US 3,957,764 AGrant
6-Aminopenicillanic Acid Derivatives
Issue Date:1976-05-18
•21 Claims
Abstract
The invention relates to hitherto unknown derivatives of 6-aminopenicillanic acids of the formula ##SPC1## In which R.sub.1 and R.sub.2 are similar or different aliphatic, cycloaliphatic, aromatic or heterocyclic substituents linked directly or through alkyl groups to the nitrogen atom, or R.sub.1 and R.sub.2 together with the nitrogen atom form a heterocyclic ring, and R.sub.3 is a hydroxyl or substituted hydroxyl group; to pharmaceutically acceptable salts, and to methods for producing these new compounds having a strong antibacterial effect, especially on gram-negative bacteria, to pharmaceutical preparations in dosage unit forms containing the compounds of the invention solely, or in synergistic mixtures with penicillins, and to methods of treating patients with the dosage units.
Metadata
Assignee
- Lovens Kemiske Fabrik Produktionsaktieselskab
Inventor
- Frantz Johannes Lund
Application Information
Application Number:US 3037150
Filing Date:1972-11-06
Priority Date:1969-11-11
Art Unit:122
Classifications
IPC:
C07D49902C07D49932
Field of Search:
260239.1;240 G;306.7 C
Patent Drawings
This patent does not have any drawings.
Description
The invention will now be illustrated by the following, non-limiting Examples.
EXAMPLE 1
Pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate
12.7 g of N-formylhexamethyleneimine were dissolved in 250 ml of dry ether. While stirring and cooling, 8.5 ml of oxalyl chloride in 50 ml of dry ether were added dropwise. The mixture was stirred overnight at room temperature. The precipitated amide chloride was filtered off and washed with dry ether, and was placed in an exsiccator.
27.5 g of pivaloyloxymethyl 6-aminopenicillanate tosylate were suspended in 1500 ml of ethyl acetate under continuous stirring and cooling in an ice bath. 950 ml of ice-cold aqueous sodium bicarbonate (2 per cent) were added. The ethyl acetate layer was separated and was shaken with 750 ml of ice-water containing 25 ml of aqueous sodium bicarbonate (2 per cent), after which it was dried over magnesium sulfate at 0.degree.C. After filtration, the solution was evaporated to dryness in vacuo. The residue was dissolved in a solution of 15.5 ml of dry triethylamine in 75 ml of dry alcohol-free chloroform. To this solution 10 g of the above prepared amide chloride dissolved in 75 ml of dry alcohol-free chloroform were added dropwise at a temperature of about -20.degree.C. After standing for half an hour at -20.degree.C, the temperature was raised to 0.degree.C within 15 minutes. The solution was evaporated to dryness in vacuo. The residue was stirred with 750 ml of ether. Undissolved triethylamine hydrochloride was filtered off, and the filtrate was again evaporated to dryness in vacuo. The residue was reprecipitated from acetone (200 ml) - water (150 ml). After recrystallization from cyclohexane, an analytically pure product was obtained with a melting point of 118.5.degree.-119.5.degree.C and [.alpha.].sub.D.sup.20 : + 231.degree. (c=1, 96% ethanol).
The starting material, N-formylhexamethyleneimine, was prepared from hexamethyleneimine and chloral and had a boiling point of 111.degree.-112.degree.C / 10 mm H.sub.g.
EXAMPLE 2
Pivaloyloxymethyl 6-(N,N-dimethylformamidino-N')-penicillinate hydrochloride
5.8 g of chlorodimethylformiminium chloride were dissolved in 40 ml of dry alcohol-free chloroform. At a temperature of -30.degree.C to -40.degree.C this solution was added dropwise to a solution of 13.3 g of pivaloyloxymethyl 6-aminopenicillanate and 12.4 ml of triethylamine in 75 ml of dry, alcohol-free chloroform while stirring. The temperature was raised to 0.degree.C within 1 hour. The solution was evaporated in vacuo, and the residue was treated with 200 ml of dry ether. After filtration from triethylamine hydrochloride the filtrate was evaporated in vacuo. The oily residue was dissolved in 40 ml of isopropanol. At 0.degree.C and while stirring, 4 ml of a solution of dry hydrogen chloride in isopropanol (9N) were added dropwise. Then 150 ml of ether were added. After filtration, washing with ether, and recrystallization from acetone-ether, the compound was obtained in analytically pure form having a melting point of 146.degree.C. [.alpha.].sub.D.sup.20 : + 209.degree. (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 3
Pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate
To a solution of pivaloyloxymethyl 6-aminopenicillanate (3.3 g) and triethylamine (2.8 ml) in dry chloroform (35 ml) was added 1,1-dichlorodimethyl ether (1.1 g) at 0.degree.C. After 20 hours at room temperature, hexamethyleneimine (1.1 ml) was added, and the solution was kept at 0.degree.C overnight. The solution was evaporated in vacuo, and the residue was triturated with water (75 ml). The aqueous phase was removed by decantation. The residue was dissolved in diluted hydrochloric acid (pH about 3) and filtered. The filtrate was made alkaline with sodium bicarbonate (pH about 7.5). The precipitate was sucked off and was washed with water to yield a product with a melting point of 117.degree.-119.degree.C. The IR spectrum was identical with that of an authentic sample.
EXAMPLE 4
Cyanomethyl 6-(N,N-diethylformamidino-N')-penicillanate oxalate
A. cyanomethyl 6-aminopenicillanate p-toluenesulfonate
To a stirred suspension of 6-aminopenicillanic acid (43.3 g) in dimethylformamide (400 ml) at room temperature was added triethylamine (35 ml) and chloroacetonitrile (25.5 ml). Stirring was continued at room temperature for 24 hours. The mixture was diluted with 400 ml of ethyl acetate, and filtered. The solid was washed with ethyl acetate. The filtrate was diluted with 800 ml of ethyl acetate, extracted four times with 200 ml of water, and dried over magnesium sulfate. After filtration, an 0.5 M solution of p-toluenesulfonic acid in ethyl acetate (320 ml) was added with stirring. The precipitate was filtered off and washed with ethyl acetate and ether. Recrystallization from methanol-ethyl acetate afforded a colourless analytically pure product, melting at 154.5.degree.-156.degree.C (dec.). [.alpha.].sub.D.sup.20 : + 146.degree. (c=1, 96% C.sub.2 H.sub.5 OH).
B. chlorodiethylformiminium chloride
1.7 ml of oxalyl chloride dissolved in 10 ml of dry ether were slowly added to a solution of 2.2 ml of diethylformamide in 50 ml of dry ether at 0.degree.C with stirring. After stirring at room temperature for three-fourths hour, the precipitate was quickly filtered with suction, washed with dry ether, and stored in an exsiccator.
C. cyanomethyl 6-(N,N-diethylformamidino-N')-penicillanate oxalate
Cyanomethyl 6-aminopenicillanate was liberated from 4.7 g of the p-toluenesulfonate according to the procedure of Example 1 and dissolved in 15 ml of dry, alcohol-free chloroform. Dry triethylamine (3.1 ml) was added, and the solution was cooled to -30.degree.C. A solution of 1.7 g of crude amide chloride in 15 ml of dry, alcohol-free chloroform was slowly added at -20.degree.C to -30.degree.C, with stirring. In the course of three-fourths hour the temperature was allowed to raise to 0.degree.C. The solution was evaporated in vacuo, and the residue was triturated with 200 ml of ether. After filtration and evaporation in vacuo of the filtrate, the residue was dissolved in 200 ml of ether and treated with "Dicalite" filter aid (diatomaceous earth). A solution of 0.85 g of anhydrous oxalic acid in 50 ml of ether was slowly added to the filtrate with stirring. When the precipitate had settled, the supernatant liquor was decanted, and the precipitate was stirred with fresh ether. After filtration, the product was recrystallized twice from acetone-ether to yield the analytically pure material melting at 121.degree.-122.5.degree.C. [.alpha.].sub.D.sup.20 : + 214.degree. (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 5
.gamma.-Phenylpropyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride
A. .gamma.-phenylpropyl 6-aminopenicillanate
To a stirred suspension of 6-aminopenicillanic acid (21.6 g) in dimethylformamide (200 ml), triethylamine (11.4 ml) and .gamma.-bromophenylpropane (22.0 g) were added at room temperature. Stirring was continued at room temperature for 18 hours. 200 ml of ethyl acetate were added, and the mixture was filtered. The filtrate was diluted with 400 ml of ethyl acetate, extracted four times with 100 ml of water and dried over magnesium sulfate. After evaporation in vacuo, the oily residue was dissolved in a mixture of water and ether (200 ml of each) with stirring and ice-cooling. By slow addition of diluted hydrochloric acid the pH was adjusted to 3 to 4. The aqueous phase was separated, made alkaline to a pH of about 7.5 by addition of sodium bicarbonate, and extracted with ether. After drying, the ether was evaporated in vacuo to leave the crude ester as an oil.
B. .gamma.-phenylpropyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride
2.2 g of the crude ester and 2.0 ml of dry triethylamine were dissolved in 15 ml of dry, alcohol-free chloroform and cooled to -60.degree.C with stirring. A solution of 1.2 g of the amide chloride of Example 1 in 10 ml of dry, alcoholfree chloroform was slowly added. The temperature was raised to 0.degree.C during 1 hour, after which the solution was evaporated in vacuo. After trituration with 80 ml of ether, the solid formed was filtered off. The filtrate was extracted with 80 ml of water with stirring and ice-cooling, while the pH of the aqueous phase was lowered to about 3. The aqueous phase was separated, made alkaline with sodium bicarbonate, and extracted with ether. After drying, the ether was evaporated in vacuo. The oily residue was dissolved in 10 ml of isopropanol and treated with 0.35 ml of a solution of dry hydrogen chloride in isopropanol (9N), with stirring and ice-cooling. The precipitate was filtered off and washed with a little isopropanol. Two recrystallizations from methanol-ether yielded an analytically pure product melting at 163.5.degree.C. [.alpha.].sub.D.sup.20 : + 201 (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 6
6-[(Hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid.
A solution of the amide chloride of Example 1 (4.6 g) in dry, alcohol-free chloroform (20 ml) was added slowly to a solution of trimethylsilyl 6-aminopenicillanate (7.2 g) and triethylamine (3.5 ml) in dry, alcohol-free chloroform (50 ml) with stirring and cooling to -70.degree.C. The temperature was raised to 0.degree.C during 11/2 hours. The solution was evaporated to dryness in vacuo, and the residue was triturated with dry ether (200 ml). The precipitate was filtered off and washed with dry ether. The filtrate was diluted with ether (200 ml). 2-Butanol (2.8 ml) was added dropwise with stirring and cooling to 0.degree.C. The stirring was continued for 1/4 hour at 0.degree.C, after which the precipitate was filtered off, washed with ether, and dried. It was a white, amorphous powder, soluble in water. Paper chromatography was performed using the descending technique on Whatman No. 1 paper with the solvent system n-butanol-ethanol-water (4:1:5). The R.sub.f value was 0.5.
The chemical shifts are given as ppm in .delta. values with sodium 2.2.3.3-tetradeutero-3-trimethylsilylpropionate (0 ppm) as internal standard. Coupling constants (J) are in cps.
EXAMPLE 7
Butyl 6-(N,N-diethylformamidino-N')-penicillanate hydrochloride
A. butyl 6-aminopenicillanate tosylate
To a stirred suspension of 6-aminopenicillanic acid (21.7 g) in dimethylformamide (200 ml) at room temperature was added triethylamine (16.8 ml), n-butyl bromide (21.4 ml), and a catalytic amount of triethylammonium iodide. Stirring was continued at room temperature for 24 hours. Ethyl acetate (200 ml) was added, and the mixture was filtered. The solid was washed with ethyl acetate. The filtrate was diluted with ethyl acetate (400 ml), extracted four times with water (100 ml), and dried over magnesium sulfate. After eveporation in vacuo, the reddish oil was dissolved in water (250 ml) with stirring and ice-cooling, the pH being adjusted to 3.5 by slow addition of diluted hydrochloric acid. The aqueous phase was separated, filtered, made alkaline to a pH of 7.5 by addition of sodium bicarbonate, and extracted with ether (200 ml). After drying over magnesium sulfate, the ethereal phase was treated with a solution of p-toluenesulfonic acid (9.5 g) in ether (250 ml) with cooling and stirring. The precipitate was filtered off and washed with ether. The melting point of the crude product was 139.degree.-140.degree.C.
B. butyl 6-(N,N-diethylformamidino-N')-penicillanate hydrochloride
Butyl 6-aminopenicillanate was liberated from 4.9 g of the tosylate, according to the procedure of Example 1 for pivaloyloxymethyl 6-amino-penicillanate tosylate, and dissolved in 15 ml of dry, alcohol-free chloroform. Dry triethylamine (3.1 ml) was added, and the solution was cooled to -30.degree.C. A solution of chlorodiethylformiminium chloride (1.7 g) in chloroform (15 ml) was slowly added at -20.degree.C to -30.degree.C with stirring. In the course of three-fourths hour the temperature was raised to 0.degree.C. The solution as evaporated in vacuo, and the residue was triturated with ether (200 ml). The triethylammonium chloride formed was filtered off, and the filtrate was evaporated in vacuo. The residue was dissolved in water (200 ml) by addition of diluted hydrochloric acid until a pH of about 3.5. After filtration with Dicalite filter aid, the pH was brought to 7.5 by addition of sodium bicarbonate. The oily phase was extracted with ether (200 ml), dried, and evaporated in vacuo. To the residue in isopropanol (10 ml) was added 1 ml of dry hydrogen chloride in isopropanol (8.5 N) with cooling and stirring. Addition of ether (150 ml) precipitated the hydrochloride with a melting point of 126.degree.-130.degree.C. After recrystallizations from acetone-ether and isopropanol-ether the compound was obtained in analytically pure form having a melting point of 140.5.degree.-141.degree.C. [.alpha.].sub.D.sup.20 : + 241.degree. (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 8
Pivaloyloxymethyl 6-(N,N-dimethylformamidino-N')-penicillanate hydrochloride
A solution of pivaloyloxymethyl 6-aminopenicillanate (3.3 g) and 1,1-dimethoxy-trimethylamine (1.2 g) in ether (30 ml) was slowly evaporated at room temperature (1 hour) and thereafter at 40.degree.C (3 hours). The oily residue was dissolved in diluted hydrochloric acid (pH about 3), filtered and the filtrate treated with sodium bicarbonate (pH about 7.5). The liberated base was taken up in ether, which was dried and evaporated. To the oily residue dissolved in isopropanol (10 ml) was added 0.36 ml of dry hydrogen chloride (8.5 N) in isopropanol and thereupon ether (100 ml). The precipitate had a melting point of 130.degree.-144.degree.C. A recrystallization from acetone-ether raised the melting point to 143.degree.-146.degree.C. The IR spectrum was identical with that of an authentic sample.
EXAMPLE 9
Pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate
To a solution of pivaloyloxymethyl 6-aminopenicillanate (3.3 g) and N,N-diisopropylethylamine (1.7 ml) in dry chloroform (35 ml) at 0.degree.C was added 2.5 g of the N-formylhexamethyleneimine-dimethyl sulfate complex prepared according to the method of Bredereck et al. (Chem.Ber. 101, 41 (1968)). After 20 hours at 0.degree.-5.degree.C, the solution was evaporated, and the residue was crystallized from acetone-water yielding a product with a melting point of 115.degree.-117.degree.C. The IR spectrum was identical with that of an authentic sample.
EXAMPLE 10
Pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride
The free base of Example 9 (36 g) was suspended in isopropanol (165 ml) with stirring and ice-cooling. 9.7 ml of a solution of dry hydrogen chloride (8.5 N) in isoopropanol were added. From the resulting solution the hydrochloride did crystallize spontaneously. Ether (350 ml) was added. After filtration and recrystallization from methanol-diisopropyl ether, an analytically pure product was obtained with a melting point of 172.degree.-173.degree.C. [.alpha.].sub.D.sup.20 : + 219.degree. (c=1, 0.1 N HCl).
EXAMPLE 11
Pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydroiodide
To a solution of the above mentioned hydrochloride (2.6 g) in 15 ml of water was added sodium iodide (0.8 g) in water (5 ml). The precipitate was sucked off, washed with water, and dried. After recrystallizations from isopropanol-ether and ethanol-ether, the analytically pure product had a melting point of 153.degree.-154.degree.C. [.alpha.].sub.D.sup.20 : + 182.degree. (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 12
.beta.,.beta.,.beta.-Trichloroethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate
A. .beta.,.beta.,.beta.-trichloroethyl 6-aminopenicillanate hydrochloride
To a solution of phosphorus pentachloride (11.1 g) in dry, alcohol-free chloroform (110 ml) was added quinoline (12 ml) with stirring. At -20.degree.C .beta.,.beta.,.beta.-trichloroethyl benzylpenicillinate (14.8 g) was added. The stirring was continued at -15.degree.C for 20 minutes. At -40.degree.C n-propanol (37 ml) was added during 2-3 minutes. The temperature rose to -15.degree.C and was kept there for 15 minutes. The solution was poured onto a mixture of petroleum ether (330 ml), saturated aqueous sodium chloride (88 ml) and water (16 ml), while stirring and cooling with ice-water. The mixture was seeded and stirred for 30 minutes. The aqueous phase was removed, and the precipitate in the organic phase was isolated by filtration. After washing with a little isopropanol and with ether, the compound had [.alpha.].sub.D.sup.20 : + 153.degree. (c=1, 0.1 N HCl). The analytically pure compound was obtained by liberating the free base with sodium bicarbonate and reprecipitating the salt with hydrogen chloride in isopropanol. After recrystallization from ethanol-ether it had a melting point of 153.5.degree.-155.5.degree.C. [.alpha.].sub.D.sup.20 : + 160.degree. (c=1, 0.1 N HCl).
B. .beta.,.beta.,.beta.-trichloroethyl 6-[(hexahydro-1H-azepin-1-yl)-methylene-amino]-penicillanate
A solution of the amide chloride of Example 1 (1.0 g) in pure chloroform (15 ml) was added slowly to a solution of the above prepared crude ester (1.9 g) and triethylamine (2.2 ml) in pure chloroform (15 ml) at -20.degree.C with stirring. The temperature was raised to 0.degree.C during 45 minutes, after which the solution was evaporated in vacuo. The residue was triturated with ether (100 ml), and the solid formed was filtered off. The filtrate was evaporated in vacuo, and the oily residue was triturated with water (50 ml). The solid was isolated by filtration and recrystallized from acetone-water and isopropanol-water yielding an analytically pure product with a melting point of 99.degree.-101.degree.C. [.alpha.].sub.D.sup.20 : + 214.degree. (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 13
6-(N,N-Di-n-butylformamidino-N')-penicillanic acid hydrate
A solution of N-(dimethoxymethyl)-dibutylamine (4.9 g) in dry ether (100 ml) was slowly added to a solution of trimethylsilyl 6-aminopenicillanate (7.0 g) in ether (500 ml) at -30.degree.C with stirring. The temperature was raised to 0.degree.C during half an hour. Water (25 ml) was added during 10 minutes. The aqueous phase was separated, and the ethereal phase was extracted with 25 ml of water. The combined aqueous phases were freeze-dried. The solid product thus obtained was triturated with water (10 ml) at 0.degree.C, filtered, and air-dried. It melted with decomposition at 106.degree.C and was analytically pure. [.alpha.].sub.D.sup.20 : + 261.degree. (c=1, 0.1 N HCl).
EXAMPLE 14
6- [(Hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid hydrochloride dihydrate
A solution of benzyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride (4.3 g) (Ex.42) in methanol (70 ml) was hydrogenated with palladium on charcoal catalyst (10%, 4.3 g) at room temperature and under one atmosphere of hydrogen for 21 minutes. After filtration of the catalyst, the filtrate was evaporated in vacuo. The oily residue was dissolved in 95% isopropanol (28 ml). After filtration with Dicalite filter aid and washing with isopropanol (15 ml), diisopropyl ether (50 ml) was added. The precipitate was filtered off, washed with diisopropyl ether, and air-dried. The melting point was 87.degree.-89.degree.C (dec.). [.alpha.].sub.D.sup.20 : + 238.degree. (c=1, H.sub.2 O).
EXAMPLE 15
Pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate
A. methyl iodide complex of N-thioformylhexamethyleneimine
To a solution of N-thioformylhexamethyleneimine (2.9 g) in dry ether (10 ml) was added methyl iodide (1.4 ml) with stirring and cooling. The suspension formed was stirred for half an hour and filtered. The precipitate was washed with ether and placed in an exsiccator. The melting point of the crude product was 120.degree.-122.degree.C.
B. pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate
To an ice-cold solution of pivaloyloxymethyl 6-aminopenicillanate (3.3 g) and N,N-diisopropylethylamine (1.7 ml) in pure chloroform (35 ml) was added the above prepared iodide (2.9 g). After 20 hours at 0.degree.-5.degree.C, the solution was evaporated in vacuo, and the residue was crystallized from acetone-water yielding a product with a melting point of 119.degree.-120.degree.C. The IR spectrum was identical with that of an authentic sample.
EXAMPLES 16 to 47
Following the procedures of the foregoing Examples, the compounds of Table I according to formula V were obtained. ##SPC4##
In the Table II below are listed the physical constants of the compounds of Table I, and the reaction conditions are shown:
EXAMPLE 48
6-[(Hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid dihydrate
A. 1-hexamethyleneiminecarboxaldehyde dimethyl acetal was prepared from the N-formylhexamethyleneimine-dimethyl sulfate complex by reaction with sodium methoxide according to the method of Bredereck et al. (Chem.Ber. 101, 41 (1968)). The boiling point was 83.degree.-84.degree.C/12 mm Hg.
B. 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid dihydrate
A solution of the above mentioned acid amide acetal (4.1 g) in dry ether (100 ml) was slowly added to a solution of trimethylsilyl 6-aminopenicillanate (6.8 g) in ether (500 ml) at -30.degree.C with stirring. The temperature was raised to 0.degree.C within half an hour. Water (300 ml) was added. The stirring was continued for ten minutes after which the aqueous phase was separated, extracted with ether and freeze-dried. The solid product was crystallized from methanol-acetone. It melted with decomposition from 135.degree. to 142.degree.C.
EXAMPLE 49
6-[(Hexahydro-1H-azepin-1-yl)-methyleneamine]-penicillanic acid
16.7 g of benzyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride were suspended in ethyl acetate (550 ml) under continuous stirring and cooling in an ice bath. A solution of sodium bicarbonate (14.3 g) in water (400 ml) was added. The organic phase was separated and extracted with water (350 ml). After drying, the organic phase was evaporated in vacuo.
The oily residue was dissolved in methanol (150 ml) and hydrogenated with palladium on charcoal catalyst (10%, 11.4 g) at room temperature and under one atmosphere of hydrogen until the absorption of hydrogen ceased (about 15 minutes). The catalyst was filtered off and washed with methanol. The filtrate was evaporated in vacuo. The oily residue was crystallized from methanol (15 ml) - acetone (190 ml). The precipitate was filtered off, washed with acetone (2 .times. 10 ml) and dried in a vacuum exsiccator. The melting point was 156.degree.C (dec.). [.alpha.].sub.D.sup.20 : + 285.degree. (c=1, 0.1 N HCl).
EXAMPLE 50
Acetoxymethyl 6-(N,N-dimethylformamidino-N')-penicillanate hydrochloride
Acetoxymethyl 6-aminopenicillanate was liberated from 5.1 g of the p-toluenesulfonate according to the procedure of Example 1 and dissolved in dry chloroform (30 ml). Dry triethylamine (2.8 ml) was added, and the solution as cooled to -40.degree.C. A solution of chlorodimethylformiminium chloride (1.3 g) in dry chloroform (15 ml) was slowly added with stirring a -20.degree.C. In the course of three-fourth hour the temperature was allowed to raise to 0.degree.C. The solution was evaporated in vacuo, and the residue was triturated with ether (200 ml). After filtration, 1.0 ml of a solution of dry hydrogen chloride in isopropanol (8 N) was added at 0.degree.C with stirring. An amorphous product was obtained.
In this and the following Examples, the chemical shifts are given as ppm in .epsilon. values with TMS (0 ppm) an internal standard. Coupling constants (J) are in cps.
EXAMPLE 51
Pivaloyloxymethyl 6-(N-ethyl-N-.beta.-ethoxyethylformamidino-N')-penicillanate
A. n-ethyl-N-.beta.-ethoxyethylformamide
was prepared from the amine by reaction with chloral. The boiling point was 102.degree.-104.degree.C/11 mm Hg.
B. chloro-(ethyl-.beta.-ethoxyethyl)-formiminium chloride
3.4 ml of oxalyl chloride dissolved in dry ether (20 ml) were slowly added to a solution of N-ethyl-N-.beta.-ethoxyethylformamide (5.8 g) in dry ether (60 ml) at 0.degree.C with stirring. After stirring at room temperature for one hour, the ether was decanted from the oily amide chloride which was triturated twice with ether and stored in an exsiccator.
C. pivaloyloxymethyl 6-(N-ethyl-N-.beta.-ethoxyethylformamidino-N')-penicillanate
5 g of the crude amide chloride were dissolved in dry chloroform (30 ml) and added dropwise to a solution of pivaloyloxymethyl 6-aminopenicillanate (6.6 g) and triethylamine (7 ml) in dry chloroform (30 ml) at -30.degree.C to -40.degree.C with stirring. The temperature was raised to 0.degree.C within three-fourth hour. The solution was evaporated in vacuo, and the residue was treated with ether (400 ml). Afte filtration from triethylamine hydrochloride, the filtrate was evaporated in vacuo. The oily residue was dissolved in 350 ml of diluted hydrochloric acid at a pH of about 3. After filtration with Dicalite filter aid (diatomaceous earth), the filtrate was made alkaline with sodium bicarbonate to a pH of about 7.5 and extracted with ether. After drying, the ether was removed in vacuo leaving an oil which could not be crystallized.
EXAMPLE 52
Pivaloyloxymethyl 6-(N-butyl-N-.beta.-cyanoethylformamidino-N')-penicillanate
A. n-butyl-.beta.-formamidoprpionitrile
was prepared -formamidopropionitrile formylation of .beta.-N-butylaminopropionitrile with chloral. The boiling point was 114.degree.-115.degree.C/0.4 mm Hg.
B. chloro-(butyl-.beta.-cyanoethyl)-formiminimum chloride
1.7 ml of oxalyl chloride dissolved in dry ether (10 ml) were slowly added to a solution of N-butyl-.beta.-formamidopropionitrile (3.1 g) in dry ether (30 ml) a 0.degree.C with stirring. After stirring at room temperature for two hours, the ether was decanted from the oily amide chloride. The crude amide chloride was treated twice with fresh ether and kept in an exsiccator.
C. pivaloyloxymethyl 6-(N-butyl-N-.beta.-cyanoethylformamidino-N')-penicillanate
A solution of the crude amide chloride (2.3 g) in dry chloroform (15 ml) was added dropwise to a solution of pivaloyloxymethyl 6-aminopenicillanate (3.3 g) and triethylamine (3.1 ml) in dry chloroform at -20.degree.C to -30.degree.C with stirring. The temperature was kept at -20.degree.C for half an hour and then raised to 0.degree.C in the course of a quarter of an hour. The solvent was removed in vacuo, and the residue was triturated with ether (200 ml). After filtration from triethylammonium chloride, the filtrate was concentrated to a volume of 50 ml in vacuo and extracted with 75 ml of diluted hydrochloric acid (pH about 3). The aqueous phase was filtered with Dicalite and made alkaline to a pH of about 7.5. The oily product was extracted with ether. The ethereal phase was dried and evaporated in vacuo leaving an oil which did not crystallize.
EXAMPLE 53
Pivaloyloxymethyl 6-(N-methyl-N-carbomethoxymethylformamidino-N')-penicillanate
A. chloro-(methyl-carbomethoxymethyl)-formiminium chloride
3.0 g of phosgene in dry benzene (16 ml) were slowly added to a solution of methyl N-formyl-N-methylglycinate (2.0 g) in dry benzene (15 ml) a 0.degree.C with stirring. The reaction mixture was stirred overnight at room temperature and evaporated in vacuo. The oily residue was triturated twice with ether and kept in an exsiccator.
B. pivaloyloxymethyl 6-(N-methyl-N-carbomethoxymethylformamidino-N')-penicillanate
A solution of the crude amide chloride (2.4 g) in dry chloroform (15 ml) was slowly added to a solution of pivaloyloxymethyl 6-aminopenicillanate (3.3 g) and triethylamine (3.4 ml) in dry chloroform (15 ml) at -20.degree.C to -30.degree.C with stirring. The temperature was raised to 0.degree.C during three-fourth hour, and the solvent was removed in vacuo. The residue was treated with ether (200 ml). The precipitate was filtered off, and the filtrate was concentrated to a volume of 50 ml in vacuo. This solution was extracted with diluted hydrochloric acid (75 ml, pH about 3), and the aqueous phase was filtered with Dicalite. By addition of sodium bicarbonate to a pH of about 7.5, an oil was formed which was taken up in ether. The ethereal phase was dried and evaporated to leave an oil which did not crystallize.
EXAMPLE 54
Pivaloyloxymethyl 6-(N-methyl-N-carbamylmethylformamidino-N')-penicillanate
To an ice-cold solution of pivaloyloxymethyl 6-aminopenicillanate (6.6 g) and triethylamine (5.6 ml) in dry chloroform (70 ml) was added 1.1-dichlorodimethyl ether (2.3 g) with stirring. The solution was kept overnight at room temperature and then cooled to 0.degree.C. Sarcosinamide (1.8 g) was added. The reaction mixture was kept for 48 hours at 0.degree.C, after which the solvent was removed in vacuo. The residue was distributed between ether (75 ml) and diluted hydrochloric acid (75 ml, pH about 3). The aqueous phase was separated and extracted with ether (25 ml) and then made alkaline (to a pH of about 7.5) with sodium bicarbonate. The oily product was taken up in ether, which was dried and evaporated in vacuo. The residue did not cyrstallize
EXAMPLE 55.
Pivaloyloxymethyl 6-(N-ethyl-N-.beta.-hydroxyethylformamidino-N')-penicillanate
Pivaloyloxymethyl 6-aminopenicillanate (6.6 g) was treated with 1.1-dichlorodimethyl ether and triethylamine as in Example 54. To the ice-cold solution was added 2-ethylaminoethanol (1.8 g). After 48 hours at 0.degree.C, the solution was evaporated in vacuo, and the residue was triturated with acetone (25 ml). Triethylamine hydrochloride was filtered off, and the filtrate was evaporated in vacuo. The residue was distributed between ether (75 ml) and diluted hydrochloric acid (75 ml, pH about 2.5). The aqueous phase was separated and made alkaline to a pH of about 7.5. The oily reaction product was taken up in ether. Drying and evaporation in vacuo gave an oil which did not crystallize.
EXAMPLE 56
Pivaloyloxymethyl 6-(N-methyl-N-carbethoxymethylformamidino-N')-penicillanate
Pivaloyloxymethyl 6-aminopenicillanate (6.6 g) was treated with 1.1-dichlorodimethyl ether and triethylamine as described in Example 54. Ethyl N-methylglycinate (2.3 g) was added to the ice-cold solution. The reaction mixture was kept in an ice-box for 48 hours and then worked up as in Example 55. The product was an oil which did not crystallize.
EXAMPLE 57
Pivaloyloxymethyl 6-(N-methyl-N-furfurylformamidino-N')-penicillanate
By following the procedure of Example 55 and substituting 2-ethylaminoethanol with N-methylfurfurylamine (2.3 ml) an oil was obtained which did not crystallize
By following the procedure of Example 55, and substituting 2-ethylaminoethanol with N-methyl-2-thenylamine, N-n-butyl-.beta.-2-thiopheneethylamine, 3-(ethylaminomethyl)-pyridine, and 4-(methylaminomethyl)-pyridine, the pivaloyloxymethyl 6-(N-methyl-N-2-thenylformamidino-N')-penicillanate, the pivaloyloxymethyl 6-(N-n-butyl-N-.beta.-2-thiopheneethylformamidino-N')-penicillanate, the pivaloyloxymethyl 6-(N-ethyl-N-3-pyridylmethylformamidino-N-')-penicillanate and the pivaloyloxymethyl 6-(N-methyl-N-4-pyridylmethylformamidino-N')-penicillanate can be obtained.
EXAMPLE 58
Pivaloyloxymethyl 6-[4'-dimethylcarbamylpiperazinyl-1')-methyleneamino]-penicillanate
By following the procedure of Example 55 and substituting 2-ethylaminoethanol with 1-dimethylcarbamylpiperazine (3.1 g), an amorphous solid was obtained which could not be crystallized.
EXAMPLE 59
Acetoxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride
A solution of the crude amide chloride (16.9 g), prepared from N-formylhexamethyleneimine as described in Example 1, in dry chloroform (135 ml) was slowly added to a solution of acetoxymethyl 6-aminopenicillanate p-toluenesulfonate (43 g) and triethylamine (39.4 ml) in chloroform (275 ml) at -50.degree.C with stirring. The temperature was raised to 0.degree.C during one hour. The solvent was removed in vacuo, and the oily residue was triturated with acetone (250 ml). A precipitate formed and was filtered off, and the filtrate was evaporated in vacuo. The residue was dissolved in ether (350 ml) and extracted with diluted hydrochloric acid at a pH of about 3 (350 ml). The aqueous phase was made alkaline (to pH about 7.5) and extracted with ether (500 ml). After drying, the ether was removed in vacuo, and the oily residue was dissolved in tert.butanol (230 ml) and treated with 8.85 ml of a solution of dry hydrogen chloride in isopropanol (8 N) a 0.degree. C with stirring. Ether (150 ml) was added. The precipitate was filtered off and recrystallized from a mixture of acetone (400 ml) and ether (250 ml) to yield the analytically pure product with a melting point of 141.5.degree.-142.5.degree.C. [.alpha.].sub.D.sup.20 : + 226.degree. (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 60
Pivaloyloxymethyl 6-[(octahydro-1H-azonin-1-yl)-methyleneamino]-penicillanate.
A. N-Formyloctamethyleneimine was prepared from octamethyleneimine and chloral. The boiling point was 141.degree.-143.degree.C/10 mm Hg.
B. pivaloyloxymethyl 6-[(octahydro-1H-azonin-1-yl)-methyleneamino]-penicillanate
1.7 g of N-formyloctamethyleneimine was dissolved in 50 ml of dry ether. While stirring and cooling, 0.94 ml of oxalyl chloride in 5 ml of dry ether was added dropwise. The mixture was stirred for 3 1/2 hours at room temperature. The precipitated amide chloride was filtered off and washed with dry ether. It was kept in an exsiccator.
The crude amide chloride (1.3 g) was dissolved in chloroform (15 ml) and slowly added to a solution of triethylamine (1.75 ml) and pivaloyloxymethyl 6-aminopenicillanate (1.65 g) in dry chloroform (15 ml) at -40.degree.C with stirring. The temperature was raised to 0.degree.C during 45 minutes. The solution was evaporated in vacuo, and the residue was triturated with acetone (25 ml). After filtration, the filtrate was evaporated in vacuo. The residue was taken up in ether (50 ml) and extracted with diluted hydrochloric acid (50 ml) at a pH of about 3. The aqueous phase was made alkaline (pH about 7.5). The precipitate was recrystallized from a mixture of acetone (15 ml) and water (10 ml) to yield the analytically pure product with a melting point of 106.degree.-107.degree.C. [.alpha.].sub.D.sup.20 : (c=1, 96% C.sub.2 H.sub.5 OH).
EXAMPLE 61
Pivaloyloxymethyl 6-(N-ethyl-N-phenethylformamidino-N')-penicillanate
A. N-Ethyl-N-phenethylformamide was prepared from N-ethylphenethylamine and chloral. The boiling point was 107.degree.-108.degree.C/0.4 mm Hg.
B. pivaloyloxymethyl 6-(N-ethyl-N-phenethylformamidino-N')-penicillanate
To a solution of N-ethyl-N-phenethylfomamide (3.6 g) in dry ether (100 ml) at 0.degree.C was slowly added oxalyl chloride (1.7 ml) in dry ether (10 ml) with stirring. The mixture was stirred overnight at room temperature. The crude amide chloride was filtered off and washed with ether. It was kept in an exsiccator.
A solution of the amide chloride (2.6 g) in dry chloroform (15 ml) was added dropwise to a solution of triethylamine (3.1 ml) and pivaloyloxymethyl 6-aminopenicillanate (3.3 g) in chloroform (15 ml) at -20.degree.C with stirring. The temperature was raised to 0.degree.C during 45 minutes. The solution was evaporated in vacuo, and the residue was triturated with ether (200 ml). After filtration, the filtrate was evaporated in vacuo, and the oily residue was dissolved in diluted hydrochloric acid (300 ml) at a pH of about 3 and filtered with Dicalite. The filtrate was made alkaline (pH about 7.5) and extracted with ether (200 ml). The etheral phase was dried and evaporated in vacuo to leave an oil which did not crystallize.
EXAMPLE 62
Pivaloyloxymethyl 6-(N-ethyl-N-.beta.-phenoxyethylformamidino-N')-penicillanate
A. n-ethyl-N-.beta.-phenoxyethylformamide
To a solution of formic acid (3.3 ml) and N-ethyl-N-.beta.-phenoxyethylamine (14.5 g) in methylene chloride (100 ml) at 0.degree.-5.degree.C was added N,N'-dicyclohexylcarbodiimide (19.7 g) with stirring. The mixture was stirred for 18 hours at room temperature and filtered. The filtrate was evaporated in vacuo to leave an oil which was taken up in either (100 ml) and extracted with 0.4 N hydrochloric acid (2 .times. 25 ml) and water (2 .times. 25 ml). After drying, the ether was removed in vacuo to leave the above compound as an oil.
B. chloro-(ethyl-.beta.-phenoxyethyl)-formiminium chloride
1.7 ml of oxalyl chloride dissolved in dry ether (5 ml) was slowly added to a solution of the crude N-ethyl-N-.beta.-phenoxyethylformamide (3.9 g) in dry ether (25 ml) at 0.degree.C with stirring. After stirring for 3 hours at room temperature, the ether was decanted from the oily amide chloride which was twice triturated with ether and stored in an exsiccator.
C. pivaloyloxymethyl 6-(N-ethyl-N-.beta.-phenoxyethylformamidino-N')-penicillanate
2.8 g of the crude amide chloride were dissolved in dry chloroform (30 ml) and added dropwise to a solution of pivaloyloxymethyl 6-aminopenicillanate (3.3 g) and triethylamine (3.5 ml) in dry chloroform (30 ml) at -40.degree.C with stirring. The temperature was gradually raised to 0.degree.C within 45 minutes. The solution was evaporated in vacuo, and the residue was triturated with ether (200 ml). After filtration from triethylamine hydrochloride, the filtrate was extracted with diluted hydrochloric acid (100 ml) at a pH of about 3. The aqueous phase was separated, filtered with Dicalite filter aid, made alkaline with sodium bicarbonate to a pH of about 7.5, and extracted with ether. After drying, the ether was removed in vacuo to leave an oil which could not be crystallized.
EXAMPLE 63
Pivaloyloxymethyl 6-(N-methyl-N-cabobenzyloxymethylformamidino-N')-penicillanate
To a solution of pivaloyloxymethyl 6-aminopenicillanate (9.9 g) in dry ether (150 ml) was added propyl formimidate hydrochloride (4.1 g) at room temperature. The mixture was stirred for 40 minutes. Benzyl sarcosinate (5.6 g) was added, and the reaction mixture was kept in the refrigerator for 18 hours and finally stirred for 2 hours at room temperature. After that the reaction mixture was extracted with 50 ml of water at a pH about 7, and with 50 ml water at a pH of about 2.5. The acid aqueous phase was filtered with Dicalite filter aid, made alkaline with sodium bicarbonate (pH about 7.5), and extracted with ethyl acetate (150 ml), the extract being dried and evaporated in vacuo. The oily residue was taken up in ether (50 ml) and extracted with 50 ml of water (pH about 3). The aqueous phase was extracted with 2 .times. 50 ml of ethyl acetate, filtered with Dicalite filter aid, and made alkaline with sodium bicarbonate (pH about 7.5). Extraction with ethyl acetate, drying, and evaporation in vacuo yielded an oil which did not crystallize.
EXAMPLE 64
Preparation of tablets containing pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride.
The pivaloyloxymethyl ester is screened through a sieve with 1.0 mm mesh openings. The powder is then wetted with a solution of polyvinylpyrrolidone in 150 ml of a solvent composed of 1 part of ethanol (96%) and 19 parts of acetone. The moist mass is passed through a sieve with 1.0 mm mesh openings and then dried at 30.degree.C on trays or other conveient drying equipment, for instance a "fluidized bed" drying cupboard.
When the solvent has evaporated, the granules are sifted through a sieve with 0.7 mm mesh openings, and are finally mixed with the corn starch and magnesium stearate.
The granulate is compressed into tablets of 0.40 g weight using punches and dies of 12 mm diameter to yield 1000 tablets each containing 0.35 g of the pivaloyloxymethyl ester.
EXAMPLE 65
A pharmaceutical preparation for injection
In a sterile vial is placed a single dose of 250 mg of sterilized 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid. For administration by injection the compound is dissolved in 5 ml of sterile water.
EXAMPLE 66
Capsules, each containing 0.150 g of pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride (FL 1039) and 0.175 g of pivaloyloxymethyl .alpha.-aminobenzylpenicillinate hydrochloride (VD 923) are prepared according to the following procedure:
Fl 1039 and VD 923 are mixed and passed through a 20 US Standard mesh sieve. After having been mixed again, the resulting powder is moistened with a solution of polyvinyl pyrrolidone in isopropanol (150 ml). The moistened mixture is granulated by passing it through a 20 US Standard mesh sieve and is afterwards dried by 30.degree.C. For the drying operation, a conventional drying oven with trays, or other suitable drying apparatus, for instance functioning according to the fluidized bed principles, may be applied.
After drying, the granulate is passed through a 25 US Standard mesh sieve and is finally mixed with the magnesium stearate.
The finished granulate is filled into hard gelatine capsules No. 0, each capsule containing 0.349 g granulate, the above ingredients thereby corresponding to 1000 capsules.
EXAMPLE 67
Tablets, each containing 0.150 g of pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanate hydrochloride (FL 1039) and 0.175 g of pivaloyloxymethyl .alpha.-aminobenzylpenicillinate hydrochloride (VD 923) are prepared according to the following procedure:
Fl 1039 and VD 923 are mixed and passed through a 20 US Standard mesh sieve. After having been mixed again, the resulting powder is moistened with a solution of polyvinyl pyrrolidone in isopropanol (150 ml). The moistened mixture is granulated by passing it through a 20 US Standard mesh sieve and is afterwards dried by 30.degree.C. For the drying operation, a conventional drying oven with trays or other suitable drying apparatus, for instance funtioning according to the fluidized bed principle, may be applied.
After drying, the granulate is passed through a 25 US Standard mesh sieve and is afterwards mixed with the microcrystalline cellulose, the starch and the magnesium stearate. The graulate is compressed into tablets, each containing about 0.600 g, by using punches with a diameter of 13.5 mm, the above ingredients thereby corresponding to 1000 tablets each containing 0.150 g of FL 1039 and 0.175 g of VD 923.
Claims
I claim:
1. Amidino-penicillanic acid derivatives of the formula I: ##SPC5## in which R.sub.1 is selected from the group consisting of alkyl, chloroalkyl and hydroxyl-alkyl having from 1 to 7 carbon atoms, alkoxyalkyl having from 2 to 7 carbon atoms, carbalkoxyalkyl having from 3 to 4 carbon atoms, cyanoalkyl and carbamylalkyl having from 2 to 3 carbon atoms, and allyl; R.sub.2 is selected from the group consisting of alkyl, chloroalkyl and hydroxy-alkyl having from 1 to 7 carbon atoms, alkoxyalkyl having from 2 to 4 carbon atoms, carbalkoxyalkyl having from 3 to 4 carbon atoms, cyanoalkyl, or carbamylalkyl having from 2 to 3 carbon atoms and allyl; phenyl; phenyl substituted, chlorophenyl substituted, bromo-phenyl substituted, phenoxy substituted and carbobenzyloxy substituted methyl and ethyl; cycloalkyl and cycloalkyl-methyl having from 5 to 7 carbon atoms; methyl and ethyl substituted with furyl; and R.sub.1 and R.sub.2 form a straight or branched alkylene chain which together with the nitrogen atom form a saturated heterocyclic ring having from 4 to 8 carbon atoms; and R.sub.1 and R.sub.2 furthermore together with the nitrogen atom form a heterocyclic radical selected from the group consisting of morpholinyl-4, 4-methyl-piperazinyl-1, and 1, 2, 3, 4-tetrahydroisoquinolyl-2; and R.sub.3 is hydroxyl, chloroalkoxy, cyanomethyloxy, or benzyloxy, the alkoxy part of which has 1 to 4 carbon atoms; and alkanoyloxymethoxy having 3 to 7 carbon atoms; and pharmaceutically acceptable salts thereof.
2. The compounds as claimed in claim 1, in which R.sub.1 and R.sub.2 represent a pentamethylene, hexamethylene or heptamethylene radical linked into a ring with the nitrogen atom, and R.sub.3 is a hydroxyl group or an alkanoyloxymethoxy group having from 3 to 7 carbon atoms.
3. 6-[(Hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid, the pharmaceutically acceptable hydrolyzable esters thereof, and the pharmaceutically acceptable salts of the acid and of the said esters.
4. 6-[(Hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid, and the pivaloyloxymethyl ester thereof.
5. 6-[(Piperidyl-1)-methyleneamino]-penicillanic acid, and the pivaloyloxymethyl ester thereof.
6. 6-[(Hexahydro-1(2H)-azocinyl)-methyleneamino]-penicillanic acid, and the pivaloyloxymethyl ester thereof.
7. 6-(N-ethyl-N-isopropyl-formamidino-N')-penicillanic acid, and the pivaloyloxymethyl ester thereof.
8. 6-(N-methyl-N-cyclopentyl-formamidino-N')-penicillanic acid, and the pivaloyloxymethyl ester thereof.
9. 6-[(2-Methyl-piperidyl-1)-methyleneamino]-penicillanic acid and the pivaloyloxymethyl ester thereof.
10. 6-[(4-Methyl-piperidyl-1)-methyleneamino]-penicillanic acid and the pivaloyloxymethyl ester thereof.
11. [(2,6-Dimethyl-piperidyl-1)-methyleneamino]-penicillanic acid and the pivaloyloxymethyl ester thereof.
12. 6-[(Octahydro-1H-azocin-1-yl)-methyleneamino]-penicillanic acid and the pivaloyloxymethyl ester thereof.
13. 6-(N-methyl-N-cyclohexyl-formamidino-N')-penicillanic acid and the pivaloyloxymethyl ester thereof.
14. 6-(N,N-diethyl-formamidino-N')-penicillanic acid and the pivaloyloxymethyl ester thereof.
15. Amidino-penicillanic acid derivatives of formula I of claim 1, in which R.sub.1 and R.sub.2 form a straight or branched alkylene chain, which, together with the nitrogen atom represent a ring having from 4 to 8 carbon atoms, and R.sub.3 is selected from the group consisting of hydroxyl and cyanomethyloxy, chloroalkoxy, benzyloxy, or an alkanoyloxymethoxy group, the alkyl of which has from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.
16. Amidino-penicillanic acid derivatives of the formula I of claim 1, in which R.sub.1 and R.sub.2 are selecged from the group consisting of alkyl, chloroalkyl and hydroxy-alkyl having from 1 to 7 carbon atoms, alkoxyalkyl having up to 4 carbon atoms, carbalkoxyalkyl having from 3 to 4 carbon atoms, cyanoalkyl, cabamylalkyl having from 2 to 3 carbon atoms and allyl, and R.sub.3 is selected from the group consisting of hydroxyl and cyanomethyloxy, chloroalkoxy, benzyloxy, or an alkanoyloxymethoxy group, the alkoxy of which has from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.
17. Amidino-penicillanic acid derivatives of formula I of claim 1, in which R.sub.1 is methyl or ethyl and R.sub.2 is a cycloalkyl or a cycloalkyl-methyl radical having from 5 to 7 carbon atoms in the ring, R.sub.3 is selected from the group consisting of hydroxyl and cyaomethyloxy, chloroalkoxy, benzyloxy, or an alkanoyloxymethoxy group, the alkoxy of which has from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.
18. Amidino-penicillanic acid derivatives of formula I of claim 1, in which R.sub.1 is methyl or ethyl, R.sub.2 is a phenoxy or carbobenzyloxy substituted methyl or ethyl radical, and R.sub.3 is selected from the group consisting of hydroxyl and cyanomethyloxy, chloroalkoxy, benzyloxy, or an alkanoyloxymethoxy group, the alkoxy of which has from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.
19. Amidino-penicillanic acid derivatives of formula I of claim 1, in which R.sub.1 is methyl or ethyl, R.sub.2 is a phenyl or halophenyl substituted methyl or ethyl radical, and R.sub.3 is selected from the group consisting of hydroxyl and cyanomethyloxy, chloroalkoxy, benzyloxy, or an alkanoyloxymethoxy group, the alkoxy of which has from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.
20. Amidino-penicillanic acid derivatives of formula I of claim 1, in which R.sub.1 is a C.sub.1 to C.sub.4 alkyl radical, R.sub.2 is furylmethyl or furylethyl, and R.sub.3 is selected from the group consisting of hydroxyl and cyanomethyloxy, chloroalkoxy, benzyloxy, or an alkanoyloxymethoxy group, the alkoxy of which has from 1 to 4 carbon atoms, and pharmaceutically acceptable salts thereof.
21. Amidino-penicillanic acid derivatives of formula I of claim 1, in which R.sub.1 and R.sub.2 together with a nitrogen atom forms a heterocyclic radical selected from the group consisting of morpholinyl-4, 4-methylpiperazinyl-1, and 1,2,3,4-tetrahydroisoquinolyl-2, and R.sub.3 is selected from the group consisting of hydroxyl and cyanomethyloxy, chloroalkoxy, benzyloxy, or an alkaoyloxymethoxy group, the alkoxy of which has from 1 to 4 carbon atoms, and pharmaceutically acceptble salts thereof.
Patent Citations (2)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3821198 | 1974-06-01 | Lee et al. | |
| US3855233 | 1974-12-01 | Dolfini et al. |
Non-Patent Literature (1)
- Nature New Biology, Vol. 236, pp. 135-137, (1972).