FR2582308A1 - NOVEL 3-AMINO 2-OXOAZETIDINE DERIVATIVES COMPRISING IN POSITION 1 A TETRAZOLYL RADICAL SUBSTITUTED WITH A CLIABABLE ORGANIC RADICAL, THEIR PROCESS OF PREPARATION AND THEIR APPLICATION AS MEDICAMENTS - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS THE PRODUCTS OF FORMULA: (CF DRAWING IN BOPI) R H, ALKYL, ALKENYL, ALKYNYL HAVING 12 CARBON ATOMS AT MAXIMUM, POSSIBLY SUBSTITUTED, CYCLOALKYL C3-8, ACYL, ARYBS OR ARALKYL, SUBSEQUENTLY; R H, ALKYL, ALKENYL, ALKYNYL OR THIOALKYL WITH A MAXIMUM OF 12 CARBON ATOMS, POSSIBLY SUBSTITUTED, FREE CARBOXY, ESTERIFIED OR SALIFIED, ARYL, ACYL OR CARBAMOYL POSSIBLY SUBSTITUTED, AZIDO; RD TETRAZOLYL SUBSTITUTED BY AN ORGANIC RADICAL SUSCEPTIBLE BY CLIVING TO RESULT IN AN ACID HYDROGEN AND POSSIBLY BY ANOTHER SUBSTITUTE, IN THE FORM SYN OR ANTI, CIS, TRANS OR MIXTURE OF CIS-TRANS, RACEMIC OR OPTICALLY ACTIVE. THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICINAL PRODUCTS.

Description

1 2582308

  The present invention relates to novel derivatives of 3-amino-2-

  oxo azetidine comprising in the 1-position a tetrazolyl radical substituted with a cleavable organic radical, their process of preparation and their

application as medicines.

  In the European patent application EP 0.114.128, the applicant company has described new azetidinones comprising in the 1-position a nitrogen-containing heterocyclic radical containing at least one hydrogen

  acid. These products have a good antibiotic activity.

  The products of the present application, which comprise in position 1, a tetrazolyl radical substituted by an organic radical capable, by cleavage, of giving back an acidic hydrogen, has, in addition,

  the advantage of being able to be absorbed orally.

  The subject of the invention is the products of general formula (I):

R

OR R

  In which R represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at most 12 carbon atoms, an optionally substituted cycloalkyl radical having 3 to 8 carbon atoms or a radical acyl or aryl or aralkyl, optionally substituted, R1 represents a hydrogen atom, an alkyl radical, optionally substituted alkyl, alkenyl or alkynyl or thioalkyl having at most 12 carbon atoms, a free carboxy radical, esterified or salified, an aryl radical, acyl or carbamoyl, these radicals being optionally substituted, or an azido radical R2d represents a tetrazolyl radical substituted with an organic radical capable, by cleavage, of giving back an acidic hydrogen, the wavy lines signify that the radical OR may be in the syn form or anti and the products can be in the cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being in racemic or optically active form, as well as salts

  products of formula (I) with bases and acids.

  Among the values of R are:

  a) the radicals methyl, ethyl, propyl, isopropyl, butyl, sec-

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  butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, heptyl, octyl, dececyl, undecyl, dodecyl; b) vinyl, allyl, 1-propenyl, butenyl, pentenyl and hexenyl radicals; c) ethynyl, propargyl and butynyl radicals;

  d) cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals.

  These radicals indicated above in paragraphs a) to d) may be substituted by one or more radicals such as carboxy radicals.

  possibly salified or esterified.

  The ester groups, which may comprise the carboxy group which can carry R, can be included in the following values: i) alkyl such as methyl, ethyl, propyl, tert-butyl, ter-amyl; ii) optionally substituted aralkyl radicals such as benzoyl, p-nitrobenzyl, pmethoxybenzyl; iii) alkyl or alkylthioalkyl radicals such as methoxymethyl, ethoxyethyl, isopropyloxymethyl, methoxyethyl, ethoxyethyl, methylthionethyl, ethylthiomethyl, isopropylthiomethyl; iv) radicals of formula -CH-O-IB in which A represents an alkyl radical having 1 to 6 carbon atoms or a hydrogen atom and B represents an alkyl or alkoxy radical having from 1 to 6 carbon atoms; such as pivaloyloxymethyl radicals, acetoxymethyl radicals,

  propionyl oxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxy

  methyl, 1sovaleryloxymethyl, tert-butylcarbonyloxymethyl, hexadec

  noyloxymethyl, propionyloxyethyl, isovaleryloxyethyl, 1-acetyloxy-

  ethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-tert-butylcarbonyl-

  oxyethyl, 1-acetyloxypropyl, 1-hexadecanoyloxyethyl, 1-propionyloxy-

  propyl, 1-methoxycarbonyloxyethyl, methoxycarbonyloxymethyl, 1-

  acetyloxybutyl, 1-acetyloxyhexyl, 1-acetyloxyheptyl; v) radicals of formula -CH-OC-R, where R is the residue of an amino acid A such that the radicals -CH2-OC-CH2NH2, -CH2-O1-CHNH2 and

0 CH3

  corresponding radicals formed from amino acids such as valine, leucine, isoleucine, phenylalanine, tyrosine, serine, threonine, methionine, cysteine, cystine; vi) radicals of formula -CH-OC-NH 2 in which the symbol represents a disubstituted phenyl radical in the ortho, -meta and para position;

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  vii) the radicals -CH 2 0Dso2N.Pr; -CH 2 O-CO-CH 2 COO 2 Cl 3;

0 NH2

  -CH2-CH2NMe2; -CH M2CH2e; CH- (CHN Me -CHCHN 2 22 2 2 2H2CH2NEt 2) 2 C2CH2N

(D -

  -CH 2 -CH 2 NMe 3 -CH-OC-CH 3 -CH 2 -S-C-CH 3; CH 2 O NMe 2 -CH 2 OCH 3; -CH 0-CH in ortho, meta or para position

0 J O-COCH2NH

  2 2 -CH 2 -O-CH 2 oc <in the ortho / meta or para position;

NHCOCH2NH2 C

22 CH3

-CH2 OC; -CH2OC- ;; H2C'0

OCCH2NH2 NHCOCH22 NMe2

  (viii) phthalidyl, 5,6-dimethoxyphthalidyl, tert-

  butyl carbonyl methyl, ethyl, 2-chloro or methyl, methoxycarbonyl methyl, benzyl or tert-butyl, methoxyethoxymethyl, dimethylaminoethyl, cyanomethyl, tert-butyloxycarbonylmethyl, 2,2-ethylenedioxyethyl,

  cyanoethyl, 2,2-dimethoxyethyl. 2-chloroethoxymithyl, 2-hydroxy-

  ethoxyethyl, 2,3-4-epoxypropyl, 3-dimethylamino, 2-hydroxypropyl, 2-

  hydroxyethyl e, 2-methylaminoethoxymethyl e, 2-naminoethoxymethyl e, 3-

  methoxy 2,4-thiadiazol-5-yl e. 2-Tetrahydropyranyl e, 2-methoxyprop-2-

  yl, 1-hydroxyprop-2-yl, isopropyl, carbamoyl methyl, chloromethyl,

  2-chloroethyl, acetyl methyl, 2-methylthioethyl or thiocyanatomethyl e.

  2-chloro-1-acetyloxyethyl, 2-bromo-1-acetyloxyethyl, 2-fluoro-1-

  acetyloxyethyl, 2-methoxy-1-acetyloxyethyl, 2-methyl-1-acetyloxy-

  propyl e, 2-acetyloxyprop-2-yl e, 1-methoxyacetyloxyethyl, 1-acetyl-

  carbonyl oxyethyl e, 1-hydroxyacetyloxyethyl e. 1-formyl carbonyl oxyethyl e,

  1- (2-thienyl) carbonyloxyethyl, 1- (2-furyl) carbonyloxyethyl, 1- (5-

  nitro 2-furyl) carbonyloxyethyl, 1- (2-pyrrolyl) carbonyloxyethyl, 1-

  (propionyloxy) carbonyloxyethyl, 1- (propyloxycarbonyloxy) ethyl, 1-

  (isopropyloxycarbonyloxy) ethyl, 1- (methoxyethoxycarbonyloxy) ethyl,

  1- (allyloxycarbonyloxy) ethyl, 1- (2,3-4poxy) propyloxycarbonyloxy-

  ethyl, 1- (2-furyl) methyloxycarbonyloxyethyl, 1- (2-fluoro) ethyloxy-

  carbonyl oxyethyl e, 1- (methoxycarbonyloxy) propyl e, (2-methoxycarbonyl)

  oxy) prop-2-yl, (methoxycarbonyloxy) chloromithyl, 1- (methoxycarbonyl)

  oxy) 2-chloroethyl, 1- (methoxycarbonyloxy) -2-methoxyethyl e, 1 (methoxy)

carbonyloxy) 1-allyl.

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  These radicals indicated above in a) to d) can also be

  substituted with an amino, methylamino, dimethylamino, diethyl

  amino, phenyl optionally substituted with one or more radicals selected from hydroxy, methyl, methoxy, chloro, bromo, fluoro; the radicals mentioned in a) to d) may also be substituted with one of the fluoro, chloro, bromo or iodo halogens, with a nitrile radical, with a substituent CONH2 or CONHS02R5 in which R5 may represent an alkyl radical such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, an aryl radical such as phenyl, an amino radical such as aminomethyl or dimethylamino or a heterocyclic amino radical such as piperidino, morpholino or

  optionally substituted piperazino such as 4-ethyl 2,3-dioxo-1-

pi perazino.

  CH3 R can also represent a radical of the type -C-C02H or

H2C -? (CH2) H2 CH3

  -cC-02H wherein the carboxy group is salified or

  esterified and wherein nc represents an integer of 0 to 5.

  Among these values, mention may in particular be made of the substituents 02H C2HCO2H where the carboxy radicals can be salified or esterified, in particular by

  one of the ester groups mentioned above.

  R may also represent an acyl radical such as alkylcarbonyl for example acetyl or propionyl, arylcarbonyl such benzoyl; a carbamoyl radical optionally substituted with dimethylaminocarbonyl aryl such as phenyl optionally substituted by alkyl, alkoxy or halogen or aralkyl such as benzyl optionally substituted in the same way. The radical R 1 may also represent one of the optionally substituted alkyl, alkenyl or alkynyl radicals mentioned above. R1 may also represent a thioalkyl radical such as thiomethyl or thioethyl and the thioalkyl radicals derived from the alkyl radicals indicated above in a) for the substituent R. The thioalkyl radical that may represent R1 may be substituted by the same radicals as those indicated below. above for alkyl, alkenyl or alkynyl values. For the thiomethyl radical, the substituent is

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carbamoyl CONH2.

  Mention may additionally be made of alkyl, alkenyl, alkynyl or thioalkyl radicals substituted by one of the following radicals: azido, aryl such as phenyl optionally substituted by halo, trifluoromethyl, amino, hydroxyl, alkyl or alkoxy having from 1 to 4 carbon atoms. carbon, 5- or 6-membered heterocyclic aryl such as thienyl, furyl,

  pyrannyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridine

nyl, pyrimidinyl.

  The alkyl, alkenyl, alkynyl or thioalkyl radicals that can be represented by the substituent R1 can also be substituted by

  alkylthio radicals such as methylthio, ethylthio, propylthio, iso-

  propylthio, butyl or tert-butylthio; arylthio such as phenylthio, with an acyl radical such as acetyl, propionyl, benzoyl, acyloxy such as acetoxy, propionyloxy, benzoyloxy, acylamino such as acetylamino, aralkylcarbonyl such as benzylcarbonyl; carbamoyloxy; methylamino

  carbonyloxy or dimethylaminocarbonyloxy.

  The values of R 1 representing an esterified carboxy can be chosen from the values indicated above for the substituent R. When R 1 represents an aryl radical, it can be a phenyl radical optionally substituted by an alkyl radical, CF 3, alkoxy alkylthio, halogeno, hydroxylamino, hydroxyalkyl, of a 5- or 6-membered heterocyclic radical containing from 1 to 4 heteroatoms such as N, S or O. Mention may be made, for example, of the thienyl, furyl, pyrrolyl, thiazolyl and isothiazolyl radicals. , oxazolyl, isoxazolyl,

  imidazolinyl, imidazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxa-

  diazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl. These heteroxyclic radicals may optionally be substituted by a

  alkyl, carboxy or carboxyalkyl, aminoalkyl, dialkylamino-

  alkyl. Among the acyl groups that may represent R1, there may be mentioned, for example, the acetyl, propionyl, n-butyryl and benzoyl radicals.

  optionally substituted with alkoxy or hydroxy.

  Among the substituted carbamoyl groups, mention may be made of

  methyl or dimethylcarbamoyl groups.

  The tetrazolyl radical that R2d represents has a radical

  organic susceptible, by cleavage, to give an acid hydrogen.

  Preferably, this organic radical is chosen from the ester groups indicated for the carboxy radical which may comprise R. More preferably, the substituent R2d represents a radical

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  R3d AUCH OofC <O wherein A represents a hydrogen atom or an alkyl radical preferably methyl. More preferably, A represents a hydrogen atom. R3d represents an alkyl or alkoxy radical having 1 to 4 carbon atoms such as methyl or tert-butyl, preferably R3d represents the residue of an amino acid no longer containing the carboxy function such as one of those mentioned above, R3d can

  then represent the -CH 2 -NH 2 radicals; CH-NH2.-

  Among the salts of the products of formula (I) with bases, there may be mentioned more particularly the sodium and potassium salts. These salts can be formed when the radicals R1 or R have

  salivatable acid functions. Multiple salts can be obtained.

  In addition to the sodium and potassium salts mentioned above, it is possible to

  also mention the salts of lithium, calcium, magnesium, ammonium.

  It is also possible to mention organic base salts such as trimethylamine, diethylamine, triethylamine, methylamine,

  propylamine, N, N-dimethylethanol amine, tris (hydroxymethyl) amino-

  methanol, ethanolamine, pyridine, picoline, dicyclohexylamine, N ', N'-dibenzylethylenediamine, morpholine, benzylamine,

  procaline, lysine, arginine, histidine, N-methylglucamine.

  The products of formula (I) can be in the form of salts of organic or mineral acids since these products contain at least

minus a salifiable amino radical.

  Among the acids with which the amino groups of the products of formula (I) may be salified, mention may be made, inter alia, of acetic, trifluoroacetic, malelic, tartaric, methanesulfonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic and sulfuric acids. , phosphoric. The products of formula (I) can also be in the form of internal salts. From

  products of formula (I), the syn and cis products are preferred.

  The subject of the invention is more particularly the products comprised within the formula (I) pre-cited and corresponding to the general formula (I '):

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OR 'N / - 52N I NB <R' 1 (tI ')

H2N S

  in which R 'represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or a cycloalkyl radical having from 3 to 6 carbon atoms, said radicals being optionally substituted by one or more radicals selected from the group consisting of free, esterified or salified carboxy, amino, mono or dialkylamino, aryl, halogen, nitrile, CONHSO2R5 radicals in which R5 represents an optionally substituted alkyl, aryl or amino radical, or R 'represents an alkylcarbonyl radical; or arylcarbonyl or a phenyl radical, R'1 represents a hydrogen atom or an alkyl radical, possibly substituted with one or more of the radicals chosen from the group formed by the halogen, azido, hydroxyl, mercapto, aryl, amino and nitrile radicals; , optionally oxidized allylthio or arylthio, acyl, acyloxy, acylamino, aralkylcarbonyl, carbamoyloxy, alkyl or dialkylcarbamoyloxy or R'1 represents an alkene radical nyl or alkynyl optionally substituted with a phenyl radical or with one or more halogen atoms, or R'1 represents a thioalkyl radical optionally substituted by carbamoyl, or R'1 represents a phenyl radical optionally substituted by halogen, CF3, amino, hydroxy , alkyl or alkoxy or R'1 represents an esterified carboxy radical, a carbamoyl radical or an azido radical, R2d represents a tetrazolyl radical, substituted with an organic radical capable, by cleavage, of giving back an acidic hydrogen, the products having isomerism syn, the wavy line means that the products can be in the cis or trans form, or in the form of a cis-trans mixture, the products of formula (I ') being in racemic or optically active form and the salts products from

  formula (I ') with bases and acids.

  The following are the preferred groups of the following groups:

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CH CH CH CH CH-CH

H-CH - (i-OH3 CH3 3 2 \ / 2

  -H; -CH -CH; -C-CO CH-OCCH3; -C-C0 CH -OC -C-CH; -C-COH;

3 2 1 2 2 he 22 22AII 3

CH3 CH3 CH3 CH3

CH2 H2C-CH2

2 -C - CO2H% -C-CH

H 2 CCH; -CO H; H -CO CH OC-CH

-C-C02H

/ CH 2, "C

H C- / CH H 2 HC CH

HC-C2 / 2 H2C CH / 2

  1 -c-CO CH OC-tBu Co CH OC-CH -C-CO CH OC-tBu

2 2 262 3 2 2

  c CoCO2 ... X.oj _-c_CH o2; _COACE 2 o.

2O O

  Among the values. preferred from R'l we can cite the values

methyl e and fluoromethyl e.

  Among the preferred values of R2d are the values CH OC-CH C-CON CH OC-tBu ;; - C CH OC-tBu 22Il 3 2 2 g2 2 322> s t0

C H -3 -CH

C C0 - CH 'y-ON; 2H

2 2 - 2C -CH2

  It is thus that the invention has more values. Particularly, the product values of the general formula (I ') can be mentioned as described above in the example of R.sub.1', which represents a hydrogen atom, a methyl radical, phenyl, difluoromethyl, 1-methyl-1-carboxyethyl, Free or esterifile, mecanylmethyl, carboxymethyl, free or isomer, (methylsulfonyl)

  carbamoyl methyl e, 1-carboxy 1-cyclopropyl e; 1-carboxy 1-cyclobutyl e 1

  carmiboxy 1-cycled, 1-carboxyprescribed R 2d values can be mentioned said carboxy stant

NOT

  Thus, the subject of the invention is more particularly the products of general formula (1 ') as described above in which R' represents a hydrogen atom. a methyl, phenyl, difluoromethyl, 1-methyl-1-carboxyethyl, free or esterified, cyanomethyl, carboxymethyl, free or esterified, (n-methylsulfonyl) radical;

  carbamoylmethyl, 1-carboxy 1-cyclopropyl; 1-carboxy 1-cyclobutyl, 1-

  carboxy 1-cyclopentyl, 1-carboxy 1-cyclohexyl, said carboxy being

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  optionally esterified or salified,

  R'1 represents a hydrogen atom, a methyl radical, fluoro

  methyl, trifluoromethyl, ethoxycarbonyl, carbamoyl; R2d represents a 1H-tetrazol-5-yl radical, substituted with a -CH-O-C-B radical in which A represents a hydrogen atom or a radical I

A O

  alkyl having from 1 to 4 carbon atoms and B represents a radical

  alkyl or alkoxy having 1 to 4 carbon atoms.

  In particular, the invention is directed to products of formula

(I "); O-R"

NOT

H2N A A

(R ")

| B '

{B '

  ACH / t wherein R "represents a hydrogen atom, a methyl radical, a C-COO2H radical or a radical -CCO2-CH-O-CB" in which Ro and Ro R'o Ro R'o A "0 R'o each represents a hydrogen atom or a methyl radical or together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical; A "represents a hydrogen atom or a methyl radical; B "represents a radical

  methyl or tert-butyl; R "1 represents a methyl or fluorinated radical

  methyl; A 'represents a hydrogen atom or a methyl radical; B '

  represents a methyl or tert-butyl radical.

  In formula (I "), the tetrazolyl radical is substituted in position 2. It is understood that in this formula and in what

  following the tetrazolyl radical may also be substituted at the 1-position.

  The formula then becomes No-R N Rl 2 "i A'-CH

O B '

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  The invention more particularly relates to the products described hereinafter in the examples. Thus, the invention particularly relates to:

  2,2-dimethylpropanoate of / 5- [3 - [(2-amino-4-thiazolyl)] (methoxy)

  imino) acetyl / amino / 2-oxo-4-methyl-1-azetidinyl / 2H-tetrazol-2-yl / methyl syn, racemic or optically active isomer; - / 5- [3 - [(2-Amino-4-thiazolyl) -2-carboxy) -2-dimethyl propanoate

  1-methylethoxy) imino / acetyl / amino / 4-methyl-2-oxo-1-azetidinyl / 2H-

  tetrazol-2-yl / methyl syn, racemic or optically active isomer 2 - [[2- (2-acetyloxymethyl) tetrazol-5-yl] -4-methyl-2-oxoazetidin-3-yl] amino] -1- (2-aminothiazol-4-yl) 2-oxoethylidene / amino / oxy / 2-methylpropanol;

  2,2-dimethylpropanoate of / 5- [3 - [(2-amino-4-thiazolyl)] (methoxy)

  imino) acetyl / amino / 4- (fluoromethyl) -2-oxo-1-azetidinyl / 2H-tetrazol-

  2-yl / methyl isomeric syn, cis racemic or optically active; 2 - [[1- (2-Aminothiazol-4-yl) 2 -] - [[1 - [(2,2-dimethyl-1-oxo-propoxy) -methyl] -tetrazol-5-yl] -acetate - (fluoromethyl) -2-oxo-azetidin-3-yl-amino-2-oxo-ethylidene / amino-oxy-2-methyl-propanol, syn, cis racemic or optically active isomer; 2 - [[1- (2-Amino-4-thiazolyl) -2- [1- [2 - [(2,2-dimethyl-1-oxo-propoxy)]

  methyl / 2H-tetrazol-5-yl / 4- (fluoromethyl) 2-oxo-3-azetidinyl / amino / 2-

  oxoethylidene / amino / oxy / 2-methyl propanoate (2,2-dimethyl-1-oxo)

  propoxy) methyl isis cis, racemic or optically active.

  The subject of the invention is also a process for the preparation of the products of general formula (I) as defined above, characterized in that a product of formula (II) is treated: NHRb Rp () / CoNH N cis or trans, racemic or optically active, wherein Rb represents a hydrogen atom or a group protecting the amino radical, Rp represents a protecting group of the hydroxyl radical or Rp represents R, R having the meaning indicated above or Rp

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  represents a radical R in which the reactive functions are protected, R1p represents either R1, R1 having the meaning indicated above, or R1p represents the substituent R1 in which the reactive functions are protected and R2 represents a tetrazolyl radical by a reactive derivative of a an organic radical capable, by cleavage, of giving back an acidic hydrogen and then subjecting the product obtained, if necessary and if desired, to any one of the following reactions, in any order: a) cleavage by hydrolysis, hydrogenolysis or by action of the thiourea of the protective group or groups that can represent Rb and Rp or comprise Rp and R1P; b) esterification or salification of the carboxy or sulfo radicals that may comprise the radicals Rp and R1p; c) salification with an acid of the amino group (s); d) splitting the molecule to obtain an optically active product. In the case where R1p comprises a hydroxyl or amino radical, it may be advantageous to protect these radicals with removable protecting groups. The protective groups of the amino radical may be, for example, an alkyl radical, preferably tert-butyl or tert-amyl radical; they may also be included among the acyl, aliphatic, aromatic or heterocyclic and carbamoyl groups. Lower alkanoyl groups, for example formyl, acetyl, propionyl, butyryl and isobutyryl, may also be mentioned.

  valeryl, isovaleryl, oxalyl, succinyl, pivaloyl. R1p can -egale-

  have a lower alkoxy or cycloalkoxycarbonyl group such

  for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,

  cyclopropylethoxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, benzoyl, toluolyl, naphthoyl, phthaloyl, mesyl, phenylacetyl, phenyl

  propionyl, an aralkoxycarbonyl group, such as benzyloxycarbonyl.

  The acyl groups may be substituted for example by a

  chlorine atom of bromine, iodine or fluorine.

  Chloroacetyl radicals, dichloroacetyl radicals, trichlo-

  roa etyl, bromoactyl or trifluoroacetyl.

  It is also possible to use a lower aralkyl group such as

  be, zyl, 4-methoxybenzyl or phenylethyl, trityl e, 3,4-di-methoxy-

bWizyle or ibenzihydryie.

  It is also possible to use a haloalkyl group such as trichloroalkyl

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ethyl e.

  It is also possible to use a chlorobenzoyl group, para-nitro-

  benzoyl, para-tert-butylbenzoyl, phenoxyacetyl, caprylyl, n-

  edecanoyl, acryloyl, trichloroethoxycarbonyl.

  It is also possible to use a methylcarbamoyl, phenylcarbamoyl and naphthylcarbamoyl group, as well as the corresponding thiocarbamoyl groups. It is also possible to use an allyl, benzyloxyalkyl group,

  alkoxyalkoxyalkyl or else-phenylsulfonylalkyl.

  The above list is not exhaustive; it is obvious that other amine protecting groups, groups known in particular in peptide chemistry, can also be used. The protecting group of the hydroxyl radical can be chosen

in the list below.

  It may be an acyl group such as for example formyl, acetyl,

  chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trichloroacetyl,

  fluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, benzoylformyl, p-nitrobenzoyl. Mention may also be made of ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, / P / P trichloroethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 1cyclopropyl ethoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxytetrahydropyranyl,

  trityl, benzyl, 4-methoxybenzyl, benzhydryl, trichloroethyl, 1-

  methyl, 1-methoxyethyl, phthaloyl.

  Other acyls such as propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl and pivaloyl may also be mentioned. Mention may also be made of phenylacetyl, phenylpropionyl, mesyl, chlorobenzoyl, para-nitrobenzoyl, para-tert-butylbenzoyl radicals,

  caprylyl, acryloyl, methylcarbamoyl, phenylcarbamoyl, naphthyl-

  carbamoyl. Of course, the values of the substituents Rb when it does not represent a hydrogen atom, as well as the values of the protective groups that may optionally represent or include Rp, in particular when Rp comprises an amine, may be taken

  in the lists mentioned above.

  In a preferred embodiment of the process, the reactive derivative of a cleavable organic radical capable of giving back an acidic hydrogen is preferably a halide. A chloride or bromide is preferably used. More preferentially still we use a

13 2582308

  chloride. The reaction is carried out in the presence of a base such as sodium hydride. It is also possible to use a base such as

  calcium or potassium carbonate.

  It is preferably carried out in a polar solvent such as dimethyl

  formamide. It is also possible to operate in tetrahydrofuran or hexa

  méthylphosphotriamide. In cases where Rb does not represent a hydrogen atom, or Rp represents a protecting group of the hydroxyl radical or a radical R in which the reactive functions are protected, or R1p represents a radical R1 in which the reactive functions are protected or R2 represents a heterocycle comprising a protecting group, the preceding reaction is followed by the action of one or more hydrolysis agents, hydrogenolysis or thiourea which aims to eliminate the Rb radical when it represents a radical protecting the amino radical, to eliminate the radical Rp when it represents a hydroxyl protecting group and to eliminate the others

  protective groups that may include radicals Rp and R1p.

  The nature of the reagents to be used in all these cases is well known to those skilled in the art. Examples of such reactions are given

  further on in the experimental part.

  The following is a non-exhaustive enumeration of the means that can be

  be implemented to eliminate the different groups.

  The removal of the Rb group can be carried out by hydrolysis, which is acidic, basic or using hydrazine.

  Acid hydrolysis is preferably used to remove optionally substituted alkoxy and cycloalkoxycarbonyl groups, such as tert-pentyloxycarbonyl or tert-butyloxycarbonyl,

  optionally substituted aralkoxycarbonyl groups such as benzyl-

  oxycarbonyl, trityl, diphenylmethyl, tert-butyl or 4-

  methoxybenzyl. The acid which is preferably used may be selected from the group consisting of hydrochloric acid, benzene sulfonic acid or para-toluenesulphonic acid, formic acid or trifluoroacetic acid. However, we can

  use other mineral or organic acids.

  Basic hydrolysis is used preferentially to eliminate the

  acyl groups such as trifluoroacetyl.

  The base which is preferably used is a mineral base such as sodium or potassium hydrolyde. It is also possible to use magnesia, barite or an alkali metal carbonate or carbonate.

14 2582308

  such as carbonates and acid carbonates of sodium or potassium or

other bases.

* It is also possible to use sodium or potassium acetate.

  Hydrolysis using hydrazine is preferably used to remove groups such as phthaloyl.

  The group Rb can also be eliminated by the zinc-zinc system.

  acetic acid (for haloalkyl and especially trichloro

  ethyl), the diphenylmethyl, benzyloxycarbonyl groups are

  preferably removed by hydrogen in the presence of a catalyst.

  The chloroacetyl group is removed by the action of thiourea in neutral or acidic medium depending on the type of reaction described by MASAKI

J.A.C.S., 90, 4508, (1968).

  Other known methods of deprotection can also be used

in the litterature.

  Among the preferred groups, mention may be made of formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl and chloroacetyl groups,

  trityl. Trityl and chloro radicals are particularly preferred.

acetyl e.

  The acid which is preferably used is trifluoroacetic acid

or formic acid.

  The elimination of the radical Rp or the protective groups that include Rp or R1p, when this is necessary, is carried out under conditions similar to those described previously for

Elimination of Rb.

  Among other things, acid hydrolysis can be used to eliminate

  optionally substituted alkyl or aralkyl radicals.

  An acid selected from the group consisting of hydrochloric, formic, trifluoroacetic and para-toluenesulfonic acid is preferably used. The other values of the Rb or Rp radicals or of the protective groups that Rp or R1p comprise are, when desired,

  eliminated according to the processes known to those skilled in the art.

  It is preferably carried out under moderate conditions, that is to say, at

  room temperature or heating slightly.

  Naturally, one can, when for example Rb, Rp or R1p are or

  have removable groups belonging to different types

  rents, to act on the products (IV) several agents envisaged in

previous enumerations.

  Salification of the products can be carried out according to the methods

usual.

2582308

  Salification of the products in which Rp or R1p comprise a carboxy or sulpho function, can for example be obtained by action on

  a product in acid form or on a solvate, for example the solvate -

  ethanolic or on a hydrate of this acid, a mineral base such as sodium or potassium hydroxide, carbonate or sodium or potassium hydrogen carbonate. It is also possible to use the salts of mineral acids such as tri-sodium phosphate. We can also call on

to salts of organic acids.

  A list of such salts of organic acids for example

in French Patent 2,476,087.

  As sodium salts, sodium acetate is preferably used.

  sodium 2-ethyl hexanoate or sodium diethyl acetate.

  Salification can also be obtained by action of a base

organic or an amino acid.

  The optional esterification of the products in which Rp or Rlp has an acid function is also carried out under standard conditions. The possible splitting of the racemic molecules of formula (II) or

  (IV) can be performed according to the usual methods.

  It is possible to use an optically active carboxylic or sulphonic acid, such as tartaric acid, dibenzoyl tartaric acid, camphosulphonic acid or glutamic acid, the decomposition of the salt thus obtained being carried out by means of a mineral base such as sodium hydrogen carbonate or a base organic amine such as a tertiary amine,

for example triethylamine.

  The subject of the invention is more particularly a process for the preparation of the products of formula (I ") as defined above, characterized in that a product of formula (I ') is treated: / R" i

R "

N / (II ")

0 H

  0 / - N o \ H N "in which; has the meaning indicated above, Rb has the meaning indicated above, R "i has the values of R" indicated

16 2582308

  above or R "i represents a radical -C-CO2e in which Ro and R'o RoR'o have the meaning indicated above and E represents an ester group easily cleavable by a derivative of formula R7-CH-OC- B 'in

A 'O

  wherein R7 represents a radical capable of reacting with the tetrazolyl ring and then subjecting the product obtained if necessary and if desired to any one of the following reactions, in any order: a) cleavage by acid hydrolysis, hydrogenolysis or by action of the thiourea of the group Rb or group E; b) salification with an acid of the amino radical;

  c) splitting the molecule to obtain an optically active product.

  The main reaction is carried out under the conditions indicated above. R7 preferably represents a halogen atom, preferably a chlorine atom. The reaction is preferably carried out in

  presence of sodium hydride in dimethylformamide.

  The procedure is preferably carried out with a product of formula (II ") in which Rb

  represents a trityl group, E represents a tert-butyl radical.

  The products of general formula (I) have a very good antibiotic activity on gram (-) bacteria, especially on

  coliform bacteria, klebsiella, salmonella and proteus.

  These products can be used in particular as medicaments for the treatment of colibacillosis and associated infections, in proteus, klebsiella and salmonella infections and in other

  diseases caused by gram (-) bacteria.

  The subject of the present invention is therefore also, as medicinal products and in particular antibiotic drugs, the products of

  formula (I), as defined above, as well as their pharmaceutical salts.

acceptable.

  The invention particularly relates, as medicaments and especially antibiotic drugs, the products of formula (I '): / oR'

NOT

NH / R'1 (I ')

H2N <S "O v O.Rd 4O

  2

17 2582308

  in which R 'represents a hydrogen atom or an alkyl radical, linear or branched having from 1 to 6 carbon atoms, or a cycloalkyl radical having from 3 to 6 carbon atoms, said radicals being optionally substituted by one or more of radicals selected from the group consisting of free, esterified or salified carboxy, amino, mono or dialkylamino, aryl, halogen, nitrile, CONHSO2R5 radicals in which R5 represents an optionally substituted alkyl, aryl or amino radical, or R 'represents an alkylcarbonyl radical or arylcarbonyl or a phenyl radical, R'1 represents a hydrogen atom or an alkyl radical, optionally substituted by one or more of the radicals chosen from the group formed by the halogen, azido, hydroxyl, mercapto, aryl, amino and nitrile radicals, optionally oxidized allylthio or arylthio, acyl, acyloxy, acylamino, aralkylcarbonyl, carbamoyloxy, alkyl or dialkylcarbamoyloxy or R'1 represents an alkene radical nyl or alkynyl optionally substituted with a phenyl radical or with one or more halogen atoms, or R'1 represents a thioalkyl radical optionally substituted by carbamoyl, or R'1 represents a phenyl radical optionally substituted by halogen, CF3, amino, hydroxy , alkyl or alkoxy or R'1 represents an esterified carboxy radical, a carbamoyl radical or an azido radical, R2d represents a tetrazolyl radical, substituted with an organic radical capable, by cleavage, of giving back an acidic hydrogen, the products having isomerism syn, the wavy line means that the products can be in the cis or trans form, or in the form of a cis-trans mixture, the products of formula (I ') being in racemic or optically active form and the salts products from

  formula (I ') with bases and acids.

  The invention more particularly relates, as medicaments and in particular to antibiotic drugs, the products of formula (I "): ## STR1 ## in which R" represents an atom of methyl, a radical in which R "'represents a hydrogen atom, a methyl radical, a

18 2582308

  radical -C-CO2H or a radical -C-CO2-CH-O-CB "in which Ro and Ro R'o Ro R'o A" O R'o each represent a hydrogen atom or a methyl radical or form together with the carbon atom to which they are attached a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical; A "represents a hydrogen atom or a methyl radical; B" represents a radical

  methyl or tert-butyl; R "1 represents a methyl or fluorinated radical

  methyl; A 'represents a hydrogen atom or a methyl radical; B '

  represents a methyl or tert-butyl radical.

  Finally, the invention is particularly useful as medicaments and especially antibiotic drugs, the products described in the examples. Thus, the invention relates, 3 title of drugs and particularly antibiotic drugs:

  2,2-dimethylpropanoate of / 5- [3 - [(2-amino-4-thiazolyl)] (methoxy)

  imino) acetyl / amino / 2-oxo-4-methyl-1-azetidinyl / 2H-tetrazol-2-yl

  methyl isomer syn, cis racemic or optically active.

  - / 5- [3 - [(2-Amino-4-thiazolyl) -1-carboxy-2,2-dimethylpropanoate

  1-methylethoxy) imino / acetyl / amino / 4-methyl-2-oxo-1-azetidinyl / 2H-

  tetrazol-2-yl / methyl isomer syn, cis racemic or optically

active.

  2 - [(2-acetyloxymethyl) tetrazol-5-yl] -4-methyl-2-oxoazetidin-3-yl] amino] -1- (2-aminothiazol-4-) - 2 - [(2-acetyloxymethyl) tetrazol-5-yl] -4-methyl-2-oxo-azetidin-3-yl] amino yl) 2-oxoethylidene / amino /

oxy / 2-emethylpropanol.

  - / 5- [3 - [(2-Amino-4-thiazolyl) -2-dimethyl propanoate)

  imino) acetyl / amino / 4- (fluoromethyl) -2-oxo-1-azetidinyl / 2H-tetrazol-

  2-yl / methiyl isomer syn, cis racemic or optically active.

  2 - [1- (2-Aminothiazol-4-yl) 2 -] - [[2 - [(2,2-dimethyl-1-oxo-propoxy) -methyl] -tetrazol-5-yl] -acetate - (fluoromethyl) 2-oxo-azetidin-3-yl-amino-2-oxo-ethylidene / amino-oxy-2-methyl-propanol, syn isomer,

  racemic or optically active cis.

  2 - [[1- (2-Amino-4-thiazolyl) -2-N- [1 - [(2,2-dimethyl-1-oxo-propoxy)]

  methyl / 2H-tetrazol-5-yl / 4- (fluoromethyl) 2-oxo-3-azetidinyl / amino / 2-

  oxoethylidene / amino / oxy / 2-methyl propanoate (2,2-dimethyl-1-oxo)

  propoxy) methyl isis cis, racemic or optically active.

  The invention extends to pharmaceutical compositions containing

  active principle at least one of the drugs defined above.

  These compositions may be administered by oral, rectal, parenteral or topical route for topical application to the skin and mucous membranes. But as indicated above, the products of the present invention

19 2582308

  are particularly suitable for oral administration.

  The compositions may be solid or liquid and may be in the pharmaceutical forms commonly used in human medicine, for example, tablets, single or coated tablets, capsules, granules, suppositories, injectables, ointments,

  creams, gels; they are prepared according to the usual methods.

  The active ingredient (s) can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles. fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives. These compositions may, in particular, be in the form of a powder intended to be dissolved extemporaneously in a vehicle

  suitable, for example sterile pyrogen-free water.

  The dose administered varies according to the condition being treated, the subject, the route of administration and the product under consideration. It may be, for example, between 0.250 g and 4 g per day, orally in humans, with the product described in Example 6, or still included

  between 0.500 g and 1 g three times daily, intramuscularly.

  The products of formula (I) and their salts can also be

  used as disinfectants for surgical instruments.

  The products of formula (II) used at the start of the invention are

  described in European Patent Application No. EP 0 114 128.

  In addition to the products described in the examples which illustrate the invention without however limiting it, the following products constitute

  products obtainable within the scope of the present invention.

  The products mentioned correspond to the formula (IC):

/

N / it c <AR 1 (iC)

H12N- 0

Ri OR

2 3

  The substituents R, R1, R2 and R3 have the following values:

I I 1 11 1 1 1

R R1 R2 R3 R R1 R2 R3

___ ___ __ _II 11 1 II II I

  ## STR2 ##

I, I

  I I I | 137I lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

C1, 1, C1,

"tc4H9 -

  ## STR2 ## ## STR2 ## I ll I! Ca (II) (II) Phenylphenyl) (2 <I5 t IIII gc I Co- [glycy ,, I * ii pSi) CDI 1i I t - - Ipyllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll 7 '- Valylitolylmethylcellulose Alanylamine II

I I I 1 11 1 1 1 1

R 1 R 1 R2 R 3 R R 1 R2 R 3

A - 1H

  i 1121 1 CH2F H Itriptophyl% 1 1 61 "CH2F H O | l 2 Il 9qt I-J 2 h

I- I CH3

  Ithononylylglutamyl. ## STR1 ##

arginyl i, i-

IV IVlasparagylIl 1 1 zt 1 B k 3a

  It is as follows. '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' 'I

  "|" l "Isurcosyl g |" | "l" | glycyl-

glycyl

"ipyrogluta-1" "leucyl-

myl valyl l l l 11sp a 1a1y1 i

ii "aityrosyl" "valyl-

  III. IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII? I I.

I nopteuyluta {"" "u y-.

He I

1tyroSyJ. i valyt-

  I leucyl iii I I I I R I R1R2 jR3 R I R1R2 1R3 I __ _ _ _ __ _ _ _ II l 11 1 1 I I I CIOIFII I II i ll | 12H 50, where 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, 1H, II I oo 0 t, ": .... * I il 't", i 1 I, I c, zoe .. III tlocl,,,,,,,,,,, ccd - o- 1 1 1 1H

I. II.I.I.I.I.I 1C3H71-

n I | I 1 | Itttt 1 "_ l" "tnC4H9 9

I D 0 lIi 1iC34H -

I ,, I ,, IlNN. ,,, 1, o Ck ,, o 1 1 I || uI

I! I! I I ntC4H9C-

  1, 1, 2, 3, 5, 5, 7, 9, 9

ic I tC4HgC-

I, I, I

S / 9 | 1 | nx'CsÉf.C-

ilo II IfO

II, I, IIN - 1 I I

  ## EQU1 ##

R 1 R 1 R 2 R 3 R R 1 J R 2 R 3

  I_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ II II II. ii 1 1 * ti ,, t I fLeucyl II ,, I t, 1111 t ",," r @ -] "If Iflysyl

I I 11

  ## STR5 ## The phenylalanyl, ## STR1 ## III., II-1, I-1, I-1, 1H-1, 1H-1, 1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H-1H I llllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll Iistidoyl, I lon Iyl l Iyyy l l lnr: yl I l l l l l l l l

I, I, I, I asparagyl-

I -I I I

  I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I

I R 1 R 1 R 1 R 3 R 1 R 1 R 2 R 3

I ______________I_I I, 1 1.

  ## EQU1 ## 1 ## EQU1 ##

"xrt" "naleucyl" "glycyl-

1aPleucylI I 'glycyl i

"" "surcosyl" ,,. leucyl

I1 1u11 1I Ivalyl I

it "" If pyrogluta- "valyl-

III Imyl I I Ileucyl

tyrosyl! I C-

H I, Iir I c2t "5 - - I

OIIl - I 1Ce> 53O o -

  I ,,,! ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ##

"g" | "I U2N I" ""

  1,11,, CH, I I I ,,. ,, Ió% iN. <. I, I, I, I, I, I, II, I, I, I, I, I, I, I, I, I I o IIf

I ,, I ,,,, ti Il N-C-

II I, I IC4't \ I

I II I I

2582308

  I t 1 i1 11 1 I RI R11 R2tR3lR R1 R2R3 I t I 11 1 1 1 1

CHCH FH \ M N_CHF2CH F H

i 2: I E1) 2 i iC4H9-

0 0 o

t t Ertc H c-

## EQU1 ##

tt, i ,,,, o., o / o | l _

it.

GO

ol I Io.

"(i) (C2H5) QCH--

  I I I I I I I I I I I I I I I I I I I I I I II II I I I I I I I I I I I I I I I I I I I I

t '"t0% -" ",,, -

  t tt ttt it is s .. ty i | @c H-Co ilO tiifiiC4OHtjaCiiu iii I t IIO III HIIa "1 0- I itI. tI-1t1., Ii" I "Ic it 'I XY- It' i, I "1, CH 1r '. Ii Oea11 I, O I

CHF2 | l "t CH3C -" CH2F "J.

  i, II I I OC H-C- | ti ti ti t iC3H7I "" Cl_ii iI I nCHC- | t} | ("_ 4 iii 9't, 'i' I Xc X iII t I t t

26 2582308

R1

I -'I I 1 11 I 1 1 1

I R 1 R 1 to R 2 R 3 1 1 R R 21 R2 R 3

I __ _ _ _ _ _ _ _ _ III 11 I I I I

CH2F CH2F H

  C2 2 H-CHF2 CHF H asparagyl "nii, I, I, aspartyl III, II, II, II, II, II, II, II, II, II, II, II II II Iglycyl, Inorvalyl | | w | Allynyl ornithyl i-i 1 It is also useful for the treatment of liposomes in the form of a liposylmethylcellulose and a liposylmethylcellulose. I 11.1 n

i I I I II I i.

  CHF2 Iprolyl II ili, i 1.i 2 liii - il CH3 * sii Iseryl II, i IH N-o-2 ilili il iii "IGHUTAMYL CH3 CATHILDYL", (II, II, I), (1), (III), (III), (1) : o: ": ZH slllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

_xx @ "D j" I "I-z-0" ...

  -C3 (14, I-1).

I I '

-I- "" "

  EXAMPLES OF THE INVENTION OF THE INVENTION OF THE INVENTION IN THE FIELD OF THE INVENTION 'HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHQH a .XItI! oI .3 'I \ IoIiIIi o

I-I 111 I11

II IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

BOúBSZ ..

28 2582308

I II I II II I

R 1 RR1R2 1R3 R R R2 R3

1 2I 1 21 13

  CH-I l fA9. JOI + CH2FC33, CH, 4.CH2FC 1 o I I I IIGH3 II I c-I o!

III 1H-C-.

iII II '

I II1C3H7C-

I! I I I I I 1 1 1 1

I jiC3H7 -! C H i o

III0, I I I. I

  "i" "" "" "" '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' I

! o! .ctc11 24> -

  1H3411-O-III-III-III-III-III-III-1H2H5) CCHIII-Glycyl, C, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III, III and III. , III. III. II. II. II. II. IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII I II II II II II II II II II

29 2582308

111 1 1 1

I II III

R R1 R2 R3 R R R1 R2 1 R3

  I __________________I i I l 1 1 I 1 CCH

  ## EQU1 ## ## STR2 ##

  ## STR3 ## wherein R 1 is (1H) -H-Glutamyl-1H-aryl-thienyl,

I I I II I 1 I

  III. Asparagyl. II. "Aspartyl Nt., I" Iisoleucyl S, Methionyl, III, I, "Norvalyl, II II III {ithyl [iiii Ii ii I _q_

* [Norleucyl ,,,,], Iglycyl-

IgGlyl

Overosyl, leucyl-

1 l valyl

"Ipyrogluta-Il [, ,, ,," valyl-

  I I i | Myl l leucyl I *: IItyrosyl t [1 "CHO it, I, |

! ,, i, I h. I I,, -

2582308

  ## STR1 ## ## STR1 ## ## STR2 ## ## STR1 ## ## STR1 ## ## STR1 ## ## STR1 ## ## STR1 ## ## STR1 ##

I> 34'11 "I" I "I IIP I

  II-1, I-I, IC-NIIC, IOC, I, I, I, I, O, I, I I1 I, I, I, I, I, I, I, I, I, I, I, I, II, I, I, I, I, I, I, I, I, I, I, I, I, I, II, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I

H CH3-

t X n | t e4ts-j l00

i- || O 1 l 1 | H-C-

  I, I, I, I, I, I, I

I I I 1 I "I C3H7C-

  1, 2, 3, 3, 3, 3, 3, 3, 3, 4, 5, 8, 8

I J | I coZlX lilII | nC4H9C- - -

  |, I "I" IX I I I I I I I I I I I I I I I I I I I I I I II I

III I 1 1 I I I

  I, I, I, I, I, I, I, I IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

,, I ,, N (H1 "" O

o ,, _ toc o IIV nCoIó

31 2582308

II I I I

R R1 R2 R3 R R1 R1R2 IR3

  oc. 41'-c'C 2FH: MC2FHlLeucyl I I II I% II II: o 1. I II, II, II, II, II, II, II, II, II, II III JI V ', ,, triptophyl

I I 11

  ,, It ', p,: olyl I-, ITIV., IlIua "" ", seryl IIIvO ^ Co. I I I III

JIIGCo-

  I, IV Ispolybicyclo [I] ltrolyl [IV], [1], [(1)], [(1)), [(1)), [(1)), [(I)), [(I)) arginyl

I! I!

  &Numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; &numsp; ,, "ornithyl III l1 1 1, I! t, 1Valyl ,, I "- '> norleucyl I I I I I I

I 11X II I

32 2582308

I 11 I I 1 1

IR 'R lR' R

I, R12 1 3 I R2 3

1 1 _______11 11 1,1,1, _ I

1I III I I

  I.ro .. + CH2FH overcosyl d CH2FH leucyl-

  It is possible to use 1-methyl-1-valyl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl-1-yl.

[l "tyrosyl! [CHj-

I ,,> I I he ,, 1 ,, I

i C2H5O- -

! IoI O 2N5 1 Fi

I I I I 11 I%; ID I

  ## EQU1 ## ## STR1 ##

C-B3 3

I ,,, (I. _, I ,,,,, I ,,,% C.LcA, O-

  1211, I, II, II, II, II, II, II, II, II, III, II, II, II, II, II, IV, 41, II, II I, II, II, II, II, II, II, I, I, II, I, II, N, 11 ZItIin'MC - I ll I. 1l | a: "" "] 5 o I :::

In, 1,, II II IIIII XN-C-

I, I, I%,! 1 II ,,,, 3 I, 1S ';

0 | | g 1l {|, 0'r) [

II I I glycyl-

I I II II I I I

  . ,, - ILI, i. ## STR1 ## wherein: ## STR1 ##

,, I ,, i l ,,, cs \ -

33 2582308

I III I I

IR IR1R2R3 RIR1IR2 IR3

  I _ _ _ _ _ _ _ _ _ _ IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

zNt \ / oI CHF H \ 3 {CH F CH5 nC5H ,, C-

  "2 lt 2C2 I, I, I, I, I, III, I, III, I, II, III, III, III 1, 1, 1, 1, 1, 1, 1

I ', II, 11,

FIH

- II II o ..

  I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, II, etc. î "î" '! ii

I II.

nC HbC-

Itt., O 'IH /

0c HCo-

4 9 t I 4H9c

34 2582308

II I I l 11 I 1

R 1 R 1 R 1 R 1 R 1 R 1 R 1

>> 5 Sl l l ^ 3 ElCH 3 U31.

  [) ## STR2 ## ## STR2 ## ## STR2 ## 1 11I 1 1 1 1 "l" * Alanyl "l" goo

Valyl ,,, -

  i * î. l. i Inorleucyl1 I I 1 i! III. Leucyl-α, β, β-, β-phenylalanyl, Tyrosyl, triptophyl ## STR1 ## wherein: ## STR1 ## I i IL

I I. IlI I I ltiIc: 3W-

  In addition, the compounds of the present invention can be used in combination with the compounds of the present invention, such as arginyl, and aspartyl aspartylate, and the like.

258308

I I IIII1 1 I I I

IR R1 R2 R3 [R1 R1R2 R3

I 11 i I I

NH 0

  oko 0 0 1v ICH22H5.) "oiCH2C2H5C iOa

I1., I11I1.I4N (!

I x I

I I I I 1 1 I I I I e, / -

  III. III., III. T, T, I, I, I, valyl, I, I, Leucyl

C I 1CH1J1 11.O I

  II, I, I, I. 3), "", "" "" "" "" "" "" "" "" "" "" "" "" "" ""

i, | X R X E Rolsloil | X CH3-

  3C2H5O * | Itt; D [, etts- l- ,,] "[C-and 4>.% O] - I

I II! I II H-C

  I - I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, I, II, I, II, II, II, II, II, II, II, II, II, II, II, II, II, II, III He II II I I II II II II

36 2582308

* I IIII I I I RR1R2 R3l R R1R2IR3

J_______________ I11 JI I.I I

  ## STR2 ## | iJ 0nJI J J I <C

J J * JC4H C- "" "JSé1

  II l4C4H9J C lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll If, for example, the present invention is incorporated herein by reference, the disclosure in English is hereby incorporated by reference or reference of the disclosure. I lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

II JI J1 1JI I J

  i,., oJ IJ, J, X i, o! "I Leuc yl il nt il ii11 | JIJIJIJI, I, Iysyl.i IIIIIJ! 11-! ,, It hroy

IIJ 1 JJ J J J

J.J.J.JJJJ I

  J IO I J-o-Ji itj "t 'HERE t' hnylalayl

!! I II! J

I ,, J, e, peroyl

I {I

  IIJsoo-IryJ JJ J J J co-Il11II N JI IlttIl t n t, [i [threonyl 'JJiO JJ I! NOT A WORD

37 2582308

  ## STR1 ## wherein R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 arginyl "1" asparagyl aspartyl "" IIIlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll , 'norvalyl ,, 1 t4N; :: 7..c3 III Il IIII

I ornithyl I "" -

11 1 1I1 c--

t .-

"," Inorleucylt ,, glycyl-

glycyl-1-oncosyl

I llll l l I Ivalyl

niiil | Ipyrogluta- 'it' valyl-

  myl l I leucyl "'" t | I, tyrosyl t, I, o I * (| | l l - 2 5

CH U3otHl CHI? -

  I - II - CHd R-Ni CH3x, l

Ii I I I C2H50-- -

NOT

II I

Iiiiiiiiiiiiiiiiii

  ## STR1 ## wherein

I I MI (-

I II i

38 2582308

III I I1 1

  ## STR1 ## wherein

I JH-C-

g, tt | O \, E.4c - ,, JI J 3HC

I "CF WCU> z0 & I" ,, H C-

JI iII b He JI I iC3 H7c ,, 0 0

O :: R1 AJJ 1C34H97C-

  : i W JI J \ -CH! 1cii14L & 11 "" the he ,,

III I11.IOII- 49 C 1

  ",,,,,,,,,,, N-H-C-IOI'IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIO

I I 1 "-1I

  I! IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

I. I1 J ,, 1 1 I 1 I

J I I I JI 1 J 1 ,, J

t I nMfJCO -

  1, 1, 1, 1, 1, 1, 1, 1, 3, 4 Y, I,

39 2582308

I I I I I I I I

I R R1 R2 I R3 1 R R1 IR2 I R3

  ## STR2 ## ## STR1 ## ## STR1 ## ''. & nX N ,, triptophyl

I 11 1 1 1I 1

  11, 1, 1, 1, 3, 4, 5, 6, 7, 7, 9

I I I I I I I I I I

  ## STR1 ## wherein: ## STR5 ## arginylation, asparatyl tO-

I I I I A1 $ 11 I I I I I

I I I I

  wherein the present invention is described in detail in Figure 1, which is incorporated herein by reference. ll Alanyl ,,, ornithyl ,,, * Valyl I ,, "norleucyl", Leucyl ,, supersyl I ii I II II II

t: ,,, X lysyl, pyrogluta-

I __i ,. I I Ilmyl I I i i Il!

2582308

I I 1 11 1 I I

R 1 R 1 R 2 R 3 R IR 1 R 2 R 3

I I 1 11 1 1 1

  0l 0 1 e 59J1OC.- CH2F CH3 tyrosyl "rI CH2F CH3 2 3 2q 111 31 H3

I ,, f ",,, C2H50-f-

  IIIo 11 I 1 1 JI tl ,,> I II Iu.Ino l-eR 1

IIH2NH + CO- 11 "...." I "" COJL O

I I CH I I

titB o ji * 1N4-Ci It

C 1 H 1 CO 3

J (C Ir IN 'i.-c NM'

CH3 - 0

f :: A, i i i CF3) u-p i

## STR1 ##

  ! I 1Si ^ S "" "" "" "" "" "" "" "" "" "" "" "" "" "" "" "" "" "" "'' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '1' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' 1I1 '' '' '' '' , II, II, I, II, II, II. |

I! - II,

II, I, II

u ,, IensI ....- i, / iI I ,, 3 -

HAVE,,

Val I: ,, I ,, TI

I% II.H I

  1, 1, 1, 1, 1, 1, 1, 1, 1 II - * I o 1,1 1 I! H 1111

Ilycy -i-

I I I% It

"glycyI-

  _leucyl- "" "-valyl TT TT" vaLlyl- "" "

leucyl J ", -

I I I I I I I I

I RR1R2 R3 I R R1 R2 R3 I

  1, 1, 11, 11, 1, 1, 1, 1, 11, 11, 1, 1, 1 C 2 H 2 II, -K-dc OIl "IIII v" iIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII II.

II, CHC, I., C, 13.I.

I i 2 13 4l 91 i Rc-

  l In I CHl1 1 1 q I, o t ,, l ,,,,% ii

II 11C3H7L-. "3H" ó-

i I StI I I! II.tH P OI I! I

0!,> ^ 11 ,,, 1

  it,,,,,,,,,,,,,,,,,,,,,, ,, b,. (,., J ,,,, t ,,,

42 2582308

I I1 1 1 1

R 1 R 1 R 1 R 3 R R 1 R 2 R 3

J I I II I I I I I

I!

  a + CH2F C2R5 glycyl 11) (.Ci + h {CH2F C2H5 norvalyl ,,,, ,, Alanyllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll , n, l Leucyll, the overcosyl

I I I I J I I I

I ,, I ,, lysylI] l i

To |: ":: lyypyrogluta-

  ## STR2 ## ## STR2 ## ## STR1 ## ## STR1 ## ## STR1 ## 1 "I" I "

J J I IJJ I J I IN

  ## STR2 ## ## STR1 ## ## STR1 ## wherein ## STR1 ##

43 2582308

  I I 1 R 1 R 1 R 2 R 1 R 111213 IlI R2 R II i R 11 1

CH2 C25 CH2F CH5.

  I I I I I II I I I I I I I I I I I I I I I I I

'tXglycyl- Eit'i-C-

  I2H5IglycylI I - I - I - II -> lt - leucyl - tN - C <l - valylL "I - llll l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l If it is possible to use it, it will be necessary to use it as a method for its use. 11IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IlI II I o -] - - | i - 1 1 Co sZ I I n t Itrl l C ikn i i i cioe i 'f' - 'iI ó.7 "0o -i

II I O II II I

Ic% .soe- ilI I I 0

I I '' '' '' '-' '' I

0 H-C

O0 I C H C-

IH5b1, L-1 3 7 i J1 1

I, I

I HL.

I. I

II I I I I I

R R1 R2 R3 R 1 R R2 1 R3

I I.R1 [13 1

  ## EQU1 ## ## STR1 ## ## EQU1 ## ## STR1 ## ## STR2 ## ## STR2 ## l10 I l InIoC I Il Il 1! I! ## STR2 ## wherein

I I I

  I, I, I, P, I, I, P, I, I, I, P, I, I, P, I, I, P, I, I, P, I, P, I, I, P, I, I, P, I, I, P, I, I, P, I, I, I, I T 11, I, I, I, IC, I, I, I, A, threonyl

II I "S111 1 1 1I

  1-10, 1-10, 1-6, 1-6, 1-6, 1-6, 1-6, 1-4, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6, 1-6. I

., .. ,,, .. y.

2582308

1111 1 1 1 1 1

I I I I I! II I

R 1 R 1 R 2 R 3 R R R2 R 3

II I I IR I I I R3 I

  CYL 1 1 "1 1 2 2 1 2 1 2 1 2 1 2 3 4 5 6 7 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 'Asparagyl' t tlII I 'l' X 'aspartyl' l l s o

I I I I I I I

  ## STR1 ## ## '"11u1t1: 1

I I I I I I I I

"Pnorleucylt t glycyl-

* IIsucsyl leucyl-

cj "," surthosyl

$ JH O-L

  In addition, the following may be known as the following: ## STR2 ## ## STR11 ## "McClendia," ", -,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, I iii 1HNtCil III o I iii 110 ii Ii

46 2582308

  II I 1I 1 I I R 1 R1 RR2R3 I R R1 R2I R3 I

f CH 2FHIC31tS Of, t.v tCH FHjol (r-

  i 2 i 3 I I II IOC-I I I I I I I I I I I I I I I I I I I I I I I

III l 11 1 1 1 01H-C-

I ... It v 4 I II l I 1- I oCHgI

  I 'Iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii

  ## STR1 ## ## STR1 ## ## STR1 ##

I I I I 0 11 I 1 0

  I I t. '' - '' - '' '' '' '' '' - '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' - ''

I I S 4oc: - 11. * I 'I ii, i.

II I 11 I I I

  ## STR2 ## "|" I @ o ,, II ,. - ,. I, I, II, I, I, I, I, I, I, I, I, I, I, I, II IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIO The "It"

IfIfcc c-

  I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I

47 2582308

  ## STR1 ## ## STR1 ## ## STR1 ## ## STR1 ## ## STR2 ## ## STR2 ## ## STR1 ## ## STR1 ## ||. "" 1histidyl III ifo -i TT "îl" "1arginyl

II I 1 11, I I I

"" "asparagyl.

  CD-II is also available as isylmethylcellulose, isoleucyl

I IN O-C0 | I | II

LPJ 1 'f | "methionyl"

I I I I NI I IM

I I I 11 1 I I I

  "Algalyl" isoalkylsulphonylbenzylaminoalkylmethylcarbonylbenzylaminoalkylmethylbenzyloxyethylenediamine "III" * 1Itriptophylj3 dd: *. t! * ..! Chi

48 2582308

I I 11 1 I I 1

  IR RIR2 R3 R R1 R2 R3 t I IIII I I I I I L I C CH2? ## STR2 ## where ## STR2 ##

 I2F C III I CI

  ## STR1 ## ## STR1 ## ## STR1 ## ## STR1 ## 1211l111 {v> é%. O 1 l1 1 tE1-q1 i ', oN i! I I I I I Io I

"t and" Co5 f tX 'Xt $ qs -

  I, I, I, I, I, I, I, I,,,,,,,,,,,,,,,,,,,,,,, glycyl-n ""? *: 4

glycyll i 't - "

  l.Yeucyl-jITt valyl l O iI! III-1 "Xvalyl-" "TT-leucyl III ICoCIIlllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll "" i 'i

II II I I I .. I

492582308

II I I I I I I I

  I RIR1 IR2I R3 I R R1 R2 I R3 I I I I I I I I I I I

II I

  tz oe + H 2 CH? 3 (C- '% ^ 1 2F 1C2H5)

II II I-I I I

He, +, 0lltl8 | N i Iffi i f i

I I I I

1- _ ,,,,,. I I I I

  II-C-II I l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l

9WAO I I I I 11

0 I -

t 4i ,,

II C1.I "I" I Io

I I Icl3HC $ -I

, o |. "c.% - O_E" "" | clanl.

0 Co

"11 1 ,, 1, 1

  I l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l

I, I I I I I I I I I I - I-

  itI t. I - I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I

2582308

I II II II

R 1 R R 2 R 3 R 1 R R 2 R 3

  ## STR5 ## wherein R 1 is C 1 -C 2 F 2 C 1 H 5 C 1 H 5 C 1 H 5 C 1 H 5 C 1 H 5 C 1 H 5 C 1 H 5 C 1 H 5 C 1 H 5

I I 1, I 11 I I I1-

  Lysyl-pyroglutamine-1-methyl-l-l-l-l-l-l-l-l-l-l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l "I" II. II. II. CH "I

1 I "I" I "I" I "IH2N ± CO-

  I I I I I CH3 I | "I" "Ithrononyl" (II) II, IIIII, III, Iglutamyl II, III, II, II, II, II, II, II, II, II I "l (q) 9Q

I I I 1 11 I I I 0 I

  HASPARAGTIDYL "I" .CII. Arginyl III Iasparagyl "I" III. Aspartyl "I" Nu II "i" "I" Imethionyl I, II, I, II, II, II, II, II, II, II, II, II, II

51 2582308

I 1 I 11 1X 1 I I

  R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1 R 1

  > CH2F d021151 glycyl11Xo C H iEc.

  *. CH 2 2 cycycloacrylglycylbiphenylcellulose (I)

| | I | | IC2H5O-2 I C0

  11 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

I I I I I I I I I I I

  If I go go I I "I". IeC -,% 1,,,,,,,,,, II.

I II 011I I I I ICH I

  llllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll

0 H-C-

I I I Ir.e 111 1.1 l I i

I-II. I I I C H1-

  I Ill,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,? 4, 4, 7, 7, 9, 9

52 2582308

I I I I I I I I I

I R. R1 | R21 R3 RH RR1 R2 I R3 1

  ## EQU1 ## ll "cyl" ":" iCC- ". 1, II: 1l: 1l 3 (C2f C l II I1 I lHILIl I O lu 2H) CHCI "t" "glycyI tu f3O I" "Ai anyl" | '| <05 / <) 1 ",," YValyl I i I I I 1 1! ## STR2 ## ## STR2 ## ## STR2 ## II, II, I, I, I, I, I, I, I, I; 13 f "1" triptophyl nw <u 1 x prolyl

3, I ,, I ,, I -; .. 1C 11II I, 1 1!

  I he He lii I I! | 1serya1ryl lul Ce -S1-, I! I, I, I, I, I, I, I, I, I, I, I ":" | I "i:" h "" histidyl

,, I ,, I, I 1 C -I I,

  Arginyl-Asparagyl I, I I I I I I I I I I I

R A1 R2 R3 R2 R2 R3

  Aspartyl, CH 2 -CH 2 -CH 2 F

I HIS

  I, III, III, III, II, II, II, II, II, II

"i | tiTTinorvalyl" "" I

  Ornithylt, i - i. I I I

lIl Innarleucyl ,, i ,, glycyl-

glycyl

1, 1surcosyl ,, 1 1 1.leucyl-

l l Il 1 1 1 1valyl

"i" pyrogluta- ,, "" valyl-

  myl leucyl o I i 1 "tyrosyl 1 Ci 'i

I I I1 1 1 -

  I o C i 5

I! II C3 1 1 I

  ## EQU1 ## where: ## STR1 ## "II", -,,,,,,,,,,,,,,. ITT

54 2582308

II l 1i i 1

R R1 R2 R3 R R1 R2 R3

I I I I I I I I I I I I I I I I I II

"" -! "" "II I

II IC0oII I 0

I * I I I I I I I I I I I N I

  CMC ii 1, i 011 1 ,, 11 1 ,,,,,, i, I, I, I, I, II, O, I, I, I, I It is also possible to mention the products of formula (ID)

N / _ "C02R5

N NH _, R

H N2,

N N t A 4 -N (ND

R X1OR

2 3

  wherein R1, R2, R3 and R5 have the following values

R1 R2 R3 I R5

I I I I

  o 3 I I I I I I I I I I H +, c I CHZOC + I

I I. I I

  2 CH 2 CH 2 CH 2 CH 2 CH 2 0 + C 1 C 1 H 1 CH 2 O 3 +

I I I 11 I

II I I

and the product of formula:

N, -0O C02CH20C

H2XN '-_Co2F

CH -OC

258230B

  as well as the products of formula (IE): OR N N

H2NN /

  Wherein R is Co2CH2OMe Co Co2CHC., C 2 I CO2CH21Co; CO2CH2I +; 2 C2HIA +4

1HJ-N CHL.CH3 0

Me CHF2; > CO2CHO21t.

  Example 1 1- / 2- (pivaloyloxymethyl) tetrazol-5-yl I3- / 2- (2-alanine)

  zol-4-yl) 2-Mthoxylmino actamido / 4-methyl-2-oxoazitidine cis Isomer

Syn racqueque.

  Step A: 1- (2- (p-valoyloxymethyl) tetrazol-5-yl] -3- (2- (2-trylamino-thiazol-4-yl) -2-methoxyiminoacetamido] -4-methyl-2-oxoazetetidine cis

racemic isomer.

  50 mg of sodium hydride in 55% suspension in the oil are added

  to a solution of 660 mg of (3SR, 4RS) 3- / 2- / 2-tritylamino thiazol-4-yl / 2-

  Meethoxyimino acetamido / 4-methyl-1- (1H-tetrazol-5-yl) 2-azetidinone syn isomer prepared in Example 1c of European Patent Application 0.114. 128 in 10 cm3 of dimethylformamide. After evolution of hydrogen, it is stirred for a further 10 minutes at room temperature and then 0.16 cm 3 of chloromethyl pivalate is added. It is stirred for 16 hours and then again added, 0.02 cc of chloromethyl pivalate. The mixture is heated at 50.degree. C. for 3 hours, cooled to C., poured into about 50 cm.sup.3 of 0.1M solution of monosodium phosphate, extracted with ether, washed with water, dried over magnesium sulphate and dried under reduced pressure under reduced pressure. . About 300 mg of product is obtained. The mother liquors were re-extracted with methylene chloride, washed at

  water, dried over magnesium sulphate and distilled under reduced pressure.

  About 600 mg of product is obtained. We attach the two batches, chromato-

  on silica with an eluent: methylene chloride-acetone (9-1).

  500 mg of product is recovered which is purified on silica. The mixture is eluted with methylene chloride-ethyl acetate (8-2). We obtain

  290 mg of product after distillation of the solvents.

  Step B: 1- [2- (pivaloyloxymethyl) tetrazol-5-yl] -3- [2- (2-aminothiazol-4-yl)] -methoxyiminoacetamido] -4-methyl-2-oxoazetidine cis racemic isomer. A solution of 270 mg of product obtained in Stage A in 2 cm 3 of 66% aqueous formic acid is heated at 50 ° C. for 15 minutes. Allowed to warm to room temperature in 30 minutes, filter the insoluble, rinsed with 66% formic acid. The solvents are evaporated under reduced pressure, taken up in ethanol, dried under pressure and mg of product is obtained, which is taken up in 5 cm3 of ether. Scrape until solidification, stir 30 minutes, drain, wash with ether, dry under

  reduced pressure and obtains 125 mg of product. F = 145C

  NMR: CDCl3 ppm: 1.23 (s, 9H); 1.66 (d, 3H J = 7Hz); 3.98 (s, 3H); 4.72 (m, 1H); 5.78 (m, 3H, NH 2 and H at the 3 position); 6.44 (s, 2H) -;

6.78 (s, 1H); 8.48 (d, 1H J = 7Hz).

  Example 2: 1- [2- (pivaloyloxyethyl) tetrazol-5-yl] -3- (2- (2-aminothlazol-4-yl) -2 - [(1-carboxy-1-methylethoxy) imino] -acetamido] -ethyl-2-oxo

  azetidine cis Isomeere syn racqueque.

  Step A: 1/2-pivaloyloxy tetrazol-5-yl / 3- / 2- (2-tritylamino thiazol)

  4-yl) 2 - [(1-tert-butoxycarbonyl-1-methylethyloxy) imino] acetamido] -4-methyl

  2-oxo azetidine cis racemic isomer.

  65 mg of 55% sodium hydride in oil is added to a solution

  1 g of (3SR, 4RS) 3 - [2- (2-tritylamino-thiazol-4-yl) -2- (1-tert-butoxy) -2-

  carbonyl 1-methylethoxy) imino / acetyl / amino 4-methyl-1-tetrazol-5-yl) 2-azetidinone syn isomer prepared in Example 7 of European Patent Application 0 114 128 in 10 cm 3 of dimethylformamide. We keep 15

  minutes at room temperature, then add 0.2 cm3 of chloromethylpiva-

  late, stirred for 20 hours and then added 0.02 cm3 of chloromethylpivalate. It is heated at 50 ° C. overnight, poured into 50 cm3 of a 0.1M aqueous solution of monosodium phosphate and then extracted first with ether and then with methylene chloride. The organic phase is washed with water and then dried over magnesium sulphate and distilled under reduced pressure. 1.3 g is obtained

  of crude product which is chromatographed on silica (eluent: hexane

  ethyl acetate (7-3). The fraction Rf = 0.07, 550 mg is recovered.

  Step B: 1- [2- (pivaloyloxymethyl) tetrazol-5-yl] -3- [2- (2-aminothiazol-4-yl) -2 - [(1-carboxy-1-methylethoxy) imino] -acetamido] -4-methyl-2-oxo

  azetidine cis racemic isomer.

  A solution is maintained under a nitrogen atmosphere for 10 minutes.

  530 mg of the product obtained in Stage A in 1.5 cm3 of trifluoro-

  acetic. It is distilled under reduced pressure at 30 ° C. and a semi-solid residue is obtained, to which 3 cm3 of 66% formic acid is added. The mixture is kept at 50.degree. C. and allowed to come to room temperature in 30 minutes. The insoluble material is filtered off, washed with 66% formic acid and distilled to dryness under reduced pressure. It is taken twice with ethanol and dried

  under reduced pressure. We obtain 385 mg of product which is chromatographed

  silica (eluent: methylenemethanol-acetic acid 5-0.5). The interesting fraction is distilled, the residue is taken up in ether, the crystallization is initiated, the oil is wrung, washed and dried under pressure.

  scaled down. 180 mg of expected product is obtained. F = 2000C.

  NMR (CDCl3): 1.23 (s, 9H) (t-Bu); 4.72 (m, 1H) (H at position 4); 57 (m, 1H) (H at the 3 position); 6.42 (s, 2H) (CH 2 0 C); 6.88 (s, 1H)

(proton at 5 thiazole).

  Example 3: 1-12- (acetoxyethyl) titrazol-5-yl / 3- / 2- (2-minothlazol-4-)

  yl) 2 - ((1-carboxyethylithoxy) -Liro-acetamido-4-ethyl-2-oxo-azetidene

cls Racemic isomer.

  Stad A: 1- (2-acetoxymethyl) tetrazol-5-yl / 3- / 2- (2-tritylamino)

  thiazol-4-yl) 2 - [(1-tert-butoxycarbonyl-1-methylethoxy) -1mino / acetamido]

  Methyl 2-oxo azetidine cis racemic isomer.

  The procedure is as in Example 2 starting from 1.5 g of (3SR, 4RS) 3 -.

  (2-Trityl amino thiazol-4-yl) -2- (1-tertbutoxycarbonyl-1-methylethoxy) amino-acetyl-amino-4-methyl-1-tetrazol-5-yl) -2-azetidinone isomer syn in 15 cm3 of dry dimethylformamide, 100 mg of 55% sodium hydride in the oil and 250 mg of chloromethyl acetate. After chromatography on silica (eluent: hexane-ethyl acetate 5-5) and

  distillation 530 mg of expected product.

  Stage B: 1- / 2- (acetoxymethyl) tetrazol-5-yl / 3- / 2- (2-aminothiazol-4-)

  yl) 2 - [(1-carboxymethylethoxy) imino] acetamido] -4-methyl-2-oxoazetidine

cis racemic syn isomer.

  The procedure is as in Example 2 starting from 520 mg of product obtained in Stage A and 1.5 cm 3 of trifluoroacetic acid. After chromatography on silica (eluent: methylene chloride-methanol-acetic acid 95-5-0.5)

  and taken up in ether, 210 mg of expected product is obtained. Mp 240.degree.

  NMR-DMSO: ppm: 1.6 (C-CH 3); 4.61 (H at position 4) 6.52 (-CH 2 OC)

6.77 (proton in 5 thiazole).

  Example 4: 1/2-pivaloyloxyethyl tetrazol-5-yl / 3- [2- (2-aminothiazole)

  4-yl) 2 - ((1-carboxy-ethyl) oxy) Imrno / acetamido / 4-fluoro-2-yloxy

  azetetidine cis isomeric syn racemic.

  Step A: 1- [2-pivaloyloxymethyl] tetrazol-5-yl] -3- (2- (2-tritylamino-thiazol-4-yl) -2- (1-tert-butoxycarbonyl-1-methylethoxy) imino] -acetamido

  4-fluoromethyl 2-oxo azetidine cis racemic isomer.

  The procedure is as in Example 2 starting from 476 mg of (3RS, 4RS) 3 - [2- (2-tri-aminothiazol-4-yl) -2- (1-tert-butoxycarbonyl-1-methylethoxy) -imino-acetamido-4-fluoromethyl). 1-tetrazol-5-yl 2-azetidinone isomer syn

  prepared in Example 14 of the European application O 114 128. After chromatin

  tography on silica (eluent: methylene chloride-ethyl acetate

  95-5) 186 mg of expected product is recovered.

  Step B: 1 - / - 2-pivaloyloxymethyl tetrazol-5-yl / 3- / 2- (2-aminothiazol)

  4-yl) 2 - [(1-carboxy-1-methylethoxy) imino] acetamido] -4-fluoromethyloxo

  azetidine cis racemic isomer.

  The procedure is as in Example 2 starting from 170 mg of product obtained in Stage A and 0.75 cm3 of trifluoroacetic acid. After chromatography on silica (eluent: methylene-imethanol chloride-acetic acid 95-5-0.5),

  the product is taken up in 1,1,2-tri-chloroethane. We finally get

  100 mg of expected product. Fe 152 C.

  NMR (DMSO) ppm: 1.15 (s, 9H); 4.83 (m, 1H); 5.67 (m, 1H); 6.58 (s, 2H)

6.78 (s, 1H).

  Example 5: 1- [2- (pivaloyloxymethyl) tetrazol-5yl] -3- [2- (2-amtnothiazol)]

  4-yl) 2-methoxylmino acetamido / 4-fluoromethyl 2-oxo azetidine cis isomer

racemic syn.

  Step A: 1- (2-pivaloyloxymethyltetrazol-5-yl) -3- (2- (2-tritylamino-thiazol-4-yl) -2-methoxyiminoacetamido] -4-fluoromethyl-2-oxoazetidine cis

racemic isomer.

  The procedure is as in Example 2 starting from 800 mg of (3SR, 4SR) 3 - // 2-

  (Tritylamino thiazol-4-yl) 2-methoxyimino / acetamido / 4-fluoromethyl

  (1H-tetrazol-5-yl) 2-azetidinone prepared in Example 11 of European Patent Application 0 114 128. After chromatography on silica (eluent: methylene chloride-ethyl acetate 85-15), we obtain 429.6 mg of

expected product.

  Stage B: 1- [2- (pivaloyloxymethyl) tetrazol-5yl] -2- (2-aminothiazole)

  4-yl) 2-methoxyimino acetamido / 4-fluorormethyl 2-oxo azetidine cis isomer

racemic syn.

  The mixture is stirred for half an hour at 40 ° C., a mixture of 429.6 mg of product obtained in stage A in 12 cm3 of 66% formic acid. The resulting inyl carbinol is filtered and the filtrate is dried. The residue is chromatographed on silica (solvent: methylene chloride-acetone 7-3). We obtain

  199 mg of expected product. F (decomposition) = 128-130C.

  IR (CHCl 3): 258308 3490 cm -1: = C-NH 2 1795 cm -1: C = O (1 lactam) 1755 cm -1 1737 cm -1 (doublet) nonconjugated ester. RIMN (CDCl3) ppm: 1.23 and 1.27 (m, 9H); 4.08 (s, 3H); 4.54 to 5.65 (m complex, 3H, H4 and CH2F); 5.93 to 6.05 (m, 1H); 6.45 (s, 2H);

7.00 (s, 1H).

  Example 6: (3S, 4S) 1- [2- (pivaloyloxyMethyl) tetrazol-5-yl] -2- [2- (2-

  mIno thiazol-4-yl) 2- (1- (p-valoyloxyethoxycarbonyl) 1-methyl-yloxy)

  tMano / acltamido / 4-fluoromethyl 2-oxo azetidine cis 1semire syn.

  Step A: 2 - / (1- (tertbutoxycarbonyl) 1-methylethoxy) imino / 2- / 2-

  tritylamino thiazol-4-yl / phenylmethyl acetate isomer syn.

  28.58 g of 2 - [(1- (tertbutoxy) -acetate are mixed under an inert atmosphere.

  carbonyl) 1-methylethoxy-imino-2- [2-tritylaminothiazol-4-yl] -acetic acid in 250 cm3 of anhydrous dimethylformamide and 2.2 g of sodium hydride in oil. Stir 20 minutes at room temperature and then add 6 cm3 of benzyl bromide. Stir 15 hours at 50 ° C. The mixture is brought to dryness under reduced pressure and is taken up in ethyl ether. Sodium bromide precipitates. The ethereal solution is washed with water, decanted the organic phase, dried and then brought to dryness to obtain 33.8 g of expected product. After purification by mashing in isopropyl ether

  Mp = 128 ° C. R f = 0.4 (eluent: hexane-ethyl acetate 7-3).

  Stage B: 2- [2-amino thiazol-4-yl] - [(1-carboxy-1-methylbethoxy)]

  imino / phenylmethyl acetate isomer syn.

  A mixture of 33.8 g of product obtained in Stage A and 183 cm3 of trifluoroacetic acid is stirred for 45 minutes at room temperature. The mixture is brought to dryness under reduced pressure and the residue is taken up twice with 100 cm3 of acetonitrile. 330 cm3 of 66% formic acid are added and the mixture is stirred for 20 minutes at 400 ° C. It is allowed to cool and then filter the triphenylcarbinol obtained. The filtrate is concentrated to dryness under reduced pressure and taken up with 100 cm3 of water. Extracted with 200 cm3 of methylene chloride. The product crystallizes in the organic phase. It is isolated by filtration, rinsed with isopropyl ether, dried for 15 hours at 50.degree. C. and 14.4 g are obtained.

  pure product expected. F = 88 C. Rf = 0.57 (<luant: methyl chloride

ene-methanol 9-1).

  Stage C: 2- (tritylamino) thiazol-4-yl / 2 - [(1-carboxy-1-methylethoxy)]

  imino / phenylmethyl acetate isomer syn.

  Triethylamine (10.8 cc) was added to a suspension of 14.08 g of

61 2582308

* product obtained in Stage B in 220 cm3 of methylene chloride. After dissolution, 21.6 g of trityl chloride are added. Stirred 48 hours at room temperature. With vigorous stirring, 390 cm 3 of 0.1N hydrochloric acid and 390 cm 3 of monosodium phosphate M are added. The organic phase is decanted, washed with water and dried. 10 cm3 of methanol is added to the organic phase and then 28 g of silica. Stir strongly for 30 minutes. The silica is filtered, washed with 250 cm3 of a mixture of methylene chloride-methanol (9-1). The organic phase is dried, dry amnene and

  recrystallizes the residue in methylene chloride and the isopropyl ether

  lic. The 18 g of crystals obtained are impasted in ethyl ether to give 12.33 g of white crystals. Mp = 152 ° C. Rf = 0.5. (Eluent:

  methylene chloride-methanol 9-1).

  Stage D: 2- [2-tritylamino] thiazol-4-yl] -2 - [(1- (pivaloyloxymethoxy)]

  carbonyl / 1-methylethoxy) imino / phenylmethyl acetate syn isomer

  A mixture of 605.7 mg of product obtained in Stage C in 5 cm3 of dimethylformamide and 50 mg of 55% sodium hydride in oil is stirred for 10 minutes at room temperature. 150.6 mg of chloromethyl pivalate are then added. It is stirred for 15 hours at 50 ° C. It is poured into 50 cm 3 of 0.1 M sodium phosphate, extracted with ethyl ether, dried and evaporated to dryness to obtain 900 mg of an oil which is chromatographed on silica (eluent: methylene chloride-ethyl acetate 97.5-2.5). 500 mg of pure product is obtained. RF = 0.3 (<luant: methylene chloride-acetate

ethyl 97.5-2.5).

  Stage E: 2- (Tritylamino) thiazol-4-yl] -2- (pivaloyloxy)

  methoxycarbonyl) 1-methethylethoxy / imino / acetic isomer syn.

  Stirring is carried out for 30 minutes at 60 ° C. under bubbling with hydrogen, a mixture of 4 g of product obtained in Stage D, 250 cm 3 of 96% ethanol and 2 g of

  palladium on charcoal at 18%. The catalyst is filtered and rinsed with methanol. The filtrate is brought to dryness and gives 4 g of a yellow solid which is chromated.

  silica / eluent chromatography: methylene chloride-methanol (97-3) followed by methylene chloride-methanol (95-5) /. 2.1 g of product are obtained

  expected. Rf = 0.2 (eluent: methylene chloride-methanol 9-1).

  Stage F: (3S, 4S) 1- [1H-tetrazol-5-yl] -3- [2- (2-tritylamino) thiazole]

  yl) 2 - (1- (pivaloyloxymethoxycarbonyl) 1-methylethoxy) imino acetamido //

  4-fluoromethyl 2-oxo azetidine cis isomer syn.

  After dissolving 1.857 g of product obtained in Stage E in 25 cm3 of anhydrous acetone, 0.41 cm3 of triethylamine and 563 mg of tosyl chloride are added. Stirred 20 minutes and then rapidly added 700 mg of 3-amino-4-fluoroacetyl 1- (1H-tetrazol-5-yl) 2-azetidinone (3S, 4S), 12 cm3 of acetonitrile and 1.23 cm3 of triethylamine. We let 16 hours

62 2582308

  ambient temperature. 0.3 cm3 of concentrated acetic acid is then added and the reaction mixture is evaporated to near dryness.

  then taken up in 100 cm3 of ethyl acetate. The organic phase is washed

  with water, dry and evaporate to dryness. It is chromatographed on silica (eluent: 95-5 methylene chloride-methanol and 0.2% acetic acid and then methylene chloride-methanol 90-10 and 0.2% acetic acid). The oil obtained is taken up with 1,1,2-trichloroethane, dried, pasted in isopropyl ether and 1 g of crystals is obtained. F-145-150 C. Rf = 0, 46 (eluent:

  ethyl acetate-ethanol-water 7-2-1).

  Stage G: 3S, 4S-1- / 2- (pivaloyloxymethyl) tetrazol-5-yl / 3- / 2- (2-

  tritylamino thiazol-4-yl) 2- (1- (pivaloyloxymethoxycarbonyl) 1-methyl-

  ethoxy) imino / acetamido / 4-fluoromethyl 2-oxo azetidine cis isomer syn.

  A mixture of 650 mg of product obtained in Stage F, 8 cm 3 of dimethylformamide and 44 mg of hydride is stirred for 10 minutes at ambient temperature.

  of 55% sodium in the oil then add 135 mg of chlorobenzene pivalate

  methyl. The mixture is stirred for 5 hours at 50 ° C. and then 65 mg of chloromethyl pivalate are added. It is left for 16 hours at room temperature. After stirring for 6 hours at 50.degree. C., allow to return to ambient temperature and add mg of calcium carbonate. The mixture is stirred for half an hour at room temperature, 130 mg of chloromethyl pivalate are added and the mixture is then stirred for 15 hours at 50 ° C. The mixture is poured into 80 cm 3 of 0.1M monosodium phosphate.

  extracted with ethyl ether, dried and evaporated under reduced pressure.

  The oil obtained is chromatographed on silica (methylene chloride

  ethyl acetate 95-5). 200 mg of expected product is obtained.

  Stage H: (3S, 4S) 1- [2- (pivaloyloxymethyl) tetrazol-5-yl] -2- (2-)

  amino thiazol-4-yl) 2- (1- (pivaloyloxymethoxycarbonyl) 1-methylethoxy)

  imino / acetamido / 4-fluoromethyl 2-oxo azetidine cis isomer syn.

  It is stirred for 10 minutes at 40 ° C., 200 mg of product obtained in stage G in 3.5 cm 3 of 66% formic acid. Cooled to room temperature, filter triphenylcarbinol formed, washed with a few cm3 66% formic acid. The filtrate is collected, taken to dryness and taken up in acetone and 100% ethanol. We obtain 200 mg of oil that we

  chromatography on silica (eluent: methylene chloride-acetone 85-15).

  105 mg of expected product is obtained. F = 95-100 ° C. (D = -30 + 5)

(c = 0.1% in CH2 Cl2).

Analysis: C26H36FN909gS = 669.69 -

  Calculated: C% 46.63 H% 5.42 N% 18.82 Found: 46.4 5.5 18.3 3-Amino 4fluoromethyl 1- (1H-tetrazol-5-yl) 2-azetidinone 3S, 4S employed from stage F was prepared as indicated in example 11

  European application EP 0 114 128 from 3-amino-4-fluoro

  methyl 2-azetidinone 3S, 4S. This azetidinone was prepared as follows

  in the French patent application 84.00799 (in the form of hydrochloride).

  Stadec: 4-fluoromethyl-3-phthalimido-2-oxo-1- (1-phenylethyl) azetidine. 96.6 cm 3 of an aqueous solution of fluoroacetaldehyde hydrate 0.797 M / l, 100 cm 3 of a saturated aqueous solution of ice-cold sodium chloride and 9.8 cm 3 of R (+) phenylethylamine are stirred for 10 minutes. It is extracted with chloroform (192 cc), dried and cooled to -70 ° C. under an inert atmosphere. 16.8 g of chloride of phalimido acetyl in 77 cm 3 of chloroform and 7.8 g of triethylamine in 77 cm 3 of chloroform are introduced simultaneously in 15 minutes, while maintaining the temperature at -50 ° C + 2 ° C. Warmed to room temperature and allowed to stand for 1 hour. 46 cm3 of a 10% aqueous solution of sodium bicarbonate and then 77 cm3 of water are added. It is stirred vigorously, decanted, re-extracted with methylene chloride, the organic phase washed with water, dried and concentrated to dryness under reduced pressure. The residue is chromatographed on silica eluting with a benzene-acetone mixture (95-5). On- collects

  3 g of the 3S, 4S isomer and 2.5 g of the 3R, 4R isomer.

  PM analysis: 352.37 Calculated: C% 68.2 H% 4.86 N% 7.95 F% 5.40 Found (3S, 4S isomer): 68.4 4.9 8.0 5.3 Found ( isomer 3R, 4R): 67.1 4.8 7.4 5, 1 / </ D: isomer 3S, 4S = -29 + 1.5 (c = 1% CH 3 OH)

  isomer 3R, 4R = -50 + 1.5 (c = 1% CHCl3).

  Stadea: (3S, 4S) 4-fluoromethyl-3-phthalimido-2-oxo-1-azetidine.

  9.8 g of the isomer (3S, 4S) obtained previously in 150 cm 3 of acetonitrile and 96.5 cm 3 of water are boiled, then 15.9 g of ammonium peroxydisulfate are added in the course of 15 minutes. 39 cm3 of water and brought to 230 reflux for 1 hour 30 minutes. After cooling, the reaction mixture is saturated with sodium chloride, decanted, washed with water saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with 100 cm 3 of a solution containing 20 g of sodium thiosulfate per 100 cm 3 of water saturated with sodium chloride. The organic phase is dried and concentrated to dryness under reduced pressure, the residue is chromatographed on silica, eluted with a mixture of methylene chloride and 6-butylene acetate (7-25) and, after crystallization in ether, 2.33 g of

od3ut titend = F -1600C-162 C.

  Stage r: (35,4S) 4-fluoromethyl-3-amino-2-oxohydrochloride

642582308

  azetidine. 2.3 g of the product obtained in the stadium and 2.3 cm 3 of dioxane are added in the course of 20 minutes. 26 cm 3 of a solution prepared with 1 cm 3 of hydrazine hydrate supplemented with dioxane at 50 cm 3 are added. After 45 minutes at room temperature, 9.3 cm 3 of N hydrochloric acid are added. The mixture is stirred for 16 hours at room temperature under an inert atmosphere, concentrated to dryness under reduced pressure, taken up in anhydrous ethanol and then brought to dryness, dissolved. the residue in a minimum of methanol, add ethanol and again, concentrate to dryness. The residue is dissolved in a minimum of methanol under reflux, ice, drained, rinsed with cold methanol and then with ether. We

  gets in several streams 1.10 g of expected product. F> 220 C. (decomp).

  Analysis: C4H80N2ClF = 154.57 Calcd: C% 31.08 H% 5.22 N% 18.12 Cl% 22.24 FP 12.29 Found: 32.1 5.2 17.0 20.8 11.4

/, / D = -25.5 + 1 (c = 1% CH 3 OH).

Example 7

  Capsules corresponding to the formula were prepared: - Product of Example 6 ................................. ... 250 mg

  excipient q.s. one capsule completed at .................... 400 mg.

  PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

  In vitro Activity: A) Experimental Infection Escherichia Coli 250GR12 The action of the products of Examples 1, 5 and 6 was investigated on an experimental Escherichia coli infection of the mouse. We infested

  lots of ten male mice with an average weight of 22 g per intraperitoneal injection

  tonic of 0.5 cm3 of a 24-hour culture of the Escherichia coli 250GR12 strain of the Institut Pasteur diluted to 1 / 500th

by distilled water.

  Oral administration was given one hour and 5 hours after the injection.

determined amount of product.

  Mortality was noted for 8 days.

  The DP50 was calculated as the amount of product that protects 50% of the animals for each product. We obtain the following results expressed in

mg / kg: -

  Product of Example 1: DP50 2.4 mg / kg Product of Example 5: DP50 1.3 mg / kg

  Product of Example 6: DP5O 0.6 mg / kg.

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  B) Experimental Salmonella Typhimirum MZll Infection Similar conditions are used to test the product of

  Example 5 with the strain of Salmonella Typhimirum MZ11.

A DP50 of 1.55 mg / kg was obtained.

66 2582308

Claims (11)

  1.- The products of general formula (I): OR N R1 ()   R2d in which R represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl radical having at most 12 carbon atoms, an optionally substituted cycloalkyl radical having 3 to 8 carbon atoms or an acyl or aryl or aralkyl radical; , optionally substituted, R1 represents a hydrogen atom, an optionally substituted alkyl, alkenyl or alkynyl or thioalkyl radical having at most 12 carbon atoms, a free carboxy, esterified or salified radical, an aryl, acyl or carbamoyl radical; radicals being optionally substituted, or an azido radical R2d represents a tetrazolyl radical substituted with an organic radical capable, by cleavage, of giving back an acidic hydrogen, the corrugated elements mean that the radical OR may be in the syn or anti form and that the products can be in the cis or trans form or in the form of a cis-trans mixture, the products of formula (I) being or racemic or optically active form, as well as salts   products of formula (I) with bases and acids.   2. The products according to claim 1, of general formula (I '): / OR' NOT' R '(I') RN N H2N S NR 2d 67 2582308   in which R 'represents a hydrogen atom or an alkyl radical, linear or branched having from 1 to 6 carbon atoms, or a cycloalkyl radical having from 3 to 6 carbon atoms, said radicals being optionally substituted by one or more of radicals selected from the group consisting of free, esterified or salified carboxy radicals, amino, mono or dialkylamino, aryl, halogen, nitrile, CONHSO2R5 in which R5 represents an optionally substituted alkyl, aryl or amino radical or R 'represents an alkylcarbonyl radical or arylcarbonyl or a phenyl radical, R'1 represents a hydrogen atom or an alkyl radical, optionally substituted by one or more radicals chosen from the group formed by the halogen, azido, hydroxyl, mercapto, aryl, amino and nitrile radicals, optionally oxidized allylthio or arylthio, acyl, acyloxy, acylamino, aralkylcarbonyl, carbamoyloxy, alkyl or dialkylcarbamoyloxy or R'1 represents an alkene radical nyl or alkynyl optionally substituted with a phenyl radical or with one or more halogen atoms, or R'1 represents a thioalkyl radical optionally substituted by carbamoyl, or R'1 represents a phenyl radical optionally substituted by halogen, CF3, amino, hydroxy , alkyl or alkoxy or R'I represents an esterified carboxy radical, a carbamoyl radical or an azido radical, R2d represents a tetrazolyl radical, substituted with an organic radical capable, by cleavage, of giving back an acidic hydrogen, the products having isomerism syn, the wavy line means that the products can be in the cis or trans form, or in the form of a cis-trans mixture, the products of formula (I ') being in racemic or optically active form and the salts products from   formula (I ') with bases and acids.   3.- The products of general formula (I ') as described in claim   cation 2 in which R 'represents a hydrogen atom, a methyl, phenyl, difluoromethyl, I-methyl-carboxyethyl, free or esterified, cyanomethyl, carboxymethyl, free or esterified radical,   (methylsulfonyl) carbamoylmethyl, 1-carboxy 1-cyclopropyl; 1-carboxy 1-   cyclobutyl, 1-carboxy-1-cyclopentyl, 1-carboxy-1-cyclohexyl, said carboxy 3 being optionally esterified or salified,   R'I represents an atony of hydrogen, a methyl radical, fl uoro-   methyl, trifluoromethyl, ethoxycarbonyl, carbamoyl; A2d represents a 1H-tetrazol-5-yl radical substituted with a radical PH, -O-: in which A is a hydrogen atom or an alkyl radical having 1 to 4 atoms. of carbon and B represents a radical   alkyl or alkoxy having 1 to 4 carbon atoms.   4.- The products according to claim 1 of general formula (I ") RO-R " N? .N ..._. R 19 2 ASXF   Embedded image in which R "represents a hydrogen atom, a methyl radical, a -C-O 2 H radical or a -C-CoO 2 CH-OCB" radical in which Wherein R 1 and R 3 are each a hydrogen atom or a methyl radical or together with the carbon atom to which they are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; A "represents a hydrogen atom or a methyl radical; B" represents a radical   methyl or tert-butyl; R "1 represents a methyl or fluorinated radical   methyl; A 'represents a hydrogen atom or a methyl radical; B '   represents a methyl or tert-butyl radical.   5.- Any one of the products of formula (I) whose names follow:   2,2-dimethylpropanoate of / 5- [3 - [(2-amino-4-thiazolyl)] (methoxy)   imino) acetyl / amino / 2-oxo-4-methyl-1-azetidinyl / 2H-tetrazol-2-yl / methyl syn, cis-racemic or optically active isomer; - / 5- [3 - [(2-Amino-4-thiazolyl) -2-carboxy] -2-dimethylpropanoate   1-methylethoxy) imino / acetyl / amino / 4-methyl-2-oxo-1-azetidinyl / 2H-   tetrazol-2-yl / methyl syn, racemic or optically active isomer 2 - [(2-acetyloxymethyl) tetrazol-5-yl] -4-methyl-2-oxoazetidin-3-yl] amino] -1- (2-aminothiazol-4-yl) 2 - [(2-acetyloxymethyl) tetrazol-5-yl] -4-methyl-2-oxo-azetidin-3-yl] 2-oxoethylidene / amino / oxy / 2-methylpropanol;   - / 5- [3 - [(2-Amino-4-thiazolyl) -2-dimethylpropanoate (methoxy)   imino) acetyl / amino / 4- (fluoromethyl) -2-oxo-1-azetidinyl / 2H-tetrazol-   2-yl / methyl syn, racemic or optically active isomer 2 - [[1- (2-Aminothiazol-4-yl) 2 -] - [[1 - [(2,2-dimethyl-1-oxo-propoxy) -methyl] -tetrazol-5-yl] -acetate - (fluoromethyl) 2-oxo-azetidin-3-yl-amino-2-oxo-ethylidene / amino-oxy-2-methyl-propanol isomer syn, cis-racemic or optically active; 2 - [[1- (2-Amino-4-thiazolyl) -2- [1- [2 - [(2,2-dimethyl-1-oxo-propoxy)] 69 2582308   methyl / 2H-tetrazol-5-yl / 4- (fluoromethyl) 2-oxo-3-azetidinyl / amino / 2-   oxoethylidene / amino / oxy / 2-methyl propanoate (2,2-dimethyl-1-oxo)   propoxy) methyl isis cis, racemic or optically active.   6. A process for the preparation of the products of general formula (I) as defined in claim 1, characterized in that a product of formula (II) NHRb-CONH R1p II) N ORp 2 cis or trans is treated, racemic or optically active compound, wherein Rb represents a hydrogen atom or a group protecting the amino radical, Rp represents a protecting group of the hydroxyl radical or Rp represents R, R having the meaning indicated in claim 1 or Rp represents a radical; Wherein the reactive functions are protected, R1p represents either R1, R1 having the meaning indicated in claim 1 or R1p represents the substituent R1 in which the reactive functions are protected and R2 represents a tetrazolyl radical by a reactive derivative of a radical organic material susceptible, by cleavage, to give back an acidic hydrogen and then subjects the product obtained, if necessary and if desired, to any of the reagents in any order: a) cleavage by hydrolysis, hydrogenolysis or thiourea action of the protecting group or groups that may represent Rb and Rp or comprise Rp and R1p; b) esterification or salification of the carboxy or sulfo radicals that may comprise the radicals Rp and R1p; c) salification with an acid of the amino group (s); d) doubling of the molecule to obtain an optically active.   7. A process according to claim 6 for the preparation of the products of formula (I ") as defined in claim 4, characterized in that a product of formula (II ') is treated. 2582308   Wherein R "1 has the meaning indicated in claim 4, Rb has the meaning indicated in claim 6, R" ia the values of R "indicated in claim 4 where R" i represents a radical -uf COE in which Ro and R'o have the meaning indicated in Ro R'o claim 4 and E represents an ester group easily cleavable by a derivative of formula R7- H-OC-B 'wherein R7 represents an A' 0 remainder capable of reacting with the tetrazolyl ring and then subjects the product obtained if necessary and if desired to any of the following reactions, in any order: a) cleavage by acid hydrolysis, hydrogenolysis or by the action of the thiourea of the Rb group or the group E; b) salification with an acid of the amino radical;   c) splitting the molecule to obtain an optically active product.   8.- As medicaments, the products corresponding to formula (I) as defined in claim 1 and their pharmaceutically acceptable salts acceptable.   9.- As medicaments, the products corresponding to the formula (I ') as defined in claim 2 and their pharmaceutically acceptable salts acceptable.   10.- As medicinal products, the products defined in one of the claims 4 or 5.   11.- Pharmaceutical compositions containing, as active ingredient,   at least one drug according to one of claims 8 to 10.