BE738131A - Certain alpha-amino bicyclic beta-lactam carboxylic - Google Patents

Abstract

Cpds. and their derivs. such as esters and N-acylates; and salts thereof. (I) and (II) and their esters and N-acylates are active antibacterial agents. Some of the amines may be converted into fluosilicic acid salts, which are moth-proofing agents, or into aminothiocyanateformaldehyde condensation products of use as pickling inhibitors.

Description

  

   <Desc / Clms Page number 1>
 



  Antibacterial agents.



   The present invention relates to novel synthetic compounds which are useful as antibacterial agents, as dietary supplements for animal feed, as agents for the treatment of mastitis in cattle and as therapeutic agents for poultry and animals, as well as for the treatment of mastitis in livestock. human in the treatment of infectious diseases caused by Gram-positive or Gram-negative bacteria and it relates more especially to the mono-N-acylated derivatives of the two amino acids corresponding to the formulas:

 <Desc / Clms Page number 2>

 
 EMI2.1
 as well as the salts of these derivatives.



   Many chemical agents, for example already phenol itself, have been used in one way or another as antibacterial agents. The large number of compounds used proves that it is necessary to have other agents having various pharmacological, pharmaceutical and bacteriological properties. The object of the invention is to provide new antibacterial agents.



   For the purposes of the invention, use is made of compounds of formula:
 EMI2.2
 where R1 represents an acylamino radical and their pharmaceutically acceptable non-toxic salts, leads to compounds of formula:
 EMI2.3
 where R1 represents an acylamino radical, and their pharmaceutically acceptable non-toxic salts.



   The preferred compounds of the invention are those of formula:

 <Desc / Clms Page number 3>

 
 EMI3.1
 where R4 is chosen from the class formed by the atoms of hydrogen, fluorine, chlorine, bromine and iodine and by the amino, carbobenzoxyamino, phenyl, hydroxyl, lower alkanoyloxy and lower alkoxy radicals, X is chosen from the a class formed by the oxygen atom and the sulfur atom, R5 and R6 are each selected from the class formed by the hydrogen atone and by

 <Desc / Clms Page number 4>

 
 EMI4.1
 phenyl, benzyl, phenethylated @ lower alkyl radicals, 7 phenyl radicals, 'benzyl3 phenethyl and lower alkyl, R represents a lower alkyl radical, R8 and R9 are each chosen from the class formed by lower alkyl radicals lower alkylthio,

     benzylthio, cyclohexyl, cyclopentyl,
 EMI4.2
 cycloheptyl, benzyl, phenethyl, phenyl, propyl, furole, thienyl, naphthyl and R10 is chosen from the class formed by the radicals lower alkylamino, di (lower alkyl) amj cycloalkylamino of 3 to 7 carbon atoms inclusive, all3
 EMI4.3
 mino, diallylamino, phenyl lower alkylamino, rorphol3no = lower alkylmorpholino, di (lower alkyl) morpholino, may pholino-lower alkylamino, pyrrolidino 'a3kylp; lower rrolidino, di (lower alkyl) pyrrolidino, N, N-hexamethylenimino, pipiperidino, lower , di (lower alkyl piperidino, 1,2, s6-têtrahyd oprridino, N-al1Q {lower piperazino, T-phenylpiperazïno9 T - (ml3yy1 .nferlL: r) (lower alkyl piperazino, N- (lower alkyl) -di - (alkyl i.ér3:

  x = jp3.pérazīnc fzzrfurylamino, tetralaydroiurmryiaaino, N- (lower alkyl) "Nfurfurylamino, iv-a? kyl-Van ...? a and lower aleoxyanilino, z1 Z2 and Z3 are each chosen from the class formed by radicals lower alkyl and R11 is chosen from the class formed by lower alkyl, lower cycloalkyl naphthyl, benzyl, phenethyl and / ', \ - C and R represents a monovalent radical chosen wall those of formula
R1 $ R1 $ R1
 EMI4.4
 R2 / 'R2
R2
R3 where R1 R2 and R are each selected from the class formed by hydrogen, chlorine, bromine and iodine atoms and by trifluoromethyl, phenyl, lower alkyl and alkox radicals

 <Desc / Clms Page number 5>

 lower,

     It has been understood, however, that only one of the symbols R can represent a phenyl radical and w represents a drilling radical
 EMI5.1
 as well as their acceptable non-toxic salts.



   The invention is thus subject to the subject in the form of pharmaceutically acceptable non-toxic salts and in the form of these free acids, the acids corresponding to the following different formulas :.
 EMI5.2
 where R represents a lower alkyl radical
 EMI5.3
 where R1 represents a lower alkyl radical and R2 and R3 are each selected from the class forced by hydrogen and chlorine atoms;
 EMI5.4
 where R1 represents a lower alkyl radical and R2 represents a

 <Desc / Clms Page number 6>

 hydrogen or chlorine atom;
 EMI6.1
 where R represents a lower alkyl radical
 EMI6.2
 where R represents a lower alkyl radical;

   
 EMI6.3
 where R represents a lower alkyl radical;
 EMI6.4
 where R represents a lower alkyl radical;
 EMI6.5
 where R1 represents a lower alkyl radical and R2 and R3 are -

 <Desc / Clms Page number 7>

 each chosen from the class formed by the atoms of hydrogen and chlorine;
 EMI7.1
 where R1 represents a lower alkyl radical and R2 represents a hydrogen or chlorine atom;
 EMI7.2
 where R represents a lower alkyl radical;
 EMI7.3
 where R represents a lower alkyl radical;
 EMI7.4
 where R represents a lower alkyl radical.



   Another subject of the invention is the process for pre-

 <Desc / Clms Page number 8>

 parry an antibacterial agent according to which one reacts a compound of formula: '
 EMI8.1
 or a salt thereof with an organic monocarboxylic acid chloride or one of its functional equivalents and also the process for preparing an antibacterial agent according to which a compound of the formula is reacted:
 EMI8.2
 or one of its salts with an organic monocarboxylic acid chloride or one of its functional equivalents.



   According to a preferred embodiment; The subject of the invention is the process for preparing an antibacterial agent according to which a compound of formula is reacted:
 EMI8.3
 or a salt thereof with organic monocarboxy- acid chloride

 <Desc / Clms Page number 9>

 ic of formula-.
 EMI9.1
 where R4 is chosen from the class formed by hydrogen and fluorine atoms;

   chlorine, bromine and iodine and by amino radicals,
 EMI9.2
 carbobenzoxyanino, phery, hydroxyl, lower alkanoyloxy and lower alkoxy} X is selected from the class formed by the oxygen atom and the sulfur atom, R5 and are each selected from the class formed by the atom of hydrogen and by the phenyl, benzyl, phenethyl and lower alkyl radicals, R7 represents a lower alkyl radical., R8 and R9 are chosen

 <Desc / Clms Page number 10>

 each from the class formed by lower alkyl radicals lower alkylthio, benzylthio, cyclohexyl, cyclopentyl, cycloheptyl, benzyl, phenethyl, phenylpropyl, furyl, thienyl, naphthyl and - * -, R10 is chosen from the class formed by lower alkylamino radicals,

   di (lower alkyl) amino, cycloalkylamino of 3 to 7 carbon atoms inclusive, allyla- mino, diallylamino, lower phenylalkylamino, morpholino, lower alkylmorpholino, di (lower alkyl) morpholino, mor- pholino lower alkylamino, pyrrolidino, lower alkylpyrrolindino di ( lower alkyl) pyrrolidino, N, N-hexamethylene imino, piperidino, lower alkylpiperidino, di (lower alkyl) piperidino, 1,2,5,6-tetrahydrophridino N-lower alkylpiperazino, N-phenylpiperazino, N- (lower alkyl ) (lower alkyl) piperazino, N- (lower alkyl) -di- (lower alkyl) piperazino, furfuryamino tetraphdorfurfurylamino N-lower alkyl) -N- furfurylamino, N-alkyl-N-anilino and lower alkoxyanilino, Z1,

   Z2 and z3 are each selected from the class formed by lower alkyl radicals and R11 is selected from the class formed by lower alkyl, lower cycloalkyl, naphthyl, benzyl, phenethyl and # - C and # - represents a monovalent radical chosen from those of formula
 EMI10.1
 where R1, R2 and R3 are each chosen from the class formed by the atoms of hydrogen, chlorine, bromine and iodine and by the trifluormethyl phenyl lower alkyl and lower alkoxy radicals, it being understood however that only one of the symbols
R can represent a phenyl radical,

  or with a functional equivalent of such an acid chloride

 <Desc / Clms Page number 11>

 
For the purposes of the present invention, the term "lower alkyl radicals" means aliphatic hydrocarbon radicals in a straight or branched chain of 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl amyl hexyl radicals. 2-ethylhexyl, heptyl, decyl, etc. In a similar way., In the description of another radical such as lower alkoxy radical, the alkyl part of this radical - which satisfies the definition above from lower alkyl radicals.



   The functional equivalents of the above acid chlorides serving as an acylating agent for a primary amino radical are in particular the corresponding bromides, acid anhydrides, including mixed anhydrides and in particular mixed anhydrides. formed with stronger acids, such as lower aliphatic monoesters of carbonic acid, alkylsulfonic and arylsulfonic acids, and more markedly hindered acids such as diphenylacetic acid.



  Additionally, an acid azide or an active ester or thioester (e.g. with p-nitrophenol, 2,4-dinitrophenol; thiophenol or thioacetic acid) can be used, but alternatively the free acid itself can be condensed with 6-aminopenicillianic acid -after the free acid has been reacted with N.N'-dimethylchlroforminium chloride see UK Patent No. 1,008,170 and Novak and Wdichet, Experientia XXI / 6, 360 (19657 or alternatively by means of enzymes or an NW-carbonyldimidazole or an N, N'-carbonylditriazole ± see South African patent application No. 63,2684, a carbodiimide especially N.N ' -dicyclohexylcarbondiimide, N,

  N'-diisopropylcarbodiimide or N-cyclohexyl-N '- (2-morpholinoethyl)

 <Desc / Clms Page number 12>

 carbodiimide, see Sheehan and Hess J. Am Chem. Soc. 77 1067, 1955 or an alkynylamine ± see R. Buijle and H.G. Viehe,
Angew. Chem. International Edition 3 page 582 1964 or a ketene imine ± -see C. L. Stevens and M.E Monk J. Am Chem.



   Soc. 80, page 4065 1958 or an isoxazolium salt Ç see
R.B. Woodward, R.A. Olofson and H, Mayer J. Am Chem. Soc. 83 page 1010 1961 Another equivalent of the acid chloride is the corresponding azolide, that is to say an amide of the corresponding acid whose nitrogen atom of the amide function is part of a pentagonal ring quasi aromatic containing at least
2-nitrogen atoms, that is to say an imidazole, pyrazole, triazole, benzimidazole, benzotriazole ring including the corresponding substituted derivatives.

   For example, generally, to prepare an azolide, an N, N-carbonyl diimidazole is reacted with a carboxylic acid in equimolecular proportions at room temperature in tetrahydrofuran, chloroform, dimethylformamide or other inert solvent. analog, to obtain the carboxylic acid imidazolide in a practically quantitative manner with evolution of carbon dioxide and 1 mole of imidazole. Dicaroxylic acids give diimidazolides the by-product, namely imidazole, precipitates and can be separated and imidazolide can be isolated, but this is not essential. The methods of carrying out these reactions in order to obtain a pencillin as well as the methods of isolating the penicillins formed are conventional.



   Pharmaceutically acceptable non-toxic salts are in particular salts of metals, such as sodium, potassium, ¯ calcium and aluminum, ammonium salt and substituted ammonium salts, such as salts of amines such as trialkylamines, including triethylamine, procalne, dibenzylamine,

 <Desc / Clms Page number 13>

 
 EMI13.1
 -benzyl-beta-phenethylamine, 1-eph, enamine, NN-diben2yl- - ethylendiamine dehydroabiethylamine, N, N'-bis-dehydro-
 EMI13.2
 abiethylethylenediamine, N- (lower alkyl) piperidines, such as N-ethylpiperidine,

  and other amines which have been used for the formation of salts with benzylpenicillin, the subject of the invention is especially atibacterial agents prepared by the above acylation process by means of organic monocaboxylic acids or else their chlorides. acids or other equivalents which have already been used for 3'acylation of 6-aminopenicillanic acid as described for example in the patents of the United States of America
 EMI13.3
 na2.91.95; 2,951,839; 2,985,648i 2,996-501; 3,007,920; 3,025,290; 3,028,379; 3.a35.o-7; 3,040,032; 3.c40.033; 3,041,332; 3,041,333; 3,043,831; 3.os3.831; z..575; 3,071-576; 3,079.30 ?; 3,079,306; 3,080,356; 3.082-204 * -; 3,093-547; 3,093,633; 3,116,285; 3.117..9; 3,118,877; 3,120,512; 3.120.?13; 3,120,511 +; - 3,127-394; 3,140,282; 3,142,673; 3.14? .2Y7g 3-I? -. G6 ': -; 3,180,863;

   3,198-804; 3.202.6? 3; 3,202,654; 3,202-655; 3,210,337; 3,157,639; 3,134,767; 3,132,136; in British Patents Nos. 874,414; 874,416; c875.5z6; 876,662; 877,120; 877,323; 8 ^ .; 3; 878,233; 880,042; 880.yod; 882,335; 888,110; 888,552; 889,066; 889,069; 889,070; 889,168; 889,231;
 EMI13.4
 890.201; 891-174; 891,279; 891-586; 891,777; 891,938; 893.?18; &g-.2-7;89Y.457;894,460;896,072;899.199;900,666;902,703;903-785;goli-.576;905-778;906,383; 9G8.?8 ?; 9 --.- 19; 916,097; 916,204; 916.205; 916,488; 918,169; 920,176; 920,177,920,300;
 EMI13.5
 921.?13; 922.278; 924,037; 925,281; 931.56 ?;

   932,644; 938.066; 938,321; 939,708; 940,488; 943,608; 944,417; in norabreiix Belgian patents, for example n? 93,222; 595-171; 597-859; 602,494; 603,703; 609.o3g; . 6.1b.; -. 9; 617,187 and in South African patent applications, eg No. 60/2882; 6o73C? 7; 6D / 37t8i -61I16t.9; R61 / 27-1; 62/54; 62 / - + 920; 63/1612 and 63.2423.

 <Desc / Clms Page number 14>

 



   When the acylamino radical of the compounds of the invention also contains a very basic radical, for example a primary amino radical, as in the case of the preferred compounds corresponding to the formulas:
 EMI14.1
 where has the meaning given to it above (and R1
R2 and R3 in # are preferably hydrogen atoms), the products are amphoteric and normally exist as zwiterrions, but may exist as acid addition salts, for example those formed with non-toxic, pharmaceutically acceptable organic acids, such as acetic acid, citric acid, succinic acid, ascorbic acid etc. or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, l phosphoric acid etc.



   In the methods of the invention, it is also necessary to use as final reagents "the compound of formula:
 EMI14.2
 or a salt thereof formed with acids and bases, as well as

 <Desc / Clms Page number 15>

 
 EMI15.1
 compose it formula: ............ compound N - CH - #, .....- S'c / CH3 3 t N ,,, '-cx G3' C9 '3 É00a or one of its salts formed with acids and bases.



   As illustrated below, these final reagents are
 EMI15.2
 prepared, for example, either by hydrogenolysis of the compound of formula: 0 CH CH 0 - il NH - CH ## ÇH s M1- - 652 llj / f fï2 c- N CH 0- c C61I; - or by hydrogenolysis of the compound of formula:
 EMI15.3
      either by decomposition with an acid of the compound of formula
 EMI15.4
 of the compound of formula:
 EMI15.5
 
These esters are in turn prepared in general as indicated below by reaction with suitable esters of compounds of the formulas:

   

 <Desc / Clms Page number 16>

 
 EMI16.1
 where x represents a radial. primary amino blocked as understood in peptite synthesis for example a radical
 EMI16.2
 phthalimido, tritylainoc-nitrophénflxyacétaio where an equivalent radical as specified below, o-ni trophé..nylsu1: f'ényla.mino, carbobenzyloxyamino, formylaminocucarbo-t-butyloxyanino. We thus obtain compounds of formulas
 EMI16.3
   where X has the meaning above and R represents a labile ester radical capable of being easily removed, for example by hydrogenolysis or by decomposition in an acidic medium.



   These esters can then be converted into final reactants by removing the radical represented by R and by converting the radical represented by X to a free amino radical, either consecutively or simultaneously. When the blocked amino group represented by X is a phthalimido group, this is converted to the primary amino group by treatment with hydrazine hydrate in dioxane at about room temperature in at least 12 hours. When X re-
 EMI16.4
 has a carbobenzyloxyamino radical, the blocked amino radical is transformed into a primary amino radical by catalytic hydrogenation with formation of the product, namely 3-amino-4mercapto-2-azetidinone.

   When the blocked amino radical is

 <Desc / Clms Page number 17>

 
 EMI17.1
 a radical forn.y.am3no, carbo - t bztyloayaina or o - nitrophéMIsulfénylam1w.-, it is converted into a primary amino radical, either by reaction with anhydrous hydrogen chloride in a solvent which does not give out protons, such as benzene or methylene chloride, either
 EMI17.2
 by reaction with 1 - trifluoroacetic acid. The compound tritylasiine can also be converted into a compound comprising a free amino radical by addition of p-toluenesulfonic acid monohydrate to an acetone solution with formation of the amine
 EMI17.3
 free primary in the form of its p-tolueneslnlfonate, see B. K.

   Koe, Nature 195 page 1200 (1963). Furthermore, when the blocked amino group is a tritylamino or carbo-t-butyl oxyamino group the final two reactions are carried out in a single step by means of stronger acid for longer times and, if desired, higher temperatures. high.



   When the blocked amino radical represented by X
 EMI17.4
 is an o-nitrophenoxyaeetamido radical, this is converted to the primary amino radical for the formation of 3-amino-4-mercapto-2-azetidinone either a) by catalytic hydrogenation (for example in water at room temperature at 30% palladium on diatomaceous earth), then by storing the mixture in an acidic medium (for example in water acidified to a pH of 2 by means of 20% hydrochloric acid at about 10 C for at least 20 minutes or at 25 for at least 24 hours), or b) by adding the blocked compound '(for example in an amount of 7 millimoles) in cold water (for example in an amount of 30 ml) rapidly (by example in 1 to 3 minutes) to 5% palladium on charcoal (for example 0.05 g)

   suspended in a cold solution of KBH4 (for example in an amount of 14 millimoles) in water (for example in an amount of 70 ml).

 <Desc / Clms Page number 18>

 



    - Compounds of formula
 EMI18.1
 are also new and details and various methods relating to their preparation are given under the title: Preparation of the starting compounds ". In particular, the methods described herein for the conversion of the radical represented by X into a free amino radical are also applicable according to the requirements. required for the synthesis of the compounds of the invention.



   The invention is illustrated without being limited by the following examples.

 <Desc / Clms Page number 19>

 



  EXAMPLE 1
 EMI19.1
 

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 EMI20.1
 (} 11!: 1!, N: t! '1 aia: Gfl1. "Ll: plague 3 aeureE ua! 3f,. Of 1. g of 3-pht6lmid: t - :.': 'w? R? .a. '-:;.,. a'é - ;; e 6.e â'm:'? 3 ,?. â, n. ;; n 4qvivaAent: Ùoe pj, rimu #,% c: / '= b; # iij.71e # 1 <ù; s. "at" L'2 equivalent: ¯ pvl "U \ J1' - '; 6 se oessyle eè.' ;. â, 5;! l3 El {1 'colueae then refroiëit 1 & -, i' ù j% and. G -,,; le,. ,,;. ±% '., f .- - - Ë'c.9 pressure p # ii s efrQidit ::: . ===. = -; #,>: .w. 0S Z08 reduced yressio pous- get? àn 17'siJa constitutes pax eu y, "r # ^ w 3-penazy <c? rbaJzrJ gte ae 'benzJ, 10 gross Ó¯e. formuls (II) the nomenclature being in accordance with eelle'Se Sheehan and collborat6uxs $.



  ; r t 3 lUE: - cre # o Soe. ... é4 3392-3293 j? ;; 3) kar 1; frcg: 'enù.1 - :) Tse en .., r =.% s.?.6 the! - :: 13: IC! .U . ia9 ± ù3-6 = (II) in free acid XL Ecyen d .ln .; "") catsiyseur ra 'A.,. f, â .r a. G3. e 'S9 ml d' B.Cê'ta: 9 d #t; l:,: lG ,, jjn¯me ..o as C ^ f c'a.¯ v 5: Ç '.. 2: TI. S pr. ï: <o-, 's 4, ". Â ^ t .., o.; 1' 2 hydrogen of 3 kg / b3" to mp, .. rC)! 1 '?'! 'e there. 'Gtr:;' - 3r:; :( l, j.'e: 2H. "I2aJ .., n; G", After 8J ..: tm: r.nat ::: ton: ttI ca "C2. l.yser: r p-? rf 17 tra>; ion, the solvent is removed by distillation under vacuum to obtain ';.:' G1 "The residue resides in the e-si = evv>. 3": C.¯ ë SN {e 1 "oi * naX <=.

   (III) 0? mix the rfsl of the f ds'e '9 i (III) f3 with lm t'S wedge of hydrazine hydrate in 20 tsi of iiic; -tane and the mr :: 1 J2'; G j is left to stand: egiiàn.1 il hours at 1 c "i:! P.i'2; il: e 2m: ';' 18nteQ by acidification a '.? Ecyen of chloride c.: .. 1.1" tú:!: C2e! 13 OH precipitates at, e iJhÉalhz atI'aZààe GZ ± 'C12 & penaTc ..,. - - ... "1-iF" tà $ T "= the phta.ihydrazide 1f ': 1çCi separates by filtration: .- ¯ ... 6 =: .. eb- + =, e # ii-r .. '' G: e2 - C3 filtrat tme solution diacid 6 - aE! Inc - p & -najaylcai'bcxy-- '' r: 8: .I: r cc:; a: '1e i'il tra tm solution Q ') is 9.l1inf.) - liCtUe de ±) r [; 1ule (> 1) q1: ..: J0-1 directly uses I0U the reaction> "' 1.?i: and G qD. we can if we want 3rd rec.ueJ..¯.! :; ..., 2. J.

   S Ga. "(. Ue so? ± de. Ex. S stal?, In that one per; t". 1 '. <> .., amphoteric solid Cl "lS': 2..l¯1.n qu Ol? pe11 (:: e (:::: 'AS! 2.l¯) sel. âC ... Ler: 1en by dissolution 4a1; a 3 s' av. A. minia-ma' g W: e . "? then addition r":! niit: ':! I; ¯j r6, alsrr-'ar: c. ## nrenir = 5 for ic 4 5: ... ¯ .. F - .. v :: e 6r. -, "'I1"' ";." i
 EMI20.2
 isoelectric.
 EMI20.3
 



  , 4 the f.oltj.03 decides 6-a3i.c - 3-pennMylcar ':; oxyliqe.' on add three equivaleffts r :. r ": Îll0" .. "io1" 'T' de -¯) 1 ";.: eC'o" ", ....;:. !!" "6 '"' '77.' '': ::. 3'ë '' three equivalents 1 r "'xi, j, y ô,., <Zvv olrt,:; z: ir l :? a C;). 0.8 -5p14Jl0J = :;' 7-- ôZ ±. iL S eQUìaèll0S '"& ôtÂe ± -éL,: .Fmi, é ¯ L ce = tb j 5À, 1'" OE% ± s.LL =% "" ';: 1 .- =.-ô; j

 <Desc / Clms Page number 21>

   3-acetamido-penamylcarboxylic of formula (V) which is preferably isolated in the form of the crystalline potassium salt ¯ by extracting the acid from an acidic aqueous solution (for example at pH 2) in diethyl ether, by evaporating off the ether and adding at least one equivalent of a solution of potassium 2-ethylhexanoate (eg 0.373 g / ml) in anhydrous n-butanol.

   The potassium salt which forms and usually precipitates in the crystalline state is collected by filtration and is then found to be a powerful antibacterial agent against both Gram-positive and Gram-negative bacteria, since it is bactericidal. in concentrations below 1000 ppm



  EXAMPLE 2 -
 EMI21.1
 

 <Desc / Clms Page number 22>

 
 EMI22.1
 (VIII) A mixture of
 EMI22.2
 1 g of 3-carbobenzyloxyamino --- mercapto-2-azetidinoae of formula (VI) and one equivalent of benzyl pyruvate in 50 ml of toluene, then the mixture is cooled and concentrated under reduced pressure to obtain a residue consisting of by the 6-car-
 EMI22.3
 benzyl bobenzyloxyamino-3-pena.ylcarboxylate of formula (VII).



   The residue of formula (VII) is subjected to hydrogenolysis by means of a palladium catalyst in 20 ml of ethyl acetate as solvent under a hydrogen pressure of 3.5 kg / cm2 on a manometer at temperature. ambient. After separation of the catalyst by filtration, the solvent is removed by vacuum distillation to obtain a residue, formed by 6-amino-3- acid.
 EMI22.4
 penasiylearboxylic acid of formula (IV) which is used directly for the following reaction or which is isolated as a crystalline ampho tère solid, if desired.



   A solution of phenylacetyl chloride (6 g) in anhydrous chloroform is added over 10 minutes to a mixture.
 EMI22.5
 6 g of 6-arino-3-penaylcarbaxylic acid and 13% of triethylaine in 150 ml of anhydrous chlcrofcre. The mixture was stirred for 2 hours, then filtered and the residue stirred with 1N hydrochloric acid to obtain an aqueous phase having a pH of 2, then only the chloroform layer was retained, which was washed with water. water, which is filtered and stirred with a dilute aqueous solution of sodium hydroxide to make

 <Desc / Clms Page number 23>

 pass the product into the aqueous phase,

   after which the aqueous phase is collected and rapidly extracted with diethyl ether and its pH adjusted to 2 with hydrochloric acid.



  After two extractions with ether, the ethereal phase containing the 6-phenylacetamido -3-penanyl carboxylic acid of formula (VIII) is dried and at least one equivalent of a solution of potassium 2-ethylhexancate (by Example at 0.373 g / ml in anhydrous n-butanol The precipitate of potassium salt which forms is collected by filtration and which is found to be a powerful antibacterial agent against both Gram-positive and Gram-negative bacteria. , since it is bactericidal at concentrations below 800 ppm



    EXAMPLE 3 -
 EMI23.1
 

 <Desc / Clms Page number 24>

 
 EMI24.1
 
By applying the process of Example 2, equimolecular amounts of the c posed of formula VI and of formula IX are heated under reflux in toluene to give the compound of formula X which is converted by hydrogenolysis to a compound of formula XI. Acylation of the compound of formula XI gives the potent antibacterial ager of formula XII.



  EXAMPLE 4
 EMI24.2
 Decomposition in acidic medium

 <Desc / Clms Page number 25>

 
 EMI25.1
 
By applying the methods of Examples 2 and 3, equimolecular amounts of the compounds of formula (XIII) and (XIV) are reacted to obtain the compound of formula (XV) which is converted into a compound of formula (XI) by decomposition in an acidic medium, for example by reaction with anhydrous hydrogen chloride in a solvent which does not give off protons, such as benzene or methylene chloride, or else by reaction with trifluoroacetic acid.



    EXAMPLE? -
 EMI25.2
 

 <Desc / Clms Page number 26>

 
 EMI26.1
 
By applying the methods of Examples 2, 3 and 4, equimolecular amounts of the compounds of formula (XVI) and (XVII) are reacted to obtain the compound of formula (XVIII) which is converted into a compound of formula (XI) by decomposition in an acidic medium, for example by reaction with anhydrous hydrogen chloride in a solvent which does not give off protons, such as benzene or methylene chloride, or else by reaction with trifluoroacetic acid. The compound of formula (XI) obtained in the form of triethylamine salt is converted into an antibacterial agent of formula (XIX) by reaction - with- said phenoxyacetyl chloride.

   

 <Desc / Clms Page number 27>

 EXAMPLE 6 -
 EMI27.1
 
A mixture of 1 g of
 EMI27.2
 3-phthalimido - / \ '-2-azetidinone of formula (XX) and an equivalent of benzyl-mercaptopyruvate until the reaction is complete, then the mixture is cooled and concentrated under reduced pressure to obtain as crude residue benzyl 6-phthalimido-3-penamylcarboxylate of formula (II) which is then treated according to the method of Example 1 EXAMPLE 7 -
 EMI27.3
 

 <Desc / Clms Page number 28>

 
 EMI28.1
 A mixture of 1 g of
 EMI28.2
 3-carbbbenZYloxyamtno-61,4-2-azetidinone of formula (XXI) and one equivalent of benzyl p-mercaptopyruvate until the reaction is complete,

   then the mixture is cooled and concentrated under reduced pressure to obtain a resi
 EMI28.3
 formed by crude benzyl 6-carbobenzyloxyanino-3-penanylcarboxylate of formula (VII) which is then treated by the process of Example 2.



  EXAMPLE 8 -
 EMI28.4
 By applying the method of Example 6, we make
 EMI28.5
 react equiisolecular amounts of the cosposed compounds of formula (XXII) ¯and (XXIII) to obtain the compound of formula XV which then transforms by the process of Example 4

 <Desc / Clms Page number 29>

 EXAMPLE 9
 EMI29.1
 
Equimolecular amounts of the compounds of formulas (XXIV) and (XXV) are refluxed in benzene to obtain the compound of formula (XVIII) which is then modified by treating it as in Example 5, that is to say ie by decomposition in an acid medium, then acylation.



  EXAMPLE 10 -
 EMI29.2
 

 <Desc / Clms Page number 30>

 
Equimolecular amounts of the compounds of formulas (VI) and (XXVI) are heated in toluene until the reaction is complete. After having removed the solvent by vacuum distillation, the compound of formula (VII) is obtained as residue. The compound of formula (VII) is then converted to the cyclic amino acid of formula IV by the method of Example 2.



   The compound of formula (XXVI) is also replaced in this process by the reagents corresponding to the following formulas:
 EMI30.1
 The last two reagents being present in their -tautomeric forms. EXAMPLE II -
 EMI30.2
 

 <Desc / Clms Page number 31>

 
 EMI31.1
 
By reacting the compounds of formulas (IV) and
XI respectively with an equimolecular amount of diazomethane in the usual manner for esterification, the compounds of formulas (XXVII) and (XXVIII) respectively are obtained, both of which are basic amines which can be converted into moth repellants by reaction with fluosilicic acid as described in U.S. Patents 1,915,334 and 2,075,359,

   but that can also be converted into condensation products of formaldehyde and thiocyanates of amines suitable as pickling inhibitors when the reaction is carried out according to US Pat. Nos. 2,425, 320 and 2,606,115.



   The compounds of formulas (IV) and (XI) are themselves antibacterial agents active at concentrations of 5 mg / m. or even at lower concentrations, solutions of these concentrations being useful, for example, for the disinfection of glassware and surgical instruments.

 <Desc / Clms Page number 32>

 



  Preparation of the starting compounds
The starting compounds are those of formula
 EMI32.1
 where X represents a "blocked" primary amino radical as understood in peptide synthesis, for example a phthalimido, tritylamino, o-nitrophenoxyacetamido radical. o-nitrohphenylsulfenylamino, carbobenzyloxyamino, formylamino, or carbo-t-butyloxyamino Among. these compounds, the one carrying a free primary amino radical is sufficiently basic to form acid addition salts
The diacid addition salts can be formed according to conventional techniques.

   For example, 3-amino-4-mercapto-2-azetidinone can be reacted with at least a stoichiometric amount of the suitable acid, and depending on the nature of the solvent used, the desired salt will separate spontaneously or can be precipitated. by adding a solvent in which this salt is insoluble. An acid addition salt can be formed by means of acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, benzoic acid, p-toluenesulfonqieu acid, salicylic acid, acetic acid, propionic acid, tartaric acid) citric acid, succinic acid and so on. Acid addition salts are useful intermediates for the purification of the free base and any acid forming an acid addition salt is suitable.

   Examples of suitable acids include picric acid, oxalic acid and Ó-naphthoqiue acid.
A number of methods are known for the syn-!

 <Desc / Clms Page number 33>

 thesis of these compounds. These methods are summarized below in the usual way, X having the meaning given to it above.



   Process # 1
 EMI33.1
   ± 'This starting compound is obtained from the suitable 6-amino penicillanic acid "blocked" at the functional level.
 EMI33.2
 6-auimo, following the Drocedes described by Sheehan et al., J. in, Chen. Soc. 3, FL.33-5Y69 (5 December 196) and c-¯¯3 eu. . s radiss-l phthalimidoconne also specified by Y. G. Perron et. '$ Jâ. c.a'rôi.3waw; S: 1 0, J. 14ed. soc. Z, 483-487 (195Y¯g1
 EMI33.3
 

 <Desc / Clms Page number 34>

 
 EMI34.1
 
At the final stage, when the blocked amino radical represented by X is a phthalimido radical, this is transformed into the primary amino radical by treatment with hydrazine hydrate in dioxane at about room temperature. for at least 12 hours.

   In the case where X represents a carbobenzyloxyamino radical, this is converted into a primary amino radical by catalytic hydrogenation giving the desired product, namely 3-amino-4-mercapto-2-azetidinone When the blocked amino radical is a radical formylamino, carbo-t-butyloxy-amino or o-nitrophenylsulfenylamio this is transformed into primary amino radical, either by reaction with anhydrous hydrogen chloride in a solvent which does not give protons, such as benzene or methylene chloride ,

   either by reaction with trifluoroacetic acid The tritylaminated compound can be

 <Desc / Clms Page number 35>

 also converted to a compound bearing the free amine radical by treatment with a. acetonic solution of p-toluenesulfonic acid monohydrate so that the free primary amino radical appears as its p-toluenesulfonate, see
B.K, Koe, Nature, 195,1200 (1963). Further, when the blocked amino group is a tritylamino to carbo-t-butyloxyamino group, the final two reactions are carried out in one stage using a stronger acid for longer times and if desired at temperatures. higher.



   When the blocked amino radical represented by X is an o-nitrophenoxyacetamido radical, the latter is converted into a primary amino radical with formation of 3-amino-4-mercapto-2-azetidinone, or a) by catalytic hydrogenation (for example in water at room temperature by means of 30% palladium on diatomaceous earth), then by storing the mixture in an acidic medium (for example in water acidified to a pH of 2 by means of acid 20% hydrochloric acid at about 10 C for at least 20 minutes or at 25 C for at least 24 hours), or b) by addition of the blocked compound (e.g. 7 mil limoles) in cold water, (e.g. 30 ml) quickly, for example in 1 to 3 minutes, with 5% palladium on charcoal (for example 0.05 g),

   suspended in a cold solution of KBH4 (eg 14 millimoles) in water, (eg 70 ml).



  Method n
 EMI35.1
   1) Anhydrous NH3 in t-butanol or dioxane> 2) Anhydrous NH4SH or H2S in the same solvents

 <Desc / Clms Page number 36>

 
 EMI36.1
 HCl anhydrous in CH2Cl2 or benzene at 0-25 c
 EMI36.2
 N1N'-Dicyclohexvlcarbodiinide> at room temperature in benzene or dioxane
 EMI36.3
 
In this case, X has the meaning given to it above and the final transformation of the blocked amino group to a primary amino group is carried out as above for the various meanings that X can have.



  Process # 3
 EMI36.4
 HCOOH in CH2Cl2
 EMI36.5
 Ambient temperature (EC3) 3C-O-K in anhydrous tolune-dioxane
 EMI36.6
 

 <Desc / Clms Page number 37>

 
In this case, X has the meaning given to it above, but preferably represents a phthalimido radical or.
 EMI37.1
 carbobenzyloxyamino. Method n 4 .-. - .. -
 EMI37.2
 KMnO4 in dilute acetic acid buffered to pH 6 Strong base, for example OH C2H5O or weak base, for example C2H5) 3N, preferably in an anhydrous medium in a solvent which does not give protons As above, X has the meaning that it gives has already been assigned.



  Process # 5
 EMI37.3
 
As above, x has the meaning assigned to it. The starting compounds for this one-stage reaction are prepared as described by Sheehan et al., J. Am
 EMI37.4
 Chem. 'Soc. 8 ", pages 5468 and 5169 (1965) in the case of the compound in the formula 'of which X represents a phthalimide radical with oxidation of the sulfur atom to a sulfone radical.

 <Desc / Clms Page number 38>

 according to conventional techniques, preferably on 6-aminopenicillanic acid, the amino function of which at position 6 is blocked, see US Pat. No. 3,197,466 and Chow et al. J. Org. Chem 27 pp. 1381-1383 (1962) as well as references cited therein.



  Process # 6
 EMI38.1
 

 <Desc / Clms Page number 39>

 
 EMI39.1
 
In this case, 2 has the meaning given to it above and the final conversion of the blocked amino group to a primary amino group is carried out as specified above for the various meanings that X can have.



   The examples below illustrate the preparation of these starting compounds. All the temperatures are given, in C. The infrared spectra are recorded using a Perkin-Elmer recording spectrophotometer, model 237. The nuclear magnetic resonance spectra whose peaks are indicated in units # TMS = 10 are recorded at using the Varian Associates n A-60 spectrometer.

 <Desc / Clms Page number 40>

 



  EXAMPLE A
 EMI40.1
 
 EMI40.2
 tade A - 3-PhtaliB! ido-4-fl '-formyl-1' -nethylethylthio) -2-azeti-
 EMI40.3
 dinone o 1) S i3. 1 / N - J CH-CH JC, 1 C Il Bzz - CH - N = C = 0 oa go, 7% in CC12 3 hours at room temperature N - CH --- cH .......- 8, - '-c (CH 3 (II) w. 1 s 1 C = O 1 CH3 Il Il 1ili - fro
2,2-Dimethyl-6-phthali-3-penamyl isocyanate of formula (I) is dissolved by Y.G. Perron et al., J. Med.
 EMI40.4
 



  Chem., 2., 483 (196lr-)] C2i G) in 150 ml of methyl chloride and the solution is added dropwise over about 20 minutes with stirring at room temperature to a solution of 2 g
 EMI40.5
 9; formic acid ;; 7 ;; in 150 garlic of methylene chloride. After continuing to stir at room temperature for a total of 3 hours, the reaction mixture was washed with 30 ml of water, followed by washing. the organic phase is separated, it is dried over

 <Desc / Clms Page number 41>

 of anhydrous MgSO4, filtered and evaporated in vacuo to obtain 1.85 g of white crystals. These crystals are suspended in 70 ml of methylene chloride and 0.3 g of an insoluble substance melting at 210 is separated by filtration.



   The methylene chloride is evaporated in vacuo from the remaining filtered solution to obtain the desired product.
 EMI41.1
 namely 3-phthalimido-t- (l'-formyl-l'-methylethylthio) -2-azetid none, in the form of white crystals (platelets) in an amount of. 1.5 g, PF118-120 The infrared spectrum is perfectly compatible with formula (II) and is identical to the infrared absorption spectrum of the hemisolvate of the compound of formula (II) prepared as described by Sheehan and Brandt, J . Am Chem Soc., ±%. Pages 5468-5469 1965
The IR spectrum of the compound of formula (II) CH2Cl2 3400 NH 2810 and 2700 (CH aldehyde), 1790 and 1720 (CO from phthalimido), 1720 CO from aldehyde), 1770 (carbonyl from ss-lactam and 1385 cm- 1 (gem-dimethyl).

   By recrystallization from a mixture of benzene and ligroin, crystals melting at 112-117 and having an infrared spectrum identical (especially the characteristic region) to that of the hemisolvate of formula (II) are obtained. By recrystallization from a mixture of methylene chloride and petroleum ether, a product is obtained which melts at 112-114 The mixed melting point with the hemisolvate of the compound.
 EMI41.2
 se of formula (II) (m.p. 111-119) is 100-10 ".



  Analysis of the compound of formula (II) calculated for Clj Ii1R20pS: C, 6e59; ff '4.11-0; 3 Se 10.00% Found C 56.17; H, 4.68 S, 9.60%
Chromatography of the crude aldehyde on a silica gel column eluting with methylene chloride-acetone gives white crystals melting at 115-117 whose spectrum

 <Desc / Clms Page number 42>

 . infrared is characteristic of the compound of formula (II).
 EMI42.1
 



  Stage B - -Phtaliraido-t- l'-carboxv-l'-meth leth Zthio -2-azetidinone
 EMI42.2
 
The aldehyde ± of formula (II) prepared as above is oxidized in acetone by means of the reagent of Jores J. Chem Soc., Page 2548 1953 according to the technique described by Sheehan
 EMI42.3
 and Brandt, J. Am. fhem. Soc. 87, pages 5-6-t69 (1965).



  The infrared absorption spectrum of this product, namely 3-phthalimido-4- (1'-carboxy-l'-methylethylthio) -2 azetidinone, includes all necessary carboxylic vibrations. res (broad band a little weak at 3400-3300 l + '0 and 1250 th in addition to the vibrations of the carbonyl radical of phthaloyl and ss lactam
 EMI42.4
 Stage C - ± = ¯jàlimido-lF- (1'-¯earbaziào-1'-nethylethylthio) -2-aétj¯ = dinone

 <Desc / Clms Page number 43>

 
 EMI43.1
 
The above acid of formula (III) is subjected to Bergnann degradation under the usual conditions to obtain the crystalline azide of formula (IV) which is easily identified by its absorption in the infrared at 2160 cm-1
So;

   triethylamine (distilled over potassium hydroxide; 0.67 g; 6.6 millimoles) is added to a solution
 EMI43.2
 stirred 3-phthalirido --- ('l'-carboxy-l'-raethylethylthio) -2-azetidi none of formula (III) (2.20 g; 6.6 nillimoles) in 25 ml of tetrahydrofuran (distilled over hydroxide of potassium), then the resulting yellow solution was cooled to -15 ° C. To this stirred solution was added dropwise over 30 minutes a solution of ethyl chloroformate (0.72 g; 6.6 millimoles in 0.4 ml of tetrahydrofuran A colorless precipitate is obtained and the resulting mixture is stirred for 1 hour at -10.

   At the end

 <Desc / Clms Page number 44>

 
 EMI44.1
 After this time, we add a solution of ao, 3 eo szfîiam (iC -., 4-3 6.6 millimoles) in 35! 1- si d ea? .z 9a: a e; 3 ons, .a zieutes and stirring the mixture of rep.ctis-n at -10 for 1 addition. The rsastioD Bêlacge eDsuite is diluted to 23 'El with water while stirring at 100. As no C Cls Ï * 1 li52a7; lo-ç2 produced, the yolk is extracted at the hub of' crol. 3 fractions of 100 MI of zethylene chlorides gu> vn 1 at lanr iso; t = "aveo 100 vi i '. ?? â2 then qu-'OR secbe on u sr. #: t # .le of . # Ta ..? ¯'3 a == ùù = 1 ± zt ;, after which 4. : 'the resulting aëlaBge and a 7 "" pD? e 1'3 filtrate under pressure' a3 to obtain crystals of 3-altalL'13. 3- ('a? À7GC' 'è:' ;. h ''.> Thyih '?.: U i asetidinona of formula 3' (1, 'i5 gas 80%), M.P. 100-12C.



  The infrared spectrum shows bands at 33? 0 em7l (NF-) e -05 cm (aromatic EC), 2160 c 1 (azide), 1790 1720 cm (dhthaloyl carbonyl radicals), 1770 CE (p-lactam carbonyl radical) ), 1385 ca (geg-dré thyle).



  Stage D - 3 - Fhta3ido - (l 'océ2r.ato-l' -: eth-3étl? 2thioi-2azetidinone
 EMI44.2
 

 <Desc / Clms Page number 45>

 
The above formula IV is stored overnight in a vacuum desiccator to convert it to the isocyanate of formula V which is easily identified by its characteristic absorption in the infrared 2270 cm-1 This conversion is also carried out by heating under reflux in methylene chloride or tetrahydrofuran, but even brief heating under reflux in benzene or toluene gives a product not showing 1-absorption due to the isocyanate radical in the infrared.



   The conversion of the azide of formula (IV) into isocyanate does not always reach its end, as can be determined by observing the band due to the isocyanate radical in the infrared at 2270 cm-1 By storage under reduced pressure for 2 weeks, or heating under reflux in chloride. methylene, we always obtain a mixture of compounds of formulas
IV and V
Stage E - 3-phthal im ido -4-mercapt-2-azetidione
 EMI45.1
 

 <Desc / Clms Page number 46>

 
 EMI46.1
 A mixture of iorzul (moi) azide and the isocyanate of formula (V) 0.2 g) is dissolved in 15 µl of methylene chloride and the solution is added dropwise under.

   stirring and in a nitrogen atmosphere for 15 minutes with 90.7% formic acid (45 mg or approximately two equivalents) in 15 ml of methylene chloride. The reaction mixture is stirred at room temperature under a nitrogen atmosphere for 2 hours. The infrared spectrum of the reaction mixture indicates that the band due to the isocyanate group (2270 cm-1 and that due to the azide group (2160 cm-1 are significantly influenced. Then the reaction is continued for a total of 4 hours, at dull of which the infrared spectrum of the reaction mixture indicates the complete absence of the bands due to the azide radical and to the isocyanate radical.



   The reaction mixture was washed with 30 ml of water, the organic layer was dried over anhydrous sodium sulfate, or the resulting mixture was filtered and the filtrate was evaporated under reduced pressure to obtain colorless crystals of 3-.
 EMI46.2
 phthalimido-t.-mercapto-2-azetidinone of formula (VI) z-g, 65% overall yield based on the acid); P.F. 130-131 It should be noted that all these manipulations are carried out in a nitrogen atmosphere. A qualitative test for the detection of sulfur gives a positive result. The nuclear magnetic resonance spectrum in deuterochloroform gives the results
 EMI46.3
 the following states in T units: a singlet at 2.2 (phthaloyy); a wider 4.2 proton band of p-lactam).



   Infrared spectrum CH2Cl2 3350 low NH), 3050 (aromatic CH radical), 2950 (CH radical 2580 (weak SH radical), 1790 and 1720 (phthaloyl CO radical 1770 (p-lactam radical, medium).
 EMI46.4
 



  Analysis: Calculated for ClH81203S: C, 53, 21; H, 3t20; If, II, 28% Found C, 53 D .; H, 4.26; If, 10.99.

 <Desc / Clms Page number 47>

 



  EXAMPLE B
 EMI47.1
 
 EMI47.2
 -Arino --- uercano-2-azetidznflne. This product is prepared by reacting 3-phtaiimido-4-mercapto-2-azetidinone with one equivalent of hydrazine hydrate in dioxane at room temperature for 12 hours, then adding hydrogen chloride to precipitate. phthalhydrazide which is separated by filtration. By lyophilization of the filtrate,
 EMI47.3
 solid 3-amino-4-mercapto-2-azetidinone hydrochloride is obtained, - EXAMPLE C -
 EMI47.4
 
 EMI47.5
 -TritYlamino - mercanto-2-azetidinone. This compound is prepared by replacing in the operations of Example A the isocyanate of 2a2-dimethyl2-6-phthalizido-3-penaayl by an equal weight of 2,2-dimethyl isocyanate. 1-6-tritylamino-3 -pônaizyie prepared as described by Perron et al, J.

   Med Chem, 7 pages 483-487 (1964) (processes for the preparation of intermediate acid azides are also given in the Belgian patent
 EMI47.6
 n 65Ç.s97) from 6-trityla.nopénîcillaâq acid see S? .ce; a et al., J. Am. Chem. Share 84 page 2983 1962
As a variant, the conversion of the isocyanate to aldehyde is carried out according to the technique described in Step A of Example N below.

 <Desc / Clms Page number 48>

 EXEMPLED
 EMI48.1
 
 EMI48.2
 -Amino-r-mercanto-2-aztidinone.

   1 mg of 3-tritylamino-4-mercapto-2-azetidinone is dissolved in 20 ml of isopropyl alcohol and 5 ml of 1N hydrochloric acid is added thereto.After storage at room temperature for 2 hours, the reaction mixture is diluted with 100 ml of water and the triphenylcarbinol is removed by extraction in 400 ml of benzene. The aqueous phase containing the desired product, namely 3-amino-4-mercapto-2-azetidinone in the form of the hydrochloride, is lyophilized to obtain this compound in the solid state. Addition of an alkali such as sodium hydroxide or sodium bicarbonate liberates the free base of the hydrochloride in aqueous solution.



  EXAMPLE E
 EMI48.3
 
 EMI48.4
 -o-Iitronhenox acetamida - rercanto-2-azetidinone This compound is prepared by replacing in the operations of Example A from Stage C 3-piata3i.nâdo-zt - (.'- carboxy-I'- é. thylethyltM.o) -2-azêtidlnone by an equal weight of 3-o-nitrophenoxy acetaBtido-4- (l '-carboxy-1 * -methylethylthio) -2-azetidinone prepared beforehand by acylation, by means of d chloride 'o-nitropheno-
 EMI48.5
 xyacetyl in the presence of an excess of triethylamine, 3-aninoZt - El'-carbony-l'-methylethyl? thio) -2-azetidinore obtained itself

 <Desc / Clms Page number 49>

 
 EMI49.1
 by reaction of hydrazine hydrate with 3-phal.rido-4- (learboxy-1 - methylethylthio) -2-azéticïinone. EXAMPLE F
 EMI49.2
 
 EMI49.3
 ¯3-Àmino = 4-mercanto-2zazetidinone.

   A solution of 1.0 g of 3-o-nitrophenoxyacetamido-4-mercapto-2-azetidinone in 10 ml of water is treated with 1.0 g of 30% palladium on pre-hydrogenated diatomaceous earth and 9 ml of water under a hydrogen pressure of 3.5 kg / cm2 on a manometer for 1 hour at room temperature. The pH of the solution is then adjusted to 2 using 50% hydrochloric acid and the mixture is left to stand for at least 20 minutes at 5-25 C
 EMI49.4
 to obtain 3-amino-4-mercapto-2-azetidinone in the form of its hydrochloride.



   Alternatively, the reaction can be carried out in an anhydrous medium, i.e. hydrogenation in dry benzene with the acid added. then under the farm of anhydrous hydrogen chloride.



    EXAMPLE G -
 EMI49.5
 
 EMI49.6
 3-Amino-4-mercauto-2-azetidinone. 0.05 g of 5% palladium on charcoal are added to 0.75 g (14 millimoles) of KBH4 dissolved in 70 ml of water. Nitrogen is bubbled through the suspension which is stirred and cooled to 5 The pH is adjusted to a value of 8.0 to 8.6 by addition of 6 N HCl

 <Desc / Clms Page number 50>

 and keep it at this value while quickly adding
 EMI50.1
 a solution of 7 millimoles of 3-o-nitrophenoxyacetamido-1-mercapto-2-azetidinone in 30 ml of water.

   The cold mixture is stirred for 15 minutes and its pH is collected up to 2.0 by the addition of 6 N HCl. The catalyst is filtered off to obtain an aqueous solution containing 3-amino-4-mercapto-2- hydrochloride. azetidinone wanted.



  EXAMPLE H
 EMI50.2
 
 EMI50.3
 3nCarbobenzylôxyamino -% - mercaDto-2-azetidinone.



  This compound is prepared by replacing, in the operations of Example A, the 22-dimethyl-6-phthaliuido-3-penar, yl isocyanate with an equal weight of 2,2-dimethyl-6-carbobenzyloxyamino-3 isocyanate -penamyl prepared by the process described by Perron et al.
 EMI50.4
 laborers; J, 14ed. Chem., Z, pages 483-487 (1964) (the processes for preparing the intermediate acid azides are also given in Belgian Patent No. 655,997 from 6-carbo- acid.
 EMI50.5
 benzyloxyaminopenicillanic acid.



   Alternatively, the isocyanate can be converted to the aldehyde according to the technique of Step A of Example N below. : i EXAMPLE 1
 EMI50.6
 
 EMI50.7
 -Atino-4-rercanto-2-azéti.âinvne. This compound is prepared by the catalytic hydrogenation of 3-carbobenzyloxy-

 <Desc / Clms Page number 51>

 amino-4-mercapto-2-azetidinone at room temperature using a platinum catalyst in toluene as a non-proton-giving solvent until absorption of one molecular equivalent of hydrogen. After filtration to remove the catalyst, a solution of 3-amino-4-mercapto-2-azetidinone is obtained, which is isolated by lyophilization or, if desired, which is reacted in situ, for example as in example B above.



  EXAMPLE J
 EMI51.1
 
 EMI51.2
 3-Carbo-t-butylox.yanino-4-mercautc-2 - azetidinone This compound is prepared by replacing in the operations of Example A 2,2-dimethyl-6-phthalimido-3- isocyanate penamyl with an equal weight of 2,2-dimethyl-6- isocyanate
 EMI51.3
 carbo-t-butyloxyarino-3-penamyl prepared by the method described by Perron et al., J.

     Med. Chem 7 pages 483-487 (1964) (processes for the preparation of intermediate acid azides are also given in Belgian patent no.655.997)
 EMI51.4
 from 6-carbo-t-butyloxyaminopenicillanic acid, which is obtained as described in the literature or, if desired, according to the processes allowing the synthesis of 6-ethoxy- acid
 EMI51.5
 carbamidopênicilianiquev
Alternatively, the conversion of isocyanate to aldehyde is carried out as in Step A of Example II below.



  EXAMPLE K
 EMI51.6
 

 <Desc / Clms Page number 52>

 
 EMI52.1
 , rino-t.-rercapto - 2-aaétidi none. This compound is prepared by dissolving 20 mg of 3-carbo-t-butyloçoamino-Y-mercapto-2-azetidinone in 10 ml of benzene (or methylene chloride) at room temperature and passing hydrogen chloride through it. anhydrous to obtain a solution of chlor-
 EMI52.2
 3-aina -; - rercapto-2-aztidinone hydrate, which is either used immediately or from which the compound is isolated in solid form by lyophilization. EXAMPLE l
 EMI52.3
 
 EMI52.4
 -Amino - ercato-2-azeidinone.

   This compound is prepared in the trifluoroacetate state by dissolving 1.0 g of 3-carbo-t-butylox-yarciro --- rsrcauo-2-azeidsnone in 25 ml of trifluoroacetic acid and allowing the mixture to stand at room temperature for at least 30 minutes or overnight.



  EXAMPLE M -
 EMI52.5
 
 EMI52.6
 3-Amino-4-mercapto-2-azetidin p-Toluenesulfonate This compound is prepared by stirring a solution of 2 millimoles of 3-bàtj'lembto-4-zercapto-2-a2etiébnone and 2 sillinole diacids pbluenesulfonic Qonohydrate 10 years if anhydrous acetone for 30 minutes to 25. The solvent is evaporated off in a stream of nitrogen and the residue is triturated with 100 µl of anhydrous ethyl ether to dissolve the rififlénylearbi # 07 and leave the p-to.

 <Desc / Clms Page number 53>

 
 EMI53.1
 3-amino-1r-mercapto-2-azetidinone luenesulfonate in the form of a solid which is collected by filtration.



  EXAMPLE N
 EMI53.2
 
 EMI53.3
 3-Phthalimido- '! -2-azetidinone Stage A - -PhtaL, do - + - I'-form-î -? '- reth lêthv? Thio -2-azetidinone
This intermediate compound is prepared by adding
 EMI53.4
 drop by drop 17 g of 2,2-dim: '- thyl-6-phthalimid-3-penamyl isocyanate in 250 ml of methylene chloride to a mixture of 2 ?, 2 g of formic acid in 250 ml of methylene chloride over 105 minutes at room temperature, then stirring the mixture for a further 75 minutes. The solution is washed with water (3 x 200 ml), then it is dried over anhydrous MgSO4, the mixture is filtered and the filtrate is evaporated to obtain an oil which foams under reduced pressure and then solidifies.

   The product thus expanded is dissolved in methylene chloride, which leaves some impurities. By evaporation of chloride
 EMI53.5
 From methylene, the crude solid 3-phthaliiaido-4- (l'-forc! yl-ethyl-ethylthio) -2-azetidinone is obtained which is purified by chromatography. To this end, 5 g of the crude aldehyde in chloroforml solution are introduced into a column of silicic acid with a particle size of 0.15 mm soaked in benzene.

   The first eluent used is a mixture of benzene and chloroform (1: 1) and 25 ml fractions are then collected The dimension of the column is 125 x 45 mm A product is collected in fractions 18 and 19 - The compound is not the desired aldehyde and the spectrum

 <Desc / Clms Page number 54>

      infrared shows the absence of the NH valence frequency while the nuclear magnetic resonance spectrum does not include a peak due to the proton, aldehyde at 0.7 # On analysis: elemental, this compound melting at 97 is found to contain 57 , 74% C, 4) 73% H 7.58% nitrogen and 7.74% S.



   By continuing the chromatography using this particular eluent system, no further fractions are obtained. After the 23rd fraction, an elution with chloroform is carried out to obtain after evaporation of the fractions
 EMI54.1
 27-29 3-phthalimido - Zt- (l'-foyl-l'-éà? Yéhy.thio) -2¯ azetidinone as an oil. This oil is crystallized in benzene to obtain 2 g of a product melting at 117-123 The infrared spectrum indicates the presence of the absorption band due to the NH radical and is identical to the spectrum of a sample of the aldehyde obtained by the process of Sheehan and Brandi.

   The nuclear magnetic resonance spectrum includes
 EMI54.2
 two singlets for the gen-dilaethyl radicals at 8.6 (; and 87-C - the nuclear magnetic resonance spectrum is substantially the same as that shown in the literature.
 EMI54.3
 sonance 'nuclear tick (CDC'L 3): 097 1'sis singlet), 2.15 QÎ (4X, t # ifl.tipl; tj; 2; .É5' <(µX, singlet; solvation benzene), Îl -, 35 '(1:47 d () 1101et) J-5 hert3, 2i2 xH, doublet) 3-5 hertz, Si 6 er sz:;:. EL ?; 8,7't'OR: $ singlet). The optical rotation of the aldehyde thus prepared is O ;; 1p2. :: '& à ccl'15. prepared by means of tee [: the ab: 'lrof'1ranne and hydrochloric acid brick IN.

   The product synthesized in walnut! of acid: foI'G1ique a 11 ... rotatory power 0 - El 5 "(3:91 years 1" -....... - product synCf..J ':' &. 6 '0: :; - 0.1 ..,) "\ ... 1,7111.: 11:", .... '3 Ci1..r ... o. <. Vr: .rme),' 3. <. The process, which is mixed in 13 tetrahyerofuraniis in the presence of hydrochloric acid, has a rotatory power L- ¯7 5J {-6 of -6i + 2 (4.3 in chloroform 51 ,, 6

 <Desc / Clms Page number 55>

 
 EMI55.1
 Stage B - 3-Phtà! Iido-A "4¯2¯azetidinone. This product is prepared from the above 3'aldehyde by direct removal of the thiol function using a nucleotide reagent.
 EMI55.2
 phile strong.

   To this end, 3-phthalimido-4- (l'-formyl-11-methylethylthio) -2-azetidinone (0.8 g) is dissolved in an anhydrous mixture of toluene and dioxane (1: 3; 40 ml) cooled to 0 ° C. then 0.25 g of potassium t-butoxide is added to the mixture.



  The reaction mixture is stirred vigorously for 45 minutes while maintaining its temperature at 0. By removing the solvent under a high vacuum, the desired product is obtained, namely the
 EMI55.3
 3-phthalimido-ZA '-2-azetidinone as a yellow solid.



  This compound is insoluble in diethyl ether but soluble in methylene chloride. By washing the product with diethyl ether, the unchanged aldehyde residue is removed as shown by the infrared spectrum.



   The infrared absorption spectrum of -phthalimi-
 EMI55.4
 do L: 1.1, 4-2-azetidinone shows the absence of the maximum absorption ¯VL- due to adical-NH and the appearance of a maximum at 1600 cm-1 indicating the presence of a binding c = n We also find absorption maxima at 1775 and 1715 cm-1 (phthalimido) and at 1765 cm-1 (carbonyl radical ss-lactam
The action of water on this compound causes the dis-
 EMI55.5
 appearance of the C === N cooma bond shows the infrared absorption spectrum.
 EMI55.6
 zoe 'LE Q - (1 (11 iff 1 1 il 1r - mi- 1 cx 1 ul 1 c eq -' iH 0
 EMI55.7
 3-naliniQO-4-s: crcato- -aze'cidTLnone.

   Equimolecular mixtures of 3-phtaIinido-Z \ 1,7-2-azét1di- are produced.

 <Desc / Clms Page number 56>

 
 EMI56.1
 none and anhydrous hydrogen sulfide. in benzene, methylene chloride and dioxane, respectively in
 EMI56.2
 autoclaves for 1, 6, 12, 2 and 43 hours respectively at 4o, 60, 80 and 100 C respectively to obtain various amounts of 3-phthalimido -% - mercapto-2-azetidinone that is used directly for a new reaction or that It is isolated in the solid state by lyophilization until the solvent has been completely removed.



  EXAMPLE p. -
 EMI56.3
 By replacing in the operations of example N
 EMI56.4
 ¯ 2,2-ditethyl-6-ph-alimido-3-penamyl isocyanate with an equal weight of 2, 2-dîmethyl-6 '-. Tritylamino-3-penamyl isocyanate isocyanate. 2,2-diuethyl-6-carbobenzyioxyamino-3-penamyl, 2/2-dimethyl-6-o-nitrophenoxyaceaamido-3-penamyl isocyanate 2,2-ditnethyl-6-formylaminci-3-penamyl isocyanate, isocyanate of 2, (- dimethyl-6-carbo-t-butyloxyaatino-3-penamyl and key isocyanate respectively, 3-tritylatino-1'-2-azetidinone 3-carbobenzyloxyamino.-1 is obtained. -2-azetidinone 3-o-nitrophenox, yacetamido 1 '2-azetidinone, 3-formy7.amino l' -2-azetidinone,

   3..carbo - butyloxyamino rf '2 - azetidinane and 3-o-nitropliényLsulféry3.amino-.1' '- 2-azetidinone respectively
 EMI56.5
 By replacing in the operations of example 0
 EMI56.6
 Ia 3-phtalimicio-f '2-azetidinone by an equal weight of each of the above products, one obtains in turn 3-trzty2amir¯o- 4-mercapto-2-azetîdînone, 3-carbobenzyloxyamino-Y-mercapto -2tidinone, 3-o-nitrophenoxyacetami <io-Y-mercapto-2-azetidinone, 3-fortylanino - gercapto-2-azetidinone, 3-carbo-t-butyloxy amino-4-Btercapto-2-azetidinone and 3-o-nitrophenylsulfenylamin Ft - aercapto-2-azetîdinone respectively.

 <Desc / Clms Page number 57>

 
 EMI57.1
 



  EXAMPLE Q. - zozo 0 Il Il e;>, Il,., -CH -, ss CH -CH - Bzz ((', -8 - 1 1 1t, / li NH ## C "-c' 1 il 1 '1'. 0 0 o
Solid disulfide is a by-product formed in moderate quantity during the reaction of Step E in Example A and is isolated from the mother liquors remaining after
 EMI57.2
 purification of 3-phthalimido --- mercapto-2-azetidinone by fractional recrystallization, for example in a system
 EMI57.3
 methylene chloride-ether> in a benzene-petroleum ether system or similar system.



   The disulfide is converted to 3-amino-4-mercapto
2-Azetidinone by the following methods, the first of which is. prefer:
A. Catalytic hydrogenation. A solution of 10 mg of the disulfide in 10 ml of benzene is hydrogenated at room temperature by means of a large excess of a palladium or platinum catalyst, i.e., by means of 100 mg of sodium black. palladium. The catalyst is then separated by filtration and the solvent by evaporation in an inert atmosphere to
 EMI57.4
 obtain the residue, the desired 3-amino-4-mercapto-2-azetidinone. r'sidu., the
B. Double decomposition of mercaptans.

   Solutions of 50 mg of the disulfide in 20 ml of ethyl mercaptan are stored for 1, 6, 12, 24 and 48 hours respectively at temperatures of 30, 40 50 and 60, respectively, if necessary in sealed tubes, and then distilled. mixtures of

 <Desc / Clms Page number 58>

 reaction under high vacuum to remove ethyl mercaptan and diethyl disulfide, so as to obtain with variable yields the desired 3-amino-4-mercapto-2-azetidinone which constitutes the residue.



   C. Reduction by borohydride. The disulfide in solution in benzene, methylene chloride, aqueous methanol and dioxane is reduced by means of borohydru-.
 EMI58.1
 re sodium at -0-25 to obtain 3-amino-Y-mercapto-2-azetidinone.



  EXAMPLE -
 EMI58.2
 The disulfides of the above formula where X represents
 EMI58.3
 Sends a tritylamino o-nitrophenoxyacêtamidoe radical carbobqnzyl- oxyamino and carbo-t-butyloxyamino respectively are likewise by-products formed at the final stage in Examples C, E, H and J respectively and are isolated as described in Example Q to About the disulfide in which the blocking radical X is a phthalimide radical
According to the techniques applied in Example Q for the decomposition of the disulfide, these disulfides are converted here
 EMI58.4
 in 3-trityiaraino ---- mercapto-2-azetidinone in --o-nitrophno-;

   xyacetamido - mercapto-2-azetidinone, in 3 - carbobenzyloxyamino- Y-mercapto-2-azetidinone and in 3-carbo-i-butyloxyaino - mercapto-2-azetidinone respectively, or directly in 3-amino- 4- Biercapto-2-azétldinone according to the nature of the reagent used. -

 <Desc / Clms Page number 59>

 
In a preparation, use is made of a blocked amino radical which is an o-nitrophenylacetamido radical of the following formula:
 EMI59.1
   Other equally useful radicals which intervene in the same way
 EMI59.2
 are those of formula: R3 R3 / y "\ 0 2" 'il / = \ R2 j -0 - CH2C - NI! - ci Il Rl. t0 2 R2 n2 NO2 R 3 R3 CH2 Il if-q! / il 0 ITi has 1 N02 R 2 C% C R3.

   R3 Z IL li <V? \ V IJ. 1 - S - 2 NE '-1, U "' 1" 1: Rl N02 and R2 2 Ri fiIC

 <Desc / Clms Page number 60>

 where R1, R2 and R3 each represent a hydrogen, chlorine, bromine or iodine atom or a lower alkyl radical, lower alkoxy, trifluoromethyl, cyano or methylsulfonlyl
Formula intermediates
 EMI60.1
 where X with the meaning given to it above are also obtained according to the usual techniques for bringing such radicals in place on a primary amino radical of an amino acid, for example by means of o-nitrophenoxy chloride. acetyl or trityl chloride by means of the intermediate compound: re of formula:

   
 EMI60.2
 whose properties and synthesis by reaction of the hydrate
 EMI60.3
 hydrazine on 3-phthaliuido-Y- (i'-caboxy-1'-nôthyiethylthio] 2-azetidinone were clarified by Karl G. Brandt, Ph.D. Thesis; Massachusetts Institutes ouf echno9 Camryridge, Mass.) August 19t
Although various embodiments and details of embodiment have been described to illustrate the invention, it goes without saying that the latter is susceptible of numerous variations and Improvements; without going outside its framework.

 

Claims (1)

EMI61.1 ¯ ¯ BET EN PI CATION S. 1 - Compounds of formula: EMI61.2 where R represents an acylamino radical and their pharmaceutically acceptable non-toxic salts. 2 - Compounds of formula: EMI61.3 where R1 represents an acylamino radical, and their pharmaceutically acceptable non-toxic salts. 3 - Composed of formulas - ' EMI61.4 <Desc / Clms Page number 62> EMI62.1 where R is chosen from the class formed by the atoms of hydrogen, fluorine, chlorine, bromine and iodine and by amino radicals, EMI62.2 carbobenzoxyaminO} phenyl, hydroxyl, lower alkanoyioxy and lower alkoxy X is selected from. clause formed by the oxygen atom and the sulfur atom, R5 and R6 are each chosen from the class formed by the hydrogen atom and by the phenyl, benzyl, phenethyl and lower alkyl radicals, R7 EMI62.3 represents a lower alkyl radical; 3 and R9 = have each chosen from the class formed by 3, lower alkyl radicals; lower alkylthio, '23j'.F. "li'd ...' ß C: J'C3 '.' J: ±" 'é; TT.ey cycloyentyl, cycloheptyl, benzyl, phenethyl, pi ény + lpTopyle, 1 "aryl, thienyl} caphthyl and / -; RIO is chc'isi in the class formed by lower aluylaaiso radicals; E.vq ::%: .î '$. r.â.nL2?' jâ: .za <. lo cycloa13ylaraino of 3 to 7 carbon atoms' exclusive; allylaminag di "1 .. -t lower phenylalkylanino, sorpholino, lower alkylmorpholino, di (lower alkyl)! 3orpholino, lower morpholinoalkyl # ino, p # ir # oliàino, a7, kylpyrroliàino lower% dl (lower alkyl) pyrrolidinc T rexaeth; l - <Desc / Clms Page number 63> EMI63.1 amino, pipéndino, lower alkg3piperidino., di (lower alkyl) piperidino, l; 2,?, 6-tetrahydropyridino, N-lower alkylpiperazino, N - ohenylpi-oerazino, N- (lower alkyl) (lower a2ky1) piperazino, N- (lower alkyl) -di- (lower allyl) piperazino, furfurylamino, tetrahyôrofurfurylaaino , N- (lower alkyl) -Nfarlurylamino, N-alkyl-N-anilino and lower alkoxyanilino, z1, z2 and z3 are each chosen from the class formed by lower alkyl radicals and R11 is chosen from the class formed by lower alkyl radicals , lower cycloalkyl, naphthyl, benzyl, phenethyl and RC and R represents a monovalent radical of formula: EMI63.2 where R1 R2 and R3 are each chosen from the class closed by EMI63.3 the: i.J4'S cif; 2T1i03ïtP of chicory of brone and of iodine and by the trifluoromethyl phenyl, lower alkyl and lower alkoxy radicals, it being understood however that only one of the symbols R may represent a phenyl radical and W represents a radical of fornule EMI63.4 and their pharmaceutically acceptable non-toxic salts. 4 Compounds of formula EMI63.5 <Desc / Clms Page number 64> where R represents a lower alkyl radical. 5 - Compounds of formula: EMI64.1 or R1- represents a lower alkyl radical and O and R3 each represent a hydrogen or chlorine atom. 6 - Compounds of formula EMI64.2 Il OE-CH / fl a Il C- CH -CH '-0' 1 R2 0 = C - II. 1 CH-COOn 1 where R1 represents a lower alkyl radical and R2 represents a hydrogen or chlorine atom. 7 - Compounds of formula: EMI64.3 where R represents a lower alkyl radical. 8 - Compounds of formula EMI64.4 where R represents a lower alkyl radical. 9 - Compounds of formula: <Desc / Clms Page number 65> EMI65.1 where R represents a lower alkyl radical. 10 - The compound of formula: EMI65.2 11 - The compound of formula: EMI65.3 12 - The compound of formula: EMI65.4 13 - the compound of formula: EMI65.5 14 The compound of formula: <Desc / Clms Page number 66> EMI66.1 15 - Compounds of formula: EMI66.2 where R represents a lower alkyl radical. 16 - Compounds of formula: EMI66.3 where R1 represents a lower alkyl radical and R2 and R3 each represent a hydrogen or chlorine atom. 17 - Compounds of formula: EMI66.4 where R1 represents a lower alkyl radical and R2 represents a hydrogen or chlorine atom. <Desc / Clms Page number 67> 18 - compounds of formula: EMI67.1 where R represents a lower alkyl radical. 19 - Compounds of formula: EMI67.2 where R represents a lower alkyl radical. 20 - Compounds of formula: EMI67.3 where R represents a lower alkyl radical. 21 - The compound of formula: EMI67.4 <Desc / Clms Page number 68> 22 - The compound of formula: EMI68.1 23 - The compound of formula: EMI68.2 EMI68.3 Cl 24 - The compound of formula: Il C'ri --0 CFi,. S% ,, -, CH3 ci f - 1 - c - 1, ', H - cii 1 - i CI' CH: il 0 CI'Î3 0 - n, C-CF! 2-0-C-CH3 "c ? ' i COOH 25 - The compound of forcule: EMI68.4 26 - Process for the preparation of an antibacterial agent nothing, characterized in that a compound of formula is reacted EMI68.5 <Desc / Clms Page number 69> or a salt thereof with an organic monocarboxylic acid chloride or one of its functional equivalents. 27 - Process for preparing an antibacterial agent, characterized in that a compound of formula is reacted: EMI69.1 or a salt thereof with an organic monocarboxylic acid chloride or a functional equivalent thereof. 28 - Process for preparing an antibacterial agent, characterized in that a compound of formula is reacted: EMI69.2 with a mono-carboxylic organic acid chloride of the formula. EMI69.3 <Desc / Clms Page number 70> EMI70.1 where R4 is chosen from the class formed by the atoms of hydrogen, fluorine, chlorine, bromine and iodine and by the radicals, amino, EMI70.2 t; ûi'Oei ': 0.5á.I2G phenyl, hydroxyl al caroyloxjr Lower et all., Roxy inférie1.lis, X is chosen from the. class formed by the oxygen atom and the sulfur atom R5 and R6 are each chosen from the class formed by the hydrogen atom and by the phenyl, benzyl, phenethyl and lower alkyl radicals, R7 represents a radical lower alkyl R8 and R9 are each selected from the class formed by lower alkyl, lower alkylthio, benzylthio, cyclohexyl, cyclopentyl radicals EMI70.3 ecchenv- .e benzyle., phenethyl, jjiù <Enj71çz-opj? le, furyl, thianyle, taiiLL 9., .f 3-, dô is v.: S..Jrài eens ion class forced by radicals ,,: 'J'.I' '' '' V '': - ''. -1 ,, - <a "" 7 "diga-11 = jS in" .....;, 't "" "' \" '1no cycloalkylasino from 3 to 7 carbon atoms im: lusiver : 1ent) allylamino, .di a? ly '2-m ino, lower phenylalkylataino, Korpholiso, <Desc / Clms Page number 71> lower alkylmorpholino, di (lower alkyl) norpholino, mor- EMI71.1 lower pholinoalkylamino, pyrrolidino, a7.ylpyrolidino lower, di (lower alkyl) pyrrolidino, N, N-hexamethylenimino, piperidino, lower alkylpiperidino, di (lower alkyl) piperidino, 1,2,5,6-tetrahydropyridino, N-alkylpiperazino lower, N-phenylpiperazino, N- (lower alkyl) (lower alkyl) piperazino, N- (lower alkyl) -di- (lower alkyl) piperazino, furfurylamino, tetrahydrofurfurylamino, N- (lower alkyl) -N furfurylacino, N-alkyl-N-anilino and lower alkoxyanilino, Z1, Z2 and Z3 are each chosen from the class formed by lower alkyl radicals and R11 is chosen from the class formed by alkyl radicals lower, lower cycloalkyl, naphthyl; benzyl, phenethyl and and # represents a monovalent radical of formula: EMI71.2 where R1, R2 and R3 are each selected from the class forced by the atoms of hydrogen, chlorine, bromine and iodine and by the EMI71.3 radi; to tri ± 1110romethyl, phenyl, lower alkyl and lower alkoxy, it being understood, however, that only one of the symbols R may represent a phenyl radical, or with a functional equivalent of this acid chloride.