DE2752701A1 - CLAVULANIC ACID ETHER, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

"Clavulanic acid ether, process for their preparation and these Medicinal preparations containing compounds "

claimed priority:

December 3, 1976 - Great Britain - No. 50444/76

The invention relates to new ethers of clavulanic acid, which have the antibacterial effect of penicillins and cephalosporins raise. Process for their production and medicinal preparations containing these compounds.

In BE-PS 847 045 it is disclosed that clavulanic acid ether by reacting a corresponding clavulanic acid ester with an etherifying agent such as a diazo compound can be prepared,

8Ö9823 / 0S58

It has now been established that some clavulanic acid ethers are present in good yield can be produced by a simple reaction.

The invention relates to compounds of the formula I, their salts and esters

CH ₂ -O-CR ¹ R ² -XR ³

-N

in which X is an oxygen or sulfur atom, R and R Are hydrogen atoms or lower alkyl radicals, which optionally are connected to one another, R is an optionally inert substituted

is ated lower alkyl radical or optionally with the radical R one forms inert substituted 5- or 6-membered heterocyclic ring.

The term "lower" means that the remainder does not have 6 carbon atoms, especially not more than 4 carbon atoms.

"Inertly substituted" means here that the remainder with an or

4 4 • is substituted by several radicals of the formulas CH-OR or OR, in which R is a hydrogen atom, a lower alkyl ^ or acyl radical or a benzyl radical.

The oxygen atom is preferred for X in formula I.

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The hydrogen atom, the methyl and ethyl radicals are suitable for R. The hydrogen atom is preferred for R.

Preferred compounds according to the invention are compounds of Formula II, their salts and esters

₂ -O-CHR ² -OR ³

in which R and R are as defined in formula I.

In compounds of the formulas. I "and II, in which R is not attached to R or R is bonded, is for R the hydrogen atom, the methyl and ethyl radical suitable. The hydrogen atom and the methyl radical, in particular the hydrogen atom, are preferred.

For compounds of the formulas I and II in which R and R are not connected, R is methyl, ethyl, n-propyl, Isopropyl, η-butyl, isobutyl, sec-butyl and tert-butyl radicals are suitable. The methyl, ethyl or propyl radical, in particular the methyl and ethyl radical, is particularly suitable for R, preferably the methyl radical.

In compounds of the formulas I and II in which R and R are

12 3 are bound, the radical -CR R -XR is particularly useful

a remainder of the formulas a or b '.

809823/0658

- Jf ..

in which R ^a , R, R ^c , R, R ^e and R are each a Pest R or OR and

σ 4 4 4

R ^{y is} a radical R or CH ₂ R, where R is a hydrogen atom,

is a lower alkyl or acyl radical or a benzyl radical,

preferably an alkyl or acyl radical with up to 4 carbon atoms.
Particularly suitable for R to R is the hydrogen atom, the lower alkyl radical or a radical of the formula OR in which R is a hydrogen atom, an acetyl, benzoyl or benzyl radical.

The hydrogen atom, a lower one, is particularly suitable for r "

5 af alkyl radical or a radical of the formula CH ₂ OR. For R to R

preferred are hydrogen atoms or lower alkyl radicals, such as the methyl radical. The hydrogen atom is particularly preferred.

In compounds of the formula I in which R and R are connected,

I 2, for example, denotes the radical -CR R / a cyclopentyl or cyclohexyl

4 4

rest, which is optionally substituted by a radical R or OR.

Suitable salts of the compounds of the formula I according to the invention are lithium, sodium, potassium, calcium and magnesium salts as well as ammonium and substituted ammonium salts such as methylamine, dimethylamine, trimethylamine, pyrrolidine salts and other lower salts Alkylamine salts such as diralkyl, tri-alkylamine and heterocyclic Amine salts. Lithium, sodium, potassium and calcium salts are particularly suitable, lithium, sodium and potassium salts are preferred

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salts.

Suitable esters of the compounds of the formula I are compounds of the formulas III and IV

1-2 "" 3 1 ^ - \ CH ₂ -O- CrV-XR ³

^X > CO ₂ - CH - A ² (III) CIV) A ³

in which R, R, X and R are as defined in formula I and A is an alkyl radical with 1 to 8 carbon atoms, the given

4 4 if with halogen atoms or a radical of the formulas OA, OCOA,

4 4 4

SA or SO-A is substituted in which A is a hydrocarbon

A radical with up to 6 carbon atoms, A is a hydrogen atom, is an alkyl radical with up to 4 carbon atoms or a phenyl radical, optionally with halogen atoms or one Alkyl or alkoxy radical substituted with up to 6 carbon atoms is, and A is a phenyl radical, optionally with Halogen atoms or an alkyl or alkoxy radical is substituted.

12 3
For the radical O-CR R -XR in formula I, radicals of the formulas a to f are particularly suitable

- CH ₂ OCH ₃ (a) - CH (CH ₃ ) OCH ₃ (b) - CH ₂ OC ₂ H ₅ (C) - CH (CH ₃ ) OC ₂ H ₅ (d) - CH (C ₂ H ₅ ) OC ₂ H ₅ (e)

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CH ₂ -OR

In formula f, R is as defined in formulas I and II and is in particular a lower alkyl radical, such as methyl or Ethyl residue. The radical a is preferred.

Particularly interesting compounds according to the invention are 9-O-methoxymethylclavulanic acid and its lithium, sodium, Potassium, calcium and magnesium salts, as well as their salts with Ammonia and pharmacologically acceptable amines.

The invention also relates to a method for producing the Compounds of the formula loderen. Salts or esters, which thereby is characterized in that, one is a clavulanic acid ester with a Compound of formula V converts ... -

Y -CR ¹ R ² - XR ³ (V)

12 3
in which X, R, R and R are as defined in formula I and Y is an easily displaceable radical, and optionally converts the ester formed into the free acid or its salt or into another ester.

The iodine, bromine or chlorine atom, the methanesulfonyl or toluenesulfonyl group and other radicals are suitable for Y in formula V, which can easily be displaced by a nucleophilic residue. The bromine or chlorine atom is particularly suitable for Y.

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The reaction according to the invention is generally carried out in the presence a base with low nucleophilicity such as 2,4,6-collidine, Potassium carbonate, sodium bicarbonate or 2,6-lutidine, at non-extreme temperatures, such as -20 to -30 ° C; e.g. about 0 to 20 ° C.

Suitable solvents for this reaction are dichloromethane, Chloroform, dimethylformamide and tetrahydrofuran.

Another process according to the invention for the preparation of compounds of the formula I, in which X is an oxygen atom, R ^{1 is} a hydrogen atom and R is a radical with at least 2 carbon atoms, which is optionally bonded to the radical R, is characterized in that a clavulanic acid ester is used with a compound of the formula VI

R ¹¹ R ¹ C = CH-OR ³ (VI)

in which the radical R ¹¹ R ¹ C- is a radical R ² and R ^{3 is} as defined in formula I, and optionally converts the ester formed into the free acid or its salt or into another ester.

The hydrogen atom is particularly suitable for R.

The hydrogen atom or a radical bonded to R is particularly suitable for R in formula VI.

Particularly suitable compounds of the formula VI are compounds of formulas VII and VIII.

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27527Oi

(VIII)

in which R, R ^c , R, R and R ^{g are} as defined in formulas a and b.

In general, this reaction takes place in the presence of an acid or an acid precursor as a catalyst, e.g. hydrochloric acid, Phosphorus oxychloride, p-toluenesulfonic acid or boron trifluoride.

According to the invention compounds of the formula I, their salts or Esters can also be prepared by reacting a clavulanic acid ester with a compound of the formula IX

- ο - CHR ² -OR ³ (IX)

2 3 5

in which R and R are as defined in formula I and R is a tertiary alkyl radical having 4 to 6 carbon atoms, and optionally converting the ester formed into the free acid or its salt or into another ester.

The tert-butyl radical is particularly suitable for R in formula IX.

R and R in formula IX are preferably connected to one another, see above

2 3
that the radical -CHR OR forms a heterocyclic ring.

If R and R are not connected, the radicals R and R have expediently the same meaning, e.g. both mean depending on the methyl or ethyl radical.

For this reaction, it is expedient to use an excess of compound of the formula IX, generally at least 1 mole, preferably 2 to 5 moles, excess. If the compound of the formula IX. Is a volatile liquid, it can be used as Use solvents.

The compounds of the formula I according to the invention or their Salt can also be prepared by saponifying a corresponding ester of a compound of the formula I.

This saponification can be done either by hydrolysis or hydrogenation, e.g. one can use an ester of a mild basic Subject to hydrolysis, a salt of a compound of the formula I is then obtained. An * ester can also be used catalytically hydrogenate to obtain the free acid or, in the presence of a base, the salt. In particular, one can be a low one Hydrolyze alkyl esters, such as the methyl ester, at a pH of 7 to by slowly adding an appropriate base. The benzyl, methoxybenzyl or nitrobenzyl ester can be used in the presence of a transition metal catalyst, such as palladium Hydrogenate coal, if appropriate in the presence of a base such as sodium, potassium or lithium carbonate or sodium or potassium bicarbonate.

However, compounds of the formula I according to the invention can also

809 8'2 3/0658

-Vb-

with a diazo compound or a salt of one of the invention Compound of formula I can be reacted with a reactive halogen compound.

The invention also relates to medicinal preparations which are characterized by a content of a compound of the formula I, its salt or ester in combination with customary pharmacologically acceptable carriers and / or diluents.

The compounds of the formula I are preferably present in the medicinal preparations according to the invention in the form of a pharmacologically acceptable salt or an ester which can be saponified in vivo.

The medicinal preparations according to the invention can be administered orally or parenterally and are suitable for the treatment of humans and animals.

In general, the medicinal preparations according to the invention are in the form of single doses containing about 20 to 250 mg, in particular about 50 to 100 mg, of active ingredient. These preparations are administered two to six times a day, for example three to four times a day, so that a daily dose is about 60 to 1000 mg, in particular about 200 to about 1000 mg.

The medicinal preparations according to the invention advantageously contain

preferably

as even a penicillin or cephalosporin, / in a weight ratio of compound of formula I, its salt or ester to penicillin or cephalosporin is from 1:10 to 10: 1, in particular

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2: 1 to 1: 5, e.g. 1: 1 to 1: 3.

Penicillins and cephalosporins suitable for these synergistic preparations are described in BE-PS 827 926. Particularly suitable penicillins are ampicillin, amoxycillin and their precursors, such as their in vivo saponifiable ester, AmpiciHin trihydrate and amoxycillin trihydrate, as well as the pharmacologically acceptable salts of amoxycillin.

Benzylpenicillin> phenoxymethy! Penicillin, propicillin, amoxycillin, ampicillin, epicillin, cyclacillin and other orally active penicillins, their salts and in vivo hydrolysable esters, and aldehyde and ketone adducts of penicillins <- with Aminoacylamido side chains and their salts. Suitable in vivo hydrolyzable esters of penicillins are the acetoxymethyl, pivaloyloxymethyl, o ( -ethoxycarbonylc-xyethyl and phthalidyl esters of ampicillin or amoxycillin and the phenyl, tolyl and indanyl - ^ - esters of carbenicillin and ticarcillin and their salts.Suitable aldehyde and ketone adducts of penicillins with a 6-o ^ -aminoacylamido side chain are the formaldehyde and acetone adducts of metampicillin and hetacillin and their salts.

Suitable esters for infusions and injections are the salts of benzylpenicillin, phenoxymethylpenicillin, carbenicillin, Propicillin, Ampicillin, Amoxycillin, Epicillin, Ticarcillin, Cyclacillin and other well-known penicillins.

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-VZ-

Suitable cephalosporins for orally administrable according to the invention Medicinal preparations are cephalexin, cephradine, cephaloglycine and their salts as well as other known cephalosporins, their salts and in vivo saponifiable esters, as well as aldehyde and ketone adducts of cephalosporins with a 7-Λ-aminoacylamido side chain and their salts.

Suitable cephalosporins for infusions and injections are the salts of cephaloridin, cephalothin, cefazolin, cephalexin, Cephacetril, Cephamandol, Cephapirin, Cephradine, Cephaloglycine and other known cephalosporins.

The examples illustrate the invention.

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- VS -

Example 1 S-O-methoxymethylclavulanic acid benzyl ester

CH ₂ OH \ - CH ₂ OCH ₂ OCH ₃

CO ₂ CH ₂ C ₆ H ₅
(e 1) (e 2)

(el) 2.89 g (0.01 mol) of clavulanic acid benzyl ester, 1.6 ml (1.7 g) of chlorodimethyl ether and 1.3 ml of 2,4,6-collidine are stirred at 5 ° C in 20 ml of dichloromethane dissolved. After 1 hour at 10 ° C., thin-layer chromatography shows that the benzyl clavulanate has almost completely disappeared. The mixture is mixed with 50 ml of water and shaken, then separated (the aqueous solution is strongly acidic). 50 ml of 3 percent sodium bicarbonate solution are added to the dichloromethane phase. The organic phase is separated off, dried over sodium sulfate, filtered, concentrated and chromatographed on a silica gel column with ethyl acetate and cyclohexane as the eluent. 1 g of a pale yellow oil is obtained.
J (film): 1803, 1753, 1700cm " ¹ (C = C).

ΙΠ el X

6 (CDCl ₃ ): 3.01 (1H, broad, J = 17Hz, 6-β-CH), 3.33 (3H, s, OCH ₃ ),

double
3.50 (1H, / doublet, J = 3 and 17Hz, 6O <- CH), 4.14 (2K, broad doublet, J = 7Hz, CHCH ₂ O), 4.57 (3H, singlet, CH ₃ O ), 4.86 (1H, broad triplet, J = 7 and 1.5Hz, CH =), 5.10 (1H, doublet, J = 1.5Hz), 5.69 (1H, broad doublet, J = 3Hz , 5-CH), 7.36 (5H, singlet,

ORIGINAL IMSFECTED 809823/0658

- yc -

Example 2 9-O-methoxymethylclavulanic acid lithium salt

-N

^CH 2 ^OCH 2 ^OCH 3

CO ^ H

(e3)

0.7 g of benzyl O-methoxymethylclavulanate (e2) in 7 ml of tetrahydrofuran containing 0.5 ml of water are hydrogenated over 0.2 g of 10 percent palladium on carbon for 1 hour. The catalyst is filtered off from the solution of e3, the filtrate is mixed with 10 ml of water, neutralized with 1m lithium hydroxide solution to pH 7.0 and allowed to dry. evaporated. Colorless crystals are obtained which are treated with acetone, filtered, washed with Xther and air-dried. Yield: 0.45 g of compound e4. ....

(Nujol muli): 1785, 1705, 1617 cm

_f doublet,

O (DO): 2.98 (1H, doublet, J = 17Hz, 6β-CH), 3.43 (1H, double / J = 17 and 3Hz, 6c <-CH), 4.07 (2H, doublet, J = 8Hz, 9-CH-), / ^ 4.5 (under HOD, OCH ₂ O), 4.79 (1H, triplet, J = 8Hz, 8-CH =), 4.83

(1H, singlet, 3-CH), 5.61 (1H, d, J = 3Hz, 5-CH).

0 9 8 2 3/0658

Example 3 9-O-Sthoxynethylclavulanic acid benzyl ester

. ^ "Ό. .CH ₂ OCH ₂ OC ₂ H ₅

(el)>

Ö * ^C0 2

(e5)

A mixture of 5.78 g of benzyl clavulanate (el), 5.8 ml 2,4,6-collidine and 3.7 ml of chloromethyl ethyl ether in 100 ml of dichloromethane is stirred at room temperature for 2 hours. The mixture is washed with 100 ml of 2M hydrochloric acid, over anhydrous Sodium carbonate / magnesium sulfate dried and evaporated to dryness. An 01 is obtained which contains over 50 g of silica gel Cyclohexane / ethyl acetate is chromatographed as the eluent. 6.15 g of the desired compound e5 are obtained as an oil.

Γ ° ί7ΐ ° + 45.2 ° (c, 1.0; CHCl ₃ ).

Ό (CHCl,): 181ο, 1755, 1705, 1310, 1190 and 1030 cm " ¹ .

£ (CDCl ₃ ): 7.28 (5H, ArH), 5.61 (1H, doublet, J = 2.5Hz, 5-CH), 5.13 (2H, singlet, -CH ₃ Ar), 5, 03 (1H, broad singlet, 3-CHi 4.78 (1H, broad triplet,, J = 8Hz, 8-CH), 4.56 (2H, singlet, -OCH ₂ O-), 4.09 (211, broad doublet, J = 8Hz, 9-CH ₂ ), 3.52 (2H, q, J = 7.5Hz, -OCH ₂ CH ₃ ), 3.41 (1H, double doublet, J = 17Hz, J = 2 , 5Hz, 6 oL-CH), 2.99 (1H, doublet, J = 17Hz, 6ß-CH) and 1.18 (3H, triplet, J = 7.5Hz, OCH ₂ CH ₃ ) ..

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^C 18 ^H 21 ^{: JO} 6

calculated
found

Ib

C% 6th H% N% 62 , 25 6th ,1 4.05 62 , 2 , 15 3.8

Example 4 9-O-ethoxymethy! Clavulanic acid lithium salt

(e5)

ι ι

CH ₂ OCH ₂ OC ₂ H ₅

N ^ /

(e6)

A solution of 5.9 5 g of 9-O-ethoxyethylclavulanic acid benzyl ester (e5) in 80 ml of tetrahydrofuran containing 2 drops of water is at room temperature and atmospheric pressure in the presence of 3.35 g of 10 percent palladium on charcoal hydrogenated for 30 minutes. The mixture is filtered, the filtrate is washed with 250 ml of water diluted and neutralized to pH 7.2 with 1m aqueous lithium hydroxide solution. The mixture is evaporated to dryness, off the residue is obtained after treatment with ether 4.4 g of the desired compound e6.

Z ~ ° L7 _d + 34.8 "(c, 1.0; H ₂ O).
• v> (KBr): 1780, 1700, 1620, 1320 and 1030 cm

ΙΏ3.Χ

-1

S (D-O): 5.70 (1H, doublet, J = 2.5Hz, 5-CH), 4.90 (1H, singlet, 2 ~

3-CH), 4.88 (1H, broad triplet, J = 8Hz, 8-CH), 4.68 (2H, singlet, -OCH ₂ O-), 4.17 (2H, doublet, J = 8Hz, 9-CH ₂ ),

3.58 (2H, q, J = 8Hz, -OCH ₂ CH ₃ ), 3.52 (IH, double

C ³ A ⁰⁴

Doublet, J = I 7Hz, JJ_ = 2, | H

, Doublet, J = 17Hz,

1.13 (3H, triplet, J = 8Hz, -OCH ₀ CH.).

Example! J-O-methylthioinethylclavulanic acid benzyl ester

(e8)

A solution of 2.89 g (0.1 mol) of benzyl clavulanate (el) and 2 ml (0.015 mol) 2,4,6-collidine in 10 ml dimethoxyethane is with a mixture of 1.5 g sodium iodide and 0.97 g (0.01 mol)

/ Chloromethylmethyl sulfide, _o

/ added to 20 ml of dimethoxyethane at OC under argon protection. The mixture is stirred for 3 hours at 50 ° C., then for 66 hours at room temperature, then poured into 40 ml of ice water and extracted three times with 40 ml of ethyl acetate each time. The organic extract is washed with 100 ml of 5m hydrochloric acid and 100 ml of saturated sodium chloride solution, dried and evaporated. An oil is obtained which is chromatographed on 30 g of silica gel with cyclohexane / ethyl acetate as the eluent. 0.4 g of compound e8 is obtained as a colorless oil. / ~ <x_70 ° + 38.3 ° (c, 2.0; CHCl ₃ ).

-0 (liquid film): 1805, 1750, 1695, 1300, 1180 and 1035 cm " ¹ , max

b (CDCl ₃ ): 7.28 (5H, singlet, ArH), 5.61 (1H, doublet, J = 2.5Hz, 5-CH), 5.12 (2H, singlet, -CH ₂ Ar) ^ 5.03 (1H, singlet, 3-CH),

4.75 (1H, broad triplet, J = 8Hz, 8-CH), 4.49 (2H, singlet,

"~ Doublet,

-OCH ₂ SMe), 4.10 (2H, doublet, J = 8hz, 9-CH ₃ ), 3.42 (IH, double /

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-VB-

J = 17Hz, J '= 2.5K2, 6C ^ -CH), 2.99 (1H, doublet, J = 17Hz, 6β-CH) and 2.09 (3H, singlet, -SCH ₃ ).

m / e (relative intensity): 301.0968 (25, M ⁺ -MeSH), 288.0849 (10, M ⁺ -C ₂ HS), 272.0903 (5, M ⁺ -C ₂ H ₅ OS), 230 (30, M ⁺ -C ₂ H ₅ OS-C ₂ H ₅ OS-C ₂ H ₂ O) and 91 (100).

Example 6

9-0-methylthiomethyl! Clavulanic acid-lithium salt

(e8)

OCH ₂ SCH ₃

A mixture of 0.3 5 g of 9-0-methylthiomethylclavulanic acid benzyl ester, 15 ml of tetrahydrofuran and 15 ml of water is in a pH stat titrated at 24 C with 1m lithium hydroxide solution to a constant pH of 10. After 2 hours the addition of Lithium hydroxide interrupted. The solution is concentrated to 10 ml under reduced pressure, then diluted with 10 ml of water. This aqueous mixture is extracted twice with 20 ml of ethyl acetate each time

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- Vf-

and evaporated to dryness. The residue is on a column with 10 g of cellulose with butanol / water / ethanol in the ratio 5: 5: 1 (upper phase) chromatographed. 0.04 g of the desired is obtained Connection e9.

(Nujol): 1780, 1695, 1620, 1300 and 1020 cm

" ¹

6 (D ₂ O): 5.80 (1H, doublet, J = 2.5Hz, 5-CH), 5.05 (1H, singlet, 3-CH), 4.97 (1H, broad triplet, J * 8Hz, 8-CH), 4.73 (2H, singlet, -OCH ₂ SMe), 4.27 (2H, doublet, J = 8Hz, 9-CH ₂ ), 3.63 (1H, double doublet, J = 18Hz, J '= 2.5Hz, 6OC-CH), 3.14 (1H, doublet, J = 18Hz, 6β-CH) and 2.19 (3H, singlet, -SCH ₃ ).

Example 7 9-0- (1-Butoxy) -ethylclayulanic acid-4-methoxybenzyl ester

CO ₂ -CH ₂

(elO)

(express)

V ^

OMe

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- 20 -

A solution of 1 g of clavulanic acid p-methoxybenzyl ester (e1O) and 1 ml of vinyl n-butyl ether in 10 ml of ethyl acetate is mixed with 50 mg added p-toluenesulfonic acid and 30 minutes at room temperature touched. The mixture is then chromatographed through a short column of silica gel with ethyl acetate as the eluent. The solvent is evaporated, the product is purified by column chromatography on silica gel with ethyl acetate / cyclohexane in a ratio of 1: 1 isolated. 0.848 g of the desired compound e11 is obtained.

(Film): 1805, 1750, 1700 cm " ¹ .

₃ ): 8.0 to 9.0 (3H, triplet, J = 7Hz), 1.26 (3H, doublet, J = 6Hz), 1.10 to 1.70 (4H, multiplet), 2.97 ( 1H, doublet, J = 17Hz), 3.20 to 2.55 (3H, multiplet), 3.74 (3H, singlet), 4.0 to 4.2 (2H, multiplet), 4.45 to 4, 75 (1Ή, multiplet), 4.75 (1H, triplet), 4.99 (111, singlet), 5.07 (211, singlet), 5.59 (1H, doublet, J = 3Hz), 6.80 (2H, doublet, J = 8Hz), 7.20 (2H, doublet, J = 8Hz).

Example 8

9-0-Tetrahydropyran-2'-yl-clavulanic acid benzyl ester

(el)

(el2)

B09823 / 0658

1.0 g of benzyl clavulanate (el) in 5 ml of benzene and 4 ml Dihydropyran is combined with 1 drop of boron trifluoride etherate complex added and stirred overnight. The solvents are evaporated under reduced pressure, the residue is on a Silica gel column with ethyl acetate and dohexane as eluent chromatographed. After evaporation of the solvent, 1.63 g of the desired compound e12 is obtained as UI. This ul has a purity of about 80%, the impurities are believed to be polymers derived from the pyran.

\> (liquid film): 1805, 1755, 1700 cm " ¹ .

Iu el X

): 1.0 to 2.1 (excess H, broad multiplet, 3 ', 4', 5'-CH ₂ ), 2.97 (1H, doublet, J = 17Hz, 6β-CH), 3.41 ( 1H, double doublet, J = 2.5 and 17Hz, 6Oc-CH), 3.6 to 3.95 (excess H, multiplet, 6'-CH ₂ ), 3.95 to 4.4 (2H, multiplet, 9-CH ₂ ), 4.52 (1H, broad singlet, 2'-CH), 4.79 (1H, broad triplet, J = 7.5Hz, 8-CH), 5.03 (1H, singlet, 3rd -CH), 5.12 (2H, singlet, PhCH-), 5.60 (1H, doublet, J = 2.5Hz, 5-CH), and 7.27 (5H, singlet, CgH ₅ ).

Example 9 9-0-Tetrahydropyran-2 ■■ -y 1-clavulanic acid lithium salt

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1.0 g Q-O-tetrahydropyran - ^ - yl-clavulanic acid benzyl ester (e12) is in l_nl. Tetrahydrofuran and 0.05 ml of water and dissolved over 0.3 g of 10 percent for 45 minutes. Palladium hydrogenated on charcoal. A solution of the corresponding acid e13 is obtained, from which the catalyst is removed. The filtrate is diluted with an appropriate volume of water and with 1m lithium hydroxide solution titrated to pH 7.0. The solution is evaporated to a syrup, mixed with 50 ml of acetone, evaporated again, with 30 ml Treated acetone, filtered off, washed with acetone and ether and air dried. Yield: 0.46 g of the desired compound e14.

(Nujol muli): 1783, 1790, 1700, 1620, 1625 cn " ^1. ₂ ): 1.16 to 1.6 (6H, broad multiplet, 3 ', 4', 5'-CH ₂ ), 2.89 (1H, doublet, J = 17Hz, 6β-CH), 3.39 (1H, double doublet, J =

17 and 3Hz, 6 (X-CH), 3.55 to 3.91 (2H, multiplet, 6'-CH ₂ ), 4.6 (2H, doublet, J = 8Hz, 9-CH ₂ ), 4, 5 to 4.9 (3H, multiplet, 2'-CH, 8-CH, 3-CH), 5.55 (1H-, doublet.,. J = 3Hz, 5-CH). ...

Example 10 9-0-Tetrahydrofuran-2'-yl-clavulanic acid 4-methoxybenzyl ester

(elO)

(el5)

809823/0658

A solution of 3.19 g (0.1 hol) of 4-methoxybenzyl clavulanate (e10) and 4.32 g (0.3 mol) of 2-tert-butoxytetrahydrofuran in 30 ml of dry dichloromethane is p-toluenesulfonic acid with 1 crystal added and stirred for 15 minutes at room temperature. The mixture is washed with 50 ml of aqueous sodium bicarbonate solution washed and dried. After evaporation, 3.8 g of the desired compound e15 are obtained.

-0 (liquid film): 18O5, 1750, 1700, 1250, 1180 and 1025 cm " ¹ .

ItlclX

5 (CDCl,): 7.20 (2H, doublet, J = 9Hz, ArH), 6.80 (2H, J = 9Hz, ArH), 5.59 (1H, doublet, J = 2.5Hz, 5- CH), 5.08 (2H, singlet, CH ₂ 5.00 (1H, singlet, 3-CH), 5.10-5.00 (1H, m, 2-CH), 4.65 (1H, triplet , J = 7Hz, 8-CH), 3.75 (3H, singlet, OCH ₃ ), 3.40 (2H, double doublet, J = 17Hz, J '= * 2.5Hz, 60C-CH), 2, 99 (1H, doublet, J = 17Hz, 6β-CH) and 1.6 to 2.0 (4H, multiplet, 3 ¹ and 4'-CH-).

Example 11 9-0-Tetrahydrofuran-2-ylclavulanic acid, sodium salt ·

(el5)

(el6)

809823/0658

-K-

1.46 g of 9-0-tetrahydrofuran-2-yl-clavulanic acid p-methoxybenzyl ester (e15) and 0.315 g sodium bicarbonate in 30 ml tetrahydrofuran / water in a ratio of 5: 1 at room temperature and atmospheric pressure in the presence of 0.5 g of 10 percent palladium hydrogenated on charcoal for 30 minutes. The mixture is filtered and the solid is washed with a little water. The United Solutions are evaporated to remove the tetrahydrofuran. The aqueous solution is extracted with 20 ml of ethyl acetate and freeze dried. 0.9 g of the desired compound e16 is obtained.

"v> (Nujol muli): 1785, 1695, 1615. (broad" ¹ .

lit clX

■ J (KBr): 1785, 1693, 1615 (very wide) cm " ¹ , m aX

D ₂ O): 1.86 (4H, multiplet, 3 ¹ and 4'-CH ₂ ), 3.02 (1H, doublet, J = 17Hz, 6β-CH), 3.51 (1H, double doublet, J. = 17 and 2.5Hz, 6p <-CH), 3.83 (2H, multiplet, 5'-CH ₂ ), 4.11 (2H, doublet, J = 8Hz, 9-CH ₂ ), 4.82 ( 1H, triplet, J = 8Hz, 8-CH), 4.90 (1H, singlet, 3-CH), .5.20 (1H, multiplet, 2'-CH) and 5.66 (IH, doublet, J. = 2.5Hz, 5-CH).

Example 12 9-0- (1-Ethoxy) prop-1-yl-clavulanic acid benzyl ester

0-CH ₂ -CH ₃

(e 1)

0-CH-CH ₂ -CH ₃

CO ₂ CH ₂ C ₆ H ₅

(e 17)

809823/0658

A stirred solution of 578 mg of clavulanic acid benzyl ester (el) and 0.3 ml of ethyl propenyl ether in 10 ml of ethyl acetate is mixed with 5 mg of p-toluenesulfonic acid, and the mixture is stirred for 75 minutes at room temperature and then chromatographed on a short silica gel column with ethyl acetate as the eluent. After the The product is solvent by column chromatography on silica gel with a gradient of cyclohexane / ethyl acetate eluted in a ratio of 3: 1 to 1: 1. 601 mg of the desired compound e17 are obtained.

zn cix

(Film): 1805, 1750 and 1700 cm " ¹ .

S (CDCl ₃ ): 0.88 (3H, triplet, J = 7Hz), 1.17 (3H, triplet, J = 7Hz), 1.60 (2H, broad quintet, J = 7Hz), 2.99 ( 1H, doublet, J = 17Hz), 3.44 (1H, double doublet, J = 3 and 17Hz), 3.54 (2H, q, J = 7Hz), 4.0 to 4.2 (2H, multiplet) , 4.36 (1H, triplet, J = 6Hz), 4.79 (1H, broad triplet, j = 7Hz), 5.05 (1H, singlet), 5.15 (2H, singlet), 5.63 ( 1H, doublet, J = 3Hz), 7.29 (5H, singlet).

Example 13 9-0- (1-Ethoxy) prop-1-yl-clavulans acid, sodium salt

0-CH - CH,

I ^{2 3}

(e 17)

.OCH-CH ₂ -CH ₃

CO ₂ Na

(e 18)

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A solution of 572 mg of 9-0- (1 -iithoxv) -nrop-1-vl-clavulanic acid-

(e17)

benzyl ester and 128 mg of sodium bicarbonate in 22.5 ml of tetrahydrofuran and 7.5 ml of water are hydrogenated over 250 ng of 10 percent palladium on carbon for 1 hour. The solution is filtered through diatomaceous earth and diluted with water. The tetrahydrofuran is removed in a rotary evaporator. The aqueous solution is extracted with ethyl acetate and freeze-dried. 370 mg of the desired compound e18 are obtained.

\) (KDr): 1785 and 1615 cm " ¹ ,
Max

6 (D ₂ O): 0.85 (3H, triplet, J = 7Hz), 1.16 (3H, triplet, J = 7Hz), 1.59 (211, broad quintet, J = 7Hz), 3.05 (1H, doublet, J = 17Hz), 3.4 to 3.85 (4H, multiplet), 4.19 (2H, doublet, J = 7Hz), 4.90 (1H, broad triplet, J = 7Hz), 4.93 (1H, singlet), 5.71 (1H, doublet, J = 3Hz).

Example 14 9-0- (2-Ethoxy) prop-2-yl-clavulanic acid benzyl ester

Γ ³

O-C-CH ₃ (e 1)> IJT = OC ₂ H ₅

'CO ₂ CH ₂ C ₆ H ₅ (e 19)

$ 09823/0658

- vr -

A stirred solution of 1 g of benzyl clavulanate (el) and 0.5 ml of ethyl isopropenyl ether in 10 ml of ethyl acetate is mixed with 5 mg of p-toluenesulphonic acid and then at room temperature for 20 minutes touched. The mixture is chromatographed through a short column of silica gel with ethyl acetate as the eluent. The solvent is evaporated, the product is chromatographed on a silica gel column with cyclohexane / ethyl acetate in a ratio of 3: 1. 743 mg of the desired compound e19 are obtained.

Iu el X

(Film): 1805, 1750 and 1700 cm " ¹ .

6 (CDCl ₃ ): 1.12 (3H, triplet, J = 7Hz), 1.31 (6H, singlet), 2.96 (1H, doublet, J = 17Hz), 3.37 (2H, q, J = 7Hz), 3.39 (1H, double doublet, J = 3 and 17Hz), 3.9 to 4.1 (2H, multinlet), 4.73 (1H, broad triplet, J = 7Hz), 5, 01 (1H, broad singlet), 5.13 (2H, singlet), 5.60 (IH, doublet, J = 3Hz), 7.26 (5H, singlet).

Example 15 9-0- (1-Ethoxy) cyclohexylclavulanic acid benzyl ester

(e 1)

OC ₂ H ₅

(e20)

CO ₂ CH ₂ C ₆ H ₅

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20 mg of mercury trifluoroacetate are added to a rumpled vegetable of J7ö iv.g CiavalariStlure-j -. ^ Azyit.ov.cir _v e ". _; And 2 ml of ethylcyclchexenyl ether. The mixture is stirred for 90 minutes at room temperature. Most of the solvent is added removed in a rotary evaporator, the product is isolated by chromatography on silica gel with cyclohexane / ethyl acetate in a ratio of 4: 1. 767 mg of the desired compound e20 are obtained.

Iu clX

(Film): 1805, 1750, 1700 cm " ¹ .

(CDCl ₃ ): 1.14 (3H, triplet, J = 7Hz), 1.2 to 1.8 (10H, multiplet), 2.96 (1H, doublet, J = 17Hz), 3.37 (2H, q, J = 7Hz), 3.43 (1H, double doublet, J = 3 and 17Hz), 3.9 to 4.15 (2H, multiplet), 4.76 (1H, broad triplet, J = 7Hz), 5.04 (1H, singlet), 5.14 (2H, singlet), 5.60 (1H, doublet, J = 3Hz), 7.27 (5H, singlet).

Example 16 9-0-methoxymethylclavulanic acid sodium salt

CH ₂ OCH ₂ OCH ₃

(e7)

CO ₂ CH ₂ C ₆ H ₄ OCH ₃

-N

(e21)

CO ₂ Na

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BATH ORIGINAL

6.0 g S-O -. 'Lethoxynethylclavular.säurs-r-r.ethxybenzylester (e7) are dissolved in 60 ml of ethanol in a pressure bottle and treated with 1.39 g of sodium bicarbonate in 8 ml of water. The bottle is flushed with nitrogen, then 0.75 g "10 percent Palladium on charcoal added. The mixture is hydrogenated at a pressure of 1.75 kg / cm for 1 hour. Thin layer chromatography on silica gel with ethyl acetate / chloroform in a ratio of 50:50 shows that the hydrogenation is complete. The mixture is filtered through diatomaceous earth, the diatomaceous earth is washed with 10 ml of water. The filtrate is in a Rotary evaporator evaporated to a gummy product. This product is dissolved in 10 ml of acetone and placed under strong Shake with 900 ml of dry diethyl ether. You get a fine white precipitate. The suspension is cooled to 4 ° C. for 2 hours and then filtered. The solid turns twice

Cr.

Washed with 100 ml of ether each time and immediately put in a desiccator dried under low pressure. 2.1 g of the desired compound e.21 are obtained as a pale yellow hydroscopic powder.

809823/0658

Example 17

9-0- (2,3,4,6-Tetra-O-acetyl-oC-D-glucopyranosyl) clavulanic acid p-methoxybenzyl ester

OCOCH-

(elO) ^ ι - / "" 2 ^ ^ 'CH ₂ OCOCH ₃

(e22)

A solution of 6.38 g of p-nethoxybenzyl clavulanate (e1O) in 10 ml of dry dimethylformamide is added dropwise over a few minutes to a stirred solution of 16.78 g of 06-acetobromoglucose and 5.3 ml of collidine in 5O ml of dry dimethylformamide given at 0 ⁰ C under nitrogen protection. The mixture is stirred at room temperature overnight, then poured into 100 ml of ice water. The ice water is extracted three times with 100 ml of methyl acetate each time. The organic extract is washed with 200 ml of 5M hydrochloric acid, dried over anhydrous sodium carbonate / magnesium sulfate and evaporated. An oil is obtained which is chronato-granulated on a column with 100 g of silica gel using cyclohexanol thylacetate as the eluent. 5.7 g of the desired compound e22 are then obtained as an oil

7.8 g of a mixture of the desired compound e22 and a small amount of starting material.

Properties of the oil:

-1

HIcLX

£ of_ / 4 5.3 "(£. ¹ ' ⁷ ' CIICl ₃ ).

(CIICl ₃ ): 1305, 1745, 1700, 1230, 1175, 1040 and 980 cn): 7.22 (2H, doublet, J = 9Hz, ArH), 6.83 (2H, doublet, J = 9Hz, ArH) , 5.64 (1H, doublet, J = 4Hz, 1'-CH), 5.61 (1H, doublet, J = 2.5Hz, 5-CH), 5.08 (211, s, -CH ₂ Ar ), 3.76 (3H, singlet, -OCH ₃ ), 2.06 (9H, singlet, CH ₃ CO ₂ -), and 1.68 (3H, singlet, CH ₃ CO ₂ -). m / e: 649 (M ⁺ ), 621, 607, 594, 549, 403, 331, 289, 288, 271, 259,

200 and 169 calculated C% 45 5 H% 2 N% ^C 30 H ₃₅ NO 15th found 55, 1 5 , 45 1 , 15 55, , 4 , 95

Example 18 9-0- (2,3,4,6-Tetra-O-acetyl-C £ -D-glukopyranosy1) -clavulanic acid-

sodium salt / CH ₃ COQ ^ C. ie22) ^ CO ₂ Na I.
f — r I.
ι N- : also ₃
■ f—
^ CH ₂ OCOCH ₃ "0

(e23)

A mixture of 1.3 g of 9-0- (2,3,4,6-Tetra-O-acetyl-oC-D-glucopyranosyl) clavulanic acid p-methoxybenzyl ester (e22) and 0.168 g of sodium carbonate in 24 ml of tetrahydrofuran / water in a ratio 5: 1 is at room temperature and atmospheric pressure in the presence

809823/065 8

- yt -

hydrogenated by 0.4 g of 10 percent palladium on carbon for 15 minutes. The mixture is filtered, the filtrate is evaporated. Man receives 0.96 g of the desired compound e23.

/ cx_ / _D + 27.7 ° (c, 2.3, H ₂ O).

Max

(KBr): 1785, 1740, 1690, 1615 cn

-1

S (D-O): 5.83 (1H, doublet, J = 5Hz, 1'-CH), 5.75 (1H, doublet,

J = 2.5Hz, 5-CH), 3.60 (1H, double doublet, J = 18Hz, J * = 2.5Hz, 6 (X-CH), 3.07 (1H, doublet, J = 18Hz, 6β-CH), 2.15 (9H, singlet,

CH ₃ CO ₂ -) and 1.79 (3H, singlet, CH ₃ CO ₂ -).

Example 19

9-0- (2,3,5-tri-O-benzyl-D-arabinofuranosyl) -clavulanic acid p-methoxybenzyl ester

(elO)

(e24)

C ₆ H ₅ CH ₂ O

CH ₂ O

CO ₂ CH ₂ C ₆ H ₄ OCH ₃

.OCH ₂ C ₆ H ₃

CH ₂ OCH ₂ CgH ₃

A solution of 1.68 g of 2,3,5-tri-O-benzyl-ß-D-arabinofuranose, 1.06 ml of collidine and 1.29 g of tetrabutylinonium bromide in 5 ml of dry dichloromethane are mixed with 1.13 g of trifluoromethanesulfonic acid anhydride offset at -70 C. The Genisch will take 1 hour

80982 3/0658

Stirred room temperature, then mixed with a solution of 0.96 g of clavulanic acid p-methoxybenzyl ester (e1O) in 5 nl dichlorine than. The mixture is stirred at room temperature overnight, then ^{washed at 0} ° C. with 10 ml of 5m hydrochloric acid, dried over anhydrous sodium carbonate / magnesium sulfate and evaporated. An oil is obtained which is chromatographed on a column with 20 g of silica gel and cyclohexane ethyl acetate as the eluent. 0.7 g of the desired compound e24 is obtained.

(CHCl-): 1805, 1745 and 1700 cm

" ¹ .

₃ : 7.20 (17H, singlet, ArH), 6.80 (2H, doublet, J = 9Hz, ArH), 5.51 (1H, doublet, J = 2.5Hz, 5-CH), 5.30 (1H, multiplet, 1'-CH), 5.05 (2H, singlet, CH ₂ Ar), 4.98 (1H, multiplet, 3-CH), 4.48 (6H, singlet, CH ₂ Ar), 3.70 (3H, singlet, OCH ₃ ) and 2.90 (1H, doublet, J = 17Hz, 6β-CH) '.

Example 20 9-0- (1-Butoxy) ethylclavulanic acid sodium salt

(ell) T

(e25)

/ ^CH 3

CH ₂ -O-CH

OCH ₂ CH ₂ CH ₂ CH ₃

A solution of 800 mg of 9-0- (1-butoxy) -ethylclavulanic acid-

(e11)
4-methoxybenzyl ester / and 160 mg sodium bicarbonate in one

Solution of 5 ml of water and 25 ml of tetrahydrofuran is 20 minutes

hydrogenated over 400 mg of 10 percent palladium on carbon. the The solution is filtered and most of the tetrahydrofuran is removed under reduced pressure. The aqueous solution is v / ird extracted twice with ethyl acetate and freeze-dried, lan receives 447 mg of the desired compound e25.

λ) "" (KBr disk): 1780, 1690, 1610 cm " ¹ .

6 (D ₂ O): 0.84 (3H, triplet, J = 8Hz), 1.20 (3H, doublet, J = 5Hz), 1.15 to 1.65 (4H, multiplet), 3.01 ( 1H, doublet, J = 18Hz), 3.45 to 3.7 (3H, multiplet), 4.15 (2H, doublet, J = 8Hz), 4.65 to 4.95 (3H, multiplet), 5, 68 (1H, doublet, J = 3Hz).

Example 21 9-0- (1-ethoxy) -ethylclavulanic acid-4-nethoxybenzyl ester

(elO)

CH ₂ -O-CH-O-CH ₂ CH ₃

CO ₂ -CH (e26)

A solution of 1.5 g of p-methoxybenzyl clavulanate (e10) and 1 ml of vinyl ethyl ether in 15 ml of ethyl acetate is mixed with 25 mg p-Toluolsulfonsäure added and stirred for 15 minutes. The mixture is chromatographed through a short column of silica gel with ethyl acetate as the eluent. The solvent is under

809823/0658

removed under reduced pressure, the product is chromatographed on a silica gel column with cyclohexane / ethyl acetate in a ratio of 3: 1 as the eluent. 1.26 g of the desired compound e26 are obtained.

- ^? "(Film): 1805, 1750, 17OOcm ~ ¹ .

S (CDCl ₃ ): 1.16 (3H, triplet, J = 8Hz), 1.27 (3H, doublet, J = 5Hz), 2.97 (1H, doublet, J = 17Hz), 3.25-3 .7 (3H, multiplet), 3.75 (3H, singlet), 4.0 to 4.15 (2H, multiplet), 4.5 to 4.85 (2H, multiplet), 5.0- (IH, Singlet), 5.07 (2H, singlet), 5.60 (1H, doublet, J = 3Hz), 6.80 (2H, doublet, J = 9Hz), 7.21 (2H, doublet, J = 9Hz) .

Example 22

9-0- (1-Xthoxy) ethylclavulanic acid sodium salt

(e26)

(β27)

A solution of 1.185 g of 9-0- (1-Xthoxy) ethy! Clavulanic acid 4-methoxybenzyl ester (e26) and 254 mg of sodium bicarbonate in one Mixture of 5 ml of water and 25 ml of tetrahydrofuran is hydrogenated over 400 mg of 10 percent palladium on carbon for 25 minutes. The solution is filtered through diatomaceous earth and then under

809823/0658

evaporated under reduced pressure until the bulk of the tetrahydrofuran away. The aqueous solution is extracted three times with ethyl acetate and freeze-dried. The product is purified by chromatography on a silica gel column with n-butanol / ethanol / water in a ratio of 4: 1: 1. After evaporation of the Solvent, 5.89 mg of the desired compound e27 is obtained.

^) (KBr): 179s, 1695, 1615 cm " ¹ .

S (D ₂ O): 1.23 (3H, triplet, J = 8Hz), 1.34 (3H, doublet, J = 6Hz), 3.11 (IH, doublet, J = 18Hz), 3.45 to 4.0 (3H, multiplet), 4.25 (2H, doublet, J = 8Hz), 4.75-5.1 (3H, multiplet), 5.77 (1H, doublet, J = 3Hz).

Example 23 9-0-methoxymethylclavulanic acid

(e4)

A solution of 0.43 g of 9-0-methoxymethyl! Clavulanic acid lithium salt in 25 ml of water is covered with 50 ml of ethyl acetate, stirred and with a strongly acidic ion exchange resin in the H -form is added until the pH of the aqueous phase is below 2.0 (about 20 ml of wet resin). The mixture is filtered, the The filtrate is separated off. The aqueous phase is three times with each

809823/0658

30 ml of ethyl acetate extracted. The ethyl acetate extracts are combined, dried rapidly over 30 g of a molecular sieve (type 3A), filtered and in a rotary evaporator under reduced pressure Pressure evaporated to an oil. 0.3 g of the desired compound is obtained.

-J (film): 2500 to 3600 (very wide), 1805, 1750, 1695 cm ~ ¹ .

Iu et X

& (CDCl ₃ ): 3.00 (1H, doublet, J = 17Hz, 6β-CH), 3.33 (3H, singlet, OCH ₃ ), 3.45 (1H, double doublet, J = 2.5 and 17Hz, 60C-CH), 4.13 (2H, doublet, J = 7Hz, 9-CH ₀ ), 4.58 (2H, singlet, OCH-O), 4.88 (1H, triplet, J = 7Hz, 8-CH), 5.01 (1H, singlet, 3-CH), 5.63 (IH, doublet, J = 2.5Hz, 5-CH).

Example 24

Using dry ingredients are more conventional The following preparations are made in a dry atmosphere:

a) Tablets mg methoxymethylclavulanic acid sodium salt 150 anhydrous ampicillin 300 microcrystalline cellulose 600 magnesium stearate 15

b) Capsules mg methoxymethylclavulanic acid sodium salt 250 magnesium stearate 2.5

Starch glycollate natriura salt ⁵ »°

809823/0658

- ys -

c) Annulated for resumption in sterile water for the immediate injection

Methoxymethylclavulanic acid sodium salt Sodium amphicillin

mg

50

2 50

pharmacology

Using conventional procedures, the minimum inhibitory concentration is determined of ampicillin -with the addition of inventive Compounds determined as an inhibitor.

a) Compound of Example 16

Minimum inhibitory concentration
of ampicillin (pg / ml) Prot.
C 889 Glue
E 70 E. coil
JT 39 Inhibitor
concentrar
tion
(pg / ml) Staph.
Russell 1.0 - - 20th - 2.0 1.6 4th 5 - - 1.6 125 1 0.3 > 2000 1000 > 2000 0 125

809823/0658

b) Compound of Example 7

Minimum non-concentration
of ampicillin (μς / ΐηΐ) Staph.
Russell Glue
E 70 Proteus
C 889 E. coll
JT 39 E. coil
JT 410 Inhibitor
concentra
tion
(pg / ir.l) ' 0.15
1.25
500 12.5
25th
1000 15.6
125
> 2000 > 500
500
2000 62 ₇ 5
62 _; 5 20th
5
1
0

c) Compound of Example 20

Minimum atmospheric concentration
of "ampicillin (pg / ml ) Glue
E 70 Proteus
C 889 E. coil
JT 410 Inhibitor
concentra
tion '■
(jig / ml) ■ Staph.
Russell 1.6-3.1
6-12
'2000 15th
62.5
> 2000 2000
> 2000
62.5 20th
5
1
0 (0.04)
0.08
> 500

8 0.9 8 2 3 /0.6 p

Connection of the example

Minimum inhibitory concentrates
of ampicillin (pg / ml) Staph.
Russell Glue
E 70 Proteus
C 889 E. coli
JT 39 E. coli
JT 410 Inhibitor
concentra
tion
(pg / ml) - - - - - 20th 0.04 3.12 1.0 2.0 125 5 0.6 3.12 15.6 4.0 - ■ 1 250 500 > 2000 1000 250 0

e) blood levels

After subcutaneous administration of methoxymethylclavulanic acid sodium salt at a dose of 10 mg / kg on mice, the following blood level values are obtained. The fourth for clavulanic acid sodium salt are given for comparison:

Time (minutes)

yg / ml methaxmethylclavulanic acid sodium salt

Clavulanic acid sodium salt

20th

V ² Y ²

45

0.8

60

⁰ I ⁸ 0.5

809823/0658

After oral administration of ethoxyethylclavulanic acid sodium salt to mice in a dose of 20 mg / kg the following blood level values are obtained. The values for clavulanic acid sodium salt are given for comparison:

Time (minutes) 15 30 45 $ o

ug / ml methoxmethylclavulan ίο. β 7 4 > ι * a

* acid sodium salt 1 Ί * V ^{1 x} ; ^4th

yg / ml clavulanic acid- 3 _f 5 2 _? 6 1.5 0.6

natriuir.salz ''

f) Healing effects of methoxymethylclavulanic acid sodium salt and amoxycillin

The following CD ₅ values are obtained from intraperitoneal infections with Escherichia coli JT 39. The test compounds are administered either subcutaneously 1 and 5 hours after infection or orally 1.3 and 5 hours after infection:

Test compounds CD ₅₀ (mg / kg)

Amoxycillin (subcutaneous)

2.5 mg / kg methoxymethylclavulanic acid

sodium salt + amoxycillin 6.8

2.5 mg / kg clavulanic acid sodium salt

+ Amoxycillin 14

809823/065 $

1 mg / kg methoxymethylclavulanic acid

sodium salt + amoxycillin 23.4

1 mg / kg clavulanic acid sodium salt

+ Amoxycillin 4O

CD ₅₀ O χ mg / kg) amoxycillin (oral)

20 mg / kg l methoxymethylclavulanic acid

sodium salt + amoxycillin 11

20 mg / kg clavulanic acid sodium salt

+ Amoxycillin 9

809821 / 0R58

Claims (67)

Claims 1 / Compounds of the formula I, their salts and esters CH ₂ -O-CR ^X R ² -XR ³ in which X is an oxygen or sulfur atom, R and R are hydrogen atoms or lower alkyl radicals, which optionally are connected to one another, R is an optionally inertly substituted lower alkyl radical or with the radical R a optionally inertly substituted 5- or 6-membered heterocyclic ring forms. 2. Compounds according to claim 1, formula I, in which X is the oxygen atom is. 3. Compounds according to claim 1 and 2, characterized in that R is a hydrogen atom or the methyl or ethyl radical. 4. Compounds according to claim 1 and 2, characterized in that R is the hydrogen atom. 5. Compounds according to claim 1 to 4, characterized in that R is a hydrogen atom or a methyl or ethyl radical. 809823/0659 ¹ 2752 ^π 01 6. Compounds according to claim 1 to 4, characterized in that R is the hydrogen atom or the methyl radical. 7. Compounds according to claim 1 to 4, characterized in that 2
that R is the hydrogen atom. 8. Compounds according to claim 1 to 7, characterized in that R is the methyl, ethyl, n-pronyl, isopropyl, n-butyl, Isobutyl or tert-butyl radical. 9. Compounds according to claim 1 to 7, characterized in that R is the methyl, ethyl or propyl radical. 10. Compounds according to claim 1 to 7, characterized in that R is the methyl radical. 11. Compounds according to claim 1 to 7, characterized in that R- is the ethyl radical. · ·. · 12. Compounds according to claim 1 to A _1, characterized in that 12 3
that the radical -CR R XR is a radical of the formula a or b Λ • R * 80982 3/0 6 58 in which R ^a , R ^b , R ^c , R ^d , R ^e and R ^f each represent a radical R ⁴ or OR ⁴ and α 4 4 4 R ^{y is} a radical R or CH ₃ R, where * R is a hydrogen atom, a lower alkyl or acyl radical or a benzyl radical, preferably an alkyl or acyl radical with up to 4 carbon atoms. 13. Compounds according to claim 12, characterized in that R ^a , R, R ^c , R, R ^e , R and R ^{g are} each a hydrogen atom or a methyl radical. 14. Compounds according to claim 12, characterized in that R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^{g are} hydrogen atoms. 15. Compounds according to claim 1 of the formula II, their salts and esters ₂ -O-CHR ² -OR ³ (H) 2 3 in which R and R are defined according to claim 1. 16. Compounds according to claim 15, characterized in that the radical of the formula CHR ² OR ^{3 is} a radical of the formula CH ₂ OCH. 17. Compounds according to claim 15, characterized in that the radical of the formula CHR ² OR ^{3 is} a radical of the formula CH (CH ₃ ) OCH ₃ . 18. Compounds according to claim 15, characterized in that the radical of the formula CHR ² OR ^{3 is} a radical of the formula CH ₂ OC ₂ H ₅ . 809823/0658 19. Compounds according to claim 15, characterized in that the radical of the formula CHR ² OR ^{3 is} a radical of the formula CH (CH ₃ ) OC ₂ H ₅ . 20. Compounds according to claim 15, characterized in that the radical of the formula CHR ² OR ^{3 is} a radical of the formula CH (C ₂ H ₅ ) OC ₂ H ₅ . 21. Compounds according to claim 15, characterized in that the remainder of the formula CHR OR is a tetrahydropyranyl residue. 22. Compounds according to claim 15, characterized in that 2 3
the remainder of the formula CHR OR is a tetrahydrofuranyl residue. 23. Compounds according to claim 1 to 22 in the form of the free acid, 24. Compounds according to claim 1 to 22 in the form of a salt. 25. Compounds according to claim 1 to 22 and 24 in the form of a
Lithium, sodium, potassium, calcium or magnesium salt ,.
an ammonium or substituted ammonium salt. 26. Compounds according to claim 1 to 22, 24 and 25 in the form of a lithium salt. 27. Compounds according to claim 1 to 22, 24 and 25 in the form of a sodium salt. 28. Compounds according to claim 1 to 22, 24 and 25 in the form of a potassium salt. 809823/0 658 29. Esters of the compounds according to claim 1 of the form III and IV - O - CR ¹ R ² - ** ³ rVV ^^ - ° - \ CO ₂ - CH - A ² in which R, R, X and R are defined according to claim 1 and A is an alkyl radical having 1 to 8 carbon atoms, the given 4 4 if with halogen atoms or a radical of the formulas OA, OCOA, 4 4 4 SA or SO A is substituted in which A is a hydrocarbon rest with up to 6 carbon atoms, A is a hydrogen atom, an alkyl radical with up to 4 carbon atoms or a phenyl radical is, which optionally with halogen atoms or an alkyl or alkoxy radical is substituted by up to 6 carbon atoms and A is a phenyl radical, optionally with halogen atoms or an alkyl or alkoxy radical with up to 6 carbon atoms is substituted. ~ · - ·. 30. Compounds according to claim 1 to 22 and 29 in the form of a saponifiable ester. 31. Compounds according to claim 1 to 22 and 29 in the form of a hydrogenatable ester. 32. Compounds according to claim 30 in the form of the methyl ester. , 33. Compounds according to claim 31 in the form of the benzyl ester. 809823 / 06S8 34. Compounds according to claim 31 in the form of the Ilethoxybenzylesters, 35. Compounds according to claim 31 in the form of the nitrobenzyl ester. 36. 9-O-methoxymethylclavulanic acid benzyl ester. 37. 9-0-methoxymethylclavulanic acid lithium salt. 38. 9-0-Ethoxymethylclavulanic acid benzyl ester. 39. 9-0-Ethoxymethylclavulanic acid lithium salt. 40. 9-0-Methylthiomethylclavulanic acid benzyl ester. 41. 9-0-methylthiomethylclavulanic acid lithium salt. 42. 3-O- Π-butoxy) ethy! Clavulanic acid 4-methoxybenzyl ester. 43. 9-0-Tetrahydropyran-2-yl-clavulanic acid benzyl ester. 44. 9-0- 45. 9-0-Tetrahydrofuran-2-yl-clavulanic acid 4-methoxybenzyl ester. 46. 9-0-Tetrahydrofuran-2-yl-clavulanic acid, sodium salt. 47. 9-0-methoxymethyl! Clavulanic acid. 48. 9-0-methoxymethylclavulanic acid sodium salt. 809823/0658 49. S-O-i-methoxymethylclavulanic acid kaliuir.salz. 50. "J-O-Methoxymelhylclavulanic acid calcium salt. 51. A process for the preparation of the compounds according to claim 1, characterized in that one has a clavulans whore ester with a compound of formula V converts Y - CR ¹ R ² - X - R ³ (V) 12 3 in which X, R, R and R are defined according to claim 1 and Y is an easily displaceable radical, and optionally the resulting Converting ester into the free acid or its salt or into another ester ·. 52. The method according to claim 51, characterized in that a compound of the formula V is used in which Y is the iodine, Bromine or chlorine atom, the methanesulphonyl or toluenesulphonyl group is. 53. The method according to claim 51 and 52, characterized in that a compound of the formula V is used in which Y is the Is bromine or chlorine atom. 54. The method according to claim 51 to 53, characterized in that the reaction in the presence of a base with lower Performs nucleophilicity. 809823/0658 -5G- 55. The method of claim 51 to 54, characterized in that one carries out the reaction at a temperature of -20 to +30 ⁰ C. 56. A process for the preparation of compounds according to claim 1, formula I, in which X is an oxygen atom, R is a hydrogen atom and R is a radical having at least 2 carbon atoms, the is optionally bound to the radical R, characterized in that that one has a clavulanic acid ester with a compound of Formula VI implements. R ¹¹ R ¹ C = CH-OR ³ (VI) the , . - 3 in which / radical RRC is a radical R and R according to claim 1 is defined, and optionally converts the resulting ester into the free acid or its salt or into another ester, 57. The method according to claim 56, characterized in that the reaction is carried out in the presence of an acid as a catalyst performs. 58. The method according to claim 56 and 57, characterized in that the acid used is hydrochloric acid, phosphorus oxychloride, p-toluenesulfonic acid or boron trifluoride is used. 59. Process for the preparation of the compounds according to claim 1, characterized in that one has a clavulanic acid ester a compound of the formula IX 809823/0 65 8 R ⁵ - O - CHR ² - OR ³ (IX) 2 3 5 in which R and R are defined according to claim 1 and R is a tertiary alkyl radical having 4 to 6 carbon atoms, and optionally converting the ester formed into the free acid or its salt or into another ester. 60. The method according to claim 59, characterized in that there is a connection
Butyl radical. a compound of the formula IX is used in which R is a tert. 61. Process for the preparation of compounds according to claim 1, characterized in that a corresponding ester is used a compound of formula I saponified. 62. The method according to claim 61 for the preparation of a salt of a compound of the formula I, characterized in that an ester of a compound of the formula I is subjected to mild basic hydrolysis. 63. The method according to claim 61, characterized in that the ester radical is split off by hydrogenation. 64. Medicinal preparations, characterized by a content of a compound according to claim 1 as an active ingredient in combination with customary pharmacologically acceptable carriers and / or ^% Thinners. 809823/0658 65. Medicinal preparations according to claim 64 / characterized by a additional content of a penicillin or cephalosporin. 66. Medicinal preparations according to claim 64 and 65, characterized in that that the ratio of compound according to claim 1 to penicillin or cephalosporin is 1:10 to 10: 1. 67. Medicinal preparations according to claim 64 to 66, characterized in that that the ratio is 2: 1 to 1: 5, preferably 1: 1 to 1: 3. «09823/0658