BE1010962A4 - Novel 2,3-benzodiazepine. - Google Patents

Abstract

The invention relates to non-competitive antagonist derivatives of the AMPA receptors of formula I. The invention also relates to pharmaceutical compositions containing these compounds, a process for their preparation, and an intermediate.

Description

       

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   NOVEL 2,3-BENZODIAZEPINE DERIVATIVES
The present invention relates to novel 2,3-benzodiazepines substituted by one or two halogen atoms and to pharmaceutical compositions containing them.



   Several biologically active and therapeutically useful 2,3-benzodiazepines are known in which the ages cycle is substituted by two methoxy groups or by a methyenedioxy group. A description of the 7, 8-dimethoxy derivatives is found in, for example, HU-P n 155 572, 179 018, 191 702 and 195 788. These compounds exhibit, in the first place, an anxiolytic and / or anti-depressive activity as well than a positive ionotropic activity. Compounds having a methylenedioxy substituent at the same positions in the benzo ring are known from, for example, HU-P patents na 191,698, 191,702 and 206,719 and US patent 5,459,137.

   Unlike 2, 3-benzodiazepines dimethoxy, the methy) enenedioxy derivatives are mainly characterized by their antispasmodic, muscle relaxant and neuroprotective activity.



   It is known, from the literature, that the latter compounds exert their activity through the non-competitive inhibition of AMPA receptors (see, among others, SD Doncvan et al., Neuron, 10, 51-59 (1993); SD Donevan et al. J. Pharmacol Exp. Ther., 271, 25-29 (1994); as well as 1. Tarnawa et al.,
 EMI1.1
 Bioorg. Med. Chem. I. ett., 99-104 () 993).



  In addition, it is known that in the central nervous system of mammals. L-glutamic acid is the most important excitatory neurotransmitter. Under pathological conditions, the concentration of glutamic acid rises abnormally, in the extracellular space leading to acute or chronic damage to the cells of the central nervous system.



   Excitatory amino acids such as glutamic acid exert their action by activating ionotropic receptors (ie ion channels) as well as! These metabotropic receptors which bind G proteins. The types of
 EMI1.2
 ionotropic g receptors! utamatc are called se) on) es agonistes con \ e) iah! that's for! cur excitation se) ccti \ c. So, we distribute! receivers \ MDA. AMPA and kai) iate (appdé anterioroncnt qui'-; qualatc). and there exists in each of these receptors typical sounds jAnn Rc \. \ curosci ..) 7. 3) () 994).

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  It is known that AMPA-type glutamate receptors play an important role in many acute and chronic majadias affecting the central nervous system such as epilepsy, diseases accompanied by muscular spasticity and various neurodegenerative diseases. and thus, by inhibiting the AMPA receptors, one can obtain an inhibition of the spasms, a muscle relaxation and a neuroprotective effect. [see. among others: Cerebrovasc. Brain Metab. Rev ..



  6, 225 (1994); Neurology, 44 Suppl. 8, Si 4 (! 994): J. Pharmaco!. Fxp. Ther ..



  260, 742 (1992).



  AMPA receptor activation can be inhibited by competitive and non-competitive antagonists. Unlike competitive antagonists, the use of non-competitive antagonists may generally be preferred, since better protection is obtained at extremely high endogenous concentrations of excitatory amino acids [Epilepsy Res., 15. 179 (1993) 1.



  Based on the above facts. this constituted an invention of very great importance that the 2, J-benzodiazepines substituted by a methylenedioxy group exhibit, thanks to their non-competitive antagonist activity of AMPA, an antispamodic effect. muscle relaxant as well as neuroprotective, so these compounds can be used in therapy as an antispasmodic, anti-epileptic, and in addition for the treatment of acute and chronic neurodegenerative diseases and potentially in any disease where the inhibition of acid excitatory amine is desirable at the receptor.



  Surprisingly, it has been observed that the therapeutically interesting non-competitive antagonist activity at the AMPA receptor is remarkably conserved if the benzo ring contains, in place of the methylenedioxy group, one or two chlorine or bromine. In addition, it has been found that the new halogenated derivatives have more favorable properties than the known derivatives.



  This observation is surprising since it was believed that) the presence of methytenedioxy groups was an essential condition for) obtaining the activities indicated above.

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  Therefore.) A present invention relates to new 2, 3-benzode iiotive diazepmes de tbrmuie) in clipping:
 EMI3.2
 
 EMI3.3
 t 1 Ri 1 and R2 independently represent a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a Ct-C ateoxy group, a QQ nitro group, a trifluoromethyl group or a group of formula -NR "R, where R8 and R9 independently represent hydrogen, a C1-Ct alkyl group or a group of formula -COR 10. where Rio is hydrogen, a C1-C6 alkyl group and which may be substituted , a C / - CiQ aryl group, a C 1C alkoxy group, a CC cycloalkyl group ...

   a C 1 atkenyan group a C 3 -C 5 cycloalkoxy group or a group of formula il 12 - NRIIRI 2, where R 11 and R 12 independently represent a hydrogen, a (C 1 -alkyl group C 1 -C 6 alkyl group, a cycloalkyl group C3-C5 or a CC aryl group <Q.



  "" R-represents a C1-C4 alkyl group. a C-Cc cycloalkyl group or t it a group of formula -CO-R, where R has the definition given with respect to R'O: 10 R R4 and R5 independently represent hydrogen or a '3R alkyl group andR are. independently, a hydrogen, a chlorine or a bromine atom 1 \ cc this condition that if one of the groups R6 and R7 7 represents a hydrogen, the auu'e is not a hydrogen. as well as isomeric towers and their acid addition sets.



  ). a present in \ ention concerns in parucuher) a 3-acéty) -) - (4 aminophén))) - 8-ch) oro-4-méth \) - 4. 5-di) i) dro-3f f-2. 4-hen7odia7épine et ta! - (4-

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   aminophenyl) -8-chloro-4-methyl-3-methylcarbzmoyl-4,5-dihydro-3H-2,3-benzodiazepine.



     Se) on another aspect, the present invention relates to a composition
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 pharmaceutical comprising a compound of formula 1 as defined above or one of their isomers or a pharmaceutically acceptable acid addition salt of a compound or one of its isomers as active ingredient, as well as conventional carriers, solvents, diluents and excipients used for the preparation of pharmaceutical compositions.



   The present invention also relates to the use of the compounds of
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 formula 1 as a pharmaceutical product, in particular for the treatment of diseases accompanied by muscle spasticity, epilepsy and neurodegenerative diseases.



   The present invention also relates to a process for the preparation of the compounds of formula 1 as defined above as well as their isomers and their acid addition salts, which comprises the introduction of the group R3 in position 3 of a compound of formula M
 EMI4.3
 
 EMI4.4
 in which Ri, R2, R4, R5, R and R7 7 are as defined above and, where appropriate, the transformation of a compound of formula 1 into another compound of formula 1 and, if appropriate, transformation of a compound of formula 1 into its acid addition salt or the bonding of the compound of formula! from its acid addition salt.

   

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 EMI5.1
 According to a last aspect, your present invention relates to your compounds of
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 He formulas
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 in which: Ri and R "represent, independently, a hydrogen, a lialo, èiie, a, i- (itilie alkyl C C c halogen, an aikyie group C] -C, an atcoxy group C) -C, a group QQ nitro, a group trif) uorométhy) e or a group of formula-NRR where QQ R8 and R represent, independently, a hydrogen, a group a) ky! e in C 1-C -J. or a group of formula -COR 10. where RIO is hydrogen, a group a) ky) e in C.-C which can be 6 which substitutes, an aryie group in CC] o. An atcoxy group in ClC C). A cycloalkyl group in CC: a C1-4 alkyl group, t> a C, -CS cyctoatoxy group or a group of formula - I Rl. Where R II and R 12 independently represent hydrogen.

   a C alkyl group <-This. a C-Cc cyctoatkyte group or a C-C aryl group) o.



  10, R 3 represents hydrogen, and R4 and R5 mean. independently. hydrogen or C1-C3 alkyl; R6 and R7 independently represent a hydrogen. a chlorine or bromine atom, with these conditions that one of theRetdesR groups represents hydrogen, the other is not hydrogen.



  In ! cs definitions given about) a formuie!.) e group a) ky) e and) e group atkiène so <it Hnéaires or f'amiHés. If the group atk \ te is substituted. the substituent is a group a) eo \) or an atom of ha) ogene. The group cyeioa) ky) e is mi c'e) oprop \ le. cyclobut \) e or c \ c! opent \! e. 1 aryie group is a phenyie group or a naphth \) e.

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  As the compounds of formula 1 contain a chiral center, the expression isomers of the compounds of fb) 'mu) e I. means both the enantiomers and in the case of certain substitutions. E and Z stereoisomers as well as diastereoisomers. tautomers and their mixtures such as racemates.



  The acid addition salts of the compounds of formula 1 are salts formed with physiologically acceptable organic or inorganic acids.



  As suitable inorganic acids. mention may be made, for example, of hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid.



  As organic acids, there may be mentioned, for example, formic acid. acetic acid, maleic acid, fumaric acid. matic acid. tactical acid. tartaric acid. citric acid or methane sutfonic acid.



  A preferred subgroup of the compounds of the present invention consists of the compounds of formula I. in which: RI represents an amino group in position 4.



  R2, R4 and R6 represent hydrogen.



  R 'represents a methyl group, R 7 7 represents a halogen, c 1 r 3 represents an aliphatic acyl group or an alkylcarbamoyl group.



  In the preferred subgroup above, your particularly preferred motes consist of the derivatives where R3 represents an acetyl group, a group 1 ¯, i-otilie iiiétii - \ - Icai-baiiioN, le. propionyte. a cyctopropytcarbonyte group or a methy) carbamoy) group.



  The compounds of the invention can be obtained from the corresponding raw materials of formula II where R. R2. R4, R5, R6 and R7 are as defined above. by analogy with the methods described in Hungarian patent na 206,719 or US patent 5,459,137.



  One can also prepare your compounds of formula 1 in the following way: one oxidizes by air the derivative of isochromane suitably substituted to obtain a hemicétat which one reacts with a derivative oxo suitable for introducing acyl group in position 3 ( for example a carboxylic acid hydraLide, semicarbaxide, etc.) then the benzodiazepinc cycle is formed by mesytation and alkaline closure of the cycle.



  Details relating to the preparation of the compounds of formula! are illustrated by the examples.



  In your preferred preparation of the compounds of your present invention, the usual methods for the synthesis of 2,3-bcn7odia7épine are used.

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  Thus, the amino groups are a! ky) ës using an atkyte hatide or by reductive amination using an oxo derivative. The acylation is generally carried out using an acid chloride, an anhydride, a mixed anhydride or an atkyte or phenyl chlorocarbonate - in the case of your catalysis by an acid-binding agent and / or a pyridine derivative at) at room temperature - or at higher temperatures in a soh'an1.



  The carbamoyl groups are formed by reaction with the corresponding isocyanate. However, it is also possible to acylate using an active ester such as phenyl chlorocarbonate and to react the compound obtained with a primary or secondary amino derivative.



  In general, the nitro group is reduced catalytically in the presence of Raney nickel, palladium or platinum. In addition to hydrogen gas, hydrazine hydrate or, for example, ammonium formate can also be used as the hydrogen source.



  The starting derivatives of formula II are new. Therefore, the present invention also relates to these compounds. They are prepared according to the method described in Hungarian patent No. 191,702 or by a method analogous to the method used for the preparation of known compounds. Details of the process will be found in the examples.



  As indicated above, the compounds of the present invention exhibit significant non-competitive antagonist activity of AMPA receptors, therefore they can be used in therapy as antispasmodics, muscle relaxants, as well as for neuroprotection, and also in the treatment of other neurological and psychiatric disorders which can be attributed to an increased state of arousal of AMPA receptors.



  The compounds of formula 1 can be transformed into pharmaceutical compositions which can be administered enterally or parenterally. To this end, you can use your conventional, organic or inorganic carriers or excipients of the pharmaceutical industry such as water, gelatin, gum arabic, lactose, starch, magnesium stearate. , ta! c, vegetable oil, poJy (ethylene glycol), etc. all pharmaceutical compositions can be in a solid gatenic form such as tablet, dragee, suppository or capsule or they can be in gaienic form liquid! dfe as solution, suspension or emulsion.

   Hn plus the supports and excipients mentioned above. other additives with consolatory properties can be used.-talHisantcs. exhilarating. buffers. etc.

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  For parenteral administration. the dosage form consists of a sterile solution or suspension of the active ingredient. In that case. the sterile vehicle may contain) one or more ad) uvants, for example an anesthetic [ocaL a stabilizing agent or a buffer.



  The dose administered to the patient depends on the route of administration, the nature and severity of the disease, as well as the patient's weight and age. The daily dose is 0.5 to 1000 mg, preferably 20 to 200 mg. and you can be given in one or more doses.



     The AMPA receptor antagonist activity of the compounds of formula 1 was demonstrated by the following test.



  Antagonistic action on the effect of kainate (in vitro test)
The in vitro activity of the compounds has been determined on isolated chicken retina preparations [M. J. Sheardown, Brain Res. 607. 189 (1993)]. The
 EMI8.2
 decrease in enlargement was developed using 5 µM Kainate (the chemical name for kainic acid is 2-carboxy-4-isopropenyl-3pyrrolidine-acetic acid) and the IC values were determined 50 according to Sheardown. 150 selo "Slieai-dowii. 011 tested the compounds at at least three concentrations. Compounds with AMP A receptor antagonist activity inhibit the response of kainate exhibiting AMPA kainate receptor agonist activity and the inhibition obtained depends de) a concentration of the compounds.

   The ICn values are given in table L
TABLEAUI
Kainate antagonist activity in vitro
 EMI8.3
 
 <tb>
 <tb> compound <SEP> (number <SEP> decrease <SEP> from <SEP> enlargement <SEP> retinal <SEP> in <SEP> vitro
 <tb> example) <SEP> IC50 <SEP> in <SEP> microM
 <tb> 2 <SEP> 3.2
 <tb> 4 <SEP> 3.6
 <tb> 6 <SEP> 8.2
 <tb> 8 <SEP> 4.6
 <tb> 4 <SEP>: <SEP> I. <SEP> G
 <tb> 6 <SEP> 8. <SEP> 2
 <tb> 8 <SEP> 4.6
 <tb> 10 <SEP> 2.5
 <tb> 12 <SEP> 1. <SEP> 2
 <tb> A <SEP> 9.5
 <tb>
 
 EMI8.4
 Lomposc uc roocncc: A: 5- (4-L) m) nnphcn \) -9)) -). -d) o \ o! o4. 5-h2J] hc'nzodin7cpinc (GYK. I 52 466: hrc \ ct Hungarian n)) 698. c \ cmp) c 8).

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   The compounds of the present invention and their preparation process will be described using the following examples given without limitation of the
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 rl if it presents invention.



  EXAMPLE 1 3-acetyl-7-chloro-4-methyl- 1 - (4-nitrophény!) -4, 5-dihydro-3H-2, 3-benzodiazepine Agitation 0.72 g (2.2 mmol) of 7 -chloro-4-methyl-1- (4-nitrophenyl) -4,5-dihydro-3H-2. 3-benzodiazepine in 4 ml of acetic anhydride at 25 ° C. for 3 hours, then the reaction mixture is poured into 20 ml of ice water, the crystalline product is filtered and washed several times with water.



   The crude product obtained is purified by suspending it in 4 ml of hot ethanol. After filtration and drying, 0.69 g (88%) of the title compound is obtained. P. f. : 174-175 C.



   The starting material of Example 1 is prepared as follows: Step A 6-chloro-3-methyl-1- (4-nitrophenyl) isochroman
To a solution of 17.06 g (100 mmol) of 1- (3-chlorophenyl-2-propanol [prepared by a process analogous to that described in J. Med. Chem., 21, 454 (1978) and t5. H g (100 mmol) of 4-nitrobenzaldehyde in 100 ml of anhydrous benzene, 13.65 g (100 immoles) of zinc chloride (zinc chloride has been calcined before addition) are added, and HCl is passed through anhydrous gas in the reaction mixture for 3 hours.
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  The mixture was boiled for 2.5 hours, then, after cooling, 100 ml of water are added. The organic phase is separated, washed with water, using an aqueous sodium bicarbonate solution, then using a saturated sodium chloride solution, dried, then evaporated. The 30.95 g of crude residual oil are recrystallized from 200 ml of hot ethanol to give 23.49 g (77%) CD of the title compound. P. f. :! 8-120 C.



  Stage B
 EMI9.3
 6-ch) oro-3-methyl-1- (4-ritrophenYt) -2-benzopyriliurn perchlorate 26.9 g (88.5 mmol) of the isochroman derivative prepared in step A are dissolved in 270 ml of acetone, and to this solution is added)) 6m) (3.0 mmotcs) of rush reagent drop by drop while cooling in a gtacc bath for 1 hour, then the mixture is stirred for 4 hours at 25 '' (The chromium sc which precipitates during the reaction) is fihrc and the fiitrat is evaporated.



  We put all your residual crystals in! 00m! of water, then we refihrc. We say. support your crystals dated 304 m) of acetic acid gtaciaL we add '1011le

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 5.91 ml of 70% perchloric acid, then, after cooling, the crystals which separate are filtered off and washed four times with 10 m) of glacial acetic acid each time.



   6.84 g (19%) of the title compound are thus obtained. P. f .: 236-237 C (decomposition).



  Step C 7-chloro-4-methyl-1- (4-nitrophenyl) -5H-2,3-benzodiazepine
6.43 g (16 immoles) of the prepared benzopyrilium perchlorate are dissolved
 EMI10.1
 in step B in 32 ml of dimethytformamide and, to the solution thus obtained, 2, 3 1 ml (48 mm) are added dropwise of 98% hydrazine hydrate and the reaction mixture is stirred at 25 C for 1 hour. The mixture is poured into 320 ml of water, the product which separates is filtered and washed five times using 10 ml of water each time. The crude product is purified by suspending it in 50 ml of hot methanol. 4.41 g (87%) of the title compound are thus obtained.

   P. f. : 227-228 C. Stage D
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 diazéiii 7-chtoro-4-méthY) -) - (4-nitrophénY)) - 4, 5-dihvdro-311-2. 3-Benzodiazepine 1.5 g (4.78 mm) of the benzodiazepine derivative prepared in step C are suspended in 60 ml of methanol and to this suspension is added 4.64 g (57.3 immoles). concentrated hydrochloric acid, then, while cooling with cold water, 2.07 g (54.8 immoles) of sodium borohydride are added in portions. The suspension is stirred at 25 ° C. for # hour, then solid sodium bicarbonate is added to adjust the pII of the mixture to a value of approximately 8.

   The mixture is diluted with 60 m) of water, the product is separated by
 EMI10.3
 filtration, it is washed four times using 5 ml of metbano! 50% aqueous each time, and dry to obtain 1.47 g (97.4%) of the title compound.



  P. f. : 15: 2-1 54OC. EXAMPLE: 2
 EMI10.4
 3-acety 1-1- (4-aminop h él TyiJ: -7'c hloro-4-méthvt-4. 5-dihvdro-3H-2Jbenzodiazepine 0) i suspends 0.66 g (1.8 mmote) of 3-acetyl-7-ch) oro-4-methyl-1- (4-nitrophen \ l) -4, 5-dihydro-3H-2, 3-benzodiazepine (prepared in the example)) in 35 m) of methanoL then about 0.5 g of Rane nickel is added) as a wet catcher. and. with vigorous stirring. 0.32 mi (6.5 mmo) of 98% h \ drazine hydrate. The stirring of the reaction mixture is continued for an additional 45 minutes! éme) Haires. then we eliminate! e cata) \ seur by ttitration. on) with

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 EMI11.1
 methanot. your combined tittrates are evaporated and the residue is treated with 10 m of water to obtain a solid product.

   The 0.54 g of crude product is recrystallized from 2 ml of ethanol to obtain 0.44 g (75%) of the title compound. P. f. 90-92 C.



    EXAMPLE J
 EMI11.2
 7-chloro-4-methyi-3- (methylcarbamoY)) - t- (4-nitrophényi) -4. 5-dihYdro-3H-2. 3- benzodiazepine
0.72 g (2.2 mmol) of 7-chloro-4-methyl-1- (4-nitrophenyl) - 4, 5-dihydro-3H-2, 3-benzodiazepine prepared in Example 1, step is dissolved. D, in 5 ml of anhydrous dichloromethane and to this solution is added 1.3 ml (22.0 mmol) of methyl isocyanate and the reaction mixture is left to stand at 25 ° C. for 10 days. The mixture is evaporated and the residue is recrystallized from
 EMI11.3
 3 ml of hot ethanol. The crystals are filtered and washed three times using 1 1 1 isaiit 1 ml of ethanol each time. then we dry.

   0.78 g (95%) of the title compound are thus obtained. P. f. : 224-226 C. EXAMPLE 4
 EMI11.4
 1- (4-aminophenyl) - 7 -chloro-4-methyl- 3- (methylcarbamoyl) -4, 5-dihydro- 3 H -2, 3benzodiazepinc 0.75 g (2.0 mmol) of 7-ch are reduced ) oro-4-methyl-3- (methy) carbamoyt) - 1- (4-nitrophenyl) -4.5-dihydro-3H-2,3-benzodiazepine prepared as in Example 3, using the process of Example 2, and the crude product obtained is recrystallized from hot ethanol. 0.55 g (80%) of the title compound is thus obtained. P. f. :) 34-) 36 C.



  EXAMPLE 5
 EMI11.5
 3-acetYi-8-ch) oro-t- (4-nitrophenyl) -4,5-dihYdro-3H-2. 3-Benzodiazepine -acetyl-9-e Acetylated 0.69 g (2.19 mm) of 8-chloro-4-methyl-I- (4-nitrophenyl) - 4, 5-dihydro-3H-2,3- benzodiazepine by the method described in Example 1. 0.70 g (89%) of the title compound is obtained. P. f. : 227-229 C.



   The product from: starting from Example 5 is prepared as follows: Step A
 EMI11.6
 7-chtoro-3-meth \ i -) - (4-mtrophényi) -isochromane We operate according to the operating procedure of the example]. step A. except that the starting compound consists of t1. 94g (70 mmol) of] - (4-ch) orophény)) - 2ropano) J. ) el.C iem ..). 454 (1978) J and the reaction mixture is boiled for! 5 hours. 0! i (htie) it thus 6. 8g (32%) of the title compound. P. f. : t20-) 2C.

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  Step B 7-chloro-3-methyl-1- (4-nitrophenyl) -2-benzopyrilium perclorate
6.8 g (22.4 mmol) of the isochroman derivative obtained in step are oxidized
 EMI12.1
 A by your method of exempting you). step B. using Jones' reagent. The salt is obtained in glacial acetic acid using perchloric acid. 3.73 g (42%) of the title compound are thus obtained. P. f. : 247-255 C.



  Step C 8-ch) oro-4-methyt -) - (4-nitrophény [) -5H-2J-benzodiazepine ii Add 4.) 1 g (10, 25 mmol) of the benzopyrilium perchlorate obtained l L-1 in step B to a mixture of 20.5 ml of dimethytformamide and 1.5 ml (70.7 immoles) of 98% hydrazine hydrate while cooling with cold water. The reaction mixture is stirred at 25 ° C. for 1.5 hours, then 25 ml of water are added, the crude product which separates is filtered, washed four times with 5 ml of water each time. then recrystallized from 25 m) of isopropanol. 2.82 g (87%) of the title compound are thus obtained. P. f. : 199-203OC.



  Step 0 8-chloro-4-methyl-I- (4-nitrophenyl) -4,5-dihydro-3 H-2. 3-benzodiazepine
1.62 g (5.16 mmol) of the benzodiazepine derivative obtained in stage C according to the method of example 1, stage D are reduced. 1.59 g (98%) of the title compound are thus obtained. P. f. : 132 to 135OC.



  EXAMPLE 6
 EMI12.2
 3-acet \) - 1- (4-aminophenY)) - 8-chtoro-4-meth \) - 4. 5-dihydro-3Ï-2, 3-benzodiazepine
0.81 g (2.26 immoles) of 3-acetyl-8-chloro-4-methyl-1- (4-nitrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine, obtained in 1, is reduced. Example 5, according to the method of Example 2. The crude product is recrystallized from 50% aqueous ethanol to obtain 0.64 g (86%) of the title compound. P. f. : 187-t 89 C.



  EXAMPLE 7
 EMI12.3
 8-chloro-4-metlY 1-3-meth \ lcarbamoyl-t- (4-nitrophenyl) -4,5-dihydro-3H-2. 3benzodiazepine We repeat according to! not ! et) ode of Example 3 starting from 0.79 g (2.5 mmotes) of 8-ch! oro-4-methyt -) - (4-nitrophenyl) -4. 5-dih \ dro-311-2. 3benzodiazepine obtained in Example 5, step D. The crude product is recrystallized from isopropanol to obtain 0.85 g (91%) of the title compound. P. f. : 190-192 C.

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 EMI13.1
 



  EXAMPLE 8 J - (4-aminophenyl) -8-chloro-4-methyl 1- 3-methyl carbam 1-4. 5-dilwdro- 3 H -2. 3p benzodiazepine We reduce 0.65 g (t. 74 mole) of 8-chtoro-4-methy] -3-methy] carbamoyf -) - (4-nitrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine obtained in Example 7, according to the method of Example 2. This gives 0.59 g (99%) of the title compound. P. f. : 115-118'C.



  EXAMPLE 9
 EMI13.2
 3-acétY) -7. 8-dich) oro-4-methY) -) - (4-nitrophénYi) -4, 5-dihvd) 'o-3H-2. 3- benzodiazepine
0.35 g (0.99 immol) of 7,8-dichloro-4-methyl-1- (4niotrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine is acetylated by the method of Example 1 .



  0.36 g (93%) of the title compound is thus obtained. P. f. : 198-200oe.



   The raw material of Example 9 is prepared as follows: Step A 6, 7-dichloro-3-methyl-1- (4-nitrophenyl) -isochromane
The operation is carried out according to the method of example 1. step A. except that the starting product consists of 10.47 g (51.0 emotes) of J- (3. 4-dichlorophenyl) -2-propanol and that brings the reaction mixture to the boil for 3 hours. 4.29 g (25%) of the title compound are thus obtained. P. f. : 189-19) C.



  Stage B
 EMI13.3
 7, 8-dichioro-4-methY) - 1- (4-nitrophen \)) - 5H-2. 3-benzodiazepinc
4.75 g (14.0 mmol) of the isochroman derivative prepared in step A is oxidized according to the method of example l, step 8, using Jones reagent, except that instead of reacting the crude product with perchloric acid, the 1-acetonyl-3,4-dichloro-4'-nitrobenzophenone derivative (P. f .: 121-122OC) is isolated by chromatography. The solution of the above derivative is reacted in isopropanol with 98% hydrazine hydrate, at 25 ° C., to obtain the
 EMI13.4
 monohyrazone (P. f .: 67-169 C).

   Reacted) a monoilydrazone with methane) containing 5% hydrochloric acid. then the hydrochloride of the title compound is treated with triethyiamine to obtain the free base which is purified by recrystallization in) e dimeth)) hot formamid.) \ f. : 23) -233 C.



  IT (I- the i-eci-1 1'Iti 1--1-) C.



  J

  <Desc / Clms Page number 14>

 
 EMI14.1
 L-talle C 7. 8-dichioro-4-meth \ t-I- (4-nitrophén i) -4. 5-dih dro-3II-2. 3-henzodiazepine 0.74 g (2.1 mmoles) of the benzodiazepine derivative obtained in stage B using the method of example I is reduced. Stage D. 0.70 g (95%) are thus obtained of the compound in heading. P. r. : 182-184OC.



  EXAMPLE 10 3-acetyl-I- (4-aminophenyl) -7. 8-dichloro-4-methYl-4. 5-dihydro-3H-2. 3benzodiazepine 0.34g (0.8611111oles) of 3-acetyl-7,8-dichloro-4 -1111ethyl-I- (4nitrophenyt) -4 is reduced. 5-dihydro-3H-2, 3-benzodiazepinc obtained in Example 9 using the method of Example 2. The crude product is purified by suspending it in hot methanot. 0.25 g (80%) of the title compound is thus obtained. P. f. : 242-243 C.



  EXAMPLE 1 J 7, 8-dichloro-4-methYl-3-methylcarbamoyl-1- (4-nitrophenyt) -4. 5-dihydro-3H-2. 3benzodiazepine 0.33 g (0.94 mmol) of 7,8-dichloro-4-methyl-t- (4-nitrophenyl) -4,5-dihydro-311-2,3-benzodiazepine obtained in Example 9, step C, with methylisocyanate according to the method of Example 3. The crude product is purified by suspending it in hot methanol. 0.37 g (97%) of the title compound is thus obtained. P. f. 221-223 C.



  EXAMPLE 1: 2 t- (4-aminophenYt) -7. 8-dichtoro-4-méthYt-3-méthYtcarbamoYt-4, 5-dihYdro-3H- 2. 3-benzodiazepine We reduce 0.35 g (0.85 mmol) of 7. 8-dich) oro-4-methyt- 3methytcarbamoyt-t- (4-nitrophenyl) -4. 5-dihydro-3H-2. 3-Benzodiazepine obtained in Example II using the method of Example 2. The crude product is recrystallized from 50% aqueous methanol. 0.27 g (84%) of the compound cn is thus obtained. P. r. : 224-225OC.



  Example 13 3-AcetYt-8-chtoro-4-meth \ i -) - (4-nitrophenYt) -4. 5-dihYdro-3H-2. 3benzodiazepinc (t. A method of preparation is different from that described in example 5) Dissolve 6. 35g (in \ iron 16. 3 mmol) of I-2- (2-hydroxypropyt) -5chtorophen \ t-4- nitroptieny! -! iiét) i \! en] h \ dra / ide of acetic acid in 70 mt of anhydrous dictiiorométtiane, and the solution is cooled to-t5'-C. At this suggestion,

  <Desc / Clms Page number 15>

 
 EMI15.1
 4.10 ml (29.3 mmol) of triethytamine are added with stirring, then 1.65 ml (: 2 \, 2 emotes) of mesyte chloride. drop by drop, in 5 minutes. After 20 minutes, the reaction mixture is stirred with 30 ml of ice-cold 1 N hydrochloric acid and then, twice, with an aqueous cold solution of sodium chloride, using 30 mt of solution each time.

   The organic phase is dried and evaporated. The sparkling solid residue is suspended in 80 ml of ethanot. and 0.90 ml (17.1 mmol) of 50% sodium hydroxide solution is added to the suspension, dropwise, while cooling in an ice bath. Most of the intermediate dissolves, and after a few minutes yellow crystals begin to form. The mixture is stirred for an additional 4 hours, then 100 ml of water is added dropwise, while cooling in an ice bath, over 45 minutes, the precipitate is filtered and washed with water.



   The crude product is dissolved in approximately 450 ml of hot ethanol, and the solution is concentrated to approximately one third of its volume. After cooling, the solids are filtered to obtain 3.92 g of the title compound in the form of yellow crystals. P. f. : 226-228 C. (yield: 67%, calculated for isochroman described in Example 5, step A).



   The starting compound of Example 13 is prepared in the following manner:
Step A: 1-hydrox-7-chloro-3-methyl-1- (4-nitrophenyl) -isochromanc
7. 44 g (24.5 emotes) of 7-chloro-3-methyl-1- (4-nitro-phenyl) are dissolved -
 EMI15.2
 isochroman (prepared as indicated in Example 5, step A) in a mixture of 50 ml of dimethyl formamide and 24 ml of dimethyl sutfoxide. and the solution is cooled with ice water by passing air through a capillary introduced on the surface of the liquid.

   While bubbling vigorously, 2.60 ml (49.00 emotes) of 50% aqueous sodium hydroxide solution are added to the reaction mixture. which becomes purplish black. after two hours, the reaction mixture is poured into 240 ml of ice-cold 0.5 N hydrochloric acid, and the flaky precipitate is extracted three times. using 100 ml of acetyl acetate each time. The combined organic solutions are washed with 100 ml of saturated aqueous sodium bicarbonate solution. then an aqueous solution of
 EMI15.3
 sodium chloride, until necessary. dry, then evaporate.

   The S. 70 g of foam thus obtained consist of a single product, as shown by your thin layer chromatography (Rr = about 0.2, using a mixture of hexane / el acetate and a 4/1 ratio ).

  <Desc / Clms Page number 16>

 
 EMI16.1
 



  According to NMR 11-1. the compound consists of a mixture of two possible stereoisomers. and it has a purity of about 90%.



  We use ! e compound obtained in the following reaction step: Step B: rI - / 2- (2-hydroxypropyl) -5-chlorophenyll-4-nitrophenylmethylene] acetic acid hydrazide.



  A mixture of 5.85 g (16.3 mmol) of the hemicetal prepared in stage A (and having a purity of 89 to 90%) is brought to the boil. 1.45 g (19.5 emotes) of acetic hydrazide. 80 m) isopropanol, 20 ml water and 2 m) 1N hydrochloric acid. At the start of boiling. the reagents dissolve. After 3.5 hours of boiling, 0.33 g (4.45 emotes) of acetic acid hydrazide and 1 MI of ch acid are added. orhydrous) N additional to the metange. and the reaction is continued for an additional 3.5 hours. Then. the reaction mixture is evaporated, and the residue is dissolved in a mixture of 150 ml of ethyl acetate and 100 ml of aqueous sodium bicarbonate solution.

   After separation, the aqueous phase is extracted using 50 ml of additional ethyl acetate, the combined organic solutions are washed with an aqueous sodium chloride solution, dried, then evaporated. The water contained in the frothy residue is removed by adding and evaporating benzene, and the 6.35 g of yellow gum in Example 13 is used for the mesylation and ring-closing reaction.



  EXAMPLE 14 1-- (1-1-oliliii-1) -4,5-dill \ di-o-l 3-carbamoyl-8-ch! oro-4-methyl -) - (4-nitrophény)) - 4, 5-dih \ dro-3 [! -2. 3benzodiazepine 6.13 g (approximately 16.27 emotes) of 1 - ['2- (2-hydroxypropyl) -5chlorophenyll-4-nitrophenylmethylene-semicarbazide are dissolved in 60 m) of anhydrous pyridine and. 1.76.77 emotes) of mesyl chloride are added to the solution obtained, dropwise, with stirring, at -5 C. The mixture is stirred and stirred at) at room temperature for 23 hours, then 0.7 is added. m [(2.8 mmol) of additional mesyte chloride. After 3 hours, the mixture is created in 500 ml of 5N hydrochloric acid solution. and the product is extracted 3 times with dichforomethane using 90 ml of dicbioromethane each time. The organic solutions are combined using an aqueous solution of sodium chloride, dried and then evaporated.

   We resume the intermediate obtained in the form of foam so in K) 0 mi of summer! ianol. and add 1. 03 m! (19. 5 mnio) es) of an aqueous solution of sodium hydroxide at 50 "o. Drop by drop, with stirring at room temperature. After 4 hours of stirring, dropwise added drop] 50

  <Desc / Clms Page number 17>

 water to the reaction mixture by cooling in an ice bath, fiber the crystalline product which precipitates. and wash it with water.



   The 4.18 g (76%) of crude product obtained is recrystallized by dissolving it in 270 ml of ethanol. and evaporating the solution to a third of its original volume.



   3.16 g (54%) of the title compound are thus obtained. P. F.: 233-234 C (decomposition).



   The starting compound of Example 14 is prepared as follows: 1 - [/ 2- (2-bydroxypropyl) -5-chlorophenyl / -4-nitrophenyl-methylene] semi-carbazide.
 EMI17.1
 



  We react 19 g (about 18 mmol) of hemiceta! prepared as indicated in Example 13, step A, with 3.01 g (27 immoles) of semi-carbazide hydrochloride in a mixture of 140 m) of isopropanol and 60 ml of water. After 5 hours of boiling. 0.60 g (5. 4 emotes) of semicarbazide hydrochloride is added to the reaction mixture, and the boiling is continued for an additional 5 hours. The mixture is evaporated, the residue is suspended in water, the product is filtered and washed with water. 6.62 g (98%) of the title compound are obtained, which is used in the form thus obtained for the mesylation and the ring-closing reaction.



   For analysis. a sample is purified by column chromatography (silica gel. eluent: mixture of chloroform and methanol in a ratio of 1/1).



  As shown by NMR I II. the above sample consists of stereoisomers, at a ratio of approximately 1/1. and has a purity of about 90%.



  Mass spectrometry gives M = 376/378.



  EXAMPLE 15 1- (4-Aminophenyl) -3-carbamoyl-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine
 EMI17.2
 3.16 g (8. 81 mmol) of 3-carbamoyl-8-chloro-4-methyl-I- (4nitrophenyl) -4,5-dih) dro- are reduced: H 1-2. 3-bcn7. odiazepinc (obtained according to the method of example 4) in methanol in the presence of Raney nickel as catalyst, with 5 equivalents of hydrazine hydrate according to the method described in example 2. The 2.71 g of product are re-crystallized crude in 50% aqueous methanol.



   2.29 g (79%) of the title compound are obtained.



    P.F. 218-220 C.

  <Desc / Clms Page number 18>

 



    EXAMPLE! 6 3-ethoxycarbonyl-8-chloro-4-methyl-1- (4-nitrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine
2.36 g (5.81 mmol) of 3- [2-2-hydroxypropyl) -5- are dissolved
 EMI18.1
 chlorophenyl / -4-nitrophenylmethylene] ethyl carbazate in 25 ml of anhydrous dichloromethane, and to the solution thus obtained 1.46 ml (10 * 43 mmol) of triethylamine and the mixture is reacted with 0.60 ml ( 7.70 emotes) of mesyl chloride at -15OC. After one hour, the reaction mixture is diluted with 20 ml of dichloromethane, washed with ice-cold 1 N hydrochloric acid and then. using an aqueous solution of sodium chloride, dry and then evaporate.

   The residual gum is dissolved in 34 ml of ethanol, and to this stirring solution is added 0.32 ml (6.1 mmol) of aqueous sodium hydroxide solution. The reaction mixture is stirred for 2 hours, then 100 ml of water is added dropwise, while cooling in an ice bath, the product which precipitates is filtered and washed with water.



   1.83 g (81%) of the title compound are thus obtained.



  P. f. : 124-126 C.
 EMI18.2
 



  The starting compound of Example 16 is prepared as follows: 3 [/ 2- (2-hydroxypropy)) - 5-ch! orophény! / - 4-nitrophény! ethyl methy [ene] carbazate
2.10 g (approximately 6 mmol) of the hemicetal prepared according to Example 13, stage A, are reacted with 1.25 g (12.0 emotes) of ethyl carbazate in a mixture of 80 ml of ethanol and 60 ml of water containing 0.1 ml of concentrated hydrochloric acid, under boiling. After two hours of boiling, 0.12 g (!, 2 smote) of ethyl carbazate and an additional drop of hydrochloric acid are added to the mixture, which is boiled for an additional 2 hours.

   After evaporation. the residue is dissolved in an aqueous solution of sodium bicarbonate. filters the crystalline product and washing it with water.



   2.36 g (97%) of the title compound are obtained.



   The product is a mixture of stereoisomers in a ratio of approximately 1.1.



    P. f. : 123-125OC.



  EXAMPLE) 7
 EMI18.3
 1- (4-aminophént) -3-cthox) carbony! -8-ch) oro-4-méthy) -4. 5-dihydro-3H-2, 3benzodiazepine 1.93 g (-L97 mmol) of 8-chloro-3-ethoxycarbonyl-4-meth are reduced; 1-1- (4-nitrophény!) - 4. 5-di) ') ydro-3! ! -2. 3-benzodia7épine in a mixture of

  <Desc / Clms Page number 19>

 
 EMI19.1
 methanot and dichioromethane in a ratio of 4/1. in the presence of Raney nickel known as a catalytic converter. with hydrazine, using the method described in Example 2. The product is purified by column chromatography (silica gel, eluent: mixture of n-texane and ethyl acetate in a I / I ratio).



   1.46 g (82%) of the title compound are obtained in the form of a solid foam. P. f. : 95-98 C.



    EXAMPLE 18
 EMI19.2
 3-n-butytcarbamoyl-8-chloro-4-methyl-I- (4-nitrophenyl) -4, 5-dihydro-3H-2, 3ii-blitylcai 1 benzodiazepine
2.10 g (4.85 mmol) of [/ 3-chloro-6- (2-hydroxypropyl) / - 4nitrophenylmethylene] -4-n-butyl semicarbazide are acylated with 0.53 ml (6.79 mmol) of chloride of mesyl in dichloroethane in the presence of 1.22 mol (8.73 emotes) of triethylamine according to the method described in Example 14. The crude intermediate is cyclized using 0.28 ml (5.33 mmol ) of a 50% solution of sodium hydroxide as described in Example 14. The 1.40 g of crude product obtained is recrystallized from methanol.



   1.14 g (56%) of the title compound are thus obtained. P. f. : 150 C.



   The starting material of Example 18 is prepared, that is to say 1- [13-chloro-
 EMI19.3
 6- (2-hydroxypropyl) / - 4-nitrophenylmethylene] -4-n-butyl-semicarbazide from l-hydroxy-7-chloro-3-methyl-I- (4-nitrophenyl) -isochroman (Example 13, step A), and 4-n-butylsemicarbazide using the method described with respect to the starting product of Example 14. The crude product separates in the form of a gum, and it is purified by column chromatography (silica gel, eludant: mixture of hexane and ethyl acetate in a lit ratio (RF = about 0.2), then it is used in the process of Example 18.

   EXAMPLE 19
 EMI19.4
 1- (4-aminophény)) - 3-n-butytcarbamaoy 1-8-chloro-4-methyt-4, 5-dihydro-3H-2, 3benzodiazepine We reduce), 14 g (2,75 emotes) of 3- n-butytcarhamoyt-8-chtoro-4-méthyt- 1- (4-nitrophény)) - 4. 5-dihydro-3! t-2,3-benzodiazepine (prepared as in Example 18) using 0.70 ml (! 3.74 mmol) of hydrazinc hydrate in 90 ml of methanol in the presence of Raney nickel as catatyser, according to the method described in Example 2. The product is purified by chromatography on cotorme (siticage!. etuant: mixture of dichtoromethaty and methanot in a 98/2 ratio). After incorporation. the product is isolated in the form of foam which can be put into powder.

  <Desc / Clms Page number 20>

 
0.93 g (88%) of the product under heading is obtained.

   P. f. 89-91 oc.



    EXAMPLE 20
 EMI20.1
 3-acetyl-7, 8-dichtoro-4-méthy) -] - (4-nitrophényt) -4, 5-dihydro-3H-2, 3iteétyl-7, 8-dicliloi 1 benzodiazepine (the preparation method is different from that used in Example 9).



   6,26 g (about 15.3 emotes) of 1- / 2- (2-hydroxypropyl) -4.5
 EMI20.2
 dichlorophenyll-4-nitro-phenylmethylene] hydrazide of acetic acid (see step B of this example) and it is cyclized by alkaline treatment according to the method of example 13.



   3.65 g (64%) are thus obtained calculated as an isochroman described in Example 9, step A) of the title compound, in the form of yellow crystals. P. f. :
190-1 95 C.



   The starting compounds are prepared in the following manner:
Step A 1-hydroxy-6,7-dichloro-3-methyl-1- (4-nitrophenyl) isochroman
Oxidized 6, Og (17, 7 emotes) of 6, 7-dichloro-3-methyl-1- (4-nitrophenyl) isochroman using the method described in Example 13, step A.



   6.03 g (96%) of the title compound are isolated in the form of yellow crystals. The raw product consisting of a mixture of two stereos is used.
 EMI20.3
 isomers possible, in the next reaction step, without further purification.



  Step 11 l (2-hydroxypropyt) -4,5-dichtorophenyt / -4-nitrophénytméthytène] acetic acid hydrazide
5.18 g (14.6 emotes) of the hemicetal prepared in Example 20, step A) are reacted with acetic hydrazide using the method of Example 13, step B. This gives 6. 26 g of the title compound in the form of a yellow gum which is used for the mesylation and ring-closing reactions.



    EXAMPLE 21
 EMI20.4
 7, 8-dichtoro-4-méth \) - 3-métytcarbamoyt -) - (4-nitrophén \ t) -4, 5-dihydro-3H-2, 3-benzodiazepine (the preparation method is different from that described in Example 11).



   According to the method of Example 13, mesylate and cyclize 8. 66 g (approximately
 EMI20.5
 '-0, 4 iiiiiioles) (the 20. 4 immoles) of 1- r! ]. 4-dichloro-6- (1-hydro \: ypropyl) 1-4-nitrophenylmethylene lene 1- 4-meth \ t scmi carba7ide according to the method described in the example) 3.



  The crude product obtained is recrystallized from aqueous dimeth \ tformamide.

  <Desc / Clms Page number 21>

 
3.12 g are thus obtained (33% calculated for the isochroman described in Example 9, step ^) in the form of pale yellow crystals. P. f. : 218-220oC.



   The starting material is prepared, i.e. the 1 - [/ 3,4-dichloro-6- (2-
 EMI21.1
 hydroxypropyl) / - 4-nitrophenylmethylene) -4-mdhyl semicarbazide from 1-hydroxy-6,7-dichloro-3-methyl-l- (4-nitrophen) l) isochroman (example 20, step A) and 4-methylsemicarbazide using a method analogous to that described with respect to the starting product of example 14. The crude product separates in the form of a yellow gum, and it is used in example 21 without further purification.



  EXAMPLE 22 3-acetyl-8-bromo-4-methyl-1- (4-nitrophenyl) -4.5-dihydro-3H-2, 3benzodiazepine
 EMI21.2
 0.82 g (2.28 immoles) of 8-bromo-4-meth) are acylated 1-1- (4-nitrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine according to the method of Example 1. 0.84 g (91%) of the title compound is thus obtained. P. f. : 228-230 C.



   The starting material of Example 22 is prepared as follows:
Stage A
 EMI21.3
 7-bromo-3-methyl-1- (4-nitrophenyl) isochroman The operation is carried out according to the method of example 1. step A except that 14.69 g (68.3 mmol) of] - (4- bromophenyl) -2-isopropanol [J. med. Chem., 21, 454 (1978)], as the starting compound. 10.94 g (46%) of the title compound are thus obtained. P. f. : 130-133 C.



   Step B 8-Bromo-3-methyl-1- (40-nitrophenyl) -2-benzopyrilium perchlorate
10.8 g (32.5 mmo1cs) of isochroman derivative prepared in example 22, step A, are oxidized with the Jones reagent according to the method of example!, Step B. The product is prepared in glacial acetic acid with perchloric acid.



   4.91 g (34%) of the title compound are thus obtained. P. f. : 253-256 C.



   Step C
 EMI21.4
 8-bromo-4-methyl-I-4-nitrophenyl) -511-2, 3-benzodiazepinc 4.0 g (9.0 mmotes) of benzopyrihum perchtorate prepared in example 22 is processed. hydra7inè hydrate according to IZ1 method of Example 1. step C. This gives 2.30 g (71%) of the title compound. P. f. : 200-205 C.



  D Step D S-bromo-4-meth \ i-! - (4-ml [mphén \)) - 4. 5-di) i \ dro-3 [I-2. 3-bcn7odia7épine

  <Desc / Clms Page number 22>

 
 EMI22.1
 Reduced 3.0 g (8.38 mmo [es) of the benzodiazepine derivative prepared according to example 22, step C, according to the method described in Example 1. step D. This gives 2.79 g (92 %) of the title compound. P. f. : 131-135oye.



  1-, XF-, MPLE 2 ') EXAMPLE 23 3-acety) -1- (4-aminopheny)) - 8-bromo-4-methyl-4, 5-dihydro-3H-2, 3benzodiazepine We reduce 0.80 g (2.0 emotes) of 3-acetyl-8-bromo-4-methyl-I- (4nitrophenyl) -4, 5-dihydro-3H-2, 3-benzodiazepine (prepared) using the method of the example 22).



  The crude product is recrystallized from ethanol. 0.62 g (83%) of the title compound is thus obtained. P. f. : 205-208 C.



  EXAMPLE 24 8-Bromo-4-methyl-1- (4-nitrophenyl) -3-tri fluoroacetyl-4, 5-dihydro-3 H-2, 3benzodiazepine 1.51 g (4, 20 emotes) are stirred bromo-4-methyl-! - (4-nitro-phenyl) - 4, 5-dihydro-3H-2, 3-benzodiazepine (prepared in Example 22, step D) in a mixture of 5ml anhydrous dichloromethane and 5111l of trifluoroacetic anhydride at 25 ° C. for 3 hours, then the reaction mixture is diluted with dichtoromethane. The organic phase is washed with water, and with the aid of 2% aqueous sodium bicarbonate, it is dried and evaporated. The product is purified by suspending it in 5 ml of hot methanol. After filtration and drying, 1.66 g (86%) of the title compound are obtained. P. f. : J 93-196OC.



  Example 25 1- (4-aminopheny)) - 8-lromo-4-methyi-3-trifltuoroacetyl-4. 5-dihydro-3H-2, 3benzodiazepine Reduced 1.64 g (3.60 mmol) of 8-bromo-4-lllethyl-I-4- (nitro) -phenyl) - 3-trinuoroacety) -4, 5- dihydro-3H-2, 3-benzodiazepine (prepared in Example 24) using) c process of example 2. The crude product is purified by chromatography on cotton with saturation using a mixture) angel ch [oroformc / methanol in a 99/1 ratio.



  0) t thus obtains 1. 33 g (87%) of the title compound. P. f. : 93-96 C.



  EXE IPI. E 26 be] 170 (ilazéliiiie 8-bromo-4-méthy! -) - (4-) iitmphényt) -3-propiony) -4, 5-dih \ dro-3H-2. 3henzodiazépinc On ac \! e). 33 g (3.7 mmoics) of 8-bromo-4-mé! \) -) - (4-nitrophény!) - 3n-it1uoroacét \) - 4. 5-d! h \ dro-3) 1-2. 3-hcnzod! thorn (prepared in exempt 22.

  <Desc / Clms Page number 23>

 step D) using propionic anhydride den using the method of Example 1. The product is purified by chromatography on a silica gel column, eluting with an iixane / ethyl acetate mixture in a ratio of 9 / I. 1.07 g (70%) of the title compound is thus obtained. P. f. : 178-180 C.



  EXAMPLE 27
 EMI23.1
 1- (4-aminophenyl) -8-bromo-4-methyl-3-propionyf-4, 5-dihydro-3H-2. 3- benzodiazepine
1.05 g (2.52 mmol) of 8-bromo-4-methyl-I- (4-nitrophenyl) -3propionyl-4,5-dihydro-3H-2,3-benzodiazepine (prepared in the example) are reduced 26) using the method of Example 2. The crude product is recrystallized from methanol. 0.85 g (87%) of the title compound is thus obtained. M: 99-102 C.



  EXAMPLE 28 8-bromo-3-cyclopropionyl-4-methyl-1- (4-nitrophenyl) -4.5-dihydro-3H-2, 3benzodiazepine
0.90 g (2.5 emotes) of 8-bromo-4-methyl-1- (4-nitro-phenyl) -4.5- are acylated
 EMI23.2
 dihydro-3f-f-2. 3-benzodiazepine (prepared according to Example 22, step D) using 0.271nul (3 immoles) of cyclopropanecarbonyl chloride in 15 ml of dich) anhydrous oromethane in the presence of 0.22 ml (3 immoles) of triethylamine to C. The reaction mixture is poured into 25 g of crushed ice and extracted with dich) oromethane. We ! ave) an organic phase using an aqueous sodium bicarbonate solution, dry and then evaporate. The crude product is suspended in 3 ml of hot ethanol. After filtration and drying, 0.88 Zr g (82%) of the title compound is obtained. P. f. : 172-I73OC.



  EXAMPLE 29 1- (4-aminophényi) -8-b) 'omo-3-cyclopropionyl-4-methyl-4. 5-dihydro-3H-2, 3benzodiazepine 0.76 g (L77 mmol) of 8-bromo-3-cyclopropionyl-4-methyl-l- (4-mtropheny!) - 4, 5-dihydro-3H-2 are reduced , 3-benzodiazepine (prepared in Example 28) according to the method of Example 2. The crude product is recrystallized <; é in a mixture of ethanol and hexane in a ratio of 1/4. 0.55 g (78%) of the title compound is thus obtained. P. f. :)) 3-]) 6 C.



  FXEI \ lPLE 30 8-bromo-4-methy! -3-meth \ Icarbamoy) -) - (4-nit; 'ophen) t) -4. 5-dihydro-3H-2, 3benzodiazepine 0.84 g (2.33 mmotes) of 8-bromo-4-methyl-1- (4nitrophenyi) -4 are reacted. 5-di) 'ndro-3H-2. 3-henzod! a7épine (prepare in example 22,

  <Desc / Clms Page number 24>

 
 EMI24.1
 step D) with methyl isocyanate according to the method of Example 3. The crude product is suspended in 5 ml of hot ethanol. After filtration and drying. 0.82 g (84%) of the title compound is obtained. P. f. : 197-200oC.



  EXAMPLE 31] - (4-aminophenyt) -8-bromo-4-methyl-3-methylcarbamoy) -4,5-dihydro-3H-2, 3-benzodiazepine
0. 80g (1.92 emotes) of 8-bromo-4-methyl-3-methyl-carbamoyl-t- (4-nitrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 30) according to the method of Example 2. The crude product is recrystallized from 3 ml of ethyl acetate. 0.50 g (68%) of the title compound are thus obtained. P. f. : 121-124 C.



  EXAMPLE 32 8-bromo-3-ethoxycarbonyl-4-methyl-1- (4-nitrophenyl) -4.5-dihydro-3H-2,3-benzodiazepine
8.11 g (18 mmol) of ethyl 3- [/ 5-bromo-2- (2-hydroxypropyl) phenyl / -4-nitrophenylmethylene] -carbazate are reacted with mesyl chloride and then with an aqueous solution. 50% sodium hydroxide, according to the method of Example 16. The product is extracted with dichloromethane, the organic phase is washed with water, dried and evaporated. 6.78 (87%) of the title compound is obtained in the form of a solid foam, which is used in this form in Example 33.



   The starting compounds are prepared as follows:
Step A 7-bromo-1-hydroxy-3-methyl-1- (4-nitrophenyl) isochroman
15.56 g (44.7 emotes) of 7-bromo-1-hydroxy-3-methyl-1- (4-
 EMI24.2
 nitrophenyt) isochroman (prepared in Example 22. step A) using the method described in Example 13, step A. The product is extracted with benzene, dried and evaporated. 14.80 g (91%) of the title compound are thus obtained, in the form of a mixture of the possible isomers. The product is used without further purification.



   Step B Etyl-3 - [/ 5-bromo-2- (2-hydroxypropyl) phenyl-4-nitrophenylmethylene] carbazate.
 EMI24.3
 



  The hemicetal dye prepared in Example 32 is reacted (82g (t8. 72 mmol). Step A. with carba / ate of eth) using the method described in connection with

  <Desc / Clms Page number 25>

 
 EMI25.1
 ! a preparation of the starting compound of Example 6. The product is extracted with ethyl acetate, the organic phase is washed with water. dried. then evaporates.



  Thus, 8.1 in (96%) of the title compound are obtained. The product consisting of a mixture of possible isomers is used without further purification.



  EXAMPLE 33 1- (4-aminophény 1) -8-bromo-3-ethoxycarbony 1-4-methyl-4, 5-dihydro- 3 H -2, 3benzodiazepine We reduce 1,58g (3,66 emotes) by 8- bromo-3-ethoxycarbonyt-4-methyt-t- (4-nitrophenyl) -4,5-dihydro-3H-2. 3-Benzodiazepine (prepared in Example 22) using the method of Example 2. The product is recrystallized from 4 ml of ethyl acetate. There are thus obtained t, 20g (81%) of compound in the heading. P. f. : 1 14-il 70C.



  EXAMPLE 34 8-bromo-3-carbamoyl-4-methyl-I- (4-nitrophenyl) -4, 5-dihydro-3H-2, 3benzodiazepine A solution of) is treated. 80g (5 emotes) of 8-hromo-4-methyl-1- (4nitrophenyt) -4,5-dihydro-3H-2,3-benzodiazepine in tOmt of glacial acetic acid per 0,53g (6,5 emotes) potassium cyanate. After 1 hour, the solution is poured into water, and the precipitating crystals are filtered. The crude product is suspended in 5 ml of hot ethanol. After filtration and drying, 1.56 g (77%) of the title compound are obtained. P. f. : 193-2030 (, The starting compound of Example 34 is prepared as follows: 8-bromo-4-methyl-I- (4-ni trophenyl) -4, 5 -d ihydro- 3 H - 2 .3-benzodiazepine (the compound is identical to that of Example 22, step D).



  5. 20 g (12 mmol) of 8-bromo-3-ethoxycarbonyl-4-methyl-) - (4-r) itrophény)) - 4, 5-dihydro-3H-2 are boiled. 3-benzodiazepine (prepared in Example 32) in 104 ml of methanol with 6111 l of ON sodium hydroxide solution for two hours. After cooling. the reaction mixture is diluted with t04ml of water. then the precipitating crystals are filtered. 3.99 g (92%) of the title compound are thus obtained. P. f. : 125-1300C.



  EXAMPLE 35) - (4-aminophen) t) -8-hromo-3-carbamoyt-4-methyl) -4. 5-dihyd) 'o-3! f-2, 3-benzodiazepinc We reduce 1. 55g (.). 84 Illmoles) of 8-hromo-3-carbamoyl-4-methyl-1 - (4nitrophenyt) -4. 5-di) i \ d) o-3ff-2. 3-be! izodiLt / épi) ie (prepared in Example 34) in

  <Desc / Clms Page number 26>

 
 EMI26.1
 using the method of Example 2. The crude product is recrystallized from 5m) of ethanol. Thus, Ll9g (83%) of the title compound is obtained. P. f. : 218-221 oc.



  1 1 EXAMPLE 36 8-chloro-4-methyl -] - (4-nitrophenyt) -3-triftuoroacetyl-4, 5-dihydro-3H-2. 3benzodiazepine Acyl 0.6g (1. 9 immoles) of 8-chloro-4-methyl-I- (4-nitrophenyl) -4, 5dihydro-3H-2, 3-benzodiazepine (prepared in Example 5, at 1 step D) with tri tluoroacetic anhydride according to the method of Example 24. 0.76 g (97%) of the title compound is obtained. P. t. : 150-152OC.



  The starting product is identical to the product of Example 5, step D, it can however be prepared in the following manner: 10. 98 g (27 ml) of 3-ethoxycarbonyl-8-chlloro-4-methyl-1 are hydrolyzed - (4-nitrophenyl) -4, 5-dihydro-3H-2, 3-benzodiazepine (prepared in Example 16) using the method described in connection with the preparation of the starting product of Example 34.



  8.04 g (94%) of the title compound are thus obtained. P. f. : 146-151 oC.



  ZD EXAMPLE 37 1- (4-aminophenyl) -8-chloro-4-methyl-3-tri fluoroacetyl-4. : 5-dihydro- 3 H -2. 3benzodiazepine 0.75 g (1.8 emotes) of 8-chtoro-4-methyt-t- (4-nitrophenyt) -3trifluoroacetyl-4, 5-dihydro-3I 1 -2 are reduced. 3-Benzodiazepine (prepared in Example 36) according to the method of Example 2. The crude product is purified by chromatography on a silica gel column which is eluted with a benzene-ethyl acetate mixture in a 3/1 ratio. 0.47 g (68%) of the title compound is thus obtained. P. f. : 165-167OC.



  EXAMPLE 8 EXAMPLE 38 8-chloro-4-methyt -) - (4-nitrophenyl) -3-propionyt-4, 5-dih \ dro-3f 1-2. 3benzodiazepine We acylate 0.6g (1. 9 mmol) of 8-chloro-4-methyl) -t- (4-nitro-phenyl) -4, 5dihydro-3II-2, 3-benzodiazepine (prepared in Example 5 , step D, or in example 36, starting product) with propionic anhydride following the method of example 26. The crude product is purified by chromatography on a silica gel column, eluting with the aid of 'a benzene-acetate mixture of eth) le in a 95/5 ratio. We thus obtain n. 56g (79O {,) of the title compound. P. f. : 160-161: I.

  <Desc / Clms Page number 27>

 



    EXAMPLE 39 1- (4-aminophenyl) -8-chloro-4-methyl-3-propionyl-4.5-dihydro-3H-2,3-benzodiazepine
0.46 g (1.23 mmol) of 8-chloro-4-methyl-1- (4-nitrophenyl) -3propionyl-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 38) is reduced according to the method of Example 2 "The crude product is recrystallized from 50% aqueous ethanol. 0.39 g (93%) of the title compound is thus obtained. Mp: 118-120 C.



  EXAMPLE 40
 EMI27.1
 1 - op'-0-4. 5-dili \, dro- ') 11-2, 3- 3-cyclopropionyt-8-chloro-4-methyl-I- (4-nitrophenyt) -4. 5-dihydro-3LI-2, 3benzodiazepine On acy) e 0. 6g (t. 9) mnotc) de 8-ch) oro-4-méthyi-t- (4-nitrophény)) - 4, 5-dihydro-3H -2, 3-benzodiazepine (prepared in Example 5, step D, or in Example 36, starting product) using cyclopropanecarbonyl chloride according to the method of Example 28. 0.71 g is obtained (97%) of the compound in
 EMI27.2
 section. P. f. : 58-160 C.



  EXAMPLE 41 t- (4-aminopheny 1) -3-cyclopropionyl-8-chloro-4-methyl-4. 5-dihydro-3H-2, 3-benzodiazepine
0.72 g (1.87 mmol) of 3-cyclopropionyl-8-chloro-4-methyl-1- (4nitrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 40) is reduced ) according to the method of Example 2. The crude product is recrystallized from 50% aqueous methanol. 0.57 g (86%) of the title compound is thus obtained. P. f. : 122-124OC.



  EXAMPLE 42 (+) - 3-acetyl-89-chloro-4-methyl-1- (4-nitrophenyl) -4,5-dihydro-5H-2. 3benzodiazepine
0.51 g 91.6 mmol) of (+) - 8-chloro-4-methyl-1- (4-nitrophenyl) - 4, 5-dihydro-5H-2,3-benzodiazepine are acylated with acetic anhydride according to the method of Example 1. 0.54 g of crude product is recrystallized from 28 ml of ethyl acetate to
 EMI27.3
 ambient temperature. 0.28 g (48%) of the title compound is thus obtained. P. f. : 259-260. According to a HPLC study (Chiralcel OJ, eluent: mixture of hexane and ethanot in a ratio t :)) we see that the product consists of a single isomer.



  We prepare the starting material for exempt 42 as follows:

  <Desc / Clms Page number 28>

 
 EMI28.1
 (+) - 8-ch) oro-4-méthy) - i- (4-nitrophény)) - 4. 5-dihydro-5H-2, 3benzodiazepine Is added dropwise, at -20 C, 2, 43mil (21.5 mmol) of a complex.] Olite (Totitte suH'urc dimethyl-borane to a solution of 6 03g (23. 6 immoles) of R- (+) - 2 amino-LI-diphenylc-3-methylbutane-lo] [1 Org. Chcm .. 49, 555 (1984); 1 Chum. Soc. Perkin. Trans. 1. 2039 (1985)] in 60 ml of anhydrous dichloroethane (concentration of borane: approximately 9.2 M).



  The temperature is allowed to return to 0 ° C. for 3 hours. and left at +4 C for 15 hours. To the solution thus obtained of reducing complex, a solution of 3.37 (10.7 emotes) of 8-cliloro-4-iiiethyl-1- (4nitrophenyl) -4.5-dihydro-511-2 is added dropwise. , 3-benzodiazepine (prepared in Example 5, step C) in 60ml of dich! anhydrous oromethane, at room temperature, in 30 minutes. The reaction mixture is stirred at 60 ° C for 6 hours. The orange solution is cooled to 25 ° C., treated with 50 ml of a 10% solution of aqueous sodium carbonate, washed with water until neutral, dried and then evaporated. The product is isolated on cotton silica gel using a mixture of benzene and ethyl acetate in a ratio 8 / J.



  The product in column thus obtained consists of a mixture of enantiomers in a ratio of 75/25 (HPLC: Chiralcel OJ, etuant: mixture of hexane and methanol in a ratio) /)).



  EXAMPLE 43 (-) - 3-acetyl -) - (4-aminophenyt) -8-chtoro-4-methyl) -4. 5-dihydro-5H-2, 3benzodiazepine We reduce 0.28g (0.78 smote) of (+) - 3-acetyl-1-4-aminophenyl) -8-chloro-4-methyl-4, 5-dihydro- 5H-2, 3-benzodiazepine (prepared in Example 42) according to the method of Example 2. The crude product is recrystallized from 2 ml of ethanol. 0.15 g (58%) of the title compound is thus obtained. P. f. : 219-220 C / a / p) 25 = -7t2. t (c = 0.7 chloroform). I. he product consists of a single enantiomer (HPLC: Chira) ce) J. eluent: a mixture of hexane and ethanol in a ratio of 1 (1).



  EXAMPLE 44 3- (ethyka) amoy)) - 8-ch) oro-4-méthy! -) - (4-nitrophén \)) - 4. 5-dihydro-3H-2, 3benzodiazepine We bring to the boil O. óg (1. 9 mmolcs) of 8-chloro-4-methyl-I- (4-) iitrophény)) - 4. 5-di! i \ d) o-3H-2. 3-ben / odia7épine (prepared in example 5. step (pi-éliai-é the exciiilile 5. step D or in example 36. starting point) in the presence of 0.75m) (9. 5 mmoles)

  <Desc / Clms Page number 29>

 
 EMI29.1
 of ethyl isocyanate in 251ul of anhydrous toluene for:? 4 hours. The mixture is evaporated and the residue is recrystallized from 5 ml of ethanol. 0.51 g (69%) of the title compound is thus obtained. P. f. : 170-172oye.



  EXAMPLE 45 I- (4-aminophény 1) - 3-éthy lcarbamoyl) -8-chloro-4-methyl-4, 5-dihydro- 3 H -2, 3benzodiazepine We reduce 0.48g (1, 24 smote) by 8 -chloro-3- (ethylcarbamoyl) -4-methyl-I- (4nitrophenyl) -4, 5-dihydro-3H-2, 3-benzodiazepine (prepared in Example 44) according to the method of Example 2. recrystallizes the crude product from 4 ml of 50% aqueous methanol. 0.35 g (79%) of the title compound are thus obtained. P. f. : 165-167 C.



  EXAMPLE 46 8-chloro-4-methyt-1- (4-nitrophenyl) -3- (n-propylcarbamoyl) -4, 5-dihydro-3H-2, 3benzodiazepine React 0.6g (1, 9 immoles) 8-chloro-4 methyl-1- (4-nitrophenyl) - 4, 5-dihydro-3H-2J-benzodiazepine (prepared in Example 5, step D or in Example 36, starting compound) with l n-propyl isocyanate according to the process described in Example 44. The crude product is recrystallized from ethanol.



  0.63 g (83%) of the compound is thus obtained. P. f. : 186-187Oe.



  EXAMPLE 47 t- (4-aminophenyt) -8-chtoro-4-methyt-3- (n-propytcarbamoyt) -4, 5-dihydro-3H- 2, 3-benzodiazepine We reduce O. 6g (), 5 smote) 8-ch) oro-4-methyt-1- (4-nitrophenyl) -3- (npropy lcarbamoy 1) -4. 5-dihydro- 3 H -2, 3-benzodiazepine (prepared in Example 46) according to the method of Example 2. 0.52 g (93%) of the title compound are thus obtained. P. f. : 88-90 C.



  EXAMPLE 48 3- (isopropylcarbamoy)) - 8-ch) oro-4-methyl-t- (4-nitrophenyl) -4, 5-dihydro-3n- 2, 3-benzodiazepine Reacted 0.6 g (1, 9 mmoles) of 8-chloro-4-methyi-1- (4-nitrophényi) - 4, 5-dihydro-3H-2. 3-benzodiazepine (prepared in Example 5, step D or in Example 36. starting product) with isopropyl isocyanate according to the method of example 44. The crude product is recrystallized from ethanot . 0.4 g (53%) of the product in this category is thus obtained. P. f. : 172-174 "C.

  <Desc / Clms Page number 30>

 
 EMI30.1
 



  EXAMPLE 49 1- (4-aminophenyl) -3- (isopropytcarbamoyl) -8-chloro-4-meth \ t-4, 5-dih \ dro-3H- 2, 3-benzodiazepine We reduced 0.38 g (0. 95 mmote) of 3- (isopropytcarbamoyt) -8-chtoro-4méthyt-t- (4-nitrophényt) -4. 5-dihydro-31i-2,3-benzodiazepine (prepared in Example 48) using the method of Example 2. 0.32 g (91%) of the title compound is thus obtained. P. f. : 100-1 02 C.



  EXAMPLE 50 3-ethoxycarbonyl-7,8-dichloro-4-methyl-I- (4-nitrophenyl) - .. L5-dihydro-J H-2. 3- benzodiazepine
1.41 g (about 2.7 emotes) of 3 - [/ 2- (2-hydroxypropyl) -4,5 dichlorophenyl / -4-nitophenyl-methylene] -carbazate are mesylated and cyclized as described in Example 13. 0.94 g (75% calculated as isochroman described in Example 9, step A) of the compound in the above is thus obtained. P. F.: 106-108OC.



   The starting material of Example 50 is prepared as follows:
 EMI30.2
 3- [/ 2- (2-hydroxypropyl) -4,5-dich) orophenyl / -4-nitrophenylmethy) ene] -) - [/ 2- (2-li) -droxypi 1 carbazate
0.98 g (2.8 emotes) of 1-hydroxy-6,7-dichloro-3-methyl-1- (4-nitrophenyl) isochromane (prepared in Example 20, step A) is reacted with carbazate d ethyl according to the method described with regard to the preparation of the starting compound of Example 16. This gives t. 20g (97%) of the title compound consisting of a mixture of possible isomers. The product is used without further purification.



  EXAMPLE 51
 EMI30.3
 1- (4-aminophenyt) -3-ethoxycarbonyt-7, 8-dichloro-4-methyl-4. 5-dihydro-3H-2, 3benzodiazepine 0.94 g (2.2 mmol) of 3-ethoxycarbonyt-7 are reduced. 8-dichloro-4-methyl- 1- (4-nitrophenyt) -4,5-dihydro-3H-2. 3-benzodiazepine (prepared in Example 50) according to the method of Example 2. The crude product is purified by chromatography on a silica gel column, eluting using a benzene-ethyl acetate mixture in a ratio 4'1. The product is then recrystallized from ethanol.
 EMI30.4
 



  O. 54g (63%) of the compound cn rubric is thus obtained. P. r. : 190-192OC. rXf \ 1PT. r 52 3-butyryt-7. 8-diduom-4-meth \ t-i- (4-nitrophen \ t) -4. 5-dih \ dm-3H-2. 3benzodiazepine

  <Desc / Clms Page number 31>

 
 EMI31.1
 We're mesy! e!. 3) g (approx. In 3 mmoles) of [] - / 2- (2-hydroxypropy!) - 4, 5dich) oropitény! -4-) iitrophény! -Méthy! ene-hyd) 'azide and cycise according to the mdhodc of example 13. One thus obtains 1.08 g (86% expressed in the isochroman described in example 9. stage A) of the compound in heading. P. f. : 75-77 C.



  The starting material of Example 52 of! as follows: [) - / 2- (2-h) droxypropyf) -4, 5-dichtorophény) / - 4-nitrophenytmethytene] butyric hydrazide We react], 06g (3 mmol) of the illemicetal prepared in the example 20, step A, with butyric hydrazide according to the method of example 13, step B. We obtain) J tg of the title compound in the form of a yellow amorphous substance which is used without further purification in the mesytation reactions and cycle closure.



  EXAMPLE 53 1- (4-aminophenyl) -3-butyryl-7,8-dichloro-4-methyl-4,5-dihydro-3H-2, 3benzodiazepine
1.08 g (2.6 mmoles) of 3-butyryl-7,8-dichloro-4-methyl-1- (4-
 EMI31.2
 nitrophenyl) -4. 5-dihyd) 'o-3H-2J-benzodiazepine (prepared in Example 52) according to the method of Example 2. The crude product is purified by chromatography on a column of silica gel, etching using a mixture. ethyl benzene acetate in an 8/1 ratio. The product is then suspended in hot ethanol.
 EMI31.3
 



  0.57 g (57%) of the title compound is thus obtained. P. f. : I93-I94OC.



  Using the above methods. the following products are prepared: 7, 8-dichloro-4-methyl-1- (4-nitrophenyl) -3-propionyl-4,5-dihydro-3H-2,3benzodiazepine.
 EMI31.4
 



  1- (4-aminophenyl) -7,8-dichioro-4-methyl-3-propionyl-4. 5-dihydro-3H-2, 3benzodiazepine.



  3-carbamoyl-7. 8-dichioro-4-methyl -) - (4-nitrophenyl) -4. 5-dihydro-3H-2. 3benzodiazepine.



  ] - (4-aminophény)) - 3-carhamoy) -7, 8-dichtoro-4-méthy) -4. 5-dihydro-3H-2. 3benzodiazepine. beiizodiazélillie.


    

Claims (1)

 EMI32.1   CLAIMS] .- Compounds of formula I, in! equet:  EMI32.2    EMI32.3  RI and R2 independently represent a hydrogen atom, a halogen atom, a C1-C6 alkyl group. a C1-C4 alkoxy group, a Q Q nitro group. a trifluoromethyl group or a group of formula-NRR, where 0 Q R8 and R independently represent a hydrogen atom, a C 1 -C 4 alkyl group or a group of formula-COR10, where Rio is hydrogen, a group C1-C6 alkyl which can be substituted, a (C-substituted ai-yl troop. a C-Cn ary group! a CI-C4 aoxy group 'a, i-otilie c, clo-ilk'le cry C a group cyc) oatky) e in C -.- Cc. a C -) - C alkenyl group, a C - C cycloalkoxy group or a group of formula - NR "R '. where R1 and R independently represent hydrogen, a C1 - C alkyl group.  a group cyc) oa) ky) e in C -'- Cc or an aryl group in C /.- C Q. LI 6-10. R-represents a C 1 -C alkyl group, i. a C - cycloalkyl group - (- or a group of formula -CO-Ro RoR- a] has the same definition as that which has been given in connection with R 1 (); R 4 and R represent, independently, a h \ drogen or a C1-C6 alkyl group, R6 and R independently represent a hydrogen, a chlorine atom or a bromine atom. This precondition that a group R and R represents a hydrogen, the other is not a hydrogen.  <Desc / Clms Page number 33>    EMI33.1   , i''1 l s Li 1 as well as their isomers and the acid addition salts of the compounds or their isomers. 2. - Compound according to claim 1, in which RI represents an amino group in position 4. 2 4 6 R R4 and R6 represent hydrogen, R5 represents a methyl group, R7 7 represents a halogen, and 1 R 3 represents an aliphatic acyl group or an alkylcarbamo group. c 1- 3. - A compound according to claim 2, wherein R 3 represents an acetyl group, a propionylc group. a cyctopropylcarbonyl group or a methyl) carbamoyl group. 4.-A compound according to claim 1. which is 3-acëtyt-! - (4- -inii 1 aminophény)) - 8-chtoro-4-methyl) -4,5-dihydro-3H-2. 4-benzodiazepine. 5.-Compound according to) a claim), which is 1- (4-aminophenyl) -8chtoro-4-methyl) -3-methyl) carbamoy) -4,5-dihydro-3H-2,3-benzodiazepine. 6. - A pharmaceutical composition comprising a compound according to one of claims 1 to 5 as well as carriers, solvents, diluents and conventional excipients used for the preparation of pharmaceutical compositions. 7. - Compound according to one of claims 1 to 5, intended to be used as a pharmaceutical product. 8. The use of the compounds according to one of claims 1 to 5. for the preparation of a pharmaceutical composition useful for the treatment of diseases accompanied by muscle spasticity. 9. - the use of the compounds according to one of claims 1 to 5. for the preparation of a pharmaceutical composition for the treatment of epilepsy.  <Desc / Clms Page number 34>    EMI34.1   10. - The use of the compounds according to one of claims 1 to 5, for the preparation of a pharmaceutical composition for the treatment of acute or chronic neurodegenerative diseases. ! 1. A process for the preparation of the compounds according to one of claims 1 to 5 in the RR, R- '', R, R, R and R have R a [a RRRRR and R have the meaning indicated in said claims, which comprises the introduction of the "RJ group in position 3 of a compound of formula II,  EMI34.2    EMI34.3  1 2 4 5 6 7 in which RI. R 2, R 4. R 5. R 6 and R 7 are as defined in said claims and. if necessary, the transformation of a compound of formula 1 into another compound of formula 1 and, if necessary, transformation of a compound of formula 1 into its acid addition salt or the release of the compound of formula 1 from its acid addition salt. 11. - Compound of formula H,  EMI34.4    EMI34.5  in which: RI and R2 represent. independently. hydrogen. a halogen, an aikyteenC) -Ci group. an aieoxy group in CC a nitro group, a group 0 Q tritluorometh) the or a group of formula-NR R. where 0 QR and R represent, independently, a hydrogen, a group a) ky) e in (.-Ct or a formula group-COR. where  <Desc / Clms Page number 35>    EMI35.1  Rio is hydrogen, a C) -C atkyl group which may be 1-c 1 may be z, 6 qll "substituted, an aryl group in C6-C JO. A alkoxy group in ClC4 tiii, rotipe c:  cloalk'le cri C - ', - C5, C). a cycioalkyie group in CC, a group a] kény) e in CiC, a cyctoatcoxy group in Ci-Ce or a group of formula t> or a group of formula il 12 - NRllR 'where R Il and R 12 represent, independently, a hydrogen, a C1-C4 alkyl group, a C3-C5 cycloalkyl group or a CC-aryl group) n. R 3 represents hydrogen, ct R4 and R mean, independently, hydrogen or a C1-C3 alkyl group. R6 and R7 7 independently represent hydrogen, a chlorine or bromine atom, with the proviso that if one of the groups R6 and R7 represents hydrogen, the other is not hydrogen.