DE2312976A1 - PENICILLIN, THEIR SALT, THE PROCESS FOR THEIR MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

SUMITOMO CHEMICAL COMPANY, LIMITED
Osaka, Japan

¹¹ Penicillins, their salts, processes for their preparation and medicinal products containing these compounds "

Priority: March 15, 1972, Japan, No. 26 759/1972

It is known that 6- (oc-aminophenylacetaraido) penicillanic acid (ampicillin) inhibits the growth of various gram-positive and gram-negative bacteria, but shows no noticeable antibiotic action against germs of the genus Pseudomonas. US Pat. No. 3,433,784 describes some N-acyl derivatives of ampicillin, the minimum inhibitory concentration of which against Pseudomonas pyocinea A or R59 is 125 "to 250 pg / ml. However, the compounds given in the examples have an effect on germs of the genus Pseudomonas not so high _; and the antibiotic activity against other gram-positive or gram-negative bacteria is quite low, so the N-acyl derivatives of ampicillin are less valuable for therapy.

The object of the invention is to create new broad-spectrum penicillins that are resistant to gram-positive and gram-negative germs,

309839/1193

including Pseudomonas species, a high antibiotic effect unfold. This object is achieved by the invention.

The invention accordingly relates to penicillins in general Formula I.

OY-

RC _x A ^ CH, (D

· ^Χ l · ^N C-CONH-CH-C01JH-CH-CH · C

0-UiJiNn-OH-UUiNn-un-un ■

-CH-GOOH

V ⁰ X

and their salts, in which the group { q has a 6-membered,

heteroaromatic ring with one or two nitrogen atoms, 'Y a hydrogen atom, a lower alkanoyl or lower alkoxycarbonyl radical and R ^ and R ₂ hydrogen or halogen atoms, lower alkyl, lower alkanoyl, lower alkyl mercapto or lower hydroxyalkyl radicals, benzoyl, hydroxy -, mercapto or cyano groups or R ^ and R ₀ together form a lower alkylene radical which may contain a carbonyl group.

The term lower alkyl radicals means unbranched or branched Alkyl radicals with 1 to 8 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl and isoamyl group. The term "down" in the description other groups, e.g. lower alkoxy, alkanoyl, hydroxyalkyl and alkyl mercapto groups, refer to the alkyl portion these radicals, which have the same meaning as given above for the lower alkyl radicals. The heteroaromatic Ring can, for example, be a pyridine, pyrimidine, pyridazine or pyrazine ring be.

309839/1193

Characteristic of the penicillins of the general formula I.

XL

is the structure of the grouping (\ q _} which still bears one or more YO radicals, one of which is bonded to a carbon atom which is in the α-position to the carbon atom which is connected to the ampicillin group. The compounds in which the group (^ c does not carry any YO residues, have a significantly lower antibiotic effect than those with at least one YO residue and they show an equally low antibiotic effect both against Pseudomonas and against other gram-positive and gram-negative bacteria as those in the US -PS 3 433 784 connections described.

Specific examples of particularly preferred penicillins of the general formula I are:

D-α- (4-hydroxypyridine-3 ~ carboxamido) -benzylpenicillin, D-α- (2,4-dihydroxypyrimidine-5-carboxamido) -benzylpenicillin, D-α- (3-hydroxypyridazine-4-carboxamido) -benzylpenicillin, D-α- (3-hydroxypyridine -? .- carboxainido) -benzylpenicillin, D-a- (2-hydroxypyridine-3-carboxamido) -benzylpenicillin and D-α- (2-hydroxypyrazine-3-carboxamido) benzyl penicillin.

The invention also relates to a method for producing the Penicillins of the general formula I, which is characterized in that 6- (a-aminophenylacetamido) -penicillanic acid is used in a manner known per se of formula II

C-N CH-COOH

/ 3 (II)

H ₀ N-CH-CONH-CH-CH ^{n v J}

²¹ Il

309839/1193

or its derivative with a carboxylic acid of the general formula

in or

or its reactive derivative in which the grouping ^ y

Y, R ^ and R _{2 have} the abovementioned meaning, reacts, optionally hydrolyzing or acylating the product obtained, optionally splitting off a protective group and converting the compound obtained into a salt, optionally by reaction with a base.

Derivatives of the compounds of the general formula II can be, for example, salts, esters and N-substituted compounds. Examples for salts are the alkali metal salts, such as the sodium and potassium salts, the alkaline earth metal salts, such as the calcium and Barium salts, the salts of organic bases such as trimethylamine and triethylamine, and organic sulfonic acids such as p-toluenesulfonic acid, Naphthalenesulfonic acid and tetrahydronaphthalenesulfonic acid. Examples of the esters and the N-substituted compounds are compounds of the following general formulas:

H ₂ N-CH-COM-GH-CH C ^ _CH ^

₀ * C-N- ■ CH-COOSi-R ^

3 \

R. ~ SiM-CH-CONH-CH-CH

J ΧΙ ·

^E 5 f Il ο

309 839/1193

H ₂ N-CH-CONH-CH-CH ^X ^ _n

^ G-U CH-COOSn-:

/ ~ VcH-CO

S = / II / ^s / ^CH 3

NH N-CH-CH ^g \ ch

AC-N CH-COOH

^{6 7} O

VCH-CO

NH N-CH-CH ψ

^CH

3 / ^R 3

SR

V Il I 3 /

/ \ C —N CH-COOSi— R,

R. V II \ _R ⁴

⁶⁷ O 5

in which R ^, R ^, R ^, R ^ and Ry are each lower alkyl radicals.

Further examples of the ester grouping of the esters of the compounds of the general formula II are toluenesulfonyl ethyl ester, p-nitrobenzyl ester, benzyl ester, phenacyl ester, diphenyl methyl ester, substituted diphenylmethyl esters, trityl esters, benzoyloxymethyl esters, lower alkanoyloxymethyl esters, Dirnethylmethyleneamino ester, p-nitrophenyl ester, methylsulfonylphenyl ester, Methylthiophenyl ester, tert-butyl ester, 3,5-di-tert-butyl-4-hydroxybenzyl ester and trichloroethyl ester.

These ester groupings are common carboxyl protecting groups of penicillins, cephalosporins or peptides. Furthermore, the salts of the aforementioned esters of the compounds of the general Formula II, e.g. salts with hydrogen chloride or with organic sulfonic acids such as p-toluenesulfonic acid, naphthalene

309839/1193

sulfonic acid or tetrahydronaphthalenesulfonic acid, used will. The esters which are derived from penicillin G in a manner known per se are preferred.

The carboxylic acids of the general formula III can be used as such or in salt form or in the form of a reactive derivative can be used.

Examples of salts of the compounds of the general formula III are the alkali metal, alkaline earth metal and ammonium salts, as well the salts with organic bases, such as trimethylamine, triethylamine or dicyclohexylamine.

The reactive derivatives of the carboxylic acids of the general Formula III are e.g. acid halides, acid anhydrides, reactive ones Amides, acid azides and reactive esters.

The acid chlorides are particularly preferred among the acid halides. Examples of acid anhydrides are mixed acid anhydrides and symmetrical acid anhydrides made from acids, such as toluenesulfonic acid, an alkyl halocarbonate or an aliphatic carboxylic acid such as pivalic acid. Examples of reactive amides are those that can be used, for example from Imidazo !, dimethylpyrazole, triazole or tetrazole. Examples of reactive esters are those that can be obtained using p-nitrophenol, pentachlorophenol, p-nitrothiophenol, N, N'-dimethylhydroxylamine, 1-hydroxy-2 (1H) -pyridone, N-Hydroxy-succinimide or N-Hydroxyphthalimid.

If carboxylic acids of the general formula III, in which Y is a

Hydrogen atom, or their reactive derivatives use - 309839/1193

can be det, the hydroxyl group with a usual protecting group to be protected.

Some reactive derivatives of the carboxylic acids of the general formula III are described in more detail below. the mixed anhydrides of the general formula IV

C ²

in which the grouping f ^ q R ^ and Rp have the meaning given above and Y represents an acyl or alkoxycarbonyl radical, can be prepared by reacting a compound of the general formula III, in which Y is a hydrogen atom, with an acyl halide or an alkyl halocarbonate /earth. Thus, when 1 mole of the compound of general formula III is ^{reacted with 2 moles of an acyl halide, for example pivaloylCh 1} Oi ¹ Id, or an alkyl halocarbonate, for example chloramelseioi ^ ureätliyl- or isobutyl ester, in the presence of 2 moles of a base, the compounds of general formula IV in excellent yields. This method of preparation of mixed anhydrides of the general formula IV is hereinafter referred to as the "mixed anhydride process".

The compounds of the general formula V are also reactive derivatives of the carboxylic acids of the general formula III

O ^ ^ O (V)

3 0 9 8 3 9/1193 ^R 2

c _x 2312978

in which the grouping (C, R ^ and R2 has the above

A—

have a lot of meaning. You can by reacting 1 mole of the compound of general formula III with 1 mole of phosgene in the presence from 2 moles of a base. Analog reactive Derivatives can also be made using thionyl chloride or phosphorus trichloride instead of phosgene will. The method in which the aforementioned cyclic compound of the general formula V or an analog compound is used, is hereinafter referred to as "phosgene process".

Specific examples of usable bases in the foregoing Reactions are inorganic bases, such as sodium hydroxide or potassium hydroxide, and organic bases, such as triethylamine, pyridine, Dimethylaniline, lutidine, N-methylmorpholine and N-methylpiperidine ,.

The aforementioned reactive derivatives are usually not isolated because they are extremely reactive and unstable. In general, the reaction mixture obtained during their preparation is reacted with the compounds of the general formula II.

The carboxylic acids of the general formula III also include pyridinecarboxylic acids of the general formula VI

0-Y

(VI)

one in which Y has the aforementioned meaning, R _{3 is} a hydrogen atom or a lower alkyl radical and Rg is a lower alkyl,

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231297a

Alkanoyl or hydroxyalkyl radical, a cyano or benzoyl group or Ro and Rq together form a lower alkylene radical. You can by condensation of a ketone of the general formula VII

R ₉ -CH ₂ -CO-R ₈ (VII)

in which Ro and Rq have the meaning given above, with Aminomethylene malonic acid diethyl ester of the formula VIII

H ₂ N-CH = C (COOC ₂ H ₅ ) ₂ (VIII)

, product

and cyclization of the obtained condensation ⁵ and subsequent hydrolysis produced. The aforementioned compounds of the general formula VI can also be prepared by condensation of a vinylamine of the general formula IX

R ₉ -CH = C (NH ₂ ) -R ₈ (IX)

in which R, _Q and Rq have the meaning given above, with diethyl ethoxymethylene malonate of the formula X.

C ₂ H ₅ O-CH = C (COOC ₂ H ₅ ) ₂ (X)

and cyclizing the obtained condensation product and then Hydrolysis can be produced.

The compound ^ of the general formula VI in which Rq is a lower alkanoyl radical can be reduced to compounds of the general formula VI in which R _{9 is} a lower hydroxyalkyl radical. Furthermore, the compounds of the general formula VI in which Y is a hydrogen atom can be acylated in a manner known per se to give compounds of the general formula VI in which Y is a lower alkanoyl or lower alkoxycarbonyl radical.

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Specific examples of pyridinecarboxylic acids of the general formula VI are:

4-hydroxy-2,3-cyclopentenopyridine-5-carboxylic acid, mp 263-264 ⁰ C. (Dec.);

4-Hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid,. Mp. 285 ° C (dec.); ., 4-hydroxy-2,3-cycloheptenopyridine-5 ~ carboxylic acid, mp 248-249 ⁰ C (dec.);

2-methyl-3-acetyl-4-hydroxypyridine-5-carboxylic acid, Mp 260-263 ° C (dec.);

4-hydroxy-2-methyl-3-benzoylpyridine-5-carboxylic acid, m.p.> 360 ⁰ C. 2 ~ methyl-3- (ct-hydroxyethyl) - ^ - hydroxypyridine - ^ - carboxylic acid, melting point> 360 ° C;

4-Hy'droxy-6,7-dihydro-5-oxo ~ 5H-cyclopenta / b7pyridin-3-carboxylic acid, mp.> 300 ⁰ C and

2-methyl-3 * ■■ cyano-6-hydroxypyridine-5-carboxylic acid, mp. 247-248 ⁰ C.

The reaction of the compounds of the general formula II or their derivatives with carboxylic acids of the general formula III or their derivatives is preferably carried out in an inert solvent, such as a polar solvent, for example dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, methyl isobutyl ketone, ethanol or dimethylformamide , a non-polar solvent such as benzene, toluene, petroleum ether or. η-hexane, or mixtures thereof carried out. In some cases, the reaction can also be carried out in an aqueous medium. .The reaction temperature is not critical and usually is less than 50 ⁰ C, preferably at -80 ⁰ C to 50 ⁰ C.

3 0 9 8 3 9/1193

If the carboxylic acids of the general formula III are used in the form of their free acids or their salts, a condensing ^{agent such as N, N 1} -dicyclohexylcarbodiimide, N-cyclohexyl is preferably used for the reaction with the 6- (a-aminophenylacetamido) -penicillanic acid of the formula II -N ¹ -morpholinoäthylcarbodiimid, Tripheny! Phosphine or 2-ethyl-5- (m-sulfonylphenyl) -isoxazolium hydroxide is used. When using such a condensing agent, the reaction proceeds via an activated form of the carboxyl group in the compounds of the general formula III or an activated form of the amino group in 6- (a-aminophenylacetamido) -penicillanic acid of the formula II.

If penicillins of the general formula I in which Y is a lower alkanoyl or alkoxycarbonyl radical are obtained in the process according to the invention, these can then be added in the presence of an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide or ammonia, an organic base such as methylamine, dimethylamine, Diethylamine, triethylamine, benzylamine, morpholine, piperidine, potassium 2-ethylhexanoate or sodium 2-ethylhexanoate, an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as formic acid, trifluoroacetic acid or methanesulfonic acid, with the formation of the corresponding penicillins in general Formula I, in which Y is a hydrogen atom, can be saponified. The hydrolysis is preferably carried out in an inert solvent at temperatures from -50 to 80 ^° C. and in the presence of a base.

If a protective group is still present in the product obtained is, this can be done in a manner known per se by catalytic reduction or hydrolysis, preferably under mild conditions,

309839/1193

split off v / earth.

The penicillins of the general formula I obtained can optionally converted into salts in a manner known per se. Examples of the salts are the alkali metal salts, e.g. the sodium and potassium salts, the alkaline earth metal salts, e.g.

unsubstituted or substituted

the calcium and magnesium salts, the / ammonium salts, the amine salts, e.g. salts with triethylamine, procaine, dibenzylamine, N-benzyl-ß-phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, Dehydroabietylamine and N, N'-bis-dehydroabietylethylenediamine, and the salts with arginine.

The penicillins of general formula I have a broad range of antimicrobial properties Spectrum of activity and are highly effective against gram-positive and gram-negative bacteria, including germs of the Genus Pseudomonas. They can therefore be used as such or in the form of their salts together with customary carriers and / or diluents and / or auxiliaries for oral or parenteral use Applicable drugs are processed.

The examples illustrate the invention. The purity of the connections is determined iodometrically, unless otherwise stated.

example 1

Preparation of D-α- (4-ethoxycarbonyloxy-2,3-cyclopentenopyridine-5-carboxamido) -benzylpenicillin

²⁵ / S _x ./CHI

.CONH-CH-COHH-CH-CH C

C-N CH-COOH

J.

309.839 / 1 1 9 3

1 g of 4-hydroxy-2,3-cyclopentenopyridine-5-carboxylic acid (m.p. 263

Ms 264 ° C, decomp.) Is mixed with 50 ml of methylene chloride and 1.07 g

ο triethylamine added. The mixture is cooled to -10 C, treated with 1.16 g Chloramcisensäureäthylester and stirred for 10 minutes at -10 ⁰ C. Then 2.51 g of the triethylamine salt of α-aminobenzylpenicillin are added, and the mixture obtained

* ο

is reacted for 3 hours at temperatures from -10 to +5 C.

After the reaction has ended, 0.89 g of sodium bicarbonate in 25 ml of water and 200 ml of ethyl acetate are added. the The organic phase is separated from the aqueous phase and washed with 25 ml of water. The combined aqueous phases are Washed twice with 50 ml of ethyl acetate each time, cooled with ice, with dilute aqueous hydrochloric acid to a p ^ value of

2 set and extracted with 100 ml of ethyl acetate. The ethyl acetate extract is washed with water and dried and evaporated under reduced pressure. The residue is recrystallized from ether. 2.07 g of the above are obtained Penicillins with a purity of 93 percent.

Example 2
Preparation of D-ct- (4-Hydroxy-2,3-cyclopentenopyridine-5-carboxamido) -benzylpenicillin

OH

CONH-CH-COKH-CH-CH CC_ _ot / III ^GH 3

C-N • CH-COOH

1 ι

0.9 g of the penicillin obtained in Example 1 are mixed with a solution of 0.39 g of potassium carbonate in 9 ml of water. the resulting solution is stirred for 1 hour at room temperature and

309839/1193

adjusted _{to ρ Η} 2 with dilute hydrochloric acid while cooling with ice. The separated white crystals are filtered off, washed with water and dried under reduced pressure. 0.6 g of the aforementioned penicillin is obtained in 87 percent purity.

Example 3

Preparation of D-α- (4-IIydroxy-2, 3-cyclohexenopyridine-5-carboxamido) -benzylpenicillin

COIiH-CH-COMi-CH-GH C ^ _x /

III ^CH 3

C-N -CH-COOH

Il
0 ·

Ο "9 g of 4-hydroxy-2,3-cyclohoxenopyridin-5-carboxylic acid (Heraihydrat, mp. 285 ° C, dec.) With 20 ml of methylene chloride, 0.9 g of triethylamine and finally at -30 ⁰ C 4, 4 g of a 10 percent solution of phosgene in methylene chloride are added. After 20 minutes of stirring, 2 g of Triäthylarninsalzes- of .alpha.-aminobenzylpenicillin added and the resulting solution is stirred for 3 hours at -30 ⁰ C.und then for 1 hour at -5 to 0 ° C. Then 0.615 g of potassium carbonate in 25 ml of water and 200 ml of ethyl acetate are added. The aqueous phase is separated off, washed with ethyl acetate and adjusted to p ^ 2 with dilute hydrochloric acid while cooling with ice. The precipitated crystals are filtered off, washed with water and dried under reduced pressure. 1.52 g of the aforementioned penicillin are obtained in a purity of 90.5 percent.

309839/1193

Example 4

Preparation of D-α- (3-acetyl-4-hydroxy-2-methyl-pyridine-5-carboxamido) -benzylpenicillin

• OH ■ ·

H- ^ COC

V ^ N-CONH-CH-COHH-CH-CH ■ (

, -OH, CH-COOH

S "» · ι \ ι ι κ ι *

^H 3 ^C ^ 0

A.J

(1) 2,3β g of 3-acetyl-4-hydroxy-2-methylpyridine-5-carboxylic acid are finally treated with 40 ml of methylene chloride, 2.5 g of triethylamine and at -20 ⁰ C with 2.66 g Chloramcisensäureäthylester. After 15 minutes, a solution of 5.5 g of the triethylamine salt of α-aminobenzylpenicillin in 25 ml of methylene chloride is added at the same temperature. After 4 hours, allowed to stand at -10 ⁰ C, the methylene chloride is distilled off under reduced pressure and the residue is dissolved with a solution of 1.66 g of potassium carbonate in 100 ml of water and 50 ml of ethyl acetate. The aqueous phase is separated off, left to stand for 1 to 2 hours at room temperature, cooled with ice, adjusted to Pt 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated under reduced pressure. After the residue has been recrystallized from petroleum ether, 5 g of the aforementioned penicillin are obtained in a purity of 89 percent.

(2) 2.38 g of 3-acetyl-4-hydroxy-2-methylpyridine-5-carboxylic acid 40 ml of methylene chloride, 2.5 g of triethylamine and finally 2.66 g of ethyl chloroformate at -5 ° C. are added. To The solution is stirred for 30 minutes at 0 to -5 ° C with a lo-

309839/119 3

- - 16 -

2312978

Solution of the trimethylsilyl ester of α-aminobenzylpenicillin in Methylene chloride added. The trimethylsilyl ester was obtained by adding 1.33 g of trimethylchlorosilane to a solution of 5.5 g of the triethylamine salt of α-aminobenzylpenicillin in 30 ml of methylene chloride. The resulting mixture is 5 hours reacted at the same temperature. After distilling off the methylene chloride under reduced pressure, the residue becomes 70 ml of water are added and the resulting mixture is adjusted to pvr 2 with concentrated hydrochloric acid while stirring. the The precipitate formed is extracted with ethyl acetate, and the ethyl acetate extract is washed with water, dried and evaporated under reduced pressure. The residue is with a solution of 1.66 g of potassium carbonate in 70 ml of water and 50 ml Ethyl acetate dissolved. The aqueous phase is separated off and worked up according to (1). The above is obtained Penicillin,

Example 5

Preparation of D-α- (2, ^ - Cyclohexeno- ^ pivaloyloxypyridine-S-carboxamido) -benzylpenicillin

OCOC (CIU) ₅

CONH-CE-COMi-OH-CH 9

li I

c-N CH-COOH

Il
0

0.9 g of 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid with 30 ml of methylene chloride, 0.9 g of triethylamine and then added dropwise at -10 ⁰ C was added 1.22 g Pivaloylclilorid. After stirring for 30 minutes, 1.65 g

3 0 9 8 3 9/1193

of the sodium salt of α-aminobenzylpenicillin entered. The resulting mixture is reacted for 15 to 18 hours at 'a temperature of -10 ⁰ C and then added with 30 ml of cold water and 200 ml ethyl acetate. The aqueous Ehase is separated at 0 to 5 ° C, washed with cold ethyl acetate, washed with dilute Hydrochloric acid adjusted to pH 2 and extracted with cold ethyl acetate. The ethyl acetate extract is washed with cold water, dried and evaporated to dryness under reduced pressure. The residue is recrystallized from ether. 0.8 g of the aforementioned penicillin is obtained in a purity of 88 , 3 percent.

Example 6

Preparation of D-a- (4-ethoxycarbonyloxy-2,3-cyclohexenopyridine-5-carboxamido) -benzylpenicillin

OCOCKLH
O

couH-cH-coNH-CH-cH ^c \ ch ⁵

_G _N CH-COOH

Il

0.9 g of 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid ground with 40 ml of methylene chloride, 0.9 g of triethylamine and finally with From -20 to -15 ° C, 0.975 g of ethyl chloroformate are added. After stirring for 20 minutes at the same temperature, the obtained mixture with 1.8 g of the sodium salt of α-aminobenzylpenicillin added and then reacted for 4 hours at the same temperature. The reaction mixture is according to Example 1 worked up. 0.7 g of the aforementioned penicillin is obtained in

309839/1193 a purity of 94 percent.

- 18 -

Example?

Preparation of D-α- (2,4-dihydroxypyrimidine-5-carboxamido) -benzylpenicillin

OH
Jl-

-COHII-CH-COKH-CE-CH C '-> III ^CH 3

C_N CH-COOK

(a) 1.0 g uracil-5-carboxylic acid is added to 20 ml dissolved anhydrous pyridine. This solution is made with 1.8 g of tri-fluoroacetic acid p-nitrophenyl ester. added and then stirred at A5 C for 30 minutes. Then the solution is reduced under Pressure evaporated to dryness. The precipitated crystals are separated and treated with chloroform and then with acetone washed. 1.16 g of 2,4-dihydroxypyrimidine-5-carboxylic acid p-nitrophenyl ester are obtained from m.p. 298 to 299 ° C (dec.).

(b) A solution of 1.5 g of the triethylamine salt of Ami penicillin in 30 ml of methylene chloride is obtained at room temperature with 1.01 g of the active ester and 50 ml of dimethylformamide offset. The mixture is stirred for 2 1/2 hours at room temperature and then evaporated under reduced pressure. The back 40 ml of methylene chloride are added and the solution is extracted three times with 60 ml of an aqueous sodium bicarbonate solution each time. The aqueous extracts are combined and 50 ml of ethyl acetate are added. The mixture is made with 1 η hydrochloric acid set to p .. 2. The ethyl acetate phase is separated off and the aqueous phase extracted twice with ethyl acetate. The ethyl acetate extracts are

3098 39/1193

231297Θ

agrees, washed with aqueous sodium chloride solution and dried. The ethyl acetate solution is then added dropwise with a mixture of a 50 percent solution of 1.2 g of potassium 2-ethylhexanoate added in n-butanol and 30 ml of diethyl ether. The white precipitate is filtered off, washed with diethyl ether and dried over phosphorus pentoxide under reduced pressure. 0.7 g of the potassium salt of the aforementioned penicillin is obtained in a purity of 90 percent.

Example 8

Preparation of D-α- (3-hydroxypyridazine-4-carboxamido) -benzylpenicillin

COHH-CH-COMH-CH-CH C-N

CH-COOH

(1) A solution of 3.0 g of the triethylamine salt of a-amino ~ benzylpenicillin in 50 ml of methylene chloride is mixed with 1.90 g of 3-hydroxypyridazine ~ 4-carboxylic acid pnitrophenyl ester at room temperature while stirring (Mp. 233 ° C., decomposition) and 30 ml of dimethylformamide are added and the mixture is then stirred for 17 hours at room temperature. The precipitated crystals are filtered off, washed with diethyl ether and dried under reduced pressure. You get 2.9 g of the triethylamine salt of the aforementioned penicillin in a purity of 93 percent.

30Ö839 / 1 193

(2) 3.72 g of a-aminobenzylpenicillin-3,5-di-tert-butyl-4-hydroxybenzyl ester (made from benzylpenicillin ^, 5-di-tert-butyl 4-hydroxybenzyl ester via the 3,5-di-tert-butyl-4-hydroxybenzyl

ester of 6-aminopenicillanic acid) v / earth dissolved in 50 ml of methylene chloride. 1.90 g of ^ -hydroxypyridazine - ^ - carboxylic acid p-nitrophenyl ester and 30 ml of dimethylformamide are added to the resulting solution at room temperature. The mixture is stirred at room temperature for 15 to 18 hours and then evaporated under reduced pressure. The remaining solution is poured into 200 ml of cold water. The precipitate formed is filtered off, dried and added to a mixture of 30 ml of dimethylformamide and 1.15 g of sodium thiophenolate. The resulting solution is poured into 200 ml of acetone and heated to 50 to 55 ° C. while stirring. The precipitate formed is filtered off while still hot, washed with acetone and dissolved in 50 ml V / water. The solution is adjusted to p ™ 2 with dilute hydrochloric acid. The precipitated crystals are filtered off, washed with cold water and dried over phosphorus pentoxide under reduced pressure The aforementioned penicillin is obtained in a purity of 89.5 percent.

Examples 9 to 27

The penicillins given in Table I are based on the same Way prepared as in the previous examples.

309839/1 1.93

/ S \ / CI

Z-CONH-CH-CONH-CII-CH

CH-COOM

Table I.

Wr.

link

Purity, %

OH

■ Ν-

85

10

ΊΙ

92 _; 5

11

Oil

H C-HC _n

92

12th

OH

. I.

CEL

92.5

14th

OH

OH

92

3098 3 9/1193

Table'I - continued

link NC C. I. M. • Purity, Z HC ^N Oil H N / A ■ 16 ^N if C. K 82 17th C. 91 [
τ r ^0H K 18th OH
I. 87 OH Cl K 19th f ^l 0E 89 K 20th K 21 K 85 . 22nd r K 90.5 23 93 24 85

3 0 '9 8 3 9/1 1 9 3

Tabel T _ Fortse removal Purity, Mr. link - 80 25th Z M. 26th 0-COOC ₂ H ₅
HS ^^ H δ K

The minimum inhibitory concentrations of the penicillins produced in the above examples were determined using the agar dilution method and are given in Table II.

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- 2k -

Table II Escheri
chia
coli
NIHJ Proteus
mirabilis
GN2425 Proteus
vulgaris
HX 19 2312 976 12.5 3.13 ' 0.05 25th 12.5 0.39 Ver · 12.5 6.25 0.39 Klebsiella
pneumoniae
'602 bond;
from \
At- ^;
game 12.5 6.25 0.39 6.25 pseudo
monas!
aerugi-;
nosa i
104 ^l 1 y ■ minimum inhibitory concentration, μ / ^ / ΐηΙ 12.5 6.25 0.39 12.5 6.25 j 2 Staphy
lococcus
aureus
209P 12.5 6.25 0.39 6.25 12.5 3 0.39 12.5 6.25 0.05 12.5 12.5 4th 0.39 12.5 6.25 0.05 6.25 12.5!
j 5 0.78 25th 6.25 0, -78 6.25 12.5 6th 0.78 25th 6.25 0.78 25th 12.5 i 7th 0.78 25th 12.5 0.39 6.25 3.13 j 8th 0.78 12.5 6.25 0.2 3.13 3.13 j 9 0.39 12.5 50 0.39 3.13 12.5 10 0.39 50 12.5 0.2 12.5 25th 11 0.78 25th 3.13 0.05 3.13 6.25 12th 0.78 50 12.5 0.1 25th 25th 13th 0.78 25 · 12.5 0.05 25 · 3.13 14th 1.56 12.5 50 0.39 50 6.23 15th 0.39 6.25 12.5 0.2 50 3.13 16 0.78 6.25 3.13 0.057 100 ! 6.25 17th 0.78 12.5 50 0.78 25th 3.13 18th 0.78 6.25 25th 0.2 25th 'i2.5 19th '0, 39 12.5 25th 0.2 50 12.5 20th Ό, 2 25th 25th 0.78 100 12 ^ 5 21 0.78 25th 3.13 0.05 25th 12.5 22nd 0.78 12.5 12.5 0.2 25th 6.25 23 0.78 100 50 0.39 25th 6.25 24 0.2 100 IOD 0.73 25th 3.13 25th 0.39 6.26 1.56 1.56 12.5 6.25 26th 0.78;
■ 50 3.13 I. 0.78 100 ' 50 II 0.39 50 > 2 50 Ampi
cillin 0.73 ! 00 0.78 0.1

309839/1193

23Ί2976

Remarks:

Compounds Nos. I and II are from U.S. Patent 3,433,784 known penicillins of the formulas

No. I No. II

-CONII-CH-CONH-CH-CH

I.

C-N-

Il

CONH-CH-COFrl-CH-Cif

1

C — N -

■ Il

ν / ^GH 3

h ^CH 3

CH-COONa

/ CH f-CH ₃

CH-COONa

309839/1193

Claims (27)

Claims 1 j, penicillins of the general formula I ^ / OY, ^R / ^S \ / CH, C-CONH-CH-CONH-CH-CH-C ^ ^ ^C ~ ^N CH-OOOH 0. and their salts, in which the grouping (. q a 6-membered lieteroaromatic ring with one or two nitrogen atoms, Y a hydrogen atom, a lower alkanoyl or lower alkoxycarbonyl radical and R ^ and R ₂ hydrogen or, halogen atoms, lower alkyl, mean lower alkanoyl, lower alkyl mercapto or lower hydroxyalkyl radicals, benzoyl, hydroxy, mercapto or cyano groups, or R ^ and Rp together form a lower alkylene radical which may contain a carbonyl group. 2. Penicillins according to claim 1, characterized in that they are in the D (-) - form. 3- penicillins according to claim 1 and 2, ^ edbei Y is a hydrogen atom. 4. Penicillins according to claim 1 of the general formula OH R '
1 / K / S _x / CH ·· C-CONH-Cir-COWI-CH-CH C ^R 2 [1 · * ^C ~ ^N CH-COOH 309839 / T 193 - 21 - 231797ß in which R. and R _{0 are} hydrogen atoms and the grouping (C has the meaning given in claim 1, and its salts. 5. Penicillins according to claim 1 of the general formula OH -CONH-CH-CONH-CH-CH- C ^ 5 X III ^CH 3 yβ- N CH-COOH in which the grouping \ C is a pyridazine ring and R ^ and A ~ y Rp are hydrogen atoms and their salts. 6. Penicillins according to claim 1 of the general formula OH
^{11 p} C-CONH-CH-CONIi-CH-CH C - ^^ X i ι ι ^CH 5 ^ 0-N CH-QOOH / ^C \ in which the grouping ( ^x q is a pyrimidine ring and R ^ and Rp are hydrogen atoms and their salts. 7. Penicillins according to claim 1 of the general formula OH ^ C-CONH-CH-CONH-CH-CH ^ C ^{: R} 2 Γ fl ^ ^G ~ ^N CH-COOH " in which the grouping f ^ _{0 is} a pyrazine ring and R ₁ and Are hydrogen atoms, and their salts. 309839/1193 8. Penicillins according to claim 1 of the general formula OH ^R C / "^ C-CONH-CH-CONH-CH-CH ^ I I in which the moiety (C is a pyridine ring and R ₁ and R are hydrogen atoms, and their salts. 9. D-α- (4-Hydroxypyridine-3-carboxamido) -benzylpenicillin. 10. D-α- (2,4-Dihydroxypyrimidine-5-carboxamido) -benzylpenicillin. 11. D-a- (3-hydroxypyridazine-4-carboxamido! -Benzylpenicillin. 12. D-α- (3-Hydroxypyridine-2-carboxamido) -benzylpenicillin. 13 · D-α- (2-Hydroxypyr'idine-3-carboxamido) -benzylpenicillin. 14. D-α- (2-Hydroxypyrazine-3-carboxamido) -benzylpenicillin. 15. 'D-a- / 2-methyl-3- (rx-hydroxyethyl) -4-hydroxypyridine-5-carhoxamido-7-benzylpenicillin. 16. D-a- / 3 "(a-hydroxyethyl) -4-hydroxypyridine-5-carboxamide-q7-benzylpenicillin. 17 · D-α- (4-Hydroxypyridazine-5-carboxarnido) -benzylpenicillin. 18. A process for the preparation of penicillins according to claim 1, characterized in that, in a known V, ^r else e-Ca-AminophenylacetamidoJ-peiiicillansäure of the formula II 309839/1193 H ₂ N-CH-CONII-CH-Ch C 9312976 3 JZ- N CH-COOH (II) or its derivative with a carboxylic acid of the general formula III OY H ₁ I ■ " ¹ p Γ A or its reactive derivative in which the moiety Y, P _H and R _{0 have} the meaning given in claim 1 k ² ben, reacted, optionally hydrolyzed the product obtained or acylated, optionally splitting off a protective group and the compound obtained, optionally by reaction converted into a salt with a base. 19. The method according to claim 18, characterized in that a reactive derivative of the carboxylic acid is used as the reactive derivative Ester uses. 20. The method according to claim 10, characterized in that the reaction is carried out in an inert solvent. 21. The method according to claim 18, characterized in that the reaction is carried out at temperatures from -80.degree. C. to 50.degree. 22. The method according to claim 18, characterized in that mon carries out the reaction in the presence of a base. 309839/1 193 23. Process for the preparation of the penicillins according to claim 3, characterized in that the compounds of the general Formula I. or ■ ^R 1C S C-COFH-CH-CONH-CH-CH C _X 1 II 1 CH-COOH in which Y represents a lower alkanoyl or lower alkoxycarbonyl radical and the grouping (^ «R ₁ and. R ₉ ^V A_J ^Y '^ Claim 1 have given meaning, hydrolyzed and optionally the penicillin obtained by reaction with a base in a salt transferred. 24. The method according to claim 23, characterized in that dai3 ' the hydrolysis is carried out in an inert solvent. 25. The method according to claim 23, characterized in that one carries out the hydrolysis at a temperature range of -50 ⁰ C to 8O ⁰ C. 26. The method according to claim 23, characterized in that the hydrolysis is carried out in the presence of a base. 27. Medicaments containing a penicillin or its salt according to claim 1 and customary carriers and / or diluents and / or auxiliaries. 309 839/1193