SU1326195A3 - Method of producing 7-/2-(2-aminothiazole-4-yl)-/z/-2-(2-carboxy-prop-2-oxyimino)acetamido/-3-/(1-methyl-1-pyrrolidinium)methyl/-3-cephem-4-carboxylate - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular 7- 2- (2-aminothiazol-4-yl) -g3-2- (2-carboxyprop-2-oxyimino) ai, etamido -3 | (1-methyl-1-pyrrolidinium) methyl-3-cep-4-carboxylate (CK), which exhibits antibacterial activity that can be used in medicine. The goal is to create more active substances of the specified class. Preparation of CK is from a) a mixture of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, (2-tert-butoxycarbonyl-prop-2-oxyimino) -2 :-( 2-tritylaminothiazol-4-yl) acetic acid, dicyclohexylcarbodiimide and N-hydroxybenztriazole in an organic solvent to form the benzhydryl ester 3-chloromethyl-7-

Description

The invention relates to the chemistry of heterocyclic compounds, in particular, to methods for preparing a novel (2-aminothiazol-4-yl) (2-carboxypropane-2-oxyimino) acetamido J-3- (i-methyl-1-pyrrolidinium) methylj-3 -cepheme-A-carboxylate formula

S (I) J-C-CONY -p-f @.

 H2 NAs /) CQO

HjC-fcH

soon

melting at 160 ° С (decomp.), exhibiting high antibacterial activity, which can be used in medicine.

The aim of the invention is to create, on the basis of known methods, a method for the preparation of new compounds with pharmacological properties.

Synthesis of 1.

7-anino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester.

To the PC1 suspension. (8.3 g, 40 mmol)

in CH C1. (100 ml) pyridine (3.2 g, 40 mmol) was added and the mixture was stirred for 20 minutes at 20 ° C. The 3-hydroxymethyl-7-phenylacetamido-3-defem-4- benzhydryl ester was added to the mixture for 20 minutes. carboxylic acid (5, g, 10 mmol) with stirring at -40 ° C in one portion. The mixture is stirred at -10 ° C for 15 minutes and left to stand for 7 hours at -15 ° C. To the cooled solution of f-20.C) add -; - propane-1,3-diol (10 ml) is added and the mixture is left to stand for 16 hours at -20 ° C, and then stirred for 20 minutes at room temperature. The resulting solution was washed with ice-water (2 x 20 ml) and saturated aqueous NaCl (0 ml), suspended over MgSO4 and concentrated in vacuo. The rubbery residue (12 g) was dissolved in a mixture of CHCl j and n-hexane (2: 1) and chromatographed using a silica gel column (200 g) and the same solvent as eluent. Fractions containing the desired compound are evaporated in vacuo and the residue is triturated with n-hexane to obtain the desired product; (2, g ,, 51%), melting point PO C (with decomposition).

0

15

0

25

thirty

gg 40 g 50 55

IR spectrum A} KBG, cm-: 3400, 2800, 1785, 1725.

UV spectrum ,,,. (EtoH) 265 nm (EV cm 160).

NMR d (DMSO-a (, + SVS1z), ppm: 6a, 6 (2H, s); 4.43 (2H, s); 5.09 (1H, d, 5 Hz); 5.24 ( W, d, 5 Hz), 6.87 (H, s); 7.3 (10, m).

Example I. (2-Aminoithiazol-4-yl) - g7-2- (2-carboxyprop-2-oxyimino) acetamido-3- (1-methyl-1-pyrrolidinium) methyl - 3-cephem-4-carboxyl.

A. Benzhydryl ester of 3-chloromethyl-7-Z-2- (2-tert-butoxycarbonyl-prop-2-oxyimino) -2- (2-trito-amino-thiazol-4-yl) acetamido-3-cephem- 4-carboxylic acid.

Method 1.

A mixture of (2-tert-butoxycarbonyl-prop-2-oxyimino) -2- (2-tritylamino-noiazol-4-yl) acetic acid (1.94 g, 3.6 mmol) of dicyclocarbodimimide (DCC) (742, mg, 3.6 mmol) and N-hydroxybenzotriazole (486, mg, 3.6 mmol) in tetrahydrofuran (THF) is stirred at room temperature for 45 minutes, during which the dicyclohexylmoramine is separated. Dicyclohexyl urea is removed by filtration and the filtrate is mixed with 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (1.5 g 3.6 mmol). The mixture is stirred overnight at room temperature and then evaporated in vacuo. The residual oil is dissolved in CHCl1 (20 ml), washed with saturated aqueous NaHCOj and saturated aqueous NaCl, dried over MgSO4, and evaporated to a dry residue. The residue (3.9 g) was dissolved in n-hexane: CHC1 (1: 2) and passed through a silica gel column (40 g) using the same solvent system. The fractions containing the desired compound are evaporated to give 1.3 g (39%) of the product melted at a temperature above (decomp.).

Zh-spectrum (KVg), cm: 3990, 1790, 1715, 1690.

UV spectrum Lmix. (EtoH) nm: 240 (280), 265 (EV ° 190).

NM with / - (CDC1 j), ppm:, 45 (9H, s), 1.63 E 1.66 (6H, every s), 3.49 (2H, broad s), 4.34 (2H , s), 4.96 (1H, d, 5 HZ), 5.90 (1H, dd, 5 and 7.5), 6.66 (W, s), 6.86 (W, s) .

, 3 13261954

7.0-7.5 (25H, m), 8.23 (IH, d J NMR o (), ppm: 1.44 (9H, s),

7.5 H) .1.65 (6H, s), 3.54 (1H, 4.28 (2H, s),

Method 2.4.98 (1H, d, 5 N), 5.85 (N, dd,

A solution of benzhydryl ether, 5 and 7.5 N), 6.70 (1H, s), 6.90 (1H,

amino-3-chloromethyl-3-cephem-4-carbono-c), 7.1-7.5 (25H, m),

acid (1.86 g, 4.49 mmol) of BC. (2-amino-trekol-4-yl-7. (46.5 ml) are treated with BSA2- (2-carboxyprop-2-oxinmino) acetates (3.33 MP, 13.5 mmol) at room-to-3-L (1 methyl -I-pyropolydine) temperature for 50 min from hectyl-3-cephem-4-carboxyl ylate.

a clear solution. To the rast-mixture of benzhydryl ether 7-Z, a solution of an acid chloride 2- (2-tert-butoxycarbonyl-1-hydroxyimic acid, which is obtained from but) -2- (2-tritylaminothiazol-4-yl) acetic acid (2-tert- butoxycarbonyl-2-hydroxy-amido-3-iodomethyl-3-cephem-4-carbon-imino) -2- (2-tritylaminothiazol-4-yl) g howl 1 $ of acid (538 mg, 0.51 mmol) and

acetic acid (2.56 g, 4.49 mmol) of N-methylpyrrolidine (0.079 ml,

and PClj (1.12 g, 5.38 mmol) in meth-0.076 mmol) in (10.8 ml) of left chlorine (26 ml). The mixture was stirred at room temperature for half an hour at room temperature, and then the mixture was poured into cold water for 30 hours in ether (80 ml). Forming (100 ml) and extracting ethyl acetate with the precipitate collected by filtration and volume (3x50 ml). The combined ex-washed with ether to obtain 420 mg tracts are washed with aqueous NaCl to dry the Quaternary product, which is concentrated and evaporated. The residual syrup (5 g) was worked up with 90% trifluoroacetic chromatography on a 25 g silica gel (TFA) column (4.2 ml) at room temperature (100 g) with elution at 10: 1 temperature for 1 hour. Then, a mixture of toluene and ethyl acetate. The frac-mixture is evaporated to dryness, containing the desired compound, the residue. Ether is combined with the residue and evaporated to give a crude TFA salt of the compound.

.2,84 g (65%) benzohydryl ester zo - quantitative yield),

3-butoxycarbonyl-2-oxyimino-2-which is a 1: 4 mixture

(2-Tritylaminothiazol-4-yl) acetamido isomers of l and / 1. The crude product C-cephem-4-carboxylic acid is refined by the method GHWT (LiHB. Benzhydryl ester of 7-Z-2-rosorb RP-I8, 4 x 300 mm, eluoride (2-tert-butoxycarbonylprop-1-hydroxy-out 0 , 01M ammonium phosphate buffer

imino) -2- (2-tritylaminothiazol-4-yl) (pH 7.0), containing 10%).

 acetamido-3-iodomethyl-3-cephem-4-car-1 Fraction containing the desired product,

bonic acid. G ... Chose and evaporated to small

A mixture of benzhydryl ether volume. The concentrate is adjusted to pH by about 2- (2-tert-butoxycarbonyl-Prop-1-oxido 2 by adding 1 M HCl and passing through imine) -2- (2-trithlaminothiazol-4-yl) through an HP-20 column. (2x15 cm) acetamido} -3-chlorometh-1-3-cephem-4-to remove inorganic salts. carboxylic acid (500 mg, 0.53 mmol) The column is washed (1000 ml) and ri Nal (240, mg, 1.6 mol) in acetone. Elute 30%. The eluant was evaporated (3 ml) with stirring for 1 h at room temperature and lyophilized to give 21 mg of temperature, and then evaporated in (10%) of the desired product as a vacuum. The CH2 Cl colored powder is added to the residue. M.p. 160 ° C (decomp.). (20 ml) and water (10 ml). Organic IR spectrum l) DDCBr), cm: 3400, the layer is washed with 10% (vol.) Solution 1775, 1610.

sodium thiosulfate (5 ml) and water UV spectrum Dm "x phosphate buffer pH

NaCl (5 ml), dried over MgSO4 and UPA-7 ((1 237 (15700), 257 (155500).

dredged to a dry residue with obtaining-NMR with (), ppm: 1.65 (6H, s),

I eat 540 mg (90%) of the product in the form of amorph-2,3 (4H, m), 3.09 (3N, s), 3.6 (4H, m),

powdered powder, mercaptate at, 0 (2H, m), 5.44 (W, d, 8H),

(different). .

IR spectra l) a (KVg), cm: 3350, Pharmaceutically acceptable salts

1790, 1690. Compounds of formula (I) include salts

UV spectrum of Dmake (EtoH): 240 (for omorganic bases, for example

270), 265 (E 190). salts of alkaline MeTajtnoB (in particular,

I

513261

sodium and potassium salts) and alkaline earth metal salts (in particular calcium soybeans), ammonium salts, organic bases (for example, using triethylamine 1, procaine, enethyl benzylamine, dibexile ethylene diamine and other organic bases used in the manufacture of penicillin and cephaloszorins), acid addition salts (for example, 10 salts with hydrochloric, hydrochloric, formic, nitric, sulfuric, methanesulfonic, phosphoric acetic or trifluoroacetic acid) and other acids that are used are in- producing penicillins and cephalosporins. Physiologically hydrolysable esters include acyloxyalkyl esters, for example (lower) alkanoyl) lower) alkyloxy esters, such as acetoxymethyl, acetoxyethyl, pivaloyloxymethyl, and the like. Base salts and esters can be formed | With any carboxyl groups of the compounds of formula (I).

The compounds of formula (1) exhibit high antibacterial activity of rf against gram-positive and gram-negative bacteria and are suitable for the treatment of bacterial infectious animals, as well as humans. The compounds of formula (I) can be used in the preparation of preparative forms intended for use parenterally, in the usual way using known pharmaceutical carriers and ex-dienes, and can be presented as unit dosage forms or as multiple dosage forms. same dosage forms. Positions may be presented as solutions, suspensions or emulsions in oily or aqueous diluents, and may contain conventional dispersing, suspending and stabilizing agents. Compositions may also be presented in a dry powder dosing unit, intended for a dp dilution before use, for example, sterile water that does not contain pyrogenic substances. The compounds of formula (I) may also be formulated as candles, using the usual bases for this purpose, such as cocoa butter, 55 cocoa or other glycerides. If necessary, the compounds according to the invention may be prescribed in Co95-6.

with other antibiotics, such as penicillins or other cephus losporins,

In the case of preparation in the form of unit dosage forms, the composition preferably contains 50 to 1500 mg of the active ingredient of formula (I). For the treatment of adult humans, the dosage is preferably 500-5000 mg per day, depending on the frequency and method of administration. In the case of intramuscular or intravenous administration to an adult, the full dose normally ranges from 750 to 3000 mg per day in the form of separate dosages, although some compounds may require a higher daily dose in the case of infections by bacteria of the genus Psendomonas.

During the initial evaluation of the compounds according to the invention, the minimum inhibitory concentration (MIC) of dp compounds and two compounds for comparison (cefotaxime and ceftazidime) op-. were determined by the method of double dilution of agar using No.oller-Hinton agar for 32 strains of test organisms divided into six groups. The geometric mean MIC values determined in this experiment are shown in the table.

Ue-fpomaxtUM§

 N-rr-C-CONH-r-f

 UNODC

ceftaziZim

-; j-C C014H-i- (Jji, -r.0

W-rH,

II

N

N

ABOUT

coo

H C-C SNt

Cun

Tests were also conducted to detect organisms resistant to the compound of formula (I), cefotaxime and ceftazidime. The MIC values for these three compounds against 240 strains of Euterobacteriapeae are determined in the Müller-Hinton medium, and the MF value equal to or exceeding 8 for at least one of the tested compounds is arbitrarily taken as evidence of organism resistance. Of the 240 strains, 27 were resistant to at least one of the tested compounds. Compound

(I) is more active than cefotaxne in relation to group (G) G of the test organisms and much more active than cefotaxime in relation to group (G-) - (III) of test organisms (Ps.aeruginosa). It is more active than ceftazidime in relation to all groups of gram-positive subjects. organisms, excluding (G-) - (III) (PS. aeruginosa), which are somewhat more sensitive to ceftazidime.

Thus, the inventive method allows to obtain compound (I) with valuable pharmacological properties.

F o r mula a

from gain

The method of obtaining (2-amino-α. -Azol-4-yl) (2-carboxyprop-2oxyimino) acetamido-3- (I-methyl- - pyrrolidinium) methyl} -3-cephem-4-carboxylate, melting at (decomposition, ):

N-rr-C-CCfNH

N-C-CCfNH-T-r -l @

M s 0coo ci

H C-f-CH

soon

about

sn

Recognized by the fact that the mixture of benzhydryl ether 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid

(G - "-) - Ia 1 (5 strains):

(G +) -1b (5) (G -) - Ia (5) (G -) - Ib (6) (G -) - II (5) (G -) - III (6) (G +) - Ia

(G +) - Ib

14

33

0.066

0.79

1.2

4.0

1.0 2.2 0.015 0.35

4.1 22

5.1

12

0.070

1.7

2.6

1.8

Penicillin-sensitive S.aureus (5 strains)

Penicillin-sensitive S.aureus (5 strains)

d

five

0

five

0

195 "

lots, (2-tert-butoxycarbonyl-prop-2-oxyimino) -2- (2-tritylamino-thiazol-4-yl) acetic acid, dicyclohexylcarbodiimide and N-hydroxybenztriazole are reacted in an organic solvent to give benzhydroxyhyl ether 3 - chloromethyl-7-g -2- (2-tert-butoxycarbonylprop-2-oxyimino) -2- (2-tri-tilimiNothiazol-4-yl) acetamido-3-cephem-4-carboxylic acid (compound Ii) or a mixture of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester and bis (trimethylsilyl) acetamide is reacted with the acid chloride (2-tert-buto sikarbonsh1prop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid to obtain compound (II), after which the compound (II) is reacted with sodium iodide to obtain benzhydryl ester (2-tert-butoxycarbonyl- prop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido-3-iodomethyl-3-cephem-4-carboxylic acid (compound III) and then compound (III) is subjected interaction with N-methylpyrrolidine in an organic solvent followed by removal of the protective groups by acid hydrolysis and isolation of the target product, melting state at (dec.).

5.1

12

0.070

1.7

2.6

1.8

(G -) - Ia (G -) - Ib

Sensitive to cephalotin E. coli (2 strains) K-1, pneumonias (i strain) and Pr.mirabilis (2 strains).

Resistant cephalotin E.coli (3 strains) and K1.pneumoniae (3 strains)

(G -) - II, (GI) -IIl. - average of 5 experiments.

Pr.morganii (I strain) Ent.cloacae (2 strains) and Ser.macescens (2 strains)

Ps.aeruginosa (6 strains)

Claims (1)

Claim The method of obtaining 7- [2- (2-aminothi.azol-4-yl) - [Z] -2- (2 ~ carboxyprop-2oxyimino) acetamido] -3- [(I-methyl-1'pyrrolidinium) methyl} - 3-Cephem-4-carboxylate, melting at 160 ⁶ ° C (decomp.): Н н ιί ~ ^ΰ0ΝΗ τ№1 ^Х о COO СН1 H ₃ C- | —CH ₃ SOON characterized in that, a mixture of 7-aminoZ-chloromethyl-3-Cephem-4-carbonic acid benzhydryl ether 1326195 8 lots, CZ] ~ 2 ~ (2-tert-butoxycarbonylprop-2-hydroxyimino) -2- (2-tritipaminothiazole ~ 4 ~ yl) acetic acid, dicyclohexylcarbodiimide and N-hydroxybenzotriazole are reacted in an organic solvent to produce benzhydrochloride ether -7 - [[g] -2- (2-tert-butoxy ₁ 0 carbonylprop-2-hydroxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido] -3 ~ cefem-4-carboxylic acid (compound II ) or a mixture of 7-amino-3-chloromethyl-3-cefem-4-carboxylic acid benzhydryl ester and bis (trimethylsilyl) acetamide is reacted with [Z] -2- (2-tert- butoxycarbonylprop-2-hydroxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid to give compound (II), after which compound (II) is reacted with sodium iodide to give 7-benzhydryl ether 7 - [[Z] -2 - (2-tert-butoxycarbonyl25 prop-2-hydroxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido-3-iodomethyl-3cefem-4-carboxylic acid (compound III), and further compound (III) is subjected interaction with N-methyl39 pyrrolidine in an organic solvent, followed by deprotection by acid hydrolysis and isolation of the target product, pl weight at 160 ° G (decomp.). Test subjects basics MIC, μg / ml, compounds compound (I) cefotaxime * ceftazidime * (G +) - Ia (5 strains): 14 1,0 5.1 (G +) -1b (5) sz 2.2 12 (G -) - Ia (5) 0,066 0.015 0,070 (G -) - Ib (6) 0.79 0.35 1.7 (G -) - II (5) 1,2 4.1 2.6 (G -) - III (6) 4.0 22 1.8 (G +) - Ia Penicillin-sensitive S.aureus (5 strains) (G +) - Ib Penicillin-sensitive S.aureus (5 strains) MIC, μg / ml, compounds Table continuation Test organisms compound ’(I) cefotaxime * ceftazidime * (G -) - Ia Cephalotin-sensitive E. coli (2 strains) K-1.pneumoniae (1 strain) and Pr.mirabilis (2 strains). (G -) - Ib Resistant cephalotin E. coli (3 strains) and KI.pneumoniae (3 strains) (0 -) - 11. Pr.morganii (I strain) Ent.cloacae (2 strains) (G-1) -111 and Ser.macescens (2 strains) Ps.aeruginosa (6 strains) [ average value of 5 experiments.