CA1177069A - Phenyl ketones - Google Patents

Abstract

ABSTRACT
The invention provides substituted-phenyl ketones of the general formula I
, wherein A represents a nitrogen atom which may be substituted by a methyl, cyclopropyl-methyl, di(C1-4 alkyl)aminoethyl, methoxy-methyl 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 Rb 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 lower alkyl group; R2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R3 represents a phenyl, halophenyl or 2-pyridyl group, and acid addition salts thereof which possess sedative, muscle relaxant and anti-convulsant activity.

Description

:.20328-1052 ~ ~717~

The present inventi.on is concerned with substituted-phenyl ketones and a process for the manufacture thereof.
The substituted-phenyl ketones provided by the present invention are compounds o~ the general ~ormula R,l 2 ~ A-B-CH-NH-R

R C=O

, wherein A represents -NH- or -N(CH3)- and B represents a carbonyl group or A and B together represent a grouping of the formula Ra C ~ N y ~ N-C ~

in which Ra represents a hydrogen atom or a lower alkyl or hydroxymethyl group and X represents a nitrogen atom or C-Rb wherein Rb represents a hydrogen atom or a lower alkyl or hydroxymethyl group; R represents a haloyen atom or a nitro or trifluoromethyl group; Rl represents a hydrogerl a-torn or a lower alkyl group; R2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contaln an asymrnetric carbon atom having the L- or D,L-configuration) and R- represents a phenyl, halophenyl or 2-pyridyl group, and pharmaceutically acceptable acid addition salts thereof, provided that when A is -NH- or -N(CH3)-, B is carbonyl, R is a chlorine atom, Rl is a hydrogen atom and R3 is a phenyl group, R2 does not represent L-alanyl or L--leucyl, and provided also that when A is -NH- or -N(CH3)-, B is carbonyl, R is a halogen atom, R
is a hydrogen atom and R3 is a mono-halophenyl group, R2 does not represent glycy]., L-phenylalanyl, L-valyl, L-alanyl or L-leucyl.

RAN ~008/280 K- -2-,. ...

~1~7'7~6~

It Will be appr~ciated that formula I hereinbefore embraces compounds of the general formulae I_ ~
~ ~ CH-NH-R2 Ia /~\ R 1 R3 ~.

R - C N
~ / N - C \ CH--NH-R~ Ib and Ra C ~ \ C b N - C D Ic CH-NH_R2 R C--O

"~ 3-..

5~3 wherein R, R , R , R3, R~ an~ Rb have the significance given earlier and R4 represents a hyclrogen atom or a methyl group, provided that in formula Ia when R is a chlorine atom, Rl is a hydrogen atom and R3 is a phenyl group, R does not repxesent L-alanyl or L-leucyl, and provided also that when R is a halogen atom, Rl is a hydrogen atom and R3 is a monohalophenyl group, R2 does not represent glycyl, L-phenylalanyl, L-valyl, L-alanyl or L-leucyl.
As used in this specification, the term "lower alkyl"
means a straight-chain or branched-chain alkyl group which preferably contains from 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like). The methyl group is the preferred lower alkyl group. The term "halogen" means fluorine, chlorine, bromine or iodine. The acyl group denoted by R is preferably derived from a naturally occurring ~-amino carboxylic acid such as glycine or L- or D,L-alanine, -leucine, -phenylalanine, -isoleucine, -serine, -lysine, -methionine, -proline and the like. Especially preferred acyl groups are those derived from L-amino acids, particularly from L-phenylalanine or L-lysine. The preferrec!
halogen value for R is chlorine or bromine when R3 represents a phenyl or halophenyl group and bromine when R3 represents a ~-pyridyl group. The halophenyl group denoted by R3 includes a monohalophenyl group, especially an o-halophenyl group such as o-chlorophenyl or o-Eluorophenyl, and a dihalophenyl group, especially an o,o'-dihalophenyl group such as o,o'-dichloro-0 phenyl.Preferred compounds o~ formula Ia hereinbefore are those in which R represents a chlorine or bromine atom or a nitro , 7'~ 3 group, Rl representsa hy~royen atom, R3 represents a phenyl, o-fluorophenyl, o-chlorophenyl or 2-pyridyl group and R4 represents a hydrogen atom or a methyl group.
Examp].es of compounds of formula Ia hereinbefore are:
L-phenylalanyl-N-(4-bromo-2-picolinoylphenyl)glycin-amide, glycyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L-leucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L-lysyl-N-~4-bromo-2-picolinoylphenyl)glycinamide, L-lsoleucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L- ~ -glutamyl-N-(4-bromo-2-picolinoylphenyl)glycin-amide, L-alanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L-arginyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, L- ~-glutamyl-N-(4-bromo-2-pi.colinoylphenyl)glycin-amide, glycyl-N-(2-benzoyl-4-chlorophenylJglycinamide, glycyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, L-prolyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, glycyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycin-amide, L~phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl--glycinamide, L-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycin-amide and L-phenylalanyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, L-arginyl-N-(2--benzoyl-4-chlorophenyl)glycinamide, L-alanyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, L-alanyl-N-[2-(2'-fluorobenzoyl)-4-nitrophenyl]-N-methylglycinamide and .. -5-7'~

L-phenylalanyl-N-~2-benzoyl-4-chlorophenyl)-N-methyl-L-alaninamide.

Preferred compound~ of formula Ib hereinhe~ore are tho~e in which R repre~ents a ~hlorine atom, Rl represents a hydrogen atom, R3 represent3 a phenyl or o-ahloro-phenyl group and Ra repreqents a methyl or hydroxymethyl group.

Examples of compounds of formula Ib are:
5-chloro-2-[3-~L-phenyl~lanylaminomethyl)~5-methyl-4H-1,2,4-tria~ol-4-yl~benzophenone, lo 5-chloro 2-~3-~L-lysylaminomethyl)-5-methyl 4H-1,2,4~
triazol-4-yl~benzophenone,

2',5-dichloro-2-[3-~L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-~-yl]benzophenone, 2~,5-dichloro-2-[3-(L-ly~ylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone and 2',5-dichloro-2-(3-glycylaminome~hyl-5-methyl-4H 1,2,4 triazol-4-yl)benzophenone.

Pre~err~d aompound~ of formula Ic hereinbefore are those in which R repre~ents a chlorine atom, Rl represents a hydrogen atom, R3 repre~ents a phenyl or o-fluoro-phenyl group, Ra represents a methyl or hydroxymethyl group and Rb represents a hydrogen atom.

Examples of compound~ of ormula Ic are:
5-chloro-2'-fluoro 2-[5-(L-leucylaminomethyl)-2-methyl-l-imidazolyl]benzophenone and 5-chloro-2'-f luoro-2- [ 5~ -alanylaminomethyl)-2-methyl-l-imidazolyl]benzophenone.

31",,~t~t~ 69 Aceording to the proeess provided by the present invention, -the substitu-ted-pheny:L ketones aforesaid (i.e. the compounds of formula I hereinbefore and their aeid addition salts) are manufaetured by (a) eleaving off the protecting group or protecting groups present in the group R20 in a eorresponding eompound of the general formula Rll ~ \ ~ A-B-cH-N~l-R2o II

R C=o , wherein A, B, R, R and R3 have the significance given earlier and R20 represents the aeyl group of a naturally occurring amino acid in which the amino group or amino groups present is/are in protected form and any other funetional group which may be present is in proteeted Eorm where required (all sueh aeyl groups which conta:in an asymmetrie earbon atom having the L- or D,L-eonfiguration), or (b) for the manufaeture of a compound of formula I in whieh A represents -NH- or -N(CH3)- and B represents a ~r ~1 carbonyl group, R represents a nitro group and R2 represents an acyl group derived Erom a naturally occurring amino ac.id which is not affected by nitrating agen-ts (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration), nitrating a compound of the general formula N - C ~

/ \ cH_NH_R21 III

, wherein Rl and R3 have the significance given earlier, R4 represents a hydrogen atom or a methyl group and R21 represents an acyl group derived from a naturally occurring amino acid which is not affected by nitrating agents (all such groups which contain an asymmetric carbon atom ha~ing the L- or D,L-configuration), and, if desired, converting a free base obtained into a pharmaceutically acceptable acid addition sal-t or converting an acid addition salt obtained into a free base or into a different pharmaceutically acceptable acid addition salt.
The amino group or amino groups present in the acyl group denoted by R20 in formula II can be protected with any amino-protecting group which is well-known in peptide chemistry.
Especially suitable amino-protecting groups for the ,1. j 7'7~69 purpo~e o~ the present in~ention axe aralkoxycarbo~yl groups, particularly th~ benzyloxycarbonyl group~ and the tertbutoxy-carbonyl group. The amino-protecting group may also be a formyl, trityl or trifluoroacetyl group. Any car~sxy or hydroxy group which may be pre~ent in the acyl group denoted by R2~ in formula II can be protected by a conventional car-boxy-protecting or hydroxy-protec~ing group re~pectively.
For example~ a carboxy group may be protected by conv~rsion 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 aralkoxy-carbonyl group (e.g. be~zyloxycarbonyl), an alkanoyl group (e.g. acetyl, propionyl etc), an aroyl group (e.g. benzoyl), an alkyl group (e.gO t butyl~ or an aralkyl group (e.g.
benzyl). The protection of other functional group~ present in the acyl yroup denoted by R20 may be carried out in a known manner.

The removal of th~ protecting group or protecting groups presant in the acyl group denoted by R20 in a compound of formula II is carried out in accordanca with ~ethods known per ~e; that is to say, method~ in actual use for or described in the literature on the removal of protecting groups~ In a preferred embodiment of the present process, the acyl group denoted by R20 carries a protecting group or protecting groups which are removable by hydrolysi~. Thus, for example, an aralkoxycarbonyl group le.g. benzyloxycarbonyl~ or a tert-butoxycarbonyl group may be removed by treatment with a mix-ture of hydrogen bromide and acetic acid. The tertbutoxy~
carbonyl group may also be removed by means o~ hydrogen _ 9 _ chloride in an organic solvent (e.g. dioxan) or by means of trifluoroacetic acid. A benzyloxycarbonyl or a tetrabukoxy-carbonyl group may also be removed by treatment with boron trichloride or boron tribromide in an iner-t organic solvent such as dichloromethane.
The nitration of a compound of formula III
hereinbefore can be carried out according to methods known se. For example, the nitration can be carried out using an alkali metal nitrate, preferably potassium nitrate, in the presence of a strong mineral acid, preferably anhydrous sulphuric acid, or a strong organic acid, preferably anhydrous trifluoroacetic acid. The acyl group denoted by R21 in the compounds of formula III is preferably derived from glycine or L- or D,L-alanine, valine, leucine, isoleucine, lysine, proline or aspartic acid.
The starting materials of formula II hereinbefore can be prepared by a variety of routes.
Thus, starting materials of formula I:L can be prepared, for example, by condensing an amine of the general formula ~A-B-CH- Nl-12 11 ~y ~ R~OO:

, wherein ~, B, R, ~1 and ~3 ha~e the , : ~ signi~cance given earlier,:
with an appropriately protected amino~acid or a reactive S derivative thereof.~ ~

The condensation can be carried out in accordance with methods which are known per se in peptlde chemistry; for example, by the mixed anhydride, azlde, activated~ester or : acid chloride method.

10. In one method~ an appropriate ami~e o formula IV can be cond~nsed with an appropriately protectPd amin~ acid in which the terminal carboxy function is a mixed anh~dride residue formed witk an organic or inorganic acid. 5uitab1y, such ~n amino acid carrying a free carboxy functlon is ~reated with a tertiary base such as a trl~lower alkyl)amlne:(e.g. triethyl-amine) or N-ethylmorphollne in an inert organic so1vent (e.g.
tetrahydrofuran, dichloromethane or 1,2-dimethoxyethane) and the resulting ~alt is reacted with a chloroformic acid es~er : (e.g. the ethy1 or isobuty1 ester) at a 10w temperature. The mixed anhydride~obtained is then suitably conden~ed ln itu with the amine of formu1a IV.
:
In another method, an appropriate amine of formula IV

can be condensed with an appropriately protected amino acid in ~7'7~

which the terminal carboxy group is in the form of an acid azide. This condensation is preferably carriecl ou-t in an inert organic solvent such as dimethylformamide or ethyl acetate at a low temperature.
In yet another method, an appropriate amine of formula IV can be condensecl 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 suitably carried out at about -20C in an inert oxganic solvent such as dimethylformamide.
In a further method, an appropriate amine of formula IV can be condensed with an appropriately protected amino acicd 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, starting materials of formula II in which A represents -NH-or -N(CH3)- and B represents a carbonyl group can be prepared by condensing a compound of the general formula ~ / NH
~ il v R C =O

R

.~ .. .

'7~

, wherein R, R3 and R4 have the significance given earlier, with an appropriately protected dipeptide or a reactive derivative thereof using one of the methods described hereinbefore in connection with -the condensation of an amine of formula IV with a protected amino acid or a reactive derivative thereof.
The amines of formula IV hereinbefore in which A
represents -NH- or -N(CH3)- and B represents a carbonyl group can be obtained, for example, by condensing a compound of formula V hereinbefore with an appropriately protected amino acid or a reactive derivative thereof followed by removal of the protected group in the manner previously described.
Alternatively, the amines of formula IV in which A
represents -NH- or -N(CH3)- and B represents a carbonyl group and R3 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 ~ ~ - CH -Rl ~ ~ C N / VI

~ wherein A', B', R, Rl and R30 have any of the values accorded to A, B, R, R and ~h ~'7~

R3 hereinbefore with the proviso that when A' represents -NEI- or -N(OE13)- and s represen-ts a carbonyl group, then R30 represents a 2-pyridyl group, with a mineral acid. Thus, a l,4-benzodiazepine of formula VI
can be hydrolysed with sulphuric acid, nitric acid, phosphoric acid or, pre~erably, a hydrohalic acid such as hydrochloric acid. The hydrolysis is preferably carried out at a temperature of _ 20-30C.
The l,4-benzodiazepines of formula VI hereinbefore in 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 N / VII

, wherein R, Rl and R3 have the significance given earlier, to give a compound of the general formula ~' t~ 6s~
.

~ ~ N0 R ~ H-R

wherein R r Rl and R3 have the significance given earlier.

This nitro~ation may be carried out using nitrous acid which is foxmed ln 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 chlsrinated hydrocarbon or dimethylformamide, and a .~olution of nitrosyl chloride gas in an inert solvent and in the presence of an acld acceptor (e.g.
pyri.dine). Such a nitro~ation should be carried out at a temperature below room temperature ~e.g~ a temperature in the range of -20C to 25~C).

It will be appr~ciated that the grouping -N(C~3~(N0) in the 2~position of a compound of formula VIII i5 a leaving group and that equivalent leaving groups may be pre~ent in said position~ Examples of such equivalent leaving groups include groups such a~ alkoxide groups such as -OC~I3, alkyl-thio groups such as -SCH3 and phosphate groups such as ~Lt7~.7~

r ~1 --O--PO--~N ~p ~ . 2 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.

3,681l341.

A compound of formula VIII is then condensed with a nitro-alkane of the gen~ral formula Rb--~ H2--N2 lX

, wherein Rb represents hydrogen or lower alkyl, to give a compound of the general formula ~--Rb _~ N~C
f ~ I:H--R1 X

R ~ C ~ N /

wherein R, Rl, R3 and Rb have the significance given earlier.

The reaction of a compound o formula VIII with a nitro-alkane of formula IX (eOg. nitromethane, nitroethane etc) is carried out in the presence of a base which is ~ufficiently strong to generate the nitroalkane anion. Suitable bases 7~

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 ~uoh as dimethylformamide, 5 dimethyl sulphoxide or an ether ~e.g. tetrahydro~uran) at a temperature below or above room temperature ~e.g. in the range of -50~C to 150C), preferably a~ about room tempera~ure.

A compound of ormula X is then reduced by catalytic hydro-genation te.g. using hydrogen in the presence of Raney nickel) or by means of a reducing agent ~uch as lithlum aluminium hydride to give a compound o the general ormula I H; gb' ,J~ \CH R1 X 1 R C=N~
I

~3 wherein Rl, R3 and Rb have the ~ig~i~icance given earlier and R' represent~
a halogen atom or an amino or trifluoromethyl group.

The above deinition o~ R' in formula XI results from the conversion o a nitro group into an amino group under the condition~ used in ~he reduction of a compound of formula X.

Solvents suitable for the hydrogenation in the presence o~
Raney nickel include alkanols (e.g. ethanol), ethers (e.g.

i7~

tetrahydrofuran, diethyl ether etc), hydrocarbon~ ~e.g. toluene) and dimethylformamida. The temperature at which this catalytic hydrogenation is carried out may be above or below room ~empera~
ture (e.g. -50C to 150C). Thi~ catalytic hydrogenation may be carxied out with or without pressure (eOg. a pressure of one atmosphere or above).

Solvents suitable for the reduation using a reducing agent ~uch as lithium al~minium hydride includ~ ethers such as tetra-hydrofuran, dioxane and diethyl ether and mixtures of ethers and hydrocaxbons such as tetrahydrofuran and benzene. This reduction may be carried out at a temperature o~ from below room tempera-ture to the reflux temperature of the mixture, preferably at a temperature in the range o -50C to 60C.

A compound of formula XI is then acylated with an acylating agent yielding the moiety Ra C0-, in which Ra represents hydrogen or lower alkyl, ~uah as an acid halide or acid anhydride (e.g. acetic anhydride and acetyl chloride) to give a compound of the general formula IH CORa L~

il CH~Rl Xll R'~(:~ N ~
I

wherein Rl, R3, Ra and R~ have the significance given earlier, R' has ~he ~'7'î'~65~

same ~ignificance as in formula XI and Y represent~ a hydrogen atom or ~he moiety Ra C0-. .

The acylation of a compound of formula XI may yield a mix-ture consi~ting of the predominant monoacylated product ~i.e. in which the amino group i3 converted into a - NH-CORa group) and the diac,ylated produat i~ which both the amino group and nitrogen atom in tha l-position are acylated. The yield of diacylat~d product may be increased by ~ubjacting a compound of formula Xl 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 of an aclueous 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 te.g~ an alkali metal carbonate) or an inorganic ba~e (e.g. triethylamine or pyridine).

A compoun~ o ormula XII is subsequently cyclised to yield a compound of the genexal formula ~Z

N-~
~H -Rl )~

wher~in Rl, R3, Ra and Rb have the significance given earlier and R' has the sigr.ificance given in formula XI.

~1'7'~

The cyslisation of a compound o~ formula XXI is car~ied out using a dehydrating agent such as phoaphorus pentoxide, poly-phosphoric acid or other suitable acid catalysts (e.g. an organic or inorganic acid such as concentrated ~ulphuric acid). A
s qolvent is not required, but a solvent such as an aromatic hydroaarbon (e.g. toluene or xylena) may be used. The cycli-sation is carried out at a temperature of from about 100C -to 200c.

A compound of formula XI can also be reacted with an acy-lating agent such as an orthoester (eOg. triethylorthoacetate), an orthoamide (e.g. the N,N-dimethylformamide dimethyl acetal) or tri3 (dimethylamino)methane, i~ desired in the presence of an acid catalyst suah as an organic acid (e.g. paratoluenesulphonic acid) - or an inorganic acid (e.g. phosphoric acid~ and at room tempara-ture or a temperature above room temperature (e.g. 25~C to 150C), in which inB-tance the cyclisation to a compound of formula XIIX occurs spontaneou~ly. Other useful acylating agents include esters (e.g. methyl acetate), amides (e.g. acet- !
amide~, nitriles (e.g. acetonitrile) and ester imidates.

20A compound o~ ormula XIII iq then dehydrogenated to yield an imidazobenzodiazepine of the general formula ~ZN~

R ~N
~3 36~3 wherein ~ 3, Ra arld Rb hav~ th~
significance given earlier and R' has the significance given in ormula XI.

~he dehydroganation of a compound of formula XIII is pre-ferably 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 hydrocarbon~, dimet~ylformamide etc. The dehydro-genation is carried out at room temperature or at a temperature above room temperature (e.g. in the range of from about 25C to 200C~.

The foregoing procedure may be carried out from compounds of formulae X or XI without isolation of any further intérmediate compound~.

Compound~ corre~ponding to formula XIV but wherein Rb represents a hydroxymethyl group aan be prepared as ~ollows:

A compound of formula VIII~or a corresponding phosphate is reacted with dimethylmalonate, under the conditions described earlier for the reaction of these compounds with a nitroalkane 20 of formula IX, to give a compound of the general formula - 10~3 ~ ~ C-COOCH3 ,J~ CH -Rl X \~
R C---N/
I

' 7~ 9 r wherein R, Rl and R3 have the significance given earliex, whi~h is then converted into a compound of the general formula H ~ CH-coocH3 ~ ~ÇH--Rl X V 1 R IC; N

wherein R, Rl and R3 have the ~ignificance glven earlier, by reflu~ing with mathanolic potassium hydroxide. Upon treatment with nitrous acld (e.g. by adding sodium nitrite to a solution of a compound of formula XVI in glacial acetic acid) there is ~ormed a compound of the general ormula NOH
Il ~ N ~ C

R ~ / H - R1 wherein R, Rl and R3 have the significance given earlier, which is then catalytically hydrogenated (e.g. in the presence of Raney nickel) to a compound o~ the general formula lH2 H , ~;C-COO~::tl3 ~ N C

R I = N
F~3 ~L~7'7~

whereln R, Rl and R3 have the significance given earlier, which i~ then treated with an orthoestex of the general formula ~a C~OC2H5)3 XIX
wherein Ra has the significance given arlier, to yield a compound of ~he general ~ormula r ~0 ~
R a_C~ ,~- COOCH3 1~ \CH R1 Xx R' C:~N
i I

~ 3 wherein R', Rl, R3 and Ra have the significance given earlier.
The carbomethoxy group in the 3-position of the compound of formula XX can be converted into ~he hydroxymethyl group by means of lithium aluminium hydride.

l-Hydroxymethyl-4H-imidazo[1,5-a][1,4]benzodiazepines can be prepared starting from corresponding l-methyl compounds By treatment with an N-oxide providing agent such as m-chloroper-benzoic acid, there can be obtained three differant 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 l-acetoxy methyl-2-desoxy compound and it is thus not ~ecessary to separate the 2 oxide and the 2,5-dioxide for th0 preparation of the aforementioned l-acetoxymethyl-2-desoxy co~rlpound since the 5-oxide function of a product obtained by ~ubjecting a 2,5-_ 23 -.~lt~ 6~

dioxide to the eaid selective r~arrangement can be reduc~d by phosphorous trichloride. The acetoxymethyl group in the l-posi-tion of the compounds thu~ obtained can be easily converted into the h~droxymathyl group, eOg. by m~ans of sodium methoxide in methanol.

It will be appreciated that wh~n a compound o ormula XI
or XVIII in which R' represents an amino group i8 acylated,-then such amino group may be acylated to an acylamino group. An a~ylamino group can be converted back in~o an amino group by mild hydrolysis. It will also be appreciated that compounds in which R' repreqents an amino group can be converted into corresponding nitro compounds by the well-known Sandmeyer reac~ion; see, for example, E. Ro Ward, C. D. Johnson and J. G.
Hawkin~, J. Chem. Soc., 894, (196Q~ 9 The starting materials o~ formula III hereinbeforo can be prepax~d in the same manner a~ de~cribe~ hereinbefore for the manufacture o the corxesponding compoundq o~ formula I, but using appropriate compounds in which R represent~ a hydrogen atom.

The compound~ of formula I hereinbe~ore form acid addition ~alts with inorganic acids ~e.g. hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulphuric acid, phos~
phoric acid and nitric acid) and with organic acids (e.g. acetic acid, succinic acid, glycolic aoid, lactic acid, gluconic acid~
taxtaric acid, citric acid, maleic acid, malic acid, umaric acid, methanesulphonic acid, paratoluenesulphonic acid, oxalic acid, ascorbic acid, benzoic acid, hyd-~7'7~69 roxyethane sulphonic acid, 1,2-diethane sulphonic acid etc).
The phaxmaceutically acceptable acid addition salks are pre-ferred. The acid addition salts can be prepared according to well-known methods; for example, by treating a base ~lith S an appropriate acid. An acid addition salt may also be con-verted into a different acid addi~ion salt by means of a suitable anion exchange resin (e.g. Amberlite IRA-401 in the chloride form).

The compounds of formula I hereinbefore and their acid addition salts possess sedative, muscle relaxant and anti-convulsant activity. Of particular interest are those pharmaceutically acceptable acid addition salts which are water-soluble since they can be readily administered by injection; for example, in dentistry for the induction o~
anaesthesia and in the management of acute convulsive dis-orders and status epilepticus.

The anticonvulsant activity of the substituted-phenyl ketones of the present invention is demonstrated by adminis-teri~g them to mice and then subjecting the thus-treated mice to the well-known pentatetramethylenetetrazole test. In this test, L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-glycinamide hydrobromide, which has an LD50 of 70 mg/kg i.v.
in mice, has an ED50 of 2.0 mg/kg i.v. in miceO Also in this test, 5-chloro-2'-fluoro-2-[5-(L-leucylaminomethyl)-2-methyl-l-imidazolyl]benzophenone~ which has an LD50 of 119 mg/kg 1.v.
in mice, has an ED50 of 2.0 mg/kg l.v. ln mice. The muscle relaxant activity can be demonstrated in ~he well-known rotating rod test. In this test, L-phenylalanyl-N-(2-* TRADE MARK

-25 _ .~

~ 3L t~ ~7 ;(} ~ 9 benzoyl-4-chlorophenyl3-N-methylglycinamiae hydrobromide has an ED50 o 4.2 mg/kg i.v. in mice. Also in thi~ test, 5-chloro-2'-fluoro-2-[5-~L-leucylaminomethyl)-2-methyl~l-imi-dazolyl~benzophenone has an ED50 of 20 mg/kg l.v. in mice.

The compounds of formula I and their pharmaceutically acceptable acid addition sal~s may be used a~ medicaments;
for example, in the form of pharmaceutical prepara~ions which contain them in as~ociation with a compatible pharmaceutical carrier material. This carrier material can be an organic or inorganic carrier material suitable for enteral or paxenteral administration (e.g. water, lactose, gelatin, starches, mag-ne~ium stearate, talc, vegetable ol1 , gums, polyalkylene-glycols, petroleum jelly etc). The pharmaceutical prepara-tions can be made up in a solid form ~e.g. a~ tablets, dra-gées, capsules etc) or in a liquid form (e.g. solutions, suspensions or emulsions). Pharmaceutical preparations in a form adapted for injection purposes are preferred. The pharmaceutical preparations may be subjected to conventional pharmaceutical operation~ such as st~rilisation and/or may contain conventional pharmaceutical adjuvants such as pre-servatives, stabiliser3, wetting agents, emulsifiers, buffers etc.

The dosages in which the compounds of formula I and their pharmaceutically acceptable acid addition salts may be admini~tered can vary depending on the requirements of the patient and the directions of the attending physician. A
dosage of from 0.01 mg/kg/day to 1 mg/kg/day is, however, preferred.

- 26 _ ~ 7~ 3 The following Examples illustrate the proces~ provided by the present in~ention. The ~tructure of all products obtain~d was confirmed by standard procedures including infra-xed and nuclear magnetic resonance spectroscopy.

Exampl~ 1 ~) The preparation of ~he startin~ material:
(i) 100 g of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-~enzodiazepln-2-one were dissolved in 750 ml of 2-N hydro chloric acid and let at room temperature overnight. ~he olution was evaporated to an oil which was dis~olved in water and re-evapora~ed. The final trac~s of water were removed by shaking the oil with 50% methanol/toluene followed by evapor-ation. Thi~ treatment was repeated three time~ wi~h 50%
methanol/*oluene and twice with toluene. There was obtained a pale-yellow to orange solid which was dried at 50C ln vacuo, The product was characterised by its spectral data and was ~hown by 1-itration to contain 2.5 moles of hydrogen chloride to one mole o~ 2~amino-N~(4-bromo-2-picolinoyl-phenyl)acetamide (133.5 g; 99~). After prolonged drying over sodium hydroxide, there was obtained an analytical sample which was stoichiometric.
Analysis for C14H14BrC12N302 (407.11~:
Calculated: C: 41.31; H: 3.47; N: 10.32; Br: 19.63;
Cl: 17.42.
25Found: C: 41.02; H: 3.61; N: 10.11; Br: 20.08;
Cl: 17.82.

6~

(ii~ 7.24 g of N-benzyloxycarbonyl-L-phenylalanine N-h~droxysuccinimide ester were dissolved in 80 ml of dimethyl-formamide, ~he solution was cool~d to -20C and 8.48 g of the dihydrochloride, prepared as described in paragraph (i), were added. 5.16 ml of N~ethylmorpholine were then added over a period of 0.5 hour to the vigorously stirred su~pension. The resulting mixture was subsequently s irred for 1 hour at -20C
ana overnight at room $emperature. The solvent was removed in vacuo and the residue dissolved in a mixture of chloroform and water. The }ayers were separ~ted 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-benzyloxycarbonyl-L-phenylalanyl~-N-(4-bromo-2-picolinoylpheny})glycinamide o melting point 157-183C ~slow decomposition~.
Analysis for C31~27BrN4S (615-50) Calculated: C: 60.49; H: 4.42; N: 9.10.
Found: C: 60.44; H: 4.41; N: 8.90.

B) The process:

4.0 g of (N-benzyloxycarbonyl-L~phenylalanyl)-N-(4-bromo~2-picolinoylphenyl)glycinamide were stirred for 1 hour in a solution of 35% hydrogen bromide in glacial acetic acid.
Dry diethyl ether was then added and the separated solid was filtered off, washed with diethyl ether and dried ln vacuo.
The crude product was dissolved in a minimum amount of dry methanol and trea~ed with e hyl acetate, whereby the product separated. There were obtained 308 g (91%) of l._phenylal-anyl-N-(4-bromo-2-picolinoylphenyl~glycinamid2 dihydrobromide - 28 _ '7~

of melting point 182C ~decomposition); ~]20 _ +28.4~ (c =
1 .in water).
Analygis for C23~23~r3N43 (643.20):
Calculated: C: 42.95; H: 3.60; N: 8.71; Br: 37.27.
Found: C: 42~53; ~: 3.68; N: 8.35; Br: 37.04.

2.0 g of the foregoing dihydrobromide were di~solved in 10 ml of water and dilute ammonium hydroxide solution was added slowly with stirring until the solution was basic. The yellow oil which separated crystallised on standing~ The product was filtered off, washed with water, dried ln vacuo and recrystallised from ethanol/water. There were obtained 1.18 g (79~) of the free base, L-phenylalanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, of melting point 60C (decompo-sition) and t~]20 = +26.7 (c = 1 in l-N hydrochloric acid).
Y 23 21 4 3 ( Calculated: C: 57.39; H: 4.40; N: 11.64; ~r: 16.60.
Found: C: 56.96; H: 4.42; N: 11.48; Br: 16.42.

Example 2 In a manner analogous to that described in Example 1, there was obtained glycyl-N~(4-bromo-2-picolinoylphenyl)-glycinamide of melting point 97-100C.

Analysis for C16H15BrN403 ~391.23):
Calculated: C: 49.11; H: 3.87; N: 14.32; Br: 20.42.
Founda C: 48~95; H: 3.92; N: 14.15; Br: 20.55.

Example 3 ~n a manner analogous to that described in Example 1, _29 -~ 7~ ~ ~

thexe was obtained L-lysyl-N~(4~bromo-2-picolinoylphenyl)-glycinamide trihydrobromide of melting point 220C (decompo-sition); [a]2C - +16.8 (c = l in water).
y s for C20H27Br4N53 (705-11) 5Calculated: C: 34.07; H: 3.86; N: 9.93; Br: 45.34;
Br ion: 34.00.
Found: C: 34.29; H: 4.25, N: 9.73; Br: 44.60;
Br ion: 33.32; H20: 0.~6.
Wat~r-free. C: 34.62; ~: 4.18; N: 9.82; Br: 45.03;
Br ion: 33.64.

Example 4 A) The pre~ ation of the ~tarting material:
3.18 g of N-benzyloxycarbonyl-L-isvleucine were dis-solved in 25 ml of dry tetrahydrofuran and cooled to -10C.
1.57 ml of l butylchloroformate and 1.52 ml of N-ethylmor-pholine were added and the resulting ~olutivn was stirred at -lOQC for 20 minutes. 4.24 g of 2-amino-N-(4-bromo-2-pico-linoylphenyl)acetamide dihydrochloride, prepared as de~cribed in part A)i) of Example 1, were added and the resulting SU5-pension was cooled to -20C. 3.13 ml of N-ethylmorpholine in 25 ml of dimethylformamide were added to the vigorously sti.r-red suspension over a period of 0.5 hour. The resulting mixture was stirred at -20C for a further 40 minutes and left at room temperature overnight. ~he product was worked up in a manner analogous to that describ0d in part a)ii) of Example l. Recrystallisation from ethanol yielded 4.2 g (60~) of (N-benzyloxycarbonyl-L-l leucyl)-N-(4-bromo-2-picolinoylphenyl)-glycinamide of melting point 174-176C.

~30 -~ 7'7~6C~

Analysis ~or C28H29BrN~05 (581.48):
Calculated: C: 57.84; H: 5.03; N: 9.64; Br: 13.74.
Found: C: 57.84; ~: 5.02; N: 9.39; Br: 13.67.

B) ~ : ~
2.0 g of ~N-benzyloxycarbonyl-L-i leucyl~-N (4-bromo-2-picolinoylphenyl)glycinamide were stirred for 1 hour in`a solution of 35% hydrogen bromide in glacial acetic acid. Dry diethyl ether was then added and the solid which separated was filtered off, washed with dlethyl ether and dried in vacuo.
Two precipitation~ ~rom methanol/ethyl acetate yielded l.9 g (91~):of ~ oleucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide dihydrobromide of melting point 174C (decomposltion).

1.0 g of the foregoing dihydrobromide was dissolved in 10 ml of water and dilute ammonium hydroxide solution was added with 9 tirring until the solution was basic. The resulting oil crystallised on standing, the crystals were fiItered off, wa~hed with water and dried in vacuo to give 0.65 g (89~) of the free base, L-isol.eucyl-N-(4-bromo 2-picolinoylphenyl)glycinamide, o melting point rom 54C (slow decomposition); [a]20 = ~29.6 (c = l in l-N hydrochloric acid~.
Analysis for C20H23BrN403 (447.34):
Calculated: C: 53.70, H: 5.18; N: 12.52; Br- 17.87.
Found: C: 52.97; H: 5023; N: 12.26; Br: 17.85;
. H20: 1.75.
Water-~ree: C: 53.37; H: 5.18; N: 12.35~ ~r: 17.98.

'7~69 In a ~anner analogous to that described in Example 4, but using N~-benzyloxy~arbonyl-L-arginine monohydrobromide, there was obtained L-arginyl-N-(4-bromo-2-picolinoylphenyl)-~lycinamide trihydrobromide hydrate as a lyophilised solid [a]20 = +10.9 (c = 1 in water).

Y 20H2g~r4N74 (751,14~
Calculated: C: 32.00; H: 3.&9;~ N: 13.05, Br ion 31.92.
Found: C: 31.85; H: 3.88; N: 13.00; Br ion 32.20.

Example 6 In a manner analogous to that described in Example 4, but using N-benzylaxycarbonyl-L-glutamic acid ~- ertbutyl ester r there was obtained ~-glutamyl-N-~4-bromo-2-picolinoyl-phenyl)glycinamide hydrobromide (1:1.85) o~ melting point 153-170C (slow decomposition); ~a]20 = +20.0 tc = 1 in water).
Analysis for ClgHlg~rN405 . 1.8S HBr ~612.98):
Calculated: C: 37.23; H: 3.43; N: 9014; Br: 37.15.
Eound: C: 36.68; H: 3.69; N: 8.64; Br: 36.55;

H20: 1.28.
Water-free: C: 37016; H: 3.59; N: 8.75; Br: 37.02.

Example 7 A) The preparation of the starting material:
In a manner analogous to that described in Example 4A

there was obtained (Na,N~-ditertbutoxycarbonyl-L-lysyl)-N-(4-7~7~if3 bromo-2~pic31inoylphenyl)glycinamide o~ melting poink 135-137C.
Analysis for C30H40B~N57 (662.59):
Calculated: C: 54.38; H: 6.09; ~: 10~57; Br: 12.06.
~ound~ C: 54.33; ~: 5.87; N: 10.34; Br: 12.24.

B) The process:
1.0 g of (N~,N~-ditertbutoxycarbonyl~L-lysyl)-N-(4-bromo-2-picolinoylphenyl)glycinami~e was stirred for 1 hour in a~solution of:hydrogen chloride in dioxan (4-M). Diethyl ~ther was added and the solid which separated was filter~d off~ washed with~diethyl ether and dried. The solid was dis-solved in methanol and precipitated with ethyl acetate. The precipitate was dissolved in 20 ml of water and, after ex-traction with chloroform, the aqueous ~olution was lyophilised to yield 0.7 ~ (88%) of L-lysyl-N-(4-bromo-2-picolinoyl-pheny~)glycinamide trihydrochloride 1.5 H20; [a]~ = ~20.1 ~c = 1 in water).
Analy8is for C20H27BrC13N503 l-S H20 ( Calculated: C: 40.12; H: 5.05; N: 11.70; Cl: 17.76.
Found: C: 40.27; ~: 4.92; N: 11.57; Cl: 17~62.

Example 8 In a manner analogous to that described in Example 4, there was obtained L-~-glutamyl-N-(4~bromo-2-picolinoylphenyl~-glycinamide of melting point 158 161C (decomposition);
~a]20 = ~121.1 (c = 1 in l-N hydrochloric acid).
Analysis for ClgHlgBrN405 (463.30):
Calculated: C: 49.26; H: 4.13; N: 12.09; Br: 17~25.

~ ~r7~7~

Found: C: 48.26; H: 4.40; N: 11.94; Br: 17,35;
H20: 1.24.
Watex-free: C: 48.87; H: 4.31; N: 12.09; Br: 17.57.

Example 9 In a manner~analogous to t~at described in Example 1, there was obtained ~-alanyl-N-(4-bromo-2-plcolinoylphenyl)-glycinamidP of melting point 76-78C; [a]D - ~17.4 (c =
1.0225 in methanol).
Analysis for C17H17~N43 (405.26~:
Calculated: C: 50.38; H: 4.23; N: 13.82; Br: 19.71.
Found: C: 50.43; H: 4.21; N: 13.56, ~r- 19.74.

Example 10 A) The preparation of the 6tarti~ material:
6.5S g of tertbutoxycarbonyl-L-leucyl N-hydroxysuc-cinimide ester were dissolved in 80 ml of dimethylformamide, the 601ution wa~ cooled ~o 20C and 8.48 g of ~-amino-N-(4-bromo-2-picolinoylphenyl)acetamide dihydrvchloride were add~d.
6.16 ml of N-ethylmorpholine were then added over a period of 30 minutes to the vigoroll~ly stirred suspension. The mixture wa~ then stirred for 1 hour at -20C and overnight at room temperature.

The working-up was carried out in the same manner as described in Example 1 A)ii). The resultiny oil was cry~tal-lised from a mixture o ethanol and water and recrystallised rom the same solvent mixture to yield 5.1 g (47~) of pure (N-_ 34 -7'~

tertbutoxycarbonyl-L-leucyl)-N-(4-bromo-2-picolinoylphenyl~-glycinamide ~f m~lting poin~ 129-132C.
AnalySiS or C25H31BrN405 t547.46~:
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.

B) The proce8S:
2.0 g of (N-tertbutoxycarbonyl-L-leucyl)-N-(4-bromo-2-picolinoylphenyl)glycinamide were stirred for l hour in a ~olution o~ hydrogen chloride in dioxan l4-~). Ethyl acetate was ad~ed and the solid which separated was filtered off, washed with ethyl acetate and dried in vacuo. The solid was di~solved in a minim~m amount of methanol and the product, L-leucyl-N-(4-bromo-2~picolinoylphenyl)glycinamide hydro-chloride, separated on the addition of ethyl acetate.

The hydrochloride was dissolved in 50 ml of water a~d dilute ammonium hydroxide solution was added slowly with stir-ring until the ~olution was basic. The yellow oil whlch separated cry~tallised on standing. The product was filtered off, washed with water and dried in vacuo. There was obtain-ed 0.85 g ~53~) of L-lellcyl-N-(4-bromo-2-picolinoylphenyl)-glycinamide of melting point 53C (decomposition); [~]20 =
+26.0 (c - 1 in l-N hydrochloric acid).
Y 20H23BrN43 t447.34):
Calculat~d: C: 53.70; H: 5.18; N: 12.52.
~ound: C: 53.35; H~ 5.14; N: 12.21; H20 1.32.
Water-free: C: 54.06; H: 5.06; N: 12.37.

r '7~

Example 11 A) The preparation of the startin~ material:
15.9 g of N-benzyloxycarbonylglycylglycine ware sus-pended in 600 ml of dry 1,2-dimethoxyethane and the suspension was cooled to -5C. 6.06 g of N-methylmorpholine and 8.22 g of l butylchloroformate were added and the resulting mixture was stirred at -5C to -10C for 2 hours. Unreacted starting material and N-methylmorpholine hydrochloride were separated by filtration and the filtrate (stored at -5C to 0C) was added portionwise over a period of several hours to a reflux-ing 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 magneslum sulphate and then evaporated to give 30 g of a yellow gum. Column chro-matography of this gum on Florisil using mixtures of benzene ~o and methanol yielded 12 g (40%) of pure (N-benzyloxycarbonyl-glycyl)-N-(2-benzoyl-4-chlorophenyl~-N-methylglycinamide as an almost colourless light-sensitive gum which was characterised by its spectroscopic properties and elemental analysis~
~nalysis for C26H24ClN305 (493.95):
25Calculated: C: 63.23; H: 4.90; N: 8.51; Cl: 7.18.
Yound: C: 63.61; H: 4.87; N: 8.37; Cl: 7.02.

* TRADE MARK

~}~ 36 ,~

1 ~7'~

B) ~he process:
9.87 g of (N-benzyloxycarbonylglycyl)-N-(2-benæoyl-4-chlorophenyl3~N-methylglycinamide were dissolved in 50 ml of glacial acetic acid and treated with 50 ml of a 30% solution of hydrogen bromid~ in glacial acetic acid. Th~ resulting solution was stirred at room temperature for 1 hour, trea~ed with excess dxy diethyl ether and the separated solid washed with several additional portions o dry diethyl ether and then dried in vacuo. The thus-obtained hygroscopic solid (7.5 g) wa~ mainly glycyl-N-(2-benzoyl-4-chlorophenyl)-N-mathylglycin-amide hydrobromide of melting point 140~-150~C (decomposition).
Analysis for Cl8Hl8ClN303. 1.2 ~Br (456.9):
Calculated: C: 47.32; H: 4.24; N: 9.20; Br ion5 20099.
~ound: C: 46.86; H: 4.59; N: 9.11; Br ion: 20.70.

4.6 g of the foregoing crude hydrobromide were purified by solution in 100 ml o~ 0.2-N sodium acetate and extraction of the solution with ether in order to remove b~products~ The aqueous solution was~then basified with excess sodium carbon-ate and extracted with dichloromethane to yield, after evapor-ation and de-gassing ln vacuo, glycyl-N-(2-benzoyl~4-chloro-phenyl)-N-methylglycinamide as an almost colourless light-sensitive glassy foam which was characterised by its spectro-scopic properties.

Example 12 A~ The preparation of the starting materlal:
In a manner analogous to that described in Example ll A), there was obtained (N-benzyloxycarbonylglycyl)-N~(4-bromo-~ r :1~'7'7~63 2-picolinoylphenyl)ylycinamide of melting point 139~-141C
(from ethanol).

B) The process:
In a manner analogous to that described in Example 11 B), (N-benzyloxycarbonylglycyl)-N-(4-bromo-2-picolinoyl-phenyl)glycinamide was converted into glycyl-N-(4-bromo-2-picolinoylphenyl)glycinamide o.f melting point 97-100C.

Example 13 A) The preparation of the starting material:
(a) 20.9 g of N-ben~yloxycarbonylglycine were suspended in 150Q ml of dry 1,2-dimethoxyethane and the suspension was cooled to -20C. 10.1 g of N-methylmorpholine and 13.7 g OL
isobutylchloroformate were added, the resul-ting solution was stirred at -20C for 1 hour and then filtered. The filtrate (stored at -10C to 0C) was added portionwise over a period of several hours to a refluxing solution of 24.55 g of S-chloro-2-methylaminobenzophenol1e in 200 ml of 1,2-dimethoxy-ethane, the resultinq mixture was boiled ov~rnight and then evaporated to dryness in vacuo. The yellow residue was dis-solved in ethyl acetate, washed with two portions of water andone portion of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and then evaporated in vacuo.
Column chromatography of the residue on Florisil using mixtures of benzene and chloroform yielded 35 g (80~) of pure 2-~N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methyl-acetamide as a pale yellow gum.

* TRADE MARK

~ r Analysis for C24H21ClN204 ~436.9) Calculated: C: 65.98; H: 4.85; N: 6.41.
Found: C: 65.91; ~1: 5.03; N: 6.51.

43.7 g of 2-(N-benzyloxycarbonylamino)-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide were dissolved in 200 ml of a 30% solution of hydrogen bromide in glacial acetic acld and the resulting solution was stirred overnight at room tempera-ture. The mixt~re 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 con-secutively with the minimum amount of acetone and dry diethyl ether and dried ln vacuo to give 29.5 g (77~) of 2-amino-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide hydrobromide as a white hygroscopic powder of melting point 194-195C (decom-position).
Y 16 16 22 (383.7) Calculated: C: 50.10; H: 4.21; N: 7.30; Br ion: 20.83.
Found: C: 4~.98; H: 3.83; N: 7.15; Br ion: 21.14.

(b~ 84 g of N-benzyloxycarbonylglycine were suspended in 5Q0 ml of alcohol-free chloroform and the suspension was cooled to -20C. The stirred suspension was treated portion-wise 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 (-5C) vigorously stirred emulsion consisting of 82 g of 5-chloro-2-~ .pj _ 39 -. . .
.; -~1~7'~

methylaminobenæophenone, 347 g of potassium bicarbona-te, 700 ml of chlo~oform and 1400 ml of water. The resulting mixture was stirred for a further l hour at -5C and then overnight at room temperature. The stirring was then discontinued and the liquid phases allowed to separate. The chloroform layer wa~
washed three times with 500 ml of water each time and evap-orated ln vacuo to give 150.7 g of a viscous yellow gum which was shown by physical methods to be almost pure (above 95%) 2-(N-benzyloxycarbonylamino)-N-(2-benzoyl 4-chlorophenyl)-N-methylacetamide.

The product obtained according to the preceding para-graph 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) o~ this Example to give 2-amino-N-(2-benzoyl-4-chlorophenyl~-N-methylacetamide hydro-bromide in a 77% overall yield from 5-chloro-2 methylamino-benzophenone.

(c) 3.96 g of N-benzyloxycarbonyl-~-phenylalanine N-hydroxysuccinimide ester were dissolved in 50 ml of dry di-methylformamide. The resulting solution was cooled to -20C
and there were added 3.84 g of 2-amino-N-~2-benzoyl-4-chloro-phenyl)-N-methylacetamide hydrobromide ollowed by the drop-wise addition of 1.15 g of N-ethylmorpholine. The resulting mixture was vigorously stirred for 1 hour at -20C and then overnight at room temperature. The solvent was evaporated in vacuo and the residue dissolved in a mixture of dichloro-methane and water. The organic and aqueous layers were separated and the aqueous phase extracted with further portions f of dichloromethane. The combined oryanic phases (250 ml) were washed three times with 50 ml of water each time, dried over ~nhydrous magnesium sulphate and evaporated ln 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-1,3-dihydro-l-methyl-5-phenyl-2~-1,4-benzodiazepin-2-one and (N-benzyloxycarbonyl-L-phenylalanyl)-N-(2-benzoyl-4-chloro-phenyl)-N-methylglycinamide in the approximate proportions of 1:3.

The foregoing mixture can be purified by column chro-matography on Florisil*to give pure tN-benzyloxycarbonyl-~-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colourless light-sensitive brittle foam; [~]D0 =
-13.6 (c = 1 in ethanol).

y 33H30clN3o5 (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; C1: 6.16.

Alternatively, the foregoing mixture can be subjected directly to removal of the protecting group as follows:

B) The process:

(i) 5.8 g of the mixture aforesaid were dissolved in 20 ml of a 30% solution of hydrogen bromlde in glacial acetic acid and the solution was stirred at room temperature for 3 hours. 200 ml of dry diethyl e~her were then added. The solid which separated was collected and dissolved in lO0 ml o~
water, treated with excess sodium carbonate and extracted with four 75 ml portions of diethyl ether. The combined ether * TRADE MARK

_41 -... i ~ '7~

extracts were then shaken with six S0 ml portions of 0.1-N
acetic acid in order to separate the more strongly basic products from the more weakly basic byproduct (the benzodiaz-epin-2-one). The combined aqueous acidic solution was washed with 100 ml of diethyl ether, made basic with excess sodium carbonate and extracted with four 75 ml portions of dichloro-methane. The dichloromethane extracts were then combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated in vacuo. Thorough de-gassing in vacuo gave 3.1 g ~8~) of pure L-phenylalanyl-N- -(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colourless light-sensitive brittle foam; [a]20 = -11.6 (c =
1 in ethanol).
Y 25 24 1 3o3 (449.9) lS Calculated: C: 66.74i H: 5.38; N: 9.34; Cl: 7.88.
Found: C: 66.71; H: 5.47; N: 9.23; Cl: 8.14, Treatment of the foregoing free base with an equimolar amount of anhydrous (~ tartaric acid in warm i~opropanol gave colourless crystal~ of the hydrogen (~)-tartrate of melting point 198 200C.
Analysis for C29H30ClN309 (600.00):
Calculated: C: 58.05; H: 5.04; N: 7.00; Cl: 5.91.
Found: C: 58.32; H: 4.98; N: 6.73; C1: 5.90.

(ii) 5.8 g of the mixture aforesaid were dissolved in 75 ml of dry nitromethane and a slow stream of hydrogen bromide was passed through the solution for lo-15 minutes. The solution was then stirred for a further 2 hours at room tem-perature and then treated with an excess of dry diethyl e~her.

~IL3L 7 706a3 The solid which separated was treated in an identical manner to that described in part (i) of this Example to give Z.4 g (53%) of L-phenylalanyl-N-~2-benzoyl-4-chlorophenyl)-N~methyl-glycinamide.

The foregoing free base was converted into the hydro-chloride as follows:

4.5 g of L-phenylalanyl-N-(2~benzoyl-4-chlorophenyl)-N-methylglycinamide were dissolved in a minimum volume of m~thanol at room temperature and treated, by titration, with an exact equivalent of 1-N hydrochloric acid. The solvent was removed from the resulting ~olution by evaporation ln vacuo at room tempera~ure and finally by lyophilisation to give, in quantitative yield, L-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide hydrochloride as a hygro scopic white light-sensitive amorphous powder of melting point 1~0-150C (slow decomposition): ~a]20 = +41.7 (c = 1 in water).
AnalYSls for C25~25C12N32 ( Calculated: C: 61.74; H: 5.18; N: 8.64; C1 ion: 7.29.

20Found: C:~ 6~.24; H: 5.22; N: 8.30; C1 ion: 7.31;
H20: 2.17.

Water-free: C: 61.58; H: 5.08; N: 8.48; Cl ion: 7.47.

Example 14 In a manner analogous to that described in Example 13, there was obtained glycyl-N-(2-benzoyl-4-chlorophenyl)-glycin-amide o melting point 136-138C ~from ethanol).

Analysis for C17H16ClN3O3 (3~5.79) Calculated: C: 59.05; H: 4.66; N: 12.15; Cl: 10.26.
Found: C: 59.03; Ff: 4.63; N: 11.79; Cl: 10.26.
Example 15 In a manner analogous to Example 13, there was obtained glycyl-N-(2-benzoyl-4-nitrophenyl)glycinamide of melting point 121-123C (from ethanol).

Analysis for C17H16N4O5 (356.34):
Calculated: C: 57.31; H: 4.53; N: 15.72.
Found: C: 57.54; H: 4.58; N: 15.73.
Example 16 In a manner analogous to that described in Example 13, there was obtained L-prolyl-N-(2-benzoyl-4-nitrophenyl)gly-cinamide of melting point 165-167C.

i~

~e~ .

A) The preparation of the startin~ material:
In a manner analogous to that described in Example 13 A), there was obtained (N~,N~-bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colourless light-sensitive gum; ~3D ~ -9.3 (c = 1 in ethanol).
Analysis ~or C38H39ClN~07 ~699.2):
Calculated: C: 65.28; N: 5.62; N: 8.02; Cl: 5.07.
Eound: C: 64.90; H: 5.56; N- 7.84; Cl: 5.25.

B) The process:
(i) (N~,N~-Bisbenzyloxycarbonyl-L-lysyl)-N-~2-benzoyl-4-chlorophenyl)-N-methylglycinamide was converted using a 30 solution of hydrogen bromide in glacial acetic acid into L-lS lysyl-N-t2-benzoyl-4-chlorophenyl)-N-methylglycinamide di-hydrobromide which wa~ obtained as a hyyroscopic powder of melti.ng point 145-160C ~decomposition); ~a~2 = ~15.6 (c = 1 in water).
Analysls for C22H29Br2ClN43 ( Calculated: C: 44.58; H: 4.93; N 9.45; Br ion 26096.
Found: C: 43.58; ~: 5.17; N: 9.21; Br ion: 27.43;
H20: 0.99.
Water-free: C: 44~02; H: 5.11; N: 9.30; Br ion: 27.70.

Treatment of the foregoinq dihydrobromide in aqueous solution by passage over an excess of an anion~exchange resin such as AMBERLIT~ IRA-401 in the chloride form followed by lyophilisation of the eluate gave, in quantitative yield, ~-* TRADE MARK

~ _45 -l~.t~'7~

lysyl-N-(2-benzoyl 4-chlorophenyl)-N-methylglycinamide di-hydrochloride as a hygroscopic white light-sensiti~e powder of melting point 125-145C (slow decomposition)j [~]D0 = +19.3 ~c = 1 in water).
Analysis for C22H29C13N403 (503.86):
Calculated: C: 52.45; H: 5.80; N: 11.12; ~1: 21.12.
Found: C: 51.58; Ho 5.80; N: 11.18; Cl: 20.80;
H20: 0.99.
Water-free: C0 52.10; ~: 5.75; N: 11.29; Cl: 21.10.

(ii) 1.4 g of (Na,N~-bisbenzyloxycarbonyl-L-lysyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide were dissolved in 30 ml of dry dichloromethane, cooled to approximately 70C
and treated, while stirring, with 2 ml of pre-cooled boron trichloride. The mlxture was stirred under anhydrous con-ditions at approximately -70C for 30 minutes and then allowed to warm slowly to room temperature over a period of 2 hours.
The mixture was evaporated to dryness in vacuo, the residue re-dissolved in 30 ml of fresh dry dichloromethane and the solution again evaporated to dryness ln vacuo. This opera-tion was repeated twice using dichloromethane and then four times using methanol in order to remove the residual boron compounds as volatile trimethyl borate. A concentrated methanolic solution of the residue was added slowly to 750 ml of anhydrous diethyl ether with vigorous stirring, the solid hygroscopic product collected by filtration and dried in vacuo. This product was di6solved in 30 ml of water, shaken with three 20 ml portions of ethyl acetate to remove traces of

5-chloro-2-methylaminobenzophenone and the aqueous solution lyophilised to give 0.7 g of L-lysyl-N-(2 hen~oyl-4-chloro-_ 46 -phenyl)-N-methylglycinamide dihydrochloxide which was identical to that described in part (i) of this E~ample.
Example 18 In a manner analogous to that described in Example 13, there was obtained L-phenylalanyl-N-~2-benzoyl-4-nitrophenyl)-glycinamide of melting point 144-146C (from methanol);
[~]20 = -29.4 (c = 1 in aioxan).
AnalysiS for c24H22N4O5 (446.47):
Calculated: C: 64.56; H: 4.97; N: 12.55.
Found: C: 64.39; E: 4.95; N: 12.74.
Example 19 A) The preparation of the starting material:
In a manner analogous to that described in Example 13A) there was obtained (N~,N~,N~-trisbenzyloxycarbonyl-L-arginyl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide as an almost colourless light-sensitive brittle foam; [~]d = -2.4 (c = 1 in ethanol). , Analysi~ for C46H45ClN609 (861.3$):
Calculated: C: 64.14; H: 5.27; N: 9.76; Cl: 4.12.
Found: C: 63.44; H: 5.17; N: 9.59; Cl: 4r65~
SolventDfree*: C: 63.90; H: 5.20; N: 9.68; Cl: 3.91u *The dichloromethane content was estimated by nuclear magnetic resonance spectroscopy to be 0~10 + 0.0~ moles.
Calculated for C~6H45ClN609, 0.1 CH2C12 t869.84~:
C: 63.66; H: 5.24; ~0 9.66; Cl: 4.80.

B) he process:
(i) 5.0 g of ~N,N~,N~-trisbenzyloxycarbonyl-L-argin-yl)-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide were dissolved in 60 ml of dry dichloromethane, cooled to o4c and treated, while stirring, with 4 ml of boron tribromide. The mixture was stirred under anhydrous condition~ at 0C for 2 hours and then allowed to warm to room temperature overllight.
EXCe5S boron tribromide was neutralised by the dropwise addition of a solution of anhydrQus methanol in dry dichloro-methctne until no further reaction was observed. The mixture was evaporated to dryness ln vacuo, the residue re-dissolved in 30 ml of anhydrou~ methanol and the solution again ~vapor-ated to dryness. This operation was repeated a further twice using methanol in order to remove the residual boron compounds as vola~ile trimethyl borate. A concentrated solution of the residue in methanol was added slowly to 1 litre of anhydrous diethyl ether with vigorous stirring. The ~olid hygroscopic product was collected by filtration and dried in vacuo. This product was dis~olved in 100 ml of water, shaken with thre~ 50 ml portions of ethyl acetate to remove traces of 5-chloro~-methylaminobenzophenone and the aqueous solution lyophilised - 4~ _ 7'~65~

to give 3.2 g o L~arginyl-N~(2-benæoyl-4-chlorophenyl)-N-ma~hylg}ycinamide dihydrobromide as an almost colourle~s light-sensitive amorphous powder; [a~20 _ +12.3C tc = 1 in water).

Analysi~ for C22H27Br2ClN603 (620.77):
Calculated: C: 42.56; ~: 4.71; N: 13.53; Br ion: 25.74.
Found: C: 40.74; H: 4.91; N: 13.29; Br ion: 26.08;
H20: 1.8g.
Water-free: C: 41.52; H: 4.79; N: 13.55; Br ion: 26.58.

10. Calcula~ed for C22H25ClN603.2.1 HBr (631.29):
C: 41~86; H: 4.65; N: 13.31; ~r ion: 26~96.

The foregoing dihydrobromide was treated in a manner analogous to that de~cribed in part ~(i) of Example 18 to give, in qua~titative yield, L-arginyl-M-~2-benæoyl-4~chloro-~henyl)-N-methylglycinamide dihydrochloride as a white light-sensitive amorphou~ powd~r of melting po.int 1$5a-160C (slow decompo~ition); [a)20 = ~14.9~ (c - 1 in water).
Analysis for C22H27C13N6 3 ( Calculated: C: 49.68; H: 5.49; N: 15~80; Cl~ 19.99.

Found: C: 48.47; H: 5.75; N: 15.845 Cl~ 20.16 ~ 2 1~17.
Water-free: C 49.04; H: 5.69; N: 16.03; Cl: 20.40.

Calculated for C22H25ClN603. 2.1 HCl (535.52):

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

Example 22 A) The re aration of the ~tartin material:
. P P .. g 13Lt7'7~9 (a) In a manner analogous to that descri~d in ~xample 13A)(b) there was obtained 2-(N-benzyloxycarbonylamino)-N-t2-benzoyl-4-chlorophenyl)-N-methylpropionamide as a pale yellow gum; [~20 = _3.75o (~ = 1 in ethanol).
Analysis for C25H23ClN204 ~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 pxeceding para-graph was di~solved in an excess of a 30% solution of hydrogen bromide and treated in a manner identical to that described in ~xample 13A)(a) to give 2-amino~N-(2-benzoyl-4-chlorophenyl)-N-methylpropionamide hydrobromide as an almost colourless hygroscopic powder of melting point 140-145C ~slow decom-position) (from acetone/diethyl ether); [a]20 _ +13.2 ~c = 1 in ethanol).
~nalysiS f~r ~17~18ClN202 ( Calculated: C: 51.34; H: ~.56; N: 7.0S; ~r ion: 20.10.
Found: C: 50.98; H: 4.73; N: 6.78; ~r ion: 20~05s H20: 0.75.
20Water-free: C: 51.377 H: 4,68; N: 6.83; Br ion: 20.20.

(b) In a manner analogous to that described in Example 13A)(c) there was obtained a mixture of 7-chloro~1,3-dihydro-1,3-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and (N-ben-zyloxycarbonyl-L-phenylalanyl)-N-(2-benzoyl-4-chlorophenyl)~
N-methyl-L-alaninamide in t.he approximate proportions of 2:1.

L~ The process:

6.0 g of the mixture obtained arcording to the preceding r 1~7'7~9 paragraph were dissolved in 40 ml of a 30% solution of hydro-gen bromide in glacial acetic acid and the solution was stir~
red at room tempe~ature for 3 hours. The mixture was worked-up in a manner analogous to that described in Example 13B)(i) to give 0.6 g of L-~phenylalanyl-N-~2-benzoyl-4-chloroph nyl)-N-methyl-L-alaninamide as an almost colourless light-~ensi.tive brittle foam; [~]20 = _34.9o (c = 1 in ethanol).
An ly 26 26 3 3 ~ ) Calculated: C: 67.30; H: 5.65; N: 9.06; Cl: 7.64.
Found: C: 66.98; H: 5.79; N: 8.82; Cl: 7.74.

The foregoing free base was converted into the hydro-chloride as follows:

0.5 g of L-phenylalanyl-N-(2-banzoyl-4-chlorophenyl)-N-methyl-L-alaninamide was dissolved in a minimum amount of methanol at room temperature and treated, by titrat.ion, with an exact equivalent of l-N hydrochloric acid. The solvent was removed from the resulting solution by evaporation in vacuo at room temperature and finally by lyophilisation to give, in quantitative yield, ~-phenylalanyl-N-(2-benzoyl-4~
chlorophenyl)-N-methyl-~-alaninamide hydrochloride as a white hygroscopic light-sensitive amorphous powder of melting point 130-140C (slow decomposition): [al20 = -48.0 ~c - 1 in water) 7 Analysis for C26~27C12N33 (5 25Calculated: C 62.39; H: 5.44; N,: 8~40; Cl ion: 7.09.
Found: C: 60.84; H: 5.65; N: 8.03; Cl ion: 7.36;
H20: 2.05.
Water-free: C: 62.11; H: 5.53; N: 8.20; Cl ion: 7051.

11~7'7~i9 Calculated for C26H26ClN303. 1.05 HCl (502.28):
C: 62.17; ~: 5.42; N: 8.36; C1 ion: 7.41.

A) The preparation of the startins material:
(a~ In a manner analogou~ to that described in Example 13A) ~here was obtained 2-(N-benzyloxycarbonyIamino~-N~2-benzoylphenyl)-N-me~hylacetamide as a pale yellow gum.
Ana~ysis for C~4~I22N204 ~402.45):
Calculated: C: 71.63; H: 5.51; N: 6~96G
Found: C: 71.33; H: 5.45; N: 5.90.

(b) Treatment of the compound obtained according to the preceding paragraph in a manner analogous to that described in Example 13A) gave L-alanyl-N-~2-benzoylphenyl)-N-me~hyl-glycinamide as an almost colourless light~sensitive foam.
Analysi8 for ClgH21N303 (339.40) Calculated: C: 67.24; H: 6.24; N: 12.38.
Found: C: 66.93; H: 6401; N: 11.98.

In addition, 1,3-dihydro-1-methyl~5-phenyl-2H-1,4~benzo-diazepin-2-one of melting point 151-154C was isolate~ as a major by-product.

B) The process:
3 g of L-alanyl-N-~2-ben20ylphenyl)-N-methylglycinamide were dissolved in 10 ml of anhydrous sulphuric ~cid at room temperature. The resulting mixture was c0012d to -5C and ~5 treated dropwise by the addition of a solution of 0.94 g of

7'7~

potassium nitrate in 3 ml of anhydrous sulphuric acid. The resulting mixture was stirred at 0C or 10 hour~ and finally allowed to warm to room temperature overnight. The mixture was then poured into an excess of ice-water~ The pH of the mixture was adjusted to approximately pH 9 by the addition of concentrated ammonium hydroxide, care being taken to maintain the temperature at ca 0C. Th~ mixture obtained was extracted with several portions of dichloromethane. The combined organic phases were washed successively with 2-N sodium car-bonate solution and water, dri~d over anhydrous magnesium sulphate and evaporated ln vacuo. The residue (ca 3 g) was dissolved in a minimum amount of chloroform and subjected to column chromatography on Florisil*using mixtures of methanol in chloroform in increasing proportions. Fractions were collected using 5~ (vol/vol) methanol in chloroform and evaporated 1n vacuo to give 1.75 g (52%) of pure L-alanyl-N-(2-benzoyl-4 nitxophenyl)-N-methylglycinamide as an almost colourless light-sen~itive foam; 1~]20 = +2.1 (c = 1 in ethanol).
Analysis or C~gEI20M~05 (384.40):
Calculated: C: 59.37; H: 5.25; N: 14.57.
Found: C: 59.94; H: 5.43; N: 14.17.

The foregoing ~ree base was dissolved in a minimum amount of methanol at room temperature and treated, by titra-tion, with an exact equivalent of l~N hydrochloric acid.
The solvent was removed from the resulting solution by evap-oration in vacuo at room temperature and finally by lyophil-isation to give, in quantitative yield, L-alanyl-N (2-benzoyl-4-nitrophenyl)-N-methylglycinamide hydrochloride as a white * TRADE MARK

~. ~,.,., .;

amorphous solid of melting point 165-175C (slow decomposi-tion): [a]20 = ~7.5 ~c = 1 in water).
Analysis ~or ClgH2lClN405 (420.85):
Calculated: C: 54.23; H: 5.035 N: 13.31; Cl ion: 8.42.
Found: C: 54.12; H: 5.30; N: 13.05; Cl io~: 8~42.

Example 24 A) The preparation of the startln~ material:
~i) 2.0 g of 8-chloro-1-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] 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 wate~ and re-evaporated. The final traces of water were removed by shaking the oil with 50% methanol/
toluens 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-1,2~4-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 ~-benzyloxy-carbonyl-L-phenylalanine N-hydroxy~uccinimide ester. The solution obtained was then cooled to -20C. A solution of 2.1 ml of N-ethylmorpholine in 8.4 ml of dimethylformamide was added to the vigorously stirred solution ovex a period of 0.5 hour. The resulting mixture was stirred for l hour at -20C
a~d left overnight at room temperature. The solvent was ~,.l.t~'7C~6~

removed in vacuo and the resiaue was dissolved in a mixture of dichloromethane and water. The layers were separated and the aqueous layer was extracted with addi~ional 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% me~hanol in chloroform, 15 ml fractions being collected. Fractions 1-25 comprised the chloroform eluate and the product was contained in fractions 48-57. The~e 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-benzyloxycarbonyl-L-phenylalanyl)aminQmethyl]-5-methyl~4H-1,2,4-triazol-4-yl 7benzophenone of melting point 84-88C
were obtained.

B~ The process:
0.50 g of 5-chloro 2-/ [(N-benzyloxycarbonyl-L-phenyl-alanyl)aminomethyl]-5-methyl~4H-1,2,4-triazol-4-yl_7benzo-phenone was treated with a 35% solution of hydrogen bromide in glacial acetic acid for 1 hour. Dry diethyl ether was then added and the separated solid was filtered off, washed with ether and dried in vacuo. The crude product was purified by precipitation from methanol/ethyl acetate. There was obtained 0.36 g (79%) o 5-chlvro-2-t3-(L-phenylalanylamino-methyl)-5-methyl-4H-1,~,4-triazol-4-yl]benzophenone dihydro-bromide of melting point 164-171C ~slow decompo~ition).
Analysis for C26~l26Br2ClN52 Calculated: C: 49.12; ~: 4.12; N: 11.02; Cl: 5.58 Br: 25.14.

'7~

Found: C: 48~15î H: 4.14; N: 10.65; Cl: 5.32;
Br: 24.52; H20: 1.83.
Water-free: C: 49.05; ~l: 4.01; N: 10.86; Cl: 5.42;
Br: 24.98.

Example 25 ~ In a manner analogous to that described in Example 24, but using N~,N-ditertbutoxycarbonyl-L-lysine N-hydroxysuc-cinimide ester, there was obtained 5-chloro-2-~3-(L-lysyl-aminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone tri~

hydrobromide as a lyophilised solid; [~1~ = ~11.0 (c = 1 in water).
Analysis for C23H30Br3C102 (697.71~:
Calculated: C: 39.60; H: 4.33; N: 12.05; Br: 34.36.
Found: C: 38.23, H: 4.38; N: 11.55; Br: 33.40;

H20: 2.58.
Water-free: C: 39.24; H: 4.21; N: 11.86; Br: 34.28.

Example 26 In a manner analogous to that described in Example 24, there was obtained 2',5-dichloro-2-~3-(L-phenylalanylamino-methyl)-5-methyl-4H-1,2,4-triazol-4 yl]benzophenon2 dihydro-bromide of melting point 188-193C.
AnalysiS for C26H25~r2C12N52 (6 Calculated: C: 46.59; H--3.76; N: 10.45; Br: 23.~4, Cl: 10.58.

Found: C: 46.02; H: 3.83; N: 10.03; Br: 23.33;
Cl: 10.35; H~0: 1.90.

-56 _ '117Jt7~

Water-free: C: 46~91; H: 3.69; M: 10.22; Br: 23.78;
C1: 10. 55 .

Example 2 7 In a manner analogous to that described in E~eample 24, there was obtained 2',5-dichloro-2-~3-(L-lysylaminomethyl)-5-methyl-4H-1,2,4-triazol-4~yl]benzophenone hydrvbromide ( 1: 2 . 9 ) of melting point 240-245C; [~J~ = +9.8 (c = 1 in water).
AnalySis for C23H26C12N62 Calculated: C: 38.15; H: 4.02; N: 11.61; Br ion: 32.00.
10Found: C: 37.84; H: 4.13; N: 11.18; Br ion: 31.30;
H20: 1.23.
Water-free: C: 38.31; H: 4.04; N: 11.32; Br ion: 31.69.

Example 28 In a manner analogous to that descrihed in ~xample 24, there was obtained 2',5-dichloro-2-(3-glycylaminometh~1-5-methyl-4H 1,2,4-triazol-4-yl)benzophenone dihydrobromide methanolate of melting point 235-240C.
Analygis for C2oH23Br2cl2Nso3 (612~15)~
Calculated: C: 39.24; H: 3.79; N: 11.44; Br: 26~11;
Cl: 11058.
Found: C: 39.39; H: 3.67; N: 11.30; Br: 26.10;
Cl: 11.58.

A) T _ preparation of the starting material:
(a)(i) A solution of 200 g of 7-chloro-1,3-clihydro-5-.Y'7C~

~2~fluorophenyl)-2H-1~4-benzodiazepin-2-one in 2 litres o~
tetrahydrofuran and 250 ml of benzene was saturated with methylamine with cooling in an ice-bath. ~ solution of 190 g of titanium tetrachloride in 250 ml o benzene was added through a dropping funnel within 15 minutes~ Ater comple-tion of the addition, the mix~ure wa5 stirred and refluxed for 3 hours. 600 ml of water were added slowly to ~he cooled mixture. The inorganic material was separated by filtration and was washed well with tetrahydrofuran. The water layer was separa~ed and ~he organic phase dried over sodium sulphate and evaporated. The crystalline residue was collected to ~ive 7-chloro-5-t2-fluorophenyl)-2-methylamino 3H-1,4-benzo-diazepine of melting point 204-206C. An analytical sample was recrystallised from methylene chloride/ethanol and had a melting point of 204-206C.

(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-1,4-benzodiaz-epine 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 dime~hylformamide, 50 ml of nitromethane and 11.1 g of potassium tert.butoxide which '7~

had been stirred under nitrogen for 15 minutes. After stir-ring for 1 hour at room temperature, the mixture was acidified by the addition of glacial acetic acid, diluted wikh water and extracted with methylene chloride. The extract~ were washed with water, dried over sodium sulph~te and evaporated. Crys-tallisation of the residue from diethyl ether yielded 7-chloro-1,3-dihydro-5-(2 fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine of melting point 170 172C. An ana-lytical sample was recrystallised from methylene chloride/
ethanol and~had a melting point of 174-176C.

(a)(iii) A solution of 16.5 g of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine in 5C0 ml of tetrahydrofuran and 250 ml of methanol wa~ hydrogen-ated with 5 teaspoons~ul of Raney nickel for 205 hours at atmospheric pressure. Separation of the cataly~t and evap-oration left 14 g of crude 2-aminometh~1-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH 1,4-benzodiazepine.

(a)~iv) 7 ml of acetic anhydride were added to a solu-tion of 6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was layered with 2Q0 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 evapor-ated to leave 6.2 g of resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH-1,4-benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150C
for 10 minutes. The cooled mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methyl-ene chloride. The extracts were dried and evaporated and the residue (5.7 g) was chromatographed over 120 g of silica g81 using 20% methanol in methylene chloxide. The clear ractions were combined and evapor~ted to yield resinous 8~
chloro-3a,4-dihydro-6-(2-1uorophenyl)-1-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 ~elite. The filtrate was evaporated and ~he residue crystallised from diethyl ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]~1,4~benzodia~-epine of melting point 152-154C. An analytical sample was recrystallised from methylene chloride/hexane.

(b)(i~ 2.0 g of 8-chloro-6-(2-fluorophenyl)-1-methyl-4~-imidaæo[1,5-a][1,4]benzodiazepine were dissolved in 15 ml of dilute hydrochloric acid and left at room temperature overnight. The ~olution was evaporated to an oil which was dissolved in water and re-evaporated. The final traces of water were removed by ~haking the oil with 50~ methanol/
toluene followed by evaporation. This treatment was repeated three times with 50% methanol/toluene and ~wice with toluene.
This gave 5-chloro-2l-fluoro-2-~5-aminomethyl-2-methyl-1-imidazolyl)-benzophenone dihydrochloride as a pale yellow solid.

(b)(ii) The solid prepared as described in the pre-ceding paragraph was dissolved in 20 ml of dry dimethylform-amide and to the resul~ing solution were added 1.56 g of N-_ 60 _ IL~'7~ i9 benzyloxycarbonyl-L-leucyl N-hydroxysuccirlimide ester~ The solution obtained was then cooled to -20C. A solution of 2.5 ml of N-ethylmorpholine in 10 ml of dimethylformam}de was added dropwise with vigorous stirring over a period of 20 S minutes. The mixture was stirred for 1 hour at -20C and le~t overnlght 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 th~ aqueous layer was extracted with additional chloroform. The organic layers were combined, washed five times with water, dried over mag-nesium sulphate and evaporated to an oil which was chromato-graphed on 100 g of silica gel. Elution was carried out using 4% methanol in chloroform, 15 ml fractions being col-lected. The product was eluted in frac~ions 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 63-75C (decomposition~ were obtained.
y for C32~32ClFN404 (591.09):
Calculated: C: 65.02; H: 5.46; N: 9.48.
Found: C: 64.66; H: 5.61; N: 9.19.

B) The process:
0.40 g of 5~chloro-2'-fluoro-2- r5-~(N-benzyloxycar-bonyl-L-leucyl)aminomethyl]-l-imidazolyl_7benzophenone was treated with a 35~ solution of hydrogen bromide in glacial ac~tic acid for 45 minutes. Dry diethyl ether was then added, an oily solid being obtained. The product was pre-cipitated from methanol/ethyl acetate, dissolved in water and - 61 ~

7'7~

freeze-dried~ There was obtained 5-chloro-2'-fluoro-2-[5-(L-leucylaminomethyl)~2~methyl-1-imidazolyl]benzophenone dihydrobromide in a yield of 0.25 g t60%); [a]20 = -5.5 (c = 0.2708 in water).
Analysis for C24H28Br2ClFN402 (618.77):
calculated: 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.
Water-free: C: 46.58; H: 4.50; N: 8.87; Br: 25.96.

Example 30 In a manner analogous to that described in ~xample 29, there wa~ obtained 5-chloro~ fluoro-5-[(L-alanylaminomethyl)-2-methyl-1-imidazolyl]b~nzophenone dihydrobromide of melting point 90-110C (sl~w decomposition)~

- 6~ -7'7~

The ~ollowing Exampla illustrate~ a typical pharmaceutical prepara~ion containing one of the substituted-phenyl ketones provided by this invention:

~ Exam~le A

An injection solution containing the following ingredient~
is prepared in a conventional manner:

L-lysyl~N-(2-benzoyl-4-chlorophenyl)-N-methyIglycinamide dihydrochloride 10~00 mg Sodium acetate 3H20 22.32 mg Acetic acid 2.16 mg Chlorocresol 1.00 mg Sodium chloride q.s.
Water ~or injec~ion ad 1.00 ml The ~oregolng solution should be protected ~rom light prior to use.

Claims (90)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of substituted-phenyl ketones of the general formula I

wherein A represents -NH- or -N(CH3)- 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 Rb 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 lower alkyl group; R2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R3 represents a phenyl, halophenyl or 2-pyridyl group, and pharmaceutically acceptable acid addition salts thereof, provided that when A is -NH- or -N(CH3)-, B is carbonyl, R
is a chlorine atom, R1 is a hydrogen atom and R3 is a phenyl group, R2 does not represent L-alanyl or L-leucyl, and provided also that when A is -NH- or -N(CH3)-, B is carbonyl, R is a halogen atom, R1 is a hydrogen atom and R3 is a mono-halophenyl group, R2 does not represent glycyl, L-phenylalanyl, L-valyl, L-alanyl or L-leucyl, which process comprises (a) cleaving off the protecting group or protecting groups present in the group R20 in a corresponding compound of the general fromula II

wherein A, B, R, R1 and R3 have the significance given earlier and R20 represents the acyl group of 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- or D,L-configuration), or (b) for the manufacture of a compound of formula I in which A represents -NH or -N(CH3)-, B represents a carbonyl group, R represents a nitro group and R2 represents an acyl group derived from a naturally occurring amino acid which is not affected by nitrating agents (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration), nitrating a compound of the general formula III
wherein R1 and R3 have the significance given earlier, R4 represents a hydrogen atom or a methyl group and R21 represents an acyl group derived from a naturally occurring amino acid which is not affected by nitrating agents (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration), and, if desired, converting a free base obtained into a pharmaceutically acceptable acid addition salt or converting an acid addition salt obtained into a free base or into a different pharmaceutically acceptable acid addition salt.

2. A process according to claim 1, wherein the starting material is a compound of formula IIa wherein R, R1, R20 and R3 have the significance given in claim 1, and R4 represents a hydrogen atom, or a methyl group.

3. A process according to claim 2, wherein the starting material is a compound of formula IIa given in claim 2 in which R represents a chlor-ine or bromine atom or a nitro group, R1 represents a hydrogen atom, R3 represents a phenyl, o-fluorophenyl, o-chlorophenyl or 2-pyridyl group and R4 represents a hydrogen atom or a methyl group.

4. A process according to claim 1, wherein the starting material is a compound of formula IIb wherein R, R1, R20, R3 and Ra have the significance given in claim 1.

5. A process according to claim 4, wherein the starting material is a compound of formula IIb given in claim 4 in which R represencs a chlorine atom, R1 represents a hydrogen atom, R3 represents a phenyl or o-chlorophenyl group and Ra represents a methyl or hydroxymethyl group.

6. A process according to claim 1, wherein the starting material is a compound of formula IIC

wherein R, R1, R20, R3, Ra and Rb have the significance given in claim 1.

7. A process according to claim 6, wherein the starting material is a compound of formula IIc given in claim 6 in which Ra and Rb each represent a hydrogen atom or a lower alkyl group.

8. A process according to claim 6, wherein the starting material is a compound of formula IIc given in claim 6 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 Rb represents a hydrogen atom.

9. A process according to claim 1, wherein there the starting material is a compound in which the acyl group denoted by R20 is derived from an L-amino acid.

10. A process according to claim 9, wherein said L-amino acid is L-phenylalanine or L-lysine.

11. A process according to claim 3, wherein the starting material is an L-(protected)-phenylalanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

12. A process according to claim 3, wherein the starting material is a (protected)-glycyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

13. A process according to claim 3, wherein the starting material is an L-(protected)-leucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

14. A process according to claim 3, wherein the starting material is an L-(protected)-lysyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

15. A process according to claim 3, wherein the starting material is an L-(protected)-isoleucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

16. A process according to claim 3, wherein the starting material is an L-(protected)-.gamma.- glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

17. A process according to claim 3, wherein the starting material is an L-(protected)-alanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

18. A process according to claim 3, wherein the starting material is an L-(protected)-arginyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

19. A process according to claim 3, wherein the starting material is an L-(protected)-.alpha.-glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide.

20. A process according to claim 3, wherein the starting material is a (protected)-glycyl-N-(2-benzoyl 4-chlorophenyl)glycinamide.

21. A process according to claim 3, wherein the starting material is a (protected)-glycyl-N-(2-benzoyl-4-nitrophenyl)glycinamide.

22. A process according to claim 3, wherein the starting material is an L-(protected)-prolyl-N-(2-benzoyl-4-nitrophenyl)glycinamide.

23. A process according to claim 3, wherein the starting material is a (protected)-glycyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide.

24. A process according to claim 3, wherein the starting material is an L-(protected)-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-glycinamide.

25. A process according to claim 3, wherein the starting material is an L-(protected)-lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide.

26. A process according to claim 3, wherein the starting material is an L-(protected)-phenylalanyl-N-(2-benzoyl-4-nitrophenyl)glycinamide.

27. A process according to claim 3, wherein the starting material is an L-(protected)-arginyl-N-(2-benzoyl-4-chlorophenyl)glycinamide.

28. A process according to claim 3, wherein the starting material is an L-(protected)-alanyl-N-)2-benzoyl-4-nitrophenyl)-N-methyl-glycinamide.

29. A process according to claim 3, wherein the starting material is an L-(protected)-alanyl-N-[2-(2'-fluorobenzoyl)-4-nitrophenyl]glycinamide.

30. A process according to claim 3, wherein the starting material is an L-(protected)-phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alaninamide.

31. A process according to claim 5, wherein the starting material is a 5-chloro-2-[3-(L-(protected)-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzo-phenone.

32. A process according to claim 5, wherein the starting material is a 5-chloro-2-[3-(L-(protected)-lysylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.

33. A process according to claim 5, wherein the starting material is a 2',5-dichloro-2-[3-(L-(protected)-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.

34. A process according to claim 5, wherein the starting material is a 2',5-dichloro-2-[3-(L-(protected)-lysylaminomethyl)-5-methyl-4H-1,2,4-trlazol-4-yl]benzophenone.

35. A process according to claim 5, wherein the starting material is a 2',5-dichloro-2-(3-(protected)-glycylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone.

36. A process according to claim 8, wherein the starting material is a 5-chloro-2'-fluoro-2-[5-(L-(protected)-leucylaminomethyl)-2-methyl-1-imidazolyl]benzophenone.

37. A process according to claim 8, wherein the starting material is a 5-chloro-2'-fluoro-2-[5-(L-(protected)-alanylaminomethyl)-2-methyl-1-imidazoyl]benzophenone.

38. Compounds of the general formula I as defined in claim 1, and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 1 or by an obvious chemical equivalent thereof.

39. Compounds of the general formula Ia wherein R represents a halogen atom or a trifluoromethyl group; R1 represents a hydrogen atom or a lower alkyl group; R2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R3 represents a phenyl, halophenyl or 2-pyridyl group, and R4 represents a hydrogen atom or a methyl group, and pharmaceutically acceptable acid addition salts thereof, provided that when R is a chlorine atom, R1 is a hydrogen atom and R3 is a phenyl group, R2 does not represent L-alanyl or L leucyl, and pro-vided also that when R is a halogen atom, R1 is a hydrogen atom and R3 is a monohalophenyl group, R2 does not represent glycyl, L-phenylalanyl, L-valyl, L-alanyl or L-leucyl, whenever prepared according to the process claimed in claim 2 or by an obvious chemical equivalent thereof.

40. Compounds of formula Ia given in claim 39, wherein R represents a chlorine or bromine atom or a nitro group, R1 represents a hydrogen atom, R3 represents a phenyl, o-fluorophenyl, o-chlorophenyl or 2-pyridyl group and R4 represents a hydrogen atom or a methyl group, and pharmaceutically acceptable acid addition salts thereof, provided that when R is a chlorine atom, R1 is a hydrogen atom and R3 is a phenyl group, R2 does not repre-sent L-alanyl or L-leucyl, and provided also that when R is a halogen atom, R1 is a hydrogen atom and R3 is a monohalophenyl group, R2 does not re-present glycyl, L-phenylalanyl, L-valy], L-alanyl or L-leucyl, whenever prepared according to the process claimed in claim 3 or by an obvious chemi-cal equivalent thereof.

41. Compounds of the general formula Ib wherein R represents a halogen atom or a trifluoromethyl group; R1 represents a hydrogen atom or a lower alkyl group; R2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R3 represents a phenyl, halophenyl or 2-pyridyl group, and Ra represents a hydrogen atom or a lower alkyl or hydroxymethyl group, and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 4 or by an obvious chemical equivalent thereof.

42. Compounds of formula Ib given in claim 41, wherein R represents a chlorine atom, R1 represents a hydrogen atom, R3 represents a phenyl or o-chlorophenyl group and Ra represents a methyl or hydroxymethyl group, and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 5 or by an obvious chemi-cal equivalent thereof.

43. Compounds of the general formula Ic wherein R represents a halogen atom or a trifluoromethyl group; R1 re-presents a hydrogen atom or a lower alkyl group; R2 represents an acyl group derived from a naturally occurring amino acid (all such groups which contain an asymmetric carbon atom having the L- or D,L-configuration) and R3 represents a phenyl, halophenyl or 2-pyridyl group, Ra represents a hydrogen atom or a lower alkyl or hydroxymethyl group and Rb represents a hydrogen atom or a lower alkyl or hydroxymethyl group, and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 6 or by an obvlous chemical equivalent thereof.

44. Compounds of formula Ic given in claim 43, wherein Ra and Rb each represent a hydrogen atom or a lower alkyl group, and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 7 or by an obvious chemical equivalent thereof.

45. Compounds as set forth in claim 43, wherein R represents a chlorine atom, R1 represents a hydrogen atom, R3 represents a phenyl or o-fluorophenyl group, Ra represents a methyl or hydroxymethyl group Rb represents a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, whenever prepared according to the process claimed in claim 8 or by an obvious chemical equivalent thereof.

46. Compounds as set forth in claim 38, wherein the acyl group denoted by R2 is derived from an L-amino acid, and pharmaceutically accept-able acid addition salts thereof, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.

47. Compounds as set forth in claim 38, wherein an acyl group de-noted by R2 is derived from L-phenylalanine or L-lysine, whenever prepared according to the process claimed in claim 10 or by an obvious chemical equivalent thereof.

48. L-Phenylalanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, when-ever prepared according to the process claimed in claim 11 or by an obvious chemical equivalent thereof.

49. Glycyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, whenever prepared according to the process claimed in claim 12 or by an obvious chemical equivalent thereof.

50. L-Leucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, whenever prepared according to the process claimed in claim 13 or by an obvious chemi-cal equivalent thereof,

51. L-Lysyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, whenever pre-pared according to the process claimed in claim 14 or by an obvious chemical equivalent thereof.

52. L-Isoleucyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, whenever prepared according to the process claimed in claim 15 or by an obvious chemical equivalent thereof.

53. L-.gamma.-glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, whenever prepared according to the process claimed in claim 16 or by an obvious chemical equivalent thereof.

54 L-Alanyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, when-ever prepared according to the process claimed in claim 17 or by an obvious chemical equivalent thereof.

55. L-Arginyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, when-ever prepared according to the process claimed in claim 18 or by an obvious chemical equivalent thereof.

56. L-.alpha.-glutamyl-N-(4-bromo-2-picolinoylphenyl)glycinamide, when-ever prepared according to the process claimed in claim 19 or by an obvious chemical equivalent thereof.

57. Glycyl-N-(2-benzoyl-4-chlorophenyl)glycinamide, whenever prepared according to the process claimed in claim 20 or by an obvious chemical equivalent thereof.

58. Glycyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, whenever prepared according to the process claimed in claim 21 or by an obvious chemical equivalent thereof.

59. L-Prolyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, whenever prepared according to the process claimed in claim 22 or by an obvious chemical equivalent thereof.

60. Glycyl-N-(2 benzoyl-4-chlorophenyl)-N-methylglycinamide, whenever prepared according to the process claimed in claim 23 or by an obvious chemical equivalent thereof.

61. L-Phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-glycinamide, whenever prepared according to the process claimed in claim 24 or by an obvious chemical equivalent thereof.

62. L-Lysyl-N-(2-benzoyl-4-chlorophenyl)-N-methylglycinamide, whenever prepared according to the process claimed in claim 25 or by an obvious chemical equivalent thereof.

63. L-Phenylalanyl-N-(2-benzoyl-4-nitrophenyl)glycinamide, whenever prepared according to the process claimed in claim 26 or by an obvious chemical equivalent thereof.

64. L-Arginyl-N-(2-benzoyl-4-chlorophenyl)glycinamide, when-ever prepared according to the process claimed in claim 27 or by an obvious chemical equivalent thereof.

65. L-Alanyl-N-(2-benzoyl-4-nitrophenyl)-N-methylglycinamide, whenever prepared according to the process claimed in claim 28 or by an obvious chemical equivalent thereof.

66. L-Alanyl-N-[2-(2'-fluorobenzoyl)-4-nitrophenyl]-glycinamide, whenever prepared according to the process claimed in claim 29 or by an obvious chemical equivalent thereof.

67. L-Phenylalanyl-N-(2-benzoyl-4-chlorophenyl)-N-methyl-L-alaninamide, whenever prepared according to the process claimed in claim 30 or by an obvious chemical equivalent thereof.

68. 5-Chloro-2-[3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, whenever prepared according to the process claimed in claim 31 or by an obvious chemical equivalent thereof.

69. 5-Chloro-2-[3-(L-lysylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, whenever prepared according to the process claimed in claim 32 or by an obvious chemical equivalent thereof.

70. 2',5-Dichloro-2-[3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, whenever prepared according to the process claimed in claim 33 or by an obvious chemical equivalent thereof.

71. 2',5-Dichloro-2-[3-(L-lysylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone, whenever prepared according to the process claimed in claim 34 or by an obvious chemical equiva-lent thereof.

72. 2',5-Dichloro-2-(3-glycylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone, whenever prepared according to the process claimed in claim 35 or by an obvious chemical equi-valent thereof.

73. 5-Chloro-2'-fluoro-2-[5-(1,-leucylaminomethyl)-2-methyl-1-imidazolyl]benzophenone, whenever prepared according to the process claimed in claim 36 or by an obvious chemical equi-valent thereof.

74. 5-Chloro-2'-fluoro-2-[5-(L-alanylaminomethyl)-2-methyl-1-imidazolyl]benzophenone, whenever prepared according to the process claimed in claim 37 or by an obvious chemical equi-valent thereof.

75. A process for preparing which comprises cleaving the benzyloxycarbonyl protecting group (Z) from

76. A compound of the formula whenever prepared by the process of claim 75 or an obvious chemical equivalent.

77. A process for preparing which comprises cleaving the benzyloxycarbonyl protecting group (Z) from

78. A compound of the formula whenever prepared by the process of claim 77 or an obvious chemical equivalent.

79. A process for preparing which comprises cleaving the benzyloxycarbonyl protecting group (Z) from

80. A compound of the formula whenever prepared by the process of claim 79 or an obvious chemical equivalent.

81. A proeess for preparing wherein X is chlorine or bromine which comprises cleaving the benzyloxycarbonyl protecting group (Z) from

82. A compound of the formula wherein X is chlorine or bromine whenever prepared by the process of claim 81 or an obvious chemical equivalent.

83. A process for preparing wherein Z is benzyloxycarbonyl which comprises condensing Z ? Gly ? OH with to form the peptide bond.

84. A compound of formula wherein Z is benzyloxycarbonyl whenever prepared by the process of claim 83 or an obvious chemical equivalent.

85. A process for preparing wherein T is a protecting group selected from benzyloxycarbonyl and trityl which comprises condensing T ? Gly ? Gly ? OH with to form the peptide bond.

86. A compound of the formula wherein T is a protecting group selected from benzyloxycarbonyl and trityl whenever prepared by the process of claim 85 or an obvious chemical equivalent.

87. A process for preparing wherein RH is hydrogen or methyl and X is hydrogen or chlorine which comprises cleaving the benzyloxycarbonyl protecting group (Z) from

88. A compound of the formula wherein RH is hydrogen or methyl and X is hydrogen or chlorine whenever prepared by the process of claim 87 or an obvious chemical equivalent.

89. A process for preparing wherein X is chorine or bromine, which comprises cleaving a benzyloxycarbonyl or trityl protecting group (T) from

90. A compound of the formula wherein X is chlorine or bromine, whenever prepared by the process of claim 89 or an obvious chemical equivalent.