CH620900A5 - Process for the preparation of substituted phenylketones - Google Patents

Description

The present invention relates to the production of substituted phenyl ketones of the general formula

R1

A-B-CH-NH-R2

wherein either A represents a nitrogen atom which can be substituted by a methyl, cyclopropylmethyl, di (C1-C4) alkylaminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group or A and B together the group of the formula

Ra - C

N

N-cr

10th

45

50

55

60

65

mean in which Ra is hydrogen, lower alkyl or hydroxymethyl and X is a nitrogen atom or the group C-Rb, in which Rb is hydrogen, lower alkyl or hydroxymethyl, R is halogen, nitro or trifluoromethyl, R1 is hydrogen or lower alkyl, R2 is Means acyl residue of a naturally occurring amino acid, where all such acyl residues containing an asymmetric carbon atom have the L or D, L configuration, and R 3 denotes phenyl, halophenyl or 2-pyridyl,

and their acid addition salts. It should be noted that Formula I comprises compounds of the following general formulas:

R4

15

20th

25th

30th

35

xx

N-C <

0 = 0 Ri!.

CH-NH-R2

I.

Yes

R * - C

, ^ N

N

R

XX ^

- ^ S = 0 *

H-NH-R2

lb

40 and

Ra_c ^ N> Rb xc,

R3

CH-NH - R2

ic wherein R, R \ R2, R3, Ra and Rb have the meaning mentioned above and R4 is hydrogen, methyl, cyclopropylmethyl, di- (C1-C +) - alkylaminoethyl, methoxymethyl or hydroxyethyl.

The term "lower alkyl" used in this description means a straight or branched alkyl group with preferably 1 to 6 carbon atoms, such as. As 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 identified as R2 is preferably derived from a naturally occurring a-amino acid such as glycine or L- or D-, L-alanine, -leucine, -phenylalanine, -isoleucine, -serine, -lysine, -methionine, -proline and the like. Especially

5

620 900

preferred acyl groups are those derived from L-amino acids, especially L-phenylalanine or L-lysine. If R3 is phenyl or halophenyl, the preferred halogen for R is chlorine and if R3 is a 2-pyridyl group, the preferred halogen for R is bromine. The 5 halophenyl group identified as R3 comprises monohalo-phenyl groups, in particular o-halophenyl groups such as o-chlorophenyl or o-fluorophenyl, and dihalophenyl groups, preferably o, o'-dihalophenyl groups such as o, o'-dichlorophenyl. 10th

Preferred compounds of the formula Ia are those in which R is chlorine, bromine or nitro, R1 is hydrogen, R3 is phenyl, o-fluorophenyl, o-chlorophenyl or 2-pyridyl, and R4 is hydrogen, methyl, diethylaminoethyl or methoxymethyl . 15

Examples of compounds of the formula Ia are: L-phenylaIanyl-N- (4-bromo-2-picolinoyIphenyl) glycinamides,

Glycyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, L-leucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, 20

L-lysyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, L-isoleucyl-N- (4-bromo-2-picolinoylphenyl) glycine amide,

L-y-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycine

amide, 25

L-alanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, L-arginy] -N- (4-bromo-2-picolinoylphenyl) glycinamide, la-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycine amide,

Glycyl-N- (2-benzoyl-4-chlorophenyl) glycinamide, 30

Glycyl-N- (2-benzoyl-4-nitrophenyl) glycinamide,

L-prolyl-N- (2-benzoyl-4-nitrophenyl) glycinamide, glycyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycine amide,

L-Alanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycine-35

amide,

L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-glycinamide,

L-lysyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycine-

amide and * o

L-leucyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycine amide,

L-phenylalanyl-N- (2-benzoyl-4-nitrophenyl) glycinamide, L-arginyl-N- (2-benzoyl-4-chlorophenyl) glycinamide, L-alanyl-N- (2-benzoyl-4-nitrophenyl) glycinamide , 45

L-Alanyl-N- [2- (2'-fluorobenzoyl) -4-nitrophenyl] -

N-methylglycinamide and L-phenylylanyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-L-alaninamide.

Preferred compounds of the formula Ib are those in which R is chlorine, R1 is hydrogen, R3 is phenyl, o-chlorophenyl and Ra is methyl or hydroxymethyl.

Examples of compounds of the formula Ib are:

5 -Chlor-2- [3 - (L-phenylalanylaminomethyl) -5 -methyl-

4H-l, 2,4-triazol-4-yl] benzophenone, 55

5-chloro-2- [3- (L-lysylaminomethyl) -5-methyl-4H-l, 2,4-

triazol-4-yl] benzophenone, 2 ', 5-dichloro-2- [3- (L-phenylalanylaminomethyl) -5-methyl-4H-l, 2,4-triazol-4-ylibenzophenone, 2', 5-dichloro -2- [3- (L-lysylaminomethyl) -5-methyl-60

4H-1,2,4-triazol-4-yl] benzophenone and 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-methyl-4H-l, 2,4-triazol-4-yl) benzophenone.

Preferred compounds of the formula Ic are those in which R is chlorine, R1 is hydrogen, R3 is phenyl or o-fluoro-65-phenyl, Ra is methyl or hydroxymethyl and Rb is hydrogen.

Examples of compounds of the formula Ic are:

5-chloro-2'-fluoro-2- [5- (L-leucylaminomethyl) -

2-methyl-1-imidazolyl jbenzophenone and 5-chloro-2'-fluoro-2- [5- (L-alanylaminomethyl) -2-methyl-l-imidazolyl] benzophenone.

Substituted phenyl ketones, which have a certain structural similarity to the compounds of the formula I, are known from Belgian patents 605 327 and 757 598 and from German laid-open publications 2 233 682, 2 240 043 and 2 322 045. However, these known compounds do not contain the acyl residue of a naturally occurring amino acid which is characteristic of the compounds of the formula I.

The substituted phenyl ketones of the general formula I and their acid addition salts can be prepared according to the invention by using a compound of the general formula

R1

A-B-CH-NH-R

C = 0

20th

11

wherein A, B, R, R1 and R3 have the above meaning and R20 is the acyl residue of a naturally occurring amino acid, in which all amino groups present are in protected form and any other functional groups, if necessary, are also in protected form, all of which are such asymmetric carbon atom-containing acyl radicals which have the L or D, L configuration,

the protective group (s) present are removed and, if desired, a free base obtained is converted into an acid addition salt or an obtained acid addition salt into the free base or into another acid addition salt.

Compounds of the formula I, in which R1 and R3 have the above meaning, A denotes a nitrogen atom which can be substituted by a methyl, cyclopropylmethyl, di (C1-C4) -alkyl, aminoethyl, methoxymethyl or hydroxyethyl group, B a Carbonyl group means R means nitro and R2 means the acyl residue of a naturally occurring amino acid which is not adversely affected by nitrating agents, all such acyl residues containing an asymmetric carbon atom having the L or D, L configuration, and their acid addition salts can also be prepared thereby that you can from a compound of the general formula

CH-NH-R

21st

111

620 900

6

wherein R1 and R3 are as defined above, R4 is hydrogen, methyl, cyclopropylmethyl, di- (C1-C4) alkylaminoethyl, methoxymethyl or hydroxyethyl and R21 is the acyl residue of a naturally occurring amino acid which is not impaired by nitrating agents, in which all those present Amino groups are in protected form and any further functional groups, if necessary, are also in protected form, all of which have an asymmetric carbon atom and acyl radicals of this type which have the L or D, L configuration and remove the protective group (s) present, the compound obtained is nitrided and, if desired, a free base obtained is converted into an acid addition salt or an obtained acid addition salt into the free base or into another acid addition salt.

If desired, a racemic product obtained can be separated into its optical isomers and the L isomer isolated.

The amino groups present in the acyl group R20 in formula II and in the acyl group R21 in formula III can be protected by any protective group known in peptide chemistry. Particularly preferred amino protecting groups for the purposes of the present invention are aralkoxycarbonyl groups, in particular benzyloxycarbonyl groups, and tert-butoxycarbonyl groups. The amino protecting groups can also be formyl, trityl or trifluoroacetyl groups. Any carboxy or hydroxy group that may be present in the acyl group R20 or R21 can be protected by a conventional carboxy or hydroxy protecting group. A carboxy group can e.g. B. by transfer into an alkyl ester, such as. B. a tert-butyl ester, or an aralkyl ester, e.g. B. a benzyl ester are protected. Furthermore, a hydroxy group z. B. by an aralkoxy-carbonyl group, e.g. B. benzyloxycarbonyl, an alkanoyl group, e.g. B. acetyl, propionyl and the like, an aroyl group, e.g. B. benzoyl, an alkyl group, e.g. B. tert-butyl, or an aralkyl group, e.g. B. tert-butyl, or an aralkyl group, e.g. As benzyl, are protected. The protection of other functional groups which may be present in the acyl group R20 or R21 can be carried out in a manner known per se.

The protective group (s) present in the acyl group R20 or R21 is removed by methods known per se; this means methods which are in current use or which are described in the literature for the removal of protective groups. According to a preferred aspect of the present process, the acyl groups R20 and R21 carry a protective group which can be split off by hydrolysis. So z. B. can be an aralkoxy-carbonyl group, e.g. B. benzyloxycarbonyl, or a tertiary butoxycarbonyl group by treatment with a mixture of hydrogen bromide and acetic acid. The tertiary butoxycarbonyl group can also be treated with hydrogen chloride in an organic solvent, e.g. B. dioxane, or by treatment with trifluoroacetic acid. A benzyloxycarbonyl or tert-butoxycarbonyl group can also be removed by treatment with boron trichloride or boron tribromide in an inert organic solvent such as dichloromethane.

The nitration of a compound obtained by splitting off the protective group (s) from a compound of the formula III can be carried out according to methods known per se. So z. For example, the nitration can be carried out using alkali metal nitrate, advantageously potassium nitrate, in the presence of a strong mineral acid, preferably anhydrous sulfuric acid, or a strong organic acid, preferably anhydrous trifluoroacetic acid. The acyl group R21 in the compounds of the formula III is preferably derived from glycine or L- or D, L-alanine, valine, leucine, isoleucine, lysine, proline or aspartic acid.

A racemate of the formula I can be separated into the optical isomers by methods known per se; so z. B. 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 diastereoisomeric salts obtained.

The starting materials of Formula II can be prepared by a variety of methods.

So z. B. a starting material of formula II is obtained by using an amine of the general formula

R1

A-B-CH-NH

C = 0

wherein A, B, R, R1 and R3 has the meaning mentioned above, with a correspondingly protected amino acid or a reactive derivative thereof, condensed.

The condensation takes place according to methods known per se in peptide chemistry; e.g. B. after the mixed anhydride, azide, activated ester or acid chloride method.

According to one method, a corresponding amine of formula IV is reacted with an appropriately protected amino acid in which the terminal carboxy group is in the form of a mixed anhydride with an organic or inorganic acid. Advantageously, such an amino acid, which carries a free carboxy function, with a tertiary base such as tri (lower alkyl) amine, e.g. B. triethylamine or N-ethylmorpholine treated in an inert organic solvent such as tetrahydrofuran, dichloromethane or 1,2-dimethoxyethane and the salt obtained is treated at low temperature with a chloroformate, such as. B. the ethyl or isobutyl ester. The mixed anhydride thus obtained is then preferably reacted in situ with the amine of the formula IV.

According to another method, a suitable amine of the formula IV is reacted with a suitably protected amino acid in which the terminal carboxy group is in the form of an acid azide. The reaction is preferably carried out in an inert organic solvent, such as dimethylform amide or ethyl acetate, at a low temperature.

In a further method, a suitable amine of formula IV with a suitably protected amino acid in which the terminal carboxy group is in the form of an active ester (e.g. p-nitrophenyl, 2,4,5-trichlorophenyl or N-hydroxysuccinimide ester) is present, implemented. The reaction is conveniently carried out at about -20 ° C in an inert organic solvent such as dimethylformamide.

According to a further method, a suitable amine of the formula IV is reacted with a suitably 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.

On the other hand, starting materials of the formula II are obtained in which A is a nitrogen atom which is derived from methyl, cyclopro-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

620 900

pylmethyl, di- (C1-C ') - alkylaminoethyl, methoxymethyl or hydroxyethyl can be substituted, and B represents a carbonyl group, by reacting a compound of the general formula

R4

XX ""

c = o

R3

wherein R, R3 and R4 have the meaning mentioned above, with a suitably protected dipeptide or the reactive derivative thereof, using one of the methods mentioned above in connection with the reaction of an amine of the formula IV with a protected amino acid or a reactive derivative thereof .

The amines of the formula IV, in which A is a nitrogen atom which can be substituted by methyl, cyclopropylmethyl, di- (C1-C4) -alkylaminoethyl, methoxymethyl or hydroxyethyl and B is a carbonyl group, can, for. B. by reacting a compound of formula V with a suitably protected amino acid or a reactive derivative thereof and then removing the protective group in the manner described above.

On the other hand, amines of the formula IV in which A is a nitrogen atom which is substituted by a di- (C1-C4) -alkylaminoethyl group and B is a carbonyl group and / or R3 is 2-pyridyl or in which A and B together are one Group of formula i form by hydrolysis of a 1,4-benzodiazepine of the general formula

10th

NH - CH3

CH — R1

VII

wherein R, R1 and R3 have the meaning mentioned above and provide a compound of the formula

CH,

N-NO

25th

30th

35

CH — R1

VI

wherein A ', B', R, R1 and R30 have any of the meanings given for A, B, R, R1 and R3, with the exception that if A 'represents a nitrogen atom, which is represented by methyl, cyclopropylmethyl, methoxymethyl or hydroxyethyl may be substituted and B represents a carbonyl group, R30 represents 2-pyridyl,

can be obtained with mineral acid. A 1,4-benzodiazepine of the formula VI can thus be hydrolyzed 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 about 20-30 ° C.

The 1,4-benzodiazepines of the formula VI, in which A 'and B' together form group i, in which X represents C-Rb, do not form the subject of the present invention, but their preparation is mentioned for the sake of completeness. These connections can e.g. B. be prepared by nitrosifying a compound of the general formula vm wherein R, R1 and R3 have the meaning mentioned above.

The nitrosation can be carried out using nitrous acid formed in situ. Suitable reagents for this purpose include alkali metal nitrites, e.g. B. sodium nitrite, in the presence of an inorganic or organic acid, e.g. B. glacial acetic acid, and an aqueous or non-aqueous solvent; Alkyl nitrites, e.g. B. methyl nitrite in the presence of an inert solvent such as an alkanol, a halogenated hydrocarbon or dimethylform amide; and a solution of nitrosyl chloride gas in a 40 inert solvent and in the presence of an acid acceptor, e.g. B. pyridine. Such nitrosation should be carried out at a temperature below room temperature, e.g. B. a temperature in the range of -20 to 25 ° C.

It should be noted that the group —N (CH3) (NO) in the 2-45 position of a compound of formula VIII represents a leaving group and that other equivalent leaving groups may be present in this position. Examples of such equivalent leaving groups include groups such as alkoxide groups such as -OCH3, alkylthio groups such as -SCH3 and such phosphate groups as

55

60

65

Reactions to form alkoxide and alkylthio groups are well known; see. e.g. B. G. A. Archer and L. H. Sternbach, Journal of Organic Chemistry, 29, 231 (1964) and U.S. Patent No. 3,681,341.

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

Rb'-

• CH-

, 2 — NO2

where Rb 'is hydrogen or lower alkyl,

implemented and provides a compound of the general formula

IX

620 900

8th

C — Rb '

CH — R1

10th

wherein R, R1, R3 and Rb 'have the meaning mentioned above.

The reaction of a compound of formula VIII with a nitroalkane of formula IX, e.g. B. nitromethane, nitroethane, etc., is carried out in the presence of a base which is strong enough to generate the nitroalkanion. Suitable bases include alkali metal and alkaline earth metal alkoxides, e.g. Potassium tert-butoxide, amides, e.g. B. lithium amide, and hydrides, e.g. B. sodium hydride. The reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethyl sulfoxide or an ether, e.g. B. tetrahydrofuran, at a temperature below or above room temperature, e.g. B. in the range of -50 to 150 ° C, preferably at about room temperature.

A compound of formula X is then catalytically hydrogenated (e.g. using hydrogen in the presence of Raney nickel) or reduced using a reducing agent such as lithium aluminum hydride to provide a compound of general formula

NHo

H! "B., CH — Rb

XI

wherein R1, R3 and Rb 'have the meaning mentioned above and R' is halogen, amino or trifluoromethyl.

The above-mentioned meaning of R 'in formula XI results from the conversion of a nitro group into an amino group under the conditions which are used for the reduction of a compound of formula X.

Suitable solvents for hydrogenation in the presence of Raney nickel include alkanols, e.g. B. ethanol, ether, e.g. B. tetrahydrofuran, diethyl ether, etc., hydrocarbons, e.g. B. toluene, and dimethylformamide. The catalytic hydrogenation is carried out at a temperature above or below room temperature, e.g. B. at -50 to 150 ° C performed.

This catalytic hydrogenation can be carried out with or without pressure, at atmospheric pressure or above.

Suitable solvents for reduction using a reducing agent such as lithium aluminum hydride include ethers such as tetrahydrofuran, dioxane and diethyl ether, and mixtures of ethers and hydrocarbons such as tetrahydrofuran and benzene. This reduction can take place at a temperature from below room temperature to

Reflux temperature of the reaction mixture, preferably at a temperature in the range of -50 to 60 ° C, are carried out.

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) to form the group Ra'CO— in which Ra 'is hydrogen or lower alkyl , and provides a compound of the general formula

NH — COR3 '

15

20th

25th

30th

35

40

45

1

CH — Rb xc

—CH ^

CH- /

Xll

R3

wherein R \ R3, Ra 'and Rb' have the meaning mentioned above, R 'has the meaning as in formula XI and Y represents a hydrogen atom or the group Ra'CO—.

Acylation of a compound of Formula XI can provide a mixture consisting primarily of the monoacylated product, i.e. H. the product in which the amino group was converted to the -NH-CORa 'group and the di-acylated product in which both the amino group and the nitrogen atom are acylated in the 1-position. The yield of diacylated product can be increased by subjecting the compound of Formula XI to more rigorous conditions, i. H. Use of excess acylating agent and prolonged acylation time.

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

A compound of the formula XII then becomes a compound of the formula

N

50

55

Ra —C CH— Rb

^ N-ch

R3

Xill

60

wherein R \ R3, Ra 'and Rb' have the meaning mentioned above and R 'has the meaning given for formula XI, cyclizes.

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. B. an organic or inorganic acid such as concentrated sulfuric acid.

9

620 900

A solvent is not required per se, but a solvent such as an aromatic hydrocarbon, e.g. As toluene or xylene can be used. The cyclization is carried out at a temperature of approximately 100 to 200 ° C.

A compound of the formula XI can also be reacted with an acylating agent, such as an orthoester (e.g. triethylorthoacetate), an orthoamide (e.g. N, N-dimethylformamide-dime-thylacetal) or tris (dimethylamino) methane, if desired, acylated 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 at temperatures above room temperature (e.g. 25 to 150 ° C), wherein the cyclization to a compound of formula XIII occurs spontaneously. Other acylating agents that can be used include esters (e.g. methyl acetate), amides (e.g. acetamide), nitriles (e.g. acetonitrile) and ester imidates.

A compound of formula XIII then becomes an imidazobenzodiazepine of the general formula

H

N - C

^ C-cooch3

CH— R1

XV

wherein R, R1 and R3 has the meaning mentioned above, which is then refluxed with methanolic potassium hydroxide in a compound of the general formula

H ^ CH-COOCH3 N-C ^

N -,

10th

20th

25th

30th

XVi wherein R, R1 and R3 have the meaning mentioned above, is transferred. After treatment with nitrous acid (e.g. by adding sodium nitrite to a solution of a compound of formula XVI in glacial acetic acid), a compound of general formula

NOH

II

C-COOCH3

^ w -

N =

\

c czz

1

N /

1

R3

XVII

wherein R1, R3, Ra 'and Rb' have the meaning mentioned above and R 'has the meaning given for formula XI, dehydrates.

The dehydrogenation of a compound of formula XIII is preferably carried out using manganese dioxide or palladium-carbon, although potassium permanganate can also be used. Halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide can be used as solvents. etc. can be used. The dehydrogenation is carried out at room temperature or at a temperature above room temperature, e.g. B. in the range of about 25 to 200 ° C, performed.

The process described above can be carried out starting from compounds of the formulas X or XI without isolating any other intermediate products.

Compounds corresponding to formula XIV, but in which Rb 'denotes hydroxymethyl, can be prepared as follows:

A compound of the formula VIII or a corresponding phosphate is reacted with dimethylmalonate under the conditions mentioned above for the reaction for these compounds with a nitroalkane of the formula IX, giving a compound of the general formula

COOCH,

35

wherein R, R1 and R3 have the meaning mentioned above, which then catalytically (z. B. in the presence of Raney nickel) to a compound of the general formula

40

45

50

55

XVIII

wherein R, R1 and R3 have the meaning mentioned above, is hydrogenated, which then with an orthoester of the general formula

Ra, C (OC2H5) 3 XIX

where Ra 'has the meaning mentioned above,

is implemented and a compound of the general formula

60

620 900

10th

where R ', R1, R3 and Ra' have the meaning given above. The carbomethoxy group in the 3-position of a compound of formula XX can be converted into the hydroxymethyl group by treatment with lithium aluminum hydride.

l-Hydroxymethyl-4H-imidazo [1,5-a] [1,4] benzodiazepines can be prepared from corresponding 1-methyl compounds. By treating with an N-oxide donor such as m-chloroperbenzoic acid, three different N-oxides, namely 5-oxide, 2-oxide and 2,5-di-oxide, can be obtained, which can be separated by chromatography . The 2-oxide function can be selectively rearranged with acetic anhydride and provides a 1-acetoxymethyl-2-deoxy compound. To produce this 1-acetoxy-methyl-2-deoxy compound, it is not necessary to separate the 2-oxide and the 2,5-dioxide, since the 5-oxide function of a product obtained by selective rearrangement of a 2,5-dioxide was reduced by phosphorus trichloride. The acetoxymethyl group in the 1-position of a compound thus obtained can easily be converted into the hydroxymethyl group, e.g. B. by treatment with sodium trioxide in methanol.

It should be noted that when acylating a compound of formula XI or XVIII wherein R 'is an amino group, that amino group can be acylated to acylamino group. An acylamino group can be converted back to the amino group by mild hydrolysis. It should also be noted that compounds in which R 'represents an amino group can be converted into corresponding nitro compounds by the known Sandemeyer reaction; see. e.g. B. E. R. Ward, C. D. Johnson, and J. G. Hawkins, J. Chem. Soc., 894 (1960).

The starting materials of formula III can be prepared in the same manner as previously described for the preparation of the corresponding compounds of formula II, but corresponding compounds in which R is hydrogen are used.

The compounds of the formula I form with inorganic acids (for example hydrohalic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid) and with organic acids (for example 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, i, 2-diethansulfonic acid, etc.) acid addition salts. The pharmaceutically acceptable acid addition salts are preferred. The acid addition salts can be prepared by methods known per se, e.g. B. by treating the base with a suitable acid. An addition salt can be converted to another acid addition salt by treatment with a suitable anion exchanger (e.g. Amberlit IRA-401 in the chloride form).

The compounds of formula I and their acid addition salts have sedative, muscle relaxant and anticonvulsant activity. Of particular interest are those pharmaceutically acceptable acid addition salts which are water soluble since they can be administered very easily by injection, e.g. B. in dentistry to initiate anesthesia and in the treatment of acute convulsive conditions and in the case of status epilepticus.

The anticonvulsant activity of the substituted phenyl ketones of the present invention can be demonstrated by administering these compounds to mice, which are then subjected to the known pentatetramethylene tetrazole test. In this test, L-phenylaIanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide hydrobromide, which has an LDS0 of 70 mg / kg i. v. (Mouse) has an EDS0 of 2.0 mg / kg i. v. (Mouse). Also in this test shows 5-chloro-2'-fluor2- [5- (L-leucylaminomethyl) -2-methyl-l-imidazolyl] benzophe-non, which has an LD50 of 119 mg / kg i. v. (Mouse) has an ED 50 of 2.0 mg / kg i. v. (Mouse). The muscle-relaxing activity can be shown in the well-known rotarod test. In this test, L-phenylaIanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide hydrobromide showed an ED50 of 4.2 mg / kg i. v. (Mouse). Also in this test, 5-chloro-2'-fluoro-2- [5- (L-leucylaminomethyl) -2-methyl-l-imidazolyl] benzophe-non shows an ED50 of 20 mg / kg i. v. (Mouse).

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, e.g. B. in the form of pharmaceutical preparations which they contain together with a pharmaceutically acceptable carrier material. This carrier material can be an organic or inorganic carrier material which is suitable for enteral or parenteral administration, e.g. As water, lactose, gelatin, starches, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. B. as tablets, dragees, capsules, etc., or in liquid form, for. B. solutions, suspensions or emulsions. Pharmaceutical preparations which are adapted for injection purposes are preferred. Pharmaceutical preparations can be subjected to conventional pharmaceutical operations, such as sterilization and / or can contain conventional pharmaceutical auxiliaries, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.

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

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

example 1

a) 100 g of 7-bromo-l, 3-dihydro-5- (2-pyridyl) -2H-l, 4-benzodiazepin-2-one are dissolved in 750 ml of 2N hydrochloric acid and left overnight at room temperature. The solution is evaporated to an oil, which is dissolved in water, and then 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 50 ° C. in vacuo. The product was characterized by its spectral data; by titration, it was found to contain 1 mol of 2-amino-N- (4-bromo-2-picolinoylphenyl) acetamide per 2.5 mol of hydrochloric acid. After prolonged drying over sodium hydroxide, an analytical sample was obtained which was stoichiometric.

Analysis for Ci4H14BrCl2N302 (407.11):

Calc .: C 41.31 H 3.47 N 10.32 Br 19.63 Cl 17.42

Found: C 41.02 H 3.61 N 10.11 Br 20.08 Cl 17.82.

b) 7.24 g of N-benzyloxycarbonyl-L-phenylalananine N-hydroxysuccinimide ester are dissolved in 80 ml of dimethylformamide and the solution is cooled to −20 ° C., after which 8.48 g of the dihydrochloride obtained in accordance with paragraph a) are added. 6.16 ml of N-ethylmorpholine are then added over a period of 0.5 hours with vigorous stirring. The reaction mixture obtained is then at −20 ° C. for a further hour and then at overnight

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Room temperature stirred. The solvent is evaporated in vacuo and the residue is dissolved in a chloroform / water mixture. 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 gives (N-benzyloxycarbonyl-L-phenyl-ala-nyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide with a melting point of 157-183 ° C. (slight decomposition).

Analysis for C31H27BrN405 (615.50):

Calc .: C 60.49 H 4.42 N 9.10 Found: C 60.44 H 4.41 N 8.90.

c) 4.0 g of (N-benzyloxycarbonyl-L-phenylaIanyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide are stirred for 1 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 vacuo. The crude product obtained is dissolved in a minimum amount of dry methanol and treated with ethyl acetate, the product precipitating. L-phenylalanyl-N- (4-bromo-2-picolinoylphenyl) glycino-amide dihydrobromide of melting point 182 ° C. (decomposition) is obtained; [alo20 = + 28.4 ° (c = 1 in water).

Analysis for C23H23Br3N403 (643.20):

Calc .: C 42.95 H 3.60 N 8.71 Br 37.27 Found: C 42.53 H 3.68 N 8.35 Br 37.04.

d) 2 g of this dihydrobromide are dissolved in 10 ml of water, after which dilute ammonium hydroxide solution is slowly added with stirring until the solution is basic. The precipitated yellow oil crystallizes on standing. The product obtained is filtered off, washed with water, dried in vacuo and recrystallized from ethanol / water. In this way, the free base L-phenylalanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide with a melting point of 60 ° C. (decomposition) and an optical rotation of [alo20 = + 26.7 ° (c = 1 in In hydrochloric acid).

Analysis for C23H21BrN403 (481.36):

Calc .: C 57.39 H 4.40 N 11.64 Br 16.60

Found: C 56.96 H 4.42 N 11.48 Br 16.42.

Example 2

Glycyl-N- (4-bromo-2-picolinoyl) glycinamide with a melting point of 97-100 ° C. is obtained in an analogous manner to that in Example 1.

Analysis for Ci6H15BrN403 (391.23):

Calc .: C49, II H 3.87 N 14.32 Br 20.42

Found: C 48.95 H 3.92 N 14.15 Br 20.55.

Example 3

In an analogous manner as in Example 1, L-lysyl-N- (4-bromo-2-picolinoylphenyl) glycinamide trihydrobromide of melting point 220 ° C. (decomposition); [a] D20 = + 16.8 ° (c = 1 in water).

Analysis for C2oH27Br4N503 (705.11):

Calc .: C 34.07 H 3.86 N 9.93 Br 45.34

Br ionic 34.00 Found: C 34.29 H 4.25 N 9.73 Br 44.60

Br ionic 33.32 H20 0.96.

Anhydrous: C 34.62 H 4.18 N 9.82 Br 45.03 Br ionic 33.64.

Example 4

a) 3.18 g of N-benzyloxycarbonyl-L-isoleucine are dissolved in 25 ml of dry tetrahydrofuran and cooled to -10 ° C. Then 1.57 ml of isobutyl chloroformate and 1.52 ml of N-ethylmorpholine are added and the resulting solution is stirred at -10 ° C for 20 minutes. 4.24 g

2-Amino-N- (4-bromo-2-picolinoylphenyl) acetamide dihydrochloride (prepared as described in paragraph a) of Example 1) are added and the suspension obtained is cooled to -20 ° C. With vigorous stirring, 3.13 ml of N-ethylmorpholine in 25 ml of dimethylformamide are added over a period of 0.5 hours. The mixture obtained is stirred for a further 40 minutes at -20 ° C. and then left to stand at room temperature overnight.

The product obtained is worked up in an analogous manner to that described in paragraph b) of Example 1. By recrystallization from ethanol (N-benzyloxycarbonyl-L-isoleucyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide with a melting point of 174-176 ° C.

Analysis for C28H29BrN4Ö5 (581.48):

Calc .: 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 (N-benzyloxycarbonyl-L-isoleucyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide are stirred in a solution of 35% hydrogen bromide in glacial acetic acid for 1 hour. The solid precipitated after the addition of diethyl ether is filtered off, washed with diethyl ether and dried in vacuo. Two precipitations from methanol / ethyl acetate yield L-isoleucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide dihydro-bromide with a melting point of 174 ° C. (decomposition).

c) 1 g of this dihydrobromide is dissolved in 10 ml of water, whereupon the solution is made basic with stirring by adding dilute ammonium hydroxide solution. The oil obtained crystallizes on standing. The crystals are filtered off, washed with water and dried in vacuo and give the free base L-isoleucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide, which begins to melt at 54 ° C. with slight decomposition; [u] D20 = + 29.6 ° (c = 1 in hydrochloric acid).

Analysis for C2oH23BrN403 (447.34):

Calc .: C 53.70 H 5.18 N 12.52 Br 17.87 Found: C 52.97 H 5.23 N 12.26 Br 17.85 H20 1.75.

Anhydrous: C 53.37 H 5.18 N 12.35 Br 17.98.

Example 5

Using a procedure analogous to that in Example 4, but using Na-benzyloxycarbonyl-L-arginine-monohydro-drobromide, L-arginyl-N- (4-bromo-2-picolinoylphe-nyl) glycinamide trihydrobromide hydrate is obtained as a lyophilized solid; [a] d20 = + 10.9 ° (c = 1 in water).

Analysis for C2oH29Br4N704 (751.14):

Calc .: C 32.00 H 3.89 N 13.05 Br ionic 31.92

Found: C 31.85 H 3.88 N 13.00 Br ionic 32.20.

Example 6

In an analogous manner as in Example 4, but using N-benzyloxycarbonyl-L-glutamic acid y-tert. butyl ester gives a-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycinamide hydrobromide (1: 1.85) with a melting point of 153-170 ° C. (slight decomposition); [a] D20 = + 20.0 ° (c = 1 in water).

Analysis for C19H19BrN405 • 1.85 HBr (612.98):

Calc .: 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 H20 1.28.

Anhydrous: C 37.16 H 3.59 N 8.75 Br 37.02.

Example 7

a) Using an analogous procedure as in paragraph a) of Example 4, (Na, NE-di-tert-butoxycarbonyl-L-lysyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide with a melting point of 135-137 ° C.

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Analysis for C3oH4oBrNs07 (662.59):

Calc .: C 54.38 H 6.09 N 10.57 Br 12.06 Found: C 54.33 H 5.87 N 10.34 Br 12.24.

b) 1.0 g (NQ, Ne-ditertbutoxycarbonyl-L-lysyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide is stirred for 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 precipitated with ethyl acetate. The precipitate is dissolved in 20 ml of water and, after extraction with chloroform, the aqueous solution is lyophilized and gives L-lysyl-N- (4-bromo-2-picolinoylphenyl) glycinamide trihydrochloride 1.5 H 2 O; [alD20 = + 20.1 ° (c = 1 in water).

Analysis for C20H27BrCl3N5O3 • 1.5 H20 (598.76): Calc .: C40.12 H 5.05 N 11.70 Cl 17.76 Found: C 40.27 H 4.92 N 11.57 Cl 17, 62.

Example 8

In an analogous manner as in Example 4, L-y-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is obtained, melting point 158-161 ° C. (decomposition); [a] D20 = + 121.1 ° (c = 1 in hydrochloric acid).

Analysis for C ^ H ^ BrNiOs (463.30):

Calc .: C 49.26 H 4.13 N 12.09 Br 17.25 Found: C 48.26 H 4.40 N 11.94 Br 17.35 H20 1.24.

Anhydrous: C 48.87 H 4.31 N 12.09 Br 17.57.

Example 9

L-Alanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide of melting point 76-78 ° C. is obtained in an analogous manner to that in Example 1; [«] D20 = + 17.4 ° (c = 1.0225 in methanol).

Analysis for Ci7H17BrN403 (405.26):

Calc .: 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 10

a) 6.56 g of tert-butoxycarbonyl-L-leucyl-N-hydroxysuccin imide ester are dissolved in 80 ml of dimethylformamide, and the solution is cooled to -20 ° C. 8.48 g of 2-amino-N- (4-bromo-2-picolinoylphenyl) acetamide dihydrochloride are then added. 6.16 ml of N-ethylmorpholine are then added to the suspension over a period of 30 minutes with vigorous stirring. The reaction mixture is then stirred at −20 ° C. for a further hour and then at room temperature overnight.

Working up is carried out in the same manner as described in paragraph b) of Example 1. The oil obtained is crystallized from a mixture of methanol water and recrystallized from the same solvent and gives pure (N-tert-butoxycarbonyl-L-leucyl) -N- (4-bromo-2-picolinoyl-phenyl) glycinamide with a melting point of 129-132 ° C.

Analysis for C2sH31BrN40s (547.46):

Calc .: C 54.85 H 5.71 N 10.23 Br 14.60 Found: C 54.73 H 5.83 N 10.02 Br 14.95.

b) 2.0 g (N-tert-butoxycarbonyl-L-leucyl) -N- (4-bromo-2-picolinoyIphenyl) glycinamide are stirred for 1 hour in a 4N solution of hydrogen chloride in dioxane. The solid precipitated after the addition of ethyl acetate is filtered off, washed with ethyl acetate and dried in vacuo. The solid is dissolved in a minimum amount of methanol and precipitated by adding ethyl acetate to give L-leucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide hydrochloride.

c) The hydrochloride is dissolved in 50 ml of water and the solution is made basic while stirring by slowly adding a dilute ammonium hydroxide solution. The precipitated yellow oil crystallizes on standing. The product is filtered off, washed with water and dried in vacuo. L-Leucyl-N- (4-bromo-2-picolinoyl) glycine amide with a melting point of 53 ° C. (decomposition) is obtained; [a] D20 = + 26.0 ° (c = 1 in hydrochloric acid).

Analysis for C20H23BrN4O3 (447.34):

Calc .: C 53.70 H 5.18 N 12.52 Found: C 53.35 H 5.14 N 12.21 H20 1.32.

Anhydrous: C 54.06 H 5.06 N 12.37.

Example 11

a) 15.9 g of N-benzyloxycarbonylglycylglycine are suspended in 600 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 reaction mixture obtained is stirred at -5 to -10 ° C. for 2 hours. Unreacted starting material and N-methylmorpholine hydrochloride are separated by filtration and the solution (kept at -5 to 0 ° C) is portioned over a period of several hours to a refluxed solution of 14.7 g of 5-chloro-2 -methyl aminobenzophenone in 200 ml of dry 1,2-dimethoxyethane. The solution obtained is then stirred under reflux overnight.

b) The reaction mixture is evaporated in vacuo and the residue is taken up in 600 ml of ethyl acetate. The solution is washed three times with 150 ml of water and with 150 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated to a yellow gum. Column chromatography of this gum on Florisil using mixtures of benzene and methanol as a flow agent gives pure (N-benzyloxycarbonyIglycyl) -N- (2-benzoyl-4-chirophenyl) -N-methylglycinamide as an almost colorless, light-sensitive gum, which was characterized by spectroscopy and elemental analysis.

Analysis for C26H24C1N3Os (493.95):

Calc .: C 63.23 H 4.90 N 8.51 C17.18 Found: C 63.61 H 4.87 N 8.37 Cl 7.02.

c) 9.87 g of (N-benzyloxycarbonylglycyl) -N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide are dissolved in 50 ml of glacial acetic acid and treated with 50 ml of a 30% solution of hydrogen bromide in glacial acetic acid. The solution obtained is stirred for 1 hour at room temperature and the solid which has precipitated out after treatment with an excess of dry diethyl ether is washed several times with dry diethyl ether and then dried in vacuo. The hydroscopic solid thus obtained mainly consists of glycyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide hydrochloride with a melting point of 140-150 ° C. (decomposition).

Analysis for Ci8H18ClN303 • 1.2 HBr (456.9):

Calc .: C 47.32 H 4.24 N 9.20 Br ionic 20.99 Found: C 46.86 H 4.59 N9.ll Br ionic 20.70.

d) 4.6 g of this crude hydrobromide are purified by dissolving in 100 ml of 0.2N 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, provides glycyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide as an almost colorless, light-sensitive glassy foam, which is characterized by spectroscopy.

Example 12

In a manner analogous to that in paragraphs a) and b) of Example 11, (N-benzyloxycarbonylglycyl) -N- (4-bromo-2-picolinoylphenyl) glycinamide of melting point 139-141 ° C. (from ethanol) is obtained.

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In a manner similar to that in paragraphs c) and d) of Example 11, (N-benzyloxycarbonylglycyl) -N- (4-bromo-2-pico-linoylphenyl) glycinamide is converted into glycyl-N- (4-bromo-2-picolinoyl- phenyl) glycinamide from melting point 97-100 ° C transferred.

Example 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-methylmorphopholine and 13.7 g of isobutyl chloroformate are added and the solution obtained is stirred at -20 ° C. for 1 hour and then filtered. The filtrate (kept at -10 to 0 ° C.) is added in portions over a period of several hours to a solution of 24.55 g of 5-chloro-2-methylaminobenzophenone in 200 ml of 1,2-dimethoxyethane heated to reflux. The reaction mixture obtained is boiled overnight and then concentrated to dryness in vacuo. The yellow residue is dissolved in ethyl acetate, washed with two parts of water and one part of saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then evaporated in vacuo. Column chromatography of this residue on Florisil using mixtures of benzene and chloroform as flow agent gives pure 2- (N-benzyloxycarbonylamino) -N- (2-benzoyl-4-chlorophenyl) -N-methylacetamide as a pale yellow gum.

Analysis for C24H21C1N204 (436.9):

Calc .: 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-benzoyI-4-chlorophenyl) -N-methylacetamide are dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the reaction mixture obtained is overnight stirred at room temperature. The mixture is slowly added to a large excess (2000 ml) of dry diethyl ether, with vigorous stirring. The excreted product is separated by decanting away the solvents. The residue is triturated with 150 ml of acetone, filtered off, washed continuously with a minimum amount of acetone and dry diethyl ether and then dried in vacuo, giving 2-amino-N- (2-benzoyl-4-chlorophenyl) -N-methylacet-amide - contains hydrobromide as a white hydroscopic powder with a melting point of 194-195 ° C (decomposition).

Analysis for Ci6Hi6BrClN2Ò2 (383.7):

Calc .: C 50.10 H 4.21 N 7.30 Br ionic 20.83

Found: C 49.98 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 -20 ° C. The stirred suspension is treated in portions with 90 g of phosphorpene tachloride over a period of 15 minutes, after which stirring is continued until a clear solution is obtained. The cold mixture is then added in portions over a period of 30 minutes to a cold (-5 ° C.) vigorously stirred emulsion consisting of 82 g of 5-chloro-2-methylaminobenzophenone, 347 g of potassium bicarbonate, 700 ml of chloroform and 1400 ml of water . The resulting mixture is stirred for an additional hour at -5 ° C and then overnight at room temperature. The stirring is then stopped, whereupon the liquid phases separate. The chloroform phase is three times with

Washed 500 ml of water and evaporated in vacuo. A viscous yellow gum is obtained which, as has been 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 650 ml of a 30% solution of hydrogen bromide in glacial acetic acid and in a similar manner to that in paragraph a)

Example treated, giving 2-amino-N- (2-benzöyl-4-chlorophenyl) -N-methylacetamide hydrobromide.

e) 3.96 g of N-benzyloxycarbonyl-L-phenylalanine N-hydroxy-succinimide ester are dissolved in 50 ml of dry dimethylformamide. The solution obtained is cooled to -20 ° C., whereupon 3.84 g of 2-amino-N- (2-benzoyl-4-chlorophenyl) -N-methylacetamide hydrobromide are added and then 1.15 g of N-ethylmorpholine is added dropwise . The reaction mixture obtained is stirred vigorously at -20 ° C. for 1 hour and then at room temperature overnight. 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 further parts of dichloromethane. The combined organic phases (250 ml) are washed three times with 50 ml of water, dried over anhydrous magnesium sulfate and evaporated in vacuo. 5.8 g of a yellow oil are obtained, which, as was shown by physical methods, from a mixture of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine -2-one and (N-benzyloxycarbonyl-L-phenylalanyl) -N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide in an approximate ratio of 1: 3.

f) The mixture mentioned can be purified by column chromatography on Florisil and gives pure (N-benzyl-oxycarbonyl-L-phenylalanyl) -N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide as an almost colorless, light-sensitive brittle foam; [a] D20 = -13.6 ° (c = 1 in ethanol).

Analysis for C33H30CIN3O5 (584.1):

Calc .: 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 mixture mentioned above can be subjected directly to the deprotection as follows:

g) 5.8 g of the above-mentioned mixture are 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 four 75 ml portions of diethyl ether. The combined ether extracts are then shaken out with six 50 ml portions of 0.1 l acetic acid in order to separate the more basic products from the less basic by-products (the ben-zodiazepin-2-ones). The combined aqueous-acidic solutions are washed with 100 ml of diethyl ether, made basic 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 provides pure L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide as an almost colorless, light-sensitive brittle foam; [a] D20 = -11.6 ° (c = 1 in ethanol).

Analysis for C25H24C1N303 (449.9):

Calc .: 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 (H -) - tartaric acid in warm isopropa-nol gives colorless crystals of hydrogen (+) - tartrate with a melting point of 198-200 ° C.

Analysis for C29H30CIN3O9 (600.00):

Calc .: C 58.05 H 5.04 N 7.00 Cl 5.91 Found: C 58.32 H 4.98 N 6.73 CI 5.90.

i) 5.8 g of the aforementioned mixture are dissolved in 75 ml of dry nitromethane, whereupon a weak stream of hydrogen bromide is passed through the solution for 10-15 minutes.

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The solution is then stirred at room temperature for 2 hours and then treated with an excess of dry diethyl ether. The precipitated solid is treated in the same way as in paragraph b) of this example and gives L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide.

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

j) 4.5 g of L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide are dissolved in a minimal amount of methanol at room temperature and treated by titration with an exactly equivalent amount of In hydrochloric acid. The solvent is removed from the solution obtained by evaporation in vacuo at room temperature and finally by lyophilization, L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide hydrochloride as the hygroscopic, white light-sensitive amorphous powder with a melting point of 130-150 ° C (easy decomposition); [a] D20 = + 41.7 ° (c = 1 in water).

Analysis for C2SH2sa2N302 (486.4):

Calc .: C 61.74 H 5.18 N 8.64 Cl ionic 7.29 Found: C 60.25 H 5.22 N 8.30 Cl ionic 7.31 H20 2.17.

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

Example 14

Glycyl-N- (2-benzoyl-4-chlorophenyl) -glycinamide of melting point 136-138 ° C. (from ethanol) is obtained in an analogous manner to that in Example 13.

Analysis for C17H16C1N303 (345.79):

Calc .: C 59.05 H 4.66 N 12.15 Cl 10.26 Found: C 59.03 H 4.63 N 11.79 Cl 10.26.

Example 15

Glycyl-N- (2-benzoyl-4-nitrophenyl) glycinamide of melting point 121 ° -123 ° C. (from ethanol) is obtained in a manner analogous to that in Example 13.

Analysis for Ci7Hi6N4Os (356.34):

Calc .: C 57.31 H 4.53 N 15.72 Found: C 57.54 H 4.58 N 15.73.

Example 16

L-Prolyl-N- (2-benzoyl-4-nitrophenyl) glycinamide of melting point 165-167 ° C. is obtained in an analogous manner to that in Example 13.

Example 17

In an analogous manner as in Example 13, L-alanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycine amide hydrochloride is obtained with a melting point of 115-130 ° C. (slight decomposition); [a] D20 = + 7.09 ° (c = 1 in water).

Analysis for C19H21C12N303 (410.31):

Calc .: C 55.62 H 5.16 N 10.24 Cl ionic 8.64 Found: C 55.86 H 5.20 N 9.95 Cl ionic 8.42.

Example 18

a) In an analogous manner as in the paragraphs of a) - f) of Example 13, (N ", NE-bisbenzyloxycarbonyl-L-ly-syl) -N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide is obtained as an almost colorless, light-sensitive rubber, [ec] D20 = -9.3 ° (c = 1 in ethanol).

Analysis for C38H39C1N407 (699.2):

Calc .: C 65.28 N 5.62 N 8.02 Cl 5.07 Found: C 64.90 H 5.56 N 7.84 Cl 5.25.

b) (Na, N £ -bisbenzyloxycarbonyl-L-lysyl) -N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide is converted into the L-lysyl-N- using a 30% solution of hydrogen bromide in glacial acetic acid. (2-benzoyl-4-chlorophenyl) -N-methylglycinamide-di-

converted to hydrobromide, which is a hygroscopic powder with a melting point of 145-146 ° C (decomposition); [a] D20 = + 15.6 ° (c = 1 in water).

Analysis for C22H29Br2ClN403 (592.8):

Calc .: C 44.58 H 4.93 N 9.45 Br ionic 26.96 Found: C 43.58 H 5.17 N9.21 Br ionic 27.43 H20 0.99.

Anhydrous: C 44.02 H 5.11 N 9.30 Br ionic 27.70.

c) Treatment of this dihydrobromide in aqueous solution with an excess of anion exchange resin, such as amberlite IRA-401 in the chloride form and subsequent lyophilization of the eluate, gives L-lysyl-N- (2-benzoyl-4-chlorophenyl) -N in quantitative yield -methyIglycin-amid-dihydrochloride as a hygroscopic, white, light-sensitive powder with a melting point of 125-145 ° C (easy decomposition); [a] D20 = + 19.3 ° (c = 1 in water).

Analysis for C22H29C13N403 (503.86):

Calc .: C 52.45 H 5.80 N 11.12 Cl 21.12 Found: C 51.58 H 5.80 N 11.18 Cl 20.80 H20 0.99.

Anhydrous: C 52.10 H 5.75 N 11.29 Cl 21.10.

d) 1.4 g (Na, N £ -bisbenzyloxycarbonyl-L-Iysyl) -N- (2-ben-zoyl-4-chlorophenyl) -N-methylglycinamide are dissolved in 30 ml dry dichloromethane, whereupon the solution is reduced to approximately - Is cooled to 70 ° C and then treated with stirring with 2 ml of pre-cooled boron trichloride. The mixture is stirred under anhydrous conditions for 30 minutes at approximately -70 ° 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 is dissolved in 30 ml of freshly dried dichloromethane and the solution is again evaporated to dryness in vacuo. This procedure is repeated twice with dichloromethane and then four times with methanol to remove the residual 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 30 ml of water, three times with each

Shake out 20 ml of ethyl acetate (to remove traces of 5-chloro-2-methylaminobenzophenone) and the aqueous solution is lyophilized. L-Lysyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide dihydrochloride is obtained, which is identical to the product described in paragraph c) of this example.

Example 19

In an analogous manner as in Example 13, L-Leu-cyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide is obtained in the form of a pale yellow gum; [a] D20 = -2.2 ° (c = 1 in ethanol). Analysis for C22H26CIN303 (415.9):

Calc .: C 63.54 H 6.30 N 10.10 Cl 8.52 Found: C 63.25 H 6.69 N 9.75 Cl 8.33.

Example 20

In an analogous manner as in Example 13, L-phenyl-alanyl-N- (2-benzoyl-4-nitrophenyl) -glycinamide with a melting point of 144-146 ° C. (from methanol); [a] D20 = -29.4 ° (c = 1 in dioxane).

Analysis for C24H22N4Os (446.47):

Calc .: 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 manner as in paragraphs a) - f) of Example 13, (Na, Ne, N "'- trisbenzyloxycarbonyl-L-arginyl) -N- (2-benzoyl-4-chlorophenyl) -N is obtained -methylglycinamide as na5

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very colorless, light-sensitive brittle foam; [a] D20 = -2.4 ° (c = 1 in ethanol).

Analysis for C46H45ClNe, 09 (861.36):

Calc .: C 64.14 H 5.27 N 9.76 C14.12 Found: C 63.44 H 5.17 N 9.59 Cl 4.65. Solvent free *: C 63.90 H 5.20 N 9.68 Cl 3.91. * A dichloromethane content of 0.10 ± 0.02 mol was determined by NMR spectroscopy.

Ber. for C46H4SC1N609, 0.1 CH2C12 (868.84):

C 63.66 H 5.24 N 9.66 C 14.80.

b) 5.0 g (Na, NE, N "'- TrisbenzyIoxycarbonyl-L-arginyl) -N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide are dissolved in 60 ml of dry dichloromethane, and the solution is dissolved Cooled at 0 ° C. and treated with 4 ml of boron tribromide with stirring The reaction mixture is stirred under anhydrous conditions for 2 hours at 0 ° C. and then left to stand overnight, while warming to room temperature, excess boron tribromide is removed by the dropwise addition of a solution of neutralized anhydrous methanol in dry dichloromethane until no further reaction can be observed. The reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in 30 ml of anhydrous methanol and the solution is again evaporated to dryness. This procedure is repeated three times with methanol, In order to remove residual boron compounds as volatile trimethyl borates, a concentrated solution of the residue in methanol is slowly turned into a lit. he was given anhydrous diethyl ether. The hygroscopic solid is collected by filtration and dried in vacuo. The product is in

Wash 100 ml of water and shake the solution three times with 50 ml of ethyl acetate to remove traces of 5-chloro-2-methyl-aminobenzophenone and then lyophilize. L-Arginyl-N- (2-benzoyI-4-chlorophenyl) -N-methylglycinamide dihydrobromide is obtained as an almost colorless, light-sensitive powder; [a] D20 = + 12.8 ° (c = 1 in water).

Analysis for C22H27Br2ClN603 (620.77):

Calc .: C 42.56 H 4.71 N 13.53 Br ionic 25.74 Found: C 40.74 H 4.91 N 13.29 Br ionic 26.08 H20 1.89.

Anhydrous: C 41.52 H 4.79 N 13.55 Br ionic 26.58. Ber. 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 paragraph c) of Example 18 and provides L-arginyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-glycinamide dihydrochloride as a white light-sensitive amorphous powder in quantitative yield melting point 155-160 ° C (slight decomposition); [ö] d20 = + 14.9 ° (c = 1 in water).

Analysis for C22H27CI3N603 (531.87):

Calc .: C 49.68 H 5.49 N 15.80 Cl 19.99 Found: C 48.47 H 5.75 N 15.84 Cl 20.16 H20 1.17.

Anhydrous: C 49.04 H 5.69 N 16.03 Cl 20.40.

Ber. for C22H25C1N603 ■ 2.1 HCl (535.52):

C 49.34 H 5.48 N 15.69 Cl 20.52.

Example 22

a) In an analogous manner as in paragraph c) of Example 13, 2- (N-benzyloxycarbonylamino) -N- (2-benzoyl-4-chlorophenyl) -N-methylpropionamide is obtained as a pale yellow rubber; Md20 = -3.75 ° (c = 1 in ethanol).

Analysis for C2SH23C1N204 (450.92):

Calc .: C 66.60 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 paragraphs a) and b) of Example

13 and supplies 2-amino-N- (2-benzoyl-4-chlorophenyl) -N-methylpropionamide hydrobromide as an almost colorless, hygroscopic powder with a melting point of 140-145 ° C (slight decomposition) (from acetone / diethyl ether) ; [a] D20 = + 13.2 ° (c = 1 in ethanol).

Analysis for C, 7H18C1N202 (397.70):

Calc .: C 51.34 H 4.56 N 7.05 Br ionic 20.10 Found: C 50.98 H 4.73 N 6.78 Br ionic 20.05 H20 0.75.

Anhydrous: C 51.37 H 4.68 N 6.83 Br ionic 20.20.

c) In a manner analogous to that described in paragraph e) of Example 13, a mixture of 7-chloro-1,3-dihydro-

1,3-dimethyl-5-phenyl-2H-l, 4-benzodiazepin-2-one and (N-benzyloxycarbonyl-L-phenylalanyl) -N- (2-benzoyl-4-chlorophenyl) -N-methyl-L- alaninamide in an approximate ratio of 2: 1.

d) 6 g of this mixture are dissolved in 40 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the solution is stirred for 3 hours at room temperature. The mixture is worked up in a manner similar to that described in paragraph g) of Example 13 and gives L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-L-alaninamide as an almost colorless, light-sensitive, brittle foam; [a] D20 = -34.9 ° (c = 1 in ethanol).

Analysis for C26H26C1N303 (463.97):

Calc .: C 67.30 H 6.65 N 9.06 Cl 7.64 Found: C 66.98 H 5.79 N 8.82 Cl 7.74.

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

e) 0.5 g of L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-L-alaninamide are dissolved in a minimum amount of methanol at room temperature and treated by titration with an exactly equivalent amount of hydrochloric acid. The solvent is removed from the solution obtained by evaporation in vacuo at room temperature and finally by lyophilization, L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-L-alaninamide being obtained in quantitative yield. hydrochloride as a white, hygroscopic, light-sensitive amorphous powder with a melting point of 130-140 ° C (easy decomposition); [«] D20 = -48.0 ° (c =

1 in water).

Analysis for C26H27C12N303 (500.43):

Calc .: C 62.39 H 5.44 N 8.40 Cl ionic 7.09 Found: C 60.84 H 6.65 N 8.03 Cl ionic 7.36 H20 2.05.

Anhydrous: C 62.11 H 5.53 N 8.20 Cl ionic 7.51. Ber. for C26H26C1N303 • 1.05 HCl (502.28):

C 62.17 H 5.42 N 8.36 Cl ionic 7.41.

Example 23

a) In a manner analogous to that described in paragraphs a) - f) of Example 13, 2- (N-benzyloxycarbonylamino-no) -N- (2-benzoylphenyl) -N-methylacetamide is obtained as a pale yellow gum.

Analysis for C24H22N204 (402.45):

Calc .: C 71.63 H 5.51 N 6.96 Found: C 71.33 H 5.45 N 6.90.

b) By treating this compound in a manner analogous to that described in paragraph g) of Example 13, L-alanyl-N- (2-benzoylphenyl) -N-methylglycinamide is obtained as an almost colorless, light-sensitive foam.

Analysis for C19H21N303 (339.40):

Calc .: C 67.24 H 6.25 N 12.38 Found: C 66.93 H 6.01 N 11.98.

In addition, 1,3-dihydro-l-methyl-5-phenyl-2H-

1,4-benzodiazepin-2-one isolated from the melting point 151-154 ° C as the main by-product.

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c) 3 g of L-alanyl-N- (2-benzoylphenyl) -N-methylglycinamide are dissolved in 10 ml of anhydrous sulfuric acid at room temperature. The resulting solution is cooled to -5 ° C and a solution of 0.94 g of potassium nitrate in 3 ml of anhydrous sulfuric acid is added dropwise. The reaction mixture is stirred at 0 ° C for 10 hours and then left to stand overnight, warming 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 adjusted to approximately 9, the temperature being maintained at approximately 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 concentrated in vacuo. The residue is dissolved in a minimum amount of chloroform and the solution is chromatographed on a Florisil column, using mixtures of ethanol in chloroform as a mobile phase. The fractions are collected in a 5% methanol solution in chloroform and the solution is evaporated in vacuo. Pure L-AlanyI-N- (2-benzoyl-4-ni-trophenyl) -N-methylglycinamide is obtained as an almost colorless, light-sensitive foam; [ct] D20 = + 2.1 ° (c = 1 in ethanol). Analysis for C19H2oN4Os (384.40):

Calc .: 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 in hydrochloric acid. The solvent is removed from the solution obtained by evaporation in vacuo at room temperature and finally by lyophilization, L-Alanyl-N- (2-benzoyl-4-nitrophenyl) -N-methyl-glycinamide hydrochloride being quantitatively obtained as white amorphous Solid of melting point 165-175 ° C (slight decomposition) is obtained; [a] D20 = + 7.5 ° (c = 1 in water).

Analysis for C19H21C1N4Os (420.85):

Calc .: C 54.23 H 5.03 N 13.31 Cl ionic 8.42 Found: C 54.12 H 5.30 N 13.05 Cl ionic 8.42.

Example 24

a) 2.0 g of 8-chloro-l-methyl-6-phenyl-4H-s-triazolo [4,3-a] - [1,4] benzodiazepine [J. B. Hester Jr., A.D. Rudzic and B.V. Kamdar, J. Med. Chem., 1971, 14, 1078] are 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 evaporated again. The last traces of water are removed by shaking out the oil with 50% methanol / toluene and then evaporating. This treatment is repeated three times with 50% methanol / toluene and twice with toluene. 5-Chloro-2- (3-aminomethyl-5-methyl-4H-l, 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 are added to the solution obtained. The solution thus obtained is cooled to -20 ° C. A solution of 2.1 ml of N-ethylmorpholine in 8.4 ml of dimethylformamide is added over a period of 0.5 hours with vigorous stirring. The resulting reaction mixture is stirred at -20 ° C for 1 hour 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 phases are extracted with further dichloromethane. The organic phases are combined, washed five times with water, dried over magnesium sulfate and evaporated to an oil which is chromatographed on silica gel. Elution is carried out initially with chloroform and then with a 2% methanol solution in chloroform and then with a 2% methanol solution in chloroform. 15 ml fractions are collected. Fractions 1-25 contain the chloroform eluate, while fractions 48-57 contain the desired product. These last-mentioned fractions are combined, evaporated to dryness and the residue from ethyl acetate / petroleum ether is brought to crystallization. 5-Chloro-2 - {[(N-benzyloxycarbonyl-L-phenylalanyl) amino-methyl] -5-methyl-4H ~ l, 2,4-triazol-4-yl} benzophenone with a melting point of 84-88 ° C. is obtained .

c) 0.50 g of 5-chloro-2 - {[(N-benzyloxyearbonyl-L-phenylalanyl) aminomethyl] -5-methyl-4H-l, 2,4-triazol-4-yI} benzophenone are treated for 1 hour with a 35% solution of hydrogen bromide in glacial acetic acid. The solid which separates out after the addition of dry diethyl ether is filtered off, washed with ether and dried in vacuo. The crude product is purified by precipitation from methanol / ethyl acetate. 5-Chloro-2- [3- (L-phenylalanylaminomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl] benzophenone dihydrobromide with a melting point of 164-171 ° C. (slight decomposition ).

Analysis for C26H26Br2ClN502 (635.79):

Calculated: C 49.12 H 4.12 N 11.02 Cl 5.58 Br 25.14

Found: C 48.15 H 4.14 N 10.66 Cl 5.32

Br 24.52 H2Ö 1.83.

Anhydrous: C 49.05 H 4.01 N 10.86 Cl 5.42 Br 24.98.

Example 25

5-Chloro-2- [3- (L-lysylaminoethyl) -5-methyl-4H is obtained in a manner analogous to that described in Example 24, but using Na, NE-di-tert-butoxycarbonyl-L-lysine-N-hydroxysuccinimide ester -l, 2,4-triazol-4-yl] benzophenone tri hydrobromide as a lyophilized solid; [a] D20 = + 11.0 ° (c = 1 in water).

Analysis for C23H3oBr3C102 (697.71):

Calc .: C 39.60 H 4.33 N 12.05 Br 34.36 Found: C 38.23 H 4.38 N 11.55 Br 33.40 H2Ö 2.58.

Anhydrous: C 39.24 H 4.21 N 11.86 Br 34.28.

Example 26

In an analogous manner to that described in Example 24, 2 ', 5-dichloro-2- [3- (L-phenylalanylaminomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl] benzophenone is obtained. dihydrobromide melting point 188-193 ° C.

Analysis for C26H2sBr2Cl2Ns02 (670.25):

Calculated: 'C 46.59 H 3.76 N 10.45 Br 23.84 Cl 10.58

Found: C 46.02 H 3.83 N 10.03 Br 23.33

Cl 10.35 H2ö 1.90.

Anhydrous: C 46.91 H 3.69 N 10.22 Br 23.78 Cl 10.55.

Example 27

In an analogous manner to that described in Example 24, 2 ', 5-dichloro-2- [3- (L-lysylaminomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl] benzophenone hydrobromide ( 1: 2.9) melting point 240-245 ° C; [a] D20 = + 9.8 ° (c = 1 in water). Analysis for C23H26C12N6Ö2 • 2.9 HBr (724.07): Calc .: C38.15 H 4.02 N 11.61 Br ionic 32.00 Found: C 37.84 H 4.13 N 11.18 Br ionic 31.30 H20 1.23.

Anhydrous: C 38.31 H 4.04 NI 1.32 Br ionic 31.69.

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Example 28

Using an analogous procedure as described in Example 24, 2 ', 5-dichloro-2- (3-glycylaminomethyl-5-methyl-4H-l, 2,4-triazol-4-yl) benzophenone dihydrobromide methanolate with melting point 235 is obtained -240 ° C.

Analysis for C20H23Br2Cl2N5O3 (612.15):

Calc .: C 39.24 H 3.79 N 11.44 Br 26.11 Cl 11.58

Found: C 39.39 H 3.67 N 11.30 Br 26.10 Cl 11.58.

Example 29

a) A solution of 200 g of 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) -2H-l, 4-benzodiazepin-2-one in 2 liters of tetrahydrofuran and 250 ml of benzene is cooled in saturated with methylamine in an ice bath. A solution of 190 g titanium tetrachloride in 250 ml benzene is then added over 15 minutes through a drip channel. When the addition is complete, the mixture is stirred and heated to reflux for 3 hours. Then 600 ml of water are slowly added to the cooled mixture. The inorganic material is removed by filtration and washed well with tetrahydrofuran. The aqueous phase is separated off and the organic phase is dried over sodium sulfate and evaporated. The crystalline residue is collected and gives 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiaze-pin with a melting point of 204-206 ° C. An analytical sample is recrystallized from methylene chloride / ethanol and shows the melting point 204-206 ° C.

b) 8.63 g of sodium nitrite are added in three portions over a period of 15 minutes to a solution of 30.15 g of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-l, 4-benzodi-azepine placed in 150 ml of glacial acetic acid. The reaction mixture is stirred at room temperature for 1 hour, 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 azeotropically with toluene) and provide crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-l, 4-benzodiaze -pin as a yellow oil.

c) This oil is dissolved in 100 ml of dimethylformamide and added to a mixture of 200 ml of dimethylformamide, 50 ml of Ni-tromethane and 11.1 g of potassium tert-butoxide, which was stirred under nitrogen for 15 minutes. The reaction mixture is stirred for 1 hour at room temperature, acidified by adding 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 a melting point of 170-172 ° C. An analytical sample is recrystallized from methylene chloride / ethanol and shows a melting point of 174-176 ° C.

d) A solution of 16.5 g of 7-chloro-l, 3-dihydro-5- (2-fluorophenyl) -2-nitromethylene-2H-l, 4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol is added during 2. Hydrogenated for 5 hours at atmospheric pressure with 5 teaspoons of Raney nickel. Separation of the catalyst and evaporation provide crude 2-aminomethyl-7-chloro-2,3-dihydro-5- (2-fluorophe-

nyl) -lH-l, 4-benzodiazepine.

e) 7 ml of acetic anhydride are 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 200 ml of methylene chloride. The solution is covered with 200 ml of saturated sodium bicarbonate solution and the mixture is stirred for 20 minutes. The organic phases are separated off, 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-ben-zodiazepine is obtained. This product is heated to 40 ° C. with 40 g of polyphosphoric acid for 10 minutes. 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, using 20% methanol in methylene chloride as the mobile phase. The clear fractions are combined and evaporated. Resinous 8-chloro-3a, 4-dihydro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine is obtained. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide is heated to reflux for 1.5 hours. The manganese dioxide is separated off by filtering through Celite. The filtrate is evaporated and the residue is crystallized from diethyl ether, 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine melting at 152-154 ° C. An analytical sample is recrystallized from methylene chloride / hexane.

f) 2.0 g of 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine are dissolved in 15 ml of dilute hydrochloric acid, after which the solution is left overnight at room temperature. The oil obtained after evaporating the solution is dissolved in water and the aqueous solution is evaporated again. The last traces of water are removed by shaking with 50% methanol / toluene followed by evaporation. This procedure is repeated three times with 50% methanol / toluene and twice with toluene. 5-Chloro-2'-fluoro-2- (5-aminomethyl-2-methyl-l-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 are added to the solution obtained. The solution is then cooled to -20 ° C. A solution of 2.5 ml of N-ethylmorpholine in 10 ml of dimethylformamide is added dropwise with vigorous stirring over a period of 20 minutes. The mixture is stirred at -20 ° C for 1 hour and then left at room temperature overnight. The solvent is removed in vacuo and the residue is dissolved in a mixture of chloroform and water. The phases are separated and the aqueous phase is additionally 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 100 g of silica gel, using 4% methanol in chloroform as the eluent. 15 ml fractions are collected. The desired product is eluted in fractions 25-36. These fractions are combined, evaporated to dryness and the oil obtained crystallized from ether. 5-Chloro-2'-fluoro-2- {5 - [(N-benzyloxycarbonyl-L-leucyl) aminomethyl] -l-imidazolyl} benzophenone of melting point 63-75 ° C. (decomposition) is obtained.

Analysis for C32H32CIFN404 (591.09):

Calc .: C 65.02 H 5.46 N 9.48 Found: C 64.66 H 5.61 N 9.19.

h) 0.40 g of 5-chloro-2'-fluoro-2- {5 - [(N-benzyloxycarbonyl-L-leucyl) aminomethyl] -l-imidazolyl} benzophenone is stirred for 45 minutes with a 35% solution of hydrogen bromide treated in glacial acetic acid. After adding dry diethyl ether, an oily solid is obtained. The product is precipitated from methanol / ethyl acetate, dissolved in water and freeze-dried. 5-Chloro-2'-fluoro-2- [5- (L-leucylaminomethyl) -2-methyl-l-imidazolyl] benzophenone difiydrobromide is obtained; | «] D20 = _5.5 ° (c = 0.2708 in water).

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Analysis for C24H28Br2ClFN402 (618.77):

Calc .: 'C 46.59 H 4.56 N 9.05 Br 25.82 Found: C 44.93 H 4.74 N 8.56 Br 25.04 H20 3.55.

Anhydrous: C 46.58 H 4.50 N 8.87 Br 25.96.

Example 30

5-Chloro-2'-fluoro-5 - [(L-alanylaminomethyl) -2-methyl-l-imidazolyl] benzophenone dihydrobromide of melting point 90-110 ° C. 5 (easy decomposition ).

Claims (48)

620 900 1 ^ N - C ^ CH-NH-R ' C = 0 R1 Ia in which R, R1, R2 and R3 have the meaning given in claim 1, and R4 is hydrogen, methyl, cyclopropylmethyl, di- (C1-C4) -alkylaminoethyl, methoxymethyl or hydroxy-- 65 ethyl, or an acid addition salt thereof is prepared. 2. A process for the preparation of compounds of the formula I given in claim 1, in which R1 and R3 have the meaning given in claim 1, A denotes a nitrogen atom which is generated by a methyl, cyclopropylmethyl, di (C1-C4) alkylaminoethyl -, Methoxymethyl- or hydroxyethyl group can be substituted, B represents a carbonyl group, R represents nitro and R2 represents the acyl radical of a naturally occurring amino acid which is not impaired by nitrating agents, all such acyl radicals containing an asymmetric carbon atom being the L or D , L configuration, characterized in that a compound of the general formula R4 2nd PATENT CLAIMS 1. Process for the preparation of substituted phenyl ketones of the general formula R1 I. A-8-CH-NH-R2 3rd 620 900 la, wherein R is chlorine or bromine or nitro, R1 is hydrogen, R3 is phenyl, o-fluorophenyl, o-chlorophenyl or 2-pyridyl and R4 is hydrogen, methyl, diethylaminoethyl or methoxymethyl, or an acid addition salt thereof is prepared. 3. The method according to claim 1, characterized in that a racemic product obtained is separated into its optical isomers and the L-isomer is isolated. 4th 4. The method according to claim 1 or 3, characterized in that a compound of the formula 50 55 60 5 5. The method according to claim 4, characterized in that a compound of the formula given in claim 4 6. The method according to claim 1 or 3, characterized in that a compound of the formula -C ; H-NH-R R wherein R, R \ R2, R3 and Ra have the meaning given in claim 1, or an acid addition salt thereof is prepared. 7. The method according to claim 6, characterized in that a compound of the formula Ib given in claim 6, wherein R is chlorine, R1 is hydrogen, R3 is phenyl or o-chlorophenyl and Ra is methyl or hydroxymethyl, or an acid addition salt thereof. 8. The method according to claim 1 or 3, characterized in that a compound of the general formula CH-NH-R R wherein R, R1, R2, R3, Ra and Rb have the meaning given in claim 1, or an acid addition salt thereof is prepared. 9. The method according to claim 8, characterized in that a compound of the formula Ic given in claim 8, wherein Ra and Rb are each hydrogen or lower alkyl, or an acid addition salt thereof is prepared. 10th 10. The method according to claim 8, characterized in that a compound of the formula Ic given in claim 8, wherein R is chlorine, R1 is hydrogen, R3 is phenyl or o-fluorophenyl, Ra is methyl or hydroxymethyl and Rb is hydrogen, or an acid addition salt thereof becomes. 10th wherein either A represents a nitrogen atom which can be substituted by a methyl, cyclopropylmethyl, di (C1-C4) alkylaminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group or A and B together the group of the formula Ra — C N / N '< mean in which Ra represents hydrogen, lower alkyl or hydroxymethyl and X represents a nitrogen atom or the group C — Rb, in which Rb represents hydrogen, lower alkyl or hydroxymethyl, R represents halogen, nitro or trifluoromethyl, R1 represents hydrogen or lower alkyl R 2 denotes the acyl residue of a naturally occurring amino acid, all such acyl residues containing an asymmetric carbon atom having the L or D, L configuration, and R 3 denotes phenyl, halophenyl or 2-pyridyl, and their acid addition salts, characterized in that from a compound of the general formula 11. The method according to any one of claims 1, 3, 4, 5, 6, 8 and 9, characterized in that a compound in which R is bromine and R3 is 2-pyridyl, or an acid addition salt thereof is prepared. 11 wherein A, B, R, R1 and R3 have the above meaning and R20 is the acyl residue of a naturally occurring amino acid, in which all amino groups present are in protected form and any other functional groups, if necessary, are also in protected form, all of which are such asymmetric carbon atom-containing acyl radicals which have the L or D, L configuration, the protective group (s) present are removed and, if desired, if a free base obtained is converted into an acid addition salt or an obtained acid addition salt is converted into the free base or into another acid addition salt. 12. The method according to any one of claims 1 and 3 to 11, characterized in that a compound in which the acyl radical R2 is derived from an L-amino acid; or an acid addition salt thereof is prepared. 13. The method according to claim 12, characterized in that the L-amino acid is L-phenylalanine or L-lysine. 14. The method according to claim 11, characterized. that one produces L-phenylalanyl-N- (4-bromo-2-picolinoylphenyl) glycine amide. 15 15. The method according to claim 11, characterized in that one produces glycyl-N- (4-bromo-2-picolinoylphenyl) glycinamide. 16. The method according to claim 11, characterized in that producing L-leucyl-N- (4-bromo-2-picolinoylphenyl) glycinamide. 17. The method according to claim 11, characterized in that producing L-lysyl-N- (4-bromo-2-picoIinoylphenyl) glycinamide. 18. The method according to claim 11, characterized in that one produces L-isoleucyl-N- (4-bromo-2-picolinoylphenyl) glycine amide. 19. The method according to claim 11, characterized in that one produces L-y-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycine amide. 20th 20. The method according to claim 11, characterized in that one produces L-alanyl-N- (4-bromo-2-picolinoylphenyl) glycinamide. 20th N — C <^ CH-NH-R 21. The method according to claim 11, characterized in that L-arginyl-N- (4-bromo-2-picolinoylphenyl) glycinamide is prepared. 21st C = 0 III wherein R1 and R3 have the meaning given in claim 1, R4 is hydrogen, methyl, cyclopropylmethyl, di- (C1-C4) -alkylaminoethyl, methoxymethyl or hydroxyethyl and R21 is the acyl radical of a naturally occurring amino acid which is not impaired by nitrating agents, in which all the amino groups present are in protected form and any further functional groups, if necessary, are also in protected form, all of such acyl radicals containing an asymmetric carbon atom having the L or D, L configuration, the protective group (s) present are removed, the compound obtained is nitrided and, if desired, a free base obtained is converted into an acid addition salt or an acid addition salt obtained into the free base or into another acid addition salt. 22. The method according to claim 11, characterized in that one produces L-cc-glutamyl-N- (4-bromo-2-picolinoylphenyl) glycine amide. 23. The method according to claim 5, characterized in that one produces glycyl-N- (2-benzoyl-4-chlorophenyl) glycinamide. 24. The method according to claim 1, characterized in that one produces glycyl-N- (2-benzoyl-4-nitrophenyl) glycinamide. 25th 25. The method according to claim 1, characterized in that one produces L-prolyl-N- (2-benzoyl-4-nitrophenyl) glycinamide. 26. The method according to claim 5, characterized in that one produces glycyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycine amide. 27. The method according to claim 5, characterized in that L-alanyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-glycinamide is prepared. 28. The method according to claim 5, characterized in that L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methylglycinamide is prepared. ' 29. The method according to claim 5, characterized in that one produces L-lysyl-N- (2-benzoyl-4-chlorophenyl) -N-methylgly-cinamid. 30th 30. The method according to claim 5, characterized in that L-leucyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-glycinamide is prepared. 31. The method according to claim 5, characterized in that L-phenylalanyl-N- (2-benzoyl-4-nitrophenyl) glycine amide is prepared. 32. The method according to claim 5, characterized in that one produces L-ArginyI-N- (2-benzoyl-4-chlorophenyI) glycinamide. 33. The method according to claim 1, characterized in that L-alanyl-N- (2-benzoyl-4-nitrophenyl) -N-methyIgly-cinamide is prepared. 34. The method according to claim 1, characterized in that L-AlanyI-N- [2- (2'-fluorobenzoyl) -4-nitrophenyl] -N-methylglycinamide is prepared. 35 35. The method according to claim 5, characterized in that L-phenylalanyl-N- (2-benzoyl-4-chlorophenyl) -N-methyl-L-alaninamide is prepared. 35 36. The method according to claim 7, characterized in that 5-chloro-2- [3- (L-phenylalanylaminomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl-] benzophenone is prepared . 37. The method according to claim 7, characterized in that 5-chloro-2- [3- (L-lysyiaminomethyl) -5-methyl-4H-1,2,4-triazol-4-yl] benzophenone is prepared. 38. The method according to claim 7, characterized in that 2 ', 5-dichloro-2- [3- (L-phenylalanylaminomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl] benzophenone is prepared . 39. The method according to claim 7, characterized in that 2 ', 5-dichloro-2- [3- (L-lysylaminomethyl) -5-methyl-4H-1,2,4-triazol-4-yl] benzophenone is prepared . 40. The method according to claim 7, characterized in that 2 ', 5-dichloro-2- (3-glycylaminomethyl) -5-methyl-4H-l, 2,4-triazol-4-yl) produces benzophenone. 40 40 Rl I. A-B-CH-NH-R20 41. The method according to claim 10, characterized in that 5-chloro-2'-fluoro-2- [5- (L-leucylaminomethyl) -2-methyl-l-imidazolyl] benzophenone is prepared. 42. The method according to claim 10, characterized in that 5-chloro-2'-fluoro-2- [5- (L-alanylaminomethyl) -2-methyl-l-imidazolyl] benzophenone is prepared. 43. The method according to claim 2, characterized in that a racemic product obtained is separated into its optical isomers and the L-isomer is isolated. 44. The method according to claim 2 or 43, characterized in that a compound in which the acyl radical R2 is derived from an L-amino acid or an acid addition salt thereof is prepared. 45. The method according to claim 2, characterized in that one produces glycyl-N- (2-benzoyl-4-nitrophenyl) glycinamide. 45 50 55 60 65 620 900 45 C = 0 46. The method according to claim 2, characterized in that one produces L-prolyl-N- (2-benzoyl-4-nitrophenyl) glycinamide. 47. The method according to claim 2, characterized in that L-alanyl-N- (2-benzoyl-4-nitrophenyI) -N-methylgly-cinamide is prepared. 48. The method according to claim 2, characterized in that L-alanyl-N- [2- (2'-fluorobenzoyl) -4-nitrophenyl] -N-methylglycinamide is prepared.