US2645638A - Penicillin salts of nu-methyl-(2-hydroxy-1, 2-diphenylethyl)-amine - Google Patents

Description

' ethyl) amine.

Patented July 14, 1953 PENICILLIN SALTS OF N-METHYL- 2-HY- DROXY-L2-DIPHENYLETHYL) -AMINEv Vernon V. Young, Terre Haute, Ind., assignor to a Commercial Solvents Corporation, Terre Haute, -Ind., a corporation of Maryland No Drawing. Application January 22, 1952,

Serial No. 267,695

7Claims. (01260-2391) in order for the therapeutic activity of the salt to be retained, it must be refrigerated during storage or else rapid deterioration of the thera-,

peutic activity occurs. Some penicillin salts are too toxic for use therapeutically and hence must be ruled out-completely.

In addition to the stability and toxicity characteristics of penicillin salts, consideration must also be given to their solubility properties. The expression of favorable solubility properties is foundin themeasurement of blood levelsof penicillin at intervals after injection into or ingestion by the body. The longer penicillin can be found in the blood after it has been placed in the body, the more effective it is against the pathogenic organisms present in the body, provided they are penicillin susceptible. If, however, blood levels of penicillin are only maintained for short periods after injection or ingestion of the penicillin salt, the penicillin content of the salt is largely wasted and there-islittle or no alleviation of the pathological condition being treated unless there are repeated administrations of the pen icillin salt at short intervals.

Furthermore, it has been found that about 10 .per cent ofv allpatients treated with most previously known penicillin compounds are allergic to. the. drug and upon administrationthereof serious complications'in theform of hives often occur. Treatment is, therefore-denied a great "many people because of their allergy.

An object of the present invention is to provide stable penicillin salt compositions of low toxicity which give prolonged blood levels of penicillin whether given orally or by injection, and which a more people. My new compositions are penicillin hydroxy -'l',2 diphenyl} v salts of N-meth'yl- (2 N methyl (2-hydroxy-1,2-diphenylethyllamine contains two asymmetric 'carbonatoms and thus two racemic modifications and four optically active isomers arepossible. Thepenicillinsalt-of the levo isomer of the erythro pair of N -methyl (2-hydroxy-1,2-diphenylethyl) amine can be prepared by mixing one-equivalent of a water soluble penicillin salt such as potassium penicillin G in aqueous-solution with two equivalents of an aqueous solution of thehydrochloride of dl-N-methyl- (2-hydroxy-l,2-diphenylethyl) amine obtained by the reductive .amination of benzoin with monomethylamine. Thecrystalline penicillin salt of l N methyl (2-hydroxy-LZ-Giphenylethyl)- amine-precipitates from the aqueous solution and is recovered therefrom by filtration and dried. (Nitrogen analysis: calculated 7.48% found 7.38%. Carbon analysis: calculated 66.28%; found 66.33%. Hydrogen analysis: calculated 6.28%;.-found 6.18 Melting point 186-191" C. with decomposition. Specific rotation in 50% acetone-water at 2.5? C ,taken within one-half hour after dilution is +124i5.) The dextro isomer of the same pair does not form asalt with penicillin under the above-conditions but the unreacted isomer can be recovered from the filtrate by adjusting the pH between 9-10 with an aqueous solution of sodium hy'droxide. One mole of potassium penicillin is reacted with two moles of dl N methyl 2 hydroxy-LZ-diphenylethyl) amine in order-to obtain near quantitative yields of thesaltof thelevo isomer based on the quantity. of penicillin useddue to the presence of the dextro isomer.

The penicillin salt of' the dextro isomer can be prepared by reacting it with an equivalent amount of. free benzyl-penicillinic acid in an organic solvent such as ethyl ether or butyl acetate. Crystallziation can be induced by seeding or scratching. (Nitrogen analysis: calculated 7A8 found 7.33 Carbon analysis: calculated 66.28%; found 66.21%. Hydrogen analysis: calculated. 6.28% found 6.18%. Melting point 148 -151". C. with'idecomposition. Specific rota- .tion in.50% acetone-water at 25 C. taken within one-half hourafter' dilution is +220 i5.) The terms dextro and'levo or d andl as used in'this specification and the attached'claims refer to the dextro and levo isomers-"6f the erythro pair of N- 'methyl (2 hydroxy-l,2diphenylethyl)amine.

-themethod of Welsh. (Journal. American Chem- 3 ical Society, vol. 69, page 128; Journal American Chemical Society, vol. 71, page 3500) as applied to ephedrine, which consists essentially of a'cetylating the deX-tro and levo isomers of the erythro pair and hydrolyzing the acetylated product with dilute acid in order to bring about inversion. The penicillin G salts of the levo and dextro isomers forming the threo racemate of N-methyl-(Z-hydroxy-l,Z-diphenylethyl) amine are prepared by reacting an isomer of the base with free penicillin G in ethyl ether solution. The precipitated amorphous salts are isolated by decanting the ether and then drying. The dextro and levo isomers of the three racemate of N-methyl-(2- hydroxy-1,2-diphenylethyl) amine in this specification are denominated d and 1' respectively. The penicillin G salt of the d isomer has a specific rotation of +192i5 in acetone at 25 C. taken within one-half hour after dilution while the specific'rotation of the penicillin G salt of the 1' isomer taken under the same conditions is +155i5. 17he l and d isomers can be employed to form salts of other forms of penicillin just as described above for penicillin G,

Blood level tests were conducted wherein my new penicillin salts of N-methyl-(2-hydroXy-1, 2-diphenylethyl) amine were given orally. and in.- jected intramuscularly into dogs, the amount of penicillin in the blood stream being measured at definite intervals after administration. The following table shows the blood levels obtained after a portion of my new penicillin G salt of l N methyl (Z-hydroxy-1,2-diphenylethyl) amine containing the indicated number of units of penicillin was injected intramuscularly as an aqueous suspension.

TABLE I [Blood level; 120 mesh aqueous suspensionintramuscularly; units penicillin/ml. blood] Hours Dog No. 6 12 24 36 48 60 72 TABLE. II

. 0 [Blood levels; units penicillin/ml. blood; procaine penici1lin12 mesh aqueous suspension-intra.muscularly.]

Hours Dog No. gg

TABLE III [Blood levels; 100,000 unit tabletoral1y; units penicillin/ml. blood.]

Hours Dog No.

The following table shows blood levels obtained when my new penicillin G salt of d-N- methyl- (2-hydroxy-1,2-diphenylethyl) amine was administered orally, 100,000 units of penicillin being administered to each dog.

TABLE IV [Blood levels; 100,000 unit tabletorally; units penicillin/ml. blood] Hours Dog No.

The following table indicates blood levels obtained when my new penicillin G salt of l-N- methyl- (2-hydroxy-1,2-diphenylethyl) amine was injected intra'muscularly into dogs as a suspension in peanut oil.

TABLE V [Blood levels; 60,000 units; oil suspension-intramusc ularly; units penicillin/ml. blood] 7 Hours Dog No. i

TABLE VI [Blood levels; procaine penicillinoil suspension-intramusculerly; 60,000 units per dog; units penicillin/ml. blood] 1 Hours Dog No.

The following table isa*summary of clinical data obtained when my new penicillin G aner l-N-methyl- (2' hydroxy 1,2 diplienylethyltamine was used. therapeutically in'man. ideaeh oase a single 300,000 unit doseof jmy riew dmpound was injected intramuscularly "aind tlieblood level obtained in the usual manner.

TABLE VII [Blood levels; 300,000 units; aqueous 'suspe'nsionintramuscularly in man; units penicillin/ml. blood] Hours Patient 0. 125 0. 125 0.06 0. 25 0. 125 0. 03 0. 06 0. 125 0. 06 0.03 0. 03 0. 25 O. 125 0.03 0. 06 O. 25 0. 06 0 0 0. 06 0. 125 0.06 0 0. 125 0 0 0 O. 25 O. 125 0 0 0. 5 0. 125 0 0 0. 5 0.03 0.03 0 0 0.03 0 0 0. 25 O. 125 0. 06 0.03 0. 125 0. 06 0. 03 0.03 0. 125 0. 125 0 0 0.06 0. 06 0 0 0. 25 0. 06 0.06 0 0. 25 0. 125 0. 06 0. 03 0. 25 0. 125 0.06 0.06

The following table is also offered for comparison. purposes. It shows blood levels obtained when procaine penicillin G was injected intramuscularly into man, 300,000 units of penicillin being administered to each patient.

TABLE VIII [Blood levels; 300,000 units of procaine penicillin G aqueous suspension intramuscularly in man; units penicillin/ml. blood] Hours Patient It can be seen from a comparison of Tables VII and VIII that my new penicillin G salt of N methyl-(Z-hydroxy-1,2-diphenylethy1) amine gives consistently longer blood levels in man when injected intramuscularly than the form of the antibiotic currently considered most efiicient.

In another series of tests twenty-three selected patients were treated with both procaine penicillin G and the penicillin G salt of l-N-methyl-(2- hydroxy 1,2 diphenylethyl) amine. Of the twenty-three patients treated, twelve were hyper-- sensitive to procaine penicillin G, while but one was sensitive to the penicillin G salt of l-N- methyl-(z-hydroxy 1,2 diphenylethyl) amine, this patient developing an urticarial eruption. A further advantage in the use of my new penicillin salts is illustrated in the following case. Twenty-four hours after starting regular crystalline procaine penicillin G therapy for a pelvic 6 infection; thepatientdeveloped a severe urticarial rash and edema accompanied by slight elevation of temperature. The penicillin G s'altof l-N- methyl- (z-hydroxy-1;2 dipheny1ethyl) amine was immediately substituted' and all'signs of reaction cleared completely in 36 hours and did not return duringthe entire'course of treatment with my new penicillin salt. Thus it is shown to be possible to give mynewpenicillin salt even in the face of known periicillin sensitivity.

The following table shows the results of toxicity tests of the new penicillin G salt of l-N-methyl- (2 hydroxy-1,2-diphenylethyl) amine conducted on laboratory mice. The table shows the amount of my new compound which can be administered without any mouse fatalities and the amount given to produce a 50% kill or the mice tested. The penicillin salt was injected intraperitoneally and subcutaneously as indicated in the table.

The minimal dose of the pencilillin G salt of l N methyl-(Z-hydroxy-1,2-diphenylethyl)- amine showing cutaneous irritation is greater than 2100 mg. per kg. of body weight of the test mice but less than 400 mg. per kg. of body weight of the test mice. A single dose of 5,000,000 units of the penicillin G salt of l-N-methyl-(Z-hydroxy-l,2-diphenylethyl) amine in aqueous suspension was injected subcutaneously into two dogs and the dogs subsequently observed for a period of 48 hours. No toxic or irritative symptoms Were observed during the 48 hours.

The following table shows the results of acute toxicity tests of the new penicillin G salt of d- N methyl-(2-hydroxy-1,2-diphenylethyl) amine conducted on laboratory mice. The salt was given orally and injected intraperitoneally and subcutaneously as shown in the table.

TABLE X Mouse toxicity LDo D50 rug/kg. of Body Weight of Test Mice From a consideration of the above tables it can be seen that my new compounds are distinct improvements over procaine penicillin G which has been considered to be the best form of penicillin available to the trade.

My new compounds are therapeutically effective antibiotic compounds and are useful in treating diseases in man and animals caused by penicillin susceptible organisms.

7 1 Now having disclosed my invention what I 5; The penicillin G salt of dN-methyl-(2-hyclaim is: droxy-1,2.-diphenylethyl)amine.

1- The pe cill Sa Of N- t y -(iz-hy- 6. The penicillinGsalt of d1(threo)-N-methyl- Y-L iphenylethy1) amine. (2-hydroxy-1,2-diphenylethyl) amine.

The penicillin G Salts of -melJhyI-(Z-hy- 5 7. The penicillinG salt of l-(threo)-N-methyldroxy-1,2-diphenylethyl) amine. (Q-hydroxy-1,2-dipheny1ethyl) amine.

3. The penicillin G salt of dl-N-methyl-(Z- hydroxy-LZ-diphenylethyl) amine.

4. The penicillin G salt of 1-N-methyl-(2-hydroxy-1,2-diphenylethyl) amine. 10

VERNON V. YOUNG.

No references cited.

Claims (1)

1. THE PENICILLIN SALTS OF N-METHYL-(2-HYDROXY-1,2-DIPHENYLETHYL)AMINE.