NO150199B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PHENYLKETONS - Google Patents

Description

The present invention relates to an analogous process for the production of substituted phenylketones with the general formula

wherein A means a nitrogen atom, which may be substituted with a methyl group, B means a carbonyl group or A and B together form the group

in which Ra means hydrogen or lower alkyl, X means a nitrogen atom or forms the group C—R<b>,

•* b

wherein R means hydrogen or lower alkyl,

R means halogen or nitrogen,

R"<*>" means hydrogen or lower alkyl,

R 2 means an acyl residue derived from a naturally occurring amino acid (all these groups, containing an asymmetric carbon atom, have the L or D,L configuration), and

3

R means phenyl, halophenyl or 2-pyridyl, or acid addition salts thereof.

It should be noted that formula I comprises compounds of the following general formula in which R, R1, R^, R^, Ra oq R*3 have the above-mentioned meaning and

R 4 means hydrogen or methyl.

The term "lower alkyl" used in this description means a straight-chain or branched alkyl group with preferably 1-6 carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. The preferred lower alkyl group is methyl. The term "Halogen" means fluorine, chlorine, bromine or iodine. The acyl group characterized as R 2 is preferably derived from a naturally occurring α-amino acid such as glycine or L- or D,L-alanine, -leucine, -phenylalanine, -isoleucine, -serine, -lysine, -methionine, -proline and the like . Particularly preferred acyl groups are those derived from L-amino acids, especially from L-phenylalanine or L-lysine. As long as R 3 means phenyl or halophenyl, halogen is preferred for R chlorine and if R 3 means a 2-pyridyl group, halogen is preferred for R bromo. The halophenyl group characterized as R comprises monohalophenyl groups, especially o-halophenyl groups such as o-chlorophenyl or o-fluorophenyl, and dihalophenyl groups, preferably o,o'-dihalophenyl groups such as o,o'-dichlorophenyl.

Preferred compounds of formula Ia are those in which R means

1 3

chlorine, bromine or nitrogen, R means hydrogen, R means phenyl, o-fluorophenyl, o-chlorophenyl or 2-pyridyl and R 4 means hydrogen

or methyl.

Examples of compounds of formula Ia are: L-phenylalanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, glycyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L-leucy1-N-(4-bromo-2-picolinoylphenyl)glycinamide, L-lysyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L -isoleucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, h-r-glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L-alanyl-N-(4-bromo-2-picolinoylphenyl) glycinamide, L-arginyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L-α-glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, Glycyl-N-(2-benzoyl-4-chlorophenyl)glycinamide , Glycyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, L-prolyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, Glycyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide , L-alanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide, L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide, L-lysyl-N-(2- benzoyl-4-chlorophenyl)-N-methylglycinamide and L-leucyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide, L-phenylalanyl-N-(2-benzoyl-4-nitrogenyl)glycinamide, L- arginyl-N-(2-benzoyl-4-chlorophenyl)glycinamide. L-alanyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, L-alanyl-N-(2<1->fluorobenzoyl)-4-nitrophenyl7-N-methylglycinamide and L-phenylalanyl-N-( 2-benzoyl-4-chlorophenyl)-N-methyl-L-alanine amide.

Preferred compounds of formula Ib are those in which R means chlorine, R"*" hydrogen, R^ phenyl, o-chlorophenyl and R a methyl.

Examples of compounds of formula Ib are: 5-chloro-2-,/3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4t-triazol-4-yl7benzophenone,

5-chloro-2-,/3-(L-lysylaminomethyl)-5-methyl-4H-1, 2, 4-triazol-4-yl/benzophenone,

2' , 5-dichloro-2-(3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl/benzophenone,

2',5-dichloro-2-(3-(1-lysylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl7benzophenone and

2',5-Dichloro-2'(3-glycylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone.

Preferred compounds of formula Ic are those in which R is chlorine, R is hydrogen, R is phenyl or o-fluorophenyl, R is methyl or <T R is hydrogen.

Examples of compounds of formula Ic are: 5-chloro-2'-fluoro-2-(5-(L-leucylaminomethyl)-2-methyl-1-imidazolyl7 benzphenone and

5-Chloro-2'-fluoro-2-(5-(L-alanylaminomethyl)-2-methyl-1-imidazolyl/benzophenone.

In the method according to the present invention,

the substituted phenylketones of the general formula I

and their acid addition salts are prepared by

a) from a compound with the general formula

in which A, B, R, R 1 and R 3 have the meaning indicated above and R^° means the acyl group of a naturally occurring amino acid, whereby all amino groups present are in protected form and possible other functional groups, as far as necessary, are also present in protected form (all these acyl groups, which contain an asymmetric carbon atom, possess L- or

the D,L configuration)

removes the existing protective groups,

or

b) for the preparation of compounds of formula I, in which A means a nitrogen atom, which may be substituted by methyl, and B means a carbonyl group, R means nitrogen and R 2 means the acyl group of a naturally occurring amino acid, which is not replaced by nitrating agents (all these groups, containing an asymmetric carbon atom, possess the L or D,L configuration) a compound of the general formula is nitrated

13 4

wherein R , R and R have the above meaning

21

and R means a derivative acyl group derived from a naturally occurring amino acid, which is not damaged by nitrating agents (all of these groups, containing an asymmetric carbon atom, possess the L or D,L configuration),

and if desired, resolves a racemate of formula I into its optical isomers and isolates the L-isomer, and/or if desired transfers an obtained free base into an acid addition salt or an obtained acid addition salt into a free base or into another acid addition salt.

The amino groups present in the acyl group R^° in formula

II may be protected by every known protecting group

in peptide chemistry. Particularly preferred amino protecting groups for the purposes of the present invention are the aralkyloxycarbonyl groups, especially the benzyloxycarbonyl groups and tert. the butoxycarbonyl groups. However, the amino protecting groups can also be formyl, trityl or trifluoroacetyl groups. Each carboxy or hydroxy group, which may be the precursor of the acyl group R 10 , may be protected by a traditional carboxy or hydroxy protecting group. A carboxy group can e.g. is protected by conversion into an alkyl ester such as e.g. a tert-butyl ester, or an aralkyl ester, e.g. a benzyl ester. Furthermore, a hydroxy group can, for example, be protected by an aralkoxycarbonyl group, e.g. benzyloxycarbonyl, an alkanoyl group, e.g. benzoyl, an alkyl group, e.g. tert-butyl or an aralkyl group, e.g. benzyl. The protection of others

2o functional groups, which can be present in the acyl group R, can take place in and for .known ways.

The removal of the protective groups present in the acyl group R is carried out according to methods known per se, this means methods which are currently in use or which are described in the literature for the removal of protective groups. According to a preferred aspect of the present method, the acyl groups R as a protective group carry a protective group that can be removed by hydrolysis. Thus, e.g. can an aralkylcarbonyl group, e.g. benzyloxycarbonyl, or a tertiary butoxycarbonyl group is cleaved off by treatment with

a mixture of hydrogen bromide and acetic acid. The tertiary butoxycarbonyl group can also be split off by treatment with hydrogen chloride in an organic solvent, e.g. dioxane, or by treatment with trifluoroacetic acid. A benzyloxycarbonyl or tert.-butoxycarbonyl group can also be cleaved by treatment with boron trichloride or boron tribromide in an inert organic solvent such as dichloromethane.

The nitration of a compound of formula III can be carried out according to methods known per se. Thus, e.g. the nitration is carried out using alkali metal nitrate. most advantageously potassium nitrate, in the presence of a strong mineral acid, preferably anhydrous sulfuric acid, or a strong organic acid, preferably water trifluoroacetic acid. The acyl group R 21 in the compounds of formula III is preferably derived from glycine or L- or D,L-alanine, valine, leucine, isoleucine, lysine, proline or aspartic acid.

A racemate of formula I can be split into optical isomers according to methods known per se, thus e.g. with the aid of a suitable optically active acid. The desired L-isomer is obtained by methods known per se, such as by fractional crystallization of the obtained diastereoisomeric salts.

The starting materials of formula II can be prepared by a large number of methods.

Thus, one obtains e.g. a starting material down to formula II, condensing an amine of the general formula

1 3

wherein A, B, R, R and R have the above

importance,

with a correspondingly protected amino acid or a reactive derivative thereof.

The condensation takes place according to the peptide chemistry in and of itself

known methods, e.g. by the mixed anhydride, azide, activated ester or acid chloride method.

According to one method, a corresponding amine of formula IV is reacted

with a correspondingly protected amino acid, in which the terminal carboxy group is in the form of a mixed anhydride with an organic or inorganic acid. Conveniently, such an amino acid, which carries a free carboxy function, is treated with a tertiary base such as tri(lower alkyl)amine, e.g. triethylamine or N-ethylmorpholine in an inert organic solvent, such as tetrahydrofuran, dichloromethane or 1,2-dimethyloxy-

ethane and the resulting salt are treated with a chloroformic acid ester at low temperature, such as, for example, the ethyl or isobutyl ester. The mixed anhydride thus obtained is then preferably reacted in situ with the amine of formula IV.

According to another method, a suitable amine of formula IV, in which the terminal carboxy group is present in the form of an acid azide, is reacted with a suitable protected amino acid. The reaction takes place in an inert organic solvent, such as dimethylformamide or acetic acid at a low temperature.

In another method, a suitable amine of formula IV is reacted

with a suitable protected amino acid, in which the terminal carboxyl group is in the form of an active ester (e.g. p-nitrophenyl-, 2,4,5-trichlorophenyl- or N-hydroxysuccinimide ester). The turnover is appropriately carried out at approx. -2o°C in an inert organic solvent, such as dimethylformamide.

Following a further method, a suitable amine of formula IV is obtained

reacted with a suitable protected amino acid, in which the terminal carboxy group is in the form of an acid chloride.

The reaction is preferably carried out in the presence of a base and at a low temperature..;

In another way, starting materials of formula II are obtained, in which A means a nitrogen atom, which may be substituted by methyl, and B means a carbonyl group by reacting a compound with the general formula

3 4

wherein R, R and R have the above meaning,

with a suitable protected dipeptide or the reactive derivative thereof, whereby one uses one of the above-mentioned methods in connection with the reaction of an amine of formula IV with a protected amino acid or a reactive derivative thereof.

The amines of formula IV, in which A < represents a nitrogen atom. :as

may be substituted with methyl and B means a carbonyl group, e.g. obtained by reacting a compound of formula V with a suitable protected amino acid or a reactive derivative thereof and then splitting off the protective

group in the manner described above.

On the other hand, the amines of formula IV, in which A and B

means a carbonyl group and R 3 means 2-pyridyl or in which A and B together form a group of formula i upon hydrolysis

of a 1,4-benzodiazepine of the general formula

wherein A1, B', R, R<1> and R<3>° have any of the meanings mentioned for A,B,R, R-1 . and R 3,

with the exception that if A' means a nitrogen atom,

which may be substituted by methyl, and B means a

carbonyl group produces R^° 2-pyridyl,

with mineral acid is obtained. A 1,4-benzodiazepine of formula VI

can thus be hydrolysed with sulfuric acid, nitric acid, phosphoric acid or preferably a hydrohalic acid, such as hydrochloric acid. The hydrolysis is preferably carried out at a temperature of approx. 2o - 3o°C.

The 1,4-benaodiazepines of formula VI, in which A' and B' together form the group i, in which X produces C R , do not form the object of the present invention, although the production of these is mentioned with respect to the completeness. These compounds can e.g. is produced by nitrosation of a compound of the general formula

wherein R, R 1 and R 3 have the above meaning,

and gives a compound of formula

wherein R, R 1 and R 3 have the above meaning.

The nitrosation can be carried out using nitric acid formed in situ. Reactants suitable for these purposes include alkali metal nitrites, e.g. sodium nitrite, in the presence of an inorganic or organic acid, e.g. acetic acid and an aqueous or non-aqueous solvent, alkyl nitrite, e.g. methyl nitrite in the presence of an inert solvent, such as an alkanol, a halogenated hydrocarbon or dimethylformamide, as well as a solution of nitrosyl chloride gas in an inert solvent and in the presence of an acid acceptor^ e.g. pyridine. Such nitrosation should be carried out at a temperature below room temperature, e.g. a temperature in the range from - 2o to 25°C.

It should be noted that the group -N(CH 3 ) (NO) in the 2-position of a compound of formula VIII produces a leaving group and that other equivalent leaving groups may be present at this position. Examples of such equivalent leaving groups include groups such as alkoxide groups such as -OCH3, alkylthio groups such as -SCH3 and phosphate groups such as

Reactions for the formation of alkoxide and alkylthio groups are very well known, cf. e.g. GO. Archer and L.H. Sternbach, Journal of Organic Chemistry, 29, 231 (1964) and US Patent No. 3,681,341.

A compound of formula VIII is then reacted with a nitroalkane of the general formula

wherein R has the above meaning and gives a compound of the general formula

13b

wherein R, R , R and R have the above meanings.

The reaction of a compound of formula VIII with a nitroalkane

of formula IX, eg nitromethane, nitroethane, etc., is carried out in the presence of a base strong enough to generate the nitroalkane ion. Suitable bases include alkali metal and alkaline earth metal alkoxides, e.g. potassium tert.-butoxide, amides, e.g. lithium amide and hydrides, e.g. sodium hydride. The reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethylsulfoxide or an ether, e.g. tetrahydrofuran, at a temperature below or above room temperature, e.g. in about-

advised from -50 - 150°C, preferably at approximately room temperature.

A compound of formula X is catalytically hydrogenated (e.g. using hydrogen in the presence of Raney nickel) or reduced with a reducing agent such as lithium aluminum hydride to give a compound of the general formula wherein r\ R<3> and R <b> has the above meaning and R' means halogen or amino.

The above meaning of R<1> in formula XI follows from the conversion of a nitro group into an amino group under conditions used for the reduction of a compound of formula X.

Suitable solvents for the hydroenation in the presence of Raney nickel include alkanols, e.g. ethanol, ether, e.g. tetrahydrofuran, diethyl ether, etc, hydrocarbons, e.g.

toluene and dimethylformamide. The catalytic hydrogenation is carried out at a temperature below or above room temperature, e.g. at -5o° - 15o°C. This catalytic hydrogenation can be carried out with or without pressure, at or above atmospheric pressure.

Suitable solvents for the reduction during use

of a reducing agent, such as lithium aluminum hydride, includes ethers such as tetrahydrofuran, dioxane and diethyl ether, and mixtures of ethers and hydrocarbons, such as tetrahydrofuran and benzene.

This reduction can be carried out at a temperature of

below room temperature to the reflux temperature of the reaction mixture, preferably at a temperature in the range from -5o -60 C.

A compound of formula XI is then acylated with an acylating agent, such as an acid halide or an acid anhydride (e.g. acetic acid chloride or acetic acid hydride), whereby the group Ra CO-, in which Ra has the above-mentioned meaning, is formed and gives a compound of the general formula in which R"<*>", R<3>, R<3> and R<b> have the above meaning,

R has the meaning as in formula XI and

Y means a hydrogen atom or group

R<3> C0-.

The acylation of a compound of formula XI can give a mixture consisting mainly of the monoacylated product, i.e. the product in which the amino group was converted into the -NH-COR<3> group, and the diacylated product, in which both the amino group and the nitrogen atom are acylated . The yield of diacylated product can be increased by subjecting the compounds of formula XI to rigorous conditions, i.e. using an excess of acylating agents and extending the acylation time.

The acylation is preferably carried out in the presence of an aqueous

or non-aqueous solvent, e.g. water, methylene chloride, benzene, chloroform etc., and preferably in the presence of an acid acceptor, such as an organic base, e.g. an alkali metal carbonate or an inorganic base, e.g. triethylamine or pyridine.

A compound of formula XII is then cyclized to

a compound of formula

wherein R1, R<3>, Ra and Rb have the above meaning and

R' has the meaning indicated by formula XI.

The cyclization of a compound of formula XII is carried out using a dehydrating agent, such as phosphorus pentoxide, polyphosphoric acid or other suitable acid catalysts, e.g. an organic or inorganic acid: as concentrated sulfuric acid. A solvent is not necessary per se,

however, a solvent such as an aromatic hydrocarbon,

e.g. toluene or xylene, are used. The cyclization is carried out at a temperature of approx. loo° - 2oo°C.

A compound of formula XI can also be acylated with an acylating agent, such as an orthoester (e.g. triethyl orthoacetate), an orthoamide (e.g. N,N-dimethylformamide-dimethylacetal)

or tris(dimethylamino)methane, if desired in the presence of an acid catalyst such as an organic acid (e.g. paratoluenesulfonic acid) or an inorganic acid (e.g. phosphoric acid) and at room temperature or temperatures above room temperature (e.g.

25°C - 15°C), whereby the cyclization to a compound of formula XIII follows spontaneously. Other useful acylating agents include esters (eg, methyl acetate), amides (eg, acetamide), nitriles (eg, acetonitrile), and ester amidates.

A compound of formula XIII is then dehydrated to an imidazo-benzodiazepine of the general formula wherein r\R3, Ra and -R*5 have the meanings given above and

R' has the meaning given in formula XI.

The dehydrogenation of a compound of formula XIII is carried out preferably using manganese dioxide or palladium carbon, although potassium peraranganate can also be used. Halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide etc. can be used as solvents, the hydrogenation is carried out at room temperature or at a temperature above room temperature, e.g. in the range of about 25° to 2oo°C.

The procedure described above can be carried out by walking

from compounds of formulas X or XI without isolation of any further intermediates.

It should be noted that in the acylation of a compound of formula XI, in which R" means an amino group, this amino group can be acylated to the acylamino group. By mild hydrolysis, an acylamino group can be re-changed to the amino group. It should also be noted that the compound, in which R' means an amino group, can be transferred by the known Sandemeyer reaction to corresponding nitrofuran compounds, see, e.g., E. Rtfard, CD. Johnson and J. G. Hawkins, J. Chem. Soc., 894, (1960) .

The starting materials of formula II can be prepared in the same way

as described for the preparation of the corresponding compounds of formula I, however, corresponding compounds, in which R means hydrogen, are used.

The compounds of formula I form with inorganic acids (e.g. hydrohalic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid) and with organic acids (e.g. acetic acid, succinic acid, glycolic acid, lactic acid, gluconic acid, tartaric acid, citric acid , maleic acid, malic acid, fumaric acid, methanesulfonic acid, paratoluenesulfonic acid, oxalic acid, ascorbic acid, benzoic acid, hydroxyethanesulfonic acid, 1,2-diethanesulfonic acid, etc.) acid addition salts. The pharmaceutically usable acid addition salts are preferred. The acid addition salts can be prepared according to methods known per se, e.g. by treating the base with a suitable acid. An addition salt can be converted by treatment with a suitable anion exchanger (eg "Amberlite IRA-4ol" in the chloride form) into another acid addition salt.

The compounds of formula I and their acid addition salts possess sedative, muscle relaxant and anticonvulsant activity. Of particular interest are the pharmaceutical acid addition salts, which are water-soluble, as these can very easily be administered by injection, e.g. in dentistry for induction of anesthesia and in the treatment of acute convulsive conditions as well as in status epilepticus.

The anticonvulsant activity of the substituted phenylketones according to the present invention can be demonstrated by administering these compounds to mice, which are then subjected to the well-known pentatetramethylenetetrazole test. In this test, L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide hydrobromide, which has an LD,_o of lo mg/kg i.v. (mouse), an ED^Q of 2.o mg/kg i.v. (mouse). Likewise, in this test, 5-chloro-21-fluoro2-/5-(L-leucylaminomethyl)-2-methyl-1-imidazolyl7 benzophenone, which has an LD^Q of 119 mg/kg i.v. (mouse), an eD^q of 2.o mg/kg i.v. (mouse). The muscle relaxing activity can be shown in the familiar rotarod test. In this test, L-phenyl-alanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylgycinamide hydrobromide shows an ED of 4.2 mg/kg i.v. (mouse). Likewise in this test shows

5o

5-chloro-2<1->fluoro-2-/5-(L-leucylaminomethyl)-2-methyl-1-imidazolyl/benzophenone an ED^o of 2o mg/kg i.v. (mouse}.'

The compounds of formula I and their pharmaceutically usable acid addition salts can be used as medicaments, e.g.

in the form of pharmaceutical preparations, which contain these together with a pharmaceutical tolerable carrier material. This carrier material can be an organic or inorganic carrier material, which is suitable for enteral or parenteral administration, e.g. water, lactose, gelatin, starches, magnesium stearate, talc, plant oils, gums, polyalkylene glycol, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, capsules, etc., or in liquid form, e.g. solutions, suspensions or emulsions. Pharmaceutical preparations adapted to injection purposes are preferred. Pharmaceutical preparations can be subjected to normal pharmaceutical operations, such as sterilization and/or may contain normal pharmaceutical aids, such as preservatives, stabilizers, cross-linking agents, emulsifiers, buffers, etc.

The dosages at which the compounds of formula I and their pharmaceutically usable acid addition salts are to be administered may vary according to the needs of the patient and the guidelines of the attending physician. A daily dose of approx. however, 0.01 mg/kg to 1 mg/kg is preferred.

The following examples illustrate the method according to the present invention. The structures of all products obtained were confirmed by standard methods including infrared and NMR spectroscopy.

EXAMPLE 1

a) loo g of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1;4-benzodiazepine-2-one is dissolved in 75o ml of 2N hydrochloric acid and left overnight

at room temperature. The solution is evaporated to oil, which is dissolved in water, after which it is evaporated again. The last traces of water are removed by shaking with a 50% methanol/toluene mixture followed by evaporation. This treatment is repeated three times with a 50% methanol/toluene mixture and twice with toluene. A pale yellow to orange solid is obtained, which is dried at 5o°C in vacuum. The product was characterized by its spectral data, by titration it was found that 2.5 mol of hydrochloric acid contained 1 mol of 2-amino-N-(4-bromo-2-picolinoylphenyl)acetamide. After prolonged drying over sodium hydroxide, an analytical sample was obtained)

which was stoichiometric.

Analysis for C^H^BrCl^O (4o7.ll):

Calculated: C: 41.31, H: 3.47, N: lo,32, Br: 19.63, Cl: 17.42 Found: C: 41.o2, H: 3.61, N: lo,11 , Br: 2o.o8, Cl: 17.82.

b) 7.24 g of N-benzyloxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester are dissolved in 80 ml of dimethylformamide and

the solution is cooled to -2o°C, after which 8.48 of the dihydrochloride obtained according to paragraph a) is added. 6.16 ml of N-ethylmorpholine are then added over a period of 0.5 hour with vigorous stirring. The resulting reaction mixture is then stirred for a further hour at -20°C and then overnight at room temperature. The solvent is evaporated in vacuo and the residue is dissolved in a mixture of chloroform/water. The phases are separated and the aqueous phase is extracted once more with chloroform. The combined organic phases are washed five times with water, dried over magnesium sulfate and evaporated to an oil. Crystallization from hot ethanol yields (N-benzyloxycarbonyl-L-phenylalanyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide with m.p. 157-183°C (slight decomposition).

Analysis for C,,H_„BrN,Oc (615.50)'

ol z / 4 O

Calculated: C: 6o.49, H: 4.42, N 9.lo.

Found: C: 6o.44, H: 4.41, N: 8.9o.

c) 4.0 g of (N-benzyloxycarbonyl-L-phenylalanyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide is stirred for one hour

in a solution of 35% hydrogen bromide in glacial acetic acid. Dry diethyl ether is then added, and the precipitated solid is filtered off, washed with diethyl ether and dried in vacuum. The crude product obtained is dissolved in a minimum amount of dry methanol and treated with acetic acid, whereby the product is precipitated. One obtains L-phenylalanyl-N-(4-bromo-2-picolinoylphenyl) glycinamide dihydrobromide with m.p. 182°C (decomposition), [' aj 0 = +28.4° ( c = 1 in water). D Analysis for C23H23Br3N4C>3 (643.2o): Calculated: C: 42.95, H: 3.60, N: 8.71, Br. 37,27

Found: C: 42.53, H: 3.68, N: 8.35, Br. 37,o4.

d) 2 g of this dihydrobromide are dissolved in 10 ml of water, after which dilute ammonium hydroxy solution is slowly added while stirring until the solution is basic. The precipitated

the yellow oil crystallizes when allowed to stand. The product obtained is filtered off, washed with water, dried in vacuum and recrystallized from ethanol/water. In this way, the free base L-phenylalanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide with m.p. 6o°C (cleavage) and an optical rotation of /q7^°= +26.7°

(c = 1 in 1N hydrochloric acid). D Analysis for C^H^BrN^ (481.36);

Calculated: C: 57.39, H: 4.4o, N: 11.64, Br: 16.60.

Found: C: 56.96, H: 4.42, N: 11.48, Br: 16.42.

EXE MPEL 2

In an analogous manner to example 1, glycyl-N-(4-bromo-2-picolinoylphenyl)glycinamide is obtained with m.p. 97 - 100°C.

Analysis for c16H15BrN4O3 (391.23):

Calculated: C: 49.11, H: 3.87, N: 14.32, Br: 2o.42.

Found: C: 48.95, H: 3.92, N: 14.15, Br: 20.55.

EXAMPLE 3

In an analogous manner to example 1, L-lysyl-N-(4-bromo-2-picolinoylphenyl)glycinamide trihydrobromide is obtained with m.p. 22o°C (decomposition), lh£<2>° = +16.8° ( c = 1 in water).

Analysis for C^H Br4N50 ( 7o5.ll).:

Calculated: C: 34.o7, H: 3.86, N: 9.93-, Br:. 45.34

Br ionic: 34,oo.

Found: C: 34.29, H: 4.25, N: 9.73, Br: 44.6o,

Br ionic: 33.32, H 2 O: o.96.

Anhydrous: C: 34.62, H: 4.18, N: 9.82-, Br: 45.o3

Br ionic: 33.64.

EXAMPLE 4

a) 3,18 N-benzyloxycarbonyl-L-isoleucine is dissolved in 25 ml of dry tetrahydrofuran and cooled to -10°C. From now on it will be 1.57

ml of isobutyl chloroformate and 1.52 ml of N-ethylmorpholine are added and the resulting solution is stirred for 20 min. at -10°C.

4.24 g of 2-amino-N-(4-bromo-2-picolinoylphenyl)-acetamide dihydrochloride (prepared as in section a) described in Example 1)

is added and the resulting suspension is cooled to -2o°C. Under vigorous stirring, 3.13 ml of N-ethylmorpholine in 25 ml of dimethylformamide are added over a period of 0.5 hour. The resulting mixture is stirred for a further 40 min. at -2o°C and then left overnight at room temperature.

The product obtained is worked up in an analogous way as described in example 1, section b). By recrystallization from ethanol, (N-benzyloxycarbonyl-L-isoleucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide is obtained with m.p. 174-176°C.

Analysis for C2gH2gBrN4O5(581.48):

Calculated: C: 57.84, H: 5.03, N: 9.64, Br: 13.74.

Found: C: 57.84, H: 5.02, N: 9.39, Br: 13.67.

b) 2.0 g of (N-benzyloxycarbonyl-L-isoleucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide is stirred in a solution of 35% hydrogen bromide

in glacial acetic acid over the course of 1 hour. The solid that precipitates after the addition of diethyl ether is filtered off, washed with diethyl ether and dried in a vacuum. Two precipitations from methanol/acetic ester give L-isoleucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide-dihyro-

bromide with m.p. 174°C (decomposition).

c) 1 g of this dihydrobromide is dissolved in 10 ml of water, after which the solution is made basic with stirring by adding dilute ammonium hydroxide solution. The oil obtained crystallizes when left to stand. The crystals are filtered off, washed with water and dried in vacuo to give the free base L-isoleucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, which starts melting from 54°C with slight cleavage, Za/p°

= + 29.6° ( c = 1 in 1N hydrochloric acid).

-Analysis for C^H^BrN^ (447.34):

Calculated: C: 53.7o, H: 5.18, N: 12.52, Br: 17.87,

Found: C: 52.97, H: 5.23, N: 12.26, Br: 17.85, H 2 O: 1.75. Anhydrous: C: 53.37, H: 5.18, N: 12.35, Br: 17.98.

EXAMPLE 5

In an analogous way as in example 4, however using N -benzyloxycarbonyl-L-arginine monohydrobromide obtains

man L-arginyl-N-(4-bromo-2-picolinoylphenyl)glycinamide trihydrobromide hydrate as lyophilized solid, / a/ °='+lo,9° ( c =

1 in water). D

Analysis for C2oH2gBr4N7O4 (751.14):

Calculated: C: 32.oo, H: 3.89, N: 13.o5. Br ionic: 31.92.

Found: C: 31.85, H: 3.88, N: 13.oo, Br ionic: 32.2o.

EXAMPLE 6

In an analogous way as in example 4, however using N-benzyloxycarbonyl-L-glutamic acid r-tert. butyl ester gives α-glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide hydrobromide (1:1.85) with m.p. 153-I7o<0>C (slight decomposition), fqj^ = +2o,o° ( c 1 in water).

Analysis for CigH gBrN405 . 1.85 HBr (612.98):

Calculated: C: 37.23, H: 3.43, N: 9.14, Br: 37.15.

Found: C: 36.68, H: 3.69, N: 8.64, Br: 36.55, H 2 O: 1.28. Anhydrous: C: 37.16, H: 3.59, N: 8.85, Br: 37.o2.

EXE MPEL 7

a) In the case of an analogous process as in example 4, section a) obtains

one (N<a>,N^-di-tertbutoxycarbonyl-L-lysyl)-N-(4-bromo-2-picolinbyl-phenyl)glycinamide with m.p. 135-137°C.

Analysis for C 3 o H 4 QBrN 5 O 7 (662.59);

Calculated: C: 54.38, H: 6.o9, N: lo.57, Br: 12.06.

Found: C: 54.33, H: 5.87, N: lo, 34, Br: 12.24.

b) 1,0 g (N ry ,N £ -di-tertbutoxycarbonyl-L-lysyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide is stirred over the course of 1 hour in a

4N hydrochloric acid solution in dioxane. The solid precipitated after the addition of diethyl ether is filtered off, washed with diethyl

ether and dried. The solid is dissolved in methanol and treated with acetic acid. The precipitate is dissolved with 20 ml of water and the aqueous solution lyophilized with chloroform after extraction to give L-lysyl-N-(4-bromo-2-picolinoylphenyl)glycinamide trihydrochloride 1.5 H 2 O, /q/<2>°= + 2o, ( c = 1 in water).

Analysis for 82oH27BrCl3N503. 1.5 H2O (598.76):

Calculated: C: 4o.12, H: 5.o5, N: 11.7o, Cl: 17.76.

Found: C: 40.27, H: 4.92, N: 11.57, Cl: 17.62.

EXAMPLE 8

In an analogous manner to example 4, L-γ-glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide is obtained with m.p. 158-161°C

(spaltni<ng>),<faj2>° = +121/1o (c= ± . m hydrochloric acid) .

Analysis for CigHigBrN4O5 (463.3o):

Calculated: C: 49.26, H: 4.13, N: 12.o9, Br: 17.25.

Found: C: 48.26, H: 4.4o, N: 11.94, Br: 17.35, H2O: 1.24 Anhydrous: C: 48.87, H: 4.31, N: 12.o9 , Br: 17.57.

EXAMPLE 9

In an analogous manner to example 1, L-alanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide is obtained with m.p. 76-78°C, /q7D°= + 17.4°

(c = 1.0225 in methanol).

Analysis for C17H17BrN4C>3 (4o5.26):

Calculated: C: 50.38, H: 4.23, N: 13.82, Br: 19.71.

Found: C: 50.43, H: 4.21, N: 13.56, Br: 19.74.

EXAMPLE lo

a) 6.56 g of tert,-butoxycarbonyl-L-leucyl-N-hydroxycuccinimide ester are dissolved in 80 ml of dimethylformamide and the solution is cooled

to -2o°C. 8.48 g of 2-amino-N-(4-bromo-2-picolinoyl-phenyl)acetamide dihydrochloride are then added. 6.16 ml of N-ethylraorfoline is then, over a period of 30 min. under vigorous stirring added to the suspension. The reaction mixture is then stirred for a further hour at -2o°C and then overnight at room temperature.

Processing is carried out in the same way as described in example 1, section b). The oil obtained is crystallized

from a methanol/water mixture and from the same solvent recrystallized to give pure (N-tert-butoxycarbonyl-L-leucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide with m.p. 129-132°C. Analysis for C25H31BrN4O5 (547.46):

Calculated: C: 54.85, H: 5.71, N: lo,23, Br: 14.6o.

Found: C: 54.73, H: 5.83, N: 10,02, Br: 14.95.

b) 2.0 g of (N-tert.-butoxycarbonyl-L-leucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide is stirred for one hour in a 4N solution

of hydrochloric acid in dioxane. The solid precipitated after the addition of vinegar is filtered off, washed with vinegar and dried in a vacuum. The solid is dissolved in a minimum amount of methanol and precipitated by the addition of acetic ester, whereby L-leucyl-N-(4-bromo-2-picolinoylphenyl) glycinamide hydrochloride is obtained. c) The hydrochloride is dissolved in 50 ml of water and the solution is made basic by slow addition of a dilute ammonium hydroxy solution while stirring. The precipitated yellow oil crystallizes on standing. The product is filtered off, washed with water and dried in a vacuum. L-leucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide is obtained with m.p. 53°C (decomposition), ^a/<20> = + 26.o° (c = 1 in 1N hydrochloric acid).

Analysis for C_ Ho,BrN,0, (447.34):

2o 23 4 3

Calculated: C: 53.7o, H: 5.18, N: 12.52.

Found: C: 53.35, H: 5.14, N: 12.21, H 2 O: 1.32.

Anhydrous: C: 54.06, H: 5.06, N: 12.37.

EXAMPLE 11

a). 15.9 g of N-benzyloxycarbonylgycylglycine are suspended in 6oo ml of dry 1,2-dimethoxyethane and the suspension is cooled

to -5°C. 6.06 g of N-methylmorpholine and 8.22 g of isobutyl chloroformate are added and the resulting reaction mixture is stirred.

2 hours at -5° to -lo°C. Non-traded starting material

and N-methylmorpholine hydrochloride are separated by filtration and the solution (kept at -5 - 0°C.) is added over a period of several hours to a refluxed solution of 14.7 g of 5-chloro-2-methylaminobenzophenone in 2oo ml of dry 1,2-dimethoxy-

ethane. The solution obtained is then stirred overnight at reflux.

b) The reaction mixture is evaporated in vacuo and the residue is taken up in 600 ml of acetic acid. The solution is washed three times

with 15o ml of water and with 15o ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to a yellow gum. By soil chromatography of this gum on Florisil using mixtures of benzene and methanol as a flux, pure (N-benzyloxycarbonylglycyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylgycinamide is obtained as an almost colorless, light-sensitive gum, which was characterized by spectroscopy and elemental analysis.

Analysis for C26H24C1N3°5 ( 493'95)--

Calculated: C: 63.23, H: 4.9o, N: 8.51, Cl: 7.18.

Found: C: 63.61, H: 4.87, N: 8.37, Cl: 7.o2.

c) 9.87 g of (N-benzyloxycarbonylgycyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide are dissolved in 50 ml of glacial acetic acid and treated

with 5o ml of a 3o'ig solution of hydrogen bromide in glacial acetic acid.

The obtained solution is stirred for 1 hour with room temperature and, after treatment with an excess of dry diethyl ether, the precipitated solid was washed several times with dried diethyl ether and then dried in vacuo. The hygroscopic solid thus obtained consists mainly of glycyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide hydrochloride with m.p. 14o-15o°C (decomposition). Analysis for C18H18C1N303. 1.2 HBr (456.9):

Calculated: C: 47.32, H: 4.24, N: 9.2o, Br ionic: 2o.99.

Found: C: 46.86, H: 4.59, N: 9.11, Br ionic: 2o.7o.

d) 4.6 g of this crude hydrobromide is purified by dissolving in 10 ml o.2N sodium acetate solution and extracting

the solution with ether. The aqueous solution is then made basic with an excess of sodium carbonate and extracted with dichloromethane and after evaporation and degassing in vacuo gives g-lycyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colorless, light-sensitive glassy foam, which is characterized by spectroscopy.

EXAMPLE 12

In an analogous manner to sections a) and b) in example 11, (N-benzyloxycarbonylgjj.ycyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide is obtained with m.p. 139-141°C (from ethanol).

In a similar way as in sections c) and d) in example 11

(N-benzyloxycarbonylglycyl)-N-(4-bromo-2-picolinoyl-phenyl)glycinamide is converted into glycyl-N-(4-bromo-2-picolinoylphenyl)glycinamide with m.p. 97-100°C.

EXE MPEL 13

a) 20.9 g of N-benzyloxycarbonylglycine are suspended in 1500 ml of dry 1,2-dimethoxyethane and the suspension is cooled to -20°C.

10.1 g of N-methylmorpholine and 13.7 g of isobutyl chloroformate are added and the resulting solution is stirred for 1 hour at -2o°C and then filtered. The filtrate (kept at 0°C) is, over a period of several hours, added portionwise to a reflux heated solution of 24.55 g of 5-chloro-2-methylaminobenzophenone in 200 ml of 1,2-dimethoxyethane. The resulting reaction mixture is boiled overnight and then evaporated in vacuo to dryness. The yellow residue is dissolved in acetic acid, washed with 2 parts water and 1 part saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated in vacuo. By soil chromatography of this residue on Florisil using mixtures of benzene and chloroform as flux, pure 2-(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide is obtained as a pale yellow gum.

Analysis for C24H21C1N20 (436.9):

Calculated: C: 65.98, H: 4.85, N: 6.41.

Found: C-. 65.91, H: 5.03, N: 6.51.

b) 43.7 g of 2-(N-benzyloxycarbonylamino)-N-(2-*benzoyl 1-4-chlorophenyl)-N-methylacetamide are dissolved in 200 ml of a 30%

solution of hydrogen bromide in glacial acetic acid and the resulting reaction mixture is stirred overnight at room temperature. The mixture is slowly added to a large excess (2ooo ml) of dry diethyl ether, whereby it is stirred vigorously. The precipitated product is separated by decanting off the solvent. The residue is rubbed with 15o ml of acetone, filtered off, continuously washed with a minimum amount of acetone and dry diethyl ether and then dried in vacuo, whereby 2-amino-N-(2-benzoyl-

4-chlorophenyl)-N-methylacetamide hydrobromide as white hygroscopic powder with m.p. 194-195°C (decomposition).

Analysis for C, CH_cBrClNnO„ ( 383.7):

lb 16 2 2

Calculated: C: 5o,lo, H: 4.21, N: 7.3o, Br ionic: 2o.83.

Found: C: 44.98, H: 3.83, N: 7.15, Br ionic: 21.14.

c) 84 g of N-benzyloxycarbonylglycine are suspended in 500 ml of alcohol-free. chloroform and the suspension is cooled to -2o°C.

The stirred suspension becomes in the course of a time of 15 min.

treated in portions with 90 g of phosphorus pentachloride, after which stirring is continued until a clear solution is obtained.

The cold mixture is then added in portions over time

a time of 3o min. to a cold (-5°C) vigorously stirred emulsion consisting of 82 g of 5-chloro-2-methyl-aminobenzophenone, 347 g of potassium bicarbonate, 7oo ml of chloroform and 14oo ml of water. The resulting mixture is stirred for a further hour at -5°C and then overnight at room temperature. The stirring is then interrupted, after which the liquid phases are separated. The chloroform phase is washed three times with 500 ml of water and evaporated in vacuo. A viscous yellow gum is obtained which, as shown by physical methods, consists mainly of pure 2-(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide.

d) The product obtained according to the preceding paragraph is dissolved in 65o ml of a 3o% solution of hydrogen bromide in glacial acetic acid

and treated in a similar manner as in section a) of this example, whereby 2-amino-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide hydrobromide is obtained. e) 3.96 g of N-benzyloxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester are dissolved in 50 ml of dry dimethylformamide.

The resulting solution is cooled to -2o°C, after which 3.84 g of 2-amino-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide hydrobromide are added and then 1.15 g of N-ethylmorpholine are added dropwise . The resulting reaction mixture is stirred for 1 hour

at -2o°C and then overnight at room temperature vigorously. The solvent is evaporated in vacuo and the residue is dissolved in a mixture of dichloromethane and water. The organic and aqueous phases are separated and the aqueous phase is extracted with additional portions of dichloromethane. The combined organic phases (25o ml)

was washed 3 times with 50 ml of water, dried over dry magnesium sulfate and evaporated in vacuo. 5.8 g of a yellow oil is obtained, which, as was shown by physical methods, consists of a mixture of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4- benzodia-sepin-2-one and (N-benzyloxycarbonyl-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl-N-methylgycinamide in an approximate ratio of 1:3. f) The aforementioned mixture can be purified by soil chromatography on Florisil and delivers pure (N-benzyloxy-carbonyl-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methyl-glycinamide as an almost colorless, light-sensitive foam, /a/p°= -13 .6° (c = 1 in ethanol). Analysis for C33H3oGlN3O5 (584.1):

Calculated C: 67.86, H: 5.18, N: 7.19, Cl: 6.07.

Found: C: 67.76, H: 5.08, N: 6.84, Cl: 6.16.

On the other hand, the above mixture can be subjected directly to the deprotection as follows: g) 5.8 g of the above mixture is dissolved in 20 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the solution is stirred for 3 hours at room temperature. The solid precipitated after the addition of 200 ml of dry diethyl ether is collected, dissolved in 100 ml of water, treated with an excess of sodium carbonate and extracted with 4 75 ml portions of diethyl ether. The combined ether extracts are then shaken with six 50 ml portions of 0.1 N acetic acid to separate the strong basic products from the less basic by-products (benzodiazepine-2-ones).

The combined aqueous-acid solutions are washed with 100 ml of diethyl ether, basified with an excess of sodium carbonate and extracted with four 75 ml portions of dichloromethane. The dichloromethane extracts are combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. Thorough degassing in a vacuum gives pure L-phenyl-alanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colorless, light-sensitive thin foam, /a/<2o>= -11.6° ( c

1 in ethanol).

Analysis for.C25H24C1N303 (449.9):

Calculated: C: 66.74, H: 5.38, N: 9.34, Cl: 7.88.

Found: C: 66.71, H: 5.47, N: 9.23, Cl: 8.14.

h) Treatment of this free base with an equimolar amount of anhydrous (+)-tartaric acid in hot isopropanol gives colourless

crystals of hydrogen (+)-tartrate with m.p. 198-2oo°C.

Analysis for C^H^ClN-jOg (600.00):

Calculated: C: 58.o5, H: 5.o4, N: 7.oo, Cl: 5.91..

Found: C: 58.32, H: 4.98, N: 6.73, Cl: 5.9o.

i) 5.8 g of the above mixture becomes. dissolved in 75 ml of dry nitromethane, after which a weak stream of hydrogen bromide is passed through the solution for 15 minutes. The solution is then stirred for 2 hours at room temperature and then treated with an excess of dry diethyl ether. The precipitated solid is treated in the same manner as in section b) of this example to give L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide.

The free base thus obtained is transferred into the hydrochloride as follows:

j) 4.5 g of L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-

glycinamide is dissolved in a minimal amount of methanol at room temperature and treated by titration with an exactly equivalent amount in 1N hydrochloric acid. From the solution obtained, the solvent is removed by evaporation in vacuo at room temperature and finally by lyophilization, whereby L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylgycinamide hydrochloride is obtained in quantitative yield as hygroscopic, white light-sensitive amorphous powder with m.p. 13o-15o°C (slight cleavage),

/a7<2o>= + 41.7° (c = 1 in water).

Analysis for <C>25<H>25<C>12N3°2 ^486'4):

Calculated: C: 61.74, H: 5.18, N: 8.64, Cl ionic: 7.29.

Found: C: 60.25, H: 5.22, N: 8.3o, Cl ionic: 7.31,

H 2 O: 2.17.

Anhydrous: C: 61.58, H: 5.08, N: 8.48, Cl ionic: 7.47.

EXAMPLE 14

In an analogous manner as in example 13, Glycyl-N-(2-benzoyl-4-chlorophenyl)-glycinamide is obtained with m.p. 136-138°C (from ethanol).

Analysis for C^H^ClN^ (345.79)'

Calculated: C: 59.o5, H: 4.66, N: 12.15, Cl: lo,26

Found: C: 59.o3, H: 4.63, N: 11.79, Gl: lo,26.

EXAMPLE 15

In an analogous way as in example 13, glycyl-N-(2-benzoyl-4-nitrphenyl)glycinamide is obtained below m.p. 121-123°C (from ethanol).

Analysis for C17<H>lfiN4<0>5 (356.34):

Calculated: C: 57.31, H: 4.35, N: 15.72.

Found: C: 57.54, H: 4.58, N: 15.73.

EXAMPLE 16

In an analogous manner to example 13, L-prolyl-N-(2-benzoyl-4-nitrophenyl)glycinamide is obtained with m.p. 165-167°C.

EXAMPLE 17

In an analogous manner to example 13, L-alanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide hydrochloride is obtained with m.p. 115-

13o°C (slight cleavage), /q72°= + 7.o9° ( c = 1 in water).

Analysis for c19H2iC12N303 (41°'31):

Calculated: C: 55.62, H: 5.16, N: 10.24, Cl ionic: 8.64.

Found: C: 55.86, H: 5.2o, N: 9.95, Cl ionic: 8.42.

EXAMPLE 18

a) In an analogous way as in sections from a) - f) in example 13, (N a ,N <£->bisbenzyloxycarbonyl-L-lysyl)-N-(2-bénzoyl-4-chlorophenyl)-N-methylglycinamide is obtained as an almost colorless, light-sensitive gum, /a/<2o>= -9.3° (c = 1 in ethanol).

Analysis for C3gH3gClN4O7 (699.2):

Calculated: C: 65.28, N: 5.62, N: 8.62, Cl: 5.07.

Found: C: 64.9o, H: 5.56, N: 7.84, Cl: 5.25.

b) (Na , N 2'-bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl 1-4-chlorophenyl)-N-methylglycinamide is, using a

30% solution of hydrogen bromide in glacial acetic acid converted to L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylgycinamide-dihydro-

bromide, which is a hygroscopic powder with m.p. l45-16o°C (decomposition), /a/<2>° + 15.6° ( c = 1 in water).

Analysis for C22H2gBr2ClN4C>3 (592.8):

Calcd: C: 44.58, H: 4.93, N: 9.45, Br ionic: 26.96.

Found: C: 43.58, H: 5.17, N: 9.21, Br ionic: 27.43,

H 2 O: o.99.

Anhydrous: C: 44.o2, H: 5.11, N: 9.3o, fir ionic: 27, lo.

c) By treating this dihydrobromide in aqueous solution with an excess of anion exchange resin, such as "Amberlite IRA-4ol"

in the chloride form and then lyophilization of the eluate, L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide~dihydrochloride is obtained in quantitative yield as hygroscopic, white, light-sensitive powder with m.p. 125-145°C (slight cleavage),

/q/<2>° = ■+ 19.3° ( c= 1 in water).

Analysis for C22H2gCl3N4O3 (5o3.86):

Calculated: C: 52.45, H: 5.8o, N: 11.12, Cl: 21.12.

Found: C: 51.58, H: 5.8o, N: 11.18, Cl: 2o.8o, H 2 O: 0.99. Anhydrous: C: 52.lo, H: 5.75, N: 11.29, Cl: 21.lo.

d) 1.4 g of (N ot ,N £ -bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide is dissolved in 30 ml of dry dichloromethane, after which the solution is cooled to approx. -7o°C and then treated with stirring with 2 ml of pre-charged boron trichloride. The mixture is stirred under anhydrous conditions for 30 min. at approx. -7o°C

and then slowly brought to room temperature over a period of 2 hours. The reaction mixture is evaporated to dryness in vacuo, the residue dissolved in 30 ml of freshly dried dichloromethane and the solution again evaporated to dryness in vacuum. These conditions are repeated twice with dichloromethane and then four times with methanol, to remove the remaining boron compounds. as volatile trimethyl borates. A concentrated methanolic solution of the residue is slowly added to a solution of 750 ml of anhydrous diethyl ether with vigorous stirring. The hygroscopic solid is collected by filtration and dried in vacuo. This product is dissolved in 3o ml of water, shaken 3 times with each 2o ml of acetic ester (to remove traces of 5-chloro-2-methylaminobenzophenone), after which the aqueous solution is lyophilized. L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide dihydrochloride is obtained, which is identical to the

product that is described in section c) of this example.

EXAMPLE 19

In an analogous manner to example 13, L-leucyl-N-(2-benzoyl-4-chlorophenyl)-N-methylgycinamide is obtained in the form of eh pale yellow gum /a/^<0> = -2.2° (c = 1 in ethanol).

Analysis for C^H^ClN^ (415.9):

Calculated: C: 63.54, H: 6.3o, N: lo,lo, Cl: 8.52.

Found: C: 63.25, H: 6.69, N: 9.75, Cl: 8.33.

EXAMPLE 2o

In an analogous manner to example 13, L-phenylalanyl-N-(2-benzoyl-4-nitrcfenyl)-glycinamide is obtained with m.p. 144-146 C (from methanol), /^/p0 = -29.4° (c = 1 in dioxane).

Analysis for C24H22N4°5 (446.47):

Calculated: C: 64.56, H: 4.97, N: 12.55.

Found: C: 64.39, H: 4.95, N: 12.74.

EXAMPLE 21

a) In an analogous way as in sections a) - f) in example 13, (Nft,N7Ntu -trisbenzyloxycarbonyl-L-arginyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide is obtained as almost colorless, light sensitive shirt foam, /a/D = -2.4° ( c = 1 in ethanol). Analysis for C.,H CC1N,0_ (861.36): J 46 45 6 9

Calculated: C: 64.14, H: 5.27, N: 9.76, Cl: 4.12.

Found: C: 63.44, H: 5.17, N: 9.59, Cl: 4.65. Solvent free : C: 63.9o, H: 5.2o, N: 9.68, Cl: 3.91.

By NMR spectroscopy, a dichloromethane content of o.lo - o.o2 mol was found.

Calculated for C46H45ClN6Og, o,l CH2C12 (868.84):

C: 63.66, H: 5.24, N: 9.66, Cl: 4.8o.

b) 5.0 g of (N1>, N~, NUJ-trisbenzyloxycarbonyl-L-arginyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide is dissolved in 60 ml

dry dichloromethane and the solution is cooled to 0°C and treated with stirring with 4 ml of boron tribromide. The reaction mixture is stirred for 2 hours at 0°C and then allowed to stand overnight, whereby it warms to room temperature. Excess boron tribromide is neutralized by dropwise addition of a solution of anhydrous methanol in dry dichloromethane, until no further reaction can be observed. The reaction mixture is evaporated to dryness and the residue is dissolved in 30 ml of anhydrous methanol and the solution is again evaporated to dryness. This process is repeated three times with methanol, to remove residual boron compounds such as volatile trimethyl borates. A concentrated solution of the residue

in methanol is added slowly with vigorous stirring to one liter of anhydrous diethyl ether. The hygroscopic solid is collected by filtration and dried in vacuo. The product is washed in 100 ml of water and the solution is shaken three times with 50 ml of acetic acid to remove traces of 5-chloro-2-methylaminobenzophenone, and then lyophilized. L-arginyl-N^(2-benzoyl-4-chlorophenyl)-N-ethylgycinamide dihydrobromide is obtained as an almost colorless, light-sensitive powder, /<q>72<o>= +12.8° ( c = 1 in water).

Analysis for c22H27<B>r2ClN6°3 (62o'77);

Calcd: C: 42.56, H: 4.71, N: 13.53, Br ionic: 25.74.

Found: C: 4o.74, H: 4.91, N: 13.29, Br ionic: 26.08,

H 2 O: 1.89.

Anhydrous: C: 41.52, H: 4.79, N: 13.55, Br ionic' 26.58. Calculated for C22H25C1N603. 2.1 HBr (631.29): C: 41.86, H: 4.65, N: 13.31, Br ionic: 26.96. c) This dihydrobromide is treated in an analogous manner as in section c) of example 18 and gives in quantitative yield L-arginyl-N-(2-benzoyl 1-4-chlorophenyl)-N-methylglycinamide dihydrochloride as white luminous amorphous powder with m.p.

155-16o°C (slight cleavage), Za7^° = + 14.9° ( c = 1 in water).

Analysis for c22H27Cl3N6°3 (531'87>p

Calculated: C: 49.68, H: 5.49, N: 15.8o, Cl: 19.99.

Found: C: 48.47, H: 5.75, N: 15.84, Cl: 2o.16, H 2 O: 1.17. Anhydrous: C: 49.o4, H: 5.69, N: 16.o3. Cl: 2o, 4o.

Calculated for C22H25C1N3. 2.1 HCl (535.52):

C: 49.34. H: 5.48, N: 15.69, Cl: 20.52.

EXAMPLE 22

a) In an analogous manner to section c) in example 13, 2-(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methylpropionamide is obtained as a pale yellow gum, /q7^°= - 3, 75° (c= 1

in ethanol).

Analysis for c25H23ClN204 *45o'92)!

Calculated: C: 66.6o, H: 5.14, N: 6.21, Cl: 7.86.

Found: C: 66.27, H: 5.18, N: 5.88.

b) This product is dissolved in an excess of a 30% solution of hydrogen bromide and treated in a similar manner as

in sections a) and b) in example 13 and gives 2-amino-N-(2-benzoyl-4-chlorophenyl)-N-methylpropionamide hydrobromide as an almost colorless, hygroscopic powder with m.p. 14o-145°C (slight decomposition) ( from acetone/diethyl ether), /q/ ° = +13.2° ( c = 1 in ethanol).

Analysis for C^H^CIN^ (397, 7o):

Calculated: C: 51.34, H: 4.56, N: 7.o5, Br ionic: 2o.lo.

Found: C: 5o.98, H: 4.73, N: 6.78, Br ionic: 2o.o5,

H 2 O: o.75.

Anhydrous: C: 51.37, H: 4.68, N: 6.83, Br ionic: 2o.2o.

c) In an analogous manner to section e) in example 13, a mixture of 7-chloro-1,3-dihydro-1,3-dimethyl-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained and (N-benzyloxycarbonyl-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alanine amide in an approximate ratio of 2:1. d) 6 g of this mixture is dissolved in 40 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the solution becomes

stirred for 3 hours at room temperature. The mixture is worked up in a similar way as in section g) in example 13 and gives L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alanine amide

2o 9 as almost colourless, light-sensitive shirt foam, =34.9

(c - 1 in ethanol).

Analysis for C^H^ClN.O. (463.97):

26 26 3 3

Calculated: C: 67.30, H: 6.65, H: 9.06, Cl: 7.64.

Found: C: 66.98, H: 5.79, N: 8.82, Cl: 7.74.

The free base thus obtained is transferred into the hydrochloride as follows: e) o.5 g of L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alanine amide is dissolved at room temperature in a minimum amount

of methanol and treated by titration with an approximately equivalent amount of IN hydrochloric acid. From the solution obtained, the solvent is removed by evaporation in vacuo at room temperature and then by lyophilization, whereby L-phenyl-alanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alaninamide hydrochloride is obtained

in quantitative yield as white, hygroscopic, light-sensitive amorphous powder with m.p. 13o-14o°C, (slight cleavage),

/o/20 = -4o,o° ( c = 1 in water).

Analysis for <C>26H27Cl2N3°3 ^ 5oo.43):

Calculated: C: 62.39, H: 5.44, N: 8.4o, Cl ionic: 7.o9.

Found: C: 6o.84, H: 6.65, N: 8.o3, Cl ionic: 7.36,

H 2 O: 2.05.

Anhydrous: C: 62.11, H: 5.53, N: 8.2o, Cl ionic: 7.51.

Calculated for C26H26C1N303. 1,o5 HC1 (5o2,28):

C: 62.17, H: 5.42, N: 8.36, Cl ionic: 7.41.

EKS EMPEL 23

a) In an analogous manner as described in sections a) to f) in example 13, 2-(N-benzyloxycarbonylamino)-N-(2-benzoylphenyl)-N-methylacetamide is obtained as a pale yellow gum.

Analysis for <C>24<H>22<N>2°4 (<4>o2'45):

Calculated: C: 71.36, H: 5.51, N: 6.96.

Found: C: 71.33, H: 5.45, N: 6.9o.

b) By treating this compound in an analogous manner as in section g) in example 13, L-alanyl-N-(2-benzoyl-phenyl)-N-methylgycinamide is obtained as an almost colorless, light-sensitive foam.

Analysis for <c>19<H>2iN3°3 (<3>39.4o):

Calculated: C: 67.24, H: 6.25, N: 12.38.

Found: C: 66.93, H: 6.01, N: 11.98.

Furthermore, 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 151-154°C isolated as the main by-product.

c) 3 g of L-alanyl-N-(2-benzoylphenyl)-N-methylglycinamide are dissolved in 10 ml of anhydrous sulfuric acid at room temperature. It obtained

the solution is cooled to -5° and added dropwise with a solution of 0.94 g of potassium nitrate in 3 ml of anhydrous sulfuric acid. The reaction mixture is stirred for 1 hour at 0°C and then allowed to stand overnight, whereby it warms to room temperature. The reaction mixture is then poured onto an excess of ice/water.

By adding concentrated ammonium hydroxide, the pH of the reaction mixture is set to approx. 9, whereby the temperature is kept at approx. 0°C. The reaction mixture is extracted several times with dichloromethane. The combined organic phases are washed continuously with 2N sodium carbonate solution and water, dried over anhydrous magnesium sulfate and evaporated in vacuo.

The residue is dissolved in a minimum amount of chloroform and the solution is chromatographed on a florisil column, whereby mixtures of ethanol in chloroform are used as flux. The fractions are collected in a 5% methanol solution in chloroform,

after which the solution is evaporated in vacuo. L-alanyl-N-(2-benzoyl-4-nitrophenyl)-N-methylglycinamide is obtained as

almost colorless, light-sensitive foam, / a/^^ = + 2.1° (c = 1

in ethanol),

Analysis for <C>19<H>20N4°5 (384.4o):

Calculated: C: 59.37, H: 5.25, N: 14.57.

Found: C: 59.94, H: 5.43, N: 14.17.

The free base thus obtained is dissolved in a minimum amount of methanol at room temperature and treated by titration with an exactly equivalent amount of 1N hydrochloric acid. From the solution obtained, the solvent is removed by evaporation in vacuo at room temperature and then by lyophilization, whereby L-alanyl-N-(2-benzoyl-4-nitrophenyl)-N-methylgycinamide hydrochloride is obtained as a white, amorphous solid with m.p. 165-175°C

(easy cleavage), /tt/2°= +7.5° ( c = 1 in water).

Analysis for C,.H_C1N,0C (42o.85):

19 21 4 5

Calculated: C: 54.23, H: 5.03, N: 13.31, Cl ionic: 8.42.

Found: C: 54.12, H: 5.3o, N: 13.o5, Cl ionic : 8.42

EXAMPLE 24

a) 2.0 g S-chloro-1-methyl-6-phenyl-4H-s-triazolo/4,3-a/_ /I,4/benzodiazepine /J.B. Hester Jr., A.D. Rudzic and B.V.

Kamdar, J. Med. Chem., 1971, 14, lo78/ is dissolved in 40 ml of dilute hydrochloric acid and left overnight at room temperature. The solution is evaporated to an oil, which is dissolved in

water and again evaporated. The last traces of water are removed by shaking the oil with 50% methanol/toluene and then evaporation. The treatment is repeated three times with 50% methanol/toluene and twice with toluene. 5-Chloro-2-(3-amino-methyl-5-methyl-4H~1,2,4-triazol-4-yl)benzophenone hydrochloride is obtained as a foam.

b) This foam is dissolved in 25 ml of dry dimethylformamide and 2.64 g of N-benzyloxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester is added to the resulting solution. The solution thus obtained is cooled to -2o°C. Over a period of 0.5 hours, a solution of 2.1 ml of N-ethylmorpholine in 8.4 ml of dimethylformamide is added with vigorous stirring. The resulting reaction mixture is stirred for 1 hour at -2o°C and then left overnight at room temperature. The solvent is removed in vacuo and the residue is dissolved in a mixture of dichloromethane and water. The phases are separated and the aqueous phase is extracted with additional dichloromethane. The organic phases are combined, washed 5 times with water, dried over magnesium sulfate and evaporated to an oil, which becomes chromato-

graphed on silica gel. The elution is first carried out with chloroform and then with a 2% methanol solution in chloroform.

15 ml fractions are collected. Fractions 1-25 contain chloroform eluate, while the desired product will be found in fractions 48-57. These latter fractions are combined, evaporated to dryness and the residue brought to crystallization from acetic acid/petroleum ether. 5-Chloro-2-[ ,/(N-benzyloxycarbonyl-L-phenylalanyl)aminomethyl]-5-methyl-4H-1,2,4-triazol-4-ylbenzophenone with mp 84-88°C is obtained.

c) o, 5o g of 5-chloro-2-:^/TN-benzyloxycarbonyl-L-phenylalanyl)-aminomethyl7-5-methyl-4H-1,2,4-triazol-4-yl3benzophenone becomes

in the course of 1 hour treated with a 35% solution of hydrogen bromide in glacial acetic acid. The solid precipitated after the addition of dry diethyl ether is filtered off, washed with ether and dried in vacuum. The crude product is purified by precipitation from methanol/acetic acid. One obtains 5-chloro-2-(3-(L-phenylalanyl-aminomethyl)-5-methyl-4H-1,2,4Ttriazol-4-yl7benzophenone-dihydrobromide with smo. 164-171 (slight cleavage).

Analysis for C 26 H 26 Br 2 ClN 5 C> 2 (635.79): Calcd: C: 49.12, H: 4.12, N: 11.02, Cl 5.58, Br: 25.14.

Found: C: 48.15, H: 4.14, N: lo,66, Cl: 5.32, Br: 24.52,

H 2 O: 1.83.

Anhydrous: C: 49.o5, H: 4.ol, N: lo.86, Cl: 5.42, Br: 24.98.

EKS EMPEL 25

In an analogous manner as in example 24, however using N<a>,N^-di-tertbutoxycarbonyl-L-lysine-N-hydroxysuccinimide ester, 5-chloro-2-(3-(L-lysylaminoethyl)-5-methyl- 4H-1,2,4-triazol-4-yl/benzophenone trihydrobromide as a lyophilized solid, /α/^'° = +11, o° ( c = 1 water) .

Analysis for C23H3Q<B>r3Cl02 (697.71):

Calculated:' C: 39.60, H: 4.33, N: 12.05, Br: 34.36.

Found: C: 38.23, H: 4.38, N: 11.55, Br: 33.4o, H 2 O: 2.58. Anhydrous: C: 39.24, H: 4.21, N: 11.86, Br: 34.28.

EKS EMPEL'26

In an analogous manner to example 24, 2',5-dichloro-2-(3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl/benzophenone dihydrobromide is obtained with m.p. . 188-193°C.

Analysis for Cn,H„cBr„C1.NC0_ (67o.25):

26 2b 2 2 b 2

Calculated: C: 46.59, H: 3.76, N: lo.45, Br: 23.84, Cl: lo.58. Found: C: 46,o2, H: 3,83, N: lo,o3, Br: 23,33, Cl: lo,35,

H2O: 1.9o.

Anhydrous: C: 46.91, H: 3.69, N: lo,22, Br: 23.78, Cl: lo,55.

EXAMPLE EL 27

2',5-dichloro-2-[3-(L-lysylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl/benzophenone hydrobromide ( 1:2.9) with m.p. 24o-245°C, / a7^ = + 9.8°

(c = 1 in water).

Analysis for C._,H„,C1 N 0„ . 2.9 HBr ( 724.o7 ):

. 23 2b 2 6 2

Calculated: C: 38.15, H: 4.o2, N: 11.61, Br ionic: 32.oo.

Found: C: 37.84, H: 4.13, N: 11.18, Br ionic: 31.3o,

H 2 O: 1.23.

Anhydrous: C: 38.31, H: 4.04, N: 11.32, Br ionic: 31.69.

EXAMPLE EL 28

By an analogous process as described in example 24, 21,5-dichloro-2-(3-glycylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone dihydrobromide methanolate is obtained with m.p. 235-24o°C. Analysis for c20H23Br2 C12N5°3 (612.15): Calcd: C: 39.24, H: 3.79, N: 11.44, Br: 26.11, Cl: 11.58. Found: C: 39.39, H: 3.67, N: 11.3o, Br: 26.lo, Cl: 11.58.

EXAMPLE 29

a) A solution of 200 g of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 2 L of tetrahydrofuran and 250 ml of benzene

is saturated with methylamine during dressing in an ice bath. An up-

solution of 190 g of titanium tetrachloride in 250 ml of benzene is then added over the course of 15 min. through a drop channel. After completion of the addition, the mixture is stirred and heated for 3 hours to reflux. Hereafter, 6oo ml of water is slowly added to the cooled mixture. The inorganic material is removed by filtration and washed well with tetrahydrofuran.

The aqueous phase is separated and the organic phase dried

over sodium sulfate and evaporated. The crystalline residue is collected to give 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine of m.p. 2o4-2o6°C. An analytical sample is recrystallized from methylene chloride/ethanol and shows m.p. 2o4-2o6°C. b) 8.63 g of sodium nitrite is added in three portions over a period of 15 min. to a solution of 30.15 g of 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine in 150 ml of glacial acetic acid. The reaction mixture is stirred for 1 hour at room temperature,

then diluted with water and extracted with methylene chloride. The extracts are washed with saturated sodium carbonate solution, dried over sodium sulfate and evaporated (finally azeotroped with toluene) and give crude 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethyl-amino)-3H-1, 4-benzodiazepine as yellow oil.

c) This oil is dissolved in loo ml of dimethylformamide and added to a mixture of 2oo ml of dimethylformamide, 5o ml of nitromethane

and 11.1 g of potassium tert.-butoxide, which is stirred for 15 min. under nitrogen. The reaction mixture is stirred for one hour at room temperature, acidified by the addition of glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts are washed with water,

dried over sodium sulfate and evaporated. Crystallization of the residue from diethyl ether gives 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine with m.p. 17o-172°C. An analytical sample is recrystallized from methylene chloride/ethanol and shows m.p. 174-176°C.

d) A solution of 16.5 g of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine in 500 ml of tetrahydrofuran and

25o ml of methanol is hydrated in the loop. of 2.5 hours at atmospheric pressure with 5 teaspoons of Raney nickel. Separation of the catalyst and evaporation gives crude 2-amino-methyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine.

e) 7 ml of acetic anhydride is added to a solution of

6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 206 ml of methylene chloride. The solution is overlaid with 200 ml of saturated sodium bicarbonate solution and the mixture is stirred for 20 min. The organic phases are separated. washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. Resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine is obtained. This product is heated with 4o g of polyphosphoric acid in the course of lo min. to 15o°C. The cooled mixture is dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts are dried and evaporated. The residue is chromatographed over 120 g of silica gel, whereby 20% methanol in methylene chloride is used as flux. The clear fractions are combined and evaporated. Resinous 8-chloro-3α,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazole/1,5-α7benzodiazepine is obtained. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide is heated to reflux over the course of 1.5 hours. The manganese oxide is separated by filtration over celite. The filtrate is evaporated and the residue crystallized from diethyl ether, whereby 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazole/1,5-α7/1,47benzodiazepine with m.p. 152-154°C. An analytical sample is recrystallized from methylene chloride/hexane. f) 2.0 g of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-/1,5-§7/1,47benzodiazepine is dissolved in 15 ml of dilute hydrochloric acid,

after which the solution is left overnight at room temperature. The oil obtained after evaporation of the solution is

dissolved in water and the aqueous solution is again evaporated.

The last traces of water are removed by shaking with 50% methanol/toluene followed by evaporation. This process is repeated 3 times with 50% methanol/toluene and twice with toluene. 5-chloro-2'-fluoro-2-(5-aminomethyl-2-methyl-1-imidazolyl)-benzophenone dihydrochloride is obtained as a pale yellow solid.

g) This solid is dissolved in 20 ml of dry dimethylformamide and 1.56 g of N-benzyloxycarbonyl-L-leucyl N-hydroxysuccinimide ester is added to the resulting solution. The solution is then cooled to -2o°C. In the course of a time of 2o min. a solution of 2.5 ml of N-ethylmorpholine in 10 ml of dimethylformamide is added dropwise with vigorous stirring. The mixture is stirred for 1 hour at -2o°C and then left overnight at room temperature. The solvent is removed in vacuo and the residue dissolved

in a mixture of chloroform and water. The phases are separated and the aqueous phase is further extracted with chloroform.

The organic phases are combined, washed five times with water, dried over magnesium sulfate and evaporated. The oil obtained is chromatographed on loo g silica gel, whereby 4% methanol in chloroform is used as eluent. There will be a total of 15

ml fractions. The desired product is eluted in fractions 25-36. These fractions are combined, evaporated to dryness and the resulting oil crystallized from ether. One obtains 5-chloro-2'-fluoro-2-in 5-[(i<*>N-benzyloxycarbonyl-L-leucyl)-amino-methyl7-1-imidazolyl]benzophenone with m.p. 63-75°C (decomposition). Analysis for C^H^ClFN^ (591.o9):

Calculated: C: 65.02, H: 5.46, N: 9.48.

Found: C: 64.66, H: 5.61, N: 9.19. h) o.40 g of 5-chloro-2'-fluoro-2-\,S-Z^N-benzyloxycarbonyl-L-leucyl)aminomethyl7-1-imidazolyl}benzophenone is treated

in the course of 45 min. with a 35% solution of hydrogen bromide in glacial acetic acid. After addition with dry diethyl ether, an oily solid is obtained. The product is precipitated from methanol/acetic acid, dissolved in water and freeze-dried. 5-Chloro-2'-fluoro-2-(1-leucylaminomethyl)-2-methyl-1-imidazolyl-7-benzophenone-dihydrobromide is obtained, α/2β = -5.5° (c = 0.27°8 in water).

Analysis for C24H28<B>r2ClFN4O2 (618.77):

Calculated: C: 46.59, H: 4.56, N: 9.o5, Br: 25.82.

Found: C: 44.93, H: 4.74, N: 8.56, Br: 25.04, H 2 O: 3.55. Anhydrous: C: 46.58, H: 4.5o, N: 8.87, Br: 25.96.

E XAMPLE 3o

in an analogous manner to example 29, 5-chloro-2'-fluoro-5-((TL-alanylaminomethyl)-2-methyl-1-imidazoly7benzophenone-dihydro-

bromide with m.p. 9o-llo°C (slight decomposition).

EXAMPLE 31

A) Preparation of the starting material:

20

18.3 g of N-benzyloxycarbonyl-L-phenylalanylglycine, [a]^ =

- 9.5 (c 1 in glacial acetic acid) was slurried in 600 ml of dry 1,2-dimethoxyethane and the slurry was cooled to -5°C. 4.95 g of N-methylmorpholine and 6.8 g of isobutyl chloroformate were added and the resulting mixture was stirred at -5°C to -10°C for 2 hours. Unreacted starting material and N-methylmorpholine hydrochloride filtered from under anhydrous conditions and the filtrate (stored -5°C to 0°C) was added portionwise over several hours to a refluxing solution of 19.5 g of 5-chloro-2-methylaminobenzophenone in 200 ml of dry 1 ,2-dimethoxyethane. The resulting solution was then stirred overnight under reflux.

The mixture was evaporated in vacuo and the residue taken up in 600 ml of ethyl acetate, washed three times with 150 ml of water each time and with 150 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to give 38.8 g of a dark yellow rubber. Column chromatography of this gum on Florisil using mixtures of benzene and methanol gave 9.5 g (32%) of pure (N-benzyloxycarbonyl-phenylalanyl)-N-(2-benzoyl-4-chloro jphenyl)-N-methylglycinamide as an almost colorless light sensitive brittle foam containing different proportions of L and D enantiomers; ft]<2>^ = -9.2° (c = 1 in ethanol).

Analysis for C^I^Cl^O,- (584 >1):

Calculated: C: 67.86, H: 5.18, N: 7.19, Cl: 6.07

Found: C: 6.7.97, H: 5.20, N: 6.99, Cl: 6.16

B) Removal of the protecting group:

5.84 g of the aforementioned (N-benyzyloxycarbonyl-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide was dissolved in 20 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the solution stirred at room temperature for 3 hours . 200 ml of dry diethyl ether was added. The solid that separated was collected and dissolved in 100 ml of water, treated with excess sodium carbonate and extracted with four 75 ml portions of diethyl ether. The combined diethyl ether extracts were then shaken with six 50 ml portions of 0.1-N acetic acid to separate the stronger basic products from the neutral and weaker basic by-products (5-chloro'-2-methyl-aminobenzophenone and 7-chloro'-1 ,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-ene resp.) The combined aqueous acidic solution was washed with 100 ml of diethyl ether, made basic with excess sodium carbonate and extracted with four 75 ml's portions of dichloromethane. The dichloromethane extracts were then combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. Thorough degassing in vacuo gave 3 g (67%) of pure phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-glycinamide as an almost colorless light-sensitive brittle foam containing various proportions of the L and D enantiomers:

[a]2^= -6.0° (c = 1 in ethanol).

Analysis for C25H24C1N303 (449.9):

Calculated: C: 66.74, H: 5.38, N: 9.34, Cl: 7.88

Found : C: 66.69, H: 5.45, N: 9.25, Cl: 8.10

C) The fission

2.25 g of the aforementioned phenylalanyl-N-(2-benzoyl-4-

chlorophenyl)-N-methylglycinamide was dissolved in 40 ml of hot isopropanol and treated with a solution of 1.6 g of D-(l)-di-paratoluoyl-tartaric acid in 40 ml of hot isopropanol. The resulting mixture was allowed to cool slowly to room temperature overnight and the white microcrystalline solid that separated was collected by filtration, washed with two 10 ml portions of isopropanol and dried in vacuo. The resulting salt (2.8 g) had a melting point of 205-206°C (decomposition); [a]<20>= -5.2° (c = 1 in N,N dimethylformamide). Repeated fractional recrystallization

from ethanol gave 1.6 g (38%) of pure L-phenylalanyl-N-(2-benzoyl-4-chloro phenyl)-N-methyl-glycinamide hydrogen D-(-)-di-paratoluoyl tartaric acid as a white microcrystalline solid with melting point 216-217°C (decomposition); [ct]<2>°= -6.6° (c = 1 in N,N-dimethylformamide).

Analysis for C45H42C1N30ii (836.3):

Kalk<ulert:> c. 64f63/ H. 5-06j N. 5>02, Cl: 4.24

Found: C: 64.56, H: 5.00, N: 4.84, Cl: 4.33.

The preceding salt was transferred into the free base as follows: 1 g of L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide hydrogen D-(-)-di-paratoluoyl tartaric acid was slurried in a strong stirred mixture of 75 ml water and 100 ml diethyl ether at room temperature while slowly adding approx. 24 ml of 0.1-N sodium hydroxide solution. When all the slurried material had dissolved, the mixture was allowed to settle, the diethyl ether solution was shaken with 50 ml of water and then with six 25 ml portions of 0.1-N acetic acid. The combined aqueous acidic solutions were washed with 50 ml of diethyl ether, made basic by an excess of sodium carbonate and extracted with four 50 ml portions of dichloromethane. The dichloromethane extracts were then combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. Primer degassing in vacuo gave in almost quantitative yield L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colorless light-sensitive

brittle foam; [a]<2>^= -11.6° (c = 1 in ethanol).

Analysis for C25H24C1N303 (449.9):

Calculated: C:66.74, H: 5.38, N: 9.34, Cl: 7.88

Found : C:66.71, H: 5.47, N: 9.23, Cl: 8.14.

The preceding free base was transferred into hydrochloride as follows: 4.5 g of L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide was dissolved in a minimum volume of methanol at room temperature and, by titration, treated with an exact equivalent 1-N-hydrochloric acid. The solvent was removed from the resulting solution by evaporation in vacuo at room temperature and finally by lyophilization, which gave in quantitative yield L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide hydrochloride as a hygroscopic white light-sensitive amorphous powder with melting point 130-150°C (slow decomposition); [a]2^ = + 41.7° (c = 1 in water)

Analysis for C25H25C12N3°2 (486-4);

Calculated: C: 61.74, H: 5.18, N: 8.64, Cl ion: 7.29

Found : C: 60.24 , H: 5.22, N: 8.30, Cl ion: 7.31

H20: 2.17

Anhydrous: C: 61.58, H: 5.08, N: 8.48, Cl ion: 7.47

Claims (4)

1. Analogy method for the production of therapeutically effective substituted phenylketones with the general formula h/ ori A means a nitrogen atom, which may be substituted with a methyl group/ and B means a carbonyl group and A and B together form the group with the formula wherein Ra means hydrogen, or lower alkyl X forms a nitrogen atom or the group C—R , where R<b> means hydrogen or lower alkyl R means halogen or nitro R"*" hydrogen or lower alkyl, R 2 an acyl residue derived from a naturally occurring amino acid (all these groups containing an asymmetric carbon atom possess the L or D,L configuration) and R^ means phenyl, halophenyl or 2-pyridyl, as well as acid addition salts thereof, characterized in that the protective groups present are removed from a compound of the general formula 1 3 wherein A, B, R, R and R have the above meaning and R<2>° means the acyl group of a naturally occurring amino acid, whereby all the occurring amino groups are present in protected form and all further functional groups, if necessary, also present in protected form (all these acyl groups, which possess an asymmetric carbon atom, possess the L or D,L configuration) or b) for the preparation of compounds of formula I, in which A means a nitrogen atom which may be substituted by methyl and B means a carbonyl group, R means nitro and R 2 the acyl group of a naturally occurring amino acid which is not affected by nitrating agents (all these groups ,containing an asymmetric carbon atom, possessing the L or D,L configuration) nitrates a compound of the general formula in which R ■i and R o have the meanings given above, R^ means hydrogen or methyl, and R means an acyl group derived from a naturally occurring amino acid, which is not affected by nitrating agents (all these groups, containing an asymmetric carbon atom, possess the L or D,L configuration) and, if desired, resolves a racemate of formula I in their optical isomers and isolates the L-isomer and/or, if desired, transfers an obtained free base into an acid addition salt or an obtained acid- addis ion salt is transferred in the free base or in another acid addis ion salt. 2. Method according to claim 1, characterized in that a compound of formula in which R, R1, R<20>, R<3> and R<4> have the meaning specified in claim 1 or in which R, R<1>, R<2>, R<3> and Ra have the meaning stated in claim 1, are used as starting material. 3. Method according to claim 1, characterized in that a compound with the general formula in which R, R1, R<2>, R<3>, Ra and R<2> have the meanings given in patent claim 1, are used as starting material. 4. Process according to claim 1 or 2, characterized in that L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide is prepared.