DE1470043A1 - alpha-guanidinobenzylpenicillin and process for its preparation - Google Patents

Description

DR.-ING. WALTER ABITZ DR. DIETER MORF

Patent attorneys

8 Munich 27, Pienzenauerstraße 28 Telephone 483225 and 486415 Telegrams: Chemlndus Mündten

August 1, 1968 8400 (N 57 »4)

P 14 70 043. 7
New documents

MERCK Jb 00., INC. 126 Baet Lincoln Avenue "Rahway, N.J. 07065, V.St.A.

α-Ouanidinobenzylpenllnlln and method for its production

The penicillins of the general formula

R-C-NH-CH

I O = C-

CH

CH
COOH

in which R means an organic radical, have in the Therapy of infections, especially the duroh oramposltive Bacteria-related infections, proven valuable.

New Untertaflerv ^, viiAb ^ aKrae.ttSiKeXMwunfl ^ a.v.A.M.iiik /.

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BATH ORIGINAL

H7Q043

80 penicillins, such as benzylpenicillin, for example and phenoxymethylpenioillin, largely sur treatment used in various infections. Although penicillins have found widespread use, the sur Tent well-known penicillin disadvantages. For example, some penicillins, such as benzyl penicillin, are among acidic Conditions are unstable and are therefore not suitable for oral use Administration. Some penicillins are resistant to resistance Bacteria * tMnme ineffective; the use of these penicillins must therefore be limited to the treatment of infections who are sensitive to the action of penicillin Caused by bacteria *

The present invention relates to a stable penicillin and its salts, which are effective against various microorganisms resistant to penicillin. :

Bs has now been found that α-quanidinobenzylpenioillin and its non-toxic acid salts are valuable antibacterial Products are.

OHOuanldinobenzylpeniollline and its nontoxic salts know to be made by adding an acid addition salt of an ester of 6-aminopenicillanic acid in the presence of a

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Carbodiimide with α-Guanidlnophenylessigsäure reacts, the obtained acid addition salt of a-quanidinobenzylpenioll-1inester by catalytic hydrogenation cleaves and optionally the obtained a-quanidinobenzylpenioillin into one transferred to non-toxic salt.

Suitable esters of 6-aminopenicillanic acid are those which can easily be split by catalytic hydrogenation, preferably allyl, benzyl, substituted benzyl, phenyl, substituted phenyl esters and the like esters. Because the benzyl ester at is most conveniently prepared, this ester is preferably used in the preparation of the novel penicillins according to the invention used.

α-Ouanidinophenylacetic acid can be produced »ground duroh Reaction of a-aciinophenylacetic acid with Q-methylisourea.

The implementation of the acid addition salt of 6-aminopenicillan acid esters and dor a-guanidinophsnylessigsäure is in the presence of a carbodiimide, such as, for example, 1,3-Dloy clone. xyloarbodilmide or 1,3-diisopropylcarbodiimide, two-fold made in the presence of a suitable solvent at room temperature. After the reaction has ended, the

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Urea formed from the carbodiimide from the reaction mixture separated, and the desired penlollllnester is from the solution obtained according to known methods won

The ester of the new penicillin obtained in this way lets see easily by catalytic hydrogenation into the free acid convict. This catalytic hydrogenation is preferred using a precious metal catalyst such as palladium, platinum or rhodium, preferably Iq on an inert carrier, such as carbon «barium carbonate Diatomaceous earth and the like, applied form, continuous. After the hydrogenation has ended, the free penioillinal acid becomes from the hydrogenation reaction mixture. ι known method won.

The new penicillin can be obtained in the form of its internal salt or with acid to the corresponding Penilollnsgurealzen implemented. The internal salts and the non-toxic acid salts can be mixed with suitable non-toxic substances liquid or solid pharmaceutical carriers for administration to humans and animals. These

Pharmaceuticals can also contain other active therapeutic agents and administered orally or parenterally.

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The new α-auanldlnobenzylpenlolln and its non-toxic Sj & lze are useful antibacterial agents that also help Can be used for sterilizing instruments and the like are. They are also valuable as additives and animal feed. Aiuseerdem they are used as therapeutic agents for poultry and other animals as well as for humans, especially for treatment of infections caused by susceptible Gram-positive and Gram-negative bacteria.

example

D-a-auajiidinobenzylpeniollllnbenzylester-hydrochloride is by reacting benzyl-6-aminopenioillanate with D-a-Quani « dinophenylessigs & ure ^ hydrochlorld in Oegenwart von Dioyolo-

hexyloarbodilmid made as follows:

• χ.

To a solution of 0.2 g Benayl-6-aminopenioillanat and 0.25 g of Dloyolohexyloarbodiimid in 3 ml of methylene chloride is drop by drop under! {Watch a solution of 0.23 g of D-a-Guani » Phenyl acetic acid hydrochloride in 1 ml of dimethylformamide added within 5 minutes · after standing still necessary at room temperature the solution is cooled and the Niederaohlag filtered off from dicyolohexylurea. The filtrate is diluted with 50 ml of ether, and the supernatant liquid

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Kelt is decanted from the precipitated Sohmlere · Another 25 ml of ether are added to the smear, which is then smelted with a spatula until it solidifies. The solid Do-auanidinobenzylpeniollllnbenzylester-hydroohlorld is filtered off and washed with Steher. This gives 0.5 S substance from P> 75 to 135 ^° C. (gradual decomposition). This product is used in the reduction stage without further purification.

0.41 g of Da-Ouaiiidinobenzylpeniolllinbenzylester-hydrochloride, which can be prepared as described above, are added to a previously reduced suspension of 0.1 g of 10J & ger palladium carbon in 10 ml of 50 # methanol, and the Oemisoh is under hydrogen at room temperature and atmosphere Krendruok 45 Shaken for minutes. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. When the methanol evaporates, Da-0uanldinobenzylpenicillin crystallizes out of the aqueous acidic solution in the form of the inner salt. The precipitation is completed by adding 1 ml of aqueous 0.5N sodium bicarbonate solution. The precipitate is filtered off and washed with water and with ethanol; P - 220 ⁰ C (dec.).

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The benzyl-6-aminopenloilianate is produced as follows!

2 g of finely ground 6-aminopenioillanic acid become one Solution of 1 g of phenyldiazomethane in 10 ml of methylene chloride and

3 ml of methanol were added. The suspension is stirred for 3 hours while nitrogen is being released and the initially red solution is discolored. The oil is diluted with 30 ml of ether and 6-aminopenicillanic acid (0.5 g) which has not reacted is filtered off. An anhydrous solution of hydrogen chloride in ether is added dropwise to the piltrate until further addition no longer causes precipitation. The precipitated benzyl 6-aminopenioillanate hydrochloride (2.2 g) is filtered off and washed with Xther. The precipitate is shaken with 30 ml Xther and a slight excess of aqueous Natriumbioarbonatlösung, and the ethereal layer% l ^ a separated and dried over anhydrous magnesium sulfate. When the ether evaporates, an oily residue of benzyl-6-aminopenioillanate remains. For purification, the oily residue is dissolved in methanol and a solution of oxalic acid hydrate in methanol is added. The precipitated oxalate of benzyl-6-aminopenioillanats is filtered off and washed with Xther; P 133 to 134 ⁰ C (sera.) The oxalate is treated in the same way as the obiga hydrochloride with Xther and sodium bicarbonate solution in order to obtain benzyl-6-ainopenioillanate in the form of white crystals from P 82 to 83 ⁰ C.

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Oae Da-auanldlnophenyleeigelure-hydrochloride is prepared as follows: 10 g of Da-aminophenylesslgs & ure are put into 200 ml of water and 60 ml of 28% aqueous ammonia. 20 g of 0-methyl isourea ether hydrochloride are added and the solution is left to stand at room temperature for 24 hours. The precipitate of da-auanldinophenylacetic acid is filtered off and washed with water. Yield 2.5g. The product melts at 255 ⁰ C * solidified βloh and melts again at about 260 ⁰ C with decomposition.

The hydrochloride was produced by dissolving the acid in dilute salt and evaporating the solvent in a vacuum. P - 157 to 159 ⁰ C (dec.).

The antibacterial effectiveness of D-a-Guanldlnobenzylpenloillin In vitro, benzylpenicillin (penicillin 0) was tested in 24-hour test glass yerdthinungate tests against Staphyloooool, Streptoooool and Pneumoeoool compared. The minimum Inhibitory concentration (minimum concentration of M.I.C.) these two antibiotics against the pathogenic organisms 1st shown in the following table:

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8400

Minimal »Inhibitory Coagentration In υκ / tnl Organism D-a-Ouanidino- Benaylpeni-

benzylpenioillin

Staph. aureua Smith Staph. aureu * 2957 Staph. aureus 314? Staph. aureus 305I Staphaureus 5036 Staph. aureus 3106 Staph. aureufl 50Θ9 D. pneumonia • 1-37 Strp • pyrogenic C-203

0.97 0.12 3.9 1000 1.9 125 3.9 1000 3.9 1000 3.9 1000 5.9 1000 0.06 0.05 0.05 0.05

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Claims (2)

JO 1470D4S 1st August 1968 Claims 1, α-euanidlnobenzylpenicllline and its non-toxic Salts. 2. Process for the preparation of α-ouanidinobenzylpenioillin and its non-toxic salts according to Claim 1, daduroh characterized in that one is an acid addition salt of an ester of 6-aminopenioillanic acid in (legend a carbodiimide reacts with a-Ouanldinophenylessigslure, the obtained acid addition salt of the α-Ouanidinobenzyipenlollllnester cleaves by catalytic hydrogenation and optionally the a-tuanidinobenzylpenioillin obtained converted into a non-toxic salt. 3 · Medicines, consisting of a-suanidinobenzylpenloillln or its non-toxic salts. New teda 909822/1297