NL8501002A - CHEMICAL CONNECTIONS. - Google Patents

Description

- Ί V0 7062

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Chemical connections.

The invention relates to 7- (2- (5-amino-1,2,4-thiadiazol-3-yl ^ -2- (substituted) iminoacetamido] -3- (3- (quaternary ammonium) -1-props -11-yl] -3-cephem-4-carboxylates of formula 1, 1 2 wherein R and R are as defined herein and the group of formula 2 is a quaternary ammonia group as defined herein, as well as on salts and esters thereof, The invention also relates to methods of preparing the compounds of formula 1, to pharmaceutical preparations containing at least one compound of formula 1, and to intermediates in their preparation.

A) US Patent 4,390,534 of June 28, 1983 (Tsutomu Teraji et al.) Discloses cephem and cepham compounds of formula II, wherein R is amino or protected amino? R is hydrogen, acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkenyl, or an O- or S-containing heterocyclic 5-ring substituted with one or more oxo-3 4 groups; R is hydrogen or alkyl; R is hydrogen, acyloxyalkyl, acyl-thioalkyl, optionally substituted pyridinioalkyl, optionally substituted heterocyclylthioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazolioalkyl; and R is carboxy or protected carboxy; With the proviso that R is COO when R is optionally substituted -pyridinioalkyl or optionally substituted thiazolioalkyl; and the broken line indicates a single or double bond.

European patent application 13,762 published on August 6, 1980 is consistent with this and has the same content. U.S. Patent Nos. 4,381,299 (April 26, 1983), 4,331,665 (May 25, 1982), and 4,332,798 (June 1, 1982) are issued to parent filings of U.S. Patent 4,390,534 and have the same contents.

B) European patent application 62,321 published on October 13, 1982 shows cephem compounds of formula 4, wherein R * is amino or protected amino; R is an optionally substituted low aliphatic hydrocarbon group or cycloalkenyl; and the group of formula 5 represents an optionally substituted heterocyclic cation group containing more than one nitrogen atom; and pharmaceutically acceptable salts thereof.

1 2

Intermediates of formula 6 are also described, wherein R and R

4 as defined above, R is a protected carboxyl group and X is an acid residue.

C) European patent application 74,653, published March 23, 1983, shows cephem compounds of formula 7, wherein R 1 is amino 2 or protected amino? R represents an optionally substituted lower aliphatic hydrocarbon group, cyclo (lower) alkyl or cyclo (lower) alkenyl? R3 (low) alkylamino, N-protected (low) alkylamino, di (low) alkyl-10 amino, sulfo (low) alkylamino, hydroxy (lower) alkylamino, N-protected hydroxy (low) alkylamino, acyloxy (low) alkyl, (low) alkoxy (low) alkoxy (low) alkyl, di (low) alkylamino (low) alkyl, day) alkylthio (low) alkyl, (low) alkylthio, (low) alkoxy, day) alkoxy day) alkoxy, hydroxy (low alkoxy, acyl (lower) alkyl, hydroxy (lower) alkylthio, di (lower) alkylamino (lower) -15 alkylthio, an N-containing unsaturated heterocyclic 5-ring, an N-containing unsaturated heterocyclichio 5-ring, or N -containing unsaturated heterocyclicthiothio (lower) alkyl 5- or 6-ring containing one or more 4

any suitable substituents may be substituted? and R

is hydrogen or (lower) alkyl? or a salt thereof.

D) U.S. Patent 4,332,800 of June 1, 1983 (Tsutomu Teraji et al), describes compounds of formula 1, among others, wherein R is amino or protected amino? R is (lower) alkyl and X is hydrogen or carbamoyl.

E) European patent application 47,977 published March 24, 1982 shows cephem compounds of formula 9, wherein m equals 0 or 1; Am is optionally substituted amino; T represents a thiadiazolyl group (which is joined to the other groups by two of its carbon atoms); R 1 is hydrogen, optionally substituted alkyl, cycloalkyl, or optionally substituted carbamoyl? and R 1 represents optionally substituted thiazolio, optionally substituted pyrazolio, tri (low) alkylammonio, or a pyridini group of formula 10, wherein Ra represents substituted (low) alkyl [wherein the substituent is cycloalkyl, phenyl, hydroxy, alkoxy, halogen , cyano, carbamoyl, carboxyl or sulfo], (low) alkenyl, or carboxy-substituted (low) alkenyl, (1a-35e) alkylthio or carboxy-substituted (low) alkylthio, amino or mono-substituted amino [wherein the substituent is formed by (low) al- 8501002 t ..... --it * 3. skyl, (low) alkanoyl or aminobenzenesulfonyll, di (low) alkylamino, substituted carbamoyl [in which the substituent is (low) -alkyl, hydroxy (low) alkyl, (low) alkoxy, hydroxy or cyano], di (low) ) alkylcarbamoyl, thiocarbamoyl, cycloalkyl, phenyl, hydroxy, (lower) alkoxy, halogen, (lower) alkoxycarbonyl, (lower) alkanoyloxy, (lower) alkanoyl, car-

Jj boxyl, sulfo, cyano, nitro or hydroxysulfo (lower) alkyl; R hydrogen or

Q. Q

carbamoyl, or has the same meaning as R; and R is hydrogen or a has the same meaning as R; and salts thereof.

Although formally unrelated, XI March 1981 10 published European patent application 25,017 has an equal content.

P) European patent application 30,630 published June 24, 1981 shows 3-vinylcephal compounds of formula 11, wherein R * represents an optionally protected amino-substituted heterocyclic group which may also contain halogen, or a group of formula 12, 2 15 wherein R is (lower) alkyl; R is carboxy or protected carboxy; and A represents lower alkylene which may have a substituent selected from amino, protected amino, hydroxy, oxo and a group of the formula £ 3, wherein 4 R is hydrogen, cyclo (lower) alkenyl, (lower) alkynyl, (lower) alkenyl [optionally substituted by carboxy or protected carboxy], (lower) alkyl [des-20 substituted by one or more carboxy, protected carboxy, amino, protected amino, cyano, phosphono, protected phosphono, and a heterocyclic group which may be itself substituted] proposes; and salts thereof.

In particular, this application shows compounds of formula 14 wherein OR represents methoxy, carboxymethoxy, tert-butoxycarbonylmethoxy or 1-tert-butoxycarbonylethoxy.

G) British patent publication 1,399,086 published June 25, 1975 generally shows a large number of cephalosporins of formula 15, wherein R represents hydrogen or an organic group, Ra is an e-forming monovalent organic group which the oxygen is connected via a carbon atom, B stands for S or S - ^ O, and P is an organic group. In one embodiment, P may include, inter alia, a vinyl group of formula 16, wherein R and R may independently represent hydrogen, nitrile, (lower) alkoxycarbonyl, or substituted or unsubstituted aliphatic, cycloaliphatic, araliphatic or aromatic groups . However, the 5-amino-1,2,4-thiadiazol-3-yl-8501002 1 µm m 4 t group is not listed as a possible R substituent, nor is it disclosed or suggested that P is a quaternary ammonio-substituted propenyl group. United States Patent 3,971,778 and United States Patent Nos. 5 4,024,133; 4,024,137; 4,064,346; 4,033,950; 4,079,178; 4,091,209; 4,092,477 and 4,093,803 have the same content.

H) European patent application 88,385 published September 14, 1983 shows compounds of formula 17 wherein R is (unsubstituted) thiadiazolyl; R carboxy (lower) alkyl or protected car3-3

10 is boxy (lower) alkyl; R is hydrogen, halogen or (low) alkenyl; and R

carboxy or protected carboxy. Although 1-propenyl is listed as a 3 of the possible meanings of R, the applicant only gives examples of compounds in which R 1 is hydrogen, chloro or vinyl.

I) U.S. Patent 4,037,233, December 22, 1981 (Daniel Farge et al), shows, inter alia, 3-vinyl cephalosporin derivatives of formula 18, wherein R 1 may include alkyl, vinyl, cyanomethyl or a protecting group such as 2-methoxyprop-2-y1, 3 4 and R and R represent alkyl groups (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R 4 and 4 20 R together with the nitrogen atom to which they bonded to form a saturated 5- or 6-membered heterocyclic ring, optionally containing another heteroatom selected from N, O and S, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl-cephalosporin derivatives. No compounds are described or suggested with a 5-amino-1,2,4-thiadia-zol-3-yl group in place of the 2-aminothiazo 1-4-yl substituent or with a quaternary ammonia substituted chpropenyl group instead of the 3 substituent. Published British patent application 2,051,062 is similar and has the same content.

J). European patent application 53,537 published on June 9, 1982 shows, inter alia, 3-vinylcephalosporin derivatives of formula-Si mule 19, wherein R 1 and R 1 represent equal or different groups and represent hydrogen or alkyl, or together form an alkylene group containing 2 or 3 carbon atoms, R ^ is an acid protecting group, R ^ is an acid protecting group such as an ester, and R ^ is the same or different and represents hydrogen, alkyl (optionally substituted by 85 0 1 0 0 2 «t * 5 hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or R 1 and R 2 together with the nitrogen atom to which they are attached can form a saturated 5- or 6-membered heterocyclic ring optionally contains another heteroatom selected from N, O and S, and optionally substituted by an alkyl group. The compounds are useful as intermediates in the preparation of 3-thiovinyl-cephalosporin derivatives. No compounds are described or suggested with a 5-amino-1,2,4-thiadiazol-3-yl group in place of the 2-aminothiazol-4-yl substituent or with a quaternary ammonio-substituted propenyl group instead of 10 the 3-substituent „%

United States Patent 4,423,214 is consistent with this and has the same content.

K) European patent application 53,074 published on June 2, 1982 generally shows a large number of 3-vinylcephalosporin-15 derivatives of formula '20, wherein R ° ^ (in one of several embodiments) may be a group of formula 21, wherein others may represent hydrogen, alkyl, vinyl, cyanomethyl, an oxime-protecting ab group such as trityl, etc., or a group of formula 22, wherein R 1 and R 1 are the same or different and may be hydrogen, alkyl or, taken together, an alkylene group having 2 or 3 carbon atoms, and R 2 stands for hydrogen or an acid protecting group; R represents hydrogen or an acid protecting group such as methoxymethyl; R ° (in one of several embodiments) may be a methyl group substituted by a 5- or 6-membered heterocyclic ring containing a single heteroatom, such as 2- or 3-pyridyl, 2- or 3-pyridyl, 2- or 3-thienyl or 2- or 3-furyl; and is a group of the formula R 1 SO 2 O- wherein R 1 is alkyl, trihalomethyl or optionally substituted phenyl.

These compounds are referred to as intermediates in the preparation of compounds in which the 3 substituent is a group of formula 23 said to have antibacterial activity.

Although this patent includes the possibility that R ° is a methyl group substituted by an N-containing heterocyclic ring, it shows only a bond of the heterocyclic ring for both the intermediates and the final products (whereby a heterocyclic substituted propenyl group is obtained) through one of its 8501002 * ί 6 carbon atoms. Therefore, there is no question of suggesting a quaternary ammonium-substituted propenyl group. In the examples, in both the intermediates and the final products, R ° is only methyl.

Furthermore, the propenyl group in both the intermediates and in the final product must contain a second substituent (-O-SR or -SR, respectively).

Also, no compounds are disclosed or suggested with a 5-amino-1,2,4-thiadiazol-3-yl group in place of the 2-aminothiazol-4-yl substituent.

L) European patent application No. 53,538 published June 9, 1982 shows, inter alia, 3-vinylcephalosporin intermediates of formula 24, wherein n represents 0 or 1, R 1 represents hydrogen, alkyl, vinyl, cyanomethyl or an oxime. protecting group, and R 1 is halogen. No compounds are described or suggested with a 5-amino-1,2,4-thiadiazol-3-yl group in place of the 2-aminothiazo1-4-y1-15 substituent, and with a 3-halo-1- propen-1 -y 1 substituent at the 3-position.

The present application relates to new cephalosporine derivatives which are strong antibacterial agents. More particularly, the invention relates to compounds of formula 1, wherein R is hydrogen or a conventional amino protecting group, 2

R represents hydrogen, a straight or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group or cycloalkenyl group of 3 to 6 carbon atoms, or a group of any one of formulas 25-28, wherein R

stands for hydrogen, (lower) alkyl or carbonyl, X stands for halogen, 4 5 25 hydroxy or (low) alkoxy, and R and R each independently represent 4 - 5 for hydrogen, methyl or .ethyl, or R and R together with the carbon atom to which they are attached can form a cycloalkylidene ring of 3 to 5 carbon atoms, and the group of formula 2 is a quaternary ammonio group, as well as non-toxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof. The invention also includes the solvates (including hydrates) of the compounds of formula 1, as well as the tautomeric forms of the compounds of formula 1, for example the 2-iminothiazolin-4-yl form of the 2-aminothiazol-4 -yl group.

In another aspect, the invention relates to.

a process for the preparation of the compounds of formula 1 and on 8501002 β * 7 certain intermediates in their preparation.

As the structural formula shows, the compounds of formula 1 have the "syn" or "Z" configuration with respect to the alkoxyimino group. Since the compounds are geometric isomers, a small amount of the "anti" isomer may also be present.

The 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 "anti" isomers.

In addition to allowing geometric isomers with respect to the alkoxyimino group, the compounds of formula 1 (and the intermediates of formulas 68 and 69) also form geometric (cis and trans) isomers around the double bond of the propenyl group. Both the cis ("Z") and trans ("E") isomers of these compounds are specifically included in the invention.

The non-toxic pharmaceutically acceptable salts of the compounds of formula 1 include salts with inorganic acids such as hydrogen chloride, hydrobromide, phosphoric acid and sulfuric acid, and with organic carboxylic or sulfonic acids such as acetic acid, trifluoro-acetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid , benzoic, tartaric, fumaric, mandelic, ascorbic, malic, methanesulfonic, benzenesulfonic, p-toluenesulfonic and other known acids used in the fields of penicillins and cephalosporins. The preparation of these acid addition salts is carried out according to conventional techniques.

Examples of physiologically hydrolyzable esters of the compounds of formula 1 include indanyl, phthalidyl, methoxymethyl, acetoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl and other physiologically hydrolysable esters known and used in the field of penicillins and cephalosporins. Such esters are prepared according to conventional techniques known per se.

The compounds of formula 1 wherein R * is hydrogen exhibit high antibacterial activity against several gram-35 positive and gram negative bacteria, and are useful in the treatment of bacterial infections in animals, including humans. The "8501002 ί 8 compounds of formula 1" may be formulated for conventional use parenterally using known pharmaceutical carriers and excipients, and may be presented in unit dosage form or in multiple dose containers. The compositions may be in the form of solutions, suspensions or emulsions in oily or aqueous carriers, and may contain conventional dispersants, suspending agents or stabilizers. The compositions can also take the form. have a dry powder to be reconstituted before use, for example, with sterile, pyro-10 free water. The compounds of formula 1 can also be formulated as suppositories using conventional suppository bases such as cocoa butter or other glycerides. The compounds of the invention may, if desired, be administered in combination with other antibiotics such as penicillins or other cephalosporins.

When supplied in dosage unit form, they will preferably contain about 50 to about 1500 mg of the active ingredient of formula 1. The dosage of the compounds of formula 1 depends on factors such as the weight and age of the patient as well as on the nature and severity of the disease, and will have to be determined by the physician. Usually, however, the dosage for the treatment of adult humans will be in the range of about 500 to about 5000 mg per day depending on the frequency and route of administration. When administered intramuscularly or intravenously to an adult human, a total dose of about 750 to about 3000 mg per day in divided doses will usually suffice, although higher daily doses of some of the compounds may be desirable in the case of Pseudomonas infections.

The quaternary ammonio group of formula 2 may be acyclic, cyclic or a combination of the two, and may contain one or more hot atoms selected from nitrogen, sulfur and oxygen.

An example of an acyclic quaternary ammonia 6 7 8 group is a group of formula 29, wherein R, R and R may be the same or different and may represent, for example, (lower) alkyl or substituted (lower) alkyl in which the substituents for example can be formed by halogen, amino with the proviso that the amino group 8501002 9 f »+ · * 2ich is not on an α-carbon atom, hydroxy on the understanding that the hydroxy group is not on an α-carbon atom, (low) al -koxy with the proviso that the alkoxy group is not on an α-carbon atom, (low) alkylthio, (low) alkylamino, di (low) alkylamino, 5 carbamoyl, (low) alkenyl, phenyl (lower) alkyl, phenyl or substituted phenyl (wherein the substituents may be, for example, halogen, hydroxy, amino, (low) alkylamino, di (low) alkylamino, acylamlno, (lower) alkyl, (lower) alkylthio, (lower) alkoxy and the like.

c

Examples of cyclic quaternary ammonia groups 10 are fully unsaturated monocyclic heterocyclic ring systems and bicyclic heterocyclic ring systems, in which at least one N-containing ring is completely unsaturated. Suitable cyclic quaternary ammonium ring systems include, for example, those of formulas 30 to 9 10 43, and the like, wherein R and R are the same or different and may, for example, be hydrogen, halogen, amino, (lower) alkyl, (lower) alkenyl, (lower) alkylthio, carboxy, hydroxy, (lower) alkoxy, (lower j-alkyl (lower) alkyl, halogen (lower) alkyl, hydroxy (lower) alkyl, amino (lower) -alkyl, (lower) alkylamino (low) alkyl, di (low) alkylamino (low) alkyl, (low) alkylamino, di (low) alkylamino, carboxy (low) alkyl, carboxy (low) alkyl-20 amino, carboxy (low) alkylthio, carbamoyl, N- (Low) alkylcarbamoyl, formylamino, acylamino, acyloxy, phenyl, pyridyl, amidino, guanidino, etc. When the structure of the heterocyclic ring permits, R and R together may form an alkylene group containing 3 to 5 carbon atoms contains, for example, propylene.

Examples of combined acyclic / cyclic quaternary ammonia groups include, for example, those of formulas 44 11 to 55, and the like, wherein R may represent, for example, (lower) alkyl, (lower) alkoxy (lower) alkyl, hydroxy (lower alkyl with the proviso that the hydroxy is not on an α-carbon, carboxy (lower) -30 alkyl, amino (lower) alkyl with the proviso that the amino group is not on an α-carbon, (low) alkenyl, halogen (lower) alkyl, allyl 12 and the like, and R may for example represent hydrogen, hydroxy, halogen, (lower) alkyl, hydroxy (lower) alkyl, (lower) alkoxy (lower) alkyl, halogen (lower) alkyl, amino (lower) alkyl, (lower) alkoxy, (lower) alkylthio, (lower 35) alkenyl, amino, (lower) alkylamino, di (lower) alkylamino, acylamino, acyloxy, carbamoyl, amidino (lower) alkyl, phenyl, pyridyl, amidino, guanidino 8501002 * 10 and the like.

Preferred quaternary ammonia groups are those of formulas 56 to 61, wherein R 1 and R are the same or different and represent (lower) alkyl, (lower) alkenyl, amino (lower) alkyl with the proviso that the amino is not is on an α-carbon atom, or hydroxy (lower) alkyl with the proviso that the hydroxy group is not on an α-carbon atom; R stands for hydrogen, (low) alkyl, (low) alkoxy, (low) alkylthio, amino, (low) alkylamino, di (low) alkylamino, formylamino, (low) alkanoylamino, carboxy, hydroxy, carboxy (la-10) ge) alkyl, carboxy (lower) alkylthio, hydroxy (lower) alkyl, halogen (lower) alkyl, amino (lower) alkyl, (lower) alkoxy (lower) alkyl, carbamoyl or N- (lower) alkyl-16 carbamoyl, or R can represent a divalent alkylene group of 3 to 5 carbon atoms; R represents (lower) alkyl, (lower) alkoxy) lower alkyl, halogen (lower) alkyl, allyl, hydroxy (lower) alkyl with the proviso that the hydroxy group is not on the α-carbon atom; amino (lower) alkyl with the proviso that the amino group is not on the α-carbon atom, or phenyl (lower) alkyl; R stands for hydrogen, (low) alkyl, (low) alkoxy, (low) alkoxy (low) alkyl, (low) alkylthio, amino, (low) alkylamino, di (low) alkylamino, carboxy, hydroxy, carboxy (low) alkyl, hydroxy (lower) alkyl, amino (lower) alkyl, formylamino, (lower) alkanoyl-amino, carbamoyl or N- (lower) alkylcarbamoyl; n is an integer from 1-3; Z stands for CH- or, if n equals 2, Z can also stand for 19 ^ 19 20 21

S, O, or N-R, wherein R is hydrogen or (lower) alkyl; and 1 and R.

are the same or different and represent hydrogen, (lower alkyl, 25 (lower) alkoxy, (lower) alkylthio, amino, (lower) alkylamino, di (lower) alkyl-amino, carboxy, hydroxy, hydroxy (lower) alkyl, amino (lower) alkyl, (lower) alkoxy (lower) alkyl, carboxy (lower) alkyl, carboxy (lower) alkylamino, (lower) al-kanoylamino, carboxy (lower) alkanoylamino, carbamoyl or N- (lower) alky1-carbamoyl .

Particularly preferred quaternary ammonia groups are N- (low) alkylpyrrolidinio (and in particular N-methylpyrrolidinio), tri (low) alkylammonio (and in particular trimethylammonio), pyridinio, aminopyridinio, formylaminopyridinio, carbamoylpyridinio, amino carboxy pyridinio, hydroxy (lower) alkyl pyridinio, N- (low) -35 alkyl carbamoyl pyridinio, (lower) alkylene pyridinio, 2-methylthiazolio and 2-amino-5-thiazolo- [4,5-pyridinio.

8501002 t * 11 *

In the compounds of formula 1, particularly preferred meanings of R (lower) alkyl (and in particular methyl), cycloalkyl of 3 to 5 carbon atoms, 1 -carboxycycloalk-1 -y 1 of 3 to 5 carbon atoms, allyl, propargyl and carboxy (lower) alkyl (and especially 2-carboxyprop-2-yl) - The most preferred compounds of the invention are 1) 7- [2- (5-amino-1,2, 4-thiadiazol-3-yl) -2-methoxyiminoacetamido 1 -3- (3- '(trimethylammonio) -1-propen-1-yl] -3-cef em-4-carboxy late, 2) 7- [2 - (5-amino-t, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— [3-10 (1-methylpyrrolidinio) -1-propen-1-yl] -3-cephem-4 -carboxylate, 3) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-pyridinio-1-propen-1-yl] -3 -cef em-4-carboxylate, 4) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-3. (3-aminopyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, IS 5) 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2 -methoxyiminoacetamido] -3- [3- (3-formy laminopyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 6) 7- [2- (5-amino-1,2,4,4) -thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3- (3-aminomethylpyridinio) -1-propen-1-yl] -3-cep em-4-carboxylate, 7) 7- [2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-20 (3-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate , 8) 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cep em-4-carboxy late, • 9) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3 — Γ3— (2-methylthiazolio ) -1-propen-1-yl] -3-cep em-4-carboxylate, 25 IQ) 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— (3— (2-amino-5-thiazolo [4,5-c] pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 1-1) 7- [ 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3- (4-hydroxymethylpyridinio) -1 -propen-1-yl] -3-cep em-4-carboxylate, 30 12) 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3 - [3- (3-hydroxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 13) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl -2-methoxyiminoacetunido] -3- [3- (4- [N-methylcarbamoyl] pyridinio) -1-propen-1-yl] -3-cep em-4-carboxylate, 35 14) 7- [2- ( 5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— [3— (2,3-propylene-pyridinio) -1-propen-1-yl] -3-cephem-4- carboxylate, 8501002 1 * 12 15) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-props -1-yl] -3-cephem-4-carboxylate, 16) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyimino-acetami-do] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 5 17) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl ) -2-allyloxyimino-acetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 18) 7- [2- (5-amino-1 2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetamido] - 3- [3- (4-carbamoylpyridin io) -1-propen-1-yl] -3-cephem-4-carboxylate, \ 19) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— [3— 10 (4-carboxypyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 20) 7- [2- (5-amino-1,2,4-thiadiazole) 3-yl) -2-ethoxyiminoacetamido] —3— [3— (4-carboxypyridinio) -2-propen-1-yl] -3-cephem-4-carboxylate, 21) 7- [2- (5-amino- 1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3 "Carboxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate and 22) 7 - [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— [3— (4-earboxymethylthiopyridinio) -1-propen-1-yl-3-cef em-4-carboxylate.

The numbering system used in this description for the various reactants, intermediates and final products is as follows; 20 [Arabic numeral] - Arabic numeral ~~ Letter (if applicable) (if applicable).

The first arabic number refers to the formulas on the formula sheet. When the general class (genus) of the compounds is meant, no second arabic number and letter follow.

The second arabic number indicates the determined meaning of the substituent R 2. When the particular R group contains a carboxyl group protected by a conventional carboxyl protecting group, an accent t is used after the second arabic numeral to indicate this fact. When the carboxyl group is protected, no accent is used. An accent is also used in the general R-2r substituent (i.e. R) when reference is generally made to 2 an R group containing a protecting carboxyl group.

The letter given at the end indicates the definite meaning of the quaternary ammonia group of formula 2.

The meaning of the second Arabic numeral and the letters 8501002 f t / * 9 13 2 ters for some of the preferred R groups and quaternary ammonio groups is given below for clarification.

2

Second Arabic numeral> _R_ 1 = * methyl 5 2 * ethyl 3 = allyl 4 = propargyl 5 s cyclopentyl

Letter Group of formula 2 10 A * 1-methylpyrrolidinio B = pyridinio C = 2-amino-5-thiazolo [4,5-c] pyridinio ♦ * D = triaethylammonio E = 3-aminopyridlnlo 15 F = 3-formylaminopyridinio G * 3 -carbamoylpyridinio H '= 4-carbamoylpyridino I = 3-aminomethylpyridinio J »2-methylthiazolio 20 K * 3-hydroxymethylpyridinio L = 4-hydroxymethylpyridinio M * 4- (N-methylcarbamoyl) pyridinio N * 4-carboxypyridinio O = propylene pyridinio F = 3-carboxymethylpyridinio Q =. 4-carboxymethylthiopyridinio

In the primary evaluation of the compounds of the invention, the minimum inhibitory concentrations (MIC values) of the compounds were determined by the two-fold serial agar-3Q dilution method in Mueller-Hinton agar against 32 punches of test organisms in six groups. Table A shows the geometric means of the MIC values determined in these tests.

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16 (G +) - Ia: Penicillin-sensitive S.aureus (5 strains) (G +) - Ib Pen Penicillin-residual S_. aureus (5 strains) (G -) - Ia r Cephalothine-sensitive E. coli (2 strains), KI.pneumoniae (1 strain) and Pr. mirabilis (2 strains) 5 (G -) - Ib: Cephalothine resistant E. coli (3 strains) and KI. pneumoniae (2 strains) (G -) - II: M. morganii (1 strain), Ent, cloacae (2 strains) and Ser.

marcescens (2 strains) (G -) - no; Ps. aeruginosa (7 strains) Table B below shows the protective dose (PD / q) in mice for a number of compounds of formula 1 against selected microorganisms. Table C shows the blood levels of various compounds of formula 1 after intramuscular administration of the test compounds to mice at a dose of 20 mg / kg.

TABLE B

15 * PDS0 (mg / kg) S, aureus E. coli P. aeruginosa

20 Vegbinding Smith · Juhl A9843A

1-1S 0.44 0.028 7.7

1-1B 0.65 0.072 NT

1-1C 0.22 0.013 'NT

1-1 (2 0.95 0.021 5.92 25 1-1H 0.39 0.015 3.9

1-1J 0.35 0.029 NT

L-1K 0.53 NT NT

1-1 »0.96 NT NT

1-1K 2.0 'NT NT

1-10 0.26 0.17 NT

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1-3H 19 47 2S

1-4H 27 22 16 15 1-SH 22 32 18

In another aspect, the invention relates to methods of preparing the compounds of formula 1. The preferred procedures are shown in reaction schemes 1a, 1b and 1c, while an alternative procedure is shown in reaction scheme 2. The abbreviation "Ph" indicates a phenyl group. The -CH (Ph) ^ group is therefore the benzhydryl group, which is a preferred carboxyl protecting group.

2

When R contains a carboxyl group, it is desirable that the carboxyl group be protected with a conventional carboxyl protecting group such as the tert-butyl group. Y stands for chloro, bromo or jodo.

Reaction Scheme 1a shows two alternative methods of getting from compound 69 to compound 72. The direct route, using a tertiary amine of formula 71, is useful for the preparation of all compounds of formula 1. The indirect route via the compound of Formula 70, uses a secondary amine as a reactant, and is quaternized in the next step. The secondary amine RR'NH can be acyclic (e.g. dimethyl amine) or cyclic (e.g. pyrrolidine), and this indirect procedure is therefore suitable for the preparation of compounds of formula 1 wherein the quaternary ammonia group is acyclic or "mixed" acyclic / is cyclic. This indirect route is not suitable for the preparation of compounds of formula 1, in which the quaternary nitrogen is contained in a complete 8501002

ΐ X

18 unsaturated heterocyclic ring (e.g. pyridinio, thiazolio, 2-amino-5-thiazolo (4,5-c] pyridinoo, and the like).

Reaction scheme lb is a variation of. reaction scheme 1a wherein the 7-amino group of the starting material of formula 62 is protected in the form of a Schiff base during most reaction steps, and wherein the desired acid is added on the 7 side chain later in the synthesis. Otherwise, the general procedure is the same.

Reaction scheme lc is a further variation of reaction scheme lb. In the reaction schemes 1a and 1b, quaternization of the 10 3 side chain is the last step, but in reaction scheme 1c is. the last step acylation of the 7-amino group. The relationship between the reaction schemes 1a, 1b and 1c is shown in the flow chart shown on the formula sheet.

In reaction schemes 1a, 1b and 1c, the benzhydryl-15 group was shown as the preferred carboxyl protecting group. However, those skilled in the art will understand that other carboxyl protecting groups, which are well known per se, can be used. The acylating acid of formula 63 can be used in the form of a derivative thereof such as the acid halide, the activated ester, the mixed acid anhydride, etc., all of which are well known per se. Preferably it is used in the form of the acid chloride. The amino group of the acylating acid of formula 63 may also be protected by one of the usual amino protecting groups, for example N-trityl, N-for-myl and the like. The base used to convert the phosphonium iodide (formules 66 or 75) to obtain the phosphorylide (formules 67 or 76) can be NaOH, Na2Cu3, IRA-41Q (QH ~) resin, IRA (C032 " ) resin, or the like, or a mixture thereof. The chloroacetaldehyde used to convert the phosphorylide of formula 67 to the 3-chloropropenyl-3-cephem compound of formula 68 (or to convert compound 76 to compound 77) may be commercially available 40-50 % aqueous solution, be a distilled solution (e.g. 70%) or be the anhydrous aldehyde.

It has been found that the compound of formula 68 prepared from the compound of formula 67 (Scheme 1a) typically had a Z s E-35 ratio of about 2: 1 at the propenyl double bond. On the other hand, the compound of formula 68 prepared from compound 78 (Scheme 1b) typically consisted almost exclusively of the 2-isomer. The difference 8501002 f * 19 does not have to be due to the route used, but may have been caused by the conditions used in the Wittig reaction (67 in 68 or 76 in 77).

It has also been found that the use of a suitable silyl reagent such as N, 0-bis (trimethylsilyl) acetamide in the Wittig reaction (67 in 68 in Scheme 1a and 76 in 77 in Scheme 1b) improves yields and purity. of the compounds of formulas 68 and 77. The reaction is preferably carried out with 2-5 equivalents of the silyl reagent. When the chloropropenyl cephem of the formula 68 was reacted with Nal in acetone to form the iodopropenyl cephem of the formula 69, the double bond in the propenyl group was found to isomerize from Z to E during the iodination. In the case of a short reaction period, the configuration of the starting compound of the formula 68 was largely retained, while in the case of a long reaction period the primary »E isomer of the compound of the formula 69 was obtained. However, an excessive reaction time at high temperature gives a compound of formula 69 of lower purity. It has been found that about 10 minutes at 25 ° C and 2 hours at 5 ° C gives a pure compound of formula 69 in good yield. When using reaction scheme lc, it has been found that when iodination of.

% the compound of formula 74 with Nal, a purer compound was obtained if the acetone solution is diluted with CCl 4 when the iodination is essentially complete, and the isomerization portion of the reaction is carried out in the acetone-CCl 2 - mixture. When iodination of the chloropropenyl cephem of formula 77 to the iodopropenyl cephem of formula 79 was carried out with KI in DMF, the isomerization of the double bond from Z to E proceeded as fast as the iodination. The entire reaction was completed at room temperature within 45 minutes to form a pure compound of formula 79 without dilution with CCl 4 in the course of the reaction.

The compound of formula 72 was usually unblocked without purification, and the final product of formula 1 was purified by reverse phase column chromatography using a glass column containing the packing, removed from a Waters' Associates PrePAK-500 / Cg g- pattern.

Reaction Scheme 2 is similar to Reaction Scheme 1a except that the compound of Formula 83 (equivalent to compound 69 of Reaction Scheme 1a) is converted to the S oxide prior to quatemization.

8501002 T r 20

The compound of formula 85 is then reduced, and the rest of the reaction scheme. 2 is as reaction scheme 1a. In reaction scheme 2, it is preferred that the amino group of the 7 side chain be protected with a known amino protecting group such as the trityl group.

The acylating acids of formula 63 are either known compounds or are readily prepared according to published procedures. European Patent Publication 7.47Q published on October 12, 1983 (the application was published on February 6, 1980) gives examples for the preparation of compounds of formula 63, wherein R 10 represents methyl, ethyl, propyl and isopropyl. The aforementioned

U.S. Patent 4,390,534 gives examples of the preparation 2 of a wide variety of compounds of formula 63, wherein R represents, for example, cyciopentyl, 2-cyclopents -1-yl, allyl, 2-propenyl, 1-tert-butyloxycarbonyl- 1-methyl ethyl 1,1-tert-butyloxycarbonyl-1-15 cyciopentyl, 1-ethoxycarbonyl-1-methyl-ethyl, tert-butyloxycarbonylmethyl, 1-tert-butyloxycarbonyl-2-methylpropyl, trityl and the like.

The compound of formula 62 (7-amino-3-chloromethyl-3-cephem-4-earboxylate), which is used as starting material in reaction schemes 1a, 1b and 1c, is a known compound.

The tertiary amines of formula 71 (and the secondary aines RR'NH) used to prepare the quaternary ammonia compounds of the invention are either known compounds or readily prepared by those skilled in the art. Many of the amines are commercially available.

The present invention also provides a method of preparing compounds of formula 1, wherein R * hydrogen or 2 is a conventional amino protecting group, R hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl- or cycloalkenyl ring with 3 to 6 carbon atoms, or one of the groups of the formulas 25 - 28, wherein R represents hydrogen, (lower) alkyl or carboxyl, 4 5 X halogen, hydroxy or (lower) alkoxy and R and R are each independently hydrogen, methyl or ethyl or R and R together with the carbon atom to which they are attached may form a cycloalkylidene ring of 3 to 5 carbon atoms, and the group of formula 2 a quaternary ammonium group, as well as non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof, comprising a »8501002 2 * t« 21 reaction of a compound of the formula 87 wherein R equals «2 R or a group is with one of formulas 88 or 89, wherein X, 4 5 1 R and R are as defined above, B is a conventional carboxyl protecting group, B is hydrogen or a conventional amino protecting group, Z is chloro, bromo or iodo and m is equal to 0 or 1, with a tertiary amine of the formula 71 (or successively with a secondary amine RR'NH and a compound of the formula R "Z) and when m is equal to 1, a reduction of the sulfoxide by conventional means, and subsequent removal of all blocking groups by conventional means.

The present invention also provides a process for preparing compounds of formula 1 wherein R * hydrogen or 2 is a conventional amino protecting group, R hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring with 3 to 6 carbon atoms, or one of the groups of formulas 25 to 28, wherein hydrogen is (lower) alkyl or carbon-4 xyl, X is halogen, hydroxy or (lower) alkoxy, and R and R each independently is hydrogen, methyl or ethyl, or R and R together with the carbon atom to which they are attached may form a cycloalkylidene ring 20 having 3 to 5 carbon atoms, and the group of formula 2 a quaternary ammonia group, as well as non-toxic pharmaceutically acceptable salts and physiologically hydrolysable esters thereof, comprising an acylation of a compound of formula 82 with an acid of the 2 '* formula 90, or with an acylating derivative of this acid, wherein R - 2 Is R or is one of the groups of formulas 88 and 89, wherein 4 5 1 X, R and R are as defined above, B is a conventional carboxyl protecting group and B is hydrogen or a conventional amino -protective group.

The reactions are performed in a non-aqueous organic solvent such as dimethyl sulfoxide, hexamethylphosphoramide, methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, acetonitrile and the like, or mixtures of such solvents. The reactions are conveniently conducted at a temperature from about -10 ° C to about + 50 ° C? it is usually preferred to carry out the reactions at room temperature. During the quaterization step, preferably at least 1 mole of the tertiary amine should be used 8501002 22 * 1 τ r 'per mole of the compounds of formulas 69, 79, 83 or 84; usually it is preferred that about 25 to 100% excess of the tertiary amine be used.

Carboxyl protecting groups, suitable for use as B1 in the above reactions, are known to those skilled in the art and include aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl and diphenylmethyl (benzhydryl); alkyl groups such as tert-butyl; haloalkyl groups, such as 2,2,2-trichloroethyl, and other carboxyl protecting groups described in the literature, for example, in British Patent 1,399,086. It is preferred that carboxyl protecting groups are used which can be easily removed by acid treatment. Particularly preferred carboxyl protecting groups are the benzhydryl and tert-butyl groups.

phmino protecting groups, suitable for use as 2B, are also well known, and include the trityl group and acyl groups such as chloroacetyl, formyl and trichloroethoxycarbonyl. Preferred are amino protecting groups which can be easily removed by acid treatment, for example the trityl group.

When the cephalosporin core is used in the form of the 1-oxide (m-1), the 1-oxide is prepared according to known procedures, for example, by oxidation with m-chloroperbenzoic acid, peracetic acid, sodium tungstate, etc. The 1-oxide can are then reduced according to known procedures, for example, by reduction of the corresponding alkoxysulfonium salt with iodide ions in an aqueous medium.

The alkoxysulfonium salt itself can be readily prepared by treating the 1-oxide with, for example, acetyl chloride.

In another aspect, the invention relates to new intermediates of the formula 91, wherein Z is chloro, bromo or 2 iodo, R is hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring having 3 up to 6 carbon- 3

atoms, or one of the groups of formulas 25-28, wherein R

hydrogen, (lower) alkyl or carboxyl, X is halogen, hydroxy or (low) al-4 5 koxy, and R and R are each independently hydrogen, methyl or 4 5 ethyl or R and R together with the carbon atom to which they are bonded to form a cycloalkylidene ring with 3 to 5 carbon atoms, as well as salts and esters thereof. Also included are compounds of "8501002] $ 23 mulch 91, wherein the amino and / or carboxyl groups are protected by conventional amino protecting or carboxyl protecting groups.

In yet another aspect, the invention relates to novel intermediates of formula 92 wherein R is hydrogen or a conventional carboxyl protecting group, and R, R and R are the same or different and represent hydrogen, hydroxy, (lower) alkyl or (lower) alkoxy; or a salt, solvate, hydrate or ester thereof.

In yet another aspect, the invention relates to novel intermediates of formula 82, wherein the group of formula 10L 2 is a quatera ammonia group; or a salt, ester, solvate or hydrate thereof.

The terms acylamino and acyloxy used herein refer to an acylated amino or acylated hydroxy group in which the acyl group (lower) alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, etc.), aroyl (eg benzoyl, etc.). ), (low) alkanesulfonyl (eg mesyl, ethanesulfonyl, etc.) or azylsulfonyl (eg benzenesulfonyl, tosyl, etc.).

The terms "(lower ialkyl", "(lower) alkoxy",, r (lower) alkylthio ", and the like used herein refer to straight or branched chain alkyl, alkoxy, alkylthio (and the like) groups having 1 to 6 carbon atoms.

The terms (lower) alkenyl and (lower) alkynyl refer to alkenyl or alkynyl groups with 2 to 6 carbon atoms.

8501002 * r 24

Example I

7- [2- (5-amino-1,2,4-thiadiazol-4-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinio) -1-propen-1-yl] -3- cefem-4-carboxylate (1-1A with: formula 93) 5 To a. solution of diphenylmethyl 7— [2— (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-ce -fem-4-carboxylate (65-1) (Z / E = 2/1, 150 mg, 0.21 mmol) in 2 ml ethyl acetate in one portion stirring in a solution of 1-methylpyrrolidine (36 mg, 0.42 mmol) in 1 ml ethyl acetate. The mixture was stirred for 15 min and diluted with 10 ml of isopropyl ether to form a precipitate which was collected by filtration. A mixture of the solid (130mg), formic acid (1ml) and concentrated HCl (0.1ml) was stirred at room temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure, diluted with 20 ml of water and filtered. The aqueous solution was passed through an inverted phase column (the packing of PrepPAK-500 / Cg cartridge, 100 ml) eluting with water and 10% CHgOE. The desired fractions were collected, concentrated under reduced pressure to a small volume and freeze-dried. 13 mg (12%) of the title compound (1-1A) (Z / E = 20 1/1), melting point above 280 ° C (decomposition), were obtained.

IR 1 V cm 1, 3400, 1760, 1660, 1610. max UV UV phosphate buffer (pH 7) nm (E1%) 236 (372), 288 (322).

max 1 cm NMR s ê D2 ° 2.31 (4ff, », K ~), 3.12 (3Ö, s, N-CH,), 3.6 (5H, m, PPm \ - - 3 25 ^ 1 2-fl '& Γ I), 3.78 (1H, s, 2-H), 4.1 (2H, d, J = 8, CH ^ N),

H

4.2 (3H, s, OCH ^), 5.36 (1H, d, J = 4.5, 6-H), 5.95 (3H, m, 7-H & 3 ~ CH = GH), 6.66 (1 / 2H, d, J = 10, 3-CH cis), 7.0 (1 / 2H, d, J = 16, 3-CH trans).

30 Example. II

7- E2- (S-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-pyridinio-1-propen-1-yl] -3-cephem-4 -carboxylate (1-1B with formula 54)

A mixture of diphenyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) "2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cefem-4-carboxy-35 Iate (69-1) (E, 716mg, 1mmol), pyridine (158mg, 2mmol) in 1ml of dim-8501002 '- - 25 ethyl sulfoxide (DMSO) was added for X stirred at room temperature for an hour.

20 ml of ethyl acetate was added to the mixture to precipitate a solid (620 mg) / which was added to 6 ml of formic acid containing 60 mg of sodium bisulfite. The mixture was stirred at 40 ° C for 30 min and evaporated to dryness. The residue was dissolved in 40 ml of water and insoluble matter was removed. The aqueous solution was placed on a reverse phase column (PrepPAK-500 / Cg, 100ml) eluting with 300ml water and 800ml 5% aqueous CH2 OH, and the eluate was monitored with UV (254 nm) and HPLC. The fractions (5% aqueous CH 2 OH) containing the desired product were combined, concentrated to a small volume and lyophilized. The yield was deceived 40 mg (8%) of the title compound (1-1B), melting point above 200 ° C (decomposition).

IR s y1® * cm "1 3350, 1760, 1660, 1600. r max UV * \ phosphate buffer (pH: 7) m (EJ%} 24Q (352) 258 (366) / 267 (279), max 1 cm 15 290 (469).

NMR ï | D2 ° + DHS0-d6 3.74 (2H / br-s, 2-H), 4.20 (3H, s, OCH,), 5.92 (IH, ppm d, J = 4.5 , 7-H), 6.15 (1H, m, 3-CH = CH), 7.04 (1H, d, J »16, 3-CH trans), 8.2 (2H, m, Py-Hg s), 8.62 (1H, m, Py-H4), 8.97 (2H, m, '^ 2.6 ^ 20

Example III

7- [2- (5-fimino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-pyridinio-1-propen-1-yl] -3-cephem- 4-carboxylate (1-1B of formula 95)

The chloropropenyl compound, diphenylmethyl 7-C2— (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-chloro-1-25-propen-1-yl) - 3-cephem-4-carboxylate (68-Ί) (Z, 937 mg, 1.5 mmol) was added to a stirred solution of pyridine (237 mg, 3 mmol) in 3 ml DMSO containing Nal (11 mg, 0.075 mmol). The mixture was left overnight at room temperature in the dark. The mixture was diluted with 30 ml of ethyl acetate to separate a precipitate which was then collected by filtration, washed with 10 ml of ethyl acetate and dried to give 350 mg of the blocked product. The precipitate was treated with 3.4 ml of formic acid, containing 34 mg of sodium bisulfite, for 30 min at 40 ° C. After removal of the formic acid, the residue was purified by reverse phase column chromatography (packing of PrepPAK-5Q0 / Cg cartridge, 100 ml) by eluting with 5% aqueous CHgQH. The fractions containing the desired product were combined by HPLC analysis, evaporated under reduced pressure and lipilized. 41 mg (5.5%) of the title compound (1-1B) were obtained (Z / E = 4/1). Melting point above 200 ° C (decomposition).

IR Ï VKBrcm "1 3300, 1760, 1660, 1600. r max OV: Λ phosphate buffer. (PH7) ^ (EJ%) 237 (386), 250 (377), 258 (369), λ max 1 cm 5 265 (347), 280 (311).

NMR? SD2 ° 3.45 & 3.76 (1Η, d, J = 16, 2-H), 4.18 (3H, s, OCH.), Ppm j 5.34 (3H, m, CH =: CH -CH2 & 6-H), 5.92C2H, d, H = 4.5, 7-H), 6.58 (4 / 5H, d, J * 11, 3-CH cis), 7.03 ( 1 / 5H, d, J = 16, 3-CH trans), 8.12 (2H, m, Py-H3 g), 8.56 (1H, m, Py-H4), 10.822 (2H , m, Py-H 2 · 6).

Example IV

7- [2- (5-amino-1,2,4-thladiazol-3-yl) -2-methoxyiminoacetamido3-3- [3- (2-amino-5-thiazolo [4,5-c 3 pyridinio) -1-propen-1-yl 3 -3-cephem-4-carboxylate (1-1C of formula 96) 15 A stirred solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazole-3) -yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3 'cephem-4-carboxylate (69-1) (E-isomer, 714 mg, 1 mmol), 2 -aminothiazolo- [4,5.-c] pyridine [prepared according to the procedure of T. Takahashi et al., Pharm. Bump (Japain), 2.34 (1954)] and 1 ml dry DMSO was kept at room temperature for 1 hour. 20 ml of ethyl acetate were added to the reaction mixture, whereby a yellow spear (710 mg) was obtained. 7 ml of formic acid and 70 mg of sodium bisulfite were added to the powder (70 mg), and the mixture was stirred at 40 - 45 ° C for 30 min. After evaporation, the residue was triturated with 40 ml of water. Insoluble was filtered off, and the filtrate was chromatographed on a reverse phase column (PrepPAK-500 / Cg, 100ml), with water and 10% CH 2 OH as eluent. The fractions containing the desired product were combined, and the solvent was removed under reduced pressure. Lyophilization gave the desired product (1 - 1C) as a colorless amorphous powder of the E isomer.

The yield was 110 mg (19%). Melting point was above 200 ° C (decomposition).

IR. VV cm cm 1 3300, 1760, 1660, 1630, 1600. r max ÜV r fos phosphate buffer (PS'7) nn (E1%) 245 (499), 285 (286).

Amax 1 cm NMR t ppm ° "" ^ 6 + D2 ° 3.86 (3H, s, OCHg), 4.98 (1H, d, J = 4.5, 6-H), 5.2 35 ( 2H, m, CH = CH-CH2), 5.57 (1O, m, 3-CH = CH), 5.96 (1H, m, 7-H), 7.16 (1H, d, J = 16) .3-GH trans), 8.36 & 8.45 (1H, d, J = 7, Py-H), 8.92 (1H, s, Py-H).

8501002 1 * 27

Example V

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-trimethylammonio-1-propen-1-yl) -3-cephem- 4-carboxylate (1-1D with formula 97)

To a solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-y 1) -3- cefem-4-carboxylate (69-1) (Z / E = 2 / l, 490 mg, 0.68 mmol) in 14 ml ethyl acetate was dissolved in a portion of 0.1 M trimethylamine in 13.6 ml of ether were added. The mixture was stirred and evaporated to dryness for 10 min, and the residue was triturated with 20 ml of ether. The solid obtained (490 mg) was added to 0.2 ml of trifluoroacetic acid containing a drop of anisole. After stirring for 1.5 hours, the mixture was evaporated to dryness under reduced pressure and the residual oil was triturated with 20 ml of ether. The resulting precipitate was collected by filtration and dissolved in 20 ml of water. Some insoluble matter was removed and the aqueous solution was eluted on a C 1 g reversed phase column (the packing of PrepPAK-500 / C 2 g cartridge, Waters' 30 ml) with water as eluent. Fractions containing the desired compound were combined and concentrated to a small volume and lyophilized. 30 mg (9.2%) of the title compound (1-1D) / Z / E * 1/1) were obtained as a colorless amorphous powder, melting point above 150 ° C (decomposition).

IR γKBr cm 1 1 3300, 1770, 1670, 1605. max UV j phosphate buffer (pH 7) ((EJ%.) 236 {389) 287 (343).

* max 1 cm NMRs £ ° 2 ° 3.45 & 2.7 (1H, d, J = 16, 2-H), 3.81 (1H, s, 2-H), PE® $ 25 4.1 (2H, d, J = 8, -CT ^ H), 4.21 (3H, s, OCHg), 5.39 (1H, d, J = 4.5, 6-H), 5.95 (2fi , m, 3-CH = CH & 7-H), 6.61 (1 / 2H, d, J = 11, 3-CH cis), 7.05 (1 / 2H, d, J = 16, 3- CH trans).

Example VI

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminopyridinii) -1-propen-1-yl3-3- cefem-4-cafboxylate (1-1E of formula 98) Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1 -propen-1-yl) -3-cephem-4-carboxylate (69-1), (S, 716 mg, 1 mmol) was added to a stirred solution of 3-aminopyridine (188 mg, 2 mmol) in 1 ml DMSO. The mixture was stirred for 1 hour and diluted with 20 ml of ethyl acetate. The resulting 8501002 * 28 'precipitate was collected by filtration, washed with ethyl acetate and dried, yielding 520 mg of a yellow powder. A mixture of the powder (500 mg), formic acid (5 ml) and sodium bisulfite (50 mg) was stirred at 40 ° C for 30 min. The mixture was concentrated under reduced pressure, dissolved in 40 ml of water and filtered to remove insolubles. The aqueous solution was chromatographed on a reverse phase column (packing of PrepPAK-500 / C. Q, 100 ml) with 7.5% aqueous CH, OH elution. The fractions containing the desired compound were evaporated and lyophilized. The title compound (1-1E) was obtained in an amount of 7 mg, 1.4%. It melted above 185 ° C (decomposition).

IR s V ** cnT1 3400, 1765, 1675, 1620, 1600. r max UV. X phosphate buffer (pH 7) ^ (J>%.} 246 (40 = 3), 290 (468). E max 1 cm NMR iD2 ° 3.72 (2H, m, 2-H), 4.14 (3H, s, OCH,), 5.35 (3H, m, 6-H & 15 ppm o CH = CH-CH2) , 5.9 (1H, d, J = 4.5, 7-H), 6.1 (1H, m, 3-CH = CE), 7.05 (1H, d, J = 16, 3-CH , trans), 8.1 (1H, m, Py-Bg), 8.54 (1H, br-s, Py-Bg), 8.68 (1Ö, m, Py-H4), 9.4 (1H , m ,.

Py-B ^).

Treatment of compound 69-1 (716 mg, 1 mmole) with 3-tert-butoxycarbonylaminopyridine (324 mg, 2 mmole) according to a similar procedure as described above gave 12 mg (2.3%) of the compound 1-1E.

Example VII

22 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido3-3- [3-amino-1-pyridiniO) -1-propen-1-yll-3- cefem-4-carboxylate (1-1E with formula 99)

A mixture of diphenylmethyl 7- (2- (5-amino-1,2,4-thia-diazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (69-1) (Z / E = 2 / l, 500 mg, 0.7 mmole) and 3-aminopyridine (66 30 mg, · 0.7 mmole) in 1 ml of dimethyl sulfoxide stirred at room temperature for 20 min. The mixture was diluted with 10 ml of ethyl acetate and 10 ml of ether, and the resulting precipitate was collected by filtration, washed with 10 ml of ether and dried. The quatemized salt was dissolved in 3 ml of formic acid Contained 3 ml of concentrated HCl and stirred at room temperature for 1.5 h The mixture was evaporated to dryness under reduced pressure The residue was dissolved in 10 ml of 2% HCl and filtered with 8501002 V * 29 f. aqueous layer was chromatographed on a reverse phase column (PrepPAK-500 / C, 100 ml) After washing with 500 ml of water, the column was eluted with 5% aqueous CH 2 OH. The fractions containing the title compound thing containing were combined, under vermi third pressure concentrated 5 and lyophilized. 15 mg (4.2%) of the title compound (1-1FE) (Z / E = 1/1) were obtained as a colorless amorphous powder. The melting point was above 160 ° C (decomposition).

ITBR-1 IR: V cm 3400, 1765, 1675, 1620, 1600.

max UV 1 ° phosphate buffer (pH 7) nm (E.1%) 244 (434), 287 (333).

max 1 cm

NMR: ^ DMS0-d6 + D20 3 73 (2H, a) 4 14 (3H, Sf OCH,), 5.35 (3H, m, 6-H

ppm j & CH = CH-CH2), 6.0 (2fi, m, 7-H & 3-CH = CH), 6.6 (1 / 2H, d, J * U, 3-CH cis), 7 0.05 (1 / 2H, d, J = 16,3-CH trans), 8.08 (1H, m, Py-Hg), 8.6 (2H, m, Py-H4 6), 9.4 ( 1H, m, 15 *

Example VIII

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-formylaminopyridinio) -1-propen-1-yl-3-cephem- ° 4-carboxylate (1-1F of formula 100)

A mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thia-20-diazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) 3-cephem-4-carboxylate (69-d), (E, 716 mg, 1 mmctl) and 3-formylaminopyridine [prepared according to the procedure of N. Enomoto et al., Bull. Chem. Soc. Japan, 45, 2665 (1972)] (244 mg, 2 mmol) in 2 ml of DMSO was stirred at room temperature for 1 hour and poured into 200 ml of ethyl acetate. The precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (50 mg) and sodium bisulfite (50 mg) in 5 ml of formic acid was stirred at 40-50 eC for 80 min and evaporated to dryness under reduced pressure. The residue was dissolved in 40 ml of water, neutralized with NaHCO 3 and then filtered to remove insoluble material. The clear filtrate was chromatographed on a reverse phase column, PrepPAK-500 / C ^ (100 ml), with water and 5% CRjOH, 10% CH3 OH, 20% CEjOH and 30% CH2 OE. The fractions containing the desired compound were combined, concentrated under reduced pressure and lyophilized. 16 mg of 35 (2.9%) of the title compound (II-IF) (-E) were obtained as a tan powder. The melting point 8501002 was 30 ° C above decomposition.

IR ï V ^ cnf1 3340 (br), 1760, 1670, 1620 (br), 1590. max OV r Xphosphate buffer (pH 7) ^ (1%) 21Q (42q) 248 (3è2) 290 (474) # max 1 cm r NMR: S 3.68 (2H, br, 2-H), 4.15 (3H, s, OCH.), 5.91 (1H, d, 5 ppm. -i J = 4.5, 7- > H), 6.25 (1H, m, CH = CH-CH2), 6.98 (1H, d, J = 16, 3-CH trans), 8.8 - 7.9 (4Ξ, m, Py -H), 9.38 (1H, br, NHCHp.

Example IX

7- [2- (5-Amino-1,2,4-thiadiazole-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-10 carbamoylpyridinio) - "i -propen-1 ° yl] 3 ° Cefem-4-earboxylate (1-1G with formula 101)

To a solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -1-methoxyiminoacetarnido] -3- (3-iodo-1-propen-1-yl) -3 -cephem-4-carboxylate (69-1) (E, 716 mg, 1 mmol) in 2 ml of DMSO, nico-15 tinamide (244 mg, 2 mmdl) was added, and the mixture was stirred at ambient temperature for 1.5 hours and poured into 200 ml of ethyl acetate while stirring. The resulting precipitate was collected by filtration. The quaternized salt (500 mg) was dissolved in 5 ml of formic acid in the presence of 50 mg of sodium bisulfite, and the mixture was heated at 40-50 ° C for 20 min with stirring, and evaporated to dryness. The residue was dissolved in 40 ml of water and an insoluble solid was filtered off and washed with a small amount of water.

The filtrate and washings were combined and chromatographed on an inverted phase column, PrepPAK-500 / Cg (100ml). After eluting with water and successively 5%, 10% and 20% aqueous CH 2 OH, the fractions containing the desired material were combined, concentrated under reduced pressure and freeze dried. The yield was 21 mg (3.8%) of the title compound (1-Ig) (OE) as a yellow powder. The melting point was above 175 ° C (decomposition).

30 IR V ncrn "1 3340 (br), 1760, 1670, I6Q0. R max ί phosphate buffer (pH <7) (EJ»,, 235 (236), 274 (sh, 405>, 290 'max 1 cm (446).

NMR ί 3.68 (2Ö, br, 2-Ή), 4.15 (3H, s, OCH.), 5.32 (1H, d, ppm o J = 4.5, 6-H), 5, 45 (1H, d, J = 7, CHCH-CBg), 5.88 (1H, d, 35 J = 4.5, 7-H), 6.15 (1Ξ, dt, J = 16 & 7, 3 -CH = CH), 7.00 (1H, d, J = 16, 3-CH trans), 8.23 (1H, .. m, Py-Hj), 9.03 (2H, m, Py-H4g 6), 9.34 (1H, s, Py-B2).

8501002 * * 31

Example X.

7- [2- (5-Amino-1,2,4-thiadiazol-i-3-yl) -2-methoxyijninoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (1-1H of formula 102) 5 To a stirred solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3-cephem-4-carboxylate (69-1) (E ', 716 mg, 1 mmol) in 2 ml dry DMSO became isonicotinamide (244 mg , 2 mmol). The mixture was stirred at room temperature for 1 hour and then poured into 200 ml of ethyl 10 acetate. The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of the quaternised material (400 mg) and sodium bisulfite (40 mg) in 4 ml of formic acid was heated at 40-50 ° C for 1 hour, and evaporated under reduced pressure. The crude solid was dissolved in 40 ml of water.

After filtration of an insoluble material, the filtrate was chromatographed on a reversed phase column (packing vein PrepPAK / Cig, 100 ml) using water and 5%, 10%, 20% and 30% aqueous CH2 OH as eluent. The fractions containing the desired compound were combined, evaporated and lyophilized. 21 mg (3.8%) of the title compound (1-1H) (> E) were obtained as a pale yellow powder. The melting point was above 180 ° C (decomposition).

IR: V cm 1, 3340 (br), 1760, 1670, 1600.

r max UV: ^ phosphate buffer (pH-7) ^ (E [1%;} 222 (362), 285 (452).

max 1 cm NMR 3,6 3.68 (2H, br, 2-H), 4.15 (3H, s, OCH,), 5.33 (lfi, d, ppm j J = 4.5, 6-H) , 5.46 (2fi, d, J = 7, CH = CH-CH2), 5.90 (1H, d, 25 J = 4.5, 7-H), 6.17 (1H, dt, H = 16 & 7, 3-CH = GH), 7.02 (1fi, d, J = 16, 3-CH trans), 8.43 & 9.09 (2H, d, J = 7, Py-H each) .

Example XI

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido3-3- [3-30 aminomethylpyridini] -1-propen-1-yl] -3-cephem-4 -carboxylate (l-II of formula 103)

A mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thia-diazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) - 3-cephem-4-carboxylate (69-1) (E, 716 mg, 1 mmol) and 3- (t-butyloxycarbonylamino-35 methyl) pyridine (516 mg, 2 ramol) in 2 ml DMSO was added for 30 min at 8501002 Κ λ '32 stirred at room temperature. The mixture was poured into 200 ml of ethyl acetate, and the precipitate was collected by filtration, washed well with ethyl acetate and dried. A mixture of the quaternized salt (500 mg), sodium bisulfite (50 mg) in 5 ml of formic acid was stirred at 40-50 ° C for 80 min and evaporated to dryness under reduced pressure. The residual solid was dissolved in 40 ml of water, and the mixture was neutralized with NaHCO 2. Insoluble material was filtered off and the filtrate was chromatographed on an inverse phase column (packing of PrepPAK-500 / C, cartridge, 100 ml) eluting 1 w 10 successively with water, 5%, 10%. s, 20% and 30% aqueous CH 2 OH.

The fractions containing the desired compound were combined, evaporated and lyophilized. Obtained. 10 mg (1.8%) of the title compound (1-lil) 0E) as a tan powder.

IR 1 cm-1 3380 (br), 1760, 1650 (sh), 1620 (sh). f max 15 UV = λfosate buffer ί®8'7 »n» (ij *.) 235 (sh, 260), 2.86 (370).

"max 1 cm NMR t SD 2 ° * NaHCO 3 3f, 68 (2H, br, 2-H), 4.16 (3O, s, OCH.), 6.98 (1H, ppm, 3 d, J = 16 , 3-CH trans), 8.05 (1H, m, Py-Hg), 8.50 (1H, m, Py-H4), 8.80 (2H, m, Py-E2.

Example XII

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetoamido3-3- [3- (4-carbamoylpyridino) -1-propen-1-ylI-3-cephem -4-carboxylate (1-1H of formula 102)

A mixture of diphenylmethyl 7- (2- (5-amino-1,2,4-thia-diazol-3-yl) -2-methoxyiminoacet amidol -3- (3-iodo-1-propen-1-yl) - 3-cefem-25 4 car carboxylate (69!!) (E 'isomer, 4.1 g, 5.7 mmol) and isonicotinamide (1.4 g, 11 mmdl) in 6 ml of dry DMSO was added for 2 hours at stirred at room temperature while the reaction was monitored by TLC (silica gel plate, CHCl 4 ICHgOH = 3 1) The reaction mixture was diluted with 100 ml ethyl acetate to separate a yellow gum which was treated at 45 ° C for 30 min with 40 ml of formic acid and 390 mg of sodium bisulfite The resulting solution was evaporated to dryness, the residue was dissolved in 100 ml of water and insoluble matter was removed by filtration.

The combined filtrate and water used as washing liquid were placed on top of a column containing a reverse phase packing (PrepPAK-500 / Cg, 120 ml). The column was eluted with water. The eluate was collected in 8501002 <33. 300 ml fractions and followed with UV (254 nm) and HPLC (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer, pH 7.2 containing 20% CH 2 OH). Fractions 4 and 5 were combined and concentrated to a small volume. Lyophilization gave 250 mg (8.1%) of the title compound 1-1 H, melting point above 180 ° C (decomposition).

The spectra showed that the product was identical to the product obtained in Example X.

Preparation of the hydrochloride. - To a suspension of the compound 1-1H (98 mg, 0.18 mmol) in 1 ml CH 2 OH, 0.1 ml 10% 10 HCl was added, and the mixture was stirred for 5 min. To the resulting yellow solution, 100 ml of acetone was added to give a precipitate which was collected by filtration, washed with 2 x 10 ml of acetone and dried under reduced pressure. The hydrochloride salt of 1-1H was obtained in the form of a colorless powder. The yield was 88 mg (79%). The melting point was above 190 ° C (decomposition).

IR: V KBr cm-1 3300, 1770, 1680, 1620.

max TO: λ phosphate case <1®7) mi «J *} 227 <385), 286 (374).

^ max 1 cm NMR: è ° 2 ° 2.32 (IB, s, acetone-H), 3.79 (2S, br-s, 2-II), 4.17 (3H, s, ppm 0CB3), 5.34 (IS, d, J = * 4.5, 6-H), 5.49 (2H, d, J * 7, 20 CS = CH-CH2), 5.93 (1H, d, J = 4.5, 7-H), 6.28 (IS, dt, J-16 & 7, 3-CH = GH), 7.15 (IS, d, J = 16, 3-GH), 8.43 & 9.1 (2H, d, J «7> Py-H each).

Example XIII

7- (2- ° (5-Amino-1-2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido3-3- [3- (2-25 methylthiazolio) -1-propen-1-ylj-3- cefem-4-carboxylate (1-1J with formula 104)

To a mixture of diphenylmethyl 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido1-3- (3-iodo-1-propen-1-yl) -3- ce-fem-4-carboxylate (69-1) (E, 714 mg, 1 mmol) and 2-methylthiazole [prepared according to the procedure of RP Kurkjy, EV Brown, J.Am.Chem.Soc., 74 5778 (1952)] (198 mg, 2 mmol) in 10 ml of dry CH 2 Cl 2, AgB? 4 (90% pure, 217 mg, 1 mmdl) was added at -20 ° C. The mixture was stirred at room temperature for 30 min and filtered The precipitate was extracted with 3 x 20 ml 10% CH 3 OH-CHCl 3 The combined extracts were washed with 2 x 5 ml brine, dried over MgSO 4 and evaporated to give a yellow residue with isopropyl ether, 85 0 1 0 0 2

V

34. *> was crushed and filtered. 350 mg of the quaternized product were obtained. A mixture of this solid, 35 mg of sodium bisulfite and 3.5 ml of formic acid was stirred at 40 ° C for 30 min. The mixture was concentrated to remove the formic acid, and the residue was diluted with 40 ml of water. Some solid was removed by filtration. The filtrate was placed on a reverse phase column (PfepPAK-500 / Cg, 100 ml). The column was successively aqueous with 200 ml water, 400 ml 5% * a. CH2 OH and 300 ml 10% aqueous CH30H dined. The fractions containing the desired product were combined on the basis of HPLC analysis 10 (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer pH 7.2, containing 20% CH 2 OH). The combined solution was concentrated to a small volume and lyophilized. 40 mg (7.7%) of the title compound (1-U) CE) were obtained. The melting point was above 195 ° C (decomposition).

IS I; v ** CmT1 3300, 1760, 1660, 1600.

max sf03faatbu £ fer (pB 7). You; 238 ^ 292 ^.

'' max 1 cm. JC D.O + DMSO-cL 3.06 (3E, s, thiazole-CB-), 3.74 (2H, br-s, 2-H), NMR%. 9 2 o —3

Ppm 4.19 (3Ö, s, OGH3>, 5.92 (IS, d, J = 4.5, 7-H), 6.1 (1H, m, 3-CH = GH), 6.8 (1H, d, J = 16, 3-CH trans), 8.04 & 8.23 '(1H, d, J = 4, thiazole-B each).

Example XIV

7 ° P 2 ° (5-flmino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamidol -3- [3- (4- 'hydroxymethylpyridinio) -1-propen-1-ylj -3 ° cefem -4-carboxylate (1-lL with formula 105)

A mixture of diphenyl 7 - [2- (5-amino-1,2,4-thiadiazol-25 3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) - 3-cephem-4-carboxylate (69-1 ((E-isomer, 1.07 g, 1.5 mmol), 4-hydroxymethylpyridine (818 mg, 7.5 mmdi) in 4.5 ml CH3CN and 3 ml of CH 3 OH was stirred under a nitrogen atmosphere for 1 hour at room temperature After removal of the solvents by evaporation, the residual oil was triturated with isopropyl ether, collected by filtration, and washed with 10 ml of a mixture of isopropyl ether and methanol (3: 1) yielding 1.28 g of the quaternized cefemester in the form of a yellow powder A solution of the quaternized ester (1 ', 25 g) and 600 mg of sodium bisulfite in 10 ml of 85% formic acid was added for 1 Stirred under a nitrogen atmosphere at room temperature for one hour After adding 5 ml of 85% formic acid to the mixture, the mixture was stirred under the same conditions for an additional hour, Toluene was added and h The reaction mixture was azeotrope evaporated under reduced pressure. The residue was triturated with acetone to give 1.17 g of the crude formate of the title-5 compound. A suspension of this compound (Γ, 15 g) in 100 ml of water was filtered to remove insolubles, which were washed with 2 x 10 ml of water. The filtrate and washings were combined and subjected to reverse phase column chromatography. The column packed with the packing removed from a prepPAK-500/10 C, 0 cartridge column (Waters, 60 ml) was developed with water, 5% methanol and 10% methanol successively. The fractions containing the desired compound were combined, concentrated under reduced pressure and precipitated by addition of acetone to give 100 mg of the title compound (1-UL) or a light yellow powder.

To a suspension of 90 mg of the powder in 9 ml of methanol, 1 M HCl was added in 0.5 ml of CH 2 OH and the mixture was stirred at room temperature and concentrated under reduced pressure. Isopropanol was added to the concentrate, precipitating 77 mg of the hydrochloride of the title compound. It was a light yellow powder. The melting point was above 190 ° C (decomposition).

IR iy ^ cm ”1, 1775, 1670, 1635, 1530. Max phosphate buffer (pH> 7) ÜV: X nm (£), 230 (22600), 264 (sh, 16300) max NMR: & ΰ2 ° 3.83 (2H, br, 2-CH), 4.17 (3H, s, OCH,), 5.06 (2H, s, ppm, 25 O -CH2aH), 5.36 (1H, d, J = 4, 5 Hz, 6-H), 5.41 (2H, d, J = 7Hz, CH = CH-CB2), 5.94 (1fi, d, J = 4.5 Hz, 7-H), 6.36 (1fi, dt, J »16 and 7 Hz, CS = CHCH2), 7.13 (1H, d, J = 16 Hz, CH = CH-CB2), 8.08 and 8.83 (2H, d each, J = 7 Hz, Py-H).

Example XV

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- [3- (4-carbamoylpyridiniio) -1-propen-1-yl] -3 -cephem-4-carboxylate (1L2E with formula 106)

To a solution of 200 mg of 7-amino-3- [3- (4-carbamoyl-35-pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride (E-isomer) in 5 ml 50% aqueous acetone in portions 190 mg of 2-ethoxyimino-2- (5-8501002 * 36 amino-1,2,4-thiadiazol-3-yl) acetyl chloride hydrochloride [prepared according to the procedure described in the published Japanese Patent Application (Kokai) 57-24389 (2/8/8 = 2)] was added and the mixture was adjusted to a pH with about 1 ml 2N Na 2 CO 2. from 6.5 - 7.0. The reaction mixture 5 was stirred at 10 ° C for an hour, acidified with 1N HCl to a pH of 2 and evaporated under reduced pressure. The residue was filtered and the filtrate was chromatographed on an HP-20 column which was successively eluted with 500 ml of water and 25% aqueous propanol. Fractions containing the desired product were combined and evaporated under reduced pressure. The oily residue was treated with 20 ml of isopropanol to give 263 mg (93%) of the title compound (1-2H). The melting point was 170 ° C (decomposition).

To a stirred suspension of 225 mg (0.40 mmol) of the above-mentioned zwitterion in 10 ml of methanol, 1 ml of 1N HCl in CH 2 OH was added and the mixture was stirred at room temperature for 30 min. The solution was filtered and concentrated under reduced pressure. 15 ml of isopropyl alcohol were added to the residue and the resulting precipitate was collected by filtration and dried under reduced pressure. The title compound was obtained in the form of its hydrochloride. The yield was 146 mg (57%). Melting point 160 ° C (decomposition). Estimated purity 65%.

IR 1, cm -1, 3300, 1780, 1680, 1620. max. Phosphate buffer (pH-1) m * max (22300), 288 (22800).

25 NMRi; 1 *! 0 1.44 (3E, t, J07 Hz, OCH -CE.), 3.74 (2H, br, s, 2-H) 4.45 ppm i -j (2fi, q , J = 7 Hz, 0CH2-CH3), 5.36 (1H, d, J = 4.5 Hz, 6-H), 5.46 (2H, d, J = 7Hz, 3-CH = CH-CH2 ), 5.92 (1H, d, J = 4.5 Hz, 7-H), 6.20 (1H, m, 3-CH = GH), 7.04 (1H, d, J = 16 Hz, 3-CH = CH), 8.43 (2H, d, J = 7 Hz, Py-H ^), 9.10 (2H, d, J = 30 7 HZ, Ργ-Ηβ).

Example XVI

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3 -cephem-4-carboxylate (1-1H with formula 102, E isomer)

This example shows the preparation of the compound 1-1H

via the last few steps of reaction scheme 1a or 1b, wherein the intermediate product is 8501002 * * * 37 benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino- acetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate formate is isolated.

A. Benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-metioxyiminoacetami-5 do] -3- [3- (4-carbamoyl-1-pyridinio) -1 -propen-1-yll-3-cefem-4-carboxylate formate (E isomer) 0 0

A solution of 22-1H (Y * I, E isomer) (34 g, 75% pure) in a mixture of acetone and CH 2 QH (1/1/200 ml) was placed on a column of Amberlite IRA-41Q (formate form 340 ml). The column was eluted with the same solvent system. The first fraction (11) was evaporated to about 100 ml by volume and the brown residue triturated with 400 ml isopropyl ether. The resulting powder was collected by filtration and dried under reduced pressure to obtain 29 g (75% pure by HPL'C) of the title compound (E 'isomer) as a brown powder, melting point above 150 ° C (decomposition).

TTBif-1 IR 1 cm 3300, 1780, 1680, 1630, 1600. max DV; ^ EtOH nm (E1%:) 282 (186). max 1 cm NMR i S acetone-d6 / CH3OH-d4 (1/1) 4Q (3H qqE) 5.26 (1H, d, J = 4.5 20 Ppm ~ 3 +

Hz, 6-H), 5.43 (2H, d, J = 7 Hz, CH2N), 5.99 (1fi, d, J = 4.5 Hz, 7-H), 6.5 (1Ö, m , 3-CH = CT), 6.92 (1H, s, CHPh2), 7.1 (1H, d, J = 16 Hz, 3-CH), 7.35 (1 OH, m, Ph-H), 8.36 (1H, s, HCCfO), 8.46 & 9.12 (2H each, d, J = 8 Hz, Py-H).

B. 7- [2- (5-fimino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoyl-1-pyridinio) -1-props- 1-yl] -3-cephem-4-carboxylate (1-1H of formula 102, E isomer)

A mixture of the E isomer obtained in step A (29 g, 75% pure) and 290 ml of 85% fs formic acid was stirred at room temperature for 2 hours. Evaporation of the mixture gave a brown oil which was triturated with 500 ml of acetone. The powder was collected by filtration, washed with 2 x 100 ml acetone and dried under reduced pressure. 24 g (50% pure by HPLC) of the crude title compound were obtained. The brown solid was treated 2 times with 2 N HCl (1 L and 0.5 µ). The water extracts were combined and placed on a column packed with Diaion HP-20 (1, 5> 1). The column was washed with 8 L of water and eluted with 5.130% CH 2 OH. The fraction containing the desired product contained 850: ..

38 was evaporated to about 30 ml. The concentrate was treated with 200 ml of acetone to give a precipitate, which was collected by filtration and dried under reduced pressure. 10.1 g (85% pure) of the title compound (in the form of the zwitteriön) were obtained as a yellow powder. To a suspension of this product in 100 ml CH2 OH, N HCl in 55 ml CH2 OH was added at room temperature and the mixture was stirred for 30 min. The resulting clear solution was filtered to remove insolubles, concentrated to about 50 ml by volume and precipitated with 200 ml of isopropanol. The resulting powder was collected, washed with 50 ml of isopropanol and dried under reduced pressure. 10.5 g (85% pure) of the title compound I-1 H (E 'isomer) (HCl salt) were obtained, with a melting point above 180 ° C (decomposition). It was a light yellow powder.

Example XVII

7 ° [2- (5-Amino-1,2,4-thiadiazo 1- 3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-props-1 -yl] -3-cephem-4-carboxylate (1MH) (E 'isomer)

This example shows the preparation of the compound I-1H through the last few steps of reaction scheme 1a or 1b, wherein the intermediate (the aforementioned formate) is not isolated.

A solution of 69-1 (E 'isomer) (27.6 g, 38.5 mmol) and isonicotinamide (22.8 g, 187 mmole) in a mixture of 120 ml CH 2 CN and 100 ml CH 2 OH was Stirred under a nitrogen atmosphere at room temperature for 1 hour. After evaporation of the organic solvents, the oily residue was triturated with isopropyl ether to obtain 50.5 g of a mixture of the quaternized salt and isonicotinamide. A solution of the mixture (50.3 g) and 16 g of sodium bisulfite in 160 ml of 85% formic acid was stirred at room temperature for 40 min and then at 40 ° G for 1 h under nitrogen. The mixture was evaporated under reduced pressure. The remaining oil was mixed with 50 ml of toluene, evaporated azeotrope and triturated with 400 ml of acetone. 27.8 g of the crude title compound were obtained. This material was treated 2 times with 2 N HCl (11 and 0.5 L). The acidic extracts were combined and applied to a column of HP-20 resin (1.5 L). The column was eluted with 9 L of water and 10 L of 30% methanol. The fractions containing the desired compound were combined and concentrated to give a yellow oil, which was triturated with 300 ml of acetone. 9.35 g of the zwitterion form of the title compound were obtained.

8501002%. ., .., 39

To a suspension of the product (9.3 g) in 180 ml CH2 OH, 1N HCl in 55 ml CH2 OH was added to give a clear solution. The solution was concentrated to about 100 ml and diluted with isopropanol to precipitate 9.50 g (75% purity) of the title-5 compound 1-1H (E isomer) as the hydrochloride. It was a light yellow amorphous powder. The melting point was above 195 ° C (decomposition). Example 18 7 ° [2- (5-Amino-1,2,4-thiadiazol-3-yl3-3-cephem-4-carboxylate (1-1H) (E isomer)

This example shows the preparation of the compound 1-1H

via the last step (7-N-acylation) of reaction scheme lc.

To an ice-cooled suspension of the 7-amino-ce-fem hydrochloride 82-H (E1 isomer, 5.0 g, 12.6 mmol) in 50% aqueous acetone (100 ml), sodium bicarbonate was added in small portions added. The pH of the mixture was monitored with a pH meter during the reaction.

The cold neutralized solution (pH about -7) was added 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride in small portions over a period of 1 hour (4.02 g, 15.6 mmol) was added and the pH of the reaction mixture was kept in the range of 6.8-7.5 by adding sodium bicarbonate occasionally. The reaction was also monitored with ylc. After the compound 82-H was completely consumed, the mixture was acidified to a pH of 3 by the addition of 2 N hydrochloric acid. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was diluted with 400 ml of acetone 2 to separate a precipitate, which was collected by filtration. 9.59 g of the crude title compound were obtained as a pale yellow powder. Estimated purity was 40% by HPLC. A suspension of the crude product (9.5 g) in 150 ml of 2 N hydrochloric acid was filtered, and the filtrate was adsorbed on a column of HP-20 resin (500 ml). After washing with 1.5 L of water, the column was eluted with 25% aqueous isopropyl alcohol and the eluate was collected in 100 ml fractions. The desired fractions were combined, acidified with 10 ml of 2 N hydrochloric acid and concentrated. The residual oil was triturated with 200 ml of isopropyl alcohol and the precipitate was collected by filtration. After drying over phosphorus-35 pentoxide, 5.18 g of the title compound 1-1H (E isomer) hydrochloride were obtained as a yellow amorphous powder. The melting point was above 190 ° C (decomposition). The estimated purity was 75%.

8501002 * r 40

Example XIX

Purification and crystallization of the compound 1-1H (E "isomer)

The hydrochloride of the compound 1-1H obtained in Example XVI was a pale yellow amorphous powder with a purity of 85%.

Procedure 1 6 g of the 85% pure hydrochloride was dissolved in 20 ml of water and filtered through a pad of celite. The amber filtrate (pE 2) was passed through an inverted phase column (the packing of prepPAK-500 / Cg cartridge, Waters, 120 nil), which was eluted with water. The eluate was collected in 120 ml fractions while the course was followed by HPLC (Lichrosorb RP-18 column, 4 x 300 mm: mobile phase, 0.01 M phosphate buffer (pH 7.2) / CH 2 OH = 85/15 : detection, UV (254 nm)). Fraction No. 3 to Fraction No. 5 were combined and concentrated to about 10 µl, and precipitated with 100 ml of acetone to give 3.3 g of the zwitterionic form of 1-1 H (pale yellow amorphous powder; estimated purity 95).

To a suspension of the 95% pure powder (3.2 g) in 32 ml CH 2 OH, N HCl in CH 2 OH (18 ml) was added, and the mixture was stirred at room temperature until a clear solution was obtained .

The solution was filtered and the filtrate was concentrated to about 10 ml. 100 ml of isopropanol were added to the concentrate, a pale yellow precipitate separated, which was collected by filtration, washed with 5 ml of isopropanol and dried. 2.6 g of the HCl salt (amorphous powder; estimated purity 95%) were obtained.

A solution of the 95% pure hydrochloride (1 g) in 4 ml of water was adjusted to a pH of 6.5 with 200 ml of NaHCO 2 and stirred for 30 min. The crystals that separated during stirring were collected by filtration, washed with 2 x 5 ml water and dried under reduced pressure. 710 mg of 1-1H (seater ion form) was obtained as pale yellow prisms. The melting point was above 185 ° C (decomposition). Microanalysis showed that it was the trihydrate.

IR t V1 cm -1 1780, 1695, 1660, 1630, 1610. max UV 1 phosphate buffer (PH 7) nm (g) 227 (22000), 290 (23000).

A max 5 DMSO-d + D „0 35 ppm 3.45 (2H, br, s, 2-H), 3.9 (3H, s, OCHg), 4.99 (1H, d, J = 4, 5 Hz, 6-H), 5.16 (2H, d, J = 7 Hz, CH2N +), 5.61 (1H, d, J = 4.5 Hz, 7-H), 5.8 (1H, dt, J = 16 & 7 Hz, 8501002 41 · „-ψ i - * 3-CH = CH), 6.93 (1Η, d, J = 16 Hz, 3-CH), 8.18 & 8.89 (2H, d each, J = 7 Hz, Py-H).

Analysis calculated for 1 ^ 20 ^ 8C 42.14; H 4.38; N 18.72; S 10.71.

5 found: C 42.41; H 4.35; N 18.86; S11.00.

Procedure 2

Once crystalline 1-1H was obtained by procedure 1, it was possible to obtain the crystalline 1-1H di-10 zwitterion form from the crude 1-1H hydrochloride by seeding with a few crystals of the pure 1 -1H.

A solution of the 85% pure hydrochloride (250 mg) in 1 ml of water was treated with charcoal. The solution was adjusted to pH 6.5 with 60 mg NaHCO2 and decolorized with charcoal. The filtrate was seeded with a few pieces of the crystals obtained in procedure 1 and stirred at room temperature overnight. The separated crystals were collected by filtration, washed with 2 x 2 ml water and dried under reduced pressure. 170 mg (80% yield) of pale yellow prisms of 1 - 1H (zwitterion form) with a melting point above 185 ° C (decomposition), identical to the product obtained by procedure 1 (as shown by the IR , UV and NMR spectra).

The crystalline zwitterion form of compound 1-1H was slightly soluble in water (6 mg / ml in saline at 23 ° C).

Example XX

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-hydroxymethylpyridinio) -1-propenyl] -3-cephem-4- carboxylate (1-1K with formula 107, E isomer)

Ao Diphenylmethyl 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methylethoxyimlno-acetamido] -3- [3- (3-hydroxymethylpyridinio) -1-propenyl] -3 -cephem-4-car-30 boxy late iodide (E-isomer) (72-1-K)

3-Hydroxymethylpyridine (545 mg, 5 mmol) was added to a solution of 69-1 (E-isomer, 1.79 g, 2.5 mmol) in 2.5 ml CH ^ OH and 7.5 ml CH ^ CN. , and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 100 ml of ethyl acetate while stirring vigorously. The resulting precipitate was collected by filtration, washed with a small volume of ethyl acetate and dried.

2.06 g (100%) of the title compound 72-1K were obtained as a tan color 8501002 42, τ

St * rig powder. Melting point 170-110 ° C (decomposition).

IR: V. (KBr) in cm -1 1780, 1725, 1675, 1615, 1530, 1385, 1225, 1040, max 750, 700.

ÜV: λ (C.H OH) in nm (E1%) 290 (196).

, max 2 5 1 cm 5 NMR; £ (DMSO + D20) in ppm 3.7 (2H, br.s, 2-H), 3.91 (3H, s, OCH3), 4.70 (2H, s, Py-CH2-OH), 5 .28 (2H, m, CH2-N +), 5.23 (1H, d, J = 5Hz, 6-H), 5.90 (1H, d, J = 5Hz, 7-H), 6.34 ( 1H, m, 3-CH = CH), 6.86 (1H, d, J = 16HZ, 3-CH), 6.89 (1H, s, CHPh2), 7.35 (10H, m, Ph-H ), 7.9-8.9 (4H, m, Py-H).

10 B. 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- [3- (3-hydroxymethylpyridinio) -1-propenyl] - 3-cephem-4-carboxylate (1-1K with formula 107, E isomer)

A mixture of 72-IK (E isomer, 2.0 g, 2.4 mmol) and 1 g of sodium bisulfite in 10 ml of 85% formic acid was left at room temperature for 2 hours. stirred. The reaction mixture was concentrated to about 5 ml under reduced pressure. The oily residue was taken in 100 ml. acetone while stirring vigorously. The precipitate was collected by filtration, washed with a small amount of acetone and dried.

1.1 g of a tan powder was obtained, which was purified by column chromatography (using the packing of a PrepPAK-500 / Cq cartridge (Waters)] to obtain 283 mg (22%) of 1- 1K as 10 an amorphous powder The powder was crystallized from 4N H 2 SO 4 and acetone to give 144 mg of the title compound 1-1K as colorless needles, melting point 185-188 ° C (decomposition).

IR: V (KBr) in cm -1, 1775, 1680sh, 1660, 1630, 1225, 1045, 850.

max 1% UV: 1 (phosphate buffer, pH 7) in nm (E,) 236.5 (283), 275 sh (280), λ max 1 cm 292.5 (330).

NMR: $ (D20) in ppm 3.75 (2H, s, 2-H), 4.18 (3H, s, 0CH3), 4.97 (2H, s,

Py-CHOH), 5.35 (1H, d, J = 4Hz, 6-H), 5.43 (2H, d, J = 6.5, 30 Hz, CH2 ~ N), 5.92 (1H, d , J = 4Hz, 7-H), 6.18 (1H, dt, J = 16Hz, J = 6.5Hz, 3-CH = CH-), 6.97 (1H, d, J = 16Hz, 3- CH), 8.13 (1H, dd, J = 8Hz, J = 6Hz, Py-H), 8.60 (1H, d, J = 8Hz, Py-H), 8.84 (1H, d, J = 6Hz, Py-H), 8.90 (1H, s, Py-H).

Example XXI

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (2) -methoxyimino-acetamido] -3- (3- (4-N-methylcarbamoylpyridinio) -1- propenyl 3 -3-cephem-4-carboxylate (1-1M with 8501002 43 <% 1 t Vep, "r * formula 108 / E isomer)

A mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thia-diazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propenyl) -3-cephem- 4-carboxylate (69-1) (E-isomer, 450 mg, 0.62 mmol) and 4-N-methyl 1 carbamoyl-5 pyridine (prepared according to the procedure of M. Samejima, Yakugaku Zasshi, 80, 1706 ( 1960) 1 (215mg, 1.58mmol) in 2ml acetonitrile was stirred at room temperature under nitrogen atmosphere for 5 hours The mixture was evaporated under reduced pressure and the residue triturated with ether to give 530mg of the quaternary salt A mixture of the solid and 150 mg of sodium bisulfite in 2 ml of 85% formic acid was stirred for 4 hours and then heated at 40 ° C for 30 min. The mixture was evaporated under reduced pressure. acetone triturated and the crude product collected by filtration The crude product was chromatographed on a column of 15 HP-20 (1.5 x 18 cm) and the column was washed with water and 30% aqueous methanol eluted. The methanolic eluate was evaporated under reduced pressure and the residue was lyophilized. 140 mg of an amorphous powder were obtained, which was further purified by HPLC (column: Lichrosorb EP-18, solvent: 15% CH2 OH) and the eluate of HPLC was lyophilized to give 60 mg (18%) of the title product 1 -1M was obtained. Melting point 180 -183 ° C (decomposition). Estimated purity: 80%.

IRi v (KBr) in cm * 1760 1660, 1600.

* max uv (phosphate buffer, pH 7) in nm (£) 230 (22100), 286 (22100). a max NMRs £ (Ώ2Ό) in ppm 3.08 (3H, s, CONHCH ^), 3.72 (2H, s, 2-H), 4.16 (3H, 25s, 0CH3), 5.35 ( 1H, d, J = 4.5Hz, 6-H), 5.95 (1H, d, J «4.5Hz, 7-H), 7.00 (1H, d, J = 16Hz, 3-CH) , 8.35 (2H, d, J = 6Hz, pyridine-H), 9.05 (2H, d, J = 16Hz, pyridine-H).

Example XXII

7- [2- (5-amino-1,2,4-thiadlazol-3-yl) -2-methoxyimlnoacetamido] -3- (3- (4-car-30-boxypyridinio) -1-propenyl] -3-cephem -4-carboxylate (1-1N of formula 109)

To a stirred suspension of isonicotinic acid (340 mg, 2.8 mmol) in 3.5. ml of dry DMF, 0.7 ml, 2.8 mmol of Ν, Ο-bis (trimethylsilyl) acetamide were added under nitrogen atmosphere. The clear solution obtained was added in a portion of diphenyl 7- [2- (5-amino-1,2,4-thiadia-35-zol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1- propenyl) -3-cephem-4-carboxylate (69-1) (E isomer, 720 mg, 1 mmol added, and the red solution- 850 1 0 02

V

44 * ring was stirred at room temperature for 1.5 hours. The reaction mixture was added dropwise to 50 ml of a stirred saturated sodium chloride solution containing 150 mg of sodium thiosulfate. The yellow precipitate was collected by filtration, washed with water, and dried to obtain 722 mg of a light yellow powder. The powder (700 mg) and 70 mg sodium bisulfite were dissolved in 5 ml of 85% formic acid, and the solution was allowed to stand at room temperature for 1.5 hours. The mixture was suspended in 50 ml of toluene and concentrated. The residue was triturated with 70 ml of acetone, and the precipitate 10 was isolated by filtration to yield 421 mg of a yellow powder. This crude powder (400 mg) was suspended in 2 ml of water and sodium bicarbonate was added to the suspension. The resulting dark solution was adsorbed onto a column of the packing (50 ml) Prep-PAK / C-O cartridge (Water's system 500), and the column was eluted through 200 ml of water. The eluent was fractionated into 10 fractions of 20 ml each, and the desired fractions (fractions Nos. 4.-7) were combined, acidified with 2N hydrochloric acid to a pH of 3, and concentrated. The residue was triturated with 30 ml of acetone and the precipitate was collected by filtration. 201 mg (37%) of the title compound 1-1N was obtained as a yellow powder. E / Z = 7/1; 80% pure. Melting point above 189 ° C (decomposition).

IR 5v (KBr) in cm * 1770, 1665, 1600.

r max ÜV ί V (phosphate buffer, pH 7) in nm (£) 227 (22500), 290 (22100).

/ "Max NMR; $ (D ^ O + NaHCO ^) in ppm 3.7 (2H, br.s), 4.16 (3H, s), 5.32 (1H, d, J = 4Hz), 5.39 (2H, d, J = 6Hz), 6.14 (1H, dt, J = 15, S and 25Hz), 7.03 (1H, d, J = 15.5Hz), 8.31 (2H, d, J = 7Hz), 8.94 (2H, d, J = 7Hz).

Example XXIII

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -methoxyimino-acetamido] -3- [3- (2,3-cyclopentenopyridinio) -1-propenyl ] -3-cephem-4-carboxylate (1-10 with .30 formula 110, E isomer)

A mixture of diphenylmethyl 7- [2- (5-amino-1,2,4-thia-diazol-3-yl) -2-methoxyiminoacetamido3-3 - (3-iodo-1-propenyl) -3-cephem-4 -carboxylate (69-1) (E isomer; 450 mg, 0.62 mmol) and 2,3-cyclopentenopyridine (217 mg, 1.83 mmol) in 2 ml of acetonitrile was left at room temperature under nitrogen atmosphere for 4 hours stirred. After evaporation under reduced pressure, the mixture was triturated with ether to yield 560 mg of 8501002> 45 of the quaternary salt. A mixture of the solid and 2 ml of 85% formic acid was stirred at room temperature under nitrogen for 3 hours and then heated at 40 ° C for 30 min. The mixture was evaporated under reduced pressure and trituration of the residue gave 391 mg of the crude product, which was purified by chromatography on a column of HP-20 (1.5 x 18 can). The column was eluted with water and 30% aqueous methanol. Evaporation of the methanolic eluate under reduced pressure, followed by freeze drying, gave 160 mg of an amorphous powder, which was further purified by HPLC (column: Lichrosorb, solvent 10% CH 2 QH). The eluate from HPLC was lyophilized to yield 50 mg (15%) of the title product 1-10. The melting point was above 190 ° C (decomposition). Estimated purity 75%.

IR s y (KBr) in cm ^ 1765, 1670, 1600.

max ÜV: X (phosphate buffer, pH 7) in nm (c) 235 (20000), 283 (25000).

max • 15 NMRs 0 (D20 + NaHCO3) in ppm 2.2 - 2.6 (2H, m, -CH2-), 3.1 - 3.6 (4H, m, -CH2 »), 3.72 (2H, s, 2-H), 4.17 (3H, 0CH3), 5.33 (1H, d, J = 4.5Hz, 6-H), 5.90 (1H, d, J = 4, 5Hz, 7-H), 6.75 (1H, d, J-16HZ, 3-GH), 7.65 - 8.2 (3H, m, pyridine-H).

Example XXIV

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyimino-acetamido] —3— [3- (4-carboxypyridinio) -1-propenyl ] -3-cephem-4-carboxylate (1-2N of formula III, S isomer) and ... 7-C2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (Z ethoxyimino-acetamido] -3- [3-25 (4-carboxypyridinlo) -1-propenyl] -3-cephem-4-carboxylate (1-2N of formula III, Z isomer)

A cooled mixture of BSA (1.0ml, 4.12mmol) and isonicotinic acid (506mg, 4.12mmol) was added 69-2 (from Preparation No. 21; 1.0g, 1.37mmol) , and the mixture was stirred under nitrogen at room temperature for 2 hours. The mixture was poured into 20 ml of 10% rs Na2S2 <33 precipitating out 1.3 g of the quaternary salt, which was collected by filtration, washed with water and dried. A mixture of the solid and 0.3 g of sodium bisulfite in 5 ml of 98% formic acid was heated at 40 ° C for 1 hour and evaporated under reduced pressure. The residue was triturated with acetone and filtered to yield 900 mg of the crude product (E-propenyl isomer: Z-propenyl isomer = 2 s 1). Separation of the isomers was performed by 8501002 *> '46 HPLC (column Lichrosorb, solvent: 15% CH2 OH) * The faster-running fractions of HPLC were collected, evaporated under reduced pressure and lyophilized to give the E-propenyl isomer of 1-2N (44 mg, yield 6%). The slower fractions gave the Z-propenyl-5 isomer of. 1 - 2N (32 mg, yield 4%) in a similar procedure. 1-2N, Ξ isomer

Melting point:> 200 ° C (decomposition).

IR: V (KBr), in cm -1, 1765, 1660, 1620, 1380.

max ÜV: \ (Water) ia na (Ê) 228 (222200), 291 (2360.0).

A max 10 NMR: (D20) in ppm 1.45 (3H, t, J = 6Hz, CH2CH3), 3.72 (2H, s, 2-H), 4.45 (2H, q, CH2CH-3) , 5.40 (Ifi, d, J = 4Hz, 6-H), 5.90 (1H, d, J = 4Hz, 7-H), 7.05 (1H, d, J = 15Hz, 3-CH ), 8.30 (2H, d, J-6HZ, Py-H), 8.95 (2H, d, J = 6Hz, Py-H).

1-2N, Z isomer 15 Melting point: 200®C (decomposition).

IR: V (KBr) in cm -1, 1760, 1660 (sh), 1620, 1370.

max UV r X (phosphate buffer, pH 7) in na (£) 225 (22400), 275 (sh, 16000).

NMR: J (D20) in ppm 1.45 (3H, t, J = 7Hz, CH2CH3), 3.50 (1H, d, J = 17Hz, 20 2-H), 3.75 (1H, d, J = 17Hz, 2-H), 5.38 (1H, d, J = 4Hz, 6-H), 5.95 (1H, d, J = 4Hz, 7-H), 6.62 (1H, d, J = 11Hz, 3-GH), 8.35 (2H, d, J = 6Hz, Py-H), 8.92 (2H, d, J = 6Hz,

Py-H).

Example XXV

7- [2- (Amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetamido] -3- [3- (4-carbamylpyridinio) -1-propenyl ] -3-cephem-4-carboxylate (1-3H with formula 112, E isomer)

To a solution of 35 mg (0.08 mol) 7-amino-3- [3- (4-carbamoylpyridinio) -1- (E) -propenyl] -3-cephem-4-carboxylate hydrochloride 30 in 2 ml 50% Aqueous acetone was added 52 mg of "2- [5-amino-1,2,4-thiadiazol-3-yl)] -2- (propen-3-yloxyimino) acetyl chloride hydrochloride (from preparation no.

25) and the mixture was adjusted to a pH of 6.5-7.0 with 2N Na2CO3. The mixture was stirred at room temperature for 1 hour, acidified with 1N HCl to a pH of 2 and concentrated under reduced pressure. The residue was chromatographed on a column of HP-20 resin eluted with 300 ml of water and 30% CH 3 OH-H 2 O. Fractions containing the product were combined and evaporated under reduced pressure. The residue, 73 mg, was purified through a reverse phase support column, which was removed from a PrepPAK-500 / C 4 cartridge (Waters, 1a, 30 ml). The column was eluted successively with water, 5% CHgOH, 10% CEL 4 OH and 20% CH 2 OH. Fractions containing the product were combined and lyophilized. 26 mg (62%) of the title product 1-3H were obtained. Melting point 160 ° C (decomposition).

IRV (KBr) ^ cm -1 3400, 1765, 1680, 1605, 1400. max OV: χ (phosphate buffer, pH 7) in im (£) 226 (24600), 288 (22800). · NMRt è (D .0) in ppm 3.75 (2H, s, 2-H), 5.41 (1H, d, J = 5Hz, 6-H), 5.50 -Ir 10. (4H, m, CH2N & CH = CH2), 5.98 (1H, d, J = 5Hz, 7-H), 6.20 (1H, .m, 3-CH = CH), 7.09 (1H , d, J = 17Hz, 3-CH), 8.50 (2H, d, J-7Hz, Py-H), 9.16 (2H, d, J = 7Hz, Py-H).

Example XXVI

7- [2 ° (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyimino-acetamido] -3- [3-15 (4-earbamoyipyridinio) -1-propenyl] -3-cephem -4-carboxylate (1-4B with formula 113, E isomer)

To a solution of 86 mg (0.19 mmol) 7-amino-3- [3- (4-carbamoylpyridinio) -1-CE) -propenyl] -3-cep em-4-carboxylate hydrochloride (82-H) in 2 ml of 50% aqueous acetone, 63 mg of 2-propargyloxyimino-2- (5-20 amino-1,2,4-thiadiazol-3-yl) -acetyl chloride hydrochloride (from Preparation No. 26) was added. The suspension was kept at a pH of 6.5-7.0 with 2N Na2CO3 and then stirred at room temperature for 1 hour.

The reaction mixture was acidified with 1N HCl to a pH of 2 and concentrated under reduced pressure. The residue was diluted with 30 ml of water, neutralized with NaHCO 2 and filtered. The filtrate was transferred to the top of a column packed with reverse phase support (30 ml) removed from a PrepPAK-500 / Cg cartridge (Waters). The column was eluted sequentially with water, 5% CH 2 OH, 10% CH 2 OH and 20% CH 2 OH. Fractions containing the product were combined and lyophilized. 13 mg (12%) of the title product 1-4H were obtained.

The estimated purity was 70%. Melting point 160 ° C.

IRγ (KBr) in cm -1 3400, 2120, 1765, 1680, 1610.

UV: \ (phosphate buffer, pH -7) in nm (β) 229 (24000), 288 (21200).

Λ max _ NMR: <$ (D-0) in ppm 3.78 (2H, s, 2-H), 5.15 (2H, d, J = 1Hz, -CH'-CHZH), 35 5.40 (1H, d, J = 5Hz, 6-H), 5.50 (2H, m, CH-N), 5.98 (1H, d, J = 5Hz, 7-H), 6.20 (1H, m, 3-CH = CH), 7.05 (1H, d, J-17Hz, 3-CH), 8.50 (2H, d, J = 7Hz, Py-H), 9.16 (2H, d , -J = 8501002 <tt 48% 7 Hz, Py-H).

Example XXVII

7 - [2 - (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyimino-acetamido] -3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cephem- 4-carboxylate (1-5H with 5 formula 114, E isomer)

A stirred solution of 139 mg (0.31 mmol) of 7-amino-3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-cell-4-carboxylate-hydrochloride in 3, 5 ml of 50% aqueous acetone in an ice-cooled bath was aliquoted 120 mg (0.44 mmol.) 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclo- 10 pentyloxyiminoacetyl chloride hydrochloride (from Preparation No. 27) added. The mixture was adjusted to pH 6.5-7.0 with 0.9 ml 2N Na 2 CO 2 and stirred at 10 ° C for 1 hour. The reaction mixture was acidified with 1N HCl to a pH of 2 and evaporated under reduced pressure The residue was chromatographed on a column of HP-20 resin 15 (20 ml) and eluted with 300 ml of water and 30% successively. GH OH-HO Fractions containing the product were combined and concentrated under reduced pressure The residue was treated with 60 ml of acetone to give 111 mg (83%) of the title compound 1-5H, melting point 160 ° C (decomposition). Estimated purity 70%.

IR s V (KBr) ~ ca 1, 3400, 1770, 1680, 1605, 1530.

. XQgLX

UVs I (phosphate buffer, pH 7) in nm (½) 224 (23300), 286 (24600).

NMR; $ (DMSO-dg) in ppm 1.70 (8H, br.s, H- /), 4.68 (1H, br.s,

S

\ D

X), 5.05 (1H, d, J = 5Hz, 6-H), 5.30 (2H, m, 25 q7 CH2N +), 5.67 (1H, dd, J = 5Hz & 7Hz, 7-H ), 6.20 (1H, m, 3-CH = CH), 7.08 (1H, d, J = 17Hz, 3-CH), 8.34 (2H, d, J = 7Hz, Py-H) , 9.11 (2H, d, J = 7Hz, Py-H), 9.38 (1H, d, J = 7Hz, 7-NH).

Example XXVIII

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-carboxymethylpyridinio) -1-propenyl] -3-cephem-4- carboxylate (1-1P of formula 115, S isomer), A. Diphenylmethyl 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-35 amidol -3- [3- (3-carboxyme thypyridinio) -1-propenyl 3 - 3-cefem-4-c arboxylate (72-1P, iodide, Ξ isp)

To a suspension of 3-carboxymethylpyridine-hydrochlo-8501002 β-49 ride (0.89 g, 5 mmol) in 10 ml CH 2 Cl 2 was added N, 0-bis (trimethylsilyl) acetamide (4.97 ml, 18 mmol), and the mixture was stirred at room temperature until a clear solution was obtained. To the solution was added 69-1 (1.79 g, 2.5 mmol) and the mixture was allowed to stand at room temperature for 5 hours. After 3 hours, 3 ml of CH 2 OH was added to the cooled mixture and the solution was evaporated under reduced pressure evaporated to give an oil which was triturated with ethyl acetate.

Thus, 2.28 g of the title compound 72-1P were obtained as a tan powder. Melting point 161 ° C (decomposition).

10 IR ï V (KBr) in cm -1 1780, 1720, 1675, 1630, 1530, 1385, 1225, max 1045, 755, 700.

UV: \ (C.H-CH) in nm (e}%) 295 (188).

/ vmax 2 5 1 cm NMR: & (DMSO + DO) in ppm 3.70 (2H, br.s, 2-H), 3.90 (5H, s, OCH. & ^ 4 »

Py-CH2CO), 5.25 (3H, m, -CH2N & 6-H), 5.92 (1H, d, J = 15 4.5Hz, 7-H), 6.35 (1H, m, 3 -CH = CH-), 6.90 (IS, d, J * 16Hz, 3-CH), 6.92 (1H, s, CHPh2), 7.35 (1QH, m, Ph-H), 8, 8-9.0 (4H, m, Py-H).

B. 7 ° [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- [3- (3-carboxymethylpygidinio) -1-propenyl] -3- cefem-4-carboxylate (1-1P) (formula 115, E isomer)

A mixture of 72-1P (iodide) (2.28 g) and 1.1 g of sodium bisulfite in 10 ml of 85% formic acid was stirred at room temperature for 2 hours. The reaction mixture was concentrated to about 5 ml under reduced pressure. The oily residue was triturated with 100 ml of acetone to yield 1.22 g of the crude product which was purified by column chromatography (HP-20, 420 ml). 533 mg of the title compound 1-1P (38%, from 69-1) were obtained as a pale yellow amorphous powder. Melting point 165 ° C (decomposition).

IR 1 (KBr) in cm -1, 1770, 1670, 1530, 1385, 1140, 1040.

UVI1 (phosphate buffer, pH 6.2) in nm (Ε%) 234 (374), 277sh (390), max 1 cm 290 (402).

NMRs 5 (D20 + NaHCO3) in ppm 3.78 (2H, s, 2-H), 3.92 (2H, s, Py-CH2CO), 4.22 (3H, S, 0CH3), 5.40 ( 1H, d, J = 4Hz, 6-H), 5.44 (2H, d, J = 6.5Hz, -CH2-N +), 5.97 (1H, d, J = 4Hz, 7-H), 6.20 (1H, 35 dt, J = 16 & 6.5Hz, 3-CH = CH), 7.08 (1H, d, J = 16Hz, 3-CH), 8.11 (1H, dd, J = 8 & 7Hz, Py-H5), 8.53 (1H, d, J = 8Hz, 85 0 1 0 0 2 50).

Py-S4), 8.82 (1H, d, J = 7Hz, Py-Hg), 8.86 (1H, s, Py-H2).

Example XXIX

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carboxymethylthiopyridinio) -1-propenyl] -3-cephem-4- carboxylate (1-1Q with 5 formula 116, E isomer) A. Diphenylmethyl 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-amido] -3- [3 - (4-carboxymethylthiopyridinio) -1-propenyl] -3-cephem-4-carboxylate (72-1Q, iodide, E isomer)

To a suspension of 4-carboxymethylthiopyridine (0.88 10g, 5mmol) in 10ml CH 2 Cl 4 was added Ν, Ο-bis (trimethyl Isilyl) acetamide (5ml, 18mmol), and the mixture was stirred at room temperature until a clear solution was obtained. 69 -1 (E isomer, 1.79 g, 2.5 mmol) was added to the solution and the mixture was allowed to stand at room temperature. After 3 hours, 3 ml of CH 2 OH was added to the cold mixture and the solution was evaporated under reduced pressure to obtain an oily residue, which was triturated with ethyl acetate. 2.43 g of the title compound 72-1Q (iodide) were obtained as a tan colored powder. Melting point 155 ° C (decomposition).

IRγ (KBr) in cm -1 1780, 1720, 1670, 1625, 1525, 1385, 1225, 1115, 20 1040, 755, 700.

UV ï 5 (C „H OH) in nm (E1%) 312 (299).

Λ max 2 5 1 cm NMRs $ (DMSO-dg + D20) in ppm 3.70 (2H, br.s, 2-H), 3.93 (3H, s, 0CH3), 5.07 (2H, m , CH2 ~ N +), 5.23 (1H, d, J = 5Hz, 6-H), 5.90 (Ifi, d, J = 5Hz, 7-H), 6.29 (1E, m, 3- CH = CH), 6.87 (1Ë, d, 25 J-ΙβΗζ, 3-CH), 6.91 (1Ë, s, CHPh2), 7.35 (10H, m, Ph-H), 7, 88 & 8.58 (2H, d, J = 6Hz, Py-H each).

B. 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- £ 3- (4-carboxymethylthiopyridinlo) -1-propenyl] -3- cefem-4-carboxylate (1-IQ of formula 116, E isomer) 30 A mixture of 72-1Q (iodide, 2.43 g) and 1.1 g of sodium bisulfite in 10 ml of 85% 9 s formic acid was added for 2 stirred at room temperature for an hour. The reaction mixture was concentrated to about 5 ml under reduced pressure. The oily residue was triturated with 100 ml of acetone, filtered and dried to yield 1.39 g of a crude product which was purified by column chromatography (HP-20, 20 ml) to obtain 577 mg of the title compound 1-1Q ( 39% from 69-1) as an i 8501002 <Λ 51 light yellow amorphous powder. Melting point 188 ° C (decomposition).

IR: V (KBr) in cm -1 1765, 1670, 1625, 1530, 1380, 1110, 1035.

max. UV: \ (phosphate buffer, pH 6.2) in nm (E.) 234 (459), 310 (678).

Λ max 1 cm NMRI (D20 + NaHCO3) in ppm 3.79 (2H, br.s, 2-H), 4.10 (2H, s, S-CH2), 5 4.23 (3H, s, 0CH3), 5.25 (2fi, d, J = 6.5Hz, CH2-N +), 5.39 (1H, d, J = 4.0Hz, 6-H), 5.97 (IS, d, J = 4Hz, 7-H), 6.18 (1H, dt, J = 15.5Hz & 6.5Hz, 3-CH = CH), 7.05 (1H, d, J * 15.5Hz, 3-CH ), 7.84 & 8.55 (2H, d, J = 7Hz, Py-H each).

Example XXX

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoac etamido 3—3— [3— (11-methylpyrrolidinio) -1-propenyl] -3-cephem- 4-carboxylate sulfate (1-1A of formula 117, sulfate) A. Diphenylmethyl 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetami-do] -3- (3- (1-methylpyrrolidinio) -1-propenyl] -3-cephem-4-carboxylate (72-15 IA, iodide)

To a cold solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodopropenyl) -3-cephem-4-carboxylate ( 69-1) (from Preparation No. 14) (21.5 g, 30 mm -1) in 300 ml ethyl acetate was added dropwise to a solution of 1-methylpyrrolidine (2.55 g, 30 mmol) in 30 ml ethyl acetate added over a period of 1 hour at -5 to 0 ° C while stirring. After stirring for an additional 10 min, the resulting precipitate was collected by filtration and washed with 200 ml of chloroform. 23.0 g (95.8%) of the title compound (69-1A, iodide), melting point above 175 ° C (decomposition), were obtained.

IR: V (KBr) in cm -1 3300, 1780, 1685, 1615.

max 4 UV1 (CLH_0H) in nm (E7%) 218 (435), 295 (188).

max 2 5 1 cm B. Diphenylmethyl 7- (2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- (3- (1-methylpyrrolidinio) -1 -propenyl-3-cephem-4-carboxylate (72-1A, chloride) The compound 72-1A, iodide (23 g, 28.7 mmol) was dissolved in a mixture of acetone and methanol (1: 1 , 230 ml) and applied to an ümberlite IRA-410 (chloride form, 230 ml) column previously treated with the same mixed solvent The column was developed with the solvent and the fractions containing the desired compound 35 were combined and concentrated on an oily residue.

This was triturated with 300 ml of ethyl acetate to give 17.9 g (87.7%) of 85 0.1 0 0 2 * Jk 52 of the title compound 72-1A, chloride with a melting point at 190 ° C (decomposition).

IR: V (KBr) in cm3 * 1 3380, 1780, 1680, 1620.

max.

OV: \. (C-H-OH) in run (E1) 220 (369), 290 (262).

2max 2 a 1. cm 5 C. 7- [2- (5-Mino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1 ° methylpyrrolidinio) - 1-propenyl] -3-cephem-4-carboxylate sulfate (1-1A of formula 117, sulfate)

A mixture of the compound 72-1A, chloride (17.8 g, 25 council!) In 178 ml of 85% formic acid was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was evaporated under reduced pressure and the oily residue triturated with acetone to give 9.80 g of crude 1 = 1A. Concentration of the filtrate and the acetone washings gave an additional 2.95 g of crude 1-1A. Two harvests of the crude material were combined and extracted with 2N HCl (1 L and 0.5> 1). The combined extracts were adsorbed on a Diaion HP-20 resin (1.5 L column), eluting with water and 30% aqueous methanol. The desired fractions were collected and evaporated under reduced pressure to an oily residue, which was triturated with 200 ml of isopropanol and then 200 ml of acetone to give 7.09 g of 20. of a light yellow powder was obtained. This material (6.80 g) was dissolved in 20 ml of water and then column chromatographed on the packing of PrepPAK-500 / C.Q cartridge (90 ml) using water and 10% strength 10 aqueous methanol as the eluent. The eluate was collected in 20 ml fractions following the course by HPLC. [Column,

25 Nucleocil SSC-ODS-262, 8 x 100 mm? Mobile phase, 0.01M phosphate buffer (pH

7, 2) / CH 2 OH = 90 t 10; Detection, UV (254 nm)] "Fractions 4 to 10 were combined, evaporated under reduced pressure and lyophilized. 2.28 g of a yellow powder (E / Z = 7/1, 70% pure) were obtained [harvest 11.

Fractions 11 to 85 were worked up in the same manner as described above, yielding 3.27 g of a yellow powder (E / Z = 5/1, 70% pure) [Harvest 21. Part of Harvest 1 (1.0 g) was purified by re-chromatography on the packing of PrepPAK-500 / C, Q cartridge (90 ml). The column was eluted with water and then 5% aqueous methanol. The eluate containing the desired compound was concentrated and lyophilized. 638 mg (E / Z = 7/1, 80% pure) of a yellow powder were obtained. A second part of crop 1 (1.14 g) was worked up in 8501002 53 in the same manner to obtain 880 mg (E / Z = 7/1, 80% pure) of a yellow powder. The two purified samples were combined and a portion (1.45 g) was dissolved in 5 ml of 1N sulfuric acid. The solution was diluted with 315 ml of acetone while stirring. The cream-5 colored precipitate was collected by filtration to yield 1.48 g of the titeL compound 1-1A, sulfate (E / Z = 7/1, 80% pure), melting point above 185 ° C (decomposition).

IR: V (KBr) in cm-1 3380, 1765, 1675, 1630, 1535, 1390, 1115.

max UV% Xmair (phosphate buffer, pH 7) in nm (E) 236 (19900), 291.5 (22500).

NMRs δ (D20 + NaHCO3) in ppm 2.36 (4fi, br.,), 3.15 (3H, s, CH3 ± N \ ZI ') r 3.62 (5fi' br * '2 "H 611 I 3.83 (1H, br., 2-H), 4.13 (2H, d, J = 8Hz, CH2N +), 4.22 (3H, s, 0CH3), 5.39 41H, d, J = 4.5Hz, 6-H), 5.96 (1H, d, J = 4.5Hz, 7-H), 6.00 (1H, m, 3-CH = CH), 6.67 (1 / 8H d, J = 10Hz, 3-CH, cis), 7.04 (7 / 8H, d, J = 16Hz, 3-CH, trans).

Example XXXI

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-trimethylaramonio-1-propenyl] -3-cephem-4-carboxylate (1-1D with formula 118)

Ao Diphenylmethyl 7- [2- (5-amino-1,2,4-thladiazol-3-yl) -2-methoxyimlnoacet-amidol-3- (3-trimethylammonio-1-propenyl) -3-cephem-4-carboxylate (72-1D, iodide) 25 To a solution of 13.0 g (19 mmol) diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yi) -2-methoxyiminoacetamido] - 3- (3-iodo-propenyl) -3-cephem-4-carboxylate (69-1, from preparation No. 10) in 38 ml dry ethyl acetate became 1.75 ml (19.1 mmol) 1.1N trimethylamine in ethyl acetate added at -5 ° C, and the mixture was stirred at -5 ° C for 1 hour. The resulting precipitate was filtered off, washed well with CHCl 3 and dried. 2.5 g (88%) of the title compound 72-1D were obtained as the iodide.

IR ί V (KBr) in cm 1 3300, 1765, 1720, 1665.

UV r \ (C, OH) in nm (·) 300 (18400).

35 b. Diphenylmethyl 7- [2- (5-fimino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-amido] -3- (3-trimethylammonio-1-propenyl) -3-cephem-4-carboxylate (72-1D, chloride) 8501002 9 * l 54

The iodide 72-ID (12.5 g) was dissolved in 60 ml of CH 2 OH-acetone (1: 1) and passed through an ion exchange resin column [IRA-410 (Cl · ””}, 125 ml] The column was eluted with 300 ml of CH2 OH-acetone (1: 1>), and the eluate was evaporated under reduced pressure and triturated with 300 ml of isopropyl ether to yield 10.4 g (91%). ) of the quaternary salt 72-1D, chloride.

IR ί V (KBr) in cm -1 3300, 1765, 1710, 1665. max UV r 1 (ClH-QH) in nm (&) 298 (15100).

^ max δ 5

Co 7- [2- ° (5-Amino-1,2,4-thiadiazol-3-yi) -2-methoxyimino-acetamido] -3- [3-10 trimethylammonio-1-propenyl] - ° 3-cephem- 4 ° carboxylate (1M.D with formula 118, sulfate, E isomer)

A solution of 10.4 g (16.0 mmol) of 72-1D (chloride) in 20.8 ml of 85% formic acid was allowed to stand at room temperature for 3 hours and concentrated under reduced pressure. The residue 15 was treated with 210 ml of isopropanol and the precipitate was filtered off.

The solid (10.1; g) was triturated with 210 ml of water and neutralized with sodium bicarbonate. The slurry was filtered and the filtrate was chromatographed on a column of HF-20 (300ml) which was successively washed with 1000ml water, 200ml 10% CH 2 OH and 150ml 20 30% CH 2 OH was eluted. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was purified by reverse phase chromatography. The column was packed with a packing obtained from a PrepPAK-500 / Cg cartridge (Whters, 200 ml). Elution with 600 ml water and then 200 ml 30% CH 2 OH, followed by concentration of fractions containing the desired product, gave 2.52 g (18%) of the title compound. A solution of the zwitterion product (1.5> g) in 5 ml 1N H 2 SO 4 was added portionwise to 300 ml acetone and the third precipitate obtained was filtered and dried. The yield of 1-1D sulfate was 1.42 g (80%). The E / Z ratio was about 10/1, based on HPLC.

IR t V (KBr). cm 1 3380, 1765, 1665.

r max UV r I (phosphate buffer, pH <7) in nm. (&) 237 (19500), 293 (22400).

Λ max NMRi è (D2O) in ppm 3.25 (9H, s, N + -CH3), 3.94 (2H, s, 2-H), 4.14 - (2H, d, J = 7Hz, CH2N +) , 4.23 (3H, s, O-CHg), 5.42 (1fi, d, J = 35 4.5Hz, 6-H), 6.00 (1H, d, J * 4.5Hz, 7 -H), 6.23 (1H, dt, J = 7 & 16ΗΖ, 3-CH = CH), 7.23 (1H, d, J = 16HZ, 3-CH).

8.5 0 1 0 0 2 <* 55

Example XXXII

7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-C 3- (4-carbamoylpyridinio) -1-propenyl-3-cephem-4-carboxylate (1-1H with formula 102, E isomer) 5 To a mixture of 7-amino-3- [3- (4-carbamoylpyridinio) -1 ”0'E) -propenyl] -3-cephem-4-carboxylic acid hydrochloride (82-H, 397 mg, 1 mmol) and NaHCO3 (168 mg, 2 mmcfl) in aqueous OMF (water, 3.5 ml and DMF, 7.5 ml) became benzotriazol-1-yl-2- (5 -amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate (479 mg, 1.5 mmol) (from Preparation No. 28). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to a pH of 3-4 with 3N HCl and diluted with 200 ml of acetone to form a precipitate which was collected by filtration. The crude product was dissolved in a small volume of aqueous THF and the solution was adjusted to pH 6.8 with NaHCO 2, treated with decolorizing charcoal, concentrated to about 1 ml and seeded with a few pieces of crystalline 1 - 1H. After stirring overnight, the crystalline precipitate was collected by filtration to give the title compound I-1H (zitteritterion-vosm). The yield was 83 mg (16%). The melting point was above 185 ° C (decomposition). Physico-chemical data for this product 20 was identical to that of the compound of Example X.

Preparation No. 1

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamino] -3-chloromethyl-3-cephem-4-carboxylate (64-1)

To a stirred suspension of 2- (5-amino-1,2,4-thiadia-25-zol-3-yl) -2-methoxyiminoacetic acid (63-1? 2.1 g, 10 mmol) in 50 ml dry C3 ^ C1 ^ 2.9 g, 10 mmol PCl ^ was added at -30 ° C, and the mixture was stirred at -15 to -20 ° C for 20 minutes. To the above-described acid chloride solution was added a solution of diphenylmethyl 7-amino-3-chloramethyl-3-cephem-4-carboxylate hydrochloride 30 (62; 4.5 g, 10 mmol) in 50 ml CH 2 Cl, 10 g, 50 mmol N, 0-bis- (trimethylsilyl) acetamide, at -30 ° C. After stirring at -10 ° C for an hour, the mixture was concentrated to remove the CH2 Cl2 and diluted with 200 ml of ethyl acetate. The mixture was washed successively with 2 x 40 ml 10% aqueous NaHCO 2, 2 x 20 ml water and 10 ml brine, and dried over MgSO 4. The solvent was evaporated under reduced pressure and the resulting oily residue (10 µl was dissolved in 20 85 O 1 Q 0 2 * 56 ml CHCl 4 and chromatographed on a silica gel (Wako gel C-200, 100 g containing 10 ml 1 / 1.5 M pH 7 phosphate buffer) using 1-3% CH 2 OH-CHCl 2 Fractions containing the title compound were evaporated to give 5.7 g (95%) of the compound 64-1 as a Yellow amorphous powder, melting point above 140 ° C (decomposition).

IR ί y ^ cnf1 3300, 1780, 1.720, 1680, 1620. max UV ί X Et0Hnm (&) 245 (1800), 280 (9900). max NMRj $ DMS0 "dÖ 3.53 (2H, ABq, 2-®), 3.94 (3H, s, OCH-), 4.42 (2H, s, ppm j - 3-CH2) f 5.22 (1H, d, J = 4.5, 6-Ή), 5.92 (1H, dd, J = 4.5 & 6, 7-Ή), 6.93 (1H, S, CHPh2), 7, 36 (10H, m, Ph-H), 8.1 (2H, br-s, HH), 9.58 (1fi, d, J = 6, 7-NH).

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamid 15. do] -3-iodomethyl-3-cephem-4-carboxylate (65-1)

A mixture of 64-1 obtained from preparation No. 1 (5.7 g, 9.5 ml) and Na! (4 ', 3g, 29mmol) in 50ml dry acetone was stirred at room temperature for 5 min. The mixture was concentrated under reduced pressure and the resulting oil was shaken with a mixture of 100 ml of ethyl acetate and 10 ml of H 2 O. The organic layer was separated and washed successively with 10% w / v sodium thiosulfate and brine. After drying, the ethyl acetate was removed under reduced pressure to yield 6.1 g (93%) of the title compound (65-1) as a yellow amorphous powder, m.p. 120 ° C (decomposition).

IR. V KBrcm ”: L 3300, 1780, 1725, 1680, 1620. max UV S Λ EtOHnm (4) 245 (17000), 282 (12000). max NMRt & DMSO-d & ^ 72 ^ 2-H), 3.94 (3H, s, OCH-.), 4.23 (2H, s, ppm j 3-CH2), 5.21 (1H, d, J = 4.5, 6-H), 5.89 (1H, dd, J = 4.5 & 6.7-H), 6.94 (1H, s, CHPhL), 7.35 (10H, m , Ph-H), 30.8 8.12 (2H, br-sr. NE), 9.65 (1H, d, J = 6, 7-NH).

Preparation No. 3

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetami-do] -3-triphenylphosphoniomethyl 1-3-cephem-4-carboxylate iodide (66-1)

A mixture of 65-1 obtained with preparation No. 2 35 (690 mg, 1 mmole) and triphenylphosphine (786 mg, 3 mmol) in 20 ml ethyl acetate was stirred at room temperature overnight. The solid 8501002 57 which separated was collected, washed with 2 x 10 ml ethyl acetate and dried. 950 mg (100%) of the phosphonium iodide 66-1 were obtained.

Melting point 186 ° C (decomposition).

IR ï V KBrcm ™ 1 3300, 1780, 1710, 1680, 1610. r max 5 ÜV ï Λ EtOHnm (£>) 268 (15000), 275 (13000), 300 (7300).

max NMRI $ DMSO-dg 3 ^ 52 (2H ^ br_s ^ 2H), 3.94 (3H, s, OCH,), 5.34 (1H, d, ppm —i J = 4.5, 6-H) 5.9 (1H, m, 7- «), 6.3 (1fl, s), 7.3 (10H, m, Ph-H), 7.8 (15H, m, Ph-H).

10 Preparation No. 4

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamidol-3-C (triphenylphosphoranylides) methyl] -3-cephem-4-carboxylate (62-1 )

A mixture of 66-1, obtained according to preparation No. 3

(952 mg, 1 mmol), Amberlite IRA-410 (OH form, 500 mg) and 4 ml N NaOH

15 in 10 ml CH2 Cl2 was stirred at room temperature for 1 hour. The mixture was filtered and the separated organic layer was dried over MgSO 4 and concentrated under reduced pressure. The resulting oil was triturated with ethyl acetate and the resulting yellow precipitate was collected by filtration. 740 mg (90%) of the title compound 67-1 were obtained. The melting point was above 180 ° C (decomposition).

IR ί V cm'1 3400, 1750, 1630. max ÜV: X EtOH na (fi?) 268 (12000), 276 (10000), 384 (23000).

H2cL2 £

Preparation No. 5 Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetami-do] -3- (3-chloro-1-propen-1-yl ) -3-cefem-4-carboxylate (68-1)

To a solution of 67-1, obtained according to preparation No. 4 (6.9 g, 8.4 mmol), 3 g of MgSO 4 and 810 mg, 8.4 mmol of 40% chloroacetaldehyde were added. The mixture was stirred at room temperature for 1.5 hours and then filtered. The filtrate was eluted on silica gel (Wakogel C-2O0, 100 g containing 10 ml 1 / 1.5 M phosphate buffer) column using CHCl 2, as well as CHCl 2 containing CH 2 OH. Fractions containing the desired product (0.5-1% CH2 OH-CHCl2) were evaporated under reduced pressure to yield 1.6 g (30%) of the title compound 68-1 as a yellow amorphous powder, which was a mixture of the Z and E isomers with respect to the chloropropenyl group (Z / E = 2 / l, vol- 8501002

* · V

58 gens weird). The melting point was above 130 ° C (decomposition).

IR: V ™ * cm ”1 3300, 1780, 1725, 1680, 1620.

max OV: X EtOH nm (&) 240 (20000), 286 (12000).

^ max · 'X DMSO-d- + D_O 3.56 & 3.8 (m, 2-fi), 3.94 (3fi, s, OCH,), 4.16 (d, NMR: 0 6 2 3 5 Ppm J-7.5, CH2G1), 5.26 (1fi, d, J = 4.5, 6-H), 5.87 (1Ö, d, J = 4.5, 7-> H), 6.28 (2 / 3H, d, J-11, 3-CH cis-H), 6.72 (1 / 3H, d, J = 16, 3-CH trans-Ή), 6.81 (2 / 3H, s, CHSh2), 6.92 (1 / 3H, s, CHPh2, 7.4 (10H, m, Ph-H).

Preparation No. 6 10 Diphenylmethyl 7-benzylideneamino-3 - [(triphenylphosphoranylidene) methyl3-3-cephem-4-carboxylate (76)

To a solution of diphenylmethyl 7-benzylideneamino-3 - = [(triphenylphosphonio) methyl] -3-cephem-4-carboxylate iodide [75; prepared according to the procedure of published Japanese Patent Application (Kókai) 15 56 ”86187 (7/31/81); (60 g, 70 mmol)] in 350 ml CH 2 Cl 2 were added at 5 ° C 140 ml N NaOH and 35 g Amberlite IRA-410 (OH form). The mixture was stirred at 5 ° C for 1 hour and filtered. The organic layer was separated, dried over MgS0 4, concentrated to a volume of about 100 ml and precipitated with 500 ml of ethyl acetate. The resulting yellow solid was collected by filtration and dried under reduced pressure. 48 g (94%) of the title compound 76 were obtained, m.p. 195-198 ° C (decomposition).

IR s. V KBr cm "1 1770, 1620. Max

Preparation No. 7 25

Diphenylmethyl 7-benzylideneamino-3- (3-chloro-1-propen-1-yl) -3-cephem-4-earboxylate (77)

To a stirred solution of 76 obtained according to preparation No. 6 (2.9 g, 4 mmole) in a mixture of 40 ml CH 2 Cl 2 and 10 ml H 2 O, was added 800 mg anhydrous chloroacetaldehyde at room temperature. An additional 800 mg of chloroacetaldehyde was added to the mixture in three portions over a 1 hour period, while the pH of the mixture was kept between 6 and 9 by addition of N NaOH. After 15 min, the water layer was removed and the organic layer was dried over MgSO4. Evaporation of the solvent gave a red oil which was dissolved in a mixture of ethyl acetate and isopropyl ether (1/2, 80 ml).

The solution was washed successively with 10 ml saturated water 8501002 tf '59 g NaHCO 3 and 10 ml 10 O. After drying over MgSO4, removal of the solvent gave 3.3 g of yellow oil. A solution of the oil in 50 ml was filtered using silica gel (12 g, Wakogel C-200) containing 1 / 1.5 M phosphate buffer (1.2 ml, pH 6.4) and the silica gel was 5 washing with 50 ml CH 2 Cl 2 The filtrate and the washing liquid were combined and evaporated to dryness. The residue was triturated with n-hexane to obtain 1.7 g (80%) of the title compound 77 as a yellow powder. The nmr spectrum showed that the chloropropenyl group had the Z configuration.

The melting point was above 50 ° C (decomposition).

IR: V KBr cm -1 3400, 1775, 1720, 1630.

max UV: 1 E6 ° Bnm (£;) 253 (11000), 258 (11000), 265 (10000), 273 (8300), * w max 281 (7000), 290 (6300).

NMRs <5DMSCHi6 3.63 (2H, br-s, 2- * H), 4.0 (28, m, CH.-Gl), 5.42 (-2H, ppm -¾m, 6-H & 3 -CH = CH}, 5.72 (1H, d, J = 4.5, 7-H), 6.27 (18.15 d, J = 11, 3-CH), 6.85 (18, s , CHPh2), 7.33 (10H, m, Ph-H).

Preparation of anhydrous chloroacetaldehyde

Anhydrous calcium chloride was added with stirring to a cooled solution of 50% aqueous chloroacetaldehyde (50ml), separating into two layers. The chloroacetaldehyde hydrate-20 layer v '(the top layer) was separated and diluted with 100 ml CHCl 2, mixed with 20 g MgSO 4, refluxed for 5 min, and filtered. The solvent and water were removed aseotropically (boiling point 56-64 ° C 0 v), and the residue was distilled to give anhydrous chloroacetaldehyde, bp 70-82 ° C / 760 mm.

IR: cm -1, 1720.

max (• 1) R.P. Kurkjy, E.V. Brown, J. America. Chem. Soc., 74, 5778 (1952).

(2) So Trippett, D.M. Walker, J. Chem. Soc., 1961 1266.

(3) H.0. House, U.K. Jones, G.A. Frank, J. Org. Chem., 29, 3327 (1964).

Preparation No. 8 30 phenylmethyl 7-amino-3- (3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate C78)

A solution of 77 obtained according to preparation No. 7 (180 mg, 0.34 mmol) in 10 ml of ethyl acetate was added at 5 ° C to a solution of Girard reagent T [(carboxymethyl) trimethyl ammonium chloride-35 hydrazide] (251 mg, 1.5 mmol) in 10 ml CH 2 H, containing 0.25 ml acetic acid 8501002

* X

60 contained. After stirring at 5 ° C for 30 min, the mixture was concentrated to remove the CEiOH and then 20 ml of ethyl acetate was added. The thy lace solution was washed successively with 2 x 5 ml H 2 O, 5 ml saturated aqueous NaHCO 3 and 5 ml brine, and dried over 5 MgSO 2. Evaporation of the solvent gave 145 mg (97%) of the title compound 78 (Z: isomer) as a yellow powder. Melting point above 100 ° C (decomposition).

IR t V cm @ -1 3400, 1770, 1720. max. V; XEtOHnm (&) 252 (3700), 258 (3800), 260 (4000), 274 (4000), 10 285 (4000).

Preparation No. 9

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-iminoacetami-do] -3- (3-chloro-1-propen-1-yl) -3 -cephem-4-carboxylate (68-1)

A mixture of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-15 methoxyiminoacetic acid (63-1; 10.1 g, 50 mmole) and PCl 4 (10.4 g, 50 mmol) in 100 ml of dry C 1 Cl 2 was stirred at -5 to -15 ° C for 2 hours.

The clear solution was poured into 500 ml of n-hexane to obtain a precipitate. The organic layer was removed by decantation and the residual solid was triturated with 100 ml of n-hexane. The yellow precipitate was collected by filtration and dried under reduced pressure. 12.5 g (99%) of the acid chloride with a melting point at 80 ° C (decomposition) were obtained.

XR: y nujQl cm "1 1770.

max

The acid chloride (25mg, 0.1mmol) was added to a solution of the compound 78 (Z isomer) obtained according to preparation No. 8 (44mg, 0.1mmol) in 5ml of dry CH 2 Cl 2 at room temperature, while was stirred. After 30 min, the mixture was concentrated under reduced pressure and diluted with 20 ml of ethyl acetate and 5 ml of saturated aqueous NaHCO 2. The organic layer was washed with 5 ml of saturated aqueous NaHCO 4, 5 ml of brine, 5 ml of 10% HCl and 5 ml of brine.

The solvent was dried over MgSO4 and then evaporated to dryness. product was obtained as a yellow foam. The foam was purified by silica gel (wakogel C-200, 1 g containing 0.1 ml 1 / 1.5 M phosphate buffer pH 6.4) column chromatography eluting with CH 2 Cl 2 CH 2 H (100: 1), whereby 31 mg (50%) of the title compound 68-1 (Z isomer) was obtained as a yellow powder. The melting point was above 150 ° C (decomposition).

8501002 i 61 TCRr -1 IR: y cm 3400, 1775, 1720, 1675, 1630.

Max UV: X EtOH nm (£;) 240 (17000), 280 (10000).

max NMR: ί DMSO-dg ^ (2H, 2-B), 3.92 (3H, s, 0-CH-), 4.0 (2H, m, ppm 3 CH2C1), 5.27 (2H, m .6-H & 3-CH = GH), 5.83 (1H, dd, 5 J = t4.5 & 10, 7-H), 6.25 (1H, d, J = 11,3-CH) , 6.83 (1H, s, COTh2), 7.33 (10H, m, Ph-H), 8.0 (2fl, br-s, NH2), 9.57 (1H, d, J = 10, 7-NH).

Preparation No. 10

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cefem-4-carboxylate (69 - 1)

A solution of 68-1, obtained according to preparation no.

5 (Z / E »2/1, 480 mg, 077 mmol) in 10 ml dry acetone containing 346 mg, 2.3 mmol Nal was stirred at room temperature for 30 min.

The reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between 50 ml of ethyl acetate and 10 ml of water. The top layer was washed successively with 10 ml of 10% w / v aqueous sodium thiosulfate solution and 10 ml of brine, and dried over MgSO 4.

Evaporation of the solvent gave 540 mg (98%) of the title compound 69-1 (Z / E = 1/1) as a reddish amorphous solid, m.p. 120 ° C (decomposition).

IR .mu. Cm @ -1 3300, 1780, 1720, 1680, 1620. max UV t 1 EtOH nm ()) 240 (21000), 290 (12000).

Λ max NMR: £ ΕΜΒΟΛΟ ^ ^ ^ 2-H), 5.29 (1H, d, J «4.5, 6-H), ppm

5.95 (1H, d, J = 4.5, 7-H), 6.27 (1 / 2H, d, J = 11, 3-CH

Cis), 6.72 (1 / 2H, d, J = 16, 3-CH trans), 6.87 & 6.96 (1 / 2H, s, CHPh2 each), 7.4 (10H, m, Ph -H).

Preparation No. 11

Diphenylmethyl 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetami-30-do] -3- (3-iodo-1-propen-1-yl) -3- cefem-4-carboxylate (69-1)

A mixture of 68-1 (Z isomer), obtained according to preparation No. 9 (5.6 g, 9 mmol) and 4 g, 27 mmol Nal in 100 ml dry acetone was stirred at room temperature for 1.5 hours. The mixture was evaporated and the resulting oil was diluted with 90 ml of ethyl 35 acetate. The ethyl acetate layer was washed with 10 ml 10% w / v aqueous sodium thiosulfate solution and 10 ml H 2 O. Removal of the top MgSO ^ 8301002 62

i X

dried solvent gave a yellow oil, which solidified by trituration with isopropyl ether. Filtration of the precipitate gave 4.3 g (67%) of the title compound 69-1 as the E isomer. The melting point was above 165 ° G (decomposition).

IR: Y ^ cm "* 1 3400, 1780, 1725, 1680, 1610.

max UV r λΚ <3ΒηΐΒ * (A) 240 (18000), 297 (11000). max

NMR; I DMSO-dg + D ^ O 3 ^ gQ (3 & ocH j 5.25 (1H, m, 6-H), 5.95 (1H, ppra J

m, 7-H), 6.72 (d, J = 16, 3-CH trans), 6.96 (1H, s, CH-Ph> 2) 10 7.4 (10H, m, HHH).

Preparation No. 12

Benzhydryl 7-amino- 3 - [3-chloro-1-propen-1-y 1) -3 -ce fem-4-carboxylate (Z isomer> r) (78)

Compound 78 is the common intermediate 15 used in reaction schemes 1b and 1c.

A. Benzhydryl 7-benzylideneamino-3-triphenylphosphoniomethyl-3-cephem-4-earboxylate chloride (7: 5)

To a suspension of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride (62, hydrochloride; 200 g, 0.44 20 mol) in 940 ml CH Cl_ was added 440 ml IN NaOH at room temperature added.

2 ^

The mixture was shaken for 10 min and the organic layer was separated. To the organic layer, 75 g of MgSO 4 and 51 g, 0.48 mol of benzaldehyde were added and the mixture was allowed to stand for 3 hours.

The reaction mixture was filtered and the insoluble matter was washed with 200 ml of CH 2 Cl 2. 126 g, 0.48 mol of triphenylphosphine was added to the combined filtrate and washing liquid. The mixture was concentrated to about 400 ml and left for 4 days. The resulting viscous oil was diluted with 1 L of ethyl acetate and triturated to yield the title compound 75 as a pale yellow crystalline powder which was collected by filtration and dried under reduced pressure. The yield was 322 g (96%). Melting point was 185-190 ° C (decomposition).

IR; V * Br 'cm "1 1780, 1720, 1630.

max UV; ACH2G12 nm (£ |) 260 (24100).

J B. Benzhydryl 7-benzylideneamino-3 - [(triphenylphosphoranylidene) methyl 3-3 -ce fem-4-carboxylate (76)

A mixture of 75 (322 g, 0.42 mol) and 5 N Na 2 CO 3 (252 8501002 I 63 ml) in CH 2 Cl 2 (1.6 -1) was stirred vigorously at room temperature for 15 min. The organic layer was separated, dried over MgSO 4, and concentrated to a volume of about 500 ml. The concentrate was added to 1 L of acetone with stirring to give a pale yellow crystalline powder which was collected by filtration. A yield of 237 g (78%) of the compound of formula 76 was obtained, which melted at 195-198 ° C (decomposition).

IR µ cm -1, 1770, 1620. max UV 1 nm (ft) 254 (23000), 389 (22000).

Λ max 10 NMRs S CDC13 2.56 & 3.16 (2H, ABq), 5.00 (1H, d, J = 4 Hz), 5.23 (1H, ppm d, J = 4 Hz), 5, 47 (1H, d, J = 22Hz), 6.95 (1fi, s), 7.2-7.8 (3H, m), 8.55 (1H, s).

C. Benzhydryl 7-amino-3- [chloro-1-propen-1-yl] -3-cephem-4-carboxylate hydrochloride (Z isomer) (73-hydrochloride) 15 At a refluxing solution of the compound with formula 76 (214 g, 0.294 mol) and Ν, Ο-bis- (trimethylsilyl) -acetamide (40 ml, 0.15 mol) in 2.9 L were added dropwise with a 50% * solution of chloroacetaldehyde (93) with stirring g, 0.59 mol) in CHCl 3 added over a period of 15 min. After standing for 30 min, the mixture was evaporated to dryness. To the residual oil were added 1.5 L of C 4 Cl 4, 99 g, 0.59 mole of Girard reagent T and 300 ml of 10% aqueous HCl, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed with 200 ml of water and 200 ml of a saturated NaCl solution, dried over MgSO 4, treated with 5 g of charcoal and filtered. The filtrate was cooled to -10 ° C and treated with 1N HCl in 300 ml CH 2 OH. The mixture was stirred at room temperature for 30 min and concentrated to about 300 ml. The concentrate was diluted with 400 ml ethyl acetate and seeded with a few crystals of 78 hydrochloride. After 2 hours, the separated crystals were collected by filtration, washed with 200 ml of ethyl acetate and dried under reduced pressure. 74 g (53%) of the title compound 78 were obtained in the form of its hydrochloride having a melting point above 185 ° C (decomposition). They were light yellow needles.

IR ï V ** cm "1 2830, 1780, 1720. max 35 UV; X EtOH nm (&.) 286 (8800). Max 8501002

4 X

64 NMR: 1 DMSO-dg 3; 3 (2H / 2-Ή), 3.97 (2H, m, CHOI), 5.22 (1H, d, J = 4.5 Hz, 6-H) , 5.37 (1H, d, J = 4.5 Hz, 7-H), 5.77 (1fi, m, 3-CH = CH), 6.45 (Ifi, d, J-Π Hz, 3 -CH), 6.88 (1H, s, CHPh '), 7.33 (10H, br, s, Ph-H).

M'5 Analysis calculated for C23H21N2 ° 3SG1 '* HCl''C 57.87; H 4.65; N 5.87; S 6.72; Cl, found 14.85; C 57.62? Η 4.53; N5.70; S 6.64; Cl 14.89.

Preparation No. 13 IQ Benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetami-do] -3- [3-chloro-1-propen-1 -yl] -3-cephem-4-carboxylate (z1 isomer) (68-1), to a stirred solution of 78 (Z 'isomer; 20 g, 42 mmol) in 420 ml CH 2 Cl 4 which 34 ml, 125 mmol Ν, Ο-bis (trimethylsilyl) -acetamide was added in three 15-part portions 15.2 g, 59 mmol 2- (5-amino-1,2,4) over a period of 30 min at -10 to 0 ° C. -thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride. The mixture was stirred at 0-5 ° C for 30 ml and under reduced pressure. concentrated. The residual brown oil was dissolved in 420 ml of ethyl acetate and the solution was washed successively with 3x15 ml of saturated aqueous NaHCO3, 15 ml of saturated aqueous NaCl, 15 ml of 10% HCl and 15 ml of saturated aqueous

NaCl and concentrated to a volume of about 50 ml. 200 ml of n-heptane were added to the concentrate, whereby 28.5 g (90% pure) of the title compound 68-1 (Z isomer) were obtained as a colorless powder. The melting point was above 150 ° C (decomposition).

IR 1 V cm 2, 3400, 1780, 1720, 1680, 1620.

max OV s X EtOH nm (£:) 240 (20000), 283 (12000).

W max w NMR; $ acetone-dg (2fi, m, 2-H), 3.95 (3E, s, OCH.), 4.0 (2E, m, ppm —j CH2Cl), 5.32 (1E, d, J = 4.5 Hz, 6-H), 5.62 (1H, m, 3-

CH = CH), 6.03 (1H, d, J = 4.5 Hz, 7-Ή), 6.32 (1H, d, J = U

30 Hz, 3-CH), 6.87 (IS, s, CHPh ^), 7.33 (1QH, br, s, Ph-H).

Preparation No. 14

Benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetami-do] -3- [3-1odo-1-propen-1-yl] -3 -cephem-4-carboxylate (E isomer) (69-1)

A mixture of 68-1 (Z isomer; 28.5 g, 90% pure) 35 and 19 g sodium iodide in 420 ml dry acetone was stirred at 850 ° C> 65 ° C for 10 min and left at 5 ° for 2 h C stand. The mixture was concentrated under reduced pressure. 420 ml of ethyl acetate and 30 ml of 10% w / v aqueous sodium thiosulfate solution were added to the residue, and the mixture was shaken. The organic layer was washed with 30 ml of water, dried over MgSO 4 and evaporated to a volume of about 50 ml. The concentrate was diluted with 200 ml n-heptane to give a yield of 30.6 g (95% pure) of the title compound 69-1 (E isomer) as a yellow powder, m.p. 120 ° C (decomposition) .

1 ° IR -1 cm @ -1 3400, 1780, 1725, 1680, 1620.

UV: X EtOH nm (&) 306 (15000).

max NMRI acetone-dg 3? 1 (2Hj, m 2-H), 3.97 (3H, s, OCH.), 4.0 (2H, d,

ppm —J

J = 8 Hz, CH2-I), 5.26 (1H, d, J = 4.5 Hz, 6-H), 6.03 (1H, dd, J = 4.5 & 8 Hz, changed to doublet J = 4.5 Hz by 15 D20, 7-H), 6.32 (1H, dt, J = 15 & 8 Hz, 3-CH = CH), 6.79 (1H, d, J = 15 Hz, 3-GH), 6.98 (1H, s, CHPh2), 7.35 (10H, m, Ph-Ή), 7.63 (2H, br, s, disappeared by D20, NH ^, 8.52 ( 1H, d, J = 8Hz, disappeared by D 2 O, 7-NH).

Preparation No. 15 20 Benzhydryl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] - 3- [3- (4-carbamoyl-1-pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate iodide (E isomer) (72-1H)

To a suspension of 69-1 (E isomer, 30.5 g) and 26 g, 212 mmol isonicotinamide in 120 ml CH 2 CN was added 100 ml CH 2 OH; until the mixture became clear. The solution was stirred under a nitrogen atmosphere at room temperature for 2 hours and concentrated under reduced pressure to about 100 ml. The remaining semi-solid was triturated with 200 ml of isopropyl ether. The solvent was removed by decantation and the residual yellow powder was washed with a mixture of isopropyl ether and CH 2 OH (3/1, 120 ml). The powder was collected by filtration and dried under reduced pressure. 36 g (75% pure estimated by HPEC) of the title compound 72-1H (E isomer) were obtained as a pale yellow powder, m.p. 150 ° C (decomposition).

IR.Ï V cm 3300, 1780, 1720, 1680, 1620. max 35 UV ï Λ Et ° H η® (eJ% ^> 282 (170) max 1 cm 8501002 Λ.

* V

66 NMR: & DMSO-dg 3f72 (2H ^ 2-S), 3.90 (3fi, s, OCH.), 5.25 (3H, m, ppm -3 6-H & CH ^ N), 5 .9 (1H, dd, J = 4.5 & 8 Hz, changed into a doublet J = 4.5 Hz by D20 addition, 7-H), 6.35 (1H, m, 3-CH = CH), 6.89 (1H, s, CHPh2), 6.9 (IS, d, J = 5 16 Hz, 3-CH), 7.35 (10H, m, Ph-H), 8.06 (2H, br , s, disappeared by D20, NH2), 8.21 (2E, br, s, disappeared by D20 addition, NH2), 8.36 & 9.07 (each 2H, d, J = 6 Hz,

Py-R), 9.57 (1H, d, J = 8 Hz, disappeared by D20 addition, 7-NH).

10 Preparation no »16

Benzfaydryl 7-benzylideneamino-3- [3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate (77.2 isomer)

To an ice-cooled mixture of the crystalline 7-amino-cephem intermediate of formula 78 (Z'isomer, 13.4 g, 28 mmol) and 3.3 g, 31 mmol of benzaldehyde in 150 ml of ethyl acetate over a period of 56 ml, 28 mmol 0.5 N sodium hydroxide were added dropwise over 20 min, keeping the temperature of the reaction mixture below 10 ° C. The mixture was stirred for an additional 15 min under cooling, and the organic layer was separated, washed with 2 x 100 ml of saturated aqueous sodium bicarbonate and dried over magnesium sulfate. A small amount of charcoal was added to the dried solution and the mixture was filtered. The filtrate was evaporated to dryness. The residual oil was dissolved in 50 ml of carbon tetrachloride and concentrated again. This procedure was repeated 3 times, and the mixture was followed with reverse phase tic to confirm that all 7-amino-cephalosporin used as starting material had been converted to the Schiff * s base. Removal of the solvent under reduced pressure gave 16.45 g of the title compound 77 (Z isomer) as a pale yellow powder (estimated purity 85%; mp 74 ° C (decomposition)), which was used for the next step without purification.

IR i V ^ cm "* 1 i-780, 1725, 1635.

T max - CH2 Cl2 ^ (E1%. J 257 (400).

Λ max 1 cm NMR: 1CDC13 6.18 (1H, d, J = 11 Hz), ppm 'Preparation No. ♦ 17 35 Benzhydryl 7-benzylideneamino-3- [3- (4-carbamoyl-1-pyridini'o) - 1-props-l-

* I

8501002 rf 67 yll-3-cefem-4-carboxylate iodide (81-"H) (El isomer)

To a cooled mixture of 16.4 g of the 3-chloro-propenylcephem of the formula 77 (z isomer) in 5 ml of acetone was added dropwise a solution of 5 6.3 g, 42 mmol in the course of 10 min under a nitrogen atmosphere. sodium iodide in 30 ml of acetone, and the mixture was stirred at room temperature. The reaction was followed by the 1% 1% attitude of UV absorption [E. (255 n ») / E. (320 nm)]. When the ratio of 1 cm reached a value below 1.30 (after 45 min), the mixture was diluted with 400 ml of carbon tetrachloride and allowed to stand at room temperature. When the ratio fell below 1.10 (after 3 hours), the mixture was concentrated to half its volume. The concentrate was treated with a small amount of charcoal and diatomaceous earth, and filtered. The filter cake was washed with 100 ml of a III mixture of methylene chloride and carbon tetrachloride. To the combined solution of the filtrate and washings was added a solution of 3.5 g, 28.7 mmol of isonicotinamide in 20 ml of dimethylformamide and the mixture was concentrated under reduced pressure.

The concentrate was allowed to stand at room temperature for 1.5 hours and washed with 3 x 100 ml isopropyl ether. The residual brown semi-solid was dissolved in 50 ml of methylene chloride and the solution was added dropwise with stirring to 1.5 L of ethyl acetate. The resulting precipitate was collected by filtration and washed with 200 ml of ethyl acetate. After drying over phosphorus pentoxide under reduced pressure, 17 g of the title compound 81-H (E isomer) were obtained. It was a yellow amorphous powder with a melting point of 150-155 ° C (decomposition). The estimated purity was 80% by nmr.

IR; V KBr cm ”1 1775, 1725, 1690, 1635. r max UV: X ^ 2 ° ½ nm (Ε? *) 258 (335), 298 (255).

dcL2 £ 1 Ol 25 NMR: & DMSCHd6 3.4 - 3.8 (2H, br (.), 5.35 (2H, br.), 5.41 (1H, d, J = ppm 4Bz), 5, 73 (1H, d, J = 4 Hz), 6.93 (1H, -s), 6.97 (1H, d, J = 16 Hz), 7.3 - 7.5 (15H, br. -S ), 8.40 (2H, d, J = 6.5 Hz), 9.15 (2H, d, J = 6.5 Hz).

Preparation No. 18 30 7-Amino-3- [3- (4-carbamoyl-1-pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate (82-B, E isomer)

To a suspension of the quaternised cefem 81-H

8501002 * 68 <(17 fg) in 25 ml of 85% formic acid, 5 ml of concentrated hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for 1.5 hours and treated with a small amount of charcoal. The mixture was filtered and washed with 5 ml of 85% formic acid. The filtrate was combined with the washing liquid and poured into 1 L of acetone with stirring. The resulting precipitate was collected by filtration to obtain 9.52 g of a yellow-colored crude product. A small amount of charcoal was added to a slurry of the crude material (9.5 µg) with 50 ml of water, and the mixture was filtered. The filtrate was added dropwise to 700 ml of isopropyl alcohol with stirring. The resulting precipitate was collected by filtration, washed with a small amount of 30 ml methanol, and dried. 7.58 g of the title compound 82-Η (E isomer) were obtained as the hydrochloride. It was a light yellow powder. The estimated purity was 85% by UV. Melting point 15 was 173-188 ° C (decomposition).

IR ί V ^ cnf1 1795, 1680, 1620, 1575, 1540.

* max.

ον, ï Μ (E1 4) 294 (457).

Λ max 1 cm NMRs D20 + DC1 3.82 (2H, s), 5.17 (1H, d, J = 5 Hz), 5.33 (2Ö, d, J = ppm 7Hz), 5.43 ( 1H, d, J = 5 Hz), 6.37 (lfi, dt, J = 16 & 7 20 Hz), 7.23 (1H, d, J = 16 Hz), 8.34 (2H, d, J = 7 Hz), 9.00 (2H, d, J = 7 Hz).

Preparation No. 19 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (63-1 as the acid chloride hydrochloride) 25 A. 2-Cyano-2- methoxyiminoacetamide

To a stirred mixture of 252 g, 3 moles of α-cyanoacetamide and 414 g, 6 moles of sodium nitrite in 600 ml of water was added 371 ml, 10 moles of acetic acid at 5-10 ° C over 1.5 hours. The mixture was stirred for an additional 1.5 hours and adjusted to a pH of 8.5 with 6 N NaOH.

To the mixture was added 568 ml, 6 moles of dimethyl sulfate at 15-20 ° C, and the mixture was stirred at 45 ° C for 1.5 hours. The reaction mixture was adjusted to pH 8.5 with 6N NaOH and left overnight at 5 ° C to separate a precipitate which was collected by filtration, washed with cold water and aired was dried. 292 g (77%) of the title compound were obtained as brown needles, m.p. 170-172 ° C.

8501002 ^ 69 IR: ^ cm 2, 34 3400, 3180, 1720 (sh), 1715, 1690, 16.15, 1570.

max OV: 1 H2 ° im (£) 238.5 (8290), 268 (sh, 3870).

max NMR: & DMSO-dg 4 2Q (3Hf s> qch} f 7.85 (2H, br. NH).

ppm ο i

Analysis calculated for C 14 H N N O O: C 37.80; H3.97; N 33.06 found C 37.43; H 3.75; N 32.51.

B. 2-Methoxyiminopropanedinitrile

A stirred mixture of 88.9 g, 0.7 mole of 2-cyano-2-metho-xyiminoaetamide, 70 g of sodium chloride and 97 ml, 1.05 mole of phosphorus oxychloride in 350 ml of dry 1,2-dichloroethane was stirred for 16 hours refluxed. The insoluble matter was filtered through a dicalite pad and washed with dichloroethane. The filtrate and washings were combined, and poured into 1.5 L of stirred ice water to decompose excess phosphorus oxychloride. The organic phase was washed with 500 ml of 10% NaHCO 2, 3 x 500 ml of water and 500 ml of the saturated NaCl solution and dried over MgSO 2. The filtrate was distilled under reduced pressure to obtain 61.5 g (81%) of the title compound which boiled at 62 ° C / 24 mm Hg. (Lit., bp 47-48 ° C / 12 mm Hg).

IR: v v] * oil film cm 1 3020f 2960, 2245, 2020 <, 1530yr 1455 <, 1080.

max 20 NMR; CDCl3 4.35 (3H, s, OCH2).

ppm 3 C. 2-Cyano-2-methoxyiminoacetamidinium acetate

To a solution of 28.4 g, 0.53 mol ammonium chloride in 355 ml 28% aqueous ammonia and 180 ml ethanol was added dropwise over a period of 30 min with stirring at -15 to -10 ° C. solution of 58.0 g, 0.53 mol of 2-methoxyiminopropanedinitrile in 120 ml of ethanol was added. The mixture was stirred at -10 ° C overnight and then at room temperature (20-25 ° C) for 1 day. The reaction mixture was partitioned between 350 ml of water and 350 ml of CH2 Cl2, and the aqueous phase was saturated with sodium chloride and extracted again with 300 ml CH2 Cl2. The organic extracts were combined, dried over MgSO 4 and evaporated under reduced pressure. A solution of the residue in 1.6 L of ethyl acetate was adjusted to a pH of 3-4 with acetic acid to precipitate the title compound as crystals, which were collected by filtration and washed with ethyl acetate. The yield was 67.6 g (69%). Melting point 152-154 ° C (decomposition). [Lit., 8501002 * 4.

70 mp 150-155 ° C (decomposition)].

IR: cm 2, 1 3160, 2900, 2360, 2235, 2000, 1665, 1555, 1495, 1415.

max UV: XEt0Hnm (£) 243 (8500), 265 (sh, 5380), 305 (sh, 1400).

Λ max NMRr ί DMSO-dg χ 88 (3H ch C00H), 4.15 (3H, s, OCH-), 7.60 (4H, ppm - 5 br.).

Analysis calculated for C 4 H N N O O CH C C OH: C 38.71; H 5.41; N 30.09 found: C 38.71; H 5.59; N 29.51.

D. 2- (5-Amino-L, 2,4-thiadjazol-3-yl) -2-methoxyimino-acetonitrile

To a suspension of 2-cyano-2-methoxyiminoacetamidini-10 µm acetate (125 g, 0.672 mol) in 1.25 1 CH 3 OH was added dropwise at -10 ° C 234 ml, 1.68 mol triethylamine, then in 20 min at -15 to -10 ° G 41.6 ml, 0.806 mol) Br2. The mixture was stirred for 20 min. A solution of 78.3 g, 0.806 moles KSCN in 550 ml CH2 OH was added dropwise to the mixture over 1 hour at -15 to -10 ° C. After stirring at 0-5 ° C for 1 hour, the mixture was poured into 12 L of ice water to form a crystalline precipitate, which was collected by filtration, washed with water and air dried. 12Q g (98%) of the title compound were obtained. The melting point was 263 - 265 ° C (decomposition). The melting point of the compound thus prepared is about 60 ° C higher than the melting point reported in the literature (Japanese Patent Application Kokai 57-158769, published September 30, 1982, from Fujisawa, British application 3/6/81; melting point 210 - 215eC (decomposition)), but the spectral and microanalytical data below are consistent with the structure.

IR: V KBr cm ”1 3435, 3260, 3120, 2960, 2245, 2020, 1630, 1545, 1455, 7 max 1415.

UV; 1 Et 2 S nm (lb) 248 (13300), 310 (3470).

^ max NMRt $ DMS0 "d6 4.21 (3H, s, OCH-), 8.30 (2H, br. NH-). ppm 3 2

Analysis calculated for C 8 H 15 N 3 OSi C 32.78; E 2.75; N 38.23; S 17.50 found C32.76; H 2.51; N 38.02; S, 17.50.

E. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (63-1)

A mixture of 2- (5-amino-1,2,4-thiadiazol-3-yl-2-methoxyiminoacetonitrile (18.3 g, 0.1 mol) in 250 ml 4 N NaOH was stirred for 3 hours heated at 50-55® C. The reaction mixture was adjusted to pH 1 with H3PO4, and washed with 100 ml ethyl acetate, 8501002 Γ - * 71 saturated with NaCl, and extracted three times with a mixture of ethyl acetate and tetrahydrofuran (3: 1, 2 x 300 ml, and 1 x 200 ml) The extracts were combined, dried over MgSO 4 and concentrated under reduced pressure The residue was triturated with isopropyl ether to give pale yellow crystals of the title acid The yield was 16.8 g (83%) Melting point 184-185 ° C (decomposition) [Lit. *, melting point 180-182 ° C (decomposition) (* Japan Kokai 57-158769, published September 30, 1982, from Fujisawa, British Application 3/6/81).

IR} V KBr cm -1 3460, 3260, 3140, 1725, 1620, 1605, 1545. max 10 µV: X µm (µ) 234 (13200), 288 (sh, 3620).

F. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride

To a suspension of 2- (5-amino-1,2,4-thiadiazol-3-yl) -15 2-methoxyiminoacetic acid (63-1, 40.4 g, 0.2 mol) in 400 ml dry CH 2 Cl 41.6 g, 0.2 mol PClg was added in a portion at -50 ° C. The mixture was stirred at -20 to -5 ° C for 4 hours and poured into a mixture of n-heptane and isopropyl ether (2: 1, 21). The yellow precipitate was collected by filtration, washed with the same solvent mixture, and dried under reduced pressure with KOE. 46.0 g (90%) of the title acid chloride are obtained.

IR: y Nujo; L cm "1 1775 max

Preparation No. 20

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacet-25 amidol-3- [3-chloro-1-propenyl] -3-cephem -4-carboxylate (68-2, Z isomer of formula 119)

To a mixture of Ν, Ο-bis (trimethylsilyl) acetamide (2.3ml, 9mmol) and crystalline diphenylmethyl 7-amino-3- [3-chloro-1- (Z) -pro-1-yl] 3-cephem-4-carboxylate hydrochloride (78-1.338 g, 2.8 mmol, 30 obtained according to preparation No. 12) in 10 ml methylene chloride was stirred with 2- (5-amino-1,2,4-thiadiazole) 3-yl) -2- (Z) -ethoxyiminoacetyl chloride hydrochloride (800 mg, 2.95 mmol) in portions at -10 ° C and the mixture was allowed to stand at 0 ° C for 2 hours. The mixture was diluted with 200 ml of ethyl acetate, washed with water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave the title product 68-2 as an amorphous powder. The yield was 1.70 g (95%). The 8501002 * 72 melting point was above 150 ° C (decomposition).

IRV (KBr) in cm -1 3300, 1780, 1720, 1690, 1380, 1220.

max OV 1 (C 1 H-OH) in nm (() 285 (11000).

/ v max 2 5 NMR: & (DMSO-dg) in ppm 1.26 (3fi, t, J = 7Hz, CH2CH3), 4.25 (2H, q, J = 5 7Hz, CH2CH3), 5.90 ( 1H, dd, J = 4 & 8Hz, 7-H), 6.26 (1H, d, J = 11Hz, 3-CH), 6.85 (1H, s, CHPh2), 9.53 (1H, d , J = 8Hz, 7-NH).

Preparation No. 21

Diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacet-10 amido] -3- [3-iodo-1-propenyl] -3- cefem-4-carboxylate (69-2 with formula 120)

A mixture of the compound 68-2, obtained according to preparation No. 20 (1.90 g, 3 mmol) and 1.4 g, 9 mmol sodium iodide in 20 ml of acetone was stirred at room temperature for 10 min and then left for 3 stand at 5 ° C for hours. The mixture was evaporated under reduced pressure, diluted with 100 ml of ethyl acetate, washed with 10% sodium thiosulfate and water, and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gave 1.82 g (84%) of the title product 69-2 as a light brown amorphous powder.

IR s V (KBr) in cm -1 3290, 1770, 1720, 1670, 1530, 1370, 1220.

max 20 07; (CLH-OH) in nm (E1% J '304 (199).

A max 25 1 cm

Preparation No. 22

Diphenylmethyl 7 ° benzylideneamino-3 - [(E) -3- (4-carbamoyl-pyridinio) -1-propenyl] -3-cephem-4-carboxylate (81-H iodide, E isomer of formula 121)

To a cooled solution of the 3-chloropropenyl-25 cephem (77.2 isomer obtained with preparation No. 16; 42.8 g, 90 mmol) in 80 ml of dry DMF was added in a portion of 20 g, 120 mmol of KI, and the mixture was stirred at room temperature. The reaction was followed by the ratio of UV absorption [E ^ (255 nnO / E ^ ^ (320 nm)].

When the ratio fell below 1.10. (after 45 min), the mixture was diluted with 800 ml of methylene chloride, treated with 4 g of activated carbon and filtered. The filter cake was washed with 100 ml. 14.64 g of isonicotinamide was added to the combined filtrate and washings and the mixture was concentrated under reduced pressure. The concentrate was kept at room temperature for 1.5 hours and washed with a mixture of toluene and n-heptane <1 '; 1,600 ml). The remaining brown 8501002 * 73 semi-solid was dissolved in 100 ml and the solution was added dropwise to 3 L ethyl acetate with vigorous stirring. After drying under reduced pressure above P2 ° 5 ', 57/37 ≤ 7 (88%) of the quaternized title product 81-H as the iodide was obtained. It was a yellow amorphous powder with a melting point of 150-155 ° C (decomposition). This product was identical to the product obtained by iodination with Nal (preparation no. 17).

Preparation No. 23

Diphenylmethyl 7-amino-3- (3-chloro-1-propenyl) -3-cephem-4-carboxylate-10 hydrochloride (2 isomer, 78-hydrochloride of formula 122)

A 25% * solution of 69 g, 0.22 mmol chloroacetaldehyde in CHCl 3 was added portionwise at -10 ° C to a solution of the compound of formula 76 (80 g, 0.11 mol) in 1.1 L CH 2 Gl 4 containing 16.2 ml, 0.06 mol N, Obis (trimethylsilyl) acetamide, and the mixture was allowed to stand overnight at 5 ° C. The mixture was concentrated to about 0.3 L, diluted with a mixed solvent of ethyl acetate and isopropyl ether (1/2, 0.6 L), treated with silica gel (Wa bullet C-100, 60 g) and filtered through a decalite To kiss. The filter cake was washed with the same solvent system (0.2 L). The combined filtrate and washings were concentrated to about 0.2 L, treated with 60 g, 0.26 mol of Girard reagent T and 220 ml of 4N HCl, and seeded with a few crystals of the hydrochloride of the compound with formaldehyde. mule 78. After stirring for 3 hours, the crystals obtained were collected by filtration, washed with 0.5 l of water and 0.5 l of ethyl acetate and dried under reduced pressure. 37 g (70%) of the title compound 78 hydrochloride were obtained, which was melted above 185 ° C (decomposition). They were pale yellow needles. This product was identical to the product obtained in preparation No. 12.

Preparation No. 24 30 Diphenylmethyl 7-amino-3- (3-chloro-1-propenyl) -3-cephem-4-carboxylate hydrochloride (Z isomer, 78 hydrochloride of formula 122)

Asm a solution of chloroacetaldehyde (25% solution in CHCl 3, 628 mg, 2 mmol) in 10 ml CH 2 Cl 2 was successively at 5 ° C 0.135 ml, 0.5 mmol Ν, Ο-bis (trimethylsilyl) acetamide and 728 mg, 1 mmol of the compound of formula 76. The mixture was allowed to stand at 5 ° C overnight. The mixture was evaporated and diluted with a mixture of ethyl acetate and isopropyl ether (1/2, 10 ml), 85 1 1 0 0 2 * * 74. Insoluble matter was removed by filtration and the filtrate was concentrated to about 5 ml. The concentrate was treated with 2 ml of 4N HCl, inoculated with the hydrochloride of compound 78 and stirred at room temperature for 1 hour. The crystals were collected by filtration, washed with 10 ml of ethyl acetate and 10 ml of water and dried under reduced pressure. 384 mg (80%) of the title compound were obtained 78-hydrochloride, melting above 185 ° C (decomposition). They were light yellow needles. This product was identical to the product obtained with preparation No. 12.

Preparation No. 25 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetyl chloride hydrochloride (63-3 as the acid chloride hydrochloride A. Methyl 2 - ° (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (propen-3-15 yloxyimino) acetate

A mixture of 685 mg (3.37 mmol) N- (propen-3-yloxy) phthalimide [prepared according to the procedure of E. Grochosaki & J. Jurczak, Synthesis 1976 682] and 175 mg (3.35 mmol) hydrazine hydrate in 5 ml of C 1 H H OH was stirred at room temperature for 1 hour. The resulting precipitate was filtered off and the filtrate and washings were combined. To the solution was added 967 mg (3.37 mmol) of methyl 2- (5-t-butoxycarbonyl-amino-1,2,4-thiadiazol-3-yl) -2-oxoacetate, and the mixture was left for 1 hour at room temperature and concentrated with a rotary evaporator. The residue was purified by silica gel chromatography. The column was eluted with n-hexane / ethyl acetate (4: 1) and fractions containing the main product were combined and evaporated under reduced pressure. The yield was 514 mg (46%). Melting point 83-86eC.

IR s V (KBr) in cm -1, 3100, 1745, 1710, 1610.

1 max 30 GVV (C-H-OH) in nm (£) 223 (9700), 242 (10000).

** max 2 5 NMRi i (CDCl 3) in ppm 1.55 (9H, s, BOC-H), 4.40 (2H, d, J = 5Hz, O-CH ^, 5.21 (2H, m, CH 2 * CH), 5.90 (1H, m, -CH = CH 2), 9.50 (1H, br.s, NH).

B. 2- (5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxy-35 xmi.no) acetic acid

A solution of 770 mg (2.3 mmol) methyl 2- (5-t-buto-8501002 h * 75 xycarbonylamino-1,2,4-thiadiazol-3-y 1) -2- (propen-3-yloxyimino) acetate and 3.5 ml of 2N NaOH solution (7.0 mmol) in 15 ml of CH 2 OH were refluxed for 30 min. The reaction mixture was concentrated under reduced pressure and diluted with 10 ml of ethyl acetate (1L). The water layer was separated, acidified with 6N HCl to a pH of 2 and extracted with 2 x 10 ml ethyl acetate. The ethyl acetate solution was dried over MgSO 4 and concentrated by rotary evaporator. 596 mg (81%) of the title compound were obtained. Melting point 134-135 ° C [lit., Melting point 135-136 ° C].

10 IR γ y (Nujol) in cm * 3150, 1745, 1710, 1550.

fflcLX

UV i x (C 1 H 2 OH) in nm (&) 223 (11000), 242 (11300).

max 2 o NMR: $ (DMSO-dg) in ppm 1.55 (9H, s, BOC-H), 4.77 (2H, d, J = 5Hz, O-CHj), 5.22 (2H, m , CH 2 = CH), 6.0 (1H, m, CH = CH 2).

V I. Csendes, et al., J. Antibiotics, 36, 1020 (1983).

15 C. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetic acid (63-3) 1}

A solution of 570 mg (1.74 mmol) 2- (5-t-butoxycarbonyl-amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetic acid in 6 ml of trifluoroacetic acid was allowed to stand at room temperature for 1 hour.

Evaporation followed by trituration with 30 nnL isopropyl ether gave 376 mg (95%) of the title compound, mp 109 ° C (decomposition).

IR γ y (Nujol) in cm 3 3180, 1710, 1545, 1460.

* max UV X (C-H_OH) in nm (£) 245 (13500).

* max 2 w NMR; $ (DMSO-dg) in ppm 4.77 (2H, d, J = 5Hz, O-CH 2), 5.20 (2H, m, CH = 25 CH 2).

Japanese Kokai 57-112396 (7/13/82, Fujisawa) British Patent Application 7935538 (10/12/79).

D. 2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) -acetyl chloride hydrochloride. A solution of 350 mg (1.54 mmol) of the compound 63-3 and 410 mg (1.97 mmol) of phosphorus pentachloride in 5 ml of dichloromethane were stirred at 25 ° C for 1 hour. The reaction mixture was poured into 60 ml of n-hexane and the precipitate was filtered off. The yield was 323 mg.

IR: V (Nujol) in cm 1 1765.

r max 8501002 ► l 76

Preparation No. 26 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-proparloxy-aminoacetyl chloride hydrochloride (63-4 as the acid chloride hydrochloride) A. Methyi-2- (5- t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxy-5 iminoacetate

A suspension of 870 mg (4.32 mmol) N-propargyl oxyphthalimide (available from Aldrich) and 200 mg (4.0 mmol) hydrazine hydrate in 5 ml ethanol was stirred at 25 ° C for 1 hour and filtered.

To the combined filtrate and washing liquid was added 1.0 g of 10 (3.86 mmol) methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-oxoacetate (I. Csendes et al., J. Antibiotics 36, 1020 (1983) The solution was allowed to stand for 1 hour and concentrated under reduced pressure.

Purification by silica gel chromatography followed by evaporation gave 319 mg (27%) of the title product, mp 72-75 ° C.

IR: V (KBr) in ca-1 3200, 2380, 1745, 1710, 1610. max UV \ (CH OH) in nm (£) 235 (12200).

Λ max 2 5 NMRs $ (DMSO-dg) in ppm 1.56 (9H, s, BOC-H), 3.55 (1H, t, J = 2Hz, C-CH), 4.85 (2H, d , J = 2Hz, -CH2-C-CH), 8.9 (1H, br.s, NH).

B. 2- (5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-proparqyloxyimino-20 acetic acid

A solution of 490 mg (1.4 mmol) of methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetate and 2.2 ml of 2N aqueous NaOH solution (4.4 mmol) in 14 ml CH 3 OH was refluxed for 30 min. The reaction mixture was concentrated under reduced pressure and 10 ml of ethyl acetate-HO (1; 1) was added to the solution. The separated aqueous layer was acidified to a pH of 2 with 6N HCl and extracted with 2 x 10 ml ethyl acetate. Drying over MgSO 4 followed by evaporation of the organic layer gave 149 mg (89%) of the title product, mp 135 ° C (decomposition).

IR: \? (Nujol) in cm * 3350, 1720, 1670, 1550.

r max UV: V (C_H_0H) in nm (£) 233 (11500).

ΙΏ \ · ΙΏ3Κ 2a 5 NMR: J (DMSO-dg) in ppm 1.55 (9H, s, BOC-H), 3.55 (1H, t, J = 2Hz, C-CH), 4.89 ( 2H, d, J = 2Hz, CHCl 3 CH), 9.0 (1H, s, NH).

1) C. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyimino-acetic acid (63-4) 35 A solution of 410 mg (1.26 mmol) 2- ( 5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid in 5 ml trifluoroacetic acid was allowed to stand at 25 ° C for 1 hour. Evaporation, 8501002 · r * 77 followed by trituration of a residue with 25 ml of isopropyl ether, gave 204 mg (72%) of the title compound, mp 156-158 ° C (decomposition).

IR: V (Nujol) in cm * 3300, 2480, 1730, 1610.

Max 5 UV: \ (α, Η-ΟΗ) in nm (£,) 234 (12000).

Λ max 25 _ NMRi 5 (DMSO-d-) in ppm 3.52 (1H, t, J = 2Hz, C-CH), 4.86 (2H, d, J = b _ 2H, CH2-C-CH ), 8.10 (2H, br. S, N ^).

Japanese Kbkai 57-112396 (7/13/82, Fujisawa) British Patent Application 7935538 (10/12/79).

- D. 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyimino-acetyl chloride hydrochloride

A mixture of 175 mg (0.07 mmol) of the compound 63-4 and 182 mg (0.88 mol) of phosphorus pentachloride in 2 ml of dichloromethane was stirred at -5 ° C for 1 hour. The reaction mixture was poured from 15 into 30 ml of n-hexane and the precipitate was filtered off. The yield was 65 mg (34%).

IRV (Nujol) in cm ^ 1770.

Max

Preparation No. 27 2- (5-fimino-1,2,4-thiadiazol-3-yl) -2-σ7σ1ορ6ηίγ1οχγΐπάηοηο6ί7ΐ-σίι1θΓΐά6-20 hydrochloride (63-5 as the acid chloride hydrochloride) A. Methyl 2- (5- t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyl oxyiminoacetate

A suspension of 860 mg (3.7 mmol) of N- (cyclopentyloxy) phthalimide ^ and 185 mg (3.7 mmol) of hydrazine hydrate in 5 ml of C 1 H 2 OH was stirred at room temperature for 1 hour and filtered. The filtrate and washings were combined and added to 1.06 g (3.7 mmol) of methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-2) oxoacetate . The solution was allowed to stand at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Reaction with n-hexane-ethyl acetate (4: 1) followed by evaporation gave the title product. The yield was 906 mg (81%). The melting point was 115-118 ° C.

IR: V (KB *) cm-1 3200, 1745, 1710, 1550.

r max UV: Λ (Ο, Η OH) in nm (£) 217 (1800), 252 (7600).

max 2 5 35 NMR: ((CDCL1) in ppm 1.51 (9H, s, BOC-H), 1.60 (8H, Br.s, <1), 3.88 (3H, s, 0CH3), 4.90 (1H, br.s, 8501 002 1)

* I

78 Η) J J), 8.70 (1H, br.s, NH).

U.S. Patent 3,971,778 (7/27/76; Glaxo), British Patent Application 49255 (10/25/72).

^ X. Csendes et al., J. Antibiotics 36, 1020 (1983).

5 B. 2- (5-t-Butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetic acid

A solution of 500 mg (1.34 mmol) of methyl 2- (5-t-bu-toxycarbonylamino-1,2,4-thiadiazol-3-y 1) -2-cyclopentyloxyiminoacetate and 2N NaOH solution (2 mL, 4 mmol ) in 15 ml CH 2 OH was refluxed for 30 min. The reaction mixture was evaporated and 10 ml of ethyl acetate-H 2 O (1 1 1) was added to the solution. The water layer was separated, acidified to a pH of 2 with 6N HCl and extracted with 2 x 10 ml of ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. 377 mg (78%) of the title compound with a melting point of 185 ° C (decomposition) were obtained.

IR; y (KBr) in cm -1, 3160, 1710, 1550.

IQaX

IV i H (C-H-OH) in nm ()) 238 (13300).

λ max ά 5 NMRs $ (DMSO) in ppm 1.51 (9H, S, BOC-H), 1.70 (8H, br.s,

H

20 H ~ d) '4'82 ilHf m' XI>.

0

Go 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetic acid (63-5,2 isomer) ^

A solution of 348 mg (0.97 mmol) of 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetic acid in 2 ml of trifluoroacetic acid was left at room temperature for 1 hour stand.

The reaction mixture was concentrated under reduced pressure. The residue was triturated with 5 ml of isopropyl ether and 10 ml of hexane. 215 mg (86%) of the title compound were obtained. Melting point 162-165 ° C (decomposition) [lit ^: mp. 160-165 ° C (decompn.)].

IR: V (Nujol) in cm -1 3290, 3200, 1710, 1615, 1600.

max OV: \ (C_H_OH) in nm (£) 238 (13300).

^ max d NMR: A (DMSO-d_) in.ppm 1.17 - 2.10 (8H, m), 4.60 - 4.98 (1H, m),

O

8.22 (2H, s).

8501002 * 79 ^ Japanese Kokai 57-158769 (9/30/82, Fujisawa) British Patent Application 8107134 (3/6/81).

D. 2- (5-flmino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetyl chloride hydrochloride 5 A 190 mg (0.74 mmol) solution of the compound 63-5 and 219 mg (1.0 mmol) of phosphorus pentachloride in 5 ml of dichloromethane was stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml n-hexane. The resulting precipitate was collected by filtration. The yield was 122 mg (60%).

10 IR i (Nujol) cm cm 1760.

max

Preparation No. 28

Benzotriazol-1-yl-2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetate A mixture of 2.7 g, 20 mmol of 1-hydroxybenzotriazole and 4.12 g, 20 mmol dicyclohexylcarbodiimide in 65 ml DMF was stirred at room temperature. After 15 min, compound 63-1 (4.04 g, 20 mmol) was added to the stirred mixture at 0 ° C, and stirring was continued for 3 hours. The reaction mixture was filtered to remove the insoluble urea. The filter cake was washed with a small volume of DMF. The filtrate and washings were combined and poured out into 800 ml of ice water. The precipitate was collected by filtration.

5.24 g (82%) of the title compound were obtained as a light gray powder. Melting point was 189-192 ° C (decomposition).

IRi v (KBr) in cm -1 1815, 1620, 1540, 1415, 1090, 1060, 1005, max 945, 865, 740.

25 V: X (C 1 H-OH) in nm (E 4) 246 (580), 283sh (228).

^ max 2 5 1 cm 8501002

Claims (67)

A compound of the formula 1 wherein R 1 represents hydrogen or a conventional amino protecting group, R hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring having 3 to 6 carbon atoms, or one of the groups 5 of formulas 25-28, wherein R 1 is hydrogen, (lower) alkyl or 4, carboxyl, X is halogen, hydroxy or (lower) alkoxy, and R and R are each 4 independently hydrogen methyl or ethyl or R and R 4 together with the carbon atom to which they are attached may form a cycloalkylidene ring of 3 to 5 carbon atoms, and the group 10 of formula 2 is a quaternary ammonia group; or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. A compound according to claim 1, wherein the group of formula 2 is selected from the groups of formulas 56 - 61, wherein R, 14, 15 and R are the same or different and represent (lower) alkyl, ( lower - alkenyl, amino (lower) alkyl with the proviso that the amino group is not on an α-carbon atom, or hydroxy (lower) alkyl on the understanding that the hydroxy group is not on an α-carbon atom; 16 R stands for hydrogen, (low) alkyl, (low) alkoxy, 20 (low) alkylthio, amino, (low) alkylamino, di (low) alkylamino, formylamino, (low) alkanoylamino, carboxy, hydroxy, carboxy ( lower) alkyl, carboxy (lower) alkylthio, hydroxy (lower) alkyl, halogen (lower) alkyl, amino (lower) alkyl, (lower) alkoxy (lower) alkyl, carbamoyl or N- (lower) alkylcarbamoyl, 16 or R may represent a divalent alkylene group having 3 to 5 carbon atoms; 17 R stands for (lower) alkyl, (lower) alkoxy (lower) alkyl, halogen (lower) alkyl, allyl, hydroxy (lower) alkyl with the proviso that the hydroxy group is not attached to the α-carbon, amino (low) -alkyl with the proviso that the amino group is not attached to the α-carbon atom, or phenyl (lower) alkyl; 18 R stands for hydrogen, (low) alkyl, (low) alkoxy, (low) alkoxy (low) alkyl, (low) alkylthio, amino, (low) alkylamino, di- (low) alkylamino, carboxy, hydroxy, carboxy ( lower) alkyl, hydroxy (lower) - 8 5 0 iu 01 \ F alkyl, amino (lower) alkyl, formylamino, (lower) alkanoylamino, carbamoyl or N- (lower) alkylcarbamotl? n is an integer from 1 to 3; Z stands for CH- or, when n equals 2, Z can also be 19 × 19 5 for S, O or N-R, where R is hydrogen or (lower) alkyl; and 20 21 R and R are the same or different and represent hydrogen, (lower) alkyl, (lower) alkoxy, (lower) alkylthio, amino, (lower) alkylamino, di (lower) alkylamino, carboxy, hydroxy, hydroxy (lower) alkyl, 10 amino (lower) alkyl, (lower) alkoxy (lower) alkyl, carboxy (lower) alkyl, carboxy- (lower) alkylamino, (lower) alkanoylamino, carboxy (lower) alkanoylamlno, carbamoyl or N- ( lower) alkyl carbamoyl. 2 A compound according to claim 2, wherein R represents (lower) alkyl, cycloalkyl of 3 to 5 carbon atoms, 1-carboxycycloalk-1-yl of 3 to 5 carbon atoms, allyl, propargyl or carboxy (lower) alkyl. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3— [3- (trimethylammonio) -1-propen-1- 1 -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. % The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidinone) -1- propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-pyridinio-1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- {5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-amino-pyridinio) -1- propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable ± out, solvate, hydrate or physiologically hydrolyzable ester thereof. 3.5. A compound according to claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-formylamino-8501002 W'k) pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 9. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminomethyl-pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 10. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3 - [3 - (3-carbamoy 1-. pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 11. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoyl-pyri-) dinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 12. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (2-methyl-thiazolio) 1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. • 13. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (2-amino-5-thiazolo-) [4,5-c] pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 14. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-hydroxymethylpyridinio) -1-propen-1-yl] -3 · -cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 15. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-hydroxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiological hydro-8501002. lysable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-N-methylcarbamoyl) ] pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (2,3-propylene-pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- [3- (4-carbamoyl-pyridinio) - 1.-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1- propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1- propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetamido] -3- [3- (4-carbamoyl-pyridinio) -1- propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-4 1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— [3— (4-carboxypyridinio) -1-props -1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 8501002 ï The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- [3- (4-carboxypyridino) -2-propen- 1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-carboxymethylpyridinio) -1- propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. The compound of claim 3, which is 7- [2- (5-amino-, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carboxymethylthiopyridinio) - 1-propen-1-yl] -3-cephem-4-carboxylate, or a non-toxic pharmaceutically acceptable salt, solvate, hydrate or physiologically hydrolyzable ester thereof. 26. A compound of formula 123, wherein hydrogen is a 2 or a conventional amino protecting group, R represents hydrogen, a straight or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing 3 to 6 carbon atoms, or one of groups 3 20 of formulas 25-28, wherein R is hydrogen, (lower) alkyl or carboxyl, X is halogen, hydroxy or (lower) alkoxy, and R and R are each independently 3 4 of each other are hydrogen, methyl or ethyl or R and R together with the carbon atom to which they are attached may form a cycloalkylidene ring with 3 to 5 carbon atoms represents hydrogen or a conventional carboxyl protecting group and Z represents chloro, bromo or iodo ; or a salt, hydrate, solvate or ester thereof. A compound according to claim 26, wherein Z is chloro or 2 iodo, and R represents (lower) alkyl, cycloalkyl of 3 to 5 carbon atoms, 1-carboxycycloalk-1-yl of 3 to 5 carbon atoms, alkyl, pro-30 pargyl or carboxy (lower) alkyl; or a salt, hydrate, solvate or ester thereof. 2 The compound of claim 27, wherein R represents methyl, ethyl, cyclopentyl, allyl or propargyl. 29. The compound of claim 28, wherein B represents hydrogen or a benzhydryl group and R1 represents hydrogen or a trityl group. 8501002 f * A compound according to claim 29, namely diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1- yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. A compound according to claim 29, namely diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-thoxyiminoace tamido] -3- (3-iodo-1-props -1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. The compound of claim 29, which is diphenylmethyl 10 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyimino-acetamido] - 3- (3-iodo-1-) propen-1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 33. A compound according to claim 29, which is diphenylmethyl 7-C2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] -3- (3-15 iodo-1-propen-1) -yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. The compound of claim 29, which is diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetamido] -3- (3-yo-do-1-props -1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. A compound according to claim 29, namely diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-chloro-1-propen-1) -yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. The compound of claim 29, which is diphenylmethyl 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- (3-chloro-1-propen-1) -yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof Compound according to claim 29, namely diphenylmethyl 30 7- [2- (5-amino-1,2,4-thiadiazole) -3-yl) -2-cyclopentyloxyimino-acetamido] - 3- (3-chloro-1-propen-1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. A compound according to claim 29, namely diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] -3- (3-35 chloro-1-propen- 1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 8501002 * Ί A compound according to claim 29, namely diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyimino-acetamido] -3- (3-chloro-1-props -1-yl) -3-cephem-4-carboxylate, or a salt, hydrate, solvate or ester thereof. 40. A compound of formula 82, wherein the group of formula 2 is a quaternary ammonio group; or a salt, ester, solvate or hydrate thereof. A compound according to claim 40, wherein the group of formula 2 is selected from one of the groups of formulas 56 - 61, wherein 13 14 15 R, R and R are the same or different and stand for (Low) alkyl, (low) -alkenyl, amino. (Low) alkyl with the proviso that the amino group is not attached to an α-carbon atom, or hydroxy (low) alkyl with the proviso that the hydroxy group is not on an α-carbon atom; 16 R stands for hydrogen, (low) alkyl, (low) alkoxy, 15 (low) alkyIthio, amino, (low) alkylamino, di (low) alkylamino, formylamino, (low) alkanoylamino, carboxy, hydroxy, carboxy ( lower alkyl, carboxy- (lower) alkylthio, hydroxy (lower) alkyl, halogen (lower) alkyl, amino (lower) alkyl, (lower) alkoxy (lower) alkyl, carbamoyl or N- (lower) alkylcarbamoyl, or 16 R a divalent alkylene group of 3 to 5 carbon atoms; 17 R stands for (lower) alkyl, (lower) alkoxy (lower) alkyl, halogen (lower) alkyl, allyl, hydroxy (lower) alkyl with the proviso that the hydroxy group is not attached to the α-carbon, amino (low) alkyl with the proviso that the amino group is not on the α-carbon atom, or phenyl (lower) alkyl; 18 R stands for hydrogen, (low) alkyl, (low) alkoxy, (low) alkoxy (low) alkyl, (alga) alkylthio, amino, (low) alkylamino, di- (low) alkylamino, carboxy, hydroxy, carboxy (lower) alkyl, hydroxy (lower) alkyl, amino (lower) alkyl, formylamino, (lower) alkanoylamino, carbamoyl or N- (lower) alkylcarbamoyl; n is an integer from 1 to 3; Z stands for CEL or when n equals 2, Z can also be 19 1 19 for S, O or N-R, wherein R is hydrogen or (lower) alkyl; and R 21 and R 21 are the same or different and represent hydrogen, (lower) alkyl, (lower) alkoxy, (lower) alkylthio, amino, (lower) alkyl-amino, di (lower) alkylamino, carboxy, hydroxy, hydroxy (lower) alkyl, amino-8501002 * € β (lower) alkyl, (lower) alkoxy (lower) alkyl, carboxy (lower) alkyl, carboxy (lower) -alkylamino, (lower) alkanoylamino, carboxy (lower) alkanoylamino, carbamoyl or N- (lower) alkyl carbamoyl; or a salt, ester, solvate or hydrate thereof. The compound of claim 40, wherein the group of formula mule 2 represents 1-methyl-pyrrolidinio. The compound of claim 40, wherein the group of formula 2 represents pyridinio. The compound of claim 40, wherein the group of formula 2 represents 2-amino-5-thiazolo [4,5-c] pyridinio. The compound of claim 40, wherein the formula 2 group represents trimethylammonio. The compound of claim 40, wherein the group of formula 2 represents 3-amino-pyridinio. A compound according to claim 40, wherein the group of formula-mule 2 represents 3-formylamino-pyridinio. The compound of claim 40, wherein the group of formula 2 represents 3-carbamoyl-pyridinio. The compound of claim 40, wherein the formula 2 group represents 4-carbamoyl-pyridinio. The compound of claim 40, wherein the group of formula 2 represents 3-aminomethyl-pyridinio. The compound of claim 40, wherein the group of formula 2 represents 2-methyl-thiazolio. The compound of claim 40, wherein the group of formula 2 represents 3-hydroxymethyl-pyridinio. A compound according to claim 40, wherein the group of formula 2 represents 4-hydroxymethyl-pyridinio. A compound according to claim 40, wherein the group of formula 2 represents 4- (N-methyl-carbamoyl) pyridinio. The compound of claim 40, wherein the group of formula 2 represents 4-carboxypyridinio. The compound of claim 40, wherein the group of formula 2 represents 2,3-propylene pyridinio. The compound of claim 40, wherein the group of formula-mule 2 represents 3-carboxymethyl-pyridinio. 58. The compound of claim 40, wherein the group having form 8501002 s * 22 mule 2 represents 4-carboxymethyl-thiopyridinio. 59. A compound of formula 92, wherein R represents hydrogen or a conventional carboxyl protecting group, and R, R and 25 R are the same or different and represent hydrogen, hydroxy, (lower) -5 alkyl or ( lower alkoxy and Z stands for chloro, bromo or iodo; or a salt, solvate, hydrate, or ester thereof. 22 The compound of claim 59, wherein R represents the benzhydryl group and Z is chloro or iodo. 23 24 25 The compound of claim 60, wherein R, R and R 10 represent hydrogen. A compound according to claim 61, namely benzhydryl 7-benzylideneamino-3- [3-chloro-1-propen-1-yl] -3-cephem-4-carboxylate. A compound according to claim 61, namely benzhydryl 7-benzylideneamino-3 - [3-yodo-1-propen-1-yl] -3-cep em-4-carboxylate. 64. Process for preparing compounds of formula 1, wherein R * represents hydrogen or a conventional amino-protecting 2 group, R represents hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring having 3 to 6 carbon atoms, or one of the groups of formulas 25 to 28, wherein R 20 represents hydrogen, (lower) alkyl or carboxyl, X represents halogen, 4 hydroxy or (lower) alkoxy, and R and R each independently represents hydrogen, methyl or ethyl or R and R together with the carbon atom to which they are attached can form a cycloalkylidene ring of 3 to 5 carbon atoms, and the group of formula 2 a quaternary ammonium -25 group, as well as non-toxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, comprising a reaction of a 2 '2 compound of formula 87, wherein R is equal to R or one of the groups of formulas 88 or 89, wherein X, R and R are as defined above, B is a conventional carboxyl protecting group 2, B is hydrogen or a conventional amino protecting group, Z is chloro, bromo or iodo, and m is zero or one, with a tertiary amine of the formula 71 (or successively with a secondary amine RR'NH and a compound of the formula R "Z), and, when m equals 1, a reduction of the sulfoxide by conventional means, and subsequent removal of all blocking groups by conventional means. 8501002 O Φ 65. A process for preparing compounds of formula 1, wherein R * represents hydrogen or a conventional amino protecting group, R hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring containing 3 to 6 carbon -5 atoms, or any of the groups of formulas 25-28, wherein 3 R represents hydrogen, (lower) alkyl or carboxyl, X represents halogen, 4-hydroxy or (lower) alkoxy, and R and R each independently represent hydrogen, methyl or ethyl, or R and R together with the carbon atom to which they are attached may form a cycloalkylidene ring containing 3 to 5 carbon atoms, and the group of formula 2 represents a quaternary amino group, as well as non-toxic pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, comprising reacting a compound of formula 82 with an acid of formula 90 or 2'2 with an acylating derivative of this acid , wa arin R equals asui R or 4 represents one of the groups of formulas 88 or 89, wherein X, R and R ^ are as defined above, B * is a conventional carboxyl-protecting group and B is hydrogen or a conventional amino -protective group. 66. The method of claim 64, wherein the following compounds 1-22 are prepared 1) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3 - C3— (trimethylammonio) -1-propen-1-yl] -3-cephem-4-carboxylate, 2) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2 -methoxyiminoacetamido] —3— £ 3— (1-methylpyrrolidinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 25 3) 7- [2- (5-amino-1,2,4,4) -thiadiazol-3-yl) -2-raethoxyiminoacetamido] -3-C3-pyridinio-1-propen-1-yl] -3-cephem-4-carboxylate, 4) 7- [2- (5-amino-1, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminopyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 5) 7-C2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- 30 (3-formylaminopyridinio) -1-propen-1-yll -3-cep em-4- carboxylate, 6) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminomethylpyridinio) -1-propen-1-yl ] -3-cephem-4-carboxylate, 7) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-carbamoylpyridinio) -1-propen-1-yl] -3 -cephem-4-carboxylate, 35 8) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— 3— (4-carbamoylpyridinia) -1 -propen-1-yl] -3-cephem-4-carboxylate, 9). 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] —3— £ 3— '8501002' * * (2-methylthiazolio) -1-propen-1-yl] -3-cephem-4-carboxylate, 10) 7- [2- (5-amino-1,2,4-thiadiazole -3-y1) -2-methoxyiminoacetamido] —3— [3— (2-amino-5-thiazolo [4,5-c] pyridinio) -1-propen-1-yl] -3-cephem-4- carboxylate, 5 11) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-hydroxymethylpyridinio) -1-props- 1-yl] -3-cephem-4-carboxylate, 12) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3 -hydroxymethylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 13) 7- [2- (5-amino-1,2,4-thiadiazo-3-yl) -2-methoxyiminoace tamido] -3- [3-10 (4-N-methylcarbamoyl pyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 14) 7- [2- (5-amino-1,2) , 4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (2,3-propyl enpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 15) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] - 3— [3 - (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 15 16) 7- [2- (5-amino-1,2,4-thiadiazole-3) -yl) -2-cyclopentyloxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 17) 7- [2- (5-amino-1 2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] - 3- (3- (4-carbamoylpyridinio) -1-propen-1-yl] -3-cephem-4-carboxylate, 18) 7 - [2 = (5-amino-1,2,4-thiadiazo 1-3-y 1) -2-propargyloxyimino-acetamido] - 20 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl ] -3-e fem-4-carboxylate, 19) 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carboxypyridinio ) -1-propen-1-yl] -3-cep em-4-carboxylate, 20) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxy iminoace tamido ] -3- [3- (4-carboxypyridinio) -2-propen-2-yl] -3-cep em-4-carboxylate, 25 21) 7- [2- (5-amino-1,2,4-) thiadiazo 1 -3-y 1) -2-methoxyiminoacetamido] -3- [3- (4-carboxym the thypyridinio) -1-propen-1-yl] -3-cep em-4-carboxylate, and 22) 7- (2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- [3- (4-carboxythythiopyridinio) -1-propen-1-yl] -3-cep em-4-carboxylate. 67. Process for preparing compounds of formula 22, wherein R represents hydrogen or a conventional carboxyl-protecting 23 24 25 group, and R, R and R are the same or different and represent hydrogen, hydroxy, (low alkyl or (lower) alkoxy and Z represents chloro, bromo or iodo, * or a salt, sol dish, hydrafc or ester thereof, comprising a reaction of the compound of formula 124, wherein R, R 25 and R as defined above, with a compound of formula 125, wherein R is a conventional carboxyl protecting group, 8501002 i * é to form a compound of formula 126 / then a reaction of the compound of formula 126 with sodium iodide or potassium iodide to form a compound of formula 127, then a reaction of the compound of formula 127 with triphenylphosphine to form a compound of formula 128, or a reaction of a compound of formula 126 with triphenylphosphine there is formed a compound of formula 128, then a reaction of a compound of formula 128 with a base to form a compound of formula 129, then a reaction of a compound of formula 129 with ZCH 2 CHO, where Z is chlorine, bromine 10 or iodine, to form a compound of formula 92, and finally, if desired, removal by conventional means of the carboxyl protecting group R to form the corresponding free acid and a conversion of the free acid to a salt or ester thereof. 68. Process for preparing compounds of formula 123, wherein R represents hydrogen or a conventional amino-protecting 2 group, R represents hydrogen, a straight or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl- or cycloalkenyl ring with 3 to 6 carbon atoms, or one of the groups of formulas 25-28, 3 in which R represents hydrogen, (lower) alkyl or carboxyl, X represents halogen, hydroxy or (lower) alkoxy , and R and R each independently represent hydrogen, methyl or ethyl or R and R together with the carbon atom to which they are attached may form a cycloalkylidene ring with 3 to 5 carbon atoms, B * represents hydrogen or a conventional carboxyl protecting group and Z represents chloro, bromo or iodo, or a salt, hydrate, solvate or ester thereof, comprising a reaction of a compound of formula 130 with a compound of formula 131, wherein 12 1 R, R and B as defined above to form a compound of formula 132, then reaction of the compound of formula 132 with sodium iodide or potassium iodide to form a compound of formula 133, then reaction of the compound of formula 133 with triphenylphosphine to form a compound of formula 134, or a reaction of a compound of formula 132 with triphenylphosphine to form a compound of formula 134, then a reaction of a compound of formula 134 with a base to form a compound of formula 135, then a reaction of the compound of formula 135 with CICH ^ CHO to form the compound of formula 8501002 -F> 136, then reaction of the compound of formula 136 with sodium iodide or potassium iodide to form a compound of formula 137, or a reaction of the compound of formula 136 with sodium bromide or potassium bromide to form a compound of formula 138, and finally e removal of all blocking groups by conventional means and, if desired, conversion of the free acid compound to a salt or ester thereof. 69. A process for preparing compounds of formula 82, wherein the group of formula 2 is a quaternary ammonia group; or a salt, ester, solvate or hydrate thereof, comprising a reaction of a compound of formula 139 with a compound of formula 62 to form a compound of formula 73, then a reaction of a compound of formula 73 with sodium iodide or potassium iodide to form a compound of formula 74, then a reaction of the compound of formula 74 with triphenylphosphine or a reaction of the compound of formula 73 with triphenylphosphine to form a compound of formula 75, then a reaction of a compound of the formula 75 with a base to form a compound of the formula 76, further a reaction of a compound of the formula 76 with CICH 4 CHO to form a compound of the formula 77, then a reaction of the compound of formula 77 with sodium iodide or potassium iodide to form a compound of formula 79, then a further reaction of a compound of formula 79 with a secondary amine ne RR'NH, wherein - R, R 'each represent methyl, or together form pyrrolidine, to form a compound of formula 80, then a reaction of the compound of formula 80 with a compound R "Y, wherein R" a tertiary amine of formula 71 and Y represents chloro, bromo or iodo, to form a compound of formula 81, or a reaction of the compound of formula 79 with a tertiary amine of formula 71, wherein Q as above is defined, to form a compound of formula 81, then treatment of the compound of formula 81 with Girard reagent T or HCl to form a compound of formula 82 and, optionally, conversion of the free acid to a salt, ester, solvate or hydrate thereof. 70. Pharmaceutical composition comprising an effective antibacterial amount of at least one compound of formula 1, or 8501002 <> β a salt, hydrate, solvate or ester thereof, plus a pharmaceutically acceptable carrier. 71. A method of treating bacterial infections in warm-blooded mammals, including humans in need thereof, comprising administering to the mammal an effective antibacterial amount of at least one compound of formula 1, or a salt, hydrate, solvate or ester thereof, in a pharmaceutically acceptable carrier. 85 0 1 0 02