BE848545A - N-METHYLENE DERIVATIVES SUBSTITUTES THIENAMYCINE, - Google Patents

Description

       

  Substituted N-methylene derivatives of thienamycin.

  
The present invention relates to certain N-methylene substituted derivatives of the novel thienamycin antibiotic. These compounds and their pharmaceutically acceptable salt, ethers, ester and amide derivatives are useful as antibiotics. The present invention also relates to processes for the preparation of these compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising the administration of such compounds and such compositions when an antibiotic effect is indicated.

  
Thienamycin is described and claimed in US Patent Application 526,992, filed November 25, 1974 (US Patent 3,950,357

  
  <EMI ID = 1.1>

  
thienamycin can be used as a starting material in the preparation of the compounds of the present invention.

  
Thienamycin is known to have the following structure

  

  <EMI ID = 2.1>


  
The N-methylene substituted thienamycin derivatives according to the present invention can be represented by the structural formula

  

  <EMI ID = 3.1>


  
which, depending on the basis of the nitrogen of the amino group (which is a function of the identity of the X and Y substituents of the methylene group), can be represented in an equivalent manner as being an internal salt:

  

  <EMI ID = 4.1>
 

  
which is a canonical form of a single resonance structure which, by

  
  <EMI ID = 5.1>

  

  <EMI ID = 6.1>


  
For convenience, the compounds according to the present invention can be represented as follows:

  

  <EMI ID = 7.1>


  
where "Th" represents the bicyclic ring of thienamycin and its hydroxyl, amino and carboxyl functional groups are represented, where X and Y are chosen.

  
  <EMI ID = 8.1>

  
independently selected from R, hydrogen and nitro, hydroxyl, alkoxyl groups having 1 to 6 carbon atoms, amino, mono-, di- and trialkylamino wherein the alkyl moieties each comprise from 1 to 6 carbon atoms; R

  
and R <2> can be linked to form a substituted or unsubstituted mono- or bicyclic heteroaryl or heterocyclyl group comprising (together with the nitrogen atom to which they are attached) from 4 to 10 atoms, one or more of which may be additional hetero atoms chosen from oxygen, sulfur

  
  <EMI ID = 9.1>

  
carboxyl; alkoxycarbonyl and alkyl having from 1 to about 10 carbon atoms; alkenyl having from about 2 to 10 carbon atoms; alkenyl having from about 2 to 10 carbon atoms; alkynyl having about 2 to 10 carbon atoms; cyaloalkyl having 3 to 10 carbon atoms; cycloalkylalkyl and cycloalkylalkenyl having 4 to 12 carbon atoms; cycloalkenyl, cycloalkenylalkenyl and cycloalkenylalken having 3 to 10, 4 to 12 and 4 to 12 carbon atoms, respectively; aryl having 6 to 10 carbon atoms, aralkyl, aralkenyl and aralkynyl having 7 to 16 carbon atoms;

   mono- and bicyclic heteroaryl and heteroaralkyl which typically comprise from 4 to 10 atoms in the rings, one or more of which are hetero atoms selected from oxygen, sulfur or nitrogen and wherein the alkyl portion of the heteroalkyl radical comprises from 1 to 6 carbon atoms approximately; mono- and bicyclic heterocyclyl and heterocyclylalkyl. which typically include 4 to 10 carbon atoms in rings one or more of which are hetero atoms selected from oxygen, sulfur or nitrogen and where the alkyl portion of the heterocyclolalkyl radical contains approximately 1 to 6 carbon atoms; and where the

  
  <EMI ID = 10.1>

  
by the junction of R <1> and R2 are chosen from the following: halo, such as chloro, bromo, iodo and fluoro; azido; alkyl having 1 to 4 carbon atoms; thio; sulfo; phosphono; cyanothio (-SON); nitro; cyano; friend no; hydrazino; mono-, di- and trialkyl amino and-hydrazino, where the alkyl group has

  
  <EMI ID = 11.1>

  
n having 2 to 10 carbon atoms; carbamoyl and mono- and dialkoylcarbamoyl where the alkyl groups have 1 to 4 carbon atoms.

  
The compounds according to the present invention also include

  
following structure:

  

  <EMI ID = 12.1>


  
which can also exist in the form of a salt:

  

  <EMI ID = 13.1>


  
or can be represented more conveniently using the symbol Th defined above as:

  

  <EMI ID = 14.1>
 

  
where the non-critical antagonist anion, A, is chosen representatively so as to give pharmaceutically acceptable salts such as halides (chloro, bromo, etc.), sulfate, phosphate, citrate, acetate, benzoate,

  
  <EMI ID = 15.1>

  
below:

  
  <EMI ID = 16.1>

  
  <EMI ID = 17.1>

  
  <EMI ID = 18.1>

  
acyl group) and pharmaceutically acceptable amide known in the art of bicyclic beta-lactam antibiotics; such portions are listed in more detail below; and R <3> is: 1) an acyl group (generically, the OR group <3> can be classified as an ester); or 2) R <3> is selected from alkyl, aryl, alkenyl, aralkyl, etc. (such that the group OR <3> can be generically classified as an ether).

  
  <EMI ID = 19.1>

  
alkanoyl groups, including their derivatives and analogues such as thio analogs in which the oxygen of the carbonyl group is replaced by sulfur; as well as sulfur and phosphorus acyl analogs such as sulfonyl, sulfinyl and sulfenyl substituted radicals and substituted radicals derived from P (III and V) such as phosphorous, phosphoric, phosphonous and substituted phosphonic radicals. Such radicals, R <3>, according to the present invention are listed in more detail below.

  
There is a continuing need for new antibiotics. Indeed, unfortunately, there is no static efficacy of a given antibiotic because prolonged use on a large scale of any given antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics have the drawback of being effective only against certain types of microorganisms.

  
. As a result, research relating to. new antibiotics continues.

  
Unexpectedly, the compounds of the present invention have been found to be broad spectrum antibiotics, which are useful in the treatment of animals and humans and in inanimate systems.

  
Thus, the present invention aims to provide a new class of antibiotics which possess the basic nuclear structure of thienamycin (I), but which are characterized as being its substituted N-methylene derivatives. These antibiotics are active against a broad spectrum. a range of pathogens which representatively include

  
  <EMI ID = 20.1>

  
subtilis as Gram-negative such as E. coli, Proteus morganii, Kelbsiella, Serratia and Pseudomonas. The antibiotics according to the invention can be used in particular for staphylococcal infections. Further objects of the present invention are to provide chemical processes for the preparation of these antibiotics and their pharmaceutically acceptable non-toxic salt, ethers, esters and amide derivatives; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is desired.

  
The compounds according to the present invention (Structures II and IIa, above) can be divided into four classes:

  
  <EMI ID = 21.1>

  

  <EMI ID = 22.1>


  
which can be represented by the resonance structure

  

  <EMI ID = 23.1>


  
  <EMI ID = 24.1>

  
represented in a similar way:

  

  <EMI ID = 25.1>


  
  <EMI ID = 26.1>

  
Sentatives of these amidine embodiments (the substituent plus the amino group of thienamycin forms the amidine structure) are:

  
  <EMI ID = 27.1> <EMI ID = 28.1>

  
Piperidinyl methylenimine: Y = 1-piperidyle,

X = H.

  
Other preferred amidines are those in which

  
  <EMI ID = 29.1>

  
the following groups, substituted or not: alkyl having from 1 to. 6 carbon atoms, such as methyl, ethyl, isopropyl, butyl, t-butyl, N, N-dimethyl aminoethyl, 2,2,2-trifluoroethyl, 2-methylthioethyl, etc; alkenyl having 3 to 6 carbon atoms, such as allyl, methallyl, 2-butenyl, 1-buten-3yl, etc; cycloalkyl, cycloalkylalkyl, cycloalkenyl and cycloalkenylalkyl having 3 to 6, 4 to 7, 4 to 6 and 4 to 7 carbon atoms, respectively, such as cyclopropyl, cyclopentyl, cyclohexyl ,, cyclopropyl-

  
  <EMI ID = 30.1>

  
aralkyl and aralkenyl having from 7 to 10 carbon atoms, such as benzyl, p-methoxybenzyl, p-dimethylaminobenzyl, cinnamyl, etc; and monocyclic heteroaralkyl having 5 to 6 ring atoms, one or more of which is selected from oxygen, sulfur and nitrogen and from 1 to 3 carbon atoms

  
  <EMI ID = 31.1>

  
dialkyllamino having 1 to 3 carbon atoms in each alkyl portion.

  
  <EMI ID = 32.1>

  
; alkenyl having 2 to 6 carbon atoms; alkoxyalkyl having 2 to about 6 carbon atoms, such as methoxymethyl, ethoxyethyl, etc; mono-, di- and tri (lower alkyl) aminoalkyl having from 2 to 12 carbon atoms such as dimethylaminomethyl, methylaminomethyl, trimethylammoniummethyl, etc;

  
  <EMI ID = 33.1>

  
alkylthioalkyl having 2 to about 6 carbon atoms such as methylthiomethyl, ethylthioethyl, etc; groups chosen from the following, substituted or not: aryl and aralkyl such as phenyl and benzyl; monocyclic heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl such as

  
  <EMI ID = 34.1>

  
are as defined above. The amidine embodiments of the present invention represent a preferred class. In addition, the modes of

  
  <EMI ID = 35.1>

  
hydrogen are particularly preferred.

  
Especially preferred are the amidines of the present invention.

  
  <EMI ID = 36.1>

  
hydrogen and the substituted or unsubstituted alkyl and alkenyl radicals indicated above.

  
  <EMI ID = 37.1>

  

  <EMI ID = 38.1>


  
where all symbols are as defined above.

  
Representative examples of these embodiments guanidine (the substituent plus the amino group of thienamycin form the

  
guanidine structure) are:

  

  <EMI ID = 39.1>
 

  

  <EMI ID = 40.1>


  
  <EMI ID = 41.1>

  
and R2 are independently chosen from hydrogen and the following groups, substituted or not: alkyl having from 1 to 6 carbon atoms, such as methyl,

  
  <EMI ID = 42.1>

  
roethyl, 2-methylthioethyl, etc; alkenyl having 3 to 6 carbon atoms, such as allyl, methallyl, 2-butenyl, 1-buten-3-yl, etc; cycloalkyl, cycloalkyl, cycloalkenyl and cycloalkenylalkyl having from 3 to 6, from 4

  
  <EMI ID = 43.1>

  
cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclohexylmethyl, 2-cyclopro-

  
  <EMI ID = 44.1>

  
in the ring, one or more of which are selected from oxygen, sulfur and nitrogen and from 1 to 3 carbon atoms in the alkyl portion, such as 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 1-methyl -5-tetrazolylmethyl, etc. where the substituent at the nucleus or in the chain with respect to the

  
  <EMI ID = 45.1>

  
alkoxyl having 1 to 3 carbon atoms, dialkylamine having 1 to 3 carbon atoms in each alkyl moiety and alkylthio having 1 to 3 atoms

  
  <EMI ID = 46.1>

  
X = -OR or -SR:

  

  <EMI ID = 47.1>


  
  <EMI ID = 48.1>

  
Representative examples of these substituted pseudourea embodiments (the substituent plus the amino group of thienamycin forms the substituted pseudourea structure) are:

  

  <EMI ID = 49.1>
 

  

  <EMI ID = 50.1>


  
Particularly preferred compounds are those in

  
  <EMI ID = 51.1>

  
4) Imido ethers and Imido thioethers

  

  <EMI ID = 52.1>


  
  <EMI ID = 53.1>

  
hydrogen, R, -OR and -SR.

  
Representative examples of these imido ester and imido thioester embodiments (the substituent plus the amino group of thienamycin forms the imido ester or imido thioester structure) are:

  

  <EMI ID = 54.1>


  
Identification of starting materials

  
The compounds according to the present invention are conveniently prepared from thienamycin (I, above). Modes of realization

  
  <EMI ID = 55.1>

  
secondary alcohol group and / or carboxyl group are derivatized are conveniently prepared from the corresponding 0-, carboxyl or 0- and carboxyl derivative or from II or from thienamycin

  
  <EMI ID = 56.1> <EMI ID = 57.1>

  
more fully in the following US patent applications which are incorporated herein by reference: NO 634,006 of November 21, 1975 which relates to the 0- derivatives of thienamycin (ester and ether derivatives of the secondary alcoholic group of thienamycin and its continuation which describes compounds having the following structural formula:

  

  <EMI ID = 58.1>


  
U.S. Patent Application N [deg.] 634,291 of November 21, 1975 and its Continuing Application which relate to N-acyl derivatives of thienamycin having the following structural formula:

  

  <EMI ID = 59.1>


  
  <EMI ID = 60.1>

  
"acyl" is defined in the same way as in the patent application hereinafter incorporated by reference. These N-acyl thienamycins are useful starting materials for the preparation of the pseudo-substituted urea (3) and imido ether and imido thioether embodiments of the present invention.

  
US Patent Application No. 634,298 of November 21, 1975 and its Continuing Application which relate to carboxylated derivatives of thienamycin having the following structural formula:

  

  <EMI ID = 61.1>


  
US Patent Application No. [deg.] 634,295 of November 21, 1975 and its application thereon.

  
  <EMI ID = 62.1>

  
having the following structural formula:

  

  <EMI ID = 63.1>


  
  <EMI ID = 64.1>

  
Termination which relate to N-acylated, 0- and carboxylated derivatives of thienamycin having the following structural formula:

  

  <EMI ID = 65.1>


  
Thus, embodiments of the present invention represented by IIa above can be prepared from the derivative la, Ib, Ic,

  
  <EMI ID = 66.1>

  
as described in the US patent applications cited above and incorporated by reference.

  
In. as regards the structures la, Ib, le, Id and le, the

  
  <EMI ID = 67.1>

  
  <EMI ID = 68.1>

  
radicals known to be effective as ester, anhydride radicals (R <3> 'is an acyl) and amide group which are pharmaceutically acceptable in the art of bicyclic beta-lactam antibiotics, such as cephalosporins and penicillins and their nuclear analogues.

  
Usable radicals (R3 ') include conventional carboxyl protecting or blocking groups. The term "blocking group" as used herein is employed in the same manner as in the US patent.

  
3,697,515 and in accordance with the teachings of this patent which is incorporated

  
  <EMI ID = 69.1>

  
according to the present invention included in this category are indicated below.

  
The blocking esters which can be used thus include those chosen from the following list which is representative and should not be considered as a

  
  <EMI ID = 70.1>

  
  <EMI ID = 71.1>

  
organic substituent groups. Usable ester groups of this type

  
  <EMI ID = 72.1>

  
electron withdrawer, for example benzoyl, &#65533; -nitrophenyl, 4-pyridyl, trichloromethyl, tribromethyl, isodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulphonylmethyl, 2-dimethyl-sulphoniummethyl, 0-nitrophenyl or cyano. Usable esters of this type include benzoylmetho- groups.

  
  <EMI ID = 73.1>

  
is hydrogen. Usable esters of this type include t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl groups.

  
  <EMI ID = 74.1>

  
nyl, 4-methylthiophenyl or tetrahydropyran-2-yl.

  
Silyl esters, in this class of blocking groups, can conveniently be prepared from a halosilane or a silazane.

  
  <EMI ID = 75.1>

  
halogen such as chlorine or bromine and the various R 'groups, which may be the same or different, represent hydrogen atoms or alkyl groups, for example methyl, ethyl, n-propyl, iso-propyl; aryl, for example phenyl; or aralkyl, for example benzyl.

  
More generally, the pharmaceutically acceptable carboxylated derivatives according to the present invention are those obtained by reacting thienamycin or an N-protected thienamycin, such as an N-acylated thienamycin, with alcohols, phenols, mercaptans, thiophenols. , acylating agents, etc. For example, interesting esters and amides are the starting materials given above and the end products having the

  
  <EMI ID = 76.1>

  
having 1 to 10 carbon atoms, straight or branched chain, such as methyl, ethyl, t-butyl, pentyl, decyl etc., carbonylmethyl, including phenacyl, p-bromophenacyl, p -t-butylphenacyl, acetoxyacetylmethyl, piva-

  
  <EMI ID = 77.1>

  
of carbon; but can be branched, straight or cyclic and the alkyl portion has 1 to 6 carbon atoms, such as methoxymethyl, ethoxymethyl, isopxopoxymethyl, decycloxymethyl, ethoxypropyl, decyloxypentyl, cyclohexyloxymethyl etc; alkanoyloxyalkyl where the alkanoyloxy portion is straight or branched and

  
  <EMI ID = 78.1>

  
xypropyl, etc; haloalkyl where the halogen is chlorine, bromine,

  
  <EMI ID = 79.1>

  
6 carbon atoms, e.g. 2,2,2-trichloroethyl, trifluoroethyl, 2bromopropyl diiodomethyl, 2-chloroethyl, 2-bromoethyl, etc., alkenyl having 1 to 10 carbon atoms, straight or branched chain, e.g. allyl , 2-propenyl, 3-butenyl, 4-butenyl, 4-pentenyl, 2-butenyl, 3-pentenyl,

  
  <EMI ID = 80.1>

  
alkynyl having from 1 to 10 carbon atoms, straight or branched chain, for example 3-pentenyl, propargyl, ethynyl, 3-butyl-1-yl, etc; alkanoyl,

  
straight chain or branched, having 1 to 10 carbon atoms, such as pivaloyl, acetyl, propionyl, etc; aralkyl or heteroaralkyl where the group alkyl has 1 to 3 carbon atoms and "hetero" indicates that there are 1 to 4 hetero atoms selected from 0, S or N, such as benzyl, benzhydryl, benzyl

  
and benzhydryl substituted or, for example, benzyl or benzhydryl substituted with 1 to 3 substituents such as benzyl, phenoxy, halogen, lower alkyl, lower alkanoyloxy of 1 to 5 carbon atoms, lower alkoxy, hydroxy,

  
  <EMI ID = 81.1>

  
o-nitrobenzyl, 3,5-dinitrobenzyl, p-methoxybenzyl, m-benzoylbenzyl, pt-butylbenzyl, m-phenoxybenzyl, p-benzoylbenzyl, p-nitrobenzyl, 3,5dichloro-4-hydroxybenzyl, p-methoxycarbonylbenzyl, p-methoxy, p-carboxybenzyl, the latter being the free acid, an ester or the salt of so-

  
  <EMI ID = 82.1>

  
benzyl, p-benzamidobenzyl, o-pivaloyloxybenzyl, m-pivaloyloxhbenzyl, p-isopropoxybenzyl, pt-butoxybenzyl, as well as their cyclic analogues 2,2-dimethyl-5-coumaranmethyl, 5-indanylemethyl, p-trimethylsilylbenzyl, 3,5- -t-butoxy-4-hydroxybenzyl; 2-thienylmethyl, 2-furylmethyl, 3-t-butyl-

  
  <EMI ID = 83.1>

  
zolylmethyl, etc; (the use of the terms lower alkyl or lower alkoxy in this context means a chain of 1 to 4 carbon atoms; or phthalidyl; or phenylethyl, 2- (p-methyl-phenyl) ethyl and the alkylthioalkyl, aryloxyalkyl analogs in which the aryl group is preferably a phenyl group having 0 to 3 substituents, preferably 0 or 1 substituent in the ortho or para positions and the alkyl group has from 1 to

  
  <EMI ID = 84.1>

  
(4-chloro) phenoxymethyl, (4-nitro) phenoxymethyl, (4-benzyloxy) phenoxymethyl,
(4-methyl) phenoxymethyl, (4-benzyloxy) phenoxymethyl, (1-phenoxy) -ethyl,
(4-amino) phenoxymethyl, (5-methoxy) phenylthiomethyl, (4-chloro) phenylthiomethyl, phenylthioethyl; 'aryl, where the aryl group is a phenyl, 5-indanyl or substituted phenyl group having 0 to 3 substituents, preferably

  
  <EMI ID = 85.1>

  
(4-hydroxy) -phenyl, (4-t-butyl) phenyl, p-nitrophenyl, 3,5-dinitro-phenyl, or p-carboxyphenyl, the latter having the free acid form or the sodium salt form; aralkenyl, where the aryl group is a phenyl group and the alkenyl group has 1 to 6 carbon atoms, such as 3-phenyl-2-propenyl group and the alkyl group has 1 to 3 carbon atoms, such as benzyloxymethyl,

  
  <EMI ID = 86.1>

  
the alkylthio portion has 1 to 6 carbon atoms, but can be branched, straight or cyclic, and the alkyl portion has 1 to 6 carbon atoms, such as methylthioethyl, ethylthioethyl, cyclohexylthiomethyl, decylthiobutyl, methylthiopropyl, isopropylthioethyl, methyl .

  
In addition to the esters (and thio esters) indicated above, amides are also included in the present invention, i.e. compounds

  
  <EMI ID = 87.1>

  
methyl, ethyl, phenyl, p-methoxyphenyl, benzyl, carboxymethyl, methylthioethyl, and hetero-aryl; are also encompassed by -COX'R the anhydrides

  
  <EMI ID = 88.1>

  
carbonyl, benzoyl and pivaloyl.

  
-COX'R radicals <3> particularly preferred according to the pre-

  
  <EMI ID = 89.1>

  
  <EMI ID = 90.1>

  
lower alkenyl, such as methallyl, 3-methylbutenyl, 3-butenyl, etc;

  
  <EMI ID = 91.1>

  
  <EMI ID = 92.1>

  
3-phthalidyl and acetoxymethyl, propionyloxymethyl, acetylthiomethyl, pivaloythiomethyl, allyl, 4-butenyl, 2-butenyl, 3-methyl-2-butenyl, phenacyl, acetoxyacetylmethyl, methoxymethyl, p-acetoxy-poxybenzyl, p-acetyl-poxy-penzoxy-poxybenzyl, 5-poxy-penzyl-poxybenzyl, poxy-poxybenzyl, 5-poxy-poxybenzyl, poxy-poxy-penzyl, poxy-poxybenzyl, 5-poxy-poxybenzyl indanylmethyl, 5-indanyl, benzyloxymethyl, ethylthioethyl, methylthiopropyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,

  
  <EMI ID = 93.1>

  
In the general representation of the present invention, structure IIa (above), the radical R <3> can be, in addition to hydrogen, 1) an acyl group (generically the group -OR <3> can be classified as an ester); or 2) R <3> is chosen from alkyl, aryl, aralkyl, etc., so that the -OR group <3> can be classified as an ether. For the modes of <EMI ID = 94.1>

  
acyl radicals (p = 1). In the so-called ether (2) embodiments of the present invention, R <3> is chosen from the same acyl radicals in

  
0

  
  <EMI ID = 95.1>

  
which all symbols are defined below:

  

  <EMI ID = 96.1>


  
  <EMI ID = 97.1>

  
which p = 1. Thus, with regard to the definition of R, R er R, the acyl radical can be, inter alia, an aliphatic, aromatic or heterocyclic, araliphatic or heterocyclyaliphatic carboxylic acid radical, substituted or not, a carbamyl radical substituted or not or a carbothiolque acid radical. A group of acyl radicals can be represented by

  
the general formula

  

  <EMI ID = 98.1>


  
in which X is 0 or S and R "represents hydrogen or an amino group; amino substituted as alkyl- and dialkoyl-amino where the alkyl radical comprises from 1 to 6 carbon atoms approximately; the following radicals, substituted or not : straight or branched chain alkyl in which the

  
  <EMI ID = 99.1>

  
or alkynyl typically comprising 2 to 6 carbon atoms; aryl, such as phenyl; aralkyl, such as benzyl; cycloalkyl, typically comprising 3 to 6 carbon atoms; or a heteroaryl or heteroaralkyl (non- and bicyclic) group in which the alkyl portion typically comprises 1 to 3 carbon atoms and the heterocyclic ring typically comprises 4 to 10 atoms and

  
  <EMI ID = 100.1>

  
above may be unsubstituted or they may be substituted with radicals such as OH, SH, SR (R is lower alkyl or aryl such as phenyl), alkyl or alkoxy groups having 1 to 6 carbon atoms about, halogens, such as Cl, Br, F and I, cyano, carboxy, sulfamino, carbamoyl, sulfonyl, azido, amino, substituted amino groups such as alkyl-lamino, including quaternary ammonium where the alkyl group comprises from

  
1 to 6 carbon atoms, haloalkyl such as trifluoromethyl, carboxyalkyl, carbamoylalkyl, N-substituted carbamoylalkyl, where the alkyl portion of the above four radicals comprises about 1 to 6 carbon atoms, amidino, guanidino, N-substituted guanidino, alkyl guanidino lower, etc. Representative examples of such acyl groups which might be mentioned are those in which "R" is benzyl, p-hydroxybenzyl, 4-amino-4-carboxybutyl, methyl, cyanomethyl, 2-pentenyl, n-.

  
  <EMI ID = 101.1>

  
, methyldiphenylmethyl; triphenylmethyl, 2-methoxyphenyl, 2,6-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,5-dimethyl-4-isoxazolyl, 3-butyl-5-methyl4-isoxazolyl, 5-methyl-3-phenyl-4- isoxazolyl, 3- (2-chlorophenyl) -5-methyl-

  
  <EMI ID = 102.1>

  
4-isoxazolyl, 3-phenyl-4-isoxazolyl, 5-methyl-3- (4-guanidinophenyl) 4-isoxazolyl, 4-guanidinomethylphenyle, 4-guanidinomethylbenzyle, 4-guanidinobenzyle, 4-guanidinophenyl, 2,6-dimethoxy-4 -guanidino, o-sulfobenzyl, p-carboxymethylbenzyle, p-carbamoylmethylbenzyle, m-fluorobenzyl, m-bromobenzyl, pchlorobenzyl, p-methoxybenzyl, 1-naphthylmethyle, 3-isothiazolylmethyle, 4-

  
  <EMI ID = 103.1>

  
xazolylmethyl, 1-imidazolylmethyl, 2-benzofuranylmethyle, 2-indolylmethyl, 2-phenylvinyl, 2-phenylethynyl, 1-amino-cyclohexyl, 2- and 3-thienylaminomethyl, 2- (5-nitrofuranyl) -vinyl, phenoxyphenyl, o-methylvinyl , o-chlorophenyl, o-phenylphenyl, p-aminomethylbenzyle, 1- (5-cyanotriazolyl) -methyl,

  
  <EMI ID = 104.1>

  
2- (5-nitrofuryl) methyl, 3-furylmethyl, 2-thienylmethyle, 3-thienylmethyl, tetrazolylmethyl, benzamidinomethyl and cyclohexylamidinomethyl.

  
The acyl group can also be a radical of the formula:

  

  <EMI ID = 105.1>
 

  
  <EMI ID = 106.1>

  
sulfur, carbonyl or nitrogen and R "is as defined above. Illustrative examples of the substituent

  

  <EMI ID = 107.1>


  
which might be mentioned are the allylthiomethyl, phenylthio-

  
  <EMI ID = 108.1>

  
3-imidazolethyl, 3-imidazolylpropyl, 3-imidazolylbutyl, 1-pyrroloethyl, 1-pyrrolopropyl, and 1-pyrrolobutyl.

  
Alternatively, the acyl group can be a radical of the formula:

  

  <EMI ID = 109.1>


  
  <EMI ID = 110.1>

  
balcoxy, phosphono, etc. Representative examples of the substituent

  

  <EMI ID = 111.1>


  
  <EMI ID = 112.1>

  
  <EMI ID = 113.1> <EMI ID = 114.1>

  
Other acyl radicals of interest in this class when X = oxygen are

  

  <EMI ID = 115.1>


  
  <EMI ID = 116.1>

  
halogen, such as chlorine, fluorine, bromine, iodine, amino, guanidino, phosphono group; hydroxy, tetrazolyl, carboxy, sulfo or sulfamino and R5 represents a phenyl group, substituted phenyl, a mono- or bicyclic heterocyclyl group containing one or more atoms of oxygen, sulfur or nitrogen in the ring, such as furyl, quinoxalyl, thienyle, quinolyle, quina-

  
  <EMI ID = 117.1>

  
and substituted heterocycles of the same kind, phenylthio, phenyloxy, lower alkyl of 1 to 6 carbon atoms, heterocyclic or heterocyclic-thio substituted; or cyano. Substitutes on portions

  
  <EMI ID = 118.1>

  
guanidinomethyl, carboxamidomethyl, aminomethyl, nitro, methoxy and methyl.

  
When R4 is chosen from hydrogen and hydroxy, amino or carboxy groups

  
  <EMI ID = 119.1>

  
nal or hexagonal having one or two hetero atoms of sulfur, oxygen or nitrogen, such as tetrazolyl, theinyl, furyl and phenyl groups, the radi-

  
  <EMI ID = 120.1> <EMI ID = 121.1>

  
The acyl radical can also be chosen from acid radicals of sulfur (1) or phosphorus (2):

  
""

  

  <EMI ID = 122.1>


  
where, with regard to 1.m and n are integers chosen from 0

  
  <EMI ID = 123.1>

  
alkali metal cations and organic bases; and R "is as defined above, for example an alkyl, alkenyl, aryl or hetero group.

  
  <EMI ID = 124.1>

  
as defined above, for example R "and ZR" are, representatively, alkyl, alkenyl, aryl, heteroaryloxy, Y 'and Y ", y

  
  <EMI ID = 125.1>

  
'"

  
sulphonyl) thienamycin, 0- (p-chlorophenylsulphinyl) thienamycin, 0- (o-nitro-

  
  <EMI ID = 126.1>

  
A particularly interesting class of acyl radicals are those acyl radicals which are selected from the group consisting of conventionally known N-acyl blocking or protecting groups such as carbobenzyloxy, ring-substituted carbobenzyloxy such as o- and p-nitrocarbobenzyloxy, p- methoxycarbobenzyloxy, chloroacetyl, bromoacetyl, phenylacetyl, t-butoxycarbonyl, trifluoroacetyl, bromoethoxycarbonyl, 9-fluorenylmethoxy-

  
  <EMI ID = 127.1>

  
bonyl, bromo-t-butoxycarbonyl, phenoxyacetyl, nonacyl protecting groups such as tri- (lower alkyl) silyl, eg trimethylsilyl and t-butyldimethyl are also of interest.

  
The following radicals, in accordance with the preceding definition

  
  <EMI ID = 128.1>

  
formyl, acetyl, propionyl, butyryl, chloroacetyl, methoxyacetyl, aminoacetyl, methoxycarbonyl, ethoxycarbonyl, methylcarbamoyl, ethylcarbamoyl, phenylthiocarbonyl, 3-amino-propionyl, 4-aminobutyryl, N-methylamino -acetyle, Namino, acetyl, Namino-acetyl, Namino, acetyl, Namino-acetyl, Namino, acetyl N-trimethylaminoacetyle, 3- (N, N-dimethyl) -aminopropionyl, 3- (N, N, N-trimethyl) aminopropionyl, N, N, N-triethylaminoacetyle,

  
  <EMI ID = 129.1>

  
nopionyl, hydroxyacetyl, 3-hydroxypropionyl, acryloyl, propynoyl, malonyl, phenoxycarbonyl, amidinoacetyl, acetamidinoacetyl, amidinopropionyl, acetamidinopropionyl, guanylureidoacetyl, guanylcarbamoyl, carboxycarbonyl, sulfacetyloaminoacetino <3> -dimethylaminoacetamidinopropiQnyle, ureidocarbonyl, dimethylaminoguanylthioacetyle, 3- (1 -methyl-4-pyridinium) propionyl, 3- (5-aminoimidazol-1-yl) propionyl, 3-methyl-1-imidazoliumacetyl, 3-sydazoliumacetyl, 3-sydazoliumacetyl, 3-sydazoliumacetyle aminomethylbenzoyl, oaminobenzoyl, sulfo, phosphono
  <EMI ID = 130.1>
 Another class of acyl radicals are those terminally substituted acyl radicals in which the substituent is

  
a basic group such as the following groups, substituted or not: amino, amidino, guanidino, guanyl and mono- and bicyclic heterocycles (aromatic and non-aromatic) containing nitrogen, where the heteroatom (s), in addition to nitrogen, are chosen from oxygen and sulfur. Such substituted acyl groups can be represented by the following formula

  

  <EMI ID = 131.1>


  
wherein m and n are integers selected from 0 to 5; A is 0, NR '(R' is hydrogen or a lower alkyl group having 1 to 6

  
  <EMI ID = 132.1>

  
if in the following group:

  
1) amino or substituted amino groups

  

  <EMI ID = 133.1>


  
in which the meanings of R [deg.] are independently chosen from:
hydrogen; N (R ') 2 (R' is hydrogen or a lower alkyl group having 1 to 6 carbon atoms); lower alkyl and lower alkoxyl having 1 to 6 carbon atoms; (lower alkoxy) lower alkyl in which the alkoxyl portion comprises from 1 to 6 carbon atoms and the alkyl portion comprises from 2 to 6 carbon atoms; cycloalkyl and cycloalkyl where the cycloalkyl portion comprises from 3 to. 6 carbon atoms and the portion

  
  <EMI ID = 134.1>

  
linked together to form with the nitrogen atom to which they are attached a ring having 3 to 6 carbon atoms.

  
  <EMI ID = 135.1>

  

  <EMI ID = 136.1>


  
in which the meaning of R [deg.] is independently selected from: hydrogen; N (R ') 2 (R' is hydrogen or a lower alkyl group having 1 to 6 carbon atoms); lower alkyl and lower alkoxyl having from 1 to 6 carbon atoms, (lower alkyl) lower alkyl where

  
the alkoxyl portion contains from 1 to 6 carbon atoms and the alkyl portion comprises from 2 to 6 carbon atoms (when the lower alkoxy) lower alkyl radical is attached to a carbon atom, the alkyl portion comprises

  
  <EMI ID = 137.1>

  
  <EMI ID = 138.1>

  
can be linked together to form with the atoms to which they are attached a ring having 3 to 6 atoms;

  
3) guanidino and substituted guanidino groups:

  

  <EMI ID = 139.1>


  
in which R [deg.] is as defined in 2) above;

  
  <EMI ID = 140.1>

  

  <EMI ID = 141.1>


  
in which R [deg.] is as defined in 2) above;

  
  <EMI ID = 142.1>

  
matic and non-aromatic) containing nitrogen having 4 to 10 nuclear atoms, in which the heteroatom (s), in addition to nitrogen, are selected from oxygen and sulfur. Such heterocyclic groups are represented representatively by the following list of radicals:
(R 'is H or a lower alkyl group having 1 to 6 carbon atoms:

  

  <EMI ID = 143.1>
 

  
The following particular acyl radicals included in this class are also representative:

  

  <EMI ID = 144.1>
 

  
Preparation of starting materials Ia, Ib, le, Id and Ie -

  
The starting materials described above are conveniently prepared from an N-protected thienamycin (1) such as thiena

  
  <EMI ID = 145.1> <EMI ID = 146.1>
  <EMI ID = 147.1>
  <EMI ID = 148.1>

  
  <EMI ID = 149.1>

  
is an easily removable blocking group such as the following: carbobenzyloxy, ring-substituted carbobenzyloxy such as o- and p-nitrocarbo-

  
  <EMI ID = 150.1>

  
tyl, t-butoxycarbonyl, trifluoroacetyl, bromoethoxycarbonyl, 9-fluoroenylemethoxycarbonyl, dichloroacetyl, o-nitrophenylsulfenyl, 2,2,2-trichloroethoxycarbonyl, bromo-t-butoxycarbonyl, phenoxyacetyl, protective groups such as lower tri (alkyl) non-acyl , for example trimethylsilyl and t-butyldimethylsilyl are also of interest. Particularly preferred blocking groups on nitrogen are substituted or unsubstituted carbobenzyloxy radicals:

  

  <EMI ID = 151.1>


  
  <EMI ID = 152.1>

  
nitro: and bromo-t-butoxycarbonyl

  

  <EMI ID = 153.1>


  
The final nitrogen deblocking operation for the preparation of the, or is carried out by any of a variety of well-known techniques which include hydrolysis or hydrogenation; when hydrogenation is used, suitable conditions include a solvent such as a lower alkanol in the presence of a hydrogenation catalyst such as palladium, platinum or their oxides.

  
  <EMI ID = 154.1>

  
example an acyl halide or acyl anhydride such as an aliphatic, aromatic, heterocyclic, araliphatic or heterocyclic-aliphatic carboxylic acid halide or anhydride. Other acylating agents can also be used, for example mixed carboxylic acid anhydrides and in particular lower alkyl esters of mixed carboxylic carbon anhydrides: also carboxylic acids in the presence

  
  <EMI ID = 155.1>

  
a carboxylic acid such as p-nitrophenyl ester.

  
Such N-acylated thienamycins starting materials are fully disclosed in US patent application 634,291 filed November 21, 1975 and in its continued application. These patent applications are incorporated herein by reference.

  
The acylation reaction can be carried out at a temperature between approximately -20 [deg.] C and approximately 100 [deg.] C, but preferably at a temperature between -9 and 25 [deg.] C. Any solvent in which the reactants are soluble and substantially inert can be used, for example polar solvents such as water, alcohols and polar organic solvents in general such as dimethyl formamide (DMF), l 'Hey-

  
  <EMI ID = 156.1>

  
(THF), acetonitrile, heterocyclic amines such as pyridine, ethyl acetate, aqueous mixtures of the above solvents, as well as halogenated solvents such as methylene chloride and chloroform. The reaction

  
is carried out for a period of between about five minutes and a maximum of three hours, but in general a reaction time of about 0.5 to about 1 hour is sufficient. The following equation illustrates this process using a carboxylic acid halide; however, it should be understood that by substituting a carboxylic anhydride or other functionally equivalent acylating agent, similar products can be obtained.

  

  <EMI ID = 157.1>
 

  
Generally, when the acylation reaction described above uses an acid halide (halides which can be used are chlorides, iodides or bromides) or an anhydride, the reaction is carried out in water or in an aqueous mixture of a. polar organic solvent such as acetone,

  
  <EMI ID = 158.1>

  
In carrying out the reactions described above, it is generally not necessary to protect the 2-carboxy group or the 1-carboxy group; however, in cases where the acylating agent is excessively water sensitive, it is sometimes advantageous that the acylation be carried out in a non-aqueous solvent system. Triorganosilyl derivatives
(or tin) of thienamycin are formed rapidly to give the derivative tris-

  
  <EMI ID = 159.1>

  

  <EMI ID = 160.1>


  
Such derivatives, which are easily soluble in organic solvents, are conveniently prepared by treating thienamycin with an excess of hexamethyldisilazane and a stoichiometric amount of trimethylchlo-

  
  <EMI ID = 161.1>

  
resulting is removed by centrifugation and the solvent is removed by evaporation to give the desired silyl derivative.

  
The intermediate starting materials are prepared according to the following scheme; however, it should be noted that direct esterification, without protection of the amino group, is also possible.

  

  <EMI ID = 162.1>


  
where all the symbols are as defined previously.

  
  <EMI ID = 163.1>

  
by conventional methods known to those skilled in the art. These methods include the following:

  
1) Reaction of ^ (or I) with a diazoalkane such as diazomethane, phenyldiazomethane, diphenyldiazomethane, etc., in a solvent such as dioxane, ethyl acetate, acetonitrile, etc., at a temperature between 0 [deg.] C and reflux temperature for a period of a few minutes to 2 hours.

  
2) Reaction of an alkali metal salt of 1 with an activated alkyl halide such as methyl iodide, benzyl bromide or

  
  <EMI ID = 164.1>

  
pivaloylocymethyl, etc. Suitable reaction conditions include solvents such as hexamethylphosphoramide and the like at a temperature between [deg.] C and 60 [deg.] C for a period ranging from a few minutes to 4 hours.

  
3) Reaction of ^ _, with an alcohol such as methanol, ethanol, benzyl alcohol, etc. This reaction can be carried out in the presence of a carbodiimide condensing agent such as dicyclohexylcarbodiimide or similar solvents. The solvents which can be used, at a temperature between 0 [deg.] C and the reflux temperature for 15 minutes at 18 h.

  
  <EMI ID = 165.1>

  
4) Reaction of an N-acylated acid anhydride of 1 prepared

  
by reacting the free acid 1 with an acid chloride such as ethyl chloroformate, benzyl chloroformate, etc., with an alcohol such as those indicated "in 3) under the same reaction conditions as indicated above for 3 The anhydride is prepared by reacting 1 and the acid chloride in a solvent such as tetrahydrofuran (THF), CH2C12, etc., to

  
  <EMI ID = 166.1>

  
15 minutes to 10 hours.

  
5) Reaction of labile esters of ^ such as tri-methyl ester

  
  <EMI ID = 167.1>

  
  <EMI ID = 168.1>

  
  <EMI ID = 169.1>

  
reflux temperature for 15 minutes to 16 hours. For example, according to the following diagram:

  

  <EMI ID = 170.1>
 

  

  <EMI ID = 171.1>


  
  <EMI ID = 172.1>

  
other symbols are as defined previously.

  
The amides according to the present invention are very conveniently prepared by reacting the acid anhydride (le, X '= 0, R3' = acyl) with ammonia or the chosen amine, for example the alkyl-, dialkoyl -, aralkyl amines or heterocyclic amines listed above.

  
The esterification schemes given above are well known in the art of bicyclic beta-lactam antibiotics of the same kind and indeed in all the synthesis of organic compounds in general and it should be noted that there is no no undue criticality of the reaction parameters in the preparation of the N-acylated and carboxylated derivatives useful as starting materials in the practice of the present invention.

  
The starting materials Ia and Ie are conveniently prepared by any of various well known reactions of deterification or etherification on the secondary alcoholic group of Id.

  
Such methods include:

  

  <EMI ID = 173.1>


  
1) For the preparation of ethers' embodiments

  
the present invention, the acid catalyzed reaction of Id with a diazoalkane such as diazomethane, phenyldiazomethane, diphenyldiazomethane, etc., in an inert solvent such as dioxane, tetrahydrofuran

  
  <EMI ID = 174.1>

  
presence of a catalytic amount of a strong acid or a Lewis acid such as toluenesulfonic acid, trifluoroacetic acid, fluoboric acid, boron trifluoride, etc., at a temperature between -78 [deg .] C and 25 [deg.] C for a period of a few minutes to 2 hours.

  
2) For the preparation of embodiments of ethers

  
the present invention, the reaction of Id with an alkylating agent such as active halides, for example methyl iodide, benzyl bromide, m-phenoxybenzyl bromide, etc; alkylsulfonates such as

  
dimethyl sulfate, diethyl sulfate, methylfluorosulfonate, etc., in the presence of a strong base capable of forming the alcoholate anion of Ib. Usable bases include hydrated oxides and oxides of alkali metals and alkaline earth metals , alkali metal alcoholates such as potassium tert-butoxide, tertiary amines such as triethylamine, alkyl and aryl derivatives of alkali metals such as phenyllithium and amides of alkali metals such as sodium amide. Solvents which can be used include any inert anhydrous solvent such as

  
  <EMI ID = 175.1>

  
(HMPA), dioxane and similar solvents at a temperature between -78 [deg.] C and 25 [deg.] C for a period ranging from a few minutes to 4 hours.

  
3) For the preparation of ester embodiments of the present invention, reaction of Id with any of the acyl groups listed above in their acid form. This reaction can be carried out in the presence of a carbodiimide condensing agent such as dicyclohexylcarbodiimide or the like. Suitable solvents include

  
  <EMI ID = 176.1>

  
period of 15 minutes to 12 hours.

  
4) For the preparation of ester embodiments of the present invention, reaction of Id with an acyl halide or an acid anhydride, where the acyl moiety is. described above. Generally, when the acylation reaction described above uses an acid halide
(the halides which can be used are chlorides, iodides or bromides) or an acid anhydride, the reaction is carried out in an anhydrous organic solvent such as acetone, dioxane, methylene chloride, chloroform, DMF or solvents of the same kind in the presence of a suitable acceptor base such as NaHCO3, MgO, triethylamine, pyridine, etc., at a temperature between 0 [deg.] C and 40 [deg.] C for 1 to 4 hours.

  
Usable acyl halides and anhydrides include:
acetic anhydride, bromoacetic anhydride, propionic anhydride, benzoyl chloride, phenylacetyl chloride, azidoacetyl chloride, 2-thienyl-acetyl chloride, 2-, 3- and 4-nicotinyl chloride, p-nitro- chloride <EMI ID = 177.1>

  
acetyl, methanesulfonyl chloride, dibenzyl phosphorochlorate, dimethyl thiophosphorochlorhydrate, 2-furoyl ethyl anhydride

  
  <EMI ID = 178.1>

  
the), etc.

  
5) For the preparation of ester embodiments of the present invention, the reaction of Id with an appropriately substituted ketene or isocyanate, such as ketene, dimethyl ketene, methyl isocyanate, methyl isothiocyanate, l chlorosulfonyl isocyanate, etc. Useful solvents include dioxane, tetrahydrofuran, chloroform, etc., at a temperature between -70 [deg.] C and 60 [deg.] C for a period of 15 minutes to 18 hours.

  
The intermediate product is then released with nitrogen

  
  <EMI ID = 179.1>

  
and the. From it, we prepare it by unblocking the carboxyl group

  

  <EMI ID = 180.1>


  
The starting material 1a is conveniently and preferably obtained.

  
  <EMI ID = 181.1>

  
easily removable cage (see above). Starting material 1a is prepared by deblocking according to any of a variety of well known methods which include hydrolysis and hydrogenation. When preferred carboxyl blocking groups are used (hereinafter), the preferred deblocking technique is hydrogenation, wherein the intermediate species (Ie) in a solvent such as a lower alkanol is hydrogenated in the presence of a hydrogenation catalyst such as palladium, platinum or their oxides.

  
In this regard, it should be noted that "blocking groups"

  
  <EMI ID = 182.1> .haloalkyl, alkanoyloxyalkyl, alkoxyalkyl, alkenyl, substituted alkyl or aralkoxyalkyl, also including alkylsilyl groups, where the alkyl portion has from 1 to 10 carbon atoms. For example, "blocking groups" R Suitable <3> 'include benzyl, phenacyl, p-nitrobenzyl, methoxymethyl, trichloroethyl, trimethylsilyl, tributyltin, p-methoxybenzyl, benzhydryl. These blocking groups are preferred because they are easily removable blocking groups generally well known in the cephalosporin and penicillin art.

  
Preferred blocking groups of the carboxyl group are benzyl and substituted benzyl:

  

  <EMI ID = 183.1>


  
where n is from 0 to 2 (n = 0, R '= H) and RI is a lower alkoxyl group

  
or nitro.

  
As a variant, it should be noted that the compounds according to the present invention, IIa, can be obtained by operating on the substituted derivatives of N-methylene thienamycin, II, so as to form derivatives

  
  <EMI ID = 184.1>

  
written above, except that species II replaces the starting materials described above, such as la, le and le and that, of course, we have not

  
no need to unlock N.

  
Preparation

  
The preparation of the compounds according to the present invention is conveniently described according to the four classes or four embodiments defined above, namely:

  
1) Amidines; .2) Guanidines; 3) Substituted pseudo-ureas and

  
4) Imido esters and imido thioesters.

  
1) Amidines. In general, compounds of Class 1) can be conveniently prepared by reacting thienamycin (I) or a

  
  <EMI ID = 185.1>

  
  <EMI ID = 186.1>

  
imido ester (a) or a substituted imido halide (b):

  

  <EMI ID = 187.1>
 

  
  <EMI ID = 188.1>

  
chlorine; and -OR "is a leaving group, where R" is a lower alkyl group such as methyl, ethyl, etc. Alternatively, class 1 compounds can be prepared by reacting a class 4 compound with

  
  <EMI ID = 189.1>

  
the desired species of class 1. Representative examples of reagents a), b) and c) are listed below.

  
The solvents which can be used for the preparation of the compounds

  
Class 1 according to the reaction schemes above, depending on the identity of the starting thienamycin and the reagent, include water, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, acetone, acetonitrile or mixtures thereof. The reaction is conducted

  
  <EMI ID = 190.1>

  
about. There are no critical conditions regarding the precise identity of the reaction solvent or the reaction variables between the limits described above, provided only that the reaction solvent is inert.

  
or substantially inert with respect to the expected course of the reaction. Representative examples of reagents that can be used include the following:

  

  <EMI ID = 191.1>


  
Methyl formimidate, ethyl formimidate, methyl acetimidate, ac-

  
  <EMI ID = 192.1>

  
methyl midate, methyl chloroacetimidate, methyl cyclohexylcarboximidate, methyl 2-furylcarboximidate, methyl p-nitrobenzimidate,

  
  <EMI ID = 193.1>

  
methyl formimidate, methyl N-isopropyl formimidate, etc.

  
These imido ester reagents (a) are conveniently prepared by any of a variety of well known methods, such as:

  
1) Reaction of a nitrile, RCN, with a lower alkanol in the presence of HCl according to the well known Pinner synthesis.

  
2) Reaction of a nitrile, RCN, with a lower alkanol in the presence of a base. Typically the reaction is carried out at -0-40 [deg.] C in the presence of an excess of the alcohol with a catalytic amount of an alkali metal alcoholate for a period of 15 minutes to 4 hours.

  
0

  
  <EMI ID = 194.1>

  
alkyl, such as methyl chloroformate, at 25-45 [deg.] C for 1-4 hours.

  
  <EMI ID = 195.1>

  
  <EMI ID = 196.1>

  
triethyloxonium in an inert solvent such as ether, chloroform or a similar solvent at 0-23 [deg.] C for 10 minutes to 2 hours.

  
5) The transformation of a readily available imido ester,

  
  <EMI ID = 197.1>

  
by reacting the first-mentioned compound with an alkyl amine, R'NH2, in a mixture of water and an immiscible solvent such as ether or chloroform at 0-23 [deg.] C for a period of 5 minutes to 1 hour.

  
b) Imido substituted halides:

  
Chloropiperidino methylium chloride, chlorodimethylforminium chloride, chlorodiethyl forminium chloride, etc.

  
These imido halide reagents (c) are conveniently prepared by any of a variety of known methods, such as:

  
1) The reaction of an N, N-disubstituted amide, &#65533; 1 2 with a

  
  <EMI ID = 198.1>

  
3-aminomethyl pyridine, 2-aminomethyl thiophene, ethanolamine, dimethylamino-. thylamine, N-2- (aminoethyl) pyrrolidine, cyclohexylamine, n-heptylamine, iso-

  
  <EMI ID = 199.1>

  
The reaction involving the reagents (a) can typically be represented by the following diagram:

  

  <EMI ID = 200.1>


  
  <EMI ID = 201.1>

  
gene and X 'is oxygen.

  
The reaction involving reagents (b) can typically be represented by the following diagram:

  

  <EMI ID = 202.1>


  
  <EMI ID = 203.1> The reaction involving reagents (c) can typically be represented by the following diagram:

  

  <EMI ID = 204.1>


  
where all the symbols are as defined above and X is -OR or -SR, where R is preferably a lower alkyl group such as methyl or ethyl.

  
  <EMI ID = 205.1>

  
nable, they can be removed independently by well known methods to give species 3, 4 and 5.

  
  <EMI ID = 206.1>
  <EMI ID = 207.1>
 2) Guanidines:

  
In general, Class 2 compounds can be conveniently prepared by reacting thienamycin or an O- or carboxyl derivative.

  
  <EMI ID = 208.1>

  
example 0-alkyl, 0-aryl) pseudothiourea or an S-alkyl or S-aryl pseudothiourea; or (b) by reacting a Class 3 compound (above) with ammonia or an amino compound such as an alkyl, aralkyl or -hetero-aralkyl amine.

  
Solvents useful for these reactions include water and aqueous mixtures of polar organic solvents buffered to pH

  
from 7 to 9 or anhydrous polar organic solvents such as dimethylformamide or hexamethylphosphoramide at a temperature between 0 and 40 [deg.] for a period of 1 to 24 hours.

  
Usable reagents (a) and (b) include the following:
(a) -OR pseudo-urea and -SR pseudothiourea:

  
0-methyl pseudo-urea, S-methylpseudothiourea, S-methyl-pseudo-

  
  <EMI ID = 209.1>

  
urea, 0-N, N-trimethylpseudo-urea, etc.

  
(b) Amino reagents:

  
These reagents are the same as indicated for the preparation of class 1, (c), above.

  
The reaction involving the reagents (a) can typically be represented by the following diagram:

  

  <EMI ID = 210.1>


  
  <EMI ID = 211.1>

  
  <EMI ID = 212.1>

  
  <EMI ID = 213.1>

  
The reaction involving the reactants (b) can be represented typically by the following diagram

  

  <EMI ID = 214.1>


  
in which all the symbols are as defined above.

  
3) Substituted pseudo-ureas:

  
In general, one can conveniently prepare them. class compounds

  
3 by reacting a thienamycin carbamyl or N-substituted thiocarbamyl compound
(a), for example
  <EMI ID = 215.1>
 in which all the symbols are as defined above. 3) Substituted pseudo-ureas:

  
In general, Class 3 compounds can be conveniently prepared by reacting an N-substituted thienamycin carbamyl or thiocarbamyl compound (a), for example

  

  <EMI ID = 216.1>


  
with an alkylating agent (b) such as an active alkyl or aralkyl halide or sulfuric ester.

  
Solvents useful for the above reaction include lower alkanols, dioxane and acetonitrile. a temperature

  
  <EMI ID = 217.1>

  
The reagents (a) which can be used for the reaction scheme above include N-acyl thienamycins:

  

  <EMI ID = 218.1>


  
  <EMI ID = 219.1>

  
an alkyl group as defined above and preferably is chosen from Q

  
fi <EMI ID = 220.1> methylcarbamyl, ethylcarbamyl, phenylcarbamyl, p-bromophenylcarbamyl, phenylthiocarbamyl, methylthiocarbamyl, dimethylcarbamyl, etc.

  
Reagents (b), - alkylating agents, 'which can be used include the following: methyl iodide; benzyl bromide, dimethyl sulfate, diethyl sulfate, allyl bromide, 2-thienyl bromide, methallyl bromide, p-nitrobenzyl bromide, chloromethyl, ether, etc.

  
The reaction involving reagents (a) and (b) above can typically be represented by the following diagram:

  

  <EMI ID = 221.1>


  
  <EMI ID = 222.1>

  
  <EMI ID = 223.1>

  
  <EMI ID = 224.1>

  
4) Imido esters and imido thio esters:

  
In general, Class 4 compounds can be conveniently prepared by reacting an appropriate protected N-acyl, N-thioacyl or N-alkoxy carbonyl derivative of thienamycin (a) with an alkylating agent.
(b).

  
Solvents usable for the above reaction include methylene chloride, tetrahydrofuran, dioxane, chloroform, etc., at a temperature between -78 [deg.] C and 25 [deg.] C, for a period of 5 minutes to 3 hours.

  
Suitable N-acyl thienamycins (a) starting materials

  

  <EMI ID = 225.1>


  
  <EMI ID = 226.1>

  
Suitable alkylating agents (b) include the following: triethyl oxonium fluoroborate, methyl fluorosulfonate and trimethyloxonium hexafluorophosphate.

  
The reaction involving the above reagents (a and b) can typically be represented by the following diagram:

  

  <EMI ID = 227.1>


  
  <EMI ID = 228.1>

  
the deblocking is conveniently carried out by moderate aqueous hydrolysis at a pH of 3 to 6. It should be noted that the above reaction mixture can be used directly in the reaction with the amine (c) as described in

  
  <EMI ID = 229.1>

  
ceptables which can be used as an active ingredient in suitable unit dosage forms. Also, they can be combined with other drugs to give compositions having a broad spectrum of activity.

  
The novel compounds are valuable antibiotics active against a variety of Gram-positive and Gram-negative bacteria and, therefore, find utility in human and veterinary medicine. The compounds according to the present invention can therefore be used as antibacterial drugs to treat infections caused by Gram-positive or Gram-negative bacteria, for example against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia, Salmonella typhosa,

  
  <EMI ID = 230.1>

  
  <EMI ID = 231.1>

  
animal feed, for the preservation of food articles and as disinfectants. For example, they can be used in aqueous compositions at concentrations between 0.1 and 100 parts of antibiotic per million parts of solution in order to destroy and inhibit the growth of harmful bacteria on medical equipment.

  
and dental and as bactericides in industrial applications, for example in water-based paints and in white water of paper mills to prevent the growth of harmful bacteria.

  
The products according to the present invention can be used singly or in combination as an active ingredient in any of various pharmaceutical preparations. These antibiotics and their corresponding salts can be used in the form of capsules, tablets, powders, liquid solutions, suspensions or elixirs. They can be administered orally, intravenously or intramuscularly.

  
The compositions are preferably presented in a

  
suitable form for absorption through the gastrointestinal tract. Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as binders, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, starch,

  
corn, calcium phosphate, sorbitol or glycine; lubricants, for example magnesium stearate, talc, polyethylene glycol; silica; disintegrating agents, for example potato starch or acceptable wetting agents such as sodium lauryl sulfate. Tablets can be coated according to methods well known in the art. Liquid preparations for oral administration may be in the form of an aqueous or oily suspension, solution, emulsions, syrups, elixirs, etc., or may be presented as a dry product, for reconstitution with water or other suitable vehicles before use.

   These liquid preparations may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, gelatin. aluminum stearate or hydrogenated edible oils, for example almond oil, fractionated coconut oil, oily esters, propylene glycol or alcohol

  
  <EMI ID = 232.1>

  
or propyl or sorbic acid. Suppositories will contain conventional suppository bases, for example cocoa butter or other glycerides.

  
Compositions for injection may be presented under

  
in unit dose form in ampoules or in multiple dose containers with an added preservative. The compositions can be in forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain processing aids such as suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, for example sterile water free.

  
of pyrogen, before use.

  
The compositions can also be prepared in forms suitable for absorption through the mucous membranes of the nose and the nose.

  
throat or bronchial tissue and can conveniently take the form of powder or liquid for spraying or inhalation, lozenges

  
to suck, whitewash for the throat, etc. For eye treatment or

  
ears, the preparations can be presented as individual capsules, in liquid or semi-solid form, or they can be used in the form of drops, etc. Compositions for topical application can be prepared in hydrophobic or hydrophilic bases in the form of ointments, creams, lotions, washes,

  
powders, etc.

  
Also, in addition to a vehicle, the present compositions can include other ingredients such as stabilizers,

  
binders, anti-oxidants, preservatives, lubricants, suspending agents, viscosity agents or flavoring agents, etc. In addition, there may also be other active ingredients in the composition so that a wider spectrum of antibiotic activity is obtained.

  
For use in veterinary medicine, the composition can be presented, for example, as an intramammary preparation in slow or rapid release bases.

  
The doses to be administered depend to a large extent on the condition of the subject being treated and the weight of the host, route and

  
the frequency of administration, the parenteral route being preferred for generalized infections and the oral route for intestinal infections. In general, a daily oral dose consists of approximately

  
2 to about 600 mg of active ingredient per kg of subject's body weight

  
in one or more applications per day. A preferred daily dose for adult humans is between about 15 and 150 mg of active ingredient per kg of body weight.

  
The present compositions can be administered in various unit dosage forms, for example solid or liquid forms suitable for oral ingestion. Unit dose compositions, whether liquid or solid, may contain from 0.1% to 99% of

  
  <EMI ID = 233.1>

  
composition will generally contain from about 15 mg to about 1500 mg of the active ingredient; however, in general, it is preferable to use an amount of between about 100 and 1000 mg. For parenteral administration, the unit dosage form is usually the pure compound dissolved in sterile slightly acidified water or as a soluble powder intended for dissolution.

  
The following examples illustrate, but do not limit, the product, process, composition or process aspects of the invention.

  
  <EMI ID = 234.1>

  
presented by the following symbol:

  

  <EMI ID = 235.1>


  
wherein the secondary alcoholic group, the amino group and the carboxyl group are represented. Thus, the compounds according to the present invention can be conveniently represented as follows:

  

  <EMI ID = 236.1>


  
  <EMI ID = 237.1>

  

  <EMI ID = 238.1>


  
Preparation of silylated thienamycin

  
Thienamycin (80.0 mg) is suspended in 40 cm2

  
  <EMI ID = 239.1>

  
at 25 [deg.] C with vigorous stirring. The suspension is then centrifuged to remove the ammonium chloride. The supernatant liquid is stripped under a stream of nitrogen to give an oil for subsequent reaction.

Example 1a

  

  <EMI ID = 240.1>


  
  <EMI ID = 241.1>

  
Thienamycin (57 mg, 162 pmoles) is silylated according to the procedure described above. The silylated antibiotic Th (TMS) 3 is dissolved in methylene chloride (6 cm <3>) in a flask stoppered by a diaphragm under positive nitrogen pressure and cooled in a dry ice-acetone bath. A. the magnetically stirred solution, a solution is added

  
  <EMI ID = 242.1> is followed by the addition of a solution of chloropiperidinomethylium chloride (67 mg, 405 moles) in methylene chloride (465 µl) After 1 hour in the dry ice bath, the reaction solution is added rapidly to a tetrahydrofuran-0.1N phosphate buffer solution pH 7.0 (1: 1)

  
  <EMI ID = 243.1>

  
trahydrofuran (after elution with water) to give 12.9 mg (22%) of product
(as measured in solution assuming [pound] 8,030 as for thienamycin.

  
  <EMI ID = 244.1>

Example 2

  

  <EMI ID = 245.1>


  
Preparation of N-benzimidoyl thienamycin

  
Thienamycin (59 mg, 212 µmol) is dissolved in a 33% solution of N, N-dimethylformamide-phosphate buffer (0.05N) at pH 7

  
  <EMI ID = 246.1>

  
HCl methylbenzimidate (340 mg, 1981 µmoles) is added all at once. After 30 minutes the solution is extracted twice with an equal volume of chloroform and adjusted with dilute aqueous phosphoric acid.

  
  <EMI ID = 247.1> 10% aqueous hydrofuran which elutes the product. This fraction is concentrated to half of its volume and dried by freezing to give 50 mg of the product. Electrophoretic mobility (50 V / cm, 20 min, 0.1 N phosphate buffer <EMI ID = 248.1>

  
0.1N phosphate pH 7.

Example 3

  

  <EMI ID = 249.1>


  
Preparation of N-benzimidoyl thienamycin p-tert-butylbenzyl ester

  
thienamycin

  
Benzimidoyl thienamycin (3.2 mg) is suspended in hexamethylphosphoramide (75 µl) containing p-tertbutylbenzyl bromide (3.8 µl) and the suspension is stirred magnetically at 22 [deg.] vs. After 45 minutes, a solution results which is stirred further. The product is then precipitated from solution with ether and the crude product is chromatographed on a thick plate of sili- gel.

  
  <EMI ID = 250.1>

  
  <EMI ID = 251.1>

  

  <EMI ID = 252.1>


  
  <EMI ID = 253.1>

  
Benzimidoyl thienamycin (5.9 mg) is dissolved in hexamethylphosphoramide (100 µl) containing 1-bromo-3-methyl-2-butene
(4.8 µl) and triethylamine (0.5 µl) and the solution stirred magnetically at 22 ° C. After 1 hour, the crude reaction mixture is chromatographed

  
  <EMI ID = 254.1>

  
ge 8: 2 chloroform-ethanol. The band of Rf 0.1 - Rf 0.3 is removed and eluted

  
  <EMI ID = 255.1> midoyl thienamycin is isolated as a solid after precipitation from a solution in an ethanol-chloroform mixture with

  
hexane.

Example 5

  
Preparation of N-formimidoyl thienamycin

  

  <EMI ID = 256.1>


  
Thienamycin (517 mg) is dissolved in phosphate buffer

  
  <EMI ID = 257.1>

  
maintaining a pH of 8.5, methyl formimidate hydrochloride (711 mg) is added portionwise over a period of 2-3 minutes. After an additional 10 minutes, the pH of the solution is brought to 7.0 using 2.5N hydrochloric acid. The solution is chromatographed on an XAD-2 resin column (150 cm <3>) which is eluted with water. The N-formimidoyl thienamy- derivative

  
  <EMI ID = 258.1>

  

  <EMI ID = 259.1>


  
  <EMI ID = 260.1> solution at pH 9.5 by addition of 2.5N sodium hydroxide solution.

  
To the magnetically stirred solution was added acid sulfate O-methylisourea (43 mg) causing a slight drop in pH. An additional quantity of sodium hydroxide solution is added so as to make

  
  <EMI ID = 261.1>

  
The solution is then acidified to pH 7.0. A sample of the solution containing a mixture of thienamycin and N-guanyl thienamycin indicates two bioactive zones after electrophoresis (50 V / cm, 20 minutes, 0.05N phosphate buffer pH 7) and bioautography on plates containing S. aureus .

Example 7

  

  <EMI ID = 262.1>


  
  <EMI ID = 263.1>

  
0.1N by means of an automatic dispensing burette. To the magnetically stirred solution is added portionwise CI-30-2,4.5 -trichlorophenylisourea hydrochloride (76 mg) so as to allow the automatic burette to maintain a nearly constant pH. The reaction is carried out for

  
  <EMI ID = 264.1>

  
diluted. A sample of this solution containing thienamycin and N-guanyl thienamycin is subjected to electrophoresis (50 V / cm, 25 minutes, phosphate buffer, 0.1N ph 7.0) and shows a Sakaguchi spreading zone. positive 2.0 cm towards the anode and an area of positive ninhydrin spreading 1.5 cm in the same direction.

Example 8

  

  <EMI ID = 265.1>


  
  <EMI ID = 266.1>

  
is mixed with 2,4,5-trichlorophenol (12.5 g); the mixture is heated <EMI ID = 267.1>

  
reaction is flushed quickly with nitrogen. Dry hydrochloric acid gas is then bubbled slowly through the melt and the reaction mixture allowed to cool to 22 ° C. The resulting solid material is washed thoroughly with ether and filtered to give the hydrochloride.

  
  <EMI ID = 268.1>

  
che, melting point 205-206 [deg.] C.

Example 9

  

  <EMI ID = 269.1>


  
Preparation of N-dimethylaminoethylene thienamycin

  
Thienamycin (16.5 mg) is silylated with hexamethyldisilazane (200 µl) and trimethylchlorosilane (60 µl) in the usual manner. Silylated thienamycin is suspended in chloroform

  
  <EMI ID = 270.1>

  

  <EMI ID = 271.1>


  
  <EMI ID = 272.1> <EMI ID = 273.1>

  
22 [deg.] C. After 2 hours, the hexamethylphosphoramide solution is dissolved in 2 cm <3> methylene chloride and the product is precipitated with so-

  
  <EMI ID = 274.1>

  
was 10% tetrahydrofuran and chromatographed on a column packed with XAD-2 resin. N-formimidoyl thienamycin pivaloyloxymethyl ester is isolated as a solid after elution from the column with tetrahydrofuran and lyophilization.

Example 11

  
Preparation of N-trifluoroacetamidoyl thienamycin

  

  <EMI ID = 275.1>


  
Thienamycin (199 mg) is dissolved in 0.1N phosphate buffer at pH 7

  
  <EMI ID = 276.1>

  
While maintaining this pH with an automatic burette, one adds in a single

  
  <EMI ID = 277.1>

  
  <EMI ID = 278.1>

  
in the first half column volume. The eluate is rechromatographed in a similar manner on Dowex 50-X4 (100 cm ', Na cycle, particles 0.037-0.074 mm) and the first column volume is concentrated and chromatographed.

  
  <EMI ID = 279.1>

  
Thienamycin elutes in 2.5 to 5.0 column volumes, which is lyophilized to obtain a white solid (15 mg). UV (0.1N phosphate buffer pH 7)

  
  <EMI ID = 280.1>

  
mobility 2.0 cm (towards the cathode)

Example 12

  
Preparation of N-acetimidoyl thienamycin
  <EMI ID = 281.1>
 Thienamycin (190 mg) is dissolved in phos- buffer.

  
  <EMI ID = 282.1>

  
with agitation, magnetic. The solution is adjusted to pH 8.5 using

  
a 2.5N solution of sodium hydroxide distributed by an automatic burette. While maintaining a pH of 8.5, ethyl acetimidate hydrochloride (400 mg) is added portionwise over a few minutes - After an additional 40 minutes, the pH is adjusted to 7.0 with hydrochloric acid 2.5N.

  
  <EMI ID = 283.1>

  
Na + cycle, particles 0.074-0.149 mm) and eluted with water.

  
  <EMI ID = 284.1>

  
and is lyophilized to give a white solid (88 mg). UV (tam-

  
  <EMI ID = 285.1>

  

  <EMI ID = 286.1>


  
  <EMI ID = 287.1>

  
at 25 [deg.] C. Methyl isonicotinimidate (80 mg, 0.588 mmol) is dissolved in the solution and the progress of the reaction is monitored by aliquots at set times using high performance liquid chromatography (HPLC): Waters instrument. ; phase column

  
  <EMI ID = 288.1>

  
completely complete in 40 minutes and the reaction solution is chromatographed directly on an 18.4 x 270 mm XAD resin column, elution being carried out first with distilled deionized water and then with

  
  <EMI ID = 289.1> <EMI ID = 290.1>

  
(m, m, 4-pyridyl); HPLC, 1.58x thienamycin retention, conditions as above.

Example 14

  
Following the procedure of Example 13, but replacing

  
  <EMI ID = 291.1>

  
4H, (m, m, m, 2-pyridyl); EPLC, 1.8x thienamycin retention.

  
example 15

  
Following the procedure of Example 13, but replacing the reagent with methyl nicotinimidate, we obtain

  
  <EMI ID = 292.1>

  
4H, (m, m, m, 3-pyridyl); HPLC, 1.57x thienamycin retention.

Example 16

  
Following the procedure of Example 13, but replacing the reagent with methyl 4-thiazolecarboximidate, one obtains

  
  <EMI ID = 293.1>

  
HPLC, 1.8 x retention time of thienamycin.

Example 17

  
  <EMI ID = 294.1>

  
A mixture of allylamine (5.00 g, 87.6 mmol) and methyl formate (5.26 g, 87.6 mmol) is stirred at 25 [deg.] C for 2 hours. At the end of this time, the reaction flask is fitted with a distillation head.

  
  <EMI ID = 295.1>

Example 18

  
Ethyl allylimidate hydrochloride Ethyl chloroformate (2.66 g, 24.47 mmol) is added by syringe to N-allylformamide (2.08 g, 24.47 mmol) in a flask

  
  <EMI ID = 296.1>

  
gas evolution (2 hours). The viscous product is then cooled and maintained under a vacuum of 0.2 mm for 2 hours to remove all volatiles.

  

  <EMI ID = 297.1>


  
Thienamycin (105 mg) is dissolved in phos-

  
  <EMI ID = 298.1>

  
(2 cm <2>). The pH of the solution is adjusted and maintained at 8.5 using an autoburette dispensing 1N NaOH. After 30 minutes, the pH is adjusted to 7.0 with 2.5N HCl. The solution is chromatographed on a column

  
  <EMI ID = 299.1>

  

  <EMI ID = 300.1>


  
Thienamycin (105 mg) is dissolved in 0.1N phosphate buffer at pH 7 (5 cm <3>) and we add to this solution a solution of N-

  
  <EMI ID = 301.1>

  
The pH of the solution is adjusted and maintained at 8.5 using an autoburette dispensing 1N NaOH. After 30 minutes, the pH is adjusted to 7.0 with 2.5N HCl. The solution is chromatographed on a resin column

  
  <EMI ID = 302.1>

  
of ice water and eluted with deionized water. The fractions containing the title product are combined and lyophilized.

Example 21

  
  <EMI ID = 303.1>

  

  <EMI ID = 304.1>


  
Thienamycin (126 mg) is dissolved in 0.1N phosphate buffer at pH 7 (6 cm <3>) and the pH of the solution is adjusted to 8.5 using an automatic burette dispensing 1N NaOH. To this stirred solution was added ethyl N-1-methyl-2-propenyl-formimidate hydrochloride (

  
  <EMI ID = 305.1>

  
0.037 to 0.074 mm) surrounded by a jacket of ice water and eluted with deionized water. The 'N' (1-methyl-2-propenyl) N-formimidoyl derivative elutes in 2-4 column volumes and is lyophilized to give a solid material.

  
  <EMI ID = 306.1>

Example 22

  
Preparation of N- (1-buten-3-yl) formamide

  
A solution of 3.5 g (0.05 mol) of 3-amino-1-butene in

  
12 cm <3> methyl formate is maintained at 25 [deg.] C for 20 hours; the solution is then concentrated under reduced pressure to remove excess methyl formate. The residual N- (1-buten-3-yl) formamide is distilled off under reduced pressure. A fraction of 3 g of N- (buten3-yl) formamide (boiling point 58-60 [deg.] C at 0.5 mm) is obtained.

Example 23

  
  <EMI ID = 307.1> <EMI ID = 308.1>

  
ethyl mimidate.

Example 24

  
Preparation of methyl N-dimethylaminoformimidate

  
To a stirred solution of N, E = dimethylformamide (0.22 g) in 2.0 cm <3> chloroform, under nitrogen, methyl chloroformate is added

  
  <EMI ID = 309.1>

  
vapor under nitrogen. The mixture is triturated with anhydrous ether. The supernatant solution is decanted and the residue is dried in a stream of nitrogen.

  
  <EMI ID = 310.1>

Example 25

  
Preparation of cyclopropylamine (5.00 g, 87.6 mmol) and formate

  
  <EMI ID = 311.1>

  
initial heat release). The mixture is then placed on a rotary evaporator for removal of the MeOH formed in the reaction. The remaining material is distilled through a molecular distillation head to give 6.92 g (93%) of the desired N-cyclopropyl formamide as a

  
  <EMI ID = 312.1>

Example 26

  
Preparation of ethyl N-cyclopropyl formimidate

  
Ethyl chloroformate (0.078g, 37.58mmol) was added by syringe to N-cyclopropylformamide (3.194g, 37.58mmol) in a dry flask under N2. After an induction period of 30 seconds, rapid gas evolution begins. The resulting reaction mixture is stirred

  
  <EMI ID = 313.1>

  
hours), then the viscous product is subjected to a vacuum of 0.5 mm for 1 hour to remove any ethyl chloroformate not having

  
  <EMI ID = 314.1>

  
the shape of a broad singlet. (solution in CDC13).

Example 27

  
Preparation of N (ethyl methylthioethyl formimidate

  
In a 60 cm settling funnel <3>, we introduce

  
  <EMI ID = 315.1>

  
of beta-methylthioethylamine (0.80 g, 8.8 mmol) in CH2C12 (35 cm <3>) and

  
  <EMI ID = 316.1>

  

  <EMI ID = 317.1>


  
Thienamycin (1.15 mg) is dissolved in phosphate buffer

  
  <EMI ID = 318.1>

  
an automatic burette dispensing 1N NaOH. To this stirred solution was added methyl N-dimethylamino formimidate hydrochloride (284 mg) while the pH was maintained at 8.5. After 20 minutes, the pH of the solution is adjusted to 7.0 using 2.5N HCl and the solution is chromatographed.

  
  <EMI ID = 319.1>

  

  <EMI ID = 320.1>


  
Thienamycin (105 mg) is dissolved in phosphate buffer

  
  <EMI ID = 321.1>

  
automatic burette dispensing NaOH. 1 N. To this solution, we add <EMI ID = 322.1>

  
particles of 0.037 to 0.074 mm) eluted with deionized water. Chromatography is carried out on a column surrounded by a jacket of water at 3 [deg.] C.

  
The methyl oxalimidoyl derivative elutes in 2 column volumes and is lyophilized to give a white solid (44 mg), UV (phos- buffer.

  
  <EMI ID = 323.1>

  
(s, -OCH3).

Example 30

  
Preparation of N-propionimidoyl thienamycin

  

  <EMI ID = 324.1>


  
Thienamycin (114 mg) is dissolved in phosphatic buffer.

  
  <EMI ID = 325.1>

  
an automatic burette dispensing 1N NaOH. Solid ethyl propionamidate hydrochloride (231 mg) is added in portions as quickly as possible, keeping the pH near 8.5. After 30 minutes,

  
  <EMI ID = 326.1>

  
at 0.074 mm) read with deionized water. The N-propionimidoyl derivative elutes in 2 column volumes and is lyophilized to give material

  
  <EMI ID = 327.1>
  <EMI ID = 328.1>
  <EMI ID = 329.1> pH is maintained at 8.5. After 40 minutes, the pH is adjusted to 7.0 using 2.5N HCl and the solution is chromatographed on Dowex 50-X4 resin.

  
  <EMI ID = 330.1>

  
column and lyophilized to give a solid solid (43 mg). UV (0.1 N phosphate buffer at ph 7 \ max 298 nm '(&#65533; 7.250) ir. (Paste of

  
  <EMI ID = 331.1>
2.92 (s, N-CH3) 7.80 (s, N-CH)

Example 32

  
  <EMI ID = 332.1>

  

  <EMI ID = 333.1>


  
Thienamycin (110 mg) is dissolved in phospha- buffer.

  
  <EMI ID = 334.1>

  
added to the buffered solution while the pH is maintained at 8.5. After

  
  <EMI ID = 335.1>

  
particles 0.037 to 0.074 mm) eluted with deionized water. Chromato- <EMI ID = 336.1>

  

  <EMI ID = 337.1>


  
  <EMI ID = 338.1> an automatic burette dispensing 1N NaOH. A solution of methyl N-isopropyl formimidate hydrochloride (300 mg) in p-dioxane is added.

  
  <EMI ID = 339.1>

  
deionized. The chromatography is carried out in a column surrounded by a jacket of water at 3 [deg.] C. The N'-isopropyl-N-formimidoyl derivative elutes in 2 column volumes and is lyophilized to give a white solid.
(12 mg). W (0.1N phosphate buffer at ph 7) &#65533; max 299 nm (&#65533; 8.130), ir

  
  <EMI ID = 340.1>

  

  <EMI ID = 341.1>


  
Has a pre-cooled sample of thienamycin (123 mg, 0.452

  
  <EMI ID = 342.1>

  
to pH 9 with 1N sodium hydroxide. To this basic solution at 2 [deg.] C,

  
0.3 g of ethyl N-allyl-formimidate hydrochloride is added all at once. The pH drops to 7.3 and is restored to 8.5 with additional sodium hydroxide. The reaction mixture was stirred at 2 [deg.] C for a further 30 minutes and the pH was adjusted to 7 with 0.1 N sulfuric acid. The reaction mixture was analyzed using high-speed liquid chromatography. pressure on a C18-Porosil column, developed with tetrahydro-

  
  <EMI ID = 343.1>

Example 35

  
  <EMI ID = 344.1>

  

  <EMI ID = 345.1>


  
Has a pre-cooled sample of thienamycin (123 mg, 0.452

  
  <EMI ID = 346.1>

  
lution to pH 9 with 1N sodium hydroxide. To this basic solution at 0-2 [deg.] C is added ethyl trifluoroethylformimidate (0.3 cm) in dioxane (2 cm <3>) in portions over 30 minutes. The pH of the mixture is maintained for a few minutes. After the addition of the imidate is complete and after the pH has been brought to 7 with 0.1N H2SO4, HPLC, in phase

  
  <EMI ID = 347.1>

  
shows a new peak at 12.2 m in corresponding to the desired product. The mixture is chromatographed on a Dowex 50x4 column (6Ccm <3> particles from 0.037 to 0.074 mm). The column is eluted with water at the rate of

  
  <EMI ID = 348.1>

  

  <EMI ID = 349.1>


  
Thienamycin (130 mg) is dissolved in phos- buffer.

  
  <EMI ID = 350.1>

  
solid ethyl ethyl (500 mg) all at once. The pH of the solution is adjusted to 8.5 using an automatic burette dispensing 1N NaOH. After 25 minutes at pH 8.5, the solution is adjusted to pH 7.0 with 2.5 N HCl. The solution is then chromatographed on a column of

  
  <EMI ID = 351.1>

  
surrounded by a jacket of ice water and eluted with deionized water.

  
  <EMI ID = 352.1>

  
This solution is then chromatographed on a column of XAD-2 resin. <EMI ID = 353.1>

  

  <EMI ID = 354.1>


  
Has a solution of thienamycin (133 mg) in 10 cm 'of buffer

  
  <EMI ID = 355.1>

  
10-minute ration instead of the 4.8-minute starting material

  
  <EMI ID = 356.1>

  
5 mm electrophoretic towards the cathode at 50V / cm for 20 minutes in phosphate buffer.

Example 38

  
  <EMI ID = 357.1>

  

  <EMI ID = 358.1>


  
  <EMI ID = 359.1>

  
Electrophoresis of the resulting mixture indicates a new bioactive product which travels towards the cathode (50V / cm for 20 minutes in 0.05M phosphate buffer at pH 7.0) in addition to the starting material (I) which moves 5 mm towards the cathode. The electrophoretic mobility of the product is in agreement with that of the expected product (II).

  
The reaction mixture from the hydrogenation reaction is neutralized with 2.5 N HCl and filtered to stand the catalyst. The filtrate is concentrated to 10 ml and chromatographed on XAD-2 resin (column of -2.3 x 16 cm). The column is eluted with water to obtain the desired product II in the form of hydrochloride after lyophilization.
(23 mg of N- (3-aminopropionimidoyl thienamy-

  
  <EMI ID = 360.1>

  
(multiplet, 11) &#65533; 4.18 (multiplet, 2).

Example 39

  
  <EMI ID = 361.1>

  
1-nitro-2-thiopseudourea (0.3 g). The solution is heated in a water bath to 45 [deg.] C. while vigorously bubbling a stream of nitrogen through the solution. After 50 minutes, the solution is concentrated under high vacuum to 1.0 cm <3> and

  
  <EMI ID = 362.1>

  
0.037 to 0.074 mm, Na + cycle) - and eluted with water. The N-nitroguanyl derivative elutes in the first column volume and is lyophilized to give a solid material (23%).

  
  <EMI ID = 363.1>

  
(40 V / cm, 0.1N phosphate buffer at pH 7, 20 min), 3.0 cm to the cathode.

Example 40

  
Preparation of N-isobutyrimidoyl thienamycin

  
Following the procedure of Example 12, but replacing the ethyl acetimidate hydrochloride with isobutyrimidate hydrochloride and allowing the reaction to take place at 20 [deg.] C and at pH 8.2, one obtains N-isobutyrimidoyl thienamycin (14%).

  
  <EMI ID = 364.1>

  
Following the procedure of Example 12, but replacing

  
ethyl acetimidate hydrochloride with methyl-N-methyl acetimidate <EMI ID = 365.1>

(S, NCH)

Example 42

  
Preparation of N'-methyl-N-formimidoyl thienamycin

  
Following the procedure of Example 12, but replacing the ethyl acetimidate hydrochloride with ethyl N-methyl forminidate hydrochloride, N'-methyl-N-formimidoyl thienamycin (the

  
  <EMI ID = 366.1>

Example 43

  
Following the procedure of Example 12, but replacing the reagent with an equivalent amount of methyl methoxyacetimimidate, N (methoxyacetimidoyl) thoenamycin (34%) is obtained;

  
  <EMI ID = 367.1>

  
x retention time of thienamycin.

Example 44

  
  <EMI ID = 368.1>

  
A mixture of methoxynamine hydrochloride (0.020 mole, 1.6700 g) and anhydrous potassium carbonate (0.010 mole, 1.3821 g) is dissolved in 7.0 cm <3> of water. Add 80 cm <3> ether and the reaction mixture is treated with ethyl formimidate hydrochloride (0.02 mole, 2.1900 g). The mixture is shaken for 15 minutes. The ethereal layer is separated and the aqueous layer is extracted with two portions of ether (30

  
  <EMI ID = 369.1>

  
&#65533; 6.56 (singlet)

Example 45

  
Ethyl N- (2.2.2-trifluoroethyl) formimidate

  
  <EMI ID = 370.1>

  
2,2,2-trifluoroethylamine hydrochloride (0.677 g, 5 mmol) and carbo-

  
  <EMI ID = 371.1>

  
  <EMI ID = 372.1> for 3 minutes. The organic phase is separated and the aqueous phase is

  
  <EMI ID = 373.1>

  
Ethyl formimidate hydrochloride (0.55 g, 5 mmol), ethyl glycinate hydrochloride (0.697 g, 5 mmol) and carbonate of

  
  <EMI ID = 374.1>

  
and treated with 2 cm <3> of H20. The mixture is shaken vigorously for 4 minutes. The organic phase is separated, the aqueous phase is treated with

  
  <EMI ID = 375.1>

(N-CH).

Example 47

  
Preparation of potassium N-ethoxycarbonylmethyl-formimidate

  

  <EMI ID = 376.1>


  
Potassium (0.18 g) is dissolved in a mixture of 0.6 g of

  
  <EMI ID = 377.1>

  
product. The solid is filtered off, washed with ether and dried in vacuo to obtain potassium N-ethoxycarbonyl-methylformimidate.

  
  <EMI ID = 378.1>
8.06 S, N = CH.

Example 48

  
  <EMI ID = 379.1> <EMI ID = 380.1>

  
placed under a nitrogen atmosphere. Stir the solution while adding

  
  <EMI ID = 381.1>

  
thyloxonium in methylene chloride. After a reaction time of

  
45 minutes, the mixture is concentrated to dryness under reduced pressure at room temperature.

  
  <EMI ID = 382.1>

  
Nuclear magnetic resonance spectrum of the product in deuterochloroform is completely in agreement with the fact that the product is an ethyl N-benzylformimidate fluoroborate etherate complex.

  
  <EMI ID = 383.1>

  
Preparation of N-isopropyl formamide

  
  <EMI ID = 384.1>

  
Isopropyl formamide (535 mg) is treated with an amount

  
  <EMI ID = 385.1>

  
at 40-45 [deg.] C. The mixture is washed successively with petroleum ether, anhydrous ether and benzene, leaving the product as an oil.

Example 51

  
  <EMI ID = 386.1>

  

  <EMI ID = 387.1>


  
  <EMI ID = 388.1> Fractions 40 to 90 are combined, concentrated and dried by. freezing to give 15 mg of the solid product. Electrophoresis of the product at 50 uCM

  
  <EMI ID = 389.1>

  
(formimidoyl CH).

Example 52

  
  <EMI ID = 390.1>

  

  <EMI ID = 391.1>


  
  <EMI ID = 392.1>

  
0.1M at pH 7.0 is adjusted and maintained at a pH of 8.5-9.0 while 300 mg of ethyl N-cyclopropylformimidate hydrochloride is added dropwise to the solution. The mixture is stirred at 23 [deg.] C for 40 minutes, then neutralized and chromatographed on an exchange resin column.

  
  <EMI ID = 393.1>

  
column with water, collecting fractions of 6.5 cm. Fractions 45 to 95 are combined, concentrated and freeze dried to

  
  <EMI ID = 394.1>

  
and 7.80 ppm (formimidoyl CH).

Example 53

  
Following the procedure described in the text and the preceding examples, the following compounds of the present invention are obtained. Reagents; imido-ethers and imido halides, used in the reaction

  
  <EMI ID = 395.1>

  
can be prepared as described above.

  

  <EMI ID = 396.1>
 

  

  <EMI ID = 397.1>
 

  

  <EMI ID = 398.1>
 

  

  <EMI ID = 399.1>
 

  

  <EMI ID = 400.1>
 

  

  <EMI ID = 401.1>
 

  

  <EMI ID = 402.1>
 

  

  <EMI ID = 403.1>
 

  

  <EMI ID = 404.1>
 

  

  <EMI ID = 405.1>
 

  

  <EMI ID = 406.1>
 

  

  <EMI ID = 407.1>
 

  

  <EMI ID = 408.1>
 

  

  <EMI ID = 409.1>
 

  

  <EMI ID = 410.1>
 

  
  <EMI ID = 411.1>

  
Preparation of pharmaceutical compositions

  
Such a unit dosage form is obtained by mixing
120 mg of N-acetimidoyl thienamycin (product of Example 12) with 20 mg of lactose and 5 mg of magnesium stearate and placing the 145 g of m-

  
  <EMI ID = 412.1>

  
With more of the active ingredient and less lactose, other dosage forms can be prepared in gelatin capsules

  
  <EMI ID = 413.1>

  
dients, you can also make larger capsules, such as tablets and pills. The following examples illustrate the preparation of pharmaceutical compositions.

  

  <EMI ID = 414.1>


  
The active ingredient is mixed with the dicalcium phosphate,

  
lactose and about half of the corn starch. The mixture is then

  
  <EMI ID = 415.1>

  
mesh opening. The rest of the corn starch and magnesium stearate are added and the mixture is pressed into tablets, about 1.27 cm in diameter, each weighing 800 mg.

  
Parenteral solution
  <EMI ID = 416.1>
 
  <EMI ID = 417.1>
 The active ingredient in the above compositions can be administered alone or in combination with other biologically active ingredients such as, for example, other antibacterial agents, such as lincomycin, penicillin, streptomycin, novobiocin, la gentamicin, neomycin, colistin and kanamycin, or with other therapeutic agents such as probenecid.

  
Preparation of other starting materials

  
In addition to thienamycin, those skilled in the art will understand that its various isomers, singly or as a mixture, can be used.

  
starting materials in the preparation of the compounds of the present invention. Some of these isomers can be obtained from natural fermentation products (see below). However, by total synthesis, all isomers are made available (below) as a mixture of 4 diastereomers which possess antibacterial activity and which can be isolated by

  
  <EMI ID = 418.1>

  
are separable by chromatography. The doubling of a pair

  
d / 1 given any given with optically active acids or bases is carried out according to conventional techniques. Note that the absolute configuration of the starting material (I) identified first is 5R 6S 8R.

Preparation of thienamycin by total synthesis

  

  <EMI ID = 419.1>


  
Step A

  
  <EMI ID = 420.1>

  

  <EMI ID = 421.1>


  
  <EMI ID = 422.1> dre is cooled under N2 in a -20 [deg.] C bath.

  
A solution of 2.5 g of 1-acetoxybutadiene (22 mmol) in 2.5 cm <3> anhydrous ether is cooled in a similar manner

  
  <EMI ID = 423.1>

  
The chlorosulfonyl isocyanate solution is added dropwise to the acetoxybutadiene solution by means of a Teflon tube immersed in the CSI solution and pressurized with N 2. The addition takes 10 minutes. Little or no color was observed and the mixture was stirred at -20 [deg.] C for 0.5 hour. The solution is clear and has a faint yellow color.

A solution of 2 g of sodium sulfite and 5 g of

  
  <EMI ID = 424.1>

  
0.5 hour above and is cooled in an ice bath; we

  
  <EMI ID = 425.1>

  
ice bath. At the end of the 30 minute reaction period, the reaction mixture, again using N2 pressure and the Teflon tube, is transferred from the reaction flask which is kept in the bath at -20 [deg.] C to vigorously stirred hydrolysis mixture.

  
The rapid dropwise addition is complete in 5 minutes. The hydrolysis is allowed to continue for a further 5 minutes. The hydrolysis mixture has a pH of 6 to 8, preferably pH 8.

  
The phases are separated, leaving a gum of a yellowish orange with the aqueous phase. The ethereal phase is dried directly with MgSO4. The aqueous phase containing the gum is treated by extraction three more times with 50 car portions of ether, each time adding to the initial ethereal extract dried over MgSO4.

  
The dried extracts are filtered and concentrated under a

  
  <EMI ID = 426.1>

  
Stadium.

  
A column of 10 g of Baker's silica gel, packed in ether, is prepared and the ethereal concentrate is applied to the top of the column and descends therein. The ball and the solids

  
  <EMI ID = 427.1>

  
lifted with a pipette and passed through the column. The elution is then started with ether. The initial fraction of 25 cm <3> is mostly empty volume. We collect the five fractions

  
  <EMI ID = 428.1>

  
product crystallizes from fractions 4 to 6, with traces in 3 and 7. Fractions 1 to 3 contain a yellowish material with a strong odor which resinifies on leaving. Yield: 100 mg as a mixture of the cis and trans isomers.

  
Step B

  
Preparation of 4- (3-acetoxyethyl) -2-azetidinone

  

  <EMI ID = 429.1>


  
A solution of 4- (2-acetoxyvinyl) -2-azetidinone (10.0 g,

  
  <EMI ID = 430.1>

  
10% Pd / C analyzer is hydrogenated on a Parr shaker at
25 [deg.] C under hydrogen pressure of 2.8 kg / cm3 for 15 minutes. The mixture is filtered through a bed of Supercel and washed with additional ethyl acetate. The combined filtrate is evaporated in vacuo to give 4- (2-acetoxyethyl) -2-azetidinone

  
(10.0 g) as a crystalline solid. Recrystallization from ether gives white crystals: point

  
  <EMI ID = 431.1>

  
OCOCH3, respectively)

  
Step C

  
Preparation of 4- (2-hydroxyethyl) -2-azetidinone
  <EMI ID = 432.1>
   <EMI ID = 433.1>

  
is treated with sodium methoxide solution (77 mg, 1.4

  
  <EMI ID = 434.1>

  
hour, the solution is neutralized with glacial acetic acid. Removal of the methanol in vacuo gives crude 4- (2-hydroxyethyl) -2-azetidinone as an oil. The product is purified by chromatography on silica gel, eluting with

  
  <EMI ID = 435.1>

  
6.24 and 6.28 (m over t, total 3, C-4H and CH20H respectively),

  
  <EMI ID = 436.1>

  
  <EMI ID = 437.1>

  
by C-4H and NH, 1, C-3H, Jgem = 13, OHz, Jyic = 2.2Hz, JNH = 1.1Hz), 8.16 (m, 2, CH2CH20H).

  
Step D -

  
  <EMI ID = 438.1>

  

  <EMI ID = 439.1>


  
A solution of 4- (2-hydroxyethyl) -2-azetidinone (1.87 g, 0.016 mole) and 2,2-dimethoxypropane (1.69 g, 0.016 mole) in

  
  <EMI ID = 440.1>

  
The resulting reaction is stirred for ten minutes. Elimination

  
solvent under reduced pressure gives an oil (2.5 g). Chromatography of the crude product on silica gel using a 2: 1 mixture of ethyl acetate / benzene as the eluting solvent gives

  
  <EMI ID = 441.1>

  
as a crystalline solid. Recrystalllization from ether / hexane gives a product with a melting point of 60-61 [deg.] C.

  
  <EMI ID = 442.1> 6.22 - 6.62, m, 1H, C-6 methine

  
  <EMI ID = 443.1>

  
C-7 proton trans' to C-6H

  
7.82 - 8.68, m, 2H, C-5 methylene.

  
  <EMI ID = 444.1>

  

  <EMI ID = 445.1>


  
  <EMI ID = 446.1>

  
freshly prepared lithiated in anhydrous tetrahydrofuran under a nitrogen atmosphere at -78 [deg.] C, a solution of 8-oxo-

  
  <EMI ID = 447.1>

  
in water. The aqueous phase is saturated with sodium chloride and treated by extraction with ethyl acetate. The combined ethyl acetate solutions are dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give the crude product. Purification by chromatography on silica gel using an ethyl acetate / benzene mixture gives 8-

  
  <EMI ID = 448.1> <EMI ID = 449.1>

  
+ C-6 methine

  
3.33, broad s, OH

  
  <EMI ID = 450.1>

  
1.23, d, J = 6.5Hz, C-10 methyl

  
Step F

  
  <EMI ID = 451.1>

  

  <EMI ID = 452.1>


  
  <EMI ID = 453.1> stirring at 25 [deg.] C for an additional 15 hours. The mixture is partitioned between 1M phosphate buffer at pH 7 and additional ether. The ethereal phase is washed with water and brine, dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives 67 mg of a colorless oil. Purification by preparative thick-layer chromatography on silica gel, developing with a 1: 9 mixture of e- acetate

  
  <EMI ID = 454.1>

  
form of a mixture of diastereomers.

  
ir (CH2C12) u: 5.68 (&#65533; -lactam and carbonate), 6.19 and 6.54

  
(nitro)

  
rmn (CDCl3): 1.67, d, 2H, ArH

  
2.37, d, 2H, ArH

  
4.67, s, 2H, Arc%

  
  <EMI ID = 455.1>

  
5.98 - 6.25, m, 2H, C-4 methylene 6.25 - 6.62, m, 1H, C-6 methine 6.75 - 7.12, m, 1H, C-7 methine 7, 75 - 8.83, m, 2H, C-5 methylene 8.22, s, 3H, C-2 methyl

  
  <EMI ID = 456.1>

  
isomers or the mixture of 7alpha and beta.

  
Step G

  
  <EMI ID = 457.1>

  
4- (2-hydroxyethyl) -2-azetidinone

  

  <EMI ID = 458.1>


  
  <EMI ID = 459.1> <EMI ID = 460.1>

  
65 [deg.] C for 1.25 hours. The acetic acid and the water are removed under reduced pressure and the residue is taken up in benzene and

  
  <EMI ID = 461.1>

  
ethyl) -4- (2-hydroxyethyl) -2-azetidinone. in the form of a mixture of diastereomers.

  
  <EMI ID = 462.1>

  
(nitro)

  
rmn (CDCl3): 1.73, d, 2H, J = 8.5Hz, ArH

  
  <EMI ID = 463.1>

  
4.72, s, 2H, ArCHg

  
6.07 - 6.53, m, 1H, C-4 methine

  
  <EMI ID = 464.1>

  
8.53, d, J = 6.5Hz, CH CH

  
The cis diastereoisomers or the cis-trans mixture are obtained in an analogous manner.

  
  <EMI ID = 465.1>

  
xyethyl) azetidinone

  

  <EMI ID = 466.1>


  
  <EMI ID = 467.1>

  

  <EMI ID = 468.1>


  
  <EMI ID = 469.1>

  
The resulting solution is stirred for a period of 60 minutes.

  
  <EMI ID = 470.1>

  
traction a second time with ethyl acetate. The combined ethyl acetate solutions are washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated

  
under reduced pressure to give 216 mg of crude product. Purification by preparative thick-layer chromatography developing with ethyl acetate gives 80 mg of 1- (2-tetrahydropy-

  
  <EMI ID = 471.1>

  
form of an oil.

  
  <EMI ID = 472.1>

  
  <EMI ID = 473.1>

  
  <EMI ID = 474.1>

  

  <EMI ID = 475.1>


  
Following the procedure described for the preparation of

  
  <EMI ID = 476.1>

  
(2-tetrahydropyranyl) oxyethyl7-2-azetidinone, obtains a diastereomeric mixture of cis and trans -1- (2-tetrahydropyranyl) -3- (1-hydro-

  
  <EMI ID = 477.1>

  
dinone

  

  <EMI ID = 478.1>


  
Following the procedure described for the preparation

  
  <EMI ID = 479.1> <EMI ID = 480.1>

  
4- (2-hydroxyethyl) -2-azetidinone

  

  <EMI ID = 481.1>


  
  <EMI ID = 482.1>. The reaction is stirred for a period of 2 hours and then neutralized with 1M phosphate buffer to pH 7. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered.

  
The filtrate is evaporated under reduced pressure to give

  
  <EMI ID = 483.1>

  
azetidinone. The cis diastereomers are obtained in an analogous manner.

  
Step H

  
  <EMI ID = 484.1>
  <EMI ID = 485.1>
 Under nitrogen, at 25 [deg.] C, a mixture of anhydrous pyridine

  
  <EMI ID = 486.1>

  
for a period of 30 minutes. To the resulting dark brown solution, 250 mg of anhydrous Supercel is added and then a solution.

  
  <EMI ID = 487.1>

  
  <EMI ID = 488.1>

  
tion is filtered through a mixed packed bed consisting of 2 g of gel

  
  <EMI ID = 489.1> <EMI ID = 490.1>

  
Over a period of 15 minutes, this solution is partitioned between an aqueous solution of dipotassium acid phosphate (1.5 g in

  
  <EMI ID = 491.1>

  
treated by extraction a second time with ethyl acetate. The combined ethyl acetate solutions are washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give 229 mg of an oil. The product is purified by preparative chromatography in thick layers of silica gel, with development in ethyl acetate,

  
  <EMI ID = 492.1>

  
2.28, d, J = 8.5Hz, 2H, ArH

  
  <EMI ID = 493.1>

  
  <EMI ID = 494.1>

  
The cis diastereomers are obtained in an analogous manner. Alternatively, the mixed diastereomers are obtained when the starting materials comprise a mixture of the diastereomers.

  
Step

  
  <EMI ID = 495.1>
  <EMI ID = 496.1>
  <EMI ID = 497.1>

  
  <EMI ID = 498.1>

  
bis (2-hydroxyethyl) thioethyl7-2-azetidinone in 5 cm <3> tetrahydrofuran (THF) (distilled from lithium aluminum hydride) at 0 [deg.] C, 103 mg of mesyl chloride (molecular mass

  
  <EMI ID = 499.1>

  
134 µl of triethylamine (molecular weight = 101; f = 0.729; 0.967 mmol). The reaction mixture is stirred for 1 hour under

  
  <EMI ID = 500.1>

  
  <EMI ID = 501.1>

  
pushed for 10 minutes. The dimesylate is immediately dissolved

  
  <EMI ID = 502.1>

  
thyle (EA). We separate the layers, the aqueous layer is washed too often

  
  <EMI ID = 503.1>

  
The cis diastereomers or the cis-trans mixture are obtained in an analogous manner.

  
Step J

  

  <EMI ID = 504.1>


  
A freshly prepared solution (H. Davies and M.

  
  <EMI ID = 505.1>

  
(29 mmol) in 150 car of ether is added, with stirring, to a solution of 1.0 g of oxomalonic acid monohydrate (molecular mass = 136 7.35 mmol) in 50 cm3 of ethyl acetate
(EÂ) at 0 [deg.] C. After 2 1/2 hours, the yellow solution is concentrated on a rotary evaporator with moderate heating to about half the volume, dried over anhydrous sodium sulfate, filtered and concentrated to an oil as above. To ester de.

  
  <EMI ID = 506.1>

  
Toluene (dried over Linde 3A molecular sieves

  
  <EMI ID = 507.1>

  
azeotropic drying three more times. The solution is then

  
  <EMI ID = 508.1>

  
second azeotropic drying and heating under reflux is continued for an additional hour. The concentration of the solution

  
  <EMI ID = 509.1>

  
crude material is chromatographed on silica gel to give

  
1. The cis or N diastereoisomers are obtained in an analogous manner.

  
the cis-trans mixture.

  
Step K
  <EMI ID = 510.1>
 Has a solution of 2.80 g of 1 (molecular weight = 912;

  
  <EMI ID = 511.1>

  
(molecular mass = 79; e = 0.982; 3.73 mmol) (distilled from NaH and stored on Linde 4A molecular sieves). While stirring under N2, 0.438 g of thionyl chloride (molecular mass = 119; 3.68 mmol) is added dropwise in 1 cm. <3> of

  
  <EMI ID = 512.1> <EMI ID = 513.1> <EMI ID = 514.1>

  
benzene (dried over 1.59mm Linde 3A molecular sieves). The combined filtrate and washings are concentrated under a stream of N2, slurried in a small volume of benzene

  
  <EMI ID = 515.1>

  
an oil is obtained. To this freshly prepared chlorinated compound is added, with stirring, 0.885 g of triphenyl phosphine (molecular weight

  
  <EMI ID = 516.1>

  
mamide (DMF) / H20 and then 550 mg of K2HP04 (molecular mass =
174; 3.16 mmoles). The reaction mixture is stirred at 25 [deg.] C for
35 minutes. After dilution with EA and brine, the layers are separated and the aqueous layer is extracted three times with EA. The combined EA layers are washed with brine, dried over anhydrous MgSO4, filtered and concentrated under a stream of N2 to give crude 2. The material is chromatographed on silica gel to give 2. In an analogous manner,

NOT

  
cis diastereoisomers or cis-trans mixture.

  
Step L
  <EMI ID = 517.1>
 A 7.8 cm <3> pentane (dried over molecular sieves

  
  <EMI ID = 518.1>

  
Br2 above (1.13 moles). After stirring for 10 minutes at 0 [deg.] C, 114 µl of cyclohexene (molecular mass = 82,

  
  <EMI ID = 519.1>

  
57% NaH (57% of 53 mg = 30.2 mg, molecular weight = 24, 1.26 mmol) in mineral oil to the stirred reaction mixture. This

  
  <EMI ID = 520.1>

  
In the layers, the aqueous layer is saturated with NaCl and treated again by extraction with EA. The combined organic layers are extracted once with brine, dried over anhydrous MgSO4, filtered and concentrated under a stream of N2, then pumped by a high vacuum pump to give crude 3. Preparative thin-layer chromatography of silica gel gives 3. The cis diastereomers or the cis-trans mixture are obtained in an analogous manner.

  
Step M
  <EMI ID = 521.1>
 A 9.16 ci -de pentane (dried over molecular sieves

  
  <EMI ID = 522.1>

  
3.9 mmol). A 474 mg of 3 (molecular mass = 793; 0.598 mmol)

  
  <EMI ID = 523.1>

  
1.59 mm) at 0 [deg.] C under N2, with stirring, added dropwise

  
  <EMI ID = 524.1>

  
15 minutes at 0 [deg.] C, 33 mg of 57% NaH (57% of 33 mg =
18.8 mg; molecular mass = 24; 0.78 mmol) and immediately

  
  <EMI ID = 525.1>

  
under 40 mm and stored on Linde 4A molecular sieves). The reaction mixture is stirred for 1 1/2 hours at 0 [deg.] C, then it is

  
  <EMI ID = 526.1>

  
NaCl and re-extracted with additional EA. The combined organic layers are washed once with brine, dried over anhydrous MgSO4 and filtered. The filtrate is

  
  <EMI ID = 527.1>

  
to give 4 gross. Preparative thin-layer chromatography of silica gel gives 4. In an analogous manner,

  
  <EMI ID = 528.1>

  
cis diastereoisomers or cis-trans mixture.

STEP N:

  

  <EMI ID = 529.1>


  
  <EMI ID = 530.1> cis diastereomers or cis-trans mixture.

  
STEP 0:

  

  <EMI ID = 531.1>


  
A solution of 187 mg of 5 (molecular weight = 791;

  
  <EMI ID = 532.1>

  
sprayed under a pressure of 30 mm) is added to 45 mg of

  
  <EMI ID = 533.1> 6 raw. Preparative thin-layer chromatography of

NOT'

  
silica gel gives 6. The cis diastereomers or the cis-trans mixture are obtained in an analogous manner.

STEP P:

  

  <EMI ID = 534.1>


  
Has a solution of mixed diastereomers, 6
(34 mg; molecular mass = 612; 0.055 mmol) in 0.2 ce

  
  <EMI ID = 535.1>

  
and trans.

STEP Q:

  

  <EMI ID = 536.1>


  
  <EMI ID = 537.1>

  
2.8 kg / cm for 4 hours. The reaction mixture is then filtered through Celite, washing with 2 cm <3> of

  
  <EMI ID = 538.1>

  
at the cloud point, the aqueous mixture is worked up by extraction with ethyl acetate. The aqueous layer is concentrated to a small volume and applied to a column of 100 g of resin

  
  <EMI ID = 539.1>

  
initial, the fractions containing the product are lyophilized

  
  <EMI ID = 540.1>

  
cis and trans mothers.

  
The following method for the enzymatic N-deacylation of thienamycin is applicable to all isomers of thienamycin, in particular to the separate N-acetyl isomers 890A

  
  <EMI ID = 541.1>

  
N-acetyl thienamycin deacetylation

  
A 1% (w / v) suspension of fertile turf soil is prepared by suspending 1 g of turf soil in 100 cm <3> sterile phosphate buffered saline solution, the phosphate buffered saline solution having the following composition:

  

  <EMI ID = 542.1>


  
  <EMI ID = 543.1>

  
Aliquots of this 1% soil stock suspension are used to prepare dilutions.

  
  <EMI ID = 544.1>

  
of agar at 48 [deg.] C. The mixtures are quickly poured onto the surface of sterile 85 mm diameter Petri dishes.

  
  <EMI ID = 545.1>

  
boasts:

  

  <EMI ID = 546.1>


  
  <EMI ID = 547.1>

  
and sterilized using a membrane. This solution is added after passing through an autoclave.

  
For solid media: add 20 g of agar

  
The Petri dishes are incubated for

  
18 days at 28 [deg.] C. A well-isolated colony is taken and applied in streaks to a Petri dish containing Medium B. Medium B has the following composition:

  

  <EMI ID = 548.1>


  
pH: adjusted to 6 using NaOH

  
For solid media: add 20 g of agar

  
An individual clone is selected and cultured for 2 days at 28 [deg.] C in tilted culture on Medium B. Part of the vegetative development of this culture on tilted medium is streaked on the surface of six tilted solid media. consisting of Medium B. These media are

  
incubated for 2 days at 28 [deg.] C. This culture has been identified as Protaminobacter ruber and has been named

  
  <EMI ID = 549.1>

  
Rahway, New Jersey, United States of America, and a sample

  
has been filed with the Agricultural Research Service, U.S. Department

  
  <EMI ID = 550.1>

  
of Medium C. Medium C has the following composition:

  

  <EMI ID = 551.1>


  
  <EMI ID = 552.1>

  
N-acetylethanolamine is diluted to 10x in H20 and sterilized at the membrane. This solution is added after autoclaving.

  
  <EMI ID = 553.1>

  
rpm (5.1 cm stroke) for 4 days. A portion of this taken from the vial is centrifuged for 15 minutes at 8000 rpm. The supernatant liquid is removed and the cells on the surface of the solid particles of the medium are passed

  
  <EMI ID = 554.1>

  
Ultrasonic destruction using a Branson Instrument Model LS-75 ultrasonic generator with a 1.27 cm probe at setting 4 for 4 periods of 15 seconds, while the suspension is cooled in ice water for and between periods of operation of the device. A port-

  
  <EMI ID = 555.1>

  
the whole night. Controls containing antibiotic and buffer only are also subjected to this incubation; and cells treated with ultrasound and tampon without antibiotics.

  
  <EMI ID = 556.1>

  
are applied to cellulose-coated TLC (thin layer chromatography) plates, which are developed

  
  <EMI ID = 557.1>

  
is placed on a test plate containing Staphylococcus aureus ATCC 6538P for 5 minutes.

  
The test plates are prepared as follows:
A culture, dating from the day before, of the test organism. Staphylococcus aureus ATCC 6538P, in nutrient broth

  
  <EMI ID = 558.1>

  
wavelength of 660 nm. This suspension is added to

  
  <EMI ID = 559.1>

  
maximum).

  
  <EMI ID = 560.1> incubated overnight at 37 [deg.] 0. In addition to the stain of unreacted bioactive N-acetyl thenaraycin

  
  <EMI ID = 561.1>

  
due to thienamycin. Incubation of the control mixtures of antibiotic plus buffer, ultrasonically treated cells plus buffer, and antibiotic plus buffer to which cells treated.

  
  <EMI ID = 562.1>

  

  <EMI ID = 563.1>


  
  <EMI ID = 564.1>

  
you

  

  <EMI ID = 565.1>


  
This suspension is used to inoculate four solid media for slant culture consisting of medium A having the following composition:

  

  <EMI ID = 566.1>
 

  
The inoculated slant media are incubated for one week at 27-28 [deg.] C and then stored at 4-6 [deg.] C until use.

  
A portion of 1/3 of the vegetative development of the three cultures on inclined medium is used to inoculate

  
  <EMI ID = 567.1>

  
place B having the following composition:

  

  <EMI ID = 568.1>


  
  <EMI ID = 569.1>

  
+ Ardamine: Yeast Products Corporation

  

  <EMI ID = 570.1>


  
The sprout growing flask is shaken for one day at 27-28 [deg.] C on a shaker at 220 rpm (running

  
  <EMI ID = 571.1>

  
  <EMI ID = 572.1>

  
33 production Erlenmeyer flasks of 2 liters, containing

  
  <EMI ID = 573.1>

  
con of the vegetative development of the sprout development flask. Medium 0 has the following composition:

  

  <EMI ID = 574.1>
 

  
After inoculation, the production vials are

  
  <EMI ID = 575.1>

  
(stroke 5.1 cm) for 4 days. The production of the vials is harvested and its activity is determined using plates.

  
  <EMI ID = 576.1>

  
Vibrio percolans ATCC 8461, using 1.27 cm test discs dipped in centrifuged broth samples. Samples are diluted with phosphate buffer

  
  <EMI ID = 577.1>

  
felt in the table below:

  

  <EMI ID = 578.1>


  
Seven liters of whole fermentation broth are

  
  <EMI ID = 579.1>

  
rpm for 15 minutes each.

  
To the combined supernatant liquids, 7 cm <3> of neutral 0.1M EDTA and the entire sample is adsorbed onto

  
  <EMI ID = 580.1>

  
  <EMI ID = 581.1>

  
of deionized water containing 50 g of sodium chloride and the column is then washed with 300 cc of deionized water. We

  
  <EMI ID = 582.1>

  
appearance of salt at the exit of the column. Bioactivity appears in fractions 1 to 10, with a peak at the fraction

  
  <EMI ID = 583.1>

  
applied activity.

  
  <EMI ID = 584.1>

  
by evaporation on a rotary evaporator under reduced pressure-3

  
  <EMI ID = 585.1>

  
The pH adjusted concentrate 4 is applied to an XAD-2 column, bed size 3.8 by 50 cm, which has been washed beforehand with 3 liters of 60% (v / v) aqueous acetone, and then

  
  <EMI ID = 586.1>

  
  <EMI ID = 587.1>

  
(w / v) sodium chloride in deionized water. The concentrate applied is allowed to descend to the level of the bed. The antibiotic is eluted with deionized water at a flow rate of

  
  <EMI ID = 588.1>

  
cune, from the first application of the sample. Bioactivity appears in fractions 6 to 22, with a peak in fractions 9 and 10. Fractions 9 to 20 are combined for further processing. Fractions prepared in a manner

  
  <EMI ID = 589.1>

  
by evaporation on a rotary evaporator under reduced pressure.

  
The concentrate is adsorbed on a column of Dowex-1 x 4 (Cl-) in particles of less than 0.037 mm with dimensions.

  
  <EMI ID = 590.1>

  
deionized water and the antibiotic is eluted with 2 liters of

  
  <EMI ID = 591.1>

  
The main antibiotic peak elutes in fractions 142 to 163. Fractions 146 to 157 contained therein are combined for further processing.

  
The combined fractions 146 to 157 are concentrated

  
  <EMI ID = 592.1>

  
nized. After having lowered the concentrate to the level of

  
  <EMI ID = 593.1> per minute. 2.9 cm fractions are collected <3>.

  
The major antibiotic peak elutes in fractions 63-70. Fractions 64 and 65 are combined for further processing.

  
The combined fractions 64 and 65 are evaporated on a rotary evaporator under reduced pressure to 2 cm. <3> and then frozen in shell and lyophilized in a flask of

  
14 cm <3> screw cap for 8 hours to give 2.25 mg of antibiotic 890A &#65533; substantially pure. The N-acetyl group is cleaved as described above to give the free base:

  

  <EMI ID = 594.1>


  
  <EMI ID = 595.1>

  

  <EMI ID = 596.1>


  
A lyophilized culture tube of Streptomyces

  
  <EMI ID = 597.1>

  
are contained is suspended in a tube containing 0.8 cm <3> sterile Davis salts having the following composition:

  

  <EMI ID = 598.1>
 

  
This suspension is used to inoculate four solid media for slant culture consisting of medium A having the following composition:

  
Medium A

  

  <EMI ID = 599.1>


  
pH: adjusted to 7.2 using NaOH

  
The slanted media inocr '&#65533; s are incubated for one week at 27-28 [deg.] C and then stored at 4-6 [deg.] C until use (no more than 21 days).

  
A portion of 1/3 of the vegetative development of the four cultures in inclined medium is used to inoculate
12 Erlenmeyer flasks of 250 cm <3> with baffles containing 50 cm <3> of medium B having the following composition:

  
Medium B

  

  <EMI ID = 600.1>


  
pH: set to 6.5 using HCl or NaOH

  
+ Ardamine: Yeast Products Corporation

  
* Phosphate buffer solution

  

  <EMI ID = 601.1>


  
The sprout growing flask is shaken for one day at 27-28 [deg.] C on a shaker at 220 rpm (running

  
  <EMI ID = 602.1>

  
44 production erlenmeyer flasks of 2 liters, each containing 200 cm <3> of Medium C, are inoculated with 8 cm <3> per vial of the production of the germ development vial. Medium C has the following composition:

  

  <EMI ID = 603.1>


  
pH: adjusted to 7.2-7.4 using NaOH

  
After inoculatio, the production vials are

  
  <EMI ID = 604.1>

  
The production of the vials was harvested and its activity determined using normal assay plates containing

  
  <EMI ID = 605.1>

  
using 1.27 cm test disks dipped in centrifuged broth samples. Samples .-- Are

  
  <EMI ID = 606.1>

  
necessary. The results are shown in the table below:

  

  <EMI ID = 607.1>


  
  <EMI ID = 608.1>

  
by this fermentation -is cooled to 3 [deg.] C and centrifuged in portions of 200 cm <3> at 9000 rpm for 15 minutes each. To the

  
  <EMI ID = 609.1>

  
The above fermentation is repeated under identical conditions, except that the 44 production Erlenmeyer flasks of 2 liters are inoculated with 7 cm <3> per bottle of the bed 4.9 cm x 47 cm) which has been washed with 5 liters of ac-

  
  <EMI ID = 610.1>

  
nized and 5 liters of 50 g / 1 solution of NaCl in water

  
  <EMI ID = 611.1>

  
which is made to flow each time in the column at the level of the bed. When the application is complete, apply three portions of 20 cm <3> deionized water and we bring them down

  
  <EMI ID = 612.1>

  
deionized water at a flow rate of 20 cm <3> per minute. All the

  
  <EMI ID = 613.1>

  
room temperature (24 [deg.] C) and the fractions which are eluted are cooled rapidly in an ice bath immediately

  
  <EMI ID = 614.1>

  
Antibiotic activity appears in fractions 2 to 21, as measured by assay on plates containing

  
  <EMI ID = 615.1>

  
first application of deionized water). Combine fractions 6 to 21.

  
The combined fractions 6 to 21 are concentrated to

  
  <EMI ID = 616.1>

  
reduced pressure and then diluted to 112 cm <3> by adding deionized water. The concentrate is applied to a column (bed size 2.2 cm x 21 cm) of Dowex-1 x 4 (Cl-) in particles of less than 0.037 mm. The column is washed with 20 cm <3> deionized water and the antibiotics are eluted with 2 liters of 0.07M

  
  <EMI ID = 617.1>

  
a flow rate of 1.6 cm <3> per minute. We collect fractions of

  
  <EMI ID = 618.1>

  
activity and are combined.

  
These combined fractions are concentrated by evaporation on a rotary evaporator under reduced pressure at

  
  <EMI ID = 619.1>

  
NaOH. The solution is further concentrated to 5 cm &#65533; and applied

  
  <EMI ID = 620.1>

  
0.037 to 0.074 mm. The sample is washed in the column bed with two portions of 1 cc deionized water each producing the check developing flask. The pH and test results are shown in the table below:

  

  <EMI ID = 621.1>


  
  <EMI ID = 622.1>

  
by this fermentation is cooled to 3 [deg.] C and centrifuged in portions of 200 cm <3> at 9000 rpm for 15 minutes each. At

  
  <EMI ID = 623.1>

  
The supernatant liquid from the centrifuged broth resulting from the two fermentations above in this example is combined to give a total volume of 13 liters.

  
The combined supernatant liquid is passed through a column of Dowex-1-x 2 (Cl-), particles 0.149-0.297

  
  <EMI ID = 624.1>

  
60 cm <3> per minute. The column is washed with 1 liter of deionized water and the antibiotic eluted with 5 liters of solution.

  
  <EMI ID = 625.1>

  
test fractions on plates containing Salmonella gallinarum MB1287.

  
Antibiotic activity appears in fractions

  
3 to 26, with a peak at fractions 5 and 6. Fractions 5 to

  
9 are combined for further processing. The pH of the fractions

  
  <EMI ID = 626.1>

  
The combined fractions 5 to 9 are concentrated to
150 cm by evaporation on a rotary evaporator under reduced pressure and applied to a column of XAD-2 (dimensions and eluted with deionized water at a flow rate of 0.6 cm <3> per minute. Ten fractions of 3.3 cm are collected <3> followed by

  
  <EMI ID = 627.1>

  
Fractions 62, 63, 64 and 65 are frozen and freeze-dried individually in 14 cm glass vials <3> and preserved

  
  <EMI ID = 628.1>

  
takes advantage of the relatively greater resistance of antibiotic 890A3 to degradation by penicillinase, as follows:

  
Fraction 63 from the Bio-Gel column is combined with fractions 61, 66, and 67 from the Bio-Gel column. To these four fractions combined, 0.2 cm <3> buffer

  
  <EMI ID = 629.1>

  
at room temperature, a further 0.2 cm <3> of penicillinase and after an additional two hours at room temperature, the reaction mixture is cooled in an ice bath. The final reaction mixture is diluted to 15 cc by adding 5 cm. <3> deionized water.

  
The reaction mixture is adsorbed on a column

  
  <EMI ID = 630.1>

  
combined.

  
  <EMI ID = 631.1>

  
by evaporation on a rotary evaporator under reduced pressure and the concentrate is applied to a column (2.2 x 70 cm) of

  
  <EMI ID = 632.1> fifty fractions of 2.65 CET.

  
Fractions 66-70 are combined and the combined samples are concentrated to 1.5 cc by evaporation on a rotary evaporator under reduced pressure and the concentrate is con- centrated.

  
  <EMI ID = 633.1>

  
N-acetyl is cleaved as described above to give the free base

  

  <EMI ID = 634.1>



    

Claims (1)

1 - A compound having the structure: <EMI ID = 635.1> and its pharmaceutically acceptable salt, esters, ethers and amide derivatives; or : X and Y are independently selected from hydrogen, R, -OR, <EMI ID = 636.1> while Y or X, respectively, is R, and X and Y cannot both be hydrogen or R at the same time; R1 and R2 are independently selected from R, hydrogen and nitro, hydroxyl, alkoxyl groups having 1 to 6 carbon atoms, amino, mono-, di- and trialkylamino where the alkyl moieties each comprise from 1 to 6 carbon atoms. carbon; R <1> and R <2> can be linked together to form a substituted or unsubstituted mono- or bicyclic heteroaryl or heterocycle group comprising (together with the nitrogen atom to which they are attached) from 4 to 10 atoms carbon, one or more of which may be additional heteroatoms chosen from oxygen, sulfur or nitrogen; R, R <1> and R2 are radicals chosen from the following, substituted or not: cyano; hydrogen, carbamoyl; carboxyl; alkoxycarbonyl and alkyl having from 1 to 10 carbon atoms; alkenyl having 2 to 10 carbon atoms; alkynyl having 2 to 10 carbon atoms; cycloalkyl having <EMI ID = 637.1> from 4 to 12 carbon atoms; cycloalkenyl, cycloalkenylacenyl and cycloalkenylalkyl having 3 to 10, 4 to 12 and 4 to 12 carbon atoms, respectively; aryl having 6 to 10 carbon atoms, aralkyl, aralkenyl and aralkynyl having 7 to 16 carbon atoms; Mono- and bicyclic heteroaryl and heteroaralkyl comprising from 4 to 10 atoms in the rings, one or more of which are heteroatoms selected from oxygen, sulfur or nitrogen, and the alkyl portion of the heteroaralkyl radical comprises from 1 to 6 carbon atoms; mono- and bicyclic heterocyclyl and heterocyclylalkyl comprising from 4 to 10 carbon atoms in the rings of which one or more are. heteroatoms chosen from oxygen, sulfur and nitrogen and the alkyl portion of the heterocyclylalkyl radical comprises from 1 to 6 carbon atoms approximately; <EMI ID = 638.1> <EMI ID = 639.1> the following: chloro, bromo, iodo and fluoro; azido; alkyl having 1 to 4 carbon atoms; thio; sulfo; phosphorus; cyanothio (-SCN); nitro; cyano; amino; hydrazino; mono-, di- and trialkylated amino and hydrazino where the alkyl group has 1 to 6 carbon atoms; hydroxyl; alkoxyl having 1 to 6 carbon atoms; alcolthio having 1 to 6 carbon atoms; carboxyl; oxo; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxyl portion; acyloxy having 2 to 10 carbon atoms; carbamoyl and mono- and dialkoylcarbamoyl where the alkyl groups each have 1 to 4 carbon atoms. 2 - A compound according to claim 1, characterized in that Y is -NR <1> R <2> and X is hydrogen or R. 3 - A compound according to claim 1, characterized in that <EMI ID = 640.1> 5 - A compound according to claim 1, characterized in that Y is chosen from hydrogen, R, -OR and -SR and X is -OR or -SR. 6 - A compound according to claim 2, characterized in that <EMI ID = 641.1> following, substituted or not: alkyl having 1 to 6 carbon atoms; alkenyl having 3 to 6 carbon atoms; cycloalkyl, cycloalkylalkyl <EMI ID = 642.1> from 4 to 7 carbon atoms, respectively; aralkyl and aralkenyl having from 7 to 10 carbon atoms; and monocyclic heteroaralkyl having 5 or 6 ring atoms, one or more of which is selected from oxygen, sulfur and nitrogen and from 1 to 3 carbon atoms in the alkyl portion; the substituent (s) on the ring or on the chain with respect to the definition <EMI ID = 643.1> my carbon; It is chosen from: hydrogen and alkyl groups having 1 to 6 carbon atoms; alkenyl having 2 to 6 carbon atoms; <EMI ID = 644.1> having 1 to 6 carbon atoms; alkylthioalkyl having 2 to 6 carbon atoms; and the following radicals, substituted or not: phenyl, benzyl, <EMI ID = 645.1> monocyclic coyles; where the substituent (s) are chosen from the following: chloro, fluoro, hydroxyl, alkoxyl having from 1 to 3 carbon atoms, <EMI ID = 646.1> 7 - A compound according to claim 3, characterized in that <EMI ID = 647.1> Vants, substituted or not: alkyl having from 1 to 6 carbon atoms; alkenyl having 3 to 6 carbon atoms; cycloalkyl, cycloalkylalkyl, cyclo- <EMI ID = 648.1> with 7 carbon atoms, respectively; aralkyl and aralkenyl having 7 with 10 carbon atoms; and monocyclic heteroaralkyl having 5 to 6 carbon atoms, one or more of which is selected from oxygen, sulfur and nitrogen and having 1 to 3 carbon atoms in the alkyl portion; where the substituent (s) at the ring or on the chain relative to the definition <EMI ID = 649.1> alkoxyl having 1 to 3 carbon atoms, dialkylamino having 1 to 3 carbon atoms in each alkyl moiety and alkylthio having 1 to 3 atoms of carbon. 8 - A compound according to claim. 6, characterized in that R <1> and R <2> are independently selected from hydrogen and alkyl groups having 1 to 6 carbon atoms and alkenyl having 2 to 6 carbon atoms and R is independently selected from hydrogen, alkyl, alkoxy-alkyl, mono - and dialkylaminoallyl groups where the alkyl moieties each comprise from 1 to 6 carbon atoms, aminoalkyl having <EMI ID = 650.1> and the following groups, substituted or not; phenyl, benzyl, phenethyl, heteroaryl, heteroalkyl, heterocyclyl and hetero- <EMI ID = 651.1> <EMI ID = 652.1> <EMI ID = 653.1> alkenyl, nitro, amino and phenyl. 10 - A compound according to claim 8, characterized in that R is chosen from hydrogen and methyl, ethyl, propyl, iso-propyl, methoxymethyl, hydroxyethyl, hydroxymethyl, aminomethyl, aminoethyl, aminopropyl, dimethylaminoethyl, methylaminomethyl, trifluoromethyl, methylthiomethyl, ethylthiomethyl, phenyl, benzyl, <EMI ID = 654.1> R <2> are independently selected from hydrogen and methyl, ethyl, propyl, isopropyl, butyl, tbutyl, allyl and benzyl groups. 11.- A compound according to claim 8, characterized <EMI ID = 655.1> hydrogen and alkyl and aminoalkyl groups having 1 to 6 carbon atoms and alkenyl having 2 to 6 carbon atoms. 12.- A compound according to claim 11, characterized <EMI ID = 656.1> smells of aminoalkyl groups. 13. A compound according to claim 12, characterized in that R represents an aminoethyl group of structure <EMI ID = 657.1> <EMI ID = 658.1> <EMI ID = 659.1> alkyl groups having 1 to 6 carbon atoms and alkenyl groups having 2 to 6 carbon atoms. 15 - A compound according to claim 8, characterized in that it has the structure <EMI ID = 660.1> 1.6 - A compound according to claim 11, characterized in that it has the structure <EMI ID = 661.1> <EMI ID = 662.1> to the structure <EMI ID = 663.1> <EMI ID = 664.1> the structure <EMI ID = 665.1> where A is a pharmaceutically acceptable anionic salt portion. 19 - A compound according to claim 11, characterized in that it has the structure <EMI ID = 666.1> 20- A compound according to claim 8, characterized in that it has the structure <EMI ID = 667.1> 21 - A compound according to claim 8, characterized in that it has the structure <EMI ID = 668.1> where R is a 4-thiazolyl group. <EMI ID = 669.1> to the structure <EMI ID = 670.1> 23 - A compound according to claim 11, characterized in that it has the structure <EMI ID = 671.1> 24 - A compound according to claim 10, characterized in that it has the structure <EMI ID = 672.1> 25 - A compound according to claim 11, characterized in that it has the structure <EMI ID = 673.1> 26 - A compound according to claim 11, characterized in that it <EMI ID = 674.1> <EMI ID = 675.1> to the structure <EMI ID = 676.1> <EMI ID = 677.1> to the structure <EMI ID = 678.1> <EMI ID = 679.1> 29 - A compound according to claim 11, characterized in that it has <EMI ID = 680.1> where A is a pharmaceutically acceptable anionic salt portion. 30 - A compound according to claim 1, characterized in that it has the structure <EMI ID = 681.1> in which : <EMI ID = 682.1> hydrogen and alkyl groups having 1 to 10 carbon atoms; phenacyl substituted at the ring where the substituent is chlorine, bromine, fluorine or an alkyl group having 1 to 6 carbon atoms; alkoxyalkyl wherein the alkoxyl portion is open chain or cyclic and has 1 to 6 carbon atoms and the alkyl portion has 1 to 6 carbon atoms; alkanoyloxyalkyl having 2 to 12 carbon atoms, halo and perhaloalkyl where the halogen is chlorine, bromine, fluorine and the alkyl chain has 1 to 6 carbon atoms; alkenyl having from 2 to 10 atoms-of <EMI ID = 683.1> aminoacetoxyalkyl having 4 to 21 carbon atoms; alkanoyla midoalkyl having 2 to 13 carbon atoms; aralkyl where the alkyl portion has 1 to 3 carbon atoms and the aryl portion has 6 to 10 atoms <EMI ID = 684.1> zote; aralkyl and heteroaralkyl substituted at the ring where the substituent is selected from chlorine, fluorine, bromine, iodine and in- alkyl groups. <EMI ID = 685.1> gene, sulfur or nitrogen and the alkyl portion comprises from 1 to 6 carbon atoms; aryl and aryl substituted at the ring comprising 6 to 10 atoms of carbon in the ring and where the substituent on the ring is chosen from the following: hydroxy, lower alkyl comprising from 1 to 6 carbon atoms, chloro, fluoro, bromo, alkylthioalkyl comprising from 2 to 12 carbon atoms; cycloalkylthioalkyl comprising from 4 to. 12 carbon atoms; acylthioalkyl where the acyl portion comprises 2 to 10 carbon atoms and the por- <EMI ID = 686.1> gene, an acyl group and R3. 31- A compound according to claim 30, characterized in that: <EMI ID = 687.1> formyl, acetyl, propionyl, butyryl, chloroacetyl, methoxyacetyl, aminoacetyl, methoxycarbonyl, ethoxycarbonyl, methylcarbamoyl, ethylcarbamoyl, phenylthiocarbonyl, 3-aminopropionyl, 4-aminobutyryl, N-methylaminoacetyl, N, N-dimethylaminoacetyl, N, N, N-trimethylaminoacetyl, <EMI ID = 688.1> propionyl, N, N, N-triethylaminoacetyl, pyridiniumacetyl, guanylthioacetyl, guanidinoacetyl, 3-guanidinopropionyl, N <3> -methylguanidinopropionyl, hydroxyacetyl, 3-hydroxy- propionyl, acryloyl, propynoyl, malonyl, phenoxycarbonyl, amidinoacetyl, acetamidinoacetyl, amidinopropionyl, acetamidinopropionyl, guanylureidoacetyl, guanylcarbamoyl, carboxymethylaminoacetyl, sulfoacetylaminoacetyl, phosphono- <EMI ID = 689.1> benzoyl, 0-aminobenzoyl, <EMI ID = 690.1> where M is hydrogen or an alkali or alkaline earth metal cation and <EMI ID = 691.1> t-butyl, phenacyl, p-bromophenacyl; pivaloyloxymethyl, 2,2,2-trichloroethyl, allyl, 3-methyl-2-butenyl, 2-methyl-2-propenyl, benzyl, benzylhydryl, p-t-butylbenzyl, phthalidyl, phenyl, 5-indanyl, acetylthiomethyl, <EMI ID = 692.1> pivaloylthiomethyl, methylthiomethyl. 32 - A process for the preparation of a compound as defined in claim 2, according to which one treats <EMI ID = 693.1> or an appropriate 0- and / or carboxylated derivative of this compound with an imido <EMI ID = 694.1> or an imido halide <EMI ID = 695.1> <EMI ID = 696.1> 33 - A process for preparing a compound as defined in claim 2, according to which one treats <EMI ID = 697.1> or an appropriate 0 - and / OR carboxylated derivative of this compound with an amine, -j 2 <EMI ID = 698.1> 34 - A process for preparing a compound as defined in claim 3, characterized in that one treats <EMI ID = 699.1> or an appropriate 0- and / or carboxylated derivative of this compound with <EMI ID = 700.1> <EMI ID = 701.1> <EMI ID = 702.1> Claim 3, characterized in that <EMI ID = 703.1> <EMI ID = 704.1> the group that leaves is -OR or -SR. 36 - A process for preparing a compound as defined in claim 4, according to which one treats <EMI ID = 705.1> or an appropriate 0- and / or carboxyl derivative of this compound with an alkylating agent chosen so as to give <EMI ID = 706.1> <EMI ID = 707.1> 37 - A process for preparing a compound as defined in claim 5, according to which one treats <EMI ID = 708.1> or an 0- and / or carboxylated derivative of this compound with an alkylating agent chosen so as to give <EMI ID = 709.1> <EMI ID = 710.1> 38.- As a new medicament, a compound according to one of claims 1 to 31 and a pharmaceutical vehicle. 39. A pharmaceutical composition comprising, in unit dosage form, a therapeutically effective amount of at least one compound according to one of claims 1 to 31 and a pharmaceutical carrier. The undersigned is aware that no document attached to the file of a patent for invention can be of a nature to make, either to the description or to the drawings, substantive modifications and declares that the content of this note no 'make no such changes and has no other purpose than to report one or more material errors. He acknowledges that the content of this note cannot have the effect of making the aforementioned patent application fully or partially valid if it is not fully or partially valid. partly under the legislation currently in force. He authorizes the administration to attach this note to the patent file and to issue a photocopy thereof.