KR810001091B1 - Process for preparing penicillin compounds - Google Patents

Abstract

Title compds. [I; R = formyl, acetyl , useful as antibiotics, were prepd. by reacting compd. II, salts or reactive derivs. at carboxyl group with 6-α-amino-p-hydroxybenzylpenicillin [compds.III Thus, NaOH soln. was added to a mixture of compd. III and N-[5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d pyrimidine-6-carbonyloxy succinimide at 0-2oC stirred for 30min. and filtered, Ice-water was added to the filtrate and controlled pH to give precipitate, which was washed with ice-water & dissolved with 4% NaOH soln. Filtering the soln. and freeze-drying of filtrate gave I.

Description

[Name of invention]

Method for preparing penicillin compound derivative

Detailed description of the invention

The present invention relates to a method for producing a novel penicillin compound derivative having excellent antibacterial action.

The novel compounds according to the invention are compounds of the formula and pharmacologically acceptable non-toxic salts thereof.

Wherein R is a formyl or acetyl group.

Pharmaceutically acceptable non-toxic salts are salts produced during periods of penicillin compounds of formula (I) and pharmacologically acceptable inorganic or organic salts, such as alkali metal salts (e.g. sodium or potassium salts) and alkaline earth metal salts (e.g. calcium Salts or magnesium salts) and non-protic metal salts of penicillin compounds).

The penicillin compound of formula (I) exists as two tautomers (ketoche and enol type) of the following formula and formula (I '). In the present application, these tautomers are mainly represented by the keto form of the following structural formula (I).

In the structural formulas (I) and (I), the carbon atom marked by a-carbon of the p-hydroxyphenylglycine residue is an absent carbon atom, and is represented by the structural formula (I) according to the steric configuration associated with this carbon. Penicillin compounds include D-isomers, L-isomers, and mixtures of these isomers (called D, L mixtures). These isomers and mixtures thereof are represented by the above formula (I).

Occasionally, the penicillin compound of formula (I) also exists in the form of anhydrides, such anhydrides also falling within the scope of the penicillin compounds of the present invention, also represented by formula (I).

It is an object of the present invention to provide a novel method for producing penicillin having excellent antimicrobial activity against gram positive bacteria as well as gram negative bacteria.

Another object of the present invention is to provide a novel penicillin compound having excellent antimicrobial activity against Pseudomonas species, such as Pseudomonas aeruginosa, empicillin resistant bacteria, and extremely low toxicity to warm-blooded animals including humans.

The novel penicillin compounds of the present invention are mainly represented by the structural formula (I), but are represented by the following structural formulas (Ia) and (Ib), respectively.

In each of the structural formulas (Ia) and (Ib), the asterisk carbon atom is a subtitle carbon, and by stereoconfiguration thereof, each of them includes D-isomer, L-isomer, and D, L-mixture. For convenience, the penicillin compound of formula (Ia) is sometimes referred to as the "formyl piperazine derivative" and the penicillin compound of formula (Ib) will be referred to as the "acetyl piperazine derivative".

Among the formyl and acetyl piperazine derivatives, the D-isomers show particularly good antimicrobial activity and are named as fraud.

D-formyl piperazine derivatives:

D-α-5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxido-p-hydride Roxybenzylphenicillin,

D-acetyl piperazine derivatives:

D-α-5,8-dihydro-2- (4-acetyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxamido-p-hydroxy Benzylpenicillin

U.S. Patent No. 4,003,887 and the corresponding British Patent No. 1,446,484 describe N-acyl amoxicillin derivatives of the following formula (X).

Wherein A ring is a benzene ring or a 5- or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as a hetero atom, which contains one or more lower alkyl, lower alkoxy, lower alkylthio, lower Roalkyl, lower alkylenedioxy, halogen, hydroxyl, nitro, free or protected amino, lower alkylamino, di (lower) alkylamino and lower alkanoyl amino may be present, X is oxygen or sulfur, Y is hydrogen, Lower alkoxycarbonyl or lower alkanoyl.

The novel penicillin compounds of the present invention represented by the formulas (I) (Ia) and (Ib) are not included within the definition of formula (X) described in US Pat. No. 4,004,887 and its corresponding British patent.

U.S. Pat. No. 4,003,887 describes 0-octyl derivatives of compounds of formula (Xa).

This derivative of the amoxicillin derivative (Xa) (called 2-dimethylaminopyridopyrimidine derivative) in which the amino group of amoxicillin is acylated by a pyridopyrimidine carboxylic acid residue substituted with a dimethylamino group in the second position. It is produced by the acylation of the hydroxyl group on the benzene nucleus.

Compound (Xa) is similar in structure to the novel penicillin compound of the present invention. However, as shown in Tables I to II, the novel penicillin compounds of the present invention are characterized by extremely superior antibacterial action against Pseudomonas ayeruginosa and extremely low toxicity to warm-blooded animals than compound (Xa).

The inventors have already described that the compound of formula (Xi) has an excellent antimicrobial activity, particularly against Gram-negative bacteria, when R ¹ is a hydrogen atom and R ₂ is an ethyl group (pipemidic acid) (US Pat. No. 3,887,557). )

As shown in Tables I to III, this compound shows no significant antimicrobial activity against Gram-positive bacteria, but the novel penicillin compound of the present invention has excellent antimicrobial activity against Gram-positive bacteria as well as Gram-positive bacteria.

It can be seen that the novel penicillin compound of the present invention is different from the above compound because the second position of the pyridopypyrimidine carboxylic acid residue as a structural factor is particularly 4-formyl-1-piperazinyl. This is because it is substituted by a group or a 4-acetyl-1-piperazinyl group, and the nitrogen atom at the 8th position is not substituted by a substituent such as an ethyl group.

Examination of the novel penicillin compound of the present invention and a number of compounds having a structure similar to the structure thereof shows that the second position of the pyrido pyrimidine moiety is substituted by 1-piperazinyl group containing two nitrogen atoms. Therefore, the penicillin compound of the present invention represented by the structural formula (I) has a second position by a substituted amino group containing one nitrogen atom, for example, a dimethylamino group or a heterocyclic group containing one nitrogen atom, for example, 1-pitolidinyl group. The penicillin compound of the present invention is particularly toxic to warm-blooded animals because its antibacterial activity is significantly higher than that of the substituted penicillin compound, and the fourth position of the piperazinyl group is replaced by a formyl group or an acetyl group. While this was extremely low, it was found that the antipolar action in vivo remained high.

The novel penicillin compounds of formula (I) and their pharmacologically acceptable nontoxic salts can be prepared, for example, by the process shown below.

The outline of the process can be represented by the following scheme.

[Scheme]

Where R in structural formulas (I) and (II) are the same as described above.

Penicillin compounds of the present invention of formula (I) or pharmacologically acceptable non-toxic salts thereof include 2- (4-formyl- or 4-acetyl-1-piperazinyl) -5,8-dihydro of formula (II) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (generally referred to as 2-substituted pyridopyrimidinecarboxylic acid, the 4-formyl substitution product thereof being X2- Instead of substitution, it is called "2-FP substitution" and its 4-acetyl substitution product is called "2-AP substitution instead of" 2-substitution ") or its inorganic or organic salt or its reactive derivative in carboxyl group. α-amino-p-hydroxybenzylphenicillin (abbreviated AHBP) or its inorganic or organic salt or derivative convertible to AHBP in an aqueous or non-aqueous medium, and then the resulting reaction product is converted to the compound of formula (I) , The reaction product is hydrolyzed or connectedly hydrogenated in the present invention. The other is made of a penicillin compound, if further desired is made to call the nontoxic salt acceptable for the reaction product of Pharmacology.

Reactive derivatives in the carboxyl groups of the 2-substituted pyridopyrimidinecarboxylic acids of formula (I) can be exemplified by all reactive derivatives known in the art of penicillin or cephalosporin preparation. Specific examples include alkylcarboxylic acids (e.g. ethyl carboxylic acid, isopropylcarboxylic acid, iso- or sec-butylcarboxylic acid), alkyl carboxylic acids (e.g. pivalic acid, pentanoic acid, iso-pentanoic acid, 2-ethyl Acid anhydrides formed with a phase such as butyric acid, 2-ethylhexanoic acid), diacids (such as diethyl phosphoric acid) and sulfonic acids (such as methylsulfonic acid); Reactive esters thereof such as p-nitrophenyl ester, trichlorophenyl ester, p-nitrophenylthioester, N-hydroxypiperidine ester, N-hydroxysuccinimide ester or N-hydroxyphthalimide ester ; Reactive amides thereof such as N-carbonylimidazole or N-carbonyltetrazole; Acid halides and acid azides thereof, such as acid chlorides.

AHBP convertible derivatives represented by formula (III) are those well known in the art of semisynthetic penicillin production and can be used in the present invention. Representative examples of such derivatives are trimethylsilyl ester, trityl ester P-nitrobenzyl ester, phenazyl ester and O, N-bistrimethylsilyl derivatives. For example, a derivative obtained by protecting the hydroxyl group of the benzene nucleus of AHBP with an acyl group such as ethoxycarbonyl or benzyloxycarbonyl group can also be used.

Inorganic or organic salts of the 2-substituted pyridopyrimidylcarboxylic acids of formula (II) and or AHBP of formula (II) include alkali metal salts such as sodium or potassium salts, and triethylamine or N-ethylmorpholine Salts with organic bases such as;

The reaction is accommodated in the presence of a base, preferably from 1 to 10 hours at -40 ° to + 40 °. Solvents, bases and other reaction conditions are essentially the same as those used in penicillin chemistry.

For example, when an anhydride derived from an acid and ethyl chloroformate is used as the 2-substituted pyridopyrimidinecaro of formula (II), the reaction is cooled in the presence of a higher amine such as triethylamine or N, N-dimethylaniline. Under or silol, in an inert solvent such as acetone, tetrahydrofuran, dimethylformamiro, chloroform, dichloroform or methylphosphoramide, a mixture of these inert solvents, water, or a hydrated organic solvent.

When the 2-substituted pilidopyrimidinecarboxylic acid of formula (II) is used, the reaction is carried out in the presence of triethylaminelutidine, sodium hydroxide or sodium carbonate in dimethylformamide, dichloromethane, dioxane, water or a mixture of these solvents. To 10 ° C. for 1 to 2 hours.

The reaction of the 2-substituted pyridopyrimidinecarboxyl of formula (II) or a salt thereof with AHBP of formula (III) or a salt thereof is advantageously carried out in the presence of a condensing agent such as N 2 N′-dicyclohexylcarbodiimide do.

A portion of AHBP capable of converting a 2-substituted pyridopyrimidine carboxylic acid or a salt thereof or a carboxyl group thereof into a derivative capable of converting into an AHBP of structural formula (III), sometimes converting to a penicillin compound of the present invention according to reaction conditions Excitation reaction product is produced. For example, when the carboxyl group of the reaction product is an ester type such as silester, or when the hydroxyl group of the benzene nucleus of the reaction product is protected with a protecting group such as an acyl group. In such cases, the product is further hydrolyzed or catalytic hydrocracked by methods known in penicillin chemistry to give the penicillin compounds of the present invention.

If necessary, the penicillin compound of formula (I) thus produced can be converted into its pharmacologically acceptable non-toxic salt by known methods.

In Scheme (a), the carbon atom starred at α-carbon of the P-hydroxyphenylglycine residue of formula (III) is an asymmetric carbon atom, so AHBP in formula (III) is D-isomer, L-isomer and D And L-mixtures.

When the D-isomer of AHBP is used as starting material in the present invention, the corresponding penicillin compounds of the present invention can be obtained in D-form. When the starting material is a D, L-mixture of AHBP, a penicillin compound of the present invention of type D, L is obtained.

As described above, the novel penicillin compound of the D-type of the present invention has particularly high antibacterial action.

Therefore, the type of isomer of AHBP of formula (III) used as starting material is selected according to the type of isomer of the desired final product.

The penicillin compound thus obtained may be in the form of a free carboxylic acid or salt depending on the choice of starting materials, reaction conditions and the like. This carboxylic acid is converted into a salt when treated with a basic substance such as 2-ethylhexane sodium, sodium hydroxide or sodium carbonate. On the other hand, the salt is treated with an acidic substance to generate free carboxylic acid if necessary.

Isolation, purification, extraction and recrystallization of the product and other pretreatments are carried out by methods known in penicillin chemistry.

The starting material of formula (II) is a compound of formula (IX) which is obtained by subjecting the compound of formula (VII) to ring closure in a molecule to obtain a compound of formula (VII) and hydrolyzing the compound (VIII). The compound of Compound (IX) is obtained by formylation or acetylation.

In the above formula, R 'is an alkyl group having 1 to 6 carbon atoms.

The formylation reaction is carried out by reacting a compound of formula (IX) with a known formylating agent, such as N-formylimidazole, formic acid P-nitrophenyl, a mixture of acetic anhydride and formic acid, in the presence of an inert solvent such as dimethylformamide. By reaction with a mixture with formamide. This reaction can generally proceed for 30 minutes to several hours, preferably for one to three hours. The reaction temperature is 20 ° to 120 ° C, preferably 60 ° to 90 ° C. When the formylating agent used is a liquid, it may be used in excess so that it also functions as a solvent.

The acetylation reaction is carried out by reacting a compound of formula (IX) with a known acetylating agent such as acetic anhydride, acetyl chloride, N-acetylimidazole, acetoxypyridine or ketone in an active solvent such as dimethylformamide. Can be. The reaction progress time is generally 30 minutes to several hours, preferably 1 to 3 hours. The reaction temperature is 20 ° to 120 ° C, preferably 60 ° to 90 ° C.

If the acetylating agent used is a liquid, it may be used in excess so that it also acts as a solvent.

2-AP substituted pyridopyrimidinecarboxylic acids can also be obtained, for example, by hydrolyzing the compound of formula (VIII) under mild health in a mixture of hydrochloric acid and ethanol.

Intramolecular cyclization reactions in which compounds of formula (VII) are converted to compounds of formula (VIII) and hydrolysis reactions in which compounds of formula (VIII) are converted to compounds of formula (IX) are described in accordance with the description of US Pat. No. 3,887,557. Can be performed.

The preparation of the novel penicillin compounds of the present invention and their pharmacological actions are described below. The following description consists of 5 parts.

Part I

Reference Examples 1 to 7 showing the preparation of the starting compound of formula II.

Part II

Examples 1 to 13 showing the preparation of the novel penicillin compound of the present invention

Part III

Reference Examples 8 and 9 which show a manufacturing method whose production method is unknown as a compound outside the scope of the present invention These reference examples are for evaluating the pharmacological action of the penicillin compound of the present invention.

Part IV

Reference Example 10 showing the preparation of a medicament using the penicillin compound of the present invention.

Part V

Test Examples 1,2 and 3 and Tables I, II and III showing the pharmacological action of the penicillin compounds of the present invention, amoxicillin (known antibiotics), penicillin derivatives outside the scope of the present invention having a structure similar to the penicillin compounds of the present invention.

In Examples I and III, in each of the Examples and Comparative Examples, the outline of the method used therein is represented by the reaction scheme.

(Part 1) Reference Examples 1 to 7 showing the preparation of starting compounds for use in the present invention.

Reference Example 1

Diethyl ether (16 ml) maintained at a temperature of 250 ° C. to 255 ° C. was replaced with N-2- (4-acetyl-1-piperazinyl) -4-pyrimidinyl-aminomethyltenonate diethyl (2.0). g) was added. The mixture was refluxed gently for 10 minutes and then cooled to room temperature. N-hexane (12 ml) was added to this mixture. The resulting precipitate was collected, washed with ethanol and recrystallized from ethanol to give 2- (4-acetyl-1-piperazinyl) -5,8-dihydro-5-oxopyrido [2,3-d] pyridine Midine-6-ethyl carboxylate (1.52 g) was obtained. Melting Point 300 ~ 302 ℃ (Decomposition)

Reference Example 2

5,8-dihydro-2- (4-acetyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-ethyl carboxylic acid (1000 g) with hydrochloric acid (80 ml) The suspension suspended in a mixture with water (1200 ml) and ethanol (1000 ml) was left under reflux for 8 hours at reflux.

The precipitated crystals were collected, washed with ethanol and heated to dissolve in aqueous sodium hydroxide (250 g) solution (10 L). The solution was filtered, adjusted to pH 7-8 with acetic acid, and left overnight under ice-cooling. The crystalline precipitates were collected, washed with water and dried at 110 ° C. to give 5,8-dihydro-2- (1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid ( 625 g). Melting Point 229 ~ 305 ℃ (Decomposition)

Elemental Analysis Value: C ₁₂ H ₁₃ N ₅ O ₃

Reference Example 3

Formic acid (140 ml) was added dropwise to acetic anhydride (200 ml) cooled in an ice jade bath. The solution was heated to 50 ° C. for 15 minutes and then cooled to 5 ° C. To this solution was added 5,8-dihydro-2- (1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (70 g). This mixture is heated to 80 ° C. for 3 hours. Negative cooling. The precipitated crystals were collected by filtration and washed with ethyl ether to give 5,8-dihydrodo-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6 -Carboxylic acid (72.5 g) was obtained. Melting point over 300 ℃

Elemental Analysis Value: C ₁₃ H ₁₃ N ₅ O ₄

Reference Example 4

By the same method as described in Reference Example 3, 5,8-dihydro-2- (1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid ( 900 g) and 5,8-dihydro-2- (4-acetyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxyl from acetic anhydride (3200 ml) Acid (933 g) was obtained. Melting Point 298-200 ℃

Elemental Analysis Value: C ₁₄ H ₁₅ N ₅ O ₄

Reference Example 5

5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (273 g) and triethylamine ( 299 ml), suspended in dry dichloromethane (3500 ml), was stirred sufficiently at room temperature for 1 hour.

Chloro formic acid isopropyl (221 g) was added dropwise to the suspension with stirring at 0 to 10 ° C, and the mixture was stirred for 2 hours. A solution of N-hydroxysuccinimide (207 g) and dimethylformamide (350 ml) was added to the mixture and the final mixture was kept at 5-10 ° C. for another 2 hours.

The crystalline product was collected by filtration and washed successively with water (2000 ml) and acetone (2000 ml) to give N-5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido- [2,3-d] -pyrimidine-6-carbonyloxy] succinimide (326 g) was obtained.

Melting point over 300 ℃

Elemental Analysis Value: C ₁₇ H ₁₆ N ₆ O ₆

Reference Example 6

5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (6 g) and triethylamine ( 6.1 ml), suspended in dry dichloromethane (100 ml), was sufficiently stirred at room temperature for 1 hour.

Ethyl chloro formate (3.8 ml) was added dropwise to this suspension at 0-5 占 폚, and the mixture was stirred at 5-7 占 폚 for 1 hour.

The insoluble material was filtered off and a solution of N-hydroxyphthalimide (7.19 g) and dimethylformamide (10 ml) was added to the filtrate. The resulting mixture was kept at room temperature for 2 hours.

The crystalline product was collected by filtration and washed successively with dichloromethane and acetone to give N- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido- [2,3 -d] -pyrimidine-6-carbonyloxy] protalimide (8.4 g) was obtained.

Melting Point 285 ~ 288 ℃ or higher

Elemental Analysis Value: C ₂₁ H ₁₆ O ₆ N ₆

Reference Example 7

5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (6 g) and triethylamine ( 6.1 ml) was suspended in dry dichloromethane (100 ml), and the mixture was sufficiently stirred at room temperature for 1 hour. Chloro formic acid (3.8 ml) was added to this suspension at 0-5 degreeC, and the reaction mixture was stirred at 5-7 degreeC for 1 hour.

Insoluble material was filtered off and a solution of 2,4,6-trichlorophenol (8.68 g) and dimethylformamide (30 ml) was added to the filtrate.

The reaction mixture was kept at room temperature for 3 hours. The crystalline product was collected by filtration and washed with dichloromethane to give 5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido- [2,3-d] -pyrimidine -6-carmoxyl acid 2,4,6-trichlorophenyl (8.2 g) was obtained.

Melting Point 285 ~ 290 ℃ (Decomposition)

Elemental Analysis Value: C ₁₉ H ₁₄ O ₄ N ₅ Cl ₃

Example 1

D-α-amino-P-hydroxybenzylphenicillin (230 g) and N- [5,8-dihydro-2- (4-formyl-1-piperazinyl) in an aqueous solution of sodium hydroxide (22 g) (1000 ml) -5-Oxopyrido [2,3-d] pyrimidine-6-carbonyloxy succinimide (200 g) was added continuously at 0-2 DEG C under cooling, and the mixture was stirred for half an hour. Sodium hydroxide solution (550 ml) was added to the mixture, at which time the resulting mixture was held for an additional hour and then filtered. Ice water (3000 ml) was added to the filtrate. This solution was adjusted to pH 2 with 10% hydrochloric acid. At this time, the resulting precipitate was collected by filtration, washed twice with ice water (4000 ml), and dissolved in a sufficient amount of 4% sodium hydroxide solution to adjust the pH to 6.5.

The aqueous solution was filtered and the filtrate was lyophilized to give D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl-5-oxopyrido [2,3-d] pyrimidine -6-carboxamido] -p-hydroxy benzene penicillin sodium salt (324 g) was obtained.

IR (KBr): ν C = O 1760cm

NMR (DMSO-d ₆ , δ):

)8.10 (1H, s, -N, N-CHO). 3.98 (1 H, s,

)

5.80 (1H, d, J = 8 Hz,

9.14 (1 H, S,

Elemental Analysis Value: C ₂₉ H ₂₉ N ₈ O ₈ SNa · 2H ₂ O

Example 2

N- [5,8-dihydro-2- (4-) in a solution in which D-α-amino-P-hydroxybenzylphenicillin (230 g) and triethylamine (76 ml) were dissolved in dry dimethylformamide (1000 ml). Formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carbonyloxy] succinimide (200 g) was added at 0 ° C. and the reaction mixture was stirred for 1.5 hours. It was.

A 30% solution of sodium 2-ethylhexanoate in n-butanol (335 ml) and acetone (7000 ml) was added continuously to the mixture. The resulting precipitate was collected by filtration, washed with acetone and dissolved in ice water. The aqueous solution was acidified with 10% hydrochloric acid, the precipitated crystals were collected, washed with water sufficiently and dissolved in 2% sodium hydroxide solution. The solution was adjusted to pH 6.5 and filtered. The filtrate was lyophilized to afford D-α- [5,8-dihydro-2- (4-formyl-2-pyreaginyl) -5-oxopyrido [2,3-d] pyrimidine-6-carbox Voxamido] -P-hydroxybenzylphenicillin sodium salt (289 g) was obtained.

It was confirmed that this compound was the same as the compound of Example 1 as a comparison of IR and NMR spectra.

Example 3

To a solution of D-α-amino-P-hydroxybenzylphenicillin (4.61 g) and triethylamine (1.53 ml) in dry dimethylformamide (30 ml), N- [5,8-dihydro-2- ( 4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carbonyloxy] phthalimide (4.48 g) is added and the reaction mixture is allowed to stand at room temperature 1. Stirred for time.

The insoluble material was filtered off and a 30% solution of sodium 2-ethylhexanoate in n-butanol (7.3 ml) and acetone (300 ml) was continuously added to the filtrate. The resulting precipitate was collected by filtration, washed with acetone and dissolved in ice water. The aqueous solution was adjusted to pH 2 with 10% hydrochloric acid. The precipitate was collected, washed with water and dissolved in dimethylformamide (60 ml). The solution was treated with activated carbon (1.5 g) and filtered. To the filtrate was added successively a 30% solution of sodium 2-ethylhexanoate in n-butanol (7 ml) and acetone (300 ml). The precipitate was collected and dissolved in ice water. This aqueous solution was adjusted to pH 2 with 10% hydrochloric acid. The resulting precipitate was collected, washed with water and dissolved in 2% sodium hydroxide solution to adjust to pH 6.5. The aqueous solution was filtered and D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine as a lyophilization aid -6-carboxamido] -P-hydroxybenzylphenicillin sodium salt (4.83 g) was obtained.

This compound was confirmed to be the same as the compound of Example 1 as a comparison of IR and NMR spectra.

Example 4

D-α-amino-P-hydroxybenzylphenicillin (1.11 g) and triethylamine (0.38 ml) were added to 5,8-dihydro-2- (4-formyl) in a dry dimethyl podamime (10 ml) solution. -1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid 2,4,6-trichloro phenyl (2.16 g) was added and the mixture was stirred at room temperature. Stir for days. The insoluble material was filtered off and to this filtrate was continuously added a 30% solution of sodium 2-ethylhexanoate in n-butanol (1.5 ml) and acetone (150 ml).

The resulting precipitate was collected by filtration, washed with acetone and dissolved in ice water. This aqueous solution was adjusted to pH 2 with 10% hydrochloric acid. The precipitate was collected, washed with water and dissolved in dimethylformamide. This large methylformamido solution was treated with activated carbon and filtered. To the filtrate was added successively a 30% solution of 2-ethyl sodium hexanoate in n-butanol and acetone. This aqueous solution was adjusted to pH 2 with 10% hydrochloric acid. The precipitate was collected, washed with water and dissolved in 2% sodium hydroxide solution to pH 6.5.

The aqueous solution was filtered and lyophilized to give D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine- 6-carboxamido] -P-hydroxybenzylphenicillin sodium salt (1.15 g) was obtained.

It was confirmed that this compound was the same as the compound of Example 1 by comparison of IR and NMR spectra.

Example 5

5,8-dihydro-2- (4-formyl-1-piperidinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (90 g) and triethylamine ( 42 ml) was suspended in dry dichloromethane (100 ml) and the mixture was stirred sufficiently for 1 hour at room temperature.

Chloro formic acid (36.8 g) was added thereto while cooling the suspension, and the mixture was kept at 5-7 ° C. for 1 hour. A solution of D-α-amino-P-hydroxy benzylphenicillin (126 g) and trimethylamine (46 ml) in dry dimethylformamide (350 ml) was added to the mixture. The mixture at this time was further stirred at 5 to 7 ° C for 1.5 hours, and left at -10 ° C overnight.

The insoluble material was filtered off, and to the filtrate was continuously added a 30% solution of sodium 2-ethylhexanoate in butanol (250 ml) and acetone (300 ml).

The resulting precipitate was collected by filtration and dissolved in ice water. This aqueous solution was adjusted to pH 2 with 10% hydrochloric acid. The precipitate was washed with water and dissolved in dimethylformamide (380 ml). The solution was treated with activated charcoal (20 g), followed by successively adding butanol (130 ml) and acetone (5000 ml) to the solution.

The resulting precipitate was collected, washed with acetone and dissolved in ice water. This aqueous solution was adjusted to 2 with 10% hydrochloric acid. The precipitate was collected, washed with water and dissolved in a 2% sodium ammonium solution to adjust to pH 6.6.

The solution was filtered and lyophilized to give D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine- 6-carboxamido] -p-hydroxy benzyl penicillin sodium salt (78.7 g) was obtained.

This compound was found to be consistent with the compound of Example 1 by comparison of IR and NMR spectra.

Example 6

5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6- according to the same method as described in Example 5 D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido from carboxylic acid (152 g) and chloro-l isopropyl acid (79 ml) 2,3-d] pyrimidine-6-carboxamido] -p-hydroxybenzylphenicillin sodium salt (155 g) was obtained.

This compound was found to be consistent with the compound of Example 1 by comparison of IR and NMR spectra.

Example 7

5,82-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6 by the same method as described in Example 5 D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyri from carboxylic acid (30 g) and chloro formic acid sec-butyl (13.7 g) Fig. [2,3-d] pyrimidine-6-carboxamido] -p-hydroxybenzylphenicillin sodium salt (29 g) was obtained.

This compound was confirmed to be consistent with the compound of Example 1 by comparison of IR and NMR spectra.

Example 8

5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxo by the same method as described in Example 5 except that the reaction is carried out at -10 ° C. D-α- [5,8-dihydro-2- (4- from pyrido [2,3-d] pyrimidine-6-carboxylic acid (30 g) and 2-ethylhexanoyl chloride (19.5 g) Formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxamido] -p-hydroxybenzylphenicillin sodium salt (15 g) was obtained.

This compound was found to be consistent with the compound of Example 1 by comparison of IR and NMR spectra.

Example 9

5,8-dihydro-2- (4-propyl-1-piperazinyl-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (3.0 g) and triether (1.66 ml) was suspended in anhydrous dimetalformamide (50 ml) and stirred for 30 minutes at room temperature To the reaction mixture, chloro formic acid (1.14.) was added at 5 to 10 ° C., and the mixture was stirred for 1 hour. It was.

On the other hand, a suspension of D-α-amino-p-hydroxybenzylphenicillin (5.0 g), triethylamine (2.77 ml) and anhydrous magnesium sulfate (2.0 g) suspended in dry dimetalformamide (60 ml) at room temperature Stir for 30 minutes and filter out insolubles. The filtrate was first added to the suspension at 5-10 ° C., and the mixture was stirred for another 2 hours. The non-condensate was filtered off and to the filtrate was added a solution of 20% 2-Ethylhexanosodium in n-butanol (10 ml). Next, ether ether (500 ml) was added thereto. The precipitated crystals were collected and dissolved in water (300 ml). This aqueous solution was acidified with dichloric acid.

The precipitates were collected, washed and dried to give D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine- 6-carboxamido] -p-hydroxybenzylphenicillin (3.4 g) was obtained.

IR (KBr): ν C = O 1770cm ^-1

NMR (DMSO-d ₆ , δ):

), 4.19(1H, s,

)8.10 (1M, s,

), 4.19 (1H, s,

)

), 9.12(1H, s,

)5.77 (1H, d, J = 8 Hz,

), 9.12 (1H, s,

)

Elemental Analysis Value: C ₂₉ H ₃₀ N ₈ O ₈ S · 3H ₂ O

Example 10

5,8-dihydro-2- (4-acetyl-1-piperazinyl-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (9.31 g) and triethamine ( 4.98 ml) suspended in dry dichloromethane (180 ml) was stirred sufficiently for 1 hour at room temperature To this suspension, chloro formic acid ether (3.42 ml) was added dropwise with stirring at 3-5 ° C. and the mixture was added 3 Stirred for 1 hour at ˜8 ° C. To the reaction mixture was added a solution of D-α-amino-p-hydroxybenzylphenicillin (15 g), triethylamine (7.5 ml) and dimetalformamide (120 ml), The mixture was stirred for 2 hours, insolubles were filtered off, and to the filtrate was added a solution of sodium 2-etherhexanoate in n-butanol (27 ml) and acetone (1000 ml).

The precipitate produced at this time was filtered and dissolved in ice water. The aqueous solution was adjusted to pH 2 with 10% hydrochloric acid, and the precipitate was filtered and washed with water to dissolve in dimetalformamide (250 ml).

After treating the dimetalformamide solution with activated carbon, a 20% 2-ethylhexanoic acid solution in n-butanol (27 ml) and acetone (1000 ml) was added successively to this solution.

The precipitate was filtered off and landed in ice water. This aqueous solution was adjusted to pH 2 with 10% hydrochloric acid. The precipitated crystals were collected, washed with water and dissolved in 2% sodium hydroxide solution to adjust the pH to 6.5. The solution was filtered and lyophilized to give D-α- [5,8-dihydro-2- (4-acetyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine- 6-carboxamido] -p-hydroxybenzylphenicillin sodium salt (8.5 g) was obtained.

IR (KBr): ν C = O 1760cm ^-1

NMR (DMSO-d ₆ , δ):

), 3.95(1H, s,

)2.05 (3H, s,

), 3.95 (1H, s,

)

)5.79 (1H, doublet, J = 8 Hz,

)

)9.12 (1 H, s,

)

Elemental Analysis Value: C ₃₀ N ₃₁ N ₈ O ₈ SNa · 4H ₂ O:

Example 11

5,8-dihydro-2- (4-acetal-1-piperazinyl-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (20 g) in 4% hydrochloric acid (60 ml ) And the suspension suspended in ethanol (20 ml) were refluxed for 1.5 hours at 120 ° C. After cooling, the precipitate was collected, washed with water and washed with warm water to dissolve in 10% sodium hydroxide solution. The resulting precipitate was collected and recrystallized from dimetal sulfoxide to give 5,8-dihydro-2- (4-acetal-1-piperazinyl (-5-oxopyrido [2,3-d] -Pyrimidine-6-carboxylic acid (10 g) was obtained, melting point 298 ~ 300 ℃

5,8-dihydro-2- (4-acetal-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (1.57 g) and trie The suspension in which teramine (0.73 ml) was suspended in dry dimetalformamide (20 ml) was stirred at room temperature for 30 minutes.

Chloro formic acid (0.5 ml) was added to this mixture at -5 ° C to -10 ° C, and the mixture was stirred for 1 hour.

On the other hand, D-α-amino-p-hydroxybenzylphenicillin (2.10 g), triethanolamine (1.05 ml) and anhydrous magnesium sulfate (1.0 g) were suspended in dry dimetalformamide (20 ml) at room temperature 30 Stirred for a minute and the insolubles were filtered off.

The filtrate was first added to the suspension at −5 ° C. to −10 ° C. and the mixture was stirred for another 2 hours. The insolubles were filtered off, and to the filtrate was added a solution of 20% sodium 2-etherhexanoate in n-butanol (7.5 ml), followed by addition of ether. Precipitated crystals were collected and dissolved in sodium bicarbonate solution. The aqueous solution was acidified with dilute hydrochloric acid, and the precipitate was collected, washed with water and dried to give D-α- [5,8-dihydro-2- (4-acetal-1-piperazinyl-5-oxopyrido [2, 3-d] pyrimidine-6-carboxboxamido] -p-hydroxybenzylphenicillin (1.35 g) was obtained.

IR (KBr): ν C = O 1770cm ^-1

NMR (CMSO d ₆ , δ):

), 4.20(1H, s,

)2.06 (3H, s,

), 4.20 (1 H, s,

)

),5.78 (1H, doublet, J = 8 Hz,

),

)9.12 (1 H, s,

)

Elemental analysis value: C ₃₀ H ₃₂ N ₈ O ₈ S · 4H ₂ O

Example 12

D-α-amino-p-hydroxybenzylphenicillin and N-5,8-dihydro-2- (4-acetal-1-piperazinyl) -5- by the same method as described in Example 1 An oxopyrido [2,3-d] pyrimidine-6-carboxboxamido-p-hydroxybenzylphenicillin sodium salt was obtained.

This compound was found to be consistent with the compound of Example 10 by comparison of IR and NMR spectra.

Example 13

5,8-dihydro-2- (4-acetal-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-cart in the same manner as described in Example 5 D-α- [5,8-dihydro-2- (4-acetyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6- from acid and chloroformic acid isopropyl Carboxy amido] -p-hydroxybenzylphenicillin sodium salt was obtained.

This compound was found to be consistent with the compound of Example 10 by comparison of IR and NMR spectra.

(Part III)

Reference Examples 8 and 9 below show the preparation of compounds outside the scope of the present invention that are not known to date in order to evaluate the pharmacological action of the novel penicillin compounds according to the present invention.

Reference Example 8

5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (1.29 g) and triethylamine (0.73 ml) were dried. To a suspension suspended in a mixture of toamide (25 ml) and dry dichloromethane (5 ml) was added ethyl chloro formate (0.5 ml) at -8 ° to -10 ° C and the mixture was added at -8 ° to 0 ° C for 1 hour. Stirred.

Thus, in this mixture, a solution of D-α-amino-P-hydroxybenzylphenicillin (2.10 g) and triethylamine (1.0 ml) in a mixture of hexamethylphosphoramide (20 ml) and dichloromethane (10 ml) was dissolved. It was added at -10 ° C and the mixture was stirred for 1 hour. Dichloromethane (40 ml) and ice water were added, then the mixture was adjusted to pH 2 with 10% hydrochloric acid. The organic layer was separated, washed with water and extracted with saturated sodium bicarbonate solution. The extract was adjusted to pH 1.5 with 10% hydrochloric acid.

The precipitates were filtered off, washed with water and dried to afford D-α- [5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carcassamido] -P Hydroxybenzylphenicillin (1.6 g) was obtained.

IR (KBr): ν C = O 1770cm ^-1

NMR (DMSO d ₆ , δ):

), 5.78(1H, d, J=8Hz,

)4.20 (1 H, s,

), 5.78 (1H, d, J = 8 Hz,

)

)9.06 (1 H, s,

)

Elemental Analysis Value: C ₂₈ H ₂₉ N ₇ O ₇ S.3H ₂ O

Reference Example 9

5,8-dihydro-2-dimethylamino-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (1.8 g) and D by the same method as described in Reference Example 8 D-α- (5,8-dihydro-2-dimethylamino-5-oxopyrido [2,3-d] pyrimidine-6 from -α-amino-P-hydroxybenzylphenicillin (1.58 g) -Carboxamido) -P-hydroxybenzylphenicillin (0.56 g) was obtained.

IR (KBr): ν C = O 1770cm ^-1

NMR (DMSO d ₆ , δ):

), 4.20(1H, s, CH-COO-)3.20 (16 H, s,

), 4.20 (1H, s, CH-COO-)

), 9.08(1H, s,

)5.78 (1H, doublet, J = 8 Hz,

), 9.08 (1 H, s,

)

Elemental Analysis Value: C ₂₆ H ₂₇ N ₇ O ₇ S.3H ₂ O

(Part VI)

Reference Example 10 relates to the preparation of a medicament using the penicillin compound of the present invention.

Reference Example 10

(1) D-α-5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxamido -P-hydroxybenzylphenicillin sodium salt (251 g) was dissolved in 2008 ml of distilled water for main use.

This solution was filtered with a membrane filter (pore diameter 0.22 micron; Millipore Corporation, Belford City, USA). This solution was lyophilized by injecting 1000 vials (dose 10 ml) in amounts of 2.0 ml each. Each vial was then sealed with a rubber stopper and an aluminum cap. In this way, a vial (No. B) containing 250 mg of the active ingredient was obtained. Injectable physiological chlorine was filled in an amount of 2.0 ml, respectively, to obtain sealed ampoules (No. B). Physiological saline in ampoule (B) was injected into the vial (A) to obtain an intravenous injection.

(2) Distilled water for injection was injected into the vial (No. A) in an amount of 2.0 ml, and the solution was dissolved in a 5% glucose solution for injection. Thus, a persistent dipping solution was prepared.

(3) D-α- [5,8-dihydro-2- (4-acetyl-1-piperazinyl-5-oxopyrido [2,3-d] pyrimidine- in the same manner as described above 6-carboxamido] 1000 vials (No. C) each containing 500 mg of -P-hydroxybenzylphenicillin sodium salt were prepared, but 502 g of this active ingredient was used.

(Part V)

Experimental Examples 1 and 2 below show the pharmacological action of the compounds outside the scope of the present invention.

Compound 1: D-α- [5,8-dihydro-2- (4-formyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxami -P-hydroxybenzylphenicillin sodium salt.

(Compound of the present invention)

Compound: 2: D-α- [5,8-dihydro-2- (4-acetyl-1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxami Sodium salt of -P-hydroxybenzylphenicillin.

(Compound of the present invention)

Compound A: D-α- [5,8-dihydro-2-pyrrolidino-5-oxopyrido [2,3-d] pyrimidine-6-carboxamido] -P-hydroxybenzylphenicillin

(Compound obtained by Reference Example 8)

Compound B: D-α- [5,8-dihydro-2-dimethylamino-5-oxopyrido [2,3-d] pyrimidine-6-carboxamido] -hydroxybenzylphenicillin

(Compound obtained by Reference Example 9)

Compound C: 5,8-dihydro-8-ethyl-2- (1-piperazinyl) -5-oxopyrido [2,3-d] pyrimidine-6-carboxyl phase (pipemidic acid)

(Compounds described in US Pat. No. 3,887,557)

Compound D: D-α-Amino-P-hydroxybenzylphenicillin Sodium Salt (Adoxicillin)

(Compound described in US Pat. No. 3,674,776)

[Test Example 1]

The minimum inhibitory concentrations (μg / ml) in vitro are shown in Table 1.

TABLE I

Note: The numbers in the table represent the minimum inhibitory concentration (MIC) (µg / ml).

Method: Chemotherapy, Volume 22 (b) 1126 (1974)

*: Clinically isolated impicillin and cephalexin resistant strains.

The following conclusions can be drawn from Table I.

(1) Compound C described in US Pat. No. 3,887,557, such as Staphylococus aureus, Streptococcus pyogenes and Corynebacterium pyogenes Antimicrobial activity against Gram-positive bacteria is inferior to penicillin compounds 1 and 2 of the present invention.

(2) Amoxicillin, a widely used and known antibiotic as indicated by “Compound D” in Table I, is a Gram-negative pathogen such as Escherichia coli P-140a from clinically isolated ampicillin and cephalexin resistant strains. And other Gram-negative bacteria, especially low-grades such as Klebsiella pneumonia, Enterobacter cloacae, Pseudomonas aeruginosa, and Serratia marcescens. Although substantially ineffective against gram negative bacteria, the penicillin compounds of the present invention have a very high antibacterial activity against these bacteria. Test Example 2 (In vivo Effects)

The contents of the vials (No. A and C) prepared in Reference Example 10 were dissolved in deionized water, respectively, to prepare injections having various concentrations.

Compound D was dissolved in deionized water. Compounds A, B and C were dissolved in aqueous sodium carbonate pH8 (9) solution to prepare injections of various concentrations.

Each of these injections is administered to mice under the following conditions and the 50% effective amount (ED ₅₀ ) obtained is shown in Table II.

Experimental condition:

Mice: Male males (dd Y) weighing approximately 20 g

Infection: Staphylococcus aureus No. 50774: Intravenous infection with bacterial saline suspension 50 to 100LD ₅₀ (approximately 5 × 10 ₈ cells / mouse), Escherichia coli P-5101:

Intraperitoneal infection with 50 to 100LD ₅₀ (approximately 9 × 10 ⁶ cells / mouse) of bacterial Tritosoy broth-4% mucus suspension.

Pseudomonas aeruginosa No. 12;

Intraperitoneal infection with a bacterial tryptoiso broth-4% mucus suspension 50 to 100LD ₅₀ (approximately 5 × 10 ³ cells / mouse).

Dosing: Twice 5 minutes and 6 hours after infection.

Observation: Staphylococcus aureus No. 50, 774... … 14 days

TABLE II

Note: Numbers in the table refer to ED ₅₀ (mg / kg).

1931)에 의해 계산하였음.The value of ED ₅₀ is determined by the Behrens-Kaerber method (Arch. Exp. Path. Pharm., 162,480).

Calculated by 1931).

sc: subcutaneous administration

iv: intravenous administration

The following conclusions can be drawn from Table II above.

(1) Compounds 1 and 2 of the present invention exhibit excellent antimicrobial activity in vivo.

(2) Compounds 1 and 2 of the present invention have a particularly high antimicrobial activity against Pseudomonas aeruginosa, and have an ED ₅₀ value of 2 to 6 mg / kg upon parenteral administration.

(3) Antimicrobial activity of Pseudomonas aeruginosa of Compounds 1 and 2 of the present invention upon parenteral administration is reduced to Compound 1 by 1-pyrrolidinyl or dimetalamino groups instead of 4-substituted-1-piperazinyl groups. And 6 to 20 times higher than the antibacterial action of Compounds A and B, which are penicillin compounds obtained by substituting the second position of the pyridopyrimidine moiety of 2.

(4) Compounds 1 and 2 of the present invention exhibited an antimicrobial activity against Pseudomonas aeruginosa at parenteral administration compared to Compound C (Pipemidic acid, which is known as a drug which has a particular action against Pseudomonas aeruginosa). Extremely excellent.

[Test Example 3 (winning)]

Injections containing various concentrations of Compounds 1 and 2, Compounds A, B, and C prepared in Trial 2 were administered to male mice (ddY) at a dose of 0.1 ml per 10 kg of body weight. The number of dead mice was measured after 7 days and the value of 50% lethal dose was calculated. The results are shown in Table III.

Pseudomonas aeruginosa No. in Table II. The ratio of LD ₅₀ to ED ₅₀ relative to 12, ie the chemotherapy coefficient, was calculated and the results are also shown in Table III.

TABLE III

Note: LD ₅₀ value was calculated by Behres-Kaeber method.

The following conclusions can be drawn from Table III.

(1) The value of LD ₅₀ of the compounds of the invention 1 and 2 is about 4 to 10 times the value of A and B, a very high safety.

(2) The chemotherapy coefficients of compounds 1 and 2 of the present invention are about 10 to 100 times higher than those of compounds A, B and C.

This indicates that the penicillin compound of the present invention is excellent in antibacterial activity against Pseudomonas aeruginosa.

As shown in Tables I to III, the novel penicillin compounds of the present invention show a wide range of antimicrobial activity against various Gram-positive and Gram-negative bacteria in vitro and in vivo. In particular, the penicillin compound of the present invention exhibits excellent antimicrobial activity against ampicillin resistant strains in which amoxicillin does not exhibit antimicrobial activity upon parenteral administration. They exhibit good antimicrobial activity, particularly against bacteria belonging to the genus Pseudomonas, where amoxicillin and many other known antibiotics are substantially ineffective. Among the various penicillin compounds of the present invention, formyl derivatives of structural formula (Ia), particularly the D-isomers thereof, are excellent in antibacterial activity.

The penicillin compounds of the present invention are also very safe and have good chemotherapy coefficients as indicated by the LD ₅₀ values described above. This high stability is also confirmed by blood action experiments and histopathological experiments of experimental animals after continuous parenteral administration.

The penicillin compounds of the present invention also have high plasma concentrations even after hours of parenteral administration to warm-blooded animals and maintain high urinary concentrations over long periods of time.

Selected novel penicillin compounds of the present invention have extremely superior properties compared to various known antimicrobial agents because they have a broad antimicrobial range, high antimicrobial activity, high safety, and high blood and urine concentrations after administration.

It has been found by the present inventors that parenteral administration is more advantageous than oral administration in using the penicillin compounds of the present invention in warm-blooded animals including humans.

When not administered, the penicillin compound of the present invention is preferably dissolved in a nontoxic medium for injection, and the solution injected intramuscularly, intravenously or subcutaneously.

The compounds of the present invention may be dissolved in non-toxic media or mixed with the meat ash to apply the solution or mixture directly to the external trauma. In addition, it may be mixed with the suppository base material or dissolved therein and used as a suppository.

Non-toxic media used to prepare injectables containing the present penicillin compounds as active ingredients include sterile deionized water, physiological saline solution, clocose solution, Ringer's solution, and injectable amino acid solution.

The penicillin compounds can also be dissolved in other injections and administered parenterally as such.

The dosage of the penicillin compound of the present invention when administered to humans should be adjusted according to the age, weight and condition of the patient, route of administration, frequency of administration, and the like. Usually, the dosage for adults is 0.1 to 10 g / 1 day, preferably 0.2 to 4 g / 1 day. As described above, the penicillin compounds of the present invention, in view of their pharmacological properties, are preferably administered in the form of injections dissolved in a pharmacologically acceptable liquid medium, preferably invisible (e.g., intravenously, intramuscularly or subcutaneously). .

Claims (1)

Reacting a compound of formula (II), or a salt thereof, or a reactive derivative thereof in a carboxyl group, with 6-α-amino-P-hydroxybenzylphenicillin or a salt thereof or a derivative thereof of formula (III) A method for producing a novel penicillin compound of formula (I) or a salt thereof.

Wherein R is a formyl or acetyl group.