FR2530238A1 - - Google Patents

Abstract

COMPOUNDS OF FORMULA: (CF DRAWING IN BOPI) POSSIBLY IN THE FORM OF PHARMACEUTICALLY ACCEPTABLE SALTS, FORMULA IN WHICH: -X IS PREFERREDLY A RADICAL OF FORMULA: -R IS PREFERREDLY A HYDROGEN ATOM OR A RADICAL METHYL; -R IS A HYDROGEN ATOM, A METHYL RADICAL OR A RADICAL OF THE FORMULA - (CH) NH, PROVIDED THAT R IS A HYDROGEN ATOM ONLY IF R IS NOT ITSELF A HYDROGEN ATOM; -R IS PREFERREDLY A RADICAL PHENYL; -R IS PREFERREDLY A BENZYL RADICAL; -R IS A CYCLOHEXYL OR PHENYL RADICAL;

Description

i

  SUBSTITUTED PEPTIDES WITH THERAPEUTIC ACTION

  The present invention relates to substituted peptides of formula (1) and their salts. In formula X is an amino acid residue or

O R R O

he t I 1 He

R 3 -CH-C-CH 2-N CH C-X

1 (L)

NH C = O

I: R 2

of imino-acid of formula -Nt-COOR

-N 1 () 6

H J

R 10 R 10

21 1 2

-N C-COO

I (L) H -C-Ce R 6

I (L) 6

H

-N CCO

1 (L) H

-N C-COQOR

  ## STR2 ##

I (L) I (L) 6

H H

-N -C-COOR 6

1 (L) _N-C-COOR 6

H 1 (L) 6

H (L)

2 2530238

or -N-CH-COOR

R 4 R 5 '

  R 7 is a hydrogen atom, a lower alkyl radical, a halogen atom, a ketone functional group, a hydroxyl group, a radical of formula -NH-C-lower alkyl, an azide or amine functional group; a radical of formula -NR

XR 2 -NH-C- (CH 2) (

(R 14) p

H (E) O,

2 (2)

  (R 13) p - (CH 2) m Fl, - (CH 2) m 3 to - (CH 2) M 70 to a 1 or 2 naphthyl radical of formula (CH 2 - (CH 2 R 14) p a radical - (CH 2) m-cycloalkyl, R / R 15

-O-C-N

  R 15 O-lower alkyl, -O- (CH 2) - a 1 or 2-naphthyloxy radical of formula

-O (CH 2) m.

  2 (R 14) p a -S-lower alkyl radical, -S- (CH 2) m 1 A - (R 13) p or a 1 or 2-naphthylthio radical of formula -S- (CH 2) m (R 14)

2 R 1)

3 2530238

  R 8 is a ketone function, a halogen atom, a radical of formula O -O-CN R 'o (CH 2) (R * R: 5 (R 13) p a radical -O-lower alkyl, a radical 1 or 2-naphthyloxy of formula -O (CH 2) m (R 14) p a lower alkyl radical, a radical of formula (C) mm R, (R 13) p or a 1 or 2-naphthylthio radical of formula - S - (CH 2) m (R 14) p R 9 is a ketone function or a radical of formula -

(2) n

(R 13) p

  R 10 is a halogen atom or a radical of formula -Y-R 16.

  R11, R11, R12 and R12 are independently selected from hydrogen atoms and lower alkyl radicals, or R11, R and R 'are hydrogen atoms and R11 is a rad: R11, R 12 12 cal of formula (R 14) p R 13 is a hydrogen atom, a lower alkyl radical of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms (or lower alkylthio of 1 to 4 carbon atoms). carbon, a chlorine, bromine or fluorine atom, a trifluoromethyl radiocarbon, hydroxy,

  phenyl, phenoxy, phenylthio or phenylmethyl.

  R 14 is a hydrogen atom, a lower alkyl radical of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms or lower alkylthio of 1 to 4 carbon atoms, a chloro atom;

  bromine or fluorine, or a trifluoromethyl or hydroxy radical.

  m is zero, one, two, three or four.

  p is equal to one, two or three, provided that p is no longer -

  bigger than one only if R 13 or R 14 is a hydrogen atom, a

  methyl or methoxy radical or a chlorine or fluorine atom.

  R 15 is a hydrogen atom or a lower alkyl radical

from 1 to 4 carbon atoms -

  Y is an oxygen or sulfur atom.

  R 16 is a lower alkyl radical of 1 to 4 carbon atoms

16 - ne or a radical of formula

(CH 2)

  (R 13) p or the R 16 substituents together form a pentagonal ring,

  or hexagonal, one or more of the carbon atoms of which are

  replaced by a lower alkyl radical of 1-4 ato-

  carbon monoxide or by di (lower alkyl) radical of 1 to 4 atoms

of carbon).

  R 4 is a hydrogen atom, a lower alkyl radical or a radical of the formula * - (CH 2) m -cycloalkyl, - (CH 2) mp 4 1 "(C H 2) m -O,.

2

  -I (CH, or OR 5 is a hydrogen atom, a lower alkyl radical or a radical of formula - (CH 2) ## STR1 ## NH 2 H 2) r '- (CH) -S H 1, - (Cl 2 R NH

- (CH) -NH-C

  NH 12 -S lower alkyl, Ir II 8 or C 2 r CNH 2

r is an integer from 1 to 4.

  R is a lower alkyl, benzyl or phenethyl radical.

  R 2 is a hydrogen atom or a lower alkyl radical

benzyl or phenethyl.

  R is a hydrogen atom, a lower alkyl or cycloalkyl radical, or a radical of the formula ## STR2 ##

  - (CH 2> 4-NH 2, - (CH 2) 2 -OH, - (CH 2) 3 -OH,

  - (CH) -OH, - (CH 2> 2-SH, - (CH 2> 3 SH, Or

(CH) 4-SH.

  R 1 is a hydrogen atom, a lower alkyl or halo-lower alkyl radical, a radical of formula

(CH 2) CH) 5 <H

_ (CH), 5 #

  2 r (CH 2) r 5 - (CH 2) n OH (CH 2) r Ir H

(CH 2) U

  2 Hzr i -Ny I H To (CH 2) r -NH 2 '(CH 2) r -SH, - (CH 2) r -OH, - (CH 2) r -S lower alkyl,

O

O

NH {

  (CH 2) r NHC or - (CH 2) r-C-NH (H 2 NHCN 2 r 2 NH 2 with the proviso that R 1 is a hydrogen atom only

itself a hydrogen atom.

  R 2 is a radical of formula - (C 2) m (R 14) p (CH 2

2 O 2

  if R is not 3, - (CH 2) m, or R 3 is a hydrogen atom, a lower alkyl radical, a radical of formula (CH 2) m M (R 14) p

- (CH 2),

- (CH 2) m -

I - (CH 2) mn)

  a halo-lower alkyl radical or - (CH 2) m -cycloalkyl, or a radical

  cal-of formula - (CH 2) r OH 2 (CH) - (CH 2) r -OH, OH (CÉ 2) r - (H 2 R 3 H N H - (CH) -o

2 m O -

  - (CH 2) r -N <2, - (C 52) rs H, - (CH 2) r -S lower alkyl

NH O

  a II - (CH) -NH-C, or - (CH 2) r-C-NH 2 2 r NH 2

  m, R 14, p and r having the same definitions as above.

  R 6 is a hydrogen atom, a lower alkyl, benzyl or benzhydryl radical, or a radical of formula

R

not

-CH-O-C-R 18 C-O-R 23

R R

R 17 22

C 2 C C

  -CH (CH-OH) 2, or -CH 2 -CH 2 R 17 is a hydrogen atom or a lower alkyl radical,

cycloalkyl or phenyl.

  R 18 is a hydrogen atom or a lower alkyl, lower alkoxy or phenyl radical, or R 17 and R 18 together form a radical of formula - (CH 2) 2-, - (CH 2) 3, -CH = CH-, or R 21 and R 22 are independently selected from hy

21 22

  and lower alkyl radicals.

  R 23 is a lower alkyl radical.

  The broadest aspects of the invention are the substituted peptides of formula I above, the compositions and method of use of these compounds as pharmaceutical agents, and intermediates useful for preparing these compounds.

  The term "lower alkyl" used to define various

  boles means straight or branched chain radicals

  The preferred lower alkyl radicals have at most 4 carbon atoms, the methyl and ethyl radicals being the best choice. Similarly, the terms lower alkoxy

  and "lower alkylthio" refers to such lower alkyl radicals.

  attached to an oxygen or sulfur atom.

  The term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms, cyclopentyl and cyclohexyl radicals

constituting the best choice.

  The term "halogen" refers to a chlorine, bromine or fluorine atom.

  The term "halo-lower alkyl" refers to a radical al-

  lower kyle as defined above, in which one or more hydrogen atoms have been replaced by atoms

  chlorine, bromine or fluorine, for example the trifluoro-

  preferably the preferred rosemethyl, or pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc. The symbols (2 U 'IH 2) m' and - (CH 2) correspond to the case where the alkylene bridge is attached. to an atom of

free carbon.

  Compounds of formula I in which

  R is a hydrogen atom by transforming a carboxymeric ester

  peptide thyle, of formula (II) O R O

_ 1 1 II

HO-C-CH-N-CH-C-X

11 2 (L)

O R 40

  in its acid chloride, and by reacting the latter with an oxazolone of formula

(III) N

R 2-C C-R 3

I I

O C-C = O

  R 40 and R 6 (in the definition of X) being R 6 dfnto protecting groups, R 40 being for example a benzyloxycarbonyl radical;

  and R 6 a benzyl radical. The elimination of the protecting groups

  R 40 and R 6, for example by hydrogenation, provide the

  compounds of the formula wherein R 6 is a hydrogen atom.

  The carboxymethyl ester of the peptide of formula

  II by reacting the peptide ester of formula

(IV) R O

H 2 N-CHC-X

(L) M

  with tert-butyl bromoacetate and then introducing the

  protective composition R 40, for example by chloroformate treatment

of benzyl.

  The compounds of formula I can also be prepared by reacting a ketone of formula

(V) O

R 2 _C-NH-CH-C-CH 2 -halo He I

R 3

  R 3 in which "halo" is a chlorine or bromine atom, with the peptide ester of formula (VI)

R R O O

he

HN CH C-X

  (L) in the presence of a base such as sodium bicarbonate, and

eliminating the ester group R 6.

  The intermediate ketone of formula V can be prepared by treating a ketone of formula (VII) ## STR2 ##

- R 3

  wherein R 40 is a protecting group such as the benzyloxycarbonyl radical, with hydrobromic acid and acid

  acetic acid, then reacting the resulting product with the

Formula acid treatment

(VIII)

R 2-C-halo

  in the presence of a base such as sodium bicarbonate.

  The compounds of formula I can also be prepared by reacting an aminoketone of formula

(IX) O R

0 O R

R 2-C-NH-CH-C-CH 2-NH

  Especially its hydrochloride, with the haloacetyl amino acid or imino acid ester of the formula

R 1 O

(X) 1 He

halo-CH C-X.

  (L) wherein R 6, in the definition of X, is an easily removable ester protecting group, and "halo" is an atom

chlorine or bromine.

  The compounds of formula I can also be prepared by combining a carboxylic amino ketone acid of formula (XI)

0 O 'RR 1 O

He p I t 1Il

R 2 _C-NH-CH-C-CH 2 -N CHC-OH

HE)

  R 3 with the amino acid or imino acid ester of formula

(XII)

HX

  in the presence of a combination agent such as dicyclohexyl-

  carbodiimide, R 6 being, in the definition of X, a grouping

  easily removable protector Elimination of the protective group

  R detector provides the products of formula I in which R 6

is a hydrogen atom.

he

  The aminoketone of formula IX can be prepared in the form of

  the carboxyalkylamine of formula

(XIII)

5. -R

HO-C-CH 2-N-R 40

  Wherein R 40 is a protecting group such as the benzyloxycarbonyl radical, in its acid chloride, and then reacting the resulting product with an oxazolone of formula III, to obtain a compound of formula (XIV)

O O R

He He I

R 2-C-NH-CH-C-CH 2 -N-R 4

2 2 40

R 3

  The elimination of the protective group R 40 by hydrogenation

  nation, for example, provides the intermediate product of

the IX.

  It is also possible to prepare the aminoketone of formula IX in which R is other than a hydrogen atom, by reacting the ketone of formula V with a substituted amine of formula

(XV) R-NH 2

  The carboxylic amino ketone acid of formula XI can be prepared by reacting the aminoketone of formula IX with a haloacetic acid ester of formula

(XVI)

  1 1

R O

  halo-CH C-O-Prot (L) wherein "prot" is a protecting group of the ester

  easy to remove, for example the t-butyl radical, to obtain

form the ester of formula

(XVII)

  The removal of the protective group from the ester provides a protective, non-protective

  the reactant of formula XI.

  In the above reactions, if any or all

  R 1, R 1, R 3 and R 3 are radicals of the formula ## STR5 ## wherein R 2, R 3, R 3 and R 3 are as defined in formula (II). CH 2) -, - CH 2) rs HH

: / NH

<CH 2) r-OH, or: (H 2 R N-

  NH; The hydroxyl, amine, imidazolyl, mercaptan or guanidinyl functions must be protected during the reaction.

  suitable protectants include benzyloxycarbonyl radicals

  nyl, t-butoxycarbonyl, benzyl, benzhydryl, trityl, etc.,

  as well as the nitro group in the case of the guanidinyl radical.

  The protecting group is removed by hydrogenation, by treatment with an acid, or by other known methods, after

the completion of the reaction.

  The esters of formula I in which R 6 is a lower alkyl, benzyl or benzhydryl radical may be subjected to a chemical treatment, for example with sodium hydroxide in aqueous dioxane, or with trimethylsilyl bromide to obtain the

  products of formula I wherein R 6 is a hydrogen atom.

  The benzyl and benzyl esters can also be hydrogenated.

  by treating them with hydrogen, for example, by

  it is a catalyst based on palladium on carbon.

  The esters of formula I in which R 6 is a radical of formula

-CH-O-C-R 18

R 17

  using in the above reactions the peptide of formula IV or VI or the haloacetyl amino acid or imino acid ester of formula X, with this ester group already in place. Such esters can be prepared by treating the peptide of formula IV or VI, that is the haloacetyl ester of amino acid or imino acid of formula X, in which R 6 is a hydrogen atom, with an acid chloride such that

O O

  <9> CH 2 -O-C-C 1 or (H 3 C) 3-C-O-C-Cl so as to protect the nitrogen atom. The protected compound is then reacted, in the presence of a base, with a compound of formula

(XVIII)

O He

L-CH-O-C-R 18

In which L is a labile substituent such as a chlorine or bromine atom or a tolylsulfonyl radical, etc., then the nitrogen-protecting group is removed, for example by

  treatment with an acid or by hydrogenation.

  It is also possible to obtain the esters of formula I in which R 6 is a radical of formula

-CH-O-C-R 18

I 1 '

R 17 R 17

  by treating the product of formula I in which R 6 is an ato-

  of hydrogen, by a molar excess of the compound of formula XVIII.

  Esters of formula I in which R 6 is a radical of formula

R O

R 21 he

-C-0-R 23

  R 22 treating the product of formula I wherein R 6 is a hydrogen atom by a molar excess of the compound of formula

(XIX) 21

21 O

I-C C-O-R 23

I

R 22

  The esters of formula I in which R 6 is a radical of formula -CH (CH-OH) 2 or -CH -CH CH can be prepared.

2 2

OH OH

  by combining the product of formula I wherein R 6 is a hydrogen atom with a molar excess of the compound of formula (XX) * CH 2 (CH-O Prot) 2 OH or the compound of formula 1XXI)

CH CH CH 2

I I I.

OH O Prot O Prot

  in the presence of a combination agent such as dicyclohexyl-

  carbodiimide, and by eliminating the protective groups of

hydroxyl functions.

  The esters of formula I in which

  R 6 is a lower alkyl radical from carbon acids

  corresponding xyl, that is to say compounds in which

  R is a hydrogen atom, by conventional procedures

  esterification, for example by treatment with a halogen

  alkyl compound of formula R 6 -halo, or with an alcohol of formula

R 6 -OH.

  The peptide esters of formulas IV and VI can optionally be obtained by combining the hydrochloride salt of the amino acid or imino acid ester of formula XII in which R 6 is, for example, a benzyl radical, with the amino acid N- protected formula

(XXII)

R R

  in which "prot" is a protecting group such as the radical of formula O.

-C-O- (CH 3) 3

  reaction in the presence of a combination agent such as

  dicyclohexylcarbodiimide The elimination of the protective group

  nitrogen, by treatment with trifluoroacetic acid

  For example, provide the peptide esters of formulas IV and VI.

  The haloacetyl amino acid ester or

  imino acid of formula X by reacting the amino ester

  acid or imino acid of formula XII with a halogen halide

Formula acetyl

(XXIII) W

  Halo-CH 2-C-halo The products of formula I may be obtained

  wherein R 7 is an amine function by reducing the

  corresponding products of formula I in which R 7 is a

azide.

  The preferred compounds according to the invention with regard to

  the peptide part of structural formula I are those in which: R is a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, or a

phenyl radical.

  R 1 is a hydrogen atom, a lower alkyl radical

  straight or branched chain of 1 to 4 carbon atoms, a radical

  trifluoromethyl cal, a radical of formula - (CH 2) r -NH 2 in which r is an integer from 1 to 4, or a radical of formula

-CH 2, -CH 2 DOH,

-CH z he -H Tl '

I -

H H

-CH 2 OH

OH

-CH 2-SH,

/ NH

- (CH 2) 2 -S-CH 3 '(CH 2 3)

N 1 H 2

-CH 2-OH,

O O

  II-CH-H or -HC-NH CH 2 -C-NH 2, or (CH 2) 2 2 provided that R 1 is a hydrogen atom only if R is

  not itself a hydrogen atom.

  R is a hydrogen atom or a cyclohexyl radical or

phenyl -

  R 5 is a hydrogen atom, a lower alkyl radical with a straight or branched chain of 1 to 4 carbon atoms, or a radical of formula -CHOH

_CH 2 OH,

-CH 2 ^^ 5 OH, -CH 2 QOH

OH

- (CH 2) 4-NH 2

-CH 2 O'H

H -CH 2 VI g N I H NH

  -CH 2 -SH, - (CH 2) 2 -S-CH 3, - (CH 2) 3 NHC /

NH 2 -CH H 5 Ir t

0 0

O o

-CH 2-C-NH 2 or - (CH 2) 2 C-NH 2.

  R 6 is a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, an alkali metal salt, or a radical of formula

O, O

He He

-CH-O-C-R-CH 2-C-OR 23

8

R -CH- (CH-OH> 2, or -CH-CH -CH

J I

OH OH

  R 23 is a lower alkyl radical with a straight or branched chain of 1 to 4 carbon atoms, in particular a radical of

formula -C (CH 3) 3.

  R 17 is a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms or a

cyclohexyl radical.

  R 18 is a straight chain lower alkyl radical or

  branched from 1 to 4 carbon atoms, or a phenyl radical.

  R is a lower alkyl radical with a straight or branched chain of 1 to 4 carbon atoms, in particular a radical of formula -C (CH 3) 3

R 7 is a hydrogen atom.

R 7 is a hydroxyl group.

  R 7 is a straight-chain lower alkyl radical or

  branched from 1 to 4 carbon atoms or a cyclohexyl radical.

R 7 is an amine function.

  R 7 is an O-lower alkyl radical whose radical

  lower alkyl is a straight or branched chain of 1 to 4 atoms

my carbon.

R 7 is a radical of formula

(CH 2) R R 1

  in which m is zero, one or two and R 13 is a hydrogen atom, a methyl, methoxy or methylthio radical, an atom

  chlorine, bromine or fluorine, or a hydroxy group.

  R is a radical of formula -O (CH 2) m 49 R 13 il or a 1 naphthyloxy or 2-naphthyloxy radical, m being equal to zero,

  one or two, and R 13 being a hydrogen atom, a methyl radical,

  methoxy or methylthio, an atom of chlorine, bromine or

fluorine, or a hydroxy group.

  R is an S-lower alkyl radical, the lower alkyl part of which is a straight or branched chain of 1 to 4

carbon atoms.

  R is a radical of formula -S- (CH 2) m R 13 R 3 or a 1-naphthylthio or 2-naphthylthio radical, m being equal to zero, one or two and R 13 being a hydrogen atom, a methyl radical, methoxy or methylthio, a chlorine atom, bromine

  or fluorine, or a hydroxy group.

  R 8 is an O-lower alkyl radical, the lower alkyl part of which is a straight or branched chain of 1 to 4

carbon atoms.

  R 8 is a radical of formula -O (CH 2) m R

_ R

  in which m is zero, one or two and R 13 is a hydrogen atom, a methyl, methoxy or methylthio radical, an atom

  chlorine, bromine or fluorine or a hydroxy group.

  R 8 is an S-lower alkyl radical, the lower alkyl part of which is a straight or branched chain of 1 to 4 carbon atoms.

carbon.

R 8 is a radical of formula

-S- (CH

  R in which m is zero, one or two and R 13 is a hydrogen atom, a methyl, methoxy or methylthio radical, a

  chlorine, bromine or fluorine atom, or a hydroxy group.

  R is a phenyl, 2-hydroxyphenyl or 4-hydroxy radical

9 y

phenyl.

  The two substituents R 1 are fluorine or chlorine atoms. The two substituents R O are radicals of formula -Y-R 6 in which Y is an oxygen or sulfur atom, R 16

16 1

  is a straight or branched chain lower alkyl radical of

  1 to 4 carbon atoms, or the two substituents R 16 formally

  together a hexagonal or pentagonal cycle of which one or more

  if available carbon atoms are eventually

  substituted with a methyl or dimethyl radical.

  R 1, R'11, R 12 and R'12 are all hydrogen atoms, i Rl, 11 12 R 12

  or R1 is a phenyl, 2-hydroxyphenyl or 4-hydroxy radical

  xyphnyl and R'11 R 12 and R'12 are hydrogen atoms

  Constitute the best choice of compounds according to the invention

  with regard to the peptide part of the formula developed

  I, those in which: X is a radical of formula

-N-CH 2-COOR 6

R 4

R 7 S

H 2 f 2 H 24 H

-N C-COOR 6 -N -C-COOR 6

1 (L) 1 (L)

H H

or -N

COOR 6

  R is a hydrogen atom or a methyl radical.

  R is a hydrogen atom, a methyl radical, or a radical of formula (CH 2 y 4 NH 2, especially a methyl radical, provided that R 1 is a hydrogen atom only if R is

  not itself a hydrogen atom.

  R 6 is a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, or a

alkali metal salt.

  R 4 is a cyclohexyl or phenyl radical.

  R 7 is a hydrogen atom, a cyclohexyl radical, a

  alkoxy radical of 1 to 4 carbon atoms, or a radical

cal of formula (CH 2) m i

M R 1

R 13 1

  -O (CH 2) O 13 or -S (CH 2) 4> R 13

13 R 13

  where m is zero, one or two and R 13 is an ato-

  of hydrogen, a methyl, methoxy or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxy group, very particularly preferred in the case where R 7 is a hydrogen atom.

  t is two or three, preferably two.

  Preferred compounds of this invention with respect to

  the ketone part of structural formula I are those in which: R 2 is a radical of formula - (CH 2) m-14 R 14 in which m is zero, one or two and R 14 is an atom of hydrogen, a methyl, methoxy or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxyl group,

especially a phenyl radical.

  R 3 is a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, a radical of formula - (CH 2) r -NH 2,

2 2

<-CH 2) m, or (CH 2) m J

RN

  where m is zero, one or two, R 14 is an atom.

  hydrogen, a methyl, methoxy or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxyl group, and r is an integer from 1 to 4, in particular the benzyl radical. The compounds of formula I wherein R 6 is a hydrogen atom form salts with various mineral bases or

  Organic non-toxic and pharmaceutical salts are preferred.

  acceptable, although other salts are also

  readable to isolate or purify the product.

  acceptable salts include metal salts such as sodium, potassium or lithium salts,

  alkaline earth metals such as calcium salts or

  gnesium, and salts derived from amino acids such as arginine, lysine, etc. The salts are obtained by reacting the acid form of the compound with one equivalent of the base providing the desired ion in a medium in which the salt precipitates, or in

  an aqueous medium, followed by lyophilization.

  Similarly, the compounds of formula I, especially those in the formula of which R 6 is an ester group, form salts

  with various mineral and organic acids Here again, we prefer

  Non-toxic and pharmaceutically acceptable salts, although other salts can also be used to isolate or purify the product. These pharmaceutically acceptable salts include those formed with hydrochloric acid, methanesulfonic acid, sulfuric acid, and the like. maleic acid, etc. The salts are obtained by reacting the product with an equivalent amount of the acid in a medium in which the

salt precipitates.

  As seen above, the peptide portion of the molecule of the products of formula I represented by

* 25 RR 1 O

He

-N CH C-X

(L)

  is in the laevorotic configuration (L) A center of asyl-

  metry is also present in the ketone part of the molecule.

  When R 3 is other than hydrogen, the compounds of formula I may exist in diastereomeric forms or in mixtures. The methods described above may be used as starting materials for racemates, enantiomers or

  diastereoisomers When preparing diastereo-

  isomers, they can be separated by conventional methods of

  chromatography or fractional crystallization.

23 2530238

  The products of formula I in which the imino nucleus

  monosubstituted acid give rise to a cis-trans isomerism The configuration of the final product will depend on the configuration of the substituents R 7, R 8 and R 9 in the starting material of formula

XII.

  The compounds of formula I, as well as their pharmaceutical salts,

  are acceptable, are antihypertensive agents.

  They inhibit the conversion of a decapeptide, angiotensin I, to angiotensin II, and are therefore useful for reducing or alleviating angiotensin-induced hypertension. The action of an enzyme, renin, on the angiotensinogen, pseudoglobulin in blood plasma, gives angiotensin I Angiotensin I is converted by angiotensin converting enzyme (ETA) to angiotensin II This is a pressure product

  active person who has been held responsible for various forms of

  tension in various species of mammals, man for example.

  The compounds according to the invention are involved in the angiotensinogenic b (renin) angiotensin I> angiotensin II sequence by inhibiting the angiotensin-converting enzyme and by

  reducing or eliminating the formation of the pressing product, the angio-

  tensin II so by administering a composition that contains

  one or more of the compounds according to the invention, the hy-

  angiotensin-related perturbation in a mammalian species, (man for example) who suffers from it A single dose, or

  preferably two to four divided daily doses, administered

  about 0.1 to 100 mg, preferably about 1 to 50 mg per kg of body weight per day, is suitable for

  reduce the blood pressure The substance is preferably

  administered by the oral route, but it is also possible to use the

  parenteral routes such as subcutaneous, intramuscular

  cular, intravenous or intraperitoneal.

  The compounds of the present invention may also be combined with a diuretic for the treatment of hypertension. A combination comprising a compound of the present invention and a diuretic may be administered at an effective dose which comprises a total daily dosage of 30 to 600 mg, preferably about 30 to 330 mg, of a

  compound of the invention, and from about 15 to 300 mg, preferably

24 2530238

  from about 15 to 200 mg of diuretic to a mammalian species

  Examples of diuretics for which use is considered in combination with a compound

  the present invention are thiazides, for example chloro

  thiazide, hydrochlorothiazide, flumethiazide, hydroflume

  thiazide, bendroflumethiazide, metclothiazide, trichloro-

  methiazide, polythiazide or benzthiazide, as well as

  etchrynic acid, ticrynafene, chlortalidone, furo

  semide, musolimine, bumetanide, triamterene, amiloride

  and spironolactone, as well as the salts of these compounds.

  The compounds of formula I can be used for the reduction of blood pressure, in the form of compositions such as tablets, capsules or elixirs for oral administration, or in the form of solutions or

  sterile suspensions for parenteral administration.

  About 10 to 500 mg of a compound of formula I are combined with a carrier, a carrier, an excipient, a binder, a preservative, a

  stabilizer, a flavoring agent, etc., physiologically acceptable

  tables, in unit dosage form as required by the accepted pharmaceutical practice The amount of active ingredient contained in these compositions or preparations is such that

  an appropriate dosage is obtained in the above-mentioned range.

  than. The compounds of formula I in which X is a radical

  of the formula -NH-CH-COOR 6 also possess an activity of inhibiting

* Encephalinase bition and are useful as analgesics.

  Thus, by administering a composition which contains one or more

  compounds of formula I or more

  acceptable for the latter, the pain is reduced in the host mammal A single dose, or preferably two to four divided daily doses, administered from about 0.1 to about 100 mg per kg of body weight per day, of

  preferably from about 1 to about 50 mg per kg per day,

  The desired analgesic effect is preferred. The composition is preferably administered orally, but

  parenteral routes such as the subcutaneous route.

  The following examples serve to illustrate the invention.

  Temperatures are in degrees Celsius "LH-20" means a Sephadex chromatography gel put on the market

  by the company Pharmacia Fine Chemicals.

Example 1

  1 IN 3- (benzoylamino) -2-oxo-4-phenylhydrochloride

butyl 3-L-alanyl-L-proline

  a) Para-toluenesulfonic acid salt of the phenyl ester

  Methyl L-Alanyl-L-Proline

  O-1,1-dimethylethoxy) carbonyl is mixed with

  alanine (310.7 g), L-proline phenylmethyl ester hydrochloride (396.2 g), dicyclohexylcarbodiimide (338.6 g),

  hydroxybenzotriazole hydrate (251.5 g), diisopropyl-

  ethylamine (285.7 ml) and 5 liters of tetrahydrofuran (dicyclo

  hexylcarb Sodiimide is added last), and shake everything

  the ambient temperature during one night We filter and

  The reaction mixture is dissolved in 4 l of acetonitrile.

  ethyl acetate and washed with twice two liters of bicarbonate

  sodium acetate 5%, twice two liters of 5% potassium bisulfate, and with water The ethyl acetate layer is dried over magnesium sulfate and concentrated. The residue is dissolved in 3 l of water. diethyl ether and is left

  stand at 0 overnight The mixture is filtered and

  center the filtrate to obtain 620 g of phenylmethyl ester

  crude N1 (1,1-dimethylethoxy) carbonyl-L-alanyl-L-proline.

  275 g of N (1,1-dimethylethoxy) carbonyl-L-alanyl-L-proline phenyl methyl ester are cooled in an ice bath and treated with 500 ml of cold trifluoroacetic acid (freshly distilled) under argon. The mixture is stirred at room temperature for one hour. The mixture is concentrated under vacuum and azeotropic double distillation is carried out with toluene. The crude trifluoroacetic acid salt is dissolved in 500 ml of toluene in the form of an oil. ether, and the solution is slowly treated with a solution of para-toluenesulphonic acid hydrate (one equivalent) in 6 liters of ether. The resulting precipitate is collected by filtration. The solid is dissolved in one liter of methanol and the solution is treated by

  4 l of ether, then cooled. The resulting precipitate is collected.

  and dried to obtain 300 g of the paratoluene acid salt.

  Nesulfonic acid of the phenylmethyl ester of L-alanyl-L-

proline; mp 156-158.

  b) Phenylmethyl ester of 1-lN-1 2- (1,1-dimethyl-

  ethoxy) -2-oxoethyl-N L (phenylmethoxy) carbonyl-L-alanyll-L-

  Proline is stirred at room temperature for 72 hours.

  mixture of the para-toluenesulphonic acid salt of the phenyl ester

  L-alanyl-L-proline methyl (32.16 g, 72 mmol), tert-butyl bromoacetate (14.2 g, 72 mmol), triethylamine (20.1 mL, 144 mmol) and tetrahydrofuran (290 ml) Benzyl chloroformate (12.4 ml, 87.8 mmol) and triethylamine (12.5 ml, 87.8 mmol) were added and the mixture stirred overnight The product was evaporated. reaction and partition between water and ethyl acetate Wash

  the part soluble in ethyl acetate with chloroacid

  diluted with water and then evaporated.

  solution in ethyl acetate and is subjected to a

  matography on silica gel (37 to 62 micron grain) using

  using a 1: 1 mixture of ethyl acetate and hexane (pressure of 0.7 atm) as solvent to obtain 19.5 g of phenyl methyl ester of 1CN-l 2- (1,1-dimethylethylethoxy) -2-oxoéthyll

  N C (phenylmethoxy) carbonyl-L-alanyl-L-proline.

  c) Phenylmethyl ester of 1-lN- (carboxymethyl) -N-

  (Phenylmethoxy) carbonyll-L-alanyll-L-proline

  The phenylmethyl ester of 1-lN-1 2-

  dimethylethoxy) -2-oxoethyl-N (phenylmethoxy) carbonyl] -L-alanyl

  L-proline (18 g, 34.3 mmol) in 50 ml of trifluoroacetic acid

  and allowed to stand at room temperature for one hour and a half. The mixture is evaporated and then filtered into a

  small column of silica gel (200 g) using as sol-

  9.6 / 0.2 / 0.2 mixture of chloroform, methanol and

  of acetic acid, to obtain 11.4 g of the phenyl methyl ester.

  1- (N-carboxymethyl) -N (phenylmethoxy) carbonyl-L-

alanyli-L-proline.

27 2 2530238

  d) Phenylmethyl ester of 1-lN-L 3- (benzoylamino)

  2-oxo-4-phenylbutyll-N (phenylmethoxy) carbonyl-L-alanyll-L-

proline

  The phenylmethyl ester of 1-lN- (carboxy-

  methyl) -N-phenylmethoxy) carbonyl 13-L-alanyll-L-proline (7.0 g; 0 mmol) in 50 ml of dry tetrahydrofuran and cooled

  the solution in an ice bath

  lyle (1.57 ml, 18 mmol), then 4 drops of dimethylformamide.

  After 15 minutes, the reaction mixture is stirred at room temperature.

  The mixture is evaporated, redissolved in 30 ml of tetrahydrofuran and the solution is cooled in an ice bath. This solution is added dropwise over a period of 5 minutes to a cooled solution.

  in 2-phenyl-4- (phenylmethyl) -5 (4H) -oxazolone ice -

  (3.96 g, 15.75 mmol) in 24 ml of tetrahydrofuran Triethylamine (2.5 ml, 17.1 mmol) was added and the reaction mixture was stirred at room temperature overnight. The triethylamine hydrochloride solution is separated and the filtered tetrahydrofuran solution is evaporated and redissolved in 16 ml of pyridine. 50 mg of 4-dimethylamino pyridine are added and the solution is stirred at room temperature.

  room temperature for 3 hours 16 ml of glacial acetic acid

  and the reaction mixture is heated to 100 for 45 minutes.

  The reaction mixture was then cooled, evaporated in vacuo, dissolved in ethyl acetate and extracted with aqueous sodium bicarbonate solution and dilute hydrochloric acid. After evaporation, subject the ethyl acetate extract to chromatography on silica gel (37-62 micron grain) using

  solvent a 4/6 mixture of ethyl acetate and benzene,

  obtain 4.9 g of phenyl methyl ester of 1-lN-C 3- (benzoylamino) -

  2-oxo-4-phenylbutyll-N l (phenylmethoxy) carbonyl L-alanyl L-

  proline. Anal calc for C 4 H 4 N 3 O 0.42 HH 0:

41 3 7 0, 2

C, 70.31; N, 6.15; H, 6.17

Found: C, 70.31; N, 6.13; H, 6.08.

2530238 -

  e) 1-1 N-1 3 (benzoylamino) -2-oxo-4- monohydrochloride

  phenylbutyld 11-L-aianyl-Lp-oline 1.0 g of 1- (3-benzoylamino) -2-oxo-4-phenylbutyl-N (phenylmethoxy) carbonyl-L-phenylmethyl ester are dissolved Alanyl 3-L-proline in 30 ml of absolute ethanol and 2.25 ml of 1N hydrochloric acid. Palladium-on-charcoal catalyst (10%, 200 mg) is added as the catalyst, and the solution is shaken.

  under a hydrogen atmosphere for one night.

  lyser by filtration and the solution is evaporated.

  nitrate the crude product (700 mg) to 300 mg of the crude product from a small-scale anterior reaction, and the whole is passed through a column of "LH-20" (2.5 cm × 38 cm) in

  methanol The fractions containing the desired product are pooled

  they are evaporated, dissolved in water and

  The filters are lyophilized to obtain a clear aqueous solution to obtain

  800 mg of 1-lLN-1-3- (benzoylamino) -2-oxohydrochloride

  4-phénylbutyll-L-alanyll-L-proline; 2 59.6 (c = 1.4, 1D)

  methanol); 98-130 (decomposition).

  TLC (silica gel, 4: 1: 1 mixture of n-butanol, acetic acid

and water) Rf = 0.44.

  Anal calc for C 25 H 30 N 305 C 1 0.75 H 20:

  C, 59.88; H, 6.33; N, 8.38; Cl, 7.07 -

  Found: C, 59.82; H, 6.30; N, 8.42; Cl, 6.85,

Example 2

  1-IN-1 7-amino-3- (benzoylamino) -2-dihydrochloride

  oxoheptyl-L-alanyll-L-proline a) N -benzoyl-N 6 1 (phenylmethoxy) carbonyl-L-lysine

  To a cooled solution in N 6 (phenyl)

  methoxy) carbonyl-L-lysine (10.09 g, 36 mmol) in aqueous sodium hydroxide (1 N, 26 ml) is added simultaneously benzoyl chloride (5 ml, 43.2 mmol) and an aqueous solution of

  sodium hydroxide (4 N, 10.8 ml) in five times, in a total of 30 minutes.

  The ice bath is removed and stirring is continued for a further hour at room temperature. The reaction mixture is then extracted with ethyl acetate (discarded), the aqueous mother liquor is acidified with hydrochloric acid. diluted and extracted with ethyl acetate. The extract is concentrated in ethyl acetate and the residue is crystallized from a mixture of ethyl acetate and hexane to obtain 12.9 g. N 2-benzoyl-N 6-1 (phenylmethoxy) carbonyl-L-lysine; pf 110-112

(109)

  b) 2-Phenyl-4-1-4-lphenylmethoxy) carbonylaminaminol butyl -5 (4H) oxazolone

  N 2 -Benzoyl N 6 (phenylmethoxy) carbonyl

  L-lysine (11.53 g, 30 mmol) in 55 ml of tetrahydrofuran

  and the solution is stirred in an ice bath to this reaction mixture.

  a dicyclohexyl solution is added dropwise.

  carbodiimide (6.8 g, 33 mmol) in tetrahydrofuran, in minutes After 1 hour, the ice bath is removed and stirring is continued at room temperature for a further 18 hours The dicyclohexylurea is separated by filtration and The tetrahydrofuran solution is concentrated under vacuum. The residue is crystallized from a mixture of ethyl acetate and hexane to give 9.4 g of 2-phenyl-4-methylphenylmethoxy.

  carbony 11 aminolbutyll-5 (4H) -oxazolone; 72-73 (68).

  c) Phenylmethyl ester of 1-lN-1 3- (benzoylamino)

  7-C (phenylmethoxy) carbonylaminol-2-oxoheptyl-N-E1 (phenyl)

  methoxy) -carbonyl-L-alanyll-L-proline The ester is dissolved in 20 ml of tetrahydrofuran

  1- (N-carboxymethyl) -N (phenylmethoxy) phenylmethyl

  Carbonyl-L-alanyl-L-proline (2.82 g, 6 mmol) of Example 1 (c), and the solution is stirred in an ice bath. Oxalyl chloride (0.63 ml; 7.2 mmol), then 4 drops of dimethylformamide. After stirring this reaction mixture in an ice bath for 20 minutes, it is stirred at room temperature for a further hour. The solvents are removed under vacuum and the residue is redissolved in vacuo. 10 ml of tetrahydrofuran and cooled in an ice bath to this solution

  stirred cold, add a cold solution of 2-phenyl-4-

  1- (4-phenylmethoxy) carbonyllamino-3-butyll-5 (4H) -oxazolone (2.2 g;

  6 mmol) in 14 ml of tetrahydrofuran, followed by triethyl

  lamine (0.85 ml, 6 mmol) The ice bath is removed and the reaction mixture is stirred at room temperature for 1 hour.

  overnight The triethylhydrochloride is filtered off

  laminate which precipitated and concentrated the mother liquor under vacuum.

2530238

  The residue is then redissolved in 6 ml of pyridine, 4 mg of dimethylaminopyridine is added, and the solution is stirred at room temperature for 3 hours. Then 6 ml of acetic acid are added and the reaction mixture is heated at 105 for 45 minutes. It is then evaporated, taken up in ethyl acetate and then washed with water, with dilute hydrochloric acid, and with an aqueous solution of sodium bicarbonate. After evaporating the solvent the crude product (3.8 g) is chromatographed on 230 g of silica gel using a 4: 3 mixture of ethyl acetate and hexane to elute, followed by a 2: 1 mixture. acetate

  of ethyl and hexane, to obtain 1.8 g of phenyl methyl ester.

  1N-C3-benzoylamino) -7-ephenylmethoxy) carbonylamino-2-oxoheptyl-N-1 (phenylmethoxy) carbonyl-L-alanyll-L-proline.

  d) 1-11N-17-amino-3- (benzoylamino) -2-dihydrochloride

oxoheptyl 11-L-alanyl -L-proline

  The phenylmethyl ester of 1-IN-3 is dissolved

  (benzoylamino) -7 (phenylmethoxy) carbonylamino -2-oxoheptyl-

  N1 (phenylmethoxy) carbonyl-L-alanyll-L-proline (1.3 g, 1.6 mmol) in 75 ml of ethanol and aqueous hydrochloric acid (1 N, 5 ml). sure

  (10%, 450 mg) and the mixture is hydrogenated

  at atmospheric pressure overnight The catalyst is filtered off and the solution is evaporated.

  under vacuum The residue is dissolved in water and lyophilized

  The lyophilizate is triturated with ether to obtain

  0.6 g of 1-lN-17-amino-3- (benzoylamino) -2-oxohydrochloride

  heptyl I-L-alanyll-L-proline; 80-155; D = 22-5

  D (c = 1.1, methanol) Rf 0.09 (silica gel, 4: 1: 1 mixture of

  n-butanol, acetic acid and water).

  Anal calc for C 22 H 32 N 405 2 H Cl At 1.5 H 20:

223245 2

  C, 49.63; H, 7.00; N, 10.52; C 1, 13.55

  Found: C, 49.63; H, 6.82; N, 10.48; Cl, 13.36.

Example 3

  1-N-1-3- (benzoylamino) -2-oxoheptyl-L-alanyl-L-proline monohydrochloride

2530 38

  a) N-benzoyl-D, L-norleucine D, L-norleucine (39.3 g, 300 mmol) is taken up in sodium hydroxide (2N, 150 ml) and, with stirring in a bath of

  ice, soda (2 N, 150 ml) and benzyl chloride are added.

  After 30 minutes, the ice-bath was removed and the reaction mixture was extracted with ether (1.5 mm, 38.3 ml). The reaction mixture was acidified with acid 2N hydrochloric acid and the crystals are filtered to obtain

  68.9 g of N-benzoyl-D, L-norleucine; 131-133 (125).

  b) 4-Butyl-2-phenyl-5 (4H) -oxazolone N-benzoyl-D, Lnorleucine (40 g, mmol) is taken up in 300 ml of tetrahydrofuran, with stirring in an ice bath. A solution of dicyclohexylcarbodiimide (38.52 g;

  187 mmol) in 195 ml of tetrahydrofuran in 15 minutes.

  The ice bath is removed and stirring is continued at room temperature for a further 18 hours.

  dicyclohexylurea by filtration and concentrate the tetrahydro-

  The residue is purified (31.7 g) on silica in a 2: 1 mixture of hexane and ether to obtain

  32.1 g of 4-butyl-2-phenyl-5 (4H) -oxazolone.

  c) 1- (3-Benzoylamino) -2-oxoheptyl-Nl (phenylmethoxy) carbonyl-L-alanyl-L-proline phenyl methyl ester. A solution of phenylmethyl ibmethyl ester is cooled in an ice bath. 1N (carboxymethyl) -N (phenylmethoxy) carbonyl-L-alanyl-L-proline (1.41 g, 3 mmol), from Example 1 (c), in 10 ml of tetrahydrofuran. add oxalyl chloride (0.32 ml, 3.7 mmol),

  then 4 drops of dimethylformamide The reaction mixture is stirred

  In the ice bath for 20 minutes, then at room temperature for 1 hour, it is evaporated in vacuo, redissolved in 5 ml of tetrahydrofuran and cooled in an ice bath. A cold solution is added dropwise. 4-butyl-2-phenyl-5 (4H) -oxazolone (0.65 g;

  3 mmol) in 5 ml of tetrahydrofuran, followed by triethyl

  Amine (0.43 mL, 3.1 mmol) The reaction mixture is stirred at room temperature overnight After filtering off the triethylamine hydrochloride, the tetrahydrofuran solution is concentrated in vacuo and the residue is redissolved in 3 mL. pyridine, 15 mg of 4-dimethylamino pyridine is added, and the reaction mixture is stirred at room temperature for 3 hours. 3 ml of acetic acid are added and the reaction mixture is heated to 100.degree.

  for 40 minutes It was then evaporated, it was redissolved

  in ethyl acetate and washed with water, with saturated sodium bicarbonate solution, with

  diluted hydrochloric acid, and with water after evapo-

  The residue is subjected to chromatography on silica gel using a 4: 6 acetate mixture as the solvent.

  of ethyl and benzene to give 0.8 g of phenylmethyl ester.

  1-U N-L 3- (benzoylamino) -2-oxoheptyl-N-L (phenylmethoxy) salt

carbonyll-L-alanylf-L-proline.

  d) 1-IN-1 3- (benzoylamino) -2-oxohydrochloride

heptyll-L-alanyll-L-proline

  The phenylmethyl ester is dissolved in 75 ml of ethanol.

  1-L-3- (benzoylamino) -2-oxoheptyl-N- (phenylmethoxy) -carbonyl-L-alanyl-L-propyl ester (0.96 g, 1.5 mmol) was added hydrochloric acid (1N). 2 ml), followed by a palladium-on-charcoal catalyst (10%, 200 mg). The solution is stirred under a hydrogen atmosphere overnight.

  catalyst by filtration, the ethanol solution is evaporated.

  league, and the residue is dissolved in water, and then

  philise to obtain 0.62 g of 1-N-1 monohydrochloride.

  (Benzoylamino) -2-oxoheptyl} -L-alanyli-L-proline; 86-123; I <D = 62.9 (c = 1.05, methanol) Rf 0.57 (silica gel,

  4: 1: 1 mixture of n-butanol, acetic acid and water).

  Anal calc for C 22 H 31 N 305 H Cl At 2H 20: C, 53.85; H, 7.40; N, 8.57; Cl, 7.23

  Found C, 53.85; H, 7.20; N, 8.73; Cl, 7.29.

Example 4

  1-N-1-3- (benzoylamino) -2-oxo-4- dihydrochloride

  (3-pyridinyl) butyll-L-alanyll-L-proline a) 2- (benzoylamino) -3- (3-pyridinyl) -2-propenoic acid

  2-Phenyl-4- (3-pyridinylmethylene) -5 (4H) - is dissolved

  oxazolone (3 g, 12 mmol), see Griffith et al., J. Org Chem, Vol 29, p 2659 in 24 ml of acetic acid and hydrochloric acid (0.5 N, 150 ml). overnight at room temperature. Then evaporated, then re-evaporated from absolute ethanol Triturated with tetrahydrofuran, filtered, and the filtered solid recrystallized with absolute ethanol to obtain 2.8 g.

  2- (benzoylamino) -3- (3-pyridinyl) -2-propenoic acid; p 215-

216 (2030).

  b) 2- (Benzoylamino) -3- (3-pyridinyl) -2-propanoic acid 2- (benzoylamino) is dissolved in 500 ml of water

  3- (3-pyridinyl) -2-propenoic acid (14 g, 46 mmol) and

  Using a palladium-on-charcoal catalyst (10%, 1.8 g) overnight The catalyst was filtered off and the reaction mixture was evaporated to a small volume (100 ml) and freeze-dried to obtain 13.1 g of product The lyophilisate is triturated with a mixture of absolute ethanol and ether and filtered to obtain 12 g of acid

  2- (benzoylamino) -3- (3-pyridinyl) -2-propano; 99-115.

  c) Phenylmethyl ester of 1-lN-1 3- (benzoylamino)

  2-oxo-4- (3-pyridinyl) butyl-N-1 (phenylmethoxy) carbonyl-L-

  Alanyll-L-proline The phenylmethyl ester of 1- (N-carboxymethyl) -N (phenylmethoxy) carbonyl-Lalanyl 3-L-proline (6.2 g, 13.1 mmol) was dissolved in 20 ml of tetrahydrofuran, from Example 1 (c), and the solution is stirred in a bath of

  ice Oxalyl chloride is added, followed by 4 drops of di-

  After stirring this reaction mixture in an ice bath for 20 minutes, it is stirred at room temperature for an additional hour.

  vacuum and redissolved the residue in 20 ml of tetrahydrofuran.

  2 (benzoylamino) -3- (3-pyridinyl) -2-propanoic acid (4 g, 13 mmol) is suspended in 45 ml of tetrahydrofuran,

  and while waving in an ice bath, we add

  ethylamine (1.96 ml, 14 mmol) and dicyclohexylcarbodiimide

  (2.96 g, 14 mmol) The reaction mixture is stirred at room temperature.

  The mixture is then filtered, and the filtrate is evaporated to dryness. The residue is dissolved in 1 ml of tetrahydrofuran and the solution is stirred in an ice-bath. To this solution, the previous solution of sodium chloride is added. 1-N- (carboxymethyl) -N (phenylmethoxy) carbonyl-3-L-aanyl-L-proline phenylmethyl ester acid in ml of tetrahydrofuran was added triethylamine (1.9 ml; 6 mmol); and the reaction mixture is stirred at

  room temperature overnight. It is filtered to eliminate

  The filtrate is evaporated in vacuo, redissolved in 15 ml of pyridine, added

  mg of 4-dimethylamino pyridine, and the reaction mixture is stirred

  At room temperature for 3 hours 16 ml of acetic acid are added and the reaction mixture is heated at 100 for 45 minutes. It is then evaporated, redissolved in ethyl acetate and washed with water. An aqueous solution of sodium bicarbonate and with water. After evaporation, the ethyl acetate extract is subjected to chromatography on silica gel, using ethyl acetate for elution, to obtain 3.3 g of phenyl methyl ester of 1-CN-1 3- (benzoylamino) -2-oxo-4- (3-pyridinyl)

  butyl-N-1 (phenylmethoxy) carbonyl-L-alanyl-13-L-proline.

  (d) 1-N-1-3- (benzoylamino) -2-oxo-4- dihydrochloride

  (3-pyridinyl) -butyl-L-alanyl-L-proline The phenylmethyl ester obtained in part (c) (2.6 g, 3.84 mmol) is dissolved in 75 ml of ethanol, and aqueous hydrochloric acid (1 N, 8 ml), then a catalyst

  palladium on carbon (10%, 0.6 g) After hydrogenation

  nation for 16 hours, an additional 0.5 g of

  catalyst and o-continues the hydrogenation for a further 6 hours.

  The mixture is filtered, evaporated and combined with a similar reaction product obtained by hydrogenation of 0.8 g of the ester obtained in part (c). The hydrogenated substance is then subjected to "LH-20" in water to obtain the homogeneous product An aqueous solution of this substance is treated with aqueous hydrochloric acid (1N, 3 ml) and the solution is lyophilized to obtain

  1.0 g of 1-LN-L 3- (benzoylamino) -2-oxo-4- dihydrochloride

  (3-pyridinyl) butyll-L-alanyll-L-proline; p. 120-135;

2530? 38

  22 = 55.5 (c = 1.1, methanol) Rf 0.11 (silica gel;

  4: 1: 1 mixture of n-butanol, acetic acid and water).

  Anal calc for C 24 H 2845 2 HC 1, 2 H 20:

P 24 28 4 5 HC 2 HO

  C, 51.35; H, 5.75; N, 9.98; C 1, 12.63

  Found: C, 51.35; H, 5.84; N, 9.96; C 1, 12.84

Example 5

  1-N N-1 3- (benzoylamino) -4- (4-hydroxy) monohydrochloride

  phenyl) -2-oxobutyl) -L-alanyfl-L-proline

  a) 2-phenyl-4-rt 4- (phenylmethoxy) phenylmethyl-5 (4H) -

  oxazolone O-benzyl-L-tyrosine (11.0 g, 40.5 mmol

  in 81 ml of 0.5 N sodium hydroxide and 81 ml of water with vigorous stirring.

  In an ice-bath, to the resulting mixture is added, in five equal parts, a total of 52 ml of benzoyl chloride.

  45 ml of 1N sodium hydroxide and another 400 ml of water in 25 minutes.

  The ice bath is removed and the reaction is continued for 2 hours at room temperature. The mixture is extracted twice with ethyl acetate. The aqueous portion is filtered, acidified with 1N hydrochloric acid and filter the crystals to obtain 12.9 g of Nbenzoyl-O-benzyl-L-tyrosine;

mp 166-168 (162).

  This N-benzoyl-O-benzyl-L-tyrosine (12.76 g, mmol) is taken up in 50 ml of dry tetrahydrofuran, with stirring in an ice bath. To the mixture obtained, dicyclohexylcarbodiimide (7, 7 g; 37.4 mmol) in 18 ml of tetrahydrofuran. After 20 minutes, the bath is removed.

  of ice and the reaction continues for one night at the

  The dicyclohexylurea was filtered off and the filtrate was concentrated to dryness. The crude product was crystallized from a mixture of ether and hexane to give

  26 g of 2-phenyl-4- [4- (phenylmethoxy) phenyl] methyl -5 (4H) -

oxazolone; 85-87 (83).

  b) 1-N 3- (benzoylamino) -2-oxo-4 (phenylmethoxy) phenylbutyl-N-1 (phenylmethoxy) carbonyl-L-alanyl-Lproline phenyl methyl ester

  The phenyl ester is dissolved in 20 ml of tetrahydrofuran.

  1-N- (carboxymethyl) -N-1 (phenylmethoxy) carbonyl-L-alanyl 14-L-proline methyl ester (2.82 g, 6 mmol), from the example

03038

  1 (C), and the solution is stirred in an ice bath Oxalyl chloride (0.63 ml, 7.2 nuols) and then 4 drops of dimethylformamide are added after stirring this reaction mixture in an ice bath. for 20 minutes, it is stirred at room temperature for a further hour. The solvents are removed in vacuo and the residue is redissolved in 10 ml of tetrahydrofuran.

  and it is cooled in an ice bath to this solution.

  cold solution, add a cold solution of 2-phenyl-4-

  4-phenylmethoxy) -phenylmethyl-5 (4H) -oxazolone (2.14 g;

  6 mmol) in 40 ml of tetrahydrofuran are added.

  ethylamine (0.84 ml, 6 mmol) and a basic atmosphere is maintained throughout the reaction by adding the necessary additional amounts of triethylamine.

  reaction mixture at room temperature overnight.

  Then, it is filtered and the filtrate is evaporated and

  redissolved in 7 ml of pyridine 30 mg of 4-dimethyl-

amino pyridine and the reaction mixture is stirred for 3 hours.

  at room temperature 7 ml of acetic acid

  and the reaction mixture is heated at 100 for 45 minutes.

  It is then evaporated, the residue is redissolved in ethyl acetate and washed with a saturated solution of

  sodium bicarbonate and with dilute hydrochloric acid.

  The neutral extract is evaporated in ethyl acetate and chromatographed on 300 g of silica gel using a 6.5: 3.5 acetate mixture as the solvent.

  of ethyl and benzene, to obtain 2.7 g of the phenyl ester

  LN-1 3- (benzoylamino) -2-oxo-4-l-4-methyl (phenyl)

  methoxy) phenyl butyll-N 1 (phenylmethoxy) carbonyl-L-alanyl-

L-proline.

  (c) 1 N-1 3- (benzoylamino) monohydrochloride

  (4-hydroxyphenyl) -2-oxobutyl-L-alanyll-L-proline The ester obtained in part (b) (1.8 g;

  2.26 mmol) in 150 ml of ethanol containing chlorinated

  aqueous solution (1N, 3.5 ml) Palladium-on-charcoal catalyst (10%, 500 mg) was added and the solution was stirred under hydrogen overnight The solution was then evaporated, the residue dissolved in water and we

  lyophilized to give the monohydrochloride of the 1-lN-1 (benzoyl)

37 '2530238

  amino) -4- (4-hydroxyphenyl-2-oxobutyl) L-alanyl-L-proline;

  mp 118-152; = 63.1 (c = 1.07, methanol).

  D Rf 0.47 (silica gel, 4: 1: 1 mixture of n-butanol, acid

acetic and water).

  Anal calc for C 2 H 29 N 306 HC 1, H 20: C, 57, -42; H, 6.16; N, 8.04; Cl, 6.78

  Found: C, 57.42; H, 6.03; N, 8.04; Cl, 7.11.

  Examples 6 to 62 Following the procedure of Examples 1 to 3 and 5, the peptide ester shown in column I below was treated to obtain the carboxymethyl peptide ester shown in column II below. of this ester to its acid chloride, and a further reaction with the oxazolone of column III below, give as

  produces the N-protected ester of column IV below.

  of the nitrogen protecting group and the ester group gives the final product of column V below in

which R is a hydrogen atom.

Col I R 1 O l d

H 2 N-CH-C-X

(L) Col II R O

HO-C-CH 2-N-CH-C-X

I | (L)

C-O-CH 2 -

II Col III N

R-C C-R 3

OI i

0 C: O

38 2530238

IV collar

0 R 1 O

He I He

R -CH-C-CH-N-CH-C-X

3 2

NH

C-0-CH

C = O He R V-neck

0 R O

R 3 -CH-C-CH 2 -NH-CH-C-X

NH C = O R 2 X 1- on? p H. R 3

OE CH 2-

  R 2 ci Example R 1 6 the 5 C 2 w CH -

) 2

H-

7 ii 3 c-

1 oc (CH 3 3

-N COOCH - (D

L) 2

  ## STR1 ## ## STR1 ## ## STR2 ##

CO> HOOO N-

D-U ú 1 N -Z Ho 00

-Z BD J 00

J (? HD -

OT

1 H

ú (úHD) DM -I) n

a -W z HD-?

-Z BD-)

-D z H:) ú úZ) H

(Di H 'lt -

DOOD i -q-co> BD x

-Z HD-

  -Z (E Il Di - c - -D 'q B aldmax 2 l 1 E o E CM CD m ui CM H

(1) 1

(HDMD Di - L-X-

  z HD-p -ZDcH ú 1. H (, I) (Di HDOOD JHD-JHDo D -C (z UD) -Dc H -JH TE 1-1 aldmexg úli zu s rL 3 M Ci CD M n M (II)

H Doe D -

  H L RD _ (D _.p s s -D t it 9 T H - (Ii (D i HDM, 3 N_

0 O

CHD-L j

JHD 00

  J (z 140) -OCR ST (Dil I '(r HO) -J 00 -DEH E u O

RD O R

  1 E x Ela JRD O_i Di (D-i HDO Cr C> en .n CM -Z (z HD) -D -DuH H (Di Hcoe he O s -Eil (D CEH el H

H N-

s s L-) z

HD-â

- (P-ODúH

  -D to LI úE zla Id to Tdui-ax 2 r x

Example

R 1 R 2 R 3 X

0 D

## EQU1 ##

N 30 CH 2-

H COH C-

e 2 2,

CH 2-

-NU-CH-COOCH

1 (he)

CH 2 7 (D

CH (CH 3) 2

H 3 c-

H 3 c-

H 3 c-

s 7D -

22 H 5 C 2-

  H rlj j Ln LM c> r%) Lm an M VU CD t'O Lri (M VI) Il

(O-, g HDOOD 1 N-

C (Y) HD-0 u

-0 ú 1

  -C (Oz H) -DEH -DEH -JH _YH cu -0119 z (úRD) m D 0 - T the aldmaxg x

-Z RD O -

7 IL-11

E Id c M CM C> M Ln cm H

(È'Pll Do 3 l m-

  -%, (z BD) -JOO '-DEH -C (z HD) - -Z a -I H -0 t q S (ri) cmj HDMD

% .-, Z-

(II) 9

E (EHO) OW a-

s (CD u

- - 00 '

-ZHD CD

  ú (ZHO) no% e 1 0-Edtuexa t Id x cla Exemp 1 e Rf R 2 R 3 x (CH) -

2 3

H 3 c-

-N H H 3 Cs O-CH: i -N

(LOOCH D

H

31 H c-

e

(CD CH 2-

32 H 5 C 2-

j-1 -N -COOCH e

(L) 2.

H

H 5

DCH 2-

33 H 3 c-

  ri ti ui rc) u 4 on 1 1 s F 7 m C% 11 CD iin iii rm H z (Il

0 HDOO n

j z

HN-9 O

-Z RD-

- (5 -C (D z H) -NH-D / N

NH 9 ú

HDOOD L N-

I c H

Di HJA) tq-

-Z H D- (D

-E RD - 00 z Id -DEH SE

J 09 H

x Ela aldtuaxg z m

RD UÈ

  -z RD -CO 14 Co m 1 t \ j C> Ln cm H 0 d HDO

017 b-

  H. z OD read - :) ll He__ 6 o From -00 -E (z H D) OD

DZ E 0)

"45-00 M 4% -I

HO-C 01, -M VI) H

<E-j Hoo-

  s s 1 - -V (eye) mo O jn- Lú il 1 eldmoxsl

-ZHD- (D

  ## EQU1 ## 1A. M Cu Cu Po Ln Cu H ((I)

(O> HDOOD N-

  J (z HD) e -Z (Oz H) -S-DcH o- 14 D -DZ rim) I, m z -RD-Ln m

e> ZR n

H N z o

D H% <

J RD- -

  ,,,,--------,,,,,,,,,,,,,, HD HD HD HD (((((((11)

Di Hnwz) -1 N-

9 s t He

(II-) 1 n-

pi Moez) u H f N '

-.Dz:H-

  - (D -DEH SP 1 O Dz H-no -Z 14 D-4 OD Zil O -Dc H t'VI H (i

-IOOZ) 1) 1 _m-

(5 z H-

  u NH-K z O E z (D H) -M-D c IlNl NE -au-H x 1 Id aldwaxa úId zla Co in cm Ln Cu EHOO Q 1 E (II) l

Q HDWD-HD-HN-

z (HD E) HD z 1 HD

(1) 1 '.

e 14 D (MD-HD-Hti-

E HD z (1) 1

(5 HOOOD-Hi-nm-

HD-ri O 1 __. J -H 1 tr z

(HD) _ "D

J D 5 H

-3 z H-no -D Ea Lt,

DOOD-EHD-HN

  & H x J HD-n -DEH 9 t, Ela T Id aldtuexa Eu op in cm CD m Ln Cu <O -,> i Hi m ri li z AD z VI) i

Q HDOOD-HO-HN-

H 1 1 CO) ni -EHD z vi) 1

C 5 HDOOD-14 i-tiri

CO> t HOO co z HDO HO z (II) 1 '

<O- H OOD-HD-HN-

-Z HD m - (D J Ho-no

-ZHD-

c Id nt H on

-D H'E

  -: acts in uli 1 it aldmexg x op M Ci rfl Ln cm it z RU-D-z (z H) z (11)

<05 HOOOD-90-mu-

-0 úH

-z HD-: D -

z ONEN c Z. RN 'ee Dntq (RD)

(11) 1

co Hooeo-HD-Htq-

-Z HD-D

JE 04 D

J Dt H z BD-S-zno z VI) 1

BOOOD-HO-contentious

z% O t CO> HDOD Htq (HO

% -., (11) 1

  co-z How:) - HO-Hti x -pl io EH -p -0 H -9 (D "R) -Dn úla T Id aldmaxg z E Co K) CV CD Po in Cu

ú HD H

S 'E 1-

H D-D-0-HO O ti-

lt 1

0 O

s

E (úHD) HD H

9 of 1

J-D-0-HD-ID'D) K-

it t

0 O

s s 1, - H

9 E 9 VI) 1

H Z-D-0-HD-0-D-U -

He he

0 O

x

-C (EHD) - (D

  -Z H-JBD- DE H -a EH -3 úH aldmaxn z Id m cm CD Ln, c "i H -Z RD - (D - ú (Dz 11) -D Eil H O-Oi HD-0-D (> i he

0 O

-Z HD-DTD

  -CD -DEH Dúa aldmaxg x úId z Id úE z (11) (HD) DD-ORD-0-D z (z HO) s There It 0 O il -il It eliminates, in the last step of the synthesis, the protective groups R of Examples 20, 36 to 39 and 41, the

  groups R of Examples 43 and 44, and the groups

  protective elements R 5 of Examples 49, 50 and 52 to 55

  does not mine the R 6 ester groups of Examples 57 to 62.

Example 63

  1-UN-1 (S) -3- (benzoylamino) -2-oxohydrochloride

  4-Phenylbutyll-L-alanyll-L-proline a) (S-3-Amino-1-chloro-4-phenyl-2-butanone) hydrobromide 51.4 g of the (S) -l-phenyl methyl ester are dissolved 3-chloro-2-oxo-1 (phenylmethyl) propyl-13-carbamic acid in a mixture of 252 ml of acetic acid and hydrobromic acid in

  acetic acid (3.45 N, 348 ml), and the solution is maintained

  The reaction mixture is then concentrated in vacuo and is precipitated with ether to give 36.6 g of the (S) -3-amino-1-chlorohydrobromide. 4phényl-2-butanone; p f (175)

177-179.

  b) (S) -N-1-chloro-2-oxo-1- (phenylmethyl) propylbenzamide

  (S) -3-Amino-1-chloro-4-phenyl-hydrobromide is used.

  2-butanone (36.3 g, 130.3 mmol) in suspension in 520 ml of dry tetrahydrofuran and 18.2 ml of triethylamine (130.3 mmol) with stirring for 10 minutes The mixture is then placed in an ice bath and 15.2 ml of benzoyl chloride and then 10.95 g of sodium bicarbonate are added. After 5 minutes, the ice bath is removed and the reaction mixture is maintained.

* at room temperature for one and a half hours

  The reaction mixture is then added under vacuum and the residue is taken up in 1 l of aqueous methanol (10% of water). The precipitate is collected, filtered and washed with methanol to obtain 25.3 g of (S) 3-chloro-2-oxo-1- (phenylmethyl) propyl-benzamide; p (160) 170-172 (decomposition);

  D 23 = 129 (c = 1.7, dimethylformamide).

D

  c) 1,1-Dimethylethyl Ester of N-1 (S) -3- (benzoyl)

  amino) -2-oxo-4-phénylbutyll-L-analyfl-L-proline

  It is mixed in 50 ml of dimethylformamide, under atmospheric

  argon sphere, at room temperature, with stirring overnight, L-alanyl-L-proline 1,1-dimethylethyl ester (2.42 g, 10 mmol), 840 mg sodium bicarbonate and 3.01 g of (S) -N-1E-3-chloro-2oxo-1- (phenylmethyl) propyllbenzamide The reaction mixture is then concentrated in vacuo to about one-half its original volume and the residue is taken up in from room temperature. ethyl acetate and then washed with saturated sodium bicarbonate solution to obtain 2.25 g of crude product. This material is taken up in a 95: 5 mixture of ethyl acetate and methanol, it is passed through in a column of 135 g of

  silica gel and eluted with a 95: 5 mixture of ethyl acetate

  and methanol to obtain 860 mg of 1,1-dimethylethyl ester.

  1N (S) -3- (benzoylamino) -2-oxo-4-phenylbutyl-L-alanylllLoline.

  d) 1H-N-1 (S) -3- (benzoyl-amino) monohydrochloride -2-

  oxo-4-phenylbutyl-L-alanyll-L-proline The 1,1-dimethylethyl ester of the

  1-N 1 (S) -3 (benzoylamino) -2-oxo-4-phenylbutyl-L-alanyll-L-

  proline (740 mg, 1.46 mmol) in a solution of

  water in acetic acid (1.5 N, 10 ml), and

  hold the solution at room temperature for 30 minutes.

  It is then concentrated, the residue is taken up in water, filtered and lyophilized to give 600 mg of LN-(S) -3 (benzoylamino) -2-oxo-4-phenylbutyll-L-monohydrochloride. alany 13

  -L-proline; 83-163; l = 109 (c = 1.04, methanol).

  Rf 0.6 (silica gel, 4: 1: 1 mixture of butanol, acetic acid,

tick and water) -

  Anal calc for C 25 H 2 N 305 HC 1 1.65 H 20:

  C, 57.99; H, 6.48; N, 8.12; C, 6.85

  Found: C, 57.99; H, 6.39; N, 8.09; Cl, 6.95.

Example 64

  (S) -1-t N 2 -1- (benzoylamino) -2-oxo-4- dihydrochloride

phénylbutyll-L-lysyll-L-proline

  a) 1,1-Dimethylethyl ester of 1-r N 6 -tl (1,1-dimethyl)

  thylethoxy) carbonyl-N 2 1 (phenylmethoxy) carbonyl-L-lysyl-L-

  25 g of dimethylformamide (9.51 g) of N 6-1 (1,1-dimethylethoxy) carbonyl-N 2 (phenylmethoxy) carbonyl-L-lysine and 3.825 g of hydroxybenzotriazole are taken up in stirring in an ice-bath. Argon atmosphere To the resulting product was added 4.49 g of L-proline 1,1-dimethylethyl ester, followed by 2.2 ml of N, N'-diisopropylethylamine and 5.15 g of dicyclohexylcarbodiimide. minutes, the ice bath is removed and the reaction is allowed to proceed for 6 1/2 hours at room temperature. The dimethylformamide is removed in vacuo. The residue is taken up in ethyl acetate and the dicyclohexylurea is filtered off. The filtrate was washed with 10% potassium bisulfate solution and saturated sodium bicarbonate solution until neutral. The crude product (13.26 g) was purified in a silica gel column. eluting with a 2: 1 mixture of ethyl acetate and hexane to give 13.0 g. 1-1N-6-l (1,1-dimethylethoxy) carbonyl 1,1-dimethylethyl ester

  N-1 (phenylmethoxy) carbonyl-L-lysyl-L-proline.

  b) 1,1-Dimethylethyl Ester of (S) -1-lN 2-

  3- (benzoylamino) -2-oxo-4-phenylbutyll-N-6 (1,1-dimethylethoxy) carbonyl-L-lysyl-L-proline The ester obtained in part (a) is reduced in ethanol with palladium on charcoal as a catalyst (10%) to obtain 3.99 g of 1,1-N, 6-l (1,1-dimethylethoxy) -carbonyl-L-lysyl-L-proline 1,1-dimethylethyl ester. in 40 ml of dimethylformamide and treated with 3.01 g of (S) -Nl 3chloro-2-oxo-1- (phenylmethyl) propylbenzamide, from Example 63 (b), and 840 mg of sodium bicarbonate. After stirring for 18 hours at room temperature, the reaction mixture is concentrated in vacuo, taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The crude product is purified (7%). (G) in a column of silica gel, eluting with ethyl acetate containing 1% methanol, to obtain 1.7 g of the 1,1-dimethylethyl ester of

  (S) -1 N- (benzoylamino) -2-oxo-4-phenylbutyll-N 6 (1,1-

  dimethylethoxy) carbonyll-L-lysyll-L-proline.

6 * 2530238

  c) (S) -1 -NH-1-3- (benzoylamino) -2-oxo-4-phenyl-butyl-L-lysyl-L-proline dihydrochloride

  The ester obtained in part (b) (1.6 g) is treated

  30 minutes at room temperature, with 20 ml of a mixture of 1.5 N hydrochloric acid and acetic acid,

  concentrated to dryness, and triturated with ether until

  hold a solid, to have 1.37 g of crude product This product is taken up in water, filtered on "Millipore", and lyophilized to obtain 1.28 g of product is carried out a new purification in a column of "LH 20" in water

  to obtain 740 mg of (S) -1-NR 2 -I 3-dihydrochloride

  (Benzoylamino) -2-oxo-4-phénylbutyll-L-lysylj-L-proline; p f.

  -180 L; (25 = 84.8 (c = 1.05, methanol) Rf 0.61 (trace D at 0.9) (silica gel, 60:40:20 mixture of chloroform,

  methanol and 38% acetic acid).

  Anal calc for C 28 H 36 N 405 2 HC 1 3 H 20:

836 4 5 '2

  C, 52.98; H, 6.98; N, 8.83; C 1, 11.17

  Found: C, 52.98; H, 6.93; N, 8.66; C 1, 11,31 -

Example 65

  N-11N (S) -3- (benzoylamino) -2-oxohydrochloride monohydrochloride

  4-Phenylbutyl-L-alanyll-N-cyclohexylglycine a) 1,1-Dimethylethyl N-cyclohexylglycine ester 70.35 ml of cyclohexylamine and 12.9 g of sodium bicarbonate are suspended, with stirring, in 200 ml of Absolute ethanol in an ice bath To the resulting mixture is added dropwise 20.78 ml of bromoacetic acid 1,1-dimethylethyl ester. The ice bath is then removed. After 24 hours at room temperature, the mixture is concentrated under reduced pressure. reaction mixture to dryness, it is taken up in chloroform and

  washed with water. The crude product (42 g) is subjected to

  matography on silica gel, eluting with a 2: 1 mixture of ethyl acetate and hexane to obtain 27.4 g of -ester

  1,1-dimethylethyl N-cyclohexylglycine.

  (b) 1,1-dimethylethyl ester of N-cyclohexyl-N-

  IN-L (phenylmethoxy) carbonyl-L-alanyl glycine-4.26 g of N1 (phenylmethoxy) carbonyl-L-alanine, 4.26 g of N-cyclohexylglycine 1,1-dimethylethyl ester are stirred,

  3.06 g of hydroxybenzotriazole, 4.12 g of dicyclohexylcarbonyl

  diimide and 2.8 ml of triethylamine in 40 ml of dimethylformate

  at room temperature for 20 hours.

  Then the reaction mixture is taken up in vacuo, taken up in ethyl acetate, the dicyclohexylurea is filtered off and the filtrate is washed with a solution of 10% potassium bisulfate and with a saturated solution of sodium bicarbonate. sodium until it is neutral, to obtain 5.9 g of crude product The crystallization of this product in a mixture

  of ether and hexane gives 3.97 g of the 1,1-dimethylethyl ester.

  N-cyclohexyl-N-1N-1 (phenylmethoxy) carbonyl-L-alanyl glycine; p 104-105 a

  c) 1,1-Dimethylethyl Ester of N- (L-alanyl) -N-

  cyclohexylglycine 3.9 g of the ester obtained in part (b) are taken up in methanol with palladium on carbon as catalyst (10%, 700 mg) and stirred under hydrogen atmosphere for 4 hours. The reaction mixture is concentrated to dryness to give 2.65 g of the 1,1-dimethylethyl ester.

  crude N- (L-alanyl) -N-cyclohexylglycine.

  d) 1,1-Dimethylethyl ester of N-11N (S) -3- (benzoyl)

  amino) -2-oxo-4-phenylbutyl} -L-alanyll-N-cyclohexylglycine

  It is stirred for 20 hours in 25 ml of dimethylformate.

  2.6 g of the crude ester obtained in part (c), 764 mg

  sodium bicarbonate and 2.75 g of (S) -N-1 3-chloro-2-oxo

  1-phenylmethyl) propyllbenzamide from Example 63 (b).

  The reaction mixture was concentrated to dryness, taken up in ethyl acetate, and washed with saturated sodium carbonate solution to obtain 4.7 g of crude product by purification in a column of silica gel. eluting with a 99: 1 mixture of ethyl acetate and methanol,

  1.5 g of the 1,1-dimethylethyl ester of N-1N-

  ll (S) -3- (benzoylamino) -2-oxo-4-phénylbutyll-L-alanyll-N-cyclo-

hexylglycine.

  e) N lN ll (S) -3- (benzoylamino) -2-oxohydrochloride

  4-phenylbutyl-L-alanyl-N-cyclohexylglycine The ester obtained in part (d) (500 mg) is treated for 30 minutes with 5 ml of a mixture of 1.5 N hydrochloric acid and acetic acid. then concentrated to dryness at room temperature. The crude product is taken up in methanol and purified in a column of "LH 20" to obtain 413 mg of product. The latter is then semi-crystalline in a mixture of acetonitrile and ether to give NN 11 (S) -3 (benzoylamino) -2-oxo-4-phenylbutyl-L-alanyl -N-cyclohexylglycine monohydrochloride; 154-157 (132); l 2 l 3 = 67.4 D (c = 1.35, methanol) Rf 0.60 (minor impurity at 0.92) (gel of

  silica, 30: 10: 2 mixture of chloroform, methanol and amine

concentrated monique).

  Anal calc for C 28 H 35 N 305 at HCl H 20 C, 61.35; H, 6.99; Neither 7.67; C, 6.47

  Find; C, 61.08; H, 6.79; N, 7.65; Cl, 6.46.

Example 66

  N-1N-11 (S) -3 (benzoylamino) -2-oxohydrochloride monohydrochloride

  4-Phenylbutyll L-alanyll-N-phenylglycine a) 1,1-dimethylethyl ester of N-phenylglycine A solution of triethylamine (11.25 g, 0.11 mol) was cooled to 0 ° C. in an ice bath. aniline (9.3 g, 0.10 mol) in 100 ml of ether under an argon atmosphere To the resulting mixture was added bromoacetic acid 1,1-dimethylethyl ester (18 g, 0.093 mol). in 30 minutes The resulting mixture is stirred at 0 for one hour, then warmed to room temperature, and stirred overnight. The solution is filtered and rinsed with ether and

  the filtrate is concentrated to give 6.9 g of a yellow oil.

  Rf 0.6, 0.7 (silica gel, ethyl acetate) by chromatography

  on "LPS-1", using a 7: 3 mixture of hexane and ethyl acetate as eluent, 2.3 g of the N-phenylglycine 1,1-dimethylethyl ester are obtained. the form

  a pale yellow liquid Rf 0.7 (silica gel, ethyl acetate).

  b) 1,1-Dimethylethyl Ester of N-Phenyl-N-1 N N (phenylmethoxy) carbonyl-L-alanyl glycine

  Cool in a bath of dry ice and ethanol.

  a solution of N 1 (phenylmethoxy) carbonyil-L-alanine (2.8 g;

  12.7 mmol) in 50 ml of dry tetrahydrofuran under argon.

  To this solution is added N-methylmorpholine (1.28 g, 12.7 mmol) and isobutyl chloroformate (1.73 g, 12.7 mmol). ester

  N-phenylglycine 1,1-dimethylethyl (3.7 g, 12.7 mmol).

  The resulting mixture is stirred at -20 for one hour and then at room temperature overnight. The mixture is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is washed successively with water. 1N hydrochloric acid and 10% sodium bicarbonate, dried over magnesium sulfate, and concentrated by "LPS-1" chromatography, eluting with a gradient (3: 1: 1) of acetate

  of ethyl and hexane, 4.0 g of the 1,1-dimethyl ester are obtained.

  N-phenyl-N 1 (phenylmethoxy) carbonyl-L-alanyllethyl

  glycine, in the form of a clear oil Rf 0.4, (silicone gel)

this, ethyl acetate).

  c) 1,1-Dimethylethyl Ester of N- (L-alanyl) -N-

  phenylglycine A solution of the ester obtained in part (b) (4.0 g, 9.7 mmol) in 125 ml of ethanol and 10% of palladium on sodium hydroxide is stirred under a stream of hydrogen for 18 hours.

  coal as catalyst The solution is filtered and concentrated

  The residue is dissolved in ethyl acetate and the solution is extracted with 1N hydrochloric acid. The aqueous layer is treated with sodium bicarbonate until it is basic and extracted with ethyl acetate

  dried on magnesium sulphate the extracts united in

  ethyl acetate and concentrated to give 1.3 g of N- (L-alanyl) -N-phenylglycine 1,1-dimethylethyl ester as a white solid R 0.52, minor stain at 0.64

  (silica gel, 1: 1 mixture of ethyl acetate and methanol).

  d) 1,1-dimethylethyl ester of N-IN-1 (S) -3-

  (Benzoylamino) -2-oxo-4-phénylbutyll-L-phenylglycine-N-alanyll

  To a stirred solution of (S) -N-13-chloro-2-oxo-1-

  (phenylmethyl) propyllbenzamide (1.4 g, 4.7 mmol), from Example 63 (b), and N- (L-alanyl) N-phenylglycine 1,1-dimethylethyl ester (1 g. 3.0 g, 4.7 mmol) in dry dimethylformamide, sodium bicarbonate is added

  (0.38 g, 4.7 mmol) and sodium iodide (0.7 g;

  After stirring overnight at room temperature, the mixture is concentrated, the residue is dissolved in ethyl acetate and filtered. The filtrate is washed with

  10% sodium bicarbonate is dried over magnesium sulphate

64 2530238

  sium, and concentrate until a yellow oil is

  LPS-1, eluting with a gradient of ethyl acetatehexane (1: 1) ethyl acetate, gave 1.8 g of the N-11N-11 dimethylethyl ester. (S) -3- (benzoylamino) -2-oxo-4-phenylbutyl L-alanyl-N-phenylglycine Rf 0.34 (gel)

silica, ethyl acetate).

  e) N-IN-11 (S) -3 (benzoylamino) -2-oxohydrochloride

  4-phenylbutyll-L-alanylf-N-phenylglycine The mixture is stirred at room temperature for 30 minutes.

  solution of the ester obtained in part (d) (1.6 g, 2.9 mmol

  1c) in a mixture of hydrochloric acid and acetic acid (1.77N, 17.0ml). The solution is concentrated and triturated.

  residue with ether until a pale yellow solid.

  By recrystallization from a mixture of methanol and ether,

  0.84 g of N-11N-11 (S) -3-1 (benzoyl) monohydrochloride is obtained.

  amino) -2-oxo-4-phenylbutyll-L-alanyll-N-phenylglycine, under the

  form of a white crystalline solid, p f 147-159 (decomposed

  Rf 0.8 (silica gel, 1: 1: 1 mixture of butanol,

  acetic acid and water) ΔD = 12.7 (c = 1.5, methanol).

  Anal calc for C 28 H 29 N 305 H Cl 0.65 H C, 62.77; H, 5.89; Ni 7.84, Cl, 6.62 Found: C, 62.77; H, 5.70; N, 7.84; Cl, 6.12

Example 67

  (S) -1 N- (3- (benzoylamino) -2-oxohydrochloride monohydrochloride

  4-phenylbutyll 3-N-methyl-L-alanyl-L-proline a) Nl (phenylmethoxy) carbonyl-L-alanine L-alanine (89.1 g, 1 mole) was dissolved in 500 ml of sodium hydroxide 2 N and the solution is cooled to OA this solution

  chloro is added simultaneously dropwise in 1 hour.

  benzyl formate (204.5 g, 1.2 mol) and 250 ml of 4N sodium hydroxide solution. The reaction mixture is stirred overnight (between 0 and room temperature) and washed with twice 500 ml of The aqueous portion is acidified to pH 2.0 with 6N hydrochloric acid and extracted with ethyl acetate (3 × 600 ml). The combined extracts are dried over sodium sulfate. in ethyl acetate, concentrated on a rotary evaporator, and the solid residue triturated with petroleum ether to obtain 194.0 g of Nl (phenylmethoxy) carbonyl 1 L-alanine, in the form of a white solid. b) N-methyl-N1 (phenylmethoxy) carbonyl-L-alanine To a cold solution (O) of N1 (phenylmethoxy) carbonyl-L-alanine (22.3 g, 0.1 mol) and methyl iodide ( 50 ml;

  0.8 mole) in 250 ml of tetrahydrofuran is added

  Deposit the sodium hydride dispersion (14.25 g, 0.3 mole) with gentle stirring. The suspension is then stirred overnight under a nitrogen atmosphere (between 0 and room temperature).

  te), poured slowly into 200 ml of saturated sodium bicarbonate solution, diluted with 300 ml of acetate

  of ethyl, and the layers are separated. The organic layer is extracted.

  Once again with saturated sodium bicarbonate solution, the combined aqueous layers were acidified to pH 2.0 with 10% potassium bisulfate and extracted with ethyl acetate. extracts combined in ethyl acetate and concentrated under vacuum

  until a dark oily residue (23.0 g) is obtained.

  This crude acid is treated with 20 ml of dicyclohexylamine in 150 ml of ether. The resulting crude dicyclohexylamine salt (37.0 g) is collected and recrystallized from a mixture of chloroform and ether (35.0 g). and is converted back into the acid by partitioning it between 1N hydrochloric acid and ethyl acetate, giving a pale yellow oil which

crystallizes at rest (17.4 g).

  Recrystallization (11.2 g) in an acetate mixture

  of ethyl and petroleum ether, 4.0 g of N-methyl-

  NI (phenylmethoxy) carbonyl-L-alanine in the form of a

  white crystalline duit; 65-66.5; l 125 = 31.10 * D

(c = 2, acetic acid).

  c) 1,1-Dimethylethyl ester of 1-N-methyl-N-

  phenylmethoxy) carbonyl-L-alanyll-L-proline

  To a solution of N-methyl-N-1 (phenylmethoxy) carbonyl -L-

  (4.74 g, 20 mmol) in 50 ml of distilled tetrahydrofuran is added 1,1-dimethylethyl ester of

  L-proline (3.42 g, 20 mmol), hydroxybenzotrial hydrate,

  zole (3.06 g, 20 mmol) and dicyclohexylcarbodiimide (4.12 g, mmol) The reaction mixture was stirred overnight, the precipitated dicyclohexylide was filtered off and the filtrate was concentrated. 50 ml of ethyl acetate and the solution is washed twice with saturated sodium bicarbonate solution, twice with 10% potassium bisulfate solution and twice with water, dried over sodium sulfate. sodium, and concentrate to

  obtain 6.4 g of the 1,1-dimethylethyl ester of 1-lN-methyl-

  N-1 (phenylmethoxy) carbonyl-L-alanyl-L-proline in the form

an oily residue.

  d) 1- (N-methyl-L-alanyl) L-proline 1,1-dimethylethyl ester A mixture of the ester obtained in part (c) (6.4 g) is hydrogenated at atmospheric pressure overnight. 16.4 mmol) and 0.8 g of 10% palladium on carbon as catalyst, in ethanol (95%, 150 ml). The catalyst is filtered off and the filtrate is evaporated. The oily residue resulting solidifies by drying under a vacuum

  grown to an oily solid residue (3.8 g) by tritu-

  with ether, 1.5 g of the monohydrochloride are obtained.

  1- (N-methyl-L-alanyl) -1,1-dimethylethyl ester

  proline, in the form of a white solid; Rf 0.44 (gel of

  silica, mixture of 20% methanol and chloroform).

  l = 102.1 (c = 2, acetic acid).

  The filtrate of the ether gives 2.3 g of the 1,1-di-

  1- (N-methyl-L-alanyl) -L-proline methylethyl as an oil; Rf 0.44 (silica gel, 20% mixture of methanol and chloroform) (101.6 a (c = 2, acetic acid).

  e) 1,1-Dimethylethyl Ester of (S) -i-11N-11 3-

  (benzoylamino) -2-oxo-4-phenylbutyll-N-methyl-L-alanyll-L-proline A reaction mixture composed of sodium hydroxide and potassium hydroxide is stirred under nitrogen at room temperature overnight.

  1,1-dimethylethyl ester of 1- (N-methyl-L-alanyl) -L-

  proline (2.1 g, 8.19 mmol), (S) -N-1,3-chloro-2-oxo-1-

  (phenylmethyl) propyl benzamide (2.46 g, 8.19 mmol) from

  Example 63 (b), an excess of sodium bicarbonate, and sodium iodide (1.22 g, 8.10 mmol) in 15 ml of

  dimethylformamide The reaction mixture is concentrated,

  The residue is partitioned between water and ethyl acetate, the layers are separated, and the aqueous layer is extracted once more with ethyl acetate. The combined organic extracts are washed with saturated solution. of sodium bicarbonate and

  with water, it is dried over magnesium sulphate and concentrated

  To an oily residue (3.5 g) is obtained. By flash chromatography (200 g of silica gel, mixture of 1% of methanol and ethyl acetate), 2.8 g of the 1,1-ester are obtained. dimethylethyl

  (S) -1-EN-11 3- (benzoylamino) -2-oxo-4-phenylbutyll-N-methyl-

  L-alanyll-L-proline, in the form of a yellow oil.

  f) (S) -I-1N-11 3- (benzoylamino) -2-dihydrochloride monohydrochloride

  oxo-4-phenylbutyl-N-methyl-L-alanyl-L-proline The ester obtained in part (e) (1.4 g, 2.7 mmol) is treated with 20 ml of an acid mixture hydrochloric acid 2N and

  Acetic acid After stirring for 2 hours at room temperature

  at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (4 times) to obtain 1.05 g of the dihydrochloride monohydrochloride.

  (S) -1 LN-1- (3- (benzoylamino) -2-oxo-4-phenylbutyll-N-methyl)

  L-alanyl-L-proline, in the form of a whitish solid; mp 125-135; Rf 0.24 (silica gel, 4: 1: 1 mixture of 25-87 (c: 1 n-butanol, acetic acid and water) (J = 870 (c = 1, methanol). Anal calc for C 26 H 31 N 305 O HC 1 0.7 H 2 O: C, H, 6.41; N, 8.16; Cl, 6 88

  Found: C, 60.68; H, 6.36; N, 7.95; C, 6.48.

Example 68

  (S) -1H-N-1 3- (benzoylamino) -2-oxohydrochloride (20: 3)

  4-phénylbutyll-4-phénylglycyll-L-proline

  a) 1- (bromoacetyl) -1,1-dimethylethyl ester

proline

  To a cooled (-10) solution of 1,1-dimethyl ester

  L-proline ethyl (34.2 g, 0.2 mol) in 250 ml of methylene chloride, diisopropylethylamine (38.3 ml, 0.22 mol) and bromoacetyl chloride (16.5 ml) were added. 0.2 mole) drip in 20 minutes while maintaining

  the temperature between 10 and 5 is stirred.

  dark overnight (between -10 and

  room temperature) and concentrated under reduced pressure.

  The oily residue is dried in ethyl acetate, washed twice with saturated sodium bicarbonate solution twice with 10% potassium bisulfate solution and two times with water. dried over sodium sulphate and concentrated to a dark oily residue (28.0 g). By flash chromatography (silica gel "LPS-1", methylene chloride containing 10% ethyl acetate), we obtain

  11.0 g of 1,1-dimethylethyl ester of 1- (bromoacetyl) -

  L-proline, in the form of a pale yellow oil.

  b) 1- (N-Phenylglycyl) L-proline 1,1-dimethylethyl ester A solution of 1- (bromoacetyl) -L-proline 1,1-dimethylethyl ester (2.1 g, 7.5 g) mmol) in 40 ml of distilled tetrahydrofuran is added aniline (1.5 g, mmol), and the reaction mixture is stirred overnight under nitrogen. The reaction mixture is diluted with 200 ml of ethyl acetate, it is washed twice with 50 ml of saturated sodium bicarbonate solution and twice with

  water, dried over sodium sulphate and concentrated

  under a vacuum to a dark oily residue (4.0 g).

  flashgraphy (silica gel "LPS-1", methyl chloride

  lene containing 10% ethyl acetate), 2.2 g are obtained

  1- (N-phenylglycyl) 1,1-dimethylethyl ester

  proline, in the form of a dark oil that solidifies

by drying under a high vacuum.

  c) 1,1-Dimethylethyl ester of (S) -1H-lN 4 1-3 (benzoyl)

  amrino) -2-oxo-4-phenylbutyll-N-phenylglycyil-L-proline A reaction mixture composed of 1- (N-phenylglycyl) 1,1-dimethylethyl ester is stirred at room temperature under a nitrogen atmosphere overnight. Lproline (1.06 g, 3.5 mmol), (S) -N-3-chloro-2-oxo-1- (phenylmethyl) propyllbenzamide (1.06 g, 3.5 mmol) from Example 63 (b), Excess Sodium Bicarbonate, and Iodide

  sodium (0.52 g, 3.5 mmol) in 10 ml of dimethylformamide.

  The reaction mixture is poured into 50 ml of water and extracted with three times 50 ml of ethyl acetate. The combined ethyl acetate extracts are washed with saturated sodium bicarbonate solution (twice). ) and with water

  (3 times), dried over sodium sulfate, and con-

  center under reduced pressure to obtain a dark oily residue (2.0 g) By flash chromatography (silica gel "LPS-1", gradient methylene chloride 5% ethyl acetate methylene chloride 15% acetate d ethyl), 0.3 g of (S) -ILN-1 3- (benzoylamino) -2-oxo-4-phenylbutyll-N-phenylglycylll 1,1-dimethylethyl ester are obtained.

  L-proline, in the form of a pale yellow foam.

  d) Hydrochloride (20: 3) from (S) -1-N-3- (benzoylamino) -

  2-oxo-4-phenylbutyl) -N-phenylglycyl-proline The ester obtained in part (c) (0.28 g, 0.49 mmol) is treated with a mixture of 2N hydrochloric acid and After stirring for 1 hour at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (4 times) to obtain 0.14 g of the hydrochloride (20: 3).

  (S) -1H-N-1-3- (benzoylamino) -2-oxo-4-phenylbutyll-N-

  phenylglycyll-L-proline, in the form of a whitish solid; mp 110140; Rf 0.76 (minor spot at 0.53) (silica gel,

  3: 1: 1 mixture of n-butanol, acetic acid and water).

  Anal calc for C 30 H 31 N 305 0.15 HC 1 0.5 H 20: C, 68.22; H, 6.13; N, 7.95; Cl, 1.00

  Found: C, 68.22; H, 6.00; N, 8.25; Cl, 0.99.

  Examples 69-90 Following the procedure of Examples 63-68, but using the ketone shown in column I below, the acid chloride shown in column II below and the peptide ester represented in In column III below, the ester shown in column IV below is obtained as the product. Removal of the ester group R 6 and the other possible protecting groups makes it possible to obtain the corresponding final product in the form of the 'acid. col 1 R 3 H 2 N-CH-C-CH 2 Cl il Col II Il R 2-C-Ci Col III

R R 10

1 i he

HN CH-C-X

(L) Co 1 IV

0 R R O

He 1 1 1il

R 3 -CH-C-CH 2 -N CH-C-X

1 (L)

  NH -C = O R 2 OD Po CM -CD> 1 L (H -D Ea

E (ú HD)

  N o EH z (z HD) f e EL H -DEH -H ee 4 z) E: H -H z HD-Dj -H (, HD,) e 1 i r-

-Z HD- 5

-Z HD-00

-Z HD- 00

OL -0 s s t úE aldmaxg 1 x

-Z HO 9

LID,

Eú (11)

(HD) DWD n

D H H. (, I)

c (ú HD) DWD N-

H Ec (11)

1 (HD) DOOD a-

* m cm CD m L (CM

-H E (úHD) DMD-z HD-N-

  JHD md (Dz H) -DEH -DEH SL C (dd HD m z H O IL a -D E'q C-qZH ri 9 -J, -H - EL aldmaxn zil H

E E (1) -

-H (HO) DWD there n

IF)

H -H c ú (II)

(Ho) DOOD tq-

the x T u

-E HD-G

  OD M clli CD N) Ln ti XH-m E O ú z (D H) Il-Il

NH SL

H 11) c E '1

(HD) Dmz) it-

s -H

-1 HD 4 (D

  ## EQU1 ## -H -P (DZH) NHDOD ZR-no

he -

9 L c oldmoxa id x a

ú E (11)

(HD) DOOD

  CK) rn Cm CD M tn ir (in, HD E E el) 1

(HD) OMD-HD-HN-

-Z H Dm 7 D -0 z H-e -H

z HDO z HD.

(Di (11) 1

c (úHO) OWD-HD-HN-

-Z HD-

-DEH -H H

-0 c (c HO) DWD 2M-

ODEH-no -oeg 400 th H - 5

J HD-

  J (z HO) -Z) ú or H xO -z H -% - Co lq -Dz H, O H

-9 ú (c HO) zoe p) li-

(O O

  6 L -DuH aldtuaxg z Id x CX) m CM C> m Ln Cj E il t, z

(O> HOODHN (HO)

EE vi) 1

-H (HD) OOOD-HD-HM-

-Z HD-0

  -0 EH - (D this HO Qi 1N Ni - LIEHD úú '(II) l

(HO) DWD-HD-HN-

-OEH -H

(05-E HDO

Y

HZ) 1

E E (1) 1

(HD) 0003-HD-HN H

  J HD-e -Z Os H ES aldwexa x -Z Hz O IL -i -0 z H-1, s j 1 Co m CY CD m tn cm E E

(HO) HD H

z 1 (11)

H D-D-O-HZ) 0-

he he

0 O

-H

-E HD-00

-0 EH se -H -DEH The s he z Z: z

HM-D (HD)

E ú (l) 1

(HO) DWD-HD-Hu-

  -e zla 21 (t HD) - <O-) O ca -H EE to Tdwaxa x X R 1

Example

R 3 R

89 (P

-, l (CH

N 2

fi 1 C-

  I-, S the -H 2 H- -J -la r%) vi L 4 c> LM Co

0 O

H 3 C il he C-o-CH 0-C-C (CH)

2 3 3

H

0 O

H 3 C He He -

N -O-CH-O-C-C H

1 2 5

H CH 3

  In the last stage of the synthesis, the protective groups R 1 of examples 74, 76 and 77 are eliminated, the

  protecting groups R 3 of Examples 78 and 80 and the groups

  Protecting agents R 5 of Examples 81 and 83 to 85 The ester groups R 6 shown in Examples 87 to 90 are not removed.

Example 91

  (T) -I-1N-r 3- (benzoylamino) -2-oxohydrochloride

  4-phénylbutyll-N-méthylglycyll-L-proline

  a) Methyl 3- (benzoylamino) phenyl methyl ester

  2-oxo-4-phenylbutyllmethylcarbamic N-methyl-Nl (phenylmethoxy) carbonyl glycine (2.23 g, 10 mmol) is dissolved in 30 ml of tetrahydrofuran and the solution is cooled in an ice bath. oxalyl (1 ml, 11.5 mmol) and then 2 drops of dimethylformamide After stirring for 30 minutes in the ice bath, the mixture is stirred at room temperature.

  for 1 hour 0.25 ml of oxychloride are then added.

  The mixture is evaporated and redissolved in 15 ml.

  of tetrahydrofuran, and stirred in an ice bath.

  To the resulting solution, stirred in the bath of

  ice, a solution of 2-phenyl-4- (phenylmethyl) -5 (4H) -

  oxazolone (3.1 g, 12.4 mmol) in 15 ml of tetrahydrofuran.

  Triethylamine (1.4 ml, 10 mmol) is added and the solution is stirred at room temperature overnight The precipitated triethylamine hydrochloride is filtered off and the residue is removed from the residue, which is then redissolved. in 5 ml of pyridine, and ml of para-dimethylamino pyridine is added. After stirring at room temperature for 3 hours, 5 ml of acetic acid are added and the reaction mixture is kept at 105 for a minute. The mixture is then evaporated. The residue is dissolved in ethyl acetate and washed.

  the solution with aqueous sodium bicarbonate and water.

  After trituration with a mixture of ethyl acetate and hexane, 2.2 g of homogeneous phenylmethyl ester of 1-3- (benzoylamino) -2-oxo-4-phenylbutyllmethylcarbamic acid are obtained;

mp 140-1410.

  b) (T) -N-1-3- (methylamino) -2-oxo-1- hydrochloride

  (Phenylmethyl) pyropyllbenzamide 0.5 g of 3- (benzoylamino) -2-oxo-4-phenylbutyl methylcarbamic acid phenyl methyl ester are dissolved in 50 ml. Ethanol containing 2 ml of 1 N hydrochloric acid Palladium-on-charcoal catalyst (10%, 100 ml) was added and the hydrogenation was continued overnight. The reaction mixture was then filtered, evaporated, dissolves it in

  water, and freeze-dried to obtain 300 mg of chlorine

  (t) -N L 3- (methylamino) -2-oxo-11 (phenylmethyl) propyl] hydrate

  benzamide, in the form of a homogeneous white powder.

  c) 1,1-Dimethylethyl Ester of (t) -1-lN-1 3-

  (benzoylamino) -2-oxo-4-phenylbutyll-N-methylglycyll-L-proline A reaction mixture of (b) -NL 3- (methylamino) -2 hydrochloride is stirred at room temperature under nitrogen overnight. oxo-1 (phenylmethyl) propylibenzamide

  (1.65 g, 5 mmol), 1,1-dimethylethyl ester of

  (bromoacetyl) -L-proline (2.9 g, 10 mmol) from Example 68 (a), and diisopropylethylamine (1.74 ml, mmol) in 20 ml of dimethylformamide. water and ethyl acetate

  and the aqueous layer is extracted once more with acetylene.

  ethyl acetate The extracts are dried over sodium sulphate

  in ethyl acetate and concentrated to a water residue

  Yellow (4.0 g) by flash chromatography (150 g of gel

  Merck Silica 60), 0.7 g of the 1,1-ester are obtained.

  (t) -1-N-1 3- (benzoylamino) -2-oxoethyl dimethylethylamine

  4-phenylbutyll-N-methylglycyll-L-proline, in the form of a

yellow moss.

  (d) (1H) -N-1-3- (benzoylamino) -2-monohydrochloride

  oxo-4-phenylbutyll-N-methylglycyll-L-proline The ester obtained in part (c) (0.4 g, 0.79 mmol) is treated with 5 ml of a mixture of 2N hydrochloric acid and After stirring for 45 minutes at room temperature, the reaction mixture is concentrated under reduced pressure and the resulting oily residue is triturated with ether (3 times) to obtain 0.2 g of the monohydrochloride.

  (1) N-L 3 (benzoyllamino) 2-oxo-4-phenylbutyll-N-methyl-

  glycyll-L-proline, in the form of a white solid; p 125-

    Rf 0.73 (silica gel, 3: 1: 1 mixture of n-butanol, acetic acid and water Anal calc for C 25 29 35 5 HC 1 0.23 H 20:

C, 61.01; H, 6.24; N, 8.54

  Found: C, 61.01; H, 6.10; N, 8.36.

Exeraple 92

  Trifluoroacetate (1: 1) of (S) -7-III-3- (benzoyl)

  aminho) -2-oxo-4-phenylbutyll-methylaminolacetyl -1,4-dithia-7-

  azaspiro 4 4 1-nonane-8-carboxylic acid a) (S) -7- (bromoacetyl) -1,4-dithia-7-azaspiro-1,4-nonane-8-carboxylic acid

  (S) -1,4-Dithia hydrochloride is dissolved

  7-azaspiro-4-nonane-8-carboxylic acid (2.1 g, 8.7 mmol) in 1N sodium hydroxide solution, the solution is cooled to 0 ° and bromoethyl bromide (2.1) is added dropwise to it. 0.91 ml, 10.4 mmol) in 10 minutes The reaction mixture is stirred for 2 hours (from 0 to room temperature), washed twice with ethyl acetate, and acidified. the aqueous layer at pH 2, then extracted with ethyl acetate (3 times) The combined organic extracts are dried over sodium sulfate and concentrated to obtain 2.25 g of

  (S) -7- (bromoacetyl) -1,4-dithia-7-azaspiro [4] nonanea

  8-carboxylic acid. b) (S) -7- (bromoacetyl) 1,4-dithia-7-azaspiro-1,4-nonane-8-carboxylic acid diphenylmethyl ester

  (S) -7- (bromoacetyl) -1,4-dithia-

  7-Azaspirol 4-nonane-8-carboxylic acid (2.25 g, 6.9 mmol) in ml of ethyl acetate Diphenyldiazomethane (1.3 g, 6.9 mmol) was added and the reaction mixture was stirred. while

  overnight at room temperature The reaction mixture is washed

  discolored with saturated sodium bicarbonate solution (2 times), with 10% potassium bisulfate (2 times) and with water, dried over sodium sulfate, and concentrated to give 2, 5 g of the diphenylmethyl ester

2530238.

  (S) -7- (bromoacetyl) -1,4-dithia-7-azaspirol 4 (4) nonane-

  8-carboxylic acid, in the form of a white solid residue.

  c) Diphenylmethyl ester of (S) -7-III-acid 3-

  (benzoylamino) -2-oxo-4-phenylbutyllmethylaminosacetyl-1,4-

  dithia-7-azaspiro-4-nonane-8-carboxylic acid A mixture of the ester obtained in part (b) (2.4 g, 4.87 mmol) of (+) is stirred at room temperature overnight. 3- (methylamino) -2-oxo-1- (phenylmethyl) propyllbenzamide (0.81 g, 2.43 mmol) prepared as in Example 91 (b), and diisopropylethylamine (0.85 ml). 4.87 mmol) in 20 ml of dimethylformamide The reaction mixture is poured into water (50 ml) and extracted with 3 times 100 ml of acetate

  The combined organic extracts are washed with a solution of

  saturated sodium bicarbonate, with 10% potassium bisulfate and with water, are dried over

  sodium, and concentrated to a dark oily residue (2.8 g).

  By flash chromatography (200 g Merck silica gel, methylene chloride containing 10% ethyl acetate, ethyl acetate containing 20% methanol), 1.1 g of

  diphenylmethyl ester of (S) -7-III-3- (benzoylamino) -

  2-oxo-4-phenylbutyl-methylaminol acetyl-1,4-dithia-7-azaspiro

  4.41 nonane-8-carboxylic acid, in the form of a yellow oil.

  d) trifluoroacetate (1: 1) of the acid (S) -7-III 3- (benzoyl)

  amino) -2-oxo-4-phénylbutyil-méthylaminolacétyll-, 4-dithia-7-

  azaspiro 4 4 nonane-8-carboxylic acid The ester obtained in part (c) (10.5 g;

  0.72 mmol) to 2 ml of cooled trifluoroacetic acid (O)

  After stirring for one hour, the volatiles were removed in vacuo and the residue was taken up with toluene (2 times). The oily residue was triturated with ether (4 times), which gives 0.36 g of (S) -7-11H 3- (benzoylamino) -2oxo-4-phenylbutylmethylaminol acetyl-1,4-dithia-7-azaspiro [4] nonane-8-carboxylic acid trifluoroacetate (1: 1); mp 120-125 Rf 0.45 (drag) (silica gel, 4: 1: 1 mixture

  n-butanol, acetic acid and water).

  Anal calc for C 27 H 31 N 30552 C HF 3 02

2731 3 5 2 2 3 2

C, 53.11; H, 4.92; N, 6.40; S, 9.78

  Found C, 52168; H, 5.03; N, 6.53; S, 9.97.

82 2530238

Example 93

  (S) -2-III 3 (benzoylamino) monohydrochloride

  oxo-4-phenylbutyl-1-methylaminolacetyl-1,2,3,4-tetrahydro-3-

isoquinoline

  a) 2- (tbromacetyl) 1- (2-Dimethylethyl) Ester

  1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid To a cooled solution of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid 1,1-dimethylethyl ester (7.7 g, 33 mmol) in 100 ml of methylene chloride is added diisopropylethylamine (6.23 ml, 36.3 mmol) and then, in 15 minutes, bromoacetyl bromide (6.6 g, 2.87 ml, 33 mmol) while maintaining the The reaction mixture is stirred overnight (-5 to room temperature), concentrated to about one third of its volume, diluted with 100 ml of ethyl acetate, washed twice with saturated sodium bicarbonate solution, 2 times with 10% potassium bisulfate and 2 times with water, dried over sodium sulfate, and concentrated to a dark yellow semi-solid residue

  (11.0 g) Recrystallization from a mixture of ethyl acetate

  and hexane, 4.2 g of the 1,1-dimethylethyl ester are obtained.

  2- (bromoacetyl) -11,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid;

  boxylic, in the form of a cream-colored solid; p f 92-

  (85) -

  B) 1,1-Dimethylethyl ester of (S) -2-ll-3- acid

  (benzoylamino) -2-oxo-4-phenylbutyllmethylaminolacetyl-1,2,3,4-

  tetrahydro-3-isoquinolinecarboxylic acid To a solution of 2- (bromoacetyl) -1,2,3,4-tetrahydroisoquinolinecarboxylic acid, 1,1-dimethylethyl ester (2.12 g, 6 mmol) in 20 ml of dimethylformamide (t) -N1 3- (methylamino) -2-oxo-1-phenylmethyl) propylbenzamide (2.0 g, 6 mmol), prepared as described in Example 91 (b),

  and diisopropylethylamine (0.77 g, 1.04 mL, 6 mmol).

  The reaction mixture is stirred overnight, poured into 50 ml of water and extracted with 3 times 50 ml of ethyl acetate. The combined ethyl acetate extracts are washed with saturated aqueous solution. of sodium bicarbonate (2 times) and with water (2 times), dried over magnesium sulfate 83 to 2530238 and concentrated to a yellow oily residue (2.9 g) by flash chromatography (200 g Merck silica, chloroform

  containing 2% methanol), 0.68 g of the

  (S) -2-EI 3- (benzoylamino) -2-oxoethyl dimethylethyl

  4-phenylbutylmethylaminoiacetyl-1,2,3,4-tetrahydro-3-isoquino

  leinecarboxylic, in the form of a yellow dried foam.

  c) S (-2) 3- (benzoylamino) monohydrochloride

  2-oxo-4-phenylbutyl methylaminoacetyl-1,2,3,4-tetrahydro-3-

  Isoquinolinecarboxylic acid The ester obtained in part (b) (1.67 g, 1.17 mmol) is treated with 5 ml of a mixture of 2N hydrochloric acid and

  After stirring for 1 hour at room temperature

  ambient temperature, the reaction mixture is concentrated under

  reduced and the resulting oily residue was triturated with ether (4 times) to give 0.55 g of (S) -2-Llll 3 (benzoylamino) -2-oxo-4-phenylbutyl) monohydrochloride. methylamino-3-acetyll-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, in the form of a whitish solid; p f 123-126 Rf 0.47 '(gel of

  silica, 4: 1: 1 mixture of n-butanol, acetic acid and water).

  Anal calc for C 30 H 31 N 305 HC 1 0.32 H 20: C, 64.82; H, 5.92; N, 7.56; Cl, 6.38

  Found: C, 64.82; H, 6.22; N, 7.55; Cl, 6.13.

Example 94

  Hydrochloride salt () (4 S) 1-1-lN-1 3- (benzoylamino) -

  2-oxo-4-phenylbutyl-N-methylglycyll-4- (phenylthio) -L-proline a) (4S) -1 (bromoacetyl) -4- (phenylthio) -L-proline to a suspension of (4S) -4 - (phenylthio) -L-proline (2.2 g;

  mmol) in 50 ml of freshly

  After stirring, bis (trimethylsilyl) acetamide (7.35 ml, 30 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours until it became almost clear. Bromoacetyl chloride (1.9 g, 1.0 ml, 12 mmol) was added dropwise, keeping the temperature at room temperature after stirring overnight (-5 to room temperature). reaction mixture at about half its volume, partitioned between saturated sodium bicarbonate solution and ethyl acetate, and the layers are separated. The organic layer is extracted once more with a solution.

  saturated with sodium bicarbonate The aqueous layers are acidified

  at pH 2.0 with 10% potassium bisulfate and extracted 3 times with ethyl acetate. The ethyl acetate fractions are pooled, dried over sodium sulfate.

  and concentrated to give 3.5 g of (4 S) -1- (bromoacetyl) -

  4- (phenylthio) -L-proline, in the form of a viscous oil.

  b) (4S) -1- (Bromoacetyl) diphenylmethyl ester

(Ph Cnylthio) -L-proline

  A diphenyldiazole solution is added dropwise

  methane (2.0 g, 10.2 mmol) in 50 ml of ethyl acetate in a solution of (4 S) -1- (bromoacetate) -4- (phenylthio) -L-proline in 50 ml of The violet solution is stirred at room temperature overnight. The decolorized reaction mixture is washed with saturated sodium carbonate solution (2 times) and with water (2 times), dried over sulfate. sodium, and concentrated to obtain 4.78 g of

  (4 S) -1- (bromoacetyl) -4- (phenyl) diphenylmethyl ester

  thio) -L-proline, in the form of a viscous yellow oil.

  (c) Diphenylmethyl ester of 1 (t), 4Si-1N-1 3-

  (benzoylamino) -2-oxo-4-phenylbutyll-N-methyl-yl-4-phenylethio-L-proline To a solution of (4S) -1 (bromoacetyl) -4-diphenylmethyl ester ( phenylthio) -L-proline (4.78 g, 9.4 mmol) in 20 ml of dimethylformamide, add (T) -Nl 3-

  (methylamino) -2-oxo-1- (phenylmethyl) propyllbenzamide (2.42 g, 7.2 mmol) prepared as in Example 91 (b), and diisopropylethylamine (0.93 g; 7.2 mmol) After stirring overnight at room temperature, the reaction mixture is poured into 50 ml of water and extracted 3 times with ethyl acetate. ethyl acetate with a saturated solution of sodium bicarbonate (2 times) and with water (2 times), they are dried over

  sodium sulfate and concentrated to a yellow oil (6.2 g).

  By flash chromatography (Merck silica gel, methylene chloride containing 2% methanol), 3.2 g of the ester are obtained.

  diphenylmethyl of li (t), 4Si-14-N-1 3- (benzoylamino) -2-oxo

  4-phenylbutyll-N-methylglycyll -4- (phenylthio) -L-proline, under the

form of a pale yellow foam.

  (d) Monohydrochloride of 11 (4) -L-N-1-3- (benzoylamino) -

  2-oxo-4-phenylbutyll-N-methylglycyll-4- (phenylthio) -L-proline The ester obtained in part (c) (1.6 g, 2.2 mmol) is treated with 20 ml of mixture of 2 N hydrochloric acid and

  After stirring for 2 hours at room temperature

  ambient temperature, the reaction mixture is concentrated under

  reduced and the oily residue is triturated with diethyl ether.

  one night to obtain 1.2 g of the monohydrochloride

  1 (t), 4 S1-1 ELN-1 3- (benzoylamino) -2-oxo-4-phenylbutyl-N-methyl-

  glycyll-4- (phenylthio) -L-proline, in the form of a whitish solid; 131-133; Rf 0.38 (silica gel, mixture

  4: 1: 1 n-butanol, acetic acid and water).

  Anal calc for C 31 H 33 N 305 S HC 1 * 0.9 H 20:

31 33 3 5 2

  C, 60.82; H, 5.90; N, 6.87; S, 5.24; Cl, 5.79

  Found: C, 60.82; H, 5.74; N, 6.94; S, 5.25; Cl, 5.75.

Example 95

  (4S) -1-N-3 (benzoylamino) -2-oxohydrochloride monohydrochloride

  4-phenylbutyll-N-methylglycyll-4- (4-fluorophenoxy) -L-proline

  a) (4S) -1- (bromoacetyl) 1,1-dimethylethyl ester

  4- (Fluorophenoxy) -L-proline To a solution of (S) -4- (fluorophenoxy) -L-proline 1,1-dimethylethyl ester (2.1 g, 7.5 mmol) in 50 ml of tetrahydrofuran distilled, bromoacetic acid (1.04 g, 7.5 mmol), hydroxybenzotriazole hydrate (1.14 g, 7.5 mmol) and dicyclohexylcarbodiimide (1.54 g; 5 mmol) The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated. The residue is dissolved in 50 ml of ethyl acetate and washed with saturated bicarbonate solution. of sodium (twice), with 10% potassium bisulfate (twice) and with water (twice), it is dried over sodium sulphate and

  it is concentrated to give 3.1 g of the 1,1-dimethylethyl ester.

  that (4 S) -1- (bromoacetyl) -4- (fluorophenoxy) -L-proline, under

the form of an oily residue.

  (b) Ester 1,1-dimethylethyl ester of 4- (3-benzoyl)

  amino) -2-oxo-4-phenylbut 13-N-methyl-4- (4-fl uorophenoxy) -

  L-Proline to a solution of (4 S) -1 (bromoacetyl) -4- (fluorophenoxy) -L-proline (1,4 g, 8.5 mmol)

  in 20 ml of dimethylformamide, (t) -N-5-

  (Methylanmino) -2-oxo-1- (phenylmethyl) propylbenzamide (2.83 g; 5 mmol) prepared as described in Example 91 (b), and diisopropylethylamine (1.43 g, 1, After stirring overnight at room temperature, the reaction mixture is poured into 100 ml of water and extracted 3 times with ethyl acetate. ethyl acetate with saturated sodium bicarbonate solution (2 times), with 10% potassium bisulfate (2 times), and with water (2 times), dried over sodium sulfate and concentrated to a dark residue (5.5 g) by flash chromatography ("LPS-1" silica gel, methylene chloride containing

  % ethyl acetate), 1.2 g of the 1,1-dimethyl ester are obtained.

  (4S) -1H-N-1- (3- (benzoylamino) -2-oxo-4-phenyl) ethylether

  butyll-N-metylglycyll-4- (4-fluorophenoxy) -L-proline, in the form of a pale yellow foam

  c) (4 S) -1H-N-1H 3 (benzoylamino) monohydrochloride

  oxo-4-phenylbutyl-N-methylglycyll-4- (4-fluorophenoxy) -Lvproline The ester obtained in part (b) (1.2 g, 1.95 mmol) is treated with 20 ml of a mixture of 2N hydrochloric acid and

  Acetic acid After stirring for 2 hours at room temperature

  ambient temperature, the reaction mixture is concentrated under

  reduced and the oily residue is triturated with diethyl ether.

  one night to obtain 0.92 g of (4 S) -1 N-1 3- (benzoylamino) -2-oxo-4-phenylbutyll-N-methylglycyl monohydrochloride

  4- (4-fluorophenoxy) -L-proline as a white solid

  castrated; 131-140 Rf 0.54 (silica gel, 3: 1: 1 mixture of

  n-butanol, acetic acid and water).

  Anal calc for C 31 H 32 N 3 FO 6 HC 1 0.55H 2 O: C, 61.24; H, 5.65; N, 6, 91; Cl, 5.83

* Find; C, 61.24; H, 5.66; N, 7.09; Cl, 5.70.

  In the same way, one can use the procedure of the

  Examples 91 to 95 to prepare the compounds of Examples 1 to 90.

87 2530238

Example 96

  N-1N-L 3- (benzoylamino) -2-oxo-4-phenylhydrochloride monohydrochloride

  butyll-N-methylglycyi-N-cyclohexylglycine

  a) 1,1-dimethylethyl ester of (t) -N-1 3- (benzoyl)

  amino) -2-oxo-4-phénylbutyll-N-methylglycine

  To a solution of () -N-1 3- (methylamino) -2-oxo-1- (phenyl)

  methyl (propyl benzyl) (5.0 g, 15 mmol) prepared as described in Example 91 (b), in 20 ml of dimethylformamide, is added 1,1-dimethylethyl-bromoacetic acid ester (13). 8 g, 3.15 ml, 19.5 mmol) and diisopropylethylamine (2.5 g, 3.4 ml, 19.5 mmol) After stirring overnight at room temperature, the reaction mixture is poured into the reaction mixture. in 10 ml of water and extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with saturated sodium bicarbonate solution (twice), with sodium bisulfate 10% potassium (2 times), and with water (2 times), dried over sodium sulphate, and concentrated to a yellow oil, which becomes a desiccated foam by drying under a high vacuum, giving 5.4 g of the 1,1-dimethylethyl ester

  () N-1 3- (benzoylamino) -2-oxo-4-phenylbutyll-N-methyl-

glycine.

  (b) (T) -N-E 3- (benzoylamino) -2-oxohydrochloride

  4-Phenylbutyll-N-methylglycine The ester obtained in part (a) (4.51 g, 11 mmol) is treated with 20 ml of a mixture of 2N hydrochloric acid and acetic acid. 2 1/2 hours at room temperature, the reaction mixture is concentrated under reduced pressure and the oily residue is triturated with ether.

  to obtain 3.3 g of the (1) -N-L 3- (benzoyl) monohydrochloride

  amino) -2-oxo-4-phenylbutyll-N-methylglycine, in the form of a

whitish solid.

  c) 1,1-Dimethylethyl Ester of N-1N-1,3-benzoylamino)

  2-oxo-4-phénylbutyll-N-méthylglycyl'-N-cyclohexylglycine

  To a solution of (t) -N-L 3- (benzoyl) hydrochloride

  amino) -2-oxo-4-phenylbutyll-N-methylglycine (1.0 g, 2.6 mmol) in distilled tetrahydrofuran (50 ml) was added N-cyclohexylglycine 1,1-dimethylethyl ester (0.55 g 2.6 mmol) prepared as indicated in 13 example 65 a) of the hydrate

  hydroxybenzotriazole (0.39 g, 2.6 nmioles) and dicyclohexyl-

  carbodiimide (0.55 g, 2.6 mmol) The reaction mixture is stirred

  During one night, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated. The residue is dissolved in 50 ml of ethyl acetate and the solution is washed twice with saturated sodium bicarbonate solution. with 10% potassium bisulfate and 2 times with water, dried over sodium sulfate, and concentrated to an oily residue (1.5 g) by flash chromatography (100 g, silica gel). Merck), 0.49 g of the 1,1-dimethylethyl ester of

  N LN-1 3- (benzoylamino) -2-oxo-4-phenylbuty-13-N-methylglycyll-N-

  cyclohexylglycine, in the form of a foam.

  (d) N-1-N-1-3- (benzoylamino) -2-oxohydrochloride

  4-phenylbutyll-N-methylglycyll-N-cyclohexylglycine The ester obtained in part (c) (0.48 g, 0.87 mmol) is treated with 10 ml of a mixture of 2N hydrochloric acid and

  Acetic acid After stirring for 2 hours at room temperature

  ambient temperature, the reaction mixture is concentrated under

  reduced and the oily residue is triturated with ether overnight to obtain 0.32 g of the monohydrochloride

  N N-1 3- (benzoylamino) -2-oxo-4-phenylbutyll-N-methylglycyl-N-

  cyclohexylglycine, in the form of a whitish solid; p f.

  131-145 Rf 0.36 (silica gel, 4: 1: 1 mixture of n-butanol,

acetic acid and water).

Anal calc for C 28 HN H Cl 0.7 H 2

283535 2

  C, 61.95; H, 6.95; N, 7.74; Cl, 6.53

  Found: C, 61.95; H, 6.74; N, 7.7%; Cl, 6.23.

Example 97

  Methyl ester of (S) -7-ll (t) -3- (benzoylamino) -2-oxo-4-phenylbutyl-methylamino-butyl-1,4-dithia-7-azaspiro acid 4.4 4 nonane-8-carboxylic acid

  To a solution of the monohydrochloride of () -N-1 3- (benzoyl)

  amino) -2-oxo-4-phenylbutyl-N-methylglycine (1.0 g, 2.5 mmol),

  prepared as shown in Example 96 (b), in 50 ml of tetra-

  distilled hydrofuran, ester monohydrochloride is added

  (S) -1,4-dithia-7-azaspirol 4 nonane-8-carboxylic acid methyl

  xyl (0.66 g, 2.5 mmol), dicyclohexylcarbodiimide (0.54 g, 2.5 mmol), hydroxybenzotriazole hydrate (0.39 g;

  2.5 mmol) and diisopropylethylamine (0.9 ml, 5 mmol).

  The reaction mixture is stirred overnight, the precipitated dicyclohexylurea is filtered off and the filtrate is concentrated. The residue is dissolved in 100 ml of ethyl acetate and washed twice with saturated sodium bicarbonate solution. and twice with water, it is dried over sodium sulphate,

  and concentrated to a yellow oily residue (1.3 g)

  flash matography (Merck silica gel, methylene chloride

  containing 25% ethyl acetate, methylene chloride,

  1% methanol), 0.53 g of the (S) -7-ll () -3- (benzoylamino) -2-oxo-4-phenylbutyic acid methyl ester are obtained.

  methylamino-acetyl-1,4-dithia-7-azaspiro [4] nonane-8-carboxy-

  lique, in the form of a white foam; p f 60-62 Rf 0.52

  (silica gel, methylene chloride containing 5% methanol).

Anal calc for C 28 HN S 0.33 H 20:

  C, 59.87; H, 6.04; N, 7.48; S, 11.42

  Found: C, 59.87; H, 5.94; N, 7.56; S, 11.36.

Example 98

  Monohydrochloride of the methyl ester of the acid (S) -7-

  11 () - 3- (benzoylamino) -2-oxo-4-phenylbutylmethylaminoacetyl 1,4dithia-7-azaspiro 41 nonane-8-carboxylic acid The methyl ester obtained in Example 97 (0.26) was treated 0.46 mmol) with a mixture of 2 N hydrochloric acid and acetic acid until it becomes homogeneous (2 minutes), concentrated under reduced pressure, and the residue is triturated.

  oily with ether (twice), to obtain 0.26 g of the mono-

  (S) 7-Lll (t) -3-methyl-methyl ester hydrochloride

  (benzoylamino) -2-oxo-4-phenylbutyl methylaminol -acetyl -1,4

  dithia-7-azaspirol 4-nonane-8-carboxylic acid, in the form of a white solid; pf 79-85 Rf 0.53 (silica gel, chloride of

  methylene containing 5% methanol).

  Anal calc for C 28 H 33 N 30 SHC 0.56 H 20

28 33 3 5 2 2

  C, 55.84; H, 5.88; N, 6.98; S, 10.64; Cl, 5.88

  Found: C, 55.84; H, 5.95; N, 6.78; S, 10.43; Cl, 5, 66.

Example 99

  (4S) -1-LN-methyl ester monohydrochloride

  (benzoylamino) -2-oxo-4-phenylbutyll-1-N-methyl-glycy 1-4 (4-

  fluorophenoxy) -L-proline a) (45) -4- (Fluorophenoxy) -L-proline methyl ester hydrochloride to a suspension of (4 S) -4 (fluorophenoxy) -L-proline (2.5 11 mmol) in methanol at -30 under atmosphere

  of argon, thionyl chloride (8.09 ml, 11 mmol) was added.

  The reaction mixture is stirred at -20 for 2 hours, then

  at room temperature for 16 hours.

  under reduced pressure and the residue is dissolved in methylene chloride (150 ml) and the mixture is washed twice with 1 N sodium carbonate and twice with water after drying.

  on magnesium sulphate, an excess of hydrochloric acid is added

  methanolic gauge and the solvent was removed under reduced pressure. Addition of ether gave a light brown solid (2.6 g). Recrystallization from a mixture of methanol and ether gave 1.49 g of the monohydrochloride salt. (4S) -4- (fluorophenoxy) -L-proline methyl ester, under the form of a light brown solid; 147148; li O = + 6.960

(c = 1.55, methanol).

  b) Methyl ester of (4S) -1H-lN-1 3- (benzoylamino) -

  2-oxo-4-phenylbutyll-N-methylglycyll-4- (4-fluorophenoxy) -L-

proline

  To a solution of the monohydrochloride of (t) -N-1 3-

  (benzoylamino) -2-oxo-4-phenylbutyll-N-methylglycine (1.17 g, 3 mmol), prepared as described in Example 96 (b), in

  ml of distilled tetrahydrofuran, monochlorine

  (4 S) -4- (fluorophenoxy) -L-proline methyl ester hydrate (0.82 g, 3 mmol), hydroxybenzotriazole hydrate (0.46 g;

  3 mmol) and dicyclohexylcarbodiimide (0.62 g, 3 mmol).

  The reaction mixture is stirred overnight, separated

  dicyclohexylurea which has precipitated, and

  The residue is dissolved in 50 ml of ethyl acetate and the solution is washed twice with saturated sodium bicarbonate solution and twice with water.

  sodium sulfate, and concentrated to an oily residue (1.1 g).

  By flash chromatography (200 g of Merck silica gel 60, chloroform containing 3% of methanol), 0.15 g of

  (4 S) -1H-N-3- (benzoylamino) -2-oxo-4- methyl ester

  phenylbutyl-N-methylglycyll-4- (4-fluorophenoxy) -L-proline,

in the form of a foam.

  (c) Monohydrochloride of the methyl ester of (45) -1-

  3- (benzoamino) -2-oxo-4-phenylbutyll-N-methylglycyll-4-

  (4-fluorophenoxy) -L-proline The methyl ester obtained in part (b) (0.15 g, 0.26 mmol) is treated with a mixture of 2 N hydrochloric acid and acetic acid to give it is homogeneous (2 minutes), concentrated under reduced pressure, and the residue is triturated.

  oily with ether (twice) to obtain 0.14 g of mono-

  (4S) -I-1N-1 3- methyl ester hydrochloride

  (benzoylamino) -2-oxo-4-phenylbutyl-N-methylglycyll, 4- (4-

  fluorophenoxy) -L-proline, as a whitish solid; mp 105125 Rf 0.27 (silica gel, chloroform containing% methanol). Anal calc for C 32 H 34 F 6 HC 1 C, 62.79; H, 5.76; N, 6.86; F, 3.10; Cl, 5.79

  Found: C, 62.78; H, 5.73; N, 6.87; F, 2.83; Cl, 5.33.

Example 100

  (4S) -1H-Nl (S) -3- (benzoylamino) monohydrochloride

  oxo-4-phenylbutyil-L-alanyll-4- (4-fluorophenoxy) -L-proline

  a) 1,1-Dimethylethyl ester of (S) -N-13- (benzoyl)

  amino) -2-oxo-4-phenylbutyl-L-alanine

  To a stirred solution of (S) -N-1,3-chloro-2-oxo-1- (phenyl)

  methyl) propyl benzamide (10.0 g, 33.1 mmol) in 80 ml of dimethylformamide, L-alanine 1,1-dimethylethyl ester hydrochloride (6.0 g, 33.1 mmol), bicarbonate of sodium (6.1 g, 72 mmol) and sodium iodide (4.9 g, 33.1 mmol) The resulting solution is stirred overnight at room temperature, poured into ether and it is washed twice with water and once with

  10% sodium bicarbonate.

  3 times with 1N hydrochloric acid, alkalize

92 2530238

  the combined extracts by adding solid sodium bicarbonate and extracted four times with ethyl acetate The organic extracts are combined, dried over magnesium sulfate

  and concentrated to give 8.9 g of a pale yellow solid.

  Part of this material is recrystallized from ethyl acetate to give (S) -N 3- (benzoylamino) -2oxo-4-phenylbutyll-L-alanine 1,1-dimethylethyl ester under the form of a white solid; p f 106.5110

  (b) (S) -N- [3- (benzoylamino) -2-monohydrochloride)

  oxo-4-phenylbutyll-L-alanine A solution of the ester obtained in part (a) (2.95 g, 4 mmol) in 1.4 hydrochloric acid is stirred at room temperature for 2 hours. N in 39 ml of acetic acid. The resulting white precipitate is collected, rinsed with ether and dried to give 2.27 g of

  (S) -N-1 3- (benzoylamino) -2-oxo-4- monohydrochloride

  phenylbutyll-L-alanine; 208-209 (decomposition); L 1 D = 71 (c = 0.38% in methanol) Rf 0.51 (silica gel, 4: 1: 1 mixture of chloroform, methanol and acid

acetic).

  Anal calc for C 20 H 22 N 204 H Cl: C, 61.64; H, 5.93; N, 7.17; Cl, 9.07

  Found: C, 61.33; H, 5.97; N, 7.17; Cl, 8.79.

  c) (S) -N N benzoylamino) -2-oxo-4-phenylbutyll-N-

  (phenylmethoxy) carbonyl 11-L-alanine Triethylamine (2.1 ml, 15 mmol) was added to

  a mixture of (S) -N-1 3- (benzoylamino) monohydrochloride

  2-oxo-4-phenylbutyll-L-alanine (2.0 g, 5.1 mmol),

  Benzyl formate (730 L, 5.1 mmol), 7 ml of water and 7 ml of dioxane were stirred at 25 for 3 hours, after which time it was poured into a solution.

  aqueous 5% sodium bicarbonate and washed with ether.

  The aqueous layer is acidified with hydrochloric acid and extracted 3 times with ethyl acetate. The extract is dried over magnesium sulfate and concentrated to give a colorless oil. Trituration with ether a white granular solid (150 mg) is obtained which is collected and discharged.

  obtain 1.75 g of (S) -N-1N- (benzoylamino) -2-oxo-4-phenylbuty 13-

  N (phenylmethoxy) carbonyl-L-alanine in the form of a white glass. d) Phenylmethyl ester of (4 S) -1-lN-1 (S) -3-

  (Benzoylamino) -2-oxo-4-phénylbutyll-N-l (phenylmethoxy) carbonyli-

  L-alanyll-4- (4-fluorophenoxy) -L-proline

  A mixture of (S) -N-

  1N- (benzoylamino) -2-oxo-4-phenylbutyll-N-1 (phenylmethoxy) carbonyl-Lalanine (300 mg, 0.62 mmol), acid salt

  Phenylmethyl ester para-toluenesulfonic acid (4 S) -4- (4-

  fluorophenoxy) -L-proline (300 mg, 0.62 mmol),

  (90/1, 0.62 mmol), dicyclohexylcarbodiimide (130 mg, 0.62 mmol) and hydroxybenzotriazole hydrate (90 mg, 0.62 mmol) in 7 ml of tetrahydrofuran. diluted with ethyl acetate Washed

  the resultant solution successively with chlorinated

  1 N water and a 10% aqueous solution of sodium bicarbonate, dried over magnesium sulphate, filtered, and concentrated to obtain 500 mg of the phenylmethyl ester of

  (4S) -1-1N-1 (S) -3- (benzoylamino) -2-oxo-4-phenylbutyll-N-

  1 (phenylmethoxy) carbonyl-L-alanyll-4- (4-fluorophenoxy) -L-

  proline, in the form of a pale yellow oil.

  e) (4 S) -1H-N-1 (S) -3- (benzoyl) monohydrochloride

  amino) -2-oxo-4-phenylbutyl-L-alanyll-4- (4-fluorophenoxy) -L-

  A mixture of 1-ester obtained in part (d) (500 mg, 0.6 mmol), palladium-on-charcoal catalyst (10%, 100%), is hydrogenated under 1 atmosphere and 25 hours for 17 hours. mg), 15 ml of absolute ethanol and 1N aqueous hydrochloric acid (800 ml, 0.8 mmol), after which the mixture is filtered and concentrated to give the residue by chromatography on "HP-20". using a linear gradient from a 9: 1 mixture to a 1: 1 mixture of 0.01 N aqueous hydrochloric acid and methanol. The fractions containing the desired product (TLC) are pooled and concentrated. The residue is dissolved. in a minimal amount of methanol

253-0238

  add ether, which causes the formation of a precipitate

  which is collected and dried under vacuum to

  hold 200 mg of (4 S) -1-lN-1 (S) -3-monohydrochloride

  (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyll-4- (4-fluoro)

  phenoxy) -L-proline; 152-153 (decomposition); illD 5 = -50 (c = 0.5, methanol) Rf 0.75 (silica gel, 4: 1: 1 mixture of

  chloroform, methanol and acetic acid).

  Anal calc for C 31 H 32 FN 306 HC 1 1.5 H 20:

  C, 59.57; H, 5.80; N, 6.72; C, 1.67

  Found: C, 59.68; H, 5.56; N, 6.67; Cl, 5.99.

Example 101

  1 (S) monohydrochloride, 4 Rl-1-IN-1 3- (benzoylamino) -

  2-oxo-4-phénylbutylo-L-alanyfl-4-phenyl-L-proline

  a) Succinimide ester of (S) -N-1N- (benzoylamino)

  2-oxo-4-phenylbutyl-N-1 (phenylmethoxy) carbonyl-L-alanine

  A mixture of (S) -N-

  LN- (benzoylamino) -2-oxo-4-phenylbutyll-N 1 (phenylmethoxy) carbonyl-Lalanine (800 mg, 1.6 mmol) prepared as in Example 100 (c), dicyclohexylcarbodiimide (340 mg; , 6 mmol) and N-hydroxy-succinimide (190 mg, 1.6 mmol) in 5 ml of tetrahydrofuran. After this time, the mixture is filtered and concentrated to give 950 mg of the

  succinimide of (S) -N-1N- (benzoylamino) -2-oxo-4-phenylbutyll-

  N (phenylmethoxy) carbonyl) -L-alanine.

  b) V (S), 4 Rf-1-IN-1 3- (benzoylamino) -2-oxo-4-phenyl-

  butyl-N- (phenylmethoxy) carbonyl-L-alanyl-4-phenyl-L-proline

  To a solution of the succinimide ester of (S) -N-1N-

  (benzoylamino) -2-oxo-4-phenylbutyil-N-1 (phenylmethoxy) carbonyl -

  L-alanine (950 mg, 1.6 mmol) in 5 ml of dimethylformamide was added (4 R) -4-phenyl-L-proline hydrochloride (375 mg;

  1.7 mmol) and triethylamine (40 L, 3.2 mmol).

  The resultant mixture is stirred for 24 hours, after which it is poured into an excess of 1 N hydrochloric acid and extracted 3 times with ethyl acetate. The extracts are combined, dried over sodium sulfate. magnesium, we filter them, and we

  Concentrate to obtain 1.1 g of l 1 (S), 4 Rl-1-lN-l 3-

  (benzoylamino) -2-oxo-4-phenylbutyl-N-1 (phenylmethoxy) carbonyl

L-alanyl-4-phenyl-L-proline.

  c) R 1 (S) monohydrochloride, 4 R 1-1-N- (3- (benzoylamino) -2-oxo-4-phenylbutyl-L-alanyl-4-phenyl-L-proline

  It is hydrogenated under one atmosphere and at 25 for 18 hours.

  The product obtained in part (b) (1.0 g, 1.5 mmol), 20 ml ethanol, 5 ml water, 1.0 N hydrochloric acid (1.5 ml; 1.5 mmol), and palladium on carbon serving as

  catalyst (10%, 100 mg), after which it is filtered and concentrated.

  The residue is chromatographed on "HP-20" using a linear gradient from a 40:60 mixture to a

  10:90 mixture of 0.01 N aqueous hydrochloric acid and methanol.

  Fractions containing the desired product (TLC) are pooled and concentrated. The residue is dissolved in a minimal amount of methanol. Ether is added and the resulting white precipitate is collected and dried to obtain 300 mg.

  1 (S) monohydrochloride, 4R 3-1H-N-3- (benzoylamino) -2-

  oxo-4-phénylbutyll-L-alanyll-4-phenyl-L-proline; 160-162 (decomposition); (C = 1.5, methanol) Rf 0.8 (silica gel, 4: 1: 1 mixture of chloroform, methanol and

acetic acid).

  Anal calc for C 31 H 33 N 305 HC 1 o 1.35 H 2 O: C, 63.27; H, 6.29; N, 7, 14; Cl, 6.02

  Found: C, 63.27; H, 6.17; N, 7.19; Cl, 5.97.

Example 102

  Monohydrochloride of 11 (S), 451-1-, N-1 3- (benzoylamino) -

  -qxo-4-phenylbutyll-L-alanyll-4-phenyl-L-proline Following the procedure of Example 101, but

  using in part (b) the hydrochloride of (45) -4-

  phenyl-L-proline, the monohydrochloride of 1 (S) is obtained,

  4Si-1-i N 3 (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyl-

  4-phenyl-L-proline; p 138-143; D = -61 (c = 0.3% in methanol) Rf 0.84 (silica gel, 4: 1: 1 mixture of

  chloroform, methanol and acetic acid).

  Anal calc for C 31 H 33 N 35 HC 1 2.13 H 2 O

31 3-3 3 5 2

  C, 61.80; H, 6.35; N, 6.98; Cl, 5.88

  Found: C, 61.80; H, 6.06; N, 7.05; Cl, 5.65.

96 2530238

Example 103

  Monohydrochloride of Li 1 (S), 4 R 1-1-lN-r 3 - (benzoyl-amino) -

  2-Axa 4-phenylbutylil-L-alanyl-4-cyclohexyl-L-proline Following the procedure of Example 101 but using in part (b) the hydrochloride of (4 R) -4-cyclohexyl -L-proline, the monohydrochloride of the

  Li (S), 4 R 1-1-L-N- {3 (benzoylamino) -2-oxo-4-phenylbutyll-L-

  alanyfl-4-cyclohexyl-L-proline; mp 140-154 o (decomposition) I = 83 o (c = 0.36% in methanol) Rf 0.84 (silica gel, 4: 1: 1 mixture of chloroform, methanol and acetic acid) ). Anal calc for C H N O H Cl 0.79 H 0:

31-39352

  C, 63.71; H, 7.17; N, 7.19; Cl, 6.06

  Find; C, 63.71; H, 7.21; N, 7, 5; Cl, 5.82.

Example 104

  Monohydrochloride of 1 (S), 4Si 1 -1-N-13 (benzoylamino) -

  2-oxo-4-phenylbutyl-L-alanyl-4-cyclohexyl-proline Following the procedure of Example 101, but

  using in part (b) the hydrochloride de là (AS) - 4-

  cyclohexyl-L-proline gives the monohydrochloride of the 1 (S), 453-1 1N (3-benzoylamino) -2-oxo-4-phenylbutyll -L, alanyl-4-cyclohexyl-Lproline, mp 139-141; (decomposition); v <il D = 80 '(c = 0.2% in methanol) R f 0.83 (silica gel; 4: 1: 1 mixture of chloroform, methanol and acid)

acetic).

  Anal calc for C H N O H Cl 1.54H O: C, 62.28; H, 7.26; N, 7.03Cl, 5.93

  Found C, 62.28; H, 7.01 N, 7.02 Cl, 6.16.

Example-105

  (S) -7 (S) -3- (benzoyl-n) monohydrochloride

  amino) -2-oxo-4-phenylbutyllamino-7-l-oxopropyl-1,4-dithia;

  azaspiro 41 nonane-8-carboxylic acid Following the procedure of example 101 but using in part (b) for the reagent Lproline the

  hydrochloride salt (S) - 1,4-dithia-7-azaspiro 4 4 inonane

  8-carboxylic acid, the monohydrochloride of the (S) -7-

  r (S) -2-11 (benzoylamino) -2-oxo-4-phenylbutyl aminol-1, oxo-4

  4-nonane-8-carboxylic pyil-1,4-dithia-7-azaspirol; 170-172 °; 25 = -26 (c = 1.4% in methanol) Rf 0.78 (silica gel-gel, 6: 1: 1 mixture of chloroform, methanol and acetic acid). Anal calc for C 27 H 31 N 30552 HC 1 0.77 H 20:

  C, 54.77; H, 5.71; N, 7.10; S, 10.83; C 1, 5.99

  Found: C, 54.77; H, 5.70; N, 6.94; S, 10.82; Cl, 6.07.

Example 106

  EI (S), S-1-LN-1 3- (benzoyl) monohydrochloride

  amino) -2-oxo-4-phenylbutyll-L-alanyll-4,5-dihydro-3-phenyl-1H-

  pyrazole-5-carboxylic acid Following the procedure of Example 101 but using in part (b) (S) -4,5-dihydro-3-phenyl-

  1H-pyrazole-5-carboxylic acid for the L-proline reagent, we obtain

the above-named compound.

Example 107

  (S) -2-LN E (S) -3- (benzoyl) monohydrochloride

  amino) -2-oxo-4-phenylbutyl-L-alanyl -1,2,3,4-tetrahydro-3-

  Isoquinolinecarboxylic acid Following the procedure of Example 101 but using in part (b), instead of the proline reagent,

  (S) -1-, 2,3,4-tetrahydro-3-isoquino hydrochloride

  leinecarboxylic acid (S) -2-1N (S) -3- (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid monohydrochloride is obtained . Example 108

  1 N 1 (S) -3- (benzoylamino) monohydrochloride

  2-oxo-4-phenylbutyll-L-alanyl-2- (2-hydroxyphenyl) -4 (R) -

  thiazolidinecarboxylic acid Following the procedure of Example 101 but using in part (b) instead of the proline reagent,

* hydrochloride of 2-1 (2-phenylmethoxy) phenyl-4 (R) -

  thiazolidinecarboxylic acid, after elimination of the

  protecting the hydroxy function, the monohydrochloride

  1-EN-1 (S) -3- (benzoylamino) -2-oxo-4-phenylbutyll-L-acid

  Alanyl -2- (2-hydroxyphenyl) -4 (R) -thiazolidinecarboxylic acid.

  In the same way, the methods of Examples 96, 97, 99 and 100 to 108 can be used to prepare the compounds

98 2530238

Examples 1 to 95.

Example 109

  Monohydrochloride of the methyl ester of (t) -1-lN-

  3- (benzoylamino) -2-oxo-4-phenylbutyll -L-alanyll-L-proline a) 1,1-N- (2-Ethoxy-2-oxoethyl) -N-E1 (phnylmethoxy) carbonyl 1,1-dimethylethyl ester The L-alanyl-L-proline 1,1-dimethylethyl ester (25.44 g, 105 mmol) is taken up in 400 ml of tetrahydrofuran, with stirring. acetate

  bromethyl (11.64 ml, 105 mmol) and diisopropyl-

  Ethylamine (18.3 mm, 105 mmol) After 6 hours,

  cools the reaction mixture in an ice bath and on-

  add benzyl chloroformate (16.5 ml, -115.5 mmol)

  and diisopropylethylamine (20.1 ml, 115.5 mmol).

  After one hour, remove the ice bath and maintain

  the reaction mixture overnight at room temperature

  The mixture is then concentrated to dryness, the residue is taken up in ethyl acetate and washed with 10% potassium bisulfate and saturated bicarbonate solution.

  sodium, until it is neutral.

  crude product (52.3 g) in a silica gel column, eluting with a 1: 1 mixture of ethyl acetate and hexane, to give 42.4 g of the 1,1-dimethylethyl ester of the

  1 N- (2-ethoxy-2-oxoethyl) -N L (phenylmethoxy) carbonyl-L-

alanyli-L-proline.

  b) 1,1-N- (carboxy: methyl) -N1 (phenylmethoxy) carbonyl-L-alanyll-Lproline 1,1-dimethylethyl ester The ester obtained in part (a) (21 g; mmol) in 150 ml of methanol and 1N sodium hydroxide

  (50 ml, 50 mmol) with stirring at room temperature.

  After 5 1/2 hours, the methanol is removed in vacuo and the aqueous portion is extracted with ethyl acetate.

  acidifies the aqueous part with hydrochloric acid

  centered and extracted with ethyl acetate to obtain

  16.95 g of 1,1-dimethylethyl ester of 1-N- (carboxy)

  methyl) -N (phenylmethoxy) carbonyl-L-alanyll-L-proline.

  c) 1,1-Dimethylethyl Ester of (t) N-1

  (benzoylamino) -2-oxo-4-phenylbutyll -N (phenylmethoxy) carbonyl

  L-Alanyl-L-Proline The ester obtained in part (b) (10.0 g, 23 mmol) is taken up in 75 ml of dry tetrahydrofuran, with stirring in an ice bath, then chloride is added dropwise.

  oxalyl (2.4 ml, 27.6 mmol), then 15 drops of dimethyl

  formamide After 20 minutes, the ice bath is removed and the reaction mixture is maintained at room temperature for 1 hour. The mixture is then concentrated to dryness under

  vacuum and taken up in 40 ml of tetrahydrofuran,

  In an ice bath, 2-phenyl-4- (phenylmethyl) -5 (4H) -oxazolone (6 g;

  23.8 mmol) in 35 ml of tetrahydrofuran, followed by

  Ethylamine (3.22 ml, 23 mmol) is added.

  Ethylamine to maintain a basic atmosphere After minutes, remove the ice bath and maintain the

  reaction mixture at room temperature overnight.

  The triethylamine hydrochloride is filtered off and the filtrate is concentrated to dryness in vacuo.

  25 ml of pyridine and 75 mg of 4-dimethyl-

  aminopyridine, then the solution is stirred for 3 hours under an argon atmosphere 25 ml of acetic acid are added and the reaction mixture is stirred for 45 minutes at 100 ° C.

  a positive current of argon The reaction mixture is concentrated

  To dryness, it is taken up in ethyl acetate, and the solution is washed with saturated sodium bicarbonate solution and with dilute hydrochloric acid until it is neutral. crude product (12.8 g) chromatography on silica gel, eluting with a 1: 1 mixture of ethyl acetate and hexane, to obtain 9.05 g of

  1,1-dimethylethyl ester of (t) -i-11N-1N- (benzoyl)

  amino) -2-oxo-4-phenylbutyll -N 1 (phenylmethoxy) carbonyl-L-

alanyl -L-proline.

  d) (+) - 1-N-1N 3- (benzoylamino) -2-oxo-4-phenylbutyl

  N, F (phenylmethoxy) carbonyl-L-alanyl-L-proline The ester obtained in part (c) (11.4 g, 17.7 mmol) is taken up in 50 ml of trifluoroacetic acid and maintained

2530238

  at room temperature for 45 minutes.

  After drying and triturating with a mixture of ether and hexane, to obtain 10.3 g of crude product, this substance is purified in a column of silica gel, eluting with an 8: 2 mixture of benzene and acid. acetic to get 9.7 g

  (h) -1 N-1N 3- (benzoylamino) -2-oxo-4-phenylbutyll-N-

  (phenylmethoxy) carbonyl-L-alanyll-L-proline; 70-91; 3 = 53.0 O (c = 1.22, methanol) Rf 0.41 (silica gel,

  8: 2 mixture of benzene and acetic acid).

Anal: calc for C 33 H 35 N 307

C, 67.68; H, 6.02; N, 7.17

  Found: C, 67.95; H, 6.02; N, 6.82.

  e) Methyl ester of () -1-1N-LN-1 '3- (benzoylamino) -

  2-oxo-4-phenylbuty-1-phenylmethoxycarbonyl-L-alanyl

  L-Proline The acid obtained in part (d) (3.5 g, 6 mmol) is taken up in 12 ml of dimethylformamide, stirring at room temperature, then sodium bicarbonate (630 mg, 7.5 g) is added. mmol) and methyl iodide (0.47 ml, 7.5 mmol) After 18 hours, a further addition of methyl iodide (7.4 mmol) and sodium bicarbonate (7.4 After stirring for a further 4 hours, the reaction mixture is concentrated to dryness in vacuo, taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The crude product is purified (3%). 7 g) in a column of silica gel eluting with a 2: 1 mixture of ethyl acetate and hexane to obtain 3.5 g

  (t) -1H-N-1N-3- (benzoylamino) -2-methyl ester

  oxo-4-phenylbutyl -N (phenylmethoxy) carbonyl-L-alanyl

L-proline.

  (f) monohydrochloride of the methyl ester of (t) -1-

  N1- (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyl-L-proline The ester obtained in part (e) (900 mg, 1.5 mmol) in ethanol ( 95%, 100 ml) and 1.8 ml of hydrochloric acid. Palladium on charcoal was added as the catalyst (10%, 180 mg) and the reaction mixture was stirred.

  under hydrogen overnight The reaction mixture was filtered

  To remove the catalyst, concentrate to dryness and lyophilize twice in water to obtain 700 mg of

  monohydrochloride methyl ester of (t) -1-lN-l 3-

  (benzoylamino) -2-oxo-4-phenylbutyl-L-alanyl-L-proline; p f.

  118 (90); 23-69 (c = 1.18, methanol) Rf 0.63 (silica gel, 9: 1: 1 mixture of chloroform, methanol and

acetic acid).

  Anal calc for C 26 H 31 N 305 HC 1 0.92 H 20: 26 31 3 5 1 O, 2 HO C, 60, 22; H, 6.58; N, 8.11; Cl, 6.84

  Found: C, 60.22; H, 6.28; N, 8.10; C, 1.76.

Example 110

  Methyl ester monomethanesulfonate of (t) -1-lN-

  - (benzoylamino) -2-oxo-4-phénylbutyill-L-alanyll-L-proline

  The methyl ester of the (t) -1-lNN-lN-L 3-

  (Benzoylamino) -2-oxo-4-phénylbutyll-N-l (phenylmethoxy) carbonyll-

  L-alanyl-L-proline (600 mg, 1 mmol) prepared as in Example 109 (e) in 60 ml of methanol and acid

  methanesulfonic acid (0.066 ml, l mmol) is added palladium

  carbon dioxide as a catalyst (10%, 120 mg) and

  The reaction mixture is stirred under hydrogen for 2 1/2 hours.

  The reaction mixture is filtered to remove the catalyst and then concentrated in vacuo The crude product is triturated with ether and filtered. The precipitate is taken up in water and lyophilized to obtain 470 mg of the monomethanesulfonate.

  () -1-N-1-3- (benzoylamino) -2-oxo methyl ester

  4-phenylbutyl-L-alanyll-L-proline; 80-140; 11 D 3 = -61.4 (c = 1.10, methanol) Rf 0.63 (silica gel, mixture

  9: 1: 1 chloroform, methanol and acetic acid).

Anal calc for C 26 31 N 305 C 4035

C, 56.98; H, 6.34; N, 7.30; S, 5.63

  Found: C, 56.98; H, 6.32; N, 7.47; S, 5.63.

Example 111

  (T) -1H-NMR (benzoylamino) -2-oxo-4-phenylbutyil-L-alanyl-L-proline methyl ester halide

  It is taken up in 40 ml of methanol and 0.9 ml of sulfuric acid.

  Furic acid 1 N methyl ester of (t) -1-lNN-lN-l 3- (benzoylamino)

  2-oxo-4-phenylbutyll-N (phenylmethoxy) carbonyl-L-alanyl-L-

  proline (600 mg, 1 mmol) prepared as in Example 109 (e) Palladium-on-charcoal catalyst (10%, -120 mg) was added and the reaction mixture was stirred under hydrogen for 2 hours. The reaction mixture was concentrated to dryness, triturated with ether and filtered. The crude product (446 mg) was taken up in water, filtered through "Millipore" and lyophilized to obtain 405 g. mg of the methyl ester hemisulfate of the

  () -1 N-3- (benzoylamino) -2-oxo-4-phenylbutyl-L-alanyl-L-alanyl

l 23 -03 c = 11, mta

  proline; 98-112 (85); D 3 = 60.3 (c = 1.16, methanol)

  0.63 (drag) (silica gel, 9: 1: 1 mixture of chloroform)

  form, methanol and acetic acid).

  Anal calc for C 26 H 31 N 300.5 HSO 0.91 H 0:

26 31 3 5 0, 2 4 2

C, 58.81; H, 6.42; N, 7.92; S, 3.01

  Found: C, 58.81; H, 6.11; N, 7.91; S, 3.09,

Example 112

  Propyl ester monomethanesulfonate of (t) -1-lN-1 3-

  (benzoylamino) -2-oxo-4-phenylbutyl -L-alanyll-L-proline

  a) Propyl ester of (t) -1-lNN-lN-l 3- (benzoylamino) -

  2-oxo-4-phenylbutyll-N 1 (phenylmethoxy) carbonyl-L-alanyl

  L-proline is taken up in 2 ml of tetrahydrofuran, with stirring

  in an ice-bath, the () -1-N-1N-1 3- (benzoylamino) -2-oxo

  4-phenylbutyll-N-1 (phenylmethoxy) carbonyl 11-L-alanyll-L-proline

  (1.17 g, 2 mmol) prepared as in Example 109 (d).

  N-propanol (3.0 ml, 40 mmol) is then added, followed by

  4-dimethylamino pyridine (122 mg, 1 mmol) and dicyclo

  hexylcarbodiimide (412 mg, 2 mmol) The mixture is left

  reaction to warm to room temperature then the reaction

  continue for one night. Dicyclohexyl-

  urea by filtration and the filtrate is concentrated to dryness in vacuo The crude product (1.2 g) is chromatographed in a column of silica gel eluting with a 9: 1 mixture of benzene and acetic acid to obtain 1.0 g of

  propyl ester of (t) -1-lN-lN-l 3- (benzoylamino) -2-oxo

  4-phenylbutyll-N 1 (phenylmethoxy) carbonyl-L-alanyl-L-proline.

  (b) Monomethanesulphonate of the propyl ester of

  (1) 3- (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyll-L-

  proline The ester obtained in part (a) (500 mg, 0.8 mmol) is taken up in 50 ml of methanol. Methanesulphonic acid (0.72 ml of a 1N solution in methanol) is added and palladium on carbon as catalyst (10%, 100 mg) and

  the reaction mixture is stirred under hydrogen overnight.

  The reaction mixture was filtered to separate the catalyst, concentrated to dryness, triturated with ether and filtered to give 406 mg of crude product. This was taken up in water, filtered through Millipore. and lyophilized to obtain 390 mg of propyl ester monomethanesulfonate

  (t) -1-N-1 3- (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyll-

  L-proline; 82-94 (690); 3 = -60.5 (c = 0.95, methanol) Rf 0.46 (silica gel, 90: 5: 5 mixture of chloroform,

methanol and acetic acid).

  Anal calc for C 28 H 35 N 3 O CH 403 S 0.5 H O

283535 432

C, 58.15; H, 6.73; N, 7.01; S, 5.34

  Found: C, 58.15; H, 6.63; N, 7.05; S, 5.34.

Example 113

  Monomethanesulfonate ethyl ester of (t) -l-IN-1 3-

  (Benzoylamino) -2-oxo-4-phénylbutyll-L-alanyil-L-proline

  a) Ethyl ester of (t) -1-lN-lN-l 3- (benzoylamino) -

  2-oxo-4-phenylbutyll-N-1 '(phenylmethoxy) carbonyl-L-alanyl-L-

  Proline is taken up in 2 ml of tetrahydrofuran, with stirring

  in an ice bath, the (t) -1-lN-lN-l 3- (benzoylamino) -2-oxo

  4-phenylbutyll-N-1 (phenylmethoxy) carbonyl-L-alanyl] -L-proline

  (1.17 g, 2 mmol) prepared as in Example 109 (d).

  Absolute ethanol (2.3 ml, 40 mmol) is then added, followed by 4-dimethylamino pyridine (122 mg, 1 mmol) and dicyclohexylcarbodiimide (412 mg, 2 mmol). The dicyclohexylurea is then filtered off, the filtrate is concentrated to dryness, the residue is taken up

  ethyl acetate and washed with potassium bisulfate

  10% sium and saturated sodium bicarbonate solution until neutral The crude product (1.2 g) is purified in a silica gel column eluting with an 8: 2 mixture of benzene and of acetic acid to obtain the ethyl ester

  (t) -1H-N-1N-1 3 (benzoylamino) -2-oxo-4-phenylbutyl-N-

  (phenylmethoxy) carbonyl-L-alanyl-L-prolineo

  b) Ethyl ester monomethanesulphonate of (t) -1-1 N-

  3- (benzoylamino) -2-oxo-4-phenylbutyl-L-alanyl; L-proline The ester obtained in part (a) (500 mg, 0.8147 mmol) is taken up in 50 ml of a mixture of methanol and methanesulfonic methanolic acid (1N, 0.733 ml). coal as a catalyst (10%, 100 mg) and

  the reaction mixture is stirred under a positive pressure of

  during 3 hours The reaction mixture is then filtered

  to remove the catalyst, concentrate to dryness,

  triturated with ether and filtered.

  (428 mg) in water, filtered through "Millipore", and lyophilized to obtain 360 mg of the monomethanesulfonate of

  the ethyl ester of (t) -1-lN-1 3- (benzoylamino) -2-oxo-4-

  phénylbutyll-L-alanyll-L-proline; 91-96 (72) ID 23 57.2 (c = 1.04, methanol) Rf 0.44 (silica gel, m.p.

  90: 5: 5 mixture of chloroform, methanol and acetic acid).

  Anal calc for C 27 H 33 N 35 CH 4 SO 3 06 H 20:

27 33 3 5 C 4 SO 3 O 2

C, 57.33; H, 6.56; N, 7.17; S, 5.47

  Found: C, 57.33; H, 6.43; N, 7.12; S, 5.47.

Example 114

  1-methylethyl ester monomethanesulfonate of (t) -1-

  IN-L 3- (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyl 11-L-proline

  a) 1-methylethyl ester of (t) -1-N-1N-1 3- (benzoyl)

  : mino) -2-oxo-4-phenylbutyll-N-1 (phenylmethoxy) carbonyl-L-

  elany 11-L-proline is taken up in 2 ml of tetrahydrofuran, with stirring

  in an ice bath, the (t) -1-lN-lN-l 3- (benzoylamino) -2-oxo

  4-phenylbutyll-N-1L (phenylmethoxy) carbonyl-L-alanyl-L-proline (1.17 g, 2 mmol) prepared as in Example 109 (d), and isopropanol (3.0 ml) 40 mmol) Dicyclohexylcarbodiimide (412 mg, 2 mmol) is then added.

  reaction continue overnight at room temperature.

  The reaction mixture is then concentrated to dryness,

  it is taken up in ethyl acetate and the dicy-

  The filtrate is washed with bisulphonate.

  10% potassium fate and a saturated solution of bicarbonate

253023 &

  The crude product (-1.2 g) is purified in a silica gel column eluting with an 8: 2 mixture of benzene and acetic acid to obtain the sodium hydroxide solution.

  1.0 g of the 1-methylethyl ester of () -1-lN-lN-l 3-

  (benzoylainino) -2-oxo-4-phenylbutyll-N-1 (phenylmethoxy) carbonyl -

L-alanyl-L-proline.

  b) Monomethanesulfonate of 1-methylethyl ester

  (t) -1-4 N-1 3- (benzoylamino) -2-oxo-4-phenylbuty-11-L-alanyl -L-

  proline The ester obtained in part (a) (815 mg;

  1.3 mmol) in 20 ml of methanol and methanolic acid.

  methanolic sulfonic acid (1 N, 1.17 ml) and stirred under

  gene in the presence of palladium on charcoal as a catalyst

  (10%, 160 mg) for 3 hours. The reaction mixture is filtered

  To remove the catalyst and evaporate to dryness in vacuo The residue is triturated with ether and the precipitate is filtered to give 704 mg of crude product. This is taken up in 35 ml of water (2% solution). , we filter on

  "Millipore", and lyophilized to obtain 600 mg of mono-

  methanesulfonate of the 1-methylethyl ester of () -l-N-

  1- (benzoylamino) -2-oxo-4-phenylbutyl-3-L-alanyl-L-proline; 88-105 e l = 2-55.2 (c = 1.05, methanol) Rf 0.33 (silica gel, 9-1: 1 mixture of chloroform, methanol and

of acetic acid.

  Anal calc for C 28 H 35 N 305 CH 403 S 66 20:

C, 57.89; H, 6.75; N, 6.99; S, 5.33

  Found: C, 57.89; H, 6.62; N, 6.62; S, 5.32.

Examples 115 to 123 -

  Following the procedure of Examples 109, 11-2, 113 and 114, (t) -1H-N-1-3- (benzoylamino) -2-oxo-4-phenylbutyl-N (phenylmethoxy) carbonyl is treated. L-alanyll-L-proline

  by the reagent indicated in column I below.

  nation the alanyl protective group provides as product

  the ester shown below in column II.

ú ND-D-0-z RD-

  He ú (EHD) D-D-o-z RD he EHD-D-0 zil :) -xa he

ú ú Z '

(HD) D-D-O HD ID

he sil Lil z.E

(RD) Ho -

s z 1

H D-D-O-HD-

  it Hz D-D-O-HD- it z (ERD) RD s Z: 1

N D-D-O-HD-ID

he

i 1 TOD.

Sil a Tdtuox 2 t E HZ) z 1

D HD-HN HD-D -

He E 1 He He

0 HD O O

II 110 D

H 1 HOOD 2 Diq tt r

107 2530238

Example

Col i R 1 to Il

-CH 2-0-C

he

-CH 2-C-O-C (CH 3) 3

CH 3 O -

1 He

-C-0-CH 3

CH 3

-CH (CH 2 -OH) 2

-CH 2-CH CH 2

1 1

a one He

CI-CH -0-C

  ## STR2 ##

I-C C-O-CH 3

CH 3 t -

CH- (CH 2 -0-CH 2 - '"D) 2

OH

C 112 CH CH 2 -

1 1 1 1

OH O v

1 1

CHC-CO

2 2

* 108 2530238

Example 124 -

  Sodium salt of 1-F N- (S) -3- (benzoylamino) -2-oxo

4-phenylbutyl-L-alanyl -Lproline

  1-IN-1 (S) hydrochloride is dissolved in 50 ml of water.

  3- (benzoylamino) -2-oxo-4-phenylbutyl-L-alanyl-L-proline (424 mg, 1 mmol) Aqueous sodium bicarbonate (0.1 N, 20 ml) was added and the aqueous solution was lyophilized It is then dissolved in 10 ml of water and a Sephadex chromatography G-10 gel is passed through a column (5 cm x 60 cm), eluting with water. The fractions containing the desired product are collected and freeze-dried to obtain salt

  1-7 N-4 (S) -3- (benzoylamino) -2-oxo-4-phenylbutyl

L-alanyl-L-proline.

Example 125

  1000 tablets, each containing the following ingredients, are prepared from sufficient total quantities:

  Sodium salt of 1-lN f (S) -3-benzoyl-

  amino) -2-oxo-4-phénylbutyll-L-alanyll-

  L-Proline 100 mg Corn Starch 50 mg Gelatin 7.5 mg "Avicel" (Microcrystalline Cellulose) 25 mg Magnesium Stearate 2.5 mg

  by mixing the sodium salt of 1-LN-L (S) -3- (benzoylamino) -

  2-oxo-4-phenylbutyll-L-alanyll-L-proline and mal starch with an aqueous solution of gelatin The mixture is dried

  then it is ground into a fine powder.

  lation, "Avicel" and then magnesium stearate This mixture is then compressed in a tablet press to form

  1000 tablets each containing 100 mg of the active ingredient.

  In the same way, it is possible to prepare tablets containing 100 mg of the product of any of the

Examples 1 to 123.

  A similar procedure can be used to formulate

  sea tablets containing 50 mg of the active ingredient.

Example 126

  N 1 capsules each containing 50 mg of

  sodium salt of 1-lN-1 (S) -3- (benzoylamino) -2-oxo-4-phenyl-

  butylf-L-alanyll-L-proline, of a mixture of the following ingredients:

lowing:

  Sodium salt of 1-lN-1 (S) -3- (benzoyl)

  amino) -2-oxo-4-phenylbutyl -L-alanyll-L-

  proline 500 mg Magnesium stearate 7 mg Lactose 193 mg 250 mg In a similar manner, it is possible to prepare capsules containing 50 mg of the product according to any one of

examples 1 to 123.

Example 127

  An injectable solution is prepared from the ingredients

following factors:

  Sodium salt of 1-LN-1 (S) -3- (benzoyl)

  amino) -2-oxo-4-phenylbutyll-L-alanyl 2 -L-

  proline 500 g Methyl paraben 5 g Propyl paraben 1 g Sodium chloride 25 g Water for injection 5 1 The active ingredient, preservatives and sodium chloride are dissolved in 3 liters of water for injection, then the volume is increased to 5 liters The solution is filtered through a sterile filter and aseptically filled with pre-sterilized vials which are closed with pre-sterilized rubber stoppers Each vial contains 5 ml of solution at a concentration of 100 mg of active ingredient per ml of solution

for injection.

  In the same way, it is possible to prepare an injectable solution containing 100 mg of active ingredient per ml of solution for the product of any of the examples.

1 to 123.

Example 128

  1000 tablets, each containing the following ingredients, are prepared from sufficient total quantities:

-110 2530238

  Sodium salt of 1-EN (S) -3- (benzoyl)

  amino) -2-oxo-4-phenylbutyll-L-alanyll -L-

  proline 100 mg "Avicel" 100 mg Hydrochlorothiazide 12.5 mg Lactose 113 mg starch 17.5 mg stearic acid 7 mg

  by forming disks of the sodium salt of 1-IN-1 (S) -3-

  (benzoylamino) -2-oxo-4-phenylbutyll-L-alanyll-L-proline, "Avicel" and a portion of the staric acid These discs are ground and passed through a sieve. 2, then mixed with hydrochlorothiazide, lactose, corn starch and the remainder of the stearic acid The mixture is compressed into 350 mg capsule-shaped tablets in a tablet press A groove is formed in tablets

to share them in two.

  In the same way, it is possible to prepare

  products containing 100 mg of the product according to any of the

Examples 1 to 123.

i 111

Claims (83)

1 Compound of formula O R R 1 O he I 1 he R -CH-C-CH 2 -N CH-C% -X 31 2 (L)   NH c 1. R 2 optionally in the form of a pharmaceutically acceptable salt table,   formula in which X is a radical of formula R 7 H 2 C i 12 -N C-COOR (L) 6H H 2 C CH 2 21 2 -N C-COOR, HE H H 2 C 1 -R 8 -N -C-COOR 1 (L) 6 H q, -N C-COOR 6, Y I CL) H R 9 CH 'Y CH 2 -N -C- COOR 1 (L) 6 H l Sy 12 -N C-COOR 6 1 (L) 6 H -N C-COOR 6   C L), 6 to H -N b-COOR 6 1 (L) H (L) H R 24 -N CCOO'R r 1 (L) 6 H -N-C COOR 6 HE H C-COOR (L) 6H O -N CH COOR R R R 4 R 5   R is a hydrogen atom, a lower alkyl or cycloalkyl radical, or a radical of formula (CH 2) -5 i C 2) 4 N 2 (CH 2) 2 -NH 2, - (CH 2) 3 -NH 2, - (CH 2> 2 OH, - (CH 2) 3-OH, (CH 2) 4-OH 1, (CH 2) 2-SHP (CH 2) 3-SH,   or - (H) SH R 1 is a hydrogen atom, a lower alkyl or halo-lower alkyl radical, or a radical of formula (CH 2) - OR   ## STR2 ## ## STR2 ## (CH 2) r -NH-C NH 2 II or - (CH 2) r CNH 2 'provided that R 1 is a hydrogen atom only when R is not itself a hydrogen atom ; R 2 is a radical of formula (CH 2) m i s - (CH 2) m 4-   or (CH 2) m {; R 3 is a hydrogen atom, a lower alkyl radical, a radical of formula C (-CH 2), t - (CH 2) 2, (R 1 4 p a halo-lower alkyl radical; or - (CH 2) m -cycloalkyl, or a radical of formula - (CH 2) r, OH 'OH - (CH 2) r -OH, - (CH) N   NH - (CH 2) r -NH 2 NH - (CH 2) r -NH-C NH 2 - (CH 2) r -SH, - (CH 2) rS lower alkyl, O il or - (CH 2) r -C-NH 2 (CH 2) (R) #   14 P '- (PH) O y 2 M 9 M - (CH) M -, - u O 2 O   (CH 2) wherein R 4 is a radical of a hydrogen atom, a lower alkyl radical, or formula (CH 2) -cycloalkyl, - (CH 2) M (CH 2) mf or is or a radical a hydrogen atom, a lower alkyl radical, of formula - (CH 2 ' - (CH 2) OH   ## STR5 ## ## STR2 ## CH 2) n - (CH 2) rO * H, INH r -SH, - (CH 2) rS lower alkyl, O II. o (CH 2) r-C -NH 2 i r is an integer of 1 to 4; R is a hydrogen atom, a lower alkyl radical, a halogen atom, a phosphine group, a hydroxyl group, a halogen atom, a ketone group, a hydroxyl group or a radical radical of O 11 NH- C-lower alkyl, azide or amine, or a formula / R 19 -N t R 20 -NH-C- (CH 2) (CH 2) m 4 (R 13) p (CH 2)) O - (CH 2) -0   ## STR5 ## wherein a 1 or 2-naphthyl radical of formula (CH 2)% m 2 (R 14) p a radical - (CH 2) m -cyclo   alkyl, a radical of formula -O-C-N R 15 i cal -O-lower alkyl, a radical of formula -O- (CH 2) mnd f, (13) p a 1 or 2-naphthyloxy radical of formula -O (CH 2)   O (R 14)> p a radical -S-lower alkyl, a radical -S (CH 2) (R 13)   (R 13) p or a 1 or 2-naphthylthio radical of formula -S (CH 2) m (R 14) (R 14) p R 8 is a ketone function, a halogen atom, a GOLD radical of formula II Z 15 -0-C-N 4 R 15 -0- (CH 2) 13, u-   (R 13) n -O-lower alkyl radical; a radical / he 116 2530238   a 1 or 2-naphthyloxy radical of formula -O- (CH 2) m R 1 p, a lower -alkyl radical, O (R 14) P   a radical of formula G S (CH 2) m <(R) 2 M (R 13) p or a radical 1 or 2 naphthylthio of formula -S (CH 2) _   Sl (R 14) p R 9 is a ketone function or a radical of formula (CH 2) m (R 13) p R 10 is a hydrogen atom or a radical of formula -Y-R 16;   R ', R 1, R 12 and R' 2 are independently selected from 11, 11,212 hydrogen atoms and lower alkyl radicals, or R 11, R 12 and R 12 are hydrogen atoms and R 11 is a radical of formula (R 14) p   R 13 is a hydrogen atom, an alkyl radical   1 to 4 carbon atoms, a lower alkoxy radical of 1 to 4 carbon atoms, a lower alkylthio radical of 1 to 4 carbon atoms, a chlorine, bromine or fluorine atom, a trifluoromethyl radical, a group hydroxy, or a phenyl, phenoxy, phenylthio or phenylmethyl radical;   R 14 is a hydrogen atom, an alkyl radical   1 to 4 carbon atoms, a lower alkoxy radical of 1 to 4 carbon atoms, a lower alkylthio radical of 1 to 4 carbon atoms, a chlorine, bromine or fluorine atom, a trifluoromethyl radical or a group hydroxy; m is zero, one, two, three or four; p is equal to one, two, or three, provided that p does not   is greater than one than if R 13 or R 14 is a hydrogen atom   gene, a methyl or methoxy radical or a chlorine or fluorine atom;   R 15 is a hydrogen atom or a lower alkyl radical;   1 to 4 carbon atoms; Y is an oxygen or sulfur atom; R 16 is a lower alkyl radical of 1 to 4 carbon atoms or a radical of formula (CH) (R 13) p   or the R 16 substituents together form a pentagonal ring   gonal or hexagonal one or more of the carbon atoms of which are optionally substituted by a lower alkyl radical   from 1 to 4 carbon atoms or by a radical di (lower alkyl) 1 to 4 carbon atoms);   R 19 is a lower alkyl, benzyl or phenyl radical   Thyle; R 20 is a hydrogen atom or a lower alkyl, benzyl or phenethyl group;   R 6 is a hydrogen atom, an alkyl radical   benzyl or benzhydryl, or a radical of the formula VI   -CH-O-C-R 18, -C -C-O-R 23, -CH- (CH 2 -OH) 2, RI R 17 22 CH-CHCH, (CH 2) 2-N (CH 3) 2, or -CH &; t O 1 I OH OH 1 & 2530238   Ri is a hydrogen atom or a lower alkyl radical; cycloalkyl or phenyl;   R 18 is a hydrogen atom, an alkyl radical   lower, lower alkoxy or phenyl, or R 17 and R 18 together form a radical of formula - (CH 2) 2-, - (CH 2) 3, -CH = CH or   R 24 is a hydrogen atom, an alkyl radical   or a radical of formula 4 (14 p 31 years of age, or NOT   R 2 and R 22 are independently selected from atoms 21 22   hydrogen and lower alkyl radicals; and   R 23 is a lower alkyl radical.   Compound according to Claim 1, in the formula of which: R a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, or a phenyl radical;   R 1 is a hydrogen atom, an alkyl radical   straight chain or branched chain of 1 to 4 carbon atoms, a trifluoromethyl radical, or a radical of formula - (CH 2 R 2 CH 2 -CH 2 OH, -CH 2 (OH, OH-CH) >, -CH tyt N -CH 2-SH, 2 I H H   NH (CH 2) 2 -S-CH 3, - (CH 2) 3 3 NHC if -C Hf 2 OH 119 2530238 O O I 1 J   -CH 2-C-NH 2 or - (CH 2) 2-C-NH 2 with the proviso that R 1 -ne is a hydrogen atom only if R is not itself a hydrogen atom; R 4 is a hydrogen atom or a cyclohexyl or phenyl radical; R 5 is a hydrogen atom, a straight-chained or branched-chain lower alkyl radical of 1 to 4 carbon atoms, or a radical of formula -CH 2 -CH 2 OH -CH 2 <-OH, -CH 2-OH, OH OHH -CH, -CH, - (CH 2) 4 -NH 2, NOT H H NH   -CH 2 -SH, - (CH 2) 2-S-CH 3, - (CH 2) 3 -NHC NH 2  O   R 6 is a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, an alkali metal salt ion, or a radical of formula O O he i i -CH 2-CO 23 -CH-O-C-R 18-C-OR 23   R 17 -CH- (CH 2 -O H) 2, -C CHCH-HH 2, - (CH 2) 2 -N (CH 3) 2 ' OH OH 2530238   or -CH 2 R 17 is a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, or a cyclohexyl radical; R 18 is a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms or a phenyl radical; R 23 is a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms; R 2 is a radical of formula - (CH 2);   R 14 R is a straight-chain or branched-lower alkyl radical of 1 to 4 carbon atoms, or a radical of formula - (CH 2) r NH 2 ' - (CH 2)   or (CH 7 R 7 is a hydrogen atom, a hydroxyl group, a lower alkyl radical with a straight or branched chain of 1 to 4 carbon atoms, a cyclohexyl radical, an amine function, a -O-lower alkyl radical whose lower alkyl part is a straight or branched chain of 1 to 4 carbon atoms, a radical of formula (CH 0 (CH 2) m) P P 3 R 13 "13 a 1-naphthyloxy or 2-naphthyloxy radical, a radical -S - lower alkyl whose lower alkyl part is a straight chain 121 2530238   or branched from 1 to 4 carbon atoms, a radical of formula S_ (CH 2) m_.   R 3 R 13 or a 1-naphthylthio radical or; 2-naphthylthio;   R is -O-lower alkyl or -S-lower alkyl   in which the lower alkyl part is a straight or branched chain of 1 to 4 carbon atoms, or a radical of formula -O (CH 2) or -S (CH 2) m 13 13   R 9 is a phenyl, 2-hydroxyphenyl or 4-hydroxy radical   phenyl; The two substituents R 10 are both fluorine or chlorine atoms or radicals of formula -Y-Ri 6; Y is an oxygen or sulfur atom; R 16 is a straight-chain lower alkyl radical or   branched from 1 to 4 carbon atoms, or both   R 16 together form a hexagonal or pentagonal ring of which one or more of the available carbon atoms are optionally substituted by a methyl or dimethyl radical; Rll, R, R 12 and R 2 are all hydrogen atoms, R11 R 1, R 12, R 1   Or R11 is a phenyl, 2-hydroxyphenyl or 4-hydroxy radical   xyphenyl and R R and R 'are all hydrogen atoms; R 12 12 r is an integer from 1 to 4; m is zero, one or two; R 13 is a hydrogen atom, a methyl, methoxy or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxyl group; R 14 is a hydrogen atom, a methyl, methoxy or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxyl group; and R 24 is a phenyl radical. 22 2530238   Compound according to claim 2, in the formula of which: X is a radical of formula -N-CH, -COOR 1e 6 R 4 H 2 C CH 2 H C 22 2 CH 2 I I -N C-COOR TO -N C-COO Rt I (L) (L) 6 {t H or * L) COOR 6.   R is a hydrogen atom or a methyl radical; R 1 is a hydrogen atom, a methyl radical or a radical of formula - (CH 2) 4 -NH 2, provided that R 1 is not   hydrogen atom than if R is not itself a hydrogen atom   gene; R 4 is a cyclohexyl radical R 6 is a hydrogen atom, a straight or branched chain lower alkyl radical of 1 to 4 carbon atoms, or an alkali metal salt ion; R 7 is a hydrogen atom, a cyclohexyl radical, a lower alkoxy radical of 1 to 4 carbon atoms or a radical of formula R 13 (<CH 2) 'R -O- (CH 2 to or -S (CH 32) m 13 1 3   m is zero, one or two; R 13 is a hydrogen atom, a methyl, methoxl or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxyl group; t is 2 or 3.   Compound according to Claim 3, in the formula of which X is a radical of formula -N-CH 2 -COOR 6 R 4. Compound according to Claim 4, in the formula of which: R is a phenyl radical, and R 3 is a benzyl radical.   A compound according to claim 5 wherein R is hydrogen, R is methyl, R is cyclohexyl, and R 6 is a hydrogen atom.   Compound according to claim 5, wherein: R is a hydrogen atom, R is a methyl radical, i - R 4 is a phenyl radical, and R 6 is a hydrogen atom.   8 A compound according to claim 5, in the formula wherein R is a methyl radical, R 1 is a hydrogen atom, R is a cyclohexyl radical, and R 6 is a hydrogen atom.   Compound according to Claim 3, in the formula of which X is a radical of formula H C -C 2 1 l S S 2 CH 2 I I -N C-COOR 6   I (L) H A compound according to claim 9 in the formula which: - R 2 is a phenyl radical, and R 3 is a benzyl radical.   Compound according to claim 1, wherein R is a methyl radical, R is a hydrogen atom, and R 6 is a hydrogen atom.   Compound according to claim 1, wherein R is a methyl radical, R is a hydrogen atom, and R is a methyl radical.   Compound according to claim 1, wherein R is a hydrogen atom, R is a methyl radical, and R 6 is a hydrogen atom.   Compound according to claim of which X is a radical of formula, in the formula, in the formula, in formula 3, in the formula -N COOR 6 2530238   A compound according to claim 14 wherein R 2 is phenyl and R 3 is a benzyl radical.   The compound of claim 15 wherein R is a methyl radical, R 1 is a hydrogen atom, and R 6 is a hydrogen atom.   The compound of Claim 15 wherein R is hydrogen, R is methyl, and R is a hydrogen atom.   Compound according to Claim 3, in the formula of which X is a radical of formula HC H 2 CH 2 -NC-C 00 R 6   Compound according to claim 18, in the formula   of which R 7 is a hydrogen atom.   A compound according to claim 19, wherein R 2 is a phenyl radical, RR is a radical of the formula - (CH -NH R is a hydrogen atom, R 1 is a methyl radical, and R 6 is a hydrogen atom.   Compound according to Claim 19, in the formula of which R is a phenyl radical, R 3 is a radical of formula - (CH 2) 3 -CHV R is a hydrogen atom, R 1 is a methyl radical, and R 6 is a hydrogen atom. 126 2530238   Compound according to Claim 19, in the formula of which: R 2 is a phenyl radical, R is a radical of formula N -CH H   Remains a hydrogen atom, R 1 is a methyl radical, and R 6 is a hydrogen atom.   Compound according to Claim 19, in the formula of which: R 2 is a phenyl radical, R 3 is a radical of formula -CH D OH   R is a hydrogen atom, R 1 is a methyl radical, and R 6 is a hydrogen atom.   The compound of claim 19, wherein R 2 is phenyl and R is a benzyl radical.   The compound of Claim 24 wherein R is hydrogen, R 1 is methyl, and R 6 is a hydrogen atom.   Compound according to claim 25, which is mono-   1- (1N) -3- (benzoylamino) -2-oxo-4-phenylhydrochloride hydrochloride butyil-L-alanyll-L-proline.   A compound according to claim 24 wherein: R 1 is hydrogen, R 1 is methyl, and R 6 is a methyl radical.   Compound according to Claim 24, in the formula of which: R is a hydrogen atom R 1 is a radical R 6 is a radical 29 Compound according to methyl, and ethyl. the claim of which: R is a hydrogen atom, R is a methyl radical, and R 6 is an n-propyl radical. * Compound according to claim wherein R is a hydrogen atom, R 1 is a methyl radical, and R 6 is an isopropyl radical.   Compound according to claim 1, wherein R 1 is a hydrogen radical, and R 1 is a hydrogen atom; R 6 is a hydrogen atom.   Compound according to claim 24, in formula 24, in formula 24, in formula 24, in the formula R is a hydrogen atom, R 1 is a radical of formula - (CH 2) 4 -NH 2, and R 6 is a hydrogen atom.   A compound according to claim 18, wherein R 7 is a radical of the formula -S <34 A compound according to claim 33 wherein: R 2 is R 3 is a radical and benzyl. Claim 34 in the formula R is a methyl radical, R is a hydrogen atom, and R is a hydrogen atom.   Compound according to Claim 18, in the formula 36 Compound according to Claim 18, in the formula 128 2530238   of which R 7 is a radical of formula -0 F-   The compound of claim 36, wherein: R 2 is a phenyl radical, and R 3 is a benzyl radical.   Compound according to claim 1, wherein R is a methyl radical, R 1 is a hydrogen atom, and R 6 is a hydrogen atom. Compound according to claim 1, wherein R is a methyl radical, R is a hydrogen atom, and R 6 is a methyl radical.   Compound according to claim of which R is a hydrogen atom, R 1 is a methyl radical, and R is a hydrogen atom. 41 Compound according to claim of which R 7 is a phenyl radical.   Compound according to claim 1 wherein R is a radical R 3 is a radical 43 A compound according to formula 37, in formula 37, in formula 37, in formula 18, in formula 41, in the formula phenyl, and benzyl . claim 42 wherein R is hydrogen, R is methyl, and R is a hydrogen atom.   Compound according to claim 18, in the formula   of which R is a cyclohexyl radical.   The compound of Claim 44 wherein R 2 is phenyl and R 3 is a benzyl radical.   The compound of claim 45, wherein R is hydrogen, R 1 is methyl, and R 6 is a hydrogen atom.   A compound according to claim 1 wherein R is a lower alkyl or cycloalkyl radical or a radical of formula (CH 2) n (CH 2) 4-NH 2 - (CH 2) 4-OH l (CH 2) 2 -NH 2 1 - (CH 2) 2 -OH (CH 2) 25H $ (C 2) 2-S At (CH 2) 3-NH (CH 2) 3-OH - (CH 2) 3-SH u - (CH 2) 4-SH   m is zero, one, two, three 48 Compound according to claim of which R is a methyl radical. 49 Formula compound or four. 47, in the formula O RO He 1 lil R 3 -CH-C-CH 2 -NH-CH-C-X 2 (L)   Optionally, in the form of a pharmaceutically acceptable salt, in which: X is a radical of formula and wherein X is a radical of formula 1 -N -C-COOR 6 s 1 (L) H Rlo:> <Rj ( H 2 C CH 2 1 1 -N C-COOR 6 J 1 (L) H CH- H Cdl -R 2 1 1 8 -N C-COOR 6 1 (L) Id R 9 CH Z, Y CH 2 -N C-COOR, 1 (L) 6   H R 12 R 'j 2 C-C R 6 p 1 (L) H Re -N C-COOR 6 f i (L) H n -N C-COOR 1 (L) 6 1   H 1 C H H or -NH-cn-COOR 6 R 5 -N-C-Co OR 6 p 1 (L) H -N C-COOR - 1 (L) 6 # H   R 1 is lower alkyl or halo-lower alkyl.   or a radical of formula O (CH 2) Hr-OH g - <CH 2 (D OH OH (CH 'Ir I' 0. ): D 2 'T-N O   H (CH) r -NH 2 - (CH 2) r -SH, (CH 2) n -N (CH 2) n -H 2 H (C 2) n NH lower alkyl - (CH 2) -N C   ## STR2 ## wherein R 2 is a radical of formula (CH 2) 1ffi (CH 2) M_ U   or 2 O o N R 3 is a hydrogen atom, a lower alkyl radical, a radical of formula (R 14) - g (CH) __ 9 2 m (R 14) p (C) S O C) -C   it is a halo-lower alkyl radical or - (CH 2) m -cycloalkyl, a radical of formula (CH 2) OH   ## STR2 ## wherein R is a radical (CH) n-lower alkyl, or a radical of formula NE (CH 2) n -CH 2 2) ## STR2 ## ## STR2 ## ## STR2 ## (C H 2) OH - (H OH OH (CH 2) q N E II (CH 2) p 7 y N H (CH) -OH -   2 r - (CH 2) n N 2 SCH 2) r 5 (CH 2) -S lower alkyl, g - (CH) O 2 r-011 (CH 2) r SH, - (CH 2) r NH 2 # 133 2530238   NH (CH 2) r -NH-C NH o or (CH 2) -C-NH t 2 r 2 ú r is an integer of 1 to 4; R is a hydrogen atom, a lower alkyl radical,   a halogen atom, a ketone function, a hydroxyl group,   an -NH-1-lower alkyl radical, an azide or amine functional group, a radical of formula _ R 20 O (CH 2) m P ((R 13) p - (CH) '(CH   a 1 or 2-naphthyl radical of formula a radical - (CH 2) m -cyclo   - (c "2) m (R 14) p alkyl, a radical of-formula   R. XI the 15th -O-C-N   R 1 is a radical -O-lower alkyl, a radical of formula -O- (CH 2) fm a radical 1 or 2-naphthyloxy of formula -O- (CH 2 m ,,, '(R 14) p a -S-lower alkyl radical, 134 2530238   a radical of-formula or a -5 (CH 2) o a (R 13) p 1 or 2 naphthylthio radical of formula -S-c (CH 21); () (R 14) p   R 8 is a ketone function, a halogen atom, a radi- Formula O   R. He O __ / 15 -o (CH 2) m.   (R 13) p a -O-lower alkyl radical, a 1 or 2-naphthyloxy radical of formula -O- (CH 2) (R 14) p 2 an -S-alkyl radical, a radical of formula a radical - S-lower alkyl, a radical of formula or a radical 1 or 2-   ## STR5 ## wherein R 9 is a ketone function or a radical of formula (CH) (R 13) p (R 13) p Ri O is an atom of halogen or a radical of formula -Y-R 16;   R 1, R 2, R 12 and R 12 are independently selected from _S_ (CHP (R 14) p -2530238   hydrogen atoms and lower alkyl radicals, or beer   R 1 ', R 12 and R' 12 are hydrogen atoms and R 1 is a radical   formula cal; (R 14) p R 13 is a hydrogen atom, an inferior alkyl radical of 1 to 4 carbon atoms, a lower alkoxy radical of 1 to 4 carbon atoms, a lower alkylthio radical of 1 to 4 carbon atoms, a chlorine, bromine or fluorine atom,   a trifluoromethyl radical, a hydroxy group, or a radical   phenyl, phenoxy, phenylthio or phenylmethyl; R 14 is a hydrogen atom, a lower alkyl radical of 1 to 4 carbon atoms, a lower alkoxy radical of 1 to 4 carbon atoms, an alkylthioinferrous radical of 1 to 4 carbon atoms, a chlorine atom, bromine or fluorine, a trifluoromethyl radical or a hydroxyl group; m is zero, one, two, three or four; p is one, two or three, provided that p is no greater than one if R 13 or R 14 is a hydrogen atom, a methyl or methoxy radical or a chlorine or fluorine atom   R 15 is a hydrogen atom or a lower alkyl radical;   1 to 4 carbon atoms; Y is an oxygen or sulfur atom; R 16 is a lower alkyl radical of 1 to 4 carbon atoms   carbon-or a radical of formula (CH- (R 1 p I 13 p   or the substituents R 16 together form a pentagonal ring   nal or hexagonal one or more of the carbon atoms are optionally substituted with a lower alkyl radical of 1 to 4 carbon atoms or a di (lower alkyl of 1 to 4 carbon atoms) radical; R 19 is a lower alkyl, benzyl or phenethyl radical;   R 20 is a hydrogen atom or a lower alkyl radical; benzyl or phenethyl; and 136 2530238   R 6 is a hydrogen atom, a lower alkyl, benzyl or benzhydryl radical, or a radical of formula II -CH-O-C-R 18   R in which R 17 is a hydrogen atom or an alkyl radical   lower, cycloalkyl or phenyl, and R 18 is a hydrogen atom   gene, or a lower alkyl radical, - lower alkoxy or phenyl, or else R 17 and R 18 together form a radical of formula - (CH 2) 2, - (CH 2) 3, -CH = CH or   Pharmaceutical composition for use in the treatment   of hypertension, characterized in that it comprises a pharmaceutically acceptable carrier and a compound with antihypertensive action, of formula O R R 1 O * It I I II I (NH I I 2   R 2 in which R, R 1, R 2, R 3 and X have the same definitions as in claim 1.   Pharmaceutical composition for use as analgesic   characterized in that it comprises a pharmaceutical carrier   acceptable and an encephalinase inhibiting compound of the formula O R R O He 1 He He R 3 -CH-C-CH 2 -N CH C-NH-CH-COOR 31 H 2 (1) 6 NH R_   Wherein R, R 2, R 3, R 5 and R 6 have the same definitions that in claim 1. 52 Compound of formula O O   II R 2-C-NH-CH-C-CH 2 -halo IR 3 in which "halo" is R 2 is a - (CH 2) m 's radical or - (CH 2) m a chlorine atom or bromine; of formula (CH 2) (R 14) p - (, H 2) m R 3 is a hydrogen atom, a lower alkyl radical, a radical of formula - (C Hm - (CH 2) <' ((CH) mc H 2 _ (m 4 ps OD 138 2530238   a halo-lower alkyl radical or - (CH 2) m -cycloalkyl, or a radical of formula - (CH 2) r OH <2 OH   OH - (CH '{, - (CH 2) r -OH, IH ** - (CH 2) N (H 2 R N -C -C 2) = - s H, H NH - (CH 2) -S-alkyl lower, - (CH 2) r -NH-C 2 r 2 N NH 2 oh - (CH 2) r-C-NH 2;   R 14 is a hydrogen atom, an alkyl radical   1 to 4 carbon atoms, a lower alkoxy radical of 1 to 4 carbon atoms, a lower alkylthio radical of 1 to 4 carbon atoms, a chlorine, bromine or fluorine atom, a trifluoromethyl radical or a group hydroxy; m is zero, one, two, three or four; p is equal to one, two or three, provided that p is not   greater than one than if R 14 is a hydrogen atom, a radi-   methyl or methoxy cal or a chlorine or fluorine atom; and r is an integer from 1 to 4.   A compound according to claim 52, wherein R is a radical of the formula (CH 2) m R 14 R 3 is a radical of the formula - (CH 2) m- (R 14 m is zero, one or two, and R 14 is a hydrogen atom, a methyl, methoxyl or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxy group.   The compound of claim 53 wherein R 2 is a radical of formula; R 3 is a radical of formula -CH 25; and "halo" is a chlorine atom. Formula compound O R -C-NHR-CH- R 2-C-NH-CH-C-CH 2 -N-CH-C-OH   Wherein R is a hydrogen atom, "Prot", a lower alkyl or cycloalkyl radical, a radical of the formula H - (CH 2) 4 -N-Prot, - (CH 2) 4 -O-Prot, H - (CH 2) 2 -N-Prot - (CH 2) 2 -O-Prot - (CH 2) 2 -S-Prot HW - (CH 2) 3N-Prot, - (CH 2) 3-O- Prot, - (CH 2) 3 -S-Prot, or - (CH 2) 4 -S-Prot; R 1 is a hydrogen atom, a lower alkyl or halo-lower alkyl radical, or a radical of formula (CH 2) n 2530238   - (CH 2) 1 O-O-Prot, - (CHe O-Prot, O-Prot I) FN H (H 2 FUI i - (CH 2) rS Prot, (CH 2) rS lower alkyl, tl i ## STR2 ## with the proviso that R is a hydrogen atom only if R.sub.n is not itself a hydrogen atom, "Prot" is a protective group easy to eliminate R 2 is a radical of formula - (CH (R 14 (CH) M-O 1) # S (H) 4 7   (CH 2> i -E O R 3 is an atom a radical of formula - <(CH 2)   hydrogen, a lower alkyl radical, R 1 -S-, - (CH 2) M O s Prot (CH 2) ro-p Zot 1 or - (CH) - 2, O (D he - (CH 2) 4   a halo-lower alkyl or (CH 2) m -cycloalkyl radical, or a radical, of formula (C) OH 2 m- (CH 2) n OH OH (Ci 2) r W-J H (CH 2) -OH,   (CH 2) n H H - (CH 2) r -NH 2, (CH 2) r -SH, NH - (CH 2) r -S-lower alkyl, (CH 2) r, NH-C NH O   or - (CH 2) r-C-NH 2; R 14 is a hydrogen atom, a lower alkyl radical of 1 to 4 carbon atoms, a lower alkoxy radical of 14 carbon atoms, a lower alkylthio radical of 1 to 4 carbon atoms, a chlorine atom, bromine or fluorine, a trifluoromethyl radical or a hydroxyl group; m is zero, one, two, three or four; p is equal to one, two or three, provided that p is not O 142 2530238   greater than one if R 14 is a hydrogen atom, a methyl or methoxy radical or a chlorine or fluorine atom; and r is an integer from 1 to 4.   Compound according to Claim 55, in the formula of which: R is a radical of formula 2- - (CH 2)   R 14 R 3 is a radical of the formula - (CH 2) -m R 14 m is zero, one or two; R 14 is a hydrogen atom, a methyl, methoxy or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxyl group; R is a methyl radical; and R 1 is a hydrogen atom.   Compound according to claim 56, in the formula   of which R 2 is a phenyl radical and R 3 is a benzyl radical.   A compound according to claim 55, wherein R 2 is a radical of the formula - (CH 2 m 4) R 3 is a radical of the formula - (CH (CH 2) m j R 14   m is zero, one or two R 14 is a hydrogen atom, a methyl, methoxy or methylthio radical, a chlorine, bromine or fluorine atom, or a hydroxyl group; R is a protective group easy to eliminate; and R is a methyl radical.   Compound according to claim 58 in the formula which: -   R is a phenyl radical, R 3 is a benzyl radical, and R is a radical of formula O -C-O- H - <)