DE2927004A1 - PENICILLANIC ACID 1,1-DIOXIDES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS AS MEDICINAL PRODUCTS - Google Patents

Description

BAYER AKTIENGESELLSCHAFT - £ - 5090 Leverkusen, Bayerwerk central area

Patents, trademarks and licenses Jo / klc

03,

Penicillanic acid-1,1-dioxide, its manufacture and their use as medicines

The present invention relates to penicillanic acid 1,1-dioxides, Process for their production and their use as pharmaceuticals in human and. Veterinary medicine, as feed additives and in particular their use as ß-lactamase inhibitors.

1,1-Dioxides of certain penicillanic acids, for example penicillanic acid 1,1-dioxide, are synthetically accessible and have been recommended as inhibitors of β-lactamases (Nature 2T8, 360 - 361; DE-OS 28 24 535).

The invention relates to new compounds of the general formula (I)

(D

CH-,

Le A 19 650

130022/0009

ORIGINAL INSPECTED

and their pharmaceutically acceptable salts, in which R. is hydrogen or an ester-forming radical,

R _{2 is} hydrogen, bromine, optionally substituted alkoxy, optionally substituted alkylthio, azido, optionally substituted alkyl, optionally substituted cycloalkyl, aryl, aralkyl, heterocyclyl, acyl, carboxyl or cyano,

R _{3 is} hydrogen, halogen, azido, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, aralkyl, aryl, optionally substituted alkylthio, heterocyclyl, acyl or a radical of the formula

^R 9

or

R- and R ₃ together for a radical of the formula O =,

^R 5. ^R <^ R ₄ -ON =, '^ NN = or ^ C =

^R 6 ' ^R 8

stand, but R ₂ and R ₃ cannot be hydrogen, azido or acyl at the same time,

130022/0009

R. optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, aryl or heterocyclyl,

R ₁ . Hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, aryl, heterocyclyl or optionally substituted alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl or aminosulfonyl,

R _fi acyl, hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, aryl or heterocyclyl or

R ₅ and Rg together with the nitrogen atom and optionally including further heteroatoms form a 4- to 7-membered heterocyclic ring,

R- and Rg hydrogen, optionally substituted Alkyl, aryl, optionally substituted cycloalkyl, Aralkyl or optionally substituted amino or together with the carbon atom to which they are attached bonded are a 3- to 7-membered carbocyclic or - including heteroatoms - heterocyclic ring and

R _g denotes hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, aryl, aralkyl, heterocyclyl or optionally substituted alkylsulfonyl.

130022/0000

X) RJGINAL. INSPECTED

Ar -

The ester-forming radicals R. are, for example, optionally substituted alkyl, optionally substituted aralkyl, aryl or heterocyclyl.

Under hydrogen R- and R-, is in particular that

Δ -ι

Understand hydrogen isotropic deuterium.

In the general formula (I), the optionally substituted alkyl R ₃ , R ₃ , R ₄ , R ₅ , & _g , R ₇ / R ₈ and R _g , straight-chain or branched alkyl with preferably 1 to 6, in particular 1 to 4 Carbon atoms. Optionally substituted methyl, ethyl, η- and i-propyl, n-, i- and t-butyl may be mentioned as examples.

Optionally substituted alkyl R. is for example C.-Cg-alkyl, preferably Cj-C ₃ -ADCyI, which can be substituted 1 to 3 times, preferably once, by the following substituents: halogen, preferably fluorine, chlorine, bromine and iodine , especially fluorine, chlorine and bromine; Amino; Mono-lower alkylamino, preferably! -! Ethylamino, ethylamino, especially methylamino; Di-lower alkylamino, preferably dimethylamines, diethylamino, especially dimethylamines; Pyrrolidyl; Piperidyl; HCO-NH-; Lower alkyl-CO-NH-, preferably CH ₃ -CO-NH-; H-CO-N (lower alkyl) -, PREFERREDSWSiSeH-CO-N (CH ₃ ) -, K-CO-N (C ₂ H ₅ ) -; Lower alkyl-CO-N (lower alkyl) -, preferably CH ₃ -CO-N (CH ₃ ); (Lower alkyl); ₂ C = N-; Lower alkyl-SO ₂ -NH-, preferably CH ₃ -SO ₂ -NH-, C ₂ H ₅ -SO ₂ -NH-, in particular CH ₃ -SO ₂ -NH-; Lower alkyl-SO ₂ -N (lower alkyl) -, preferably CH _{3 -SO 2} -N (CH ₃ ) -; HO-

Le A 19 650

130022/0009

ORIGINAL INSPECTED

-46-

SO ₂ -NH-y HO-SO ₂ -N (lower alkyl) -, preferably HO-SO ₂ -N- (CH ₃ ) -, HO-SO ₂ -N (C ₂ H ₅ ) -? Amidino? (Lower alkyl) ₂ -N-CH = N-, especially (CH ₃ ) ₂ N-CH = N-;

I N-CH = N-, guanido, nitro, azido, hydroxy, lower alkyl

5 oxy-, preferably CH ₃ -O-, C ₂ Hc-O-, in particular CH ₃ O-, H-CO-O-, _{lower alkyl-CO-0-, preferably CH 3} -CO-O, C ₂ H ₅ -C0-0-. (CH ₃ J ₃ C-CO-O-? Lower alkyl-O-CO-0-, preferably CH ₃ -O-CO-O-, C ₂ H ₅ -O-CO-O-, (CH ₃ J ₃ CO -CO-O-? H ₂ N-CO-O-? Lower alkyl-NH-CO-0-, preferably CH - NH-CO-O-, C ₃ H ₅ -NH-CO-O-, (lower alkyl) 2N-C0-0-, preferably (CH ₃ J ₂ N-CO-O-, (C ₂ H ₅ ) ₂ N-CO-O-,

-CO-O-, H ₂ N-SO ₂ -O-; Lower alkyl-NH-SO ₂ -O-, preferably CH ₃ -NH-SO ₂ -O-, C ₂ H ₅ -NH-SO ₂ -O-; (Lower alkyl) ₂ N-SO ₂ -O-, preferably (CH ₃ J ₂ N-SO ₂ -O-, (C ₂ H ₅ ) ^ - SO ₃ -O-; HOOC-, H ₃ N-CO-? (Lower alkyl) ₂ N-CO-, especially (CH ₃ J ₂ N-CO- and (C ₂ H ₅ J ₂ N-CO-; OHC-, HO-SO ₂ -O-, HS-; lower alkyl-S- , preferably CH ₃ -S-, CF ₃ -S-, C ₂ H ₅ -S-, (CH ₃ J ₂ CH-S-; lower alkyl-S-, preferably CH ^ -S-, C ₉ Hc-S- ? HOoS-; low-

0 0 0

alkyl-SO ₂ -, preferably CH ₃ -SO ₂ -, CF ₃ SO ₂ -, C ₂ H ₅ -SO ₂ -; the group H ₂ N-SO ₂ -? Lower alkyl-NH-SO ₂ -, preferably CH ₃ -NH-SO ₂ -, C ₂ H ₅ -NH-SO ₂ -; (Lower alkyl) ₂ N-SO ₂ , preferably

Γ N-SO ₀ -; the group HO-SO ₀ -S-; Preferred heterocyclyl

Le A 19 650

130022/0008

ORIGINAL INSPECTED

wise furyl, thienyl, pyridyl, 2-oxo-benzimidazolinyl; Lower alkylcarbonyl, especially acetyl; Benzoyl; Lower dialkylamino-lower alkoxycarbonyloxy, in particular dimethylamine- and diethylamino-C, -C2-alkoxycarbonyloxy; Morpholino, piperidino and pyrrolidino C .. C2 alkoxycarbonyloxy; Lower alkoxy-carbonylaitiino; Lower alkylcarbonylthio.

Optionally substituted cycloalkyl R ₂ , R ₃ , R ₄ , R ₅ , Rg, R ₇ , Rg and R _Q is mono-, bi- and tricyclic and preferably contains 3 to 10, in particular 3, 5 or 6 carbon atoms. Examples are optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, bicyclo- £ 2.2. XJ- heptyl, bicyclo- ^ 2.2.2_7-octyl and adamantyl called.

As optionally substituted aryl R ^, R- t R ₃ / R 4 / R _5, Rg / R7 / R ₈ and R _g represents aryl having preferably 6 to 10 carbon atoms in the aryl moiety. Optionally substituted phenyl or naphthyl may be mentioned as examples. Substituents in the phenyl ring are in the o, m or p position.

Optionally substituted aralkyl R ^, R-, R ₃ , ^R 4 ' ^R 5' ^R ₆ ' ^R 7' ^R 8 ^{and R} 9 are optionally substituted aralkyl or aralkoxy with preferably 6 or 10, in particular in the aryl part and / or alkyl part 6 carbon atoms in the aryl part and preferably 1 to 4, in particular 1 or 2 carbon atoms in the alkyl part,

Le A 19 650

130022/0009

- sr --4L-

wherein the alkyl part can be straight-chain or branched. Optionally substituted benzyl and phenylethyl may be mentioned as examples.

Optionally substituted heterocyclyl R ^, R ₂ / R ₃ R, R, Rg and R _g are heteroparaffinic, heteroaroxatic and heteroolefinic 5- to 7-membered, preferably 5- or 6-membered rings with preferably 1 to 3, in particular 1 or 2 identical or different heteroacomes. The heteroatoms are oxygen, sulfur or nitrogen. Examples are optionally substituted thienyl, furyl, oxazolyl, isxazolyl, thiazolyl, isothiazolyl, pyrrolyl, inidazolyl, pyrazolyl, oxdiazolyl, thiadiazolyl, triazolyl, sydncnyl, oxtriazolyl, thiatriazolyl, pyrydrazidinyl, tetrahydrazolyl, pyrydrazidinyl, tetrahydrazolyl, pyrydrazidinyl, thiatriazolyl, pyrydrazidinyl, , Piperidinyl, korpholinyl, pyronyl-2 and -4, 2-oxo-tetrahydrofuryl-5, and 2-oxo-2,5-dihydrofuryl-5. The abovementioned heterocycles can be fused with carbocyclic or other heterocyclic rings, in particular benzofused. As examples are

and (^ Tf ~ μΞ called.

The alkyl, cycloalkyl, aryl and aralkyl listed above can carry one or more, preferably 1 to 3, in particular 1 or 2, identical or different radicals R _1n .

The radicals mentioned are very particularly preferably unsubstituted or contain a substituent

^R 10

Le A 19 650

130022/0009

ORIGINAL INSPECTED

Heterocyclyl can carry one or more, preferably 1 to 3, in particular 1 or 2, identical or different radicals R _11. Heterocyclyl is very particularly preferably unsubstituted or contains a substituent R .. ₁ .

In the following statements, the term "lower alkyl" means everywhere, including in connection with others Atoms or groups (e.g. lower alkoxy, NCON (lower alkyl) etc.) straight or branched chain alkyl with preferably 1 to 6, in particular 1 to 4 carbon atoms. Optionally substituted are exemplary Methyl, ethyl, η- and i-propyl, n-, i- and t-butyl called. "Lower alkyl" can be represented by 1 to 5, in particular 1 to 3, identical or different halogen atoms, where as halogen atoms are preferably fluorine, chlorine and bromine, in particular fluorine and chlorine, be substituted. Examples are trifluoromethyl, chloro-di-fluoromethyl, Bromomethyl, 2,2,2-tri-fluoroethyl and pentafluoroethyl called.

R ₁ Q is preferably halogen, preferably fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine; Amino; Mono-lower alkylamino, preferably methylamine ethylamino, especially methylamino; Di-lower alkylamino, preferably dimethylamino, diethylamino, especially dimethylamine; Pyrrolidyl; Piperidyl; HCO-NH-; Lower alkyl-CO-NH-, preferably CH ₃ -CO-NH-; H-CO-N (lower alkyl) -,

Le A 19 650

130022/0009

ORlQJNAL INSPECTED

preferably HHZO-N (CH ₃ ) -, H-CO-K (C ₂ H ₅ ) -; Di-lower alkylamino-lower alkyl; Lower alkyl-CO-Ni-lower alkyl) -, preferably CH ₃ -CO-N (CH ₃ ); (Lower alkyl) ₂ C = N-; Lower alky1-SO ₂ -NH-, preferably CH ₃ -SO ₂ -NH-, C ₂ H ₅ -SO ₂ -NH-, in particular CH ₃ -SO ₂ -NH-; Lower alkyl-SO ₂ -N (lower alkyl) -, preferably CH _{3 -SO 2} -N (CH ₃ ) -; HO-SO ₂ -NH-; HO-SO ₂ -N (lower alkyl) -, preferably HO-SO ₂ -N- (CH ₃ ) -, HO-SO ₂ -N (C ₂ H ₅ ) -; Amidino; (Lower alkyl) ₂ -N-CH = N-, especially (CH ₃ ) ₂ N-CH = N-;

n-CH = N-, guanido, nitro, azido, hydroxy, lower alkyl

oxy-, preferably CH ₃ -O-, C ₂ H-O-, in particular CH ₃ O-, H-CO-O-, _{lower alkyl-CO-0-, preferably CH 3} -CO-O, C ₂ H ₅ -CO-O-, (CH ₃ J ₃ C-CO-O-; lower alkyl-O-CO-0-, preferably CH ₃ -O-CO-O-, C ₂ H ₅ -O-CO-O-, (CH ₃ J ₃ CO-CO-O-; H ₂ N-CO-O-; lower alkyl-NH-CO-0-, preferably CH ₃ -NH-CO-O-, C ₂ H ₅ -NH-CO- O-, (lower alkyl) ₂ N-CO-O-, preferably (CH ₃ J ₂ N-CO-O-, (C ₂ H ₅ ) ₂ N-CO-O-,

[^ N-CO-O-, H ₂ N-SO ₂ -O-; Lower alkyl-NH-SO ₂ -O-, preferably CH ₃ -NH-SO ₂ -O-, C ₂ H ₅ -NH-SO ₂ -O-; (Lower alkyl) ₂ N-SO ₂ -O-, preferably (CH ₃ J ₂ N-SO ₂ -O-, (C ₂ H ₅ J ₂ N-SO ₂ -O-; HOOC-, H ₂ N-CO- ; (Lower alkyl) ₂ N-CO-, especially (CH ₃ J ₂ N-CO- and (C ₂ H ₅ J ₂ N-CO-; OHC-, HO-SO ₂ -O-, HS-; lower alkyl-S -, preferably CH ₃ -S-, CF ₃ -S-, C ₂ H ₅ -S-, (CH ₃ J ₂ CH-S-; lower alkyl-S-, preferably CH, -S-, C ₃ He-S -; HO, S-; low-

It ·> Il ^{A 3} Il ^J

0 0 0

alkyl-SO ₂ -, preferably CH ₃ -SO ₂ -, CF ₃ SO ₃ -, C ₃ H ₅ -SO ₂ -; the group ^ N-SO ₂ -; Lower alkyl-NH-SO ₂ - # preferably

Le .A 19 650

130022/0009

ORIGINAL INSPECTED

CH ₃ -NH-SO ₂ -, C ₂ H ₅ -NO-SO ₂ -; (Lower _{alkylJ 2} N-SO ₂ - / preferably (CH ₃ ) ₂ N-SO ₂ -, (C ₂ H ₅ I ₂ N-SO ₂ ^;

Q \ -SO ₂ -; the group HO-SP ₂ -S-; straight-chain or branched alkyl with 1 to 6 carbon atoms, in particular methyl, ethyl, propyl * isopropyl, η-butyl, sec-butyl or tert-butyl, preferably methyl; and phenyl or phenoxy. ":;, .. ^; / '

As substituents of the alkyl groups R ₂ and R ₃ come. also oxo and groups of the formulas R ₄ -ON =,

Rr '

wherein R _4, R ^ and R * ₆ are as defined ^{#: questioned:;} /..■: - -; ' ^: , ■. - ■ -, .-. ' ^: _-:; '

In the event that R _{11 is} on one or more carbon atoms in the heterocyclyl, R is preferably lower alkyl, preferably methyl, ethyl, isopropyl, in particular methyl; the trifluoromethyl group; Halogen, preferably fluorine, chlorine, bromine; Amino; Lower alkylamino, preferably CH ₃ -NH-, C ₂ H ₅ -NH-; Di-lower alkylamino, preferably (CH ₃ ) 2 ^ -f (C ₂ Hg) ₂ N-; Formylamino; Acetylamino; CH ₃ -O-CO-NH-, C ₂ H ₅ O-CO-NH-; CH ₃ -SO ₂ -NH-; Hydroxy; Methoxy, ethoxy; Methylthio, ethylthio; CH ₃ -SO ₂ -; CH ₃ -SO-; the groups HOOC-; HO ₃ S-; HCO-; Lower alkyl-CO-, preferably CH ₃ -CO-; Lower alkyl-O-CO-, preferably CH ₃ -O-CO-, C ₂ H ₅ O-CO-; -CN; the oxo group = 0, the thiono group = S and the imino group «NH.

Le A 19 650

130022 / OOOa

ORIGINAL INSPECTED

In the event that R in a nitrogen-containing heterocyclyl is a substituent on one or more nitrogen atoms, R _{11 is} preferably lower alkyl, preferably methyl, ethyl, propyl, isopropyl, in particular methyl and ethyl; the group -C ^ N; -CHO; -COO-lower alkyl, preferably -COO-CH _{3 , -COOC 2} H ₅ , -COOCH (CH ₃ ) ₂ , -COO-C (CH ₃ ) ₃ ; -CO-NH ₂ ; -CO-NH-lower alkyl, preferably -CO-NH-CH ₃ , -CO-NH-C ₂ H ₅ , -CO-NH-CH (CH ₃ ) ₂ ; and -CO-lower alkyl, preferably -CO-CH ₃ , -CO-C ₂ H ₅ , -CO-CH (CH ₃ ) 2 '

The rings which can be formed by R., and R _g together with the carbon atom to which they are attached are saturated or unsaturated. Unsaturated rings preferably contain 1 or 2 double bonds. The rings can contain 1 or more, preferably 1 or 2, in particular 1, heteroatom or hetero group. Oxygen, sulfur and / or nitrogen may be mentioned as heteroatoms. Examples of hetero groups include the SO 2 group and the lower alkyl-N group, in the case of 6 rings preferably one heteroatom or one hetero group is in the 4-position (based on the carbon atom to which R and R _{Q are} bonded) . Particularly preferred rings are:

O, C-. O, O.

Le A 19 650

130022/0009

ORIGINAL INSPECTED

Lower alkyl NV = O ₂ S) = Q \ =

ο.

0_S) = and lower alkyl-N

The rings which can be formed by R ₅ and Rg together with the nitrogen atom to which they are attached are saturated or unsaturated / unsaturated rings preferably contain 1 or 2 double bonds. The rings can have a further 1 or 2 heteroatoms, in particular 1 further heteroatom, for example oxygen, sulfur or nitrogen, also in the form of SO-- or lower alkyl-N groups. Piperidino, morpholino, pyrrolidino, pyrroline piperazino, N'-lower alkylpiperazino may be mentioned as preferred.

The rings which are formed by R ₇ and R _g or R ₅ and R _Q together with the carbon atom or nitrogen atom to which they are bonded can be one or more, preferably 1 to 3, in particular 1 or 2, the same or contain various substituents such as halogen, preferably fluorine, chlorine, bromine; Oxo; Hydroxy, lower alkoxy, preferably methoxy and ethoxy; Lower alkylthio, preferably methylthio, ethylthio; Amino; Lower alkylamino, preferably CH 1 -NH-, C 1 -C Hc-NH-; Di-lower alkylamino, preferably dimethylamines and diethylamino; the groups -CN; -COOH; -COOCH ₃ , -COOC ₂ H ₅ ; and straight or branched chain lower alkyl, preferably methyl and ethyl.

Le A 19 650

~ 130022/0009

- -T3 -

Optionally substituted alkoxy R ₂ and R ₃ is, for example, alkoxy having 1 to 6, in particular 1 to 3 carbon atoms, which _{can be substituted one or more times, preferably once, by R 10} as defined above.

Optionally substituted alkylthio R ₂ and R ₃ and alkylsulfonyl R ₅ and R _g are, for example, alkylthio and alkylsulfonyl with 1 to 6, in particular 1 to 3 carbon atoms, which _{can be substituted one or more times, preferably once, by R 10} as defined above.

Acyl R-, R3 and R _g are in particular optionally substituted alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, optionally substituted cycloalkylcarbonyl, and the corresponding sulfonyl compounds, furthermore optionally substituted alkoxycarbonyl, and optionally substituted aminocarbonyl, where alkyl, aralkyl, aryl, cycloalkyl, alkoxy and amino den correspond to the definitions given above.

Optionally substituted amino is NH ₂ and mono- or disubstituted amino, optionally substituted alkyl, aryl, optionally substituted aralkyl, heterocyclyl, optionally substituted cycloalkyl, being possible as substituents, the meaning of the amino substituents being the definitions given above for the individual radicals correspond.

Le A 19 650

130022/0009

- vt -

Optionally substituted arylsulfonyl, heterocyclylsulfonyl and aminosulfonyl corresponds to those listed above with respect to aryl, heterocyclyl and amino Definitions.

Preferred compounds correspond to the general formula (II)

(II)

wherein

/ COCH ₃ R ₁₀ . Hydrogen, sodium, -CH. , -CH ₀ -OCO (CH-.) ,,

-4 S = Q, -CH-O-COO-lower alkyl or

CH ₃

-CH-OCONH-lower alkyl
CH ₃

R _{13 is} hydrogen or methoxy

R _{14 is} hydrogen or together with R ₁ C ⁵⁵ ^ CH-R ₁₁

R _{15 is} hydrogen, SO ₃ -R ₁₇ or together with R ₁₄ 15

16

16

Le A 19 650

130022/0009

~ * 4-fr -

C _{1 -C 4} -alkylsulphonyl or phenyl optionally substituted by chlorine, bromine, methyl, methoxy, nitro or carboxy,

R ₁₈ and R ₁₉ is hydrogen, C ₁ -C ₄ -alkyl] CyI or together C ₄ -C _fi alkylidene.

Preferred compounds are also 6-ß-chloropenicillanic acid-S-dioxide, β-dibromopenicillanic acid-S-dioxide, S-jL - and 6-ß- (1-hydroxyethyl) -penicillanic acid-S-dioxide and the corresponding sulfuric acid half-esters, 6-ß -Phthalimidopenicillanic acid-S-dioxide and 6-ß-succinimidopenicillanic acid-S-dioxide, 6-ß-saccharinyl-penicillanic acid-S-dioxide and 6- / -Methoxy-ö-ß-succinimidopenicillanic acid-S-dioxide.

The compounds according to the invention surprisingly show a significantly higher inhibitory effect of ß-lactamases than those known from the prior art Penicillin-1,1-dioxide. The compounds according to the invention thus represent an enrichment of the pharmaceutical treasure.

it was also found that you can get the new penicillin 1,1-dioxide of the general formula (I) is obtained when compounds of the general formula (III)

CK-

CH ₃

Le A 19 650

130022/0009

ORIGINAL INSPECTED

- 4-6- -

wherein

R ₁ , R 1 and R _{3 have} the meanings given above

to have,
oxidized in a suitable solvent.

The penicillanic acids of the formula (III) used as starting materials are either already known or can be prepared by known methods.

Particularly suitable solvents are polar solvents / for example water, acetic acid, tetrahydrofuran and mixtures of these three. The reaction temperatures are generally between -20 and + 5O ⁰ C, preferably between 0 and 2O ° C. The reaction is generally carried out under normal pressure. The pH of the reaction solution can be between 2 and 8, preferably between 3.5 and 7.5.

When carrying out the reactions, stoichiometric amounts of the reactants are preferably used in each case. But it can definitely be one of the Reactants are added in excess, preferably the oxidizing agent. The work-up the reaction products are carried out according to the methods customary in preparative organic chemistry.

The oxidation is preferably carried out with the following oxidizing agents: potassium permanganate, ozone, water

Le A 19 650

130022/0009

- JrI -

substance peroxide / hydrogen peroxide in the presence of catalytic Amounts of ammonium molybdate, hydrogen peroxide in Glacial acetic acid, organic peracids such as peracetic acid, chromium trioxide, ruthenium tetroxide, nitric acid, and N-chlorosuccinimide in methanol / water.

If free amino groups are present in the compounds of the formula (III) used as starting material, then these generally according to methods customary in peptide chemistry before the oxidation with protective groups such as benzyloxylcarbonyl, tert-Butyloxycarbonyl or ß-Dicarbonyl derivatives provided, which after the oxidation in the usual Way to be split off again.

The compounds of the formula (I) according to the invention have antimicrobial efficacy with low toxicity. These properties enable them to be used as chemotherapeutic agents in medicine and as substances for the preservation of inorganic and organic Materials, especially organic materials of all kinds, e.g. polymers, lubricants, Paints, fibers, leather, paper and wood, of food and of water.

Microorganisms against which the active ingredients according to the invention of the formula (I) are, for example, Micrococcaceae, such as staphylococci, e.g. staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus aerogenes and Gasskya tetragana; Lactobacteria cea such as Strep-

Le A 19 650

130022/000

ORIGINAL INSPECTED

- J-8- -

toocci, e.g. pyogenes streptococcus and diplococcus pneumoniae; Meissiriaceae such as Neisseria, e.g. Neisseria gonorrhoeae, Neisseria meningitides, Neisseria catarrhalis and Neisseria vlava; Bazilla cea such as aerobic spore formers, e.g. Bacillus anthracis, Bacillus subtilis and Bacillus cereus.

The above list of pathogens is only exemplary and in no way restrictive.

The present invention includes pharmaceutical preparations, In addition to non-toxic, inert pharmaceutically suitable carriers, one or more contain active ingredients according to the invention or which consist of one or more active ingredients according to the invention, as well as processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. tablets, coated tablets, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. the Dosage units can contain, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient that is administered in one application and which usually corresponds to a whole, a half, or a third or a quarter of a daily dose.

Le A 19 650

130022/0009

ORIGINAL INSPECTED

Non-toxic, inert pharmaceutically acceptable carriers are solid, semi-solid or liquid diluents, To understand fillers and formulation auxiliaries of all kinds.

Preferred pharmaceutical preparations are tablets, coated tablets, capsules, pills, granules, suppositories, Solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the customary excipients contain, such as (a) fillers and extenders, e.g. B. starches, lactose, cane sugar, glucose, mannitol and silica, (b) binders, e.g. carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerine, (d) disintegrants, e.g. agar-agar, calcium carbonate and sodium carbonate, (e) Solution retarders, e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g., cetyl alcohol, glycerol monostearate; (h) adsorbents, e.g., kaolin and bentonite and (i) lubricants, e.g., talc, calcium and magnesium stearate, and solid polyethylene glycols or mixtures the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can optionally be used with the usual opacifying agents containing coatings and casings

Le A 19 650

130022/0009

ORIGINAL INS " ^r "'~ n = D

and also be composed in such a way that they Release active ingredients only or preferentially in a certain part of the intestinal tract, possibly delayed, polymer substances and waxes, for example, can be used as embedding compounds.

The active ingredient (s) can optionally also be combined with one or more of the above-mentioned excipients are in microencapsulated form.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble carrier substances, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C. ₄ alcohol with

C ₁ , fatty acid) or mixtures of these substances. 1 b

Ointments, pastes, creams and gels can contain the usual carrier substances in addition to the active ingredient (s), e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, Silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays can contain the usual carrier substances in addition to the active ingredient (s), e.g. lactose, Talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can additionally contain the usual propellants e.g.

Chlorofluorocarbons contain.

Le A 19 650

130022/0009

ORIGINAL INSPECTED

In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, Solubilizers and emulsifiers, e.g. water, ethyl alcohol, Isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, Dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, Contain polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form are present.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. water, ethyl alcohol, propylene glycol, suspending agents, e.g. ethoxylated isostearyl alcohols, Polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving agents Contains additives, e.g. peppermint oil and eucalyptus oil and sweeteners, e.g. saccharin.

Le A 19 650

130C22 / OOO9

The therapeutically active compounds should preferably be used in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably from about 5 to 95% by weight of the total mixture, to be available.

The pharmaceutical preparations listed above In addition to the active ingredients according to the invention, they can also contain further pharmaceutical active ingredients.

The pharmaceutical preparations listed above are produced in the customary manner according to known methods Methods, e.g. by mixing the active ingredient (s) with the carrier (s).

The present invention also includes the use of the active ingredients according to the invention and of pharmaceuticals Preparations which one or more according to the invention Contain active ingredients in human and veterinary medicine to prevent, ameliorate and / or cure the above Diseases.

The active ingredients or the pharmaceutical preparations can be used locally, orally, parenterally, intraperitoneally and / or administered rectally, preferably orally or parenterally such as intravenously or intramuscularly.

In general, it has proven beneficial in both human and veterinary medicine to

Le A 19 650

130022/0009

- 3-3 -

the active ingredient (s) according to the invention in total amounts from about 5 to about 1000, preferably 10 to 200 mg / kg of body weight per 24 hours, optionally in In the form of several single doses to be administered to achieve the desired results. A single gift contains the or the active ingredients according to the invention, preferably in amounts of about 1 to about 250, in particular 10 to mg / kg body weight. However, it may be necessary to deviate from the stated dosages, namely in Depending on the type and weight of the object to be treated, the type and severity of the disease, the type of preparation and application of the drug as well as the period or interval, within which the administration takes place. So in some cases it can be sufficient with less than the above-mentioned active ingredient get along, while in other cases the above-mentioned amount of active ingredient is exceeded must become. The determination of the optimal dosage and type of application of the active ingredients required in each case can easily be done by any skilled person on the basis of their specialist knowledge.

The new penicillanic acid 1,1-dioxide derivatives stand out through antibacterial effects that have been tested in vivo and in vitro and through oral absorbable · Out.

The penicillanic acid 1,1-dioxide derivatives according to the invention can, for the purpose of expanding the spectrum of activity and increasing the activity, specifically to achieve ß-lactamase-producing bacteria, with other

Le A 19 650

130022/0009

ORIGINAL INSPECTED

antimicrobial agents, e.g. with ß-lactam antibiotics such as penicillins.

The penicillanic acid 1,1-dioxide derivatives according to the invention can for the purpose of expanding the spectrum of activity and to achieve an increase in effectiveness also with aminoglycoside antibiotics such as gentamicin, kanamicin, sisomicin, amikacin or tobramicin can be combined.

The penicillanic acid 1,1-dioxide derivatives according to the invention inactivate - by inhibiting or destroying the bacterial enzymes that split the ß-lactam ring (ß-lactamases). This prevents the breakdown of other penicillins, e.g. amoxicillin, Mezlocillin, ampicillin, azlocillin, penicillin G, carbenicillin, ticarcillin and thus once prevented them Maintain activity and, on the other hand, its spectrum of effects extended to ß-lactamase producing bacteria. In Table 1 this is based on the improvement of the minimum Inhibitory concentrations (MIC) demonstrated.

Table 1

MIC in U / ml
Bacterial strain AB

E. coli T 7 256

Klebsiella pneum. 1852 128 Staphylococcus anreus 1756 256

64 + 64 256 64 + 64 256 64 + 64 256

Le A 19 650

130022/0009

A = mezlocillin; B = mezlocillin + compound according to Example 1; C = connection according to example 1.

Table 1 shows the improvement (equal to reduction) in the maximum inhibitory concentration (MIC) of mezlocillin in strains otherwise resistant to mezlocillin.

In vitro experiments

The compound of Example 1, which is more typical Representatives of the compounds according to the invention can be considered, was taken with Müller-Hinton nutrient broth Addition of 0.1% glucose to a content of ΙΟΟμ, / ml diluted. The nutrient solution contained 10 to 10 bacteria once per ml. The tubes with this batch was incubated for 24 hours and then the degree of turbidity was determined. Freedom from haze indicates effect. With a dosage of 1μ / ml were the bacterial cultures inoculated with Staphylococcus aureaus 133 cloud free.

Le A 19 650

130022/0009

ORIGINAL INSPECTED

- 26 -

example 1

6-aminopenicillanic acid-1,1-dioxide

11.7 g of sodium δ-benzyloxycarbonylaminopenicillanate 1,1-dioxide are dissolved in 100 ml of water. The pH is increased to 6.5 by adding a little dilute hydrochloric acid
adjusted, then enough methanol is added until everything is clearly dissolved (- 40 ml). This solution is added to a suspension of 11.7 g of palladium black in 240 ml of water (pre-hydrogenated for one hour). It is then hydrogenated at normal pressure for 2 1/2 hours. The catalyst is then filtered off and the filtrate is collected
adjusted to pH 3.5, concentrated a little on a rotary evaporator to remove the methanol and then

freeze-dried. The residue is dissolved in a little methanol and precipitated again by adding ether, the precipitate is filtered off with suction and washed with ether. After cleaning with an ion exchange column 5.8 g of 6-aminopenicillanic acid 1,1-dioxide are obtained.

Le A 19 650

130022/0009

Example 2

δ-Benzyloxycarbonylaminopenicillanic acid-1,1-dioxide

18.6 g (0.05 mol) of sodium 6-benzyloxycarbonylaminopenicillanate are dissolved in 260 ml of water. At ^{0 0-5} ° C. and pH 6-7.5, a solution of 9.5 g of potassium permanganate in 300 ml of water is added over the course of one hour. Excess permanganate is then destroyed by adding bisulfite solution and the mixture is suctioned off through kieselguhr. The filtrate is adjusted to pH 2 and extracted twice with ethyl acetate. The organic phase is washed with anhydrous NaSO. dried and concentrated. The residue is dissolved in methanol and an equimolar amount of sodium caprylate solution (ether / methanol) is added. A precipitate forms, which is filtered off with suction and washed with ether. There are 12 g (59% of theory) of sodium 6-benzyloxycarbonylaminopenicillanat-1,1-dioxide, mp. 168 - 17O ⁰ C obtained.

Le A 19 650

130022/0009

ORIGINAL INSPECTED

Example 3

H H

! = SO-, CH ₃ -SO ₂ -NH Ι-γ X) ^CE 3

/ tnA "

0 \ CH ₃

COOH, Na

In the cooled to 0 ⁰ C solution of 3.3 g of 6-Mesylaminopenicillansaurem sodium in 30 ml water (using 1 η NaOH to pH 7.0 to 7.5 adjusted) was added dropwise in about 20 minutes, the solution of 2, 05 g KMnO, in 50 ml water and 0.68 ml 58% phosphoric acid. 7.5 - In this case the temperature below 1O ⁰ C and the pH using 10% phosphoric acid at 6 is maintained. The mixture is then stirred for a further 10 minutes, the excess of KMnO is eliminated with a little bisulfite solution and the precipitate is filtered off with suction through Celite and washed with water. The combined aqueous solutions are covered with a layer of ethyl acetate, acidified to pH 2 with 2 HCl while stirring and, after the organic phase has been separated off, shaken out three more times with ethyl acetate. After the solvent has been distilled off, the combined and dried ethyl acetate extracts leave behind the mesylaminopenicillanic acid sulfone as an oil, which, however, crystallizes on trituration with ether. The crystal needles are filtered off, washed with ether and dried.

Yield: 1.0g

Le A 19 650

130022/0009

- 29- -

NMR (CD ₃ OD; 60 MHz) 5.55 (d, 1H); 5.1 (d. 1H);

4.5 (s, C-3H); 3.1 (s, 3H);

1.6 (s, 3H) and 1.45 ppm (s; 3H)

After dissolving in methanol and adding sodium 2-ethylhexanoate the sodium salt can be precipitated with ether in methanol-containing ether (approx. 1 molar).

NMR (DC ₃ OD; J> 60 MHz) 6.1 (d; 1H); 5.25 ppm (d; 1H).

The used Mesy 6-aminopenicillanic acid as the starting product of disilylated 6-aminopenicillanic acid and mesyl chloride in chloroform in the presence of triethylamine (1 hr 0 ⁰ C..; 3 0 min 20 ⁰ C) was firstly obtained as a free acid (foam). The sodium salt was obtained therefrom by dissolving the water / sodium hydroxide solution (at pH 7) and freeze-drying.

NMR (TLC ₃ OD;

60 MHz) 5.4 (d; 1H), 5.1 (d; 1H);

4.0 (s; C-3H) 2.9 ppm (s; 3H)

In game 4

Le A 19 650

COOH

130022/0009

INSPECTED

2927Q04 - as.

Is obtained in the manner described in Example 1 from 2.2 g of 6-tolylaminopenicillanic acid.

Yield: 1.6g

NMR (DC ₃ OD, ζ, 60 MHz) 7.8 (d; arom.H); 7.3H (d;

arom.H); 5.5 (d; 1H); 4.85 (d? 1H); 4.4 (s; C-3H); 2.4 (s; 3H); 1.5 (s; 3H) and 1.35 ppm (s; 3H).

Example 5

8.3 g of 6- (dimethylaminomethyleneamino) penicillanic acid are dissolved in 50 ml of water. At 0 to 5 ⁰ C and a pH of 6 to 7.5, 180 ml is added dropwise of a 0.2 molar solution KMnO.. The reaction mixture is stirred for a further 15 minutes and then filtered through kieselguhr. The filtrate is freeze-dried. net, the residue is purified by chromatography. 5.2 g of 6- (dimethylaminomethyleneamino) penicillanic acid 1,1-dioxide are obtained.

Le A 19 650

130022/0009

ORlGlMAl ...

-Vr-

In the manner described in Example 5 are further obtained

^R 2 OO

I W-

CH ₇

U λ

CO ₂ H

Example R ₃ 'R.

(N-CH = N-

-CH = N- H

^H 5 ^C 2 _X

^) N-CH = N-H

H ₅ C ₂

^H 9 ^C 4 _X

N-CH = N-H

H ₃ C
/ N-CH = N-OCH

^H 3 ^C

Le A 19 650

130022/0009

292700A

Example-11

This penicillanic acid S-dioxide was used in the example 2 described manner from 2 g of 6-ß-pyrrolidin-2,5-dion-1-yl-penicillanic acid produced in 54% yield.

NMR signals at Ύ = 4.1 (1H), 4.9 (1H), 5.6 (1H), 7.4 (4H)

and 8.6 ppm (6H).

In the manner described in Example 2, the following are also obtained:

CH ₃

COOH R ₃

12. (N-H

14. ^ Jl- H

^ \ ₀ OCH-

15. "

Le A 19 65Q

130022 / Q009

ORIGINAL INSPECTED

33 "-

R.

16. 17th

18th

Example 19

H
OCH-

OCH.

COONa

This penicillanic acid S-dioxide was used in the example 2 described manner from 3.5 g of 6-ß-phthaloyliminopenicillanic acid obtained in 48% yield.

NMR signals at '/ "= 2.15 (4H), 4.1 (1H), 4.9 (1H)

5.5 (1H), 8.6 ppm (6H).

Example 20

-2

cc /

N-

CH-

COONa

Le A 19 650

130022/0009

ORIGINAL INSPECTED

M -

This penicillanic acid S-dioxide was used in the example 2 from 3 g of 6-ß- (4,5-benzoisothiazolin-3-one-S-dioxid-2-yl) -penicillanic acid obtained in 40% yield.

NMR signals at 't = 1.8 - 2.6 (4H), 4.1 (1H), 4.9 (1H),

5.5 (1H) and 8.6 ppm (6H).

Example 21

ö-ß-Isopropylamino-penicillanic acid-S-dioxide

4.4 g of 6-ß-Isopropylainino-penicillanic acid were placed in 75 ml of water with 5% NaOH to pH 7 and cooled to 0 ⁰ C. 2.4 g KMnO ₄ and 0.8 ml 85% phosphoric acid in 60 ml water were gradually added so that the internal temperature was kept below TO ⁰ C and the pH between 6 and 7.5 (with NaOH or 10% iger H ₃ PO-). The mixture was stirred 10 minutes, sucked through celite, and added again 0.47 g of KMnO ₄ and 0.15 ml of phosphoric acid in 12 ml of water at 10 ^ ⁰ C inner temperature, stirred another 10 minutes, sucked through celite, and placed pH 6 with 1 η HCl. This was followed by freeze-drying. Yield: 5.2 g (61% according to analysis; corresponds to 73% yield)

Le A 19 650

130022/0009

NMR signals at 'Ύ =

-W-

4.95 (1H), 5.09 (1H), 5.7 (1H), 7.0 (1H), 8.4 (3H), 8.6 (3H) and 8.9 ppm (6H).

The following penicillanic acid S-dioxides are obtained in the same way:

Rr

COOH

R ₉

R,

CH,

CH

CH-

CH ₃ CO-

25th, 26th, 23rd, 29th, 30th

-CO-

CH ₃ SO ₂ -

CH ₃ CH ₂ CO-

-CH _n -CO-

CH ₃ SO ₃ -

CH ₃ SO ₃ -

CH ₃ CH ₂ SO ₂ -

CH ₃ ..

CH-

-0-CH ₂ CO- CH ₃ SO ₂ -

OCH.

Le A 19

130022/0009

ORIGINAL INSPECTED

Claims (15)

1. ) Compound of the general formula R ₂ H * ¹ ^ ⁷ 'CH ₃ CO ₂ R ₁
as well as their pharmaceutically acceptable salts, wherein R _{1 is} hydrogen or an ester-forming radical, R2 is hydrogen, bromine, optionally substituted Alkoxy, optionally substituted alkylthio, azido, optionally substituted alkyl, optionally substituted cycloalkyl, aryl, aralkyl, heterocyclyl, acyl, carboxyl or cyano, R- hydrogen, halogen, azido, optionally substituted alkyl, optionally substituted Alkoxy, optionally substituted cycloalkyl, aralkyl, aryl, optionally substituted alkylthio, Heterocyclyl, acyl or a radical of the formula or
and R, together for a radical of the formula O = Le A 19 650 130022/0009 ORIGINAL INSPECTED 292700A ^R 5 ^R 7 \ R ₄ -ON =, ^ NN = or ^ C = ^R 6 ^R 8 stand, but R_ and R, not at the same time Can be hydrogen, azido or acyl, R. optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, aryl or heterocyclyl, R _{5 is} hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, aryl, heterorocyclic or optionally substituted alkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl or aminosulfonyl, Rg acyl, hydrogen, optionally substituted Alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, aryl or heterocyclyl or R ₅ and Rg together with the nitrogen atom and optionally including further heteroatoms form a 4- to 7-membered heterocyclic ring, R and Rg hydrogen, optionally substituted Alkyl, aryl, optionally substituted cycloalkyl, aralkyl or optionally substituted Amino or together with the carbon atom to which they are attached a 3 to 7-membered carbocyclic or - including heteroato- Le A 19 650 130022/0000 men - heterocyclic ring and Rg hydrogen / optionally substituted alkyl, optionally substituted cycloalkyl, aryl, aralkyl, heterocyclyl or optionally substituted Mean alkylsulfonyl. 2. Compounds according to claim 1 of the general formula CO ₉ R ...,
worxn i 12 -COCH, R ₁ , hydrogen, sodium, -CH ^, -CH ₇ -OCO (CH-J,., ¹ ^ ^ COOCH, ^{Λ ό J} - ^ v _n S = O , -CH-O-COO-lower alkyl or CH ₃ -CH-OCONH-lower alkyl
CH-, R _{13 is} hydrogen or methoxy R ₁ . Hydrogen or together with RI ₅ = CH-R _{1 (} R _{15 is} hydrogen, SO ₂ -R ₁₇ or together with R ₁₄ V-Xl-It ₁ r Le A 19 650 130022/0009 R ₁₆ NC.! ^{18 16 R} 19 _{1 14} or if necessary by Chlorine, bromine, methyl, methoxy nitro or carboxy substituted phenyl, Ro and R _{19 are} hydrogen, C.-C.-alkyl or together C.-Cg-alkylidene. 3. ö-ß-chlorophenicillanic acid-S-dioxide. 4. 6-Dibromopenicillanic acid S-dioxide. 5. 6--7L- and 6-ß- (1-hydroxyethyl) -penicillanic acid-S-dioxide and the corresponding sulfur half esters. 6. ö-ß-phthalimidopenicillanic acid-S-dioxide. 7. ö-ß-succinimidopenicillanic acid-S-dioxide. 8. ö-ß-saccharinyl penicillanic acid S-dioxide. 9. 6- X- -Methoxy-ö-ß-succinimidopenicillanic acid-S-dioxide. 10. Process for the preparation of compounds according to claim 1, characterized in that compounds the general formula R ₂ H CC ₂ R. Le A 19 650 130022/0009 ORIGINAL INSPECTED - Φβ- - wherein R ₁ , R ₂ and R ^ have the meaning given in claim 1 to have,
oxidized in a suitable solvent. 11. The method according to claim 3, characterized in that the reaction is carried out in a polar solvent at temperatures between -20 and +50 C at a pH value between 2 and 8 with potassium permanganate, Ozone, hydrogen peroxide, hydrogen peroxide in the presence of aaimonium molybdate, hydrogen peroxide in glacial acetic acid, organic peracids, chromium trioxide, ruthenium teroxide, nitric acid or N-chlorosuccinimide performs as an oxidizing agent. 12. Medicament characterized by a content of a compound according to claim 1. 13. Medicament according to claim 6, characterized in that that it also contains a ß-lactam antibiotic. 14. Use of compounds according to claim 1 to increase the effectiveness of a ß-lactam antibiotic. 15. Use according to claim 7 for increasing the Effectiveness of a ß-lactamase unstable ß-lactam antibiotic. Le A 19 650 130022/0009 ORIGINAL INSPECTED