DD159074A5 - PROCESS FOR THE PREPARATION OF DIOXIDE COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of dioxide compounds for use as a medicament for the control of infections, d. caused by beta-lactamase-producing microorganisms. The aim of the invention is the provision of v. new connections with considerations. Beta-lactamase-inhiebierenden properties. According to the invention, 2,2-dimethyl-penam-3-carboxylic acid-1,1-dioxide compound. d. Formula I wherein R 1 is deeply hydroxy or etherified or esterified hydroxy, and R 2 is carboxyl or protected carboxyl, and salts of such compounds having a salt-forming group.

Description

230 153 7 - '"" 28.9.1981

^^ ^/ 59 263 12

APCO7D / 23O 153/7

Process for the preparation of dioxide compounds Area of application of the invention

The invention relates to processes for the preparation of novel 2, 2-dimethylpenam-3-carboxylic acid 1,1-dioxide compounds, their use for the inhibition of β-lactamases, pharmaceutical preparations which, if appropriate, together with another antibiotically active β-lactamases. Lactam compound and the use of such preparations «

Characteristic of the known technical solutions

Some 1,1-dioxides of penam-3-carboxylic acid compounds having β-lactamase-inhibiting properties have already been disclosed. Thus, the 2,2-dimetnyl-pentam-3-carboxylic acid 1,1-dioxide and esters thereof are known from the Belgian patent PS 867, 859 known. The 1,1-dioxides of the 2-position optionally substituted by a methyl group penam-3-carboxylic acid and its esters are described in European Patent Application 8917 "Corresponding substituted in the 6-position by an amino group Penemverbindungen are from European Patent Application 2927 and substituted in the 6-position by substituted hydrocarbon radicals having more than one carbon atom, are known from European Patent Application 5889.

Object of the invention

The aim of the invention is to provide novel compounds with valuable pharmacological, in particular superior β-lactamase-inhibiting properties.

230 153?

28.9.1981 APCO7D / 23O 153/7 59 263 12

Explanation of the essence of the invention

The invention has for its object to find new dioxide compounds with the desired properties.

According to the invention, substituted methyl-substituted 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide compounds are prepared in the 6-position. These are not yet known. It has been made the surprising plague that such compounds in addition to antibiotic particular superior β-lactamase-inhibiting properties. They are therefore especially in combination with ß-lactamase-sensitive

153

ß-lactam antibiotics, for controlling infections, especially those caused by ß-lactamase-producing microorganisms suitable.

The invention particularly relates to 2,2-dimethyl-penain-3-carboxylic acid 1,1-dioxide compounds of the formula

(D,

^R 2

wherein R represents hydroxy or etherified or esterified hydroxy and R ^ represents carboxyl or protected carboxyl, and salts of such compounds having a salt-forming group, processes for the preparation of these compounds, their use for the inhibition of β-lactamases, pharmaceutical preparations, such Compounds optionally together with an antibiotically active ß-lactam compound and the use of such preparations.

In the present description of the invention, the term "lower" used in connection with definitions of groups and compounds, e.g. in groups such as lower alkyl, lower alkylene, lower alkoxy or lower alkanoyl or in compounds such as lower alcohol and the like, that the corresponding groups or compounds, unless expressly defined otherwise, contain up to 6, preferably up to 4 C atoms.

An etherified hydroxy group R .. is a group R-O-,

a in which R - represents in particular an optionally substituted Kohlenw, fabric residue or an organic silyl or stannyl group.

230153 7

An optionally substituted hydrocarbon radical R has up to 18 C atoms and is, for example, a lower aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radical which is, for example, lower alkyl, lower alkoxy, halogen, oxo, hydroxy, optionally functionally modified carboxy, optionally lower alkylated amino or a corresponding protected group, or may be substituted by heterocyclyl.

A lower aliphatic radical R is, for example, lower alkyl, in particular having 1-6, preferably 1-4, C atoms, e.g. Methyl, ethyl, propyl or butyl, lower alkenyl, especially with 2-5 C atoms, e.g. Vinyl, propenyl or butenyl, or lower alkynyl, especially with 2-5 C atoms, e.g. Ethinyl or propynyl.

A cycloaliphatic radical R is cycloalkyl having 3-8, in particular 3-6 C atoms, z.3. Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

A cycloaliphatic-aliphatic radical R is one of the said aliphatic radicals which is substituted by one of said cycloaliphatic radicals, e.g. Cyclopropylmethyl, or ethyl, or cyclohexylmethyl or ethyl.

An aromatic radical R is in particular phenyl or naphthyl.

An araliphatic radical R is one of the said aliphatic radicals which is substituted by one to three of said aromatic radicals, for example mono-, di- or triphenyl-lower alkyl, e.g. Benzyl, phenethyl, diphenylmethyl or trityl.

Among the substituted hydrocarbon radicals R may be mentioned niaderalkoxyniederalkyl, e.g. Methoxymethyl, 1- or 2-methoxyethyl and 1- or 2-ethoxyethyl, halo-lower alkyl, e.g. 2-fluoro-,

3 0 15 3 7

2-chloro, 2-3-romo and 2-iodoethyl, oxo-lower alkyl, e.g. Acetonyl, optionally protected, e.g. acylated hydroxy lower alkyl, e.g. 2-hydroxyethyl and acetoxyethyl, optionally esterified carboxy-lower alkyl, e.g. 2-carboxymethyl and 2-ethoxycarbony! Methyl, amino and mono- or di-lower alkylamino-lower alkyl, z.3. 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl and acylamino-lower alkyl, e.g. 2-acetamidoethyl, lower alkylphenyl, e.g. Tolyl and xylyl, lower alkoxyphanyl, z.3. Methoxyphenyl, halophenyl, e.g. Fluoro or chlorophenyl, hydroxyphenyl, 'carboxyphenyl and aminophenyl, where the substituents may be in the o-, ta- or p-position of the phenyl carmine, phenacetyl, and heterocyclyl-lower alkyl, in particular heterocyclylmethyl, in which heterocyclyl is for example optionally. represented by lower alkyl, hydroxy, esterified hydroxy, halogen, sulfo, sulphido, amino or aminomethyl substituted furyl, thienyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyridazinyl or pyrimidyl, For example, 2-furyl, 5-aminomethyl-2-furyl, 2-thienyl, 5-Aminomethyi-2-thienyl, 2-imidazolyl, l, 2,3-triazol-4-yl, 2-amino -l, 3-thiazol-5-yl-methyl, or 5-amino-l, 2,4-thiadiazol-3-ylmethyl.

An organic silyl or stannyl group R is primarily one in which the silicon or tin atom is preferably lower alkyl, especially methyl, further lower alkoxy, e.g. Methoxy, and / or halogen, e.g. Chlorine, as a substituent. Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, e.g. Methoxy-methyl-chloro-silyl, or di-lower alkyl-halosilyl, e.g. Dimethyl-chloro-silyl, or appropriately substituted stannyl, e.g. Tri-n-butylstannyl.

An esterified hydroxy group R is a group R-O-, h

wherein R is the acyl radical of an organic carboxylic or sulfonic acid or an inorganic acid.

Z3Ü 153 7

-X- e-

The acyl radical R _{1 of} an organic carboxylic acid has up to 19 carbon atoms, also includes the acyl radical of a half ester of carbonic acid and an optionally substituted carbamic acid. Such acyl radicals have, for example, the formula H-CO-, R-CO-, heterocyclyl-CO-, R 1 -O-CO-, HJ-CO- and R 4 WcO-, where R 1 and heterocyclyl are those given above. Have meanings.

The acyl radical R of an organic sulfonic acid has, for example, the formula R-SO-, where R has the meanings given above of an optionally substituted hydrocarbon radical.

The acyl radical R of an inorganic acid is for example that of an oxygen-containing sulfuric or phosphoric acid, for example HOSO ₂ - or H ₂ PO ₃ -.

R is preferably hydroxyl, lower alkoxy, for example methoxy, phenyl-lower alkoxy, for example benzyloxy, or lower alkanoyloxy, for example formyloxy or acetoxy, aminothiazolylcarbonyloxy, for example 2-amino-1,3-thiazol-4-ylcarbonyloxy, aminothiadiazolylcarbonyloxy, for example 5-aminol, 2, 4-thiadiazol-3-ylcarbonyloxy, lower alkoxycarbonyloxy, for example methoxycarbonyloxy or ethoxycarbonyloxy, carbamoyloxy, N-mono- or Ν, Ν-di-lower alkylcarbamoyloxy, for example N-methylcarbamoyloxy or Ν, Ν-dimethylcarbamoyloxy, lower alkanesulfonyloxy, for example methanesulfonyloxy, arenesulfonyloxy, for example benzenesulfonyloxy or toluenesulfonyloxy , or hydroxysulfonyloxy (or a salt thereof, eg the sodium salt). , _:

First and foremost, R is hydroxy.

The functional groups present in compounds of formula (I), in particular carboxyl and amino, furthermore hydroxy and sulfo groups, are optionally protected by protecting groups used in penicillin, cephalosporin and peptide chemistry.

153 7

Such protecting groups are light, that is, without unwanted side reactions take place, for example, solvolytic, reductive, photolytic or even under physiological conditions, cleavable.

Protecting groups of this type, as well as their cleavage, are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, also in "The Peptides", Vol. I, Schröder and Lubke, Academic Press, London, New York, 1965, as well

in "Methods of Organic Chemistry", Houben-Weyl, 4th edition, 3d. 15 ../ 1, Georg Thietne Verlag, Stuttgart, 1974.

Thus, carboxyl groups, e.g. the carboxyl group R, usually protected in esterified forin, wherein such ester groups are easily cleavable under mild conditions. Carboxyl groups protected in this manner contain as lower end groups branched lower-alkyl groups, which are branched in the first step or are suitably substituted in the 1- or 2-position. Preferred esterified carboxylic groups include i.a. tertiary lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals, these being optionally substituted, e.g. by lower alkyl, such as tert-lower alkyl, e.g. tert -butyl, lower alkoxy, such as methoxy, hydroxy, halo, e.g. Chloro, and / or nitro, mono- or polysubstituted phenyl radicals, as appropriate, for example. as mentioned above, substituted 'benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, or optionally, e.g. as mentioned above, substituted diphenylmethoxycarbonyl, e.g. Diphenylmethoxycarbonyl or di (4-methoxyphenyl) methoxycarbonyl, 1-lower alkoxy-lower alkoxycarbonyl such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl, 1-lowerthiothio-lower alkoxycarbonyl such as 1-methylthiomethoxycarbonyl or 1-ethylthiomethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is optionally substituted, e.g. substituted by halogen, such as bromine

230 153 7

- S-

Benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2., 2., 2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyl) -ethoxycarbonyl, in which the substituents independently of one another each represent an optionally substituted, Z.3. by lower alkyl, lower alkoxy, aryl, halogen and / or nitro substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical with z.3. up to 15 carbon atoms, such as corresponding, optionally substituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, e.g. 2-tri-lower alkylsilylethoxycarbonyl such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

Other protected carboxyl groups present in esterified form are corresponding silyloxycarbonyl, in particular organic silyloxycarbonyl groups, furthermore corresponding stannyloxycarbonyl groups. In these, the silicon or tin atom preferably contains lower alkyl, in particular methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, e.g. Chlorine, as a substituent. Suitable silyl or stannyl protecting groups are primarily tri-lower alkylsilyl, especially trimethylsilyl, further dimethyl-tert-butylsilyl, lower alkoxy-lower alkyl-halo-silyl, e.g. Methoxy-methyl-chloro-silyl, or di-lower alkyl-halo-silyl, e.g. Dimethyl-chloro-silyl, or appropriately substituted stannyl groups, e.g. Tri-n-butylstannyl.

Preferred protected; Carboxyl groups are tertiary-lower alkoxycarbonyl, such as tert-butyloxycarbonyl, and especially optionally, e.g. As mentioned above, substituted benzyloxycarbonyl, such as 4-nitro-benzyloxycarbonyl, or diphenylmethoxycarbonyl.

2301 53 7

A physiologically cleavable esterified carboxyl group is primarily an acyloxymethyloxycarbonyl group wherein acyl is e.g. the residue of an organic carboxylic acid, primarily an optionally substituted lower alkanecarboxylic acid, or wherein acyloxymethyl forms the residue of a lactone, or else l-lower alkyloxycarbonyloxy-lower alkyloxycarbonyl, wherein lower alkyl is methyl, propyl, butyl or especially ethyl. Such groups are lower alkanoyloxymethoxycarbonyl, e.g. Aeetyloxymethyloxycarbonyl or Pivaloyloxymethoxycarbonyl, Aminoniederalkanoylmethoxycarbonyl, in particular a-amino-lower alkanoyloxymethoxycarbonyi, e.g. Glycyloxymethoxycarbonyl, L-VaIyloxymethoxycarbonyl, L-Leucyloxymethoxycarbonyl, Phthalidyloxycarbonyl, e.g. 2-phthalidyloxycarbonyl, 4-crotonolactonyl or gamma-butyrolactor-4-yl, indanyloxycarbonyl, e.g. 5-indanyloxycarbonyl or 1-aethyloxycarbonyloxyethyloxycarbonyl.

A protected amino group may e.g. in the form of an easily cleavable acylamino, arylinethyl-amino, etherified mercaptoamino-2-acyl-lower alk-1-en-yl-amino, silyl or stannylamino group or as azido group.

For example, in a corresponding acylamino group, acyl is the acyl radical of an organic carboxylic acid with e.g. up to 18 carbon atoms, especially an optionally, e.g. by halogen or aryl, substituted alkanecarboxylic acid or optionally, e.g. by halogen, lower alkoxy or nitro, substituted benzoic acid, or a carbonic monoester. Such acyl groups are, for example, lower alkanoyl, such as Fonnyl, acetyl or propionyl, halo-lower alkanoyl, such as 2-haloacetyl, in particular 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2 , 2-trichloroacetyl, optionally, for example halo, lower alkoxy or nitro substituted benzoyl, e.g. Benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, or lower alkoxycarbonyl branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, in particular

230153 7

particular tertiary lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, arylmethoxycarbonyl having one or two aryl radicals, preferably optionally, e.g. by lower alkyl, especially tertiary-lower alkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, e.g. Chlorine and / or nitro, mono- or polysubstituted phenyl, such as optionally substituted benzyloxycarbonyl, e.g. 4-nitro-benzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, e.g. Benzhydryloxycarbonyl or di (4-methoxyphenyl) methoxycarbonyi, aroylmethoxycarbonyl wherein the aroyl group is preferably optionally, e.g. by halogen, such as bromine, substituted benzoyl, e.g. Phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyi, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or 2- (trisubstituted silyloethoxycarbonyl, in which the substituents independently of one another each have an optionally substituted, for .3, By lower alkyl, lower alkoxy, aryl, halogen or nitro, substituted, aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical having, for example, up to 15 carbon atoms, such as corresponding, optionally substituted lower alkyl, phenyl, alkyl, cycloalkyl or phenyl, for example 2-tri-lower alkylsilylethoxycarbonyl such as 2-trimethylsilylethoxycarbonyl or 2- (di-n-butylmethylsilyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl such as 2-triphenylsilylethoxycarbonyl.

Further acyl radicals which may be used as amino-protecting groups are also corresponding radicals of organic phosphoric, phosphonic or phosphinic acids, such as diloweralkylphosphoryl, z. Dimethylphosphoryl, diethylphosphoryl, di-n-propylphosphoryl or diisopropylphosphoryl, dicycloalkylphosphoryl, e.g. Dicyclohexylphosphoryl, optionally substituted diphenylphosphoryl, e.g. Diphenylphosphoryl, if appropriate, e.g. nitro-substituted diphenyl-lower alkylphosphoryl, z.3. Dibenzylphosphoryl or di-4-nitrobenzylphosphoryl,

2301 53

optionally substituted phenyloxy-phenyl-phosphonyl, e.g. Phenyloxy-phenyl-phosphonyl, di-lower alkylphosphinyl, e.g. Diethylphosphinyl, or optionally substituted diphenylphosphinyl, e.g. Diphenylphosphinyl.

In an arylmethylamino group which represents a mono-, di- or especially triarylmethylamino group, the aryl radicals are in particular optionally substituted phenyl radicals. Such groups are for example benzyl, diphenylmethyl and especially tritylamino.

An etherified mercapto group in an amino group protected with such a radical is primarily arylthio or Arylniederalkylthio, wherein aryl in particular, optionally, z.3. such as methyl or tert-3utyl, lower alkoxy, via methoxy, halogen, such as chlorine and / odet is nitro by NiederalkyI ₃ substituted phenyl. "Sine corresponding amino is, for example, 4-nitrophenylthio.

In a 1-acyl-lower-alk-1-en-2-yl radical useful as an amino-protecting group, acyl is e.g. the corresponding residue of a lower alkanecarboxylic acid, an optionally, e.g. by Niederalky1, 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 monoester, such as a carbonic acid lower alkyl. Corresponding protecting groups are primarily 1-lower alkanoylprop-1-en-2-yl, e.g. 1-acetyl-prop-1-en-2-yl, or 1-lower alkoxycarboyl-prop-1-en-2-yl, e.g. l-ethoxycarbonyl-prop-l-en-2-yl.

A silyl or stannylamino group is primarily an organic silyl or stannylamino group, in which the silicon or tin atom is preferably lower alkyl, in particular methyl, furthermore lower alkoxy, e.g. Methoxy, and / or halogen, e.g. Chlorine, as a substituent. Corresponding silyl or stannyl groups are primarily tri-lower alkylsilyl, in particular trimethylsilyl

2301 53 7

Dimethyl-tert-butyl-silyl, lower alkoxy-lower alkyl-halo-silyl, e.g. Methoxy-methyl-chloro-silyl, or di-lower alkyl-halosilyl, e.g. Dimethyl-chloro-silyl, or appropriately substituted stannyl, e.g. Tri-n-butyl-stannyl.

An amino group can also be protected in protonated form; suitable anions are primarily those of strong inorganic acids, such as hydrohalic acids, e.g. the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid in question.

Preferred amino-protecting groups are Äcylreste of carbonic monoesters, especially tert-butyloxycarbonyl, optionally 2.B. as indicated, substituted benzyloxycarbonyl, e.g. 4-nitrobenzyloxycarbonyl, or diphenylinethoxycarbonyl, or 2-halo-lower alkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl or foratyl.

Hydroxy protecting groups are z.3. Acyl radicals, such as optionally for example halo-substituted lower alkanoyl, such as 2,2-dichloroacetyl, or in particular the additives in amm enhang with a protected amino acyl radicals of carbonic acid semiesters mentioned, in particular 2,2,2-trichloroethoxycarbonyl, or organic silyl or stannyl- R =, furthermore easily cleavable etherifying groups, such as tert-lower alkyl, for example tert-butyl, 2-halo-lower alkyl, for example 2,2,2-trichloro, 2-chloro, 2-bromo or 2-iodoethyl, 2- oxa or 2-thiaaliphatic or cycloaliphatic hydrocarbon radicals, in particular 1-lower alkoxy-lower alkyl or 1-lower alkylthione-lower alkyl, for example methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-0xa- or 2-thiacycloalkyl having 5-7 ring atoms, eg 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues, and optionally substituted 1-phenyl-lower alkyl, such as optionally substituted benzyl or diphenyl lmethyl, being suitable as substituents of the phenyl radicals, for example halogen, such as chlorine, lower alkoxy, such as methoxy and / or nitro in question.

A protected sulfo group is primarily an esterified one such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic alcohol, e.g. a lower alkanol, or sulfo group esterified with a silyl or stannyl group such as tri-lower alkylsilyl. For example, in a sulfo group, the hydroxy group, like the hydroxy group, may be etherified in an esterified carboxy group.

Salts of erfindungsge mass compounds are primarily pharmaceutically acceptable, non-toxic salts, such as those of compounds of formula I with acidic groups, z.3. with a free carboxyl or sulfo group. Such salts are primarily metal or ammonium salts, such as alkali metal and alkaline earth metal, e.g. Sodium, potassium, magnesium or Calciura salts, and ammonium salts with ammonia or suitable organic amines, wherein primarily aliphatic ^, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the Salt formation come into question, such as lower alkylamines, eg Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. A-aminobenzoic acid Z-diethylaminoethyl ester, lower alkylene amines, e.g. 1-ethyl-piperidine, cycloalkylamines, e.g. Dicyclohexylamine, or benzylamines, e.g. Ν, Ν'-dibenzylethylenediamine, further pyridine-type bases, e.g. Pyridine, collidine or quinoline. Compounds of formula I having a basic group may include acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulphonic acids, e.g. Trifluoroacetic acid, as well as with amino acids such as arginine and lysine. In the presence of several acidic or basic groups, mono- or polysaccharides can be formed. Compounds of formula I with an acidic, e.g.

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free carboxyl group, and a free basic group, e.g. an atnino group, may also be in the form of internal salts, i. in zwitterionic form, or it may be a part of the molecule as an inner salt, and another part as a normal salt.

For isolation or purification it is also possible to use pharmaceutically unsuitable salts. For therapeutic use, only the pharmaceutically acceptable, non-toxic salts, which are therefore preferred.

The compounds of the formula (I) have the R configuration in the 3- and 5-position and the R- or S-configuration in the 6-position or may also represent mixtures of the 6R and 6S configuration. Compounds with 6R configuration (where the substituent R 1, - is CH-in β-position and the two hydrogen atoms in 5

and 6-position ice) are preferred.

More particularly, the invention relates to compounds of formula (I) wherein functional groups are either not protected or protected in physiologically cleavable form, and their pharmaceutically acceptable salts, since these compounds have the stated activity and can be used for the stated purpose, while the protected ones Compounds serve mainly as intermediates.

Of particular note are compounds of formula (I) wherein R is hydroxy, lower alkoxy, e.g. Methoxy, phenyl-lower alkoxy, e.g. Benzyloxy, lower alkanoyloxy, 2.B. Formyloxy or acetoxy, aminothiazolecarbonyloxy, e.g. 2-amino-1, S-thiazol-A-ylcarbonyloxy, aminothiadiazolylcarbonyloxy, e.g. 5-amino-1, 2,4-thiadiazol-3-ylcarbonyloxy, lower alkoxycarbonyloxy, carbamoyloxy, N-mono- or Ν, Ν-di-lower alkylcarbamoyloxy, e.g. N-methylcarbamoyloxy or Ν, Ν-dimethylcarbamoyloxy, lower alkanesulfonyloxy, ζ .B. Methanesulfonyloxy, arensulfonyloxy, e.g. Benzenesulfonyloxy or toluenesulfonyloxy, or hydroxysulfonyloxy (or a salt thereof, for example, the sodium salt), and

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R is carboxy or in physiologically cleavable form esterified carboxy, e.g., lower alkanoyloxymethoxycarbonyl, e.g. Acetyloxymethyloxycarbonyl or pivaloyloxymethoxycarbonyl, amino-lower alkanoylmethoxy, especially α-amino-lower alkanoyloxymethoxycarbonyl, e.g. Glycyloxymethoxycarbonyl, L-valyloxymethoxy.carbonyl, L-leucylmethoxycarbonyl, phthalidyloxycarbonyl, e.g. 2-phthalidyloxycarbonyl, 4-crotonolactonyl or gamma-3-butyrolactone-4-yl, indanyloxycarbonyl, e.g. 5-Indanyloxycarbonyl or 1-Aethyloxycarbonyloxyäthvloxycarbonyl, as well as the pharmaceutically acceptable salts of such compounds containing a salt-forming group, e.g. the alkali metal salts, e.g. the sodium salts of these compounds wherein R is carboxy.

The invention relates in particular to the compounds of the formula (I) in which R represents hydroxy, methoxy or benzyloxy and R ^ carboxy-b-eductate, and the pharmaceutically acceptable salts, z.3. the sodium salts of it.

The invention relates in the first place to the compounds described in the examples, in particular the compound of the formula (I) in which R is hydroxy and R is carboxy, and the pharmaceutically acceptable salts thereof, e.g. the sodium salt.

The compounds of formula (I) and salts thereof are prepared in a manner known per se.

Compounds of formula (I) and salts of such compounds having a salt-forming group are prepared, for example, by reacting a) a compound of formula

H (O) / ; -'- '-λ' , η R ₁ -CH ₀ I S 1 v2 f ~ I 9 - / ^CH 3 \ CD

(Ha),

wherein R and R have the meanings given under formula (I) and the index η has the value 0 or 1, oxidized in the 1-position, or b) in a compound of formula

(Hb),

^R 2

wherein R represents a protected carboxyl group, the group R-CH- introduces, or

c) in a compound of the formula

(Hc),

^R 2

in which R and R have the meanings given under formula (I) and Y represents a group which can be converted into a hydrogen atom, the group Y is converted into a hydrogen atom and, if desired or necessary, in an available compound one group R into another group R transferred, and / or a group R "converted into another group R, and / or converted an available salt into the free compound or into another salt, and / or salted an available free compound with a salt-forming group, and / or an available mixture of isomeric compounds of the formula (I) in the individual isomers.

a) Oxidation of the! -position

The oxidation of compounds of formula (Ha) 'is carried out by treatment with sulfide or sulfoxide groups in sulfonic acid converting agents, especially with hydrogen peroxide, organic peracids, especially aliphatic percarboxylic acids, e.g. Peressigsäura, perbenzoic acid, chloroperbenzoic acid, e.g. m-chloroperbenzoic acid, or monoperphthalic acid with oxidizing inorganic acids or their salts, e.g. Nitric acid, chromic acid, potassium permanganate or an alkali metal hypochlorite, e.g. Natriunihypochloritj and also by anodic oxidation. The oxidation is preferably carried out in a suitable inert solvent, for example a halohydrocarbon, e.g. Methylene chloride, chloroform or carbon tetrachloride, an alcohol, e.g. Methanol or ethanol, a ketone, e.g. Acetone, an ether, e.g. Diethyl ether, dioxane or tetrahydrofuran, an amide, e.g. Dimethylformamide, a sulfone, e.g. Dimethyl sulfone, a liquid organic carboxylic acid, e.g. Acetic acid, or in water or a mixture of these. Solvent, especially a hydrous mixture, e.g. aqueous acetic acid, at room temperature, or with cooling or gentle heating, i. at about -20 to about + 90 °, preferably at about +18 to about + 30 °. The oxidation may also be carried out in stages by first starting at low temperature, i. is oxidized at about -20 to about 0 ° to the sulfoxide stage, which is optionally isolated, whereupon in a second step, preferably at a higher temperature, at about room temperature, the sulfoxide to the sulfone, i. the 1,1-dioxide of formula (I)., Oxidized.

For work-up, any remaining excess oxidant may optionally be obtained by reduction, in particular by treatment with a reducing agent such as a thiosulphate, e.g. Sodium thiosulfate, to be destroyed.

\ j

b) introduction of a group R- , -CH ₀ -: The group R-CH- is replaced by a

* J. 2. χ 2.

Alkylation reaction introduced, for example, by reacting a mono- or dianion of a compound of formula (lib) with formaldehyde or a reactive functional derivative thereof and then treating the reaction product with a proton source.

Mono anions of compounds of the formula (lib) have a negative charge in the 6-position, dianions in the 6- and in the 3-position instead of a hydrogen atom. Such compounds are usually prepared in situ, for example, by reacting a compound of formula (lib) with one or two moles of a metallating reagent. Suitable metalating reagents are substituted and unsubstituted alkali metal acetamides, alkali metal hydrides or lower alkyl alkali metal compounds wherein the alkali metal is sodium or, in particular, lithium, e.g. Sodium or lithium amide, lithium bis-trimethylsilylamide, sodium hydride, lithium hydride, and preferably lithium diisopropylamide and butyl lithium. Another method for preparing monoanions is to react a 6-halo compound of a compound of formula (lib) wherein the 6-position is replaced by halogen, e.g. Chlorine, bromine or especially iodine is substituted with magnesium or a Grignard reagent, e.g. with a lower alkyl magnesium halide, e.g. Methylmagnesiumbromid, or reacted with activated zinc or zinc amalgam.

Reactive functional derivatives of formaldehyde are, for example, paraformaldehyde and compounds of the formula R-CH ₁₇ -X, wherein R is an etherified or esterified hydroxy group and X is a nucleofuge leaving group, for example a halogen atom, for example chlorine, bromine or iodine, a sulfonyloxy group, eg mesyloxy or Tosyloxy, or a group RO- represents.

ZJU 153 7

The preparation of the mono- and dianion is carried out in an inert, non-protic solvent, for example in a hydrocarbon, e.g. Hexane, benzene, toluene or xylene, a weakly polar ether, e.g. Diethyl ether, tetrahydrofuran or dioxane, or an acid amide, e.g. Hexainethylphosphorsäuretriamid, or mixtures thereof, at temperatures between about -80 ° and about room temperature, the preparation by means of Metallierungsreagentien, magnesium or Grignard reagents, preferably at low temperatures, about -70 ° to about -30 °, while the preparation by means of zinc, preferably at about 0 ° to 30 °, in particular at room temperature.

The conversion of the mono- or dianion with formaldehyde or the reactive functional derivative thereof takes place in the same solvent or solvent mixture and under the same temperature conditions above. The mono- or dianion may also be formed in the presence of the formaldehyde or the reactive derivative thereof.

In a preferred embodiment, gaseous, dry formaldehyde at about -78 ° in a monoanion-containing reaction mixture, preferably by reaction of a 6-halo, especially 6-bromo or 6-iodo-substituted compound of formula Hb with a lower alkyl magnesium halide, in particular Methylmagnesiumjodid, in an ether, in particular tetrahydrofuran, is obtained, passed.

After the alkylation reaction, the reaction product becomes

230153 7

· - 20-

treated with a proton source, 2.3. with water, an alcohol, e.g. Methanol or ethanol, an organic or inorganic acid, e.g. Acetic acid, hydrochloric acid, sulfuric acid or a similar proton donating. Compound, again preferably at low temperatures.

c) Exchange of -Y for Hydrogen : In a compound of the formula (lic) Y is a hydrogen-exchangeable group, for example an isonitrile group C =N- or halogen, eg chlorine, iodine or in particular bromine.

The replacement of Y with a hydrogen atom is carried out by treatment with a suitable reducing agent. Suitable reducing agents are, for example, metal hydrides, in particular tin hydrides such as tri-lower alkyltin hydrides or di-lower alkyltin hydrides, in particular tri-n-butyltin hydride, or triphenyltin hydride, lithium aluminum hydride or sodium borohydride, hydrogen in statu nascendi ^ z. produced from a metal and a proton source, in particular zinc and acetic acid, or sodium and alcohol, e.g. Amyl alcohol, or catalytically, e.g. Palladium-carbon activated hydrogen.

The reduction takes place in a suitable, optionally inert solvent. Metal hydrides are used, for example, in a hydrocarbon, e.g. Pentane, hexane, benzene, toluene or xylene, while the reduction with hydrogen in statu nascendi in the proton source used, which may optionally be diluted by an inert solvent is performed. In one of the solvents or solvent mixtures mentioned, the catalytic reduction may also take place. Depending on the reducing agent used, the reaction is carried out at room temperature or at a reduced or elevated temperature at about -80 to + 100 °.

A preferred reduction method is the treatment of a

Compound of formula (lic), wherein Y is an isonitrile group or bromine, with tri-n-butyltin hydride in an inert solvent, e.g. Benzene at room temperature to the boiling point of the solvent used, i. to about 80 °, optionally in the presence of catalytic amounts of azobisisobutyronitrile (DI John, EJ Thomas and ND Tire11, JCS Chem. Comm. 1979, p. 345; JA Aimetti, ES Hamanaka, DA Johnson and MS Kellogg, Tetrahedron Letters, No. 48 , 1979, p. 4631).

In an available compound of the formula (I), the substituents R and R can be converted into other substituents R or R within the scope of their meanings and in any desired order. Thus, a hydroxy group R can be converted into an etherified or esterified hydroxy group R-O- or -R-O by etherification or esterification. A free carboxyl group R can be esterified and an esterified carboxyl group R- can be converted into a free carboxyl group. Optionally present in the radical R protecting groups can also be removed. These subsequent operations are carried out in a manner known per se, for example as follows:

Etherification and esterification of a hydroxy group R ₁ : In a compound of the formula (I) ₅ in which the group R is present as a functionally modified carboxyl group and other functional groups which may be present are preferably protected, a hydroxy group R can be etherified in a manner known per se Hydroxy group RO- be converted.

Suitable etherifying agents are, for example, diazo compounds ^ ₁ N ₂ , such as optionally substituted diazonium halides, for example diazomethane, diazoethane, diazo-n-butane or diphenyldiazomethane. These reagents are reacted in the presence of a suitable inert solvent, such as an aliphatic, cycloaliphatic

or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. Methylene chloride, or an ether such as a di-lower alkyl ether, e.g. Diethyl ether, or a cyclic ether, e.g. Tetrahydrofuran or dioxane, or a solvent mixture, and, depending on the diazo reagent, with cooling, at room temperature or with gentle heating, further, if necessary, in a closed vessel and / or under an inert gas, e.g. Nitrogen atmosphere, brought to application.

Other suitable etherifying agents are esters of

a Alcohols R-OH, primarily those with strong inorganic

or organic acids, such as mineral acids, e.g. Hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, also sulfuric acid, or halosulfuric acids, e.g. Fluorosulfuric acid, or strong organic sulfonic acids, as appropriate, e.g. by halogen, such as fluorine, substituted lower alkanesulphonic acids, or aromatic sulphonic acids, e.g. optionally benzenesulfonic acids substituted by lower alkyl, such as methyl, halo, such as bromo, and / or nitro, e.g. Methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid. Such esters are e.g. R-

a halides, u.a. Lower alkyl halides, di-R-sulphates, e.g. Dimethylsulfates, such as dimethylsulfate, furthermore, fluorosulfonic acid R .. esters, such as lower alkyl esters, e.g. Fluorosulphonic acid methyl ester, or

if appropriate, halo-substituted methanesulfonic acid R 1 -esters, such as lower alkyl esters, e.g. Trifluoromethanesulfonate. They are usually in the presence of an inert solvent, such as an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Methylene chloride, an ether, such as dioxane or tetrahydrofuran, or a mixture. It is preferable to use suitable condensing agents such as alkali metal carbonates or bicarbonates, e.g. Sodium or potassium carbonate or bicarbonate (commonly

Example, together with a sulfate), or organic bases, such as, usually sterically hindered, Triniederalkylamine, for example N, N-diisopropyl-N-ethyl-amine (preferably together with Halogensulfonsäureniederalkylestern or optionally halogen-substituted Methansulf onssäure-niederalkylestam), wherein with cooling, at room temperature or with heating, for example at temperatures of about -20 ⁰ C to about 50 ⁰ C and, if necessary, in a closed vessel and / or in an inert gas, eg nitrogen atmosphere, is worked.

The above-described etherification reaction can be substantially accelerated by phase transfer catalysis (see Dehmlow, Angewandte Chemie _5, 3d, 5, p.1187 (1974)) as phase transfer catalysts quaternary phosphonium salts and, in particular, quaternary ammonium salts, such as optionally substituted tetraalkylammonium halides, For example, tetrabutylammonium chloride, bromide or iodide, or benzyltriethylaminonium chloride, may be used in catalytic, or up to equimolar amounts as the organic phase, any of the water-immiscible solvents, for example, one of the optionally halogenated, such as chlorinated lower aliphatic, cycloaliphatic or aromatic hydrocarbons, such as tri- or tetrachlorethylene, tetrachloroethane, carbon tetrachloride, chlorobenzene, toluene or xylene, the alkali metal carbonates or bicarbonates suitable as condensing agents, for example potassium or sodium carbonate or bicarbonate, Alk alimetallic phosphates, for example potassium phosphate, and alkali metal hydroxides, for example sodium hydroxide, can be added to the reaction mixture in the case of base-sensitive compounds titrimetrically, for example by means of a titration machine, so that the pH during the etherification remains between about 7 and about 8.5.

30 153 7

Further ethereal agents are suitable acetal compounds, such as gem-di-R 0- lower alkanes , for example according to di- lower alkoxy

J.

lower alkanes such as 2,2-dimethoxy-propane prepared in the presence of strong organic sulfonic acids such as p-toluenesulfonic acid and a suitable solvent such as a di-lower alkyl or lower alkylene sulfoxide, e.g. Dimethyl sulfoxide, or suitable

3. 3.

R ₁ containing orthoester, z.3. Orthoformic acid tri-R, esters, for example -triniederalkylester, eg triäthyl Orthoameisensäure, in the presence of a strong mineral acid, for example sulfuric acid, or a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as an ether, eg dioxane , be used.

Further etherifying agents are corresponding trisubstituted oxonium salts (so-called Mesrweinsalze), or disubstituted carbenium or halonium salts, wherein the substituents etherifying

a radicals R ₁ are, for example Trraiederalkyloxoniumsalze, and Diniederalkoxycarbenium- or Diniederalkylhaloniumsalze, in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachloroantimonates. Such reagents are z.3. Trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachloroantimonate, hexafluorophosphate or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoroantimonate. It is preferable to use these etherifying agents in an inert solvent such as an ether or a halogenated hydrocarbon, eg. Diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof, if necessary, in the presence of a base such as an organic base, for example a preferably sterically hindered Triniederalkylamins, for example N, N-diisopropyl-N-ethyl-amine, and with cooling. at room temperature or under slight heating, for example at about -20 ° to about 50 ⁰ C, if necessary in einem'geschlossenen vessel and / or in an inert gas, for example nitrogen atmosphere.

O U I D J /

Further Verätherungsinittel are finally corresponding! -Substituted 3-Aryltriazenverbindungen, wherein the substituent is the etherifying radical.R, and Aryi preferably optionally substituted phenyl, eg Niederalky! Phenyl, such as 4-methyl phenyl. Such triazene compounds are 3-aryl-1-lower alkyltriazenes, eg 3- (4-methylphenyl) -1-methyl-triazene, 3- (4-methylphenyl) -1-ethyl-triazene or 3- (4-methylphenyl) - 1-isopropyl-triazene. These reagents are usually in the presence of inert solvents, such as optionally halogenated hydrocarbons or ethers, for example benzene, or solvent mixtures, and with cooling at room temperature and preferably at elevated temperature, z.3. if necessary, used at about 20 ° to about 100 ⁰ C in a closed vessel and / or in an inert gas, for example nitrogen atmosphere. ·

In an available compound of the formula (I) in which the group R "is present as a functionally modified carboxyl and other functional groups optionally present are preferably protected, a hydroxy group R may be esterified in a manner known per se. Thus, by treating a hydroxymethyl compound of the formula (I) with an acylating agent which introduces the desired acyl radical R _{1 of} an organic carboxylic acid, the hydroxy group can be converted into an acyloxy group RO-. In this case, use is made of the carboxylic acid corresponding to R or a reactive derivative thereof, in particular an anhydride, including a mixed or internal anhydride of such an acid. Mixed anhydrides are z.3. those with hydrohalic acids, ie the corresponding acid halides, in particular chlorides, also with hydrocyanic acid, or then those with suitable carbonic acid half derivatives, such as corresponding half esters (such as those with a halo-formic acid-lower alkyl, such as ethyl chloroformate or isobutylester formed mixed anhydrides.) or with optionally substituted, for example halogen, such as chlorine, containing

230153 7

Lower alkanecarboxylic acids (such as the mixed anhydrides formed with pivaloyl chloride or trichloroacetic acid chloride). Internal anhydrides are e.g. those of organic carboxylic acids, i. Ketenes, such as ketene or diketene, or those of carbamic or thiocarbamic acids, i. Isocyanates or isothiocyanates. Other reactive derivatives of organic carboxylic acids useful as acylating agents are activated esters such as suitably substituted lower alkyl, e.g. Cyanomethyl ester, or suitably substituted phenyl, e.g. Pentachlorophenyl or 4-Nitrophenylester. The esterification may, if necessary, in the presence of suitable condensing agents, using free carboxylic acids e.g. in the presence of carbodiimide compounds such as dicyclohexylcarbodiimide, or carbonyl compounds such as diimidazolylcarbonyl, and using reactive acid derivatives e.g. in the presence of basic agents, such as tri-lower alkyl amines, e.g. Triethylamine, or heterocyclic base, e.g. Pyridine, be carried out. The acylation reaction may be carried out in the absence or presence of a solvent or solvent, with cooling, at room temperature or with heating, and if necessary in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere, are performed. Suitable solvents are e.g. optionally substituted, in particular optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene and toluene, it being possible to use suitable esterification reagents, such as acetic anhydride, from diluents.

b One by an organic sulfonic acid R-OH, e.g. Low-

alkanesulfonic acid, such as methanesulfonic acid, or an aromatic sulfonic acid, such as p-toluenesulfonic acid, esterified hydroxy group may preferably be prepared by treating a hydroxy methyl compound of formula (I) with a reactive sulfonic acid derivative, such as a corresponding halide, e.g. Chloride, if necessary, in the presence

an acid-neutralizing basic agent, e.g. an inorganic or organic base, e.g. in an analogous manner as the corresponding esters with organic carboxylic acids.

A hydroxy group esterified by an inorganic acid R-OH is prepared in a conventional manner by treating a hydroxymethyl compound of the formula (I) in which the 3-carboxyl group is preferably esterified with the inorganic acid, optionally in the presence of a condensing agent, or with a reactive derivative, for example an anhydride or halide thereof, or else by alkylating the inorganic acid or a salt thereof with a reactive derivative of the hydroxymethyl compound of the formula (I), for example where R is halogen, for example chlorine, bromine or iodine. For example, in a compound of formula (I) wherein R _{n is} hydroxy and R- is preferably in protected form, the hydroxy group R may be treated by treatment with sulfuric acid, chlorosulfonic acid, the adduct of sulfur trioxide and a tertiary amine, eg triethylamine, or with amidosulfonic acid and optionally subsequent neutralization, for example with sodium bicarbonate, into a sulfonyloxy group HOSO-O or a salt thereof, or by treatment with concentrated phosphoric acid, if appropriate in the presence of a condensing agent, for example carbodiimide or trichloroacetonitrile, with a salt thereof, eg a di-tertiary-ammonium phosphate, such as Ditriäthylammoniumphosphat, or with an anhydride of phosphoric acid, for example with polyphosphoric acid, metaphosphoric acid or phosphorus (V) oxide, or a mixed anhydride, such as phosphorus oxychloride, and optionally subsequent hydrolysis and / or neutralization, in one Group H-PO-O- or a salt thereof are converted ,

esterification; a free carboxy group: The conversion of free carboxyl, primarily a corresponding group R ₉ , in a compound of formula / Ί) in esterified carboxyl, in particular in an esterified carboxyl group which is cleavable under physiological conditions, takes place per se known Veresterungsaechoden, for example by reacting a compound of the formula 1 (1) wherein

1 5 3

optionally present funktionella groups optionally present in protected form, or a reactive fractional carboxy derivative, including a salt thereof, ax a corresponding alcohol or a reactive functional derivative thereof, is reacted.

The esterification of free carboxyl with the desired alcohol is carried out in the presence of a suitable condensing agent. Typical condensation agents are, for example, carbodiimides, for example Ν, Ν'-diethyl, Ν, Ν'-dipropyl, NjN'-dicyclohexyl or N-ethyl-N ¹ - (3-dimethylaminopropyl) -carbodiimide, suitable carbonyl compounds, for example Carbonyldiimidazole, or 1,2-oxazolium compounds, z, 3 2-ethyl-5-phenyl-l, 2-oxazolium - 3'-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate, or a suitable Acylamino compound, eg 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, z.3. Methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran and, if necessary, carried out under cooling or heating and / or in an inert gas atmosphere.

Suitable reactive functional derivatives of the carboxyl compounds of formula I to be esterified are e.g. Anhydrides, especially mixed anhydrides, and activated esters.

Mixed anhydrides are e.g. those with inorganic acids, such as hydrohalic acids, i. the corresponding acid halides, e.g. chlorides or bromides, also hydrazoic acid, i. the corresponding acid azides, as well as phosphorus-containing acids, e.g. Phosphoric acid, diethylphosphoric acid or phosphorous acid, or sulphurous acids, e.g. Sulfuric acid, or hydrocyanic acid. Mixed anhydrides are further e.g. those with organic carboxylic acids, such as with optionally, e.g. halo, such as fluoro or chloro, substituted lower alkanecarboxylic acids, e.g. Pivalic acid or trichloroacetic acid, or with half-esters,

, - 23-

in particular, lower alkyl halides of carbonic acid, such as ethyl or isobutylene of carbonic acid, or with organic, in particular aliphatic or aromatic, sulphonic acid, e.g. p-toluene sulfonic acid.

Activated esters suitable for reaction with the alcohol are e.g. Esters with vinylogous alcohols (i.e., enols), such as vinylogous lower alkenols, or iminomethylastar halides, such as dimethyiiminomethyl ester chloride (prepared from the carboxylic acid and dimethylformamide);

® Q

chlonnethyliden-isninium chloride of the formula [(CH) ^ N = CHCl] Cl), or aryl esters, such as pentachlorophenyl, 4-nitrophenyl or 2,3-dinitrophenyl ester, heteroaromatic esters, such as benzotriazole, c.3. l-3-triazole esters, or diacylimino esters, such as succinyliniyno.no- or phthalylimino esters.

The acylation with such an acid derivative, such as an anhydride, especially with an acid halide is preferably in the presence of an acid-binding agent, for example an organic base, such as an organic amine, ζ.3. a tertiary amine such as tri-lower alkylamine, e.g. Trimethylamine, triethylamine or ethyl-diisopropylamine, or Ν, Ν-di-lower alkyl-aniline, e.g. N, N-dimethylaniline, or a cyclic tertiary amine, such as an N-lower alkylated morpholine, such as N-methylmorpholine, or a pyridine-type base, e.g. Pyridine, an inorganic 3ase, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

A reactive functional derivative of the esterifying alcohol is primarily a corresponding ester, preferably with a strong inorganic or organic acid, and especially a corresponding halide, e.g. Chloride, bromide or iodide, or a corresponding alkylene alkyl or aryl, such as methyl

VOYYY /

or 4-Mathylpfaenylsulfonyloxyverbindung.

Such a reactive ester of an alcohol can be reacted with the free carboxy compound of formula I or a salt such as an alkali metal or ammonium salt thereof, preferably using the acid in the presence of an acid-binding agent when using the free acid.

The above esterification reactions are carried out in an inert, usually anhydrous solvent or solvent mixture, for example in a carboxamide, such as a formamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, z.3. Acetone, an eater, ζ.3. Ethyl acetate, or a nitrile, z.2. Acetonitrile, or mixtures thereof, if necessary, with cooling or heating, 2.3. in a temperature range from about -4O ⁰ C to about + 100 ° C, preferably at about -10 ⁰ C to about + 40 ³ C ₅ and / or in an inert gas, z.3. Nitrogen atmosphere.

Furthermore, if desired, the acid derivative may be formed in situ . Thus, for example, a mixed anhydride is obtained by treating the carboxylic acid compound with appropriately protected functional groups or a suitable salt thereof, such as an ammonium salt, eg, with an organic amine, such as piperidine or 4-methylmorpholine, or a metal, eg, alkali metal, salt with a suitable acid derivative such as the corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, eg trichloroacetyl chloride, with a halide of a carbonic acid halide, eg ethyl chloroformate or isobutyl ester, or with a halide of a di-lower alkylphosphoric acid, eg diethyl phosphor bromide, and uses the thus obtained mixed anhydride without isolation.

Cleavage of protective groups: In an obtained compound of the formula I in which one or more functional groups are protected, these, for example protected carboxyl, amino, hydroxyl and / or sulfo groups, in a conventional manner, by solvolysis, in particular Hydrolysis, alcoholysis or acidolysis, or by reduction, in particular hydrogenolysis or chemical reduction, optionally be released gradually or simultaneously.

Thus, tert-lower alkoxycarbonyl or lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl substituted in the 2-position by an organic silyl group or in the 1-position by lower alkoxy or lower alkylthio may be used. by treatment with a suitable acid, such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound, such as phenol or anisole, in free carboxyl. Optionally substituted benzyloxycarbonyl may be e.g. by means of hydrogenolysis, i. by treatment with hydrogen in the presence of a metallic hydrogenation catalyst, such as a palladium catalyst. Further, suitably substituted benzyloxycarbonyl such as 4-nitrobenzyloxycarbonyl may also be obtained by means of chemical reduction, e.g. by treatment with an alkali metal, e.g. Sodium dithionite, or with a reducing metal, e.g. Zinc, or metal salt, such as a chromium-II salt, e.g. Chromium II chloride, usually in the presence of a hydrogen donating agent capable of producing nascent hydrogen with the metal, such as an acid, primarily a suitable carboxylic acid, such as an optional, e.g. by hydroxy, substituted lower alkanecarboxylic acid, e.g. Acetic acid, formic acid, glycolic acid, diphenyl glycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, preferably adding water, converted into free carboxyl. By treating with a reducing metal or metal salt as described above, one can also use 2-halo-lower alkoxycarbonyl (as appropriate).

if necessary after conversion of a. 2-bromo-lower alkoxycarbonyl-Grtippe) into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl convert to free carboxyl, wherein aroylmethoxycarbonyl can also be cleaved by treatment with a nucleophilic, preferably salt-forming reagent such as Natriumthiophenolat or sodium iodide. Substituted 2-silylethoxycarbonyl may also be prepared by treatment with a hydrofluoric acid hydrofluoric acid salt such as an alkali metal fluoride, e.g. Sodium or potassium fluoride, in the presence of a macrocyclic polyether ("crown ether") or with a fluoride of an organic quaternary base, such as tetra-lower alkylammonium fluoride or tri-lower alkylaryl ammonium fluoride, e.g. Tetraäthylammoniumfluorid or tetrabutylammonium fluoride, in the presence of an aprotic solvent such as dimethyl sulfoxide or Ν, Ν-dimethylacetamide, are converted into free carboxyl. With an organic silyl or. Stannyl group such as tri-lower alkylsilyl or -stannyl, e.g. Trimethylsilyl, esterified carboxyl may be solvolytically, e.g. by treatment with water, an alcohol or acid.

A protected amino group, e.g. Am, one sets in per se known and, depending on the nature of the protecting groups in various ways, preferably by solvolysis or reduction, free. 2-Halo-lower alkoxycarbonylamino (optionally after conversion of a 2-bromo-lower alkoxycarbonylamino group to a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be e.g. by cleavage with a suitable chemical reducing agent such as zinc in the presence of a suitable carboxylic acid such as aqueous acetic acid. Aroylmethoxycarbonylamino can also be prepared 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. Sodium dithionite, are split. Possibly

-yt- 33-

substituted Diphenylmethoxycarbonylamiiio, tert-Niederalkoxycarbonylamino or 2-trisubstituted Silyläthoxycarbonylainino by treatment with a suitable acid, for example ants or trifluoroacetic _s optionally substituted Benzyloxycarbonylamino eg by hydrogenolysis, ie by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, optionally substituted triarylmethylamino, Formylamino or 2-acyl-lower-alk-1-en-yl-amino, z.3. by treatment with an acid, such as mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, optionally in the presence of water, and an amino group protected by an organic silyl or stannyl group, for example by hydrolysis or alcoholysis become. An amino group protected by 2-haloacetyl, for example 2-chloroacetyl, can be liberated by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate, of the thiourea 3 and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting condensation product. An amino group protected by 2-substituted silylethoxycarbonyl may also be converted to the free amino group by treatment with a hydrofluoric acid salt yielding fluoride anions, as indicated above in connection with the release of a suitably protected carboxyl group. A phosphorus, phosphine or phosphine amido group can be obtained, for example, by treatment with a phosphorus-containing acid, such as a phosphoric, phosphonic or phosphinic acid, for example orthophosphoric acid or polyphosphoric acid, an acidic ester, for example monomethyl, monoethyl, dimethyl or diethyl phosphate or Monomethylphosphonic acid, or an anhydride thereof, such as phosphorus pentoxide, are converted into the free amino group.

An azido-protected amino is e.g. converted by reduction into free Aniiao, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, or also

23

a * -

by treating with zinc in the presence of an acid such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent such as a halogenated hydrocarbon, eg methylene. chloride, or else in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at about 20 to 25 ⁰ C, or else carried out under cooling or heating.

A hydroxy group protected by a suitable acyl group, an organic silyl or stannyl group or by optionally substituted 1-phenyl-lower alkyl is liberated as a suitably protected amino group. A protected by 2, 2-dichloroacetyl hydroxy group is, for example, by basic hydrolysis, etherified by tert-lower alkyl or by a 2-oxa or 2-thiaaliphatic or cycloaliphatic hydrocarbon radical hydroxy acid by acidolysis, for example by treatment with a mineral acid or a _fc strong carboxylic acid, for example trifluoroacetic acid. A 2-halo-lower alkyl group is cleaved reductively.

A protected, in particular esterified, sulfo group is liberated analogously to a protected carboxyl group.

The Sp.altungsreaktionen described are carried out under known conditions, if necessary with cooling or heating, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere.

The known reductive cleavage methods of 2-Halogenniederalkoxycarbonyl- and. 2-halo-lower alkoxy groups can be advantageously carried out under particularly mild conditions in the presence of a catalytic amount of a transition metal complex of a corrin or porphine compound, with usually poorly cleavable groups, e.g. 2-Chloräthoxy-

carbonyl and 2-chloroethoxy groups can be cleaved.

Transition metal complexes of corrin and porphine compounds, which are used as reductive cleavage catalysts, are derived from those transition metals that occur in more than one valence state, such as copper, palladium, rhodium, and especially cobalt. Preferred as a catalyst are model compounds for the synthesis of vitamin B, for example derivatives which differ from the 2, 2, 3, 3, 7, 8, 8, 12, 12, 13, 13, 17, 17, 18, 18-Hexadecamethyl-lO, 2O-diazahexahydroporphin-cobalt (III) cation, and especially vitamins of the B "group, including especially cyanocobalamin, aquocobalamin and hydroxycobalamin, and their derivatives and degradation products, such as cobyaric acid and its esters, corphyrinic acid, Corphinic acid, Cobamic acid and Cobamid. The amount of catalyst is normally about O ₃ I to about 0.001, preferably about 0.03 to about 0.003 molar equivalent, based on the component to be reduced, in a favorable experimental arrangement, eg in an optimized Slektroreduktion, but you can still the lowest limit far below.

The reduction is carried out in a manner known per se by conventional methods in the presence of a proton source. As these may serve any inorganic and organic acids and common protic solvents; Acids are advantageously used in a buffered form or as salts, wherein the pH is preferably between about 4.0 to 9.5, in particular between about 5.5 to 7.5 and especially in the vicinity of the neutral point.

As one of the most gentle reduction methods, cathodic electroreduction under conventional conditions, such as mercury or other commonly used for electroreduction cathode, such as carbon cathode, is recommended in the presence

L ö υ \ ό ο

from. customary auxiliary electrolytes, such as ammonium and / or alkali metal salts, in particular lithium salts, strong inorganic acids, in particular halides and perchlorates, preferably those which are distinguished by good solubility in the aqueous-organic medium used. The solvents used, in addition to water, are common water-miscible organic solvents, for example lower alkanols, such as methanol, ethanol and isopropyl alcohol, or dimethylformamide, and similar lower aliphatic amides, and also nitriles, such as acetonitrile, ethers, such as diethyl ether, 1,2-dimethoxy- and 1 , 2-diethoxy-ethane and cyclic ethers of the tetrahydrofuran type, ketones, such as acetone, carbonates, such as dimethyl and diethyl carbonate, and sulfoxides, in particular dimethyl sulfoxide. The temperature of the electroreduction can be varied within a wide range, ie from about -20 ⁰ C to the boiling temperature of the reaction mixture, preferably it is at room temperature or below.

As e-ine further suitable variant of the reductive cleavage is the reduction with a metal ', especially with zinc or with magnesium into consideration. Under certain circumstances, it is possible to use the usual energetic conditions, for example about 90% strength aqueous acetic acid as the medium and / or elevated temperature up to the boiling point of the mixture with a correspondingly shorter reaction time. But preferably the reaction is carried out under mild conditions possible, for example, in the above-mentioned preferred pH range near the neutral point and at temperatures of about 0 ° to about 40 ⁰ C, preferably about 10-25 ⁰ C; It is customary to work with an approximately ten-fold molar excess of the metal, preferably zinc in the form of zinc dust, which is advantageously activated immediately before the reaction in a conventional manner, for example by stirring with dilute hydrochloric acid and thorough neutral washing. To achieve the desired buffer effect, it is advantageous to use ammonium salts of hydrohalic acids, in particular of those which occur in the particular group of formula I to be eliminated. The reduction takes place

in the above-mentioned organic solvents or mixtures thereof; protic solvents are preferred. Other conventional variants of the reduction process are applicable: as an example, reduction with metal cations in low valence states, e.g. with chromium (II) salts, such as chromium (II) chloride or acetate, and also reduction with complex metal hydrides, e.g. with sodium borohydride and related lower alkoxy sodium borohydrides and lower alkoxylithium norbydrides, as well as catalytic hydrogenation, e.g. on a palladium catalyst.

Preferably, in the presence of multiple protected functional groups, the protecting groups are selected to simultaneously cleave more than one such group, for example acidolytically, such as by treatment with trifluoroacetic acid or formic acid, or reductive, such as by treatment with zinc and acetic acid, or with Hydrogen and a hydrogenation catalyst, such as a palladium / KohleyHatalysator.

Salt formation : Salts of compounds of the formula I having salt-forming groups can be prepared in a manner known per se . Thus, salts of compounds of the formula I with acidic groups, for example by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of a-ethyl-caproic acid, or with inorganic alkali metal or alkaline earth metal salts, 2.3. Sodium bicarbonate, or with ammonia or a suitable organic amine, using preferably stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formula I are obtained in the customary manner, for example by treatment with an acid or a suitable anion exchange solvent. Internal salts of compounds of the formula I which contain, for example, a free carboxyl group, can be obtained, for example, by neutralizing salts, such as acid addition salts

/ 30 153 7

d'en isoelectric point, ζ. 3- be formed with weak bases, or by treatment with liquid ion exchangers.

Salts can be converted into the free compounds in the usual way, metal and ammonium salts e.g. by treatment with suitable acids, and acid addition salts e.g. by treating with a suitable basic agent.

The sulfoxide of formula (Ha), wherein the index η is 1, can be used in the IR or IS configuration or as a mixture of the two isomers.

Similarly, in a starting material of formulas (Ila-c), the 6-position may have the R, S or R, S configuration. In the oxidation, the configuration at the 6-carbon atom is retained. If a mixture of the 6R and 6S compounds of the formula (Ha) is used, a mixture of the 6R and 65 compounds of the formula (I) is obtained. If a mixture of the 6R and 63 compounds of the formulas (lit)

and (lic) is used, it is preferable to obtain the 6R compound of the formula (I).

Mixtures of isomers may be prepared in a manner known per se, e.g. fractionated crystallization, chromatography, etc. are separated into the individual isomers.

The process also includes those embodiments in which intermediate compounds are used as starting materials and the rough process steps are carried out with them, or the process is stopped at any stage; furthermore, starting materials may be used in the form of derivatives or formed during the reaction.

Preferably, such starting materials are used and the ReakticiiSbedingungen chosen so that one reaches the compounds listed above as particularly preferred.

- '39 -

Starting materials : The starting materials of the formulas (Ha) and (lic) used in the process for preparing the compounds of the present invention are novel. They can be produced in a familiar way. Together with the processes for their preparation, they also form an object of the present invention. Compounds of formulas (Ha) and (lic) wherein R is carboxyl or physiologically cleavable esterified carboxyl and the pharmaceutically acceptable salts of such compounds having a salt-forming group have similar pharmaceutical properties to the compounds of formula (I ).

The compounds of formula (Ha) can be prepared, for example, by

a ') into a compound of the formula

(III)

^R 2

where the index η is 0 or 1 and R _? represents an esterified carboxyl group which introduces the group R ₁ -CH ₂ ", or

b ^T ) in a compound of the formula

(IV) ₅

W KJ · ** £ ν / 5

wherein R, R and the index η have the meanings given under formula (HA) and Y represents a group which can be converted into a hydrogen atom, the group Y is converted into a hydrogen atom and, if desired or necessary, in an available compound a group R in converts another group R, and / or converts one group R into another group R-, and / or converts an available 1-sulfide into a 1-sulfoxide or an available 1-sulfoxide into a 1-sulfide, and / or converting an available salt into the free compound or into another salt, and / or converting an available free compound with a salt-forming group into a salt, and / or separating an available mixture of isomeric compounds of the formula (I) into the individual isomers.

The introduction of a group R-CEL and exchange Y against hydrogen is carried out analogously to the processes described under b) and c).

The compounds of formula (Ha) obtainable according to processes (a ^f ) and (b ¹ ) can be converted by post-operations into other compounds of formula (Ha), where for the conversion of R ₁ into another R, R into R R ', salt preparation and the preparation of the free compounds from the salts, as well as the separation of the isomer mixtures into the individual isomers, the same methods can be used as for the corresponding re-operations in the processes for the preparation of compounds of formula (I) is specified.

The preparation of the! -Sulfoxide of the compounds of formula (Ha), wherein the index η is 1, from the 1-sulfides of the formula (Ha), wherein the index η is 0, analogous to the oxidation of compounds of the formula (Ha) to the sulfones of the formula (I), wherein the amount of the oxidizing agent is to be reduced accordingly, if an over-oxidation is to be avoided.

The reduction of 1-Sulf oxides of the formula (Ila) to the! -Sulfiden takes place by means of the methods known in penicillin and cephalosporin, for example by treatment with phosphorus trichloride or bromide.

The compounds of formula (lib) are known or can be prepared in a manner known per se.

The compounds of the formula (IIIa) can be prepared from compounds of the formula (IV) by oxidation analogously to process a).

The starting compounds of the formula (III) and their 6-halo derivatives are known or can be prepared in a manner known per se.

The starting compounds of the formula (IV) can be prepared in a manner known per se, for example by adding to a compound of the formula

(0). C = N

(V)

^R 2

(VI)

R 2

2301 53 7

in which the index η has the value O or 1, R represents an esterified carboxyl group, for example chlorine, iodine or especially bromine, the group ^R 1 ~ ^CH 2 ~ ^analo S in one of the processes mentioned under b) for the preparation of compounds of the formula ( IYa). If a compound of the formula (V) is used as the starting material, the anion is preferably prepared using potassium carbonate in dimethylformamide, for example in accordance with P, H. Bentley and JP Clayton, J, CS Chem. Comm. 1974, p. 278.

The compounds of the formulas (V) and (VI) are known or can be prepared in a manner known per se.

The compounds of the present invention are characterized by an excellent β-lactamase-inhibiting activity, for example, in vitro by the inhibition of β-lactamases from Staphylococcus auraus, Enterobacter cloacae, Psaudomonads, Morganella morganii, Sscherichia coli, Haemophilus influenzae and Bacteroides fragilis can be detected. In particular, the preferred compounds are characterized by an I. (concentration of the test substance which inhibits 50% of the β-lactamase) from about 1.2 to 0.026 μM.

Because of this β-lactamase inhibiting action, the compounds of the present invention enhance the effect of β-lactani- canibiotics in vitro and in vivo , as can be seen by comparing the antibiotic effects of compounds of the present invention and β-lactam antibiotics alone and in combination , For example, in vitro, the MIC values are 1: 1 combinations of the compound according to the invention of the formula (I) in which R _{1 is} hydroxy and R "is carboxy, or the sodium salt thereof with ampicillin, cefsulodin (CGP7174 / E) or cefotiam (CGP14221 / E) against a number of the above-mentioned β-lactamase-producing microorganisms significantly lower than the MIC values of the individual compounds. In vivo, for example, in subcutaneous administration to mice, the

infected with β-lactamase producing microorganisms, e.g. with Escherichia coli 205R TEM or Morganella morganii 2359, a significant decrease in ED values was observed over those of the individual components. Some values are listed in the following table:

infecting microorganism sc ED ₅₀ (mg / kg, mouse) 100 100 B A + B-Cl: l) Esch.coli: 205 RT Morganella raorg. 2359 A 70 75 14 18

A = (3R, 5R, 6R) -2., 2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid

1,1-dioxide sodium salt B = cefotiam.

The β-lactamae-inhibiting compounds of the present invention, including their pharmaceutically acceptable Saiza, are thus of value in the treatment of human and animal infections caused by β-lactamase-producing microorganisms and in their control β-lactamase. sensitive antibiotics are used. The active compounds of the present invention can be administered either before or in particular simultaneously with the actually active antibiotic. The dose of β-lactamase inhibitors according to the invention is about 1/10 to about 10 times, in particular about 1/5 to about 5 times, the amount of antibiotic to be used.

The pharmacologically useful compounds of the present invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient according to the invention, either alone or in admixture with

Inorganic or organic, solid or liquid, pharmaceutically acceptable excipients and optionally a .beta.-lactam antibiotic which may be added to the oral or parenteral, i. intramuscular, subcutaneous or intraperitoneal administration.

The pharmacologically useful compounds of the present invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient according to the invention, either alone or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable excipients and optionally a β-lactam antibiotic which for oral or parenteral, ie intramuscular, subcutaneous or intraperitoneal administration.

For the preparation of pharmaceutical preparations containing, in addition to a β-lactamase inhibiting compound of the present invention, another β-lactam antibiotic, any antibiotics containing the β-lactam structure may be used, with penicillin, cephalosporin, and further penicillin antibiotics which are unstable to β-lactamases are preferred.

Suitable penicillins and cephalosporins can be found in the abstract publications of EH Flynn, Cephalosporins and Penicillins, Academic Press, New York and London, 1972, ".G. Samtnes, Chem. Rev., 1976, Vol. 1, pages 113-155, J.Cs. Jäszberenyi and Τ.Ξ. Gunda, Progr. Med. Chem., Vol. 12, 1975, pages 395-477, J. Elks, Recent Advances in the Chemistry of β-lactam antibiotics, The Chemical Society, Burlington House, London WIV OBN, 1977, p Merck Index, 9th Ed, Merck h Co., Inc., Rahway, NJ, USA ', 1976, and the Encyclopaedia of Antibiotics, sec. Ed., John Wiley the Sons (1978).

Suitable penicillins are, for example, penicillin V (for example as potassium salt), benzylpenicillin (for example as potassium or sodium salt), propicillin (for example as potassium salt), epicillin, cyclacillin, azidocillin or penicillins from the group of optionally substituted a-aminobenzylic penicillins, eg. third Ampicillin, amoxicillin, apalcillin, pirbenicillin, hetacillin, metampicillin or 4-acetoxyampicillin.

Suitable penicillins are also those from the groups of the carboxypenillicillins, sulfopenicillins, ureidopenicillins, acylureidopenicillins and methylene aminopenicillins.

Examples of carboxy and sulfopenicillin groups include carbenicillin (sodium salt), carfecillin, indanylcarbenicillin, ticarcillin (disodium salt), and sulfocillin (sulbenicillin, e.g., disodium salt).

Ureidopenicillins and acylureidopenicillins suitable for said pharmaceutical mixtures are, for example, azlocillin, mezlocillin and furazlocillin and the 6β- [D-2 (4-A ~ 2,3-dioxo-1-piperazinocarboxamido) phenylacetamido-penicillanic acid wherein A is hydrogen or a substituent, in particular lower alkyl , eg Methyl or ethyl. Particularly noteworthy is the piperacillin. The ureidopenicillins and acylureidopenicillins are preferably used as salts, in particular as sodium salts.

Suitable Methylenaminopenicilline are, for example, oß-d-Azacyclylmethylenaminoi penicillansäuren, in particular mecillinam and their salts, such as sodium salts, and Pivmecillinam.

Suitable cephalosporins are, for example, cefaclor, cefadroxil, cefamandole, cefamandol nafate; Cefaparol, cefatrizine, cefazolin, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam (as dihydrochloride), cefroxadin, cefsulodin, ceftezol, cephalexin, cephaloglycine, cephaloridine, cephalothin, cephapyrin (sodium salt), cepha-

230153 7

in, gefatriaxone, 7β- [2- (2-amino-thiazol-4-yl) -2- (2-carboxy-prop-2-yloxyimino) acetamido] -2-pyridinio-3-cephem-4-carboxylate ( GR 20263), 7β- [2- (2-aminothiazol-4-yl) -2-methoxyimino-acetamido] -3- (1-methyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid sodium al2 (SCE 1365 ), 7β- [2- (2-aminothiazol-4-yl) -2-syn-methoxyimino) acetamido] -3-acetoxymethyl-3-cephein-4-carboxylic acid (CGP 17845), 7β- [2- (2- Aminothiazol-4-yl) -2-syn-methoxyimino) acetamido] -3-acetoxymethyl-3-cephein-4-carboxylic acid pivaloyloxymethyl ester (optionally as hydrochloride (CGP 18658 / A)), 7β-l (2R) -2- [4 - ((2R) -2-amino-2-carboxyethoxycarbonylamino) phenyl] -2-hydroxyacetylaminoj-S-Cd-methyl-1H-tetrazole-S-yD-thiomethyl-S-cephem-4-carboxylic acid (sodium salt, CGP 17520). , as well as! -Oxacephalosporins, ζ B. 7ß- [2- (p-hydroxyphenyl) -2-carboxy-acetamido] -3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -l- dethia-l-oxa-3-cephem-4-carboxylic acid (disodium salt, LY 127935 or S 6059).

Suitable penem antibiotics are known from European Patent Application 3960 and include, for example, 6-R... 2-R_-penem-3-carboxylic acids wherein R is lower alkyl or hydroxy lower alkyl and R is hydrogen, optionally substituted lower alkyl or lower alkylthio, e.g. (SR) -j-hydroxymethylpenem-S-carboxylic acid and (5R, 6R) -6 - [(1R) -l-hydroxyethyl] -penic-3-carboxylic acid and its salts, for example the sodium salts.

In place of the free carboxylic acids of said β-lactam antibiotics or their salts, the usual physiologically cleavable esters, for example the pivaloyloxymethyl esters, acetoxymethyl esters, 1-Aethoxycarbonyloxymethyl- or ethyl ester or phthalidyl esters, in place of said free compounds and their pharmaceutically acceptable salts, Including the inner salts and hydrates, and in place of the salts mentioned also their free compounds are used in the mixture. The choice depends on the mode of administration, the desired pH and / or the desired concentration of a solution to be injected.

U i J J

The ratio of β-lactamase-inhibiting compounds of the "present invention to the actually effective antibiotic can vary widely in the pharmaceutical preparations according to the invention and is approximately between 1:10 to 10: 1, preferably 1: 5 to 5: 1, and is for example 3: 1, 2: 1, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5 or 1: 6. The penicillin and cephalosporin antibiotics are either in the otherwise übliehen'Mgege in the preparations processed, with a longer duration of action can be achieved, or in less than usual amount, but the amount should be such that the antibiotic activity is about the same as when the preparation is administered without the addition of ß-Lactamasehemmers.

Pharmaceutical preparations or combination preparations containing a β-lactamase inhibiting compound of the present invention optionally together with a β-lactam antibiotic may be prepared in the same manner as known for the β-lactam antibiotics alone. In the combination preparations, the addition of the β-lactamase-inhibiting compounds according to the invention takes place within the specified mixing ratios. In the combination preparations, the two active substances can either be homogeneously mixed or present next to each other in separate compartments.

Preferably, the ρ-pharmacologically active compounds of the present invention are used in the form of parenteral, e.g. intramuscular or intravenous, administrable or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, e.g. from lyophilized preparations containing the active substances alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for reuse

28.9.1981 APC07D / 230 153/7 59- 263 12

regulation of the osmotic pressure and / or buffer. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances are prepared in a conventional manner, for. Example by means of conventional solution or lyophilization, prepared and contain from about 0.1 % to 100%, in particular from about 1 % to about 50 %, lyophilizates up to 100% of the active compounds, compounds of formula I, in particular those in which Rp is a physiologically cleavable, esterified carboxyl group, ζ. B # pivaloyloxymethoxycarbonyl, may also be administered orally, ζ. Β. as granules in the form of capsules. The pharmaceutical preparations contain the active ingredient, or optionally the two active ingredients, optionally together with suitable excipients, in doses of about 0.05 g to about 1.0 g per dose unit.

Depending on the nature of the infection, the condition of the infected organism and, if appropriate, the. Antibiotic activity of the .beta.-lactam, daily doses of about 0.1 g to about 5 g are used for the treatment of warm-blooded animals weighing about 70 kg. In general, the dose for the combination preparations will be on the order of the dose in which the β-lactam antibiotic is used alone.

Certain compounds of the present invention synergistically enhance the antibiotic activity of some β-lactam antibiotics. In such cases, the dose may be reduced *

28.9.1981 APCO7D / 23O 153/7 59 263 12

Execution example

The following examples serve to illustrate the invention. Temperatures are given in degrees centigrade ^ DC means thin-layer chromatography »

- ό'ύ -

Example 1: (3R, 5R, 6R and 6S) -Z ^ -dimethyl-o-hydroxymethyl-penam-S-carboxylic acid diphenylmethyl ester

A solution of 1.0 g (2.12 mmol) of (3R, 5R, 6S) -2,2-dimethyl-6-iodo-penam-3-carboxylic acid diphenylmethyl ester in 25 ml of tetrahydrofuran is cooled to -78 ° and with 1.2 ml (2.12 mmol) of a 1.8 molar solution of methylmagnesium bromide in diethyl ether. After 10 minutes at -78 °, with good stirring, formaldehyde gas is passed over the solution. After 1/2 hour, a TLC sample indicates complete conversion. After 40 minutes, the reaction solution is neutralized with 0.4 ml of glacial acetic acid, diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on 100 g of silica gel with the solvent system toluene / ethyl acetate 2: 1 and a mixture of the 6R and 6S title compound in the ratio 2: 3,

TLC: silica gel, toluoL / ethylacatate Rf = 0.38 IR spectrum (CHCl): absorption bands at 2.79; 5.63; 5.73 a ',

Example 2: (1R, 3R, 5R, 6R) -, (IS, 3R, 5R, 6R) - and (IS, 3R, 5R, 6S) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1-oxide

A solution of 1.22 g (3 mmol) of a 2: 3 mixture of (3R, 5R, 6R) - and (3R, 5R, 6S) -2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid diphenylmethyl ester in 30 ml of chloroform is cooled to -6 ° and treated with 590 mg (3.09 mmol) of 90% m-chloroperbenzoic acid. After 20 minutes, the reaction solution is washed with aqueous sodium thiosulfate and aqueous sodium bicarbonate solution. The water phase is back-extracted twice with chloroform. The combined chloroform solutions are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is added to 45 g

Silica gel with the solvent system ToluoL / ethyl acetate 1: 2 chromatographed. The three title compounds were eluted in the order listed:

1. (1R, 3E, 5R, 6R) isomer: TLC: silica gel, toluene / ethyl acetate Rf = O, 23-

IR spectrum (CH CT "): absorption bands at 2.75; 2.94; 5:59; 5.69p _v ..

2. (1S, 3R, 5R, 6R) isomer: TLC: silica gel, toluene / ethyl acetate Rf = 0.21

IR spectrum (CH-Cl): absorption bands at 2.75 ;. 2.95; 5.57; 5,69μ.

3. (1S, 3R, 5R, 6S) isomer: TLC: silica gel toluene / ethyl acetate R f = 0.16;

Mp. 135 ° to 138 ⁰ C.

IR spectrum (CH ₇ Cl ₇ ): absorption bands at 2.76; 2.9; 5:58; 5.69 μ: ""

Example 3: [(3R, 5R , 6R) -2,2-dimethyl-6 -hydroxyethylpRaE-3-carboxylic acid diphenylmethacrylate l, 1-dioxide

a) 3, 81 g (9.22 mmol) of a mixture of (1R, 3R, 5R, 6R) - and (IS, 3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-4 -carboxylic acid diphenylmethyl ester 1-oxide are dissolved in 114 ml of chloroform and treated with 1.86 g (10.8 mmol) of 90% m-chloroperbenzoic acid at room temperature. After stirring for 1½ hours, it is worked up with aqueous sodium thiosulfate, aqueous sodium bicarbonate and aqueous sodium chloride solution. The aqueous phases are back-extracted twice with chloroform. The combined organic solutions are dried with sodium sulfate and concentrated on a rotary evaporator. The residue is dried under high vacuum and purified by chromatography on 38 g of silica gel with the solvent system toluene / ethyl acetate 3: 1. The title compound is obtained from Rf = 0.23 (silica gel, toluene / ethyl acetate). IR spectrum: (CHCl ₇ ): absorption bands at 2.78; 5:55; 5.68; 7.52 μν . . ·

230153

The same compound can also be obtained as follows:

b) 0.5 g (1.26 mmol) of (3R, 5R, 6R) -2,, 2-dimethyl-4-hydroxymethylpenam-4-carboxylic acid diphenylmethyl ester are dissolved in 13 ml of chloroform and treated with 0.5 g (2 , 6 mmol) 90% m-chloroperbenzoic acid at room temperature. After stirring for 1½ hours, it is worked up with aqueous sodium thiosulfate, aqueous sodium bicarbonate and aqueous sodium chloride solution. The aqueous phases are back-extracted twice with chloroform. The combined organic solutions are dried with sodium sulfate and concentrated on a rotary evaporator. The residue is dried under high vacuum and purified by chromatography on 10 g of silica gel with the solvent system toluene / ethyl acetate 3: 1. The title compound is obtained with the same analytical data as indicated under a).

Example 4: (3R, 5R, 6R> -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid 1,1-dioxide-sodium salt

a) 3.34 g (7.78 mmol) of (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid diphenylmethyl ester 1, 1-dioxide are dissolved in 100 ml of tetrahydrofuran, with 1 , 3 g Pd / C 10% and hydrogenated under atmospheric pressure at room temperature. After a reaction time of 6 hours, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. The residue is taken up in water / ethyl acetate and admixed with 653 mg (7.78 mmol) of sodium bicarbonate. The aqueous phase is extracted three times with ethyl acetate. The organic phases are washed twice with water. After lyophilization of the combined aqueous phases, the title compound is obtained as a white powder.

IR spectrum (KBr): absorption bands at 2.9; 5.63; 6.18; 7.19; 7.61 /. 1

The same compound can also be obtained as follows:

-SB-

b) A solution of 0.1 g (0.38 mmol) of (1R, 3R, 5R, 6R) -2,2'-dimethyl-6-hydroxymethyl-penain-S-carboxylic acid 1-oxide in 10 ml of water / tetrahydrofuran 1: 1 is offset with 80 mg (o, 41 mmol) of 90% m-chloroperbenzoic acid at Raumteniperatur. After 1 1/2 hours stirring is treated with aqueous sodium thiosulfate solution. The aqueous phase is adjusted to pH = 6.8 with 1 N sodium hydroxide solution and lyophilized. The title compound obtained is purified by chromatography on UP G ,, plates (eluent, H "0, Rf = 0.58).

c) The title compound is also analogous to b), starting from 0.1 g (0.37 mmol) of (1S, 3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid l-oxide sodium salt dissolved in 10 ml of water / tetrahydrofuran 1: 1.

d) A solution of 0.15 g (0.59 mmol) of (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid, sodium salt in 10 ml of water / tetrahydrofuran 1: 1 with ο, 172 g (0.88 mmol) of 90% m-chloroperbenzoic acid at room temperature. After stirring for 1 1/2 hours, it is mixed with aqueous sodium thiosulfate solution. The aqueous phase is adjusted to pH = 6.8 with 1 N sodium hydroxide solution and lyophilized. The title compound is purified by chromatography on UPC "plates (eluent, H ₂ O, R f = 0.58).

e) 821 mg (1.58 mmol) of (3R, 5R, 6R) -6-benzyloxymethyl-2,2-dimethylpenanr-3-carboxylic acid diphenylmethyl ester 1,1-dioxide are dissolved in 10 ml of tetrahydrofuran, with 400 mg of Pd / C 10% and hydrogenated under atmospheric pressure at room temperature. After a reaction time of 6 hours, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. The residue is taken up in water / ethyl acetate and adjusted to pH = 6.5 with aqueous saturated sodium bicarbonate solution. The aqueous phase is extracted three times with ethyl acetate, the organic phases are washed twice with water and, after lyophilization of the combined aqueous phases, the title compound is obtained as a white powder, the IR spectrum being identical to that of Example 4a).

230 1 53

Example 5: (3R, 5R, 6S) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide

A solution of 1.5 g (3.6 mmol) (1S, 3R, 5R, 6S) -2,2-dimethyl-6-hydroxymethyl-penam-3-carbonsaurediphenylmethyl ester 1-oxide in 45 ml of chloroform is stirred at room temperature 0.73 g of 90% m-chlorobenzobenzoic acid added. After stirring for 1 1/2 hours, it is worked up with aqueous sodium thiosulphate, aqueous sodium bicarbonate and aqueous sodium chloride solution. The aqueous phases are extracted twice with chloroform, the combined organic solutions are dried with sodium sulfate and concentrated on a rotary evaporator. The residue is dried under high vacuum and purified by chromatography on 16 g of silica gel with the eluent toluene / ethyl acetate 3: 1. The pure title compound is obtained.

TLC: silica gel, toluene / ethyl acetate 3: 1, Rf = 0.22; IR spectrum: absorption bands at 2.76; 5.55; 5.67 μ (CH-Cl ₉ ).

Example 6: (3R, 5R, 6S) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid 1,1-dioxide-sodium salt

A solution of 0.82 g (1.9 mol) (3R, 5R, 6S) -2,2-di-ethylethylhydroxymethyl-penam-S-carbonyldiphenylmethyl ester 1,1-dioxide in 25 ml of tetrahydrofuran is added in the presence of Pd / C 10% - hydrogenated under normal pressure at room temperature. 'After 8 hours of reaction time, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. The residue is taken up in water / ethyl acetate and slowly admixed with 1.9 ml of 1 N NaOH (pH - 6.9). The aqueous phase is extracted three times with ethyl acetate. After lyophilization of the water phase, the title compound is obtained as a white powder.

TLC: UPC _l2 plates, H ₃ O, Rf = 0.58; IR spectrum (KBr): absorption bands at 2.9; 5.63; 6.20 μ. '

Example 7: (1R, 3R, 5R, 6R) - and (lS, 3R, 5R, 6R) -2,2-dimethyl-o-tert- butyl-dim ethylsilyloxymethyl-penam-S-carboxylic acid diphenylmethyl ester -1-oxide

24.3 g (58.9 mmol) of a mixture of

(1R, 3R, 5R, 6R) - and (lS, 3R, 5R, 6R) -2 ^ -dimethyl-δ-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1-oxide are dissolved in 97 ml of dimethylformamide and at room temperature 18.31 g (117.8 mmol) of tert-butyldimethylchlorosilane (97% strength) and 16.2 g (235.6 mmol) of imidazole were added under nitrogen. After stirring for 70 minutes, it is diluted with ethyl acetate and the organic phase is washed three times with aqueous sodium chloride solution. The ethyl acetate solution is dried with sodium sulfate and concentrated on a rotary evaporator. The crude product is chrotnatographiert on 1.1 kg of silica gel with the eluent system toluene / ethyl acetate 5: 1. The two title compounds are eluiart in the order listed:

1. (1S, 3R, 5R, 6R) isomer TLC: silica gel, toluene / ethyl acetate 5: 1, R f = 0.54

IR spectrum (CH-Cl ₉ ): absorption bands at 3.42; 5.61; 5.71 μ,

2. (LR, 3R, 5R, 6R) isomer TLC: silica gel, toluene / ethyl acetate 5: 1 RF = 0.4

IR spectrum (CH Cl-): absorption bands at 3.42; 5.61; 5.71 μ.

Example 8: (IS, 3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1-oxide

A solution of 3.13 g. (5.9 mmol) (1S, 3R, 5R, 6R) -2,2-dimethyl-6-tert-butyl-dimethylsilyloxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1-oxide in a mixture of 46 ml of tetrahydrofuran, 93.9 ml of acetic acid and 31 ml of water is heated to 50 ⁰ C for 7 hours. The reaction solution is on a rotary evaporator

υ ι b ό 7

- se -

concentrated and the oily residue taken up in ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution. After drying the organic phase over sodium sulfate, the solution is concentrated on a rotary evaporator and the crude product was purified on 76 g of silica gel with the eluent system toluene / ethyl acetate 1: 1. The pure title compound is obtained. TLC: silica gel, toluene / ethyl acetate 1: 1, R f = 0.15; IR spectrum (CH ₂ Cl ₂ ): absorption bands at. 2.75 ;. · 2.95; 5.57; 5.68 μ.

The compound can be converted into the 1,1-dioxide analogously to Example 3.

Example 9: (1R, 3R, 5R, 6R) -2,, 2-Dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenyl methyl ester 1-oxide

Analogously to Example 8, the (1R, 3R, 5R, 6R) -2,2-dimethyl-otert.butyl-dimethylsiIyloxymethyl-penam-3-carboxylic acid diphenylmethy1-ester-1-oxide can be converted into the title compound. TLC: silica gel, toluene / ethyl acetate 1: 1, Rf = 0.16; IR spectrum (CH "C1): absorption bands at. 2.75; 2,95 ;, 5,59; 5.69 / i. -

Example 10: (IS, 3R, 5R, 6R) - 2, 2-Dimethyl-6-hydroxymethyl-penam-3-carboxylic acid 1-oxide sodium salt

A solution of 1.62 g (3.92 mmol) (1S, 3R, 5R, 6R) .- of 2, 2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1-oxide in 8 ml of tetrahydrofuran is hydrogenated after addition of 1.95 g Pd / C 10% at room temperature. After 5 hours, another 2 g of Pd / C 10% are added and while. Hydrogenated for another 22 hours. Then it is filtered through Hyflo and the clear solution on a rotary evaporator

concentrated. The residue is mixed with ethyl acetate and water.

Under pH measurement, 1N NaOH is slowly added dropwise until pH = 6.9. The ethyl acetate base is separated off and the aqueous phase is lyophilized, giving the sodium salt of the title compound as a white powder.

TLC: UPC plates, HO ₁ Rf = 0, .62;

IR spectrum (Nujol): absorption bands at 3.05; 5.60; 6th, 20th μ.

Example 11: (1R, 3R, 5R, 6R) -2., 2-Dimethyl-o-hydroxymethyl-penam-3-carboxylic acid

A solution of 638 mg (1.54 mmol) of (2R, 3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenyin-ethyl ester in 8 ml of tetrahydrofuran is added after addition of 766 mg of Pd / C hydrogenated 10% at room temperature. To. 23 hours is added 766 mg d / C 10%, followed by further hydrogenation for 7.5 hours. The reaction solution is filtered through Hyflo and concentrated on a rotary evaporator. The residue crystallizes from methylene chloride, TLC: UPC ₂ plates, H ₂ O, R f = 0.64; IR spectrum (Nujol): absorption bands at 2.8; 5.60; 5.75 u.

Example 12: (3R, 5R, 6R) -2,, 2-Dimethyl-6-tert-butyl-dimethylsilyloxymethyl-penam-3-carboxylic acid diphenyl methacrylate

a) A solution of 4.0 g (7.59 mmol) of (1S, 3R, 5R, 6R) -2,, 2-dimethylol-tert-butyl-dimethylsilyloxymethyl-penatrrO-carboxylic acid diphenylmethyl ester 1-oxide in 80 ml Methylene chloride and 20 ml of dimethylacetamide are added at 0 ° C under N with 2.8 ml (30.36 mmol) of phosphorus tribromide. After a reaction time of 30 minutes, cooled sodium bicarbonate solution is added. The organic phase is separated, washed twice with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solution is

evaporated and the residue chromatographed on 45 g of silica gel with the solvent system toluene / ethyl acetate 10: 1. TLC: silica gel, toluene / ethyl acetate 10: 1, Rf = 0.61; IR spectrum (CH-Cl ₂ ): absorption bands at 3.4; 5.64; 5,72u.

b) The same title compound is obtained analogously to a) starting from (1R, 3R, 5R, 6R) -2,, 2-dimethyl-6-tert-butyl-dimethylsilyloxymethylpenam-3-carboxylic acid diphenylmethyl ester 1-oxide.

Example 13: (3R, 5g, 6R) .- 2, 2-Dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenyl methyl ester

a) A solution of 3.4 g (6.65 mmol) of (3R, 5R, 6R) -2,, 2-dimethylol-tert-butyl-dimethylsilyloxymethyl-penam-S-carboxylic acid diphenylmethyl ester in a mixture of 52 ml of tetrahydrofuran , 105 ml of acetic acid and 35 ml of water is heated to 50 ⁰ C for 7 hours. The reaction solution is concentrated on a rotary evaporator and the oily residue is taken up in ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution and twice with saturated sodium chloride solution. After drying the organic phase over sodium sulfate, the solution is concentrated on a rotary evaporator. The crude product is on 50 g of silica gel with the eluent system toluene / ethyl acetate 2: 1 g-purified. To give the title compound of melting point 120.5 ⁰ C.

TLC: silica gel, toluene / ethyl acetate 2: 1, Rf = 0.37; IR spectrum (CH-Cl): absorption bands at. 2.8; 5.65; 5,7 u.

b) The same compound can also be obtained as follows: A solution of 4.4 g (9.2 mmol) (3R, 5R, 6R) -6-bromo-2,2-dimethyl-6-hydroxymethyl-penam-3 -carboxylic acid diphenylmethyl ester in 40 ml of toluene and 3.2 ml (12 mmol) of tributyltin hydride is heated at 80 ° under nitrogen atmosphere for 2.5 hours. Then the reaction

230153

-yf-

concentrated and the residue crystallized from hexane. After recrystallization from methylene chloride / hexane gives the title compound.

c) The title compound is obtained in an analogous manner as described under b), also starting from (3R, 5R, 6S) -6-bromo-2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid diphenylmethyl ester.

Example 14: (SR ^ R ^ RX-Z ^ HDimethyl-o-hydroxymethyl-pena-S-carboxylic acid sodium alz

A solution of 1.9 g (4.98 mmol) of (3R, 5R, 6R) -2,, 2-dimethyl-hydroxymethyl-penam-S-carboxylic acid diphenylmethyl ester in 82 ml of tetrahydrofuran is added after addition of 2.1 g of Pd / C hydrogenated 10% at room temperature. After 16 hours and 24 hours still 2.1 g Pd / C 10% are added. After a total reaction time of 40 hours, the hydrogenation mixture is filtered through Hyflo and concentrated on a rotary evaporator. The oily residue is taken up in water / ethyl acetate and treated carefully with 2.7 ml of 1N NaOH (pH 6.9). The aqueous phase is extracted three times with ethyl acetate and then lyophilized. The title compound is obtained as a white powder.

TLC: UPC ₁₂ plates, H ₂ O, R f = 0.45;

 IR spectrum (Nujol): absorption bands at 2.93; 5.63; 6.27 / i.

Example 15 : (3R, 5R, 6R and 6S) -6-bromo-2,2-dimethyl-6-hydroxymethyl- penam-3-carboxylic acid diphenylmethyl ester

A solution of 50 g (3R, 5R) -6,6-dibromo-2,2-dimethyl-penam-3-carboxylic acid diphenylmethyl ester in 370 ml of tetrahydrofuran is cooled to -78 ° and treated with 52.2 ml (95 mmol) of a 1.82 molar solution of methylmagnesium bromide in diethyl ether. After 10 minutes at -78 °, with good stirring, formaldehyde gas is passed over the solution.

230153 7

- 3 - 60 -

After 2 hours, a TLC sample indicates complete conversion. 25 ml of glacial acetic acid are added and the solution is concentrated on a rotary evaporator. The residue is then taken up in ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on 480 g of silica gel with the solvent system toluene / ethyl acetate (6: 1). . A mixture of the title compounds in the ratio 3 (6R): 1 (6S).

(6R) -isomer: TLC: silica gel, toluene / ethyl acetate (6: 1) Rf = 0.36 IR spectrum (CH ClJ: 5.70 μ, mp: 144 ° -146

IR spectrum (CH Cl): absorption bands at 2.75; 5.57;

(6S) isomer: TLC: silica gel, toluene / ethyl acetate (6: 1), R f = 0.30 IR spectrum (CH Cl ₂ ): absorbance bands at 2.75; 5.57; 5,7Oji. Mp .: 158 ° -161 °.

Example 16 : (3R, 5R, 6R) -2,2-Dimethyl-6-hydroxymethyl-penam-3-carboxylic acid 1,1-dioxide

a) 2 g (4.66 mmol) of (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide in 20 ml of tetrahydrofuran is treated with 1 g of Pd / C 10% and under normal pressure, hydrogenated at room temperature. After one hour of reaction time, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. The residue is crystallized from methylene chloride / cyclohexane. The title compound of mp. 150 ° (decomposition) is obtained.

b) The same compound can also be obtained as follows:

2 g (3.86 mmol) of (3R, 5R, 6R) -6-benzyloxymethyl-2,2-dimethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide are dissolved in 20 ml of tetrahydrofuran, with 1 g of Pd / C 10% and one hour less than normal

hydrogenated at room temperature. After a reaction time of 16 hours, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator. The residue is crystallized from methylene chloride / cyclohexane.

Example 17 : (3R, 5R, 6R) -6-Benzyloxymethyl-6-bromo-2, 2-dimethylpenam-3-carboxylic acid diphenylmethyl ester

a) A solution of 10 g (19 mmol) of (3R, 5R) -6,6-dibromo-2,2-dimethylpenanr-3-carboxylic acid diphenyl ethyl ester in 50 ml of tetrahydrofuran is cooled to -30 ° and slowly added with 10.4 ml (19 mmol) of a 1.8 molar solution of methylmagnesium bromide in diethyl ether. After 5 minutes at -30 °, 5.2 ml (38 mmol) of benzyl chloroethyl ether are added. The reaction mixture is stirred for one hour at -30 ° and then heated to 0 ° within a 3/4 hour. The solution is then concentrated on a rotary evaporator, the residue taken up in ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on 130 g of silica gel with toluene as the eluent. Obtained after evaporation of the solvent, the title compound.

TLC: silica gel, toluene, Rf = 0.16

IR spectrum (CH Cl ₂ ): absorption bands at 3.45; 5.60; 5.74; 6.28 y.

b) The same compound can also be prepared as follows: A solution of 5 g (9.5 mmol) of (3R, 5R) -6,6-dibromo-2,2-dimethyl-penam-3-carboxylic acid diphenylmethyl ester in 25 ml of tetrahydrofuran is cooled to -78 ° and slowly treated with 5 ml (9.5 mmol) of a 1.9 molar solution of methylmagnesium bromide in diethyl ether. After 5 minutes at -78 °, 3.8 g of benzyl bromomethyl ether are added. The reaction mixture is warmed to room temperature within 40 minutes and then concentrated on a rotary evaporator. The residue is in

Aethylacetat and washed with aqueous sodium bicarbonate solution and brine. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on 70 g of silica gel with toluene as the eluent. The physico-chemical data of the title compound obtained are identical to those mentioned under a).

Example 18 : (3R, 5R, 6R) -6-Benzyloxymethyl-2,2-dimethyl-penam-3-carboxylic acid diphenyl methacrylate

A solution of 2.4 g (4.24 mmol) of (3R, 5R, 6R) -6-benzyloxymethyl-6-bromo-2,2-dimethyl-penam-3-carboxylic acid diphenylmethyl ester and 1.5 ml (5, 6 mmol) of tributyltin hydride in 20 ml of toluene under nitrogen atmosphere

heated to 82 ° for 80 minutes. Then, the reaction mixture is concentrated, and the residue is crystallized from isooctane. Nach.ümkristallisation from methylene chloride / isooctane gives the title compound of mp. 78 ° -8O °.

TLC: silica gel, toluene / ethyl acetate (.20: 1), Rf = 0.27. IR spectrum (CHCl): absorption bands at 3.44; 5.65; 5.73 u.

Example 19 : (3R, 5R, 6R) -6-Benzyloxymethyl-2,2-dimethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide 1.68 g (3.45 mmol) (3R, 5R, 6R ) -6-Benzyloxymethyl-2,2-dimethyl-penam-3-cafbonsäure diphenylmethylester are dissolved in 16 ml of chloroform and treated with 1.43 g (8.3 mmol) of 90% m-chloroperbenzoic acid at room temperature. After 50 minutes, work up successively with aqueous sodium thiosulfate, aqueous sodium bicarbonate and aqueous sodium chloride solution. The aqueous phases are back-extracted twice with chloroform. The combined organic solutions are dried with sodium sulfate and concentrated on a rotary evaporator. The residue is dried under high vacuum and purified by preparative thin-layer chromatography with the solvent system ToluoiyAethylacetat (20: 1). The crystalline title compound of mp. 124 ° -126.5 °.

TLC: silica gel, toluene / ethyl acetate (20: 1), Rf = 0.52 IR spectrum (CH Cl): absorption bands at 3.45; 5.57; 5.71 μ.

Example 20 : (3R _> 5R, 6R) -6-bromo-2,2-dimethyl-6-methoxymethyl-penam-3-carboxylic acid diphenylmethyl ester <s>

A solution of 10 g (19 mmol) of (3R, 5R) -6,6-dibromo-2,2-dimethyl-penam-3-carboxylic acid diphenylmethyl ester in 50 ml of tetrahydrofuran is cooled to -78 ° and treated with 9.2 ml C9 mmol) methylmagnesium bromide in diethyl ether. After 5 minutes at -78 ", 2.82 ml of chlorodimethyl ether are added, the reaction is warmed to -20 ° and concentrated on a rotary evaporator after 95 minutes The residue is taken up in ethyl acetate and washed with aqueous sodium bicarbonate solution and brine The residue is chromatographed on 30 g of silica gel with toluene as the mobile phase, giving the pure title compound: TLC: silica gel, toluene / ethyl acetate (20: 1), R f = 0.34, IR spectrum (CH ₂ Cl ₂ ): absorption bands at 5.62, 5.73 y.

Example 21 ; (3R, 5R, 6R) -2,2-dimethyl-6-methoxymethyl-penain-3-carboxylic acid d-phenylmethyl ester

A solution of 7.45 g (15.1 mmol) of (3R, 5R, 6R) -6-bromo-2,2-dimethyl-6-methoxymethyl-penam-3-carboxylic acid diphenylmethyl ester and 5.22 nil (19, 7 mmol) of tributyltin hydride in 72 ml of toluene is heated to 82 ° under nitrogen atmosphere for 45 minutes. Then, the reaction mixture is concentrated and crystallized from hexane. After recrystallization from methylene chloride / hexane gives the title compound of mp. 84 °. - ·

TLC: silica gel, toluene / ethyl acetate (20: 1), Rf = 0.31. IR spectrum (CH ₉ Cl ₂ ): absorption bands at 5.63; 5.72 u.

Example 22 : (3R, 5R, 6R) -2,2-dimethyl-6-methoxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide

4.8 g (11.6 mmol) of (3R, 5R, 6R) -2,2-dimethyl-6-methoxymethyl-penam-3-carboxylic acid diphenylmethyl ester are dissolved in 48 ml of chloroform and at 35 ° with 5.5 g (28.9 mmol) 90% m-chloroperbenzoic acid, After 2.5 hours, worked up with aqueous sodium bisulfite solution and sodium bicarbonate solution. The aqueous phases are back-extracted twice with chloroform. The combined organic solutions are dried with sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethyl acetate / hexane to give the title compound of mp. 120-126 °. TLC: silica gel, toluene / ethyl acetate, R f = 0.29. IR spectrum (CHCl "): absorption bands at 5.55; .5.69 μ.

Example 23 : (3R, 5R, 6R) -2,2-dimethyl-6-methoxymethyl-penam-3-carboxylic acid 1,1-dioxide

4.7 g (10.6 mmol) of (3R, 5R, 6R) -2,2-dimethyl-6-methoxyme'thyl-penain-3-carboxylic acid diphenylmethyl ester lj-dioxide are dissolved in 52 ml of tetrahydrofuran, with 2 g Pd / C 10% and hydrogenated under atmospheric pressure at room temperature. After one hour of reaction, the catalyst is filtered off and the filtrate is concentrated on a rotary evaporator The residue is crystallized from ethyl acetate / hexane to give the title compound of mp 145 ° C. TLC plates: water / acetonitrile (95: 5). , Rf = 0.37 IR spectrum (CH Cl): absorption bands at 5.55, 5.75, 7.5 ^ u.

Example 24 : (3R, 5R, 6R) -2,2-Dimethyl-6-methoxymethyl-penam-3-carboxylic acid 1'-ethoxycarbonyloxyethyl ester 1,1-dioxide

12 g of sodium iodide are dissolved in 37 ml of acetone and treated with 2.75 ml of ethyl-1-chloroethyl carbonate. The mixture is stirred at room temperature for 3 hours. The solution is then added dropwise to 150 ml of methylene chloride and precipitated from the precipitated inorganic salts.

filtered. The methylene chloride solution is concentrated to 10 ml and concentrated at 0 ° to a solution of 2.5 g (8.05 mmol) (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3 -carboxylic acid 1, 1-dioxide-natriunisalz in 40 ml of dimethylacetamide. The mixture is then stirred for 3 hours at 0 °, then diluted with ethyl acetate and washed three times miö • water.'Die organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The crude product is purified on 30 g of silica gel with the eluent system toluene / ethyl acetate (2: 1) to give the title compound as a white foam: TLC: silica gel, toluene / ethyl acetate (2: 1), R f = 0.48 IR. Spectrum (CH Cl): absorption bands at 2.75, 5.55, 5.65 u.

Example 25 : (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid pivaloyloxymethyl ester 1,1-dioxide 6 g of sodium iodide are dissolved in 20 ml of acetone and treated with 1.5 ml of pivaloyl chloroethyl ! ester. The mixture is stirred at room temperature for 3 hours and then added dropwise to 75 ml of methylene chloride. The precipitated inorganic salts are filtered off. The methylene chloride solution is concentrated to 1 ml and added to a solution of 1.3 g (4 mmol) of (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid 1-l-dioxide sodium salt in 20 ml of N, N-dimethylacetamide at 0 °. The mixture is then stirred for 3 hours at 0 °, 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 mixed with 30 g of silica gel. the eluent system 'toluene / ethyl acetate (3: 1). The title compound is obtained as a white foam, TLC: silica gel, toluene / ethyl acetate (3: 1), R f = 0.2; IR spectrum (CH ₂ Cl ₂ ): absorption bands at 2.75; 5:55; 5.62; 5.68 μ. Example 26: (3R, 5R, 6R) -2,2-dimethyl-6-benzyloxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide

A solution of 237 g (0.487 mol) of (3R, 5R, 6R) -2,2-dimethyl-6-benzyloxymethyl-penam-3-carboxylic acid diphenylmethyl ester in 237 ml of tetrahydrofuran and 1 1 of glacial acetic acid are mixed with 169.4 g of potassium permanganate .

wherein the reaction temperature rises to 36 °. At this temperature for 2 3/4 hrs. Stirred, whereupon successively 100 ml of hydrogen peroxide solution (30%) and 4 1 of water are added. The precipitated title compound is washed with water, dissolved in ethyl acetate and washed successively with water, aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulfate and purified with activated charcoal. The title compound obtained is purified by crystallization from ethyl acetate / hexane.

Example 27: (3R, 5R, 6S and 6R) -2,2-dimethyl-6-bromo-6-hydroxymethyl- p-pentam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide

A solution of 30 g (53.7 mmol) of (3R, 5R) -2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide in 150 ml of tetrahydrofuran is added Cooled and mixed with 28.2 ml (53.7 mmol) of a 1.9 M solution of methylmagnesium bromide in diethyl ether. After 10 minutes at -78 °, formaldehyde gas is passed over the solution with stirring. After 2 hours, 25 ml of glacial acetic acid are added and the solution is concentrated on a rotary evaporator. The residue is taken up in ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on 250 g of silica gel with the solvent system toluene / ethyl acetate 6: 1 to give a mixture of the title compounds. Mixture: TLC: silica gel, ToI./Aethyl acetate 6: 1 Rf = 0.28 IR spectrum (CH ₂ Cl ₂ ): Absorbance bands at 2.74; 5.53; 5,7 u.

Example 28: - (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide

A solution of 25 g (49.2 mmol) of a mixture of (3R, 5R, 6S and 6R) -2,2-dimethyl-6-bromo-6-hydroxymethyl-penam-3-carboxylic acid diphenylmethyl ester-1,1- dioxide and 15.7 ml (59 mmol) of tributyltin hydride in 250 ml of toluene is heated to 80 ° under nitrogen atmosphere for 2.5 hours. The reaction mixture is concentrated and the residue

crystallized from tetrahydrofuran / hexane. Mp. 70 ⁰ -75 ⁰ ..

Example 29: (3R, 5R, 6R) -2,2-Dimethyl-6-bromo-6-benzyloxymethyl-penaII- 3-carboxylic acid di- phenyl-ethyl ester-1,1-dioxide.

A solution of 5 g (8.96 mmol) of (3R, 5R, 6S and 6R) -2, 2-dimethyl-6-, 6-dibromo-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide in 25 ml Tetrahydrofuran is cooled to -78 ° and slowly treated with 4.7 ml (8.96 mmol) of a 1.9 molar solution of methylmagnesium bromide in diethyl ether. After 5 minutes at -78 °, 3.6 g of benzyloxymethyl bromide are added. The reaction mixture is warmed to room temperature over 40 minutes and then concentrated on a rotary evaporator. The residue is taken up in A. ethyl acetate and washed with aqueous sodium bicarbonate solution and brine. The organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on 70 g of silica gel with toluene and the title compound is obtained. TLC: silica gel, toluene, R f = 0.13 IR spectrum (CH Cl): absorption bands at 5.53; 5.74 u.

Example 30: (3R, 5R, 6R) -2'-dimethyl-o-benzyloxymethyl penatn-S-carboxylic acid diphenylmethyl ester 1,1-dioxide. , , - -----

A solution of 2.4 g (4 mmol) of (3R, 5R, 6R) -2,2-dimethyl-6-bromo-6-benzyloxymethyl-penam-3-carboxylic acid diphenylmethyl ester 1,1-dioxide and 1.5 ml (5.6 mmol) Tributylzinnhydrid'in 20 ml of toluene is heated under nitrogen atmosphere for 80 minutes at 82 °. Then, the reaction mixture is concentrated and the residue is crystallized from isooctane. After recrystallization from ethyl acetate / hexane gives the title compound of mp. 119-123 °

TLC: silica gel, toluene / ethyl acetate 6: 1, R f = 0.52 IR spectrum (CH ₀ Cl): absorption bands at 3.44; 5.57; 5.73 / i.

Pharmaceutical preparations

Example A Dry Ampoules or Vials Containing 1 g (3R, 5R, 6R) .- 2, 2-Dimethyl-6-hydroxymethylpenam-3-carboxylic acid 1,1-dioxide sodium azide as active substance are prepared as follows:

Composition (for 1000 ampoules or vials):

Active substance 1 000 g

• ι loo g

The components are mixed homogeneously and each 1.1 g of the mixture is filled under aseptic conditions in an ampoule or a vial. The ampoules or vials are closed and tested.

In the same way are ampoules or vials with

corresponding amounts of other active ingredient components according to the invention.

Example B Drug vials or vials containing 2 g of (3R, 5R, 6R) -2,2-dimethyl-δ-hydroxymethylpenam-S-carboxylic acid 1,1-dioxide sodium salt as active substance A and 0.2 g of cefotiam as active substance B. are prepared as follows: Composition (for 1000 ampoules or vials):

Active substance A '1 000 g

Active substance B 100 g

Mannitol 100 g

1 200 g

The components are mixed homogeneously and depending. 2.4 g of the mixture is filled under aseptic conditions into an ampoule or a vial. The vials or vials are closed and tested.

In the same way are ampoules or vials with

corresponding amounts of other active ingredient components according to the invention.

Example C Containing dry ampoules or vials. 2.0 g (3R, 5R, 6R) .- 2., 2-Dimethyl-6-hydroxymethylpenaiii-3-carboxylic acid 1,1-dioxide sodium salt as active substance A and 0.4 g of cefotiam as active substance 3 are as follows manufactured:

Composition (for 1000 ampoules or vials):

Active substance A 2 000 g

Active substance B 400 g

Mannitol . 200 g

2 600 g

The components are mixed homogeneously and depending. 2.6 g of the mixture under aseptic conditions in an ampoule or vial filled. The ampoules or vials are closed and tested.

In the same way ampoules or vials are prepared with appropriate amounts of other active ingredient components according to the invention.

Example D Dry ampoules or vials containing 2 g (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethylpenani-3-carboxylic acid 1,1-dioxide sodium salt as active substance A and 1 g of cefotiam as active substance B (2: 1 ) are made as follows:

Composition (for 1000 ampoules or vials):

Active substance A active substance B mannitol

3 300 g

2 000 G 1 000 G 300 G

230 153 7

The components are mixed homogeneously and each 3.3 g of the mixture is filled under aseptic conditions in an ampoule or vials. The ampoules or vials are closed and tested.

In the same way, ampoules or vials are prepared with appropriate amounts of other active ingredient components of the invention.

Example E Dry ampoules or vials containing 1 lb (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid 1,1-dioxide sodium salt as active substance A and 1 g of cefotiam as active substance B. made as follows:

Composition (for 1000 ampoules or vials) :.

Active substance A 1 000 g

Active substance B 1 000 g

Mannitol 200 g

2 20Og

The components are mixed homogeneously and filled into 2.2 g of the mixture under aseptic conditions in an ampoule or vial. The ampoules or vials are closed and tested.

In the same way, ampoules or vials are prepared with appropriate amounts of other active ingredient components according to the invention.

Example F Dry ampoules or vials containing 1 g (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid 1,1-dioxide sodium salt as active substance A and 3 g of cefotiam as active substance B are as follows manufactured:

b ό Ί

1 000 G 3 000 he σ 300 G

Composition (for 1000 ampoules or vials) .:

Active substance A active substance B mannitol

4 300 g

The components are mixed homogeneously and each 4.3 g of the mixture is filled under aseptic conditions in an ampoule or vials. The ampoules or vials are closed and tested.

In the same way ampoules or vials are prepared with appropriate amounts of other active ingredient components according to the invention.

Example G Dry ampoules or vials containing 0.25 g (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid sodium 1,1-dioxide sodium salt as active substance A and 1,25 g of cefotiam as active substance B are made as follows:

Composition (for 1000 ampoules or vials):

Active substance A 250 g

Active substance B 1 250 g

Mannit '. 200 g

1 700 g

The components are mixed homogeneously and each 1.7 g of the mixture is filled under aseptic conditions in an ampoule or vial. The ampoules or vials are closed and tested.

In the same way ampoules or vials are prepared with appropriate amounts of other active ingredient components according to the invention.

Example H Dry ampoules or vials contain 0.25 g (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethylpenam-3-carboxylic acid l, l-dioxide-sodium

230153 7

salt as active substance A and. 2.5 g of cefotiam as active substance B (1:10) are prepared as follows:

Composition (for 1000 ampoules or vials):

Active substance A 250 g

Active substance B 2 500 g

Mannitol 200 g

2 95Og

The components are mixed homogeneously and each 2.950 g of the mixture. Bottled under aseptic conditions in an ampoule or vial. The ampoules or vials are closed and tested.

In the same way ampoules or vials are prepared with appropriate amounts of other active ingredient components according to the invention.

Claims (9)

28.9.1981 APC07D / 230 153/7 59 263 12 Invention claim 1. A process for the preparation of 2,2-dimethyl-penam-3-carboxylic acid-1,1-dioxide compounds of the formula (D, wherein R _{1 represents} hydroxy or etherified or esterified hydroxy and Rp represents carboxyl or protected carboxyl, and salts of those compounds having a salt-forming group, characterized in that a) a compound of the formula (Ha), wherein R "and Rp have the meanings given under formula (I) and the index η is 0 or has, oxidized in the 1-position, or b) in a compound of the formula 28.9.1981 APC07D / 230 153/7 59 263 12 (Ha) wherein R- and R _{2 have} the meanings given under formula (I) and the index η has the value 0 or 1, oxidized in 1 »position, or b) in a compound of the Pormel CH. jf 0 ' CIIB) wherein Rp represents a protected carboxyl group, the group R ^ -CH ₂ - introduces, or c) in a compound of the Pormel -76 "- fs / H. ΌΗ. 28.9.1981 APCO7D / 23O 153/7 59 263 12 (Lic) in which R * and Rp have the meanings given under formula (I) and Y represents a group convertible to a hydrogen atom, the group Y is converted into a hydrogen atom and, if desired or necessary, in an available compound a group R. in a other group R- transferred, and / or a group R _? converted into another group Rp, and / or converts an available salt into the free compound or into another salt, and / or salified an available free compound having a salt-forming group, and / or a obtainable mixture of isomeric compounds of Formula (I) separates into the individual isomers. 2 »method according to item 1, characterized in that a compound of formula Vf - 28.9.1981 APC07D / 230 153/7 59 263 12 wherein R and R _{2 have} the meanings given under formula (I) and the indes η has the value 0 or 1, oxidized in the 1-position, and, if desired or necessary, in an available compound a group R in another group R _{1 is} converted, and / or a group Rp is converted into another group Rp, and / or an available salt is converted into the free compound or into another salt, and / or salted into an available free compound having a salt-forming group, and / or an available mixture of -isomeren connections of the formula (I) separates into the individual isomers. 3 · Process according to item I, characterized in that compounds of the formula (I) in which R-hydroxy, lower alkyloxy, ζ. For example, methoxy, phenyl-lower alkoxy, e.g. B. benzyloxy, lower alkanoyloxy, z. B. formyloxy or acetoxy, aminothiazolylcarbonyloxy, z. 2-amino-1,3-thiazol-4-ylcarbonyloxy, arainothiadiazolylcarbonyloxy, e.g. 5-amino-1,2,4-thiadiazol-3-yl-carbonyloxy, lower alkoxycarbonyloxy, carbamoyloxy, F-mono- or Ν, Ν-di-lower alkylcarbamoyloxy, e.g. B. N-methyl-carbamoyloxy or Ν, Ν-dimethylcarbamoyloxy, lower -n- 28 * 9.1981 APG07D / 230 153/7 59 263 12 alkanesulfonyloxy, ζ. For example, methanesulfonyloxy, arenesulfonyloxy, ζ. B. benzenesulfonyloxy or toluenesulfonyloxy, or hydroxysulfonyloxy (or a salt thereof, ζ. Das. Das- Hatriumsalz) and Rp carboxy or in physiologically cleavable form esterified carboxy, ζ »Β. Lower alkanoyloxymethoxycarbonyl, ζ. Acetyloxymethyloxycarbonyl or Pivaloyloxymethoxycarbonyl, Aminoniederalkanoylrnethoxycarbonyl, in particular 06-amino-lower alkano-oyloxymethoxycarbonyl, z. B »glycyloxymethoxycarbonyl, 1-valyloxy-methoxycarbonyl, L-leucyloxymethoxycarbonyl, phthalidyloxycarbonyl, z, B. 2-phthalidyloxycarbonyl, 4-crotonolactonyl or gamma-butyrolactone-4-yl, indanyloxycarbonyl; z. 5-indanyloxycarbonyl, or I-Aethyloxycarbonyloxyäthyloxycarbonyl, as well as the pharmaceutically acceptable salts of such "compounds containing a salt-forming group. 4. The method according to item 1, characterized in that compounds of the formula (I), wherein R represents hydroxy, methoxy or benzyloxy and Rp is carboxy, or the pharmaceutically acceptable salts thereof, manufactures * Process according to item 1, characterized in that compounds of the formula (I) in which R 1 is hydroxy are prepared. 6. The method according to item 1, characterized in that one produces compounds of formula (I) whose 6-position has the R-configuration. 7. The method according to item 1, characterized in that (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl - penain ~ 3-carbonsäurediphenylmethylester-1, 1-dioxide produces * Method according to item 1, characterized in that (3R, 5R, 6R) 2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid 1,1-dioxide-sodium salt is prepared » 9. A process according to item 1, characterized in that (3R, 5R, 6R) -2,2-dimethyl-6-hydroxymethyl-penam-3-carboxylic acid pivaloyloxymethyl ester 1,1-dioxide is produced,