NL8300755A - CHEMICAL CONNECTIONS. - Google Patents

Description

* x * s «- 1.3 VO 4588

Chemical connections.

This invention relates to new cephalosporin derivatives of the formula 1 of the formula sheet, wherein R is hydrogen or 2 a conventional amino protecting group and R is a straight or branched chain alkyl group of 1-4 carbon atoms, allyl, 2-butenyl or a 5 group in which 3 '4

R-C-R

COOH

3 4 3

wherein R and R are each independently hydrogen, methyl or ethyl, or R.

4 and R taken together with the carbon atom to which they are attached are a cycloalkylidene ring having 3-5 carbon atoms, and non-toxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof. Processes for its preparation are also described.

British Patent No. 1,399,086 gives a general description of a large number of cephalosporins of the formula 18 to 15 of the formula sheet wherein R is hydrogen or an organic group, R is an etherifying monovalent organic group bonded to the oxygen via a carbon atom. B ^ S or ^ S—> O and P is an organic group. However, the 2-aminothiazol-4-yl group has not been identified as an R substituent and there is no suggestion that P may refer to N-20 methylpyrrolidiniummethyl (or any other fully saturated nitrogen-containing ring which, through its nitrogen atom, the 3-methyl unit is bonded and which contains an additional substituent on its nitrogen atom). U.S. Patents 3,971,778 and Nos. 4 024 133, 4 024 137, 4 064 346, 4 033 950, 4 079 178, 10 91 209, 4 092 477, and 4 093 803 give similar descriptions.

United States Patent 4,278,793 contains a general description of a large number of cephalosporin derivatives of the formula 19 of the formula sheet in which the variables R 1, R 1, R 1, R 1, X and A give general definitions of the corresponding substituents of the 30 compounds of formula 1 claimed herein, however, in the 20 columns definitions of the various substituent groups, the 78 page long table 8300755 PI »2 of structural formulas and the 225 examples, it is not described that A A-methylpyrrolidiniummethyl (or any other fully saturated nitrogen-containing heterocyclic ring), which is attached to the 3-methyl unit via its nitrogen atom and which contains an additional substituent on its nitrogen atom. British Patent No. 1 604 971 corresponds to this and gives an almost identical description. Published British Patent Application No. 2 028 305 A, although apparently not formally related, contains the same overall general description but, as Example A, provides only hydrogen.

The West German Offenlegungsschrift 2 805 655 discloses 7- [2- (2-aminothiazol-4-yl) -2- (syn) methoxyimino acetamido] cephalosporic acid derivatives of the formula sheet wherein 1 2 R NH an optionally protected amino group, R is halogen or an optionally substituted hydroxyl-thiol or amino group, and COOR is an optionally esterified carboxyl group. It is also disclosed that when 2 R is an amino group it can be disubstituted and that the substituents taken together with the N atom inter alia can form a pyrrolidino group. However, no mention is made of an N-methylpyrrolidiniummethyl group (or any other quaternary ammonium group) and substituent R cannot be bonded to the 3-position via a methylene group.

U.S. Patent No. 4,278,671 discloses 7- [2- (2-aminothiazol-1-4-yl) -2- (syn) -methoxy-iminoacetamido] cephalosporin derivatives of the formula ## STR2 ##, wherein R2NH an optionally protected amino group and R 1 is hydrogen or "the rest of a nucleophilic compound". The term. "remainder of a nucleophilic compound" is broadly defined and it is stated that R1 'may be a quaternary ammonium group. "Pyridinium, differently substituted pyridinium, quinolinium, picolinium and lutidinium are described as quaternary ammonium groups. There is no suggestion that the quaternary ammonium group may consist of a fully saturated nitrogen-containing heterocyclic ring system bonded via its nitrogen atom and containing an additional substituent on its nitrogen atom.

British Patent No. 1,581,854 corresponds to this and gives an almost identical description. Other patents from the same applicant, which are not fully related but which provide similar disclosures, include 8300755 - * 3, including U.S. Pat. No. 4,098,888 and its divisions, U.S. Pat. Nos. 4 203 899, 4 205 180 and 4 298 606 , and British Patent 1 536 281.

U.S. Patent No. 4,168,309 describes

5 cephalosporin derivatives of the formula 22 of the formula sheet, wherein R

a b is phenyl, thienyl or furyl; R and R are independently hydrogen, alkyl, cycloalkyl, phenyl, naphthyl, thienyl, furyl, cazboxy, alkoxycarbonyl or ab cyano, or R and R taken together with the nitrogen to which they are attached form a cycloalkylidene or cycloalkenylidene ring; 10 and m and n are each 0 or 1 such that the sum of m and n is 0 or 1; and R together with the nitrogen atom to which it is attached is broadly defined but may not be a saturated 5-ring inter alia. The compound has the formula 23 of the formula sheet, and is mentioned as an example in example V. British patent no. 1 591 439 is similar to this and gives an almost identical description. There is no suggestion in this patent that the R substituent may be the 2-aminothiazol-4-yl unit or that the imino substituent should not contain a carboxyl group.

This invention relates to cephalosporin derivatives of the formula 1 of the formula sheet, wherein R 1 is hydrogen or 2 a known amino protecting group, and R is a straight or branched chain alkyl group containing 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or 3 * 4 3 4 is a group R -CR, wherein R and R are each independently hydrogen, methyl or

COQH

3 4 25 are ethyl, or R and R taken together with the carbon atom to which they are attached may be a cycloalkylidene ring containing 3-5 carbon atoms, as well as non-toxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof. Also included within the scope of the invention are the solvates (including hydrates) of the compounds of formula 1, as well as the tautomeric forms of compounds of formula 1, for example the 2-iminothiazolin-4-yl form of the 2-aminothiazol-4-yl unit.

As shown in the structural formula, the compounds of formula 1 have the "syn" or "Z" configuration relative to the alkoxyimino (or alkenyloxyimino) group or the carboxy-substituted alkoxyimino group. Since the compounds are geometric isomers 8300755 * 4, some of the "anti" isomers may also be present. This invention includes compounds of formula 1 containing at least 90% of the "syn" isomer. Preferably, the compounds of formula 1 are "syn" isomers that are essentially free of the corresponding 5 "anti" isomers.

The pharmaceutically acceptable salts of the compounds of formula 1 include the inorganic basic salts, such as the alkali salts (eg, the sodium and potassium salts) and the alkaline earth salts (eg, the calcium salts), ammonium salts, organic basic salts (eg, triethylamine, procaine, phenethylbenzyl amine, dibenzylethylenediamine and other organic bases used in the art of penicillin and cephalosporin), and the acid addition salts (e.g., the salts with hydrochloric, hydrobromic, formic, nitric, sulfuric, methanesulfonic, phosphoric, or acetic acids ) and other acids used in the penicillin and cephalosporin techniques. The physiologically hydrolysable esters include the acyloxyalkyl esters, for example, (lower) al-kanoyl (lower) alkyl esters, such as acetoxymethyl, acetoxyethyl, pivaloyl-oxymethyl and the like. The basic salts and esters can be formed with any of the carboxyl groups of the compounds of formula 1. "

The compounds of formula 1 wherein R * is hydrogen exhibit high antibacterial activity against various Gram positive and Gram negative bacteria and are effective in the treatment of bacterial infections of animals and humans. The compounds of formula 1 can be formulated for parenteral use in conventional manner using known pharmaceutical carriers and diluents and can be formed into unit dosage forms or multi-dose containers. The composition may be in the form of solutions, suspensions or emulsions in oily or aqueous carriers and may contain conventional dispersing, suspending or stabilizing agents. The compositions may also be in the form of a dry powder which is prepared before use with, for example, sterile pyrogen-free water. The compounds of formula 1 can also be formulated as suppositories using a conventional suppository base, such as cocoa butter or other glycerides. The compounds of this invention are 8300755 «. If desired, it can be administered in combination with other antibiotics such as penicillin or other cephalosporins.

When supplied in unit dosage forms, the compositions will preferably comprise about 50 to about 1500 mg of the active ingredient of formula 1. Preferably, the dose for adult humans will be in the range from about 500 to about 5000 mg per day depending on the frequency and route of administration. When administered intramuscularly or intravenously to adults, a total dose of about 750 to about 3000 microns per day in 10 divided doses will normally suffice, although in the case of Pseudomonas infections higher daily doses of some of the compounds may be desired.

The preferred compounds of formula 1 are those 1 2 3 4 wherein R is hydrogen and R is methyl or ethyl and R and R are each independently hydrogen or methyl. In the preferred compounds, R is methyl 34 or R and R are each methyl. In the primary evaluation of the compounds of this invention, the minimal inhibitory concentrations (MRCs) of the compounds and the two reference compounds (cefotaxime and ceftazidime) were determined by the dual agar dilution method in 20 Mueller-Hinton agar against 32 strains of test organisms in six groups. The geometric mean of the MRCs determined in this test is given in Tables A and D.

(See formulas 24, cefotaxime; for comparison and 25, ceftazidime, for comparison to formula 1, the test compounds).

It can be observed that all test compounds were more active than cefotaxime against the (G -) - II and (G -) - III groups of test organisms, with the most preferred compound Ia being clearly more active. All test compounds were more active than ceftazidime against the (G +) - Ia and (G +) - Ib groups of test organisms, with the most preferred compound la being significantly more active than ceftazidime against all groups of test organisms except (G- III, which was somewhat more sensitive to ceftazidime.

The absorption of the most preferred compound Ia and reference compounds (cefotaxime and ceftazidime) were determined in mice after a single intramuscular injection of the test compound (dissolved in µM phosphate buffer; pH 7) at a dose of 20 mg Ag . Blood 8300755. 6 samples were collected from the orbital cavity in heparinized capillary tubes and analyzed in Mueller-Hinton medium using Morganella Morganii A9695 as test organism. The blood levels at different time intervals, the half-life values (t ^) and the areas under the curve (AUC) are listed in Table B.

Tests to identify organisms resistant to the preferred compound of formula la were also performed with cefotaxime and ceftazidime. The MRC of these three compounds against 240 strains of Enterobacteriaceae were determined in a Mueller-Hinton medium and an MRC equal to or greater than 8 for at least one of the test compounds was randomly selected as an indication of a resistant organism. Of the 240 strains, 27 were found to be resistant to at least one of the test compounds. The results, which indicate 3 organisms resistant to compound 1a, 15 organisms resistant to ceftazidime and 18 organisms resistant to cefotaxime are listed in Table C.

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TABLE C

Resistance (MRC = è 8 .ug / ml) against one or more test compounds of 240 strains Enterobacteriaceae in Mueller-Hinton medium

Geometric mean MRC (^ ug / ml)

Organism Number * "T

5 _._ simming I Ia .__ Ceftazidime 1 Cefotaxime

Escherichia coli 1 0.25 32 8

Escherichia coli 14 0.5 8 10 Klebsiella pneumoniae 12 16 0.13

Enterobacter aerogenes 3 0.25 32 13

Enterobacter is -: - aerogenes 1 48 32

Snterobacter cloacae 1 0.13 4 8

Snterobacter / 20. cloacae / 3 0.5 40 50

Enterobacter cloacae 3 1.6> 63> 63

Enterobacter cloacae 1> 32> 63> 63 25 Citrobacter freundii 2 0.35 45 32

Citrobacter species 1 0.03> 63 32

Proteus 30 vulgaris 1 0.06 8 8

(^ organella J

inorganii 1 0.06 32 32

Serratia j marcescens 11 1 16 35 Serratia marcescens 12 8 16 l i 8300755 10 'TABLE, C (Continued) _ Geometric mean MRC (/ iig / ml)

Number · [] 7 ~. Organism strains 13 Ceftazidime Cs fOtaxims

Serratia 5 marcescens 2 2j8 2 11

Serratia * marcescens 14 8 63

Serratia marcescens 18 16 8 10 Serratia 1 marcescens · 1 32> 63> 63 ✓ -Total number of resistant 15 strains 27 3 15 18

See compound Ie of the formula sheet.

20 TABLE D

_ Geometric gem, from MRC (mcg / mL) _ _ Connection__

Trial Connection. ,. .

organism Ie Cefotaxime1 Ceftazidime1 25 (G +) -Ia (5 strains) 14 1.0 5.1 (G +) - Ib (5) 33 2.2 12 (G -) - Ia (5) '0.066 0.015 0.070 (G- ) -Ib (6) 0.79 0.35 1.7 30 (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: Penicillins-resistant S. aureus (5 strains) 8300755 11 (G -) - Ia ï Cephalotin-sensitive E. coli (2 strains ), KI. pneumoniae (1 strain) and Pr. mirabilis (2 strains) (G -) - Ib: Cephalotin resistant E. coli (3 strains) and KI. pneumoniae (3 strains) 5 (G -) - II ï Pr. Morgani (1 strain), Bat, cloacae (2 strains) and Ser.

Marcescens (2 tribes) (G -) - III: Ps. aeruginosa (6 strains) "(a) Average of 5 trials

It should be noted that the compound Ie was more active than cefotaxime against the (Ge -) - II group of the test organisms and markedly more active than cefotaxime against the (G -) - III group of the test organisms (Ps. Aeruginosa). He was more active than ceftazidime against all groups of Gram-negative test organisms with the exception of (G -) - III (Ps. Aeruginosa), which was more sensitive to ceftazidime.

In another aspect, the invention relates to methods of preparing compounds of formula 1. There are two basic procedures for converting an easily available starting cephalosporin into another cephalosprin with different substituents at the 7 and 3 positions . The 7 substituent can first be removed and replaced with the desired 7 substituent, and then the desired 3 substituent introduced. Optionally, the desired 3-substituent can be introduced first and subsequently the 7-substituent can be exchanged. The compounds of formula 1 can be prepared by either procedure, and both are within the scope of this invention, but it is preferred to first introduce the desired 7 substituent and then the desired 3 substituent. The preferred procedure is shown in reaction scheme A and the alternative procedure in reaction scheme B of the formula sheet. The abbreviation "Tr" represents the trityl (diphenylmethyl) group which is a preferred amino protecting group. Abbreviation "Ph" represents the phenyl group. Thus, the -CH (Ph) 1 moiety is the benzhydryl group, which is a preferred carboxyl protecting group. The reaction schemes C and D of the formula sheet show the preparation of compound (le) where 1 3 4 in R is hydrogen and R and R are each methyl.

While the above reaction schemes indicate preferred multi-stage 35 procedures for the preparation of the compounds of formula 1, it is understood that other starting materials and procedures can also be used to prepare the key stage of each reaction scheme. intermediates. Thus, the key step in reaction scheme A is the reaction of compound 7 with N-methylpyrrolidine. Compound 7 can be prepared by itself by other procedures. Similarly, the key stage in reaction scheme B is the acylation of compound 12 with compound 4. Both compounds 12 and 4 can be prepared by other procedures.

The key step in reaction scheme C is the reaction of compound 6a with N-methylpyrrolidine. Compound 6a can be prepared by itself via 10 other procedures. Similarly, the key stage in reaction scheme D is the acylation of compound 12 with compound 3a '. Both compounds 12 and 3a 'can be prepared by other procedures.

The present invention provides a process for the preparation of compounds of the formula 1, wherein R is a straight or branched chain alkyl group of 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or a group 4

_3 - C - R R

CQOR

3 wherein R and R are each independently hydrogen, methyl or ethyl or 3 4 R and R taken together with the carbon atom to which they are attached may be a 3-5 carbon cycloalkylide ring as well as non-pharmaceutically acceptable salts, physiologically hydrolyzable esters and solvates thereof according to which a compound 2 of the formula 14 of the formula sheet, wherein R has the aforementioned meaning, B is a known carboxyl protecting group and B is a known amino protecting group, is reacted with N-methylpyrrolidine to form a. compound with the formula. 15 of the formula sheet, and then all protecting groups are removed by conventional means, or a compound of formula 14a 3 4 of the formula sheet, wherein R and R have the above meanings, 13 2 30 B and B are conventional carboxyl protecting groups and B is a known amino protecting group, is reacted with N-methylpyrrolidine to form a compound of the formula 15a of the formula sheet, and subsequently all protecting groups are removed by conventional means.

The reaction is carried out in a non-aqueous organic solvent, such as methylene chloride, chloroform, ethyl ether, hexane ethyl acetate, tetrahydrofuran, acetonitrile and the like, or mixtures of such solvents. The reaction is conveniently conducted at a temperature from about -10 to about + 50 ° C; with normal preference being given to conducting the reaction at room temperature. At least one mole of N-methylpyrrolidine is used per mole of compound 14 or 14a; it is normally preferred to use a 50-100% excess of N-methylpyrrolidine.

Carboxy1-protecting groups suitable for use as B * and in the aforementioned reaction are known to those skilled in the art and include aralkyl groups such as benzyl, p-methaxybenzyl, p-nitro-benzyl and diphenylmethyl (benzhydryl); alkyl groups such as t-butyl; haloalkyl groups such as 2,2,2-trichloroethyl and other carboxy-1 protecting groups as described in the literature, for example in British Patent 1 399 086. It is preferred to use carboxy-protecting groups which are easily be removed by acid treatment. Particularly preferred carboxyl protecting groups are the benzhydryl and t-butyl units.

2

Amino protecting groups suitable for use as B are also known in the art and include the trityl group and acyl groups such as chloroacetyl. Preferred are amino protecting groups that can be easily removed by acid treatment, for example a trityl group.

The present invention also provides a process for preparing compounds of the formula 1, wherein R is a straight or branched chain alkyl group containing 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, or a group 3 4

R - C - R

COOH

3 4 wherein R and R are each independently hydrogen, methyl or ethyl, or 1 8300755 4 R and R taken together with the carbon atom to which they are attached may be a 3-5 carbon cycloalkylidene ring, as well as non-toxic pharmaceutically acceptable salts, physiologically hydrolyzable esters and sulfates thereof, according to which method a compound of the formula 16 of the formula sheet, or an N-silyl derivative%.

14 of wherein B * hydrogen is a known earboxyl protecting group, with an acylation derivative of an acid of the formula 17 of the formula sheet, wherein B is a known amino protecting group, and R has the aforementioned meanings, is acylated, whereby a compound is formed by the formula 15 of the formula sheet, and then all protective groups are removed or compound 16 or an N-silyl derivative thereof is acylated with an acylation derivative 2 of an acid of the formula 17a of the formula sheet, wherein B is a known amino protecting group, and B1 is a known carboxyl protecting group and R and R are each independently hydrogen, methyl or ethyl 3,4, or R and R taken together with the carbon atom to which they are attached can be a cycloalkenylidene ring having 3-5 carbon atoms to form a compound of the formula 15a of the formula sheet, and then all the protecting groups are formed. er-15 removed.

The acylation derivatives of the acid of formula 17 or 17a include the acid halides (and in particular the acid chloride), mixed acid anhydrides (such as the acid anhydrides formed with pivinic acid or a halogen formate such as ethyl chloroformate), and activated esters ( as can be formed with N-hydroxybenzthiazole in the presence of a condensing agent such as dicyclohexylcarbodixmide). . The acylation can also be carried out using the free acid of formula 17 or 17a in the presence of a condensing agent, such as dicyclohexy learbodilmide, carbonyldilmidazole or an isoxazolium salt.

As used herein, the term "acylation derivative" of the acid of formula 17 or 17a means the free acid itself in the presence of a condensing agent as described above. The preferred acylation derivative of the acid of formula 17 or 17a is the acid chloride used, for example, in the presence of an acidic binder (and in particular.

30, a tertiary amic acid binder, such as triethylamine, dimethylaniline or pyridine).

When the acylation is carried out with an acid halide, it is possible to use an aqueous reaction medium, although a non-aqueous medium is preferred. When acid anhydrides, activated esters or the free acid are used for the acylation in the presence of a condensing agent, the reaction medium should be non-aqueous. Particularly preferred solvents for the acylation reaction are halogenated hydrocarbons such as methylene chloride and chloroform, but tertiary amides such as dimethylacetamide or dimethylformamide can be used as well as any other conventional solvents such as tetrahydrofuran, acetonitrile and the like.

The activation reaction can be carried out at a temperature from about -50 to about + 50 ° C. However, it is preferred to run it at or below room temperature and most preferably at about -30 to about 0 ° C. It is usually preferred to acylate the compound of formula 16 with about a stoichiometric amount of the acylating agent of formula 17 or 17a, although a slight excess (eg 5-25%) of the acylating agent may also be used.

It is preferred that the compound of Formula 16 be acylated in the form of its N-silyl derivative (if a non-aqueous reaction medium is used). This is conveniently performed in situ by simply adding a suitable silylating agent (e.g. N, Pbistrimethylsilylacetamide) to the solution of compound 16 before adding the acylating agent 20 of formula 17 or 17a. It is preferred to use about 3 moles of silylating agent per mole of compound 16, although this is not critical. The silyl compound is easily removed after addition by addition of water.

The acylating acids of formula 17 or 17a including carboxyl and amine-protected derivatives thereof are known in the art or can be prepared according to known procedures. The (2) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylamino-thiazol-4-yl) acetic acid (3a) was prepared according to the general procedure described in U.S. Patent 4,258,041 and British Patent Application 30 2 025 398. The melting point mentioned therein was 152-156 ° C (decomposition), but this present compound melted at 174-175 ° C (decomposition). Preparation No. 1

See formula 3 of the formula sheet.

Ethyl (Z) -2-methoxyitirir> o-2- (2-tritylamlnothiazol-4-yl) -acetate (3a) 35 A mixture of ethyl (Z) -2-hydraxyimino-2- (2-tritylamino-thiazole) -4-yl) acetate (2) (5.00 g, 10.9 mmol), CH ^ X (2.04 ml, 8300 75 5 16 Λ * i 32.8 nmol) and I ^ COg (4.54 g, 32.8 mmol) in dry dimethyl sulfoxide (DMSO) (100 ml) was stirred at room temperature overnight and then poured into water (250 ml). The precipitate formed was collected by filtration, washed with water and dried to give the title compound (5.15 g, quantitative yield). Melting point 115 ° C (decomposition).

NMR: 1 CDCl 3 ppm 1.32 (3H, t), 3.98 (3H, s), 4.30 (2H, q), 6.42 (1H, s), 7.2 (1H, m), 7.25 (15H, s).

Compounds 3b, 3c and 3d were prepared according to the general procedure described above, but replacing the methyl iodide with the appropriate iodide.

2 (1) Compound R Yield (%) Melting Point (° C) Literature _ _ _ _ Smp. (° C) 3a methyl 100 115 ° (dec.) Approx. 120 ° (dec.) 15 3b ethyl 67 97-98 ° 36 3c isopropyl 26 51-55 ° x 3d allyl x x x X.

The ester was hydrolyzed without isolation.

^ Tetrahedron, 34, 2233 (1978).

20 Preparation No. 2

See formula 4 of the formula sheet.

(Z) -2-Methoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (4a)

The ethyl ester 3a, (6.00 g, 12.7 mmol) prepared in ethanol (120 ml), prepared in preparation No. 1, was treated with 2N NaOH (12.7 ml) at room temperature overnight. The reaction mixture was adjusted to pH 8 by addition of dry ice powder and the solvent evaporated under reduced pressure. The residue was dissolved in water (100ml) and the solution was acidified to pH 2 with 1N HCl then extracted with ethyl acetate (3 x 50ml). The combined extracts were washed with a saturated aqueous NaCl solution, dried and evaporated. The residue was crystallized from ethyl acetate-hexane to obtain 5.56 g (98% yield) of the title product (mp 138-143 ° C (decomposition).

. cnci NMR: 03 ppm 3.89 (3H, s), 6.52 (1H, s), 7.2 (15Ξ, s).

8300755 17

Compounds 4b, 4c and 4d were prepared according to the general procedure described above »

Compound Yield (%) Melting point Literature ^ _ (° C, dec.) Mp. (° C, dec.) 5 4a methyl 98 138 - 143 ca. 140 4b ethyl 85 140 - 145 not listed 4c isopropyl 85 166 - 169 ca. 170 3d allyl 66 170 - 178 ca. 170 (1) Tetrahedron, 34, 2233 (1978) 10 Preparation No. 3

Benzhydryl-3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate (8)

To a stirred suspension of phosphate buffer (pH 7, 152.5 ml) and wheat bran (20 g, dry) was added 7-phenylacetamidocephalosporanic acid sodium salt (5 g, 12.1 mmol) at one time at room temperature. The course of the reaction was followed by HPLC until the hydrolysis was completed (5 hours). The suspension was filtered to remove the wheat bran and the filtrate cooled to 5-10 ° C for extractive esterification. Methylene chloride (82 ml) was added to the cooled solution followed by a 0.5 M solution of diphenyl-20 diazomethane in methylene chloride (24 ml). The pH was then adjusted to 3.0 with 28% phosphoric acid. After 1 hour, the temperature of the reaction mixture was allowed to rise to 20 ° C. Heptane (56 ml) was added slowly and the resulting crystalline title product recovered by filtration. The yield of the title product was 3.0 g (50%).

25 Preparation No. 4

Benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate (5)

Pyridine (3.2 g, 40 mmol) was added to a suspension of PC1 <- (8.3 g, 40 mmol) in CHlCl (100 ml) and the mixture was stirred at 20 ° C for 20 minutes. To the mixture was added benzhydryl-3-30 hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate prepared in preparation No. 3, (5.1 g, 10 mmol) with stirring at -40 ° C all at once.

The mixture was stirred at -10 ° C for 15 minutes and then left at -10 to -15 ° C for 7 hours. Propane-1,3-diol (10 ml) was added to the cooled solution (-20 ° C) and the mixture was stored at -20 ° C for 6 hours, then stirred at room temperature for 20 minutes at 8300755 . The resulting solution was washed with ice water (2 x 20 ml) and saturated aqueous NaCl (10 ml), dried with MgSO 4 and concentrated in vacuo. The gummy residue (12 g) was dissolved in a. mixture of CHCl 2 and n-hexane (2: 1), and subjected to chromatography using a silica gel column (200 g) and the same solvent as eluent. Fractions containing the title compound were evaporated in vacuo and the residue triturated with n-hexane to give the title product (2.1 g, 51%), melting point at> 110 ° C (dec.). IR: γ 3400, 2800, 1785, 1725 cm -1.

UV: XEtOH 265 nm (E?%. 160).

Λπβχ 1 cm NMR ï $ DMSCHd6 + 3.69 (2H, s), 4.43 (2H, s), 5.09 (1H, d, ppm J = 4.5Hz), 5.24 (1H, d, J * 4.5HZ), 6.87 (1H, s), 7.3 (10, m).

Example I

7- [(Z) -2-Methoxyimlno-2— (2-aminothiazol-4-yl) acetamido] —3— [(1-methyl-15-pyrrolidinium) methyl] -3-cephem-4-carboxylate (1a) ) A. Benzhydryl-3-chloromethyl-7-g (Z) -2-methoxyimino-2- (2-tritylamino-thiazol-4-yl) acetamido] -3-cephem-4-carboxylate (6a ')

Benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate prepared in preparation No. 4 (2.29 g, 5.52 mmol) in CH 2 CN (57 ml) was mixed with bis (trimethylsilyl acetamide (BSA 4.09 ml, 16.6 mmol) treated at room temperature for 50 minutes to give a clear solution. To the solution was added an acid chloride solution prepared from (Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (4a) (2.04 g, 4.60 mmol) and PCI ,. (1.15 g, 5.52 mmol) 25 in methylene chloride (20 ml). The mixture was stirred at room temperature for 30 minutes, poured into cold water (200ml) and with ethyl acetate. 3 x 100 ml, extracted. The combined extracts were washed with aqueous NaCl, dried and evaporated. The residue syrup (4 g) was chromatographed on silica gel (150 g) by successive elution with 10: 1 and 3: 1 mixtures of toluene and ethyl acetate. The fractions containing the desired title compound were combined and evaporated to yield 2.61 g (68%) of 6a * as an amorphous powder.

5CDC13 3.50 C2H, sj, 4.02 (3H, s), 4.33 (2H, sj, 35 4.98 (1H, dj, 5.87 (1H, qj, 6.65 (1H, sj, 6.90 (1H, sj, 7.3 (25H, mj.)

8300755 19 B. Benzhydryl-3-iodomethyl-7- [(Z) -2-methoxyifflino-2- (2-triylamino-thia-zol-4-yl) -acetamido-3-cephem-4-carboxylate (7a ' )

A mixture of the 3-chloromethyl derivative (6a ') (1.50g, 1.79mmol) and Nal (1.34g, 8.93mmol) in methylene ethyl ketone (30ml) was stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (100 ml} and washed with water, aqueous Na 2 SO 2 O 2 and aqueous NaCl, dried and evaporated to give the title compound 7a '(1.47 g, 89 %) as an amorphous powder.

10 NMRr dCDC13 ppm 3j55 (2H> 4 ^ 00 (3Hf sJt 4j25 (2fi, sJt 4.97 (1H, dj), 5.80 (1H, qj, 6 ^ 65 (1H, s), 6.90 C1H, sJ 7.3; (25H, mj.

C. 7 - [(2) -2-Methoxyimino-2- (2-aminothlazol-4-yl) -acetamido] -3 - [(1-methyl-1-pyrrolidinium) methyl 3-3 -cephem- 4-carboxylate (la)

A mixture of 7a '(4.5g, 4.83mmol) and N-methylpyrrolidine (0.65ml, 6.28mmol) in CH 2 Cl 2 (45ml) was stirred at room temperature for 20 minutes. Ether (400 ml) was added to the mixture to separate the quaternary salt from the blocked cephalosporin which was collected by filtration and treated with 90% fluoroacetic acid (TFA) for 1 hour at room temperature. The mixture was then evaporated under reduced pressure below 20 ° C. The residue was triturated with ether to give the FTA salt of 1a (2.40 g), which was dissolved in methanol (5 ml) and treated at room temperature with a 1M solution of sodium 2-ethylhexoate (SEH) for 25 minutes. ) in ethyl acetate (8 ml). After addition of ethyl acetate (100 ml), the precipitate formed (1.94 g) was collected by filtration. HPLC analysis showed that the crude product was 7% pure with a 1: 8 3 2 ratio of the Δ isomer to the Δ i some er. Purification of the product by HPLC was repeated three times (Lichrosorb RP-18, 8 x 300 mm) eluted with 5% aqueous CH 2 OH or 0.01 M ammonium phosphate buffer (pH 7.2) containing 5% CH 2 OH to give 35 mg (1.5%) of the title product as a colorless powder. Estimated purity (by HPLC) 90%. Melting point 150 ° C (decomposition).

IR "".

: vkBr cm'1 1770, 1660, 1620. max 8300755 '20 OV · χ phosphate buffer' ρΗ 7 nm (£) 235 (16200), 258 (15400).

* max NMR: 5D2 ° ppm 2.31 (4H, mj, 3.08 (3H, sj, 3.63 (4H, m), 4.09 (3H, s), 5.43 (1H, d, J = 4.8 HzJ, 5.93 (1H, d) , 7.08 (1H, s).

Example II

7- [(Z) -2-Methoxyimlno-2- (2-aminothiazol-4-yl) -acetamido] -3- [(1-methyl-1-pyrrolidinlum) methyl] -3-cephem-4-carboxylate (1a) )

To a stirred solution of 20.4 g (21.9 mmol) of 7a 'in 150 ml of dry methylene chloride, 2.242 g (28.5 mmol) of 10 l of methyl pyrrolidine were added all at once at room temperature. The mixture was stirred for 5 minutes and poured into 100Q ml of ether with vigorous stirring to form a precipitate which was filtered, washed with ether (5 x 20 ml) and dried in vacuo to give 19.3 g of the blocked product as a light yellow powder was obtained.

ms vKBr cm * 1 3400, 1780 (s), 1740, 1675, 1530. max TLC ™ solvent ethanol-CHCl 4 (1: 3), Rf = 0.30 (Rf 0 0.95 for 8a ').

The solid was dissolved in 185 ml of trifluoroacetic acid-2Q water (99: 1), stirred at room temperature for 1 hour and concentrated to about 30 ml below 10 ° C. The concentrate was poured into 1000 ml of ether with vigorous stirring to form a precipitate, which was filtered, washed with ether (5 x 40 ml) and dried in vacuo to give 10.6 g of a pale yellow powder. The powder was dissolved in 20 ml of methanol and the solution filtered. 45 ml of Q, 8M SEH ethyl acetate were added to the filtrate. The resulting suspension was poured into 400 ml of ethyl acetate and filtered and obtained. 8.08 g of a solid, which was a mixture of the title 2 3 2

compound and the corresponding Δ isomer (Δ -Δ * 1: 8) as demonstrated by HPLC analysis (Lichrosorb RP-18, 10.15% methanol in 0.01 M

Phosphate buffer pH 7). A second test of 28.9 g (31.0 mmol) of 7a, 3 2 gave 16.0 g of the crude product (Δ / Δ = 1: 8). Isolation of the desired Δ ^ isomer from the combined crude product (24.08 g) using preparative HPLC (System 500, Waters Associates, PrePAK 35 500 / c18, 5-10% CH 2 OH) provided 769 mg of compound 1a .

8300755, \ 21

Example III

7-Ε (Ζ) -2-Methoxyimino-2- (2- (2-aminothiazol-4-yl) acetamido] -3-f (1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate (la)

A series of tests were performed to determine the effect of solvent, amount of solvent and the reaction period of the yield on the compound 1a and the Δ / Δ ratio in the reaction product. The general procedure was as follows:

To a suspension of the 3-iodomethyl derivative 7a '(45mg, 0.048mmol) in the indicated amount of the indicated solvent was added a solution of N-methylpyrrolidine (0.01ml, 0.097mmol) in ether (0.1 ml) and the mixture stirred at room temperature for the specified period. The reaction mixture was diluted with ether (5ml) and the resulting precipitate collected by filtration and mixed with 90% TFA. The mixture was stirred for 1 hour and evaporated to dryness under reduced pressure below 20 ° C to obtain the product. The ratio of Δ / Δ in the product was determined by HPLC (Lichrosorb RP-18; mobile phase, 0.01M ammonium phosphate buffer 3 2 (pH 7.2) with 15% CH-QH; retention time Δ 6.60 minutes, Δ 5.56 minutes).

J 3 2

Yield of the product and the ratio of Δ / Δ isomer and for each 20 runs are given below.

TABLE

Experiment Solvent Ratio Reaction-To-No of 7a '(in g) time yield solvent to solvent (min) (%) thing (in ml) ΔΙ /

25 A

8300755 \ 22 t

Example IV

7— [(Z) -2-Ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-C (1-methyl-1-pyrrolldinluia) methyl] -3-cephem-4-carboxylate (lb) A. Benzhydryl-3-chloromethyl-7- [(Z) -2-ethoxyijnino-2- (2-tritylamino-5-thiazol-4-yl) acetamido] -3-cephem-4-carboxylate (6b)

To a solution of (Z) -2-ethoxyimino-2- (2-trityl-aminothiazol-4-yl) acetic acid (4b) (1.095 g, 2.4 mmol) in dichloromethane (20 ml) was added phosphorus pentachloride (500 mg). After stirring at room temperature for 1 hour, the mixture was added all at once to an ice-cooled solution of compound 5 (1.083 g, 2.4 mmol) and BSA <1 mL) in dichloromethane (20 mL). After stirring for 0.5 hour, the reaction mixture was poured into 10% aqueous NaHCO 2 (200 ml) and extracted with CHCl 2 (100 ml). The extract was washed with water, dried over MgSO 4 and evaporated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with CHCl 3 gave 6b as an amorphous powder (1.76 g) (86%).

NMR r <5CDC13 ppm 1,40 (3H> t * CH2CH3), 3.53 (2H, ABq, 2-CH2), 4.37 C2H, s »-C ^ Cl) ^ 4.60 (2H, q, - CH2CH3J, 4.90 ClH, dr 6-HJ, 5.89 ClH, d, 7-H), 6.88 (1H, s, thiazole -H), 6.91 (1H, s, benzhydryl-CH.) B. Diphenylmethyl 7- [(Z) -2-ethoxyimino-2- (2-tritylaminothiazol-4-yl) -acetyl-mido] -3-iodomethyl-3-cephem-4-carboxylate (7b)

A mixture of 6b (1.07g, 1.25mmol) and Nal (562mg, 2.75mmol) in acetone (20ml) was stirred for 1 hour. The mixture was filtered and the filtrate poured into water and extracted with ethyl acetate. The organic layer was washed successively with 5% aqueous Na 2 S 2 O 4, water and saturated NaCl, dried with MgSO 4 and evaporated to give 1.04 g (89%) of compound 7b.

30 NMR: __________________ CUCH PP »3.55 (2H," q, 2-CH 2), 4.27 C 2 H, CH 2 ", 5.02 ClH, d, 6-HJ, 5.87 ClH, d, 7-H), 6.68 (1H, s, thiazole ring H), 6.93 (1H, s, benzhydryl-CH).

35 C. 7- [(Z); - 2-Ethoxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3- [(1-methyl-1-pyrrolidinium) methyl] -3-cephem-4 -carboxylate (lb) 8300755 23

A mixture of 7b (333mg, 0.85mmol) and N-methylpyrrolidine (60mg, 0.7mmol in (5ml) was stirred at room temperature for 0.5h and then evaporated in vacuo. The residue was washed with ether and dissolved in 90% aqueous TFA After being stored at room temperature for 0.5 h, the mixture was concentrated under reduced pressure to the concentrate was added ether to separate the quattrified product which was filtered and dissolved in a small amount of methanol The solution was chromatographed on an HP-2 column (40 ml) Elution with 30% IQ aqueous CH-GB followed by lyophilization gave 0.062 g of a mixture 2 * 3 2 3 of the Δ and Δ isomer (Δ: Δ = 5: 1) The mixture was purified by HPLC (Lichrosorb RP-18, 8 x 300 mm, 15% methanol) and the desired Δ isomer (lb) was isolated as a light yellow powder (4.9 mg (2.7%).

UV: λ phosphate buffer, ph 7 £ 235 (15000) 258 (14000).

λ max 5D2 ° ppm 1.43 C3H, tj, 2.33 C4H, m), 3.10 (3H, s, 3S64 C4H, m), 4.36 (2H, qj, 5.44 (1H, d> .5.95 (1H, dj, 7.08 (1H, sj.

20 '

Example V

7-E (Z) -2- (2-Propoxyimino) -2- (2-aminothiazol-4-yl) -acetamido] -3 - [(1-methyl-1-pyrrolidinlum) methyl] -3-cep em- 4-carboxylate (1c) A. Diphenylmethyl 1-3-chloromethyl 1-7- [(Z) -2- (2-propoxyimino) -2- (2-trltyl-25-aminothiazol-4-yl) acetamido] -3-cephem -4-carboxylate (6c)

A mixture of (Z) -2- (2-propoxyimino) -2- (2-trityl-amino-thiazol-4-yl) acetic acid (4c) (707 mg, 1.5 mmol) and phosphorus penta chloride (344 mg , 1.65 mmol) in dichloromethane (14 ml) was stirred at room temperature for 1 hour and in a solution of compound 30 (677 mg, 1.5 mmol) and BSA (1.1 ml, 4.5 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200ml) and water, (3 x 100ml), dried with sodium sulfate and evaporated to give 1.4g (100%) of compound 6c.

IR: 3360, 3020, 3060, 2960, 1785, 1725, 1680, 1520, Raax 1500, 1450, 1375, 1300, 1250, 1160, 1090, 1060, 1010, 990, 840, 740, 700.

8300755 24 UV; xEtOHnm (c) 240 (24600), 260 (20700). max

Nmr: 5CDC13 ppm 1.35 (6H, d. J = 6HzJ, 3.50 (2H, s), 4.35 2H, s), 4.58 (1H, m, J “6HzJ, 5.00 (1H .5 -J.d, J * 4.5HzJ> 5.91 ClH, dd, J = 4.5 $ 9Hz; d by D2 ° »J = 4.5Hz), 6.68 ClH, sj, 6.88 ClH, sJ, 7.25 C25H, s).

B, Di-phenylmethyl-3-iodomethyl-7- [(Z) -2- (2-propoxyimino) -2- (2-trityl-10-aminothiazol-4-yl-acetamido] -3-cephem-4- carboxylate (7c)

A mixture of compound 6c (500mg, 0.55mmol) and sodium iodide (248mg, 1.66mmol) in acetone (10ml) was stirred at room temperature for 50 minutes. After evaporation, the residue was dissolved in ethyl acetate (15 ml), washed successively with 10% aqueous sodium thiosulfate (10 ml), water (10 ml) and aqueous NaCl (10 ml), dried with sodium sulfate and evaporated to a yield of 494 mg (90%) of the title compound 7c.

iR "j u01 ™" 1 3360, 3040, 3020, 2960, 1785, 1720, 1680,: max 1600, 1520, 1500, 1450, 1370, 1300, 1230,.

2? 115.0, 1115, 1080, 990, 900, 840, 750, 700.

UV: XETHH nmU) 240 C24900J, 260 C19400J. max 25 NMR: dCDC13 PPm 1.30 C6H, d, J = 6HzJ, 3.37 $ 3.70 ClH each, d, J = 16HzJ, 4.22 (2H, s), 4.55 ClH, m, J = 6Hz), 4.95 ClH, d, J = 4.5Hz), 5.83 ClH, dd, J = 4.5 § 9Hz; d by D20), 6.66 ClH, s), 6.87 ClH, sJ, 7.25 C25H, sj.

30 C. 7 - [(Z) -2- (2-Propoxyimino) -2- (2-aminothiazol-4-yl) acetamido3-3 - [(1-methyl-1-pyrrolidinium) methyl3-3-cephem-4 -carboxylate (lc)

A mixture of compound 7c (545mg, 0.55mmol) and 35 1-methylpyrrolidine (70mg, 0.82mmol) in dichloromethane (10ml) was stirred at room temperature for 30 minutes and diluted with ether 8300755 (100ml) ). The resulting precipitate was collected by filtration. A solution of the precipitate in 90% TFA (4.5 ml) was stirred at room temperature for 30 minutes and evaporated in vacuo. The residue was triturated with ether to give 317 mg of the crude product which was chromatographed on an HP-20 column (50 ml) eluting with water (500 ml) and 30% CH-OH (500 ml). ). The 30% * CH 2 OH eluate was concentrated 3 J 2 and lyophilized to give 109 mg of a mixture of the Δ and 3 2 3 Δ isomers (Δ / Δ = 6/1), of which 100 mg was purified by HPLC (Lichrosorb RP-18, 15% MeOH) producing 5 mg (3%) of the desired title-10 compound 1c.

ov. buffer 7 buffer ηιη (ε) 236 (15100) f 252 (14600J.

max NMR: sD2üppm 1.42 (6H, d, J = 6Hz), 2.33 (4H, s), 3.10 (3H, 15 s), 3.65 (4H, s), 3.83 § 4 .23 (1H each, d, J * 17HzJ, 5.45 (1H, d, J * 4.5HzJ, 5.95 ClH, d, J * 4> 5Hzj, 7.05 ClH, s).

Example VI

7 - [(Z) -2-Allyloxyiiniino-2- (2-aTmuothiazol-4-yl) -acetamido] -3 - [(1-methyl-1-pyrrolidinium) methyl 1-3-cephem-4- carboxylate (1d) A. Benzhydryl 7 - [(Z) -2-allyloxylmino-2- (2-tritylaminothiazol-4-yl) acetamido 1 -3-chloromethyl-3-cephem-4-carboxylate (6d)

To a suspension of compound 5 (1.35 g, 3 mmol) in 25 methylene chloride (20 ml), BSA (1.1 ml, 4.5 mmol) was added and the mixture stirred at room temperature for 30 minutes, leaving a clear solution was obtained. A mixture of (Z) -2-allyloxy-imino-2- (2-tritylaminothiazol-4-yl) acetic acid (4d) (1.40 g, 3.0 mmol) and phosphorus pentachloride (690 mg, 3.3 mmol) in methylene chloride (20 ml) 30 was stirred at room temperature for 15 minutes and poured into the solution of the trimethylsilylated compound 5 all at once. The mixture was stirred at room temperature for 20 minutes and diluted with ethyl acetate (200ml), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako gel, C-200, 30 g). The column was eluted with chloroform and the fractions containing 8300755 26 the desired product were combined. After evaporation under reduced pressure, the title compound (6d) was obtained as an amorphous powder, yield 2.32 g (89%). Melting point 100-115 ° C (decomposition).

IR: υΚΒΓαη-1 3990, 1790, 1730, 1680, 1530, 1380, 1250, 5 max 1160, 1020.

NMR: 3 ppm 3.50 (2H, 2-H), 4.32 (2H, s, 3-CH2), 4.6-6.1 (7H, m, CE ^ CE = CE ^ and 6.7 -H), 6.70 (1H, s, thiazole-H), 6.90 (1H, s, Ph2CH), 7.1-7.6 (30H, m, phenyl protons).

analysis calculated for C48il40N5 ° 5S2Cl * 1 / 3CHCl3: C, 64.05; H, 4.45; N, 7.73; S, 7.08; Cl, 7-82.

found: C, 64.13, 63.99; 15H, 4.61, 4.64; N, 7.50, 7.30; S, 6.85, 6.85;

Cl, 7.55, 7.46.

B. Benzhydryl 7 - [(Z) -2-allyloxyimino-2- (tritylaminothiazole) -4-yl) - 20 acetamido] -3-iodomethyl-3-cephem-4-carboxylate (7d)

A mixture of compound 6d (2.03g, 2.65mmol) and sodium iodide (2g, 13.3mmol) in acetone (15ml) was stirred at room temperature for 1 hour and then evaporated under reduced pressure. A solution of the oily residue in ethyl acetate (200 ml) was washed with 10% sodium thiosulfate and water, evaporated under reduced pressure and then compounded. 7.d obtained as an amorphous powder, which was used in the next step without further purification. Yield 2.52 g (99%).

C. 7- [(Z) -2-Alyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [(1-methyl-1-pyrrolidinium) methyl] -3-cephem-4 -carboxylate (ld)

A mixture of compound 7d (478 mg, 0.5 mmol) and N-methyl-pyrrolidine (0.05 ml, 0.5 mmol) in methylene chloride (5 ml) was stirred at room temperature for 20 minutes and with ether (50 ml diluted to precipitate the quaternized product (yield 500 mg). A mixture of the quaternized product and TFA (2ml) was stored at room temperature for 11 hours and diluted with ether 8300755 # 27 precipitating the product crude TFA salt (yield 265g) which was chromatographed on a column of HP-20 (1.8 x 18 cm). The column was eluted with water and 30% aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized to form an amorphous powder (yield 124 mg) containing the desired product (17%) and the corresponding 2Δ isomer (83%). The mixture was purified by HPLC / Lichro-sorb RP-18; 0.01 M NH4H2PO4 (pH 7) CH3 <3S = 87:15). The eluate was acidified to pH 3 with dilute HCl and chromatographed on a column of HP-20 (1.8 x 10 cm). The column was eluted with water and then with 30% aqueous methanol. The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized to afford the title compound (1d) as an amorphous powder (yield 13mg, 5.1%); mp 155 ° C (decomposition).

15 IR - * yKBr cm -1 3600-2800, 1770, 1670, 1610, 1530, 1200.

max ÜV: ipH 7 buffer nra (e) 235 (16600J, 253 (15600J.

max 20 X D-0 ppm 2.1 - 2.5 (4H, m, pyrrolidine-H), 3.10 (3H, s,

NnR £ ^ NCH ^), 3.4-3.8 (4H, m, pyrrolidine-H), 5.95 (1H, d, 4HZ, ~ -H), 7.10 (1H, s, thiazole-H) ).

Example VII

7- [2- (2-Aminothiazol-4-yl) - (Z) -2- (2-carboxyprop-2-oxyimino) -acetamido] - 3- {(1-methyl 1-1 -pyrrolldinium) methyl3- 3-cefaa-4-carboxylate (le) A. Benzhydryl 3-chloromethyl-7-C (Z) -2- (2-t-butoxycarbonylprop-2-oxy-imino-2- (2-tritylaminothiazol-4-yl) acetamido] -3-cefem-4-carboxylate (5a) 30 Procedure 1

A mixture of (Z) -2- (2-t-butylcarbonylprop-2-oxy-imino) -2- (2-tritylaminothiazol-4-yl) acetic acid (3a ') (1.94 g, 3.6 mmol), DDC (742 mg, 3.6 mmol) and N-hydroxybenzthiazole (486 mg, 3.6 mmol) in tetrahydrofuran (THF) (45 ml) was stirred at room temperature for 45 minutes, separating dicyclohexylurea . The dicyclohexylurea was removed by filtration and the filtrate was mixed 8300755 28 with 5 (If5 g, 3.6 mmol}. The mixture was left overnight at room temperature.

K

stirred at temperature and then evaporated in vacuo. The residual oil was dissolved in CHCl 2 (20 ml), washed with saturated aqueous NaHCO 2 and saturated aqueous NaCl, dried with MgSO 2 and evaporated to dryness. The residue (3.9 g) was dissolved in n-hexane: CHCl 3 (1: 2) and passed through a silica gel column (40 g) using the same solvent system. Fractions containing the title compound were evaporated in vacuo to give 1.2 g (39%) of 5a; melting point at 100 ° C (decomposition).

10 IR: vKBr cm -1 1.99v 1790, 1715, 1690.

max UV ^ EtOH ^ 24Q tEl * 280), 265 (El * 190) e max 1 cm 1 cm 15 ppm χ ^ 45 (9H, s), 1.63 § lf66 (6H, each sJ, 3.49 C2H, wide s), 4.34 (2H, s), 4.96 (1H, d, J = 4.5Hz), 5.90 (1H, dd, J = 4.5 § 7.5) * 6.66 (1H, si, 6.86 (1H, s), 7.0-7.5 (25H, m), 8.23 ClH, d, J-75 Hz].

Procedure 2

A solution of 5 (1.86 g, 4.49 mmol) in CH 2 CN (46.5 ml) was treated with BSA 25 (3.33 ml, 13.5 mmol) at room temperature for 50 minutes. to obtain a clear solution. To the solution was added an acid chloride solution prepared from 3a '(2.56g, 4.49mmol) and PCl 4 (1.12g, 5.38mmol) in methylene chloride (26ml). The mixture was stirred at room temperature for 30 minutes, poured into cold water (100 ml) and extracted with ethyl acetate (3 x 30 50 ml). The combined extract was washed with aqueous NaCl, dried and evaporated. The residual syrup (5 g) was chromatographed on a silica gel (100 g) column by eluting with a 10: 1 mixture of toluene and ethyl acetate. The fractions containing the desired compound were combined and evaporated to give 2.84 g (65%) of 5a.

8300755 29 B. Benzhydryl 7 - [(Z) -2- (2-t-butoxycarbonylprop-1-oxylmino) -2- (2-trl-.

ty lam -t n p thlazol-4-yl) ac edamido] -3-iodomethy 1-3 -c ef em-4-carb oxylate (6a)

A mixture of 5a (500mg, 0.53mmol) and Nal (240mg, 1.6mmol) in acetone (3ml) was stirred at room temperature for 2 hours and then evaporated in vacuo. (20 ml) and water (10 ml) were added to the residue. The organic layer was washed with 10% ss / v sodium thiosulfate (5ml) and aqueous NaCl (5ml), dried over MgSO 4 and evaporated to dryness to give 540mg (90%) 10 6a as an amorphous powder with a mp 106 ° C (decomposition).

TV. KBr -1 3350, 1790, 1690.

Cmax -15 µV: xEtHH nm 240 (E1 * 270), 265 (E1% 190).

max 1 cm 1 cm NMR: 6CDC13 ppm 1.44 C9H, s), 1.65 (6H, s), 3.54 (1H, 4.28 (2H, s), 4.98 (1H, d, 20 J = 4.5Hz), 5.85 (1H, dd, J * 4, S § 7.5Hz), 6.70. (1H, s), 6.90 (1H, s), 7.1 -7.5 (25H, m) 1 C. 7- [2- (2-Aminothiazol-4-yl) - (2) -2- (2-carboscyprop-3-oxyimino) acetamido] -3- ((1-methyl-1-pyrrolidinium) methyl3-3-cephem-4-carboxylate (ie)

A mixture of the iodomethyl derivative 6a (538mg, 0.51mmol) and N-methylpyrrolidine, (0.079ml), (0.076mmol) in CH 2 (10.8ml) was stored at room temperature for 30 minutes then with ether (80 ml) diluted. The precipitate formed is collected by filtration and washed with ether to give 420 mg of the quaternized product which was unblocked with 90% trifluoroacetic acid (TFA) (4.2 ml) for 1 hour at room temperature. The reaction mixture was then evaporated to dryness. Ether was added to the residue to give crude TFA salt of 1a (245 mg, quantitative) consisting of a 1: 4 mixture of the A and Δ isomers.

The crude material was subjected to HPLC purification [Lichrosorb RP-18, 4x. 300 mm, eluted with 0.01 M ammonium phosphate buffer (pH 7.0), 8300755.30 containing 10% CH2 OH}. The fraction containing the desired product was collected and evaporated to a small volume. The concentrate was adjusted to a pH of about 2 by addition of 1M HCl and passed through an HP-20 column (2 x 15 cm) to remove the inorganic S salt. The column was washed with (1000 ml) and eluted with 30% CH 2 OH. The eluent was evaporated and lyophilized to give 21 mg (10%) of the title product (le) as a colorless powder. Melting point 160 ° C (decomposition).

IR: KBr -1 v cm 3400 * 1775, 1610.

10 max phosphate buffer PH 7 nmCe) 237 (15700), 257 C1S5S00).

max 15nmr: 5D20 ppm ^ 65 C6H> sJj 2.3 (4H, mj, 3.09 (3H, sj, 3.6 ..; (4H, mj, 4.0 (2H, mj, 5.44 (1H) , d, J = 4.8Hz), '5.94 (1H, dj, 7.15 (1H, sJ. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 8 300 755

Example VI1X

2

The general procedure of Example 7 is followed except that the (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2-4 (2-tritylaminothiazol-4-yl) acetic acid is replaced by an equimolai 5 r amount of 6 (Z) -2-t-butoxycarbonylmethoxyimino) -2- (2-tritylaminothiazol-4-yl) vinegar 7 acid r 8 (Z) -2- (1-t-butoxycarbonylethoxyimino) -2- (2 -tritylaminothiazol-4-yl) - 9 acetic acid, 10 (Z) -2- (2-t-butoxycarbony lbut-2-oxyimino) -2- (2-tritylaminothiazol-4-yl-11 acetic acid, 12 (Z) - 2- (3-t-butoxycarbonylpent-3-oxyimino) -1- (2-tritylaminothiazol-4-yl) - 13 acetic acid, 14 (Z) -2- (1-t-butoxycarbonylcycloprop-1-oxyimino) - 2- (2-tritylamino-thiazol-15 4-yl) -acetic acid, 16 (Z) -2- (1-t-butoxycarbonylcyclobut-1-oxyimino) -2- (2-tritylamino-thiazol-4-yl) acetic acid , and ψ 31 (Ζ) -2- (1-t-butoxycarbonylcyclopent-1-oxyimino) -2- (2-tritylamino-thla-zolr-4-yl) acetic acid, respectively, thereby obtaining 7- [2 - (2-aminothiazol-4-yl) - (Z) -2- (carboxymethoxyim ino) acetamido] -3-5 CC 1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate, 7- [2- (2-aminothiazol-4-yl) - (Z) -2- ( 1-carboxyethoxyimino) acetamido] -3- [C 1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate, 7- [2- (2-aminothiazol-4-yl) - (2) -2 - (2-carphaoxybut-2-oxyimino) acetamido 3- 2- [(1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate, 10 7- [2- (2-aminothiazol-4-yl) ) - (Z) -2- (3-carboxypent-3-oxyimino) acetamido] - 3- [(1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate, 7-t 2- (2 -aminothiazol-4-yl) - (Z) -2- (1-carboxycycloprop-1-oxyimino) acetamido] -3- [(1-methyl-1-pyrrolidinium) methyl] -3-cep em-4-carboxylate - [2— (2-aminothiazol-4-yl) - (Z) -2- (1-carboxycyclobut-1-oxyimino) acetate-15 amido] -3 - [(1-methyl-1-pyrrolidinium) methyl] - 3-cephem-4-carboxylate, and 7- [2- (2-aminothiazol-4-yl) - (Z) -2- (1-carboxycyclopent-1-oxyimino) acetamido} -3- [(1-methyl- 1-pyrrolidinium) methyl] -3-cep em-4-carboxylate.

8300755

Claims (2)

A compound according to formal 1, wherein R 1 is hydrogen or 2 is a lentic amino protecting group, and R 'is a straight or branched chain alkyl group of 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl or a group - r 4 5 R, - C - R, JI COOH 3 4 wherein R and R are each independently hydrogen, methyl or ethyl, or 3 4 R and R taken together with the carbon atom to which they are attached can form a cycloalkylidene ring containing 3-5 carbon atoms, or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable esters or solvate thereof. A compound according to claim 1, namely 7 - [(Z) -2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [(1-methyl-1-pyrrolidinium) methyl ] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt or solvate thereof. A compound according to claim 1, namely 7- [(Z) -2- (2-propoxyimino) -2- (2-aminothiazol-4-yl) -acetamido J-3- [(1-methyl-1-pyrroli- dinium) methyl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt or solvate thereof. A compound according to claim 1, namely 7 - [(Z) -2- (2- 20 pr opoxy imino) -2- (2-aminothiazol-4-ylacetamido] -3- (1-methyl-1-pyrrolidinium) ) methyl] -3-cephem-4-carboxylate or a non-toxic pharmaceutically acceptable salt or solvate thereof. A compound according to claim 1, namely 7 - [(Z) -2-allyl-olcyiraino-2- (2-aminothiazol-4-yl) acetamido] -3- [(1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt or solvate thereof. A method for combating bacterial infections in warm-blooded animals in need of such treatment, characterized in that said warm-blooded animal is administered an amount of at least one compound according to claim 1 effective for antibacterial purposes. Process according to claim 6, characterized in that the 8300755 * compound according to claim 1 7- [(Z) -2-methoxyimino-2- (2-aminothlazol-1-yl) acetamido] -3 - [(1 -methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate or a non-toxic pharmaceutically acceptable salt or solvate thereof. Anti-bacterial preparation, characterized in that it contains an anti-bacterial amount of at least one compound according to claim 1 and an inert pharmaceutical carrier. 9. Preparation according to claim 8, characterized in that the compound according to claim 1 7-f (Z) -2-methoxyimino-2- (2-amnothiazol-4-yl) acetamido] -3- [(1-methyl -1-pyrrolidinium) methyl] -3-cephem-4-carboxylate or a non-toxic pharmaceutically acceptable salt or solvate thereof. 10. Antibacterial preparation in unit dosage form, characterized in that it contains about 50 to about 1500 mg of at least one compound according to claim 1 and an inert pharmaceutical carrier, Preparation according to claim 10, characterized in that the compound according to claim 1 7 - [(Z) -2-methoxyimino-2- (2-aminothla-zol-4-yl) acetamido] -3- [(1- methyl 1-pyrrolidinium) methyl] -3-cephem-4-20 carboxylate or a non-toxic pharmaceutically acceptable salt or solvate thereof. The compound of claim 1, namely 7- [2- (2-amino-thiazol-4-yl) - (Z) -2- (2-carboxyprop-2-oxyimino) acetamido] -3 - [(1-methyl - 1-pyrrolidinium) methyl] -3-cep em-4-carboxylate or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. 13. A method for combating gram-negative bacterial infections in warm-blooded animals in need of such treatment, characterized in that said warm-blooded animal is administered an anti-bacterial amount of at least one compound according to claim 1, wherein R * has the meanings according to claim 1 and R and R are each independently hydrogen, methyl 3 4 or ethyl, or R and R taken together with the carbon atom to which they are attached can form a cycloalkylidene ring with 3-5 carbon-35 substance atoms or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. 8300755 Method according to claim 13, characterized in that the compound according to claim 1 7- [2- (2-aminothiazol-4-yl) - (Z) -2- (2-carboxyprop-2-oxyimino) acetamido] - 3- [(1-methyl-1-pyrrolidiniummethyl] -3-cell-4-carboxylate or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. Antibacterial preparation active against gram-negative bacteria, characterized in that an antibacterial effective amount of at least one compound according to claim 1 1 3 4 wherein R has the meanings of claim 1. and R and R each independently 3 4 10 being hydrogen, methyl or ethyl, or R and R together with the carbon atom to which they are attached may form a cycloalkylidene ring having 3-5 carbon atoms, or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof and an inert pharmaceutical carrier. Preparation according to claim 15, characterized in that the compound according to claim 1 7- [2- (2-aminothiazol-4-yl) - (Z) -2- (2-carboxy-2-oxyimino) acetamido] - 3- [(1-methyl-3- (1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. 20 17 Antibacterial preparation active against gram-negative bacteria in unit dosage form, characterized in that it is about 50 to about 1500 mg of at least one compound according to claim 1 wherein R has the meanings of claim 1 and R and R each 3 4 are independently hydrogen, methyl or ethyl, or R and R taken together with the carbon atom to which they are attached may form a 3-5 carbon cycloalkylidene ring or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof and an inert pharmaceutical carrier. 18. A composition according to claim 17, characterized in that the compound according to claim 1, 7- [2- (2-aminothiazol-4-yl) - (Z) -2- (2-carboxyprop-2-oxyimino) acetamido ] -3- [(1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof. 19. A method of preparing compounds of formula 1, wherein R * is hydrogen or a known amino protecting group, 2 and R is a straight or branched chain alkyl group having 1 to 4 carbon atoms, allyl, 83 0 0 75 5 2- butenyl or 3-butenyl, or a group 3 '4 R - C - R t COOH 3 4' where R and R are each independently hydrogen, methyl or ethyl or 3 4 R and R taken together with the carbon atom to which they are attached -5 bonds, forming a cycloalkylidene ring with 3-5 carbon atoms, or a non-toxic pharmaceutically acceptable salt, physiologically hydrolyzable ester or solvate thereof, characterized in that a compound of formula 16 or an N-silyl derivative thereof, wherein B is hydrogen or a known protecting group, it is acylated with an acylation derivative of an acid of formulas 17 or 17a, wherein 2 3 B is a known amino protecting group, B is a known carboxyl-3 4 protecting group and R and R have the aforementioned meanings, waa a compound is formed, according to formula 15 or 15a, and all protective groups are subsequently removed. 20. A process for the preparation of compounds of formula II, wherein R is a straight or branched chain alkyl group with 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl or a group 3 * 4 R - C - R, COOH 3 4 wherein R and R are each independently hydrogen, methyl or ethyl, or 3 4 20. and R taken together with the carbon atom to which they are attached may form a 3-5 carbon cycloalkylidene ring and non-toxic pharmaceutically acceptable saline, physiologically hydrolyzable esters and solvates thereof, characterized in that a compound 2 3 4 according to the formula 14 or 14a, in which R, R and R have the aforementioned meanings, B and B are known carboxyl protecting groups, B a known amino protecting group, is reacted with N-methylpyrrolidine to form a compound of formulas 15 or 15a, and then all protecting groups are removed by conventional means. The process according to claim 19 or 20 for preparing 7- [2- (2-aminothiazol-4-yl) - (Z) -2- (2-carboxyprop-2-oxyimino) acetamido] - 3- {(methyl- 1-pyrrolidinium) methyl] -3-cephem-4-carboxylate (Ie) or a non-toxic pharmaceutically acceptable salt, physiologically hydrolysable 8300755 Λ * * * ester or solvate thereof, characterized in that a mixture of benzhydryl- 7-amino-3-chloromethyl-3-cephem-4-carboxylate, (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid, DDC, N-hydroxybenztriazole in an organic solvent is reacted with benzhydryl-3-chloromethyl-7 - [(Z) -2- (2-t-butoxy-carbonyl-prop-2-oxyimino) -2- (2- tritylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (1f) is obtained, or optionally a mixture of benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis- (tri -methylsilyl) acetamide is reacted with an acid chloride of (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-tritylaminothia) zol-4-yl) acetic acid to form (1f) then (1f) is reacted with iodide salt to form benzhydryl 7-C (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-trity laminothiazol-4-yl) acetamido J-3-iodomethyl-3-cephem-4-carboxylate (1 g), then (Ig) is reacted with N-methylpyrrolidine in an organic solvent to give ( 1h), and finally (1h) is deblocked to form the title compound (le), which melts at 160eC (decomposition) and / or optionally (le) in its non-toxic pharmaceutically acceptable salts, physiologically hydrolysable esters and solvates 20 of which are converted » A method according to claim 19 or 20, for preparing 1 2 compounds of formula 1, wherein R is hydrogen and R. is methyl, ethyl, isopropyl or allyl, or a non-toxic pharmaceutically acceptable salt or solvate thereof, characterized in that a mixture of benzhydryl-7-amino-3-chloromethyl-3-cephem-4-carboxylate and bis- (trimethylsilyl) acetamide is reacted with an acid chloride of (Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid or (Z) -2-ethoxy-imino-2- (2-tritylamino- thiazol-4-yl) acetic acid or (Z) -2- (2-propoxyimino) -2- (2-tritylamino-thiazol-4-yl) acetic acid or (Z) -2-allyloxyimino-2- (2-30 tritylaminothiazole -5-yl) acetic acid to yield the corresponding condensed derivative containing 2-methoxyimino or 2-ethoxyimino or 2-propoxyimino or 2-allyloxyimino groups, then reacting said condensed derivative with iodide salt to form the corresponding 3-iodomethyl derivative, further called 3-35 iodomethyl derivative in an organic solvent or a mixture of organic solvents with N-methylpyrrolidine in reaction 8300755 A * to form the corresponding pyrrolidinium derivative and finally unblock said pyrrolidinium derivative, 7-E (Z) -2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [(1-methyl -1-pyrrolidinium) -methyl] -3-cephem-4-carboxylate, or 7- [(Z) -2-methoxyimino-5 2- (2-aminothiazol-4-yl) acetamido] -3 - [(1 - methyl 1-pyrrolidinium) -methyl J - 3-cephem-4-carboxylate, or 7 - [(Z) -2- (2-propoxyimino) -2- (2-aminothiazol-4-ylacetamido] -3 - [( 1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate, or 7 - [(Z) -2-allyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [ (1-methyl-1-pyrrolidinium) methyl] -3-cephem-4-carboxylate is obtained and / or if desired said deblocked derivatives are converted into a non-toxic pharmaceutically acceptable salt or solvate thereof. 8300755 N - r-C-CONH - f> // V Π TrHN ^ \ s / \ qr2 / 'ηΎ ^ \ 0Η201 COOCH (Ph) - 6 _A Nal N —t-C-COOC-Ης'. , TrHH ^ s / \ 0H - N -r-C-CONH T 1 2 7ΓΤΒ TT R2X Tr HN ^^ S '\ r2 7 COOCH (Ph). 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