DE3001590A1 - PHTHALIDYLESTER OF THE ACETONE ADDUCT OF EPICILLIN AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

The invention relates to that characterized in the claims Object.

The phthalidyl esters of the general formula I can be prepared by several methods. For example, can Epicillin with acetone in the presence of triethylamine to the intermediate of the general formula II

if

CH.

COOH

CiI)

implemented. The intermediate of the general formula II / i.e. the acetone adduct of epicillin, can then with an isobenzofuran of the general formula III

.0

till)

in which L represents a hydroxyl group or a bromine atom , are converted to the phthalidyl ester of the general formula I.

The phthalidyl esters of the general formula I can also be obtained by reacting epicillin with the isobenzofuran of the general Formula III to the intermediate of the general formula IV

CIV)

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implemented. Then the intermediate of the general formula IV with acetone to the phthalidyl ester of the general Formula I implemented.

The intermediates of the general formula IV can also be prepared by reacting the phthalidyl ester of 6-aminopenicillanic acid with a reactive derivative of the α-amino-1,4-cyclohexadienylacetic acid protected on the amino group and then Cleavage of the amino protective group can be produced.

The phthalidyl esters of the general formula I are expediently isolated in the form of their salts with acids. Examples of the Acids which can be used for salt formation are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid. acid and phosphoric acid, as well as organic acids such as maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, Benzoic acid, 2-acetoxybenzoic acid, salicylic acid, succinic acid, nicotinic acid, methanesulfonic acid and cyclohexanesulfamic acid. The salts can be converted into the free bases of the phthalidyl esters of the general formula I by reaction with a base be convicted. If necessary, the free bases can then be converted into the corresponding acid by reaction with another acid

Salt to be transferred.
25th

Preferred phthalidyl esters of the invention have the general formula I-a

V ι) —V «·? ~ 1 I l ^ t; n _o " a ^ ..

(I-a)

H ₃ C CH ₃

in the X, a hydrogen, chlorine or bromine atom or a Methoxy group, X_ a hydrogen atom or a methoxy group

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BATH

pe, where X _{5 is} a methoxy group when χ is a methoxy group, and X _{4 is} a hydrogen atom or a methoxy group, where X. is a methoxy group when Xg and Xj. Represent methoxy groups. The unsubstituted phthalidyl ester of the formula Ia in which X., X ₁ is particularly preferred.

and X, represent hydrogen atoms.
ο

The phthalidyl esters of the general formula I act as drug precursors epicillin with an identical spectrum of antibacterial activity. The esters are therefore special suitable for combating infections of the respiratory tract, gastrointestinal tract and urogenital tract as well the skin and soft tissues. The compounds act against both gram-positive and gram-negative germs. Examples for sensitive gram-positive germs are ß-hemolytic Streptococci, Streptococcus viridans, Streptococcus faecalis, Diplococcus pneumoniae, Staphylococcus albus, and non-penicillinase producing strains of Staphylococcus aureus. Examples of sensitive gram-negative germs are Escherichia coli, Proteus mirabilis, Hemophilus influenzae, Salmonella typhi, Salmonella paratyphi, Shigella and Neisseria gonorrhoeae.

The phthalidyl esters of the general formula I are particularly useful as oral antibiotics because of their high rate of absorption. The compounds of the invention give higher concentrations of epicillin in serum, tissues and urine than in oral administration of epicillin. They also reduce the incidence of gastrointestinal disorders such as diarrhea and loose stools.

The compounds of the invention can be processed into medicaments in the usual manner, for example into capsule preparations or suspensions.
35

The examples illustrate the invention.

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Example i

6- [4- (1,4-Cyclohexadien-i-yl) -2,2-dimethyl-5-oxo-1-imidazolidinyl] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [ 3.2.0] heptane-2-carboxylic acid-i, 3-dihydro-3-oxo-1-isobenzofuranyl ester hydrochloride (1: 1)

a) 6- [4- (1,4-Cyclohexadien-i-yl) -2,2-dimethy1-5-OXO-1-imidazolidinyl] -3,3-dimethyl-7-oxo-4-thia-1- azabicyclo [3.2.0] heptane-2-carboxylic acid

A suspension of 10 g of epicillin in 50 ml of acetone dried over a Linde 4A molecular sieve is mixed with 7 ml of Tri äthylarain 24 hours at 25 ° C and a further 24 hours Stirred at 30 ° C. The solution obtained is then filtered and the filtrate is added dropwise to 50 ml of water which is kept at 0 to 10 ° C is held. The pH is adjusted to 2.5 to 3.0 by simultaneous addition of cold 30 percent sulfuric acid. The resulting slurry is stirred at 0 ° C. and pH 2.55 for 2 hours and then filtered. That crystalline product is washed with 20 ml of cold water and at 40 to 50 C over phosphorus pentoxide under reduced pressure Print dried. 6.19 g of compound (a) with a melting point of 186 ° C. (decomp.) Are obtained. The connection is colored at

174 C brown. C.
co in. 6th H
/ 44; N
10, 73; 8th S.
/ 19th ^C 19 ^H 25 ^SN 3 ° 4 '
ber .: 58.06 6th / 52 10, 62 7th / 99 found:

b) 6- [4-

° zolidinyl] -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid 1,3-dihydro-3-oxo-1-isobenzofuranyl ester hydrochloride (1: 1)

A mixture of 14.81 g (0.0378 mol) of the compound (a) and

5.3 ml (0.0378 mol) of triethylamine in 265 ml of acetone dried over a Linde 4A molecular sieve is 30 minutes

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~ ⁷ ~

^ stirred at room temperature. Then 3.78 g of potassium bicarbonate are added and 8 g of 3-bromophthalide were added. After 4 hours of implementation the resulting mixture is filtered and the filtrate is evaporated to about 9.5 ml under reduced pressure. That 375 ml of ethyl acetate are added to the concentrate and the resulting solution is mixed twice with 40 ml of 2 percent sodium bicarbonate solution each time and washed twice with 40 ml of water each time, dried and evaporated. There are 19.89 g of crude product obtain. The crude product is placed on a column filled with 800 g of silica gel (SiIi CAR CC-7) and with a 1: 1 Eluted mixture of ethyl acetate and benzene. There is a fraction with 3.55 g of product and a second fraction with 8.34 g of a purer product were obtained. The product of the purer fraction is in 140 ml of a 1: 1 mixture of Ethyl acetate and diethyl ether dissolved and with a 1.66 mmol / ml 'containing solution of hydrogen chloride in diethyl ether * puts. The resulting hydrochloride is immediately filtered off, washed with diethyl ether and 15 to 18 hours at room temperature dried. There are 8.33 g of the title compound from

Melting point 160 to 162 ° C.

S. .HCl; 57 C. 5 H 5 S. 6th Cl 7th N ber .: 57 .90; 5 , 40 5 , 72; 5 , 33 7th , 50 found: , 01; .78; , 61; , 93; , 25.

Examples 2 to 10

Example 1 is repeated, but the isobenzofurans listed below are used. There will be the appropriate Phthalidyl ester obtained.

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10

Ex.

Xr

X.

15th 20th

2 H 3 H 4th H 5 H 6th H 7th OCH 8th Cl 9. OCH 10 CH

H • ^CH 3 H OCH H Br H Cl OCH ₃ OCH OCH ₃ OCH H H H H H H

H H H H H H H H H

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Claims (7)

HE. SQUIBB & SONS, INC. Princeton, N.J., V.St.A. . "Phthalidyl esters of the acetone adduct of epicillin and medicinal products containing these compounds" Claims V-Vi phthalidyl ester of the acetone adduct of epicillin of the general formula I. (D in which X is a hydrogen, chlorine or bromine atom, a methyl or methoxy group and η has the value 1, 2 or 3, where η has the value 2 or 3 when X is a hydrogen atom or a methoxy group, and their salts with acids. 2. Compounds according to claim 1 of the general formula I-a (I-a) 130030/0412 in the X, - a hydrogen, chlorine or bromine atom or a b
Methoxy group, X ₁ - a hydrogen atom or a methoxy group, where X ₁ . is a methoxy group when X- denotes a methoxy group, X. is a hydrogen atom or a methoxy group, where X _{4 is} a methoxy group when both X ₅ and X _{fi denote} methoxy groups, and their salts with acids. 3. Compounds according to claim 2 of the general formula Ia, in which X., X _c and X are hydrogen atoms. 4. The hydrochloride of the compound according to claim 3. 5. Medicament, characterized by a content of a compound according to any one of claims 1 to 4. 6. Medicament according to claim 5, characterized by a content of 6- [4- (1,4-cyclohexadien-i-yl) -2,2-dimethyl-5-oxo-1-imidazolidinyl] -3,3-dimethyl-7-oxo-4-thia-1 -azabicyclo- ² ^ [3.2.0] heptane-2-carboxylic acid-1, S-dihydro-S-oxo-i-isobenzofuranyl ester. 7. Use of the compounds according to any one of claims 1 to 4 in combating bacterial infections .. 25 130030/0 4 1 1 EJAPl / -Μ3Ι / -ΜΜΛΙ