US 5,459,137 AGrant
N-Acyl-2,3-Benzodiazepine Derivatives, Pharmaceutical Compositions Containing Them and Process for Preparing Same
Issue Date:1995-10-17
•6 Claims
Abstract
The invention relates to novel N-acyl-2,3-benzodiezapine derivatives of the general formula (I), their stereoisomers and acid-addition salts, pharmaceutical compositions containing them and a process for their preparation. In the general formula (I), defined in the specification, a more complete description of the compounds may be found. The compounds of the general formula (I) possess valuable central nervous system effects, particularly muscle-relaxant, anticonvulsive and neuroprotective action. Thus, they may be useful for the treatment of various diseases of central nervous system origin.
Metadata
Assignee
- Gyogyszerku-tato Intezet Kft
Inventors
- Ferenc Andrasi
- Pal Berzsenyi
- Peter Botka
- Sandor Farkas
- Katalin Goldschmidt
- Tamas Hamori
- Jeno Korosi
- Imre Moravcsik
- Istvan Tarnawa
Application Information
Application Number:US 0806048
Filing Date:1993-06-21
Priority Date:1991-12-17
Art Unit:122
Classifications
IPC:
A61K 3155C07D24302
Field of Search:
540514557220
Patent Drawings
This patent does not have any drawings.
Description
DESCRIPTION
This invention relates to novel N-acyl-2,3-benzodiazepine derivatives of the general formula (I) ##STR1## wherein R stands for a C.sub.1-6 alkanoyl group optionally substituted by a methoxy, cyano, carboxyl, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, pyrrolidino, phthalimido or phenyl group, or by one or more halogen(s); or R is a benzoyl, cyclopropanecarbonyl, C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group; or R is absent when a double bond exists between the N(3) and C(4) atoms;
R.sup.1 means hydrogen; or R.sup.1 is absent when a double bond exists between the N(3) and C(4) atoms;
R.sup.2 means a C.sub.1-3 alkyl group; or
R.sup.1 and R.sup.2 together stand for a methylene group and no double bond is present between the N(3) and C(4) atoms;
R.sup.3 means hydrogen or a C.sub.1-4 alkanoyl group;
R.sup.4 represents hydrogen; a C.sub.1-6 alkanoyl group optionally substituted by a methoxy, cyano, carboxyl, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s); as well as a benzoyl, palmitoyl, cyclopropanecarbonyl, C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group; and
the dotted lines represent valence bonds optionally being present, with the proviso that no double bond exists between the N(3) and C(4) atoms when both R.sup.3 and R.sup.4 stand for hydrogen, and their stereoisomers as well as acid addition salts (where possible) and pharmaceutical compositions containing these compounds.
The compounds of general formula (I) according to the invention have an asymmetric molecular structure. The general formula (I) relates to all possible individual stereoisomers and their mixtures.
According to an other aspect of the invention, there is provided a process for the preparation of the new compounds of general formula (I) and the acid-addition salts thereof.
The aim of the present invention is to develop new compounds of the general formula (I) which possess valuable central nervous system (CNS), particularly muscle-relaxant and/or anticonvulsive, activity. A single compound showing such effect is only known among 2,3-benzodiazepines, namely 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (U.S. Pat. No. 4,614,740) also prepared by the authors of the present invention. In the course of detailed pharmacological screening it was revealed, however, that the above compound was positive in the Ames-test, i.e. it proved to be mutagenic. Thus, it is the specific aim of the present invention to find out novel 2,3-benzodiazepine derivatives which retain their valuable muscle-relaxant and anticonvulsive activity but are negative in the Ames test.
The new compounds of general formula (I), wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and the dotted lines are as defined above, and their pharmaceutically acceptable acid-addition salts completely satisfy this requirement.
According to the invention, the compounds of general formula (I) are prepared by
a) acylating a compound of formula (II) ##STR2## with a C.sub.1-6 aliphatic acid optionally substituted by a methoxy, cyano, carboxyl or phenyl group or by one or more halogen(s); or with benzoic, cyclopropanecarboxylic or palmitic acid or with a reactive derivative thereof; and, if desired, reacting a new compound of general formula (I) thus obtained, wherein R.sup.4 means a C.sub.1-6 alkanoyl group substituted by a halogen, with a C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amine or pyrrolidine, to obtain compounds of the general formula (I) wherein R.sup.2, R.sup.3 and the dotted lines are as defined above, R.sup.4 means a C.sub.1-6 alkanoyl group optionally substituted by a methoxy, cyano, carboxy, phenyl-C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino or pyrrolidino group or one or more halogen(s); or a benzoyl, cyclopropanecarbonyl or palmitoyl group; R and R.sup.1 are absent and a double bond is present between the N(3) and C(4) atoms; b) acylating a compound of the general formula (III), ##STR3## wherein R.sup.4 is as defined above, with a C.sub.1-6 aliphatic carboxylic acid optionally substituted by a methoxy, cyano, carboxy or phenyl group or by one or more halogen(s); or with benzoic or cyclopropanecarboxylic acid or with a reactive derivative thereof; and, if desired, reacting a new compound of general formula (I) thus obtained, wherein R.sup.4 means a C.sub.1-6 alkanoyl group substituted by a halogen, with a C.sub.1-4 alkylamine, di(C.sub.1-4 alkyl)amine or pyrrolidine, to obtain compounds of the general formula (I), wherein R.sup.1 R.sup.2, R.sup.3, R.sup.4 and the dotted lines are as defined above, R means a C.sub.1-6 alkanoyl group optionally substituted by a methoxy, cyano, carboxy, phenyl, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino or pyrrolidino group or one or more halogen(s); or a benzoyl or a cyclopropanecarbonyl group; and no double bond exists between the N(3) and C(4) atoms; or
c) acylating a compound of formula (II) with an N-phthaloylamino acid of the general formula (VI), ##STR4## wherein R.sup.5 stands for hydrogen or a C.sub.1-4 alkyl group and n is 1 in case of .alpha.-amino acids, whereas R.sup.5 means hydrogen and n is an integer of 2 to 5 in case of .beta.-.epsilon. amino acids, and, if desired, removing the phthaloyl group, to obtain compounds of the general formula (I), wherein R.sup.2 and the dotted lines are as defined above, R.sup.3 means hydrogen, R.sup.4 stands for a C.sub.1-6 alkanoyl group substituted by an amino or phthalimido group, both R and R.sup.1 are absent, and a double bond is present between the N(3) and C(4) atoms; or
d) acylating a compound of the general formula (III), wherein R.sup.4 is as defined above, with an N-phthaloylamino acid of the general formula (VI), wherein R.sup.5 stands for hydrogen or a C.sub.1-4 alkyl group and n is 1 in case of .alpha.-amino acids, whereas R.sup.5 means hydrogen and n is an integer of 2 to 5 in case of .beta.-.epsilon. amino acids, and, if desired, removing the phthaloyl group, to obtain compounds of the general formula (I), wherein R.sup.1, R.sup.2 and the dotted lines are as defined above, R.sup.3 means hydrogen, R.sup.4 is as defined above except hydrogen, R stands for a C.sub.1-6 alkanoyl group substituted by an amino or phthalimido group and no double bond is present between the N(3) and C(4) atoms; or
e) reacting a compound of the formula (II) with a C.sub.1-5 alkyl isocyanate or phenyl isocyanate, to obtain compounds of the general formula (I), wherein R.sup.2 and the dotted lines are as defined above, R.sup.3 means hydrogen, R.sup.4 represents a C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group, R and R.sup.1 are absent and a double bond is present between the N(3) and C(4) atoms; or
f) reacting a compound of the general formula (III), wherein R.sup.4 is defined as above, with a C.sub.1-5 alkyl isocyanate or phenyl isocyanate, to obtain compounds of the general formula (I), wherein R.sup.1, R.sup.2 and the dotted lines are as defined above, R.sup.3 means hydrogen, R.sup.4 is as defined above except hydrogen, R stands for a C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group and no double bond is present between the N(3) and C(4) atoms; or
g) selectively reducing a nitro compound of the formula (IV) ##STR5## to a novel compound of the general formula (V) ##STR6## wherein R means hydrogen, then either acylating the compound of general formula (V) thus obtained by using any or the above processes b), d) or f) and reducing the nitro group of the thus-obtained new compound of general formula (V), wherein R is as defined above, to an amino group, or first reducing the nitro group and then acylating the compound of general formula (III) thus obtained, wherein R.sup.4 stands for hydrogen, by using any of the above processes b), d) or f), to obtain compounds of the general formula (I), wherein R1, R.sup.3 and R.sup.4 represent hydrogen, R.sup.2, R and the dotted lines are as defined above and no double bond is present between the N(3) and C(4) atoms; or
h) acylating a new compound of the general formula (I), wherein R, R.sup.1, R.sup.2 and the dotted lines are as defined above, R.sup.3 and R.sup.4 mean hydrogen and no double bond is present between the N(3) and C(4) atoms, with a C.sub.1-6 aliphatic carboxylic acid optionally substituted by a methoxy, cyano or carboxy group or by one or more halogen(s); or with benzoic acid; or with a reactive derivative thereof, to obtain compounds of the general formula (I), wherein R.sup.1, R.sup.2, R.sup.3 and the dotted lines are as defined above, R and R.sup.4 represent a C.sub.1-6 alkanoyl group optionally substituted by a methoxy, cyano or carboxy group, or by one or more halogen(s); or a benzoyl group; and no double bond is present between the N(3) and C(4) atoms; or
i) reacting a new compound of the general formula (I), wherein R, R.sup.1, R.sup.2 and the dotted lines are as defined above, R.sup.3 and R.sup.4 mean hydrogen and no double bond is present between the N(3) and C(4) atoms, with a C.sub.1-5 alkyl isocyanate or phenyl isocyanate, to obtain compounds of the general formula (I), wherein R.sup.1, R.sup.2 and the dotted lines are as defined above, R stands for a C.sub.1-6 alkanoyl group optionally substituted by a methoxy, cyano or carboxy group, or by one or more halogen(s); or a benzoyl group; R.sup.3 stands for hydrogen; R.sup.4 represents a C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group and no double bond is present between the N(3) and C(4) atoms; or
j) acylating a new compound of the general formula (I), wherein R.sup.1, R.sup.2 and the dotted lines are as defined above, R.sup.3 and R.sup.4 mean hydrogen and no double bond is present between the N(3) and C(4) atoms, with an N-phthaloylamino acid of the general formula (VI), wherein R.sup.5 stands for hydrogen or a C.sub.1-4 alkyl group and n is 1 in case of a-amino acids, whereas R.sup.5 means hydrogen and n is an integer of 2 to 5 in case of .beta.-.epsilon. amino acids, and, if desired, removing the phthaloyl group, to obtain compounds of the general formula (I), wherein R.sup.1, R.sup.2 and the dotted lines are as defined above, R represents a C.sub.1-6 alkanoyl group optionally substituted by a methoxy, cyano or carboxy group or by one or more halogen(s); or a benzoyl group; R.sup.3 stands for hydrogen, R.sup.4 represents a C.sub.1-6 alkanoyl group substituted by an amino or phthalimido group and no double bond is present between the N(3) and C(4) atoms,
and, if desired, transforming a base of the general formula (I), obtained by any of the above processes a) to j), to an acid-addition salt.
According to a preferred embodiment of the process of the present invention the acylation of the compounds of the general formulae (I), (II), (III) and (V) can be carried out preferably with a suitable carboxylic acid, in the presence of dicyclohexyl-carbodiimide in a suitable solvent, preferably in dichloromethane, in a temperature range of 10.degree. to 30.degree. C. during 1 to 25 hours.
According to an other preferred embodiment of the present invention the compounds of the general formulae (I), (II), (III) and (V) can be acylated in a temperature range of zero to 150.degree. C. by a suitable reactive acyl derivative, i.e. carboxylic acid anhydride, mixed anhydride or acyl chloride, in the absence or presence of a solvent usually applied in acylations of such types such as chloroform or dichloromethane, in the absence or presence of an acid-binding agent such as triethylamine. If the additive acylation is performed with isocyanates, the reaction is advantageously carried out in dimethylformamide, benzene or dichloromethane in a temperature range of 15.degree. to 100.degree. C. during 0.5 to 100 hours.
The selective reduction of the compound of general formula (IV) to the compound of general formula (V), wherein R denotes a hydrogen atom, can be performed by an inorgaic or inorganic-organic complex metal hydride, preferably sodium borohydride, in a solvent or solvent mixture which has no or only low reactivity to the complex metal hydride applied. In these reactions a C.sub.1-4 alcohol or pyridine is the solvent of choice. (Similar selective reductions are described in the U.S. Pat. Nos. 4,423,044 and 4,835,152.)
The nitro group of the new compounds of general formula (V) are reduced to an amine group by hydrazine or hydrazine hydrate in the presence of a catalyst such as palladium, platinum or Raney nickel in a C.sub.1-4 alcohol, dioxane, tetrahydrofuran, benzene, dimethylformamide, dimethylacetamide or in a mixture thereof.
According to a preferred embodiment of the process of the present invention the reduction can be carried out in methanol by hydrazine or hydrazine hydrate in the presence of Raney nickel catalyst in a temperature range of 10.degree. to 65.degree. C. (U.S. Pat. No. 4,614,740) but, if desired, the reduction and the removal of the phthaloyl protecting group described in process d) can be performed in the same vessel.
The N-phthaloylamino acids of the general formula (IV) containing a chiral carbon atom, wherein R.sup.5 means a C.sub.1-4 alkyl group and n is 1, can be prepared from DL-, L- and/or D-alpha-amino acids.
The compounds of the general formula (I) of the invention, which contain a basic amine group, wherein R.sup.3 and R.sup.4 mean a hydrogen atom or R and/or R.sup.4 stand for an aminoacyl group, can be transformed to their acid-addition salts by known methods.
The preparation of the compounds of the general formula (II) used as starting materials in the process of the present invention is described in the U.S. Pat. No. 4,614,740, that of the compound of the general formula (III), wherein R.sup.4 stands for a hydrogen atom, in the U.S. Pat. No. 4,835,152, while that of the compound of general formula (IV) is published in the French patent specification No. 85,09793. The compounds of general formula (III), wherein R.sup.4 stands for various acyl grups, are new. The process for their preparation is described hereinafter, before Table 10, or they can be synthetized by methods described therein. The preparation of the new starting compounds of the general formula (V) is described in the Examples. The (.alpha.-.epsilon.)-amino acid derivatives of general formula (VI) are prepared by methods known from the literature [J. Am. Chem. Soc. 35, 1133 (1913); 41, 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 phthalimide potassium with the required halocarboxylic acid.
Preferably, the selective reduction of the compound of the formula IV to the compound of the general formula V, wherein R stands for a hydrogen atom, can be performed stereoselectively to produce either the (-) or (+) enantiomer, This enantioselective reduction uses a chiral hydride reagent, such as a chiral 1,3,2-oxazaborolidine derivative. These chiral boranes are generally produced by the reaction of borane (BH.sub.3) with a chiral 1,2-aminoalcohol. These preferred chiral boranes are prepared by the reaction of borane with 2-amino-3-methyl-1,1-diphenylbutan-1-ol, 2-amino-4-methyl-1,1-diphenylpentan-1-ol, or 2-amino-3-methyl-1,1-diphenylpentanol, that are readily prepared from valine, leucine, and isoleucine, respectively. See Itsuno, et al., J. Chem. Soc. Perkin Trans., 1, 2039,(1985). The most preferred chiral 1,2-aminoalcohol is (-) or (+)-2-amino-4-methyl-1,1-diphenylpentan-1-ol. The (+)-enantiomer of the formula V compound is prepared using the chiral boranes derived from D-valine, D-leucine, or D-isoleucine. Similarly, the (-)-enantiomer of the formula V compound is prepared using the chiral boranes derived from L-valine, L-leucine, or L-isoleucine. The reaction is typically carried out under an atmosphere of dry nitrogen in an organic solvent, such as dry dichloromethane or dry 1,2-dichloroethane, at a temperature of about 25.degree. C. to about 60.degree. C. When the reaction is carried out in 1,2-dichloroethane at 60.degree. C., using 1.5 equivalents of the chiral borane reagent, the reaction is complete after about 24 hours.
The compounds of the general formula (I) prepared by the process of the present invention possess central nervous system (CNS) activity, such as anticonvulsive, muscle-relaxant and neuroprotective effects, which can be shown by pharmacological tests.
In the comparative study 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (U.S. Pat. No. 4,614,740 in the following "reference compound"), having similar structure and efficacy as the compounds of the invention, was applied as reference compound. As already mentioned in the introduction, this compound proved to be Ames-positive in addition to its valuable pharmacological properties. In opposition to this 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 presented in Tables 1 to 8.
Narcosis-potentiating Effect in Mice
The narcosis-potentiating effect was tested with 3 oral doses in 10 mice/dose. The ED.sub.50 value is the dose prolonging the narcosis period induced by 50 mg/kg of i.v. sodium hexobarbital to its twofold value in 50% of the animals in comparison to the control group treated only with the vehicle. The ED.sub.50 values were calculated by the Litchfield-Wilcoxon method [J. Pharmacol. Exp. Ther. 96, 99 (1949)]. The results are presented in Table 1.
The data of Table 1 demonstrate that the efficacy of several compounds is similar or significantly superior to that of the reference compound. Compounds of Examples 15 (16), 45, 60, 73 and 98 proved to be especially potent.
Anticonvulsive Effect in Mice
The anticonvulsive effec of the compounds was measured by using the electroshock test [Swinyard: J. Pharmacol. Exp. Ther. 106, 319 (1952)], furthermore by using various chemical agents such as pentetrazole [Goodman: J. Pharmacol. Exp. Ther. 108, 168 (1953)], strychnine [Roskovski: J. Pharmacol. Exp. Ther. 129, 75 (1960)], bemegride, nicotine and 4-aminopyridine. The test compounds were orally administered in 3 doses , to 10 male CFLP mice per dose.
The results are presented in Table 2.
The above data demonstrate that the anticonvulsive effect of several test compounds (of Examples 15, 42, 45, 46, 73, 98, 107, 108, 109 and 115) is superior to that of the reference compound.
Muscle-relaxant Activity in Mice
The muscle-relaxant activity was measured in two tests. In Randall's inclined screen test [J. Pharmacol. Exp. Ther. 129, 163 (1960)] the compounds were applied in 3 i.p. doses to 10 CFLP mice per dose. The results are shown in Table 3.
The rotarod test was used to measure muscular tone and motor coordination [Dunham and Miya: J. Am. Pharm. Assoc. 46, 208 (1957)]. The results obtained with the three selected compounds of highest activity and that of the reference compound are presented in Table 4.
Tables 3 and 4 demonstrate that several compounds possess strong muscle-relaxant activity (compounds of Examples 15, 18, 42, 45, 48, 49, 62, 73, 98 and 115).
Effect on Spinal Function
The 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 Karpati: Pharm. Res. Comm. 20, S1, 141 (1988)].
The effect of the above compounds on the spinal root potentials in cats was tested in spinally immobilized animals Farkas et al.: Neuropharmacology 21, 161 (1989)].
The results are presented in Table 6.
Monosynaptic reflex-inhibiting ED.sub.50 values: Reference compound: 2.20 (1.02-4.75) mg/kg, i.v. Compound No. 15 (16): 2.30 (1.06-5.01) mg/kg, i.v.
Polysynaptic reflex-inhibiting ED.sub.50 values: Reference compound: 0.60 (0.32-1.13) mg/kg, i.v. Compound No. 15 (16): 0.73 (0.39-1.37) mg/kg, i.v.
Electrophysiological Tests
The inhibitory effects on the field potentials induced by electric stimulation in surviving rat neocortex slices in vitro [Fletcher et al., Br. J. Pharmacology 95, 585 (1988)] are summarized in Table 7.
The non-NMDA (quisqualate) antagonist effect was tested in rat neocortex slices by using the method of Harrison and Simmonds [Br. J. Pharmacol. 84, 381 (1981)]. In rat neocortex slices the DC-potential changes induced by quisqualate perfusion were dose-dependently inhibited by the reference compound in the concentration range of 10-50 .mu.M. At the concentration defined, the compound of Example 15 (16) proved to be twice as active as the reference compound in inhibiting the response to the 2-minute perfusion with 10 .mu.M of quisqualate. However, both molecules failed to affect the responses induced by NMDA. Accordingly, the compound of Example 15 (16) can be considered to be a selective, non-NMDA but quisqualate-type excitatory amino acid antagonist.
Acute Toxicity in Rats
Acute toxicity data obtained in rats are summarized in Table 8.
At toxic dose levels the compounds induced a dose-dependent muscle tone reduction, ataxia, adynamia, and loss of the righting reflex. The cause of mortality was respiratory insufficiency developing within 1 to 2 hours after i.p. administration and within 10 to 20 hours after oral application.
Based on the above pharmacological results, the compounds of general formula (I) according to the invention possess significant anticonvulsive, muscle-relaxant and excitatory amino acid-antagonist (neuroprotective) effects. Thus, they are therapeutically useful for the treatment of epilepsy as well as various diseases connected with spasms of the skeletal musculature and cerebral ischaemia (stroke).
The invention also relates to pharmaceutical compositions containing compounds of general formula (I) or pharmaceutically acceptable acid-addition salts thereof as active ingredients as well as to the preparation of these compositions.
For therapeutical use, the active compounds according to the invention are suitably formulated to pharmaceutical compositions by admixing them with commonly used nontoxic, inert, solid or liquid pharmaceutical carriers and/or auxiliary materials useful for enteral or parenteral administration. As carriers, e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc or vegetable oils can be used. As auxuliary materials, e.g. preservatives and wetting as well as emulsifying, dispersing and aromatizing agents and buffers can be employed.
By using the above-mentioned carriers and auxiliary materials, the active agents of the invention may be transformed to the usual pharmaceutical compositions, e.g. to solid compositions (such as tablets, capsules, pills or suppositories) or liquid compositions (such as aqueous or oily sulutions, suspensions, emulsions or syrups) as well as to injectable solutions, suspensions or emulsions.
For therapeutical purposes, the daily dose of the compounds of the invention amounts commonly to 0.2-1.5 mg/kg of body weight which is administered daily, optionally divided to several doses.
Based on the above facts, the present invention also provides:
a method of blocking one or more excitatory amino acid receptors in mammals. This method comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of the general formula (I);
a method of treating epilepsy in mammals. This method comprises administering to the mammal in need of such treatment an antiepileptic amount of a compound of the general formula (I);
a method of treating spasms of the skeletal musculature in mammals. This method comprises administering to the mammal in need of such treatment a muscle-relaxing amount of a compound of the general formula (I);
a method of treating cerebral ischaemia (stroke) in mammals. This method comprises administering to the mammal in need of such treatment a pharmaceutically effective amount of a compound of the general formula (I).
The compounds prepared by the process of the invention were identified by elementary analysis, their purity and structure were controlled and confirmed by thin-layer chromatography, IR, .sup.1 H-NMR, .sup.13 C-NMR and mass spectrometry.
The invention is illustrated in detail by the following non-limiting Examples.
EXAMPLE 1
1-(4-Diacetylaminophenyl)-3-acetyl-4-methylene-7,8-methylenedioxy-4,5-dihyd ro-3H-2,3-benzodiazepine
2.93 g (0.01 mol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were refluxed with 20 ml of acetic anhydride for 6 hours. The solution was evaporated at reduced pressure, the residue was taken up in 2.times.20 ml of anhydrous ethanol, the solution was repeatedly evaporated and the resulting residue of 4.55 g was submitted to column chromatography (adsorbent: Kieselgel 60, eluant: ethyl acetate--benzene 4:1). The raw product was triturated with 20 ml of hot isopropanol to yield 1.44 g (34.4%) of the aimed product, m.p. 240.degree.-245 .degree. C. (slight decomp.).
C.sub.23 H.sub.21 N.sub.3 O.sub.5 =419.445
EXAMPLE 2
1-(4-Formylaminophenyl)-4-methyl-7,8 -methylenedioxy-5H-2,3-benzodiazepine
3.0 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-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 100% formic acid were added and the reaction mixture was stirred for 2 hours at room temperature. The precipitated N,N'-dicyclohexylurea was filtered, the filtrate was exracted with 2.times.30 ml of 10% aqueous sodium carbonate solution, then with 2.times.30 ml of distilled water, the organic layer was dried and evaporated at reduced pressure. The residue was dissolved in ethyl acetate, filtered and evaporated under reduced pressure. The resulting raw product was recrystallized from 20 ml of 50% ethanol to yield 2.93 g (89.3%) of the aimed product, m.p. 152.degree.-154.degree. C. (slight decomp.).
C.sub.18 H.sub.15 N.sub.3 O.sub.3 =321.342
EXAMPLES 3 TO 7
The compounds of Examples 3 to 7 were prepared by the process described in Example 2.
EXAMPLE 3
1-(4-Cyanoacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazep ine
C.sub.20 H.sub.16 N.sub.4 O.sub.3 =360.380, m.p.: 241.degree.-243.degree. C. (decomp.).
EXAMPLE 4
1-(4-Methoxyacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiaz epine
C.sub.20 H.sub.19 N.sub.3 O.sub.4 =365.396, m.p: 203.degree.-205.degree. C.
EXAMPLE 5
1-(4-Valerylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
C.sub.22 H.sub.23 N.sub.3 O.sub.3 =377.450, m.p.: 217.degree.-219.degree. C. (decomp.).
EXAMPLE 6
1-(4-Phenylacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiaze pine
C.sub.25 H.sub.21 N.sub.3 O.sub.3 =411.467, m.p.: 245.degree.-247.degree. C. (decomp.).
EXAMPLE 7
1-(4-Cyclopropanecarbonylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-be nzodiazepine
C.sub.21 H.sub.19 N.sub.3 O.sub.3 =361.407, m.p.: 260.degree.-262.degree. C. (decomp.).
EXAMPLE 8
1-(4-Acetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
10 g (34 mmol) of 1-(4-aminophenyl)-4-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 5.times.10 ml of anhydrous ethanol and dried, yielding 9.2 g of raw product, m.p. 252.degree.-254.degree. C. (decomp.). This product was treated with 45 ml of hot 99.5% ethanol. After cooling the crystals were filtered, washed with 3.times.10 ml of ethanol and dried to give 8.68 g (76.1%) of the aimed product, m.p.: 256.degree.-258.degree. C. (decomp.).
C.sub.19 H.sub.17 N.sub.3 O.sub.3 =335.369
EXAMPLE 9
1-(4-Propionylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepin
C.sub.20 H.sub.19 N.sub.3 O.sub.3 =349.396, m.p.: 228.degree.-230.degree. C. (decomp.).
It was prepared by the process described in Example 8.
EXAMPLE 10
1-(4-Pivaloylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
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 (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.degree. C. for one hour. The precipitate formed was filtered, washed with 3.times.5 ml of dichloromethane, then with 3.times.20 ml of water and dried to yield 1.59 g of pure product, m.p. 225.degree.-227.degree. C. (decomp.). The other portion of the product was isolated from the organic phase. The filtrate was extracted with 3.times.20 ml of water, then with 3.times.15 ml of 4% aqueous sodium hydroxide solution, finally with 2.times.30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressure. The crystalline residue was combined with the former product of 1.59 g and suspended in 20 ml of hot ethanol. The product was filtered after cooling, washed with 3.times.3 ml of ethanol and dried to yield 3.38 g (87.8%) of the pure product, m.p.: 225.degree.-227.degree. C. (decomp.).
C.sub.22 H.sub.23 N.sub.3 O.sub.3 =377.450
EXAMPLE 11
1-(4-Benzoylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
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.degree. C. for 24 hours. The solution was extracted with 3.times.30 ml of water, 3.times.20 ml of a 4% aqueous sodium hydroxide solution and finally with 2.times.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 obtain 3.97 g of raw product, m.p. 242.degree.-243.degree. C. This raw product was repeatedly treated with 20 ml of hot ethanol, next day it was filtered at 0.degree.-5.degree. C., washed with 3.times.3 ml of ethanol and dried at 100.degree. C. to yield 3.85 g (71.3%) of the pure aimed product, m.p. 246.degree.-247.degree. C. (decomp.).
C.sub.24 H.sub.19 N.sub.3 O.sub.3 =397.40
EXAMPLE 12
1-(4-Palmitoylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepin e
By following the process described in Example 11, with recrystallization of the raw product from 50% ethanol, the pure aimed product was obtained, m.p. 138.degree.-140.degree. C.
C.sub.33 H.sub.45 N.sub.3 O.sub.3 =531.747
EXAMPLE 13
1-(4-Phenylcarbamoylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi azepine
0.22 ml (2.04 mmol) of phenyl isocyanate was added to a solution of 0.50 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 4 ml of dimethylformamide and the reaction mixture was stirred at 25.degree. C. for one hour. Then it was diluted with 20 ml of diethyl ether and filtered at 5.degree. C. The crystals were washed with 2.times.5 ml of diethyl ether and dried at 60.degree.-100.degree. C. The resulting 0.70 g of raw product, m.p. 239.degree.-240.degree. C. (sintering at 180.degree. C.) was refluxed in 15 ml of ethanol, filtered after cooling, washed wtih 3.times.1 ml of ethanol and dried at 100.degree. C. to yield 0.55 g (78.6%) of the aimed product, m.p. 240.degree.-241.degree. C. (decomp.).
C.sub.24 H.sub.20 N.sub.4 O.sub.3 =412.456
EXAMPLE 14
1-[4-(4-Carboxybutyrylamino)phenyl]-4-methyl-7,8-methylenedioxy-5H-2,3-benz odiazepine
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.degree.-25.degree. C. for 6 hours. Next day he crystals formed were filtered at 0.degree.-5.degree. C., washed with 3.times.2 ml of dichloromethane and dried at 60.degree.-80.degree. C. to give 0.60 g (87.0%) or the pure aimed product, m.p. 225.degree.-227.degree. C. (decomp.).
C.sub.22 H.sub.21 N.sub.3 O.sub.5 =407.434
EXAMPLE 15
1-(4-Aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepin e
To a solution of 3.58 g (12.1 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine in 100 ml of chloroform first 1.68 ml (12.1 mmol) of triethylamine, then under constant ice-cooling and stirring 1.15 ml (12.1 mmol) of acetic anhydride were added. Stirring was continued for additional 2 hours, then the solution was extracted with 3.times.100 ml of water, the organic layer was dried and evaporated under reduced pressure. The crystalline residue was recrystallized from 40 ml of isopropanol to obtain 3.50 g (85.7%) of the aimed product, m.p. 220.degree.-222.degree. C. After repeated recrystallization the m.p. increased to 223.degree.-225.degree. C.
C.sub.19 H.sub.19 N.sub.3 O.sub.3 =337.385
Hydrochloride: (C.sub.19 H.sub.20 N.sub.3 O.sub.3)Cl=373.850, m.p.: 248.degree.-252.degree. C. (decomp.).
EXAMPLE 16
1-(4-Aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-b enzodiazepine
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 of 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, then the reaction mixture was stirred at 20.degree.-25.degree. C. for one hour. The starting nitro derivative was dissolved within 10-20 minutes. After filtering the filtrate was evaporated under reduced pressure, the white crystalline residue was washed with 30 ml of distilled water onto a filter, it was washed with 3.times.10 ml of distilled water and dried at 100.degree. C. to give 1.50 g of a raw product, m.p. 218.degree.-220.degree. C. This raw product was purified by treating with 12 ml of hot isopropanol. After cooling it was filtered at 5 .degree. C., washed with 3.times.1 ml of isopropanol and dried at 100.degree. C. to yield 1.40 g (77.35%) of a white crystalline powder, m.p. 221.degree.-223.degree. C. On the basis of analyses and spectra it was identical to the product of Example 15 obtained by a different process.
EXAMPLE 17 TO 25
The process described in Example 16 was followed for preparing other 1-(4-aminophenyl)-3-R-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo diazepines of the general formula (I). The data of the products prepared are presented in Table 9.
The new nitro compounds of the general formula (V), wherein R=H or acyl group, used in the preparation of products of Examples 16 to 25, can be prepared by processes described in Examples 26 to 36.
EXAMPLE 26
1-(4-Nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaze pine
To a suspension of 5.0 g (15.5 mmol) of the known 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (French patent specification No. 85,09793) in 380 ml of ethanol first 22.5 ml (0.278 mol) of concentrated hydrochloric acid were added at constant stirring whereupon a solution was formed within a few minutes, then 11.5 g (0.3 mole) of sodium borohydride were charged into the solution portionwise during 30 minutes. Stirring was continued for 15 minutes, then the orange-coloured precipitate formed was filtered and extracted on the filter with 4.times.30 ml of chloroform. 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.times.20 ml of distilled water and dried at 80.degree.-100.degree. C. to yield 4.90 g (97.2%) of the aimed product, m.p.: 162.degree.-164.degree. C.
C.sub.17 H.sub.15 N.sub.3 O.sub.4 =325.331
EXAMPLE 27
1-(4-Nitrophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-b enzodiazepine
A 2.0 g (6.15 mmol) portion of the product of Example 26 was stirred with 10 ml of acetic anhydride at 25.degree. C. for 3 hours then 50 ml of distilled water were added and the stirring was continued for one hour. The yellow precipitate formed was filtered, washed with 3.times.10 ml of distilled water and dried at 80.degree.-100.degree. C. to obtain 2.6 g of raw product. After recrystallization from 10 ml of ethanol 1.94 g (85.8%) of the aimed product were obtained, m.p.: 140.degree.-142 .degree. C.
C.sub.19 H.sub.17 N.sub.3 O.sub.5 =367.369
EXAMPLE 28
1-(4-Nitrophenyl)-3-trifluoroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine
To a solution of a 1.5 g (4.61 mmol) portion of the product of Example 26 in 30 ml of anhydrous dichloromethane 0.75 ml (5.3 mmol) of trifluoroacetic acid anhydride and 0.75 ml (5.3 mmol) of triethylamine were added and the reaction mixture was stirred at 25.degree. C. for 3 hours. Subsequently, the mixture was extracted with 3.times.20 ml of water and the organic layer was dried and evaporated under reduced pressure. The crystalline residue was treated with 15 ml of hot ethanol, cooled, filtered, washed with 3.times.1 ml of ethanol and dried at 80.degree.-100.degree. C. to yield 1.84 g (94.85%) of the aimed compound as a bright yellow crystalline product, m.p.: 165.degree.-167.degree. C. (decomp.).
C.sub.19 H.sub.14 F.sub.3 N.sub.3 O.sub.5 =421. 339
EXAMPLE 29
1-(4-Nitrophenyl)-3-propionyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2, 3-benzodiazepine
A 1.54 g (4.7 mmol) portion of the product of Example 26 was stirred with 8 ml of propionic acid anhydride at 25.degree. C. for 3 hours, then 30 ml of diethyl ether were added and the solution was kept at 0.degree.-5.degree. C. overnight. The precipitate formed was filtered, washed with 3.times.8 ml of diethyl ether and dried to yield 1.32 g (73.7%) of the aimed compound as a light yellow product, m.p.: 189.degree.-190.degree. C.
C.sub.20 H.sub.19 N.sub.3 O.sub.5 =381.396
EXAMPLE 30
1-(4-Nitrophenyl)-3-valeryl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3- benzodiazepine
To a solution of a 2.5 g (7.68 mmol) portion of the product of Example 26 in 40 ml of anhydrous dichloromethane 4.75 g (23 mmol) of dicyclohexylcarbodiimide and 2.88 g (23 mmol) of n-valeric acid were added and the reaction mixture was maintained at 25.degree. C. under intermittent stirring for 24 hours. Then the N,N'-dicyclohexylurea formed as by-product was filtered, the filtrate was evaporated under reduced pressure, the residue was mixed with 2.times.40 ml of distilled water, decanted and the wet product was left to solidify under 50 ml of 50% ethanol. The solid compound was filtered, washed with 2.times.10 ml of 50% ethanol and dried at 80.degree. C. The raw product obtained was recrystallized from 24 ml of ethanol and the crystals were dried at 100.degree. C. to yield 2.20 g (70%) of the aimed product as a yellow powder, m.p.: 145.degree.-147.degree. C.
C.sub.22 H.sub.23 N.sub.3 O.sub.5 =409.450
EXAMPLE 31
1-(4-Nitrophenyl)-3-pivaloyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3 -benzodiazepine
By following the process described in Example 28 but applying pivaloyl chloride insted of trifluoroacetic acid anhydride, 1.68 g (89.4%) of the aimed product were obtained, m.p.: 164.degree.-166.degree. C.
C.sub.22 H.sub.23 N.sub.3 O.sub.5 =409.450
EXAMPLE 32
1-(4-Nitrophenyl)-3-benzoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3- benzodiazepine
By following the process described in Example 31 but using benzoyl chloride as acyl chloride, 1.72 g (86.9%) of an ochre yellow product were obtained, m.p.: 222.degree.-224.degree. C. (decomp.).
C.sub.24 H.sub.19 N3O.sub.5 =429.440
EXAMPLE 33
1-(4-Nitrophenyl)-3-phenylacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H -2,3-benzodiazepine
By following the process described in Example 30 but using 50% of the calculated molar amount of dicyclohexylcarbodiimide and phenylacetic acid, a bright yellow product was obtained, m.p.: 193.degree.-195.degree. C.
C.sub.25 H.sub.21 N.sub.3 O.sub.5 =443.467
EXAMPLES 34 TO 36
The products of Examples 34 to 36 were obtained by following the process described in Examle 33 and using the respective acid components.
EXAMPLE 34
1-(4-Nitrophenyl)-3-cyclopropanecarbonyl-4-methyl-7,8-methylenedioxy-3,4-di hydro-5H-2,3-benzodiazepine
M.p.: 225.degree.-228.degree. C. (decomp.).
C.sub.21 H.sub.19 N.sub.3 O.sub.5 =393.407
EXAMPLE 35
1-(4-Nitrophenyl)-3-cyanoacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H- 2,3-benzodiazepine
M.p.: 185.degree.-188.degree. C.
C.sub.20 H.sub.16 N.sub.4 O.sub.5 =392.380
EXAMPLE 36
1-(4-Nitrophenyl)-3-methoxyacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5 H-2,3-benzodiazepine
M.p.: 187.degree.-189.degree. C.
C.sub.20 H.sub.19 N.sub.3 O.sub.6 =397.396
EXAMPLE 37
1-(4-Nitrophenyl)-3-(4-carboxybutyryl)-4-methyl-7,8-methylenedioxy-3,4-dihy dro-5H-2,3-benzodiazepine
By using the product of Example 26 as starting material and performing the acylation according to Example 14 with glutaric acid anhydride, finally recrystallizing the raw product from ethanol the pure aimed product was obtained,
m.p.: 148.degree.-150.degree. C.
C.sub.22 H.sub.21 N.sub.3 O.sub.7 =439.434
EXAMPLE 38
1-(4-Aminophenyl)-3-phenylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine
To a solution of 0.70 g (2.3 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine in 10 ml of anhydrous benzene 0.24 ml (2.3 mmol) of phenyl isocyanate was 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 hot 50% ethanol. The suspension was cooled to 0.degree. C. and filtered to yield 0.76 g of a raw product, m.p. 190.degree.-200.degree. C. After recrystallization from 99.5% ethanol and trituration with ethyl acetate the aimed compound melts at 207.degree.-209.degree. C.
C.sub.24 H.sub.22 N.sub.4 O.sub.3 =414.472
The preparation of the starting material of this example was described in the Hungarian patent specification No. 198,494. However, the compound may also be prepared by a new method according to the process of Example 16, by using the compound of Example 26 as starting material to give excellent yields (84%). The raw product may be recrystallized from 50% ethanol, m.p.: 118.degree.-120.degree. C.
EXAMPLE 39
1-(4-Diacetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro- 5H-2,3-benzodiazepine
2.0 g <6.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine were refluxed with 40 ml of acetic anhydride for 3 hours, then 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.times.3 ml of water. After drying 2.79 g of the raw triacetyl derivative were obtained. After washing with 20 ml of isopropanol and drying at 100.degree. C. 2.39 g (84.6%) of the pure aimed product were obtained, m.p. 224.degree.-227.degree. C.
C.sub.23 H.sub.23 N.sub.3 O.sub.5 =421.461
EXAMPLE 40
N.sup.1 -[4-(3-Acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepin -1-yl)-phenyl]-N.sup.3 -methylurea
0.70 g (2 mmol) of the product of Example 15 was dissolved in benzene dehydrated over calcium hydride, 0.3 ml (5 mmol) of methyl isocyanate was added and the reaction mixture was stirred at 50.degree. C. for 4 hours. The crystals formed after coling were filtered, washed with 3.times.3 ml of benzene, then triturated with 20 ml of hot benzene. The hot mixture was filtered, the precipitate was washed with 3.times.3 ml of benzene and dried to give 0.65 g (79.6%) of the aimed product, m.p.: 168.degree.-170.degree. C. (decomp.).
C.sub.21 H.sub.22 N.sub.4 O.sub.4 =394.439
EXAMPLE 41
N.sup.1 -[4-(3-Acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepin -1-yl)-phenyl]-N.sup.3 -phenylurea
By following the process described in Example 40 but using phenyl isocyanate instead of methyl isocyanate, refluxing the reaction mixture for 10 hours, evaporating it under reduced pressure, then suspending the residue first in 50 ml of diethyl ether and then in 15 ml of ethyl acetate, 0.69 g (75.7%) of the aimed product was obtained, m.p.: 184.degree.-186.degree. C. (decomp.).
C.sub.26 H.sub.24 N.sub.4 O.sub.4 =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 mmol) of 1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3- benzodiazepine were stirred at 20.degree.-25.degree. C. with 5 ml of acetic anhydride for one hour, then the yellow solution was poured into 100 g of ice-water and stirred until the decomposition of the excess anhydride became complete. The precipitate formed was filtered, washed with 3.times.10 ml of distilled water and dried to give 1.6 g of raw product. After recrystallization from 20 ml of benzene 1.50 g (89.85%) of the aimed product were obtained, m.p.: 158.degree.-160.degree. C. (decomp.).
C.sub.21 H.sub.21 N.sub.3 O.sub.4 =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 0.degree. C. during 5 minutes while constant stirring. The stirring was continued at 50.degree. C. for 15 minutes. Thereafter 1 g (3.3 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine was added to the thus-prepared mixed anhydride. The reaction mixture was stirred at 25.degree. C. for 1.5 hours, then poured into ice-water, the precipitate formed was filtered, washed with 4.times.5 ml of distilled water and dried at 80.degree. C. to give 0.80 g of raw product. After crystallization from 3 ml of ethyl acetate 0.65 g (56.2%) of the aimed product was obtained, m.p.: 193.degree.-195.degree. C.
C.sub.19 H.sub.17 N.sub.3 O.sub.4 =351.369
EXAMPLE 44
1-(4-Trifluoroacetylaminophenyl)-3-trifluoroacetyl-4-methyl-7,8-methylenedi oxy-3,4-dihydro-5H-2,3-benzodiazepine
1.48 g (5 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine were dissolved in 30 ml of anhydrous chloroform, then 2.1 ml (15 mmol) of triethylamine and at 20.degree.-25.degree. 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.times.30 ml of water and thereafter with 20 ml of 5% hydrochloric acid. 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 give 1.41 g (57.9%) of the aimed diacyl derivative, m.p. 177.degree.-178.degree. C.
C.sub.21 H.sub.15 F.sub.6 N.sub.3 O.sub.4 =487.363
EXAMPLE 45
1-(4-Propionylaminophenyl)-3-propionyl-4-methyl-7,8-methylenedioxy-3,4-dihy dro-5H-2,3-benzodiazepine
The process described in Example 44 was followed, except that 11.2 mmol of both triethylamine and propionic acid anhydride were used and the crystalline residue was recrystallized first from 15 ml of 50% ethanol, then from 11.5 ml of 99% ethanol to give 2.48 g (60.9%) of the aimed product, m.p.: 152.degree.-154.degree. C.
C.sub.23 H.sub.25 N.sub.3 O.sub.4 =407.477
EXAMPLES 46 TO 65
Other diacyl derivatives of the general formula (I), wherein R=acyl group, R.sup.1 .dbd.R.sup.3 .dbd.H, R.sup.2 .dbd.CH.sub.3 and R.sup.4 =acyl group, where R and R.sup.4 are the same or different, are presented in Table 10. These compounds were prepared partly from compounds of the general formula (III), wherein R.dbd.R.sup.1 .dbd.R.sup.3 .dbd.H and R.sup.4 =acyl group; and partly from new compounds of the general formula (I), wherein R=acyl group, R.sup.1 .dbd.R.sup.3 .dbd.R.sup.4 .dbd.H and R.sup.2 .dbd.CH.sub.3, according to processes defined in the preceding examples.
The preparation of starting substances of general formula (III), wherein R.dbd.R.sup.1 .dbd.R.sup.3 .dbd.H and R.sup.4 =acyl group is illustrated in detail below on the derivative bearing acetyl group as R.sup.4 :
1-(4-Acetylaminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benz odiazepine
Method A)
To a solution containing 6.0 g (20 mmol) 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine 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.times.5 ml of ethyl acetate. The dry weight of the product was 7.37 g, m.p.: it sintered above 190.degree. C. and weakly decomposed at 210.degree.-212.degree. C. The thus-obtained methanesulfonate salt of the starting substance 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.times.10 ml of ethyl acetate and dried to give 6.54 g of methanesulfonate salt of the target compound, m.p. 240.degree.-241.degree. C. (with decomposition).
The base was 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 clarified by charcoal, then 3.6 g of sodium hydrogen carbonate were portionwise added to the clear solution. The precipitate was filtered, washed with 5.times.10 ml of water and dried to-obtain 5.54 g of crude product. After recrystallization from 130 ml of isopropanol, 3.11 g (yield 46%) of product were obtained, m.p.: 221.degree.-223.degree. C. (weak decomposition), the melting point of which increased to 223.degree.-225.degree. C. after digesting with 15 ml of hot benzene.
C.sub.19 H.sub.19 N.sub.3 O.sub.3 =337.385
The hydrochloride salt decomposed at 262.degree.-264.degree. C.
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 mild heating, 10.2 g (0.269 mol) of sodium borohydride were added and the mixture was stirred an an oil bath at a temperature of 100.degree. C. for 5 hours. Then the reaction mixture was cooled to about 25.degree. C., 150 ml of water were dropwise added under continuous stirring during 20 minutes, thereafter a mixture containing 180 ml of concentrated hydrochloric acid and 265 ml of water was added while cooling with ice-water. A yellowish suspension was formed. The precipitate was filtered, washed with 5.times.20 ml of water and dried to yield 15.2 g of salt, m.p. above 250.degree. C. In order to liberate the base, this salt was suspended in 150 ml of 50% ethanol and then 5.7 g of sodium hydrogen carbonate were portionwise added while stirring. The thus-formed suspension was filtered after 30 minutes, washed successively with 3.times.10 ml of 50% ethanol, 5.times.20 ml of water, finally with 20 ml of 50% ethanol and dried to obtain 10.95 g of a crude product, m.p.: 218.degree.-220.degree. C. (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%) of the aimed compound were obtained, m.p.: 220.degree.-222.degree. C. (weak decomposition).
Physical characteristics of other 1-(4-acylaminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzo diazepine are as follows:
EXAMPLE 66
1-(4-Glycylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine
To a suspension of 2.89 g (5.97 mmol) of 1-(4-phthaloylglycylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzod iazepine (Example 79) in 50 ml of methanol 0.6 ml (11.9 mmol) of 100% hydrazine hydrate was added and the mixture was refluxed 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 by-product was washed with 2.times.10 ml of dichloromethane. The solution was extracted with 3.times.15 ml of 5% hydrochloric acid the aqueous layer was made alkaline with 24 ml of aqueous 10% sodium hydroxide, the precipitate formed was filtered, washed with 3.times.10 ml of distilled water and dried at 100.degree. C. to obtain 1.67 g of raw product. After recrystallization from 73 ml of ethanol 1.50 g (71.8%) of the aimed product were obtained, m.p.: 223.degree.-225.degree. C.
C.sub.19 H.sub.18 N.sub.4 O.sub.3 =350.385
EXAMPLES 67 TO 78
Other compounds of the general formula (I), wherein R.sup.2 .dbd.CH.sub.3, R.sup.3 .dbd.H, and some of their acid addition salts, prepared by the process of Example 66, are presented in Table 11. The salts were prepared by known methods.
EXAMPLE 79
1-[4-(N-Phthaloylglycylamino)phenyl]-4-methyl-7,8-methylenedioxy-5H-2,3-ben zodiazepine
To a solution of 2.0 g (6.88 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in dichloromethane 1.84 g (8.94 mmol) of dicyclohexylcarbodiimide and 1.84 g (8.94 mmol) of powdered phthalimidoacetic acid were added and the reaction mixture was stirred at 25.degree. C. for 8 hours, then left to stand at 0.degree.-5.degree. C. overnight. The precipitate formed was filtered, washed with 3.times.3 ml of dichloromethane and dried at 60.degree.-80.degree. C. to result in 5 g of a product consisting of a mixture of the target product and N,N'-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.times.10 ml of hot ethanol, thereafter drying at 100.degree. C. to obtain 2.42 g (73.3%) of the aimed product, m.p.: 266.degree.-268.degree. C. (decomp.).
C.sub.27 H.sub.20 N.sub.4 O.sub.5 =480.489
EXAMPLE 80
1-[4-(N-Phthaloyl-.gamma.-aminobutyrylamino)phenyl]-4-methyl-7,8-methylened ioxy-5H-2,3-benzodiazepine
By following the process described in Example 79 but using -phthalimidobutyric acid, 3.8 g of a mixture were obtained, which was combined with the dichloromethane mother liquor extracted previously with 2.times.40 ml of a 10% aqueous sodium carbonate solution. After evaporating under reduced pressure the residue was submitted to column chromatography [adsorbent: Kieselgel 60 (0.063-2 mm), eluent: ethyl acetate-methanol 4:1]. She evaporation residue was triturated with 10 ml of hot ethanol, cooled, filtered, washed with 3.times.1 ml of ethanol and dried to give 3.12 g (90%) of the aimed product, m.p.: 233.degree.-235.degree. C. (decomp.).
C.sub.29 H.sub.24 N.sub.4 O.sub.5 =508.543
EXAMPLE 81
1-[4-(N-Phthaloyl-DL-alanylamino)phenyl]-4-methyl-7,8-methylenedioxy-5H-2,3 -benzodiazepine
The process described in Example 79 was followed, except that N-phthaloyl-DL-alanine (DL-2-phthalimidopropionic acid) was used. After filtering the slight 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. The purification of the residue was achieved by refluxing it with 60 ml of ethyl acetate. Crystal formation was already started in the hot solution. The crystals were filtered at 0.degree.-5.degree. C., the nearly white crystal powder was washed with 3.times.3 ml of ethyl acetate and dried at 100.degree. C. to give 2.75 g (80.95%) of the aimed product, m.p.: 243.degree.-245.degree. C. (decomp.).
C.sub.28 H.sub.22 N.sub.4 O.sub.5 =494.516
EXAMPLE 82
1-(4-Nitrophenyl)-3-glycyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-b enzodiazepine
The process described in Example 66 was followed by using the compound prepared according to Example 85 as starting material, but the dichloromethane solution was extracted only with 3.times.20 ml of distilled water and the organic layer was evaporated under reduced pressure. The crystalline residue was purified by suspending it in 7 ml of ethanol to give the pure aimed product in a yield of 86.1%, m.p.: 201.degree.-203.degree. C. (decomp.) .
C.sub.19 H.sub.18 N.sub.4 O.sub.5 =382.385
EXAMPLE 83
1-(4-Nitrophenyl)-3-(.gamma.-aminobutyryl)-4-methyl-7,8-methylenedioxy-3,4- dihydro-5H-2,3-benzodiazepine
By following the process described in Example 82 and using the compound prepared according to Example 86 as starting material, a product containing crystal solvent was obtained in a yield of 89.4%, m.p. 110.degree.-112.degree. C. (recrystallized from 50% ethanol).
C.sub.21 H.sub.22 N.sub.4 O.sub.5 =410.439
EXAMPLE 84
1-(4-Nitrophenyl)-3-(DL-alanyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H- 2,3-benzodiazepine
By following the process described in Example 82 and using the compound pepared according to Example 87 the aimed compound was obtained, m.p. 220.degree.-221.degree. C. (decomp.).
C.sub.20 H.sub.20 N.sub.4 O.sub.5 =396.412
EXAMPLES 85 TO 87
The new intermediates employed in Examples 82 to 84 as starting materials were prepared from the compound prepared according to Example 26 by the process of Example 81.
EXAMPLE 85
1-(4-Nitrophenyl)-3-(N-phthaloylglycyl)-4-methyl-7,8-methylenedioxy-3,4-dih ydro-5H-2,3-benzodiazepine
Yield: 93.3%, m.p.: 173.degree.-174.degree. C. (decomp.) .
C.sub.27 H.sub.20 N.sub.4 O.sub.7 =512.489
EXAMPLE 86
1-(4-Nitrophenyl)-3-(N-phthaloyl-.gamma.-aminobutyryl)-4-methyl-7,8-methyle nedioxy-3,4-dihydro-5H-2,3-benzodiazepine
M.p.: 218.degree.-220.degree. C.
C.sub.29 H.sub.24 N.sub.4 O.sub.7 =540.543
EXAMPLE 87
1-(4-Nitrophenyl)-3-(N-phthaloyl-DL-alanyl)-4-methyl-7,8-methylenedioxy-3,4 -dihydro-5H-2,3-benzodiazepine
M.p.: 210.degree.-212.degree. C.
C.sub.28 H.sub.22 N.sub.4 O.sub.7 =526.516
EXAMPLES 88 TO 94
The intermediates of the general formula (I), wherein R and/or R4 represent(s) C.sub.1-6 acyl group(s) substituted by a phthalimido group, are required for the preparation of compounds obtained by using the processes of Examples 73 to 78 and summarized in Table 12. They were prepared from the compound of Example 15 (16) or from a compound of the general formula (III), wherein R.sub.4 is hydrogen (see U.S. Pat. No. 4,835,152) or from 1-(4-acetylaminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-ben zodiazepine described hereinabove (before Table 10) by following the process of Example 81.
As a matter of course, in Example 93 a twofold amount of phthaloylglycine and dicyclohexylcarbodiimide have to be used. Thus, Table 12 lists new compounds of the general formula (I), wherein R and R.sup.4 are acyl groups, R.sup.1 .dbd.R.sup.3 .dbd.H and R.sup.2 .dbd.CH.sub.3.
EXAMPLE 95
1-(4-Aminophenyl)-3-(.gamma.-aminobutyryl)-4-methyl-7,8-methylenedioxy-3,4- dihydro-5H-2,3-benzodiazepine hydrogen fumarate
It was prepared from the compound of Example 83 by following Example 16, m.p.: 150.degree.-152.degree. C. (decomp.)
[C.sub.29 H.sub.25 N.sub.4 O.sub.3 ].C.sub.4 H.sub.3 O.sub.4 =496.531
EXAMPLE 96
1-(4-Aminophenyl)-3-(4-carboxybutyryl)-4-methyl-7,8-methylenedioxy-3,4-dihy dro-5H-2,3-benzodiazepine hydrochloride
It was obtained from the compound of Exyample 37, according to Example 16, m.p.: 224.degree.-226.degree. C. (decomp.).
[C.sub.22 H.sub.24 N.sub.3 O.sub.5 ]Cl=445.915
EXAMPLE 97
1-(4-Trifluoroacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi azepine
It was prepared by following Example 2, m.p.: 258.degree.-260.degree. C. (decomp.).
C.sub.19 H.sub.14 F.sub.3 N.sub.3 O.sub.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-dihydr o-5H-2,3-benzodiazepine according to Example 16, m.p. 199.degree.-201.degree. C.
C.sub.19 H.sub.20 N.sub.4 O.sub.3 =352.401
Hydrochloride m.p. 219.degree.-221.degree. C. (decomp.).
[C.sub.19 H.sub.21 N.sub.4 O.sub.3 ]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 mmol) of 1-(4-nitrophenyl)-4-methyl-7,8-methylene-dioxy-3,4-dihydro-5H-2,3-benzodia zepine (see Example 26) dissolved in 60 ml of dichloromethane and stirred for 24 hours, then evaporated under reduced pressure. The crystalline residue was triturated with 30 ml of hot ethanol at 80.degree. to 100.degree. C. to obtain 3.35 g (95%) of the lemon-yellow aimed product, m.p.: 238.degree.-240.degree. C. (decomp.).
C.sub.19 H.sub.18 N.sub.4 O.sub.5 =382.385
EXAMPLE 99
1-(4-Aminophenyl)-3-(1-pyrrolidinoacetyl)-4-methyl-7,8-methylenedioxy-3,4-d ihydro-5H-2,3-benzodiazepine
It was obtained from 1-(4-nitrophenyl)-3-(1-pyrrolidinoacetyl)-4-methyl-7,8-methylenedioxy-3,4- dihydro-5H-2,3-benzodiazepine by following Example 16, m.p.: 212.degree.-214.degree. C.
C.sub.23 H.sub.26 N.sub.4 O.sub.3 =406.493
The starting substance was obtained from 1-(4-nitrophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5 H-2,3-benzodiazepine (see Example 116) according to Example 102, m.p.: 189.degree.-190.degree. C. (decomp.).
C.sub.23 H.sub.24 N.sub.4 O.sub.5 =436.477
EXAMPLE 100
1-(4-Aminophenyl)-3-(N,N-dimethylglycyl)-4methyl-7,8-methylenedioxy-3,4-dih ydro-5H-2,3-benzodiazepine hydrogen fumarate
It was prepared fr4om 1-(4-nitrophenyl)-3-(N,N-dimethylglycyl)-4-methyl-7,8-methylenedioxy-3,4-d ihydro-5H-2,3-benzodizapine according to Example 16, m.p.: 202.degree.-204.degree. C. (decomp.).
[C.sub.21 H.sub.25 N.sub.4 O.sub.3 ]C.sub.4 H.sub.3 O.sub.4 =496.531
The starting substance was obtained from 1-(4-nitrophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5 H-2,3-benzodiazepine according to the process described in Example 103, m.p.: 158.degree.-160.degree. C.
C.sub.21 H.sub.22 N.sub.4 O.sub.5 =410.439
EXAMPLE 101
1-(4-Chloroacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiaze pine
It was prepared according to Example 2, except that chloroacetic acid was used, m.p.: 209.degree.-214.degree. C. (carbonization).
C.sub.19 H.sub.16 ClN.sub.3 O.sub.3 =369.818
EXAMPLE 102
1-[4-(1-Pyrrolidinoacetylamino)phenyl]-4-methyl-7,8-methylenedioxy-5H-2,3-b enzodiazepine
0.71 ml (8.53 mmol) of pyrrolidine was added to a suspension of 1.5 g (406 mmol) of 1-(4-chloroacetyl-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodia zepine in 60 ml of ethanol and the reaction mixture was refluxed for 4 hours, then evaporated under reduced pressure. The residue was treated with water to give a rough product (1.49 g), m.p.: 186.degree.-188.degree. C. After recrystallization from 12 ml of ethanol 1.22 g (74.4%) of the aimed product were obtained, m.p.: 210.degree.-212.degree. C.
C.sub.23 H.sub.24 N.sub.4 O.sub.3 =404.477
EXAMPLE 103
1-[4-(N,N-dimethylglycylamino)phenyl]-4-methyl-7,8-methylenedioxy-5H-2,3-be nzodiazepine
After adding 0.66 g (8.12 mmol) of dimethylamine hydrochloride and 1.86 ml (13.4 mmol) of triethylamine to a suspension of 1.5 g (4.06 mmol) of 1-(4-chloroacetyl-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodia zepine 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.times.20 ml of distilled water, dried and evaporated under reduced pressure. After treating with water, the crystalline residue was filtered to give 1.27 g of raw product, m.p. 211.degree.-213.degree. C. After recrystallization from 10 ml of ethanol 1.1 g (71.4%) of aimed product were obtained, m.p.: 213.degree.-215.degree. C.
C.sub.21 H.sub.22 N.sub.4 O.sub.6 =378.439
EXAMPLE 104
1-(4-Methylcarbamoylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodi azepine
0.8 ml (13.4 mmol) of methyl isocyanate was added to a solution containing 1.0 g (3.41 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 8 ml of dimethylformamide (DHF), then the reaction mixture was stirred at 25.degree. C. for 24 hours. After diluting with 80 ml of water, filtering at 5.degree. C. and drying at 60.degree. to 100.degree. C., 1.06 g of raw product, m.p.: 204.degree.-207.degree. C. (sintering from 160.degree. C.) were obtained which, when recrystallized from 5 ml of ethanol, gave 0.85 g (71.4%) of the aimed product, m.p.: 223.degree.-224.degree. C. (decomp.).
C.sub.19 H.sub.18 N.sub.4 O.sub.3 =350.385
EXAMPLE 105
1-(4-Acetylaminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-d ihydro-5H-2,3-benzodiazepine
It was prepared from 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydr o-5H-2,3-benzodiazepine by using the process of Example 42. The raw product was recrystallized from ethyl acetate to give 71.4% of the aimed product, m.p.: 150.degree.-152.degree. C.
C.sub.21 H.sub.22 N.sub.4 O.sub.4 =394.439
EXAMPLE 106
1-(4-Chloroacetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihy dro-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 by using the process of Example 2, m.p.: 139.degree.-140.degree. C.
C.sub.21 H.sub.20 ClN.sub.3 O.sub.4 =413.972
EXAMPLE 107
1-[4-(N,N-dimethylglycylamino)phenyl]-3-acetyl-4-methyl-7,8-methylenedioxy- 3,4-dihydro-5H-2,3-benzodiazepine
It was prepared from the product of the preceding Example by using the process described in Examle 103, m.p.: 206.degree.-208.degree. C.
C.sub.23 H.sub.26 N.sub.4 O.sub.4 =422.493
EXAMPLE 108
1-[4-(N,N-diethylglycylamino)phenyl]-3-acetyl-4-methyl-7,8-methylenedioxy-3 ,4-dihydro-5H-2,3-benzodiazepine
It was prepared from 1-(4-chloroacetylaminophenyl)-3-acetyl-4-methyl -7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine and diethylamine by using the process described in Example 102, m.p. 175.degree.-176.degree. C.
C.sub.25 H.sub.30 N.sub.4 O.sub.4 =450.547
EXAMPLE 109
1-[4-(1-Pyrrolidinoacetylamino)phenyl]-3-acetyl-4-methyl-7,8-methylenedioxy -3,4-dihydro-5H-2,3-benzodiazepine hydrogen fumarate
It was prepared from 1-(4-chloroacetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dih ydro-5H-2,3-benzodiazepine by using the process of Example 2 and isolated in the form of hydrogen fumarate, m.p. 181.degree.-183.degree. C. (decomp.).
[C.sub.25 H.sub.29 N.sub.4 O.sub.4 ].C.sub.4 H.sub.3 O.sub.4 =564.607
EXAMPLE 110
1-(4-Acetylaminophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihy dro-5H-2,3-benzodiazepine
It was prepared from the compound of general formula (III), wherein R.sup.4 .dbd.COCH.sub.3, by using the process of Examle 2 and chloroacetic acd instead of formic acid, m.p. 138.degree.-140.degree. C.
C.sub.21 H.sub.20 ClN.sub.3 O.sub.4 =413.972
EXAMPLE 111
1-[4-(N,N-diethylglycylamino)phenyl]-4-methyl-7,8-methylenedioxy-5H-2,3-ben zodiazepine
It was prepared from 1-(4-chloroacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiaz epine by using the process of Example 102, except that diethylamine was used instead of pyrrolidine, m.p.: 157.degree.-158.degree. C.
C.sub.23 H.sub.26 N.sub.4 O.sub.3 =406.493
EXAMPLE 112
1-(4-Acetylaminophenyl)-3-cyclopropanecarbonyl-4-methyl-7,8-methylenedioxy- 3,4-dihydro-5H-2,3-benzodiazepine
It was prepared from 1-(4-aminophenyl)-3-cyclopropanecarbonyl-4-methyl-7,8-methylenedioxy-3,4-d ihydro-5H-2,3-benzodiazepine by using the process of Example 42, m.p.: 242.degree.-243.degree. C.
C.sub.23 H.sub.23 N.sub.3 O.sub.4 =405.461
EXAMPLE 113
N.sup.1 -[4-(3-Methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benz odiazepin-1-yl)phenyl]-N.sup.3 -methylurea
After adding 0.5 ml (8.5 mmol) of methyl isocyanate to 0.6 g (1.7 mmol) of 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydr o-5H-2,3-benzodiazepine (see Example 98) dissolved in 45 ml of anhydrous dichloromethane, the reaction mixture was stirred at 25.degree. C. for 6 days. Then the crystalline precipitate was filtered, washed with 3.times.2 ml of dichloromethane and dried at 60.degree. to 80.degree. C. to obtain 0.55 g (79.7%) of the pure aimed product, m.p.: 181.degree.-183.degree. C.
C.sub.21 H.sub.23 N.sub.5 O.sub.4 =409.455
EXAMPLE 114
1-(4-Aminophenyl)-3-n-butylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydr o-5H-2,3-benzodiazepine
It was prepared from 1-(4-nitrophenyl)-3-n-butylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihyd ro-5H-2,3-benzodiazepine, m.p.: 173.degree.-175.degree. C.
C.sub.22 H.sub.26 N.sub.4 O.sub.3 =394.482
The starting substance was prepared as described for the starting substance of Example 98, except that n-butyl isocyanate was used instead of methyl isocyanate and the reaction mixture was stirred for 5 days at 25.degree. C., m.p. 176.degree.-178.degree. C.
C.sub.22 H.sub.24 N.sub.4 O.sub.5 =424.466
EXAMPLE 115
1-(4-Glycylaminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-d ihydro-5H-2,3-benzodiazepine
It was prepared from 1-[4-(N-phthaloylglycylamino)phenyl]-3-methylcarbamoyl-4-methyl-7,8-methyl enedioxy-3,4-dihydro-5H-2,3-benzodiazepine by using the process of Example 66 as modified in Example 82, m.p.: 16320 -165.degree. C.
C.sub.21 H.sub.23 N.sub.5 O.sub.4 =409.455
The starting substance was prepared from 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydr o-5H-2,3-benzodiazepine (see Example 98) according to Example 79, m.p. 270.degree.-271.degree. C. (decomp.).
C.sub.29 H.sub.25 N.sub.5 O.sub.6 =539.559
EXAMPLE 116
1-(4-Aminophenyl)-3-(N-methylglycyl)-4-methyl-7,8-methylenedioxy-3,4-dihydr o-5H-2,3-benzodiazepine
1.03 g (15.3 mmol) of methylamine hydrocdhloride and 2.64 ml (18.3 mmol) of triethylamine were added to a suspension containing 1.23 g (3.06 mmol) of 1-(4-nitrophenyl)-3-chloroacetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5 H-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, then 2.times.20 ml of water, dried and evaporated under reduced pressure. The residue was reduced according to the process 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.degree. C. to obtain 0.60 g (53.6%) of the aimed product, m.p. 198.degree.-200.degree. C. (weak decomp.).
C.sub.20 H.sub.22 N.sub.4 O.sub.3 =366.428)
The starting compound was obtained from 1-(4-nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine (see Examle 26) and chloroacetic acid by using the process of Example 33, m.p. 189.degree.-191.degree. C. (decomp.).
C.sub.19 H.sub.16 ClN.sub.3 O.sub.5 =401.818
EXAMPLE 117
1-[4-(N-methylglycylamino)phenyl]-3-acetyl-4-methyl-7,8-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-chloroacetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dih ydro-5H-2,3-benzodiazepine (see Example 106) 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 triturated with 3 ml of 50% ethanol at 25.degree. C. to give 0.61 g (38.6%) of the aimed product, m.p.: 220.degree.-222.degree. C. (weak decomp.).
C.sub.22 H.sub.24 N.sub.4 O.sub.4 =408.466
EXAMPLE 118
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 (compound of Examples 15 or 16) or 25 mg of 1-(4-acetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5 H-2,3-benzodiazepine (compound of Example 42) or 25 mg of 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydr o-5H-2,3-benzodiazepine (compound of Example 98) each as active ingredient were prepared by usual methods.
EXAMPLE 119
(-)-1-(4-Nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzod iazepine
A solution of (S)-(-)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (4.75 g) in dry methylene chloride was cooled to -70.degree. C. and treated with a solution of borane in THF (1.8M, 9.5 ml) over a 20 minute period under an atmosphere of dry nitrogen. The resulting solution was gradually warmed to 0.degree. C. and allowed to stand overnight at 4.degree. C. This mixture was treated with a solution of 1-(4-nitrophenyl)-4-methyl-7.8-methylenedioxy-5H-2,3-benzodiazepine (5.0 g) in dry methylene chloride (100 ml) at room temperature over a period of about 1 hour. The resulting solution was allowed to stand at room temperature for seven days. The reaction was quenched by the addition of 10% sodium carbonate (15 ml). The resulting phases were separated, and the organic layer washed with water (2.times.50 ml), dried ever sodium sulfate, and concentrated in vacuo to give a yellow crystalline solid. This solid was suspended in ethanol (50 ml), filtered, and dried to give 4.47 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc).sub.3) shows the product as 90:10 mixture of enantiomers. This material was dissolved in hot ethyl acetate (24 ml) and allowed to stand at room temperature overnight. The crystalline precipitate was separated by filtration, washed with ethyl acetate (3.times.5 ml), and dried to give 2.87 g of the title compound. Proton NMR spectroscopy using a shift reagent (Eu(hfc).sub.3) shows this material to have an enantiomeric purity of more than 98%. Melting point 171.degree.-172.5.degree. C.
[.alpha.].sub.D =-155.6.degree. (c=1, CHCl.sub.3)
EXAMPLE 120
(+)-1-(4-Nitrophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzod iazepine
The title compound was prepared as described in Example 119 using (R)-(+)-2-amino-3-methyl-1,1-diphenylbutan-1-ol. Melting point 172.degree.-174.degree. C.
[.alpha.].sub.D =+153.40.degree. (c=1, CHCl.sub.3)
Enantiomeric purity: 98%
EXAMPLE 121
(-)-1-(4-Nitrophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dih ydro-5H-2,3-benzodiazepine
A solution of the compound prepared as described in Example 119 (4.0 g) in dry methylene chloride (80 ml) was treated with methylisocyanate (2.18 ml). The resulting reaction mixture was stirred at room temperature for three days. This reaction mixture was evaporated in vacuo and the oily residue treated with water (60 ml). The resulting precipitate was filtered and dried to give 4.49 g of the title compound was a yellow powder. This material was used in the next step without further purification.
[.alpha.].sub.D =-315.3.degree. (c=1, CHCl.sub.3)
EXAMPLE 122
(+)-1-(4-Nitrophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dih ydro-5H-2,3-benzodiazepine
The title compound was prepared from the compound of Example 120 using the process described in Example 121.
[.alpha.].sub.D =+304.09.degree. (c=1, CHCl.sub.3)
EXAMPLE 123
(-)-1-(4-Aminophenyl)-3-methylcarbamoyl-4-methyl-7,8 -methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine
A suspension of the compound prepared as described in Example 122 (2.42 g) and Raney nickel (W-2, 0.5 g) in methanol (50 ml) was treated with 98% hydrazine hydrate (1.1 ml). After stirring the reaction mixture for 1 hour at 25.degree. C., the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The oily residue was treated with water (50 ml). The resulting precipitate was filtered and dried to give 2.06 g of the crude solid. This material was dissolved in ethanol (10 ml) and concentrated to a small volume in vacuo. The residue was treated with benzene (26 ml) to induce crystallization. The crystalline product was collected by filtration, and dried at reduced pressure (36 hrs., 100.degree. C., 80 torr), to give 1.98 g of the title compound as a light yellow powder. Melting point 133.degree.-135.degree. C.
[.alpha.].sub.D =-376.65.degree. (c=1, CHCl3)
Enantiomeric purity: >99%
EXAMPLE 124
(+)-1-(4-Aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dih ydro-5H-2,3-benzodiazepine
The title compound was prepared from the compound of Example 121 using the process described in Example 123. Melting point 133.degree.-135.degree. C.
[.alpha.].sub.D =+363.4.degree. (c=1, CHCl.sub.3)
Enantiomeric purity: >99%
EXAMPLE 125
(-)-1-(4-Nitrophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2 ,3-benzodiazepine
A mixture of the compound prepared as described in Example 119 (2.34 g) and acetic anhydride (11.7 ml) was stirred at room temperature. After 15 minutes, dissolution of the benzodiazepine was complete. After 2 hours, the reaction mixture was cooled in an ice-water bath and treated with water (60 ml). After stirring overnight, the crystalline product was collected, washed with water (4.times.5 ml), and dried to give 2.5 g of the title compound as pale yellow crystals. Melting point 173.degree.-177.degree. C.
[.alpha.].sub.D =-b 54.9.degree. (c=1, CHCl3)
EXAMPLE 126
(+)-1-(4-Nitrophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2 ,3-benzodiazepine
The title compound was prepared from the compound of Example 120 using the process described in Example 125, Melting point 173.degree.-177.degree. C.
[.alpha.].sub.D =+49.6.degree. (c=1, CHCl.sub.3)
EXAMPLE 127
(+)-1-(4-Aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2 ,3-benzodiazepine
A suspension of the compound prepared as described in Example 125 (2.6 g) and Raney nickel (W-2, 0.5 g) in methanol (52 ml) was treated with 98% hydrazine hydrate (1.2 ml After stirring the reaction mixture for 1 hour at room temperature, the catalyst was removed by filtration, and the filtrate evaporated in vacuo. The oil residue was treated with water (50 ml). The resulting percipitate was filtered and dried to give 2.17 g of the crude solid. This material was recrstallized from ethyl acetate (39 ml), the crystalline product collected and dried (36 hrs, 120.degree.-130.degree. C., 80 torr) to give 1.8 g of the title compound. Melting 169.degree.-171.5.degree. C.
[.alpha.].sub.D =+313.41.degree. (c=1, MeOH)
Enantiomeric purity: >99%
EXAMPLE 128
(-)-1-(4-Aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2 ,3-benzodiazepine
The title compound was prepared from the compound of Example 126 using the process described in Example 128. Melting point 169.degree.-172.degree. C.
[.alpha.].sub.D =-321.34.degree. (c=1, MeOH)
Enantiomeric purity: >99%
Claims
We claim:
1. A pharmaceutical composition having muscle-relaxant, anticonvulsive and neuroprotective activity, which comprises: a therapeutically effective amount of a compound of the formula (I) ##STR7## wherein, R is a C.sub.1 -C.sub.6 alkanoyl group optionally substituted by a methoxy, cyano, carboxyl, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, pyrrolidino, phthalimido or phenyl group, or by one or more halogen(s); or R is a benzoyl, cyclopropanecarbonyl, C.sub.1 -C.sub.5 alkylcarbamoyl or phenylcarbamoyl group; or R is absent when a double bond exists between the N(3) and C(4) atoms; R.sup.1 is hydrogen; or R.sup.1 is absent when a double bond exists between the N(3) and C(4) atoms; R.sup.2 is a C.sub.1 -C.sub.3 alkyl group; or R.sup.1 and R.sup.2 together form a methylene group; R.sup.3 is hydrogen or a C.sub.1 -C.sub.4 alkanoyl group; R.sup.4 represents hydrogen; a C.sub.1 -C.sub.6 alkanoyl group optionally substituted by a methoxy, cyano, carboxyl, amino, C.sub.1 -C.sub.4 alkylamino, di(C.sub.1 -C.sub.4 alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s); or a benzoyl, palmitoyl, cyclopropanecarbonyl, C.sub.1 -C.sub.5 alkylcarbamoyl or phenylcarbamoyl group; and the dotted lines represent valence bonds optionally being present, with the proviso that no double bond exists between the N(3) and C(4) atoms when both R.sup.3 and R.sup.4 stand for hydrogen; and their stereoisomers; or a pharmaceutically acceptable acid addition salt thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.
2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of: 1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-b enzodiazepine, 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-4-methyl-7,8-methylenedioxy-3,4-dihy dro-5H-2,3-benzodiazepine, 1-(4-propionylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine, 1-(4-acetylaminophenyl)-3-propionyl-4-methyl-7,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine, 1-(4-propionylaminophenyl)-3-formyl-4-methyl-7,8-methylenedioxy-3,4-dihydro -5H-2,3-benzodiazepine, 1-(4-trifluoroacetylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-d ihydro-5H-2,3-benzodiazepine, 1-(4-glycylaminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H -2,3-benzodiazepine hydrochloride, N.sup.1 -[4-(3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepin e-1-yl)-phenyl]-N.sup.3 -methylurea, 1-[4-(N,N-dimethylglycylamino)phenyl]-3-acetyl-4-methyl-7,8-methylenedioxy- 3,4-dihydro-5H-2,3-benzodiazepine, 1-[4-(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 hydrogen fumarate thereof, and 1-(4-glycylaminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-d ihydro-5H-2,3-benzodiazepine.
3. The pharmaceutical composition of claim 1 wherein the compound is 1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3- benzodiazepine or its stereoisomer.
4. The pharmaceutical composition of claim 3 wherein the compound is (-)-1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H- 2,3-benzodiazepine.
5. The pharmaceutical composition of claim 1 wherein the compound is 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-dihydr o-5H-2,3-benzodiazepine or its stereoisomer.
6. The pharmaceutical composition of claim 5 wherein the compound is (-)-1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-7,8-methylenedioxy-3,4-di hydro-5H-2,3-benzodiazepine.
Patent Citations (4)
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