CH662119A5 - Aminomethyl-penem compounds - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R1 is lower alkyl substituted by hydroxyl or by protected hydroxyl, R2 represents carboxyl or functionally altered carboxyl, and R3 denotes amino, amino substituted by lower alkyl, substituted methylenamino, or protected amino, optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of those compounds of the formula I which have a salt-forming group, possess antibiotic effects. The compounds of the formula I are prepared by processes which are known per se.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **. 

 characterized in that a mixture of isomeric compounds of the formula I, in which R1 is optionally protected l-hydroxyethyl and R2 and R3 have the meanings given above, is separated into the individual isomers and the (1 R) -l-hydroxyethyl isomer is isolated. 



   21st  Process for the preparation of compounds of the formula
R1
1.  -5.   
1 1. -CH2-R3 (I),
N 25
R
2 wherein R1 is lower alkyl substituted by hydroxy, R2 is esterified carboxyl which is cleavable under physiological conditions, and R3 is amino, lower alkyl-substituted amino or substituted methylene amino, optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of such compounds of the formula I which have a salt-forming group, characterized in that in a compound of the formula I in which R1 and R3 have the meanings given above and R2 is a carboxyl group, the carboxyl group R2 is converted by esterification into an esterified carboxyl group which can be split under physiological conditions. 



   22.  Compounds of the formula
EMI3. 1
 wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R'2 is protected carboxyl, R3 is amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, optical isomers of compounds of formula III and mixtures of these optical isomers for performing the method according to claim 18. 



   The present invention relates to new 2-aminomethylpenem compounds, processes for their preparation and pharmaceutical preparations which contain such compounds. 



   The invention relates to 2-aminomethyl-2-penem compounds of the formula
EMI3. 2nd
 wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R2 is carboxyl or functionally modified carboxyl, and R3 is amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of those compounds of the formula I which have a salt-forming group. 



   The definitions used above and below preferably have the following meanings in the context of the present description:
Functionally modified carboxyl R2 is in particular cleavable, esterified carboxyl or protected carboxyl R2 under physiological conditions.    



   An esterified carboxyl group R2 which can be cleaved under physiological conditions protects the compounds of the formula I from salt formation in the gastrointestinal tract when administered orally, which prevents premature excretion, and is primarily an acyloxymethoxycarbonyl group, in which acyl z. B.  is the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or wherein acyloxymethyl forms the residue of a lactone.  Such groups are e.g. B.  Never deralkanoyloxymethoxycarbonyl, amino lower alkanoyloxymethoxycarbonyl, especially a-amino lower alkanoyloxymethoxycarbonyl, 4-crotonolactonyl and 4-butyrolactone-4yl. 

  Further esterified carboxyl groups R2 which can be cleaved under physiological conditions are e.g. B.  5-indanyloxycarbonyl, 3-phthalidyloxycarbonyl, 1-lower alkoxycarbonyloxy lower alkoxycarbonyl, l-lower alkoxy lower alkoxycarbonyl or 2-oxo-1,3-dioxolen -4-ylmethoxycarbonyl, which is optionally substituted in the 5-position of the dioxolen ring by lower alkyl or phenyl. 



   Amino R3 substituted by lower alkyl is e.g. B.  Lower alkylamino or lower alkylamino. 



   In substituted methylene amino R3, the methylene radical is preferably mono- or disubstituted.  Substituted methylene amino is e.g. B.  a group of the formula
EMI3. 3rd
 wherein Xl is hydrogen, optionally substituted amino, e.g. B.  Amino, Niederalkylamino, Diniederalkylamino, Niederalkylenamino, Nitroamino, Hydrazino or Anilino, etherified hydroxy, z. B.  Lower alkoxy or phenyl-lower alkoxy, etherified mercapto, e.g. B.  Lower alkylthio, optionally substituted lower alkyl, e.g. B.  Lower alkyl, amino-lower alkyl, N-lower alkylamino lower alkyl or N, N-di-lower alkylamino lower alkyl, lower alkenyl, phenyl or monocyclic heteroaryl, such as corresponding 5- or 6-membered heteroaryl having 1 to 2 nitrogen atoms and / or an oxygen or sulfur atom, such as pyridyl, e.g. B.  2 or 4-pyridyl, thienyl, e.g. B.  2-thienyl, or thiazolyl, e.g. B. 



  Is 4-thiazolyl, and X2 optionally substituted amino, e.g. B.  Amino, Niederalkylamino, Diniederalkylamino, Niederalkylenamino, Hydrazino or Anilino, etherified hydroxy, e.g. B.  Lower alkoxy or phenyl-lower alkoxy, or etherified mercapto, e.g. B.  Lower alkylthio. 



   In preferred radicals of the formula (IA), X1 is hydrogen, amino, lower alkylamino or lower alkyl and X amino. 



   Residues of the formula (IA) which have a hydrogen atom on the a atom of the substituent Xl and / or the substituent X2, for. B.  Residues of the formula (IA), in which X is amino, lower alkylamino, nitroamino, hydrazino 'anilino or gege



  optionally substituted lower alkyl and / or X2 is amino, lower alkylamino, hydrazino or anilino can also be in one of the tautomeric forms
EMI4. 1
 or
EMI4. 2nd
 where X'l or    X'2 corresponding substituted or unsubstituted methylene or.  Imino is present. 



   In the present description, the term low used in connection with definitions of groups and compounds means that the corresponding groups or  Unless expressly defined otherwise, compounds contain up to 7, preferably up to 4, carbon atoms. 



   Lower alkyl substituted by hydroxy R1 is in particular in the a-position to the Penem ring structure by hydroxy substituted lower alkyl and means, for. B.  l-hydroxypropl-yl, 2-hydroxybut-2-yl and primarily hydroxymethyl and l-hydroxyethyl.    



   Lower alkanoyloxymethoxycarbonyl is e.g. B.  Acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl. 



   a-amino lower alkanoyloxymethoxycarbonyl is e.g. B. 



  Glycycloxymethoxycarbonyl, L-valyloxymethoxycarbonyl or L-leucyloxymethoxycarbonyl. 



      l-Lower alkoxycarbonyloxy lower alkoxycarbonyl is e.g. B. 



  Äthoxycarbonyloxymethoxycarbonyl or l-Äthoxycarbonyloxyäthoxycarbonyl. 



   l-Lower alkoxy lower alkoxycarbonyl is e.g. B.  Methoxymethoxycarbonyl or l-methoxyethoxycarbonyl. 



   A 2-oxo-1,3-dioxolen $ ylmethoxy group, which is optionally substituted in the 5-position of the dioxolen ring by lower alkyl or phenyl, is primarily a 5-phenyl and primarily a 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxy group.    



   Lower alkylamino is e.g. B.  Methylamino, Athylamino, n Propylamino, Isopropylamino or n-Butylamino, while Diniederalkylamino z. B.  Dimethylamino, diethylamino, di-n-propylamino or di-n-butylamino means. 



   Niederalkylenamino has in particular 4 to 6 carbon chain links and means, for. B.  Pyrrolidino or Piperidino. 



   Lower alkoxy is e.g. B.  Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert. -Butoxy, while phenyl-lower alkoxy e.g. B.  Is benzyloxy. 



   Lower alkylthio is e.g. B.  Methylthio, ethylthio, ngpropylthio, isopropylthio or n-butylthio. 



   Lower alkyl is e.g. B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl or tert. -Butyl. 



   Amino lower alkyl is e.g. B.  2-aminoethyl or 3-aminopropyl. 



   N-lower alkylamino lower alkyl is e.g. B.  2-methyl- or 2-ethylaminoethyl, while N, N-di-lower alkylamino lower alkyl e.g. B.  2- dimethylaminoethyl or 2-diethylamino ethyl means. 



   Niederalkenyl is e.g. B.  Allyl, n-propenyl or isopropenyl. 



   Preferred esterified carboxyl groups R2 which can be cleaved under physiological conditions are e.g. B.  Phthalidyloxycarbonyl, lower alkanoyloxymethoxycarbonyl, e.g. B.  Pivaloyloxymethoxycarbonyl, and l-lower alkoxycarbonyloxy lower alkoxycarbonyl, e.g. B.    l-ethoxycarbonyloxyethoxycarbonyl. 



   The functional groups present in the compounds of the formula I, such as hydroxyl, carboxy or amino groups, in particular the hydroxyl group in the radical R1 and the carboxyl group R3, are optionally protected by protective groups which are used in penem, penicillin, cephalosporin and peptide chemistry .  Such protective groups protect the functional groups in question from undesired condensation reactions, substitution reactions and the like during the synthesis of the compound of the formula I from its precursors. 



   Such protecting groups are easy, i. H.  without unwanted side reactions taking place, for example solvolytically, reductively or even under physiological conditions, can be split off. 



   Protecting groups of this type, as well as their introduction and separation, are described in
J. F. W.  McOmie, Protective Groups in Organic Chemistry, Plenum Press, London, New York, 1973.    



   T. W.  Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981, The Peptides, Vol.  I.  Schroeder and Luebke, Academic Press, London, New York, 1965 and
Houben-Weyl, Methods of Organic Chemistry, Volume 15/1, Georg Thieme Verlag, Stuttgart, 1974. 



   In compounds of the formula (I), the hydroxyl group in the R1 radical can be protected, for example, by acyl radicals. 



  Suitable acyl radicals are e.g. 13.     lower alkanoyl optionally substituted by halogen, e.g. B.  Acetyl or trifluoroacetyl, optionally substituted by nitro benzoyl, e.g. B.  Benzoyl, 4-nitrobenzoyl or 2,4-dinitrobenzoyl, optionally substituted by halogen-substituted lower alkoxycarbonyl, e.g. B.  2-bromoethoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, lower alkenyloxycarbonyl, e.g. B.  Allyloxycarbonyl, or optionally substituted by nitro phenyl-lower alkoxycarbonyl, e.g.  B.  4-nitrobenzyloxycarbonyl.  Other suitable hydroxy protecting groups are e.g. B.  trisubstituted silyl, such as tri-lower alkylsilyl, e.g. B.  Trimethylsilyl or tert. -Butyl-dimethylsilyl, 2-halo-lower alkyl groups, e.g. B.    2-chloro, 2-bromo, 2-iodo and 2,2,2-trichloroethyl, and optionally by halogen, e.g. B.  Chlorine, lower alkoxy, e.g. B. 

  Methoxy, and / or nitro-substituted phenyl-lower alkyl, such as corresponding benzyl.  Preferred lower hydroxy groups are tri-lower alkylsilyl and lower alkenyloxycarbonyl. 



   A carboxyl group R2 is usually protected in esterified form, the ester group under mild conditions, e.g. B.  is easily cleavable under gently reductive, such as hydrogenolytic, or gently solvolytic, such as acidolytic or in particular basic or neutral hydrolytic conditions.  A protected carboxyl group may also be an esterified carboxyl group that is readily functionally modified to another esterified carboxyl group such as an esterified carboxyl group. 

 

   Such esterified carboxyl groups contain as esterifying groups primarily branched lower alkyl groups in the 1-position or suitably substituted in the 1- or 2-position.  Preferred carboxyl groups present in esterified form include lower alkoxycarbonyl, e.g. B. 



  Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or tert. -Butoxycarbonyl, and (hetero-) arylmethoxycarbonyl with 1 to 3 aryl radicals or a monocyclic heteroaryl radical, these optionally being e.g. B.  by lower alkyl, such as tert. -Lower alkyl, e.g. B.  tert. -Butyl.  Halogen, e.g. B. 



  Chlorine, and / or nitro are mono- or poly-substituted. 



  Examples of such groups include z. B. As mentioned above, substituted benzyloxycarbonyl, e.g. B.  4-nitrobenzyloxycarbonyl, optionally, e.g. B.  as mentioned above, substituted diphenylmethoxycarbonyl, e.g. B.   



  Diphenylmethoxycarbonyl, or triphenylmethoxycarbonyl, or optionally, e.g. B.  as mentioned above, substituted picolyloxycarbonyl, e.g. B.  4-picolyloxycarbonyl, or furfuryloxycarbonyl, such as 2-furfuryloxycarbonyl.  Other suitable groups are lower alkanoylmethoxycarbonyl, such as acetonyloxycarbonyl, aroylmethoxycarbonyl, in which the aroyl group is preferably optionally, for. B.  benzoyl substituted by halogen such as bromine, e.g. B.  Phenacyloxycarbonyl, halogen-lower alkoxycarbonyl, such as 2-halogen-lower alkoxycarbonyl, e.g. B.  2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or (o-halo-lower alkoxycarbonyl, in which lower alkoxy contains o carbon atoms, e.g. B. 



  4-chlorobutoxycarbonyl, phthalimidomethoxycarbonyl, lower alkenyloxycarbonyl, e.g. B.  Allyloxycarbonyl, or in the 2-position by lower alkylsulfonyl, cyano or trisubstituted silyl, such as tri-lower alkylsilyl or triphenylsilyl, substituted ethoxycarbonyl, e.g. B.  2-methylsulfonylethoxycarbonyl, 2-cyanoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl3-ethoxycarbonyl.    



   Further protected carboxyl groups present in esterified form are corresponding organic silyloxycarbonyl groups and also corresponding organic stannyloxycarbonyl groups.  In these the silicon or  Tin atom preferably lower alkyl, especially methyl or ethyl, further lower alkoxy, e.g. B.  Methoxy, as a substituent.  Suitable silyl or  Stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl or dimethyl tert. butylsilyl, or appropriately substituted stannyl groups, e.g. B.  Tri-n-butylstannyl. 



   Preferred protected carboxyl groups R'2 are the 4-nitrobenzyloxycarbonyl, lower alkenyloxycarbonyl, in particular allyloxycarbonyl, and the 2-position by lower alkylsulfonyl, cyano or tri-lower alkylsilyl, e.g. B. 



  Trimethylsilyl or di-n-butyl-methylsilyl, substituted ethoxycarbonyl group. 



   A protected amino group in the radical R3 can be present, for example, in the form of an easily cleavable acylamino, acylimino, etherified mercaptoamino, silyl or stannylamino group or as an enamino, nitro or azido group. 



   In a corresponding acylamino group, acyl is, for example, the acyl residue of an organic acid with, for. B.  up to 18 carbon atoms, in particular one optionally z. B.  by halogen or phenyl, substituted alkane carboxylic acid or optionally, e.g. B.  by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic acid semi-ester.  Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl or propionyl, halogen-lower alkanoyl, such as 2-haloacetyl, in particular 2-fluoro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2 -Trichloracetyl, optionally substituted benzoyl, e.g. B.  Benzoyl, halobenzoyl, such as 4-chlorobenzoyl, lower alkoxybenzoyl, such as 4-methoxybenzoyl, or nitrobenzoyl, such as 4-nitrobenzoyl.  In particular, lower alkenyloxycarbonyl, e.g. B. 

  Allyloxycarbonyl, or optionally substituted in the 1- or 2-position lower alkoxycarbonyl, such as lower alkoxycarbonyl, e.g. B.  Methoxy or ethoxycarbonyl, optionally substituted benzyloxycarbonyl, e.g. B.  Benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is preferably optionally, e.g. B.  benzoyl substituted by halogen such as bromine, e.g. B.  Phenacyloxycarbonyl, 2-halo lower alkoxycarbonyl, e.g. B.  2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) ethoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, e.g. B.  2-trimethylsilyl ethoxycarbonyl or 2- (di-n-butylmethylsilyl) ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl. 



   In an acylimino group, acyl is, for example, the acyl residue of an organic dicarboxylic acid with e.g. B.  up to 12 carbon atoms, in particular a corresponding aromatic dicarboxylic acid, such as phthalic acid.  One such group is primarily phthalimino. 



   An etherified mercaptoamino group is primarily an optionally by lower alkyl, such as methyl or tert.  Butyl, lower alkoxy, such as methoxy, halogen, such as chlorine or bromine, and / or nitro-substituted phenylthioamino group or a pyridylthioamino group.  Corresponding groups are, for example, 2- or 4-nitrophenylthioamino or 2-pyridylthioamino. 



   A silyl or stannylamino group is primarily an organic silyl or  Stannylamino group, in which the silicon or  Tin atom preferably lower alkyl, e.g. B. 



  Methyl, ethyl, n-butyl or tert. -Butyl, also lower alkoxy, e.g. B.  Contains methoxy as a substituent.  Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl, and also dimethyl tert. -butylsilyl, or appropriately substituted stannyl, e.g. B.  Tri-n-butylstannyl. 



   Other protected amino groups are e.g. B.  Enamino groups which contain an electron-withdrawing substituent, for example a carbonyl group, on the double bond in the 2-position.  Protecting groups of this type are, for example, l-acyl-lower alk-l-en-2-yl radicals, in which acyl z.  B.  the corresponding residue of a lower alkane carboxylic acid, e.g. B.  Acetic acid, one optionally, e.g. B.  by lower alkyl, such as methyl or tert. -Butyl, lower alkoxy, such as methoxy halogen, such as chlorine, and / or nitro-substituted benzoic acid, or in particular a carbonic acid semi-ester, such as a carbonic acid lower alkyl half-ester, e.g. B.  methyl half-ester or ethyl half-ester, and lower alk-l-ene means in particular l-propene.  Corresponding protective groups are primarily l-lower alkanoylprop-l-en-2-yl, e.g. B. 

  I-acetylprop-l-en-2-yl, or l-lower alkoxycarbonyl-prop-l-en-2yl, e.g. B.    l-Athoxycarbonyl-prop-l-en-2-yl. 



   Preferred protected amino groups are e.g. B.  Azido, phthalimido, nitro, lower alkenyloxycarbonylamino, optionally substituted by nitro benzyloxycarbonylamino, l-lower alkanoyl-lower alk-l-en-2-ylamino or 1-lower alkoxycarbonyl-lower alk-1-en-2-ylamino.    



   Salts of compounds according to the invention are primarily pharmaceutically acceptable, non-toxic salts of compounds of the formula I.  Such salts are, for example, from the acidic groups present in compounds of the formula I, e.g. B.  of the carboxyl groups R2, are formed and are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, for. B.  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, e.g. B.  Triethylamine, hydroxy-lower alkylamines, e.g. B.  2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hy droxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. B.  4-Aminobenzoesäure-2 -di äthylaminoäthylester, Niederalkylenaminen, z. B.    1ethyl piperidine, cycloalkylamines, e.g. B.  Dicyclohexylamine, or benzylamines, e.g. B.  

  N, N'-dibenzylethylenediamine, dibenzylamine or N-benzyl-ss-phenethylamine.     Compounds of formula I with a basic group, e.g. B.  with an amino group, acid addition salts, e.g. B.  with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carbon or sulfonic acid, e.g. B.  Form acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, oxalic acid, citric acid, benzoic acid, mandelic acid, malic acid, ascorbic acid, methanesulfonic acid or 4-toluenesulfonic acid.  Compounds of formula I with an acidic and with a basic group can also be in the form of internal salts, i.e. H.  in zwitterionic form. 



   For isolation or purification, pharmaceutically unsuitable salts can also be used.  Only the pharmaceutically acceptable, non-toxic salts are used therapeutically, which is why they are preferred. 



   The penem compounds of the formula I have the R configuration on carbon atom 5 and the S configuration on carbon atom 6.  The compounds of the formula I can have a further center of chirality in the substituent R1, which can be in the R, S or racemic R, S configuration.  In preferred compounds of the formula I, an R 1 radical which is asymmetrically substituted by hydroxy in the a position (at the carbon atom 1 '), in particular 1'-hydroxyethyl, has the R configuration. 



   The invention particularly relates to compounds of the formula I in which R1 is lower alkyl substituted by hydroxy or protected hydroxy, R2 is carboxyl, esterified carboxyl or protected carboxyl R'2 which is cleavable under physiological conditions, and R3 is amino, lower alkylamino, di-lower alkylamino, a group of the formula N = C (X1, X2), in which Xl is hydrogen, amino, lower alkylamino, di-lower alkylamino, lower alkylene amino, nitroamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino lower alkyl, N lower alkylamino lower alkyl, N, N-di-lower alkylamino lower alkyl, lower alkenyl Pyridyl, e.g. B.  2 or 4-pyridyl, thienyl, e.g. B.  2-thienyl, or thiazolyl, e.g. B. 



  Is 4-thiazolyl, and X2 is amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio, or is protected amino, optical isomers of compounds of the formula I which have a chiral center in the radical R1, mixtures of these optical Isomers and salts of those compounds of formula I which contain a salt-forming group. 



   The invention relates in particular to compounds of the formula I in which R1 in the a-position is hydroxyl, tri-lower alkylsilyloxy, 2-halo-lower alkoxy, 2-halo-lower alkoxycarbonyloxy, lower alkenyloxycarbonyloxy or optionally substituted by nitro-substituted phenyl-lower alkoxycarbonyloxy, R2 carboxyl, lower alkenyloxycarbonyl, optionally substituted by nitrocarbonyl , Niederalkanoylmethoxycarbonyl, 2-Halogiederiederalkoxycarbonyl, 2-Triniederalkylsilyläthoxycarbonyl or an esterified carboxyl group cleavable under physiological conditions, e.g. B. 

   l-Lower alkoxycarbonyloxy lower alkoxycarbonyl, lower alkanoyloxymethoxycarbonyl, a-amino lower alkanoyloxymethoxycarbonyl or phthalidyloxycarbonyl means R3 is amino, lower alkylamino, di-lower alkylamino, a group of the formula -N = C (X1, X2), in which X is hydrogen, amino, lower alkyl, phenyl, pyryl, amino, lower alkylamino , e.g. B. 

   2-pyridyl, and X2 is amino, lower alkylamino or di-lower alkylamino, azido, phthalimino, nitro, lower alkenyloxycarbonylamino, optionally substituted by nitro benzyloxycarbonylamino, l-lower alkanoyl-lower alk -l-en-2-ylamino or l-lower alkoxycarbonyl-lower alk-1-ene -2-ylamino means optical isomers of compounds of the formula I which have a chiral center in the radical R1, mixtures of these optical isomers and salts of those compounds of the formula I which contain a salt-forming group. 



   The invention relates primarily to compounds of the formula I in which R1 is lower alkyl substituted by hydroxy in the a position, R2 carboxyl or an esterified carboxyl group which is cleavable under physiological conditions. 



  e.g. B.    1 -Liederalkoxycarbonyloxyniederalkoxycarbonyl or Niederalkanoyloxymethoxycarbonyl, means and R3 represents amino, Niederalkylamino or Formamidino optical isomers of compounds of formula 1.  which have a chiral center in the rest R1, mixtures of these optical isomers and salts of those compounds of the formula I which contain a salt-forming group. 



   The invention relates primarily to compounds of the formula I in which R is hydroxymethyl or 1-hydroxyethyl, R2 is carboxyl and R3 is amino, and salts thereof. 



   The invention further relates above all to the pure optical isomers of those compounds of the formula I which have a chiral center in the substituent Rl, in particular the (I'R) isomer of compounds of the formula I in which R1 is 1'-hydroxyethyl, and salts of those compounds of formula I which contain a salt-forming group. 



   The invention relates primarily to the compounds of the formula I and their salts in pure form, in particular in optically pure form. 



   The invention relates in particular to the compounds of the formula I mentioned in the examples and their pharmaceutically acceptable salts. 



   The compounds of the present invention can be prepared by methods known per se. 



   The new connections are e.g. B.  prepared by a) in a compound of formula
EMI6. 1
 wherein R1 has the meaning given under formula (I), R2 is a protected carboxyl group and Q is a group which can be converted into the radical R3, the group Q converts into the radical R3, or b) a ylide compound of the formula
EMI6. 2nd
 wherein R1 and R3 have the meanings given under formula I, R 'is a protected carboxyl group.  Z. 

  X represents oxygen or sulfur and Xf3 represents either a triple-substituted phosphono group or a double-esterified phosphono group together with a cation, ring-closes, or c) a compound of the formula
EMI7. 1
 wherein R1 and R3 have the meanings given under formula I and R2, which is a protected carboxyl group, is treated with an organic compound of trivalent phosphorus, and if desired or necessary, in a obtainable compound of the formula I, a protected hydroxyl group in the radical R1 in the free Converting the hydroxyl group and / or, if desired, a protected carboxyl group R2 ′ into the free carboxyl group in an available compound of the formula I,

   into an esterified carboxyl group cleavable under physiological conditions or into another protected carboxyl group R2 'or a free carboxyl group R2 into an esterified carboxyl group cleavable under physiological conditions or into a protected carboxyl group R2, and / or, if desired, a protected amino group R3 in converts the free amino group or a free amino group R3 to a substituted amino group, and / or, if desired, converts an available salt-forming group compound into a salt or an available salt into the free compound or another salt, and / or if desired to separate an available mixture of isomeric compounds of formula I into the individual isomers. 



   In the starting compounds of the formulas I ', II and III are functional groups, such as a free hydroxyl group in the radical R1 and in particular a free amino group R3, preferably by conventional protective groups, e.g. B.  one of the above, protected. 



   a) Introduction of the rest R3
A group Q which can be converted into a radical R3 is in particular a corresponding group which can be converted by a nucleophilic reaction.  Such groups Q are in particular esterified hydroxyl groups, such as hydrohalic acid, a lower alkyl or diarylphosphoric acid, a lower alkane carboxylic acid optionally substituted by oxo or halogen, a lower alkane optionally substituted by halogen or a benzenesulfonic acid optionally substituted by halogen or lower alkyl.  Such groups Q are e.g. B. 



  Halogen, such as chlorine, bromine or iodine, di-lower alkyl or diaryl phosphoryloxy, e.g. B.  Dimethyl, diethyl or diphenylphosphoryloxy, optionally substituted by halogen or oxo lower alkanoyloxy, e.g. B.  Formyloxy, acetyloxy or acetacetyloxy, optionally substituted by halogen-substituted lower alkanesulfonyloxy, e.g. B.  Methanesulfonyloxy or trifluoromethanesulfonyloxy, or optionally substituted by halogen or lower alkyl benzenesulfonyloxy, e.g. B.  Benzenesulfonyloxy, 4-chloro, 4-bromo or 4-methylbenzenesulfonyloxy. 



   The reaction is carried out with a compound of the formula R3-H, in which R3 has the meanings given above, or a salt, such as an alkali metal salt, for. B.  the sodium or potassium salt thereof, d. H.  with hydrochloric acid or with phthalimide or in particular with alkali metal salts, e.g. B.  the sodium or potassium salt thereof, also with ammonia, lower alkyl and di-lower alkyl amines, amidines, guanidines and the like, which may be in protected form, but at least one hydrogen atom must be present on the reacting amino group.  The reaction is carried out in an inert solvent, such as. B.  a lower alkanol, DMF, a cyclic ether, e.g. B. 

  Dioxane, or in DMSO, at room temperature or slightly higher or lower temperature, e.g. B.  at about 0 to 40 "C, especially at room temperature. 



   The starting compounds of the formula (I ') can be obtained in a manner analogous to that described under process b) by ring closure of the phosphorane of the formula
EMI7. 2nd
 wherein Z and X have the meanings given under formula (II), are prepared. 



   b) Cyclisierurtg of the compound of formula II
The group xe in the starting material of the formula II is one of the phosphonio or phosphono groups customary in Wittig condensation reactions, in particular a triaryl, for. B.  Triphenyl, or tri-lower alkyl, e.g. B.  Trin-n butylphosphono group, or one by lower alkyl, e.g. B. 



  Ethyl, double-esterified phosphono group, the symbol Xe in the case of the phosphono group additionally the cation of a strong base, in particular a suitable metal such as alkali metal ion, for. B.  the lithium, sodium or potassium ion.  Preferred as group XçD is triphenylphosphonio on the one hand and diethylphosphono on the other hand together with an alkali metal, e.g. B.  the sodium ion. 



   In phosphonio compounds of the formula II, the negative charge is neutralized by the positively charged phosphonio group.  In phosphono compounds of formula 11, the negative charge is neutralized by the cation of a strong base, which, depending on the manner in which the phosphono starting material is prepared, e.g. B.  an alkali metal, e.g. B.  Sodium, lithium or potassium ion.  The phosphono starting materials are therefore used as salts in the reaction.  The ring closure can spontaneously, i. H.  in the manufacture of the starting materials, or by heating, e.g. B.  in a temperature range from approximately 30 ° C. to 160 ° C., preferably from approximately 50 ° C. to approximately 100 ° C.  

  The reaction is preferably carried out in a suitable inert solvent, such as in an aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. B.  Cyclohexane, benzene or toluene, a halogenated hydrocarbon, e.g. B. 



  Methylene chloride, an ether, e.g. B.  Diethyl ether, a cyclic ether, e.g. B.  Dioxane or tetrahydrofuran, a carboxamide, e.g. B.  Dimethylformamide, a di-lower alkyl sulfoxide, e.g. B.  Dimethyl sulfoxide, or a lower alkanol, e.g. B.  Ethanol, or in a mixture thereof, and, if necessary, in an inert gas, e.g. B.  Nitrogen atmosphere. 



   c) cyclization of the compound of formula III
An organic compound of trivalent phosphorus derives e.g. B.  from phosphorous acid and is especially in ester thereof with a lower alkanol, e.g. B.  Methanol or ethanol, and / or an optionally substituted aromatic hydroxy compound, e.g. B.  Phenol or pyrocatechol, or an amide ester thereof of the formula (P (ORakN (Rb) 2, in which Ra and Rb independently of one another lower alkyl, e.g. B.  Methyl, or aryl, e.g. B.  Phenyl. 



  Preferred compounds of trivalent phosphorus are trialkyl phosphites, e.g. B.  Trimethyl phosphite or triethyl phosphite. 



   The reaction is preferably carried out in an inert solvent such as an aromatic hydrocarbon, e.g. B. 



  Benzene or toluene, an ether, e.g. B.  Dioxane or tetrahydrofuran, or a halogenated hydrocarbon e.g. B.  Methylene chloride or chloroform, at a temperature of about 20 to 80 "C, preferably from about 40 to about 60 C, wherein reacting 1 mole equivalent of a compound of formula III with 2 mole equivalent of the phosphorus compound.  Preferably, the compound of formula III is placed in an inert solvent and the phosphorus compound, preferably dissolved in the same inert solvent, is added dropwise over a longer period of time, e.g. B. 



  over a period of 2 to 4 hours. 



   In a preferred embodiment of the process, the starting material of the formula III is prepared as indicated below and is reacted with the organic compound of trivalent phosphorus without isolation from the reaction mixture, the end products of the formula 1 being formed. 



   Those starting materials of the formulas II and III are preferably used which lead to the compounds of the formula I mentioned at the outset as being particularly preferred. 



   In an available compound of formula I in which one or more functional groups are protected, these, e.g. B.  Protected carboxyl, hydroxyl and amino groups are released in a manner known per se by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis or chemical reduction, if appropriate in stages or simultaneously. 



   In a process according to the obtainable compound of the formula I, in which R2 denotes a protected carboxyl group, the protected carboxyl group can be released in a manner known per se.  So you can tert. -Lower alkoxycarbonyl or in the 2-position by a trisubstituted silyl group or in the 1-position by lower alkoxy substituted lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl z. B.  by treatment with a carboxylic acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole, into free carboxyl.  Optionally substituted benzyloxycarbonyl can e.g. B.  by means of hydrogenolysis, d. H.  can be cleaved by treatment with hydrogen in the presence of a metallic hydrogenation catalyst such as a palladium catalyst. 

  You can also suitably substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, also by chemical reduction, e.g. B. 



  by treatment with an alkali metal, e.g. B.  Sodium dithionite, or with a reducing metal, e.g. B.  Tin, or metal salt, such as a chromium II salt, e.g. B.  Chromium (II) chloride, usually in the presence of a hydrogen donor that can generate nascent hydrogen together with the metal, such as a suitable carboxylic acid, e.g. B.  one if necessary, e.g. B.  by hydroxy, substituted lower alkane carboxylic acid, e.g. B.  Convert acetic acid, formic acid or glycolic acid, or an alcohol or thiol, preferably with water, into free carboxyl. 



   The cleavage of an allyl protecting group can, for. B.  by reaction with a compound of palladium, e.g. B.  Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and with the addition of a carboxylic acid, e.g. B.    2-ethylhexanoic acid, or a salt thereof. 



  By treatment with a reducing metal or metal salt as described above, 2-halo-lower alkoxycarbonyl (optionally after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into free carboxyl, while aroylmethoxycarbonyl can also be converted by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, can be cleaved. 



  Substituted 2-silylethoxycarbonyl can also be treated by treating with a fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. B. 



  Sodium fluoride, in the presence of a macrocyclic poly ether (crown ether) or with a fluoride of an organic quaternary base, such as tetraniederalkylammonium fluoride, e.g. B.  Tetrabutylammonium fluoride, can be converted into free carboxyl.  Carboxyl esterified with an organic silyl or stannyl group, such as tri-lower alkylsilyl or stannyl, can be solvolytically, for. B.  by treatment with water or an alcohol. 



  A lower alkoxycarbonyl group substituted in the 2-position by lower alkylsulfonyl or cyano can, for. B.  by treatment with a basic agent such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. B.  Sodium or potassium hydroxide or sodium or potassium carbonate, can be converted into free carboxyl. 



   On the other hand, compounds of the formula I in which R2 is carboxy can also be converted into compounds of the formula I in which R2 is a protected carboxyl group, in particular an esterified carboxyl group, or an esterified carboxyl group which is cleavable under physiological conditions.  So you can the free carboxyl z. B. 



  by treatment with a suitable diazo compound, such as a diazo lower alkane, e.g. B.  Diazomethane, or a phenyldiazone lower alkane, e.g. B.  Diphenyldiazomethane, if necessary, in the presence of a Lewis acid, such as. B.  Boron trifluoride, or by reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B.  Esterify dicyclohexylcarbodiimide and carbonyldiimidazole.  Esters can also be prepared by reacting an optionally in situ salt of the acid with a reactive ester of an alcohol and a strong inorganic acid such as sulfuric acid or a strong organic sulfonic acid such as 4-toluenesulfonic acid. 

  Furthermore, acid halides such as chlorides (made e.g. B.  by treatment with oxalyl chloride), activated esters, (formed e.g. B.  with N-hydroxy nitrogen compounds, such as N-hydroxysuccinimide) or mixed anhydrides (obtained e.g. B.  with halogenated lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with suitable alcohols, optionally in the presence of a base such as pyridine, into an esterified carboxyl group. 

 

   In a compound of formula I with an esterified carboxyl group, this can be converted into another esterified carboxyl group, e.g. B.  2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, e.g. B.  Sodium iodide, in 2-iodoethoxycarbonyl.  Furthermore, in compounds of the formula I which contain a carboxyl group protected in esterified form, the carboxyl protecting group can be cleaved off as described above and a resulting compound of the formula I with a free carboxyl group or a salt thereof by reacting with the reactive ester of a corresponding alcohol in convert a compound of formula I in which R2 represents an esterified carboxyl group which is cleavable under physiological conditions. 



   In compounds of the formula I obtainable according to the process, a protected hydroxyl group contained in the radical R1 can be converted into the free hydroxyl group in a manner known per se.  For example, a hydroxy group protected by a suitable acyl group or an organic silyl or stannyl group is released, such as a correspondingly protected amino group (see. u. ); a tri-lower alkylsilyl group e.g. B.  also with tetrabutylammonium fluoride and acetic acid (under these conditions, carboxy groups protected by trisubstituted silylethoxy are not split).  A 2-halogeno lower alkyl group and an optionally substituted benzyl group are cleaved reductively. 



   In a compound of the formula I obtainable according to the invention with a protected amino group R3, this can be carried out in a manner known per se, e.g. B.  depending on the type of protective group, preferably by means of solvolysis or reduction, can be converted into the free amino group.  For example, 2-halo-lower alkoxycarbonylamino (optionally after converting a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino by treating with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid or aqueous acetic acid Be cleaved in the presence of a palladium catalyst. 

  Aroylmethoxycarbonylamino can also be treated by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal, e.g. B.  Sodium dithionite can be split.  Optionally substituted benzyloxycarbonylamino z. B.  by means of hydrogenolysis, d. H.  by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and allyloxycarbonylamino by reaction with a compound of the palladium, e.g. B.  Tetrakis (triphenylphosphine) palladium, in the presence of triphenylphosphine and treatment with a carboxylic acid, e.g. B.    2-ethylhexanoic acid, or a salt thereof. 

  An amino group protected with an organic silyl or stannyl group may e.g. B.  by means of hydrolysis or alcoholysis, a by 2-halogeno lower alkanoyl, e.g. B.  2-Chloroacetyl, protected amino group can be released by treatment with thiourea in the presence of a base or with a thiolate salt, such as an alkali metal tiolate, of the thiourea and subsequent solvolysis, such as alcoholysis or hydrolysis of the condensation product formed.  An amino group protected by 2-substituted silylethoxycarbonyl can be treated by treatment with a fluoride anion-providing salt of hydrofluoric acid, such as an alkali metal fluoride, e.g. B.  Sodium fluoride, in the presence of a macrocyclic polyether (crown ether) or with a fluoride of an organic quaternary base such as tetraniederalkylammonium fluoride, e.g. B. 

  Tetraethylammonium fluoride, are converted into the free amino group.  An amino group protected in the form of an azido or nitro group is e.g. B.  converted into free amino by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide or palladium or by treatment with zinc in the presence of an acid such as acetic acid. 



  An amino group protected in the form of a phthalimido group can be converted into the free amino group by reaction with hydrazine.  Furthermore, an arylthioamino group can be converted to amino by treatment with a nucleophilic reagent such as sulfurous acid. 



   Furthermore, a free amino group R3 can be converted into a substituted amino group in a manner known per se.  For example, amino can be reacted with a corresponding acyl halide, such as chloride, in acylamino R3 and with a ss-dicarbonyl compound, such as a 1-lower alkanoyl acetone or a lower alkyl acetoacetate, in 1-lower alkanoyl or    Transfer l-lower alkoxycarbonylprop-l-en-2-ylamino.  The conversion of amino groups into amidino, guanidino, isourea, imido ether and imidothio ether groups can be carried out, for example, according to one of the methods described in German Offenlegungsschrift No. 



  26 52 679 procedures are performed.  For example, compounds of formula I wherein R3 is amino can be reacted with an imido halide or ester of formula [(X1, Y) C = X2, HjeY2n, where X is hydrogen, lower alkyl, substituted lower alkyl, lower alkenyl, phenyl or monocoyclic heteroaryl means, X2 is optionally substituted imino, Y is halogen, e.g. B. 



  Chlorine, or lower alkoxy, e.g. B.    Is ethoxy, and Y2 is an anion, e.g. B.  Chloride, means in amidines or by reaction with a thiourea of the formula Xl-C (= S} X2, in which Xl and X2 are identical or different, optionally substituted amino radicals, or with an isourea or  Isothiourea of the formula (X1, Y3) C = X2 ', where Y3 is lower alkoxy or lower alkylthio, X is optionally substituted amino and X2, optionally substituted imino, are converted into guanidines.  Furthermore, a free amino group R3 can be converted into an amino group mono- or disubstituted by lower alkyl. 

  The lower alkyl group (s) are introduced, for example, by reaction with corresponding reactive lower alkyl esters, such as halides, for. B.  chlorides or bromides, or sulfonates, e.g. B.  -methane or -p-toluenesulfonates, in the presence of a basic condensing agent such as an alkali or alkaline earth metal hydroxide or carbonate, e.g. B.  Potassium hydroxide or sodium carbonate, in an inert solvent, such as a lower alkanol, at room temperature or elevated or reduced temperature, e.g. B.  at about -20 "to 880 C.    



   Salts of compounds of the formula I with salt-forming groups can be prepared in a manner known per se.  So you can salts of compounds of formula I with a free carboxyl or sulfo group z. B.  by treatment with metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. B.  the sodium salt of a-ethyl caproic acid, or with inorganic alkali or alkaline earth metal salts, e.g. B.  Form sodium bicarbonate, or with ammonia or with a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts of compounds of formula I are obtained in a conventional manner, e.g. B.  by treatment with a suitable acid or anion exchange reagent.  

  Internal salts of compounds of formula I can e.g. B.  by neutralizing salts such as acid addition salts to the isoelectric point, e.g. B. 



  with weak bases, or by treatment with ion exchangers. 



   Salts can be converted into the free compounds in a conventional manner, metal and ammonium salts e.g. B. 



  by treatment with suitable acids and acid addition salts, e.g. B.  by treating with a suitable basic agent.   



   Mixtures of isomeric compounds obtained can be separated into the individual isomers by methods known per se. 



   For example, a racemate obtained can be reacted with an optically active auxiliary, the resulting mixture of two diastereomeric compounds using suitable physico-chemical methods (e.g. B.  separate fractional crystallization, adsorption chromatography) and then split the individual diastereomeric compounds into the optically active compounds. 



  Racemates which are particularly suitable for separation into antipodes are those which have an acidic group, such as, for. B.  Racemates of compounds of formula I, wherein R2 is carboxy. 



  These acidic racemates can with optically active bases, for. B.  Esters of optically active amino acids, or (-) - bruein, (+) quinidine, (-) quinine, (+) - cinchonine, (+) - dehydro droietylamine, (+) - and (-) ephedrine, (+) - and (-) - 1 phenylethylamine or their N-mono- or N, N-dialkylated derivatives to form mixtures consisting of two diastereomeric salts. 



   In racemates containing carboxyl groups, this carboxyl group can also be esterified by an optically active alcohol, such as (-) - menthol, (+) - borneol, (+) - or (() -2-octanol, after which the desired diastereomers have been isolated Carboxyl group is released. 



   For racemate separation, an existing hydroxyl group can also be esterified with optically active acids or their reactive, functional derivatives, with the formation of diastereomeric esters.  Examples of such acids are (-) -bietic acid, D (+) - and L (-) - malic acid, N-acylated optically active amino acids, (+) - and (-) -camphanoic acid, (+ 3- and (-) - Ketopic acid, L (+) ascorbic acid, (+) camphoric acid, (+) camphor-1 0-sulfonic acid (ss), (+) - or (-) -a-bromocampher-7. -sulfonic acid, D (-) - quinic acid, D (-) - isoascorbic acid,

   D (-) - and L (+) -mandelic acid, (+) - 1-menthoxyacetic acid, D (-) - and L (+) -tartaric acid and their di-O-benzoyl and di-O-p-tolyl derivatives. 



   By reaction with optically active isocyanates, such as with (+) - or (-) - 1-phenylethyl isocyanate, compounds of the formula (I) in which R 2 is protected carboxy and R 1 is hydroxy-substituted lower alkyl can be converted into a mixture of diastereomeric urethanes. 



   Basic racemates, e.g. B.  Compounds of the formula I in which R3 is amino can form diastereomeric salts with the optically active acids mentioned. 



   The separated diastereomers are also cleaved into the optically active compounds of the formula I by customary methods.  The salts or the bases are freed from the salts, for. B.  by treatment with stronger acids or  Bases than the originally used.  The desired optically active compounds are obtained from the esters and urethanes, for example after alkaline hydrolysis or after reduction with a complex hydride, such as lithium aluminum hydride. 



   Another method for separating the racemates consists in chromatography on optically active adsorption layers, for example on cane sugar. 



   According to a third method, the racemates can be dissolved in optically active solvents and the sparingly soluble optical antipode can be crystallized out. 



   A fourth method uses the different responsiveness of the optical antipodes to biological material, such as microorganisms or isolated enzymes. 



   According to a fifth method, the racemates are dissolved and one of the optical electrodes is crystallized by inoculation with a small amount of an optically active product obtained by the above methods. 



   The resolution of the racemates into the optical antipodes can be carried out at any stage in the process, i. H.  e.g. B. 



  also at the stage of the starting compounds of the formulas I ', II or III or at any stage of the processes described below for the preparation of the starting compounds of the formula 1', 11 or III. 



   In all subsequent conversions of compounds of the formula I obtained, preference is given to those reactions which take place under alkaline or, in particular, neutral conditions. 



   The process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage.  Furthermore, starting materials in the form of derivatives can be used or prepared in situ, if appropriate under the reaction conditions. 



   The starting compounds of the formulas 1 ', III and III can be prepared as indicated in the following reaction scheme I: Reaction scheme I
EMI11. 1
 In the compounds of the formula II, V and VI, R4 is either the radical R3 or a group Q. 



  Level I
A thioazetidinone of the formula V is obtained by reacting a compound of the formula IV with a compound which introduces the radical = = ZCH7R4.    



   In a starting material of the formula IV, W is a nu cleofuger radical which can be replaced by the group -S-C (= Z) -CH2-R4.  Such radicals W are, for example, acyloxy radicals, sulfonyl radicals R0-SO2-, in which Ro is an organic radical, azido or halogen.  In an acyloxy radical W, acyl is e.g. B.  the rest of an organic carboxylic acid and means, for example, lower alkanoyl, e.g. B.  Acetyl or propionyl, optionally substituted benzoyl, e.g. B.  Benzoyl or 2,4-dinitrobenzoyl, or phenyl-lower alkanoyl, e.g. B.  Phenylacetyl. 

  In a sulfonyl radical R0-SO2, Ro is, for example, lower alkyl optionally substituted by hydroxy, such as methyl, ethyl or 2-hydroxyethyl, benzyl or optionally substituted phenyl, such as phenyl, 4-bromophenyl or 4-methylphenyl.  A halogen radical W is e.g. B.  Bromine, iodine or especially chlorine.  W is preferably methyl or 2-hydroxyethylsulfonyl, acetoxy or chlorine. 

 

   A compound introducing the radical -S-C (= Z) -CH2 R4 is, for example, an acid of the formula R4-CH2-C (= Z) -SH or in particular a salt, e.g. B.  an alkali metal salt such as the sodium or potassium salt thereof. 



  The substitution can be in an organic solvent, such as in a lower alkanol, e.g. B.  Methanol or ethanol, a lower alkanone, e.g. B.  Acetone, a lower alkanecarboxamide, e.g. B.  Dimethylformamide, a cyclic ether, e.g. B.  Tetrahydrofuran or dioxane, or in a similar inert solvent.  The reaction is usually carried out at room temperature, but can also be carried out at elevated or reduced temperature, e.g. B. 



  at about 0 to 40 "C.  By adding a salt of hydroiodic acid or thiocyanic acid, e.g. B.  an alkali metal such as sodium salt, the reaction can be accelerated. 



   The entering group -S-C (= Z) -CH2-R4 is preferably directed by the radical R1 into the trans position.  Both (3S, 4R) and (3S, 4RS) -configured starting compounds of the formula IV can therefore be used. 



  Although most of the trans isomers are formed, small amounts of the cis isomer can occasionally be formed.  As described above, the cis isomers are removed by conventional methods, in particular by chromatography and / or by crystallization. 



   Suitable starting compounds of the formula IV are known, for example, from European Patent Application No.    



  82113 known. 



  Level 2
A starting compound of the formula (III) is obtained by reacting an azetidinone of the formula (V), in which Z is sulfur and R4 represents the radical R3, with an acid of the formula R'2-COOH or in particular a reactive derivative such as one Ester or acid halide, e.g. B. 



  the acid chloride, thereof at a temperature of 20 to 80'C, preferably at 40 to 60'C, in an inert solvent, such as one of those mentioned in the reaction of compounds of formula III to compounds of formula I, treated.  When using an acid halide, it is preferred to work in the presence of an acid-binding agent, such as a tertiary aliphatic amine, e.g. B.  Triethylamine, an aromatic amine, e.g. B.  Pyridine, or in particular an alkali metal or alkaline earth metal carbonate or bicarbonate, e.g. B.  Potassium carbonate or calcium carbonate. 



  level 3
Compounds of formula VI, wherein X0 for a reactive esterified hydroxy group, especially for halogen, e.g. B.  Chlorine or bromine, or organic sulfonyloxy, e.g. B.  Lower alkanesulfonyloxy, such as methanesulfonyloxy, or arensulfonyloxy, e.g. B.  Benzene- or 4-methylbenzplsulfonyloxy, is prepared by preparing a compound of formula V with a glyoxylic acid compound of formula OHC-R2 'or a suitable derivative thereof, such as a hydrate, hemihydrate or hemiacetal, e.g. B.  a hemiacetal with a lower alkanol, e.g. B.  Methanol or ethanol, and in a compound of formula VI, wherein X0 is hydroxy, the hydroxy group is converted into a reactive esterified hydroxy group. 



   The compounds of formula VI are usually obtained as a mixture of the two isomers with respect to the grouping -CH (R2 ') ¯ XO].  But you can also isolate the pure isomers thereof, e.g. B.  by chromatography. 



   The addition of the glyoxylic acid ester compound to the nitrogen atom of the lactam ring in the compound of formula V takes place at room temperature or, if necessary, with heating, e.g. B.  at about 100 "C, in the absence of an actual condensing agent.  When using the hydrate of the glyoxylic acid compound, water is formed which, if necessary, by distillation, e.g. B.  removed azeotropically, or by using a suitable dehydrating agent such as a molecular sieve. 



  Is preferably carried out in the presence of a suitable solvent, such as. B.  Dioxane, toluene or dimethylformamide, or a mixture of solvents, and, if desired or necessary, in the atmosphere of an inert gas such as nitrogen. 



   The conversion of a hydroxy group X0 into a reactive esterified hydroxy group X0 in a compound of formula VI is carried out by treatment with a suitable esterifying agent, e.g. B.  with a thionyl halide, e.g. B.  -chloride, a phsophoroxyhalide, especially -chloride, a halophosphonium halide. 



  such as triphenylphosphonium dibromide or dichloride or a suitable organic sulfonic acid halide, such as chloride, preferably in the presence of a basic, primarily organic basic agent such as an aliphatic tertiary amine, e.g. B.  Triethylamine or diisopropylamine, or a heterocyclic base of the pyridine type, e.g. B. 



  Pyridine or collidine.  It is preferred to work in the presence of a suitable solvent.  e.g. B.  Dioxane or tetrahydrofuran, or a solvent mixture, if necessary with cooling, e.g. B.  at around - 30 to around 30 C. 



  and optionally in the atmosphere of an inert gas such as nitrogen. 



  Level 4
The starting material of formula (II) is obtained by combining a compound of formula (VI) with a suitable phosphine compound such as a tri-lower alkylphosphine e.g. B.  Tri-n-butyl-phosphine, or a triaryl-phosphine, e.g. B.  Triphenylphosphine, or with a suitable phosphite compound such as a tri-lower alkyl phosphite, e.g. B.  Triethyl phosphite, or an alkali metal di-lower alkyl phosphite, e.g. B.  -diethyl phosphite, treated. 



   The above reaction is preferably carried out in the presence of a suitable inert solvent, such as a hydrocarbon, e.g. B.  Cyclohexane or benzene, or an ether, e.g. B.  Dioxane, or a solvent mixture made.  Depending on the reactivity, one works under cooling or at an elevated temperature, for example between - 10; and + 100 C, preferably at about 20 'to 80 C, and or in the atmosphere of an inert gas such as nitrogen.  To prevent oxidative processes, catalytic amounts of an antioxidant, e.g. B. 

  Hydroquinone, can be added
It is usually carried out in the presence of a basic agent such as an organic base, e.g. B.  an amine such as triethylamine, diisopropylethylamine, pyridine, lutidine, or polystyrene Hunig base.  or an inorganic base, e.g. B.  an alkali metal carbonate, e.g. B.  Sodium or potassium carbonate, the primary phosphonium salt of the formula
EMI12. 1
 wherein X 'is a phosphono group or a phosphonio group together with an anion, depending on the importance of the radical Ro z. B.  Chloride, means is converted into the ylide starting material of formula II.  

  However, one can also work in the absence of a base and isolate a compound of the formula (IIa), in particular a corresponding phosphono compound, and convert it in situ into the starting material of the formula II in the preparation of the end products of the formula (I).   



  Level 5
A compound of the formula (II) can furthermore be obtained by treating a mercaptide of the formula (VII) in which M stands for a metal cation with an acylating agent which introduces the radical R4-CH2-C (= Zt). 



   In the starting material of formula (VII), the metal cation M is, for example, a cation of the formula M + or M2 + / 2, where M + in particular for a silver cation and M2 + in particular for the divalent cation of a suitable transition metal, e.g. B.  Copper, lead or mercury. 



   An acylating agent which introduces the radical R4-CH2C- (= Z) - is e.g. B.  the acid R4-CH2C- (= Z) -OH or in particular a reactive functional derivative thereof, such as an acid halide, e.g. B.  Chloride or bromide, azide or anhydride thereof. 



   The acylation takes place when a reactive, functional derivative of the acid of the formula R4-CH2-C (= ZOH, e.g. B.  the acid chloride is used in an inert solvent such as a chlorinated hydrocarbon, e.g. B.  Methylene chloride, or an ether, e.g. B. 



  Diethyl ether or dioxane, at room temperature or with heating or cooling, e.g. B.  in a temperature range of approx.  - 50 "to approx.  +60 "C, especially at approx.  - 300 to approx. 



  +20 C.
The starting compounds of formula (VII) can be prepared, for example, by using an azetidinone of the formula
EMI13. 1
 by reacting with an alkali metal salt, e.g. B.  the sodium salt, a thione lower alkane carboxylic acid, e.g. B.  Thioacetic acid, or triphenylmethyl mercaptan in a compound of the formula
EMI13. 2nd
 transferred, where W 'triphenylmethylthio or Niederalkanoylthio, e.g. B.    Acetylthio means this analogously to the process described in reaction stages 3 and 4 in a compound of the formula
EMI13. 3rd
 transferred and this in the presence of a base, e.g. B.  Pyridine or tri-n-butylamine, in a suitable solvent, e.g. B. 

  Diethyl ether or methanol, with a salt of the formula
MA, in which M has the meaning given above, but in particular stands for a silver cation, and A represents a common anion which favors the solubility of the salt MA in the chosen solvent, for. B.  the nitrate, acetate or fluoride anion. 



   The ylides of the formula II can be used directly in the cyclization reaction for the preparation of the end products of the formula I.  But you can also in compounds of formula II, wherein R1 by a protected hydroxy group, for. B.  is a hydrolytically easily cleaved protected hydroxy group, such as trisubstituted silyloxy, substituted lower alkyl, first split off the hydroxy protecting group and then use the compound of the formula II obtained, in which R1 is lower alkyl substituted by hydroxy, in the cyclization reaction. 



   In the compounds of the formulas (IIf (VII), existing functional groups can be converted into protected functional groups or existing protected functional groups into the free or other protected groups.  Furthermore, one can convert a radical R4 into another radical R4 in compounds of the formulas (II), (V) and (VI).  In the case of these conversions, taking into account the further substituents contained in the molecules, the same methods can be used as are indicated for the corresponding conversions into the compounds of the formula (I). 



   The process described in Reaction Scheme 1 for the preparation of the compounds of the formulas (II), (III) and (V} (VII), and the stated process for the preparation of the end products of the formula (I) can also be carried out with optically inactive compounds and on any process step from a diastereomer mixture or racemate obtained, as described above, isolate the optically active compounds according to the present invention. 



   The invention also relates to the new starting compounds and to new intermediates obtainable according to the process, such as those of the formulas (II), (III), (V} (VII) and (IX), and the stated processes for their preparation. 



   Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed as particularly preferred above are obtained. 



   The compounds of formula I have valuable pharmacological properties or can be used as intermediates for the preparation of such compounds with valuable pharmacological properties.  Compounds of formula I wherein R1 is hydroxy lower alkyl, R2 is carboxyl or an esterified carboxyl group cleavable under physiological conditions and R3 is amino, lower alkylamino, di-lower alkylamino or substituted methyleneamino as indicated, and pharmacologically acceptable salts of such compounds with salt-forming groups have antibacterial effects.  For example, they are in vitro against gram-positive and gram-negative cocci, e.g. B. 

  Staphylococcus, aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus faecalis, Neisseria meningitidis and Neisseria gonorrhoeae, against enterobacteria, e.g. B.  Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae, against Haemophilus influenzae, Pseudomonas aeruginosa and anaerobes, e.g. B.  Bacteroides sp. , and Clostridium sp.  in minimal concentrations of approx.  0.05 to approx.  32 llg / ml effective.  In vivo, in the systemic infection of the mouse, e.g. B.  due to Staphylococcus aureus, Escherichia coli or Streptococcus pyogenes, EDs0 values of approx.  0.3 to approx.  100 mg / kg. 



   Thus, (5R, 6S) -2-aminomethyl-6 [(1'R) -hydroxy-ethyl] 2 -penem-3-carboxylic acid (compound A) and (5R, 6S) have 2-aminomethyl -6-hydroxy-methyl -2-penem-3-carboxylic acid (Compound C) in vitro compared to that from U. S.  Patent 4,272,437 previously known racemic (1'R. 5R, 6S + 1'S, 5S, 6R) -2-aminomethyl-6 - (1 '-hydroxyethyl) -2-penem-3-carboxylic acid (Compound B) have the following superior effects:

  : Table 1 Antibiotic activity of compounds of the formula I and the known comparison compound B in vitro in vitro MIC (pg / ml) microorganism compound A compound B compound C Staphylococcus aureus 10 B 0.05 0.1 0.2 Staphylococcus aureus 2999i + p + 0.05 0.2 0.5 Staphylococcus aureus A 124 0.1 0.2 Staphylococcus aureus Wood 46 0.05 0.1 0.2 Streptococcus pyogenes Aronson 1129 0.2 0.5 2 Streptococcus pneumoniae III / 84 0.1 0.2 0.5 Neisseria meningitidis 1316 0.5 1 1 Neisseria gonorrhoeae 1317/4 0.5 1 Haemophilus influenzae NCTC 4560 1 2 Escherichia coli 205 2 8 Escherichia coli 205 R + TEM 4 8 2 Escherichia coli 16 4 8 2 Escherichia coli 2018 2 4 Escherichia coli UB 1005 4 16 2 Escherichia coli DC 2 8 16 4 Escherichia coli B-1385 4 8 2 Klebsiella pneumoniae 327 2

   4 Serratia marcescens 344 4 8 2 Enterobacter cloacae P 99 4 8 4 Enterobacter cloacae ATCC 13047 4 16 4 Proteus mirabilis 774 1 4 1 Proteus mirabilis 1219 2 8 4 Proteus rettgeri 856 0.5 1 0.5 Proteus morganii 2359 0.5 2 1 Proteus morganii 1518 2 4 2 Pseudomonas aeruginosa ATCC 12055 0.05 0.1 0.2 Pseudomonas aeruginosa K 799/61 0.1 0.2 0.5 Pseudomonas aeruginosa 143738R 0.5 2 2 Clostridium perfringens 2 4 32 Bacteroides fragilis L 01 0.5 1 2
Compared to the corresponding previously known racemate (compound B), the optically active compound A according to the invention has a higher activity by a factor of 24 in all strains tested. 

  The optically active compound C according to the invention shows a remarkably constant activity in all the strains tested and is superior to the previously known racemic homolog (compound B), in particular in the gram-negative range by a factor of 2-8. 



   The new compounds can therefore be administered orally or parenterally as antibacterial antibiotics, e.g. B.  in the form of appropriate pharmaceutical preparations, used to treat infections. 



   Compounds of the formula I in which at least one of the functional groups present is in protected form, a protected carboxyl group being different from a physiologically cleavable esterified carboxyl group, can be used as intermediates for the preparation of the above-mentioned pharmacologically active compounds of the formula I. 



   The pharmacologically useful compounds of the present invention can e.g. B.  be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for oral or parenteral, i.e. H.  intramuscular, subcutaneous or intraperitoneal, administration are suitable. 



   For oral administration, tablets or gelatin capsules are used, which contain the active ingredient together with diluents, e.g. B.  Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or clycine, and lubricants, e.g. B.  Have silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. B.  Magnesium aluminum silicate, starches such as corn, white, rice or arrowroot starch, gelatin, tragacant, methyl cellulose, sodium carboxymethyl cellulose and or polyvinylpyrrolidone, and if desired.  Explosives, e.g. B.  Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures or adsorbents, colors, flavors or sweeteners. 

 

   For parenteral administration, primarily infusion solutions, preferably isotonic aqueous solutions or suspensions, are suitable. B.  from lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. B.  Mannitol, can be prepared before use.  Such preparations can be sterilized and / or auxiliary substances, e.g. B.  Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. 



   The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. B.  by means of conventional mixing, solution or lyophilization processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient. 



   Depending on the type of infection and the condition of the infected organism, daily doses of 125 mg to about 5 g are used to treat warm-blooded animals (humans and animals) weighing about 70 kg. 



   The following examples serve to illustrate the invention.  Temperatures are given in degrees Celsius. 



   The following abbreviations are used in the examples: DC: thin-layer chromatogram, IR: infrared spectrum, UV: ultraviolet spectrum, NMR: nuclear magnetic resonance spectrum, DBU: 1, 5-diazabicyclo [5. 4th 0] undec-5-ene, THF: tetrahydrofuran, DMF: dimethylformamide. 



  Experimental part
Example (5R, 65) -2- (allyloxyvarbonylaminomethyl) -6- (tert.  butyl-dimeilylsilyloxymethyi) -2-penem-3-carboxylic acid allyl ester. 



   A solution of 3.05 g of 2 - [(3S, 4R) -3- (tert. Butyldimethylsilyloxymethyl) -4- (allyloxycarbonylamino-acetylthio) 2-oxo-azetidin-1 -yl] - 2-triphenylphosphoranylideneacetic acid allyl ester in 200 ml abs.  Toluene is stirred under an argon atmosphere for 90 minutes at the reflux temperature.  The solvent is then evaporated and the crude product is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 9: 1).  IR (CH2C12): 3435; 1785; 1710; 1580 cm- '.    



   The starting material is produced as follows: a) (3S, 4R) -3- (tert. Butyldimethylsilyloxymethyl) -4-tri phenylmethyhhioazetidin-2-one
12.5 g of triphenylmethyl mercaptan are suspended in 70 ml of methanol at 0, and a total of 2.2 g of a 55% sodium hydride suspension in oil are added in portions over 10 minutes.  An emulsion of 11.1 g (3S, 4R) -3- (tert. Butyldimethylsilyloxymethyl) -4-methylsulfonyl-azetidin -2-one (European patent application no.  82113) in 70 ml of acetone and 70 ml of water were added dropwise over 30 minutes. 

  After stirring for 30 minutes at 0 and 1 hour at room temperature, the reaction mixture is concentrated on a rotary evaporator, methylene chloride is added, and the aqueous phase is separated off.  The organic solution is washed with brine and dried over sodium sulfate.  After concentration, the crude title compound is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 19: 1).  TLC (toluene-ethyl acetate 19: 1): Rf = 0.64; IR (methylene chloride): 3390; 1760; 1117; 835 cm-l.    



   b) 2- [(3S, 4R) -3- (tert. Butyl-dimethylsilyloxymetllyl) -4 triphenylmethylthio-2-oxo-azetidin-1-yl] -2-hydroxyacetic acid really really ester
8.4 g (3S, 4R) -3- (tert. Butyldimethylsilyloxymethyl) -4-triphenylmethylthio-azetidin -2-one and 8.23 g ethyl allyl acetal in 170 ml abs.  27 g of molecular sieves (48A) are added to toluene and the mixture is stirred at 55 "for 10 hours.  After filtering off and concentrating on a rotary evaporator under reduced pressure, the crude product is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 95: 5); TLC (silica gel, toluene / ethyl acetate 10: 1); Rf = 0.37 and 0.27; IR (CH2C12): 3520, 1760, 1745 cm- '.    



   c) 2- [(3S, 4R) -3- (tert. Butyl-dimethylsilyloxymethyl) -4 triphenylmethylthio-2-oxo-azetidin-1-yl] -2-triphenylphosphoranylideneacetic acid allyl ester
To a solution of 604 mg 2 - [(3S, 4R) -3 - (tert. Butyldimethylsilyloxymethyl) -4 -triphenylmethylthio-2-oxo-azetidin-1-yl] -2-hydroxyacetic acid allyl ester in 5 ml of tetrahydrofuran are successively added with stirring at -15 "80 1ll thionyl chloride and 88 1ll pyridine within 5 minutes.  The white suspension is stirred at - 100 for 1 hour and filtered through Hyflo.  After washing the residue with toluene, the mixture is concentrated on a rotary evaporator. 



  The residue is dissolved in 3 ml of dioxane, 293 mg of triphenylphosphine and 0.13 ml of 2,6-lutidine are added and the mixture is stirred at 115 bath temperature for 2 hours.  The mixture is filtered through Hyflo and this residue is washed with toluene.  The combined filtrates are evaporated.  Chromatography of the residue on silica gel gives the pure product (eluent toluene / ethyl acetate 95: 5); TLC (silica gel, toluene-ethyl acetate 1: 1): Rf = 0.18; IR (CH2Cl2): 1745, 1605 cm-l.    



   d) 2- [(3S, 4R) -3- (tert. Butyldimethylsilyloxymellyl) -4mercapto-2-oxo-a-etidin-1-yl] -2-triphenylphosphoranylidene, allyl ester, silver salt
7.5 g 2 - [(3 S, 4R) -3- (tert. Butyl-dimethylsilyloxymethyl) -4-triphenylmethylthio-2-oxo-azetidin-1-yl] -2-triphenylphos phoranylideneacetic acid allyl ester are initially charged in 87 ml of ether and 70 ml of a 0.5 M aqueous silver nitrate solution are added at room temperature.  A mixture of 3.6 ml of tributylamine, 0.18 ml of trifluoroacetic acid and 25 ml of ether is then added dropwise and the reaction mixture is stirred for a further 20 minutes.  Then the solid is filtered off and washed with ether, water and ether. 



  For cleaning, the solid is slurried in 40 ml of ether and 40 ml of water, suction filtered and dried.  IR (CH2C12): 1760, 1620 cm- e) 2 - [(3S, 4R) -3- (tert.  Butyl-dimeiliyisilyloxymellyl) -4- (allyloxyearbonylamino-acetylthio) -2-oxo-a-etidin-1-1-yl)] - 2-triphenylphosphoranylideneacetic acid allyl ester.    



   5 g silver salt of 2 - [(3S, 4R) -3- (tert. -Butyl-dimethylsilyl oxymethyl) -4- mercapto-2-oxo-azetidine-1-yl) -2-triphenyl phosphoranlidene acetic acid allyl ester are dissolved in 20 ml abs. 



   Methylene chloride with 1.7 ml of pyridine and then at 0 'dropwise with a mixture of 1.87 g of allyloxycarbo nylaminoacetyl chloride and 10 ml of abs.  Methylene chloride ver sets.  After stirring for 30 minutes, the solid is filtered off over Hy flo and the filtrate is washed with aqueous NaHCO3-
Solution and then washed with brine.  After drying over
Na2SO4 is concentrated in vacuo.  The residue is purified by chromatography on silica gel (mobile phase toluene / ethyl acetate 4: 1).  IR (CH2 Cl2): 3435; 1750; 1735; 1695; 1615 cm-l.    

 

   The starting material allyloxycarbonylaminoacetyl chloride can be prepared as follows: ea.    A llyloxycarbonylaminoacetic acid
To a solution of 7.51 g of clycine in 20 ml of water and 44 ml of 5N NaOH solution is added dropwise at 0 'to 12 ml of allyl chloroformate.  The suspension will
Stirred for 16 hours at room temperature.  After this
Removing the insoluble by filtration, the filtrate is diluted with 100 ml of water and washed twice with CH2C12.  The aqueous phase is adjusted to pH 2 with HC1 4 N and extracted twice with CH2Cl2.  The combined organic extracts are washed once with brine, dried over MgSO4 and evaporated to the white crystals of the title compound. 

  IR in CH2Cl2: 3450; 1715 cm-1.    



   eb.    Allyloxyearbonylaminoacetyl chloride
3.18 g of allyloxycarbonylaminoacetic acid are added at 0 with 5.7 ml of thionyl chloride.  The mixture is then stirred at the same temperature for 2 hours under a protective gas. 



  It is then diluted with absolute toluene and concentrated on a rotary evaporator.  IR (CH2Cl2): 3435; 1800; 1725 cm- '. 



   Example 2 (5R, 6S) -2- (Allyloxyearbonylaminomethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid allyl ester
A solution of 1.79 g of (5R, 6S) -2- (allyloxycarbonyl aminomethyl) -6- (tert.  butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allylester in 50 ml abs.  1.83 ml of acetic acid and 80 ml of a 0.1 N tetrabutylammonium fluoride solution in THF are added to THF in succession.  After stirring for 4.5 h, the mixture is diluted with 1.41 CH2Cl2 and washed with 200 ml of a saturated NaHCO3 in H2O solution.  The organic phase is then washed with brine, dried over MgSO4 and evaporated after filtering off.  The crude product is purified by chromatography on silica gel (eluent: from toluene / ethyl acetate 1: 1 to ethyl acetate abs. ). 

  IR (CH2C12): 3600; 3435; 1785; 1695; 1615cm-1.    



   Example 3 (5R, 6S) -2-aminomethyl -6-hydroxymethyl-2-penem-3-carboxylic acid
A solution of 550 mg (5R, 6S) -2-allyloxycarbonyl-aminomethyl -6-hydroxymethyl-2-penem-3-carboxylic acid allylester in 20 ml abs.  THF is added at - 10 "with 60 mg tetrakis (triphenylphosphine) palladium and then with 1 ml tributyltin hydride.  After 20 minutes of stirring at - 10 ", 0.2 ml of acetic acid are added, and the reaction mixture is stirred for a further 30 minutes after the cooling bath has been removed.  After concentrating on a rotary evaporator, the residue is taken up in water-ethyl acetate, the aqueous phase is separated off and the organic phase is extracted three more times with water. 

  The combined aqueous phases are lyophilized after briefly concentrating on a rotary evaporator.  UV (phosphate buffer pH 7.4): X max = 309 nm.    



   Example 4 (SR, 6S) -2- (Allyloxyearbonylaminomethyl) -6 - [(I'R) -l-allyl-oxyearbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester
A solution of 2.42 g of 2 - [(3S, 4R) -3- [(l'R) -l-allyloxycarbonyloxyethyl] - 4- (allyloxycarbonylaminoacetylthio) -2-oxo-azetidin-1-yl] -2 -triphenylphosphoranylidenessigsäureallylester in 300 ml abs.  Toluene is stirred under an argon atmosphere at the reflux temperature for 24 hours.  Then the solvent is evaporated and the crude product is purified by chromatography on silica gel.  (Eluent toluene ethyl acetate 9: 1).  IR (CH2C12): 3435; 1790; 1740; 1720; 1580 cm-1.    



   The starting material is produced as follows: a) N-p-methoxybenzyl -N-tert-butylthiomethylammonium chloride
A solution of 10.69 g (23.9 mmol) of 1,3,5-tris (pmethoxybenzyl) hexahydro-1,3,5-triazine, which is analogous to the instructions in German Offenlegungsschrift DE-A-2 431 862 can be prepared in 170 ml of acetonitrile, a solution of 2.88 g (78.8 mmol) of hydrogen chloride in 20 ml of acetonitrile and 6.45 g (71.66 mmol) of tert-butyl mercaptan is added at room temperature.  The mixture is stirred for 22 hours.  Undissolved material is filtered off and the filtrate is concentrated under reduced pressure.  A crystalline residue is obtained which is stirred with ether and suction filtered. 

  F.  142 b) 625.3R) -N-p-methoxybenbyl-N-inert. -butylthiomethyl-2-bromo-3-hydroxybutyramide
A solution of 1.83 g (10 mmol) (2S, 3R) -2-bromo-3-hydroxybutyric acid, prepared analogously according to a specification by Shimohigashi et al. , Bull  Chem.  Soc.  Japan 52, 949 (1979), is treated at room temperature successively with 2.76 g (10 mmol) of Np-methoxybenzyl -N-tert-butylthiomethylammonium chloride, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and dropwise with 1.40 ml (10 mmol ) Triethylamine added.  The reaction mixture obtained is stirred at room temperature for two hours.  The precipitated dicyclohexylurea is filtered off, the filtrate is diluted with methylene chloride and washed with water and pH 8 phosphate buffer solution. 

  The organic phase is dried over sodium sulfate, evaporated and the oily residue is chromatographed on silica gel with toluene-ethyl acetate.  The title compound is obtained as a colorless, viscous oil. 



  Rf (toluene-ethyl acetate 1: 1): 0.55; IR (in methylene chloride): 3550-3200, 2950-2850, 1632, 1608, 1508, 1457, 1438, 1407, 1360, 1242, 1202, 1175, 1150, 1028. 



   c) (2S, 3R) -N-p-methoxybenzyl-N-tert-butylsulfonylmethyl -2-bromo-3-hydroxybutyramide
A solution of 1.97 g (4.89 mmol) (2S, 3R) Np methoxybenzyl-N-tert-butylthiomethyl -2-bromo-3-hydroxybutyramide in 50 ml methylene chloride is stirred at - 14 with 2.06 g ( approx.  2.2 equivalents) 90% m-chloroperbenzoic acid were added.  The reaction mixture is stirred at 00 for 80 minutes.  The m-chlorobenzoic acid which has separated out is filtered off, the filtrate is diluted with methylene chloride and this is shaken successively with 3% aqueous sodium hydrogen sulfite and 8% aqueous sodium hydrogen carbonate solution. 

  The organic phase is dried over sodium sulfate, evaporated under reduced pressure and the residue is chromatographed on silica gel with toluene / ethyl acetate (7: 1) and (6: 1).  The title compound is obtained as a colorless, viscous oil.  Rf (toluene-ethyl acetate 1: 1): 0.43; [a] = +88 zt 1 (1.01% in chloroform).  The IH NMR spectrum (400 MHz in CDCl3) indicates the existence of two rotamers in the ratio of
1.3: 1 down. 



   d) (2R, 3R) -N-p-methoxybenzyl-N-tert-butylsulfonylmethyl-2,3-epoxybutyramide
To a solution of 486 mg (1.1 mmol) (2R, 3R) -Np methoxybenzyl-N-tert-butylsulfonylmethyl-2-bromo -3-hydroxybutyramide in 8 ml of tetrahydrofuran are 340 ml of 1.5 diazabicyclo at -14 with exclusion of moisture [5th 4th 0] undec-5-ene in 1 ml of tetrahydrofuran.  The solution is stirred for 75 minutes at room temperature.  After adding methylene chloride, the organic phase is extracted with 15% aqueous citric acid solution and 8% aqueous sodium hydrogen carbonate solution.  The organic phase is dried over sodium sulfate and evaporated under reduced pressure.  

  After the residue has been chromatographed on silica gel using toluene / ethyl acetate (4: 1), the title compound is obtained as a colorless, viscous oil.  Rf (toluene-ethyl acetate 1: 1): 0.29; [a] = + 45i 1 (1.065% in CHC13).     The 'H-NMR spectrum (400 MHz in CDCl3) indicates the existence of two rotamers in a ratio of 1: 2.8. 



      e) (3S, 4R) -1-p-methoxybençyl-3- [(I 'R) -I -hydroxy-ally-4-tert-butylsulfonyl-2-a-etidinone
A solution of 398 mg (1.12 mmol) (2R, 3R) -Np methoxybenzyl-N-tert-butylsulfonylmethyl-2,3-epoxy-butyramide in 2.5 ml of tetrahydrofuran is added dropwise at 0 with stirring and moisture exclusion with 7 ml one
Solution of dewatered tetra-n-butylammonium fluoride in THF, prepared by dewatering 5 g of tetra-n-butylammonium fluoride trihydrate at 55 and 0.1 torr and made up to 20 ml of tetrahydrofuran.  The reaction mixture is set with activated molecular sieve of 4 and stirred for two hours. 

  The molecular sieve is filtered off and washed four times with 20 ml of methylene chloride each time.  Each filtrate is mixed separately with 5 parts of diethyl ether and washed successively with aqueous phosphate buffer solution of pH 8.  The combined organic phases are dried over magnesium sulfate and evaporated under reduced pressure.  The residue is chromatographed on 20 g of silica gel with toluene-ethyl acetate (3: 1) and the crystalline title compound is obtained.  F. 



     112-113 (Kofler, from methylene chloride, diethyl ether, pen tan); Rf (toluene-ethyl acetate 1: 1): 0.27; [a] = + 9+ 10 (1.105% in chloroform); 1H NMR spectrum (400 MHz in CDC13): 6 = 4.65 for proton (a) on the 4 (R) -C atom, 6 = 3.61 for proton (b) on the 3 (S) -C- Atom and 6 = 4.09 for proton (c) on the 1 '(R) -C atom of the hydroxyethyl group; J a-b: approx.  2, J b-c: approx.  7. 



      f) (3S, 4R) -I -p-methoxybenzyl-3- [(1'R) -1-allyloxyearbonyloxyethyl) -4tert-butylsulfonyl-2-azetidinone
A two phase system consisting of a solution of
1.77 g (5 mmol) (3S, 4R) -1-p-methoxybenzyl-3 - [(1'R) -1-hydroxyethyl] -4-tert-butylsulfonyl-2-azetidinone in 20 ml methylene chloride and from 20 ml of a 1 N aqueous sodium hydroxide solution, 0.68 g (2 mmol) of tetra-n-butyl ammonium hydrogen sulfate is added.  With vigorous stirring, 0.8 ml (7.5 mmol) of allyl chloroformate are added.  After 20 and 40 minutes, another 0.8 ml of allyl chloroformate is added. 

  After a reaction time of 60 minutes, the mixture is mixed with methylene chloride, the aqueous phase is separated off and the organic phase is washed successively with 5% aqueous citric acid solution and with 8% aqueous sodium hydrogen carbonate solution.  After drying the organic phase over sodium sulfate and evaporation under reduced pressure, the crude product is obtained as a residue, which is purified by chromatography on Merck silica gel with toluene-ethyl acetate (9: 1).  F.    90-91; Rf (toluene-ethyl acetate 4: 1): 0.43; [a] = + 460 + 10 (1.49% in chloroform). 



   g) (3S, 4R) -3- [(1'R) -1-allyloxycarbonyloxyethyl] -4-tert-butylsulfonyl -2-azetidinone
A solution of 518 mg (1.18 mmol) (3S, 4R) -lp methoxybenzyl-3 - [(l'R) -1- allyloxycarbonyloxyethyl] -4- tertbutylsulfonyl-2-azetidinone in 12 ml of acetonitrile is added at 0 with a Solution of 2.46 g (4.48 mmol) of cerium (IV) ammonium nitrate in 6 ml of water and stirred for one hour at room temperature.  After extraction with ethyl acetate, drying of the organic phase over sodium sulfate and evaporation under reduced pressure, the crude product is obtained, which is purified by chromatography on 20 g of Merck silica gel with toluene / ethyl acetate (4: 1 and 1: 1).  F.    137-138; [a] = + 49i 1 (1.067% in chloroform); Rf {toluene-ethyl acetate 1: 1): 0.48. 



   h) (3S, 4R) -3 - [(l'R) -I- allyloxycarbonyloxyethyl] -4- triphenylmethylthioazetidin-2-one
Analogously to Example la), 0.86 g of (3S, 4R) -3- [(l'R) -Ally- loxycarbonyloxyäthyl] -4- tert. -butylsulfonyl -azetidin-2-one converted into the title compound. 



   IR (CH2Ci): 3395; 1770; 1750 cm- '. 



   i) 2 - [(3S, 4R) -3 - [(1'R) -1-allyloxyearbonyloxyethyl] -4- triphenylmethylthio -2-oxo-azetidin-1-yl] -2-hydroxyacetic acid allyl ester
Analogously to Example 1b), 0.82 g of (3S, 4R) -3- [(1'R) -1- allyloxycarbonyloxyethyl] -4-tert.  butylsulfonyl-azetidin-2-one converted into the title compound. 



   IR (CH2 Cl2): 3510; 1770; 1745 cm- '. 



   k) 2 - [(3S, 4R) -3 - [(I'R) I-A Ilyloxycarbonyloxyät11? 1] -4- triphenylmetlivlthio-2-oxo-azetidin-l-yl] -2-triphenylphosphoranylideneacetic acid allyl ester
Analogously to Example 1c, 1 g of 2 - [(3S, 4R) -3- [(l'R) -Allyl-oxycarbonyloxyethyl] -4- triphenylmethylthio-2-oxo-azeti din-1-yl] -2-hydroxyacetic acid allyl ester Title connection transferred. 



     IR (CH2Cl2): 1745; 1620 cm-Ú
1) 2 - [(3S, 4R) -3- [(I'R) -l-allyloxycarbonyloxyethyl] -4 mercapto-2-oxoazetidin-1-yl] -2-triphenylphosphoranyl allyl ester silver acetate
Analogously to example ld), 0.46 g of 2 - [(3S, 4R) -3- [(1'R)
Allyloxycarbonyloxyäthyl] -4-triphenylmethylthio-2-oxo azetidin-1-yl3 -2-triphenylphosphoranylidenessigsäure-allyl ester converted into the title compound. 



     IR (CH2Cl2): 1765; 1745; 1630 cm-l. 



   m) 2 - [(3S, 4R) -3- - [(I'R) -I-allyloxyearbonyloxyethyl] - 4- (allyloxycarbonylaminoacetylthio) -2-oxo-azetidine-i-ylj -2 triphenylphosphoranylidene acetic acid allyl ester
Analogously to Example le), 0.385 g of 2 - [(3S, 4R) -3- [(1'R) -l allyloxycarbonyloxyethyl] -4-mercapto-2-oxo-azetidin-1 -yl] -2-triphenylphosphoranylidene-acetic acid- allyl ester (silver salt) with allyloxycarbonylaminoacetyl chloride converted into the title compound. 



   IR (CH2C12): 3440; 17501740; 1700; 1620 cm-l. 



   Example 5 (5R, 6S) -2-aminomethyl-6 - [(1 'R) -I-hydroxyethyl] -2-penem-3-carboxylic acid
A solution of 425 mg (SR, 6S) -2-allyloxycarbonylaminomethyl -6 - [(1'R) -1-allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester in 20 ml bas.  60 mg of tetrakis (triphenylphosphine) palladium and then 1.07 ml of tributyltin hydride are added to THF at - 10 ". 



  After 20 minutes of stirring at -100, 0.3 ml of acetic acid are added and the reaction mixture is stirred for a further 30 minutes after the cooling bath has been removed.  After concentrating on a rotary evaporator, the residue is taken up in water ethyl acetate, the aqueous phase is separated off and the organic phase is extracted 3 more times with water.  The combined aqueous phases are lyophilized after briefly concentrating on a rotary evaporator. 



  UV (phosphate buffer pH 7.4): X max = 308 nm. 



     α 20th
D (0.07% in water): + 220 +11. 



   Example 6 (SR, 6S) -2- (N-methyl-N-allyloxycarbonylaminomethyl) -6- [(I 'R) -I -allyloxyearbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester
Analogously to Example 4, 2.42 g of 2 - [(3S, 4R) -3- [(1'R) -l-allyloxycarbonyloxyethyl] -4- (N-methyl-N-allyloxycarbonylaminoacetylthio) 2-oxo-azetidine - 1 -yU -2-triphenylphosphoranylidenessigsäure-allylester converted into the title compound.  IR (methylene chloride): 1780; 1745; 1705; 1580 cm-l.    

 

   The starting material is produced as follows: a.    N-allyloxyearbonyl sarcosine
Analogously to Example 1 ea), 15 g of sarcosine are converted into the title compound.  IR (methylene chloride): 1705 cm- '. 



   b.  N-allyloxyearbonylaminosarcosyl chloride
Analogously to Example 1 eb), 3.46 g of N-allyloxycarbonylsarcosine are converted into the title compound with 6.27 ml of thionyl chloride.  IR (methylene chloride): 1800; 1710 cm-1.    



   c.  2 - [(3S, 4R) -3- [(1'R) -1-allyloxycarbonyloxyethyl] -4 (N-methyl-N-allyloxycarbonylaminoacetylthio) -2-oxo-azetidin-1-yl] -2-triphenyl] - allyl phosphoranylidene acetate
Analogously to Example 1 e), 3.75 g of silver salt of 2 - [(3S, 4R) -3 - [(1 'R) -Allyloxyzarbonyloxyäthyl] -4-mercapto2-oxo-azetidin-1 -yl] -2-triphenylphosphoranylidenessigsäureallylester ( see.  Example 4 1)) with 1.55 g of N-allyloxycarbonylsarcosyl chloride converted into the title compound.  IR (methylene chloride): 1750; 1700; 1620cm-Ú. 



   Example 7 2- (N-methylaminomethyl) -6 - [(1'R) -1-hydroxyethyl] -2-penem-3-carboxylic acid
Analogously to Example 5, 1.3 g (5R, 6S) -2- (N-methyl-nallyloxycarbonylaminomethyl) -6 - [(1'R) -1 -allyloxycarbonyloxyethyl] -2-penem-3-carboxylic acid allyl ester are converted into the title compound.  UV (phosphate buffer pH 7.4 X max.  = 311 nm. 



   Example 8 (5R, 6S) -2- (N-formamidinomethyl) -6-hydroxymethyl-2 peneml-3-carboxylic acid
A solution of 109.5 mg of ethyl formimidate hydrochloride and 84 mg of sodium hydrogen carbonate in 4 ml of water were mixed at room temperature with a solution of 23 mg (5R, 6S) -2-aminomethyl -6-hydroxymethyl-2-penem-3-carboxylic acid and 8.4 mg of sodium bicarbonate in 1 ml of water.  After 50 min.  Stirring at room temperature is mixed with 1 ml of 1N HCl and evaporated under a high vacuum.  The raw substance is purified by chromatography on the OPTI-UP C12.  UV (phosphate buffer pH 7.4): i, max.  306.5 nm. 



   Example 9 05R, 65) -2- (N-Formam idinometl2yl) -6 - [(I'R) -1 1-hydroxyethyl] -2-penem-3-carboxylic acid
Analogously to Example 8, 51 mg (5R, 6S) -2-aminomethyl -6 - [(1 'R) - 1-hydroxyethyl] -2-penem-3-carboxylic acid are converted into the title compound.  UV (phosphate buffer pH 7.4): X max.  310 nm. 



   Example 10 (5R, 6S) -2-chloromethyl -6- (tert. butyldimethylsilyloxymethyl) -2-penem -3-carboxylic acid allyl ester
Analogously to Example 1, 0.71 g of 2 - [(3S, 4R) -3- (tert. Butyl-dimethylsilyloxymethyl) -4-chloroacetylthio-2-oxoazetidin-1 yl] -2-triphenylphosphoranylidenacetic acid allyl ester converted into the title compound.  IR (methylene chloride): 1790; 1705; 1560 cm-Ú. 



   The starting material is prepared as follows: 2- [(3S, 4R) -3- (tert. Butyldimethylsilyloxymethyl) - 4-chloroacetylthio-2-oxo-azeitidin-1-yl] -2-triphenylphosphoranylideneacetic acid allyl ester
30 g silver salt of 2 - [(3S, 4R) -3- (tert. Butyldimethylsiyloxymethyl) -4-mercapto-2-oxo-azetidine-1-yU-2-triphenyl-phosphoranylideneacetic acid-2-allyl esters (Example 1 d) are dissolved in 600 ml of absolute methylene chloride, cooled to 0 and with 120 mg of 4-dimethylaminopyridine and 6.8 ml of pyridine were added.  After adding 5.04 ml of chloroacetyl chloride and an additional 1.5 ml of pyridine, the reaction mixture is stirred at 0 for 30 minutes. 

  The precipitate is filtered off and the filtrate is washed with aqueous NaHCO3 solution and then with brine, dried over Na2 SO4 and evaporated.  After purification on silica gel (mobile phase toluene / ethyl acetate 9: 1), the pure title compound is obtained.  TLC (silica gel, toluene / ethyl acetate 1: 1): Rf = 0.5; IR (CH2Cl2): 1750.1680.1610cm- '. 



   Example 11 (5R, 6S) -2-azidomethyl -6- (tert. butyldimethylsilyloxy.    



  methyl) -2-penem-3-carboxylic acid allyl ester
4.04 g (5R, 6S) -2-chloromethyl -6- (tert. butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allylester are dissolved in 40 ml DMF and treated with 0.9 g sodium azide.  After stirring for 6 hours, the solvent is reduced to a fifth of the volume and the residue is partitioned between ethyl acetate and water.  After drying over sodium sulfate, the solvent is evaporated off.  The crude mixture is purified by chromatography on silica gel (eluent toluene / ethyl acetate): IR (methylene chloride): 2110;
1790; 1705; 1585cm-Ú. 



   Example 12 (5R, 6S) -2-Aidometkvl -6-Idroxtmet-l-2-penm-3-carboxylic acid allyl ester
Analogously to Example 2, 1.2 g of (5R, 6S) -2-azidomethyl
6- (tert.  butyldimethylsilyloxymethyl) -2-penem-3-carboxylic acid allylester converted into the title compound.  IR (methylene chloride): 3595; 2120; 1790; 1710; 1585 cm- '. 



   Example 13 (5R, 6S) -2-azidomethyl-6-hydroxymethyl-2-penem-3-carboxylic acid
Analogously to Example 3, 0.89 g of (SR, 6S) -2-azidomethyl6-hydroxymethyl-2-penem -3-carboxylic acid allyl ester are converted into the title compound.  UV (phosphate buffer pH 7. 4): X max.  309 nm. 



   Example 14 (5R, 6S) -2-aminometh-6-hydroxymethyl-2-penem -3 carboxylic acid
0.53 g (5R, 6S) -2-azidomethyl -6-hydroxymethyl-2penem -3-carboxylic acid are dissolved in 10 ml of a mixture THF / water (1: 1) and in the presence of 0.53 g 10% Pd / C at room temperature for 4 hours  hydrogenated under normal pressure.  The mixture is then filtered, concentrated and the crude mixture is purified by reverse phase column chromatography (mobile phase: water). 



   UV (phosphate buffer pH 7. 4) X max.  = 309 nm. 



   Example 15
The following compounds can be prepared in an analogous manner to that described in the preceding examples: (5R, 6S) -2- (N-acetamidinomethyl) -6-viiroxymethyl-2-penem -3-carboxylic acid
UV (phosphate buffer pH 7. 4) X max.  = 307 nm. 



     (5R, 6S) -2- N-acetamidinomethyl) -6- [(IR) - -hydroxy-ethyl) -2-penem-3-carboxylic acid
UV (phosphate buffer pH 7. 4) X max.  = 311 nm. 



   (5R, 6S) -2- (N-guanidinylmethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid
UV (phosphate buffer pH 7. 4) X max.  = 306 nm. 



     (5R, 6S) -2- (N-Guwidinylmethyl) -6- [(1 R) - 1-hydroxyethyl] - 2-penem-3-carboxylic acid
UV (phosphate buffer pH 7. 4) # max.  = 310 nm. 



  (5R, 6S) -2- (N-ethylaminomethyl) -6 - [(1 'R) - I -hydroxyethyl] -2-penem-3-carboxylic acid
UV (phosphate buffer pH 7. 4) Ä max.  = 310 nm. 

 

  (5R, 6S) -2- (N-A thylaminomethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid
UV (phosphate buffer (pH 7. 4) X max.  = 311 nm. 



  (5R, 6S) -2- (N-propylaminomethyl) -6- [(1 R) - I-hydroxyethyl] - 2-penem-3-carboxylic acid
UV (phosphate buffer pH 7. 4) # max.  = 312 nm. 



     (5R, 6S) -2- (N-propylaminomethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid
UV (phosphate buffer pH 7. 4) X max.  = 311 nm.   



   Example 16 (5R, 6S) -2-aminomethyl -6-hydroxyntethyl-2-penem-3-carbonic acid-1-ethoxycarbonyloxyethyl ester
1.2 g of sodium iodide are dissolved in 3.7 ml of acetone and mixed with 0.275 ml of ethyl l-chloroethyl carbonate.  The mixture is stirred at room temperature for 3 hours.  The solution is then dripped onto 15.0 ml of methylene chloride and filtered off from the precipitated inorganic salts.  The methylene chloride solution is concentrated to 2 ml and added at 0 to a solution of 0.23 g (1 mmol) (5R, 6S) -2-aminomethyl -6-hydroxymethyl-2-penem -3-carboxylic acid in 4 ml of dimethylacetamide.  The mixture is then stirred at 0 for 3 hours, then diluted with ethyl acetate and washed three times with water. 

  The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator.  The crude product is purified on 10 g of silica gel with the eluent ethyl acetate.  The title compound is obtained as a white foam. 



  IR spectrum (methylene chloride): absorption bands at 1790 and 1740 cm-l.    



   Example 17 (5R, 65) -2-aminomethyl-6-hydroxymethyl-2-penem -3-carboxylic acid pivaloyloxymethyl ester
0.6 g of sodium iodide is dissolved in 2 ml of acetone and 0.15 ml of pivalic acid chloromethyl ester is added.  The mixture is stirred at room temperature for 3 hours and then added dropwise to 7.5 ml of methylene chloride.  The precipitated inorganic salts are filtered off.  The methylene chloride solution is concentrated to 1 ml and to a solution of 0.092 g (0.4 mmol) (5R, 6S) -2-aminomethyl-6hydroxymethyl-2-penem-3-carboxylic acid and 0.07 ml diisopropylethylamine in 4 ml N. , N-dimethylacetamide given at 0.  The mixture is then stirred at 0 for 3 hours, then diluted with ethyl acetate and washed three times with water. 

  The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator.  The crude product is purified on 10 g of silica gel with the eluent ethyl acetate.  The title compound is obtained as a white foam.  IR spectrum (methylene chloride): absorption bands at 1790 and 1730 cm- '.    



   Example 18
The following compounds are obtained in an analogous manner to that described in the preceding examples: (5R, 65) -2-aminomethyl-6 - [(1'R) -I 1-hydroxyethyl] -2-penem3-carboxylic acid 1-ethoxycarbonyloxyethyl ester , IR (CH2C12) 1785; 1740 cm- '. 



  (5R, 6S) -2-aminomethyl -6- [(1'R) -1-hydroxyethyl] -2 penem-3-carboxylic acid pivaloyloxymethyl ester,
IR (CH2Cl2): 1790; 1735 cm-l.    

 

   Example 19
Dry ampoules or vials containing 0.5 g (5R, 6S) -2 aminomethyl -6 - [(1 'R) - 1-hydroxyethyl] -2-penem-3-carboxylic acid as active substance are prepared as follows: Composition (for 1 Ampoule or vial): active substance 0.5 g mannitol 0.05 g
A sterile aqueous solution of the active substance and the mannitol is subjected to freeze-drying under aseptic conditions in 5 ml ampoules or 5 ml vials and the ampoules or  Vials sealed and checked. 



   Instead of the above-mentioned active ingredient, the same amount of another active ingredient from the preceding examples, such as. B.  the (5R, 6S) -2-aminomethyl -6-hydroxymethyl-2-penem -3-carboxylic acid can be used.  


    

Claims (22)

 PATENT CLAIMS 1. Compounds of the formula EMI1.1  wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R2 represents carboxyl or functionally modified carboxyl and R3 represents amino, amine substituted by lower alkyl, substituted methyleneamino or protected amino, optical isomers of compounds of formula I, mixtures of these optical isomers and salts thereof Compounds of formula 1 which have a salt-forming group.  2. Compounds of formula I according to claim 1, wherein R1 is lower alkyl substituted by hydroxy or protected hydroxyl, R2 is carboxyl, esterified carboxyl or protected carboxyl R'2 which is cleavable under physiological conditions, and R3 is amino, lower alkylamino, di-lower alkylamino, a group of the formula -N = C (X1, X2), in which X is hydrogen, amino, lower alkylamino, di-lower alkylamino, lower alkylene amino, nitroamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy, lower alkylthio, lower alkyl, amino lower alkyl, N-lower alkylamino lower alkyl, N, N-di-lower alkylamino lower alkyl, lower alkene Phenyl, pyridyl, e.g. 2- or 4-pyridyl, thienyl, e.g. 2-thienyl, or thiazolyl, e.g. Is 4-thiazolyl, and X2 is amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino, anilino, lower alkoxy, phenyl-lower alkoxy or lower alkylthio, or is protected amino, optical isomers of compounds of the formula I which have a chiral center in the radical R1, mixtures of these optical Isomers and salts of those compounds of formula I which contain a salt-forming group.  3. Compounds of formula I according to claim 1, wherein R1 in the a-position by hydroxy, tri-lower alkylsilyloxy, 2-halogeno lower alkoxy, 2-halogeno lower alkoxycarbonyloxy, lower alkenyloxycarbonyloxy or optionally substituted by nitro substituted phenyl-lower alkoxycarbonyloxy, R2 carboxyl, lower alkenyloxycarbonyl, optionally substituted by nitrocarbonyl , Lower alkanoylmethoxycarbonyl, 2-halo-lower alkoxycarbonyl, 2-tri-lower alkylsilylethoxycarbonyl or an esterified carboxyl group cleavable under physiological conditions, for example I-Niederalkoxycarbonyl- oxyniederalkoxycarbonyl, Niederalkanoyloxymethoxycarbonyl, a-Aminoniederalkanoyloxymethoxycarbonyl or Phthalidyloxycarbonyl, means, R3 amino, Niederalkylamino, Diniederalkylamino,  a group of the formula -N = C (X1, X2), where X is hydrogen, amino, lower alkylamino, lower alkyl, phenyl or pyridyl, e.g. 2-pyridyl, and X2 is amino, lower alkylamino or di-lower alkylamino, azido, phthalimino, nitro, lower alkenyloxycarbonylamino, optionally substituted by nitro benzyloxycarbonylamino, I-mederalkanoyl-lower alk-l-en-2-ylamino or 1-lower alkoxycarbonyl lower alk 1 -en-2-ylamino means optical isomers of compounds of the formula I which have a chiral center in the rest of R1, mixtures of these optical isomers and salts of those compounds of the formula I which contain a salt-forming group.  4. Compounds of formula I according to claim 1, wherein R1 is lower alkyl substituted by hydroxy in the a-position, R2 carboxyl or an esterified carboxyl group cleavable under physiological conditions, e.g. l-Niederalkoxycarbonyloxyniederalkoxycarbonyl or Niederalkanoyloxymethoxycarbonyl, and R3 represents amino, Niederalkylamino or Formamidino, optical isomers of compounds of formula I, which have a chiral center in the radical R1, mixtures of these optical isomers and salts of those compounds of formula I which contain a salt-forming group .  5. Compounds of formula I according to claim 1, wherein R1 is hydroxymethyl or l-hydroxyethyl, R2 is carboxyl and R3 is amino, and salts thereof.  6. The pure optical isomers of compounds of formula I according to claim 1.  7. The pharmaceutically acceptable salts of compounds of formula I according to claim 1.  8. Cleavable esters of compounds of the formula I according to claim 1 under physiological conditions.  9. (5R, 6S) -2-aminomethyl-6-hydroxymethyl-2-penem3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1.  10. 2- (N-methylaminomethyl) - 6 - [(1 R) - 1 -hydroxyethylj-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1.  11. (5R, 6S3-2- (N-formamidinomethyl) -6-hydroxymethyl-2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1.  12. (SR, 6S) -2- (N-formamidinomethyl) - 6 - [(l'R) -l-hydroxyethyl] - 2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof according to claim 1.  13. (5R, 6S) -2-aminomethyl-6 - [(1 "R) - 1-hydroxyethyl] - 2-penem-3-carboxylic acid and pharmaceutically acceptable salts thereof in optically pure form according to claim 1.  14. A compound according to claim 1 and its pharmaceutically acceptable salts as agents for the therapeutic treatment of the human and animal body.  15. Pharmaceutical preparations containing compounds of formula I according to claim 1 or pharmaceutically acceptable salts of such compounds with salt-forming groups.  16. Process for the preparation of compounds of the formula EMI1.2  wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R2 represents protected carboxyl and R3 represents amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula I, which have a salt-forming group, characterized in that in a compound of the formula EMI2.1  in which R1 has the meaning given under formula (I), R2 'is a protected carboxyl group and Q is a group which can be converted to the radical R3 by cleavage and which transfers the group Q to the radical R3,  and optionally converting a compound having a salt-forming group into a salt or a salt obtained into the free compound or another salt.  17. Process for the preparation of compounds of the formula EMI2.2  wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R2 represents protected carboxyl and R3 represents amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of such compounds of formula 1, which have a salt-forming group, characterized in that an ylide compound of the formula EMI2.3  in which R1 and R3 have the meanings given under formula I, R2 is a protected carboxyl group,  Z represents oxygen or sulfur and X represents either a trisubstituted phosphoniogroup or a doubly esterified phosphonogroup together with a cation, ring closes and, if appropriate, converts an obtained compound having a salt-forming group into a salt or an obtained salt into the free compound or into another salt.  18. Process for the preparation of compounds of the formula EMI2.4  wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R2 represents protected carboxyl and R3 represents amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, optical isomers of compounds of formula I. Mixtures of these optical isomers and salts of those compounds of the formula I which have a salt-forming group, characterized in that a compound of the formula EMI2.5  wherein R1 and R3 have the meanings given under formula I and R2 'is a protected carboxyl group, treated with an organic compound of trivalent phosphorus and optionally a compound obtained with a salt-forming group in a salt or a salt obtained in the free compound or in another Salt transferred.  19. Process for the preparation of compounds of the formula EMI2.6  wherein R 1 is hydroxy-substituted lower alkyl, R 2 is carboxyl, R 3 is amino, lower alkyl-substituted amino or substituted methylene amino, optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of those compounds of the formula I which have a salt-forming group , characterized in that in a compound of the formula I in which at least one functional group in the radicals R1, R2 and R3 is present in protected form, the protected functional group (s) is in the free (n) functional group (s) transferred.    20. Process for the preparation of compounds of the formula EMI2.7  wherein R1 is optionally protected (1R) -l-hydroxyethyl, R2 represents carboxyl or functionally modified carboxyl and R3 represents amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, and salts of those compounds of the formula I which have a salt-forming group , thereby  characterized in that a mixture of isomeric compounds of the formula I, in which R1 is optionally protected l-hydroxyethyl and R2 and R3 have the meanings given above, is separated into the individual isomers and the (1 R) -l-hydroxyethyl isomer is isolated.  21. Process for the preparation of compounds of the formula R1 1. -5. 1 1.-CH2-R3 (I), N 25 R 2 wherein R1 is lower alkyl substituted by hydroxy, R2 is esterified carboxyl which is cleavable under physiological conditions, and R3 is amino, lower alkyl-substituted amino or substituted methylene amino, optical isomers of compounds of the formula I, mixtures of these optical isomers and salts of such compounds of the formula I which have a salt-forming group, characterized in that in a compound of the formula I in which R1 and R3 have the meanings given above and R2 is a carboxyl group, the carboxyl group R2 is converted by esterification into an esterified carboxyl group which can be split under physiological conditions.  22. Compounds of the formula EMI3.1  wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R'2 is protected carboxyl, R3 is amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, optical isomers of compounds of formula III and mixtures of these optical isomers for performing the method according to claim 18.  The present invention relates to new 2-aminomethylpenem compounds, processes for their preparation and pharmaceutical preparations which contain such compounds.  The invention relates to 2-aminomethyl-2-penem compounds of the formula EMI3.2  wherein R1 is lower alkyl substituted by hydroxy or protected hydroxy, R2 is carboxyl or functionally modified carboxyl, and R3 is amino, amino substituted by lower alkyl, substituted methylene amino or protected amino, optical isomers of compounds of formula I, mixtures of these optical isomers and salts of those compounds of the formula I which have a salt-forming group.  The definitions used above and below preferably have the following meanings in the context of the present description: Functionally modified carboxyl R2 is in particular cleavable, esterified carboxyl or protected carboxyl R2 under physiological conditions.  An esterified carboxyl group R2 which can be cleaved under physiological conditions protects the compounds of the formula I from salt formation in the gastrointestinal tract when administered orally, which prevents premature excretion, and is primarily an acyloxymethoxycarbonyl group, in which acyl e.g. is the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or wherein acyloxymethyl forms the residue of a lactone. Such groups are e.g. Never deralkanoyloxymethoxycarbonyl, amino lower alkanoyloxymethoxycarbonyl, especially a-amino lower alkanoyloxymethoxycarbonyl, 4-crotonolactonyl and 4-butyrolactone-4yl. Further esterified carboxyl groups R2 which can be cleaved under physiological conditions are e.g. 5-indanyloxycarbonyl, 3-phthalidyloxycarbonyl, 1-lower alkoxycarbonyloxy lower alkoxycarbonyl, l-lower alkoxy lower alkoxycarbonyl or 2-oxo-1,3-dioxolen -4-ylmethoxycarbonyl, which is optionally substituted in the 5-position of the dioxolen ring by lower alkyl or phenyl.  Amino R3 substituted by lower alkyl is e.g. Lower alkylamino or lower alkylamino.  In substituted methylene amino R3, the methylene radical is preferably mono- or disubstituted. Substituted methylene amino is e.g. a group of the formula EMI3.3  wherein Xl is hydrogen, optionally substituted amino, e.g. Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, nitroamino, hydrazino or anilino, etherified hydroxy, e.g. Lower alkoxy or phenyl lower alkoxy, etherified mercapto, e.g. Lower alkylthio, optionally substituted lower alkyl, e.g. Lower alkyl, amino lower alkyl, N-lower alkylamino lower alkyl or N, N-di-lower alkylamino lower alkyl, lower alkenyl, phenyl or monocyclic heteroaryl, such as corresponding 5- or 6-membered heteroaryl with 1 or 2 nitrogen atoms and / or an oxygen or sulfur atom, such as pyridyl, e.g. 2 or 4-pyridyl, thienyl, e.g. 2-thienyl, or thiazolyl, e.g.   Is 4-thiazolyl and X2 is optionally substituted amino, e.g. Amino, lower alkylamino, di-lower alkylamino, lower alkyleneamino, hydrazino or anilino, etherified hydroxy, e.g. Lower alkoxy or phenyl lower alkoxy, or etherified mercapto, e.g. Lower alkylthio.  In preferred radicals of the formula (IA), X1 is hydrogen, amino, lower alkylamino or lower alkyl and X amino.  Radicals of the formula (IA) which have a hydrogen atom on the a atom of the substituent Xl and / or the substituent X2, e.g. Residues of the formula (IA), in which X is amino, lower alkylamino, nitroamino, hydrazino 'anilino or gege ** WARNING ** End of CLMS field could overlap beginning of DESC **.