IE42156B1 - Substituted-phenyl ketones containing a protected dipetideresidue - Google Patents

Description

The present invention is concerned with substituted-phenyl ketones.

The substituted-phenyl ketones provided by the present invention are compounds of the general formula , wherein A represents a nitrogen atom which may be substituted by a methyl, cyclopropylmethyl, di(C1_4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group or A and B together represent a grouping of the formula (i) in which Ra represents a hydrogen atom or a lower alkyl or hydroxymethyl group and X represents a nitrogen atom or C—Rb wherein R^ represents a hydrogen atom or a lower alkyl or hydroxymethyl group; R represents a halogen atom or a nitro or trifluoromethyl group; R1 represents a hydrogen atom or a 20 lower alkyl group; R represents an acyl group derived from a naturally occurring amino acid in which the amino group or amino groups present is/are in protected form and any other functional group which may be present is in protected form where required (all such acyl groups which contain an asymmetric carbon atom having the L-configuration) and R represents a phenyl, halophenyl or 2-pyridyl group.

It will be appreciated that formula I hereinbefore embraces compounds of the general formulae and (Ia) (lb) > 42156 wherein R, R1, R3, // Ra and Rb have the 4 significance given earlier and R represents a hydrogen atom or a methyl, cyclopropyl5 methyl, di(C^_4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group.

The compounds of formula 1 hereinbefore are useful as starting materials for the manufacture of the corresponding substituted-phenyl ketones [see Patent Specification Nos. and 4 215'5 3.

As used in this specification, the term lower alkyl means a straight-chain or branched-chain alkyl group which contains from 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, Isopropyl, butyl and hexyl). The methyl group is the preferred- lower alkyl group. The term halogen means fluorine, chlorine, bromine or iodine. The acyl group denoted by R30 is derived from a naturally occurring a-amino carboxylic acid such as glycine or L-alanine, -leucine, -phenylalanine, -Isoleucine, -serine, -lysine, -methionine, or -proline. Especially preferred acyl groups are those derived from L-amino acids, particularly from L-phenyl- 4 42156 alanine or L-lysine. The preferred halogen value for R is 3 chlorine or bromine when R represents a phenyl or halophenyl 3 group and bromine when R represents a 2-pyridyl group. The 3 halophenyl group denoted by R includes a monohalophenyl group, especially an o-halophenyl group such as o-chlorophenyl or o-fluorophenyl, and a dihalophenyl group, especially an o,o'-dihalophenyl group such as o,o'-dichlorophenyl.

The amino group or amino groups present in the acyl group denoted by R in formula I can be protected with any amino-protecting group which is well-known in peptide chemistry Especially suitable amino-protecting groups for the purpose of the present invention are aralkoxycarbonyl groups, particularly the benzyloxycarbonyl group, and the tertbutoxycarbonyl group. The amino-protecting group may also be a formyl, trityl or trifluoroacetyl group. Any carboxy or hydroxy group which may 20 be present in the acyl group denoted by R in formula I can be protected by a conventional carboxy-protecting or hydroxy-protecting group respectively. For example, a carboxy group may be protected by conversion into an alkyl ester (e.g. a tertbutyl ester) or an aralkyl ester (e.g. a benzyl ester). Again, for example, a hydroxy group may be protected, for example, by means of an aralkoxycarbonyl group (e.g. benzyloxycarbonyl) , an alkanoyl group (e.g. acetyl, propionyl etc), an aroyl group (e.g. benzoyl), an alkyl group (e.g. tertbutyl) or an aralkyl group (e.g. benzyl). The protection of other 20 functional groups present in the acyl group denoted by R may be carried out in a known manner.

Preferred compounds of formula Ia hereinbefore are those in which R represents a chlorine or bromine atom or a nitro 48156 3 group, R represents a hydrogen atom, R represents a phenyl, o-fluorophenyl, o-chlorophenyl or 2-pyridyl group and R represents a hydrogen atom or a methyl, diethylaminoethyl or methoxymethyl group.

Examples of compounds of formula Ia hereinbefore are: (N-Benzyloxycarbony1-L-phenylalanyl)-N-(4-bromo-2-picolinoyIphenyl)glycinamide, (N-benzyloxycarbony1-L-isoleucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide, I (Nq,Ne-ditertbutoxycarbony1-L-lysyl)-N-(4-bromo-2-picolinoyIphenyl)glycinamide, (N-tertbutoxycarbonyl-L-leucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide, (N-benzyloxycarbonylglycyl)-N-(4-bromO-2-picolinoyIphenyl) glycinamide, (N-benzyloxycarbonylglycyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide, (N-benzyloxycarbony1-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide, (Na,Ne-bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide, (Na,N£:,Na)-trisbenzyloxycarbonyl-L-arginyl) -N- (2-benzoyl-4-chlorophenyl)-N-methylglycinamide and (N-henzyloxycarbony1-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alaninamide.

Preferred compounds of formula Ib hereinbefore are those in which R represents a chlorine atom, R3 represents a hydrogen atom, R3 represents a phenyl or o-chloro-phenyl group and Ra represents a methyl or hydroxymethyl group. - 6 — 48156 An example of a compound of formula lb is: -Chloro-2-/—[(N-benzyloxycarbonyl-L-phenylalanyl)aminomethyl] -5-methy 1-4H-1, 2 ,4-triazol-4-yl_7benzophenone.

Preferred compounds of formula Ic hereinbefore are those 5 in which R represents a chlorine atom, R1 represents a hydrogen atom, R3 represents a phenyl or o-fluoro-phenyl group, Ra represents a methyl or hydroxymethyl group and R represents a hydrogen atom.

An example of a compound of formula Ic is: -Chloro-2'-fluoro-2-/—5-[(N-benzyloxycarbony1-L-leucyl)aminomethyl]-2-methyl-l-imidazolyl_7benzophenone.

The compounds of formula I hereinbefore can be prepared by a variety of routes.

Thus, compounds of formula I can be prepared, for example, 15 by condensing an amine of the general formula 3 , wherein A, B, R, R and R have the significance given earlier, with an appropriately protected amino acid or a reactive 20 derivative thereof. 421S6 The condensation can be carried out in accordance with methods which are known per se in peptide chemistry; for example, by the mixed anhydride, azide, activated ester or acid chloride method.

In one method, an appropriate amine of formula II can be condensed with an appropriately protected amino acid in which the terminal carboxy function is a mixed anhydride residue formed with an organic or inorganic acid. Suitably, such an amino aoid carrying a free carboxy function is treated with a tertiary base such as a tri(lower alkyl)amine (e.g. triethylamine) or N-ethylmorpholine in an inert organic solvent (e.g. tetrahydrofuran, diehloromethane or 1,2-dimethoxyethane) and the resulting salt’is reacted with a chloroformic acid ester (e.g. the ethyl or isobutyl ester) at a low temperature. The mixed anhydride obtained is then suitably condensed in situ with the amine of formula II.

In another method, an appropriate amine of formula II can be condensed with an appropriately protected amino acid in which the terminal carboxy group is in the form of an acid azide. This condensation is preferably carried out in an inert organic solvent such as dimethylformamide or ethyl acetate at a low temperature.

In yet another method, an.appropriate amine of formula II can be condensed with an appropriately protected amino acid in which the terminal carboxy function is in the form Of an active ester group (e.g. the £-nitrophenyl, 2,4,5-trichlorophenyl or N-hydroxysuccinimide ester group). This condensation is - 8 42186 suitably carried out at about -20°C in an inert organic solvent such as dimethylformamide.

Xn a further method, an appropriate amine of formula .II can be condensed with an appropriately protected amino acid in which the terminal carboxy function is in the form of an acid chloride. This condensation is preferably carried out in the presence of a base and at a low temperature.

Alternatively, compounds of formula I in which A represents a nitrogen atom which may be substituted by a methyl, cyclo10 propylmethyl, di(C^_4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group can be prepared by condensing a compound of the general formula 4 , wherein R, R and R have the significance 15 given earlier, with an appropriately protected dipeptide or a reactive derivative thereof using one of the methods desoribed hereinbefore in connection with the condensation of an amine of formula II with a protected amino acid or a reactive derivative 20 thereof.

The amines of formula II hereinbefore in which A represents a nitrogen atom which may be substituted by a methyl, cyclopropylmethyl, di(C^_4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group can be obtained, for example, by condensing a compound of formula III hereinbefore with an appropriately protected amino acid or a reactive derivative thereof followed by removal of the protecting group in the manner hereinafter described.

The removal of the protecting group is oarried out in accordance with methods known per se; that is to say, methods in actual use for or described in the literature on the removal of protecting groups. Thus, for example, an aralkoxycarbonyl group (e.g. benzyloxycarbonyl) or a tertbutoxycarbonyl group may be removed by treatment with a mixture of hydrogen bromide and acetic acid. The tertbutoxycarbonyl group may also be removed by means of hydrogen chloride in an organic solvent (e.g. dioxan) or by means of trifluoroacetic acid. A benzyloxycarbonyl or a tertbutoxycarbonyl group may also be removed by treatment with boron trichloride or boron tribromide in an inert organic solvent such as dichloromethane.

Alternatively, the amines of formula II in Which A represents a nitrogen atom which is substituted by a di(C^ alkyl)aminoethyl group and B represents a carbonyl group and/or 3 R represents a 2-pyridyl group or in which A and B together represent a grouping of formula (i) hereinbefore can be obtained by hydrolysing a 1,4-benzodiazepine of the general formula R· CH—R· ,1 (IV) , wherein A', B', R, R1 and R30 have any of the values accorded to A, B, R, R^ and 3 R hereinbefore with the proviso that when A* represents a nitrogen atom which may be substituted by a methyl, cyclopropylmethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group, then R30 represents a 2-pyridyl group, with a mineral acid. Thus, a 1,4-benzodiazepine of formula IV 10 can be hydrolysed with sulphuric acid, nitric acid, phosphoric acid or, preferably, a hydrohalic acid such as hydrochloric acid. The hydrolysis is preferably carried out at a temperature of ca 2O°-3O°C.

The 1,4-benzodiazepines of formula IV hereinbefore in 15 which A' and B' together represent a grouping of formula (i) wherein X represents C—Rb do not form part of the present invention, but their preparation is described herein for sake of completeness. They may be prepared, for example, by the nitrosation of a compound of the general formula , wherein R, R1 and R3 have the significance given earlier, to give a compound of the general formula R CH—RR' N—NO ,1 (VI) 3 wherein R, R and R have the significance given earlier.

This nitrosation may be carried out Using nitrous acid 5 which is formed in situ. Reagents which may be used for this purpose include alkali metal nitrites (e.g. sodium nitrite) in the presence of an inorganic or organic acid (e.g. glacial acetic acid) and an aqueous or non-aqueous solvent, alkyl nitrites (e.g. methyl nitrite) in the presence of an inert solvent such as an alkanol, a chlorinated hydrocarbon or dimethylformamide, and a solution of nitrosyl chloride gas in an inert solvent and in the presence of an acid acceptor (e.g. pyridine). Such a nitrosation should be carried out at a temperature below room temperature (e.g. a temperature in the range of -20°C to 25°C) .

It will be appreciated that the grouping -N(CH3)(NO) in the 2-position of a compound of formula VI is a leaving group and that equivalent leaving'groups may be present in said position. Examples of such equivalent leaving groups include groups such as alkoxide groups such as -OCHg, alkylthio groups such as —SCHg and phosphate groups such as — 0—PO—r—Μ Reactions to· provide alkoxide and alkylthio groups are well-known; see, for example, 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 VI is then condensed with a nitro alkane of the general formula (VII) b' wherein R represents a hydrogen atom or a lower alkyl group, to give a compound of the general formula NO, CH — S’ ,1 (VIII) R' b * wherein R, R , R and R have the significance given earlier.

The reaction of a compound of formula VI with a nitroalkane of formula VII (e.g. nitromethane or nitroethane) is carried out in the presence of a base which is sufficiently strong to generate the nitroalkane anion. 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, dimethyl sulphoxide or an ether (e.g. tetrahydrofuran) at a temperature below or above room temperature (e.g. in the range of -50°C to 150°C) ,· preferably at about room temperature.

A compound of formula VIII is then reduced by catalytic 10 hydrogenation (e.g. using hydrogen in the presence of Raney nickel) or by means of a reducing agent such as lithium aluminium hydride to give a compound of the general formula b' wherein R , R and R have the 15 significance given earlier and R' represents a halogen atom or an amino or trifluoromethyl group.

The foregoing definition of R' in formula IX results from the conversion of a nitro group into an amino group under the conditions used in the reduction of a compound Of formula VIII.

Solvents suitable for the hydrogenation in the presence of Raney nickel include alkanols (e.g. ethanol), ethers (e.g. tetrahydrofuran and diethyl ether), hydrocarbons (e.g. toluene) and dimethylformamide. The temperature at which this catalytic hydrogenation is carried out may be above or below room temperature (e.g. -50°C to 150°C). This catalytic hydrogehation may be carried out with or without pressure (e.g. a pressure of one atmosphere or above).

Solvents suitable for the reduction using a reducing agent such as lithium aluminium hydride include ethers such as tetrahydrofuran, dioxane and diethyl ether and mixtures of ethers and hydrocarbons such as tetrahydrofuran and benzene.

This reduction may be carried out at a temperature of from below room temperature to the reflux temperature of the mixture, preferably at a temperature in the range of -50°C to 60°C.

A compound of formula IX is then acylated with an acylating agent yielding the moiety Ra CO-, in which Ra represents a hydrogen atom or a lower alkyl group, such as an acid halide or acid anhydride (e.g. acetic anhydride and acetyl chloride) to give a compound of the general formula NH — COR' CH—R(X) R' R' wherein R1, R3, Ra , and R1 have the significance given earlier and Ϋ represents , 1 a hydrogen atom or the moiety R CO-.

The acylation of a compound of formula IX may yield a mixture consisting of the predominant monoacylated product (i.e a ’ in which the amino group is converted into a —NH-COR group) and the diacylated product in which both the amino group and nitrogen atom in the 1-position are acylated. The yield of diacylated product may be increased by subjecting a compound of formula IX to more rigorous conditions (i.e. the use of excess acylating agent and increased acylation time).

The acylation is preferably carried out in the presence 10 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. in alkali metal carbonate) or an inorganic base (e.g. triethylamine or pyridine).

A compound of formula X is subsequently cyclised to yield a compound of the general formula 3 a1 h' wherein R , R , R , r and R' have the significance given earlier.

The cyclisation of a compound of formula X is carried out using a dehydrating agent such as phosphorus pentoxide, poly16 phosphoric acid or other suitable acid catalysts (e.g. an organic or inorganic acid such as concentrated sulphuric acid). A solvent is not required, but a solvent such as an aromatic hydrocarbon (e.g. toluene or xylene) may be used. The cyclisation is carried out at a temperature of from about 100°C to 200°C.

A compound of formula IX can also be reacted with an acylating agent such as an orthoester (e.g. triethylorthoacetate), an orthoamide (e.g. the Ν,Ν-dimethylformamide dimethyl acetal) or tris(dimethylamino)methane, if desired in the presence of an acid catalyst such as an organic acid (e.g. paratoluenesulphonic acid) or an inorganic acid (e.g. phosphoric acid)and at room temperature or a temperature above room temperature (e.g. 25°C to 150°C), in which instance the cyclisation to a compound of formula XI occurs spontaneously. Other useful acylating agents include esters (e.g. methyl acetate), amides (e.g. acetamide), nitriles (e.g. acetonitrile) and ester imidates.

A compound of formula XI is then dehydrogenated to yield an imidazobenzodiazepine of the general formula wherein R1, R3, Ra', Rb' and R' significance given earlier. have the - 17 42156 The dehydrogenation of a compound of formula XX is preferably carried out using manganese dioxide or palladium-on-carbon, although potassium permanganate may also be used. Solvents which may be used include chlorinated hydrocarbons, aromatic hydrocarbons and dimethylformamide. The dehydrogenation is carried out at room temperature or at a temperature above room temperature (e.g. in the range of from about 25°C to 200°C).

The foregoing procedure may be carried out from compounds 10 of formula VIII or IX without isolation of any further intermediate compounds. fa i Compounds corresponding to formula XII but in which R represents a hydroxymethyl group can be prepared as follows: A compound of formula VI or a corresponding phosphate is 15 reacted with dimethyImalonate under the conditions described earlier for the reaction of such compounds with a nitroalkane of formula IX to give a compound of the general formula C— i3 , wherein R, Rb and R3 have the significance 20 given earlier, which is then converted into a oompound of the general formula (XIV) 3 , wherein R, R and R have the significance given earlier, by refluxing with methanolic potassium hydroxide. Upon treatment with nitrous acid (e.g. by adding sodium nitrite to a solution of a compound of formula XIV in glacial acetic acid), there is formed a compound of the general formula NOH (XV) 3 , wherein R, R and R have the significance 10 given earlier, which is then catalytically hydrogenated (e.g. in the presence of Raney nickel) to give a compound of the general formula CH—R C —COOCH, // 3 (XVI) 42156 I ' 1 3 , wherein R', R and R have the significance given earlier, which is then treated with an orthoester of the general formula R C(OC2H5)3 (XVII) I , wherein R has the significance given earlier, to yield a oompound of the general formula (XVIII) a' , wherein R'; R , R and R have the 10 significance given earlier.

The carbomethoxy group in the 3-position of a compound of formula XVIII can be converted into the hydroxymethyl group by means of lithium aluminium hydride. l-Hydroxymethyl-4H-imidazo[l,5-a][1,4]benzodiazepines can 15 be prepared starting from corresponding 1-methyl compounds.

By treatment with an N-oxide providing agent such as m-chloroperbenzoic acid there can be obtained three different N-oxides, viz. the 5-oxide, the 2-oxide and the 2,5-dioxide, which can be separated by chromatography. The 2-oxide function can be selectively rearranged with acetic anhydride to give a 1-acetoxymethyl-2-desoxy compound and it is thus not necessary 48156 to separate the 2-oxide and the 2,5-dioxide for the preparation of the aforementioned l-acetoxymethyl-2-desoxy compound since the 5-oxide function of a produot obtained by subjecting a 2,5-dioxide to the said selective rearrangement can be reduced by phosphorus trichloride. The acetoxymethyl group in the 1-position of the compounds thus obtained can be easily converted into the hydroxymethyl group (e.g. by means of sodium methoxide in methanol).

Xt will be appreciated that when a compound of formula IX 10 or XVI in which R' represents an amino group is acylated, then such amino group may be acylated to an acylamino group. An acylamino group can be converted back into an amino group by mild hydrolysis. It will also be appreciated that compounds in which R represents an amino group can be converted into corresponding nitro compounds by the well-known Sandmeyer reaction; see, for example, E. R. Ward, C. D. Johnson and J. G. Hawkins, J. Chem. Soc,, 894, (1960).

The following Examples illustrate the manner in which the substituted-phenyl ketones provided by the present invention can be prepared. The structure of all products obtained was confirmed by standard procedures including infrared and nuclear magnetic resonance spectroscopy.

Example 1 (i) 100 g of 7-bromo-l',3-dihydro-5- (2-pyridyl)-2H-1,4-.benzodiazepin-2-one were dissolved in 750 ml of 2-N hydrochloric acid and left at room temperature overnight. The solution was evaporated to an oil which was dissolved in water and re-evaporated. The final traces of water were removed by shaking the oil with 50% methanol/toluene followed by evaporation. This treatment was repeated three times with 50% methanol/toluene and twice with toluene. There was obtained a pale-yellow to.orange solid which was dried at 50°C in vacuo. The product was characterised by its spectral data and was shown by titration to contain 2.5 moles of hydrogen chloride to one mole of 2-amino-N-(4-bromo-2-picolinoylphenyl)acetamide (133.5 g; 99%). After prolonged drying over sodium hydroxide, there was obtained an analytical sample which was stoichiometric.

Analysis for C14Hl4BrCl2N3O2 (407.11): Calculated: C: 41.31; Cl: 17.42. H: 3.47; N: 10.32; Br: 19.63; Found: C: 41.02; H: 3.61; N: 10.11; Br: 20.08; Cl: 17.82. (ii) 7.24 g of N-benzyloxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester were dissolved in 80 ml of dimethy1- 22 42156 formamide, the solution was cooled to -20°C and 8,48 g of the dihydrochloride, prepared as described in paragraph (i), were added. 6.16 ml of N-ethylmorpholine were then added over a period of 0.5 hour to the vigorously stirred suspension. The resulting mixture was subsequently stirred for 1 hour at -20°C and overnight at room temperature. The solvent was removed in vacuo and the residue dissolved in a mixture of chloroform and water. The layers were separated and the aqueous layer extracted with a further portion of chloroform. The combined organic phases were washed five times with water, dried over magnesium sulphate and evaporated to an oil. Crystallisation from hot ethanol yielded 10.0 g (64%) of (N-benzyloxycarbony1-L-phenylalanyl)-N-(4-bromo-2-picolinoyIphenyl)glycinamide of melting point 157°-183°C (slow decomposition).

Analysis for G3iH27BrN4°5 (615.50): Calculated: C: 60.49; H: 4.42; N: 9.10.

Found: C: 60.44; H: 4.41; N: 8.90.

Example 2 3.18 g of N-benzyloxycarbony1-L-isoleucine were dissolved in 25 ml of dry tetrahydrofuran and cooled to -10°C. 1.57 ml of isobutylchloroformate and 1.52 ml of N-ethylmorpholine were added and the resulting solution was stirred at -10°C for 20 minutes. 4.24 g of 2-amino-N-(4-bromo-2-picolinoylphenyl)acetamide dihydrochloride, prepared as described in part (i) of Example 1, were added and the resulting suspension was cooled to -20°C. 3.13 ml of N-ethylmorpholine in 25 ml of dimethylformamide were added to the vigorously stirred suspension over a period of 0.5 hour. The resulting mixture was stirred at - 23 42156 -20°C for a further 40 minutes and left at room temperature overnight. The product was worked up in a manner analogous to that described in part (ii) of Example 1. Recrystailisation from ethanol yielded 4.2 g (60%) of (N-benzyloxycarbonyl-L-isoleucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide of melting point 174°-176°C.

Analysis for ^g^gBrN^Og (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.

Example 3 In a manner analogous to that described in Example 2 there was obtained (Na,NE-ditertbutoxycarbonyl-L-lysyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide of melting point 135°-137°C.

Analysis for C3oH4oBrN5°7 (662.59): Calculated: 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.

Example 4 6.56 g of tertbutoxycarbony1-L-leucyl N-hydroxysuccinimide ester were dissolved in 80 ml of dimethylformamide, the solution was cooled to -20°C and 8.48 g of 2-amino-N-(4-bromo-2-picolinoylphenyl)acetamide dihydrochloride were added. 6.16 ml of N-ethylmorpholine were then added over a period of 30 minutes to the vigorously stirred suspension. The mixture was then stirred for 1 hour at -20°C and overnight at room temperature.

The working-up was carried out in the same manner as described in Example 1 (ii). The resulting oil was crystallised from a mixture of ethanol and water and recrystallised from the same solvent mixture to yield 5.1 g (47%) of pure (N-tertbutoxycarbonyl-L-leucyl)-N-(4-bromo-2-picolinoyIphenyl)glycinamide of melting point 129°-132°C.

Analysis for C25B31Br^4°5 (547.46): Calculated: 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.

Example 5 .9 g of N-benzyloxycarbonylglycylglycine were suspended in 600 ml of dry 1,2-dimethoxyethane and the suspension was cooled to -5°C. 6.06 g of N-methylmorpholine and 8.22 g of isobutylchloroformate were added and the resulting mixture was stirred at -5°C to -1O°C for 2 hours. Unreacted starting material and N-methylmorpholine hydrochloride were separated by filtration and the filtrate (stored at -5°C to 0°C) was added portionwise over a period of several hours to a refluxing solution of 14.7 g of 5-chloro-2-methylaminobenzophenone in 200 ml of dry 1,2-dimethoxyethane. The resulting solution was then stirred under reflux overnight.

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 sulphate and then evaporated to give 30 g of a yellow gum. Column chromatography of this gum on Florisil (trade mark) using mixtures of benzene and methanol yielded 12 g (40%) of pure (N-benzyloxycarbonylglycyl)-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide as an almost colourless light-sensitive gum which was characterised by its spectroscopic properties and elemental analysis.

Analysis for C26H24C1N3O5 (493.95): Calculated: C: 63.23; H: 4.90; N: 8.51; Cl: 7.18. Found: C: 63.61; Hs 4.87; N: 8.37; Cl: 7.02.

Example 6 In a manner analogous to that described in Example 5, there was obtained (N-benzyloxycarbonylglycyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide of melting point 139°-141°C (from ethanol).

Example 7 (a) 20.9 g of N-benzyloxycarbonylglyoine were suspended in 1500 ml of dry 1,2-dimethoxyethane and the suspension was cooled to -20°C. 10.1 g of N-methylmorpholine and 13.7 g of isobutylchloroformate Were added, the resulting solution was stirred at -20°C for 1 hour and then filtered. The filtrate (stored at -10°C to 0°C) was added portionwise over a period of several hours to a refluxing solution of 24.55 g of 5-chloro-2-methylaminobenzophenone in 200 ml of 1,2-dimethoxyethane, the resulting mixture was boiled overnight and then evaporated to dryness in vacuo. The yellow residue was dissolved in ethyl acetate, washed with two portions of water and one portion of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and then evaporated in vacuo.

Column chromatography of the residue on Florisil (Trade Mark) using mixtures of benzene and chloroform yielded 35 g (80%) of pure 2-(N-benzyIoxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide as a pale yellow gum.

Analysis for c24H2iclN2°4 (436·9)’ Calculated: C: 65.98; H: 4.85; N: 6.41.

Found: C: 65.91; H: 5.03; N: 6.51. 43.7 g of 2-(N-benzyloxycarbonylamino)-N-(2-benzoy1-4-chlorophenyl)-N-methylacetamide were dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the resulting solution was stirred overnight at room temperature The mixture was added slowly to a large excess (2000 ml) of dry diethyl ether with vigorous stirring. The product which separated was allowed to settle and the supernatant liquors were decanted off. The residue was triturated with 150 ml of acetone and the product filtered off, washed consecutively with the minimum amount of acetone and dry diethyl ether and dried in vacuo to give 29.5 g (77%) of 2-amino-N-(2-benzoy1-4-chlorophenyl)-N-methylacetamide hydrobromide as a white hygroscopic powder of melting point 194°-195°C (decomposition).

Analysis for C]_6H16BrC''’N2O2 (383.7): Calculated: C: 50.10; Hi 4.21; N: 7.30; Br ion: 20.83. Found: C: 44.98; H: 3.83; N: 7.15; Br ion: 21.14. (b) 84 g of N-benzyloxyoarbonylglycine were suspended in 500 ml of alcohol-free chloroform and the suspension was cooled to -20°C. The stirred suspension was treated portionwise over a period of 15 minutes with 90 g of phosphorus pentachloride and the stirring was continued until a clear solution was obtained. At this point, the cold mixture was added dropwise 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 was stirred for a further 1 hour at -5°C and then overnight at room temperature. The stirring was then discontinued and the liquid phases allowed to separate. The chloroform layer was washed three times with 500 ml of water each time and evaporated in vacuo to give 150.7 g of ·η viscous yellow gum which was shown by physical methods to be almost pure (above 95%) 2-(N-benzyloxycarbonylamino)-N-(2-benzoy1-4-chlorophenyl)-N-methylacetamide.

The product obtained according to the preceding paragraph was dissolved in 650 ml of a 30% solution of hydrogen bromide in glacial acetic acid and treated in an identical manner to that described in part (a) of this Example to give 2-amino-N-(2-benzoy1-4-chlorophenyl)-N-methylacetamide hydrobromide in a 77% overall yield from 5-chloro-2-methylaminobenzophenone. (c) 3.96 g of N-benzyloxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester were dissolved in 50 ml of dry dimethylformamide. The resulting solution was cooled to -20°C and there were added 3.84 g of 2-amino-N-(2-benzoy1-4-chlorophenyl)-N-methylacetamide hydrobromide followed by the dropwise addition of 1.15 g of N-ethylmorpholine. The resulting · mixture was vigorously stirred for 1 hour at -20°C and then overnight at room temperature. The solvent was evaporated in vacuo and the residue dissolved in a mixture of dichloromethane and water. The organic and aqueous layers were separated and 4215 the aqueous phase extracted with further portions of dichloromethane. The combined organic phases (250 ml) were washed three times with 50 ml of water each time, dried over anhydrous magnesium sulphate and evaporated in vacuo to give 5.8 g of a yellow oily residue which was shown by physical methods to consist of a mixture of 7-chloro-l,3-dihydro-l-methy1-5-phenyl-2H-l,4-benzodiazepin-2-one and (N-benzyloxycarbonyl-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide in the approximate proportions of 1:3.

The foregoing mixture oan be purified by column chromatography on Florisil to give pure (N-benzyloxycarbonyl-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colourless light-sensitive brittle foam; [a]p = -13.6° (c = 1 in ethanol).

Analysis for Ο^Η^θΟΙΝ^Ο^ (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.

Example 8 In a manner analogous to that described in Example 7, there was obtained (Na,NE-bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost 20 colourless light-sensitive gum; [a]D =-9.3° (c = 1 in ethanol).

Analysis for C^I^gClN^O.? (699.2): Calculated: 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.

Example 9 In a manner analogous to that described in Example 7 there was obtained (Νσ,Ne,Nw-trisbenzyloxycarbony1-L-arginyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost 20 colourless light-sensitive brittle foam; [a]D = -2.4° (c = 1 in ethanol).

Analysis for C^gH^ClNgOg (861.35): 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. 10 Solvent-free*: C: 63.90; Hi 5.20; Ni 9.68; Cl: 3.91, * The dichloromethane content was estimated by nuclear magnetic resonance spectroscopy to be 0.10 ί 0.02 moles.

Calculated for C4gH45ClNgOg, 0.1 CH2C12 (869.84): C: 63.66; H: 5.24; N: 9.66; Cl: 4.80.

Example 10 (a) In a manner analogous to that described in Example 7 (b) there was obtained 2-(N-benzyloxycarbonylamino)-N-(2-benzoy1-4-chlorophenyl)-N-methylpropionamide as a pale yellow gum; [a]20 = -3.75° (c = ί in ethanol).

Analysis for.C25H23C1N2O4 (450.92): Calculated: C: 66.60; H: 5.14; N: 6.21; Cl: 7.86.

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

The product obtained according to the preceding paragraph was dissolved in an excess of a 30% solution of hydrogen bromide and treated in a manner identical to that described in Example 7 (a) to give 2-amino-N-(2-benzoy1-4-chlorophenyl)-N30 42156 -methylpropionamide hydrobromide as an almost colourless hygroscopic powder of melting point 14O°-145eC (slow decom20 position) (from acetone/diethyl ether); [a]D = +13.2° (c = 1 in ethanol).

Analysis forC17H18C1N2 02 (397.70) : Calculated: C: 51.34; H: 4.56; N: 7.05; Br ion: 20.10. Found: C: 50.98; H: 4.73; N: 6.78; Br ion: 20.05; H20: 0.75. Water-free: C: 51.37; H: 4.68; Ni 6.83; Br ion: 20.20. (b) In a manner analogous to that described in Example 7 (c) there was obtained a mixture of 7-chloro-l,3-dihydro-l,3-dimethyl-5-phenyl-2H-l,4-benzodiazepin-2-one and (N-benzyloxycarbony 1-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methy1-L-alaninamide in the approximate proportions of 2:1.

Example 11 (i) 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 Β. V. Kamdar, J. Med. Chem., 1971, 14, 1078] were dissolved in 40 ml of dilute hydrochloric acid and left at room temperature overnight. The solution was evaporated to an oil which was dissolved in water and re-evaporated. The final traces of water were removed by shaking the oil with 50% methanol/toluene followed by evaporation. This treatment was repeated three times with 50% methanol/toluene and twice with toluene. This gave 5-chloro-2-(3-aminomethyl-5-methyl-4H-l,2,4-triazol-4-yl)benzophenone hydrochloride as a foam. (ii) The foam prepared as described in the preceding paragraph was dissolved in 25 ml of dry dimethylformamide and to the resulting solution were added 2.64 g of N-benzyloxycarbonyl-L-phenylalanine N-hydroxysuccinimide ester. The solution obtained was then cooled to -20°C. A solution of 2.1 ml of N-ethylmorpholine in 8.4 ml of dimethylformamide was added to the vigorously stirred solution over a period of 0.5 hour. The resulting mixture was stirred for 1 hour at -20°C and left overnight at room temperature. The solvent was removed in vacuo and the residue was dissolved in a mixture of dichloromethane and water. The layers were separated and the aqueous layer was extracted with additional dichloromethane. The organic solutions were combined, washed five times with water, dried over magnesium sulphate and evaporated to an oil which was chromatographed on silica gel. Elution was carried out initially using chloroform and then using 2% methanol in chloroform, 15 ml fractions being collected. Fractions 1-25 comprised the chloroform eluate and the product was contained in fractions 48-57. ' These latter fractions were combined, evaporated to dryness and the residue crystallised from ethyl acetate/petroleum ether. 1.8 g (45%) of 5-chloro-2-/~[(N-benzyloxycarbony1-L-phenylalanyl)aminomethyl]-5-methyl-4H-l,2,4-triazol-4-yl_7benzophenone of melting point 84°-88°C were obtained.

Example 12 (a)(i) A solution of 200 g of 7-chloro-l,3-dihydro-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one in 2 litres of tetrahydrofuran. and 250 ml of benzene was saturated with methylamine with cooling in an ice-bath. A solution of 190 g of titanium tetrachloride in 250 ml of benzene was added through a dropping funnel within 15 minutes. After completion of the addition, the mixture was stirred and refluxed for 3 hours. 600 ml of water were added slowly to the cooled mixture. The inorganic material was separated by filtration and was washed well with tetrahydrofuran. The water layer was separated and the organic phase dried over sodium sulphate and evaporated. The crystalline residue was collected to give 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-l,4-benzodiazepine of melting point 2O4°-2O6°C. An analytical sample was recrystallised from methylene chloride/ethanol and had a melting point of 2O4°-2O6°C. (a)(ii) 8.63 g of sodium nitrile were added in three portions over a 15 minute period to a solution of 30.15 g of 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-l,4-benzodiazepine in 150 ml of glacial acetic acid. After stirring for 1 hour at room temperature, the mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated, at the end azeotropically with toluene to yield 29 g of crude 7-chloro-5-(2-fluorophenyl)-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine as a yellow oil.

This oil was dissolved in 100 ml of dimethylformamide and added to a mixture of 200 ml of dimethylformamide, 50 ml of nitromethane and 11.1 g of potassium tert.butoxide which had been stirred under nitrogen for 15 minutes. After stirring for 1 hour at room temperature, the mixture was acidified by the addition of glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts were washed with water, dried over sodium sulphate and evaporated. Crystallisation of the residue from diethyl ether yielded 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-l,45 -benzodiazepine of melting point 17O°-172°C. An analytical sample was recrystallised from methylene chloride/ethanol and had a melting point of 174°-176°C. (a)(iii) 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 was hydrogenated with 5 teaspoonsful of Raney nickel for 2.5 hours at atmospheric pressure. Separation of the catalyst and evaporation left 14 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodiazepine. (a)(iv) 7 ml of acetic anhydride were added to a solution of 6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH-l,4-benzodia2epine in 200 ml of methylene, chloride. The solution was layered with 200 ml of Saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer.was separated, washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated to leave 6.2 g of resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl) T-lH-l,4-benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150°C for 10 minutes. The cooled mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue (5.7 g) was chromatographed over 120 g of silica gel 4215 using 20% methanol in methylene chloride. The clear fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1.5 hours. The manganese dioxide was separated by filtration over Celite (Trade Mark). The filtrate was evaporated and the residue crystallised from diethyl ether to yield 8-chloro-6-(2-fluorophenyl)-1-methy1-4H-imidazo[1,5-a][1,4]benzodiazepine of melting point 152°-154°C. An analytical sample was recrystallised from methylene chloride/hexane. (b) (i) 2.0 g of 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine were dissolved in 15 ml of dilute hydrochloric acid and left at room temperature overnight, The solution was evaporated to an oil which was dissolved in water and re-evaporated. The final traces of water were removed by shaking the oil with 50% methanol/toluene followed by evaporation. This treatment was repeated three times with 50% methanol/toluene and twice with toluene. This gave 520 -chloro-2'-fluoro-2-(5-aminomethyl-2-methyl-l-imidazolyl)-benzophenone dihydrochloride as a pale yellow solid. (b)(ii) The solid prepared as described in the preceding paragraph was dissolved in 20 ml of dry dimethylformamide and to the resulting solution were added 1.56 g of N-benzyloxy25 carbonyl-L-leucyl N-hydroxysuccinimide ester. The solution obtained was then cooled to -20°C. A solution of 2.5 ml of N-ethylmorpholine in 10 ml of dimethylformamide was added dropwise with vigorous stirring over a period of 20 minutes.

The mixture was stirred for 1 hour at -2O°C and left overnight at room temperature. The solvent was removed in vacuo and the residue dissolved in a mixture of chloroform and water. The layers were separated and the aqueous layer was extracted with additional chloroform.' The organic layers were combined, washed five times with water, dried over magnesium sulphate and evaporated to an oil which was chromatographed on 100 g of silica gel. Elution was carried Out using 4% methanol in chloroform, 15 ml fractions being collected. The product was eluted in fractions 25-36. These fractions were combined and evaporated to dryness and the resulting oil was crystallised from ether. 1.4 g (43%) of 5-chloro-2,-fluoro-2-/—5-[(N-benzyloxycarbonyl-L-leucyl)aminomethyl]-l-imidazolyl_7benzophenone of melting’point 63°-75°C (decomposition) were obtained.

Analysis for C32H32C1FN4°4 (591.09) : Calculated: ’ C: 65.02; H: 5.46; N: 9.48.

Found: C: 64.66; H: 5.61; N: 9.19.

Claims (33)

CLAIMS:

1) Compounds of the general formula , wherein A represents a nitrogen atom which may be substituted by a methyl, 5 cyclopropylmethyl, di(C 1-4 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group and B represents a carbonyl group or A and B together represent a grouping of the formula -c X \ # N—C x / \ (i) in which R a represents a hydrogen atom or a lower alkyl or hydroxymethyl group and X represents a nitrogen atom or C-R wherein R b represents' a hydrogen atom or 15 a lower alkyl or hydroxymethyl group; R represents a halogen atom or a nitro or trifluoromethyl group; R 1 represents a hydrogen atom or a lower alkyl group; R 30 represents an acyl group derived from a naturally occurring amino acid in which the amino group or amino groups present is/are in protected form and any other functional group whioh may be present is in protected 5 form where required (all such acyl groups which contain an asymmetric carbon atom 3 having the L-configuration) and R represents a phenyl, halophenyl or 2-pyridyl group.

2. ) Compounds of the general formula (la) wherein R, r\ R 20 and R 2 have the significance given in claim 1 and R represents a hydrogen atom or a methyl, cyclopropyImethyl, di(C^_ 4 15 alkyl)aminoethyl, methoxymethyl or hydroxyethyl group.

3. ) Compounds of formula Ia given in claim 2, wherein R represents a chlorine or bromine atom or a nitro group, represents a hydrogen atom, R represents a phenyl, o-fluoro20 phenyl, o-chlorophenyl or 2-pyridyl group and R 3 4 * represents a hydrogen atom or a methyl, diethylaminoethyl or methoxymethyl group. 38 <2156

4. ) Compounds of the general formula (lb) 1 2 wherein R, R , R , significance given R 3 and R a have the in claim 1. 5

5. ) Compounds of formula lb given in claim 4, wherein R 1 3 represents a chlorine atom, R represents a hydrogen atom, R represent s a phenyl or o-chlorophenyl group and R a represents a methyl or hydroxymethyl group. 6

6. ) Compounds of the general formula wherein R, R 3 , R 2 , R 3 , R a and R b have the significance given in claim 1.

7. ) Compounds of formula Ic given in claim 6, wherein R a and R b each represent a hydrogen atom or a lower alkyl group.

8. ) Compounds as set forth in claim 6, wherein R represents 1 3 a chlorine atom, R represents a hydrogen atom, R represents a phenyl or o-fluorophenyl group, R a represents a methyl or hydroxymethyl group and R b represents a hydrogen atom. 5

9. ) Compounds as set forth in-any one of claims 1 to 8 inclusive, wherein the acyl group denoted by R is derived from an L-amino acid.

10. ) Compounds as set forth in claim 9, wherein said L-amino acid is L-phenylalanine or L-lysine, 10

11. ) Compounds as set forth in any one of claims 1 to 10 inclusive, wherein the amino group or groups present in the acyl group R 30 is/are protected by an aralkoxycarbonyl group.

12. ) Compounds as set forth in claim 11, wherein said aralkoxycarbonyl group is the benzyloxycarbonyl group. 15

13. ) Compounds as set forth in any one of claims 1 to 10 inclusive, wherein the amino group or groups present in the 20 acyl group R is/are protected by a tert.butoxycarbonyl group.

14. ) Compounds as set forth in any one of claims 1 to 10 inclusive, wherein the amino group or groups present in the 20 20 acyl group R is/are protected by a formyl, trityl or trifluoroacetyl group.

15. ) Compounds as set forth in any one of claims 1 to 14 inclusive, wherein a carboxy group present in the acyl group 40 42156 R is protected in the form of an alkyl ester or an aralkyl ester.

16. ) Compounds as set forth in any one of claims 1 to 14 inclusive, wherein a hydroxy group present in the acyl group 20 5 R is protected by means of an aralkoxycarbonyl, alkanoyl, aroyl, alkyl or aralkyl group,

17. ) Compounds as set forth in claim 16, wherein said aralkoxycarbonyl group is the benzyloxycarbonyl group.

18. ) Compounds as set forth in claim 16, wherein said alkanoyl 10 group is the acetyl or propionyl group.

19. ) Compounds as set forth in claim 16, wherein said aroyl group is the benzoyl group.

20. ) Compounds as set forth in claim 16, wherein said alkyl group is the tert.butyl group. 15

21. ) Compounds as set forth in claim 16, wherein said aralkyl group is the ben2yl group.

22. ) (N-Benzyloxycarbonyl-L-phenylalanyl)-N-(4-bromo-2-picolinoyIphenyl)glycinamide.

23. ) (N-Benzyloxycarbonyl-L-isoleucyl)-N-(4-bromo-2-pico20 linoyIphenyl)glycinamide.

24. ) (N a ,N e -Ditert.butoxycarbonyl-L-lysyl)-N-(4-bromo-2-picolinoyIphenyl)glycinamide. 41 42156

25. ) (N-Tert.butoxycarbonyl-L-leucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide.

26. ) (N-Benzyloxycarbonylglycyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide. 5

27. ) (N-Benzyloxy,carbonylglycyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide.

28. ) (N-Benzyloxycarbonyl-L-phenylalanyl)-N-(2-benzoy1-4-chlorophenyl)-N-methylglycinamide.

29. ) (N a ,N E -Bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoy1-410 -chlorophenyl)-N-methylglycinamide.

30. ) (Ν 2 ,Ν ε ,N W -Trisbenzyloxycarbony1-L-arginyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide.

31. ) (N-Benzyloxycarbony1-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alaninamide. 15

32. ) 5-Chloro-2-/ — [(N-benzyloxycarbony1-L-phenylalanyl)aminomethyl] -5-methyl-4H-1,2,4-triazol-4-yl_7benzophenone.

33. ) 5-Chloro-2’-fluoro-2-/ - 5-[(N-benzyloxycarbony1-L-leucylamino) methyl] -2-methy1-1-imidazolyl_7benzophenone.