), wherein R, R, R, R, R the dotted lines are as defined above, and their acid addition salts? pharmaceutically acceptable salts meet this requirement.

According to the invention, the compounds of formula (I) are prepared by a) acylation of a compound of formula (II)

NH2 /

with a C1-4 aliphatic carboxylic acid optionally substituted by a methoxy, cyano, carboxyl or phenyl group, or by one or more halogen; or with benzoic, cyclopropane carboxylic or palmitic acid or a reactive derivative thereof; and, if desired, reaction of a novel compound of formula (I) thus obtained, wherein R 4 is an aliphatic acyl group substituted by a halogen, a C 1-4 alkylamino, di (C 1-4) alkyl amipa or pyrrolidino, to provide compounds of general formula (I), wherein R 2, R 2 and the dotted lines are as defined above, R 1 means a C 1-6 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxy, phenylalkylamino, (1-4C) alkylamino, pyrrolidino, or one or more halogen; or a benzoyl, cyclopropanecarbonyl or pyridyl group; R 1 and R 1 are absent and a double bond is present between the N (3) and C (4) atoms; b) acylation of a compound of general formula (ΙΠ)

\ CH3

on what

u

R4 is as defined above, with an aliphatic carboxylic acid optionally substituted by a methoxy, cyano, carboxyl or phenyl group, or by one or more halogens; or with benzoic or cyclopropanecarboxylic acid or with a reactive derivative thereof; and, if desired, reaction of a novel compound of formula (I) thus obtained, wherein R4 is a C1-6 aliphatic acyl group substituted by a halogen, a C1-4 alkylamine, di (C1-4 alkyl) amine, or pyrrolidine, to yield compounds of general formula (I), wherein R 1, R 2, R 3, R 4 and the dashed lines are as defined above, R means a C 1-4 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxy, phenyl, alkylamino, C1-4, di (C1-4 alkyl) amino, pyrrolidino or by one or more halogens; or a benzoyl or cyclopropanecarbonyl group; and there is no double bond between the N (3) and C (4) atoms; or c) acylation of a compound of general formula (II) with an N-phthaloylamino acid of general formula (VI),

(VI) Λ)

wherein R is hydrogen or C1-4 alkyl and n is 1 in the case of alpha-amino acids, while R is hydrogen and n is an integer from 2 to 5 in the case of B-amino acids and, if desired, removal of the phthaloyl group, to give compounds of general formula (I) wherein R3 and dashed lines are as defined above, R4 represents hydrogen, R4 denotes a C1-6 aliphatic acyl group substituted by an amino group both R 1 and R 4 are absent and a double bond is present between the N (3) and C (4) atoms; or (d) acylating a compound of formula (III), wherein R 4 is as defined above, with an N-phthaloylamino acid of formula (VI), wherein R 5 is hydrogen or an alkyl group and n is 1 in the case of alpha-amino acids, while R5 is hydrogen and n is an integer from 2 to 5 in the case of B-amino acids and, if desired, removal of the phthaloyl group, to give compounds of general formula (I), wherein R 1 and R 2 are as defined above, R 2 is hydrogen, R 2 is as defined above, and R 2 is a C 1 -C 8 aliphatic acyl group substituted by an amino or phthalimido group and no bond is present between the atoms N (3) and C (4); or (e) reacting a compound of formula (II) with a C1-5 alkyl or phenyl isocyanate isocyanate to give compounds of general formula (I), wherein R2 and the

The dotted lines are as defined above, R is hydrogen, R4 is alkylcarbamoyloxy or phenylcarbamoyl, and R3 are absent and a double bond is present between the N (3) and C (4) atoms; or (f) reacting a compound of formula (III), wherein R4 is as defined above, with a C1-4 alkyl isocyanate or phenyl isocyanate to give compounds of formula of the general formula (I), in which R, R e

The dotted lines are as defined above, R is hydrogen, R 4 is as defined above, except for hydrogen, R is C 1-6 alkylcarbamoyl or phenylcarbamoyl, and a double bond is present between N (3) and C (4) ; or

g) selectively reducing a nitro compound of formula (IV)

in a new compound of general formula (V)

(V) thus obtained using any of the above processes b), d) or f) and reduction of the nitro group of the novel compound thus obtained of formula (V) , wherein R is as defined above, in an amino group, or first reduction of the nitro group and, then, acylation of the thus obtained compound of formula (III), wherein R 4 is hydrogen, using any of processes b), d) or f) above, to give compounds of general formula (I) in

R 1 and R 2 are hydrogen, R 2 and the dotted lines are as defined above and no double bond is present between the N (3) and C (4) atoms; or v J? ? (H) acylating a new compound of formula (I), wherein R 1, R 2, R 3 and the dotted lines are as defined above, R 1 and R 4 signify hydrogen and no double bond is present between the N- (3 ) and C (4), with a C1-6 aliphatic carboxylic acid optionally substituted by a methoxy, cyano or carboxy group or by one or more halogens; or with a benzoic acid; or a reactive derivative thereof, to give compounds of general formula (I), wherein R 1, R 2, R 3 and the dotted lines are as defined above, R 1 and R 4 represent a C 1-8 aliphatic acyl group optionally substituted by a methoxy, cyano or carboxy group or one or more halogens; or a benzoyl group; and no double bond is present between the N (3) and C (4) atoms; or i) reacting a novel compound of formula (I) in which R 1, R 2 and R 3 and the dashed lines are as defined above, R 2 and R 2 are hydrogen and no double bond is present between the N- (3 ) and C (4) with alkyl isocyanate or phenyl isocyanate to give compounds of general formula (I), wherein R 1, R 2 and the dashed lines are as defined, R means a C 1-6 aliphatic acyl group optionally substituted by a methoxy, cyano or carboxy group or by one or more halogens; or a benzoyl group; R is hydrogen; R3 represents a C1-6 alkylcarbamoyl group, or phenylcarbamoyl, and no linkage is present between the N (3) and C (4) atoms; or -13-

j) acylation of a novel compound of formula (I) in which R 1, R 2 and the dotted lines are as defined above, R 1 and R 2 are hydrogen and no double bond is present between N atoms (3) and C (4) with an N-phthaloylamino acid of formula (VI), wherein R 5 is hydrogen or a C 1-4 alkyl group and n is 1 in the case of alpha-amino acids, while R R4 is hydrogen or an integer of 2 to 5. in the case of B- and amino acids and, if desired, removal of the phthaloyl group, to provide compounds of general formula (I), wherein R 1, R 2 and the dotted lines are as defined above, R means an optionally substituted aliphatic acyl group by a methoxy, cyano or carboxy group or by one or more halogens; or a benzoyl group; R 2 ??? is hydrogen; R 2 denotes a C 1-6 aliphatic acyl group substituted by an amino or phthalimido group and a double bond is present between the N (3) and C (4) atoms. and if desired, transformation of a base of formula (I) obtained by any of processes a) to j) above into an acid addition salt. . According to a preferred embodiment of the process of the present invention, the acylation of the compounds of general formulas (I), (II), (III) and (V) can be carried out, preferably with a carboxylic acid, the presence of dicyclohexylcarbodiimide in a suitable solvent, preferably in dichloromethane, in a temperature range of 10 to 30øC for 1 to 25 hours.

, 5S0N

According to another preferred embodiment of the present invention, the compounds of general formulas (I), (II), (III) and (V) may be acylated in a temperature range from zero to 150øC by a suitable reactive acyl derivative , i.e., carboxylic acid anhydride, mixed anhydride or acyl chloride, in the absence of presence of a solvent normally applied in acylations of these types, such as chloroform or dichloromethane, in the absence of an acid binding agent such as triethylamine . If the addition is carried out with isocyanates the reaction is advantageously carried out in dimethylformamide, benzene or dichloromethane in a temperature range of 15 to 100 ° C for 0.5 to 100 hours. The selective reduction of the compound of formula (IV) to the compound of formula (V), wherein R denotes hydrogen, may be carried out by an inorganic or inorganic-organic complex metal hydride, preferably sodium borohydride, in a solvent or mixture of solvents which have none or only little reactivity with the applied complex nietalic hydride. In these reactions an alcohol or pyridine is the solvent of choice. (Similar selective reductions are described in U.S. Patent Nos. 4,442,044 and 4,835,152). The nitro group of the novel compounds of formula (V) is reduced to an amino group by hydrazine or hydrazine hydrate in the presence of a catalyst such as palladium, platinum or Raney nickel in dioxane alcohol, tetrahydrofuran, benzene, dimethylformamide dimethylacetamide or a mixture thereof.

According to a preferred embodiment of the process of the present invention the reduction may be carried out in methanol by hydrazine or hydrazine hydrate in the presence of Raney nickel catalyst in a temperature range of 10 to 65 ° C No. 4,614,740) but, if desired, the reduction and removal of the phthaloyl protecting group described in process d) can be carried out in the same vessel.

N-phthaloylamino acids of general formula (IV) containing a chiral carbon atom, which means a C1-4 alkyl group and n is 1, can be prepared from DL-, L- and / or D- alpha-amino acids.

The compounds of formula (I)

O of the invention, which contain a basic amino group, wherein R4 is hydrogen or R4 and / or R4 signify an amino acid group, can be converted into their acid addition salts by known methods. The preparation of the general formula (II) compounds used as starting materials in the process

No. 4,614,152, that of the compound of formula (III) wherein R 4 is hydrogen, in U.S. Patent No. 4,835,740, while that of compound (IV) is published in French patent specification No. 85.09793. The compounds of formula (III) in which R 4 stands for various acyl groups are novel.

The process for its preparation is described below, before Table 10, or can be synthesized by methods described therein. The preparation of the novel starting compounds of formula (V) is described in the examples.

The (alpha) -amino acid derivatives of formula (VI) are prepared by methods known in the literature (J. Am. Chem. Soc., 35, 133 (1913); 4J, 845 (1919); Berichte der Deutschen Chemischen Gesellschaft 40, 498, 2649 (1907); 46, 1103, 3159 (1913); 47, 3166 (1914) or by known methods using the reaction of potassium phosphate with the required halocarboxylic acid.

The compounds of formula (I) prepared by the process of the present invention have central nervous system (CNS) activity, such as anti-convulsant, muscle relaxant and neuroprotective effects, which can be demonstrated by pharmacological tests.

In the comparative study, 1- (4-amino-phenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (described in U.S. Patent No. 4,646,740, below " compound "), with similar structure and efficacy to the compounds of the invention, was applied as

As already mentioned in the introduction, this compound was shown to be Ames positive in addition to its useful pharmacological properties. In opposition thereto, the compounds of the present invention proved to be negative in the Ames test.

The pharmacological effects of the compounds of general formula (I) are given in Tables 1 to 8. u

The potency of narcosis was tested with 3 oral doses in 10 mice / dose. The EDgg value is the dose that prolongs the narcosis period induced by 50 mg / kg hexobarbital sodium i.v. twice as much in 50% of the animals as compared to the control group treated only with the vehicle. ED50 values were calculated by the Litchfield-Wilcoxon method (J. Pharmacol. Exp. Ther. 96, 99 (1949)) The results are shown in Table 1.

Effect of narcotic enhancer on rats

Compound No. Example No. ED50 P · 0 · mg / kg

Reference Compound 7.4

15 (16) 3.6 18 8.8 39 27.5 42 7.9 44 13.5 45 4.9 46 11.5 48 5-8 u J o 49 9.5 56 12.5-25 62 5 , 2 66 24.0 - 69 15-20 73 4.5 98 5.8 107 6, 25-12.5 108 12.5 -19-

Effect of narcotic enhancer on rats

Compound of

Example No. ED 50 P - ° - mg / kg 09 115 2.5 7.7

The data in Table 1 demonstrate that the efficacy of various compounds is equivalent to or significantly higher than that of the reference compound.

The compounds of Examples 15 (16), 45, 60, 73 and 98 were shown to be particularly potent.

xV

Anticonvulsive effect on rats The anticonvulsant effect of the compounds was measured using the electro-shock test (Swinyard: J. Pharmacol Exp. Ther. 106, 319 (1952), and also using various chemical agents, such as Pentetrazol / Goodman, J. Pharmacol Exp Exp. Ther. 108, 168 (1953), Streptococcus / " Roskovski: J.Pharmacol. Exp. Ther. 129, -7-5 (1960) Bemegride, Nicotine and 4-Aminopyridine.

Test compounds were orally administered in 3 doses to 10 male CFLP rats per dose.

The results are shown in Table 2. -21-

TABLE 2

Anticonvulsive effect in mice

Strychnine KJ Compound of Example No. ES Comb -; " trazol ed50 p · 0 · mg / kg Berne-gride Nicotin 4-AP? Compound of Reference 38 115 87 73 70 43 15 (16) 12.5 37> 200 16 45 9 39 53 17 0> 200> 200> 200 29 42 24 33 38 24 155 34 45 27 44> 100 51 30-80 "7 0 46 20 57 ^ 100 70-80" 100 25-30 48 10.5 35-40 or 49 25 53> 100 30-35 45 28 J 60 24 62 62 12.5 56 25- 50 or 66 42 135 100> 100 100-150 84 69 57> 100 73 16 62 50-100 / 49 53 25 98 8.4 19 20 11 19 13, 5 107 23, 5 120 -22-

. ,; \ TABLE 2 (CONT)

Anticonvulsive effect in mice

Estricinin

Compound of Comb-ED50. Berne. Nicoti 4_Ap

Example No. ES trazol mg / kg gride na 108 27 199 109 21 100 115 17.1 23.9 ES = electroshock 4-AP = 4-aminopyridine

The above data demonstrate that the anticonvulsive effect of various test compounds (from Examples 15, 42, 45, 46, 73, 98, 107, 108, 109 and 115) is higher than that of the reference compound.

5 5 0 λ

Relaxing Muscle Activity in Mice Muscle relaxant activity was measured in two tests. In the Randall tilt test (J. Pharmacol., Exp. Ther. 129, 163 (1960)), the compounds were applied in 3 i.p. doses to 10 CFLP mice per dose.

lj J

O

Relaxing muscle activity in mice

Compound of Example No. ED50 i-P · mg / kg

Reference compound 15 (16) 18 42 45 48 49 60 62 66 73 98 107 108 109 47 23, 5 31 42 35 20.5 36 150 25 52 27 18, 0; > 200 > 200 611 16, 1 * 115 -25-

(Dunham and Miya: J.Am. Pharm.Assoe 46, 208 (1957).) The results obtained with the three compounds selected from higher activity and of the reference compound are shown in Table 4. TABLE 4

Test.rotarod in rats

Compound of ED5q i.p

Example No. mg / kg 24 3.7 8.1 8.6

Reference compound 15 (16) 42 98

Tables 3 and 4 show that various compounds have strong activity. muscle relaxant (compounds of Examples 15, 18, 42, 45, 48, 49, 62, 73, 98 and 115).

or

Ο effect on spinal function was studied with the most active compound (compound of Example 15 or 16) and the reference compound. Table 5 shows the effect on polysynaptic flexor reflexes in cats (Farkas and Kárpáti, Pharm Res. Comm. 20, S1, 141 (1988).

Effect on the spinal flexor reflex

Compound of Example No.

Cumulative doses mg / kg i .v.

Inhibition of flexor reflex in control perception ED50 mg / kg

Reference Compound ui 15 (16) 0.25 12 0.5 30 1, 0 57 2.0 77 0.05 11 0.1 19 0.2 31 0.4 52 0.8 77 0.90 (0, 46-1.76) (0.19-0.62)

The effect of the above compounds on spinal root potentials in cats was tested in animals under spinal immobilization (Farkas et al., Neuropharmacology 21, 16, 1989.)

The results are shown in Table 6.

uj o

TABLE 6

Effect on spinal root potentials in cats

Inhibition of reflexes as a percentage of control

O

Compound Doses i.v. Reflection Reflection Reflection Potential Ex. Cumulative in polysi of the root

Dorsal root number

Compound 0.5 16 Reference 1.0 27 2.0 47 15 (16) 0.1 10 0.2 10 0.4 32 0.8 56 1.4 78

Reference OD5Q values of Reference Compound: 2.20 Compound No. 15 (16): 2.30

ED50 values of inhibition of

Reference Compound: 0.60 Compound No. 15 (16): 0.73 15 0 2 24 2 4 43 4 4 8 1 1 16 3 2 29 5 4 51 11 8 73 14 14 aminosynaptic reflex (1.02-4 , 75) mg / kg. i.v. (1.06-5.01) mg / kg, i.v. polysynaptic reflex: (0.32-1.13) mg / kg, i.v. (0.39-1.37) mg / kg, i.v.

ELETROFISIOLOGICAL TESTS

The inhibitory effects on field potentials induced by electrical stimulation in surviving rat neocortex slices " in vitro " (Fletcher et al., Br. J.Parmaeology 95, 585 (1988) are summarized in Table 7.

go-

vj

Inhibition of field potentials induced in rat meocortex slices Compound of Example No. Concentration μM Inhibition of induced field potentials in% of control IC 50 μM Compound of 10 22 reference 20 39 40 62 30.0 80 73 15 (16) 10 30 20 47 40 69 21, 5 80 82

The NMDA antagonist effect (quisqualate) was tested on rat neocortex slices using the method of Harrison and Simmonds (Br. J. Pharmaco, 84, 381 (1981).) In rat neocortex slices the potential changes Compound-induced CD were inhibited in dose dependence by the reference compound in the concentration range of 10-50 pM.

Example 15 (16) was shown to be twice as active as the reference compound in inhibiting the perfusion response in 2 minutes with 10æM quisqualate.

However, the two molecules were unable to affect the NMDA-induced responses. Therefore, the compound of Example 15 (16) may be considered an excitatory amino acid antagonist of the non-NMDA type, but quisqualate.

ACUTE TOXICITY IN RATZANAS

The acute toxicity data obtained in rats are summarized in Table 8.)

Acute toxicity in rats Example Compound No. Sex Route of administration LD50 mg / kg 15 (16) male i.p. 145 (128-163, 1) male p.o. " 200 female i.p. 140 (122-161) female p.o. 235 (190-291) 42 male i.p. 155 (109.9-218.5: male • o • Q-600 female ip 180 (156.5-207.0) female at 6,000 u At toxic dose levels, the compounds induced a reduction in muscle tone, ataxia , adynamia, and dose-dependent postural loss of loss.The cause of mortality was respiratory failure, developed 1 to 2 hours after ip administration and 10 to 20 hours after oral administration.

Based on the pharmacological results, the compounds of formula (I) according to the invention have significant anticonvulsive, muscle relaxant and excitatory amino acid (neuroprotective) antagonist effects. Thus, they are therapeutically usable for the treatment of epilepsy, as well as various diseases related to skeletal muscle spasms and cerebral ischemia (stroke). The invention also relates to pharmaceutical compositions containing compounds of general formula (I) or their pharmaceutically acceptable acid addition salts as ingredients, thus to the preparation of such compositions.

For therapeutic use, the. active compounds according to the invention are suitably formulated in pharmaceutical compositions by mixing with inert, non-toxic and commonly used solids or liquid pharmaceutical carriers and / or auxiliary materials for enteral or parenteral administration. As carriers, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc or vegetable oils may be used. As auxiliary materials, for example, condoms and wetting agents, as well as emulsifiers, dispersants and flavorings and buffers may be employed.

With the use of the above-mentioned carriers and auxiliary materials, the active agents of the invention can be transformed into the usual pharmaceutical compositions, for example solid compositions (as tablets, capsules, pills or suppositories) or liquid compositions (as aqueous or oily solutions, suspensions , emulsions or syrups), as well as injectable solutions, suspensions or emulsions.

daily dosage of the compounds of the invention commonly arrives at 0.2-1.5 mg / kg body weight, which is administered daily, optionally divided into several doses.

Based on the above facts, the present invention also features: a method of. blocking one or more mammalian amino acid receptor sites. This method comprises administering to the mammal in need of such treatment a pharmaceutically effective amount of the compounds of formula (I); - a method of treating epilepsy in mammals.

This method comprises administering to the mammal in need of such treatment an anti-epileptic amount of the compound of formula (I); - a method of treating skeletal muscle spasms in mammals. This method comprises administering to the mammal in need of such treatment a muscle-releasing amount of the compound of formula (I); - a method of treating cerebral ischemia (stroke) in mammals. This method comprises administering to the mammal in need of such treatment a pharmaceutically effective amount of the compound of formula (I). -35-

The method of the invention was identified by elemental analysis, its purity and structure were controlled and confirmed by thin layer chromatography, IR, 1 H-NMR, 13 C-NMR and mass spectrometry. The invention is illustrated in detail by the following non-limiting Examples. -36-

1- (4-Diacetylaminophenyl) -3-acetyl-4-methylene-7,8-methylenedioxy-4,5-dihydro-3H-2,3-benzodiazepine 2.93 g (0.01 mol) of 1- (4-amino-phenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were refluxed with 20 ml of acetic anhydride for 6 hours. The solution was evaporated under reduced pressure, the residue collected in 2 x 20 ml of anhydrous ethanol the solution was evaporated and the resulting residue (4.55 g) was subjected to column chromatography (adsorbent: Kieselgel 60, eluent: ethyl acetate-benzene 4: 1). The crude product was titrated with 20 ml of warm isopropanol to give 1.44 g (34.4%) of the desired product, m.p. 240-245 ° (slight decomp.) C 23 H 21 N 3 O 5 = 419> 445-37-

Example 2 1- (4-formylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine 3.0 g (10.2 mmol) of 1- (4-amino-phenyl) -4- 1-7,8-methylenedioxy-5H-2,3-benzodiazepine were dissolved in 160 ml of dichloromethane and first 2,75 g (13.3 mmol) of dicyclohexylcarbodiimide, then 0.51 ml (13.3 mmol) of formic acid were added and the reaction mixture was stirred for 2 hours at room temperature. The precipitated N, N1-dicyclohexylurea was filtered, the filtrate was extracted with 2 x 30 ml of distilled water, the organic layer dried and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, filtered and evaporated under reduced pressure. The resulting crude product was recrystallized from 20: 1 of ethanol and 50% to give 2.93 g (89.3%) of the desired product, m.p. 152-154 ° C (slight decomp.). C18 H15 N3 O3 = 321'342

Examples 3 to 7

The compounds of Examples 3 to 7 were prepared by the procedure described in Example 2.

Example 3 1- (4-Cyanoaminophenyl) -4-methyl-7,8-methylenoxydi-5H-2,3-benzodiazepine

C20H16N4O3 = 350 > 380 > Mp 244-243 ° C (decomp)

Example: 4 1- (4-methoxyhexyaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

C 20 H 19 N 3 O 4 = 365.396 m.p. 203-205 ° C

Example 5

O

1- (4-valerylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine. C 22 H 23 N 3 O 3 = 377> 450 P-f 217-219 ° C (decomp)

1- (4-phenylacetaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine C25H21N3O3 = 411.467, m.p. 245-247 ° C (decomp)

Example 7 1- (4-cyclopropanecarbonylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine C21H19N3O3 = 361> 407, m.p. 260-262 ° C (decomp)

Example 8 1- (4-Amino-phenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine 10 g (34 mmol) of 1- (4-aminophenyl) -4- -7,8-methylenedioxy-5H-2,3-benzodiazepine were stirred for 3 hours with. 100 ml of acetic anhydride The formed crystals were filtered, washed with 5 x 10 ml anhydrous ethanol and dried giving 9.2 g of crude product, m.p. 252-254 ° C (decomp.). -40-

-.

This product was treated with 45 ml of hot 99.5% ethanol. After cooling the crystals were filtered, washed with 3 x 10 ml of ethanol and dried to provide 8.68 g (76.1%) of the desired product, mp 256-258 ° C (decomp.). Anal. C 19 H 17 N 3 O 3 = 335> 359 k

Example 9 1- (4-propionylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine C 20 H 19 N 3 O 3 = 349.396, m.p. 228-230 ° (decomp) Was prepared by the procedure described in Example 8.

Example 10 1- (4-pivaloyloxyphenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine 1.56 ml (11.2 mmol) of triethylamine and 1.38 ml 2 mmol) of pivaloyl chloride were added to a solution of 3 g (10.2 mmol) of 1- (4-aminophenyl) -4-methyl-7,8-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 3 x 5 ml of dichloromethane, then with 3x20 ml of water and dried to provide 1.59 g of pure product, m.p. 225-227 ° C (decomp.). The other part of the product was isolated from the organic phase. The filtrate was extracted with 3 x 20 ml of water then with 3 x 15 ml of a 4% aqueous sodium hydroxide solution, finally with 2 x 30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressure. The crystalline residue was combined with the first product of 1.59 g and suspended in 20 ml of ethanol. The product was filtered after cooling, washed with 3.times.3 ml of ethanol and dried to give 3.38 g of (87.8%) of the pure product, mp 225-227øC (decomp.). ^ 3 = 377,450

Benzoylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine 1.0 ml (15 mmol) benzoyl chloride and 2.1 ml (15 mmol) triethylamine were added to a solution of 4 - (4-aminophenyl) -4- (methyl-7,8-methylenoxy-5H-2,3-benzodiazepine in dichloromethane and 4 g (13.6 mmol) The solution was extracted with 3 x 30 ml of water 3 x 50 ml of a 4% aqueous solution of sodium hydroxide and finally with 2 x 30 ml of distilled water The organic layer was dried, evaporated under reduced pressure, then the crystalline residue was treated with 20 ml of hot ethanol to give 3.97 g of crude product, mp 242-243øC. This crude product was repeatedly treated with 20 ml of hot ethanol the next day was filtered and 0-5øC, washed with 3 x 3 ml of ethanol and dried at 100øC to provide 3.85 g (71.3%) of the desired pure product, mp 246-247 ° C (decomp.)

C24 H19 N3 O3 = 397.44

1- (4-palmitoylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine,

Following the procedure described in Example 11, with recrystallization of the crude product from 50% ethanol, the desired pure product was obtained, mp 138-140 ° C. C33 H45 N3 O3 = 531.747

Example 13 1- (4-Phenylcarbamoylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine 0.22 ml (2.04 mmol) of phenyl isocyanate were added to a solution of O, 50 g (1.7 mmol) of N- (4-aminophenyl) -4-methyl-8,8-methylenedioxy-5 H -2,3-benzodiazepine in 4 ml of dimethylformamide and the reaction mixture was stirred at 25 ° C for one hour. It was then diluted with 20 ml of diethyl ether and filtered at 5 ° C.

The crystals were washed with 2 x 5 ml of diethyl ether and dried at 60-100 ° C. 0 0.70 g of crude product result mp 239-240øC (synthesized at 180øC) were refluxed in 15 ml of ethanol, filtered after cooling washed with 3 x 1 4 l of ethanol and dried at 100øC to give , 55 g (78.6%) of the desired product, mp 240-241 ° C (decomp.) C 24 H 20 N 4 O 3 = 412> 456 -44-

O

4- [4- (4-carboxybutylamino) phenyl] -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

A solution of 0.50 g (1.7 mmol) of 1- (4-aminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 30 ml of anhydrous dichloromethane was stirred with 0.18 g (1.87 mmol) of glutaric acid anhydride at 20-25 ° C for 6 hours. The following day the crystals formed were filtered at 0-5øC, washed with 3x2 ml dichloromethane and dried at 60-80øC to provide 0.60 g (87.0%) of the desired pure product, mp 225 DEG- 227 ° C (decomp.) C22H21N305 = 407.434

Example 15 1- (4-Aminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine To a solution of 3.58 g (12.1 mmol) (4-aminophenyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 100 ml of chloroform, first 1.68 ml moles) of triethylamine, then under constant ice cooling with stirring, 1.15 ml (12.1 mmol) of acetic anhydride were added. Stirring was continued for a further 2 hours, then the solution was extracted with 3 x 100 ml of water, the organic layer dried and evaporated under reduced pressure. The crystallized residue was recrystallized from 40 ml of isopropanol to give 350 g (85.7%) of the desired product, m.p. 220-222 ° C. After repeated recrystallization, the m.p. increased to 223-225 ° C.

C19 H19 N3 O3 = 337.385

Hydrochloride: (C 19 H 20 N 3 O 3) Cl: 373, 850, mp 248-252 ° C (decomp.)

Example 16 1- (4-Aminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine To a suspension of 1.91 g 5.37 mmol) of 1- (4-nitrophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (product from Example 27) in 40 ml of methanol, about 0.2 g of Raney nickel catalyst and 1.4 ml (28 mmol) of 100% hydrazine hydrate were added and the reaction mixture was stirred at 20-25Â ° C for 1 h. hour. The starting nitro derivative was dissolved in 10-20 minutes. After filtration, the filtrate was evaporated under reduced pressure, the white crystalline residue washed with 30 ml of distilled water over a filter, washed with 3 x 10 ml of distilled water and dried at 100 ° C to provide 1.50 g of a crude product,

mp 218-220 ° C. This crude product was purified by treatment with 12 ml hot isopropanol. After cooling, it was filtered at 5øC, washed with 3x1 ml of isopropanol and dried at 100øC to provide 1.40 g (77.35%) of a white crystalline powder, m.p. 221-223øC. Based on the analysis and spectra, it is identical to the product of Example 15, obtained by a different procedure.

Examples 17 to 25 The procedure described in Example 16 was followed for the preparation of other 1- (4-aminophenyl) -3R-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3 benzodiazepines of general formula (I).

The data of the prepared products are shown in Table 9.

4

Products of general formula (I) in which R 2 = R 3 = R 4 = H Example No. R pf ° C 17 trifluoroacetyl 215-217 18 propionyl 211-213 19 Valeryl 178-180 20 Pivaloyl 233-235 21 Benzoyl 220-222 22 Phenylacetyl 220-221 23 cyclopropylcarbamoyl 138-140 24 cyanoacetyl 123-126 25 methoxyacetyl 125-127 (d) = decomposition

The novel nitro compounds of formula (V), wherein R = H or an acyl group, used in the preparation of the products of Examples 16 to 25, may be prepared by the processes described in Examples 26 to 36.

Example 26 1- (4-nitrophenyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine To a suspension of 5.0 g (15.5 mmol) known (French patent specification No. 85.09793) in 380 ml of ethanol, first 22.5 ml (0.278 g) mol) of concentrated hydrochloric acid were added with constant stirring, whereby a solution formed in a few minutes, then 11.5 g (0.3 mol) of sodium borohydride were charged into the solution in portions for 30 minutes. Stirring was continued for 15 minutes, then the orange precipitate formed was filtered and extracted into the filter with 4 χ 30 ml of chloroform.

(I.e.

The combined chloroform filtrate was evaporated under reduced pressure, the crystalline residue was brought to a filter with 200 ml of distilled water, then washed with 3 x 20 ml of distilled water and dried at 80-100 ° C to provide 4.90 g (97.2%) of the desired product, mp 162-164 ° C. C r7 H15 N3 04 = 325,331

Example 27 1- (4-nitrophenyl) -3-acetyl-4-methyl-7,8-methidenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

A portion of 2.0 g (6.15 mmol) of the product of Example 26 was stirred with 10 ml of acetic anhydride at 25 ° C for 3 hours, then 50 ml of distilled water were added and stirring was continued for one hour . The yellow precipitate formed was filtered, washed with 3 x 10 ml of distilled water and dried at 80-100 ° C to give 2.6 g of crude product. After recrystallizing from 10 ml of ethanol, 1.94 g (85.8%) of the desired product were obtained, m.p. 140-142 ° C. C19 H17 N3 O5 = 367 > 369 > Γ Φ 7

Example 28 1- (4-nitrophenyl) -3-trifluoroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine To a solution of A portion of 1.5 g (4.61 mmol) of the product of Example 26 in 30 mL of dichloromethane / hydrochloric acid, 0.75 mL (5.3 mmol) of trifluoroacetic anhydride and 0.75 mL (5.3 mmol) of triethylamine were added and the reaction mixture was stirred at 25 ° C for 3 hours. Subsequently the mixture was extracted with 3 x 20 ml of water and the organic layer was foisset and evaporated under reduced pressure. The crystalline residue was treated with 15 mL of hot ethanol, cooled, filtered, washed with 3 x 1 mL of ethanol and dried at 80-100 ° C to provide 1.84 g (94.85%) of the desired compound as a bright yellow crystalline product, mp 165-167 ° C (decomp.) C 19 H 14 F 3 N 3 O 5 = 421.339%

1- (4-nitrophenyl) -3-propionyl] -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

A portion of 1.54 g (4.7 mmol) of the product of Example 26 was stirred with 8 ml of propionic acid anhydride at 25 ° C for 3 hours, then 30 ml of diethyl ether were added and the solution was maintained -dea 0-5 ° C overnight. The precipitate formed was filtered, washed with 3.times.8 ml of diethyl ether and dried to afford 1.32 g (7.37%) of the desired compound as a pale yellow product, m.p. 189-190 ° C. C 20 H19 N 3 O 5 = 381 396

Example 30. 1- (4-nitrophenyl) -3-valer-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine To a solution of one part of 2,5 (7.68 mmoles) of the product of Example 26 in 40 ml of anhydrous dichloromethane, 4.75 g (23 mmol) of dicyclohexylcarbodiimide and 2.88 g (23 mmoles) of n-valeric acid were added and the mixture The reaction mixture was maintained at 25 ° C with intermittent stirring for 24 hours. Then the Î ±, β-dicyclohexylurea formed as a by-product was filtered, the filtrate was evaporated under reduced pressure, the residue was admixed with 2 χ 40 ml of distilled water, decanted,

The wet product was allowed to solidify 50 ml of 50% ethanol. The solid compound was filtered, washed with 2 x 10 ml of 50% ethanol and dried at 80 ° C. The crude product obtained was recrystallized from ethanol (24 mL) and the crystals were dried at 100 ° C to provide 2.20 (70%) of the desired product as a yellow powder, m.p. 145-140 ° C. C22 H23 N3 O5 = 409.450

Example 31 1- (4-nitrophenyl) -3-pivaloyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

Following the procedure described in Example 28, but using pivaloyl chloride instead of trifluoroacetic anhydride, 1.68 g (89.4%) of the desired product were obtained, m.p. 164-166 ° C. C22H23N305 = 409.450

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

Following the procedure described in Example 31, but using benzoyl chloride as the acyl chloride, 1.72 g (86.9%) of the ocher yellow product were obtained, mp 222-224 ° C (decomp.). ^ 24 ^ 19 ^ 3 ^ 5 = ^ 29,440

Example 33 1- (4-nitrophenyl) -3-phenylacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-beozodiazepine.

Following the procedure described in Example 30, but using 50% of the calculated molar amount of dicyclohexylcarbodiimide and phenylacetic acid, a bright yellow product was obtained, mp 193-195 ° C. C25 H21 N3 O5 = 443> 467-54-

Examples 34 to 36

The products of Examples 34 to 36 were obtained following the procedure described in Example 33 and using the respective acid components.

Example 34 1- (4-nitrophenyl) -3-cyclopropanecarbonyl-4-methyl-7,8-methyleedioxy-3,4-dihydro-5H-2,3-benzodiazepine. 225-228 ° C (decomp.) C21 H19 N3 O5 = 393.47

Example 35 1- (4-nitrophenyl) -3-cyanoacetyl-4-methyl-8,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine, mp 185-188 ° C 20 ^ 16 ^ 4 ^ 5 = 392> 380

1- (4-nitrophenyl) -3-methoxyacetyl-4-methyl-7,8-methylenedioxy 3,4-dihydro-5H-2,3-benzodiazepine mp 187-189 ° C C 20 H 19 N 3 O 6 = 396

Example 37 1- (4-nitrophenyl) -3- (4-carboxybutyryl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

Using the product of Example 26 as the starting material and acylation according to Example 14 as glutamic acid anhydride, finally recrystallizing the crude product with ethanol gave the desired pure product, mp 148 DEG- 150 ° C. C22 H21 N3 O7 = 439.434

1- (4-Aminophenyl) -3-phenylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine To a solution of 0.70 g , 3-amino-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 10 ml of anhydrous benzene 24 ml (2.3 mmoles) of phenyl isocyanate were added and the reaction mixture was refluxed for one hour.

Thereafter, the solution was evaporated under reduced pressure and the amorphous residue was mixed with 20 ml of 50% hot ethanol. The slurry was cooled to 0øC and filtered to afford 0.76 g of a crude product, m.p. 190-200Â ° C.

After recrystallization from 99.5% ethanol and titration with ethyl acetate, the desired compound is melted at 207-209 ° C. C24 H22 N4 O3 = 414.472

The preparation of the starting material of this example has been described in the description of Hungarian patent No.198494. However, the compound may also be prepared by a novel method according to the procedure of Example 16, using the compound of Example 26 as the starting material, to provide excellent yields (84%). The crude product can be recrystallized from 50% ethanol, m.p. 118-120 ° C. -57-

2.0 g (6.7 mmol) of 1- (4-diacetylaminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 1- (4-Amino-phenyl) -4-methyl-7,8-methyleneoxyoxy-3,4-dihydro-5H-2,3-benzodiazepine were refluxed with 40 ml of acetic anhydride for After 3 hours, it was evaporated to dryness under reduced pressure. The crystalline residue was transferred with 25 ml of water to a filter and washed with 5 x 3 ml of water. After drying, 2.79 g of the crude triacetyl derivative were obtained.

After washing with 20 ml of isopropanol and drying at 100 ° C, 2.39 g (84.6%) of the pure desired product were obtained, m.p. 224-227 ° C. C23 H23 N3 O5 = 421.461

nV p \

Example 40 N - [4- (3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-

0.70 g (2 mmol) of the product of Example 15 was dissolved in benzene dehydrated over calcium hydride, 0.3 mL (5 mL) 5 mmol) of methyl isocyanate was added and the reaction mixture was stirred at 50 ° C for 4 hours.

The crystals were formed and the precipitate was filtered, washed with 3 x 3 ml of benzene, then titrated with 20 ml of hot benzene. The hot mixture was filtered, the precipitate was washed with 3 x 3 ml of benzene and dried to afford 0.65 g (79.6%) of the desired product m.p. 168-170 ° (decomp). C21 H22 N4 O4 = 394> 439 * s *

N- [4- (3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H- [3,2,3-benzodiazepin-1-yl) -phenyl] -N- -phenylurea

Following the procedure described in Example 40, but using phenyl isocyanate instead of methyl isocyanate, the reaction mixture was refluxed for 10 hours, evaporating under reduced pressure, then, The residue was first suspended in 50 ml of diethyl ether, then, in 15 ml of ethyl acetate, 0.59 g (75.7%) of the desired product were obtained mp 184-180øC. (decomp). C26H24N404 = 456.510

Example 42 1- (4-Acetylaminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 1,3 g (4, 4-amino-phenyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo diazepine were stirred at 20-25øC with 5- ml of acetic anhydride for one hour, then the yellow solution was poured into 100 g of ice water and stirred until decomposition of the excess anhydride was complete.

The precipitate formed was filtered off washed with 3 x 10 ml of distilled water and dried to give 1.6 g of the crude product.

After recrystallization from 20 ml of benzene, 1.50 g (89.85%) of the desired product were obtained, m.p. 158-160 ° C (decomp.).

C21H21N3O4 = 379 > 423

Example 43 1- (4-Formylaminophenyl) -3-formyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

To 6.0 ml (0.104 mol) of acetic anhydride, 3.0 ml (0.08 mol) of 100% formic acid were added dropwise at 0Â ° C for 5 minutes with constant stirring. (4-amino-phenyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-1H-imidazol-1-yl) 5H-2,3-benzo-diazepine, was added to the mixed anhydride thus prepared.

The reaction mixture was stirred at 25 ° C for 1.5 hours, then poured into ice water, the precipitate formed was filtered, washed with 4 x 5 ml of distilled water and dried at 80 ° C to provide 0.80 g of crude product.

After crystallization from 3 ml of ethyl acetate, 0.65 g (56.2%) of the desired product was obtained, m.p. 193-195Â ° C. Calc'd for C 19 H 17 N 3 O 4 = 351.369

Example 44 1- (4-Trifluoroacetylaminophenyl) -3-trifluoroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine- 48 g (5 mmol) of 1- (4-amino-phenyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine were dissolved in 30 ml of chloroform, then 2.1 ml (15 mmoles) of triethylamine and at 20-25 ° C 2.12 ml (15 mmol) of trifluoroacetic anhydride were added and the reaction mixture was stirred for 2.5 hours then , extracted first with 2 x 30 ml of water and thereafter with 20 ml of 5% hydrochloric acid. -62-

The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the amorphous residue was recrystallized from 10 mL of 70% ethanol to provide 1.41 g (57.9%) of the desired diacyl derivative m.p. 177-1780 ° C. ^ 21 ^ 15 ^ 6 ^ 3 ^ 4 =, 363

Example 45 (4-propionylaminophenyl) -3-propionyl-4-methyl-8,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine The described procedure in Example 44 was followed except that 11.2 mmol of both triethylamine and propionic acid anhydride were used and the crystalline residue was first recrystallized from 15 ml of 50% ethanol then 11.5 ml of ethanol 99%, to provide 2.48 g (60.9%) of the desired product, mp 152-154 ° C. C 23 H 25 N 3 O 4 * 407.477

Example 46 to 65

Other diacyl derivatives of the general formula (I), wherein R = acyl group, = R 1 = H, R 2 = CH 2 and R 4 - acyl group, wherein R 4 and R 4 are the same or different, are given in Table 10. These compounds have been prepared partially from the compounds of general formula (III); wherein R = R = R = H and R = acyl group; and partially from novel compounds of the general formula (I), wherein R = acyl group, R 1 = R 2 = R 4 = H and R 2 = CH 2, according to procedures defined in the preceding examples. And R4 = the acyl group is illustrated in detail below with the acetyl group derivative as R4: 1- (4-acetylaminophenyl) -4-methyl Method A) To a solution containing 6.0 g (20 mmol) of 1- (4-aminophenyl) -1H-imidazo [4,5-a] 4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-233-benzodiazepine in 30 ml of ethyl acetate, 1.38 ml (21 mmol) of methanesulfonic acid were added. 9 · -

O

u

The precipitated crystalline precipitate was filtered and washed with 5 x 5 ml of ethyl acetate. The dry weight of the product was 7.37 g, m.p. sintered at 190 ° C and weakly decomposed at 210-212 ° C. The thus obtained methanesulfonate salt of the starting material was acetylated as follows: 7.37 g of the powdered salt were suspended in 110 ml of acetic anhydride, the suspension was stirred at room temperature for 2 hours, then the crystalline precipitate was filtered, washed with 5 x 10 ml of ethyl acetate and dried to provide 6.54 g of methanesulfonate salt of the white powder 240-241 ° C (dec.). The base was freed from the methanesulfonate salt of the target compound, for example, as follows: 6.54 g of salt were dissolved in 90 ml of water, the solution was clarified with charcoal, then 3.6 g of sodium hydrogen carbonate were added portionwise to the clear solution. The precipitate was filtered, washed with 5 x 10 ml of water and dried to give 5.54 g of crude product. After recrystallization from 130 ml of iso-propanol 3.11 g (46% yield) of product were obtained, mp 221-223øC (poor decomposition), the melting point increased to 223-225øC upon digestion with 15 ml of hot benzene.

C 19 H 19 N 3 O 3 = 337.385 The hydrochloride salt decomposed at 262-264 ° C.

U Method B)

After dissolving 15.0 g (44.7 mmol) of 1- (4-acetylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 150 ml of pyridine under moderate heating, , 2 g (0.299 mol) of sodium borohydride were added and the mixture was stirred in an oil bath at a temperature of 100 ° C for 5 hours. Then the reaction mixture was cooled to about 25 ° C, 150 ml of water were added dropwise under continuous stirring for 20 minutes, thereafter a mixture containing 180 ml of concentrated hydrochloric acid and 265 ml of water were added added with cooling in ice water. A yellowish suspension formed. The precipitate was filtered, washed with 5 x 20 ml of water and dried to give 15.2 g of salt, mp. Above 250 ° C.

To liberate the base, that salt was suspended in 150 ml of 50% ethanol, and then 5.7 g of sodium hydrogen carbonate were added in portions while stirring. The suspension thus formed was filtered after 30 minutes, successively washed with 3 × 10 ml of 50% ethanol, 5 × 20 ml of water, finally with 20 ml of 50% ethanol and dried to give 10.95 g of a Crude product, mp 218-220 ° C (poor decomposition).

After digestion of this crude product with 50 ml hot isopropanol, and then with 100 ml hot 99.5% ethanol, 8.63 g (57.2%) of the desired compound were obtained, mp 220-222øC (poor decomposition).

The physical characteristics of the other 1- (4-acylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepines are as follows: Analog RfPF C Propionyl: 237-239 Benzoyl 247- 248 (decomp) phenylacetyl-1: 213-215 (decomp.) Palladium 1: 1: 132-135 (decomp.)

υ (1

ي

(D) r ϋ ϋ ϋ ϋ ϋ ϋ ϋ Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν * Γ &quot; ο cn Ο Ο CO χ-1 the LD ID • C1 Ή Ν 'τ-1 ιη Γ &quot; ο Ν < CN οθ L0 <0 n rH ϋ Ο t! (Μ r-1 γΗ CN t-ι τ- {rH γΗ rH I-1 (N rH ra -5-1 1! Λ Ο r r r r η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η. χ-ir-I rH rH CN rH

Ο 13 α C ji O ji ji Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ. Pd (d) where CO is the weight of the compound. m CN CN CN Γ0 ΓΟ rH cn 5-1 (¾ X Ρ3 t-4 «J u 13 * H cn cn cn cn cn m II -P 33 33 Η-1 Ht oooo O o O Pd PU cuuuuu UV <3 0 II II II II || II || H-H 13 H Ck n * n &lt; Ν 'Ν' Ν 'n * n · II 1-1 E Pd Pd Pd PÍ Pd Pd Pd (d) ??????????????????????????????????????? LO V LO LO - • k. LD * &gt;. 1 H-NMR (DMSO-d6):? x H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H- -! • - x-1 '- V-r-i

Pd d) D &amp; 1 ε or

γΗ ra 5-1 ο CP = 3 * κ

CO Ο Ο

m η &amp; 1 H-NMR (CDCl3): Î'(CDCl3)::::::::: u 1 u U U 1 U 1 U 1 U u (-HO o O o O O O O O O O O O O U O U O U U U U U U U P U P U P U P U U U U U U U U U U U U U U U U U U U + &gt; ωCM ε ο υ

(X m η η

Η

CN Ο η η η η η η η η η η η η η η η η η η η η η η CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN 1 o O O O O O O O O o o c_> u u o u u ο rH CU ε 0) χ Η οι £ 3 ιη -¾1 Γ &quot; Ν '00 Ν' σι ν < ο ιη ιΗ ιη CN ιη cn ιη ιη ιη ιη ιη Γ- ιη οο ιη

or

Λ Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ^

To a suspension of 2.89 g (5.97 mmol) of 1- (4-phthaloylglycylaminophenyl) -4- (4-methoxyphenyl) -4-methylenedioxy-5H-2,3-benzodiazepine methylenedioxy-5H-2,3-benzodiazepine (Example 79) in 50 ml of methanol, 0.6 ml (11.9 mmol) of 100% hydrazine hydrate was added and the mixture was brought to reflux for 2 hours. The reaction mixture was cooled, evaporated under reduced pressure, the partially crystalline residue was mixed with 40 ml of dichloromethane, filtered and the sub product was washed with 2 x 10 ml of dichloromethane. The solution was extracted with 3 x 15 ml of 5% hydrochloric acid, the aqueous layer was basified with 24 ml of 10% aqueous sodium hydroxide. the precipitate formed was filtered, washed with 3 x 10 ml of water-distilled and dried at 100 ° C to give 1.67 g of crude product.

After recrystallization from 73 ml of ethanol, 1.50 g (71.8%) of the desired product were obtained, m.p. 223-225 ° C. C19 H18 N4 O3 = 350.385

-70- T- V

Examples 67 to 78

Other compounds of formula 23 (I), wherein R = CH 3, R = H, and some of the acid addition salts thereof prepared by the procedure of Example 66 are set forth in Table 11.

Sb u of known

The salts were prepared by methods

Ό Ο- u u u ΐ ΐ d d d d d d d d d d d d d

Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η? Μ 3- 3- 3- 3- 3- 3- 3-------------------------------- , -. - &gt; CN, Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η η t-shirts! CN CN Ό co o N * Ο ιη ι-! m σ Η Η Η Η Η η η η η η η η η η η η Ί Ί Ί Ί Ί Ί Ί Ί Ί Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο Ο CN Ί CN \ m τΗ LD σ * Ι-Η ►-1 t-I -Q tH ιη CN iH O γΗ Γ "{CN τΗ τΗ τ-i CN 1-1 CN ιΗ CN CN CN 0 | rd 4- &gt; d rd -Η to -ρ Μ 0 rd d Β σ d * Η Ο * Η CO CN Ο < 03 03 ID 03 h Π &lt; χ &gt; C0 σι ο ι-Η γμ η οο σ σ σ σ

CN CN BBSJBI CN 1 1 MM h- (cn co * - b B hrH IU u CN <-1 MM 1-4 BB LU CN u U 1 CO »- <M 1 1 CN < u OO t-1 CO cn 1- uuut ^ -l 1 - 1 B 1 1 1 UU «3 <POOOE u QQBBB uuu CN Β Β II * -I η h- (I- (υ U Ο UU CN μ Β ΓΝ ΓΝ ΓΝ ΓΝ ΓΝ ΓΝ III Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β Β & & & & & & & & & (1) (1) (1) (1) (1) (1) (1) (1) (1) H. 1 CN B o cn B ud OBUU u BU - 'B u UI 1 1 U 1 1 1 1 1 oo Β O oo B PI O uu Ω uuu - - P u Ο γ-ι a ε a Η Η Γ CN CN. CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN CN rl 4-1 • μ o rd ri a 0 0 1-í of ε CQ a rd X • HH 0 d 0 <rd -P 0 R ird Λ • ÇJ d C 03 0 ω «» 0 rd 0 μ d rd \ D μ u CD rd • HS +1 0 du tH m rd aa ε II a rd xd HB 0 0 0 wdy-S rd 0 0 UU 4-1 rd H rd a 0 M 0 ε rd P • HS a μ da B ε 1 rd 0 EU 0 - · 0 1 44 0 0 d 4- ) CN c rd Γ- • HU d rd (d tB S 0 of 0 4-4 r ^ 0 0 0 • H 0 rd C r-4 a -Q) a rd tn ε P 0 0 0 μ x fd B 0 * rl rd Λ 0 d O d II d ε d 0 0 B 0 1 4J 0 B d 0 d -P »« 0 c cn u 0 rd addd 0 0 0 B oa

Example 79 1- [4- (N-Phthaloylglycylamino) phenyl] -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine To a solution of 2.0 g (6.88 mmol) 1- (4-aminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in dichloromethane, 1.84 g (8.94 mmol) dicyclohexylcarbodiimide and 1.84 g 8.94 mmol) of phthalimidoacetic acid powder were added and the reaction mixture was stirred at 25 ° C for 8 hours, then allowed to stand at 0-5 ° C overnight. The precipitate formed was filtered off washed with 3 x 3 ml of dichloromethane and dried at 60-80øC to give 5 g of a product consisting of a mixture of the target product and Î ±, Î'-dicyclohexylurea, a by-product.

This mixture was purified by refluxing with 210 ml of ethanol for 30 minutes, filtering the hot mixture and washing with 2 × 10 ml of hot ethanol, then drying at 100 ° C. to give 2.42 g (73.3%) of the desired product, m.p. 266-268 ° C. (decomp.) C27 H20 N4 O5 = 480.49

4- (N-phthaloyl-gamma-aminobutyrylamino) phenyl] -4-methyl-7,8-methanediyl-5H-2,3, -benzodiazepine

Following the procedure described in Example 79, but using gamma-phthalimidobutyric acid, 3.8 g of a mixture were obtained, which were combined with the mother liquor of dichloromethane, previously extracted with 2 x 40 ml of a solution aqueous sodium carbonate solution at 10%.

After evaporation under reduced pressure the residue was subjected to column chromatography (adsorbent: Kieselgel 60 (0.063-2 mm), eluent: ethyl acetate-methanol 4:17. The evaporation residue was charged with 10 ml of hot ethanol , cooled, filtered, washed with 3 x 1 ml of ethanol and dried to afford 3.12 g (90%) of the desired product, mp 233-235øC (decomp.) C 29 H 24 N 4 O 5 = 508 &gt; 543

1- [4- (N-phthalazin-1-yl) -1-aminoyl] phenyl] -4-methyl-7,8- oxy-5H-2,3-benzodiazepine The procedure described in Example 79 was followed, after which N-phthaloyl-DL-alanine (DL-2-phthalimidopropionic acid) was used. After filtration of the little precipitate formed, the filtrate was evaporated, the residue was mixed with 15 ml of dichloromethane, carefully filtered and the clear solution obtained was repeatedly evaporated. Purification of the residue was achieved by refluxing with 60 ml of ethyl acetate. The formation of crystals had already begun in the hot solution. The crystals were filtered at 0-5 ° C, the off-white crystalline powder was washed with 3 x 3 ml of ethyl acetate and dried at 100 ° C to provide 2.75 g (80.95%) of the desired product, mp 243 DEG- -245 ° C (decomp).

C28H22N405 = 494.516

The compound

Example 82 1- (4-nitrophenyl) -3-methoxy-4-methoxy-8,8-methoxy-3,4-dihydro-5H-2,3-benzodiazepine The procedure described in Example 66 was followed using the compound prepared according to Example 85 as the starting material but the dichloromethane solution was extracted only 3 x 20 ml of distilled water and the organic layer was evaporated under reduced pressure. The crystalline residue was purified by suspending in 7 ml of ethanol to afford the desired pure product, in a yield of 86.1% m.p. 201-203 ° C (decomp.) C 19 H 18 N 4 O 5 = 382 385

(4-nitrophenyl) -3- (gamma-aminobutyryl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

Following the procedure described in Example 82 and using the compound prepared according to Example 86 as the starting material, a crystal solvent-containing product was obtained in a yield of 89.4%. m.p. 110-112 ° C (recrystallized from 50% ethanol). C21 H22 N4 O5 = 410.439

Example 84 (4-nitrophenyl) -3- (DL-alanyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

Following the procedure described in Example 82 and using the compounds prepared according to Example 87, the desired compound was obtained, m.p. 220-221 ° C (decomp.) 396.412 C 20 H 20 N 4 O 5

The novel intermediates employed in Examples 82 to 84 as starting materials were prepared from the compound prepared according to Example 26 by the procedure of Example 81.

Example 85 1- (4-nitrophenyl) -3- (N-phthaloylglycyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

Yield: 93.3%, mp 173-174 ° C (decomp.) C 27 H 20 N 4 O 8 = 512.489

Example 86 1- (4-nitrophenyl) -3- (N-phthalothi-gamma-aminobutyryl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3 -benzodiazepine mp 218-220 ° C C 29 H 24 N 4 O 7 = 540> 543 78-

Example 87 1- (4-nitrophenyl) -3- (N-phthaloyl-BL-alanyl) -4-methyl-7,8-methylene dioxy-3,4-dihydro-5H-2,3-benzodiazepine mp 210-212 ° C C 28 H 22 N 4 O 7 = 526> 516

Examples 88 to 94

Intermediates of formula (I) wherein R 1 and / or R 4 represent an acyl group substituted by a phthalimido group are required for the preparation of compounds obtained using the procedures of Examples 73 to 78, summarized in Table 12.

They were prepared from. compound of Example 15 (16) or from a compound of general formula (III), wherein R 4 is hydrogen (see U.S. Patent No. 835352), or from 1- (4-acetylamino- phenyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine described above (before Table 10), followed by the procedure of Example 81.

V

SBD N

Of course, in Example 93, twice the amount of phthaloylglycine and dicyclohexylcarbodiimide must be used.

Thus, Table 12 lists novel compounds of formula (I), wherein R e are acyl groups, R 1 = R 3 = H and R 2 = CH 3. (I.e.

CM &lt; uu CQ <

u

Fusion T3 &quot; d to 3 d U d CD CN CD ca CN LO α o rH O m CD SP cn Γ &quot; The invention relates to a process for the preparation of a compound of the formula: ## STR1 ## in which R 1 is as defined in formula (I). n CN rH CN CM CM rH

SPE

CDCl3). HM HM or LO SP E u u CM CD b SP "__ U 1 'τ1 ι-1-ι The CM -> CN u - ·. 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 10, 10, Hi, how are you?

The reaction is carried out in a similar manner to that of the title compound. B LD or O 1 or CN o .-. . - cn O s hp O u. 1 U u ro * B E B 1 CN O 1 CN DU 1 CN n E U cn O r-i cn MM U - 'E u 5 hM U 1! O 1 O O O O O O U O U O U O U O H O I O O X X w

or G CO

Tp σι CM σ η cn SP σ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 - (1) (1) (1) (1) (1) . u-T3 B-

1- (4-Aminophenyl) -3- (gamma-aminobutyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine Hydrogen fumarate

It was prepared from the compound of Example 83, followed by Example 16, m.p. 150-152 ° C (decomp.). / = 496, 531

Example 96

1- (4-Aminophenyl) -3- (4-carboxybutyryl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine hydrochloride

It was obtained from compound of Example 37, according to Example 16, m.p. 224-226 ° C (decomp.): C 22 H 22 N 5 O 5 Cl 7 = 445.915

Example 97 1- (4-Trifluoroacetylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

It was prepared following Example 2, m.p. 258-260 ° C (decomp) C 19 H 14 F 3 N 3 O 3 = 389.339

Example 98 1- (4-Aminophenyl) -3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

It was prepared from 1- (4-nitrophenyl) -3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2, 3-benzodiazepine, according to with Example 16, mp 199-201 ° C. C 19 H 20 N 4 O 3 = 352 401

Hydrochloride, m.p. 219-221 ° C (decomp.) - C 19 H 21 N 4 O 3 ú7 Cl = 388.866 The starting nitro compound was prepared as follows:

1.1 ml (18.4 mmol) of methyl isocyanate were added to 3.0 g (9.22 mmoles) of 1- (4-nitrophenyl) -4-methylenedioxy-3,4-dihydro-5H -2,3-benzodiazepine (see Example 26) dissolved in 60 ml dichloromethane and stirred for 24 hours, then evaporated under reduced pressure. The crystalline residue was titrated with 30 ml of hot ethanol at 80 to 100øC to provide 3.35 g (95%) of the desired lemon yellow product, mp 238-240øC. (decomp.) C19H18N405 = 382.385

Example 99 1- (4-aminophenyl) -3- (1-pyrrolidinoacetyl) -4-methyl-7,8-methyleedioxy-3,4-dihydro-5H-2,3-benzodiazepine

It was obtained from 1- (4-nitro-phenyl) -3- (1-pyrrodinyl) acetyl) -4-methyl-8,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine followed by Example 16, mp 212-214 ° C. C23 H26 N4 O3 = 406.493

The starting material was obtained from 1- (4-nitrophenyl) -3-chloroacetyl-4-methyl-7,8-meth. benzodiazepine (see Example 116) according to Example 102, m.p. 189-190 ° C (decomp.) C 23 H 24 N 4 O 5 = 436.477

Example 100

Hydrogen 1- (4-aminophenyl) -3- (N, N-dimethylglycyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

It was prepared from 1- (4-nitrophenyl) -3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine according to the procedure described in Example 103, mp 158-160 ° C 211 224 425 = 410.439

1- (4-chloroacetylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

It was prepared according to Example 2 except that chloroacetic acid was used, m.p. 209-214Â ° C (carbonisation).

C19 H16 ClN3 O3 = 369 &gt; 818

Example 102 1- [4- (T-pyrrolidinoacetylamino) phenyl] -4-methyl-8,8-methyleedioxy-5H-2,3-benzodiazepine 0.71 ml (8.53 mmol) pyrrolidine was added to A suspension of 1.5 g (406 mmol) of 1- (4-chloroacetylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 60 ml of ethanol was added and the reaction mixture was refluxed for 4 hours, then evaporated under reduced pressure. The residue was treated with water to provide a crude product (1.49 g), m.p. 186-188 ° C. After recrystallization from 12 ml of ethanol, 1.22 g (74.4%) of the desired product were obtained, m.p. 210-212 ° C. H23 N4 O3 = 404.477 -86-

4- (N, N-dimethylglycinylamino) phenyl] -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine

After adding dimethylamine hydrochloride (0.66 g, 8.12 mmol) and triethylamine (1.86 mL, 13.4 mmol) to a suspension of 1.5 g (4.06 mmol) of 1- (4-chloroacetylaminophenyl) ) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 60 ml of ethanol, the reaction mixture was refluxed for 8 hours, then evaporated. The residue was dissolved in 30 ml of dichloromethane, washed with 20 ml of 4% NaOH solution, then 2 x 20 ml of distilled water, dried and evaporated under reduced pressure. After treatment with water, the crystalline residue was filtered to provide 1.27 g of crude product, m.p. 211-213 ° C. u

After recrystallization from 10 ml of ethanol, 1.1 g (71.4%) of desired product were obtained, m.p. 213-215Â ° C. C21H22N406 = 378.439

«Sp.

Example 104 1- (4-methylecarbamoylaminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine 0.8 ml (13.4 mmol) of methyl isocyanate were added to a solution containing 1 (4-aminophenyl) -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (0 g, 3.41 mmol) in dimethylformamide (DMF) (8 ml) was stirred at 25 ° C for 24 hours.

After dilution with 80 ml of water, filtration at 5 ° C and drying at 60 to 100 ° C, 1.06 g of crude product, mp 204-207 ° C (sintered at 160 ° C) were obtained which, when recrystallized in 5 ml of ethanol afforded 0.85 g (71.4%) of the desired product, mp 223-224 ° C (decomp.). C19H18N4O3 = 350 · 385

Example 105 1- (4-Aethylaminophenyl) -3-methylcarbamoyl-4-methyl-8,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

It was prepared from 1- (4-aminophenyl) -3-methylcarbamoyl-4-methyl-8,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine using the procedure of Example 42. The crude product was recrystallized from ethyl acetate to give 71.4% of the desired product, mp 150-152 ° C. C21 H22 N4 O4 = 394.49

Example 106 1- (4-Chloroacetylaminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

It was prepared from 1- (4-aminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine using The title compound was prepared according to the procedure of Example 2, mp 139-140 ° C. = 413.972 C 21 H 20 ClN 3 O 4

1- [4- (4-dimethylglycylamino) phenyl] -3-acetyl] -7,8-methylenedioxy] -4,4-dihydro-5H-2,3-benzodiazepine

Prepared from the product of the preceding Example using the procedure described in Example 103, m.p. 203-208 ° C.

^ 23 ^ 26 N4O4 = 422,493

EXAMPLE 108 1- [4- (N, N-Diethylglycylamino) phenyl] -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine

J O

It was prepared from 1- (4-chloroacetylaminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine using the procedure of Ex. 102, mp 175-176 ° C. ^ 25 ^ 30 * ^ 4 ^ 4 = 450,547

Claims (4)

1- [4- (1-pyrrolidinoacetylamino) phenyl] -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2: 3-benzodiazepine Hydrogen fumarate at It was prepared from 1- (4-chloroacetylamino) phenyl) -3-acetyl-4-methyl-8,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine using the procedure of Example 2 and isolated as the fumarate hydrogen, mp 181-183 ° C. (decomp.) - &quot; C25H29N404-7 * C4H3O2: 564.67 Example 110 The title compound was prepared from the compound of general formula (III): wherein R1, R2, R3, R4, R4 and R4 are each independently hydrogen, C1-4-alkyl- , where R4 = COOCH3 using the procedure of Example 2 and chloroacetic acid instead of formic acid, mp 138-140 ° C. = 413.973 C21 H20 ClN3 O4 4- [Î ±, β-di-ethylglycylamino) phenyl] -4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine Prepared from 1- (4- 4-methylenedioxy-5H-2,3-benzodiazepine using the procedure of Example 102, except dimethylamine was used in place of pyrrolidine, mp 157-158 ° C C 23 H 26 N 4 O 3 = 406, 493 Example 112 1- (4-acetylaminophenyl) -3-cyclopropanecarbonyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine Prepared from of 1- (4-aminophenyl) -3-cyclopropanecarbonyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine the procedure of Example 42 , mp 242-243 ° C. C23 H23 N3 O4 S 405.461 N - [4- (3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepin-1-yl) phenyl] -N- (3-methylurea) 0.5 ml (8.5 mmol) of methyl isocyanate was added to 1- (4-amino-phenyl) -3-methylcarbamoyl-4-methyl-7,8- methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (see Example 98) dissolved in 4.5 ml anhydrous dichloromethane, the reaction mixture was stirred at 25 ° C for 6 days. The crystalline precipitate was then filtered, washed with 3 x 2 ml of dichloromethane and dried at 60 to 80øC to give 0.55 g (79.7%) of pure desired product, mp 181-183øC. EXAMPLE 114 1- (4-Aminophenyl) -3-n-butylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3- benzodiazepine Prepared from 1- (4-nitrophenyl) -3-n-butylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine, mp 17 3-17 ° C 394,482 C22H26N405 The starting material was prepared as described for the starting material of Example 98, except that n-butyl isocyanate was used in place of methyl isocyanate and the reaction mixture was cooled. stirred for 5 days at 25 ° C, m.p. 176-178 ° C. C22 H24 N4 O5 = 424> 466 Example 115 1- (4-Methoxy-4-aminophenyl) -3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro- 3-benzodiazepine was prepared from 1- [4-N-phthalionylamino) phenyl] -3-methylcarbamoyl] -4-methyl-7,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine using the procedure of Example 66, as modified in Example 82, mp 163-165 ° C. The starting material was prepared from 1- (4-aminophenyl) -3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2 , 3-benzodiazepine (see Example 98) according to Example 79, mp 270-27 ° C (decomp.). C29 H25 N5 O6 = 539.559 -94- Example 116 1- (4-Aminophenyl) -3- (N-methylglycyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 1.03 ' (15.3 mmoles) of methylamine hydrochloride and 2.64 ml (18.3 mmoles) of triethylamine were added to a suspension containing 1.23 g (3.06 mmol) of 1- (4- 3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine in 140 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was dissolved in 30 ml of chloroform, washed with 20 ml of 4% NaOH solution, 2 x 20 ml of water, dried and evaporated under reduced pressure. The residue was reduced according to the procedure of Example 16 and the product obtained was purified by column chromatography (adsorbent: Kieselgel 60, eluent: methanol-benzene 4: 1). The crude product obtained was triturated with 5 ml of ethyl acetate at 25 ° C to give 0.60 g (53.6%) of the desired product, m.p. 198-200 ° C (decomp.). C20 H22 N4 O3 = 366.428 The starting compound was obtained from 1- (4-nitrophenyl) -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (see Example 26) and chloroacetic acid using the procedure of Example 33, mp 189 DEG-189 DEG C. (decomp.) C19 H16 ClN3 O5 = 401.88 Example 117 1- [4- (N-methylglycylamino) phenyl] -3-acetyl-4- 8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine 1.31 g (19.5 mmol) of methylamine hydrochloride and 3.24 ml (23.3 mmol) of triethylamine were added to a suspension containing 1.61 g (3.89 mmol) of 1- (4-chloroacetylphenylphenyl) -3-acetyl-4-methyl-8,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine (see Example 106) was dissolved in 100 ml of ethanol and the reaction mixture was refluxed for 10 hours, then evaporated under reduced pressure. The residue was purified by column chromatography (adsorbent: Kieselgel 60, eluent chloroform-methanol 9: 1). The crude product was titrated with 3 mL of 50% ethanol and 25øC to afford 0.61 g (38.6%) of the desired product, m.p. 220-222 ° C (poor decomp.). ^ 22 * ^ 24 ^ 4 ^ 4 = 408,466 Preparation of pharmaceutical compositions Tablets or divided tablets containing 25 mg of 1- (4-aminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine Examples 15 or 16) or 25 mg of 1- (4-acetylaminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine (compound of Example 42) or 25 mg of 1- (4-aminophenyl) -3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-2H-Z-benzodiazepine Example 98), each as an active ingredient, was prepared by standard methods. a) Composition of a tablet: Active ingredient 25 mg Potato starch 43 mg Lactose 160 mg Polyvinylpyrrolidone 6 mg Magnesium stearate 1 mg - Talc 30 mg Other preferred composition of a tablet Active ingredient 25 mg Lactose 130 mg Corn starch 25 mg Cellulose microcrystalline 10 mg Gelatin 4 mg Talc 2 mg Stearin 1 mg Magnesium stearate 1 mg Lisbon, March 5, 1992 J. PEREIRA PA CRUZ Official Agent for Industrial Property RUA VICTOR CORDON, 10-A 3. »1200 LISBOA N-acyl-2,3-benzodiazepine derivatives, characterized in that they have the general formula (I) wherein R means a C1-6 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxy, amino, C1-4 alkylamino, amino, pyrrolidino, phthalimido or phenyl group, or by one or more halogens; or R is a benzoyl, cyclopropanecarbonyl, alkylcarbamoyl or phenylcarbamoyl group; R 6 is absent when there is a double bond between the N (3) and C (4) atoms; R 2 ??? is hydrogen; or R 2 is absent when there is a double bond between the N (3) and C (4) atoms. -2- and R3 together stand for a methylene group and there is no bond present between the N (3) and C (4) atoms; means hydrogen or a C1-4 aliphatic acyl group; R 4 represents hydrogen; a C1-3 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxyl, amino, alkylamino, C1-6 di (C1-4 alkyl) amino, pyrrolidino, phthalimido or phenyl group, or by one or more halogens; as well as a benzoyl, palmitoyl, cyclopropylcarbonocarbonyl, alkylcarbamoyl or phenylcarbamoyl group; and dashed lines represent valence bonds optionally present, provided that there is no double bond between the N (3) and C (4) atoms when both R 4 and R 4 signify hydrogen, and their stereoisomers, as well as addition salts (where possible) of these compounds. 25. A compound selected from the group consisting of 1- (4-aminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2 , 3-benzodiazepine, 1- (4-aminophenyl) -3-propionyl] -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine, 1- (4-acetylaminophenyl) -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine, 1- (4-propionylaminophenyl) -3-propionyl- 8-methylenedioxy-3,4-dihydro-5H-2,3-benzodi azepine, -3- 1- (4-acetylaminophenyl) -3-propionyl] -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine, 1- (4-propionylaminophenyl) -3- -4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine, 1- (4-trifluoroacetylaminophenyl) -3-acetyl-4-methyl- dihydro-5H-2,3-benzodiazepine, 1- (4-methoxyphenyl) -3-ethyl-4-methyl-7,8-methylenedioxy-3,4-dihydro- 5H-2,3-benzodiazepine, N1 - [4- (3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-b] zodiazepin- (N, N-dimethylglycylamino) phenyl] -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2 , 3-benzodiazepine, 1 - [(N, N-diethylglycylamino) phenyl] -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine, 1- 4- (1-pyrrolidinoacetylamino) phenyl] -3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and its hydrogen fumarate, 1- (4- glycylaminophenyl) -3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H- 3-benzodiazepine, 1. A pharmaceutical composition comprising the active ingredient as a novel N-acyl-2,3-benzodiazepine derivative of 1 part of the general formula (I), in which R 1, R 2, R 3, R 4 and R 5 are dashed lines. as defined in claim 1, or pharmaceutically acceptable acid addition salts thereof, in admixture in vehicles and / or additives generally used in the pharmaceutical industry. 4. A process for the preparation of the N-acetyl-2,3-benzodiazepine derivatives of general formula (I); (I) wherein R 1 is a C 1 -C 4 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxy, amino, C 1-4 alkylamino, di (C 1-4 alkyl) amino, pyrrolidino, phthalimido or phenyl group, or one or more halogen atoms, or R is a benzoyl, cyclopropanecarbonyl, alkylcarbamoyl or phenylcarbamoyl group, or R is absent when there is a double bond between the N (3) and C (4) atoms; is absent when there is a double bond between the N (3) and C (4) atoms: R means a C1-3 alkyl group, or R and R together signify a methylene group and there is no double bond present between the atoms N (3) and C (4); R 2 is hydrogen or a C 1 -C 4 aliphatic acyl group; R 4 represents hydrogen; an aliphatic acyl group optionally substituted by a methoxy, cyano, carboxyl, amino, C1-4 alkylamino, di (C1-4 alkyl) amino, pyrrolidino, phthalimido or phenyl group, or by one or more halogen, as well as a benzoyl, palmitoyl , cyclopropanecarbonyl, C 1-6 alkylcarbamoyl or phenylcarbamoyl; the dashed lines represent valence bonds optionally present, provided that there is no bond between the N (3) and C (4) atoms when both R 1 and R 2 are hydrogen, and their stereoisomers, as well as acid addition salts , characterized in that it comprises: a) acylation of a compound of formula (II) (XI) with an aliphatic carboxylic acid optionally substituted by a methoxy, cyano, carboxyl or phenyl group, or by one or more halogenates; or with benzoic, cyclopropanecarboxylic or palmitic acid or a reactive derivative thereof, e.g. case. (I) is obtained, in which R 2 represents a - 6 C1-4 aliphatic acyl group substituted by a halogen, C1-4 alkylamine, di (C1-4 alkyl) amine or pyrrolidine, to give compounds of general formula (I), wherein R1, R2 and dashed lines are as above R 2 represents a C 1 -C 4 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxy, phenylalkylamino, C 1 -C 4 alkoxy, pyrrolidino group or one or more halogen atoms, or a benz (3) and C (4): b) acylation of a compound of formula (III): wherein R 1 and R 2 are independently selected from the group consisting of: ) CH3 (III) wherein R 4 is as defined above, with a C 1-6 aliphatic carboxylic acid optionally substituted by a methoxy, cyano, carboxyl or phenyl group, or by one or more halogens, or benzoic acid or cyclopropanecarboxylic acids or a reactive derivative thereof; and, if desired, reaction of a novel compound of formula (I) thus obtained, wherein R 4 is an aliphatic acyl group. amine or pyrrolidine to give compounds of formula (I) wherein R 2, R 4, and the dashed lines are as defined above, R signifies a C 1-4 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxy, phenyl, C1-4 alkylamino, di (C1-4 alkyl) amino, pyrrolidino, or one or more halogens; or a benzoyl or cyclopropano-carbonyl group; and there is no double bond present between the N (3) and C (4) atoms; .o.u. . &quot;. ·. ·. (C) acylating a compound of formula (II) with an N-phthaloylamino acid of general formula (VI) in which R is hydrogen or a C1 -C4 alkyl group, and η is 15 in the case of alpha-amino acids, while R is hydrogen and n is an integer of 2 to 5 in the case of B-amino acids and, if (I) wherein R 1 and the 3 dashed lines are as defined above, R 2 denotes hydrogen, R 4 denotes a C 1-6 aliphatic acyl group substituted by an amino or phthalimido group , both R 1 and R 2 are absent and a double bond is present between the N (3) and C (4) atoms; or (d) acylation of a compound of formula (III), wherein R1 is as defined above, with an N-phthaloylamino acid of formula (VI), wherein R is hydrogen or C1-4 en is 1 in the case of alpha-amino acids whereas R3 is hydrogen en is an integer of 2 to 5 in the case of B-amino acids, and, if desired, removal of the phthaloyl group, to give compounds of general formula (I) wherein R 1, R 2 and dashed lines are as defined above, R 2 is hydrogen, R 2 is as defined above, except hydrogen, R 2 is an aliphatic acyl group substituted by a amino or phthalimido group, and no double bond is present between the N (3) and C (4) atoms; or (e) reacting a compound of formula (II) with an alkyl isocyanate or phenyl isocyanate, to give compounds of formula (I), wherein R2 and dashed lines are as defined above, R 2 is hydrogen, R 2 is C 1 -C 5 alkylcarbamoyl or phenylcarbamoyl, R 2 and R 3 are absent and a double bond is present between N (3) and C (4) atoms; or (f) reacting a compound of formula (III), wherein R2 is as defined above, with a C1-4 alkylisocyanate or phenyl isocyanate to provide compounds of general formula (- - wherein R 1 and R 2 are as defined above, R 2 is hydrogen, R 2 is as defined above, except for hydrogen, R 3 is an alkylcarbamoyl or phenylcarbamoyl group and a double bond is present between the N (3) and C (4) atoms; or ch3 (IV) NO 2 a novel compound of formula (V) The N03 (V) -10- (V) thus obtained using any of processes b), d), or f) above and reduction of the nitro group of the novel compound thus obtained of general formula (V), in which R is hydrogen, then acylation of the compound of formula in which R 4 is as defined above, an amino group, or first reduction of the nitro group, and then, acylation of the compound of formula (III) thus obtained, wherein R 4 is hydrogen, using any of processes b), d) or f) above, to give compounds of general formula (I), wherein R 1, R 2 and R 2 represent hydrogen, R 2, R 3 and the dashed lines are as defined above, and no double bond is present between the N- (3 ) and C (4); or h) acylating a new compound of formula (I), wherein R 1, R 2, R 3 and the dashed lines are as defined above, R 1 and R 2 are hydrogen and no double bond is present between the N ( 3) and C (4) with a C1-6 aliphatic carboxylic acid optionally substituted by a methoxy, cyano or carboxy group or by one or more halogens; or with benzoic acid; or a reactive derivative thereof, to give compounds of the general formula (I) wherein R 1, R 2 and R 3 are the dotted lines as defined above, R 2 and R 3 represent a C 1-4 aliphatic acyl group, optionally substituted by a methoxy, cyano or carboxy group, or by a halogen atom; or a benzoyl group at no double bond is present between the N (3) and C (4) atoms; or -11- i) reacting a novel compound of formula (I) wherein R 1, R 2, R 2 and R 2 are as defined herein, R 1 and R 2 are hydrogen and no double bond is present between the N (3) and C (4) with C1-4 alkyl isocyanate or phenyl isocyanate to provide compounds of general formula (I) wherein R 3 and the above-mentioned lines are as defined above, R 2 is an acyl group aliphatic optionally substituted by a methoxy, cyano or carboxy group or by one or more halogens; or a benzoyl group; R 1 is hydrogen; R2 represents a C1-6 alkylcarbamoyl or phenylcarbamoyl group and no double bond is present between the N (3) and C (4) atoms; or (j) acylation of a novel compound of formula (I) wherein R 1, R 2 and the dotted lines are as defined above, R 2 and R 2 are hydrogen and no double bond is present between N (3) and C (4) with an N-phthaloylamino acid of formula (VI) in which R 3 is hydrogen or an alkyl group in the case of alpha-amino acids, while R 3 is hydrogen in an integer from 2 to 5 in the case of B-amino acids and, if desired, removal of the phthaloyl group to give compounds of formula (I) wherein R 1 and the dotted lines are as defined above, R5 denotes a C1-6 aliphatic acyl group optionally substituted by a methoxy, cyano or carboxy group or by one or more halogens; or a benzoyl group; R 1 is hydrogen; R 2 is a C 1 -C 4 aliphatic acyl group substituted by an amino or phthalimido group and a double bond is present between the N (3) and the (4) atoms, and, if desired, transformation of a base of formula (I), obtained by any of the foregoing (a) to (j) in an acid addition salt. 5. A process according to claim 4, processes a) or b), which comprises carrying out the acylation in a suitable solvent, preferably dichloromethane, with a carboxylic acid in the presence of dicyclohexylcarbodiimide at a temperature between 10 ° C and 30 ° C. Process according to claim 4, process a) or b), characterized in that it comprises performing the acylation in the presence or absence of a solvent using a carboxylic acid anhydride, mixed anhydride or chloride of acyl, optionally in the presence of an acid binding agent, at a temperature between 0 ° C and 150 ° C. 7. A process according to claim 6, characterized in that the reaction is carried out in chloroform or dichloromethane. 8. A process according to claim 4, process (e) or (f) characterized in that it comprises performing the additive acylation using a: The alkyl or phenyl ring is benzene or dichloromethane. at and 100 ° C. A process according to any one of claims 1 to 5, which process comprises reacting the compound of formula (I) with a compound of formula IV) using sodium borohydride in an aliphatic alcohol solution 10a. A process according to claim 4 which process comprises reducing the nitro group of a compound of general formula (V) in methanolic medium using hydrazine or hydrazine hydrate. in the presence of Raney nickel or palladium or catalyst, at a temperature between 10 ° C and 65 ° C. 11. A process for the preparation of a pharmaceutical composition comprising the mixture as an active ingredient. of a novel N-acyl-2,3-benzodiazepine derivative of formula (I). wherein R 1, R 2, R 3, R 4, R 5 and the dashed lines are as defined in claim 1, or pharmaceutically acceptable acid addition salts thereof, prepared by using any of processes a) to j) according to claim 4. with vehicles and / or additives generally used in the pharmaceutical industry and their transformation into a pharmaceutical composition. -14- The method of claiming one or more excitatory amino acid receptors in mammals comprising administering to the mammal in need of minor neurotransmission by the excipient amino acid of a pharmaceutically effective amount of the compound of claim 1 13. A method of treatment of. epilepsy in mammals, comprising administering to the mammal in need of such treatment an anti-epileptic amount of the compound of claim 1, 14a. A method of treating spasms of skeletal muscle in mammals, comprising administering to the mammal in need of such treatment a muscle relaxing amount of the compound of claim 1. 15. A method of treating cerebral ischemia (effusion) in mammals, comprising administering to the mammal in need thereof such a treatment a muscle relaxant amount of the compound of claim 1. A mammal in need of such treatment of a pharmaceutically effective amount of the compound of claim 1. Lisbon. 5 March 1992 J. PEREIRA DA CRUZ Official Property Agent Industriai RUA VICTOR CORDON, 10-A 3. »1200 USBOA