USRE28315E - Cooc.hi - Google Patents

Abstract

IN WHICH R1 IS A HYDROGEN OR HALOGEN ATOM OR A TRIFLUOROMETHYL, LOWER ALKOXY, NITRO OR AMINO GROUP R2 IS A FURYL, A THIENYL, CYCLOHEXYL, LOWER ALKYL OR A PHENYL GROUP WHICH MAY BE SUBSTITUTED BY A HALOGEN ATOM OR BY A TRIFLUOROMETHYL, NITRO, LOWER ALKOXY OR LOWER ALKYL GROUP, AND R3 IS A HYDROGEN ATOM OR A LOWER ALKYL GROUP, AND R4 IS A LOWER CARBALKOXY, CARBAMOYL, A NLOWERALKYLCARBAMOYL, A N,N-DILOWERALKYLCARBAMOYL, A N(DILOWERALKYLAMINOALKYL) CARBAMOYL, A GROUP HAVING THE FORMULA -COOC AT IN WHICH CAT IS A CATION OF AN ALKALI METAL OR A SEMICATION OF AN ALKALINE EARTH METAL.

DIAZEPINE

1-R3,2-(O=),3-R4,5-R2,7-R1-2,3-DIHYDRO-1H-1,4-BENZO-

1. A BENZODIAZEPINE HAVING THE FORMULA

Description

Jan. 21, 1975 scHMn'T Re. 248,315

1,4-BBRZODIAZEPINE-2-ONES HAVING A CARBOXYLIC ACID ESTER OR AMIDE GROUP IN THE 3-POSITION Original Filed June 14. 1965 Invenor STOMP Schfmz United States Patent O 1,4-BENZODIAZEPINE Z-ONES HAVING A CAR- BOXYLIC ACID ESTER 0R AMIDE GROUP [N THE 3-POSlTlON Josef Schmitt, deceased, late of Val. de-Mame. LHayles-Roses, France, by Marcelle Amande Georgette Schmitt, nee Lecocq, administratrix, Val-deMarne, Ll-lay-les Roses, France, assignor to Etablissements Clin-Byla, Paris, France riginal No. 3,516,988, dated June 23, 1970, Ser. No.

706,713, Feb. 19, 1968, which is a continuation of abandoned application Ser. No. 463,613. June 14. 1965. Application for reissue Mar. 8, 1972, Ser. No. 232,985 Claims priority, application France, June 15, 1964,

978,360; Apr. 12. 1965, 12,886 Int. CI. C07d 53/06 U.S. Cl. 260-239.3 D 21 Claims Matter enclosed in heavy brackets I] appears in the original patent but forms no part of this reissue specilication; matter printed in Italics indicates the addition.

made by reissue.

ABSTRACT 0F THE DISCLOSURE Novel benzodiazepne having the formula in which R, is a hydrogen or halogen atom or a triuoromethyl, lower alkyl, lower alkoxy, nitro or amino groupI R2 is a furyl, a thienyl, cyclohexyl, a lower alkyl group or a phenyl group which may be substituted by a halogen atom or by a triuoromethyl, nitro, lower alkoxy or lower alkyl group, and R3 is a hydrogen atom or a lower alkyl group, and R, is a lower carbalkoxy, carbamoyl, an N- loweralkylcarbamoyl, an N,Ndiloweralkylcarbamoyl, an N-(diloweralkylaminoalkyl)carbamoyl, a group having the formula -COOCat in which Cat is a cation of an alkali metal or a semication of an alkaline earth metal are prepared by treating an ortho-aminoarylketimine having the formula NF4-C10 in which R1, R3, R3, and R, are as defined above and R, is a lower alkyl group or, when R, is a carbamoyl or -COOCat group, a cation of an alkali metal or semication of an alkaline earth metal, but excluding the case in which R, is -COOCat and R5 is -Cat, with an anhydrous lower aliphatic acid or with an anhydrous mineral acid, or, when R. is -COOCat and R5 is -CAT, with a dilute aqueous solution of an acid salt, in particular potassium dihydrogen orthophosphate, in substantially equimolar proportion or with a weak acid.

This application is a continuation of Ser. No. 463,613, tiled June 14, 1965, now abandoned.

This invention relates to pharmacologically useful materials which are ortho-aminoarylketimines and, in their cyclic form, benzodiazepines. The invention consits in certain new compounds as well as in the processes for the production thereof.

The ortho-aminoaryl ketimines have, in one tautomeric form, the general formula -lll ICC

in which R is a hydrogen atom or a group having th general formula R1 is a hydrogen or halogen atom or a triuoromethy lower alkyl, lower alkoxy, nitro or amino group, R, is furyi, a thienyl, a lower cycloalkyl, a lower alkyl grou or a phenyl group which may be substituted by a halt: gen atom or by a trilluoromethyl, nitro, lower alkoxy o lower alkyl group and R, is a hydrogen atom or a lowe alkyl group, R4 is a hydrogen atom. a lower carbalkoxi a carbamoyl, N-loweralkylcarbamoyl, an N,N-dilowei alkylcarbamoyl, an N(diloweralkylaminoalkyl) carbarr oyl, lower alkyl or substituted lower alkyl group, a grou having the general formula -COOCat in which Cat is cation of an alkali metal or semication of an alkalin earth metal or a group which, in a naturally occurrin a-aminocarboxylic acid, is linked to the carbon ator carrying the a-amino group, and R5 is a lower alkyl grou or, when R, is a carbamoyl or COOCat group. a catio of an alkali metal or semication of an alkaline enrt metal, When R, is a halogen atom it is preferably a chit rine atom. When R2 is a lower cycloalkyl group it preferably a cyclohexyl group.

The substituted benzodiazepines, in accordance with th invention, have, [in one tautomeric form] the gener.' formula l Cunt Rt \C RPN tt in which R1, R, and R, are as defined above and R, is lower carbalkoxy, a carbamoyl, an N-loweralkylcarbarr oyl, an N,N-diloweralkylcarbamoyl, an N(diloweralky aminoalkyl) carbamoyl, a group having the general fol mula -COOCat in which Cat is a cation of an alka metal or a semication of an alkaline earth metal or group which, in a naturally occurring a-aminocarboxyli acid, is linked to the carbon atom carrying the a-amin group.

In the present specification the alkyl groups, includn those present in alkoxy and aralkyl groups have 1 to carbon atoms in a straight or branched chain; for exarr ple, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tet tiary butyl, amyl and hexyl groups.

These products corresponding to Formula I may b prepared by a reaction for which the starting materia is an ortho-amino aryl ketimine represented by the ger eral Formula III in which the groups R1, R, and R, are as above define( These ortho-aminoaryl ketimines may be obtaine according to the present invention by reacting an ortht aminobenzonitrile having the substituent R, with an er cess of magnesium alkyl halide or magnesium aryl halitl RzMgX, in which R, is as above defined and X is a halc gen atom, particularly bromine. A substantial excess c the Grignard reagent RgMgX is used, preferably abot 3 to 4 molecules per molecule of ortho-aminobenzonitril used. The process may be carried out in anhydrous cth) ether and the starting materials allowed to react in boiling solvent for up to about hours. After cooling, the magnesium complex is decomposed with an aqueous ammonium chloride solution and the solvent evaporated. The ortho-amino aryl ketimine crystallises in most cases spontaneously and may be puried by recrystallisation from a suitable solvent, in particular from a hydrocarbon such as hexane or cyclohexane.

The ortho-aminoaryl ketimines are thus obtained in the form of pale yellow, well defined crystalline compounds. The yield is generally high, frequently of the order of 80 to 90%. The infrared spectra of these compounds agree with the structure indicated and is. moreover, confirmed by elementary analysis. The compounds have, among others, two bands characteristic of the vibrational frequency of the N-H bond: a tine line in the region of 3480 crn.-1 (absent if the aromatic amine is secondary) and a wide band at 3270-3300 crn.-1 due to the N-I-I of the imine and to the chelated NH of the NH2 (or Nl-I-R) group; moreover. the infrared spectra show two bands of vibration in the region of 1600 ctn.-1 (1610-1580 cmrl) due to the aromatic C=C conjugated to C=N.

Table l sets out certain imines having the general Formula lll which are new and which may be prepare. as indicated in the examples given hereinafter.

The substituted imines having the general Formula I (with the exception of the salts of the carboxylic derivatives) may be prepared from ortho-amino aryl ketimines (III and an ester of an a-aminoacetic acid in which R, is as above defined other than -COOCat. In the simplest case, this aminoacetic acid ester may be an ester of glycine but it may also be an ester of a naturally occurring optically active or racemic a-amino acid such as alanine, leucine or methionine; lastly. the ester may be a derivative of aminomalonic acid, in particular dimethyl or diethyl aminomalonate.

These esters may be used in the form of bases but preferably in the form of salts which are easier to deal with than the base, especially the hydrochloride. The reaction is accompanied by liberation of ammonia, either free or combined in the form of a salt according to the equation given below (in which Alk denotes a lower alkyl group):

The reaction may be carried out in a solvent which is inert with respect to the imine III, in particular a lower aliphatic alcohol or a hydrocarbon such as benzene or toluene, and at a temperature between room temperature lti and the reflux temperature of the diluent. The reaction time may vary between l and 12 hours; the higher the temperature employed, the shorter will be the reaction time. In certain cases, the reaction product separates spontaneously from the alcoholic solution at room temperature. Nevertheless. it is advantageous to evaporate off the solvent when the reaction is terminated. extract the product with an inert solvent and isolate it by crystallisation from a suitable solvent.

The substituted imines I which have an ester function are obtained in the form of pale yellow products. in most cases crystalline but sometimes in the form of oils. Their structure is determined by elementary analysis` study of their infrared spectra and the results of said hydrolysis.

As could be expected theoretically. the substituted imines (l) can exist in two stereoisometric forms one of which. generally obtained in larger quantity, is characterised by an intramolecular N-l-l hydrogen bond between a hydrogen on the amino group and the nitrogen of the imino group (forming a chelate ring). ln two of the appended examples (see Examples 6 and 7) these two forms were isolated by fractional crystallisation: in the other cases. the product isolated was generally a crystalline product corresponding to the chelate form.

The infrared spectra, determined in methylene chloride. of the chelate forms have a vibration band of the N-H group in the region of 3480 cm.'l (a line line would not be seen in the case of a secondary amine) and a wide band at 3150-3300 crn.-l due to the chelate bond N-H of the group NH2 (or Niel-R); in the region of 1730-17-10 ct'n.l a vibration band of C=O of the ester radical; in the region of 1610-1620 cm.-1 a band of the aromatic C=C (and C=N1z at 1203-1180 cm.-1 a C-O--C band (ester) shifted to 1220 crn.-l in the case of malonic esters. The non-chelate forms diter from the above by the existence of a doublet formed by two fine lines due to the N-H vibrations of NH2 (a single line at 3400 Cm."l in the case of secondary amines) and by the absence of absorption bands between 3150 and 3300 cmf.

Investigation of the hydrolysis of imines (li by a strong mineral acid particularly hydrochloric acid leads to different results according to the presence or absence of an internal hydrogen bond; if there is no chelation. the action of hydrochloric acid leads to the formation of the corresponding ortho-amino ketone due to severing of the imine bond: in the case ot' internal chelation. the imino bond is not severed and the corresponding benzodiazepine is formed, the configuration of which is moreover favourable to cyclisation.

In Table 1I, a certain number of subtituted imines are shown which correspond to the general Formula I above in which R5 is an alkyl group; these imines are all new.

TABLE II NH-Rt Ri I Rl Rt ORL] No. Ri Example 4292 CB1. Cl

We have found that the action of an anhydrous lower aliphatic acid, in particular glacial acetic acid, on either of the two stereoisomerie forms of the substituted imines (l) as well as on mixtures of these two forms leads almost exclusively to the corresponding benzodiazepine. Heating for from several minutes to one hour is desirable; after removal of the acid reagent in vacuo and dilution with a suitable solvent, in particular diethyl ether or diisopropyl ether, the benzodiazepine derivative is obtained directly in crystalline state.

Thus 7-chloro 5 phenyl-2,3-dihydro 1H-benzo[fll,4 diazepine (named hereinafter compound A) which has already been described by L. H. Sternbach and E. Reeder (Journal of Organic Chemistry 1961, volume 26, page 4936) may be prepared in two stages, giving an overall yield of 80%, from the unsubstituted imine 4356 CB without having to separate the two stereoisomeric forms of the intermediate substituted imine 4292 CB', the N- methyl derivative (B) of compound A, which is already known (see above reference) is obtained in a practically quantitative yield by subjecting the substituted imine 4361 CB for several minutes to the action of acetic acid.

Employing the same technique, the derivatives of cornpound A substituted on the 3 carbon atoms are obtained. For this purpose, it is sufficient first to react, according to the process of the invention, the free imine 4356 CB with the hydrochloride .if a suitably selected a-amino acid ester without isolating the intermediate substituted imine and proceed with the acetic acid treatment in question. For example, using the hydrochlorides of analine, leucine and methionine as reagents, one obtains the 3-methyl, 3- isobutyl and S-methylthioethyl derivatives respectively of 7-chloro-5phenyl-2-oxo2,3dihydro 1Hbenzo[f]l,4-

diazepine (compounds C, D, E). The yields vary but are always much higher than those indicated in the chemical literature-fot` the same substances (Sternbach, Fryer, Metlesics. Reeder, Sach. Sancy and Stempel, Journal of Organic Chemistry 1962, volume 27, page 3788).

This method has been extended to the preparation of new benzodiazepines carrying a carbalkoxy group on the 3-carbon atom. For this purpose, it is sufficient to treat malonic acid derivatives of products of type (l) such as those indicated in Table Il with an aliphatic acid; these derivatives, obtained by the action of a free imine of Formula Ill on the hydrochloride of an alkyl aminomalonate, may or may not be isolated. However, the yield is particularly high when crystalline substituted imines (I) are reacted in acetic acid.

We have found an advantageous modification for the preparation of benzodiazepines (1I) without isolation of the substituted imines (l), which modification is particularly recommended in cases in which the group R2 in the general Formula Il denotes a phenyl or substituted phenyl group, R, is a hydrogen atom and R, is a carbalkoxy group. Although these substances are easily obtained by the process described above, starting from ketimines III such as 4356 CB the yields are somewhat low and the results are diicult to reproduce if the quantity of reactans used is increased, whilst complete purification of the products by crystallisation is, in some cases, laborious. According to this modification, the substituted imine (I) such as 4292 CB is formed by the action of the hydrochloride of an alkyl amino-malonate on the free imine (III) such as 4356 CB, the reaction being carried out in a hydrocarbon solvent, preferably benzene or toluene, whilst hydrogen chloride gas is passed through the reaction medium to control the cyclisation without first isolating the intermediate compound. The resulting benzodiazepine derivative such as 4279 CB is then isolated in the form of the hydrochloride which can subsequently be decomposed into practically pure benzodiazepine.

This improvement is suitable for the preparation of other benzodiazepines having the general Formula Il, in particular those mentioned in Table III which may or may not be substituted on the carbon atom in position 3 in the heterocycle. All that is necessary is to replace the hydrochloride of ethyl aminomalonate by the hydrochlr ride of an alkyl glycine such as ethyl glycine which ma). c may not be substituted on the methylenic carbon atom.

This procedure is recommended for the synthesis l large quantities of compound 4190 CB (Formula ll het R2=cyclohexyl, R3=H, R,=H). The use of substitute or unsubstituted amino-malonic esters or amino-acet esters is not limited to ethyl ester.

The structure of the new carbalkoxy-3-benzo-diazepine (Il) is obtained not only from the elementary analysis t these compounds but also from a study of their infrare spectra and the results of hydrolysis .The infrared specti of 3-carbalkoxy benzodiazepine (1I) dissolved in metl ylene chloride have the following features. Vibratio bands of the N--H bond of the lactam group without sul stltuent (if this is the ease): namely a ne line (fre N-H) in the region of 3400 ctn.'1 and a wide band (a tached N-H) in the region of 3200 cm.l. In potassiur bromide, the absorption due to N-H is often more con plex and may result in the presence of various bands bi twen 3100 and 3400 cm.1; characteristic bands of th ester group at 1730-1755 C=O) and in the region c 1200 cm.-l (C-O-C); a characteristic band of a secont ary amide at 1660-1700 ci'n.-l (absence of the amide l band between 1510 and 1550 cmrl); a band at 1590 1610 cm.1 (aromatic C=C and C=N-) anke by a less intense band at 1560-1580 cm.-I for compound having two phenyl groups conjugated to C=N-.

The treatment of 3carbalkoxy benzodiazepines (ll with a saponifying agent (for example, an alkali met: hydroxide, preferably aqueous or alcoholic potash) an then with a dilute acid reagent (for example. acetic acid gives rise to hydrolysis and decarboxylation and finali leads to benzodiazepines which are unsubstituted on th 3carbon atom and. for example, to compound A if corr pound 4279 CB is put into the reaction, which completel demonstrates the structure proposed. By the treatment c the 3-carbalkoxy benzodiazepines (Il) with an alkali suc as aqueous or alcoholic potash, then with an alkylatin agent such as dimethyl sulphate and thereafter with dilute acid such as acetic acid, there are obtained the 1 alkylbenzodiazepines, for example, compound B (diaz: pam) when compound 4279 CB is used. Instead of usin the 3-carbalkoxy benzodiazepines (ll) the di-salts obtair able by the action of an alkali on the compounds (1I may be treated with an alkylating agent. The action c ammonia or of a primary or secondary amine at roor temperature in a suitable solvent such as methanol cor verts the 3 carbalkoxybenzodiazepines (1I) into benzc diazepines carrying an amide function, with or withot substituent, in the 3-position.

Nitration of the benzodiazepine derivative 4352 CB i sulphuric acid leads to aromatic derivatives nitrated i the 7-position (cf. 4353 CB); the structure is determine by elementary analysis, by the infrared spectrum (nitr bands at 1530 and 1350 ctn.-l in potassium bromide) an by its hydrolysis accompanied by decarboxylation whic leads to 7nitrophenyl 2,3 dihydro-lH-benzo[f]1,4-dia zepine which is already known and has been described b Sternbach, Fryer, Keller, Metlesics, Sach and Steiger i Journal of Medicinal Chemistry 1963, volume 6, page 261 Reduction of the nitro derivative e.g. 4353 CB, for en ample by catalytic means, leads to the correspondin amono compound carrying a 7-amino group (cf. 435 CB).

The 3-carbalkoxybenzodiazepines (ll) generally hav a higher melting point than the corresponding benzc diazepines which are unsubstituted on the 3carbon atorrI their solubility in organic solvents is relatively slight.

Table Ill indicates a certain number of new benzodi azepines (those indicated by a number) carrying a sul: stituent in the 3position and obtainable by the process o the invention.

With a view to obtaining products in a convenient watersoluble form for pharmacodynamic studies and clinical use, we have saponied 3carbalkoxybenzotli azepines (Il) with an alkali metal hydroxide, preferably potassium hydroxide, in an alcoholic medium. [ln every case, the di-metal salt of the dibasic acid is obtained in accordance with the equation given below:

The infra red spectra of compounds of Table IV[A], determined in potassium bromide, agree with the structure, in particular the absence of the C=O bands (amide, acid or ester) between 1650 and 1750 crnrl; moreover, they show among other things a very wide and intense absorption band in the region of 3400 cm."l (vibrational fre- Ill) quencies of N-H of highly,l chelatcd NH2) and a wide and complex absorption in the region of l600-l50 cmf1 (aromatic C=C C=N-, C=O of carboxyliite ions).

For ease of manipulation, it is best to viorl; in 95% ethyl alcohol; the temperature should be between room temperature and the boiling point. The purest products are obtained by operating at room temperature. The reaction is accompanied by a transient yellow discoloration. For rapid discoloration, it is advisable to use at least three cquitalents of potassium hydroxide. The yield ot the dipotassium salt is practically quantitative. These dimcxil salts tl\'[-A]l. i number of which are giien in Table IV below` are colourless powders (with the exception of the nitro and amino derivatives which are yellow)l very soluble in water and strongly alkaline in reaction [reaction] On acidilcation, the aqueous solutions give rise to the corresponding benzodiazepines unsubstituted on the 3-carbon atom: thus the compound 4306 CB becomes benzodiazepine A of Table III.

The same salts (lV[-A]) can be obtained by saponification of imines having a double ester function of type l. [according to the reaction indicated below:

y-Ntt-ti,

The infra-red spectra of the dipotassiurn salts thus prepared are practically identical with those of the corresponding salts prepared by opening of the benzodiazepine ring. Moreover, the aqueous solutions of the dipotassium salts (prepared by either one or the other method) when treated with dilute hydrochloric acid undergo decarboxylation and cyclisation to give the same benzodiazepine derivative; for example, 4306 CB obtained by either one or the other of the two methods gives rise as a result of this treatment to the benzodiazepine compound (A) of Table Ill.

Lastly, in] In the case of compound 4306 CB, pharmacodynamic studies conrm the identity of the products obtained by the two methods.

9 [As regards Formula lV-A, it should be remarked that the analytical results obtained, which will be discussed below, are more easily explained if one assumes a ring structure such as IV-B or IV-C instead of the structure IV-A for the compounds considered.

Analytical studies have been carried out especially on compound 4306 CB (compound IV in which R,=Cl, R2=C5H5. R3=H).

Even after prolonged drying of this substance at 50 C. under a high vacuum, the products obtained still contain approximately of the solvent (10% aqueous ethyl alcohol) in which the preparation was carried out.

To determine the quantity of ethyl alcohol, the substance under investigation is dissolved in water and the solution obtained is distilled; the distillate is oxidised with nitrochrome reagent and the excess reagent is titrated with a solution of ferrocyanide in the presence of diphenylbenzidine.

To determine the quantity of water, the Kart Fischer method cannot be used owing to the strong basicity of the product, and therefore the product is suspended in xylene and water is driven off as an azeotropic mixture.

The determinations of ethyl alcohol and water carried out as indicated above show that, in addition to the 10% of solvent retained, the product can liberate by azeotropic distillation one molecule of water, which is not easily explained if one assumes the structure lV-B or lV-C.

Elementary analysis of the product dried at 50 C., taking into account the quantity of solvent of crystallisation present, agrees with the values calculated for one of the three Formulae IV-A, IV-B or IV-C, which are identical in their empirical formulae.

Determination of the basic functions of the molecule yields interesting results especially if, for example, one compares the potentiometric diagrams obtained for 4306 CB, for the potassium salt of (7-chloro-5-phenyl-2-oxo- 2,3-dihydro lH-benzolf]-1,4-diazepine) 3-carboxylic acid (4311 CB) and for 7chloro5phenyl2oxo2,3dihydro 1H-benzo[f] 1,4-diazepine (indicated by the reference A above and in Examples 14 and 15).

In an anhydrous medium consisting of a mixture of chloroform (3 vols.) and acetic acid (l vol.), titration with perchloric acid in acetic acid solution gives the results shown in the accompanying graph:

For compound 4306 CB (continuous line curve) a first jump in potential with an equivalent point located at -370 mv. and a second jump in potential with an equivalent point located at -600 rnv., the total volume of titrating agent added to reach the second equivalent point being 1.5 times the volume added in order to reach the hrs point.

For compound 4311 CB (discontinuous cunel. .1 tirs jump in potential with an equivalent point located a -360 mv. and a second potential jump with an equitalen point located at -590 mv., the volume added in order tt reach the second equivalent point being twice the volumi added to reach the first point;

For compound (A) (dotted line) a jump in potentia with equivalent point situated at -580 mv.

From these experimental data and tht known formulat of compound 4311 CB and compound (A). it is obviou that the second jump in potential obtained in the titratiot of compound 4306 CB corresponds to neutralisation o the imine function and that the rst corresponds to neu tralisaton of the two other functions, namely:

If one adopts the cyclic Formula lVB or lV-C. thi alcoholic (or enolic) and carboxylic functions; or

lf one adopts Formula IV-A, one of the carboxylt acid functions and the amino group. assuming that tht stcond carboxylic function has too low a pK value to bt determined owing to its proximity to the rst carboxyli` acid function.

Protometric determination in an anhydrous mediun would thus not appear to be suitable for distinguishin` between the possible structures. ln fact. the result in ai aqueous medium rather tends to favour a ring structure if this procedure is adopted, it is not possible to cnrrl out the determination below pH 7 owing to the precipita tion of compound 43ll CB and compound (A): onl functions corresponding to high pl( values can be deter mined in this way. Compound 4306 CB determined in n' aqueous medium by means of hydrochloric acid has n equivalent point at pH 9.5, which could be attributed tt an alcoholic (or enolic) function but less easily to one o the function of the isomer lV-A.

The possibility should not be excluded that under th operating conditions, the compound 4306 CB used in thes tests will assume one of the isometric forms in preferenc to another. Prolonged heating of this particular compouni in the solid state at l00 C. seems to favour the formatio of the IV-A isomer. as indicated by the protometric de termination in an aqueous medium, in addition to som alteration of the product.

Lastly, it is to be noted that the infrared spectra o compounds of type V-A` lV-B or TV-C and in partici: lar of 4306 CB and 4335 CB are compatible with th three formulae proposed.

The invention is not in any way limited to a partcula representative formula among the group of Formula IV-A. IV-B and IV-C.]

Table IV gives by way of example some dipotassiur salts prepared according to the process of the inventior TABLE TVL FORMULA TVA, IYB OR TVC] IVD No. Ri R: Rs Exaniplfl 4306 Cl ClH's H 35. 35 and 52.

ClHs CHI 3T and 3S.

ClHs H 39. CoH: H 40. Col-Ts H 4l and 53. CoFs H 42.

The dlsodlum salt and the calcium salt were also prepared. the latt (4372 CB; Example 44) by double decomposition from the dtpotassui salt.

By carrying out a reaction under the conditions iu described, compound 4348 CB, which has an amide grou in the 3-position. gives rise to the corresponding carboxylic derivatives in which the initial amide group is preserved.

(4349 CB; example 43) We have further found that the dimeral compound [dimetatl salts] such as those given in Table lV, may, under very accurate conditions, be converted into benzodiazepine derivatives (V) carrying on the 3-carbon atom a carboxylic acid function salied by the original cation.

[Compound having the general Formula lV-A, IV-B or lV-C] l N li o CH-C Rl- \OK iczN Ra (V) To bring about this reaction, it is sufficient to treat an aqueous solution of the product used with a slightly acid reagent at room temperature, [(that is to say an amount of acid which is just sufficiently strong to liberate one of the two carboxylic functions).] preferably potassium dihydrogen phosphate or carbon dioxide. The monopotassium salts (V) as a rule crystallise readily provided crystallisation is carried out in a suiciently concentrated solution since they are less soluble in water than the compounds (IV) from which they are derived. They are therefore obtainable in a high yield.

Their formula having been established by elementary analysis. their structure is obtained from the study of their infrared spectra and their chemical properties. The infra-red spectrac (determined in potassium bromide) agree with the structure (V) and show, among other things and in contradistinction to compounds (IV), a strong band in the region of 1690 crn.-1 due to the C=O of the cyclic amide; also to be noted is the absence of the amide II band between 1510 and 1550 crn.-l which is characteristic of non-cyclic secondary amides. Only the nitro group, if present, gives a band in this region. Moreover, the vibration of the NH bond of the lactam group manifests itself by two very wide bands in the regions of 3400 cm.l and 3100 cm.1. Lastly, an intense and complex band in the region of 1600-1620 cm.l may be attributed to the vibrations of the aromatic C=C and of the C=N and of the C=0 of the carboxyl ion.

Aqueous solutions of compounds V generally have a pH in the neutral region. Products V are less stable in aqueous solution than the compounds having two carboxyl groups from which they are derived. The aqueous solutions liberate the corresponding benzodiazepine derivatives unsubstituted on the 3-carbon atom after standing for several hours at room temperature or rapidly upon boiling or in the presence of acetic acid at or above room temperature.

Several potassium benzodiazepine 3-carboxylates (V) are shown in Table V to illustrate this aspect of the in- The following examples illustrate the invention; the melting points are designated by M.Pt.K. M.Pt.M or M.Pt.c according to whether they are measured on a Koer block, on a Maquenne block or in a capillary tube. [In these examples. compounds of type lV have been named according to the formulae of the "open" type IV-A without thereby intending to emphasise these formulae in favour of the cyclic Formulae lV-B and lV-C indicated earlier] EXAMPLE [EAMPLE] l (2-amino-5-chlorophenyl -phenyl-methane-imine (4356 CB) A solution of 228.7 g. (1.5 mols) of 2-amino-5-chlorobenzonitrile in 1800 ml. of dry ether is added slowly in the course of about 3.5 hours to a solution of phenyl magnesium bromide prepared from 109 g. (4.5 gram atoms) of magnesium turnings and 848 g. (5.4 mols) of bromobenzene in 3600 ml. of anhydrous ether, and the mixture then heated under reflux for l5 hours.

The complex is decomposed by stirring the reaction mixture into a solution prepared from 500 g. of ammonium chloride in 2000 ml. of water to which 3 kg. of crushed ice have been added. After extraction and washing, the ether is evaporated in vacuo at 40 C. The oily residue is taken up in 500 ml. of petroleum ether and left to crystallise by cooling at 20 C. The yellowish crystals formed are dried (309 g); MPLK: 74 C.; yield: 92%.

EXAMPLE 2 Using the method described in Example l but replacing B-amino-S-chlorobenzonitrile by an equimolecular quantity of 2-methylamino 5 chloroberizonitrile, compound 4357 CB is obtained in a yield of 61%; yellowish crystals; M.Pt.g: 97 C. (hexane).

EXAMPLE 3 (Z-aminophenyl)phenylmethaneimine (4358 CB) Proceeding as in Example 1 but replacing the 2-amino- 5chlorobenzonitrile by an equimolecular quantity of 2- amino-benzonitrile, this compound is obtained in a yield of about 80% of crude product. Yellowish crystals are obtained; M PLc: 48 C. (isopropyl ether).

EXAMPLE 4 Proceeding as in Example l but replacing the bromobenzene by the equimolecular quantity of bromocyclohexane. this compound is obtained in a yield of 81%: Yellowish crystals with double melting point; MPLK: C. and then 95 C.

13 EXAMPLE s This product is obtained by the technique employed in Example l but the bromobenzene is replaced by an equivalent quantity of lbromobutane.

A brownish oil is obtained (yield: 94%) which is used without purication in subsequent reactions. However. the product may be crystallised in small quantities from cold petroleum ether; M.Pt.c: 2728 C. (decomposition).

EXAMPLE 6 A mixture of 27,6 g. (0.12 mol) of (Z-amino-S-chlorophenyl)phenyl-methaneimine and 20.7 g. (0.15 mol) of the hydrochloride of ethyl glycine in 150 rnl. of methanol is stirred at room temperature for 2.5 hours. A suspension of a pale yellow solid is obtained which consists of the mixture of imine and ammonium chloride formed in the reaction. The solvent is evaporated under reduced pressure and the residue taken up in methylene chloride. lt is washed with a 10% aqueous solution of sodium carbonate. then with water, dried over sodium sulphate and the solvent removed by evaporation. A yellow solid remains behind which is crystallised from acetone. 32.4 g. of the crystalline product is obtained; M.Pt.K: 130-135C.; yield: 85%.

This product is a mixture of the two stereoisomeric forms and may be used as it is for further reactions.

However, each of these forms can be obtained in the pure state by fractional crystallisation from acetone. They have the following melting points: Chelate form: M.Pt.g 148-150 C., non-chelate form: M PLK 142-l44 C.: Mixing these two form lowers the melting point.

EXAMPLE 7 This compound is prepared by the method indicated in Example 6 the (2-amino-5chlorophenyl)phenylmeth aneimine being replaced by the stoichiometric quantity of (2-methylamino 5 chloro-phenyl)phenylmethane lmlne.

On crystallisation from hexane. a solid is obtained which consists of a mixture of the two stereoisomeric forms MPLK: 70-75 C., yield: 82%.

This mixture can be used as it is for subsequent reactions. However each of the two forms can be isolated in the pure state by fractional crystallisation from hexane.

The melting points of these two forms are as follows: Chelate form: M.Pt.g 110 C., non-chelate form M.Pt.g 85 C.

The mixture of the two forms has a considerably lower melting point.

EXAMPLE 8 Diethyl [2-phenyl-2-(2-amino-5-chlorophenyl)1aza vinyl] malonate (4346 CB) A solution of 9.2 g. (0.04 mol) of (2amino[amono]5 chloro-phenyl)phenylmetha.neimine in 16 ml. of absolute alcohol is added dropwise to a boiling solution of 10.6 g. (0.05 mol) of the hydrochloride of ethyl aminomalonate in 30 ml. of absolute alcohol. When this is completed, the mixture is heated under reflux for 30 minutes and the solvent is then evaporated [evaported] in vacuo.

The residue is taken up in water and in ether the ethereal solution is decanted, washed with water dried over sodium sulphate and the solvent evaporated. The product is recrystallised from diisopropyl ether. Yellow crystals are obtained (7.8 g.; yield: 50% M.Pt.x: 106 C.).

14 EXAMPLE 9 This compound is prepared by the method indicati in Example [Eaxample] 8. the (Z-:imino-5-chloro-plienyl phenyl-methane-imine being replaced by the stoichiomctr quantity of (2-methylamino 5 chlorophenyl)-pheny methane-imine. The product is a yellow solid MP1.; 88 C. (isopropyl [isophrophyl] ether). Yield: 15%.

EXAMPLE 10 This compound is obtained by the technique describe in Example 6 the (2-amin0- 5 chlorophenyll-pheny methane-imine being replaced by an equimoleculnr qua: tity of (Z-amino-phenyl)phen.'lmethnneimine.

The product is obtained in the form of yellowish cry tals; M.Pt.K: 106 C. (isopropyl ether): yicldt 58W.

EXAMPLE l1 Using the same method as described in Example 8 by replacing the (2-amino-5-chloro-phenyli-phenyl-mcthztn imine by the equimolecular quantity of (2aminophenyl phenyl-methane-imine. compound 4351 CB is obtained a yield of 31% Pale Yellow crystals are obtained; Mlt C. (diisopropyl ether).

It is to be noted that in this method of prepnrnlio a small quantity of the cyclised product of 3-carbethox S-phenyl 2 oxo-2.3-dihydro-lH-benzolfl-lA-dinzepii (4352 CB) can be isolated from the mother liquor addition to the main product.

EXAMPLE l2 EXAMPLE 13 This compound is prepared by the method indicated Example 6, substituting for (Z-amino-S-chlorophenyl phenyl-methane-imine an equivalent quantity of butyl( amino 5 chloro-phenyl)methaneimine, Yellov. crysta are obtained: MPLK: 9697 C. (isopropyl ether); yielt 55%.

EXAMPLE 14 The same procedure is employed as in Example 6 ar then, without isolating compound 4292 CB, it is tutu up in ml. of acetic acid and heated under retlux ft 30 minutes. The acetic acid is evaporated until a d residue is obtained, 250 ml. of diisopropyl ether and 2.' m1. of water are added and the mixture then stirred. yellowish solid separates which is dried and then wash:

with ether. lt is recrystallised from methyl ethyl ketone. Pale yellow crystals are obtained.

First crop 23.4 g. MPLK: 214-216 C. Second crop 2.3 g. MPLK: 214-216c C. Yield: about 80%` from the unsubstituted imine. The product is identical with the product described by Sternbach and Reeder, Journal of Organic Chemistry 1961, volume 26, page 4936).

Acetic acid is added to a solution of 0.409 g. (0.001 mol) of [the dipotassium salt of [2-phenyl(2amino5 chloro-phenyl)-1azavinyl]malonic acid] [4306 CB] in 4 rnl. of distilled water to adjust the solution to pH 4. The solution is heated on a water bath for 15 minutes; a solid precipitates which is separated, washed with water and dried; weight: 0.216 g.: M.Pt.K: 214-216c C.: yield 80%. This product is identical with the product obtained in Example 14.

6 g. of compound 436| CB are heated under reflux for l minutes in 25 ml. oi acetic acid. The acetic acid is removed in vacuo and the residue is taken up in water and a little ether. A yellowish solid separates; M.Pt.K: 130 C.; the yield is substantially quantitative. It is recrystallised from diisopropyl ether. Yellowish crystals are obtained (4.4 `2.); M.Pt.K: 132 C.: yield 85% in the first batch. The product is identical \\ith the known product (see reference above in Example 14).

EXAMPLE 17 7-chloro-3-methyl-5-phenyl2-oxo-2.3-dihydro1H- benzo[fl-l.4-diazepine (C) A mixture of 6.9 g. (0.03 mol) of 4356 CB and 51 g. (0.033 mol) of the hydrochloride of the ethyl ester of DL-alanine in 40 cc. of absolute alcohol is heated under reflux for one hour. lt is evaporated to dryness and the residue taken up in methylene chloride and a sodium carbonate solution. The organic layer is separated, washed with water and dried over sodium sulphate. The solvent is evaporated and the residue taken up in cc. of acetic acid. lt is heated under reflux for 5 minutes and the solvent then evaporated under reduced pressure. Diisopropyl ether is added and the product allowed to crystallise: clear yellow crystals are obtained (5.15 g) M.Pt.K: 224 C. Yield: 60% in the rst crop. The product is identical with that described in Journal of Organic Chemistry 1962, volume 27, page 3788.

The procedure is the same as described in Example 17 except that the hydrochloride of the ethyl ester of DL- alanine is replaced by the hydrochloride of the ethyl ester of DL-leucine in equimolecular quantity. Compound (D) is obtained in a yield of 48%; M.Pt.K: 213 C. (ethyl acetate). The product is identical with the product described in the chemical literature (reference given above).

This product is obtained utilising the procedure clescribed in Example 17, the hydrochloride of ethyl ester of DL-alanine being replaced by that of the ethyl ester of DL-methionine. (50% in excess of the theoretical quantity).

Employing the same treatment after crystallisation from ethyl acetate, 7chloro-3(3-thiobutyl)5phenyl2 oxo 2:3 dihydro-1H-benzo[f]-1,4-diazepine (MPLK:

16 184 C.) is obtained in a yield of 50%. The product is identical with the product described in the chemical literature (reference given above).

EXAMPLE 20 This compound is obtained by the procedure described in Example 16, compound 4361 CB being replaced by an equimolecular quantity of compound 4346 CB. Shiny, colourless crystals are obtained; MPLK: 244 C. (ethyl acetate). Yield: 74% in the first crop.

A mixture of 9.2 g. (0.04 mol) of compound 4356 CB. 10.6 g. (0.05 mol) of the hydrochloride of ethyl aminomalonate and 5 g. (0.05 mol) of triethylamine in 45 ml. of absolute ethyl alcohol is heated under reux for one hour. The solvent is evaporated under reduced pressure and the residue taken up in water and ether. The ethereal layer is separated. washed with water and dried over sodium sulphate. After evaporation of the solvent, the residue is dissolved in 45 ml. of acetic acid and heated under reflux for l5 minutes. The product is evaporated to dryness under reduced pressure and taken up in ether. A solid separates which is filtered by suction and recrystallised from ethyl acetate. Brilliant, colourless crystals are obtained (6.4 g.) MPLK: 244 C.; yield: 47%. The product is identical with that obtained in Example EXAMPLE 22 A solution of 9.2 g. (0.04 mol) of compound 4356 CB in 20 ml. of methanol is added dropwise, in the course of one hour 30 minutes, to a boiling solution of 9.2 g. (0.05 mol) of the hydrochloride of methyl aminomalonate in 30 ml. of methanol. When this is completed. heating under reflux is continued for 30 minutes and the product then concentrated to dryness under reduced pressure. The residue is taken up in water and ether, the ethereal layer separated, the product washed with water and dried over sodium sulphate. The solvent is evaporated under reduced pressure. The residue. which consists of the methyl ester homologous with the ethyl ester described in Example 6, could not be obtained in the crystalline state. It is dissolved in 25 ml. of acetic acid, heated under reux for 15 minutes. the product evaporated to dryness and the residual oil taken up in ether. A colourless solid separates which is ltered by suction and recrystallised from methanol. Colourless crystals are obtained (4.7 g.): M.Pt.K: 226 C. A second crop (1.5 g.) is obtained on concentration of the mother liquor; M.Pt.K: 222 C.; total quantity 6.2 g., corresponding to a yield of 47%.

EXAMPLE 23 This product is prepared by the method described in Example 22, the methyl aminomalonate and compound 4356 CB being respectively replaced by ethyl aminomalonate and compound 4357 CB in equimolecular quantities. Light yellow crystals are obtained; M.Pt.K: 180 C. (ethyl alcohol): yield: 47%.

13.6% solution of amonia in methanol are left together overnight at room temperature. The solid rapidly dissolves and after several hours a precipitate gradually forms which increases in quantity with passage of time until the whole mass has solidified. The solid is filtered by suction and washed with methanol. An additional small quantity ot" the same product is obtained by concentrating the solution to dryness. The two crops are combined and recrystallised from methanol. Colourless crystals are obtained (7 g); MPLM: 22S-256 C.; yield: 74%.

EXAMPLE 25 7-chloro-3-methylaminocarbonyl-S-phenyl2oxo2,3- dihydro-lH-benzo[fll,4diazepine (4367 CB) This product is prepared by the method of Example 24, the solution of ammonia in methanol being replaced by the equivalent quantity of a solution of monomethylamine in methanol. Colourless crystals are obtained (ethyl alcohol); M. PLM: 294 C.; yield: 90%.

This compound is obtained as in Example 24, the solution of ammonia in methanol being replaced by the equivalent quantity of a solution of dimethyla .tine in methanol. Colourless crystals are obtained: M.Pt.M= 297 C.

This compound is obtained by the procedure employed in Example 24, the solution of ammonia in methanol being replaced by a solution of 2-diethylamino-ethylamine (three times the calculated quantity) in times its volume of methanol. Colourless crystals arc obtained; MllPLK: 220 C. (ethyl acetate); yield: 90%.

EXAMPLE. 28

This compound is obtained by the method employed in Example 16, compound 4361 CB being replaced by an equimolecular quantity of compound 4351 CB. Colourless crystals are obtained; M.Pt.x: 226 C. (ethylacetate); yield: 70% in the rst crop.

EXAMPLE 29 The procedure described in Example t4 is employed, compound 4292 CB being replaced by an equivalent quantity of compound 4364 CB.

Yellowish crystals are obtained; MPLK: 208 C. (ethyl acetate); yield 44%. This product is identical with that described in the literature (see reference in Example 17).

EXAMPLE 30 This compound is obtained by the procedure described in Example 22, the hydrochloride of methylaminomalonate and compound 4356 CB being replaced by the equiv alent quantities of, respectively, the hydrochloride of ethyl aminomalortate and (Z-amino 5 methy1-phenyl)phenylmethane-imine prepared according to Example 12.

Yellowish crystals are obtained; M.Pt.K: 260 C.: yield EXAMPLE 31 7nitro3-ethoxycarbonyl-S-phenyl2-oxo-2,3-dihydrolH-benzo[f1-1,4-diazepine (4353 CB) 12.3 g. (0.04 mol) of the nely powdered compound 4352 CB are added slowly, with stirring, to 50 ml. of concentrated sulphurie acid (66 B.) in such a manner that the temperature does not rise above 25 C. 4.8 g. (0.o mol) of powdered potassium nitrate is then gradua added to the resulting solution at a rate such that t temperature remains below 25 C. When this is complex the mixture is stirred for 2 hours 30 minutes at rot` temperature. The reaction mixture is then poured on tr mixture of crushed ice and ether and allotted to stand l 0.5 hour. The solid which separates is ltered by suctit washed with water and with ether. lt is recrystallised irc aa large volume of ethyl acetate. Pale yellow crystals z obtained (7.7 g.); M.Pt.M: 271 C.; yield; 55%.

EXAMPLE 32 A solution of 4.48 g. (0.0l33 mol) of compound 43 CB dissolved in ml. of dimethylformamide and 1 ml. of ethyl alcohol is hydrogenated at ordinary tempe ture and pressure in the presence of Raney nickel. 'l theoretical absorption of hydrogen requires about 3 hot After filtration of the catalyst and evaporation of solvents under reduced pressure, a solid residue is t tained which is recrystallised from a mixture of dimenth formamide and ethyl alcohol. Pale yellow crystals are t tained (3.9 g.); MPLM: 305 C. (decomposition); yie

EXAMPLE 33 This product is prepared by the procedure described Example 17, compound 4356 CB and the hydrochlor of the ethyl ester of DL-alanine being respectively placed by equimolecular quantities of compound 4359 and the hydrochloride of ethyl glycine. Yellowish crysl are obtained; MPLK: 210 C. (n-propyl alcohol): )le 71% from the imine. In this case. the intermediate pr uct viz. 1-cyclohexyI-1(2'-amino-5'-chlorophenyl)4o 5-oxa-2aza1heptene could not be isolated in the crys line state.

EXAMPLE 34 This product is prepared by the procedure descrihet Example 22, methyl aminomalonate and compound 4 CB being respectively replaced by the stoichiometric qu tities of ethyl amiiomalonate and compound 4359 CB.

Colourless crystals are obtained, M.Pt.K: 208 C. fet acetate); yield: 40%. lt should be noted that in this c: the intermediate diethyl [2-cyclohexyl2(2-amino-5-cl rophenyl)lazavinyll-malonale could not be isolated the crystalline state.

EXAMPLE 35 50 g. of caustic potash are dissolved in 1350 ml. 96% ethyl alcohol, and 82 g. (0.25 mol) of compoi 4347 CB are then added all at once at a temperature about 70 C.

The solid dissolves rapidly to form a yellow solut which then loses colour whilst simultaneously an abund colourless precipitate appears.

After cooling, the solid is filtered by suction and was'` with alcohol at 96 C. The product is dried at ordin temperature in a high vacuum. A colourless solid is tained (quantitative yield), which is completely solu in water. The aqueous solution is strongly alkaline in reaction; when acidied with acetic acid and heated on a water bath. it yields a precipitate of 7-chlorO-5-phenyl-2- oxo-2,3-dihydro-1Hbenzo[f]1,4, diazepine (compound A).

Comments:

(l) The preparation may be carried out by replacing compound 4347 CB by the corresponding ethyl ester (4279 CB). A similar yield of compound 4306 CB is obtained.

(2) The corresponding disodium salt can be obtained in the same manner by replacing potassium hydroxide by sodium hydroxide.

EXAMPLE 36 7 chloro-2. i-dil:ydro-Z-oxo-S-phenyl-IH-I,1i-benzodiazept'rte-.-carboxylic acid. monopotassium salt, monopotassium hydroxide (4306CB) 2 g. of 4346 CB are added to a solution of 0.84 g. (0.015 mol) of potassium hydroxide in l ml. of water and ml. of methanol and the mixture then heated to reflux. The solid dissolves. giving tfse to a red solution whicl' rapidly loses its colour, a precipitate appearing at the same time. After cooling, the solid is filtered by suction and washed with methanol. A colourless solid is obtained (1.25 g.). This compound is found to be identical with that prepared in Example 35.

EXAMPLE 37 [Dipotassium salt of [l2-phenyl-2-(2-methylamino5 chlorophenyll-laLa-vinyl]malonic acid] (4350 CB, rst preparation) This product is obtained by the method described in Example 35. compound 4347 CB being replaced by a stoichiometric quantity of compound 4366 CB` lt is a colourless powder which is very soluble in water. Yield: 71%. The aqueous solution is strongly alkaline in reaction.

EXAMPLE 38 The compound may be obtained as described in Example 36, compound 4346 CB being replaced by an equimolecular quantity of compound 4362 CB. It is a colourless powder completely soluble in water and identical with the product of Example 37; yield: 50%.

EXAMPLE 39 This substance is prepared by the method described in Example 35, compound 4347 CB being replaced by a stoichiometric quantity of compound 4352 CB.

Colourless leaflets are obtained which are completely soluble in water and strongly alkaline in reaction; substantially quantitative yield.

EXAMPLE 40 This substance is prepared by the procedure given in Example 35, compound 4347 CB being replaced by an equimolecular quantity of compound 4327 CB. It is obtained in the form of a colourless solid completely soluble in water. The yield is practically quantitative.

20 EXAMPLE .t1

[Dipotassium salt of [Z-phenyl-Z- -amino-S-nitrophenyl)l-aza-\'inyl]malonic acid] (4335 CBI This compound is obtained by the procedure described in Example 35, compound 4347 CB being replaced by an equimolecular quantity of compound 4353 CB. lt is a yellow powder which dissolves completely in water and is strongly alkaline in reaction; the yield is substantially' quantitative.

EXAMPLE 42 [Dipotassium salt of [2-phenyl2(2.5-diaminophenyl)- l-aza vinyllmalonic acid] (4371 CB) This compound is obtained by the method described in Example 35, compound 4347 CB being replaced by a stoichiometric quantity of compound 4354 CB. It is a yellow solid completely soluble in water and having a strongly' alkaline reaction. The yield is quantitative.

EXAMPLE 43 This product is obtained by the method described in Example 35, compound 4347 CB being replaced by an equivalent quantity of compound 4348 CB. Fine yellow crystals completely soluble in water are obtained in quantitative yield:

EXAMPLE 44 A solution of 0.55 g. (0.00375 mol) of calcium chloride dihydrate in 5 ml. of water is added to it solution of l g. (00025 mol) of [the dipotussium salt of lZ-phenyl-Z-tlamino-S-chlordphenyl)-l-aza-vinyllmalonic acid] (4306 CB) in l5 ml. of water.

A solid separates out immediately. After it has been left to stand for l0 minutes. it is ltered by suction. then washed with a small quantity of water and finally dried at ordinary' temperature in a high vacuum. A yellowish white solid is obtained which is sparingly soluble in water (0.75 g.)', yield: 80%.

EXAMPLE 45 2.1 g. (0.005 mol) of 4306 CB and 0.68 g. (0.005 moll of monopotassium phosphate are dissolved at room temperature in 18 ml. of water. Solution proceeds rapidly and then colourless platelets slowly precipitate. The product is ltered by suction, washed first with chilled water and then with absolute alcohol. The product is dried at room temperature for 12 hours and then in a high vacuum. 1.8 g. of colourless crystals completely soluble in water are obtained. The aqueous solution has a substantially neutral reaction; yield: This product is decarboxylated within a few minutes by heating an aqueous solution thereof, compound A being obtained in the crystalline state.

EXAMPLE 46 Potassium salt of 3-t5phenyl-2-oxo2.3-dihydro-lH- benzo[f]-1,4-diazepine]carboxylic acid (4338 CB) This compound is obtained by the procedure described in Example 45 compound 4306 CB being replaced by an equivalent quantity of compound 4337 CB and the volume of water used being reduced by one-half. It is a colourless powder which dissolves in water, giving a sub' stantially neutral reaction: yield: 747e.

EXAMPLE 47 Potassium salt of 3-[7-methyl-5-phenyl-2-oxo-2.3-dihydro- 1H-benzo[f]1,4-diazepinel-carboxylic acid (4373 CB) The same procedure is employed as in Example 45 but compound 4306 CB is replaced by compound 4339 CB in stoichiometric quantity and the volume of water used is reduced by one-half.

It is a colourless solid completely soluble in water; yield; 45%.

EXAMPLE 48 Potassium salt of 3-[7-nitro-5-phenyl-2-oxo-2.3-dihydro- 1H-benzo[f]l,4diazepine]-carboxylic acid (4336 CB) This product is prepared by the method of Example 45, compound 4306 CB being replaced by a stoichiometric quantity of compound 4335 CB and the water used is reduced to one-half the volume.

It is a light yellow powder which dissolves in water to give a practicaly neutral solution; yield: 79%.

EXAMPLE 49 the course of 50 minutes. Precipitation of the hydrochloride of the ketimine (4356 CB) in the form of orangered crystals is observed to begin at the commencement of the introduction of the ketimine. Heating under reux is continued until the suspended precipitate becomes discoloured (ammonium chloride), which takes about 2 hours, and a rapid current of gaseous hydrogen chloride is then bubbled through the reaction mixture for 2 hours while the mixture is kept boiling. The hydrogen chloride of compound 4279 CB precipitates progressively in the form of an orange powder. The crystals (hydrochloride of 4279 CB and ammonium chloride) are cooled, ltered by suction and rinsed with benzene and ether. To liberate the base, the product is treated with a sodium carbonate solution in the presence of methylene chloride. The rganic layer is separated, dried, the solvent evaporated and the residue treated with ether. A practically pure white product is thus obtained (441.5 g.; yield 63.5%); M.Pt.x=243244 C.

EXAMPLE 50 423.5 g. (2 mols) of the hydrochloride of ethyl aminomalonate and 1250 mi. of benzene are introduced into an [(2 mols) of (2-amino-phenyl) phenylmethane-imine] apparatus identical with that used in Example 49. The mixture is heated under reflux and a solution of 391 g. (2 mols) of (2amino-phenyl) phenyl methane imine (4358 CB) in 1250 ml. of dry benzene is added during the course of 50 minutes. From the commencement of addition of the latter, the hydrochloride of compound 4358 CB precipitates in the form of deep red crystals. To facilitate the condensation reaction, 62.5 ml. of methanol, Le. 2.5% of the total solvent used, are added. The reaction mixure is heated under redux for 4 hours until decolorisation of the precipitate has occurred. The precipitate at the end of the reaction consists solely of ammonium chloride. Methanol is removed by azeotropic distillation meth- :mol-benzene) and a fast current of gaseous hydrogen lll chloride is then bubbled through the mixture for tu hours whilst the reaction mixture is kept boiling. The h drochloride of compound 4352 CB progressively prceip tutes in the form of an orange powder. The reaction mi ture is cooled, the crystals of the hydrochloride of 43:' CB and ammonium chloride are ltered by suction` wnshtV with benzene and with ether. To liberate the base. tl hydrochloride is treated in the manner described in E ample 49 for the hydrochloride of the compound 42'. CB. 416 g. of practically pure compound 4352 CB are 0 tained in this way. Yield: M.Pt.K=224-2257 C.

EXAMPLE l The procedure according to Example 49 is employe the hydrochloride of ethyl aminomalonate being replact by the stoichiometric quantity of the hydrochloride l ethyl glycinate, compound 4356 CB being replaced l the stoichiometric quantity of compound 4356 CB ai benzene by an equal volume of toluene. Compound 41. CB is linally obtained by decomposition of its orange-rt hydrochloride, giving a yield of 66.5%; M.Pt.x=280 t EXAMPLE 52 Compound 4306 CB (Formula [Formule] IVIC-A, B ar C R1=CL R2ZCGH5,

341.5 g. (l mol) of compound 4279 CB are added z rapidly as possible. with stirring, at 18 to 20 C. to solution o 224 g. (4 mols) of potassium hydroxide in 5 l2 ml. of ethyl alcohol containing by volume of wate A clear yellow solution forms after about 2 minutes. Sti ring is stopped; crystallisation of compound 4306 C begins after several minutes and is accompanied by pr gressive decolorisation. The product is filtered by suctit after 4 hours, washed with absolute alcohol (500 ml and then dried to constant weight at C. under z absolute pressure of 0.1 mm. 422 g. of yellowish whi leaets are obtained.

EXAMPLE 53 Compound 4335 CB (Formula [Formule] lVlf-A, B ar C in R1=NO2, R2=C5H5,

The procedure employed is that described in Examp 52 but compound 4279 CB is replaced by an equimolec lar quantity of compound 4353 CB. The reaction fol|o\ the same course and compound 4335 CB is obtained the same yield as compound 4306 CB.

EXAMPLE 54 7-chloro-5-phenyl-2-oxo-2,3-dihydrol H-benzo[f] l,4-diazepine (A) A suspension of 6.68 g. (0.02 mol) of compound 42 CB in an aqueous solution of potassium hydroxide (4.5 of potassium hydroxide in 45 ml. of water) is heatl with stirring on a water bath until completely dissolve There is obtained a strongly yellow coloured solutit which clears after a few minutes. The hot solution treated with 6 m1. of acetic acid which causes a pasty pro uct to separate accompanied by evolution of carbon t oxide. Decarboxylation is completed by heating to retti for a short time. After the reaction is complete the desirt product crystallises; it is centrifuged, washed with wat and dried at 100 C. in vacuo. M.Pt.x=2l2 C. The yie is practically quantitative. A pure product can be obtaini by crystallisation as described in Example 14.

Instead of an aqueous solution of potassium hydroxic' a solution of potassium hydroxide in ethyl alcohol, f example a percent by volume alcohol may be usi the hot solution being treated with acetic acid as describt above.

23 EXAMPLE s An aqueous solution prepared by dissolving 7 g. of potassium hydroxide in ml. of water is added to an aqueous solution of 3 g. of compound 4306 CB, then 1.8 g. of dimethyl sulphate is gradually added (about 5 minutes) with stirring. care being taken that the temperature docs' not rise above C. After the addition is ended. thc` mixture is left for 2 hours at room temperature thzn acidified with acetic acid. A pasty product separates which is covered with diisopropyl ether, and the suspension thus formed is heated to boiling for a few minutes; evolution of carbon dioxide takes place. The product is cooled. diluted with ether and the aqueous phase is separated. Upon evaporation of the solvent, there is obtained a residue which is crystallised from diisopropyl ether. Yield M.Pt.x=l32 C. The product is identical with the product obtained according to Example 16.

A certain number of the compounds described in the present application have been studied with regard to their action on the central nervous system, as psycholeptics. myorelaxants and tranquillisers. In addition. the acute toxicity has been determined for a number of these compounds.

The study of certain compounds of known pharmacodynamic and clinical activity. such as diazepame and chlorodiazeposide. has been undertaken under the same experimental conditions. with the same tests and with animais of the same origin as for thc new compounds. lt has thereby been possible to make quantitative comparisions of the activity of the diterent compounds for the di'erent test employed In the series of tests briey described hereinafter. each compound was tested with the use of v: or six scaled doses on batches of l0 or 20 animals for each dose: it was thereby possible to determine with sucient ethctitudc bythe method of probits the SOP? effective dose (FD Sill. that is to say the dose for which half the animals are nro tected and react in a predetermined manner according to a particular action.

TESTS EMPLOYED The following tests were employed:

(l) Traction test (mice) This consists in observing when the treated animals are capable of retrieving a rod grasped by the front paws only. Inability to carry this out was interpreted as a sign of myorelaxant activity.

(2) Balance test: rotating rod (mice) This test consists in observing whether the treated animals are capable of maintaining their balance on a horizontal rod kept in rotation.

Numerous neuroleptic compounds or tranquillisers disturb the equilibration reex.

(3) Anti-convulsant activity (anti-pentetrazole) (mice) Pentetrazole. injected intraperitoneally in a dose of 125 mgfkg. produced fatal convulsions in of the animals. c

Certain compounds exert a protective action preventing convulsions and permitting survival.

(4) Anti-convulsant activity (electric shock) (mice) The test consists in determining the intensity of the electric current required to produce a fatal shock in a batch of test animals.

Certain preventively administered compounds effectively protect a certain percentage of animals subjected to an electric current of an intensity which is fatal to untreated animals.

llt

lll

(5) Exploration test (mice) This extremely simple test consists in placing a mouse at the centre of a oor pierced with lioles .trut in noting how many holes the mouse explores iu 5 minutes [his test is carried out in a room in which complete silence is obsened and which contains no person enc-pt the txperimenter who is seated and still. lt appeals to the curiotity of the animals. The doses of thc compounds emplotctl are. however. \cry small and considerably less than those required to impair movement. This` simple tcst makes it possible to observe whether the compounds assayed produce a more or less pronounced lack of imc:- est in the emironment and it gives information which is interesting from the clinical point of view with regard to the treatment of anxiety and restlessness.

(6) Spontaneous motor activity in the rat and mouse and provoked motor activity The effect of drugs ort voluntary movements oi animals can be studied statistically by methods the details of which will not be discussed here. The mous-z, which is an extremely lively animal and moves about a great deal. is particularly suitable for this type of experiment.

Moreover, this spontaneous mobility can be exacerbated by preventive administration to the animals of certain substances such as bcnzedrine. mescaline and ritaline.

The experimental results obtained by these methods give minable information for clinical purposes with regard to the treatment of ambulatory psvchomotor crises.

(7) Antistrychnine activ ity This test demonstrates the acti\ity of drugs against a medullary excitant.

(8) Morphine excitation ln the cat, morphine produces a specific slitte oi et'citm tion with hallucinations which can be attenuated or suppressed by certain psycholeptic drugs.

1n the mottsc. the action of morphine is different but also manifested by nttirlsetl central evcitution.

(9) Aggressiveness (cat mouse) In general. 'l5 to 80"? of cats are aggressive when confronted with white mice. Psycholeptics and tranquilliscrs may make the cat indifferent and sometimes e\en amiable to the mouse. Similarly. in the case of cats that are furious and aggressive in relation to humans, diminution or suppression of the instinctive fear and establishment of a climate of confidence are observed.

(l0) Combativeness It is possible to make a male rat aggresive towards another male rat enclosed in the same cage by passing an electric current of more or less high voltage through the oor of the cage.

This test, like the preceding one, can obviously give information of clinical value for the treatment of aggression diseases,

(l1) Conditioning test The test used consists in educating rats to avoid an electric current passed through the oor of a cage of two compartments when they change compartments. The animal is rst warned by a lamp which lights up in the compartment through which the current is passing while the other is in relative darkness.

This test` which requires more or less daily training at the rate of 5() times for each rat, makes it possible to follow the animals and note their progress. The performances realised at the end of a certain time (3 weeks to one month of training) are fairly constant. the percentage of errors made by adequately gifted subjects being less than t0 and very often even zero.

One would imagine that disturbances produced in these performances which call upon the memory of animals would be of great importance for the choice of a new medicament. A deconditioning drug of sufi'icient intensity could have the result of partly depriving the patient of the idea of danger and would consequently require special surveillance of the sick persons.

(l2) Potcntiation of narcosis Most psycholepitics are hypnotics in large doses but many of them can in small doses, without themselves producing an hypnosis, either prolong the time of sleep obtained with a true hypnotic (for example a barbiturate) or appreciably lower the dose of barbiturate required to obtain sleep.

In the attached table are summarised all the results obtained in the different tests briey recorded above with certain compounds described in the present application. compared with various reference substances of known clinical activity.

From an examination of the figures given in the table i is found that (l) The two para-nitro derivatives 4335 and 4336 are extremely active in different tesis, especially' a myorelaxants and an anticonvulsants in the test for curi osity; on the other hand, they appear to have less effec on the faculties of displacement. Lastly, they have marked effect in diminishing aggressiveness (test for com bativeness).

(2) The compound 4306, very similar to 4335 is als( highly active and in most of the tests it is at least equa and frequently superior to diazepame.

(3) Compound 4311 is also highly active but slightl less so than 4306. Its activity is slightly less when ad ministered parenterally than when administered orally What is claimed is:

TABLE VI.-RECAPITULATING THE ACTIVITIES BTAINED WITH DIFFERENT TESTS lThe figures in the table indica*n the 50% eective doses in mgfk. and the route o1 administration: P0 per os; IP ==intrapertonealL SC =suhcuianp0ii V-intravi-nous Bcnzeilriiie Acute Spontane- Spontaneprovoked toxicity Traction Equilibra- Antl-pente- Electric Exploraons motor ous motor maior (M) DL50 (M) tion (M) trazole (M) shock (M) tion (M) activlty (R) activity (M) activity (It) Diazepame (compound 72D POcQBU 1.60 PO. 4.4 P0 1.7 PO 5 PO PO 25 P0 5 PO 100 PL).

B). 800 Nor-diazepame (com- 3.5 PO 8.6 P0 2.9 PO i) P0 '7.8 PO. 50 PO 5D IO 100 1() und A). Ctiiiirdiazepoxide 20(1);0 80 3 PO i3 P0 5 PO l? P0 20 P0 iuii ili.

` eoPo 20P eoro inoPo S 10 P() ill) Pil. i |o |'li. 25PO. 50 PU.. )50?0 lU PU ).10 l0.. I4 P0 1.7 PO- 5 PO )lili ii).

Cawthesame 1.25 PO. 9.6?0 1,7 P0 BPO 625P0 2510 1010 formula as 4306 CB but obtained by sponiiication oi the noncyclic intermediate (4346 CB). 350GB 10 PO. 7.5 PO 2010 4.3 PO 0 44 PO 3.2 PO )l0 PO i0 P0 10 PO.. 5 PO; 4.5 1.65 P0. 2.61?

336GB 80)?0 0.28P0. 1.5 P0 0. PO..." P0 610 50PO 5 PO l0 PO.-." l0P l0 }"0 10 PO. 4338 5P0 i0P0 10P0. 10P0.. 10P0. 4339 )10 PO. l0P0 l0P0 10P0 TABLE VI.RECAPITULATING THE ACTIVITIES OBTAINED WITH DIFFERENT TESTS-Continued [The figures 1n the table indicate the 50% eective doses in mgJkg. and the route administration: PO-per os; lP-intraperitoneai; SC =subcuiaiwon-` IV intravenous] Benzedririe t d Mescain Ritaiilriied vovo e rovo e mvo e factor innotor ihotor Anti- Morphine Aggres- Combat Doulile box Narmtiractivity activity activity strychexcita- Morphine aiveneas iveness conditioning pou-nim- (M) (M) (M) nine (M) tion (M) crisis (C) (CIM) (R) (R) tion (ai) 20 P0 50 P0... 2.5 P0.. 25 50-...- 25 80-..-. 25 PO.... Without atleet... 2.51'0.

Dizepame (compound Nor-diampame -compoun A Improved per iormances.

orm

but obtained by sponieation o! the noncyclic inter mediate (4346 CB). 4350 CB M-mouse. R-nt, C-eat.

1. A henzodiazepine having the formula /x man1-6:0

V CHR; Rt

CRFN

in which R1 is a hydrogen or halogen atom or a trifluoromethyl. lower alkyl. lower alkoxy, nitro or amino group R, is a furyl, a thienyl. cyclohcxyl, lower alkyl or a phenyl group which may be substituted by a halogen atom or by a triuoromethyl, nitro, lower alkoxy or lower alkyl group, and R3 is a hydrogen atom or a lower alkyl group, and R* is a lower carbalkoxy, carbamoyl, a N- loweralkylcarbamoyl. a N,Ndilowcralkylcarbamoyl, a N- (diloweralkylaminoalkyl) carbamoyl, a group having the formula -COOC at in which Cat is a cation of an alkali metal or a semication of an alkaline earth metal.

[2. A process for producing a benzodiazepine having the formula NRz-CLO in which R R3 and R, are as dened in claim 1 and R4 is a hydrogen atom, a lower carbalkoxy, a carhamoyl, a N-loweralkylcarbamoyl, a N,N-diloweralkylcarbamoyl, a N-(diloweralkylaminoalkyl)carbamoyl (an alkyl or substituted alkyl group, or a group having the general formula -COOCat in which Cat is the cation of an alkali metal or the semication of an alkaline earth metal, which comprises treating an ortho-aminoarylketimine having the formula NIIR| in which Rx. Rz, and R3 are as dened above, R. is a hydrogen atom, a lower carbalkoxy. a carbamoyl, N-loweralkylcarbamoyl, a N,Ndiloweralkylcarbamoyl, a N-(di- Ioweralkylaminoalkyl)carbamoyl, lower alkyl or, a group having the formula COOCat in which Cat is a cation of an alkali metal or semication or an alkaline earth metal or a group which, in a natural occuring waminocarboxylic acid, is linked to the carbon atom carrying the a-arnino group, and R is a lower alkyl group or, when R is a carbamoyl or -COOC at group, at a cation ot' an alkali metal or semication of an alkaline earth metal, but excluding the case in which lh is -COOCat and R5 is -Cat, with an hydrous lower aliphatic acid or with an anhydrous mineral acid, or, when R4 is -COOCat and R5 is -Cat with a dilute aqueous solution of an acid salt in particular potassium dihydrogen orthophosphate in sibstantially equimolar proportion or with a weak acid.

3. A process according to claim 2 in which the mineral acid is hydrochloric acid gas.

4. A process according to claim 2 in which R, is a hydrogen atom or a methyl group and R1 is a chlorine atom or a nitro group.

5. A process according to claim 2 in which R., is a lower carbalkoxy group and the product is thereafter treated with ammonia, a loweralkylamine, a diloweralkylamine or a diloweralkylamnoalkylamine.

6. A process according to claim 2 in which R4 is a lower carbalkoxy group and the product is thereafter saponied and then treated with a dilute reactive acid to effect decarboxylation.

7. A process according to claim 2 in which R, is a hydrogen atom and R is a lower carbalkoxy group and the product is treated with an aqueous solution of an alkali metal hydroxide in order to produce the correspending dialkali metal salt and the said dialkyl metal salt is thereafter treated with an alkylating agent and then with dilute acid.

8. A process according to claim 2 in which R1 is a hydrogen atom and R, a lower carbalkoxy, a carhamoyl, a lower N-alkylcarbamoyl, a lower N,Ndialkylcarbnmoyl or a lower N(dialkylaminoalkyll-carbamoyl group and the product is then mono-nitrated with a nitrating agent.

9. A process according to claim 8 in which the mononitrobenzodiazepine is reduced with a reagent known to be capable of reducing an aromatic nitro group to a primary amino group.

l0. A process according to claim 2 in which R4 is a lower carbalkoxy group and the product is saponied with an alkali metal hydroxide.

11. A process for the preparation of saponication products of a benzodiazepine having the formula RlO /Lll

\C H-COOAlk N wherein R1. R, and R3 are as defined in claim 1, and Alk is a lower alkyl group which process comprises treating said benzodiazepine with an alkali metal hydroxide in solution in a lower alkanol.

[12. A process according to claim 2 wherein the orthoamino aryl ketimine is the dipotassium salt of [Z-phenyl- 2(2'-amino5chlorophenyl)1azavinyl] malonic acid and the other reactant is potassium dihydrogen orthophosphate] [13. A process according to claim 2 wherein the orthoamino aryl ketimine is the dipotassium salt of [2phenyl 2-(2amino5'nitro phenyl)lazavinyl] malonic acid and the other reactant is potassium dihydrogen orthophosphate.)

16. A process for producing a benzodizepine haring the formula in which R1, and Rz and R, are as defined in claim I and R is hydrogen. lower carbalkoxy lower alkyl or i-thiobutyl) which comprises treating att ortho-aminoaryl kellmine having the formula NH R:

R| CRpN-CHRPCOORI in which R1, R2. R3. and R are as defined about and R,

is lower alkyl with an anhydrous lower aliphatic acid or with a mineral acid in substantially equimolar proportion. I7. The alkali metal hydroxide or alkaline earth metal hydroxide saponi/icarion product of a benzodiuzepmc having the formula CHR CRFN

wherein R, is a hydrogen or halogen atom or a trifuoromethyl, lower alkyl, lower alkoxy, nitro or amino group,

R, is a furyl, a thienyl, cyclohexyl. lower alkyl or a phenyl group which may be substituted by a halogen atom or by a trifluoromethyl, nitro, lower alkoxy or lower alkyl group, R, is a hydrogen atom or a lower alkyl group, and R4 is a lower carbalkory, carbamoyl. a N-lower alkyl carbamoyl. a N,Ndilower alkyl carbamoyl or a N-(diloweralkylamino alkyl) carbamoyl.

18. The .tapontfication product of claim I7 wherein the saponifying agent is an alkali metal hydroxide.

J9. The saponification product of 7-chloro-3-methoxycarbamoyI-5-phenyl2-oxo2,3dihydrol H-benz0-l,4diazepine and potassium hydroxide.

20. The alkali metal hydroxide saponi'cation product of a 3-carbalkoxybenzodiazepine.

2l. The potassium hydroxide saponifcation product of a 3-carbalkoxybenzodiazepine.

24. The alkali metal hydroxide or alkaline earth metal hydroxide .tapont'fcation product of a compound having the formula NH-Rl y CooAlk R, "-cnpN-CH cootux wherein R1. R2 and R, are as defined in claim l and Alk is a lower alkyl group.

References Cited 3,410,844 11/1968 McCawlly 260-239-3 HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner U.S. Cl. X.R.

260332.2 A, 397.3, 347.4, 471 A, 518 R, 558 A, 566 R; 424-244, 275, 309, 319, 324, 325.

Claims (1)

1. A BENZODIAZEPINE HAVING THE FORMULA

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