FI63760C - FREQUENCY REQUIREMENT FOR THERAPEUTIC THERAPEUTIC PENICILLINER - Google Patents

Abstract

1508064 N-Piperazinocarbonyl-amino acid derivatives TOYAMA CHEMICAL CO Ltd 28 April 1975 [13 Aug 1974 28 Oct 1974 17 Feb 1975] 15360/77 Divided out of 1508062 Heading C2C Novel compounds I and salts and carboxyl derivatives thereof (R is an amino acid residue; R<SP>2</SP> and R<SP>3</SP> are H or alkyl and R<SP>2</SP> and R<SP>3</SP> are both linked to the same carbon atom; and A is H or an optionally substituted alkyl, alkenyl, aryl or aralkyl group) are prepared by reaction of a compound II NH 2 RCOOR<SP>1</SP> (III) (R<SP>1</SP> is H or a cation) with a reactive derivative of a compound IV

Description

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Patent- och refi «tarftyral * an AraMun utlagd och utl.tkr) ftwi pubUcurad 29. Oh. Ö3 (32) (33) (31) Requested «tumbled —Begin! printout 09.05.7Π 13.05.7Π, 31.05.7H, 13.08.7H, 26.09.7H, 13.12.7H, 27.03.75 Japan-Japan (jP) 50663 / 7Π, 5225Π / 7Π, 60787 / 7H, 91996 / 7H, 10995Π / 7Π, 1H2H99 / 7H, 37207/75 (71) Toyama Chemical Co., Ltd., 1-18, Kayabacho, Nihonbashi, Chuo-ku,

Tokyo, Japajii-Japan (JP) (72) Isamu Saikava, Toyama-shi, Shuntaro Takano, Toyama-shi, Chosaku Yoshida, Takaoka-shi, Okuta Takashima, Toyama-shi, Kaishu Momonoi, Shinminato-shi, Seietsu Kuroda, Toyama -shi, Miwako Komatsu, Toy-ama-ken, Takashi Yasuda, Toyama-ken, Yutaka Kodama, Toyama-shi, J apan i-Japan (JP) (7Π) Oy Kolster Ab (5Π) Method for the preparation of new therapeutically useful penicillins - The present invention relates to a process for the preparation of new penicillins of the formula:.

(XL

Il n / \ / CH, AN NC-NH-CH-CONH-i- <3 / τ ') \ / π 1 o CH «V * w \ I / 0 R3 3 I hNk 1 (r2) 6' ^ COOR1 wherein R 1 is a hydrogen atom, a salt-forming cation or a phthalidyl, methoxymethyl, pivaloyloxymethyl, γ-piperidinoethyl or β-morpholinoethyl group, n is 1 or 2, X is an oxygen atom attached to the carbon atom at position 2 and / or 3 of the piperazine ring, m is 0 or 1, R is a methyl group, A is a C 1-6 alkyl group optionally substituted by chlorine or acetoxy or an allyl, C 1-5 cycloalkyl, phenyl, benzyl or C 1-4 alkanesulfonyl group and R is a phenyl, hydroxyphenyl, cyclohexadienyl or thienyl group.

63760

The compounds of formula I have a broad spectrum of gram-positive and gram-negative bacteria and are particularly effective against Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus. The new compounds are also very resistant to bacterial β-lactamase. , and also have an effective antibacterial effect on clinical bacteria that are currently relevant in hospital settings. Therefore, these new compounds are effective in treating infectious diseases caused by the above-mentioned microorganisms in humans and animals.

It is known that 6-acylaminopenicillanic acids and T-acylaminocephalosporanic acids having an amino group in the acyl group oCrasema have a strong antibacterial effect on both gram-positive and gram-negative bacteria. However, these above-mentioned known compounds have the disadvantage that they do not have an effective antibacterial effect against the bacteria Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus, which cause serious infectious diseases, nor on several bacteria currently isolated from hospitals , produced by many drug-tolerant bacteria.

In order to obtain penicillins which do not have the above-mentioned disadvantages, the present inventors have found, as a result of extensive research, that the novel compounds of formula (i) prepared by attaching the group AN NC-W δ (i2) m where A, X, R, n and m have the same meaning as above, for the amino group in the acyl group of penicillins, satisfactorily fulfill the said purpose and have excellent therapeutic effects, 3 63760

Salt-forming cations are those which have hitherto been used in connection with penicillin and cephalosporin-type compounds, but cations which form non-toxic salts are preferred. Suitable salts include e.g. alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., ammonium salt and salts with nitrogenous organic bases such as procaine, dibenzylamine, N-benzyl-N-phenethylamine, 1-efenylbenzine, N-N-phenenamine, N, N-dibenzamine . In addition to the above-mentioned cations, cations capable of forming a salt with other nitrogenous organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexyl can be used.

The above-mentioned novel compounds of formula (i) exist as optical isomers, and thus all of their D-isomers, L-isomers and racemic mixtures are within the scope of the process of the invention.

Preferred compounds of formula (i) are compounds of formula (Ia) and in particular compounds of formula (Ib) and in particular their non-toxic salts VY sc „AN NC-NH-CH-CONH —-Y '' Νς '3 (la) VSPI CH3 0 <* - n —v 1

(R2) COOR

m y- </ \ CHc-N N-C-NH-CH-CONH —- f (ib) 2 5 N_ / S I I h3

N 2 CO 2 H

12 3. .

wherein R, R, S, A and m have the same meaning as above.

63760

The novel compounds of formula (i) are prepared by either method (1) or method (2).

Method (1):

A method wherein a compound of formula u S CH.

R -NH-CH-CONH-if PI CH3 (II) $ N \ C00R1a is reacted with a reactive carboxyl derivative of a compound of formula (X) n AN NC-OH (III) v + vs (r2) Ώ1, followed by, 1a · if desired, the protecting group R is cleaved.

Method (2):

A process in which a compound of formula UVT QT N 2 C00R 1a is reacted with a compound of formula (x)

II

/ \ A-N N-C-NH-CH-C-OH (V)

\ _l_ / S PS

(R2) m or a reactive carboxyl derivative thereof, followed by cleavage of the protecting group R, if desired.

23

In the above formulas (II) to (V), R, R, A, X, n and m have the same meaning 1a as above. R is a hydrogen atom, a salt-forming cation or a protecting group. The protecting group may be any of those hitherto used in connection with penicillin-type compounds. More specifically, suitable protecting groups are 63760 mm. (1) ester groups which can be removed by catalytic reduction, chemical reduction or hydrolysis under mild conditions, e.g. arylsulfonylalkyl groups such as toluenesulfonylethyl, etc., substituted or unsubstituted aralkyl groups such as benzyl, 1-nitrobenzyl, di-nitrobenzyl, .-butyl) -1-hydroxybenzyl, etc., substituted or unsubstituted alkyl groups such as tert-butyl, trichloroethyl, etc., phenacyl group, alkoxyalkyl groups such as methoxymethyl, etc., and unsubstituted or alkyl-substituted cyclic aminoalkyl groups such as piperidinoethylethyl, 1-methylethyl, 1-methyl (2) ester groups which can be easily removed by enzymes in the body, e.g. acyloxyalkyl groups such as pivaloyloxymethyl, etc., phthalide group and indanyl group, (3) silicon, phosphorus or tin-containing groups which are easily water-treated or alcohol-treated removable, such as (CH 2) _ Si, Γ'-Ρ. C 2 H 5 O 2 p- (C, H) Sn- tms.

LO / ‘C2H50 /’ 4 y J

The protecting groups mentioned in (1), (2) and (3) are only exemplary examples, and further exemplary groups that can be used in this invention can be found in U.S. Patent Nos. 3,999,909, 3,573,296 and 3 (up to 018 and DOS Publications 2). 301 01U, 2 253 28? And 2 337 105. The salt-forming cations are those which for 1 h ....

mentioned above for R. R is a hydrogen atom or a group containing 1a or phosphorus, these groups being the same as those described above for R.

As the compound (II), the D-isomer, the L-isomer or a racemic mixture can be used.

As the reactive carboxyl derivative of the compound of the formula (III), a reactive carboxylic acid derivative commonly used in acid amide synthesis can be used. Reactive derivatives are, for example, acid halides, acid azides, acid cyanides, mixed acid anhydrides, active esters, active amides, etc. Very suitable are, for example, acid halides such as acid chlorides, acid bromides, etc. and active esters such as cyanomethyl ester, trichloromethyl ester, etc.

The reactive carboxyl derivative of the compound of formula (IIi) can be easily prepared, for example, by reacting oxopiperazine of the formula <*> „A \ AN NH (VI) v + y <E \ 6 63760 wherein A, X, R, m and n are as previously defined to react with phosgene, chloroformic acid trichloromethyl ester and the like.

Literature references: V.G. Granik, Khim-Farm. Zh., 1 (M, 16-19 (196j)) (in Russian);

Samuel R. Aspinall, J. Am. Chem, Soc., 62, 1202-1 + (19I + Q);

Kuniyoshi Masuzawa, Pharm. Bull (Japan), 38, 2078-2081 (1966);

Arthur P. Phillips, Ger. 1135 ^ 72, Aug. 30 (1962); J. L. Riehsomer, J. Org. Chem., 15, 68-73 (1950);

Jongkees, Rec. trav. Chim., 27, 305;

Patric T. Izzo, J. Am. Chem. Soc., 81, 1 + 668-1 + 670 (1959); and B. H. Chase & A. M. Downes, J. Chem. Soc., 387I + -3877 (1953).

Table 1 provides examples of compounds of formula (VI).

Table 1 (X) n AN NH (VI) (R2) m

The compound Sp. (recrystallization- IR

_____ thiol solvent) _ (cm ~ 1) _____ y_ ¢, ° $ c = o 1680 CH 3 SO 2 I ^ _NH 167-168 ° C (EtOH) 32oo __________ PSO-N 1310. 11lU0 _pc = o 1650-1630 CH 2 N ^ ^ NH oily substance ^ NH 3270 i) nh 3250 CH3 (CH2) 2CH2 ~ N ^ _ ^ NH oily substance Pc = 0 165O-1630 / - ^ 0 ...> CH_ (CH-) CH - N NH oily substance Pc = 0 1650-1620 3 2 2 2 \ _y

CH

0 p NH 3270 / —f pc = o 1650-1630 CH_ (CHc) ^ CH0-N NH oily substance hydrochloride 3 2 6 2 \ _J,> <> 0 1660 __ '_ PNH 3200. 3080_ 0. ^ Pc = o 1620 CHgN_NH kp. 10U ° C / 1+ mmHg pNH 3275 (.1 * + 'uu'

Table 1 (cont'd) 63760 · _ - "" CH_CH_-N NH olymmetic substance v C = 0 1610 i * \ / _ ^ NH 32 $ 0_ -y \? C = 0 1610

CH3 (CH2) 2CH2-N2 - oily substance>, NH 325Q

° γ-Λ ^ 0 = 0 1610 (CH3) 2CH-N_NH oily substance y ^ NH 3 ^ + 00-3200 o ^ c = o 1620 / s / ^ .... ύNH 3270 CH3 (CH2) 3CH2 ~ N_IJH oily substance chI ~~ ö i> c = o 1620 3 \ '- ^ CHCH CH -N NH oily substance ΨNH 3270 CH Nf / - <ζ ° 1 ^ 0 = 0 1620

CH3 (CH2) 14CH2-N_NH oily substance ^ NH

- \ CH_ (CH2), - CH -N NH oily substance κ * 0 = 0 1620 3 ^ d N - / _ t ^ NH 3270_ y ~ \. ^ = 0 1620

CH3 (CH2) 6CH2-1H-oily substance pNH 327Q

~~ ^ v + c = o 1620 CH3 (CH2) 10CH2-N_NH oily substance pNR 32γ () o +> c = o 1620 "τγλ y \ ..,. .... ^ nh 3300 H) - k NH oil substance MJ \ _ / 0 ^ _ ^ H3 ^ = 0 1630 CH3 (CH2) 2CH2-N_NH oily substance ^ NH 3300

Va. l> c = 0 1630 CH3 (CH2) 2CH2-N NH oily substance ^ 3300 / - _ ^ 3_ 0 PC = 0 1630 y— \ pnh 3200

ClL ^ CH ^ JjjCH ^ -N NIJ oily substance _ ^ li__ (continued) 63760

Table 1 (continued) 8 _ 0 V> C = 0 1630 / OV-C H2_N NH 157-15 & ° C (| 1> NH 3300 '/ N / _ Ό ^ _)> - v Pc = o 1650

CH2 = CHCH2 ~ N_ ^ NH oily substance ^ 33QO

V-^ ° ^ = 0 1695, 1660 CH 2 -N NH 158 ° C (IPA) i> NH 3220 ^ V> C = 0 1730-1650 CH 3 COOCH 2 CH 2 -N_NH oily substance ^, NH 3300.3200 °)> - 0 y) C = 0 1680, 165 ° WVJ® '2k ° C ([> m 3250 _ ^ 0'_ CH CH CH -N ^ m 98-100 ° C (f "^) 1) 5 dd \ -f kQ ^ V> NH 3200, 3100 ° ^ - <^ ° Pc = o 1695, 1670 CH3 (CH2) 2CH2-N_HH 111-113 ° C (CCl2) ^ 321 * 0, 3150 0} - <f .0 | λ> 0 1650 (CH3) 2CH-VJ * H 166-167 ° C (Γ Λ) ^ 3300.3200 __Nr_ ° $> - Pc = o 1700, 1660 CH3 (CH2) 3CH2-i ^ JH 10it- 106 ° C (IPE) »NH 3200, 3100 δ 5, .Mi n. **> 1700, 1660 CH 2 CH 2 CH 2 N 2 H 111-115 ° C (IPE) PNH 3200, 3100 δ ~, M; Pc = o 1700, 1660 CH. (CH) CHO ~ N NH 112-115 C (IPE). „„ Λη 3 252 y_f 'pNH 3200, 3100 .. VT pc = o 1700, 1660 CH3 (CHg) gCH2-1l_m 116-120 c (IPE) _m 3g;! 5i 3100

Pc = o 1680, 1655 ° C, 0 136-137 ° C (acetone) PNH 3200, 3100

CH 2 = CHCH 2-n_V

(continued) 9

Table 1 (continued) 63760 / -vn PC = 0 1690, 161 * 5 (O_202-20 ·. C (IPA) _ ^ V ^ ° o 1> C = 0 1700-1650 C1CH2CVNwNH 128-129 C (^ ° H) PM 3200-3100 Ö Ö ~ '~~

Pc = o 1660 CH 3 CH 2 -N 12 (-128 C <AcOEt) ^ NH 3200, 3080 ^ CH 3 -1 ° Ο. ° C P = 0 1660 CVNmNH H6-147C (Q) Pnh 3200> 3100 CH3

IPA = (CH3) 2CH0H IPE = (ChT3) 2CHOCH (CH3) 2 AcOEt = CH3C00CH2CH3 EtOH = CH3CH2OH

The compound of general formula (V) can be easily prepared, for example, by reacting the compound of formula H N-CH-COOH (VII)

d '3 R

alkali metal (D-isomer, L-isomer or racemic mixture) of the amino acid . . 3 an alkaline earth metal or nitrogen-containing parent salt of the formula wherein R: 11a has the meaning given above, to react with a reactive carboxyl derivative of a compound of general formula (lii) in a reaction-inert solvent in the presence of an acid-binding reagent,

As the reactive derivative of the carboxyl group of the compound of the general formula (V), a reactive carboxylic acid derivative commonly used in acid amide synthesis is used. These reactive derivatives include e.g. acid halides, acid anhydrides, mixed anhydrides of organic or inorganic acids7, active acid amides, acid cyanides, active esters, etc. Acid chlorides, mixed anhydrides of acids and active acid amides are very suitable. For example, mixed anhydrides of acids include mixed anhydrides of substituted acetic acids, alkylation carboxylic acids, arylcarboxylic acids and aralkylcarboxylic acids, active esters include N-cyanomethyl esters, substituted ester esters of substituted cyanomethyl esters, etc. acylimidazoles, N-acylbenzoylamides, N, N-dicyclohexyl-N-acyl ureas, N-acyl sulfonamides, etc.

The practical implementation of methods (1), and (2) will be described below.

Methods (1) and (2) can be carried out under essentially the same conditions. Thus, a compound of formula (II) or (IV) is dissolved or suspended in at least one of the following inert solvents, for example: water, acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, methanol, ethanol, methoxyethanol, diethyl ether, isopropyl ether, benzene, toluene, toluene , chloroform, ethyl acetate, methyl isobutyl ketone and the like.

The solution or suspension thus obtained is reacted with a reactive derivative of a compound of formula (IIi) or a compound of formula (V) or a reactive derivative of the carboxyl group of a compound of formula (V) in the presence or absence of a base at -60 to + 80 ° C, preferably at -40 to + 30 ° C. The reaction time is usually 5 minutes to 5 hours. Suitable bases for the above reaction are e.g. alkali hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal acetates, etc., tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, etc. (2) in the form of a free acid or salt, the reaction of method (2) can be enhanced by adding a water-binding condensing reagent such as N, N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N, N'-diethylcarbodiimide, N, N'-carbonyldi (2-methylimidazole), phosphoric acid trialkyl ester, phosphoric acid ethyl ester, phosphorus oxychloride, phosphorus trichloride, 2-chloro-1,3,2-dioxaphospholane or oxazolyl chloride. The salts of the compound of formula (V) are e.g. alkali metal salts, alkaline earth metal salts, ammonium salts and salts formed with organic bases such as trimethylamine, dicyclohexylamine and the like,

The reaction conditions used in Methods 1 and 2 are not limited to the above, but may be modified according to the reaction reagents.

Non-toxic salts of formula (I) wherein R 1 is a salt-forming cation are readily obtained by conventional methods from compounds of formula (I) wherein R 1 is hydrogen or a protecting group.

11 63760

] Q

The removal of the protecting group R is carried out in a manner known per se.

The sensitivity of some typical compounds of this invention is demonstrated by the following experiments, (1) The minimum inhibitory concentration (MIC) of the compounds for some standard strains is shown in Table 2.

The minimum inhibitory concentration (MIC) was determined by the plate method described in Chemotherapy (Japan), Vol. 16, (1968), pp. 98 to 99. Cardiac infusion agar (pH 7, b) was used as the culture medium. cells (10 cells / ml).

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Control 29 63760 (3) Tolerance to Alaktamaa produced by Pseudomonas aeruginosa strain GN 238:

The β-lactamase tolerance of the compounds was determined as follows.

Pseudomonas aeruginosa strain GN-238 was prepared. This microorganism was grown for 6 hours on a shaker at 3 ° C in 500 ml Erlenmeyer flasks containing 100 ml of medium containing 2 g of yeast extract, 10 g of polypeptone, 2 g of glucose, 7 g of disodium hydrogen phosphate, 2 g of potassium dihydrogen phosphate , 1.2 g of ammonium sulphate and 0.1+ g of magnesium sulphate per liter. The cells were centrifuged (5,000 rpm, 10 min) and washed three times with 0.1 M phosphate buffer (pH 7.0). The cells were then disrupted by sound (20 kHz, 20 min) and centrifuged for 60 minutes at 15,000 rpm. The Alactamase tolerance of the compounds was determined using an iodometric measurement method using the separated enzyme-containing liquid. The results obtained are shown in Table 1+. The figures in Table 1+ are relative tolerance values calculated by assigning a value of 100 to the potassium penicillin G used as a control.

Table 1+

Comparison of lactamase tolerances

Compound Relative tolerance _: _ m_

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Natriumsulbensilliini_50__

Compound No. 15 3

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Tables 2-3 show that the compounds of this invention have a broader antibacterial spectrum and much better antibacterial properties against Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus species, and several drug-tolerant bacteria than ampicillins used as controls. i.e., for compounds having an amino group at the o <position of the acyl group, Table 1+ shows that the new compounds tolerate β-lactamase much better than the drugs used as controls. These penicillins are generally only slightly toxic. For example, 6- [5 (-) - o (N-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -penicillanic acid and 6 - [(-} - o <- (it-ethyl-2,3) -dioxo-1-piperazinocarbonylamino-phenylacetamido-penicillanic acid has an LD value (in mice weighing 19 to 1 g) of more than 5 g / kg,

The novel compounds of the formula (I) can be administered as free acids, non-toxic salts or physiologically acceptable esters. M (also, compounds in the form of physiologically unsuitable esters may be introduced as long as they are first converted to the free acid or non-toxic salts by methods commonly used in the art. The compounds of this invention may be administered to humans and animals as long as they are first into physiological forms such as tablets, capsules, syrups, injections, etc., commonly used in connection with penicillin-type drugs,

The methods for preparing the new compounds are described below by means of examples,

Example 1 (1) To a mixture of 1.78 g of 1-methanesulfonyl-3-oxopiperazine, 2.17 g of triethylamine and 20 ml of anhydrous dioxane was added a solution of 3.71 g of trimethylchlorosilane in 10 ml of anhydrous dioxane. After the resulting mixture was refluxed for 7 hours and cooled, a precipitate of triethylamine hydrochloride separated, which was removed by filtration. The filtrate was added dropwise at 10 ° C to a solution of 1.0 g of phosgene in 30 ml of anhydrous methylene chloride. The temperature of the resulting mixture was raised, and the reaction was allowed to continue at room temperature for 30 minutes. The excess phosgene and excess solvent were then distilled off under reduced pressure to give 3.5 g of a light brown, oily β-methanesulfonyl-2-oxo-1-piperazinocarbonyl chloride, IR (film) cm -1, Q 1790, 1700, " (2) A suspension of 1.5 g of 6- [d (-) -? - aminophenylacetamide] penicillanic acid in 20 ml of tetrahydrofuran containing 20 volumes of water was adjusted to pH 8. 0-8.5 by the slow addition of triethylamine, and then the suspension was cooled to 0 ° C. A solution of 2.0 mg of the above-mentioned k-methanesulfonyl-2-oxo-1 in the above-treated suspension was added dropwise over 30 minutes at this temperature. -piperazinocarbonyl chloride in 20 ml of tetrahydrofuran.

During this time, the pH of the suspension was maintained at 7.5-8.0 by the slow addition of triethyl-31,63760 amine. The temperature of the mixture was then raised to 5 ^ 30 ^, and the reaction was allowed to continue at this temperature for one hour, while adding triethylamine to ensure that the pH remained at 7 ^ 5 ^ 8.0. The tetrahydrofuran was then distilled off under reduced pressure, and the residue was dissolved in the mixture. with 50 ml of ethyl acetate and 25 ml of water. The resulting mixture was cooled with ice while adjusting its pH to 1.0 by adding dilute hydrochloric acid, and then the organic layer was separated. The aqueous layer was extracted with another 20 ml of ethyl acetate, and the organic layers were combined. , The combined organic layer was washed with water, dried over anhydrous magnesium sulfate and cooled with ice. When a solution of 570 mg of the sodium salt of 2-ethylhexanoic acid in 25 ml of ethyl acetate was poured into this organic layer, white crystals separated. When these crystals were collected by filtration, washed with ethyl acetate and dried, 2.1 g of 6- (δ (-) -? - (U-methanesulfonyl-2-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid sodium salt were obtained, m.p. 130 ° C ( decomposes), yield 80%.

The procedure described above was repeated so that U-methanesulfonyl-2-oxo-1-piperazinocarbonyl chloride was replaced with the reactive derivatives of the compounds of formula (III) listed in Table 5 to give the corresponding final products shown in Table 5. The structure of the final products was confirmed by IR and NMR, § 32,63760

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Example 2 (1) To a solution of 6 kg of 1-formyl-3-oxopiperazine in 10 ml of anhydrous dimethylformamide was added 2.7 g of sodium hydride (53% purity) under ice-cooling, and the reaction was allowed to proceed at room temperature for 1 hour. Then, 7.1 g of methyl iodide was added to the mixture, and the reaction was continued for 10 hours. When dimethylformamide was then distilled off under reduced pressure, 1-formyl-1 + -methyl-3-oxopiperazine was obtained. This piperazine was dissolved in 70 ml of a 50% aqueous solution of acetone containing 2.2 g of sodium hydroxide, and the resulting solution was allowed to react for 3 hours at room temperature.

When the solvent was then removed under reduced pressure and the residue was poured into acetone, a precipitate separated. The precipitate was removed by filtration, and acetone was distilled off from the filtrate under reduced pressure. While the residue was further distilled under reduced pressure, 5.2 g of 1-methyl-2-oxo-piperazine, b.p. 10 ° C + 532 Pa, yield 91% · (2) To a solution of 1.9 g of phosgene in 20 ml of anhydrous dioxane was added dropwise at 10 ° C a solution of 2.0 g of 1-methyl-2-oxo- piperazine and 1.95 g of triethylamine in 20 ml of anhydrous dioxane, and then triethylamine hydrochloride crystals separated as the reaction proceeded. After the separated crystals were removed by filtration and the filtrate was evaporated to dryness, 3.0 g of a pale yellow oily 1 + -methyl-3-oxo-1-piperazinocarbonyl chloride were obtained.

IR (film) cm -1: μ 1710, 1030 (3) A suspension of 1 +, 0 g of 6- (t) (-) - oC-aminophenylacetamide-7-penicillasulfonic acid in 1 + 0 ml of tetrahydrofuran with 20 vol. water, the pH was adjusted to 8.0-8.5 with triethylamine additions, and then the suspension was cooled to 0 ° C. A solution of 2.2 g of the above-mentioned 1 + -methyl-3-oxo-1-piperazinocarbonyl chloride in 10 ml of tetrahydrofuran was added dropwise to the suspension thus treated. The pH of the suspension was kept constant at 7.5-8.5 by the addition of triethylamine. The mixture was then allowed to react at said temperature for 30 minutes, and then the temperature was raised to 10-15 ° C, where the reaction was allowed to proceed for 90 minutes, while adding triethylamine. remained at 7.5-8.0. The tetrahydrofuran was then distilled off under reduced pressure, and the residue was dissolved in 30 ml of water. The solution thus obtained was washed with ethyl acetate, and the aqueous layer was collected. When the aqueous layer was cooled with ice and adjusted to pH 1.5 with dilute hydrochloric acid, white crystals separated. The separated crystals were collected by filtration, washed several times with a small amount of water, dried and dissolved in 100 ml of acetone. When 1.9 g of the sodium salt of 2-ethylhexanoic acid was added to this solution, white crystals separated, and when 35,63760 were collected, 5.0 g of 6-β) (-) - eO- (U-methyl-3-oxo-1 -piperazino-carbonylamino) phenylacetamido7penicillanic acid sodium salt, m.p. 195 ° C (decomposes), yield 92%.

IR (KBr) cm -1: μC = Q 1760 (lactam), 1600-1660 (-CON 1, -C00 NMR / (CD 3) 2 SO + D 2 O 7 required: 2.62 (SH), U, U 8 (1H), U, 56 (2H), 5.97 (3H), 6.63-6.39 (UH), 7.13 (3H), 8, U6 (3H), 8.55 (3H).

When the above procedure was repeated, substituting the reactive derivatives of the compounds of formula (II) listed in Table 6 for U-methyl-3-oxo-1-piperazinocarbonyl chloride, the corresponding final products shown in Table 6 were obtained. The structure of the final products was confirmed by IR and NMR.

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When the aqueous layer was cooled with ice and adjusted to pH 1.5 with dilute hydrochloric acid, white crystals separated. After the separated crystals were collected by filtration, washed with water and dried, 1.8 g of 6 - [- (-) - o - ((1 + -allyl-3-oxo-1-piperazinocarbonylamino) phenylacetamido] penicillanic acid, m.p. 92 ° C (decomposed), was obtained. , yield 90%, IR (KBr) cm -1 1760 (lact Aarni), 1720-1620 (-C00H, -CON O ·

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(2) A suspension of 0.71 g of the above-mentioned 1-ethyl-2,3-dioxopiperazine in 15 ml of anhydrous dioxane was mixed with 0.70 g of trimethylsilyl chloride and 0.83 ml of triethylamine. hours at room temperature, triethylamine hydrochloride separated. This hydrochloride was filtered off, and the filtrate was added dropwise at 5-10 ° C to a solution of 0.70 g of phosgene in 10 ml of anhydrous tetrahydrofuran. After the mixture was allowed to react at 5-10 ° C for 30 minutes and at room temperature for 2 hours, and the solvent was removed under reduced pressure, 1.0 g of U-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was obtained as pale yellow crystals.

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When the above procedure was repeated so that 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by the reactive derivatives of the compounds of formula (III) mentioned in Table 8, the corresponding final products shown in Table 8 were obtained. The structure of the final products was confirmed by IR and NMR.

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When the above procedure was repeated, substituting the reactive derivatives of the compounds of formula (III) listed in Table 9 for 4-n-pentyl-2,3-dioxo-1-piperazinocarbonyl chloride, the corresponding final products shown in Table 9 were obtained. The structure of the final products was confirmed by IR.

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When the procedure described in Example 5 was repeated, taking 1.7 g of the triethylamine salt of 6- [D (-) - oC-amino-p-hydroxyphenylacetamido] penicillanic acid and 0.7 g of 1 + -methyl-2,3-dioxo-1-piperazinocarbonyl chloride, 1.2 g of the sodium salt of 6- (R) (-) -? - (h-methyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxyphenylacetamido] penicillanic acid, m.p. 170-172 ° C (decomposes), yield 75! IR (KBr) cm -1: 1 C 10 Q 1760 (lactam), 1T10-1660 (-C0nO, 1600 (-C00®) NMR / TCD) 2 CO 2.8-3.3 (1 + H), 1 +, 1 + 5 (1H), 1 +, 65 (2H), 6.05 (1H), 6.2 (1 + H), 6.97 (3H), 8.1 + 8 (3H), 8.6θ (3H) 6- [D (-) - oCr- (U-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -p-hydroxy] -nylacetamido7penicillanic acid sodium salt, m.p. 175 ° C (decomposes), yield 72%, was obtained in the same manner as above, but using 1 + -ethyl-2,3-dioxo-1-piperazinocarbonyl chloride and -) -.

Example 7

To a solution of 0.8 g of β-Zbi-β-aminophenylacetamidoypenicillanic acid phthalide ester in 10 ml of tetrahydrofuran was added 0.25 ml of triethylamine. 0.32 g of 1 + -methyl-2,3-dioxo-1-piperazinecarbonyl chloride was added dropwise to the resulting mixture while cooling under ice, and the mixture was allowed to react for 2 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in a solvent mixture of 20 ml of ethyl acetate and 20 ml of water, and the resulting solution was adjusted to 2 with dilute hydrochloric acid. The organic layer was separated, washed with water, water, dried over magnesium sulfate and concentrated to 2 mL. When 20 ml of diisopropyl ether was added to the concentrate, crystals separated, and when the crystals were collected, 0.95 g of crystalline 6 - (()) - o - (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) was obtained. -phenylacetamido penicillanic acid phthalide ester, m.p. 157-160 ° C (decomposes), yield 90.0%.

IR (KBr) cm -1: c = δ 1780 (lactam)> 1715 (ester), 1680 (-COCN) NMR / (CD 3) 2 CO + D 2 O requires: 2.12 (1 + H), 2.1+ 0 (1H), 2.58 (5H), 1 +, 25-1 +, 60 (3H), 5.1 * 5 (1H), 5.85-6.1 + 2 (1 + H), 6 , 90 (3H), 8.50 (6H).

When the above procedure was repeated, substituting the reactive derivatives of the compounds of formula (IIIi) listed in Table 10 for 1 + -methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the corresponding final products shown in Table 10 were obtained. The structure of the final products was confirmed by IR and NMR.

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Example 8

A solution of 0.86 g of 6- (i) (-) - o-aminophenylacetamido] penicillanic acid methoxymethyl ester hydrochloride in 15 ml of tetrahydrofuran with 20 volumes of water was adjusted to pH 8 with triethylamine at 0-5 ° C. 0-8.5- To this solution was added dropwise over 10 minutes a solution of 0.38 g of U-methyl-2,3-dioxo-1-piperazinocarbonyl chloride in 10 ml of tetrahydrofuran. During this time, the pH of the reaction solution was maintained at 7.5-8.0 by the addition of triethylamine. The mixture thus obtained was allowed to react for 30 minutes, during which time its pH was maintained at 7.5-8.0. After completion of the reaction, tetrahydrofuran was distilled off under reduced pressure. The residue was dissolved in a solvent mixture of 50 ml of water and 50 ml of ethyl acetate, and the pH of the resulting solution was adjusted to 1.5 with dilute hydrochloric acid while cooling with ice. When the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, crystals formed. The crystals were washed with diethyl ether to give 0.9 g of 6- (1) (-) - ((- (U-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamide] penicillanic acid methoxymethyl ester, mp 111-115 ° C (decomposes), yield 82.5% · IR (KBr) cm-1: λ max 80 (lactam), 17 + + (ester), 1700-1660 (-CNN NMR {(CD3) 2CQ7 requirements: 0.15 (1H), 2.0 (1H), 2.67 (5H), U, 3-U, 5 (3H), +, 75 (2H), 5.7 (1H), 6.55 (1H), 6.97 (3H), 7.25 (3H), 8.8 »+ (3H), 8.60 (3H).

When the above procedure was repeated substituting the reactive derivatives of the compounds of formula (IIIi) listed in Table 11 for t-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, the corresponding final products shown in Table 11 were obtained. The structure of the final products was confirmed by IR and NMR.

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Example 9

Taking 1.5 g of 6 - [(-) -? - aminophenylacetamido] penicillanic acid trimethylacetyloxomethyl ester and 0.6 g of 1 + -methyl-2,3-dioxo-1-piperazinocarbonyl chloride, and proceeding in the same manner as in Example 8, -methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamide-penicillanic acid trimethylacetyloxymethyl ester, m.p. 108-111 ° C (decomposes), yield 75% · IR (KBr) cm -1:? Α = 0 1780 (lactam), 1750 (ester), 1710-1660 (-C0N <.)

When the above procedure was repeated, replacing U-methyl-2,3-dioxo-1-piperazinocarbonyl chloride with the reactive derivatives of the compounds of formula (III) mentioned in Table 12, the corresponding final products shown in Table 12 were obtained. The structure of the final products was confirmed by IR and NMR.

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When 0.81 g of 6- (E) - (-) - O-aminophenylacetamide-7-penicillanic acid hydrochloride and 0.3 g of N-methyl-2,3-dioxo-1-piperazinocarbonyl chloride were taken and the procedure was as in Example 8, 0.75 g of 6- [1) (-? - [2- (k-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenyl] acetamide] -7-penicillanic acid / 3-piperidinoethyl ester, m.p. 166-169 ° C (decomposes), yield j8%.

IR (KBr) cm-1: λmax 1780 (lactam), λmax (ester), 1710-1670 (-C0N2) NMR (CDCl3) T values: 2.7 (5H), h, 3 ~ k, 3H), 5.7 (1H), 5.75 (2H), 6.0 (2H), 6, h (2H), 6.9 (3H), 7.5 (2H), 7.6 ( Uh), 8.5 (12H).

When the above procedure was repeated, replacing 1-methyl-1,3-dioxo-1-piperazinocarbonyl chloride with 1 + -n-octyl-2,3-dioxo-1-piperazinocarbonyl chloride to give 6- [D (-) -? 6- (1 + -n-Octyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] 7-penicillanic acid β-piperidinoethyl ester, m.p. 110-115 ° C (decomposes), yield 73.58%.

Example 11

Taking 0.93 g of 6- (f) (-) -? -Aminophenylacetamide-7-penicillanic acid A-morpholinoethyl ester hydrochloride and 0.39 g of N-methyl-2,3-dioxo-1-piperazinocarbonyl chloride, and proceeding in the same manner as in Example 8, 0.8 g of 6- [S (-) - (N- (1,4-methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] -7-penicillanic acid β-morpholinoethyl ester was obtained, m.p. 150-153 ° C (decomposes), yield 73% * IR (KBr) cm -1:? 1780 (lactam), 17? 0 (ester), 17TO-1680 (-CON) NMR (CDCl 3) T values: 2.55 (5H), U, 3-U, 55 (3H), 5.6 (1H), 5.7 (3H), 6.0 (2H), 6.3 (2H), 7, k ( 2H), 7.5 (hH), 8.5 (6h).

When the above procedure was repeated substituting N-methyl-2,3-dioxo-1-piperazinocarbonyl chloride for N-n-octyl-2,3-dioxo-1-piperazinocarbonyl chloride, 6- [b (-) - w N- (octyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido / penicillanic acid N-morpholinoethyl ester, m.p. 103 ~ 105 ° C (decomposes), yield 70%.

Example 12 (1) To a solution of 7.8 g of the sodium salt of D (-) - <* - phenylglycine in 50 ml of water were added 50 ml of ethyl acetate and 5.05 g of triethylamine. To the mixture thus obtained, 9.5 g of H-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was added in small portions over 15 minutes at 0-5 ° C, and then the mixture was allowed to react for 30 minutes at 5-15 ° C. At C, the aqueous layer was separated after completion of the reaction, washed with diethyl ether and the pH was adjusted to 1.5 with dilute hydrochloric acid, crystals separated. After the crystals were collected by filtration, washed with water and dried, 1 * +, 1 g of Di-N-N-methyl-N-dioxo-1-piperazinocarbonylamino) -phenylacetic acid, m.p. 13Ö – 1U1 ° C (decomposes), yield 8? %. Recrystallization from aqueous ethanol gave white crystals, m.p. ll + o-ll + 2 ° C (decomposes).

Elemental analysis (CH 2 Cl 2 / N 2 O 2 · H 2 O):

Calculated {%): C 52.01 H 5.30 N 13.00 Found {%): C 52.21+ H 5.32 N 12.8? IR (KBr) cm -1: 1 C> Q 1710, 1700, 1660.

(2) When a solution of 5.2 g of the above-mentioned D (-) -? - (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid in 200 ml of acetone was added dropwise with stirring. g of the sodium salt of 2-ethylhexanoic acid in 50 ml of acetone, crystals separated. The separated crystals were collected by filtration and washed with acetone to give 9.6 g of the sodium salt of D (-) -? - (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid, m.p. 165 ° C (decomposes), yield 95% · (3) To a suspension of 8.8 g of the above-mentioned sodium salt of D (-) - 06- (1+ -methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid 80 per ml of methylene chloride, 20 mg of N-methylmorpholine was added. A solution of 3.1 g of ethyl chlorocarbonate in 20 ml of methylene chloride was added dropwise to the mixture thus obtained over 5 minutes at -20 to -15 ° C, and the mixture was allowed to react at this temperature for one hour. To this reaction solution was added dropwise over 10 minutes at -1 + 0 to 3030 ° C a solution of 9.1+ g of 6-aminopenicillanic acid triethylamine salt in 1 + 0 ml of methylene chloride, and the resulting mixture was allowed to react for 1 hour. At +0 to -20 ° C. After completion of the reaction, the temperature of the solution was raised to 0 ° C in small portions over one hour, and then the mixture was extracted with 100 ml of water. The aqueous layer was separated, the methylene layer was extracted with an additional 50 mL of water, and the aqueous layers were combined. When the pH of the combined aqueous layer was adjusted to 2 with dilute hydrochloric acid while cooling with ice, crystals separated. The separated crystals were collected by filtration, washed with sufficient water, dried and dissolved in 200 ml of acetone. When a solution of i + g of the sodium salt of 2-ethylhexanoic acid in i + 0 ml of acetone was added dropwise to this solution over 10 minutes, crystals separated. The crystals were collected by filtration, washed with acetone and dried to give 11 g of 6- (T) (-) - o <c- (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido-7-penicillanic acid sodium salt, m.p. 170 ° C (decomposes), yield 80.8%.

When the above procedure was repeated, substituting the compounds of formula (V) listed in Table 13 for D (-) - o * - (1+ -methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetic acid gave the corresponding compounds shown in Table 13. ; finished product. The structure of the final products was confirmed by IR and NMR.

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58 6 3760

Example 13 (1) To a solution of 2.28 g of D (-) - c (-amino-1,1-cyclohexadienylacetic acid in 15 ml of 1N NaOH) were added 20 ml of ethyl acetate and 2.1 ml of triethylamine, and this mixture was cooled to 0. To this mixture, 1.69 g of U-methyl-2,3-dioxo-1-piperazinocarbonyl chloride was gradually added over 10 minutes, the mixture was allowed to react for 30 minutes while cooling with ice, and then the aqueous layer was separated. To the aqueous layer was added 20 ml of ethyl acetate, the pH of this mixture was adjusted to 2 with 2N hydrochloric acid while cooling with ice, and the ethyl acetate layer was separated. The separated crystals were collected by filtration to give 2.5 g of O (-) - <* - (U-methyl-2,3-dioxo-1-piponazinocarbonylamino) -1,2-cyclohexa-1-phenylacetic acid in white. as crystals, m.p. 1 h (D— 1 Uti ° C (decomposes), yield 'fU%.

IR (KBr) cm -1: λ max 3300, λ = Q 1715, 1660 NMH (d 6 -DMSO) T values: 0.57 (1H, d), U, 26 (1H, s), k, 36 (2H, s ), 5.29 (1H, d), 6.07-6.18 (2H, m), 6.38-6.1 + 9 (2H, m), 7.05 (3H, s), 7, 35 (UH, s).

(2) A suspension of 0.1 + 5 g of the above-mentioned D (-) - oC- (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) -1,1 + -cyclohexadienylacetic acid in 15 ml of anhydrous methylene chloride was stirred. 0.2 kg of N-methylmorpholine to give a solution. The solution was cooled to -10 ° C, and a solution of 3 ml of anhydrous methylene chloride and 0.2 kg of ethyl chlorocarbonate was added dropwise thereto, and this mixture was allowed to react for 90 minutes at said temperature. The reaction solution was then cooled to -20 ° C, and a solution of 0.70 g of 6-aminopenicillanic acid triethylamine salt and 0.31 ml of tri-'-' ethylamine in 5 ml of methylene chloride was gradually added dropwise thereto. This mixture was allowed to react at -20 ° C for 1 hour, at -20-0 ° C for 1 hour and at 0-5 ° C for 1 hour. The solvent was then removed under reduced pressure. The residue was dissolved in 10 ml of water and washed with 10 ml of ethyl acetate. The aqueous layer was combined with 15 ml of ethyl acetate, and the pH was adjusted to 2.0 with 2N hydrochloric acid while cooling with ice. After separating the ethyl acetate layer, washing with water, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure, 0.7 U g of 6- (T) (-) - (<- (U-methyl-2,3-dioxo-1-piperazinocarbonylamino)) was obtained. -1, U-cyclohexa-ylene] Lasetamido / penicillanic acid as white crystals, m.p. 8U-87 ° C (decomposes), island Lo 87% · 59 63760 IR (KBr) cm -1:? C = 0 1780 (lactam), δ 730-1660 (-C00H, -CON <1.) NMR (dg-DMSO ) T-values; 0.55 (1H, d), 0.95 (1H, d), 1 +, 22 (1H, s), 1 +, 35 (2H, s).

1 +, 1 + 1-1 +, 61 (2H, s), 1 +, 92 (1H, d), 5.75 (1H, s), 6.05 (2H, bs), 6.1 + 0 (2H, bs), 7.03 (3H, s), 7.35 (1 * H, s), 8.1 + O (3H, s), 8.52 (3H, s).

When this product was neutralized with aqueous sodium hydrogencarbonate solution pH 7, and then filtered and lyophilized, the sodium salt of the product was obtained.

When the above procedure was repeated, D (-) -? - (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) -1,1 + -cyclohexadienylacetic acid was replaced by the compounds of formula (V) listed in Table 11+, the final products shown in Table 11+ were obtained. The structure of the final products was confirmed by IR and NMR.

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Example 14 (1) To a solution of 2.2 g of DL-o-amino-2-thienylacetic acid in 1 ml of 1N sodium hydroxide solution was added at 0 ° C 2.2 g of triethylamine. To this solution, 3.6 g of t + -methyl-2,3-dioxo-1-piperazinocarbonyl chloride was gradually added at this temperature. The mixture was then allowed to react at 0 ° C for 30 minutes and then at room temperature for 30 minutes. When the pH of the solution was adjusted to 1.0 with dilute hydrochloric acid after completion of the reaction, crystals separated. After the crystals were collected by filtration, washed with water and dried, 3.5 g of LL-α- (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid were obtained, m.p. 211 + -215 ° C (decomposes), yield 80.5%, IR (KBr) cm-1: p 1710, 1680-1660.

(2) When a solution of 1.86 g of the above-mentioned DL-ofc- (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid in 100 ml of acetone was added dropwise. Sodium salt of 2-ethylhexanoic acid in 50 ml of acetone, crystals separated. The crystals were collected by filtration and washed with acetone to give 3.5 g of the sodium salt of DL-title- (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid, m.p. 1T5-176 ° C (decomposes).

(3) To a suspension of 3.3 g of the above-mentioned sodium salt of DL-ofc- (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid in 50 ml of methylene chloride was added 30 mg of N-methylmorpholine, and thus the resulting mixture was cooled to -20 to -15 ° C. A solution of 1.3 g of ethyl chlorocarbonate in 20 ml of methylene chloride was added dropwise to this mixture over 5 minutes, and the mixture was stirred at this temperature for 90 minutes. A solution of 3.3 g of 6-aminopenicillanic acid triethylamine salt in 50 ml of methylene chloride was then added dropwise to the mixture over 20 minutes at -50 to -1 + 0 ° C, and the resulting mixture was stirred at -1 + 0 to -30 ° C. 30 minutes, -30 to -20 ° C for 30 minutes and -20 to 0 ° C for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in water. When the pH of this aqueous solution was adjusted to 2.0 with dilute hydrochloric acid while cooling with ice, crystals separated. When the crystals were collected by filtration, washed with sufficient water and dried, 1+, 1 g of 6-ο (- (1 + -methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetamido] penicillanic acid, m.p. 185 DEG C. (decomposition) was obtained. ), yield 80.5%> IR (nujol) cm-1r ^ c = 0 1780 (lactam), 1715 (-C00H), 1685-1675 (-C0N) NMR / TCD3) 2CO7 T-value 0.5 (1H ), 1.8 (1H), 2.6 (1H), 2.85 * 3.05 (2H), U, 0 (1H), 1 +, 2-1 +, 5 (2H), 5.7 (1H), 5.8-6.0 (2H), 6.2-6.1 + (2H), 6.95 (3H), 8.1+ (3H), 8.1 + 5 (3H) .

62 63760

When the product thus obtained was neutralized with aqueous sodium hydrogencarbonate solution to pH 7.0 and then filtered and lyophilized, the sodium salt of the product was obtained.

When the procedure described above was repeated so that the sodium salt of DL- (t- (k-methyl-2,3-dioxo-1-piperazinocarbonylamino) -2-thienylacetic acid was replaced by the compounds of formula (V) listed in Table 15, the corresponding compounds shown in Table 15 were obtained. The end products. The structure of the final products was confirmed by IR and NMR.

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Example 15

To a suspension of 0.9 g of 6 - [(-) - O-aminophenylacetamido] penicillanic acid in 30 ml of anhydrous ethyl acetate was added 0.55 g of triethylamine at 0.6 ° C and 0.6 g of After reacting this mixture for 3 hours at 15-20 ° C, trimethylsilylated 6- [b (-) - CX-aminophenylacetamido] -7-penicillanic acid was formed. To this acid was added 1 g of ethyl-N, dioxo-1-piperazino. carbonyl chloride, and the mixture was allowed to react for 2 hours at 15-20 ° C. When the triethylamine hydrochloride separated in the reaction was filtered off, and 0.1 g of n-butanol was added to the filtrate, crystals separated. After the crystals were collected, 1.25 g of 6- [D (-) -? - (1 '- ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamide] penicillanic acid were obtained as white crystals. These crystals were dissolved in 30 ml of tetrahydrofuran, and when a solution of 0.38 g of the sodium salt of 2-ethylhexanoic acid in 10 ml of tetrahydrofuran was added dropwise to this solution, white crystals separated. After the crystals were collected by filtration, washed sufficiently with tetrahydrofuran and dried to give 1.25 g of the sodium salt of 6- [D (-) -? - (U-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamide] penicillanic acid, m.p. 183-185 ° C (dec.), Yield 90%.

Using the procedure described above, but substituting the compounds mentioned below for trimethylsilyl chloride, the sodium salt of 6- [D (-) -? -. 1- (1 '-ethyl-2,3-hydroxy-1-piperazinocarbonylamino) -phenylacetamido] penicillanic acid was obtained.

Compound Yield of final product (CH 3 O) 3SiCl 80% (C 2 H 2 O) 2PCl 75% -0 \ PCI 82%

"B

r ~ \ {PCI 80% \ -o '

Example 16

To a suspension of U g of 6- / D (-) - o (.-Aminophenylacetamido) penicillanic acid trihydrate in 1 x 0 ml of water was added 20 ml of ethyl acetate, and this mixture was cooled to 2 ° C. g of potassium carbonate and stirred for 2 minutes at 2-3 [deg.] C. 1.89 g of N-methyl-N, N-dioxo-1-piperazinocarbonyl chloride were then added to the mixture at this temperature over 10 minutes, and the resulting mixture was allowed to react at this temperature for 15 minutes. After 65,63760, a small amount of insoluble matter was filtered off, and the filtrate was poured into 80 ml of ethyl acetate.

After the crystals were collected by filtration, they were washed twice with 1 * ml of water and then twice with 1 * ml of isopropanol and dried to give 1.0 g of (-) - oC- (1-methyl-2,3-dioxo-1). -'-piperazinocarbonylamino) phenylacetamido (p-silanoic acid dihydrate, m.p. 156 DEG-157 DEG C. (decomposition), yield 75.1 *% · IR (KBr) cm @ -1: 1775, 17 DEG C. , 1695, 1.70 NMR (d 6 -DMSO) T values: 0.18 (1H, d), 0.77 (1H, d), 2.66 (5H, s), 1 *, 30 (1H, d), 1 », 1 * 0 (3H, hr), U, U8 (1H, g), U, 65 (1H, d), 5.00 (1H, s), 6.12 (2H, bs) , 6.1 * 5 (2H, bs), 7.06 (3H, s), 8.1 * 8 (3H, s).

When the above procedure was repeated so that 1 * -methyl-2,3-dioxo-1-piperazinocarbonyl chloride was replaced by 1 * -ethyl-2,3-dioxo-1-piperazinocarbonyl chloride, δ-Di-J-ot was obtained. U-ethyl (N (dioxo-1-piperazinocarbonylamino) phenylacetamido) penicillanic acid monohydrate, m.p. 15 DEG-156 DEG C. (decomposition), yield 8 kt8%.

IR (KBr) cm -1: 1 C = Q 1775, 1735, 1705, 1680, 1665 NMR (d 6 -DMSO) T values: 0.20 (1H, d), 0.76 (1H, d), δ , 69 (5H, s), 1 *, 32 (1H, d), lt, 53 (1H, g), 1 *, 61 * (1H, d), 5.00 (3H, br), 5.83 (1H, s), 6.13 (2H, bs), 6.1 * 9 (2H, bs), 6.62 (2H, g), 8.1 * 1 »(3H, s), 8.58 (3H, s), ), 8.91 (3 H, t).

When the monohydrate thus obtained was neutralized with aqueous sodium hydrogencarbonate solution, filtered and lyophilized to give the sodium salt of 6 - [(-) - O- (1- * ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamide] penicillanic acid.

In addition, a solution of 2 g of the above-mentioned 6- [ρ (-) - <- (1 * -methyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido] penicillan was added. acid dihydrate in 10 ml of nitromethane, stand overnight, crystals separated which were collected to give 2 g of 6-Z -> (-) - oC- (1 * -methyl-2,3-dioxo -] - piperazinocarbonylamino ) phenylacetamido7penicillanic acid nitromethane adduct monohydrate, m.p. 128-130 ° C (decomposes), yield 92.2%.

Elemental analysis (C22H25N507S * CH3NO2'H2O4

Calculated {%): C 1 * 7.1 * 2 H 5.19 N 1U, 1 * 3 Found {%): C 1 * 7.9 ** H 5.13 N 1U, 53 IR (KBr) cm -1 1: ν Q = Q 1770, 1735, 1700, 168 δ NMR (d 6 -DMSO) T values: 0.22 (1H, d), 0.80 (1H, d), 2.69 (5H, s), 3.30 (3H, br), 1 *, 30 (lit, d), 1 *, 1 * 6-1 »JO (211), 5.67 (311, s), 5.81 (lii, s) , 6.13 (2H, bs), 6.1 * 6 (2H, bs), 7.07 (3H, s), 8.1 * 5 (3H, s), 8.58 (3H, s).

6 3 7 6 0 66

Example 17

To a suspension of 1.6 g of D (-) - Λ-aminobenzylpenicillin trihydrate in 20 ml of water was added 0.5 g of potassium carbonate at 2-3 ° C, and the resulting mixture was stirred for 3 minutes. over a period of 1 minute at this temperature gradually 0.8 [mu] g of ethyl 2,3-dioxo-1-piperazinocarbonyl chloride, and the mixture was allowed to react for 15 minutes. After the reaction, a small solid was filtered off, and the filtrate was poured into 10 ml of methyl n-methylene chloride. When 1.98 ml of 2N HCl was added dropwise to this mixture over 2 minutes at 15-20 ° C, and the mixture was stirred at this temperature for 1 hour, the crystals separated, and when the crystals were collected by filtration, they were washed twice with water and then twice with methylene chloride. n-propyl ketone and dried to give 1.7 g of D (-) - c * - (U-ethyl-2,3-dioxo-1-piperazinocarbonylamino) benzylpenicillin monohydrate, m.p. 152-15 U ° C (dec); 80.2%,

When this product was neutralized with aqueous sodium hydrogencarbonate solution, filtered and lyophilized, the sodium salt of the product was obtained.

Claims (3)

67 63760 1. A process for the preparation of new therapeutically useful penicillins of the formula <χ) AN NC-NH-CH-CONH-if ΓΝη »(τι \ />» »o oH-, VlJ N -kcOOR (R2) m where R ^ is a hydrogen atom, a salt-forming cation or a phthalidyl, methoxymethyl, pivaloyloxymethyl, γ-piperidinoethyl or γ -morpholinoethyl group, n is 1 or 2, X is an oxygen atom attached to the carbon atom of the piperazine ring 2 2- and / or 3- in the position, m is 0 or 1, R is a methyl group, A is a C 1-4 alkyl group which may be substituted by chlorine or acetoxy, or allyl, C 1-8 cycloalkyl, phenyl, a benzyl or C 1-4 alkanesulfonyl group and R 3 is a phenyl, hydroxyphenyl, cyclohexadienyl or thienyl group, characterized in that (a) a compound of the formula S CH R -N 11 -CH-CONH R 3 I '3a is obtained ( II) - N - '"- COOR 1a where R is a hydrogen atom, a salt-forming cation or in the case of penicillins. U. ....... ... ... a known protecting group, R is a hydrogen atom or contains silicon or phosphorus group and 3 ... R: 11a has the meaning given above, to react with a reactive carboxyl derivative of a compound of formula (x> „AN NC-OH (III) W o (R2) m, wherein in formula 2 A, X, R, n and m are as defined above, or (b) a compound of formula k / SX / CH3 ί— <iv> (VN ^ COOR1a 68 6 3 7 60. rA and U wherein R and R are as defined above, to react with a compound of formula U) I n A AN NC-NH-CH-C-OH (V) v + ys * 3'o (r2) m or a reactive carboxyl derivative thereof, wherein 2 3 in formula A, R, R, X, n and m are as defined above; • »Ί £ L after which, if desired, the protecting group R is removed. Method according to Claim 1, characterized in that 3. .. .... R is a phenyl group, n is 2, m is 0, X is attached to the atoms 2 and 3 of the piperazine ring, A is an ethyl group and is a hydrogen atom or a cation forming a non-toxic salt. 69 63760 1. A method for the therapeutic use of a penicillin with the form of (X> n / "\ S CH AN NC-NH-CH-COM-t- ^ / T, v; h3 Π-Ρ, (r2} (f ^ COOR m color is not an atom, a salt cation or a phthalidyl, methoxymethyl, pivaloyloxymethyl, / S-piperidinoethyl or / -morpholinoethyl group, n 1 or 2, X is a cyanogen atom, each of which is a compound having a piperazine ring in the form of 2 2 och / or 3, m is 0 or 1, R is an methyl group, A is a C 1-4 alkyl group, each of which is substituted with chlorine or acetoxy ; eller en allyl-, C g-cycloalkyl-, 3. phenyl, benzyl or β-alkanesulfonyl group and R or en phenyl, hydroxyphenyl, cyclohexadienyl or thienyl group, the corresponding compounds being treated with man (a) for the preparation of the formula Λκη-ch-coito -, - f "(II) o ^ 'N ^ COOR1a 1 8r color R är en väteatom, en saltbildande katjon eller en pä penicillinomrädet känd skyddsgrupp, R ^ är en väteatom eller en grupp innehallande kisel eller phosphor och 3 R is anhydrous form with a reactive carboxylate in the formulation || ; n ^ A-N N-C-OH (III) v + y s (B2) m o color A, X, R, n and m in which the sample is the same, or (b) is the same as in the formula) | CH ,, R -Nil ___..... 3 I Cll ^ (IV) Jr-- N · ^ COOR1 a