DE2238535A1 - ALPHA-GUANIDINOPENICILLIN DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS - Google Patents

Description

"α-Guanidinopenicillin derivatives, processes for their preparation and medicinal products containing these compounds "

Priority: 4 »August 1971, Great Britain, No. J6 667/71

The invention relates to 5- (acylamino) -pe'nicil3 anäurederivate, whose oc-Eohlenst off atom in the acyl radical with a guanidine group is substituted. GoIehe penicillins are valuable antibacterial agents, animal feed additives, and treatment agents mastitis in obstacles. The aforementioned penicillins are also useful therapeutic agents for treating poultry and mammals including humans. They are particularly suitable for the treatment of infectious diseases caused by gram-positive and gram-negative bacteria.

The GB-IS 1 025 4-2> discloses, inter alia, tt-guanidinopenicillin derivative c

of the general formula I "NH R 0

H ι Il

NH ₂ - C - NH - CH - C "- NH

(D

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BATH ORIGINAL

in which R reads a hydrogen atom or an organic one, and their non-toxic salts and esters. One of the preferred compounds dor general formula I contains a radical R as a I'heny! Group.

Various compounds of the general formula I have el en Advantage that they are acid-stable and against both gram-negative and gram-positive bacteria, including determiptsr Penicillinase-producing Staphylococcus utarania are. It vairde, however, found that many compounds of general formula I, including the compound with a Phenyl group as, remainder R, in the gastrointestinal tract inadequate Much absorbed to allow generally applicable oral administration. This fact is shared by many Doctors considered a disadvantage. Furthermore, even with subcutaneous Injection of many compounds of the general formula I only inadequate values of the serum level and / or the tissue penetration obtain.

It was therefore the object of the present invention to provide new penicillins which are effective against a broad spectrum of gram-negative and gram-positive bacteria, including bacteria producing penicillinase, and some of which can also be used orally. This problem is solved by the invention. ,. ■ ....

The invention thus relates to a-guimidinopenicillin derivatives of the general formula II "'■""■ ^{; r!} ■■"■'"'■

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BATH ORIGINAL

2238138

CH - GO *

in which R _{1 is} a hydrogen atom or a hydroxyl group!

a hydrogen atom or an itlkylrest with 1 to 4 carbon

atcraen and IU a Wasserstöffatoin öder eiii _i AdylöXyallenyi-

rest with i "up to 13 carbon atoms is» with the proviso ^ that if It, and Rg are hydrogen atoms * R, no hydrogen

Gtom is, and its salts. .

Specific examples of radicals R ^ SiM according to the invention with a hydrogen atom or a methyl, ethyl, isoprbpy or terbutyl group, with a methyl group being preferred for hydrogen atoms. Specific examples Van erfinätogsiSTMeti Ristiit R * are a hydrogen atom or ö in ftfeit dif äiigemöiMii ^ (ÖH) -ö-ÖO-G L-., In which η and iö girtiaö «äHiiÄ fiiit widths of ^v / nm 2m +! ¹

1 to 6 mnd ^ iio or one in the case of fine hydrogen atoms

Öie erfihdüngögeinaiJöh VeiBiMühgerl
B (-) - Könfiiüfäti6ii ih der Adf i

Under the erfihduhgsgfeiüEßin VerBihdttfige: h ^: aiii SC ^e ^ ^s ^ p-hydroxybenzylpenieiiiine der äiigemeihgh förlei ill,

309.80ft / r ^ 3 ^

cn - co - mu

I I. I I ^ .au (in)

in which R ^, a hydrogen atom or a methyl group, and their salts are preferred. Among the compounds of general formula III, those are preferred in which R ^, a Is hydrogen atom. The compounds of the general formula III can be in zwitterionic form. The compounds of the general formula III can contain salts on the carboxylic acid or on of the guanidino group. Intended for therapeutic use these salts are non-toxic. Special carboxylic acid salts are the lithium, sodium, potassium, calcium, magnesium, aluminum, Ammonium and substituted ammonium salts, e.g. the non-toxic ones Salt of trialkylamines, such as triethylamine, of p-aminobenaoic acid diethylamino-ethyl ether hydrochloride, Bibenzylamine, N-benzyl-ß-phenylethylamine, 1-ephenamine, N, R -dibenzylethylenediamine, Dehydroabietylamine, N, N-bis-dehydroabietylethylenedianine and other amines that have been used to make salts of benzyl penicillin. Specific examples of acid addition salts of compounds of the general formula III are the hydrochlorides, hydrobromides, sulfates and phosphates.

The compounds of the general formula III give high values of the serum level when administered subcutaneously and have a very broad spectrum of activity. '

309 * 0 * 71332

The compounds according to the invention also include D (-) - a-guanidinobenzylpenicillin ester of the general formula IV

CH_

CH ₂ -O-CQ-G (CH ₅ ),

in the R-, a hydrogen atom or a hydroxyl group and R ^, is a hydrogen atom or a methyl group, and their salts preferred. Among the compounds of the general formula IV, preference is given to those in which R * is a hydrogen atom. Preferred bases of compounds of the general formula IV are acid addition salts, such as the hydrochloride, hydrobromide, Sulfates, phosphates, acetates and citrates. ,

The compounds of the general formula IY have a very broad range Spectrum of activity. Furthermore, with these compounds, high serum concentrations are obtained when administered subcutaneously, and if R-. a hydroxyl group are also used when administered orally high serum concentrations reached. In the presence of Mammalian serum are the esters of the general formula IV in the underlying penicillanic acids are broken down.

The advantageous properties of the compounds according to the invention of the general formulas III and IV are also used in the DL-forms and to a certain extent in the L-forms established. The aforementioned forms therefore also apply to the compounds according to the invention.

30 * 803/133, 1

The invention also relates to a method for producing dor Compounds of the general formula II, as characterized lot that you can use a compound of the general formula V with a compound of the general formula VI

Y-NII

(VI)

in which Ro has the meaning given above, R _{r is} a hydrogen atom or an optionally protected hydroxyl group, the radicals X and Y are such that an amide bond is formed with cleavage of these radicals, Z an optionally protected one Is a guanidino group or a suitable precursor of such a group and IL- is such that the -CO ₀ R ₆ radical is a carboxylic acid group optionally present in salt form or in the form of a silyl derivative or denotes an ester group, and optionally then the radical Z in a another radical Z and / or the radical R ^ - is converted into another radical R ^ and / or the protective group optionally contained in the radical R ^ is split off.

Special YIn radicals suitable for the process according to the invention of the general formula VI are a hydrogen atom or silyl radicals. A silyl derivative of a compound of the general formula VI is the reaction product of a compound of the alige-

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ineinen Foi ^ mel VI, in which Y is a Wasserst of fat om's, with a silylating agent verstanden..Geeignete silylating agents are Halogentrialkylsilane, Bihalogendialkoxylsilane, Bihalogendialkylsilane or corresponding aryl or Arylalkylsilane, compounds such as hexamethyldisilazane or other _# known silylating agents in the penicillin - or. Peptide chemistry has been used for analogous reactions. Halotrialkylsilanes, in particular trimethylchlorosilane, are preferred as silylating agents. When using trimethylchlorosilane v / ith the remainder Y DIE (CH ₇₎ -Si group obtained. The silyl derivative can be in the form of discrete molecules or in an oligomeric or polymeric form. Specific examples of -COpIL - radicals in the general formula VI, in which Y is a silyl radical, are ester groups and radicals of the general formula -

C.

Prevented compounds of the general formula VI in which Y is a silyl radical have the general formula VII

(VII) CO-OR ₇

in which R _{7 is} the -Si (CH-O ^ -, -CH ₂ O-CO-C (CH,), -, benzyl or phthalyl group.

In the case of the implementation of a compound of the general formula VI, in deer Y a. Is silyl radical, with a compound of the general Formula V are, as radicals X, especially «halogen atoms, acylated Hydroxyl groups or the reaction products are suitable, which are in

• situ from the compound in which X is a hydroxyl group optionally present in salt * form, and. Form a Garbodiirnid or Carbonyldiimidosol, Preferred radicals X are the chlorine and bromine atom, rait one reads the general formula -CO-OKp acylated hydroxyl groups, where R "a hydrocarbon radical with 1 to 8 carbon atoms, especially the ethyl group, or Rg another compound of the general formula V is, in which the radical X is missing, and the reaction products formed in situ from the oleic acid and dicyclohexylcarbodiimide. In such reactions, 7> should not be an unprotected guanidino group. After the reaction of the compound of the general formula V with the compound of the general formula VI, in which Y is a silyl radical, the radical Y in the acylated intermediate product can be split off by hydrolysis or alcohol under mild conditions, if- this · has not already taken place under the conditions of the previous conversion.

Special radicals -CO ₀ -Rc in a compound of the general formula VI in which Y is a hydrogen atom are, in the process according to the invention, optionally present in salt form or esterified carboxyl groups. Preferred compounds of the general formula VI, in which Y is a hydrogen atom, have the general formula VIII

(VIII)

CO-O-Rg

in which R _ß a hydrogen atom, a salt-forming ion, a

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Benzyl group, a group of the formula -CH ^ O-CO-C (CH-,), or a phthalide group. If _{-R ß is} a hydrogen atom, the compound of the general formula VIII can be in zwitterionic form. >

In the case of the implementation of a compound of the general formula VI, in which Y is a hydrogen atom, with a compound of the general Formula V are specifically alo radicals X the aforementioned radicals suitable, which are also suitable when X is a silyl radical; furthermore, radicals X are especially radicals of the general formula -0-SOp-Rq suitable, in which Rq is an organic radical, in particular a methyl-p-bromophenyl or p-'üoluylgruppe is. Preferred X radicals have already been mentioned above in the case of the reaction of a compound of the general formula VI in which Y is a silyl radical, ,called; has been,. · In .such.implementations,. Z no unprotected Guanidino group. be.

The term "protected" group is understood to mean a group which is not attacked under the conditions of the acylation reaction between the compounds of the general formulas V and VI, but can be split off by other reagents without undesired degradation of the reaction product formed during the acylation . The guanidino group is preferably protected by the formation of a salt of the general formula -NHC (IIH) NH ₀ -HA, in which A is the anion of preferably an inorganic acid, such as hydrochloric acid, hydrogen bromide.:; Acid ... or sulfuric acid, is. Preferred protecting groups for the Rr hydroxyl group are the benzyl and benzyloxyoarbonylii. In general, no protecting group is required, although-

309108/1332

probably if X is a halogenation or a highly active ester group the use of protecting groups can be beneficial.

Generally includes the conversion that may be used a radical Z into another radical Z the formation of a free guanidino group from a protected guanidino group or from a precursor of a guanidino group. A specific example of a guanidino group precursor is the amino group, the by reacting with a guanylating agent to the guanidino group can be converted. In general, however, the yields obtained in such reactions are unsatisfactory.

The conversion to be carried out if necessary according to the invention of a radical R ^ into another radical H ^ is generally the Formation of a free acid or a salt of this acid an ester, the formation of an ester from a free acid or one of its salts, the formation of a salt from a Carboxylic acid or the formation of a carboxylic acid from one of its salts. The formation of the free acid or one of its salts from an ester can be carried out by known hydrolysis processes or processes for hydrogenative cleavage. The formation of an ester a free carboxylic acid can according to the in * of GB-PS 1,215,812 procedures followed or according to other customary esterification processes take place. A particularly suitable process for the formation of an acid of the general formula III consists in the reaction; of an acid addition salt of a compound of the general Formula IX

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GO-X

\ jH-C (NH) NH «

in dei ¹ R ^, and X have the meaning given above and the hydroxyl group may optionally be protected with a compound of. general formula VI, in which Y is a hydrogen atom and -CO ₀ Rg is an ester residue that can easily be converted into a carboxylic acid. Subsequent to this reaction, the ester is converted into the free acid or one of its salts and, if the hydroxyl group is protected, it is converted into the free hydroxyl group or one of its salts. In the compound of general formula IX, the hydroxyl group is preferably not protected, R ^, iet.ein .Wasserstoffatom ,, and Rg. Is a radical j which can be easily split off by catalytic hydrogenation, such as the benzyl group, or a radical which can be easily split off hydrolytically under mild conditions Like the phthalide ester group, X is in particular a chlorine or bromine atom, an -O-GO-OCoHc group or a similar anhydride group or a radical formed in situ from the underlying acid and a carbodiimide.

Another preferred process for the preparation of an acid of the general formula III is the reaction of an acid addition salt a compound of the general formula IX, in dfei? · die Hydroxyl group may optionally be protected with a compound of the general formula VI, in which Y is a silyl radical and -COoRc is an ester radical which can easily be converted into an acid can, or is a silylated carboxyl radical. Subsequently to

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• This implementation is the N-3ilylgruppe or the Ii-Cilylpruppen split off and / or the ester group in the free acid j

or a salt thereof converted, and if the hydroxyl group is protected, it is converted into the free hydroxyl group or a \ their salts. In the compound of the general formula IX, the hydroxyl group is preferably not protected, R is

^i; t is a hydrogen atom, and R ^ is an ester residue which can be easily split off by hydrogenation or hydrolysis or a silyl residue which is the same! early with the silyl residue on the amide nitrogen of the side chain {

can be split. X is preferably a chlorine or bromine atom, a -0-00-0-02Hc group or a similar anhydride or an in situ formed from the underlying acid and a carbodiimide Rest.

A preferred method of making an ester of the general Formula IV is the reaction of an acid addition salt of a compound of the general formula X.

(X)

in which R ^ ,, Rc and X have the meaning given above, with a compound dor the general formula VI ₁ in which R ^ - is a -CH ₂ O-CO-C (CH,), - group and Y is a hydrogen atom or a Silyl radical i3t. Following this reaction, if necessary, the protective group of the hydroxyl group and the silyl radical on the amide nitrogen atom of the side chain are split off. Preferably is

309801/1332

R ^, a hydrogen atom: -. And - Sc a "hydrogen atom or a" .. - ■■ "hydroxyl group .: Y, is in particular a hydrogen atom or a - (CH _7. ) ^ Si group; Σ is especially a chlorine waste. Bromine atom, .- · a 0-CO-O-CpHr group or a similar anhydride or a radical formed in situ from the · underlying acid, and. · A carbodiimide. 'I.'" ^: · ■ '. · ■ :: '■'. -: ■ '.

Another preferred process for the preparation of esters of the general formula IV is the reaction of a compound of the general formula XI

(XI)

or a reactive esterifying derivative of such a compound with pivaloxymethanol., or a reactive esterifying derivative of this compound. Subsequent to the reaction, the protective groups are split off, if they are present. These conversions are analogous to the conversions described in GB-PS 1,215,812. Re is preferably a hydrogen atom or a hydroxyl group. R ^ is a hydrogen atom and Z is a guanidino group which is free or in the form of a salt. If the compound of the general formula XI is in the form of the free acid or one of its salts, the reactive derivative of pivaloyloxymethanol can be, for example, the corresponding bromide, chloride, alkylsulfonyloxylate or arylsulfonyloxylate. If the compound of the general form rnrj 1 XI j η. Vo an cine :; ak ti ν L π c t; c η ν ο ro jj t; ε · rnd acting η derivative

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BATH

exists, Z must be a protected Guaniuino group, y / ie the in Guanidino group present in the form of a salt. The implementation can in this case between the connection of the general Formula XI and pivaloyloxymethanol are made. Special Examples of activated derivatives include the rest of the general Formula -CQ-X, in which X is the

tion of the general formula V has given meaning. X is preferably a chlorine or bromine atom, an -O-CO-OCpHV group or a similar anhydride group or one in situ from the free Acid and, for example, a reactive residue formed by a carbodiiraide.

The invention also relates to valuable intermediates of the general Formula XII

(XII)

in which R ^ has the meaning given above, and their Derivatives, where the hydroxyl and / or guanidino group optionally are protected, and salts of these compounds. Preferred compounds of the general formula XII have the general Formula XIII

^HC M \ /) - ⁰¹ C

V // NNH-

C (NH) -NH ₂

3O9808 / 1332

BAD ORJGINAL

The compounds of general formula XII are preferred in the -D (-) form; however, the DL and L forms also fall under these compounds according to the invention. The aforementioned Compounds can be prepared from the corresponding amino compounds by reacting with a known guanylating agent, such as an O-alkyl-isouronium salt or an S-alkyl-isothi- uronium salt.

The invention also relates to medicinal preparations which contain at least one compound according to the invention as active ingredient of the general Formula II together with at least one pharmacologically acceptable carrier and / or at least one pharmacologically compatible diluents. The medicinal preparations according to the invention preferably contain as ·. Active ingredient a compound of the general formula III or IV, in which R ^ is hydrogen atom is. Particularly preferred medicinal preparations according to the invention are those which, as active ingredient, contain a compound of the general Contain formula IV, in which R ^ is a hydrogen atom. and H, especially a hydroxyl group.

Suitable daily doses of the compounds according to the invention for a Mammals weighing 70 kg are 100 to 2p 000 mg (about 1.5 to 285 mg / kg), in particular 200 to 2,000 mg (about 2.8 to 28.5 ng / kg); However, higher doses can also be used, since the compounds of the invention are non-toxic. The pharmaceutical preparations according to the invention can be used orally or parenterally Administration in undosed form or in the form of

Dosing units are available. Suitable forms of dosage units are s.B. Capsules, tablets and sachets that contain granules or Contain powders which are used in orally administrable syrups,

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Elixirs or suspensions are transferable. For injection purposes, a suitable soluble form of a compound of the general formula II can be dissolved, for example, in sterile water. The dosage units can be 20 to 2 COO mg, preferably 150 to
750 mg and in particular 200 to 600 mg of a compound according to the invention.

With the according to the invention, a compound of the general formula Medicinal preparations containing II can be used, for example, to treat bacterial infections in mammals.

The examples illustrate the invention. The structures of all the compounds mentioned in the examples were tested with the aid of customary standard methods, v / ie elemental analysis and nuclear re-source spectroscopy. All compounds gave exact analysis values within the tolerances allowed
all were in Pivaloyloxynrethylestern (CD,) p-solution nuclear magnetic resonance spectra of the pure compounds with 9 protons at 1.16 S m * 0.01 and 6 respectively protons at 6 »1.48 to 0; get 01.

example 1

D (-) q-guanidino-p-hydroxybenzyl penicillin
a) D (-) ot — guanidino-p-hydroxyphenyl acetic acid

. A solution of 50 g of D (-) - (p-hydroxyphenyl) -a-arainoic acid in
400 ml of water and 120 ml of concentrated ammonia is under
Stirring treated with 100 g of O-methylisourea hydrochloride.
The clear resection mixture is kept at room temperature for 24 hours

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ditched. The D (-) a-guanidino-p-hydroxyphenyl acetic acid Rainfall is collected, washed with water and reduced under reduced pressure Print dried. 32 g (49 percent) are colorless Get crystals. A sample suitable for analysis is made by recrystallization from aqueous ethanol with the addition of activated charcoal obtain. The corresponding hydrochloride is obtained by dissolving 2 g of D (-) a-guanidino-p-hydroxyphenylacetic acid in 20 ml of 1 η hydrochloric acid and subsequent evaporation of the solution under reduced pressure, with 2.0 g (86 percent) colorless solid are obtained.

b) Benzyl D (-) a-guanidino-p-hydroxybenzyl penicillanate hydrochloride

A solution of 3 S benzyl-6-aminopenicillanate and 2.5 g of dicyclohexylcarbodiiaiid in 30 ml of anhydrous methyl chloride v / ird dropwise with stirring for 5 minutes with a solution of 2.46 g of D (-) oc-guanidino-p-hydroxyphenyl-acetic acid hydrochloride

added in 12 ml of dimethylformamide. The mixture is stirred at room temperature for 30 minutes and then cooled in an ice bath for 15 minutes. The dicyclohexyl resin precipitate is filtered off, and the filtrate is added dropwise to 600 ml of anhydrous Xther while stirring. The solid benzyl-D (-) oc-guanidino-p-hydroxybenzylpenicillanate hydrochloride is filtered off, washed with Xther and dried under reduced pressure, whereby. 5 »6 ε product can be obtained. This product comes without

* ■

further purification used in the subsequent reduction stage.

c) D (-) tt - (} uanidino-p - hydroxybenisyapenicillin

A Lö-rmp; from V), ^r > f ·] fienzyl-D (-) a-guanidino-p-hydroxyben2yl-

BATH

penicillanate hydrochloride in 50 ml of water and 150 ml of methanol is introduced into 7 * 9 g of a precomposed suspension of 10 percent palladium-on-activated charcoal in 150 ml of water and 50 ml of methanol. The mixture is shaken for 45 minutes under hydrogen at room temperature and atmospheric pressure *. The catalyst is filtered off, and 'the filtrate is adjusted with 1 0 η Katronlauge to pH 7 _t. The neutral aqueous solution of methanol is concentrated under reduced pressure to remove the methanol and to initiate crystallization. The precipitation is completed by adding a further 1 η sodium hydroxide solution to a pH of 9 »0. The penicillin is filtered off, washed in water and dried under reduced pressure. 4.75 g (38 percent) of the reaction product are obtained.

example

2-

Pivaloyloxymethyl ester of D-α-guanidino-p-hydroxybenzylpenylcillin hydrochloride

A solution of 7 »38 β (0.03 mol) D-oc-guanidino-p-hydroxyphenyl acetic acid hydrochloride in 25 ml of dimethylformamide is stirred into a solution of 9 »71 g (0.03 mol) for 30 minutes Pivaloyloxymethyl-6-aminopenicillanate and 6.80 g (0.033 mol) Dicyclohexylcarbodiimide registered in 180 ml of anhydrous methylene chloride. The mixture is in a cold water bath for 90 minutes and then stirred for 60 minutes in an ice bath. Of the

Dicyclohexylurea precipitate is filtered off, and that The filtrate is added dropwise with stirring to 1,500 ml of anhydrous ether. The precipitate is filtered off with ether

washed and dried under reduced pressure. 15 g (91 percent) of colorless, non-crystalline pesticide are obtained.

Example 3 _# ^

Pivaloyloxy methyl ester of DL-α-guanidino-4-hydroxy-3-methylbenzylpenicillin hydrochloride

a) DL-a-guanidino-4-hydroxy-3-raethylphenyles.sisäure

A solution of 6 g (0.03 mol) of BL-α-amino-4-hydroxy-3-niethylphenyl acetic acid ionohydrate in 190 ml of anhydrous ammonia is treated at pH 10 with an excess (12 g) of Q-methylisourea hydrochloride, The reaction mixture is left to stand overnight at room temperature. The deposited precipitate is collected, washed thoroughly with water and dried. 4-.9 g (68 percent) of colorless crystals with a melting point of 202 ^° C. (decomposition) are obtained. A sample suitable for analysis is obtained by recrystallization from: 400 ml of water. The corresponding hydrochloride is prepared by dissolving 2.9 g of DL-a-guanidino - ^ - hydroxy ^ -methylphenyl acetic acid monohydrate in 17 ml of 1 ή hydrochloric acid while warming. The hydrochloride is precipitated by cooling to room temperature, 2.9 g (93 percent) of colorless crystals being obtained.

b) Pivaloyloxymethyl ester of DL-α-guanidino ^/ 1-hydroxy-3-methylbenzylpenicilin hydrochloride

To produce this penicillin, the method according to Example 2 D-α-guanidino-p-hydroxyplienyl acetic acid hydrochloride

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by an equimolar amount (2.60 g) of DL-α-guanidino-4-hydroxy-3-methylphenylacetic acid hydrochloride replaced. There are 3 * 80 g (66 percent) reaction product obtained.

Examples.

Piv aloyloxymethyleater of DL-g-guanidino - ^ - hydroxy ^ -methyl-benzylpenylcillin hydrochloride

a) DL-α-guanidino - ^ - hydroxy-2-methylphenylessisic acid

According to the method described in Example 3a), 6 g of DL-α-Araino - ^ - hydroxy-S-methylphenyl acetic acid are used, 4.1 g (52 percent) of colorless crystals being obtained. A sample suitable for analysis is obtained by recrystallization from water and has a P. of 246 to 247 ^° C. (decomposition). The corresponding hydrochloride is obtained by dissolving 2 g of DL-a-guanidino - ^ - hydroxy ^ -methylphenyleesiga acid monohydrate in 11.5 rol 1 η hydrochloric acid produced with heating. The solution is left to stand for 5 hours at room temperature. 1.8 g (84 percent) of colorless crystals are obtained.

b) Pivaloyloxymethyl ester of DL-a-guanidino - ^ - hydroxy - ^ - methylbenzylpenicillin hydrochloride

To prepare this penicillin, in the process according to Example 2, Da-guanidino-p-hydroxyphenylacetic acid hydrochloride is replaced by an equinolar amount (2.60 g) of DL-a-guanidino-4-hydrox3 ^r -2-methylphenylacetic acid hydrochloride. 3.1 g (54 percent) of the reaction product are obtained.

309308/1 ???

Example 5

D-a-guanidino-p-hydroxybenzylpenicillin by hydrolysis of the Phthalide ester. .

A solution of 1.0 g of the phthalide ester of Da-guanidino-hydroxybenzylpenicillin-hydrochloride in 50 ral V / water and 80 ml of acetone is adjusted to pH 9.4 with a 1 η aqueous sodium hydrogen carbonate solution. The mixture is stirred for 3 hours at room temperature and then filtered. The residue is washed with 100 ml of Xther and freeze-dried, 1 g of solid being obtained. The solid obtained is extracted with 10 ml of methanol, and 2 ml of water are added to the methanol solution. The aqueous methanol solution is concentrated to remove the methanol, and the residue is diluted with 15 ml of water for complete precipitation of the DC- ^ a-GuaniÄino-p-hydroxybenzylpcnicillin. The reaction product is filtered off, washed with water and dried, 0.14 g (20 percent) of the penicillin being obtained. The biochromatogram only gives a flock with an R _f value of 0.30.

Example 6

Da-Guanid i no-p-hydroxybenzylpenicillin hydrochloride

2.16 g (0.01 mol) of 6-aminopenicillanic acid in 50 ml of methylene chloride are ^{treated with?, 2 ιΤιΊ} * triethylamine. The mixture is stirred for 20 minutes at room temperature and then 3 ^ 2 _r .ml Trimcthylsilylcbloriä added. The mixture is then continued for 30 minutes at room temperature and then for 60 minutes under reflux. touched-. The LÖmmf; if Clrnm is set to Q ⁰ C, uril is deselected with a

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• s

BATH ORIGINAL

Solution of 2.5 ^ ß (0.01 mol) of Da-guanidino-p-hydroxyphenylessip; acid hydrochloride in 15 ml of dimethylformamide and then mixed with 2 g of dicyclohexylcarbodiimide. The resulting mixture is stirred for 60 hours at ⁰ ° C. and then for 30 minutes at room temperature and then filtered using kieselguhr as a filter aid. The clear filtrate is adjusted to pH 7 with triethylamine and mixed with 50 ml of water. The resulting mixture is vigorously stirred for 15 minutes. The deposited precipitate is filtered off and washed thoroughly with water. The solid is mixed with water, and the pH-Wer.t is adjusted to 2.2 with 1 η hydrochloric acid with vigorous stirring. If the pH value remains constant, the residue is filtered off and the colorless filtrate is evaporated at low temperature and under reduced pressure, the corresponding penicillin hydrochloride being obtained as a clear, non-crystalline solid. The biochromatogram shows only one inhibition zone with an R ~ -V / ert of 0.3.

Example 7

Pivaloyloxymethyl ester of D- q-guanidino-benzylpenicllline hydrochloride

According to the method described in Example 2, 1.15 g (0.005 mol) of da-guanidinophenylacetic acid hydrochloride are bound to 1.65 g (0.005 mol) of pivaloyloxymethyl ester of 6-aminopenicillanic acid in the presence of 1.03 g (0.005 mol) of dicyclohexylcarbodiimide. 2.03 g (75 percent) of non-crystalline solid are obtained. The biochromatogramra shows only one zone of inhibition at an H _f -V / crt of 0.92.

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Example 8

Pharmacological activity

a) The maximum blood level values are shown at. oral administration of 100 mg / kg of compounds of the general formula

CH-CO-

determined in squirrel monkeys. The results are in Table 1 compiled.

· Table I -. .. ·. ".

link _R lll _R 1I11 Maximum blood
mirror values,
pg / ml R ¹ R ¹¹ H II H H H H 0.5 HO H H
H CH ₂ OCOG (OH,),
CH ₂ OCOC (CH ^) ₇ »4.4 H
HO H
H - 9.9
10.5

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at Mau550η b) Table II shows the / for subcutaneous injection of

of compounds of the above general formula, in which R ¹¹ , R ¹¹¹ and R ^{1111 are} V. 'ar-hydrogen atoms, compiled blood level values obtained.

Table II

Time, minutes medium concentration ^ jig / inl R ¹ «OH 10 R ¹ = H •
13.8 20th 2.0 21.0 30th 2.7 18.2 60 2.4 13.2 120 2.4 4.4 • 240 2.0 - '0.6 • i »o

Claims (1)

in de'rli-, a hydrogen atom or a Hj ^ droxylgruppe, Kp a hydrogen atom, or an Aikylrer.fc with 1 to 4 carbon atoms and R ^ a V / assei'stoffatom or an acylöxyalkylrest with 1 to 8 carbon atoms , with the proviso that when IL and H _{0 are} hydrogen atoms, then IU is not a hydrogen atom, and their salts. . ■ 2. Compounds according to claim 1 of the general formula III • ü f2f. GH, (IH) x »gff in which I? ^ a Kothylgruppc odor preferably a V / asserstoffatora j ^r ; t . BATH ORIGINAL 3. Compounds according to claim 1 of the general formula IV - NH- -N- CIl. CH, C 'I in which R, a hydrogen atom or preferably 'a Hydroxyl group and R ^ a methyl group or preferably is a hydrogen atom. 4. Compounds according to claim 1 to 3 » ' characterized in that the N-acyl side chain is in the D (-) - form. Process for the preparation of the compounds according to claim 1, characterized in that one 309808/1332 ■ - O <: Compound of the general formula \ ^r with a compound of the general formula VI CO-X Y-HH (V) (VI) in which Rp has the meaning given in claim 1 has, Rj- a hydrogen atom or an optionally protected one Is a hydroxyl group, the radicals X and Y are of such a nature "that an amide bond is formed when these radicals are split off, Z is an optionally protected guanidine group or a suitable precursor ■ of such a group and R, -SO is such that the -COpR ^ radical is a possibly present in salt form or in the form of a silyl derivative Is a carboxylic acid group or an ester group, and optionally then the radical Z is converted into another radical Z and / or the radical R ^ into another radical R ^ and or, or the protective group optionally contained in the radical * R ^ splits off. 6. The method according to claim 5 for the preparation of the compounds of the general formula III, dadurchgekenn-ζ eic hn "et ^ that one is a compound of the general formula V, in which Sp is a hydrogen atom, R ₁ - an optionally protected hydroxyl group and Z is an optionally ge 309808/1332 Schütcte guanidino group is reacted with a compound of the general formula VI and optionally then the in the test Re and / or Z contained ßchuta groups and, if the remainder -COgRg none, possibly igt The carboxyl group present in the salt form is, this radical In unites such group convicted. 7. Process according to claim 6, characterized in that a compound of the general formula V in which R _{2 is} a hydrogen atom, Rc is a hydroxyl group and Z is a guanidino group in salt form, with a compound of the general formula VI in which Y a SiIyIrest and the radical -COpRg is an eilylated or esterified carboxyl group, reacted and the intermediate product obtained for cleavage of the Silylreetes then with a '' Treated agent containing hydroxyl groups and, if necessary. '' the remainder -COpRg by hydrolysis or hydrogenative cleavage converted into an optionally present in salt form carboxyl group. ' 8. The method according to claim 6, characterized in that the method with a compound of the general formula VI, in which Y and Rg -Si (CH,), - mean groups. 9. The method according to claim 6, characterized in that g e k e η η - ζ e 1 ch η β t that the process is carried out with a compound of the general formula VI in which Y is a -Si (CH,), - group and the radical -CO ₂ Rg is an ester radical which is hydrolytic after acylation or hydrogenation is deposited. 30980A / 1332 - PQ - lo. Process according to claim 6, since by geke η η ζ eic η η et that one is a compound of the general formula V ₁ in the E. a hydrogen atom, -R ₁ - a hydrogen atom or a hydroxyl group: and Z is in salt form The guanidino group is reacted with a compound of the general formula VI, in which Y is a hydrogen atom and -COpRg is an optionally in salt form or an ester radical, and then optionally the radical -COpR> in a known way into an optionally Carboxylgr- ^ oT present in salt form converted. 11. The method according to claim 9j characterized marked e i c h η e t that one can connect the general Formula VI is used, in which the radical -COpR ^ - an optionally is carboxyl group present in salt form. 12. The method according to claim 9 »characterized that one uses a compound of the general formula VI in which the radical -COpR, - a through Hydrolysis or hydrogenation easily convertible into the underlying carboxylic acid or one of its salts ester radical is. 13. Process according to Claim 12, characterized in that a compound of the general ol V is used, in which R _{r is} a hydrogen atom or a HydroxyIgPUpJ) O and Z a guanidino group present in salt form is. " . Method according to claim / ") for producing the compounds of the general formula IV, in which Ii ^ is a hydrogen atom, characterized in that a compound of the general formula V in which Rp is a water st off atom, Rc a hydrogen atom or an optionally protected hydroxyl group and Z is an optionally protected guanidino group, with a compound of the general Formula VI, in which Y is a hydrogen atom and R ^ is a -CHoO-CO-C (CH,), - group, is reacted and then any _{protective groups contained in R 1} - and / or Z are split off. 15 · The method according to claim 5 for the production of the compounds of the general formula IV, characterized in that a compound of the general formula II in which R is in Claim 1 has the meaning given, R ^ is a hydrogen atom or a methyl group and R, a hydrogen atom or a salt-forming ion is esterified. '. 16. Medicinal preparations containing at least one compound according to claim 1 to 15 and / or at least one pharmacologically acceptable salt of such a compound and at least one customary pharmacologically acceptable carrier and or or at least one common pharmacologically acceptable diluent .. 17. Embodiment according to claim 16, characterized through dosage units containing 200 to 2,000 mg of the active ingredient contain. 18. Ausführungsforni according to claim 16 and 17 »marked by a content of 150 to 750 mg of a compound according to Claims 1 to 15, the N-acyl side chain thereof 309808/1332 in the D (-) - form.
19 · Compounds of the general formula in which R- is a hydrogen atom or an optionally protected hydroxyl group and R ~ is a hydrogen atom or a methyl group, with the proviso that when E _{1 is} a hydrogen atom, Rp is not a hydrogen atom, their salts and acyl halide derivatives in salt form. 20. Connections according to claim. 19, ■ d a d u r c hgeken. n sign that in the general formula R 1 is a hydrogen atom and Rp is a methyl group. 21. Compounds according to claim 19 «characterized- ' that in the general formula R-, a Hydroxyl group and Rp is a hydrogen atom or a methyl group is. · C. 309008/1333