DE2058110B2 - Monoester of alpha-carboxybenzyl penicillin - Google Patents

Description

"': i ^r ; 0 ^;; f ¹ ' C-OCHO-C ^ R ₃

0 R ₁ , 0

in which R _{1 is} a hydrogen atom or the methyl radical and R _{3 is} the methyl or tert. Represents butyl radical, and their pharmaceutically acceptable salts.

2. 6- [2-Phenyl-2-carboxyacetamido] penicillanic acid - 3 - monopivaloyloxymethyl ester - sodium salt.

3. 6- [2-Phenyl-2-carboxyacetamido] penicillanic acid 3-mono-α-acetoxyethyl ester, sodium salt.

The invention relates to new monoesters of u-carboxybenzylpenicillin, which surprisingly have high antibacterial activity when administered orally.

Trying to determine the oral effectiveness of u-Carboxybenzylpenicilliii to improve led to the production of a variety of ester derivatives. The NL-PA 69,00135 describes a number of monoarylu-carboxybenzylpenicillin esters, and GB? PS 1 138 745 discloses diesters of α-carboxybenzyl penicillin including the bis (acetoxymethyl) ester.

The invention relates to monoesters of u-carboxybenzylpenicillin of the general formula

^15th > f ^CNH Tf

CO ₂ H JN-

CH ₃

C-OCHO-C-R,

Il I II

OR ₁ O

in which R _{1 represents} a hydrogen atom or the methyl radical and R _{3 represents} the methyl or tert-butyl radical, and their pharmaceutically acceptable salts.

The following unambiguous, different synthetic routes can be used to prepare the monoesters according to the invention to be taken:

H, N

+ Scheme A CO ₂ H 0-CH C-Act
H H ₂ N Γ / S. CH, R ₁ CHj Il
0 _¥ 2 XT J CH, CHj Shark CHOCOR ₃ O R. C = O
jCOCHO
Il ι CO ₂ H + R ₁ I. Il
O ►

The alkylation of the commercially available 6-aminopenicillanic acid (1) with an acyloxyalkyl halide

Shark CHOCOR ₃

55

where R ₁ , R ₃ and Hal have the abovementioned bedding, is carried out in an aprotic, reaction-inert solvent, such as dimethylformamide or acetone, in the presence of a lower tertiary alkylamine such as triethylamine.

In practice, a suspension of the aminopenicillanic acid (6-APS) in the solvent is used Room temperature and under nitrogen with at least an equimolar amount of the tertiary amine, if necessary with an up to 5fl% excess, brought into contact, and the mixture is 30 to Stirred for 60 minutes. The α-acyloxyalkyl halide is added quickly and the mixture, again at room temperature, stirred for 4 to 12 hours. A Water-immiscible solvent, such as ethyl acetate, is used until it becomes cloudy added, and the tertiary amine hydrohalide is filtered off. The mixture is then treated with water, the organic layer is separated and dried and finally concentrated. The ester of 6-APA (2) is best stored for further use as a salt, preferably as the p-toluenesulfonic acid salt, which is obtained by treating the concentrated organic ethyl acetate layer with a Solution is treated, which is an Äcjuirtiolafe Amount of p-toluenesulfonic acid in the same Contains solvent.

The ester (2) is obtained by acylation with an activated form of phenylmalonic acid

(OCH (CO ₂ H) CO-ACt

where Act is a chloride, anhydride, or a p-nitropheriyl ester is converted into the desired product I. The preferred activated form is off For reasons of economy and ease of preparation, the monoacid chloride.

This reaction is best carried out in a heterogeneous solvent system, using water and a water-immiscible, inert solvent * such as isopropyl ether or benzene is used will. In practice, a suspension of 1 mole of the 6-APA ester (2) suspended in the Solvent mixture and in an Eisbed'gekUhlU with 1 mol of the acid chloride of phenylmalonic acid.ber acts while a saturated sodium bicarbonate solution is added simultaneously at such a rate that the pH remains at 5.5 to 6.5; After the addition, which requires 15 to 20 minutes, the reaction mixture is left on the ice bath for more Stirred for 15 to 20 minutes and then at room temperature for 2 to 4 hours. The pH value is increased to 5.5 adjusted and the organic layer separated, dried over sodium sulfate and under vacuum concentrated to dryness, the crude product is dissolved in diethyl ether and added to an equimolar amount of sodium 2-ethylhexanoate, dissolved in acetone, treated, whereupon the precipitated sodium salt of I is filtered off. .

Scheme B

CO ₂ Q

2 + © CH

CO-Act

Ii

© CHCNH

I \

CO ₂ O

O C = O

R ₃ COCHO

The scheme shown above is a modification of scheme A and uses an activated phenylmalonic acid ester. The preferred activated The form of this ester is again the acid chloride.

The condensation of 2 with the acid chloride is carried out in a manner similar to Scheme A with reference on the ratio of the starting materials, the solvent, the temperature and the time. After the reaction has ended, however, the pH is adjusted to 7 and the organic layer is separated off and dried over sodium sulfate, after which the solvent is removed under reduced pressure.

The removal of the protective phenyl group from the α-carboxy group of 3 is carried out by means of basic Hydrolysis accomplished at pH 9.

Here, a solution or partial suspension of 3 in a suitable inert solvent, such as tetrahydrofuran, acetone or dimethylformamide, is treated with a borate buffer and has a pH of 9 to 9.5. When the hydrolysis is complete, the reaction mixture is treated with a water-immiscible solvent, such as diethyl ether, and the pH of the aqueous layer is adjusted to 5 to 5.5. The organic layer is separated and concentrated under reduced pressure to dryness or 2 äthylkexanoat sodium otherwise treated with acetone or ethyl acetate Einei ¹ solution of N-ethylpiperidine, or is filtered off after which the formed salt.

6-APA + φ- CH

Scheme C O
Il S. I. CH ₃ Il
OCHCNH IN CH ₃ CO ₂ O CO ₂ ?)
- ♦
O CO ₂ H CO-Act

4 + HaICHOCR,

20 58 ΠΟ

The acylation of 6-APS (I) with the monophenyl ester an activated phenylmalonic acid, such as the acid chloride, leads to the formation of the phenyl ester of u-carboxybenzylpenicillin (4) and is described in GB-PS 1 004 670 and ZA-PS 67/6472. Although the phenyl ester of phenylmalonic acid is the preferred compound for both pathways B and C, however, any aryl ester can be used with comparable success.

The alkylation of 4 with the appropriate a-acyloxyalkyl halide, which leads to 3 is in a reaction-inert solvent, such as dimethylformamide, Benzene or dimethyl sulfoxide carried out. The salt of 4 can be prepared in situ, whereby a base such as B. sodium hydride, sodium methoxide or a lower tertiary alkylamine, such as triethylamine, is used. On the other hand, the salt can be produced and isolated using conventional methods before it is used in this implementation.

In general, 1 mol of salt is at least 1 MoI halide and, optionally, ^m:! an up to 50% excess of the same implemented. Ambient conditions are used and the reaction time is 2 to 24 hours. The desired product 3 is conveniently separated off by hydrolysis of the reaction mixture and subsequent extraction with a water-immiscible solvent, such as methylene chloride, benzene or ethyl acetate. The organic layer is separated, dried and removed in vacuo to give the desired product.

The hydrolysis of the phenyl or aryl esters of compound 3, which leads to the products according to the invention of the general formula I leads, with the preferred use of a borate buffer carried out from pH 9 to 9.5, as discussed above for Scheme L.

The starting materials suitable for the synthesis of monoesters of the general formula I in schemes A, B and C. are either off-the-shelf chemicals or can be easily made. Disodium-a-carb-. Oxybenzylpenicillin is commercially available as the precursor for the preparation of the free diacid and other salts are described in US Pat. No. 3,142,673.

The abovementioned α-acyloxyalkyl halides

R ₃ CO ₂ CHR ₁ -HaI

are from the corresponding acid halide R ₃ SOHaI and the corresponding aldehyde R ₁ CHO according to the in J. Am. Chem. Soc. 43, 660 (1921), and in Acta. Chem. Scand. 20, 1273 (1966). The monoacid chloride of phenylmalonic acid and its esters are described in U.S. Patent 3,282,926.

As already mentioned, there is a characteristic feature of the compounds according to the invention of the general formula I in that they are able to form basic metal salts. the Acidic compounds according to the invention are by reaction with a suitable base in a aqueous or non-aqueous medium converted into basic salts. Such for making this Bases used in salts can be of various nature and include o / ganic amines, ammonia, Alkali metal hydroxides, carbonates, "bicarbonates, hydrides and alkoxides as well as alkaline earth metal hydroxides, hydrides, alkoxides and carbonates. Beispirje for such bases are ammonia, primary amines, such as n-propylamine, n-butylamine, aniline, cyclojiexylamine, Benzylamine, p-toluidine, ethylamine, octylamine, tertiary Amines, such as diethylaniline, N-methylpyrrolidine, N-methylmorpholine and 1,5-diazabicyclo- [4,3,0] -5-nonene, Sodium hydroxide, potassium hydroxide, ammonium hydroxide, Sodium ethoxide, potassium methoxide,

Magnesium hydroxide, calcium hydride and barium hydroxide

In a similar way, the treatment of the basic salt with an aqueous acid solution, z. B. of mono-, di- or tribasic acids to regenerate the free acid form. Such transformations are best as soon as possible and under temperature conditions and according to methods carried out, which are predetermined by the stability of these acidic products. The on this Wise formed acids could-. «. T in the same or

another basic salt can be converted back.

When taking advantage of chemotherapeutic

Effectiveness of the compounds according to the invention.

which form basic salts, pharmaceutically acceptable salts are used. It is true that water insolubility, severe toxicity or lack of crystallinity some of the products intended for use in certain make pharmaceutical preparations unsuitable or less desirable, however the water-insoluble or toxic salts by decomposition of the salts to those described above Manner converted into the corresponding acids or into any pharmaceutically acceptable basic salt will. The preferred pharmaceutical

Compatible salts are those whose cations are ammonium, sodium or potassium

The products according to the invention show a significant effectiveness in combating a large number of gram-positive and gram-negative infections in humans and animals. They can be administered alone or in combination with a pharmaceutical carrier selected according to the route of administration and standard pharmaceutical practice. So you can z. B. administered orally in the form of tablets which contain excipients such as starch, lactose, clays, etc., or in the form of capsules, alone or in admixture with excipients. They can also be administered orally in the form of elixirs or oral suspensions which contain coloring and flavoring substances, or they can be injected parenterally, ie intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile, non-aqueous solution, e.g. vegetable oils (cottonseed oil, peanut oil, corn oil, sesame oil) or other non-aqueous carriers that do not impair the therapeutic effectiveness of the preparations and are non-toxic in the amount used ( Glycerine, propylene glycol, sorbitol). In addition, preparations can be prepared for later use. Such preparations can contain liquid diluents, for example propylene glycol, diethyl carbonate, glycerine, sorbitol, etc., buffer substances as well as local anesthetics and inorganic salts which ensure the desired pharmacological properties.

The oral and parenteral dose levels for the compounds described here are generally

mean on the order of up to 200 mg'kg or 100 mg / kg body weight per day.

The Pcnicillinesler according to the invention show an improved absorption when administered orally in the Compared to the corresponding free acid or alkali metal salt forms. They are therefore comfortable and effective dosage forms of µ-carboxybenzyl penicillin represent.

In addition, some of the described substances are converted into the compound n-carboxybenzylnenicillin converted when injected parenlerally. The rate of metabolic conversion this ester in the slammic acid is so high that an effective and lasting concentration is maintained in the body. Such esters are therefore the parent acid.

The comparison between compounds of the invention and known similar penicillins or derivatives thereof gave the following results:

I. Comparison of the antibiotic effectiveness of

Compounds according to the invention, carbenicillin and the bis-aceloxymethyl ester of «-Carboxybenzyl-

penicillins

1. 6-f2-phenyl-2-carboxacetamido] penicillanic acid 3-monopivaloyloxymethyl ester, Na-SaIz.

2. 6- [2-Phenyl-2-carboxacetamidoppenicillanic acid-3- ( 1-aceloxyethyl) ester, sodium salt,

3. ö - ^ - Phenyl ^ -carboxacetamidoj-penicillansätire-3-acetoxymethylester. Na-SaIz.

4. carbenicillin;

5. Bis-aceloxymethyl ester of -carboxybenzyl penicillin.

link Activity in vitro
(MJC. Mcgmll · .. call S. aurcus 12.5 I. 0.781 12.5 2 3.125 6.25 3 0.39 1.56 4th 1.56 6.25 5 0.049 (a) = 200 mi (b> = 50mfr / : 'k ₈ .

activity γ t. in vivo % lOO (a) . schül / .l 60 (b) Jl. O. ! DO (a) 100 (a) 100 (b) 70 (b) 80 (a) 00 (a) 50 (b) 50 (b) 80 (a) 70 (a) 80 (b) 40 (b) 90 (a) 80 (a) 10 (b) 0 (b) 80 (a) 0 (b) P π 90 (a) 40 (b) 90 (a) 30 (b) 60 (a) 10 (b) 100 (a) 10 (b)

S. aurcus

II. Toxicities (LD ₅ ,,)

Compound I in the mouse po 3010 mg / kg.
Carbenicillin in the mouse ip 4400 mg / kg.

B e i s ρ i e I I

6- [2-phenyl-2-carboxyacetamido] penicillanic acid

3-monopivaIoyloxymethyl ester sodium salt

(I; R ₁ = H. R, = tert. C ₄ H ₉ ): Scheme A

a) 6-aminopenicilian acid-pivaloyloxymethyller (2); R ₁ = H. R ₃ = lert. C ₄ H ₉ )

To a stirred suspension of 10.8 g (0.05 mol) of 6-aminopenicilanic acid in 50 ml of dry dimethylformamide at room temperature and under a nitrogen atmosphere 9.8 g (0.07 mol) of triethylamine and after 30 minutes of stirring 14.8 g (0.01 mol) Given chloromethylprvalate. Stirring is continued for a further 4 hours, whereupon 150 ml of ethyl acetate are added and the triethylamine hydrochloride is filtered off. The organic phase will washed four times with 50 ml of water over sodium sulfate dried and treated with 90 ml of a 0.5 molar solution of p-TohioIsulfbnsäure in ethyl acetate. The salt formed is filtered off and dried at 45 ° C. under vacuum; Yield 9.2 g; Mp. 150 C (decomp.) The free base is used if necessary by treating the salt described above in a 1: f mixture of ethyl acetate and Water with so much saturated sodium carbonate solution. that a pH of 8.0 is obtained, and 70 (a) 40 (b) l00 (a) 70 (b) 80 (a) 60 (b) 80 (a) 80 (b)

subsequent separation of the organic layer, drying and concentration under reduced pressure obtained to an oily residue.

b) 6- [2-phenyl-2-carboxyacetamido] penicilian acid; S-monopivaloyloxymethyl ester sodium salt

(I: R ₁ = H. R ₃ = tert.C ₄ H ₉ ) A suspension of 33 g (0.1 mol) of 6-aminopenicillanic acid pivaloyloxymethyl ester in a mixture of 250 ml of isopropyl ether and 500 ml of water in an ice bath is cooled with a solution of 19.8 g (0.1 mol) of phenylmalonic acid mono-acid toric in isopropyl ether for 15 minutes . After the addition has ended, the reaction mixture is 15 ml

SS utes at ice bath temperature and then 2 hours Room temperature stirred. The organic layer

. is separated off and the aqueous layer extracted several times with diethyl ether. The ether layers are combined with the isopropyl ether layer, ti ocknet and concentrated in vacuo to a white gum: Yield: 13.5 g. The pH of the aqueous layer is adjusted to 5.3, and then extracted repeatedly with diethyl ether, whereupon it is dried and evaporated to dryness; Yield 18.6g. The combined, semi-solid material is dissolved b 30 ml of diethyl ether and treated with saturated sodium bicarbonate solution so much that a pH value of 6.4 is reached. The aqueous solution win

freeze-dried, whereby. the sodium sulfate of the desired Compound. Is obtained as a crude product. Dissolution of the sodium salt in methylene chloride with subsequent filtration of the saturated sodium bicarbonate and, evaporation of the methylene chloride provides the pure sodium salt of the product: Howling: 14.89 g (29%).

IR-Mj * lima (microns):

2.72 to 3 ₄ 28 (width 3.42. 3.48.5.65. 5.98 .. 6.24. 6.65. 7.32. 8.4. 8.S. 8/7. 9 "05. 9.8 and 10.3

NMR peaks (ppm):

1.2 (9H), 1.4WHi 4.28 to 4.62 (2H). 5.17 to 5.45 (2H). 5.66 to 6.0 (2H). 6.95 to Λ5 (5H) and 8.0 to 8.3, (1H).

Example 2

6- [2-phenyl-2-carboxyacetamido] penicillansiiurc-

3-monoaeetoxymethyle.sler-N-ethyJpiperidine salt

(I: R, = H. R, = CH,)

Scheme B

a) 6-aminopenicillanic acid acetoxymethyl ester (2: R ₁ = H. R ₁ = CH,)

Starting from 6-aminopenicillanic acid and chloromethyl acetate, following the procedure in scheme A-a of Example (the above indicated level ester is made.

b) Carbolphenoxyrjbe'izylpenicillin-rnonoacetoxymethylester: (3 ;. R ₁ ^ H: R, = CH,)

A suspension of 28.8 g (0.1 mol) acetoxymethyl 6-aminopenicillanate in 200 ml of isopropyl ether. which are located under a nitrogen atmosphere is located and is cooled to 2 C, is with 150 ml of isopropyl ether. the 27.4 g (0.1 mol) of phenylmaionyl chloride included, treated. The pH of the reaction mixture is increased by simultaneous addition a saturated sodium carbonate solution at about 5.5 to 6.5. After the addition, the 15 to Requires 20 minutes', the reaction mixture is initially stirred at 2 'C and then for 3 hours at room temperature. The pH is adjusted to 7 that The organic layer is separated and the aqueous layers are washed several times with diethyl ether extracted. The ether layers are combined, dried over sodium sulfate and reduced under reduced pressure Pressure concentrated to dryness. The crude product is used without further purification.

"Σ), $ - [2- ϊ ^^] ρ

S-mohoaceiöxymgtnytest'ef-isi-ktfeyfpiperidine salt: (f; R ₁ = H, R ₃ = CH ₃ )

To a solution of 5.26 g (0.01 mol) «/ - [Carbo-JphenoxyO-benzylpenicillin monoacetoxymethyl ester 10 ml of potassium borate buffer solution are added to 100 ml of acetone so that the solution has a pH value of 9.5. The clear reaction mixture is stirred at room temperature for 4 to 6 hours, whereupon the acetone is removed under reduced pressure. The cloudy aqueous solution is made with diethyl ether extracted, and the aqueous solution is separated and made up using 6N hydrochloric acid solution pH adjusted to 5.5. The crude product is dissolved in methyl isobutyl ketone extracted, to which so much N-ethylpiperidine is added that the salt of the desired compound fails.

IR maxima (microns):

2.7 to 3.28 (wide). 3.42. 3.48. 5.65. 6.0. 6.24. 6.65. 7.34. 8.4. 8.58. 8.7. 9.9 and 10.3.

NMR peaks (ppm):

1.4 (6H). 2.1 (3H). 4.26 to 4.65 (2H). 5.16 to 5.6 (2H), 5.62 to 5.98 (2H). 6.94 to 7.55 (5IiI and 8.0 to 8.3 (I H). · - ■■;

B e i s ρ i e I 3

6- | 2- Phenyl-2-carno \ yaeetiimido jpenit illansiiure-3-mono- <i-aceloxyeth > 1ester-Nalnumsal /

(R, --CHvR., -CH.,); Scheme C

a).! - rCarbolphenoxylbenzylpenicillin-N-ethylpiperidinsal / (4)

A 200 l- (iefiiß is with 8.75 kg (40.5 mol) 6-aminopenicillan acid and 83 l of water at 20 C are charged, and the pH of the mixture is adjusted to 18.9 1 IO% aqueous sodium hydroxide solution of 3.5 increased to 7.0. The electrodes of a pH meter are immersed in the stirred mixture, and it becomes with the slow addition of 12.92 kg

(47.1 moles) 2-phenyl-2- (phenoxycarbonyl) acetyl chloride began. During the one hour addition of the acid chloride, as much 10% sodium hydroxide solution is obtained added that the pH remains in the range 6.2 to 6.5. The addition of alkali is finished after Addition of the acid chloride continued for a further 15 minutes, so that a final pH of 6.5 results. The resulting oily solution is diluted with 75.7 1 of ethyl acetate and the pH value with 6N HCl of 20 C set to 2.0. The layers are separated and the aqueous layer is mixed with others 18.9 1 ethyl acetate extracted. The organic extracts are combined and dried over anhydrous magnesium sulfate dried. The ethyl acetate solution is stirred at 20 C, and then 5.04 kg (44.5 mol)

I-ethylpiperidine added slowly. The resulting Slurry is stirred for 1 hour at about 10 C and then filtered. The cake comes with twice 9.5 l of ethyl acetate and then washed with hexane. After drying in the atmosphere, one obtains

18.6 kg crude product (81% of the theoretical value): M.p. 140.0 to 142.5 C (dec.).

b) 6- [2-Phenyl-2-carbophenoxyacetamido] penicillanic acid <i-acetoxyethyl ester: (3: R ₁ = CH,. R, = CH.,)

To a solution of 5.0 g (8.8 millimoles). <- [Carbo- (phenoxy ^ benzylpenicillin / N-ethylpidine salt, in?> 0ml dry dimethylformamide vy 'f' (ten under a nitrogen atmosphere I ₇ OSg & 8, ΜΐΠίΜ; οϊ} and -Chiorethylacetate and 0.15 g of potassium aluminum iodide.

and the reaction mixture is 72 hours at room temperature touched. A portion of Iß ml is withdrawn and mixed with 20 ml of chloroform and 25 ml Treated water. The organic layer is additionally treated several times with chloroform, and the organic extracts are combined, washed with water and dried over magnesium sulfate. The residue remaining after removal of the solvent under vacuum is dissolved in 20 ml Dissolved ethyl acetate and the resulting solution with

stirred in the same volume of water at pH 8.0. The organic layer is then dried and concentrated in vacuo to 883 mg of a slightly brownish foam. The raw product.

read as cinematic in the Dtinnschichlchromalographie crwcisl. can be used lireki without additional cleaning.

The second half of the reaction mixture is worked up in exactly the same way, with similar Results are achieved.

c) 6- [2- Phcnyl-2-carboxyacetamido] penicillanic acid mono-II-acetoxyiithylestcr sodium salt:

IhR ₁ = CHj, R., - CH.,)

Starting from 3.02 g (0.01 mol) «- [Carbolphen- • xyIjbenzylpenicillinmono- u- acetoxyäthylester is lach the hydrolysis method of Scheme Bc of

Example 2 obtained the above ester. In case of replacement of the N-ethylpiperidine by sodium 2-ethylhexanoate one obtains the sodium salt of the desired Link.

IR maxima (microns):

2.7 to 3.5 (broad), 5.6, 6.0, 6.20, 6.5 to 6.63, 6.9. 7.27, 8,19,9,1.9,3,9,9 and 10.5.

NMR peaks (ppn) free acid:

1.4 to 1.54 (9H), 2.05 (3H), 4.36 to 4.48 (I H), 4.65 (I H), 5.45 to 5.7 (2H), 6.83 to 7.0 (I H) and 7.37 (5H).

Claims (1)

Patent claims: 1, mono-ester of α-carboxybenzyl penicillin of the general forms! (D CO ₂ H CH ₃ ίο