DE1670284C3 - Penicillins - Google Patents

Description

CH _3
co _ _N -CH- COOH

and their non-toxic salts, where R is the phenyl or the 3-thienyl group, while R ^{1 is} the phenyl or the p-ToIyJgruppe.

2. u- (Phenoxycarbonyl) -benzy! Penicillin and be Sodium salt,

3. a- ( Phenoxycarbonylj-ß-thienylmethylpenicillin and its sodium salt.

4. u-ip-tolyloxycarbonyD-benzylpenicillin and its sodium salt.

5. Pharmaceutical preparations consisting of a compound according to claim I and book ü, pharmacologically acceptable carriers and diluents.

The invention relates to penicillins of the general formula

S CH ₃

/ \ / R • CH • CO -NH-CH-CH C

COOR '

CH ₃
CO - N CH-COOH

where R is the phenyl or the 3-thienyl group and R ^{1 is} the phenyl or the p-tolyl group. The invention also relates to non-toxic salts of these penicillins.

The non-toxic salts include metallic salts, such as sodium, potassium, calcium or aluminum salts, as well as salts derived from ammonia and substituted ammonium compounds, for example salts of non-toxic amines such as trialkylamines (including triethylamine), procaine, dibenzylamine, N-benzyl '/ i-phenathylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, dehydroabietylamine, Ν, Ν'-bis-dehydroabietylethylenediamine. As a salt builder Other amines, which are usually used for the preparation of salts of benzylpenicillin, are also suitable be used.

From the prior art, penicillins are known which have a free carboxylic acid group in the side chain exhibit. Although these known penicillins are also used against Pseudomonas infections but they have the decisive disadvantage that they are poorly resorbed cannot be administered orally, but must be injected. Such infections are common, in particular in severe burns, quite painful. The penicillins according to the invention, which in the Side chain a phenyl or p-tolyester group as Have substituents now show the very surprising property that they are when administered orally result in a high serum level, which ensures a good pharmacological effect is.

Test report

Volunteers were subject to the invention Penicillins administered, in capsule and / or syrup form. Using standard methods, The mean serum level was determined in time intervals and was also determined within the first 6 hours after administration, the excretion of the penicillin in question in the urine was determined.

The results obtained are compiled in Tables I to III below, where as a comparison substance, the corresponding penicillin with a free carbonyl group in the side chain was used.

Table 1

(R - phenyl group)

(Dose of 500 mg in the form of gelaline capsules, based on the compound with R ¹ = H)

Mean Serunikon / enlration lug / ml)
0.5 hours 1 hour 2 hours

3 hours.

H <2.0 <2.0 <2, () <2.0 Phenyl <l, 0 7.1 3.8 0.8 p-tolyl 2.6 3.0 3.6 1.8

4 hours

<2.0

maximum
the serum
ko> .zenSralion Deposition
in the horn 0 to
6 hours after
administration (ug / mJ) (%) <2.0 C. 1.0 7.1 31 3.6 20th

Tables

(R = 3-thienyl group)

(Dose of 500 mg in the form of gelatin capsules, based on the compound with R ¹ = H)

Medium scrumkon / emraliim |; xg ml)

H <2.0 <2.0 <2.0

Phenyl 2.5 4.0 3.0 1.4

Tables!

(R = 3-thienyl group)

I dose of 400 mg in the form of a syrup, based on the compound with R ¹ = H)

4 hours maximum
the serum
concentration Deposition
in urine 0 to
6 hours after
administration (µg / ml) 1%) <2.0 <2.0 2.8 1.0 4.0 18th

Mean serum concentration (iig / ml) maximum

the Scrum 20 min. 40 min. 1 hour 1.5 hours 2 hours 3 hours. concentration

Phenyl 5.4

p-tolyl 5.9

7.5 5.2 3.6 2.4

8.6 6.8 4.9 3.7

(Hg / ml)

7.5
8.6

Deposition
in urine 0 to
6 hours after
administration

23 30th

The above tables confirm that the penicillins with a free carbonyl group in the side chain do not give sufficiently high serum levels when administered orally. The small amount of excretion in the urine is also an indication that only small amounts of penicillin are in the body have been absorbed. In contrast, the phenyl and p-tolyl esters show excellent activity.

The penicillins of the general formula I according to the invention can be prepared by 6-aminopenicillanic acid is reacted with a reactive acylating agent of the general formula 11

R-CH CO Q
I.
COOR ¹

(H)

in which R and R ^{1 have} the meaning given above, while Q represents a functional group which is suitable for acylating primary amines. Examples of such a functional group are chlorine or bromine atoms (in this case the compound of the general formula II is an acid halide), an azido group, an acyloxy or alkoxycarbonyloxy group (in this case the compound of the general formula II is an acid anhydride or a mixed one Anhydride). Q can also be a 1-imidazolyl group or an N, N'-zwcifac: h-substituted isourea group (in this case the compound with the general formula 11 is an intermediate product formed from the half-ester of a -substituted malonic acid and a condensing agent, the condensing agent being carbonyldiimidazole or a! ^, N'-disubstituted carbodiimide such as dicyclohexylcarbodiimide can be used). Some of the above-mentioned acylating agents of the general formula II are unstable substances, so they are preferred

in a suitable solvent at temperatures freshly prepared below room temperature • and then used in situ.

The new penicillins of the general formula I contain at least one asymmetric carbon atom, and therefore they occur in various spatial configurations. Since it is however, in the case of all these compounds of general formula I, only epimeie or stereoi> .o values Forms of the same composition. are all of these connections from the specified General Formula I includes. Dk; The invention therefore relates to both the d- and the i.-forms as well DL mixtures.

A penicillin of the general formula 1 can be so-U'ohl Used in the free acid form as well as in the form of a non-toxic salt for biological purposes and it can also be used in combination with a suitable pharmaceutical carrier will. Such carriers are, for example, diluents. Binders, solvents, flavoring agents. Dyes and other conventional Carriers and additives, as well as capsules and carriers in the form of containers, which contain a unit dose contain.

example 1
a) Mono-phenyl-phenylmalonate

27 g (0.15 mol) of phenylmalonic acid are mixed with 80 ml dry ether and then mixed with 17.85 g (10.9 ml; 1 equivalent) thionyl chloride and 4 drops Treated dimethylformamide. This mixture is refluxed on a water bath for 3 hours heated. The solvent is then evaporated off under reduced pressure and the residue in 80 ml of fresh dry ether dissolved. 14.1 g (0.15 mol) of phenol are then added all at once, and this mixture is refluxed for an additional 2 hours. The reaction mixture is then cooled to room temperature, washed with 25 ml of water and with a saturated sodium bicarbonate solution extracted until the extracts react alkaline. The combined aqueous extracts are washed with 100 ml of ether and then with Sn-hydrochloric acid acidified. The oil which separates out is extracted exhaustively with methylene chloride. The United Organic extracts are carefully washed with 6 portions of 120 ml of water, then over dried anhydrous magnesium sulfate and finally evaporated.

The solid residue thus obtained is recrystallized from benzene, and 30.2 g (78.7%) of one are obtained colorless crystalline solid with a melting point of 115 to 117 ° C.

b) a-f-phenoxycarbonyl-I-benzylpenicillin sodium salt

5.12 g (0.02 mol) of mono-phenyl-phenylmalonate will be mixed with 20 ml of thionyl chloride and then heated on a water bath at 75 ° C for 1 hour. The excess thionyl chloride is then evaporated off under reduced pressure. The residue is mixed with 10 ml of dry benzene and again evaporated to dryness to remove residues to remove thionyl chloride. The residue thus obtained is then dissolved in 100 ml of dry acetone dissolved, and then, while stirring, a temperature of 12 ° C A cooled solution of 4.32 g (0.02 mol) of 6-aminopenicillanic acid in 100 ml of water was added, soft also 20 ml of n-sodium hydroxide. 30 ml n-sodium bicarbonate solution and contains 50 ml of acetone. This reaction mixture is stirred for 2 hours at room temperature. The solution obtained is then extracted three times with 60 ml of ether each time, and these extracts are discarded. The aqueous layer is covered with 60 ml of ether and acidified with n-Sa!? acid up to a pH value of 2. the The ether layer that forms is separated off, and the aqueous layer is washed twice with 60 ml of ether each time extracted. The combined ether extracts are washed with 20 ml of water and then with aqueous n-Sodium bicarbonate solution extracted to a pH of 7. The neutral aqueous extract will evaporated under reduced pressure and at low temperature. The residue is in vacuo dried over phosphorus pen oxide, and one obtains so 6.7 g (70.4%) of the penicillin salt in the form of an amorphous solid. If you have this solid Dissolve in 50 ml of ethanol at room temperature and let it stand for 30 minutes, so you get it. Penicillin salt in the form of colorless crystals (yield 5.23 ti: 78.1%).

Example 2
a) Mono-phenyl-3-thiene \ lmalonai

A solution of 9.3 g (0.05 mol) of 3-thienylmalonic acid in 30 ml of dry ether is converted into the monoacid chloride according to the procedure of Example 1 and then reacted with 4.7 g (0.05 mol) of phenol. The crude reaction product is recrystallized from a mixture of benzene and petroleum ether (boiling range 60 to 80 C), and one thus obtained 2.89 g (22.1%) of a colorless crystalline solid with a melting point of 120 to 122.degree

b) (i- (PhenoxycarbonylJ-S-thienylmethylpenicillin sodium salt 7

2.62 g (0.01 mole) mono-phenyl-3-thienylmalonate are converted into the acid chloride and then according to the procedure of Example! with 2.16g (0.01 mol) 6-aminopenicillanic acid reacted, giving 3.4 g (70.6%) of the penicillin sodium salt obtained in the form of an off-white, non-crystalline solid.

Example 3
a) Mono-p-tolylphenylmalonate

A solution of 27 g (0.15 mol) of phenylmalonic acid in 80 ml of dry ether is converted into the monoacid chloride and then reacted with 16.2 g (0.15 mol) of p-cresol. The crude reaction product is recrystallized from a mixture of benzene and petroleum ether (60 to 8O ⁰ C), and one thus obtains 33 g (81.5%) of colorless crystals having a melting point 122-124 "C.

b) «- (p-TolyloxycarbonylI-benzylpenicillin sodium salt

2.7 g (0.01 moles) of mono-p-tolyl phenyl malonate will be used converted into the acid chloride and then with 2.16 g (0.01 mol) of 6-aminopenicillanic acid for reaction brought. 3.6 g (73.5%) of the penicillin are thus obtained in the form of a colorless, non-crystalline solid.

Claims (1)

Patent claims: 1. Penicillins of the general formula / R-CH • CO -NH- CH-CH COOR ¹ S CH ₃