DE2147417A1 - alpha aminobenzyl pemcillin pem cillanate salts - Google Patents

Description

^H ot-Aminobenzylpenieillin-penicillanatsalze "

Priority: September 22, 1970, Great Britain, No. 4-5 027/70

The present invention relates to new salts which are derived from «X-Aminobenzylpenicilliu.

oo ~ Aminobenzylpenicillin has been antibiotic because of its favorable Activity against both gram positive and gram negative bacteria found wide use. Unfortunately, oC-aminobenzy! Penicillins tend to break through the enzyme Penicillinase which is produced by many strains of staphylococci. They are other species of Peuicil J-in known which are also active against such penicillinase-producing staphylococcal strains, but show such Unfortunately, penicillins have no activity against gram-negative bacteria. It is therefore already a combination product • Have two different types of penicillin also been proposed?

^! - ''"209813/1756

for example British patent specification 1 103 425 describes pharmaceutical preparations which contain a mixture of cloxacillin and ampicillin or hetacillin ^ and in the British Patent specification 1 175 590 other pharmaceutical preparations ■ are disclosed which are a mixture of plucloxacillin and ampicillin, contain.

However, it is not easy to produce a pure and stable mixture of such different types of penicillins.

This difficulty has now surprisingly been overcome by the inventive novel stable penicillin salts, which are derived from a ⁰ ^ -Aminobenzylpenicillinester as a cationic component and an anionic component as penicillinasebeständigen penicillin.

The oC-aminobenzylpenicillins are essentially present as zwitterions, and therefore their sodium salts form with weak acids ^ ren, for example with the carboxyl group of a penicillin j molecule, not even salts. . *;

Unexpectedly, however, it has been shown that the esters of such oc-aminobenzylpenicillins are capable of forming stable penicillinate salts which, for the first time, combine an activity both against gram-negative bacteria and against bacteria producing penicillinase. The new salts according to the invention also have the advantage that when administered orally they result in a higher concentration in the blood plasma than can be obtained with a corresponding dose of an alkali ₍

209813/1756

metal salt of oC-aminobenzylpenicillin can achieve.

Accordingly, the invention relates to oil-aminobenzylpenicillin penicillanate salts of the general formula I below

NS,

R.CO.HH.CH-CH C-CH,

I -i I * CO- H - CH.COg

CH. CO. 1IH. CH- CH >. II

C-CH,

IiH,

CO-K

in which X is hydrogen or the hydroxyl group, R is an alkyl, aryl or heterocyclic group and R is an etheric group hindered group of the following formulas II, ΙΪΙ and IV marked type

(II) (HD

where Y or Y is hydrogen, chlorine and / or fluorine atoms and Z is an alkoxy group having 1 to 6 carbon atoms is.

The cationic portion of the salts of the formula I according to the invention consists in particular of a penicillanate ester of an ol-aminobenzylpenicillin, that is to say it is a

209813/1756

-A-

Penicillin of the ampicillin type, it being possible for the penicillin in question to be in the D or L configuration, but the D configuration is preferred. The benzene nucleus can be substituted by hydroxyl groups, so that esters of D-OL- aminobenzylpenicillin and D- ^f X ^ -amino-4'-hydroxybenzylpenicillin are preferably present as cations in the salts according to the invention. The ester groups are acyloxymethyl esters. The acyl group corresponds to the formula R ¹ CO- , where R 'is an alkyl, aryl or heterocyclic group »Palls R' is an aliphatic hydrocarbon chain, this chain can be straight or branched, saturated or unsaturated and it contains 1 to 6 carbon atoms . If R ^{1 is} an alicyclic radical, it can be the cyclopentyl, cyclohexyl, 1-adamantyl, 1-bicyclo (2,2,2) octyl, cyclopentenyl or. Act cyclohexenyl group. R ¹ can also be an aromatic radical, for example the phenyl group, a substituted phenyl group, the 1-kaphthyl group, the 2-naphthyl group or a substituted naphthyl group o Examples of aralkyl groups are the benzyl group or a substituted benzyl group. If R ¹

has the meaning of a heterocyclic group, it can be

to the pyridyl, pyrazinyl, pyrimidyl, thienyl, furyl or Act quinolyl group. The group R «can also, for example, by one or more lower alkyl groups, lower alkoxy · groups, lower alkylthio groups, haloalkyl groups, such as Trifluoromethyl or trichloromethyl groups, nitro groups and / or halogen atoms may be substituted.

According to a preferred embodiment of the invention, R ^{1 has}

209813/1756

the meaning of the terto-butyl group, so that it is the ester in question is a pivaloyloxymethyl penicillanate.

The anionic part of the new salts according to the invention is formed by a sterically hindered penicillin which has the required resistance to penicillinase. If R is a 3-phenyl-5-methyl-4-isoxazolyl group according to the formula II and both Y and Y are hydrogen atoms, the anionic constituent in question is penicillin oxacillin. If R is the 3- (o-chlorophenyl) -5-methyl-4-isoxa ⁱ 7, olyl group of the formula II given above, in which Y is a chlorine atom and Y is a hydrogen atom, then the anionic constituent is concerned the penicillin cloxacillin. If in formula II Y is a chlorine atom and Y is also a chlorine atom, the anionic constituent is dicloxacillin.und

•1

if Y is in the. Formula II is a chlorine atom and Y is a fluorine atom, the anionic constituent is flucloxacillin. However, R can also have a structure according to the formula III, where Y is a chlorine atom and Y is hydrogen, a chlorine atom or a fluorine atom. R then has the meaning of a 1- (o-chlorophenyl) -4-methyl-5-pyrazolyl group. The corresponding anionic constituent of the salt can then be pyrazocillin. If R is a 2-alkoxy-1-naphthyl group of the structural formula IV: ", where Z is an alkoxy group with 1 to 6 carbons. J

• ■ J

has atoms, it can be the anionic constituent. part of the penicillin nafcillin (Z is an ethoxy group) Act·

20981371756 '

^ Q «Μ

The salts according to the invention can be produced in a relatively simple manner, for example by adding equimolecular proportions an alkali metal salt of the penicillin component having penicillinase resistance and a suitable salt of the Ä-Aminobenzylpenicillxnesters in a solvent with one another mixed, in which each of the penicillin components is soluble in itself, but from which the salt formed precipitates. For this reason it is very convenient to use aqueous solutions of the; Sodium salt of the penicillinase resistant penicillin component

To use W and the corresponding hydrogen chloride salt of the ÖC-aminobenzylpenicillin ester o In this embodiment, the salt formed according to the invention generally precipitates immediately. The formation of the precipitate also confirms that actual salt formation has occurred and that this product is not simply a physical mixture of the two starting materials. The formation of a salt of a defined composition is also confirmed by the nuclear magnetic resonance spectrum (hereinafter abbreviated as nmr) ,

t which contains the two penicillin components in a molar ratio of 1: 1.

The examples illustrate the invention.

Example i

^ϊ A solution of 0.229 g (0.0005 Hol) 3- (o-chlorophenyl) -5-methyl-4-isoxazolylpenicillanate (sodium salt) in 5 ml of water is mixed with a solution of 0.258 g (0.0005 mol) of the hydrochloride of Pivaloyloxymethyl-D- ot-amino-p-hydr oxybenzylpenic illana t in 2 ml

209813/1756

Treated water. The solid which separates out is filtered off, washed well with water and dried over phosphorus pentoxide in vacuo. This gives 0.33 g (yield 73 percent) of a cream-colored pesticide. N.ra.r. (CD ^ gSO / DgO <5 * = 1.15 (9H.S. Pi-valoylmethyl groups), 8 = 1.44 (12H.S. gem-Dimethy! Groups), S = 2.68 (3H.s. Isoxazolyl-5-methyl group),

I _m

d = 4.07 (1H.S. C, proton of isoxazolylpenicillin), ο = 4.40 (1HoS. C, proton of penicillin ester), c? = 4 »91 (1H.s. oC proton), S = 5.49 (4H» m. Ss-lactam protoneii), 6 * = 5.80 (2H <.m. Methylene group), β = 6.80, 7.32 (4H.m <7 p-substituted aromatic group), d = 7.58 (4Η · ΐη. O-substituted aromatic group).

Example2

-A solution of 2.37 g (0.005 mol) 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolylpenicillauat (sodium salt) in 50 ml v / water becomes a clear solution of 2.58 g (0.005 mol) of the hydrochloride of pivaloyloxymethyl-D-oL-amino-p-hydroxy-benzyl penicillanate in likewise 50 ml of water was added. The mixture is shaken thoroughly and the precipitated reaction product is filtered off, carefully washed out with water and dried in vacuo over phosphorus pentoxide. This gives 3.72 g (yield 80.7 percent) of a pale cream-colored pesticide. The infrared spectra show strong carbonyl absorption at 5.62 to (β-lactam), at 5.99 / U (amide bond) and at 6 , 2 Ai (ionized carboxyl group). N.ra.r. (CD,) ₂ SO / D ₂ O S = 1.15 ". (9H.s. pivaloylmetliyl groups), 5 = 1.49 (12H.ni. gem-dimethyl group), 6 * = 2.72 (3H .S. Isoxazolyl-5-methyl group), 6 ^ = 4.10 (1H.S.

209813/1756

C, proton of isoxazolylpenicillin), d = 4.4θ (1H.S. C, proton · of penicillin ester), d - 5.47 (4Hom. Β-lactam protons), 6 = 5.80 (2Hom. Methylene group), d = 6.79 and 7.29 (4H.q. p-substituted aromatic group), d * = 7.52 (3H.ni. 2, 6-disubstituted aromatic group). '

Example 3

A solution of 0.982 g - (0.0002 mol) 1- (2,6-diehlophenyl) ~ 4-methyl-5-pyrazolylpenicillanate (sodium salt) in 20 ml water is added to a solution of 0.916 g (0.0002 mol) des Hydrochloride of acetoxymethyl-D-od-aminobenzylpenicillanate is also added in 20 ml of water. The reaction product which has separated out is filtered off, washed thoroughly with water and dried in vacuo over phosphorus pentoxide. 1.1 g (yield 61.7 percent) of a colorless solid are obtained in this way. Nmr (CD-, igSO / ^ O 6 ^ = 1.52 (12H.dc gem-dimethyl group), 6 * = 2.07 (3H.s. acetyl group), d = 2.33 (3H.S ., Pyrazole-4-methyl group), 6 * = 4.19 (1H.-S. C, proton from pyrazolylpenicillin), 6 = 4.40 (Hs _e C, proton from penicillin ester), d = 5.0 ( 1HoS.oi proton from penicillin ester), O = 5.47 (4HoS.ÖC-lactam proton), Ö * = 5.77 (2HcSe methylene group), d = 7.45 (5H.m.Phenyl group), 5 * = 7 , 58 (3H.So 2,6-disubstituted aromatic group), 6 * = 7.72 (1H.S. ~ 3-proton from the pyrazole ring).

Example 4

A solution of 0.952 g (0.0002 mol) 3- (2-chloro-6-fluorophenyl) _T 5-methyl-4-isoxazolyl penicillanate (sodium salt) in 20 ml water

209813/1756

is added to a solution of 0.916 g " (0.0002 mol) of the hydrochloride of acetoxymethyl-D-oi-aminobenzylpenicillanate in likewise, 20 ml of water This gives 1.04 g (yield

59.4 percent) of a colorless solid. N. 'only (CD ^ oSO / DpO ■: _ 6 = 1.50 (12Hod.gem-dimethyl group), d - 2.09. (3H.s', acetyl group), c * "= 2.72 (3H .s "isoxazolyl-5-methyl group), <? = 4.16; (iHoS.o C ₅ proton from isoxazolylpenicillin), 6" * = 4.91 (1H.s. C, proton from penicillin ester), (y - 5.03 (1Ε »ε ·« OC proton of the penicillin ester), G ⁷ = 5.50 (4H.s. od-Lactamprpton), d = 5.78. (2H »see methylene group), 6 ^ = 7.49 (3H.m. "2,6-disubstituted aromatic group) ₀

Example5

A solution of 2.37 g (0.005 mol) 3- (2-chloro-6-fluorophenyl) - ■■■ '5-methyl-4-isoxazolylpenicillanate (sodium salt) in 50 ml of water becomes a clear solution of 2.50 g (0.005 mol) of the hydro: chloride of pivaloyloxymethyl-D- oL- aminobenzylpenicillanate in likewise 50 ml of water was added. Shake this mixture; well, filter off the deposited solid, wash it well with water and dry in vacuo over phosphorus pentoxide. 3.77 g (yield 82.4 $>) of a weakly _; cream-colored solid. Nmr (CD,) ₂ SO / D ₂ O ö = 1.14 (9H.s .. pivalylmethyle), rf = 1.49 (12H.ni. gem-dimethyl group) ·, <Γ ^ = · 2.70 ( 3H.S. 1 boxazolyl-5-methyl group), € - 4 »O9 (1H.s.

^; 0, proton of isoxazolylpenicillin), (f * = 4.41 (1H.s. C, proton

209813/1758 '

£ = ^ »95 (IH.s. oUProton from penicillin ester), · from penicillin ester), / 6 * = 5.49 (4H.m _e ß-lactam proton), ti s 5.80 (2HeMo methylene group), d = 7 , 43 (5H.s. monosubstituted aromatic group), 6 ¹ = 7.51 (3H.m. 2,6-disubstituted aromatic group) _o

Example 6

A solution of 0.982 g (0.002 mol) of 1- (2,6-dichlorophenyl) -4-methyl-5-pyrazolylpenicillanate (sodium salt) in 20 ml of water becomes a solution of 1 g (0.002 mol) of the hydrochloride of pivaloyloxymethyl-De *: -aminobenzylpenicillin also added to 20 ml of water «. This mixture is shaken well, the precipitated solid is filtered off, washed thoroughly with water and dried in vacuo over phosphorus pentoxide. This gives 1.35 g (72.5 percent yield) of a colorless solid »Imr (CD ₅ ) ₂ SO / D ₂ O 6 ^ = 1.14 (9H.s. pivalylmethyl), δ" = 1.48 ( 12H.m. gem-dimethyl groups), 6 ¹ = 2.33 (3H.S. pyrazol-4-methyl group), ό '= 4.12 (IH.sG ^ proton from pyrazolylpenicilliu), 6 * = 4.41 ( 1H »S. C, proton from penicillin ester), 6 = 5.47 (4H.m. ß-lactam protons), € = .5.80 (2H.s. methylene group), 6 * = 7.46 (5H.s aromatic group), 6 * = 7.60 (3H »see 2,6-disubstituted aromatic group),, δ '= 7.72 (1H.S. 3-proton from the pyrazole ring).

209013/1756

Claims (8)

- 11 claims 1 / ^ -aminobenzylpenicillin penieillanate salts of the following general formula (I) NS ii.CO.iiE.CH ~ CH C-CH Il I · '. . . CO-N CH. CO ^ (D β < / V / .CH.CO.Iffi.CH — CH C-CE. I! I. C0_2i C2 in which X is hydrogen or the hydroxyl group, 'R is an alkyl, aryl or heterocyclic group and R is a sterically hindered group of the type characterized by the formulas (II), (III) or (IV) (ID (III) 209813/1756 where'i ³ L and Y denote hydrogen, chlorine or fluorine atoms and Z is an alkoxy group having 1 to 6 carbon atoms. 2. Salts ftemä.ss claim 1, formula (l), in v / which R is the tertiary P is butyl group. 3. Salts according to claim 1 and 2, in which II the 3- (o-chlorophenyl) -5-ynethyl-4-isoxazolyl group and X is a p-position hydroxyl group. 4. Salts according to claim 1 and 2, in which R is 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolyl group, and X ^water: fabric or is a hydroxyl in p-position. 5. Salts according to claim 1 and 2, in which R is the 1- (2,6-di chlorophenyl) -4-methyl-5-pyrazolyl group and X is hydrogen is. 6, salts according to claim 1, formula (I), in which R is the Is methyl group. 7. Salts according to claim 1 and 6, in which R is 1- (2,6-Di chlorophenyl) -4-methyl-5-pyrazolyl group and X is hydrogen is. _m - 209813/1756 2U7417 8. Salts according to claim 1 and 6, in which K the 3 ~ (2-chloro ~ 6-fluorophenyl) -5-methyl-4-isoxazolyl group and X wafer is. 209813/1756