CH669197A5 - CEPHALOSPORINE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS. - Google Patents

Description

DESCRIPTION The invention relates to 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2- (substituted) iminoacetamido] - 3- [3-quaternary ammonio) -1-propene-1 -yl] - 3-cephem-4-carboxylate of the general formula:

—Conh ch = chch_-n = q coo1

wherein Rl and R2 have the meanings given below and

NQ® denotes a quaternary ammonio group and has the meanings given below, and their salts, solvates, e.g. Hydrates and esters.

The invention also relates to processes for the preparation of the compounds of the formula I, pharmaceutical compositions which contain at least one of the compounds of the formula I and starting products for the preparation of the compounds of the formula I.

A) US Pat. No. 4,390,534 describes cephem and Ce-pham compounds of the general formula:

—R '

- conh-

R

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

669 197

10th

wherein

R1 represents an amino group or a protected amino group;

R2 represents hydrogen, acyl, optionally substituted aryl, substituted alkyl, alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkenyl or an O- or S-containing 5-membered heterocyclic ring which is substituted by one or more oxo groups;

R3 represents a hydrogen atom or alkyl group;

R4 represents hydrogen, acyloxyalkyl, acylthioalkyl, optionally substituted pyridinioalkyl, optionally substituted heterocyclylthioalkyl, alkyl, halogen, hydroxy or optionally substituted thiazolioalkyl; and

RD represents a carboxy group or a protected carboxy group; with the proviso that R5 stands for COO "when R4 stands for optionally substituted pyridinioalkyl or optionally substituted thiazolioalkyl; and the dashed line denotes a single or a double bond.

EP-A-13 762 is equivalent to this, its disclosure content is similar.

U.S. Patent Nos. 4,381,299.4,331,665 and 4,332,798, which are associated with parent applications of U.S. Patent 4,390,534, have similar disclosure content.

B) European patent application 62 321 describes cephem compounds of the general formula;

10th

wherein

R1 represents an amino group or a protected amino group;

R2 represents an optionally substituted, lower aliphatic hydrocarbon group, cyclo-lower alkyl or cyclo-lower alkenyl group;

R3 for lower alkylamino, a protected N-lower alkylamino, di-lower alkylamino, sulfo-lower alkylamino, hydroxy-lower alkylamino group, a protected N-hydroxy-lower alkylamino, acyloxy-lower alkyl, lower alk-oxy-lower alkoxy-lower alkyl, din-lower-alkyl, din-lower-alkyl, din-lower-alkyl- Lower alkoxy, lower alkoxy lower alkoxy, hydroxy lower alkoxy, acyl lower alkyl, hydroxy lower alkylthio, 15 di lower alkylamino lower alkylthio, an N-containing, unsaturated 5-membered heterocyclic group, N-containing, unsaturated, 5-membered heterocyclic unsaturated 5- or 6-membered heterocyclic thione lower alkyl which may be substituted by one or more suitable substituents; and

R4 represents a hydrogen atom or a lower alkyl group; or a salt of it.

D) US Pat. No. 4,332,800 describes inter alia compounds of the general formula:

25th

wherein

R1 represents an amino group or a protected amino group;

R2 represents an optionally substituted, lower aliphatic hydrocarbon group or a cycloalkenyl group; and the rest of the formula:

wherein

R1 represents an amino group or a protected amino group 35;

R2 represents a lower alkyl group and X represents a hydrogen atom or a carbamoyl group.

E) European patent application 47 977 relates to cephem compounds of the general formula:

40

© N-

represents an optionally substituted heterocyclic cation containing more than one nitrogen atom; and their pharmaceutically acceptable salt. In addition, intermediates of the general formula:

45

on — t — c conh n I

o-r-

coö-

described, wherein R1 and R2 have the meanings given above, R4 is a protected carboxyl protecting group and X is an acid radical.

C) European patent application 74 653 relates to cephem compounds of the general formula:

50 wherein m is 0 or 1;

Am denotes an optionally substituted amino group, "v means;

2 N 0 / T represents a thiadiazolyl unit (which is bonded to the other groups via two carbon s' 55 atoms);

R2 represents hydrogen, optionally substituted alkyl, cycloalkyl or optionally substituted carbamoyl; and

R1 for optionally substituted thiazolio, optionally-substituted pyrazolio, tri-lower alkylammonio or pyridinio of the general formula:

rvs -CONH

H 1

S?

11

669 197

stands in what

R- 'lur substituted lower alkyl [wherein the substituent is cycloalkyl, plienyl, hydroxy, alkoxy, halogen, cyano, carbamoyl, carboxyl or sullo], lower alkenyl or carboxy-substituted lower alkenyl, lower alkylthio or carboxy-substituted lower alkylthio, amino - or mono-substituted amino [where the substituent is lower alkyl, lower alkanoyl or aminobenzenesulfonyl], di-lower alkylamino, substituted carbamoyl [where the substituent is lower alkyl, hydroxy-lower alkyl, lower alkoxy, hydroxy or cyano], din-lower alkylcarbamoyl, thiocarbamoyyl, cyclo Lower alkoxy, halogen, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyl, carboxyl, sulfo, cyano, nitro or hydroxysulfo-lower alkyl;

Rb represents hydrogen or carbamoyl or has the same meaning as Ra; and

Rc represents hydrogen or has the same meanings as Ra; and their salts.

European patent application 25 017 has a similar disclosure content, although there is no formal relationship.

F) European patent application 30 630 describes 3-vinylcephem compounds of the general formula:

r - a-

■ conh ch = ch.

wherein

R1 is an optionally protected, amino-substituted heterocyclic group, which may also have a halogen atom, or a group of the formula:

rjso2hn means what

R3 represents a lower alkyl group;

R3 represents a carboxy or protected carboxy group; and

A represents a lower alkylene group, which may have a substituent which is selected from amino, protected amino, hydroxy, oxo and a group of the formula ON OR4, in which R4 represents hydrogen, cycloniedrigalken-yl, lower alkynyl, lower alkenyl [optionally by a carboxy or protected carboxy group is substituted], lower alkyl [which may optionally be substituted by one or more carboxy, protected carboxy, amino, protected amino, cyano, phosphono, protected phosphono and a heterocyclic group, which in turn can be substituted]; and their salts.

The application mentioned specifically describes the compounds of the formula:

■ y-o »

-conh-

N »

h = ch,

cooh

OR4 stands for methoxy, carboxymethoxy, tert-butoxycarbonyl-methoxy or 1-tert-butoxycarbonylethoxy.

G) GB-PS 1 399 086 contains a general disclosure which contains a large number of cephalosporin compounds 5 of the formula:

r-c-co-nh-

■ b

10th

OR

cooh comprises, wherein

15 R represents a hydrogen atom or an organic group,

R; l denotes an ether-forming, monovalent organic group which is bonded to the oxygen via a carbon atom,

20 B for ^ S or S -> O, stands and

P represents an organic group. According to one embodiment, P can include a vinyl group of the formula:

25th

30th

-ch = c mean in the

R3 and R4 independently of one another represent a hydrogen atom, a nitrite or lower alkoxycarbonyl group or a substituted or unsubstituted aliphatic, cy-cloaliphatic, araliphatic or aromatic radical. However, the 5-amino-1,2,4-thiadiazol-3-yl group is not mentioned as a substituent R. It is also not mentioned that P can be a quaternary, ammonio-substituted propenyl group. U.S. Patent Nos. 3,971,778 and associated withdrawal applications 4,024,133,4,064,346, 4,033,950, 4,079,178, 4,091,209, 4,092,477 and 4,093,803 contain a similar disclosure.

H) European patent application 88 385 describes 45 compounds of the general formula:

35

40

50

: onh-

£ r2

a,

r'4

e in which

55 R1 an (unsubstituted) thiadiazolyl group means:

R2 represents carboxy lower alkyl or protected carboxy lower alkyl;

wherein

6C R3 represents a hydrogen atom, a halogen atom or a lower alkenyl group; and

R4 represents a carboxy or protected carboxy group. Although the 1-propenyl radical is important for R3 autge-65, only those compounds are mentioned as examples in which R3 is hydrogen, chlorine or vinyl.

I) US Pat. No. 4,307,233 describes inter alia 3-vinyl cephalosporin derivatives of the general formula:

669 197

12

N T-c-CONH

x II

Ar:

\

OR

-R

• \ «4

COOH

conh-

o-c-coor5 0

ch = ch-n

\ p.

coor,

wherein

Rf and R5, which are the same or different, denote hydrogen or alkyl or together form an alkylene group having 2 or 3 carbon atoms,

Rheine acid protection group means

R2 represents an acid protecting group, for example an ester,

R3 and R4, which are the same or different, represent a hydrogen atom, an alkyl group (optionally substituted by hydroxy, alkoxy, amino, alkylamino or dialkylamino) or a phenyl group or, together with the nitrogen atom to which they are attached, a saturated 5- or form a 6-membered heterocyclic ring which may optionally have a further heteroatom selected from N, O and S and which is optionally substituted by an alkyl group. These compounds are useful as intermediates for the preparation of 3-thiovinyl cephalosporin derivatives. However, it is not described or proposed to use a 5-amino-1,2,4-thiadia-zo-3-yl unit instead of the 2-aminothiazol-4-yl substituent or a propenyl group substituted by a quaternary ammonio group 3-substituents to use.

U.S. Patent 4,423,214 is the equivalent of this and has a similar disclosure content.

K) European patent application 53 074 describes in general terms a large number of 3-vinylcephalo-sporine derivatives of the general formula:

R ° la "NH

COOR °

wherein

R5 stands inter alia for alkyl, vinyl, cyanomethyl or a protective group such as 2-methoxyprop-2-yl and

R3 and R4 are alkyl groups (which are optionally substituted by hydroxyl, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups, or together with the nitrogen atom to which they are attached can form a saturated, 5- or 6-membered heterocyclic ring, which may optionally contain a further heteroatom selected from N, O and S and which is optionally substituted by an alkyl group. These compounds are useful as intermediates for the preparation of 3-thiovinyl cephalosporin derivatives. There is no description or suggestion of a 5-amino-1,2,4-thiadia-zol-3-yl unit instead of the 2-aminothiazol-4-yl substituent or a propenyl unit substituted by a quaternary ammonio group as the third -To use substituent. The published British patent application 2 051 062 is equivalent to this and has a similar disclosure content.

J) The European patent application 53 537 describes, inter alia, 3-vinylcephalosporin derivatives of the general formula:

2a

10th

wherein

R ° ia (in one of several embodiments) for a radical of the formula:

15

/ rTT

, / orr

20 stands in the

R5 is, inter alia, for hydrogen, alkyl, vinyl, cyanomethyl, an oxime protecting group, such as trityl and the like, or a radical of the formula:

25 -C-COORC.

30 stands in the

R \ - and Rb5, which may be the same or different, stand for hydrogen, alkyl or together for an alkylene radical having 2 to 3 carbon atoms and

Rc5 represents a hydrogen atom or an acid protecting group;

Rü3a represents a hydrogen atom or an acid protecting group such as methoxymethyl;

R "(one of several embodiments) represents a methyl group which can be substituted by a 5- or 6-membered, 40 aromatic heterocyclic ring which contains a single heteroatom, such as 2- or 3-pyridyl, 2- or 3- Thienyl or 2- or 3-furyl; and

R? a remainder of the formula:

45

RaSO.O

means what

R4 represents an alkyl, trihalomethyl or an optionally substituted phenyl group.

so These compounds are intermediates for the preparation of compounds with antibacterial activity in which the 3-substituent is a radical of the formula:

55

R °

CH = C -SR

means.

Although, according to this patent application RH, both the intermediates and the end products can be a 60 N-containing heterocyclic ring (which results in a heterocyclically substituted propenyl group), this application only teaches that the heterocyclic ring is bonded via one of its carbon atoms . Thus, a propenyl unit substituted by a quaternary ammonio group is not included. In this patent application mentioned, R ° is only described as a methyl group for the intermediates as well as for the end products. Furthermore, both the

13

669 197

Intermediates as well as in the end products the propenyl group have a second substituent (-O3SR4 or -SR). Neither is it disclosed nor suggested to use a 5-amino-1,2,4-thiadiazol-3-yl unit in place of the 2-aminothiazol-4-yl substituent.

L) The European patent application 53 538 describes inter alia 3-vinylcephalosporin intermediates of the general formula:

.CONH-

: H = CH-R "

COOH

where n is 0 or 1,

R5 represents a hydrogen atom, an alkyl, vinyl, cyanomethyl or an oxime protecting group and

R3 represents a halogen atom. It is not disclosed or suggested to use 5-amino-1,2,4-thiadiazol-3-yl-a

15 unit to use instead of the 2-aminothiazol-4-yl substituent or a 3-halo-1-propen-1-yl substituent in the 3-position.

The invention is concerned with new cephalosporin derivatives of the general formula I:

20th

CONH

©

'CH = CH-CH2-N = Q

wherein

R1 represents a hydrogen atom or a conventional amino protecting group,

R2 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloal-30-kyl or cycloalkenyl group having 3 to 6 carbon atoms, or a radical of the general formulas:

R

1 3

-C-CH-CH-R

R5

R4

ç-cooh

? 3rd

- <j-C = C-R

COOH

k means what

R3 represents a hydrogen atom, a lower alkyl or carboxyl group,

X represents a halogen atom, a hydroxy or lower alkoxy group and

R4 and R5 each independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring having 3 to 5 carbon atoms, and

®-N = Q

represents a quaternary ammonio group; or their non-toxic, pharmaceutically acceptable salts, solvates, e.g. Hydrates or esters.

The invention also includes the solvates (including the hydrates) of the compounds of the general formula I and their tautomeric forms, for example the 2-iminothia-zolin-4-yl form of the 2-aminothiazol-4-yl group.

The invention relates to a process for the preparation of the compounds of the general formula I and it also relates to the starting products for their preparation. As can be seen from the structural formula, the or

45 compounds of formula I with respect to the alkoxyiminogrup-pe syn or Z configuration. Since the compounds are geometric isomers, they can also be partially present as anti-isomers. The invention encompasses compounds of the formula I which consist at least 90% of the syn-50 isomers. The compounds of the formula I are preferably syn isomers which are essentially free of the corresponding anti-isomers.

In addition to the geometric isomers possible due to the alkoxyimino group, the compounds of form 55 mei I (and the intermediates of the formulas VIII and IX) also form geometric isomers (ice and trans) due to the double bond present in the propenyl group. The invention specifically includes both the eis (Z) and the trans (E) isomers of these compounds. 60 The non-toxic, pharmaceutically acceptable salts of the compounds of general formula I include salts with mineral acids, such as hydrochloric, hydrobromic, phosphoric and sulfuric acids, or with organic carboxylic or sulfonic acids, such as acetic, trifluoroacetic, Citro-65 maleic, formic, maleic, oxalic, amber, benzoic, wine, fumaric, almond, ascorbic, apple, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and other acids based on the penicillin and cephalosporin area known

669 197

14

must be used. These acid addition salts are prepared using customary methods.

Examples of physiologically hydrolyzable esters of the compounds of the general formula I are indanyl, phthalidyl, methoxymethyl, acetoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2-oxo-1,3-dioxolen-4- ylmethyl esters and other physiologically hydrolyzable esters which are known to be used in the penicillin and cephalo-spore field. These esters are prepared using conventional methods.

The compounds of the formula I, in which R1 denotes a hydrogen atom, have a high antibacterial activity against various gram-positive and gram-negative bacteria. They are useful for the treatment of bacterial infections in humans and animals. The compounds of the formula I according to the invention can be formulated for parenteral use in a conventional manner using known pharmaceutical carriers and excipients. They can be offered in unit dose form or in multiple dose containers. The agents can be in the form of solutions, suspensions or emulsions in oily or aqueous vehicles and can contain customary dispersing, suspending or stabilizing agents. The agents can also be in the form of a dry powder which, when used, is reconstituted with, for example, sterile, pyrogen-free water. The compounds of formula I can also be formulated as suppositories using conventional suppository bases, such as cocoa butter or other glycerides. If desired, the compounds according to the invention can be administered in combination with other antibiotics, such as penicillins or cephalosporins.

When presented in unit dosage forms, the compositions preferably contain from about 50 to about 1500 mg of Formula I active material. The dosage of the compounds of Formula I will depend on various factors such as the weight and age of the patient and the type and severity of the disease and is left to the judgment of the doctor. However, the dosage in adults is usually in the range of about 500 to about 5000 mg per day depending on the frequency and the mode of administration. When administered intramuscularly or intravenously to adults, a total dose of about 750 to about 3000 mg per day in divided doses is usually sufficient. In the case of Pseudomonas infections, however, some can

5 of the compounds, higher daily doses may also be desirable.

The quaternary ammonio group of the formula

®-N = Q

10 can be acyclic, cyclic or a combination of both and can contain one or more further heteroatoms selected from nitrogen, sulfur and oxygen. An example of an acylic quaternary ammonio group is the rest of the formula

15

®

20th

-NO

i »

wherein

R6, R7 and Rs, which can be the same or different, for example for a lower alkyl or a substituted 25 lower alkyl group, the substituents for example halogen, amino with the proviso that the amino group is not on an a-carbon atom, hydroxy with with the proviso that the hydroxyl group is not at an a-carbon atom, lower alkoxy with the proviso that the alkoxy group is not at an a-carbon atom, lower alkylthio, lower alkylamino, di-lower alkylamino, carbamoyl, lower alkenyl, phenyl-lower alkyl, phenyl or substituted phenyl ( where the substituents can be, for example, halogen, hydroxyl, amino, 35 lower alkylamino, di-lower alkylamino, acylamino, lower alkyl, lower alkylthio, lower alkoxy or the like.

Examples of cyclic quaternary ammonio groups are fully unsaturated, monocyclic heterocyclic ring systems and bicyclic heterocyclic ring systems in which at least one N-containing ring is fully unsaturated. Suitable cyclic quaternary ammonioring systems include, for example, those of the formulas:

10th

©

S "V °

© -n-

X

° '^ r10

©

-n h

«

S ^ R10

© -n

0

, 10th

15

669 197

r and the like, where Rl) and R! 0, which may be the same or different, for example for hydrogen, halogen, amino, lower alkyl, lower alkenyl, lower alkylthio, carboxy, hydroxy, lower alkoxy, lower alkoxy lower alkyl, halo lower alkyl, hydroxy lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, di -lower alkylamino-non-lower alkyl, lower alkylamino, di-lower alkylamino, carboxy-lower alkyl, carboxy-lower alkylamino, carboxy-lower alkylthio, carbamoyl, N-lower alkylcarbamoyl,

Formylamino, Acylamino, Acyloxy, Phenyl, Pyridyl, Amidi-15 no, Ouanidino and the like, can stand. If it is possible due to the structure of the heterocyclic ring, R9 and R10 together can represent an alkylene group with 3 to 5 carbon atoms, e.g. a propylene group.

20 examples of combined acyclic / cyclic quaternary ammonio groups are:

, 12th

, lï

V- °

, 12th

, 11

, 1 ^ v

12

- ®N o

, 11 /

, 12th

N S

, 12th

N NH

, 12th

n n l / \ - /

, 11

./

17 ®!

r n

, 12th

y - ^

"11

-®N

/ V

. N ~ low- ~ N / alkyl, /

-' in/

"11

, 12th

, 12th

and the like, wherein

R11 is, for example, lower alkyl, lower alkoxy lower alkyl, hydroxy lower alkyl with the proviso that the hydroxy group is not on an a carbon atom, carboxy lower alkyl, amino lower alkyl with the proviso that the amino group is not on an a carbon atom, lower alkenyl, halo lower alkyl, allyl and the like , can stand and

R12 for example for hydrogen, hydroxy, halogen,

Lower alkyl, hydroxy lower alkyl, lower alkoxy lower-55 alkyl, halo lower alkyl, amino lower alkyl, lower alkoxy, lower alkyl thio, lower alkenyl, amino, lower alkylamino, di-lower alkylamino, acylamino, acyloxy, carbamoyl, amidino lower alkyl, phenyl, pyridan, amidino and the like.

60 Preferred quaternary ammonio groups are the residues of the formulas:

* y3

®-W14

669 197

16

in which

R) 3, R14 and R15, which may be the same or different, a lower alkyl, lower alkenyl, amino lower alkyl group with the proviso that the amino group is not on the a-carbon atom, or a hydroxy lower alkyl group with the proviso that the hydroxyl group is not on the a carbon atom;

R16 is a hydrogen atom, a lower alkyl, lower alkoxy, lower alkylthio, amino, lower alkylamino, di lower alkylamino, formylamino, lower alkanoylamino, carboxy, hydroxy, carboxy lower alkyl, carboxy lower rigalkylthio, hydroxy lower alkyl, halo lower alkyl, halo lower alkyl -, Lower alkoxy-lower alkyl, carbamoyl or N-lower alkyl carbamoyl group or a divalent alkyl group having 3 to 5 carbon atoms.

R17 for a lower alkyl, lower alkoxy lower alkyl, halogen lower alkyl, allyl, hydroxy lower alkyl group with the proviso that the hydroxyl group is not on the a carbon atom, an amino lower alkyl group with the proviso that the amino group is not on the a carbon atom, or for is a phenyl-lower alkyl group;

R18 is a hydrogen atom, a lower alkyl, lower alkoxy *, lower alkoxy lower alkyl, lower alkyl thio, amino, lower alkyl amino, di lower alkyl amino, carboxy, hydroxy, carboxy lower alkyl, hydroxy lower alkyl, amino lower alkyl, formylamino, lower carbanoyl amino represents an N-lower alkyl carbamoyl group;

n represents an integer from 1 to 3 inclusive;

Z is CH2 or, if n is 2, also S, 0 or N-R19, where R19 is a hydrogen atom or a lower alkyl group; and

R20 and R21, which may be the same and different, represent a hydrogen atom, a lower alkyl, lower alkoxy, lower alkylthio, amino, lower alkylamino, di lower alkylamino, carboxy, hydroxy, hydroxy lower alkyl, amino lower alkyl, lower alkoxy lower alkyl, carboxy lower alkyl , Carboxy-lower alkylamino, lower alkanoylamino, carboxy lower alkanoylamino, carbamoyl or an N-lower alkylcarbamoyl group.

Particularly preferred quaternary ammonio groups are N-Niedrigalkylpyrrolidinio (in particular N-Methylpyrroli-Dinio), tri-Niedrigalkylammonio (especially trimethyl-ammonio), pyridinio, Aminopyridinio, Formylaminopyridi-nio, Carbamoylpyridimo, Aminoniedrigalkylpyridinio, Carboxypyridinio, Hydroxyniedrigalkylpyridinio, N-Nied-rigalkylcarbamoylpyridinio, Niedrigalkylenpyridinio , 2-methyl-thiazolio and 2-amino-5-thiazolo- [4,5-c] pyridimo.

The substituent R2 in the compounds of the formula I according to the invention particularly preferably represents lower alkyl (especially methyl), cycloalkyl with 3 to 5 carbon atoms, 1-carboxycycloalk-l-yl with 3 to 5 carbon atoms, allyl, propargyl and carboxy-lower alkyl (especially Carboxyprop-2-yl). The most preferred compounds according to the invention are a) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyimino-noacetamido] - 3- [3- (trimethylammonio) - 1-propene 1-yl] -3-cephem-4-carboxylate,

b) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimi-10 noacetamido] - 3- [3- (l-methylpyrrolidinio) - 1-propene 1- yl] -

3-cephem-4-carboxylate.

c) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3-pyridinio-1-propen-1-yl] - 3-cephem-

4-carboxylate,

15 d) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminopyridinio) - 1-propen-1-yl] -3-cephem- 4-carboxylate,

e) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (3-formylaminopyridinio) - 1-propene

20 1-yl] - 3-cephem-4-carboxylate.

f) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-noacetamido] - 3- [3- (3-aminomethylpyridinio) -1-propen-1-yl ] - 3-cephem-4-carboxylate,

g) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) - 2-methoxyimi-25 noacetamido] - 3- [3- (3-carbamoylpyridinio) - 1-propene 1- yl] -

3-cephem-4-carboxylate,

h) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate,

30 i) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (2-methylthiazolio) -1-propen-1-yl] -3-cephem- 4-carboxylate,

j) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-noacetamido] - 3- [3- (2-amino-5-thiazolo [4.5-c] pyridinio) -35 1-propen- 1-yl] - 3-eephem- 4-earboxylate,

k) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (4-hydroxymethylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate,

1) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyimi-40 noacetamido] - 3- [3- (3-hydroxymethylpyridinio) - 1-propen-1- yl] - 3-cephem-4-carboxylate,

m) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (4-N-methylcarbamoylpyridinio) - 1-per-pen-1 -yl] - 3-cephem-4-carboxylate, 45 n) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (2nd , 3-propylene pyridinio) - 1-propen-l-yl] -3-cephem-4-carboxylate,

o) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyimino-acetamido] - 3- [3- (4-carbamoylpyridinio) - 1-propen-1-yl ] -50 3-cephem-4-carboxylate,

p) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyl-oxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) - 1-per-pen-1 -yl] - 3-cephem-4-carboxylate,

q) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyimi-55 noacetamido] - 3- [3- (4-carbamoylpyridinio) - 1-propen- 1- yl] -3-cephem-4-carboxylate,

r) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyl-oxyiminoacetamido] - 3- [3 - ('4-earbamoylpyridinio) - 1-propen- 1- yl] - 3-cephem-4-carboxylate,

60 s) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- [3- (4-carboxypyridinio) - 1-propen-1-yl] -3-cephem- 4-carboxylate,

t) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-ethoxyimino-acetamido] - 3- [3- (4-carboxypyridinio) - 1-propen-1-yl ] - 3-ce-65 phem-4-carboxylate,

u) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (3-carboxymethyIpyridinio) - 1-propen-i-yl] - 3-cephem-4-carboxylate, and

17th

669 197

v) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (4-carboxymethylthiopyridinio) - 1-pro-pen-1-yl ] - 3-cephem-4-carboxylate.

In the context of the present invention, the following numbering is used for the various reactants, intermediates and end products:

[Roman number] - [Arabic number lf letter 1 I (if appropriate) 11 (if appropriate) I

The Roman numeral indicates whether the compound is an end product [I] or an intermediate, or other reactants [all other Roman numerals]. The Arabic numbers and letters are not used when the overall class (gender) of the compounds is meant.

The Arabic number indicates the corresponding meaning of the substituent R2. If the R2 group in question contains a carboxyl group protected by a common carboxyl protecting group, a prime index (') after the Arabic number is used to indicate this fact. No bar index is used if the carboxyl group is unprotected. A prime index is also used for the R2 substituent (i.e. R2 ') when in general terms an R2 group that has a protected carboxyl group. should be designated.

The letter at the end of the name of the compound refers to the corresponding meaning of the quaternary ammonio group

®-N = Q

For ease of understanding, some of the Arabic numbers and the letters associated with some of the preferred R2 groups and quaternary ammonio groups are listed below.

Arabic number

R2

1

=

methyl

2nd

=

Ethyl

3rd

=

Allyl

5 4

=

Propargyl

5

=

Cyclopentyl

Letter

®-N = Q

OK A

=

1-methylpyrrolidinio

B

=

Pyridinio

C.

=

2-amino-5-thiazolo [4,5-c] pyridinio

D

=

Trimethy lammonio

E

=

3-aminopyridinio

15 F

=

3-formylaminopyridinio

G

=

3-carbamoylpyridinio

H

=

4-carbamoylpyridinio

I.

=

3-aminomethylpyridinio

J

=

2-methylthiazolio

20 K.

=

3-hydroxymethylpyridinio

L

=

4-hydroxymethylpyridinio

M

=

4- (N-methylcarbamoyl) pyridinio

N

=

4-carboxypyridinio

0

=

2,3-propylene pyridinio

25 P.

=

3-carboxymethylpyridinio

Q

=

4-carboxymethylthiopyridinio

For the primary evaluation of the compounds according to the invention, the minimum inhibitory concentrations 30 (MIC) were determined by means of the two-row agar dilution method in Müller-Hin ton agar against 32 test organism strains in six groups. The geometric mean values of the MIC values determined in these tests are summarized in Table 1.

Table 1

Connection configuration - Geometric mean of the MIC values at the (mcg / ml)

No.

Double bin

(G +) - la

(G-j -) - Ib

(G -) - Ia

(G -) - Ib

(G -) - II

(G-)

dung

(5)

(5)

(5)

(5)

(5)

(7)

I-1A

E / Z = 1/1

0.26

0.70

0.05

0.15

0.23

2.4

I-1A

H / Z = 7/1

0.13

0.35

0.029

0.05

0.17

1.4

1-1B

E

0.20

0.40

0.016

0.044

0.11

1.6

I-1B

E / Z = 1/4

0.35

0.80

0.05

0.11

0.35

3.5

1-1C

E

0.10

0.20

0.0071

0.033

0.087

3.8

I-1D

E / Z = 1/1

0.61

1.4

0.10

0.26

0.46

2.4

1-1D

E / Z = 10/1

0.30

0.53

0.05

0.076

0.26

1.3

I-1E

E

0.20

0.40

0.0094

0.029

0.10

1.4

I-1F

E

0.15

0.40

0.0094

0.033

0.099

1.2

I-1G

E

0.20

0.35

0.0094

0.033

0.10

1.4

I-1H

E

0.20

0.40

0.013

0.043

0.10

0.97

1-11

E

0.80

1.6

0.10

0.20

0.69

3.1

I-1J

E

0.17

0.35

0.025

0.076

0.15

1.6

I-IK

E

0.35

0.80

0.029

0.044

0.20

3.5

I-1L

E

0.26

0.61

0.029

0.088

0.15

2.6

I-1M

E

0.35

0.70

0.029

0.10

0.17

2.3

I-1N

E / Z = 7/1

1.2

1.6

0.013

0.066

0.30

5.7

1-10

E

0.17

0.35

0.029

0.033

0.11

14

I-2H

E

0.20

0.40

0.014

0.057

0.15

1.4

I-2N

E

1.2

2.1

0.016

0.11

0.35

4.7

I-2N

Z

1.4

3.1

0.044

0.15

0.69

10th

I-3H

E

0.23

0.40

0.057

0.10

0.52

1.9

F4H

E

0.26

0.46

0.066

0.11

0.60

2.6

I-5H

E

0.13

0.40

0.20

0.46

2.1

4.2

I-1P

E

0.8

1.6

0.013

0.087

0.34

14

l-l Q

E

0.7

0.92

0.0095

0.044

0.23

14

669 197 18

(G +) - la: Penicillin-sensitive S. aureus (5 strains)

(G +) - Ib: Penicillin-resistant S. aureus (5 strains)

(G -) - la: cephalothin-sensitive E. coli (2 strains), Kl. Pneumoniae (1 strain) and Pr. Mirabilis (2 strains)

(G -) - Ib: cephalothin-resistant E. coli (3 strains) and Kl. Pneumoniae (2 strains) (G -) - II: M. morganii (1 strain), Ent. cloacae (2 strains) and Ser. marcescens (2 strains) (G-5-III: Ps. aeruginosa (7 strains)

Table 2 below shows the protective dose50 (PD50) in mice for several compounds of the formula I against selected microorganisms. Table 3 shows blood level values of various compounds of the formula I when the test compounds were administered intramuscularly to mice in a dosage of 20 mg / kg.

Table 2

PD50 (mg / kg)

connection

S. aureus

E. coli

P. aeruginosa

No.

Smith

Juhl

A9843A

I-1B

0.44

0.028

7.7

I-1B

0.65

0.072

NT

I-1C

0.22

0.013

NT

I-1G

0.96

0.021

5.92

I-1H

0.39

0.015

3.9

I-1J

0.35

0.029

NT

I-1K

0.53

NT

NT

I-1M

0.96

NT

NT

I-1N

2.0

NT

NT

I-IO

0.26

0.17

NT

I-2N

5.0

NT

NT

Table 3

Connection Cmax T1 / 2

No. (mcg / ml) (min)

I-1B 17 21

I-1C

21st

32

18th

I-1D

20th

19th

11

I-1H

23

16

14

I-1J

19th

16

9.7

I-1K

24th

14

14

I-IM

20th

23

14

I-1N

24th

19th

18th

I-IO

28

32

17th

I-2N

22

20th

12

I-3H

19th

47

25th

I-4H

27th

22

16

I-5H

22

32

18th

The invention relates to processes for the preparation of the compounds of the formula I. The preferred processes are shown below in reaction schemes la, lb and lc ge-25, while an alternative process is shown in reaction scheme 2. The abbreviation «Ph» means a phenyl group. The -CH (Ph) 2 radical is accordingly the benzhydryl group, which is a preferred carboxyl protecting group. If R2 has a carboxyl group, it is desirable to protect the carboxyl group with a common carboxy protecting group, such as the t-butyl group. Y represents a chlorine, bromine or iodine atom.

AUC 35

(meg h / ml)

11

19th

669 197

Reaction scheme 1 a

COOCH (Ph) 2

»—5-1-C00H m

Ii ""

H N N

2 ^ 3 "VOR2

V

N n ç CONH

XJ

TI U

Ü II

H2N "s X ^ OR2 q / '

r

IV

CH2C1

COOCH (Ph) 2 Nal or KI

v

N j | C CONH •

N

XJ

h2n p

\ 2 o '

or

CH21

4th

COOCH (Ph) 2

/

P (Ph) 3

M n C CONH

n II

N

1 11

2 p

OR

COOCH (Ph) 2

base

1 "

CONH

H-.N ^ S 'n

Ndr2

CH = P (Ph) 3

COOCH (Ph) 2

VI

H2P (Ph) 3

VII

C1CH2CH0

C CONH-

II "11

H_N S

\ 2

r

VIII

OR

ch = chch2ci

COOCH (Ph).

Nal or AI

669 197

20th

X.)

conh ■

r

H2N S

IX

\ 2 4 n

OR O

ch = chch2i

COOCH (Ph).

/ *

hn ^ r '

(secondary amine)

À / ■

h2n s c CONH-

n xor2 ° '

f

"ch = chch-

COOCH (Ph).

»■ i

h2n s xii c conh ii n

^ 2 or

Q = N

XI tertiary amine)

Y /

"CH = CHCH2? N = Q -COOCH (Ph),

H2N s ^

The reaction scheme la shows two alternative ways to get from compound IX to compound XII. The direct route using a tertiary amine (XI) can be used in the preparation of all compounds of the formula I. The indirect route via the compound X runs using a secondary amine, the quaternization taking place in the subsequent step. The secondary amine RR'NH can be acyclic (e.g. dimethylamine) or cyclic (e.g. pyrrolidine). The indi-

I.

: H = chch2-N ^ Q

'ö

eoo

The right path is suitable for the preparation of those compounds of the formula I in which the quaternary ammonio group is acyclic or “mixed” acyclic cyclic. The indirect route is not suitable for the preparation of the compounds of the formula I in which the quaternary nitrogen atom 60 is in a fully unsaturated heterocyclic ring (for example pyridinio, thiazolio, 2-amino-5-thiazolo- [4,5-c] pyridinio and the like.

Deblocking

CONH

V

or

21st

Reaction scheme lb

II

^^ - CHO

^ ^ -CH-N

JO

COOCH (Ph) 2

CH2C1

Nal or AI

XIII

Û CH = N '

COOCH (Ph) 2

P (Ph).

P (Ph).

a

CH * N '

0

H2P (Ph) 3 COOCH (Ph),

base

XV

ca = N-

he

CH «P (Ph).

COOCH (Ph).

XVI

CICHjCHO

V

^ ^ -CH = N <

ff

<i ^ CH * = CHCH2Cl OOCH (Ph),

XVII

669 197

22

Girard Reagent T or HCl h2n-

r

COOCH (Ph)

'ch = chch2ci

XVIII

xccoa

III

VIII

as in scheme la

I.

The reaction scheme lb is a variation which is protected in the sight as a ship see base and the desired reaction shown in that the 7-amino group 25 7-side chain acid is added later. Otherwise, the general procedure of the starting material (II) is similar over most reaction stages.

Reaction scheme 1c

/

f cooch (Ph)

ch-ch-ch2ci

Y

Nal odèr AI

-ch- = n ch = ch-ch2i cooch (Ph),

xvii xix

HN

V "(secondary amine)

= chch - n

2 \

cooch (Ph).

r '

R "Y

V

q = n xi

(tertiary amine)

23

669 197

\ __ y_CH = N "

XXI

V

XXII

H-CHCH2 ^ = Q

COOCH (Ph),

CH = CHCH2-N = Q

COO

y '

N-acylation with III

h2n

À

'CONH

S- "

N

^ OR2

r eoo

CH = CHCH2-N = Q

I.

30th

The reaction scheme le is a further variation of the course of the reaction described in scheme 1b. In reaction schemes la and lb, the 3-side chain is quaternized in the last stage, while in reaction scheme lc the last stage is the acylation of the 7-amino group. The relationship of the reaction schemes la, lb and lc to one another is shown in the overview below.

h2n

7 ^

Ii ch2c1

C00CH (Ph) o

N -— Ç-OONH— S ss

COOCH (pl

, C1 (Ph) -.

XIII

, C1

COOCH (Ph).

lb lc

7-N acylation H-, N-

: I = CHCH2cf lb

COOCH (Ph) 2

VIII

XVIII

COOCH (Ph) 2

: = chch2ci la lb

Quaternization deblocking lc

Quaternization deblocking

VX

Compound I

7_ N-acylation

XXII

^ ~ «X ^ CH = CHCH2-N = Q

eoo0

669 197

24th

Reaction schemes 1, 1b and 1c show the benzohydryl group as the preferred carboxyl protecting group. However, it is obvious to a person skilled in the art that other known carboxyl protecting groups can also be used. The acylating acid III can be used in the form of a derivative such as an acid halide, activated ester, mixed acid anhydride and the like. These forms are all well known. An acid chloride is preferably used. The amino group of acylating acid III can also be one of the usual amino protecting groups, e.g. N-trityl, N-formyl or the like. The base for converting the phosphonium iodide (VI or XV) to the phosphorylide (VII or XVI) can be NaOH, Na2C03, IRA-410 (OH -) resin, IRA (C03 =) resin or the like or a mixture thereof . The chloroacetaldehyde used to convert phosphorylide VII to 3-chloropropenyl-3-cephem compound VIII (or compound XVI to compound XVII) can be the commercially available 40 to 50% aqueous solution, a distilled solution (e.g. 70%) or the anhydrous aldehyde.

It has been found that compound VIII (Scheme la) prepared from compound VII typically has a Z: E ratio of approximately 2: 1 on the propenyl double bond. In contrast, compound VIII (Scheme 1b) prepared from compound XVIII typically consists almost exclusively of the Z isomers. The difference is not necessarily due to the manufacturing route, but can be based on the conditions used in the Wittig reaction (VII to VIII or XVI to XVII). It was also found that the use of a suitable silyl reagent, such as N, 0-bis (trimethylsilyl) acetamide, in the Wittig reaction (VII to VIII in Scheme la and XVI

to XVII in scheme lb) leads to an improvement in the yield and the purity of VIII and XVII. The reaction is preferably carried out with 2 to 5 equivalents of the silyl reagent. If chloropropenyl cephem (VIII) is reacted with sodium 5-iodide in acetone to iodopropenyl cephem (IX), the double bond of the propenyl group is isomerized from Z to E during iodination. With a short reaction time, the configuration of the starting compound VIII is largely retained, while a long reaction time mainly leads to the E isomer of the compound IX. A too long reaction time at high temperature, however, gives compound IX in lower purity. With a reaction time of 10 minutes at 25 C and 2 hours at 5 C, pure IX is obtained in good yield. If one follows • 5 the reaction scheme lc, it was found that the iodination of the compound XIV with NaJ gives a purer compound, if the acetone solution is diluted with CC14, as soon as the iodination has essentially ended and if the part leading to the isomerization of the Reaction 20 in the acetone-CCl4 mixture is carried out. If one carries out the iodination of the chloropropenyl ephem (XVII) to the iodopropenyl cephem (XIX) with potassium iodide in DMF. the isomerization of the double bond from Z to E takes place as quickly as the iodination. The entire reaction 2 = is complete within 45 minutes at room temperature, pure XIX being obtained without dilution with CC14 during the reaction.

Compound XII is normally unblocked without purification. The final product (1) is purified by reverse phase 30 column chromatography using a glass column filled with a Waters "Associates PrepPAK-500 ClN pack (catridge)

Reaction scheme 2

35

R1- «:

Ts.

■ CONH-

"^ OR2

5 "X

CH = CH-CH2I

XXIII

COOCH (Ph).

V

-C-I! N

CONH-

XOR2

f

\>

CH = CH-CH2I

COOCH (Ph).

XXIV

R1-HN "

• CONH-

N \ 2 OR

r

©

H = CH-CH2N = Q

XXV

COOCH (Ph).

25th

669 197

reduction

-CONH

R -HN

XJ1

XOR2

P ©

CH = CH-CH2N = Q COOCH (Ph) _

XXVI

Deblocking

\ f

H2N

N -

A

~ T

s- *

-c-

II n

■ CONH-

^ OR2

P

/ ü S

ocß

©

"CH = CH2N = Q

Reaction scheme 2, shown briefly above, is similar to reaction scheme la, but compound XXIII (corresponding to compound IX, reaction scheme la) is converted into the S-oxide before quaternization. The compound XXV is then reduced and the remaining part of the reaction scheme 2 corresponds to the reaction scheme la. According to reaction scheme 2, it is preferred to protect the amino group of the 7-side chain with a known amino protecting group, such as the trityl group.

The acylating acids of formula III are either known or can be easily prepared according to published procedures. European Patent 7,470 (the application was published on February 6, 1980) exemplifies the preparation of the compounds of the formula III, in which R2 represents methyl, ethyl, propyl and isopropyl. The US Pat. No. 4,390,534 already mentioned in the above discussion of the prior art illustrates the preparation of a plurality of compounds of the formula III, in which R2 is, for example, cyclopentyl, 2-cyclopenten-l-yl, allyl, 2-propynyl, l -tert.-butyloxycarbonyl-l-methylethyl, 1-tert.-butyloxycarbonyl-1 -cyclopentyl, 1 -ethoxycarbonyl-1-me-30thethylethyl, tert.-butyloxycarbonylmethyl, l-tert.-butyloxycarbonyl-2-methylpropyl, Trityl and the like.

Compound II (7-amino-3-chloromethyl-3-cephem-4-carboxylate), which is used as the starting material in the reaction schemes la, lb and lc, is a known compound.

The tertiary amines of the formula XI (and the secondary amines RR'NH) which are used for the preparation of the quaternary ammonio compounds according to the invention are either known compounds or can be prepared easily. Many of these amines are commercially available.

The invention also relates to a process for the preparation of the compounds of the general formula I:

35

R ^ HN

XJ

Fl "

CONH-

f n> s * or2

<r-

CO <P

©

ch = ch-ch2-n:

wherein te alkyl group with I to 4 carbon atoms, a cycloal-

R1 is a hydrogen atom or a customary amino protecting alkyl or cycloalkenyl group with 3 to 6 carbon atoms

group means 55 men, or a remainder of the general formulas:

R2 is a hydrogen atom, a straight-chain or branched4 ^ 4 cooh

-c-ch-ch-r3, »c-

'5 »5

R R

or

R4 I

-c-cooh,

l5

669 197

26

means what

R3 represents a hydrogen atom, a lower alkyl or carboxyl group,

X represents a halogen atom, a hydroxyl or lower alkoxy group and

R4 and R5 each independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring having 3 to 5 carbon atoms, and

®-N = Q

represents a quaternary ammonio group; and the non-toxic, pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, which is characterized in that a compound of the general formula

(0) "

10th

-C-CH-CH-R R5

r i

-C-COOH,

COOH

-Ç-C-C-K3

l5

or n

in i 'n.

—CONH-

B -HiT ^ S ^

\ 2 'OR O

n means where

R3 represents a hydrogen atom, a lower alkyl or carb-15 oxyl group,

X represents a halogen atom, a hydroxy or lower alkoxy group and

R4 and R5 each independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring having 3 to 5 carbon atoms, and

ch = ch-ch2Z

coob

® -NsQ

25th

wherein

R2 'has the same meanings as R2 or for a rest of the formulas:

COOB-1

r4

represents a quaternary ammonio group;

and the non-toxic, pharmaceutically acceptable salts and physiologically hydrolyzable esters thereof, characterized in that a compound of the general formula 30 is used:

or h, n

• c— COOB '

35

©

ch «chch, -n = q

COO

stands in what

X, R4 and R5 have the meanings given above.

40

with an acid of the general formula:

Zen,

B1 represents a common carboxyl protecting group,

B2 represents a hydrogen atom or a conventional amino protecting group,

Z represents a chlorine, bromine or iodine atom and m represents zero or 1, with a tertiary amine of the formula Q = N (or in succession with a secondary amine of the formula RR'NH and a compound of the formula R "Z) and, if m stands for 1, the sulfoxide is reduced in the usual way and then all protective groups are removed in the usual way.

The invention also relates to a process for the preparation of the compounds of the formula I:

45

b2hn

-X.

~ \ fr

"v

-cooh

\ 2 'or or an aeylating derivative thereof, in which R2' has the same meanings as R2 or for a radical of the formulas:

50

55

ra

—CONH

R HN

X

/%

s / xOR2

0> ©

COOw

(I)

COOB

or

C - COOBJ 5

: h = chch2- n = q where

R1 represents a hydrogen atom or a conventional amino protecting group,

R2 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl group having 3 to 6 carbon atoms, or a radical of the general formulas:

where X, R4 and R5 have the meanings given above, B1 is a customary carboxyl protecting group 60 and B2 is a hydrogen atom or a customary amino protecting group, aeylated.

The reactions are carried out in a non-aqueous organic solvent such as dimethyl sulfoxide, hexamethyl-65 phosphoramide, methylene chloride, chloroform, ethyl ether, hexane, ethyl acetate, tetrahydrofuran, acetonitrile and the like or mixtures of such solvents. The reactions are expediently introduced

27th

669 197

a temperature from about -10 ° C to about +50 C; room temperature is usually preferred. For the quaternization, at least one mole of tertiary amine is used per mole of compounds IX, XIX, XXIII or XXIV. An approximately 25 to 100% excess of tertiary amine is preferably used.

The 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 t-butyl; Haloalkyl groups such as 2,2,2-trichloroethyl and other carboxyl protecting groups described in the literature (e.g. in GB-PS 1 399 086). Carboxyl protecting groups which can be easily removed by treatment with an acid are preferably used. Particularly preferred carboxyl protecting groups are the benzhydryl and t-butyl groups.

The amino protecting groups suitable for use as B2 are also known and include the tri-tyl group and acyl groups such as chloroacetyl, formyl and trichloroethoxycarbony 1. Preferably, amino protecting groups are used which can be easily removed by treatment with an acid , e.g. the trityl group.

When the cephalosporin skeleton is used in the form of the 1-oxide (m = 1), the 1-oxide is produced by known methods such as oxidation with m-chloroperbenzoic acid, peracetic acid, sodium tungstate and the like. The 1-oxide can then be processed using known methods, e.g. Reduction of the corresponding alkoxysulfonium salt with iodide ions in an aqueous medium. The alkoxysulfonium salt itself is easily prepared by treating the 1-oxide with, for example, acetyl chloride.

The invention also relates to new starting compounds of the general formula XXVIII for the process according to claim 26:

10th

Substance atom, means a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring with 3 to 5 carbon atoms, and their salts and esters.

Compounds of the formula XXVIII are also included, in which the amino and / or carboxyl groups are protected by customary amino or carboxyl protective groups.

The compounds of the general formula XXIX:

XXIX

a ^ CHCHj!

COOR

20th

wherein

R ~ represents a hydrogen atom or a conventional carboxy 1 protective group and

Rr \ R24 and R25, which may be the same or different, represent a hydrogen atom, a hydroxy, lower alkyl or 25 lower alkoxy group and

Z represents a chlorine, bromine or iodine atom; or their salts, solvates, hydrates or esters are also starting materials which are suitable for the preparation of the compounds according to the invention.

The invention further relates to new starting compounds of the general formula XXII for the process according to claim 27:

30th

35 H2N-

h2N

A

T

c — CONH 1—

>>

1

N 1

.. y

OR ^

COOH

^ ©

CH-CB-CE2-B3D

cocß

XXII

40

ch = chch2z

XXVIII

wherein Z represents a chlorine, bromine or iodine atom, R2 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl or cycloalkenyl ring having 3 to 6 carbon atoms or a radical of the formula:

R

-c-ch = ch-r3

U

R I

-c-cooh i *

cooh

-c-ce k-5

ec-r or where ® -NsQ means a quaternary ammonio group, or their salts, esters, solvates or hydrates.

In the context of the present invention, the terms acylamino and acyloxy mean an acylated amino or acylated hydroxyl group, the acyl unit for lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, isovaleryl, etc.), aroyl (e.g. benzoyl, etc. ) Lower alkanesulfonyl, (for example mesyl, ethanesulfonyl, etc.) or arylsulfonyl (for example benzenesulfonyl, tosyl, etc.).

The terms "lower alkyl", "lower alkoxy", "lower alkylthio" (or the like) mean straight-chain or branched alkyl, alkoxy, alkylthio (or the like) groups having 1 to 6 carbon atoms, inclusive. In the same way, the terms lower alkenyl and 55 lower alkynyl mean alkenyl or alkynyl groups with 2 to 6 carbon atoms.

45

50

example 1

60

means in which

R3 represents a hydrogen atom, a lower alkyl or carboxyl group,

X represents a halogen atom, a hydroxy or lower alkoxy group and

R4 and R5 are each independently a water

ii n s

"N-Vs / * \

■ CONH '

OCH,

n

S ^^ CHsCH-CH ^ -N, ch,

yU

65

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyimino-acetamido] -3- [3- (l-methylpyrrolidinio) -l ~ propen-l-yl ] - 3-ce-phem-4-carboxylate (I-1A)

669 197

28

To a solution of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-l-yl) - 3-cephem-4-carboxylate (IX-1) (Z / E = 2 / l, 150 mg, 0.21 mmol) in ethyl acetate (2 ml), while stirring, a solution of 1 methylpyrrolidine (36 mg, 0.42 mmol) in ethyl acetate (1 ml). The mixture is stirred for 15 minutes and then diluted with isopropyl ether (10 ml), a precipitate being formed, which is filtered off. A mixture of the solid (130 mg), formic acid (1 ml) and concentrated HCl (0.1 ml) is stirred at room temperature. After one hour the reaction mixture is concentrated under reduced pressure, diluted with water (20 ml) and filtered. The aqueous solution is passed over a reverse phase column (filled with PrepPAK-500 / C18-cartridge, 100 ml) and eluted with water and 10% CHjOH. The desired fractions are collected, concentrated in vacuo to a small volume and freeze-dried to give 13 mg (12%) of the title compound (I-1A) (Z, E = 1/1). Melting point> 280 C (decomposition).

IR: u ^ xr cm- '3400, 1760, 1660, 1610.

UV; k phosphate buffer (pH 7) nm (£ 1 236 ^ ^

(322).

NMR: S 2 '' ('m'

ppm

N-CH3), 3.6 (5H,

N

-H

), 3.12 (3H, s.

m, 2-H & N

H

), 3.79 (lH, s, 2-H), 4.1 (2H, d,

J = 8, CHiN), 4.2 (3H, s, OCH,), 5.36 (IH, d, J = 4.5, 6-H), 5.95 (3H, m, 7-H & 3-CH = CH), 6.66 (1 / 2H, d, J = 10, 3-CH eis), 7.0 (1 / 2H, d, J = 16, 3-CH trans).

Example 2

A

-CONH

-N / A

s- / och3 er

I-IB

CH = CH-CH.

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -3-methoxyiminoacet-amido] - 3- [3-pyridinio-l-propen-l-vl] - 3-cephem- 4-carboxv-lat (I-lB)

A mixture of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-I-propen-l-yl) -3 -cephem-4-carboxylate (IX-1), (E, 716 mg, 1 mmol), pyridine (158 mg, 2 mmol) in dimethyl sulfoxide (DMSO) (1 ml) is mixed for one hour at room temperature. Ethyl acetate (20 ml) is added to the mixture, a precipitate separating out (620 mg). This is added to formic acid (6 ml) containing sodium bisulfite (60 mg). The mixture is stirred at 40 C for 30 minutes and then evaporated to dryness. The residue is dissolved in H20 (40 ml) and a small amount of insoluble constituents is filtered off. The aqueous solution is applied to a reverse phase column (PrepPAK-500 / C] S, 100 ml) eluted with H20 (300 ml) and 5% aqueous CH3OH (800 ml) and the eluate is monitored by UV (254 nm) and HPLC. The fractions containing the desired product (5% aqueous CH3OH) are combined, concentrated to a small volume and lyophilized to give 40 mg (8%) of the title compound (1-1B). Melting point> 200 C (decomposition).

IR: v KBr cm- '3350, 1760, 1660, 1600.

Max

UV; X phosphate buffer (pH 7) max

10 (366), 267 (279), 290 (469).

D20 + DMS0-d6

1% 1 cm

) 240 (352), 258

NMR: 6

ppm

3.74 (2H, br-s, 2-H), 4.20 (3H,

s, OCH3), 5.92 (1H, 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, 15 Py-H, s), 8.62 (IH, m), Pv-H4), 8.97 (2H, m, Py-Ho6).

Example 3

20th

h2N

A

■ CONH '

* \ S '"' OCH,

X-1B

CH = CH-CH,

■ 5o

* Z / E = 4 / l

25th

7- [2- (5-Amino-1,2,4 ~ thiadia: ol-3-yl ì-2-methoxyimino-acetamido] - 3- [3-pyridinio-l-propen-l-yl] - 3-cephem-4-carboxy-lat (I-Ibi

The chloropropenyl compound diphenylmethyl-7- [2- (5-30 amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-chloro-l-propen-l-yl) - 3-cephem-4-carboxylate (VIII-1) (Z, 937 mg, 1.5 mmol) is added with stirring to a solution of pyridine (237 mg 3 mmol) in DMSO (3 ml), the NaI (11 mg, 0.075 mmol) contains. The mixture is left in the dark at 35 room temperature overnight. The mixture is diluted with ethyl acetate (30 ml) to separate a precipitate which is filtered off, washed with ethyl acetate (10 ml) and dried to give 350 mg of the blocked compound. The precipitate is treated for 30 minutes at 40 C with formic acid (3.4 ml) containing sodium bisulfite (34 mg). After the formic acid has been removed, the residue is purified by reverse phase column chromatography (filled with PrepPAK-500; C1S cartridge, 100 ml), eluting with 5% strength aqueous CH3OH. The fractions containing the desired product according to HPLC analysis are combined, evaporated under reduced pressure and lyophilized, giving 41 mg (5.5%) of the title compound (I-IB) (Z / E = 4/1). Melting point> 200 C (decomposition).

50 IR: v KBr cm-1 3300, 1760, 1660. 1600.

Max

1%

UV: X

Phosphate buffer (pH 7)

max nm (EÎ'cum) (237 (386), 250

(377), 258 (369, 265 (347), 280 (311).

53 NMR: S D; 0 3.45 & 3.76 (each IH, d, J = 16, 2-H). 4.18 ppm

(3H, s, OCH,). 5.34 (3H, m CH = CH-CH, & 6-H), 5.92 (IH, d, J = 4.5, 7-H), 6.58 (4 / 5H, d, J = 11, 3-CH eis), 7.03 (1 / 5H, d, J = 16, 3-CH trans), 8.12 (2H, in, Py-H,.,). 8.56 60 (IH, m, Py-H4), 8.82 (2H, m, Py-H2.6).

Example 4 s

65

»S ^ e

JSs-r i-1c

29

669 197

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacet-amido] -3- [3- (2-amino-5-thiazolo [4,5-c] pyridinio) - 1-pro-pen-l-yl] -3-cephem-4-carboxylate (I-1Cj

A solution of diphenylmethyl 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-l-propen-l-yl) -3- cephem-4-carboxylate (IX-1) (E-isomer, 714 mg, 1 mmol), 2-aminothiazolo [4,5-e] pyridine [prepared according to the method of T, Takahashi et al., Pharm. Bull ( Japan), 2, 34/1954)] and dry DMSO (1 ml) is stirred for 1 hour at room temperature. Ethyl acetate (20 ml) is added to the reaction mixture to give a yellow powder (710 mg). Formic acid (7 ml) and sodium bisulfite (70 mg) are added to the powder (710 mg). The mixture is stirred at 40-45 C for 30 minutes. After evaporation, the residue is triturated with H20 (40 ml). Insoluble constituents are filtered off and the filtrate is chromatographed on a reverse phase column (PrepPAK-500 / C) S, 100 ml) with HhO and 10% CH3OH as eluent. The fractions containing the desired product are combined and the solvent is removed under reduced pressure. Lyophilization gives the desired product (I-1C) as a colorless amorphous powder in the form of the E isomer. Yield 110 mg (19%). Melting point> 200 C (decomposition).

IR: v KBr cm-1 3300, 1760, 1660, 1630, 1600.

Max

Phosphate buffer (pH 7) nm (El%) 245 (499), 285 max v 1 cm 'K'

(286).

NMR: S DMS ° -d6 + D2 ° 3.86 (3H s OCH3), 4.98 (1H, d, ppm

J = 4.5. 6-H), 5.2 (2H, m, CH = CH-CTL), 5.57 (1H, m, 3-CH = CH), 5.96 (IH, m, 7-H7, 7.16 (1H, d, J = 16, 3-CH trans). 8.36 & 8.45 (each 1H, d, J = 7, Py-H), 8.92 (1H, s, Py-H).

Example 5 n r - c conh - r p "" s> s>

H2N ^ S ^ NICHj NNy ^ CH = CH-CH2 <? N (CH3) 3

eoo®

i-ld * z / e ■ = 1/1

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3-f3-trimethylammonio-l-propen-l-yl) - 3-cephem-4-carboxylate (I-ID)

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-cephem-4-carboxylate (IX-1) (Z / E = 2 / l, 490 mg, 0.68 mmol) in ethyl acetate (14 ml) is added all at once to a 0.1 M trimethylamine solution in ether (13, 6 ml). The mixture is stirred for 10 min and evaporated to dryness, the residue is triturated with ether (20 ml). The resulting solid (490 mg) is poured into trifluoroacetic acid (0.2 ml) containing a drop of anisole. After stirring for 90 minutes, the mixture is evaporated to dryness under reduced pressure and the oily residue is triturated with ether (20 ml). The precipitate obtained is filtered off and dissolved in H20 (20 ml). Small amounts of insoluble constituents are removed and the aqueous solution is passed through a C | 8 reverse phase column (filled with PrepPAK-500 / C | K cartridge, Waters, 30 ml) and eluted with water. The fractions containing the desired compound are combined, concentrated to a small volume and lyophilized to give 30 mg (9.2%) of the title compound (I-ID) (Z / E = 1/1) as a colorless amorphous powder. Melting point:> 150 C (decomposition).

IR: v KBr cm-1 3300, 1770, 1670, 1605.

max x phosphate buffer (pH 7) nm £ 1%} 236 (3g9) 2g7 max 1 cm

(343).

NMR: 5 D2 ° 3.45 and 3.7 (IH, d, J = 16, 2-H); 3.81 (1H, ppm s, 2-H); 4.1 (2H, d, J = 8, -CH-.N®); 4.21 (3H, s, OCH3); 5.39 (1H, d, J = 4.5, 6-H); 5.95 (2H, m, 3-CH = CH and 7-H); 6.61 (1 / 2H, d, J = 11, 3-CH eis); 7.05 (1 / 2H, d, J = 16, 3-CH trans).

Example 6 N p-C-CONH-q f "" 'S

2nd

eoo®

x — ie * e

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (3-aminopyridinio) -1-propen-1-yl] 3-cephem -4-carboxylate (I-IE)

Diphenylmethyl-7- [2- (5-amino-l, 2,4-thiadia-zol-3-yl) - 2-methoxyiminoacetamido] - 3- (3-iodo-l-propen-l-yl) - 3-cephem-4-carboxylate (IX-1), (E, 716 mg, 1 mmol) with stirring to a solution of 3-aminopyridine (188 mg, 2 mmol) in DMSO (1 ml). The mixture is stirred for 1 h and diluted with ethyl acetate (20 ml). The precipitate obtained is filtered off, 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) is stirred at 40 ° C for 30 min. The mixture is concentrated in vacuo, dissolved in H20 (40 ml) and insoluble components are removed. The aqueous solution is chromatographed on a reverse phase column (filled with PrepPAK-500 / C | g, 100 ml), eluting with 7.5% aqueous CH3OH. The fractions containing the desired product are evaporated and lyophilized to give the title compound (I-IE) (7 mg, 1.4%). Melting point:> 185 "C (decomposition).

IR: v KBr cm- '3400, n765, 1675, 1620, 1600. max ^

UV: X phosPhatBuffer (PH 7) nm (E1%) 246 (403), 290 max 1 cm from

(468).

NMR: 5 3.72 (2H, m, 2-H); 4.14 (3H, s, OCH3); 5.35

(3H, m, 6-H and CH = CH-CH2); 5.9 (1H, d, J = 4.5, 7-H); 6.1 (1H, m, 3-CH = CH); 7.05 (1H, d, J = 16, 3-CH, trans); 8.1 (IH, m, Py-H5); 8.54 (IH, br-s, Py-H6); 8.68 (IH, m, Py-H4); 9.4 (IH, m, Py-H2).

Treatment of IX-1 (716 mg, 1 mmole) with 3-t-butoxycarbonylaminopyridine (324 mg, 2 mmole) in a similar manner as described above gives 12 mg (2.3%) of I-IU.

Example 7

CONH- "

NH.

CH = CHCH, -N

H.

OCH

2nd

cocß

* z / e «= 1/1

i-ie

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

669 197

30th

7- [2- (5-Ammo-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacet-amido] - 3- [3- (3-amino-l-pyridinio) - l-propene-l -ylj-3-ce-phem-4-carboxylate (I-1E)

A mixture of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-l-propen-l-yl) is stirred - 3-cephem-4-carboxylate (IX-1) (Z / E = 2/1, 500 mg, 0.7 mmol) and 3-aminopyridine (66 mg, 0.7 mmol) in dimethyl sulfoxide (1 ml) 20 min at room temperature. The mixture is diluted with ethyl acetate (10 ml) and ether (10 ml), the precipitate obtained is filtered off, washed with ether (10 ml) and dried. The quaternized salt is left in formic acid (3 ml) containing concentrated HCl (0.3 ml) and stirred for 1.5 h at room temperature. The mixture is evaporated to dryness under reduced pressure. The residue is dissolved in 2% HCl (10 ml) and filtered. The aqueous phase is chromatographed on a reverse phase column (PrepPAK-500 / C | 8, 100 ml). After washing with water (500 ml), the column is eluted with 5% aqueous CH3OH. The fractions containing the title compound are combined, concentrated in vacuo and freeze-dried, giving 15 mg (4.2%) of the title compound (I-IE) (Z / E = 1/1) as a colorless, amorphous powder. Melting point:> 160 ° C (decomposition).

IR: KBr cm-1 3400.1765, 1675, 1620, 1600.

Max

UV: X PhosPhatBuffer (PH 7) nm (E1%) 244 (434), 287 max v cm 'v'

(333).

NMR: S p ^ SO ~ d6 + D2 ° 3.73 (2H, m); 4.14 (3H, s,

OCHj); 5.35 (3H, m, 6-H and CH-CH-CH2); 6.0 (2H, m, 7-H and 3-CH-CH); 6.6 (1 / 2H, d, J = 11, 3-CH eis); 7.05 (1 / 2H, d, J = 16, 3-CH trans); 8.08 (IH, m, Py-H5); 8.6 (2H, m, Py-H4.6); 9.4 (IH, m, Py-H2).

Example 8

i-1f * e

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacet-amido] - 3- [3- (3-formylaminopyridinio j-1-propen-1-yl] - 3-cephem-4-earboxylate (I-1F)

A mixture of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) is stirred - 3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmol) and 3-formylaminopyridine (prepared according to the method of N. Enomoto et al., Bull. Chem. Soc. Japan, 45, 2665 (1972)) (244 mg, 2 mmol) in DMSO (2 ml) for 1 h at room temperature and poured into ethyl acetate (200 ml).

The precipitate is filtered off, washed thoroughly with ethyl acetate and dried. A mixture of the quaternized salt (500 mg) with sodium bisulfite (50 mg) in HCOOH (5 ml) is stirred at 40-50 C for 80 min and then evaporated to dryness in vacuo. The residue is dissolved in water (40 ml), neutralized with NaHC03 and then insoluble material is filtered off. The clear filtrate is on a reverse phase column (prep

PAK-500 / Ci8, 100 ml) chromatographed with water and 5% CH3OH, 10% CH3OH, 20% CH3OH and 30% CH3OH. The fractions containing the desired compound are combined, concentrated in vacuo and lyophilized to give 16 mg (2.9%) of the title compound (I-1F) (E) as a tan powder. Melting point:> 170 C (decomposition).

IR: v cm- '3340 (br), 1760, 1670, 1620 (br), 1590.

niaX

UV; x phosphate buffer (pH 7) 1%

max 1 cm 'v'

(362), 290 (474).

NMR: 5 pp ^ + NaHC ° 3. 3.68 (2H, br, 2-H); 4.15 (3H, s,

OCH3); 5.91 (1H, d, J = 4.5, 7-H); 6.25 (1H, m, CH = CH-CH2); 6.98 (IH, d, J = 16, 3-CH trans); 8.8-7.9 (4H, m, Py-H); 9.38 (IH, br, NaCHO).

Example 9

«I>

I l N 1 ^ CONH

H n '^ - s / OCH rV N \ * ® 0 Yv

2 S 3 "CH = CHCH, -N)

cocß '2 W

i-1g * e

7- [2- (5-Amino-l, 2,4-thiadiazoI-3- \ iJ-2-methoxyiminoacetamido] - 3- [3- (3-carbamoylpyridinio) - 1-propen-1-ylJ-3 -cephem-4-carboxylate (I-1G)

To a solution of diphenylmethyl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) - 3-cephem-4-carboxylate (IX-1), (E, 716 mg,

1 mmol) in DMSO (2 ml) nicotinamide (244 mg,

2 mmol) and the mixture is stirred for 1.5 h at ambient temperature. The mixture is then poured into ethyl acetate (200 ml) with stirring. The precipitate obtained is filtered off. The quaternized salt (500 mg) is dissolved in HCOOH (5 ml) in the presence of sodium bisulfite (50 mg) and the mixture is heated to 40-50 C with stirring for 40 min and then evaporated to dryness. The residue is dissolved in water (40 ml), insoluble components are filtered off and washed with a small amount of water. The filtrate and the wash water are combined and chromatographed on a reverse phase column (PrepPAK-500 / CI8, 100 ml). It is eluted successively with water, 5%, 20% and 20% aqueous CH3OH, the fractions containing the desired material are combined, concentrated in vacuo and subjected to freeze drying, whereby 21 mg (3.8%) of the title compound (I -1G) (E) as a yellow powder. Melting point:> 175 C (decomposition).

IR: v KBr cm-1 3340 (br), 1760, 1670, 1600. max v

UV: X phosphate buffer (pH 7) nm (e \%) 235 (326), 274 max v 1cm 'v'

(sh, 405), 290 (446).

NMR: 6 pp ° + NaHC ° 3. 3.68 (2H, br, 2-H); 4.15 (3H, s,

OCH3); 5.32 (1H, d, J = 4.5, 6-H); 5.45 (1H, d, J = 7, CH = CH-CH2); 5.88 (1H, d, J = 4.5, 7-H); 6.15 (1H, d-t, J = 16 and 7, 3-CH = CH); 7.00 (1H, d, J = 16, 3-CH trans); 8.23 (IH, m, Py-H5); 9.03 (2H, m, Py-H4 and 6); 9.34 (IH, s, Py-H,).

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

31

669 197

Example 10, see

"rii ~ c0mh_l-1 i

O- -

cocß *

-CONHj 5

X-1H

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacet-10 amido] - 3-] 3- (4-carbamoylpyridinio] - 1-propen-1-yl] - 3 -ce-phem-4-carboxylate (1-1H)

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 -cephem-4-carboxylate (IX-1) (E, 716 mg, 15 1 mmol) in dry DMSO (2 ml) is isonicotinamide (244 mg, 2 mmol) is added. The mixture is stirred at room temperature for 1 h and then poured into ethyl acetate (200 ml). The precipitate obtained is filtered off, washed thoroughly with ethyl acetate and dried. 20 A mixture of the quaternized material (400 mg) with sodium bisulfite (40 mg) in HCOOH (4 ml) is heated to 40-50 C with stirring for 1 h and then evaporated to dryness under reduced pressure. The crude solid is dissolved in water (40 ml). After filtering off insoluble material, the filtrate is chromatographed on a reverse phase column (filled with PrepPAK / C18, 100 ml), using water and 5%, 10%, 20% and 30% aqueous CH3OH as eluent used. Fractions 30 containing the desired compound are combined, evaporated and lyophilized to give 21 mg (3.8%) of the title compound (I-1H) as a pale yellow powder. Melting point:> 180 C (decomposition).

(50 mg) in HCOOH (5 ml) is stirred at 40-50 C for 80 min and then evaporated to dryness under reduced pressure. The solid residue is dissolved in water (40 ml) and the mixture is neutralized with NaHCO. Insoluble material is filtered off and the filtrate is chromatographed on a reverse phase column (filled with PrepPAK-500 / Ci8, 100 ml), eluting successively with water, 5%, 10%, 20% and 30% aqueous methanol. The fractions containing the desired compound are combined, evaporated and lyophilized to give 10 mg (1.8% of the title compound (I-1I) (E) as a brown-yellow powder.

KBr cm-1 3380 (br), 1760, 1650 (sh), 1620 (sh).

IR: v max

UV: X phosPhatBuffer (PH 7) nm (g1) 235 (sh, 260), max v 1 cm v '

.1%

286 (370).

NMR: §

D20 + NaHC03 ppm

3.68 (2H, br, 2-H); 4.16 (3H, s,

OCH,); 6.98 (1H, d, J = 16, 3-CH trans); 8.05 (IH, m, Py-H5); 8.50 (IH, m, Py-H4); 8.80 (2H, m, Py-H2.6).

CH = CHCH.

?O

CONH,

I-lH

«E

TD K-Br IR: v "cm max

-i

3340 (br), 1760, 1670, 1600.

35

Phosphate buffer (pH 7)

max nm (E!%) 222 (362), 285 v 1 cm v

UV: X (452).

nmr: S D20 + nahc ° 3 3 68 (2h, br, 2-h); 4.15 (3h, s,, n ppm 40 och3); 5.33 (ih, d, j = 4.5, 6-h); 5.46 (2h, d, j = 7,

ch = ch-h-i); 5.90 (ih, d, j = 4.5, 7-h); 6.17 (ih, d-t,

j = 16 and 7, 3-ch = ch); 7.02 (ih, d, j = 16, 3-ch trans);

8.43 and 9.09 (each 2H, d, j = 7, Py-H).

45

HjN

JLJ

n

C — CONH-

Example 11

S

\

och3 <X

cocp

* © // \\ CH = »CHCH2-N / N.

CH2NH2

I-1I

50

55

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido J-3-] 3- (3-aminomethylpyridinio j-1-propen-l-yl] -3- cephem-4-carboxylate (I-1I)

A mixture of diphenylmethyl-7- [2- (5-amino-l, 2,4-60 thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- (3-iodo-l-per-pen-l-yl ) - 3-cephem-4-carboxylate (IX-1), (E, 716 mg,

1 mmol) and 3- (t-butyloxycarbonylaminomethyl) pyridine (516 mg, 2 mmol) in DMSO (2 ml) are stirred for 30 min at ambient temperature. The mixture is poured into ethyl acetate 65 (200 ml), the precipitate is filtered off, washed thoroughly with ethyl acetate and dried. A mixture of quaternized salt (500 mg), sodium bisulfite

7- [2- (5-Amino-l, 2A-thiadiazol-3-yl) -2-methoxyiminoacetamido 7-3- / 3-f4-carbamoylpyridinio) -1-propen-l-yl] -3-cephem-3 carboxylate (I-lH)

A mixture of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3-iodo-1-propen-l-yl) -3 -cephem-4-carboxylate (IX-1) (E-isomer, 4.1 g, 5.7 mmol) and isonikotinamide (1.4 g, 11 mmol) in dry DMSO (6 ml) is stirred for 2 h at room temperature , monitoring the reaction by TLC (silica gel plate, CHC13: CH30H) = 3: 1). The reaction mixture is diluted with ethyl acetate (100 ml) to form a yellow gummy material which is treated with formic acid (40 ml) and sodium bisulfite (390 mg) at 45 G for 30 min. The solution obtained is evaporated to dryness. The residue is dissolved in H20 (100 ml), insoluble constituents are filtered off. The filtrate and the wash water are combined and placed on a reverse phase column (PrepPAK-500 / CiS, 120 ml). The column is eluted with H20. The eluate is collected in 300 ml fractions and checked by means of UV (254 nm) and HPLC (Lichrosorb RP-18, 4 x 300 mm, 0.01 M ammonium phosphate buffer, pH 7.2, containing 20% CH3OH). Fractions 4 and 5 are combined and concentrated to a small volume. After lyophilization, (250 mg (8.1%) of the title compound I-1H, melting point:> 180 C (decomposition).

The evaluation of the spectra shows that the product is identical to the product obtained according to Example 10.

Production of the hydrochloride.

10% HCl (0.1 ml) is added to a suspension of the compound I-1 H (98 mg, 0.18 mmol) in CH, OH (1 ml). The mixture is stirred for 5 min. Acetone (100 ml) is added to the yellow solution obtained, a precipitate forming, which is filtered off, washed with acetone (2 × 10 ml) and dried in vacuo. You get that

669 197

32

Hydrochloride of I-lH as a colorless powder. Yield 88 mg (79%). Melting point:> 190 C (decomposition).

IR: v ^ Br cm- '3300, 1770, 1680, 1620.

Max

UV; Phosphate buffer (pH 7) 1% mm max 1 cm

(374).

NMR: 5 D2 ° 2.32 (IH, see acetone-H); 3.79 (2H, br-s, 2H); ppm

4.17 (3H, s, OCHj); 5.34 (1H, d, J = 4.5, 6-H); 5.49 (2H, i.e. J = 7, CH = CH-CH-i); 5.93 (1H, d, J = 4.5, 7-H); 6.28 (1H. D-t, J = 16 and 7, 3-CH = CH); 7.15 (1H, d, J = 16, 3-CH); 8.43 and 9.1 (each 2H, i.e. J = 7, Py-H).

Example 13

CH = chch2? I ^^) - ck2OH

10th

I-1L

H2N ^ \ S /

"P

• CONH-

\

'OCH,

I-1J

r

eoa

&

©

CH = CHCH2-tf n i1 u

H, C-kc ^

* E

7- [2- (5-Amino-1,2,4-thiadia: ol-3-ylj - 2-methoxyiminoacetamido 7-3- / 3- (2-methylthiazolio j-1-propen-l-yl] -3 -cephem-4-carboxylate (I-1J)

To a mixture of diphenylmethyl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) - 3-cephem-4-carboxylate (IX-1) (E, 714 mg, 1 mmol) and 2-methylthiazole (prepared according to the method of RP Kurkjy, EV Brown, J. Am. Chem. Soc., 74, 5778 ( 1952)) (198 mg, 2 mmol) in dry CH2C12 (10 ml) are added at -20 C AgBF4 (90% 217 mg, 1 mmol). The mixture is stirred at room temperature for 30 min and then filtered. The precipitate is extracted with 10% CH3OH-CHCI3 (3 x 20 ml). The combined extracts are washed with saline (2x5 ml),

Dried over MgSO4 and concentrated to dryness to give a yellow residue which is triturated with isopropyl ether. Filtration provides 350 mg of the quaternized product. A mixture of this solid, sodium bisulfite (35 mg) and formic acid (3.5 ml) is stirred at 40 C for 30 min. The mixture is concentrated to remove formic acid and the residue is diluted with H20 (40 ml). Small amounts of insoluble components are filtered off. The filtrate is placed on a reverse phase column (PrepPAK-500 / 'C | S, 100 ml). The column is successively eluted with H20 (200 ml), 5% aqueous CH3OH (400 ml) and 10% aqueous CH3OH (300 ml). The fractions containing the desired product are combined on the basis of an HPLC analysis (Lichrosorb RP-18, 4x 300 mm, 0.01 M ammonium phosphate buffer, pH 7.2, containing 20% CH3OH). The combined solutions are concentrated to a small volume and lyophilized to give 40 mg (7.7%) of the title compound (1-1 J) (E). Melting point:> 195 C (decomposition).

IR: v KBr cm "1 3300, 1760, 1660, 1600.

Max

-1%

UV

. y phosphate pouffei (pH 7) (441)? çp 14 ^])

- 1 cm ~

Max

NMR: 5 D20 + DMSO-dfl 3 Q6 (3H thiazo] .CH); 3 74 ppm

(2H. Br-s, 2-H); 4.19 (3H, s, OCH,); 5.92 (IH, d, J = 4.5, 7-H): 6.1 (1 H, m, 3-CH = CH); 6.8 (1H, d, J = 16, 3-CH trans); 8.04 and 8.23 (IH, d, J = 4, thiazole-H, respectively).

7- [2- (5-Amino-l, 2,4-thiadiazoI-3-ylj-2-methoxyiminoacetamido] -3- [3-t 4-hydroxymethylpyridinio) - 1-propen-l-yl] -15 3- cephem-4-carboxylcit (I-ILJ

A mixture of diphenyl-7- [2- (5-amino-l, 2,4-thia-diazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) - 3-cephem-4-carboxylate (IX-1) (E-isomer, 1.07 g, 1.5 mmol). 4-hydroxymethylpyridine (818 mg 7.5 mmol) in 20 CH3CN (4.5 ml) and CH, OH (3 ml) are stirred for 1 h at room temperature under a nitrogen atmosphere. After evaporation of the solvent, the oily residue is triturated with isopropyl ether, filtered off and washed with a mixture of isopropyl ether and methanol (3: 1, 10 ml), giving 1.28 g of the quaternized cephemester as a yellow powder. A solution of the quaternized ester (1.25 g) and sodium bisulfite (600 mg) in 85% HCOOH (10 ml) is stirred for 1 h at room temperature under a nitrogen atmosphere. After adding 85% HCOOH 30 (5 ml), the mixture is stirred for a further hour under the same conditions. Toluene is added and the reaction mixture is evaporated azeotropically under reduced pressure. The residue is triturated with acetone, giving 1.17 g of the crude format of the title compound er-35. A suspension of this compound (1.15 g) in water (100 ml) is filtered to remove insoluble matter. These will be washed off with water (10 ml x 2).

40 The filtrate and the wash water are combined and subjected to reverse phase column chromatography. The pillar. which was filled with a material which was taken from a Prep-PAK-500 C | x column palette, Waters, 60 ml., is developed successively with water, 5% methanol 45 and 10% methanol. The fractions containing the desired compound are combined, concentrated under reduced pressure and a precipitate is produced by adding acetone. This gives 100 mg of the title compound (1-1L) as a pale yellow pul-50 ver. To a suspension of the powder (90 mg) in methanol (9 ml), 1 M HCl in CH3OH (0.5 ml), the mixture is stirred at room temperature and concentrated in vacuo. Isopropanol is added to the concentrate, whereby 77 mg of the hydrochloride of the title compound precipitate out as pale yellow Pul-55. Melting point:> 190 C (decomposition).

IR: v KBl cm "1 1775, 1670. 1635, 1530.

Max

^ Phosphate buffer (pH 7)

Max

60 16300)

NMR: Ô 020 3.83 (2H, br. 2-CH); 4.17 (3H, s, OCH,):

ppm nm (g), 230 (22600), 264 (sh.

5.06 (2H, see N

CH2OH); 5.36 (1 H. d, J = 4.5 Hz,

65 6-H); 5.41 (2H. D, J = 7 Hz, CH = CH CH-.); 5.94 (IH, d, .1 = 4.5 Hz, 7-H); 6.36 (IH, d-t, J = 16 and 7 Hz, CH = CHCH2); 7.13 (IH, J = 16 Hz, CH -CH CH2); 8.08 and 8.83 (2H, d, J - 1 Hz, Py-H, respectively).

33

669 197

CH = CHCH,

©

'■ O *

OKH.

I-2H

rr »KBl" IR: v cm max nm (s) 227 (22300), 288

10th

35

7- [2- (5-Amino-l, 2,4-thiacliazol-3-yl) -2-ethoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) -1-propen-l-yl] - 3-cephem-4-carboxylate (I-2H).

To a solution of 200 mg of 7-amino-3- [3- (4-carbamo- 15 ylpyridinio) - 1-propen-l-yl] - 3-cephem-4-carboxylate hydrochloride (E-isomer) in 5 ml 50% aqueous acetone is added in portions to 190 mg of 2-ethoxyimino-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetyl chloride hydrochloride (prepared according to the method described in Japanese Patent Publication (Kokai) 20 57- 24389 (2/9/82) described methods). The mixture is adjusted to pH 6.5-7.0 with 2N Na2CO3 (approximately 1 ml). The reaction mixture is stirred at 10 C for 1 h, acidified to pH 2 with 1 N HCl and concentrated in vacuo. The residue is filtered off and the filtrate is chromatographed on an HP-20 column, which is eluted successively with 500 ml of water and 25% aqueous isopropanol. The fractions containing the desired product are combined and evaporated under reduced pressure. The oily residue is treated with isopropanol (20 ml). to obtain 263 mg (93%) of the title compound (I-2H). Melting point: 170 C (decomposition).

1 ml of 1N HCl in CH3OH is added to a suspension of 225 mg (0.40 mmol) of the above zwitterion in 10 ml of methanol. The mixture is stirred for 30 minutes at room temperature. The solution is filtered and concentrated under reduced pressure. 15 ml of isopropyl alcohol are added to the residue, the precipitate obtained is filtered off and dried in vacuo, the title compound being obtained in the form of the hydrochloride. Yield 146 mg (57%). 40 Melting point: 160 C (decomposition). Purity: 65% (estimated).

'3300,1780,1680,1620.

yy. ^ Phosphate buffer (pH 7)

max (22800).

NMR: 8 1.44 (3H, t, J = 7Hz, OCH2-CH3); 3.74 (2H,

br. 2, 2-H); 4.45 (2H, q, J = 7Hz, OŒL-CH3); 5.36 (IH, d, so J = 4.5 Hz, 6-H); 5.46 (2H, d, J = 7Hz, 3-CH = CH-CH2); 5.92 (IH, d, J = 4.5 Hz, 7-H); 6.20 (IH, m, 3-CH = CH); 7.04 (IH. D, J = 16Hz, 3-CH = CH); 8.43 (2H, d, J = 7Hz, Py-HA); 9.10 (2H. D, J = 7Hz, Py-HB).

55

Example 16

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) - 1-propen-l-yl] - 3- ce-phem-4-carboxylate (I-1H) (E-isomer)

This example shows the preparation of the compound 60 I-1H according to the last stages of the reaction scheme la or 1 b, the intermediate compound benzhydryl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- [3- (4-carbamoylpyridinio) - 1-propen-l-yl] - 3-cephem-4-carboxylate format (XXVII-IH) is isolated. 65

A. Benzhydrvl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-meth-oxyiminoacetamido] - 3- [3- (4-carbamoyl-l-pyridinio) - 1 -Per-

pen-l-vl] - 3-cephem-4-carboxvlat-format (E-Isomeres) (XXVII-IH)

A solution of XII-1H (Y9 = IQ, E-isomer) (34 g, purity 75%) in a mixture of acetone and methanol (1/1, 200 ml) is applied to an Amberlite IRA-410 column (format; 340 ml). The column is eluted with the same solvent system. The first fraction (1 L) is concentrated to approximately 100 ml and the brown residue is triturated with isopropyl ether (400 ml). The powder obtained is filtered off and dried in vacuo to give 29 g (purity 75%, determined by HPLC) of the title compound XXVII-IH (E-isomer) as a brown powder; Melting point:> 150 C (decomposition).

ir, KBr IR: v cm max

3300, 1780, 1680, 1630, 1600.

uv: x nm (e;) 282 a86).

45

EtOH, cl%

max nm ^ 1cm

NMR: ô acetone-d6 / CH3 ° H-d4 0 / l) 4 0 (3H, s, OCH3); 5.26 ppm -

(IH, d, J = 4.5Hz, 6-H); 5.43 (2H, d, J = 7Hz, CH, N +); 5.99

(IH, d, J = 4.5Hz, 7-H); 6.5 (IH, m, 3-CH = CH); 6.92 (IH,

s, CHPh,); 7.1 (IH, d, J = 16Hz, 3-CH); 7.35 (10H, m,

Ph-H); 8.36 (IH, s, HCOO); 8.46 and 9.12 (2H, d,

J = 8Hz, Py-H).

B. 7- [2- (5-Amino-l, 2,4-thiadiazoI-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoyl-l-pyridinio) -1-propene-l -yl] -3-cephem-4-carboxylate (I-1H) (E-isomer)

A mixture of XXVII-IH (E-isomer) from stage A (29 g, purity 75%) and 85% formic acid (290 ml) is stirred for 2 hours at room temperature. Evaporation of the mixture gives a brown oil which is triturated with acetone (500 ml). The powder is filtered off, washed with acetone (2 × 100 ml) and dried in vacuo, giving 24 g (purity 50%, determined by HPLC) of the crude title compound. The brown solid is treated twice with 2N HCl (11 and 0.5 1). The aqueous extracts are combined and placed on a column filled with Diaion HP-20 (1.5 l). The column is washed with water (8 1) and eluted with 30% CH3OH (5 1). The fractions containing the desired product are concentrated to approximately 30 ml. The concentrate is treated with acetone (200 ml) to give a precipitate which is filtered off and dried in vacuo. 10.1 g (purity 85%) of the title compound (zwitterion form) are obtained as a yellow powder. N HCl in CH3OH (55 ml) is added to a suspension of this product in CH3OH (100 ml) at room temperature and the mixture is stirred for 30 min. To remove insoluble matter, the clear solution obtained is filtered, concentrated to approximately 50 ml, and isopropanol (200 ml) is added to form a precipitate. The powder obtained is isolated, washed with isopropanol (50 ml) and dried in vacuo to give 10.5 g (purity 85%) of the title compound I-1H (E-isomer) (HCl salt). Melting point:> 180 C (decomposition). Pale yellow powder.

Example 17

7- [2- (5-Amino-1,2A-thiadiazol-3-yl) -2-methoxyiminoacet-amido] - 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl] - 3 -ce-phem-4-carboxylate (I-1H) (E-isomer)

This example illustrates the preparation of the compound I-1H according to the last stages of the reaction schemes la or lb, the intermediate compound XXVII-IH (as format) not being isolated.

A solution of IX-1 (E-Isomeres) (27.6 g, 38.5 mmol) and isonikotinamide (22.8 g, 187 mmol) in a mixture

669 197

34

from CH3Cn (120 ml) and CH3OH (100 ml) is stirred under a nitrogen atmosphere for 1 h at room temperature.

After the organic solvents have been evaporated off, the oily residue is triturated with isopropyl ether, giving 50.5 g of a mixture of quaternized salt and isonicotinamide. A solution of this mixture (50.3 g) and sodium bisulfite (16 g) in 85% HCOOH (160 ml) is stirred for 40 min at room temperature and then under N21 h at 40 ° C. The mixture is evaporated in vacuo. The oily residue is mixed with toluene (50 ml), evaporated azeotropically and triturated with acetone (400 ml to give 27.8 g of the crude title compound. This material is treated twice with 2N HCl (11 and 0.5 l) The acidic extracts are combined and placed on a column of HP-20 resin (1.5 1) and the column is eluted with water (9 1) and 30% methanol (10 1) The fractions containing the desired compound are combined and concentrated to give a yellow oil which is triturated with acetone (300 ml) to give 9.35 g of the title compound as a zwitterion.

To a suspension of this product (9.3 g) in CH3OH (180 ml) is added 1N HCl in CH3OH (55 ml) to give a clear solution. The solution is concentrated to approximately 100 ml and diluted with isopropanol, 9.50 g (purity 75%) of the title compound I-1H (E-Isome-res) precipitating as hydrochloride. Pale yellow, amorphous powder. Melting point:> 195 CC (decomposition).

Example 18

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yi) -2-methoxyiminoacet-amido] - 3- [3- (4-carbamoylpyridinio) - 1-propen-l-yl] - 3-ce-phem-4-carboxylate (I-1H) (E-isomer)

This example explains the last stage (7-N-acylation) according to reaction scheme lc for the preparation of the compound

1-lH.

Sodium bicarbonate is added in small portions to an ice-cooled suspension of 7-amino-cephem hydrochloride XXII-H (E-Isomeres) (5.0 g, 12.6 mmol) in 50% aqueous acetone (100 ml). During the reaction, the pH of the mixture is monitored using a pH meter. Add to the cold neutralized solution (pH about 7)

2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (4.02 g, 15.6 mmol) in small portions over 1 h. The pH of the mixture is maintained in the range of 6.8-7.5 by occasional addition of sodium bicarbonate. The reaction is also followed by TLC. After the compound XXII-H has been completely consumed, the mixture is acidified to pH 3 by adding 2N hydrochloric acid. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is diluted with acetone (400 ml), a precipitate separating out, which is filtered off. 9.59 g of the crude title compound are obtained as a slightly yellow powder. The purity is 40%, estimated using HPLC. A suspension of the crude product (9.5 g) in 2N hydrochloric acid (150 ml) is filtered and the filtrate is then adsorbed onto a column with HP-20 resin (500 ml). After washing with water (1.5 l), the column is eluted with 25% aqueous isopropyl alcohol. The eluate is collected in 100 ml fractions. The desired fractions are combined, acidified with 2 N hydrochloric acid (10 ml) and concentrated. The oily residue is triturated with isopropyl alcohol (200 ml) and the precipitate is filtered off. After drying over phosphorus pentoxide, 5.18 g of the title compound I-1H (E-isomer) hydrochloride is obtained as a yellow, amorphous powder. Melting point:> 190 C (decomposition). Estimated purity: 75%.

Example 19

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

The compound I-1H in the form of the hydrochloride, obtained according to Example 16, is a pale yellow, amorphous powder with a purity of 85%.

Procedure 1

6 g of the 85% hydrochloride are dissolved in 20 ml H20 io and the solution is filtered through a layer of celite. The amber-colored filtrate (pH 2) is passed through a reverse phase column (filled with PrepPAK-500 / C | «cartridge, Waters; 120 ml), which is eluted with water. The eluate is collected in 120 ml fractions, the progress being followed by HPLC *. Fractions 3 to 5 are combined and concentrated to about 10 ml. It is precipitated with acetone (100 ml), giving 3.3 g of I-1 H in the form of the zwitterion (pale yellow, amorphous powder; estimated purity 95%).

20 N HCl in CH3OH (18 ml) is added to a suspension of the 95% powder (3.2 g) in CHjOH (32 ml) and the mixture is stirred at room temperature until a clear solution is obtained. The solution is filtered and the filtrate is concentrated to approximately 10 ml. Isopropanol (100 ml) is added to the concentrate, a pale yellow precipitate separating out, which is filtered off, washed with isopropanol (5 ml) and dried. 2.6 g of the HCl salt (amorphous powder; estimated purity 95%) are obtained.

A solution of the 95% hydrochloride (1 g) in water 30 (4 ml) is adjusted to pH 6.5 with NaHC03 (200 mg) and stirred for 30 min. The crystals deposited during stirring are filtered off, washed with water (2x5 ml) and dried in vacuo, 710 mg of I-1 H (in the form of the zwitterion) being obtained in the form of pale yellow prisms 35. Melting point:> 185 C (decomposition).

According to the microanalysis, it is the trihydrate.

IR: v KBr cm '1780, 1695, 1660, 1630, 1610.

Max

40 UV: A. phosPhatBuffer (PH 7) nm (S) 227 (22000), 290 max '

(23000).

NMR: 6 DMSO "d6 + D20 3 45 (2H b 2H) 3 9 (3H ppm v

45 OCH3); 4.99 (IH, J = 4.5Hz, 6-H); 5.16 (2H, d, J = 7Hz,

CH-.N +); 5.61 (IH, d, J = 4.5Hz, 7-H); 5.8 (IH, d-t, J = 16

and 7Hz, 3-CH = CH); 6.93 (IH, d, J = 16Hz, 3-CH); 8.18

and 8.89 (each 2H, d, J = 7Hz, Py-H).

Analysis for CtiHi0N8O6St3H ^ O: so C "H N" S

calc .: 42.14 4.38 18.72 10.71 found: 42.41 4.35 18.86 11.00

* Column, Lichrosorb RP-18, 4 x 300 mm: mobile phase, 55 0.01 M phosphate buffer (pH 7.2) / CH3OH = 85/15: detection, UV (254 nm).

Procedure 2

If crystalline I-1H obtained according to method 1, 60 is present, it is possible to obtain the crystalline zwitterion form of I-1H directly from the crude I-IH hydrochloride by seeding with some crystals of the pure I-1H.

A solution of the 85% hydrochloride (250 mg) in water (1 ml) is treated with charcoal. The solution is adjusted to pH 6.5 with NaHCO 3 (60 mg) and removed with carbon. The filtrate is inoculated with some of the crystals obtained according to process 1 and stirred overnight at room temperature. The crystals separated off

35

669 197

filtered, washed with water (2x2 ml) and dried under reduced pressure, 170 mg (recovery 80%) of I-1H being obtained in the form of pale yellow prisms (zwitterion form). Melting point:> 185 C (decomposition). This product is identical to the product obtained according to process 1 (according to IR, UV, NMR).

The crystalline zwitterion form of compound I-1H is sparingly soluble in water (6 mg / ml in saline at 23 C).

Example! 20th

(Phosphate buffer, pH 7) 1%) m5 (283) _

max 1 cm

275 sh (280), 292.5 (330).

NMR: 8 (DiO) in ppm 3.75 (2H, s, 2-H); 4.18 (3H, see 5 OCH,): 4.97 "(2H, see Py-CH, OH); 5.35 (IH. J = 4Hz.

6-H); 5.43 (2H, d, J = 6.5Hz. CTL-N); 5.92 (IH, i.e. J = Hz,

7-H); 6.18 (IH, dt, J = 16Hz, J = 6.5Hz, 3 CH = CH 6.97 (IH, d, J = 16Hz, 3-CH); 8.13 (IH, dd, J = 8Hz, J = 6Hz, Py-H); 8.60 (IH, d. J = 8Hz, Py-H); 8.84 (IH, d, J = 6Hz,

10 Py-H); 8.90 (1H.s, Py-H).

Example 21

J | Ul ^

.As / 11 \

- CONH

och3 er N

jz h-oh ch = ch-ch.

i-1k

«E

7-f 2-t 5-amino-1,2 A-thiadiazol-3-yl) -2-methoxyiminoacetamido J-3- [3-f3-hydroxymethylpyridinioì-1-propenyl] -3-ce-pheni-4-carboxyIate (1-1K) (E-isomer) A. Diphenyimethyl-7- [2- (5-amino-l, 2A-thiadiazol-3-yI) -

2-methoxyiminoacetamido] - 3-f 3-3-hydroxymethyIpyridinio) -1-propene vi / - 3-cephem-4-carhoxvlat iodide (E-isomer)

(XII-1K)

To a solution of IX-1 (E-isomer, 1.79 g,

2.5 mmol) in 2.5 ml CH, OH and 7.5 ml CH, CN are added

3-hydroxymethylpyridine (545 mg, 5 mmol) and stir the mixture for 3 h at room temperature. The reaction mixture is poured into ethyl acetate (100 ml) with vigorous stirring. The precipitate obtained is filtered off, washed with a small volume of ethyl acetate and dried, yielding 2.06 g (100%) of the title compound XII-1K as a brown-yellow powder. Melting point: 170-180 C (decomposition).

IR: v KBr cm- '1780. 1725. 1675, 1615, 1530, 1385, fx225, max

1040, 750, 700.

,1%

UV: X (C-FLOH) in nm (E.) 290 (196).

max v - v 1 cm v

NMR: 8 (DMS0 + D, 0) in ppm 3.7 (2H, br.s. 2-H); 3.91

(3H, see OCH,); 4.70 (2H. Py-CFU-OH); 5.28 (2H, m,

CH.-N-); 5.23 (IH. D, J = 5Hz, 6-H); 5.90 (IH, d, J = 5Hz,

7-H); 6.34 (IH. M, 3-CH = CH); 6.86 (IH, d, J = 16Hz,

3-CH); 6.89 (IH, see CHPh-,); 7.35 (10H, m, Ph-H); 7.9-8.9

(4H, m, Pv-H).

B. 7- [2-t 5-Amino-1,2A-thiadiazoI-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-hydroxymethylpyridinio jl-propenyl] -3-cephem-4-carboxylate (I-lKj (E isomer)

A mixture of XII-1K (E-isomer, 2.0 g, 2.4 mmol) and sodium bisulfite (1 g) in 85% HCOOH (10 ml) is stirred for 2 h at room temperature. The reaction mixture is concentrated to about 5 ml under reduced pressure. The oily residue is poured into acetone (100 ml) with vigorous stirring. The precipitate is filtered off, washed with a small amount of acetone and dried to give 1.1 g of a yellow-brown powder. This is purified by column chromatography (using a filling of PrepPAK-500 / C | 8 cartridges (Waters). 283 mg (22%) of I-1K is obtained as an amorphous powder. Crystallization of the powder from 4N H2S04 and acetone yields 144 mg of the title compound I-1K in the form of colorless needles Melting point: 185-188 C (decomposition).

IR: v cm-1 1775, 1680sh, 1660, 1630, 1225, 1045, 850. max onhch,

i-1m

20th

7- [2- (5-Amino-l, 2A-thiadiazol-3-ylj-2- (Z) -methoxyimino-ace tumido] -3- [3- (4-N-methylcarhamoylpyridinio) -l-pro-penyl ] -3-cephem-4-carboxylate (I-1M) (E-isomer)

A mixture of diphenylmethyI-7- [2- (5-amino-l, 2,4-25 thiadiazol-3-yl) - 2-methoxyiminoaeetamido] -3- (3-iodo-l-pro-penyl) - 3- cephem-4-carboxylate (IX-1) (E-isomer, 450 mg, 0.62 mmol) and 4-N-methylcarbamoylpyridine (prepared according to the method by Samejima M. Yakugaku Zasshi, 80, 1706 (1960)) ( 215 mg, 1.58 mmol) in acetonitrile (2 ml) 30 is stirred under a nitrogen atmosphere for 5 h at room temperature. The mixture is evaporated under reduced pressure and the residue is triturated with ether to give 530 mg of the quaternary salt. A mixture of this solid and sodium bisulfite (150 mg) in 85% 35 formic acid (2 ml) is stirred for 4 h and then heated to 40 C for 30 min. The mixture is evaporated under reduced pressure. The residue is triturated with acetone and the crude product is filtered off. The crude product is chromatographed on an HP-20 column (1.5 x 18 cm) chromatogra-40. The column is eluted with water and 30% aqueous methanol. The methanolic eluate is evaporated under reduced pressure and the residue is freeze-dried to obtain 140 mg of an amorphous powder which is further purified by HPLC (column: Li-45 chrosorb RP-18; solvent: 15% CH, OH). The HPLC eluate is freeze-dried to give 60 mg (18%) of the title compound I-1M. Melting point: 180-183 C (decomposition). Estimated purity: 80%.

1760, 1660, 1600.

right KBr IR: v cm so max

Phosphate buffer (pH 7)

nm (s) 230 (22100), 286

UV: X

max (22100).

NMR: 8 (D-.0) in ppm 3.08 (3H, s, CONHCH,): 3.72 (2H, 55 s, 2-H); 4.16 ~ (3H, s, OCH,); 5.35 (IH, d, J = 4.5Hz, 6-H): 5.95 (IH, d, J = 4.5Hz, 7-H): 7.00 (IH. D, J = 16Hz, 3-CH); 8.35 (2H, d, J = 6Hz. Pyridine-H); 9.05 (2H. D = 16Hz, pyridine-H).

60

Example 22

.CT

-conh '

- A * \

65 H2N OCH3

I-lH

ch = ch-ch? (// ^

éo <p oo h

»E / z - 7/1

669 197

36

7- [2- (5-Amino-1,2A-tìrìadiazol-3-y!) - 2-methoxyiminoacetamido] -3- [3- (4-carboxypridinio) - 1-propenyl] -3-cephem-4- carboxylate (I-1N)

To a suspension of isonicotinic acid (340 mg, 2.8 mmol) in dry DMF (3.5 ml) is added, while stirring and under a nitrogen atmosphere, N, 0-bis (trimethylsilyl) acetamide (0.7 ml, 2 , 8 mmoles). Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propenyl) is suddenly added to the clear solution obtained. - 3-cephem-4-carboxylate (IX-1) (E-isomer, 720 mg, 1 mmol). The red solution is stirred for 1.5 h at room temperature. The reaction mixture is added dropwise with stirring to a saturated sodium chloride solution (50 ml) containing sodium thiosulfate (150 mg). The yellow precipitate is filtered off, washed with water and dried, yielding 722 mg of a pale yellow powder. The powder (700 mg) and sodium bisulfite (70 mg) are dissolved in 85% formic acid (5 ml). The solution is left to stand at room temperature for 1.5 hours. The mixture is suspended in toluene (50 ml) and concentrated. The residue is triturated with acetone (70 ml) and the precipitate is filtered off to give 421 mg of a yellow powder. This crude powder (400 mg) is suspended in water (2 ml) and sodium bicarbonate is added to this suspension. The dark solution obtained is adsorbed on a column (50 ml) filled with Prep-PAK / CiS cartridge (Water's System 500). The column is eluted with water (200 ml). The eluate is collected in 10 fractions (20 ml each) and the desired fractions (fractions 4-7) are combined, acidified to pH 3 with 2N hydrochloric acid and concentrated. The residue is triturated with acetone (30 ml). Filtration of the precipitate provides 201 mg (37%) of the title compound I-1N as a yellow powder. E, 'Z = 7/1; Purity 80%. Melting point:> 189 C (decomposition).

m KBr IR: v cm max

1770, 1665, 1600.

UV: À. _ (Phosphate buffer, pH 7) in nm (s) 227 (22500),

lHäX

290 (22100).

NMR: 6 (DiO + NaHCO,) in ppm 3.7 (2H, br.s); 4.15 (3H, s); 5.32 (IH, d, J = 4Hz); 5.39 (2H, d, J = 6 Hz); 6.14 (IH, d-t, J = 15.5 and 6Hz); 7.03 (IH, d, J = 15.5Hz); 8.31 (2H, i.e. J = 7Hz); 8.94 (2H, i.e. J = 7Hz).

Example 23

N r— c -

H2N ^ S / 0CH3

I-IO

-CONH

evaporated at reduced pressure. Trituration of the residue provides 391 mg of crude product, which is purified by chromatography on an HP-20 column (1.5 x 18 cm). The column is eluted with water and 30% aqueous 5 methanol. Evaporation of the methanolic eluate under reduced pressure and subsequent freeze-drying gives 160 mg of an amorphous powder which is further purified by HPLC (column: Lichrosorb; solvent: 10% CH3OH). The HPLC eluate is freeze-dried, 10 giving 50 mg (15%) of the title compound I-IO. Melting point:> 190 C (decomposition). Estimated purity: 75%.

io KBr IR: v cm max

-]

1765, 1670, 1600.

15

UV: À. (Phosphate buffer, pH 7) in nm (s) 235 (20000).

ITlaX

283 (25000).

NMR: 6 (D, 0 + NaHC0,) in ppm 2.2-2.6 (2H. M, -CH -.-); 20 3.1-3.6 (4H, m, -CH, -): 3.72 (2H. S. 2-H); 4.17 (3H, 3H, OCH,): 5.33 (IH, d, J = 4.5Hz, 6-H); 5.90 (IH, i.e. J = 4.5 Hz, 7-H); 6.75 (IH, d, J = 16Hz, 3-CH); 7.65-8.2 (3H, m. Pyridine-H.

30 H, N

CH = CB-CH.

OOH

I-2N

7-f 2-f 5-amino-l, 2 A-thiadiazol-3-yl) -2- (Z jmethoxyimino-acetamiclo] -3- [3- (2.3-cyelopentenopyridinioj-l-propenylj-3-cephem-4 carboxylate (I-10j (E-isomeresj

A mixture of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-l-propenyl) -3-cephem-4 Carboxylate (IX-1) (E-isomer, 450 mg, 0.62 mmol) and 2,3-cyclopentenopyridine (217 mg, 1.83 mmol) in acetonitrile (2 ml) are stirred under a plastic atmosphere for 4 h Room temperature. After evaporation under reduced pressure, the mixture is triturated with ether to give 560 mg of the quaternary salt. A mixture of this solid with 85% formic acid (2 ml) is stirred under nitrogen for 3 h at room temperature and then heated to 40 C for 30 min. The mixture

35 7-f2- (5-amino-l, 2A-thiadiazol-3-yl) -2- (Zi-ethoxyimino-aeet amido] - 3-f 3-f 4-carboxypyridinio) ~ 1-propenyl] - 3- ce-phem-4-carboxylate f 1-2: V, E-isomer i and

7-f 2-f 5-amino-1,2 A-tbiadiazol-3-yl i-2-f Z i-ethoxyimino-40 acelamido] - 3-] 3- (4-carboxypyridinio) - 1-propenyl] - 3-ce-phem-4-carboxylate r 1-2N, Z-isomer 1

To a cooled mixture of BSA (1.0 ml. 4.12 mmol) and isonicotinic acid (506 mg, 4.12 mmol) are added IX-2 (prepared according to preparation example 21) (1.0 g, 45 1.37 mmol) and the mixture is stirred under nitrogen for 2 hours at room temperature. Pour the mixture in 10% Na ^ S ^ O-! (20 ml), whereby 1.3 g of the quaternary salt precipitate, which is filtered off, washed with water and dried. A mixture of this solid and sodium bisulfite 50 (0.3 g) in formic acid) (98%, 5 ml) is heated to 40 C for 1 h and evaporated under reduced pressure. The residue is triturated with acetone. Filtering gives 900 mg of the crude product (E-propenyl isomer: Z-propenyl isomer = 2: 1). The isomer is separated by means of HPLC 55 (column: Lichrosorb: solvent: 15% CH, OH). The faster moving fractions are collected, evaporated under reduced pressure and freeze-dried to give the E-propyl isomer of I-2N (44 mg; yield 6%). Similarly, the slower-running fractions provide the Z-propenyl isomer of I-2N (32 mg; 4% yield).

1.-2N, E-isomer:

Melting point:> 200 C (decomposition).

KBr _ |

cm 1

Max

65 IR: v cm

1765, 1660, 1620, 1380.

UV: l (water) in nm (s) 228 (22200, 291 (23600). Max

NMR: § (D20) in ppm 1.45 (3H, t, J = 6Hz. CH2CH,); 3.72

37

669 197

(2H, s, 2-H); 4.45 (2H, q, CH, CH3); 5.40 (IH, 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).

Example 26

I-2N, Z-isomer:. Melting point; KBr

> 200 C (decomposition).

CH = CH-CH.

?O-

CONH,

cm

1 1760, 1660 (sh), 1620, 1370. (phosphate buffer, pH 7) in nm (s) 225 (22400),

IR; v max UV; X

max 275 (sh, 16000).

NMR: 5 (DiO) in ppm 1.45 (3H, t, J = 7Hz, CH, CH3); 3.50 (IH. D, J = 17Hz, 2-H); 3.75 (IH, d, J = 17Hz, 2-H); 5.38 (IH, d, J = 4Hz, 6-H); 5.95 (IH, d, J = 4Hz, 7-H); 6.62 (IH, d, J = 11Hz, 3-CH); 8.35 (2H, d, J = 6Hz, Py-H); 8.92 (2H, d, J = 6Hz, Py-H).

Example 25

I-4H

10th

15

20th

HjN

A

"iïî

CONH

o o <* H2-ch = CH2

I-3H

©

CH-CH-CH.,

COOc

* E

COMHj

7- [2- (5-Amino-], 2,4-thiadiazol-3-vl) -2- (propen-3-yl-oxyimi-noj-acetamido] -3- [3- (4-carbamoylpyridinio) - l-propenyl] -3-cephem-4-carboxylate (I-3H) (E-isomer)

To a solution of 35 mg (0.08 mol) of 7-amino-3- [3- (4-carbamoylpyridinio) -l- (E) -propenyl] -3-cephem-4-carboxy-lat hydrochloride in 2 ml 50% aqueous acetone is added 52 mg of 2- [5-amino-l, 2,4-thiadiazol-3-yl] - 2- (propen-3-yloxyimino) - acetyl chloride hydrochloride (according to preparation example 25) and the pH of the mixture with 2N Na: CO 3 to 6.5-7.0. The mixture is stirred at room temperature for 1 h, acidified to pH 2 with 1N HCl and concentrated under reduced pressure. The residue is then chromatographed on a column with HP-20 resin, which is eluted with 300 ml of water and 30% CH30H-H20. The fractions containing the product are combined and evaporated under reduced pressure. The residue (73 mg) is purified by means of a reverse phase column, the support of which has been removed from a PrepPAK-500 / C | 8 cartridge (Waters, 30 ml). The column is washed successively with water, 5% CH3OH, 10% CH3OH and 20 % CH3OH cleaned. The product-containing fractions are combined and lyophilized to give 26 mg (62%) of the title compound I-3H. Melting point: 160 C (decomposition).

KBr 3400 ^ 1765 ^ 1680 ^ 1605i 1400

7- [2- (5-Amino-l, 2A-thiadiazol-3-yl} - 2-propargyloxyimino-acetamido] -3- [3- (4-carbamoylpyridinio) - I-propenyl] -3- ce-phern- 4-carboxylate (I-3H) (E-isomer)

To a solution of 86 mg (0.19 mmol) of 7-amino-3- [3- (4-carbamoylpyridinio) - l- (E) -propenyl] - 3-cephem-4-carb-oxylate hydrochloride (XXII-H) 63 mg of 2-propargyloxyimino-2- (5-amino-l, 2,4-thiadiazol-3-yl) acetyl chloride hydrochloride (according to preparation example 26) are added to 2 ml of 50% aqueous acetone. The suspension is kept at pH 6.5-7.0 using 2N Na2C03 and then stirred at room temperature for 1 h. The reaction mixture is acidified to pH 2 with IN HCl and concentrated in vacuo. The residue is diluted with 30 ml of water, neutralized with NaHC03 and filtered. The filtrate is placed on a column which was filled with a reverse phase support (30 ml) taken from a PrepPAK-500 / Cjg-Patro-25 ne (Waters). The column is successively eluted with water, 5% CH3OH, 10% CH3OH and 20% CH3OH. The fractions containing the product are pooled and lyophilized to give 13 mg (12%) of the title compound I-4H. The estimated purity is 70%. Melting point: 160 C.

IR: v KBr cm-1 3400, 2120, 1765, 1680, 1610.

Max

UV: X, (phosphate buffer, pH 7) in nm (s) 229 (24000), ne max

288 (21200).

NMR: 8 (DiO) in ppm 3.78 (2H, s, 2-H); 5.15 (2H, d, J = 1Hz, -CH -.- C s CH); 5.40 (IH, d, J = 5Hz, 6-H); 5.50 (2H, m, CH -N +); 5.98 (IH, d, J = 5Hz, 7-H); 6.20 (IH, m, to 3-CH = CH); 7.05 (IH, d, J = 17Hz, 3-CH); 8.50 (2H, d, J = 7Hz, Py-H); 9.16 (2H, d, J = 7H, Py-H).

Example 27

CH = CH-CH.

COHH,

IR: v cm max

UV: X

max 288 (22800).

(Phosphate buffer, pH 7) in nm (s) 226 (24600),

BNR: 5 (D, 0) in ppm 3.75 (2H, s, 2-H); 5.41 (IH, d, J = 5Hz, 6-H); 5.50 (4H, m, CH, N + and CH = CH,); 5.98 (IH, d, J = 5Hz, 7-H); 6.20 (IH, m, 3-CH = CH); 7.09 (IH, d, J = 17Hz, 3-CH); 8.50 (2H, d, J = 7Hz, Py-H); 9.16 (2H, d, J = 7Hz, Py-H).

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-cyclopentyloxyimino-acetamido) -3- [3- (4-carbamoylpyridinio) -1-propenyl] -3-ce- phem-4-carboxylate (1-5H) (E-isomer)

55 To a solution of 139 mg (0.31 mmol) of 7-amino-3- [3- (4-carbamoylpyridinio) - 1-propenyl] - 3-cephem-4-carb-oxylate hydrochloride in 3.5 ml of 50% Aqueous acetone is added in portions with ice cooling and with stirring, 120 mg (0.44 mmol) of 2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-60 cyclopentyloxyiminoacetyl chloride hydrochloride (according to preparation example 27). The mixture is adjusted to pH 6.5-7.0 with 2N Na2CO3 (0.9 ml) and stirred at 10 CC for 1 h. The reaction mixture is then acidified with IN HCl

669 197

38

pH 2 and evaporated under reduced pressure. The residue is chromatographed on a column with HP-20 resin (20 ml) and eluted successively with 300 ml of water and 30% CH30H-H20. The fractions containing the product are combined and concentrated in vacuo. The residue is treated with 60 ml of acetone to give 111 mg (83%) of the title compound I-5H. Melting point: 160 C (decomposition). Estimated purity:

70%.

T £ over 10

IR: max cm ~ '3400' 1770 '1680' 1605 '153 ° -

UV: X max (phosphate buffer, pH 7) in nm (e) 224 (23300),

286 (24600).

NMR: 5 (DMSO-d6) in ppm 1.70 (8H, br.s, H-Q);

H

4.68 (IH, br.s.) Q);

5.05 (IH, d, J = 5Hz, 6-H); 5.30 (2H, m, CH2N +); 5.67 (IH, d-d, J = 5Hz and 7Hz, 7-H); 6.20 (IH, m, 3-CH = CH); 7.08 (IH, d, J = 17Hz, 3-CH); 8.34 (2H, d, J = 7Hz, Py-H); 9.11 (2H, d, J = 7Hz, Py-H); 9.38 (IH, d, J = 7Hz, 7-NH).

Example 28

15

20th

Umbisulfite (1.1 g) in 85% HCOOH (10 ml) is stirred for 2 h at room temperature. The reaction mixture is concentrated to about 5 ml under reduced pressure. The oily residue is triturated with acetone (100 ml) to give 1.22 g of the crude product which is purified by column chromatography (HP-20, 420 ml). 533 mg of the title compound I-IP (38% from IX-1) are obtained as a pale yellow, amorphous powder. Melting point: 165 C (decomposition).

K Rr

IR: v ™ "cm- '1770, 1670, 1600, 1530, 1385, 1140, 1040.

ITlaX

UV; x phosphate buffer (pH 6.2) nm 1%

max v 1 cm v

277sh (390), 290 (402).

NMR: § (DiO + NaHC03) in ppm 3.78 (2H, s, 2-H); 3.92 (2H, s, Py-CHoCO); 4.22 (3H, s, OCH3); 5.40 (IH, d, J = 4Hz, 6-H); 5.44 (2H, d, J = 6.5Hz, -CH, -N +); 5.97 (IH, d, J = 4Hz, 7-H); 6.20 (IH, d-t, J = 16 and 6 ~, 5Hz, 3-CH = CH); 7.08 (IH, d, J = 16Hz, 3-CH); 8.11 (IH, d-d, J = 8 and 7Hz, Py-H5); 8.53 (IH, d, J = 8Hz, Py-H4); 8.82 (IH, d, J = 7Hz, Py-Hfi); 8.86 (IH, s, Py-H2).

Example 29

25 N rC -

jTX

c — conh-

"Ì

och3 er n r-c - conh — i f s i

H V ",

2 3 docp

CHjCOOH

30th

NV ^ "= CH-CH®NfAS-CH2COOf cocß \ = / 2

I-IQ * E

I-IP

35

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido J-3- [3- (3-carboxymethylpyridinio) -1-propenyl] 3-ce-phem-4 -carboxylate (I-IP) (E-isomer) A. Diphenylmethyl-7- [2- (5-amino-l, 2,4-tliiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- ( 3-carboxymethylpyridinio) - 40 1-propenyl] -3- cephem-4-carboxylate (XII-1P, iodide, E-isomer)

To a suspension of 3-carboxymethylpyridine-hydrochloride (0.9 g, 5 mmol) in 10 ml CH2C12, add N, 0-bis (trimethylsilyl) acetamide (4.97 ml, 18 mmol). The mixture is stirred at room temperature until a clear solution is obtained. IX-1 (1.79 g, 2.5 mmol) is added to this solution and the mixture is left to stand at room temperature. After 3 h, 3 ml of CH3OH are added to the cooled mixture and the solution is evaporated in vacuo to give an oil which is triturated with ethyl acetate. This gives 2.28 g of the title compound XII-1P as a tan powder. Melting point: 161 C (decomposition).

1780, 1720, 1675, 1630, 1530, 1385, 1225,

tu KBr IR: v cm max

1045,755,700. , 0 /

UV: X (C, H5OH) in nm (E, / o) 295 (188).

max v - 3 v 1 cm 'v

NMR: 5 (DMSO + DiO) in ppm 3.70 (2H, br.s, 2-H); 3.90

(5H, s, OCH3 and Py-CH, CO); 5.25 (3H, m, -CH, N + and

6-H); 5.92 (IH, d, J = 4.5 Hz, 7-H); 6.35 (IH, m,

3-CH = CH-); 6.90 (IH, d, J = 16Hz, 3-CH); 6.92 (IH, s,

CHPh2); 7.35 (10H, m, Ph-H); 8.8-9.0 (4H, m, Py-H).

B. 7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (3-carboxymethylpyridinio) -1-propenyl] -3- cephem-4-carboxylate (I-IP) (E-isomer)

A mixture of XII-1P (iodide) (2.28 g) and sodium

55

60

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacet-amido] - 3- [3- (4-carboxymethylthiopyridinio) - 1-propenyl] -3-cephem- 4-carboxylate (I-IQ) (E-isomer) A. Diphenylmethyl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yi) -

2-methoxyiminoacetamido] -3- [3- (4-carboxymethylthiopyridi-nio) - 1-propenyl] -3- cephem-4-carboxylate (XII-1Q, iodide, E-isomer)

To a suspension of 4-carboxymethylthiopyridine (0.88 g, 5 mmol) in 10 ml of CH2C12, add N, 0-bis (trimethylsilyl) acetamide (5 ml, 18 mmol) and stir the mixture at room temperature until you get a clear solution. IX-1 (E-isomer 1.79 g, 2.5 mmol) is added to the solution and the mixture is left to stand at room temperature. After 3 h, 3 ml of CH3OH are added to the cold mixture and the solution is evaporated in vacuo to give an oily residue which is triturated with ethyl acetate. This provides 2.43 g of the title compound XII-1Q (iodide) as a tan powder. Melting point: 155 C (decomposition).

IR: v KBr cm "1 1780, 1720, 1670, 1625, 1525, 1385, 1225, max

1115, 1040, 755, 700.

UV: A. (G> H5OH) in nm (e!%) 312 (299). max - 3 '1 cm from

NMR: 5 (DMSO-dg + D-, 0) in ppm 3.70 (2H, br.s, 2-H);

3.93 (3H, s, OCH3); 5.07 (2H, m, CH -, - N +); 5.23 (IH, d,

J = 5Hz, 6-H); 5.90 (IH, d, J = 5Hz, 7-H); 6.29 (IH, m,

3-CH = CH); 6.87 (IH, d, J = 16Hz; 3-CH); 6.91 (IH, s, CHPhi); 7.35 (10H, m, Ph-H); 7.88 and 8.58 (each 2H, d, J = 6Hz, Py-H).

65

B. 7- [2- (5-Amino-l, 2, '4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carboxymethylthiopyridinio) -l-propenyl] -3 -cephem-4-carboxylate (I-IQ) (E-isomer)

A mixture of XII-IQ (iodide, 2.43 g) and sodium bisulfite (1.1 g) in 85% HCOOH (10 ml is stirred for 2 h at room temperature. The reaction mixture is concentrated

39

669 197

reduced pressure to about 5 ml. The oily residue is triturated with acetone (100 ml), filtered and dried to give a crude product (1.39 g) which is purified by column chromatography (HP-20, 20 ml). 577 mg of the title compound I-IQ (39% from IX-1) are obtained as a pale yellow, amorphous powder. Melting point: 188 C (decomposition).

1765, 1670, 1625, 1530, 1380, 1110, 1035.

io KBr IR: v cm max

UV: A. Phosphate buffer (pH 6.2) Qm (£ 1%

Max

1 cm i 234 (459), 310

(678).

NMR: 8 (D, 0 + NaHC0,) in ppm 3.79 (2H, br.s., 2-H); 4.10 (2H, s, S-CH,); 4.23 (3H, s, OCH,); 5.25 (2H, d, J = 6.5Hz, CHU-N-); 5.39 (IH, d, J = 4.0Hz, 6-H); 5.97 (IH, d, J = 4Hz, 7-H); 6.18 (1H, d-t, J = 15.5Hz and 6.5Hz, 3-CH = CH); 7.05 (IH, d, J = 15.5Hz, 3-CH); 7.84 and 8.55 (each 2H, d, J = 7Hz, Py-H).

Example 30

Hl "

H, N '^ OCH,

N

X

'CONH

I-1A

TT 1 •

/ -n \ ^ ch = cocß

H3C \ © / 1

: = CH-CH, -N

\ J

* E / Z «7/1

7- [2- <5-amino-l, 2 A-thiadiazol-3-yl / -2-methoxyiminoacetamido] - 3- [3-t l-methylpyrrolidinioj-1-propenyl] - 3-cephem-4-caroxylate sulfate ( 1-1A, sulfate j A. Diphenylmethyl-7- / 2- (5-amino-1,2A-thiadiazol-3-yl) -2-methoxyiminoacetamidoJ-3-] 3- (1-methylpyrrolidinio) -1-propenyl ] - 3-cephem-4-carboxylate (XII-1A, iodide)

In a cold solution of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-propenyl) -3-cephem-4 carboxylate (IX-1) (according to preparation example 14 (21.5 g, 30 mmol) in ethyl acetate (300 ml), a solution of 1-methylpyrrolidine (2.55 g, 30 mmol) in ethyl acetate (30 ml) is added dropwise for 1 h with stirring at -5 ° C. After stirring for a further 10 minutes, the precipitate obtained is filtered off and washed with chloroform (200 ml), giving 23.0 g (95.8%) of the title compound (IX-1A, iodide) Melting point:> 175 C (decomposition).

td kbr

IR: v cm max

-i

3300, 1780, 1730, 1685, 1615., 1%

UV: A. (C-> H ^ OH) in nm (E,) 218 (435, 295 (188). Max v v 1 cm '

B. Diphenylmethyl-7- [2- (5-amino-1,2A-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (1-methylpyrrolidmio) -1-propenyl] -3-eephem- 4-carboxylate (XII-1A, chloride)

Compound XII-1A (iodide) (23 g, 28.7 mmol) is dissolved in a mixture of acetone and methanol (1: 1, 230 ml) and the mixture is placed on an Amberlite IRA-410 column (chloride form, 230 ml), which was pretreated with the same solvent mixture. The column is developed with the solvent and the fractions containing the desired compound are combined and concentrated to an oily residue which is triturated with ethyl acetate (300 ml). 17.9 g (87.7%) of the title compound (XII-1A, chloride) are obtained. Melting point: 190 C (decomposition). -

TD KBr IR: v cm max

UV: A.

3380, 1780. 1680, 1620.

,1%

C. 7- [2- (5-Amino-l, 2A-thiadiazol-3-yl) -2-methoxyimino-. ace tumido] - 3- [3- (l-methylpyrrolidinioj-1-propenyl] - 3-ce-phem-4-carboxylate sulfate (I-1A, sulfate)

A mixture of compound XII-1A (chloride; 17.8 g, 5.25 mmol) in 85% formic acid (178 ml) is stirred under a nitrogen atmosphere at room temperature for 2 h. The mixture is evaporated in vacuo and the oily residue is triturated with acetone, giving 9.80 g of the crude compound I-1A. Concentration of the filtrate and the acetone-10 wash water give a further 2.95 g of crude I-1A. The two batches of crude product are combined and extracted with 2N HCl (1 1 and 0.5 0). The combined extracts are adsorbed on Diaion HP-20 resin (1.5 1 column). The column is washed with water and 30% aqueous The 15 fractions are combined and evaporated in vacuo to give an oily residue which is triturated successively with isopropanol (200 ml) and acetone (200 ml) to give 7.09 g of a pale yellow powder Material (6.80 g) is dissolved in water (20 ml) and then subjected to column chromatography, the column being filled with Prep-PAK-500 / Cis cartridge (90 ml) using water as the eluent and 10% aqueous methanol. The eluate is collected in 20 ml fractions, using HPLC (column, Nucleocil SSC-25 ODS-262, 8 x 100 mm; mobile phase, 0.0IM phosphate buffer (pH 7, 2) / CH3OH = 90:10, detection, UV (254 nm) followed, fractions 4 to 10 are combined, evaporated under reduced pressure and lyophilized ilized, 2.28 g of a yellow powder (E / Z = 7/1, purity 70%) being obtained 30 [batch 1], fractions 11 to 85 are worked up in the same manner as described above, giving 3, 27 g of a yellow powder (E / Z = 5/1, purity 70%) are obtained [batch 2], part of batch 1 (1.0 g) is obtained by renewed chromatography on a Prep-PAK-500 / C18 cartridge ( 90 ml) -35 pack cleaned. The column is successively eluted with water and 5% aqueous methanol. The eluate containing the desired compound is concentrated and lyophilized, giving 638 mg (E / Z = 7 / l, purity 80%) of a yellow powder. Another part of batch 1 40 (1.14 g) is worked up in the same way, 880 mg (E / Z = 7/1, purity 80%) of a yellow powder being obtained. The two cleaned samples are combined and part of them (1.45 g) is dissolved in 1N sulfuric acid (5 ml). The solution is diluted with acetone 45 (315 ml) with stirring. Filtering off the cream-colored precipitate provides 1.48 g of the title compound (I-1A, sulfate) (E / Z = 7/1, purity 80%). Melting point:> 185 C (decomposition).

IR: v5B.r cm- '3380, 3000, 1765, 1675, 1630, 1535, 1390,

Max

50 1115.

55

60

UV: A, PhosPhatBuffer (PH 7) nm (g) 236 (19900), 291.5 max

(22500).

NMR: 8 (D20 + NaHC03) in ppm 2.36 (4H, br.,

Qj); 3.15 (3H, s, CH3 ± iQ);

't \); 3.

3.62 (5H, br. 2-H and

83 (IH, br., 2-H); 4.13

(2H, d, J = 8Hz, CH-> N +); 4.22 (3H, s, OCH3); 5.39 (IH, d, J = 4.5 Hz, 6-H); 5.96 ~ (1H, d, J = 4.5Hz, 7-H); 6.00 (IH, m, 65 3-CH = CH); 6.67 (1./8H. D, J = 10Hz, 3-CH, ice); 7.04 (7 / 8H, d, J = 16Hz, 3-CH, trans).

Max

(C2H5OH) in nm (E * ^) 220 (369), 290 (232).

669 197

40

Example 31

I-ID * E / Z »10/1

7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3-trimethylammonio-1-propenyl] -3-cephem-4-carboxylate (I. -lD)

A. Diphenylmethyl-7- [2- (5-amino-l, 2,4-thiacliazol-3-yl) -2-methoxyiminoacetamido] -3- (3-trimethylammonio-l-propenylyl-3-cephem-4 -carboxylate (XII-1D, iodide)

To a solution of 13.0 g (19 mmoles) of diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- (3-iodopropenyl ) -3-cephem-4-carboxylate (IX-1, from preparation example 10), in 38 ml of dry ethyl acetate, 1.75 ml (19.1 mmol) of 1.1N trimethylamine in ethyl acetate are added at -5 ° C. and the mixture is stirred Mixture for 1 h at -5 ° C. The precipitate obtained is filtered off, washed thoroughly with CHC13 and dried, 12.5 g (88%) of the title compound (XII-1D) being obtained in the form of the iodide.

IR: v KBr cm- '3300, 1765, 1720, 1665.

Max

UV: X max (c2h5oh) in nm (s) 300 (18400).

B. Diphenylmethyl-7- [2- (5-amino-1,2A-thiadiazol-3-ylj-2-methoxyiminoacetamido7- 3-f 3-trimethylammonio-l-propenyl) -3-cephem-4-carboxvlate (XII- 1D, chloride J.

The iodide (XII-1D, 12.5 g) is dissolved in 60 ml CH3OH acetone (1: 1) and passed over a column filled with an ion exchange resin [IRA-410 (Cl-), 125 ml]. The column is eluted with 300 ml of CH3OH acetone (1: 1). The eluate is evaporated in vacuo and triturated with 300 ml of isopropyl ether, giving 10.4 g (91%) of the quaternary salt (XII-1D, chloride).

IR: vKBr cm- '3300, 1765, 1710. 1665.

Max

UV: X max (C2H5OH) in nm (e) 298 (15100).

C. 7- [2- (5-Amino-l, 2A-thiadiazol-3-yl) -2-methoxyimino-acetamidoJ-3- [3-trimethylammonio-l-propenyl] -3-eephem-4-carboxylate (1st -1D, sulfate, E isomer)

A solution of 10.4 g (16.0 mmol) of XII-1D (chloride) in 20.8 ml of 85% formic acid is allowed to stand for 3 hours at room temperature and then concentrated in vacuo. The residue is treated with 210 ml of isopropanol, the precipitate is filtered off. The solid (10.1 g) is triturated with 210 ml of water and neutralized with sodium bicarbonate. The suspension is filtered off and the filtrate is chromatographed on an HP-20 column (300 ml), which is eluted successively with water (1000 ml), 10% CH3OH (200 ml) and 30% CH3OH (150 ml). The fractions containing the desired product are combined and concentrated under reduced pressure. The residue is purified by reverse phase chromatography. The column is filled with the contents of a PrepPAK-500 / C | S cartridge (Waters, 200 ml). It is eluted successively with water (600 ml) and 30% CH3OH (200 ml), and then the fractions containing the desired product are concentrated, giving 2.52 g (18%) of the title compound. A solution of the zwitterion (1.5 g) in IN H2SO4 (5 ml) is added in portions to 300 ml of acetone, the precipitate obtained is filtered off and dried. The

Yield of I-1D sulfate is 1.42 g (80%). The ratio E / Z is approximately 10/1, determined by HPLC.

IR: v KBr cm- '3380, 1765, 1665.

max uv.phosphate buffer (pH 7) in nm (g), 3? (19m 293

max (22400).

NMR: § (D-.0) in ppm 3.25 (9H, see N + -CH3); 3.94 (2H, s, 2-H); 4.14 (2H, d, J = 7Hz, CH-, N +); 4.23 (3H, s, 0-CH3); 5.42 (IH, d, J = 4.5 Hz, 6-H); 6.00 (IH, d, J = 4.5Hz, 7-H); 6.23 (IH, d-t, J = 7 and 16Hz, 3-CH = CH); 7.23 (IH, d, J = 16Hz, 3-CH).

Example 32

I-lH »E

7- [2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacet-amido] - 3- [3- (4-carbamoylpyrid'mio) -l-propenyl] - 3- cephem-4-carboxylate fl-1H, E-isomer)

To a mixture of 7-amino-3- [3- (4-carbamoylpyri-dinio) -l - (E) - propenyl] -3-cephem-4-carboxylic acid hydrochloride (XXII-H, 397 mg, 1 mmol) and NaHC03 (168 mg, 2 mmol) in aqueous DMF (water, 3.5 ml and DMF, 7.5 ml) are added benzotriazol-l-yl-2- (5-amino-1,2,4- thia-diazol-3-yl) - 2-methoxyiminoacetate (479 mg, 1.5 mmol) (from preparation example 28). The mixture is stirred for 3.5 h at room temperature. The reaction mixture is adjusted to pH 3-4 with 3N HCl and diluted with 200 ml of acetone. A precipitate is formed which is filtered off. The crude product is dissolved in a small volume of aqueous THF. The solution is adjusted to pH 6.8 with NaHCO, treated with carbon for decolorization, concentrated to about 1 ml and inoculated with crystalline I-1H with a few crystals. The mixture is stirred overnight and the crystalline precipitate is filtered off, giving the title compound I-1H (zwitterion). Yield 83 mg (16%). Melting point:> 185 C (decomposition). The physicochemical data of this compound are identical to those of the compound obtained according to Example 10.

Production Example 1 Diphenylmetlni-7-f2-f 5-amino-1,2,4-thiadiazol-3-yl J-2-methoxyiminoacetamido] - 3-chloromethyl-3-cephem-4-carh-oxylate "(IV-1)

To a suspension of 2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-l) (2.1 g, 10 mmol) in dry CH2C12 (50 ml) is added with stirring PC'l5 (2.09 g, 10 mmol) at -30 C and the mixture is stirred for 20 min at -15 to -20 C. To this acid chloride solution is added a solution of diphenylmethyl-7-amino at -30 C 3-chloromethyl-3-cephem-4-carboxylate hydrochloride (II) (4.5 g, 10 mmol) in CH2C12 (50 ml), the N, 0-bis (trimethylsilyl) acetamide (10 g, 50 mmol) contains. After stirring at -10 C for 1 hour, the mixture is concentrated to remove CH2C12 and diluted with ethyl acetate (200 ml). The mixture is washed successively with 10% aqueous NaHCO (2 x 40 ml), H20 (2 x 20 ml) and brine (10 ml) and dried over MgSO4. The solvent is evaporated in vacuo and the oily residue obtained (10 g) is dissolved in CHC13 (20 ml) and on silica gel (Wako-Gel C-200, 100 containing 10 ml of 1 / 1.5 M pH 7 phosphate buffer) Use of 1-3%

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

41

669 197

CH, OH-CHCI3 chromatographed. The fractions containing the title compound are evaporated to give 5.7 g (95%) of IV-1 as a yellow, amorphous powder. Melting point:> 140 ° C (decomposition).

IR: v

KBr max cm- '3300, 1780, 1720, 1680, 1620.

UV: 1 maxH nm (s) 245 (1800) '280 (9900) -

NMR: 5

DMSO-d6 max

3300, 1780, 1725, 1680, 1620.

3.53 (2H, ABq, 2-H); 3.94 (3H, s,

OCHj); 4.42 (2H, s, 3-CH,); 5.22 (IH, d, J = 4.5, 6-H); 5.92 (IH, d-d, J = 4.5 and 6, 7-H); 6.93 (IH, s, CHPh,); 7.36 (10H, m, Ph-H); 8.1 (2H, br-s, NH,); 9.58 (IH, d, J = 6,7-NH).

Production Example 2 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl j-2-methoxviminoacetamido] - 3-iodomethyl-3-cephem-4-carboxy-lat (V-l)

A mixture of IV-1 from preparation example 1 (5.7 g, 9.5 mmol) and NaI (4.3 g, 29 mmol) in dry acetone (50 ml is stirred for 5 min at room temperature. The mixture is concentrated under reduced pressure Pressure and shake the resulting oil with a mixture of ethyl acetate (100 ml) and H20 (10 ml) The organic layer is separated and washed successively with 10% w / v sodium thiosulfate and brine Ethyl acetate removed in vacuo to give 6.1 g (93%) of the title compound VI) as a yellow, amorphous powder. Melting point:> 120 ZC (decomposition).

TD KBr IR: v cm max

UV: X nm (e) 245 (17000), 282 (12000).

NMR: S p ^ S ° "d6 3.72 (2H, ABq, 2-H); 3.94 (3H, s,

OCH,); 4.23 (2H, s, 3-CH,); 5.21 (IH, d, J = 4.5, 6-H); 5.89 (IH, d-d. J = 4.5 and 6, 7-H); 6.94 (IH, s, CHPh,); 7.35 (10H, m, Ph-H); 8.12 (2H, br-s, NH,); 9.65 (IH, d, J = 6,7-NH).

Preparation Example 3 Diphenylmethyl-7-f 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3-triphenylpliosphoniomethyl-3-ce-phem-4-carboxylate-iodide (VI- 1 )

A mixture of V-1 from preparation example 2 (690 mg, 1 mmol) and triphenylphosphine (786 mg,

3 mmol) in ethyl acetate (20 ml) is stirred at room temperature. The solid which has separated out is isolated, washed with ethyl acetate (2 × 10 ml) and dried, yielding 950 mg (100%) of the phosphonium iodide VI-1. Melting point: 186 C (decomposition).

io KBr IR: v cm max

UV: X Et0H nm (s) 268 (15000), 275 (13000), 300 (7300). Max

3300, 1780, 1710, 1680, 1610.

NMR; 6

DMSO-d6 ppm

3.52 (2H, br-s, 2H); 3.94 (3H, s,

OCH,); 5.34 (IH, d, J = 4.5, 6-H); 5.9 (IH, m, 7-H); 6.3 (IH, s); 7.3 (10H, m, Ph-H); 7.8 (15H, m, Ph-H).

Production Example 4 Diphenylmethyl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [(triphenylphosphoranylidene) methyl] -3-cephem-4-carboxylate ( VII-1)

A mixture of VI-1 from preparation example 3 (952 mg, 1 mmol), Amberlite IRA-410 (OH- form,

500 mg) and N NaOH (4 ml) in CH, C1, (10 ml) are stirred for 1 h at room temperature. The mixture is filtered, the separated organic layer is dried over MgSO4 and concentrated under reduced pressure. The oil obtained is triturated with ethyl acetate and the yellow precipitate formed is filtered off, giving 740 mg (90%) of the title compound VII-1. Melting point:> 180 C (decomposition).

KBr cm "1 3400, 1750, 1630.

IR: v

10th

UV: X

max EtOH

max nm (s) 268 (12000), 276 (10000), 284 (23000).

Production Example 5 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-15 methoxyiminoacetamidoJ-3- (3-chloro-l-propen-l-yl) -3- ce-phem-4-carboxylate (Vili-1)

MgSO 4 (3 g) and 40% chloroacetaldehyde (810 mg, 8.4 mmol) are added to a solution of VII-1 from preparation example 4 (6.9 g, 8.4 mmol). The mixture is stirred for 1.5 hours at room temperature and then filtered. The filtrate is eluted from a silica gel column (Wako-Gel C-200, 100 g containing 10 ml 1 / 1.5 M phosphate buffer) using CHC13 and CHC13 containing CH3OH. The 25 fractions containing the desired product (0.5-1% CH3OH-CHCI3) are evaporated in vacuo to give 1.6 g (30%) of the title compound VIII-1 as a yellow, amorphous powder. This powder is a mixture of the Z and E isomers with respect to the chloropropenyl radical (Z / E = 2/1, by means of NMR). Melting point: 30> 130 ° C (decomposition).

ir »KBr IR: v cm max

3300, 1780, 1725, 1680, 1620.

35

UV: X nm (e) 240 (20000), 286 (12000).

NMR: S ^ so'd6-r ^ 2 ^ 3 56 and 3 8 (ni (2_H); 3.94 (3H,

DMSO-d6 + D, 0 ppm s, OCH3); 4.16 (d, J-7.5, CH2C1); 5.26 (IH, d, J = 4.5, 6-H) 5.87 (IH, 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-H); 6.81 (2 / 3H, s, CHPh2) 40 6.92 (1 / 3H, s, CHPh,); 7.4 (10H, m, Ph-H).

Preparation Example 6 Diphenylmethyl ~ 7-benzylidenamino-3- [(triphenylphosphorylanylidene) - methyl -] - 3-cephem-4-carboxylate (XVI) 45 To a solution of Diphenylmethyl-7-benzylidenamino-no-3- [(triphenylphosphonio ) - methyl] -3-cephem-4-carboxy-lat-iodide (XV) [prepared according to the method of published Japanese patent application (Kokai) 56-86187 (7/31/81)] (60 g, 70 mmol) in CH2C12 (350 ml) are added to NaOH (140 ml) and Amberlite IRA-410 (OH form, 35 g) at 5 ° C. The mixture is stirred at 5 ° C. for 1 h and filtered. The organic layer is separated, dried over MgSO4, concentrated to a volume of approximately 100 ml and mixed with ethyl acetate (500 ml) to form a precipitate 55. The yellow solid obtained is filtered off and dried in vacuo to give 48 g (94%) of the title compound XVI. Melting point: 195-198 DC (decomposition).

IR: vKBr cm-'1770, 1620.

Max

60

Production Example 7 Diphenylmethyl-7-benzylidenamino-3- (3-chloro-l-propen-l-yl) -3-cephem-4-carboxylate (XVII)

To a solution of XVI from preparation example 6 65 (2.9 g, 4 mmol) in a mixture of CH, C12 (40 ml) and H20 (10 ml), anhydrous chloroacetaldehyde (800 mg) is added with stirring at room temperature. Three additional portions are added to this mixture over a period of 1 hour

669 197

42

800 mg of chloroacetaldehyde, keeping the pH of the mixture between 6 and 9 by adding N NaOH. After 15 minutes, the aqueous layer is separated off and the organic layer is dried over MgSO4. Evaporation of the solvent gives a red oil which is dissolved in a mixture of ethyl acetate and isopropyl ether (1/2, 80 ml). The solution is washed successively with saturated aqueous NaHCO 3 (10 ml) and H 2 O (10 ml). After drying over MgSO4, 3.3 g of a yellow oil are obtained by removing the solvent. A solution of the oil in CH2C12 (50 ml) is filtered using silica gel (12 g, Wako-Gel C-200) containing 1 / 1.5 M phosphate buffer (1.2 ml, pH 6.4). The silica gel is washed with CH2C12 (50 ml). The filtrate and the wash water are combined and evaporated to dryness. The residue is triturated with n-hexane to give 1.7 g (80%) of the title compound (XVII) as a yellow powder. It can be seen from the NMR spectrum that the chloropropenyl radical has a Z configuration. Melting point:> 50 ° C (decomposition).

IR: vKBr cm-1 3400, 1775, 1720, 1630.

Max

UV: X Et0H nm (s) 253 (11000), 258 (11000), 265 (10000), max

273 (8300), 281 (7000), 290 (6300).

NMR: S DMS0-d6 ppm

Cl); 5.42 (2H, m, 6-H and 3-CH = CH); 5.72 (IH, d, J = 4.5, 7-H); 6.27 (IH, d, J = 11, 3-CH); 6.85 (IH, s, CHPh,); 7.33 (10H, m, Ph-H).

Preparation of anhydrous chloroacetaldehyde Anhydrous calcium chloride is added to a chilled solution of 50% aqueous chloroacetaldehyde (50 ml) with stirring to separate into two layers. The chloroacetaldehyde hydrate layer (1) (upper layer) is separated and diluted with CHC13 (100 ml), mixed with MgS04 (20 g), heated under reflux for 5 min and filtered. The solvent and water are removed azeotropically (b.p. 56-64 ° C) (2) and the residue is distilled to give anhydrous chloroacetaldehyde'31. Bp 70-82 ° C / 760 mm.

3.63 (2H, br-s, 2-H); 4.0 (2H, m, CH, -

Tr) Film IR: v cm max

1720.

IR: v KBr cm-1 3400, 1770, 1720.

Max

UV: X Et ° H nm (e) 252 (3700), 258 (3800), 260 (4000), 274 5 (4000), 285 (4000).

Production Example 9 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl} -2-methoxyiminoacetamido] -3- (3-chloro-l-propen-l-yl) -3- ce-10 phem-4-carboxylate fVIII-1)

A mixture of 2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-l) (10.1 g, 50 mmol) and PC15 (10.4 g, 50 mmol ) in dry CH2C12 (100 ml) is stirred for 2 h at -7 to -15 ° C. The clear solution is poured into n-15 hexane (500 ml), a precipitate forming. The organic layer is decanted off and the remaining solid is triturated with n-hexane (100 ml). The yellow precipitate is filtered off and dried in vacuo to give 12.5 g (99%) of the acid chloride. Melting point: 20 80 ° C (decomposition).

IR: v Nu-'olcm-1 1770.

Max

The acid chloride (25 mg, 0.1 mmol) is added with stirring at room temperature to a solution of XVIII (Z-25 isomer) from preparation example 8 (44 mg, 0.1 mmol) in dry CH2C12 (5 ml). After 30 min the mixture is concentrated under reduced pressure and diluted with ethyl acetate (20 ml) and saturated aqueous NaHCO 3 (5 ml). The organic layer is washed with saturated aqueous NaHCO 3 (5 ml), brine (5 ml), 10% HCl (5 ml) and brine (5 ml). The solvent is dried over MgS04 and then concentrated to dryness, the product being obtained in the form of a yellow foam. The foam is purified by column chromatography on silica gel (Wako-Gel C-200, 1 g, containing 0.1 ml of 1 / 1.5 M phosphate buffer pH 6.4) and elution with CH2C120H (100: 1). 31 mg (50%) of the title compound VIII-1 (Z isomer) are obtained as a yellow powder. Melting point:> 150 ° C (decomposition).

40 IR: v Kbr cm-1 3400, 1775, 1720, 1675, 1630.

Max

UV: X Et ° H nm (s) 240 (17000), 280 (10000).

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

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

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

Production Example 8 Diphenylmethyl-7-amino-3- (3-chloro-l-propen-l-yl) - 3-ce-phem-4-carboxylate (XVIII)

A solution of XVII from preparation example 7 (180 mg, 0.34 mmol) in ethyl acetate (10 ml) is added at 5 C to a solution of Girard T reagent [(carboxymethyl) trimethylammonium chloride hydrazide] (251 mg, 1.5 mmol) in CH3OH (10 ml) containing acetic acid (0.25 ml). After stirring at 5 ° C. for 30 minutes, the mixture is concentrated to remove the CH3OH and ethyl acetate (20 ml) is then added. The ethyl acetate solution is washed successively with H20 (2x5 ml), saturated aqueous NaHC03 (5 ml) and brine (5 ml) and dried over MgSÒ4. Evaporation of the solvent gives 145 mg (97%) of the title compound XVIII (Z isomer) as a yellow powder. Melting point:> 100 C (decomposition).

45

NMR: 5

DMSO-d6 ppm

3.6 (2H, m, 2 -H); 3.92 (3H, s, 0-CH3);

4.0 (2H, m, CH, C1); 5.27 (2H, m, 6-H and 3-CH = CH); 5.83 (IH, d-d, J = 4.5 and 10.7H); 6.25 (IH, d, J = 11,

3-CH); 6.83 (IH, s, CHPh,); 7.33 (10H, m, Ph-H); 8.0 (2H, br-s, NH,); 9.57 (IH, d, J = 10, 7-H).

50

Production Example 10 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cephem-

4-carboxylate (IX-1)

55 A solution of VIII-1 from preparation example 5 (Z / E = 2/1, 480 mg, 0.77 mmol) in dry acetone (10 ml), which contains NaI (346 mg, 2.3 mmol), becomes 30 min stirred at ambient temperature. The reaction mixture is evaporated under reduced pressure. The oil 60 obtained is partitioned between ethyl acetate (50 ml) and water (10 ml). The upper layer is successively with 10% w / v. aqueous sodium thiosulfate solution (10 ml) and brine (10 ml) and dried over MgSO4. Evaporation of the solvent yields 540 mg 65 (98%) of the title compound IX-1 (Z / E = 1/1) as a reddish, amorphous solid. Melting point:> 120 C (decomposition).

IR: v KBr cm-1 3300, 1780, 1720, 1680, 1620.

Max

43

669 197

UV: 1 mSH nm (£) 240 (21000 ^ 290 (1200 °) -

nmr: 5

DMS0 + D20 ppm

3.67 (2H, m, 2 -H); 5.29 (1H, i.e.

J = 4.5, 6-H); 5.95 (1H, d, J = 4.5, 7-H); 6.27 (1 / 2H, d, J = 11,

3-CH ice); 6.72 (1 / 2H, d, J = 16, 3-CH trans); 6.87 and 6.96 (1/2 H, s, CHPh2 each); 7.4 (1QH, m, Ph-H).

Preparation Example 11 Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cephem-

4-carboxylate (IX-1)

A mixture of Vili] (Z isomer) from preparation example 9 (5.6 g, 9 mmol) and NaI (4 g, 27 mmol) in dry acetone (100 ml) is stirred for 1.5 h at room temperature. The mixture is evaporated and the oil obtained is diluted with ethyl acetate (90 ml). The ethyl acetate layer is 10% w / v. aqueous sodium thiosulfate solution (10 ml) and H20 (10 ml). Removal of the dried (MgS04) solvent gives a yellow oil which solidifies by trituration with isopropyl ether. Filtering off the solid gives 4.3 g (67%) of the title compound IX-1 as the E isomer. Melting point:> 165 C (decomposition).

IR: vKBr cm-'3400, 1780, 1725, 1680, 1610.

Max

UV: X Et ° H nm (e) 240 (18000), 297 (11000).

NMR: 5 DMS ° -d (. + D2 ° 3 90 (3H, s, OCH,); 5.25 (IH, m, ppm -

6-H); 5.95 (IH. M, 7-H); 6.72 (d, J = 16, 3-CH trans); 6.96

(IH. S, CH-Ph2); 7.4 (10H, m, Ph-H).

Hersteillingsbeispiel 12 Benzhydryl-7-amino-3- [3-chloro-l-propen-l-yl] - 3-cephem-4-carboxylate (Z-isomer) (XVIII)

Compound XVIII is the intermediate compound used according to Reaction Schemes Ib and LC.

A. Benzhydryl-7-benzylidenamino-3-triphenylphosphoniome-thvl- 3-cephem-4-carboxylate chloride (XV)

To a suspension of benzhydryl-7-amino-3-chloro-methyl-3-cephem-4-carboxylate hydrochloride (II hydrochloride) (200 g, 0.44 mol) in CH2C12 (940 ml) is added 1 N NaOH ( 440 ml) at room temperature. The mixture is shaken for 10 minutes and the organic layer is separated. MgSO4 (75 g) and benzaldehyde (51 g, 0.48 mol) are added to the organic layer and the mixture is left to stand for 3 hours. The reaction mixture is filtered and the insoluble components are washed with CH2C12 (200 ml). The filtrate and the washing water are combined and triphenylphosphine (126 g, 0.48 mol) is added. The mixture is concentrated to about 400 ml and left to stand for 4 days. The viscous oil obtained is diluted with ethyl acetate (11) and triturated, the title compound XV being obtained as a pale yellow, crystalline powder after filtering off and drying in vacuo. Yield 322 g (96%). Melting point:

185-190 C (decomposition).

Tt> KBr IR: v cm max

UV: À.

CH2C12 max

■ '1780, 1720, 1630. nm (s) 260 (24100).

B. Benzhydryl-7-benzylidenamino-3- [(triphenylphosphoranyliden) - methyl -] - 3-cephem-4-carboxylate (XVI)

A mixture of XV (322 g, 0.42 mol) and 5 N Na2C03 (252 ml) in CH2C12 (1.6 1) is stirred vigorously for 15 min at room temperature. The organic layer is separated, dried over MgSO4 and concentrated to approximately 500 ml. The concentrate is added to acetone (1 l) with stirring, giving a pale yellow, crystalline powder which is filtered off. 237 g (78%) of XVI are obtained. Melting point: 195-198 C (decomposition).

5 IR: v KBr cm "1 1770, 1620.

Max

UV: X ^ Cl2 nm (s) 254 (23000), 389 (22000).

10 NMR: S p ^ 3 2.56 and 3.16 (2H, ABq); 5.00 (IH, d,

J = 4Hz), 5.23 (IH, d, J = 4Hz); 5.47 (IH, d, J = 22Hz); 6.95 (IH, s); 7.2-7.8 (30H, m); 8.55 (IH, s).

C. Benzhydryl-7-amino-3- [chloro-1-propen-1-yl] -3-cephem-15 4-carboxylate hydrochloride (Z-isomer) XVIII-hydrochloridej

To a refluxing solution of XVI (214 g, 0.294 mol) and N, 0-bis- (trimethylsilyl) acetamide (40 ml, 0.15 mol) in dry CH2C12 (2.9 l) is added dropwise with stirring a 50% solution of chloroacetaldehyde (93 g, 0.59 mol) in CHC13 for 15 min. After standing for 30 minutes, the mixture is evaporated to dryness. CH2C12 (1.5 l), Girard reagent T (99 g, 0.59 mol) and 10% aqueous HCl (300 ml) are added to the oily residue. 25 The mixture is stirred for 1 hour at room temperature. The organic layer is washed with water (200 ml) and saturated brine (200 ml), dried over MgSO4, treated with coal (5 g) and filtered. The filtrate is cooled to -10 ° C and treated with 1N HCl in CH3OH (300 ml) 30. The mixture is stirred at room temperature for 30 minutes and concentrated to approximately 300 ml. The concentrate is diluted with ethyl acetate (400 ml) and inoculated with some crystals of the XVIII hydrochloride. After 2 h, the crystals which have separated out are filtered off, washed with ethyl acetate 35 (200 ml) and dried in vacuo, 74 g (53%) of the title compound XVIII being obtained in the form of the hydrochloride. Melting point:> 185 C (decomposition). Pale yellow needles.

io KBr IR: v cm

40 max

-l

2830, 1780, 1720.

UV: X Et0H nm (s) 286 (8800). max v v

NMR: 5

DMSO-d6 ppm

3.73 (2H, br, 2-H); 3.97 (2H, m.

«CH, C1); 5.22 (IH, d, J = 4.5Hz, 6-H); 5.37 (IH, d, J = 4.5 Hz, 7-H); 5.77 (IH, m, 3-CH = CH); 6.45 (IH, d, J = 11Hz, 3-CH); 6.88 (IH, s, CHPh,); 7.33 (10H, br. S, Ph-H). Analysis for C ^ N-ÄSCl-HCl:

C H N S Cl

50 calc .: 57.87 4.65 5.87 6.72 14.85 found: 57.62 4.53 5.70 6.64 14.89

Production Example 13 Benzhydryl- 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxy-55 iminoacetamido] -3- [3-chloro-1-propen-1-yl] - 3-cephem-4-carboxylate (Z-isomer) (Vili-1)

To a solution of XVIII (Z-isomer) (20 g, 42 mmol) in CH2C12 (420 ml) containing N, 0-bis (trimethylsilyl) acetamide (34 ml, 125 mmol) is added during 30 60 min at -10 to 0 C in three portions of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl chloride hydrochloride (15.2 g, 59 mmol). The mixture is stirred at 0-5 C for 30 min and concentrated under reduced pressure. The brown oily residue is dissolved in ethyl acetate (420 ml) and the solution is washed successively with saturated aqueous NaHC03 (3 x 15 ml), saturated aqueous NaCl (15 ml), 10% HCl (15 ml) and saturated aqueous NaCl ( 15 ml) and concentrated to approximately 50 ml. To

669 197

44

n-heptane (200 ml) is added to the concentrate, giving 28.5 g (purity 90%) of the title compound (VIII-1 (Z-Isome-res) as a colorless powder. Melting point:> 150 C (decomposition).

IR: v KBr cm-1 3400, 1780, 1720, 1680. 1620.

Max

UV: ~ K mSH nm (s) 240 (2000 ()) <283 (12000).

NMR: S pp ^ 0n_d6 3.6 (2H, m, 2-H); 3.95 (3H, s, OCH,);

4.0 (2H, m, CH, C1); 5.32 (IH, d, J = 4.5 Hz, 6-H); 5.62 (IH, m, 3-CH = CH); 6.03 (IH, d, J = 4.5Hz, 7-H); 6.32 (IH, d, J = 11Hz, 3-CH); 6.87 (IH, s, CHPh,); 7.33 (10H, br, s, Ph-H).

Production Example 14 Benzhydryl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- [3-iodo-l-propen-l-yl] - 3- cephem-4-carb-oxylate (E-isomer) (IX-1 j

A mixture of VIII-1 (Z-isomer) (28.5 g, purity 90%) and sodium iodide (19 g) in dry acetone (420 ml) is stirred for 10 min at room temperature and allowed to stand at 5 C for 2 h. The mixture is concentrated under reduced pressure. Ethyl acetate (420 ml) and 10% by weight, vol. Aqueous sodium thiosulfate solution (30 ml) are added to the residue and the mixture is shaken. The organic layer is washed with water (30 ml), dried over MgSO4 and evaporated to approximately 50 ml. The concentrate is diluted with n-heptane (200 ml) to give 30.6 g (purity 95%) of the title compound IX-1 (E-Isomeres) as a yellow powder. Melting point:> 120 C (decomposition).

IR: v KBr cm- '3400, 1780, 1725, 1680, 1620.

Max

UV: AEt0H nm (s) 306 (15000).

max v

NMR: 8 acetone "d6 3J1 (2H, m 2 -H); 3.97 (3H, s, OCH,); ppm

4.0 (2H, d, J = 8Hz, CH, I); 5.26 (IH, d, J = 4.5Hz, 6-H); 6.03 (IH, d-d, J = 4.5 and 8Hz, becomes doublet J = 4.5Hz by adding D-> 0, 7-H); 6.32 (IH, d-t, J = 15 and 8Hz, 3-CH = CH): 6 ~ 79 (IH, d, J = 15Hz, 3-CH); 6.98 (IH, s, CHPh,); 7.35 (10H, m, Ph-H); 7.63 (2H, br, s, disappears by adding D, 0, NH,); 8.52 (IH, d, J = 8Hz, disappears by adding D, 0, 7-NH).

Production Example 15 Benzhydryl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (4-carbamoyl-l-pyridinio) -1-propene -l-ylj-3-cephem-4-carboxylate iodide (E-isomer) (XII-1H)

CH3OH (100 ml) is added to a suspension of IX-1 (E-isomer) (30.5 g) and isonikotinamide (26 g, 212 mmol) in CH3CN (120 ml) until the mixture becomes clear. The mixture is stirred for 2 hours under a nitrogen atmosphere at room temperature and then concentrated to approximately 100 ml under reduced pressure. The semi-solid residue is triturated with isopropyl ether (200 ml). The solvent is decanted off and the remaining yellow powder is washed with a mixture of isopropyl ether and CH3OH (3 / 1.120 ml). The powder is filtered off and dried in vacuo to give 36 g (purity 75%, estimated by HPLC) of the title compound XII-1H (E isomer) as a pale yellow powder. Melting point:> 150 C (decomposition).

IR: v KBr cm "1 3300, 1780, 1720, 1680, 1620.

Max

UV: 1 Et0H-m (E!%) 282 (170).

max I cm

NMR: 8 DMS ° -d <-> 3.72 (2H, m, 2-H); 3.90 (3H, s,

ppm

OCH3); 5.25 (3H, m, 6-H and CH, N +); 5.9 (IH, d-d, J = 4.5 and 8Hz, becomes doublet J = 4.5Hz by adding DiO, 7-h); 6.35 (IH, m, 3-CH = CH); 6.89 (IH, s, CHPh,); 6.9 (IH, d, J = 16Hz, 3-CH); 7.35 (10H, m, Ph-H); 8.06 (2H, br, s, disappears by adding D, 0, NH,), 8.21 (2H, br, s, disappears by adding D, 0, NH,); 8.36 and 9.07 (each 2H, d, J = 6Hz, Py-H); 9.57 ~ (1H, d, J = 8Hz, disappears by adding D20, 7-NH).

Production Example 16 Benzhydryl-7-benzylideneamino-3- [3-chloro-l-propen-l-yl] -3-cephem-4-carboxylate (XVII) (Z-isomer J.

To an ice-cold mixture of the crystalline 7-amino-cephem intermediate (XVIII (Z-isomer)) (13.4 g, 28 mmol) and benzaldehyde (3.3 g, 31 mmol) in ethyl acetate (150 ml) are added dropwise 0.5 N sodium hydroxide (56 ml, 28 mmol) for 20 min, while keeping the temperature of the reaction mixture below 10 C. The mixture is stirred with cooling for a further 15 min and the organic layer is separated off with saturated aqueous sodium bicarbonate (100 ml x 2) and dried over magnesium sulfate. To the dried solution, add a small amount of carbon and filter the mixture. The filtrate is evaporated to dryness. The oily residue is dissolved in carbon tetrachloride (50 ml) and concentrated again. This process is followed repeated three times, monitoring the mixture by reverse phase TLC to be sure that the 7-aminocephalosporin starting material is completely transferred to the ship's base, removing the solvent in vacuo 16.45 g of the title compound XVII (Z-isomer) as a pale yellow-yellow powder (estimated purity 85%; Melting point: 74 C (decomposition)). This powder is used in the next stage without further purification.

IR: v KBr cm 1 1780, 1725, 1635.

Max

NMR: 6CDCl1 6.18 (IH. J = 11Hz).

ppm

Production Example 17 Benzhydryl-7-Benzylidenamino-3- [3- (4-carbamoyl-l-pyridinio) -1-propen-l-yl] - 3-cephem-4-carboxyhit-iodicl lXXI-H) (E-isomer)

A solution of sodium iodide (6.3 g, 42 mmol) in acetone is added dropwise to a cooled mixture of 3-chloropropenyl cepheme XVII (Z-isomer) (16.4 g) in acetone (5 ml) over a period of 10 min under a nitrogen atmosphere (30 ml). The mixture is stirred at room temperature. The reaction is based on the UV absorption ratio

ses [e! ^ (255 nm) / El / o (320 nm)] followed.

1 1 cm 1 cm J

When the ratio reaches a value below 1.30 (after 45 min), the mixture is diluted with carbon tetrachloride (400 ml) and left to stand at room temperature. If the ratio becomes less than 1.10 (after 3 h), the mixture is concentrated to half its volume. The filtrate is treated with a small amount of coal and diatomaceous earth and filtered. The filter cake is washed with a 1: 1 mixture (100 ml) of methylene chloride and carbon tetrachloride. The filtrate and the washing water are combined and a solution of isonikotinamide (3.5 g, 28.7 mmol) in dimethylformamide (20 ml) is added.

The mixture is concentrated under reduced pressure. The concentrate is left at room temperature for 1.5 hours

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

45

669 197

stand and wash it with isopropyl ether (100 ml x 3). The brown semi-solid residue is dissolved in methylene chloride (50 ml). Ethyl acetate (1.5 l) is added dropwise to the solution with stirring. The precipitate obtained is filtered off and washed with ethyl acetate (200 ml). After drying over phosphorus pentoxide in vacuo, 17 g of the title compound XXI-H (E-isomer) are obtained. Yellow amorphous powder. Melting point: 150-155 C (decomposition). Estimated purity by means of NMR 80%).

IR: v KBl cm-1 1775, 1725, 1690, 1635.

Max

UV: X CH2C12 nm (E1,%) 258 (335), 298 (255). max v 1 cm 'v'

NMR: 8 DMS0-d6 3 4_3 8 (2H, br.); 5.35 (2H, br.); 5.41 ppm

(IH, d, J = 4Hz); 5.73 (IH, d, J = 4Hz); 6.93 (IH, s); 6.97 (IH, d, J = 16Hz, 7.3-7.5 (15H, br. S); 8.40 (2H, d,

J = 6.5 Hz); 9.15 (2H, d, J = 6.5 Hz.

Production Example 18 7-Amino-3- [3- (4-carbamoyl-1-pyridinio) -l-propen-1-ylJ-3-cephem-4-carboxylate (XXII-H) (E-isomer)

Concentrated hydrochloric acid (5 ml) is added dropwise to a suspension of the quaternized cephem XXI-H (17 g) in 85% formic acid (25 ml). The mixture is stirred at room temperature for 1.5 hours and treated with a small amount of coal. It is filtered and washed with 85% formic acid (5 ml). The filtrate and the washings are combined and poured into acetone (11) with stirring. Filtration of the precipitate formed gives 9.52 g of the yellow crude product. A small amount of coal is added to a suspension of the crude product (9.5 g) in water (50 ml) and filtered. The filtrate is added dropwise to isopropyl alcohol (700 ml) with stirring. The precipitate is filtered off, washed with a small amount of methanol (30 ml) and dried, yielding 7.58 g of the title compound XXII-H (E isomer) as the hydrochloride. Pale yellow powder. Estimated purity using UV 85%. Melting point: 173-188 C (decomposition).

IR: v KBr cm-1 1795. 1680, 1620, 1575, 1540.

Max

UV: X PhosPlate buffer (PH 7) nm (g1%) 294 (457). max v 1 cm y v y

NMR: 8 p ^ + DCI 3.82 (2H, s); 5.17 (IH, d, J = 5Hz); 5.33

(2H, d, J = 7Hz); 5.43 (IH, d, J = 5Hz); 6.37 (IH, d-t, J = 16 and 7Hz); 7.23 (IH, d, J = Ì6Hz); 8.34 (2H, d, J = 7Hz); 9.00 (2H, d, J = 7Hz).

Production Example 19 2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetylchloride hydrochloride (III-1 as acid chloride hydrochloride). A. 2-Cyano-2-methoxyiminoacetamide

To a mixture of a-cyanoacetamide (252 g, 3 mol) and sodium nitrite (414 g, 6 mol) in water (600 ml) is added with stirring at 5-10 C for 1.5 h acetic acid (371 ml, 10 mol ). The mixture is stirred for a further 1.5 h and the pH is adjusted to 8.5 with 6 N NaOH. Dimethyl sulfate (568 ml, 6 mol) is added to the mixture at 15-20 C and the mixture is stirred for 1.5 h at 45 C. The pH of the reaction mixture is adjusted to 8.5 with 6 N NaOH and left at 5 C. Stand overnight, whereby a precipitate separates, which is filtered off, dried with cold water and in air. 292 g (77%) of the title compound are obtained as brown needles. Melting point: 170-172 ° C.

IR: v KBr cm-1 3400. 3180, 1720 (sh), 1715, 1690, 1615,

Max

1570.

UV: X H2 ° nm (s) 238.5 (8290), 268 (sh, 3870).

max v

NMR: 5 DMS ° -df> 4.20 (3H, s, OCH,); 7.85 (2H, br,

ppm

NH2).

Analysis: for C4H5N, 02:

C H "N Calc .: 37.80 3.97 33.06 Found: 37.43 3.75 32.51

B. 2-methoxyiminopropane nitrile

A mixture of 2-cyano-2-methoxyiminoacetamide (88.9 g, 0.7 mol), sodium chloride (70 g) and phosphorus oxychloride (97 ml, 1.05 mol) in dry 1,2-dichloroethane (350 ml ) is heated with stirring under reflux for 16 h. Insoluble constituents are filtered off through a bed of dicalite and washed with dichloroethane. The filtrate and washings are combined and poured into ice water (1.5 L) with stirring to decompose excess phosphorus oxychloride. The organic phase is washed with 10% NaHC03 (500 ml), water (500 ml x 3) and saturated NaCl solution (500 ml) and dried over MgS04. The filtrate is distilled under reduced pressure to give 61.5 g (81%) of the title compound. Sdp. 62 C / 24 mm Hg (Lit., Sdp. 47-48 C / 12 mm Hg).

IR: v FluSSlger Fllm cm -1 3020, 2960, 2245, 2020, 1530, max

1455, 1080.

NMR: S CDCl3 4.35 (3H, s, OCH3).

ppm> v '

C. 2-Cyano-2-methoxyiminoacetamidinium acetate

To a solution of ammonium chloride (28.4 g, 0.53 mol) in 28% aqueous ammonia (355 ml) and ethanol (180 ml) is added dropwise a solution with stirring at -15 to -10 ° C over 30 min 2-methoxyiminopropane nitrile (58.0 g, 0.53 mol) in ethanol (120 ml). The mixture is stirred overnight at -10 ° C. and then for one day at ambient temperature (20-25 ° C.). The reaction mixture is partitioned between water (350 ml) and CH2C12 (350 ml), the aqueous phase is saturated with sodium chloride and extracted again with CH2C12 (300 ml). The organic extracts are combined, dried over MgSO4 and evaporated in vacuo. A solution of the residue in ethyl acetate (1.61) is adjusted to pH 3-4 with acetic acid in order to precipitate the title compound in crystalline form. The crystals are filtered off and washed with ethyl acetate. Yield 67.6 g (69%). Melting point: 152-154 ° C (decomposition). [Lit. Melting point:

i50-155 ° C (decomposition)].

IR: v KBr cm-1 3160, 2900, 2360, 2235, 2000, 1665, 1555, max

1495, 1415.

UV: X Et ° H nm (s) 243 (8500), 265 (sh, 5380), 305 (sh,

Max

1400).

NMR: 8 p ^ f ° "d6 1.88 (3H, s, CH3COOH); 4.15 (3H, s,

OCH3); 7.60 (4H, br.).

Analysis for C4H6N4OCH3COOH:

C H N Calc .: 38.71 5.41 30.09 Found: 38.71 5.59 29.51

D. 2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoaceto-nitrile

To a suspension of 2-cyano-2-methoxyiminoacet amidinium acetate (125 g, 0.672 mol) in CH3OH (1.25 1)

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

669 197

46

Triethylamine (234 ml, 1.68 mol) is added dropwise at −10 ° C. and then Br2 (41.6 ml, 0.806 mol) over the course of 20 minutes at −15 to −10 ° C. The mixture is stirred for 20 min. A solution of KSCN (78.3 g, 0.806 mol) in CH3OH (550 ml) is added dropwise to the mixture at -15 to -10 ° C over 1 h. After stirring at 0-5 ° C for 1 hour, the mixture is poured into ice water (121) to form a crystalline precipitate. The precipitate is filtered off, washed with water and air-dried to give 120 g (98%) of the title compound. Melting point:

263-265 ° C (decomposition). The melting point of the compound thus prepared is approximately 60 ° C higher than the melting point given in the literature * [melting point: 210-215 ° C (decomposition)]. However, the elemental analysis and the spectral data match the structure.

IR: v ^ r cm-1 3435, 3260, 3120,2960, 2245, 2020,1630,

Max

1545, 1455, 1415.

UV: X Et ° H nm (e) 248 (13300), 310 (3470).

NMR: 5 ™ S0 "d <i 4.21 (3H, s, OCH3); 8.30 (2H, br. NH2).

Analysis for C5H5N5OS:

C H N S Calc .: 32.78 2.75 38.23 17.50 Found: 32.76 2.51 38.02 17.50

E. 2- (5-amino-l, 2,4-thiadiazol-3-yl) - 2-methoxyiminoacetic acid (III-l)

A mixture of 2- (5-amino-1,2,4-thiadiazol-3-yl-2-methoxyiminoacetonitrile (18.3 g, 0.1 mol) in 4 N NaOH (250 ml) was heated with stirring for 3 h to 50-55 ° C. The reaction mixture is adjusted to pH 1 with H3P04 and washed with ethyl acetate (100 ml), saturated with NaCl and three times with a mixture of ethyl acetate and tetrahydrofuran (3: 1, 2 x 300 ml and 1 x 200 ml) The extracts are combined, dried over MgSO4 and concentrated under reduced pressure. The residue is triturated with isopropyl ether to give pale yellow crystals of the title compound. Yield 16.8 g (83%). Melting point: 184-185 ° C (decomposition) [Lit. * Melting point: 180-182 ° C (decomposition)].

TT) KBr IR: v cm max

H2 ° nm (s) 234 (13200), 288 (sh, 3620).

Production Example 20

XJ

■ c-

II n

-CONH-

V

f

CK

CH = CH-CH2-Cl c2h5

COOCH (Ph).

viii-2

10th

Diphenylmethyl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) -2- (Z) -ethoxyiminoacetamidoJ-3- [3-chloro-l-propenyl] -3- cephem-4 carboxylate (VIII-2, Z-isomer)

To a mixture of N, 0-bis (trimethylsilyl) acet-15 amide (2.3 ml, 9 mmol) and crystalline diphenylmethyl-7-amino-3- [3-chloro-l- (Z) -propene- l-yl] - 3-cephem-4-carboxy-lat hydrochloride (XVIII) (1.338 g, 2.8 mmol) (from preparation example 12) in methylene chloride (10 ml) are added in portions at 2 with stirring at -10 ° C. - (5-Amino-l, 2,4-thiadia-20 zol-3-yl) - 2- (Z) -ethoxyiminoacetyl chloride hydrochloride (800 mg, 2.95 mmol). The mixture is left to stand at 0 C for 2 h. The mixture is diluted with ethyl acetate (200 ml), washed with water and concentrated under reduced pressure. Trituration of the residue with isopropyl 25 ether gives the title compound VIII-2 as an amorphous powder. Yield 1.70 g (95%) melting point:> 150 C (decomposition).

IR: v KBr cm- '3300, 1780, 1720, 1690, 1380, 1220.

Max

30 UV: X (C2H5 ° H) nm (E) 285 (11000).

max v 'v'

NMR: 5 (DMSO "d6)

ppm

4.25 (2H, q, J = 7Hz, CH, CH3); 5.90 (IH, d-d, J = 4 and iS 8Hz, 7-H); 6.26 (IH, d, J = 11Hz, 3-CH); 6.85 (IH, s, CHPh2); 9.53 (IH, d, J = 8Hz, 7-NH).

Manufacturing Example 21

1.26 (3H, t, J = 7Hz, CH2CH3);

40

r

CH = CH-CH2-I

3460, 3260, 3140, 1725, 1620, 1605, 1545.

UV: X -max

2 "?

c, h5 cooch (Ph),

45 *

IX-2 * A mixture of E and Z isomer

F. 2- (5-Amino-l, 2,4-thiadiazol-3-yl) -2-methoxyiminoaetyl chloride hydrochloride

To a suspension of 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetic acid (III-1) (40.4 g, 0.2 mol) in dry CH2C12 (400 ml) are added all at once at -50 C PC15 (41.6 g, 0.2 mol). The mixture is stirred at -20 to -5 ° C. for 4 h and poured into a mixture of n-heptane and isopropyl ether (2: 1, 21). The yellow precipitate is filtered off, washed with the same solvent mixture and dried with KOH under reduced pressure. 46.0 g (90%) of the acid chloride are obtained.

IR: v

Nujolf max cm- '1775.

* Japan Kokai 57-158769, published September 30, 1982, Fujisawa (British Note 6/3/81).

Diphenylmethyl-7- [2- (5-amino-l, 2,4-thiadiazol-3-yl) ~ 2- (Z) -ethoxyiminoacetamido 1-3- [3-iodo-l-propenyll-3-cephem-4 -50 carboxylate (IX-2)

A mixture of VIII-2 (1.90 g, 3 mmol) (from preparation example 20) and sodium iodide (1.4 g, 9 mmol) in acetone (20 ml) is stirred for 10 min at room temperature and then left at 5 for 3 h C stand. The mixture is evaporated under reduced pressure, diluted with ethyl acetate (100 ml), washed with 10% sodium thiosulfate and water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether gives 1.82 g (84%) of the title compound IX-2 as a light brown, amorphous powder.

IR: v KBr cm "1 3290, 1770, 1720, 1670, 1530. 1370, 1220. max '

UV: X (C2H5 ° H) nm (E1%) 304 (190). max v 1 cm 1 v

60

47

669 197

Manufacturing Example 22

COOCH (Ph) 2

xxi-h iodide * e

Diphenylmethyl-7-benzylidenamino-3- [(E) -3- (4-carbamoylpyridinio) - I-propenyl] - 3-cephem-4-carboxylate (XXI-H iodide) (E-isomer J

To a cooled solution of the 3-chloropropenyl cepheme (XVII, Z isomer, 42.8 g, 90 mmol) (from preparation example 16) in 'dry DMF (80 ml), KJ (20 g, 120 mmol) is added all at once . The mixture is stirred at room temperature. The reaction is carried out by means of the UV

1 0/1 0 /

sorption ratio [E j cm (255 nm) / E j cm (320 nm)]

tracked. When the ratio becomes less than 1.10 (after 45 min), the mixture is diluted with 800 ml of methylene chloride, treated twice with activated carbon (4 g) and filtered. The filter cake is washed with 100 ml CH2C12. The filtrate and the washing water are combined and isonikotinamide (14.64 g) is added and the mixture is concentrated under reduced pressure. The concentrate is kept at room temperature for 1.5 h and washed with a mixture of toluene and n-heptane (1: 1, 600 ml). The brown semi-solid residue is dissolved in CH2C12 (100 ml). Ethyl acetate (3 l) is added dropwise to the solution with vigorous stirring. After drying over P205 in vacuo, 57.37 g (88%) of the quaternized title compound XXI-H is obtained as iodide. Yellow amorphous powder. Melting point: 150-155 'C (decomposition). This product is identical to the product obtained by iodination with NaI (preparation example 17).

Production Example 23

hcl- h2n— p ^

o 'ch = ch-ch2 "c1

cooch (Ph) 2

XVIII * Z

Diphenylmethyl-7-amino-3- (3-chloro-I-propenyl) -3-cephem-4-carboxylate hydrochloride (Z-isomer) (XVIII, hydrochloride)

A 25% solution of chloroacetaldehyde (69 g, 0.22 mmol) in CHC13 is added in one portion at -10 ° C. to a solution of XVI (80 g, 0.11 mol) in CH2C12 (1.11) Contains N, 0-bis (trimethylsilyl) acetamide (16.2 ml, 0.06 mol). The mixture is left to stand at 5 C overnight. The mixture is concentrated to about 0.3 1, diluted with a solvent mixture of ethyl acetate and isopropyl ether (1/2, 0.6 1), treated with silica gel (Wako-Gel C-100, 60 g) and treated with a diealite Bed filtered. The filter cake is washed with the same solvent system (0.2 1). The combined filtrates and washings are concentrated to about 0.2 l, treated with Garard reagent T (60 g, 0.26 mol) and 4N HCl (220 ml) and inoculated with a few crystals of XVIII hydrochloride. After stirring for 3 hours, the separated crystals are filtered off, washed with water (0.5 1) and ethyl acetate (0.5 1) and dried in vacuo to give 37 g (70%) of the title compound XVIII hydrochloride. Melting point:> 185 C (decomposition).

Pale yellow needles. This product is identical to the product obtained according to Preparation Example 12.

Manufacturing Example 24

/ s \

HCl- h2n —— r

/ ■ - N *

he ch = ch-ch2-c1

cooch (Ph) 2

xviii * z

Diphenylmethyl-7-amino-3- (3-chloro-i-propenyl) -3-cephem-4-carboxylate hydrochloride (Z-isomer) (XVIII, hydrochloride

To a solution of chloroacetaldehyde (25% solution in CHC13, 628 mg, 2 mmol) in CH2C12 (10 ml), N, 0-bis (trimethylsilyl) acetamide (0.135 ml, 0.5 mmol) is added in succession at 5 C. ) and XVI (728 mg, 1 mmol). The mixture is left to stand at 5 C overnight. The mixture is evaporated and diluted with a mixture of ethyl acetate and isopropyl ether (1/2, 10 ml). The insoluble constituents are filtered off and the filtrate is concentrated to about 5 ml. The concentrate is treated with 4N HCl (2 ml), inoculated with XVIII hydrochloride and stirred for 1 h at room temperature. The crystals are filtered off, washed with ethyl acetate (10 ml) and water (10 ml) and dried in vacuo to give 384 mg (80%) of the title compound XVIII hydrochloride. Melting point:> 185 C (decomposition). Pale yellow needles. This product is identical to the product obtained according to Preparation Example 12.

Production Example 25 2- (5-Amino-1,2,4-thiadiazol-3-yl) - 2- (propen-3-yl-oxyimino) acetyl chloride hydrochloride (III-3 as acid chloride hydrochloride)

A. Methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiad.iazol-3-yl) -2- (propen-3-yloxyimino) acetate

A mixture of 685 mg (3.37 mmol) of N- (propen-3-yloxy) phthalimide (prepared according to the method of E. Grochosaki & J. Jurczak, Synthesis 1976, 682) and 175 mg (3.35 mmol) Hydrazine hydrate in 5 ml of C2H5OH is stirred for 1 h at room temperature. The precipitate which has separated out is filtered off and the filtrate and the wash waters are combined. 967 mg (3.37 mmol) of methyl 2- (5-t-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-oxoacetate are added to the solution. The mixture is left to stand at room temperature for 1 h and concentrated on a rotary evaporator. The residue is purified by chromatography on silica gel. The column is eluted with n-hexane / ethyl acetate (4: 1) and the fractions containing the main product are combined and concentrated under reduced pressure. Yield 514 mg (46%). Melting point: 83-86 C.

IR: v KBr cm-1 3100, 1745, 1710, 1610.

Max

UV: 1 maxl5 ° H) nm 223 (9700) '242 (1000 °) -

NMR: 6 (CDC] 3) 1.55 (9H, s, BOC-H); 4.40 (2H, d, ppm v

J = 5Hz, O-CH,); 5.21 (2H, m, CH, = CH); 5.90 (IH. M,

-CH = CH2); 9.50 (IH, br.s, NH).

B. 2- (5-t-Butoxycarbonylamino-l, 2,4-thiadiazol-3-yl) -2- (propen-3-yloxyimino) acetic acid

A solution of 770 mg (2.3 mmol) of methyl 2- (5-t-butoxycarbonylamino-l, 2,4-thiadiazol-3-yl) -2- (propen-3-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

55

669 197

48

yl-oxyimino) acetate and 3.5 ml of a 2N NaOH solution (7.0 mmol) in 15 ml of CH3OH are heated under reflux for 30 min. The reaction mixture is concentrated in vacuo and diluted with 10 ml of ethyl acetate-.H20 (1: 1). The aqueous layer is separated off, acidified to pH 2 with 6N HCl and extracted with ethyl acetate (2x10 ml). The ethyl acetate solution is dried over MgSO4 and concentrated on a rotary evaporator to give 596 mg (81%) of the title compound. Melting point: 134-135 C (Lit. 1: Melting point: 135-136 C).

IR: v (NuJol) cm- '3150. 1745, 1710, 1550.

Max

C. 2- (5-Amino-1,2A-thiacliazol-3-yl) -2- (propen-3-yl-oxyimi-no) - acetic acid (III-3! H

A solution of 570 mg (1.74 mmol) of 2- (5-t-butoxycar-bonylamino-l, 2,4-thiadiazol-3-yl) 2- (propen-3-yloxyimino) acetic acid in 6 ml of trifluoroacetic acid is left Stand for 1 h at ambient temperature. Evaporation of the mixture and subsequent trituration with 30 ml of isopropyl ether gives 376 mg (95%) of the title compound. Melting point: 109 C (decomposition).

IR: v (Nuio1) cm "1 3180, 1710, 1545, 1460.

Max

UV: X (C: H5 ° Hj nm (s) 245 (13500).

Max

NMR: 5 (DMS0 "do) 4 77 (2h, d, J = 5Hz, O-CH,); 5.20 ppm

(2H, m, CH = CH); 6.0 (IH, m, CH = CH2).

"Japan Kokai 57-112396 (July 13, 1982, Fujisawa) Brit. Note 7935538 (October 12, 1979).

D. 2- (5-Amino-1,2A-thiadiazol-3-yl) - 2- (propen-3-yl-oxyimi-no) - acetyl chloride hydrochloride

A solution of 350 mg (1.54 mmol) of III-3 and 410 mg (1.97 mmol) of phosphorus pentachloride in dichloromethane (5 ml) is stirred for 1 h at 25 C. The reaction mixture is poured into 60 ml of n-hexane and filtered the precipitation. Yield 323 mg.

IR: V (Nujo1) cm-'1765.

Max

Production Example 26 2- (5-amino-1,2A-thiadiazol-3-yl) -2-propargyloxyiminoacetyl chloride hydrochloride (III-4 as acid chloride hydrochloride A. Methyl 2- (5-t-butoxycarbonylamino-1 , 2A-thiadiazol-3-yl) - 2-propargyIoxyiminoacetat

A suspension of 870 mg (4.32 mmol) of N-propargyl oxyphthalimide "and 200 mg (4.0 mmol) of hydrazine hydrate in 5 ml of ethanol is stirred for 1 h at 25 ° C. and filtered. The filtrate and the washings are combined and added add 1.0 g (3.86 mmol) of methyl 2- (5-t-butoxycarbonylamino-l, 2,4-thia-diazol-3-yl) -2-oxoacetate2i, and the solution is left to stand for 1 hour and concentrated under reduced pressure, purification by means of silica gel chromatography and subsequent evaporation yields 319 mg (27%) of the title compound, melting point: 72-75 C.

IR: v KBr cm "1 3200, 2380, 1745, 1710, 1610.

Max

Uy. ^ QHsöH) nm (s) 235 (12200).

Max

NMR: ò (DMS ° -d <- ') 1.56 (9H, see BOC-H); 3.55 (IH, ppm t. J = 2Hz, C = CH); 4.85 (2H, d, J = 2Hz. -CH -.- C eeCH); 8.9 (IH, br.s, NH).

1'Commercial product, Aldrich.

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

B. 2- (5-t-Butoxycarbonylamino-1,2A-thiadiazol-3-yl) -2-pro-pargyloxyiminoacetic acid

A solution of 490 mg (1.4 mmol) of methyl 2- (5-t-but-oxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxy-iminoacetate and 2.2 ml of a 2N aqueous solution NaOH solution (4.4 mmol) in 14 ml CH3OH is heated under reflux for 30 min. The reaction mixture is concentrated under reduced pressure and mixed with 10 ml of ethyl acetate-H20 (1: 1. The separated aqueous layer is acidified to pH 2 with 6N HCl and extracted with ethyl acetate (2x10 ml). Drying over MgSO4 and subsequent evaporation of the organic layer provides 149 mg (89%) of the title compound, melting point: 135 C (decomposition).

IR: v (NuJol) cm-1 3350, 1720, 1670, 1550.

Max

UV: X (CÎH5OH) nm (g) 233 (11500).

Max

NMR: S (DMS ° -d <->) 1.55 (9H, s, BOC-H); 3.55 (IH, t, ppm

J = 2Hz, C = CH); 4.89 (2H, d, J = 2Hz, CH, C = CH); 9.0 (IH, s, NH).

C. 2- (5-Amino-1,2A-thiadiazol-3-yl) -2-propargyloxyimino acetic acid (HI-4) 3 '

A solution of 410 mg (1.26 mmol) of 2- (5-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetic acid in 5 ml of trifluoroacetic acid is left to stand at 25 ° C. for 1 hour . Evaporation and subsequent trituration of the residue with 25 ml of isopropyl ether gives 204 mg (72%) of the title compound. Melting point: 156-158 C (decomposition).

IR: v (NuJol) cm-i 3300. 2480, 1730. 1610.

Max

UV: X (C-H5 ° H) nm (s) 234 (12000). Max '

NMR: 6 <DMS ° -d6> 3.52 (IH, t.J = 2Hz, CeCH); 4.86 ppm

(2H, d, J = 2Hz, CH2-C = CH): 8.10 (2H, br.s, NH;).

3) Japan Kokai 57-112396 (July 13, 1982, Fujisawa) Brit. Note 7935538 (10/12/79).

D. 2- (5-Amino-l, 2A-thiadiazol-3-yl) -2-propargyloxyimino-acetyl chloride-liydrochloride

A mixture of 175 mg (0.07 mmol) III-4 and 182 mg (0.88 mmol) phosphorus pentachloride in dichloromethane (2 ml) is stirred for 1 h at -5 C. The reaction mixture is poured into 30 ml n-hexane and the precipitate is filtered off. Yield 65 mg (34%).

IR: v (Nujo1) cm "1 1770.

Max

Production Example 27 2- (5-Amino-1,2A-thiadiazol-3-yl) -2-cyclopentyloxyiniinoacetyl chloride hydrochloride (II1-5 as acid chloride hydrochloride A. Methyl 2- (5-butoxycarbonylamino-1,2A -thiadiazol-3-yl} -2-cyclopentyloxyiminoacetate

A suspension of 860 mg (3.7 mmol) of N- (cyclopentyloxyj-phthalimid1 'and 185 mg (3.7 mmol) of hydrazine hydrate in 5 ml of C2H5OH is stirred for 1 h at ambient temperature and filtered. The filtrate and the washings are combined and to 1.06 g (3.7 mmol) of methyl 2- (5-t-butoxycar-bonylamino-l, 2,4-thiadiazol-3-yl) - 2-oxoacetate 2). The solution is left to stand at room temperature for 1 h and then concentrated in vacuo. The residue is purified by means of silica gel column chromatography. Elution with n-He-xan / ethyl acetate (4: 1) and subsequent evaporation gives the title compound. Yield 906 mg (81%). Melting point: 115-118 C.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

49

669 197

IR: v KBr cm- '3200, 1745, 1710, 1550. max

UV: X (C2H5 ° H) nm (g) 217 (1800), 252 (7600).

Max

NMR: 5 (cdc13)! 51 (9H, s, BOC-H); 1.60 (8H, br.s, ppm

H-Q); 3.88 (3H, s, OCH3): 4.90 (IH,

br.s.

, 70 (IH, br.s, NH).

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

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

B. 2- (5-t-Butoxycarbonylamino-1,2A-thiadiazol-3-yl) -2-cy-clopentyloxyìminoacetic acid

A solution of 500 mg (1.34 mmol) of methyl 2- (5-t-but-oxycarbonylamino-l, 2,4-thiadiazol-3-yl) -2-cyclopentyloxy-iminoacetate and 2N NaOH solution (2 ml , 4 mmol) in 15 ml CH3OH is heated under reflux for 30 min. The reaction mixture is evaporated and 10 ml of ethyl acetate-H20 (1: 1) are added to the solution. The aqueous layer is separated. Acidified to pH 2 with 6N HCl and extracted with ethyl acetate (2x10 ml). The organic layer is washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 377 mg (78%) of the title compound. Melting point: 185 C (decomposition).

IR: v KBr cm "1 3160, 1710, 1550.

Max

UV 'X (C2H5OH)

' Max

NMR: 5 (DMS °)

ppm nm (s) 238 (13300).

-O

1.51 (9H, see BOC-H); 1.70 (8H, br.s, H

4.82 (IH, m,

O

X]

reduced pressure. The residue is triturated with 5 ml of isopropyl ether and 10 ml of hexane to give 215 mg (86%) of the title compound. Melting point: 162-165 C (decomposition) (ref. 3): Melting point 160-165 C (decomposition).

IR: v (NuJol) cm-1 3290, 3200, 1710, 1615, 1600.

Max

(C2H5OH)

' Max

10 NMR: 5 (DMS ° "df>)

ppm m); 8.22 (2H, s).

UV: X '

nm (s) 238 (13300).

1.17-2.10 (8H, m); 4.60-4.98 (IH,

3) Japan Kokai 57-158769 (9/30/82, Fujisawa) British Anm. 15 8107134 (6.3.81).

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

A solution of 190 mg (0.74 mmol) III-5 and 219 mg 20 (1.0 mmol) phosphorus pentachloride in dichloromethane (5 ml) is stirred for 1 h at room temperature. The solution is poured into 50 ml of n-hexane. The precipitate which has separated out is filtered off. Yield 122 mg (60%).

IR: v (Nujol) cm-25 max

1760.

C. 2- (5-Amino-l, 2A-thiadiazol-3-ylj-2-cyclopentyloxyimino-acetic acid (IIIS, Z-IsomeresJ3 '

A solution of 348 mg (0.97 mmol) of 2- (5-t-butoxycar-bonylamino-1,2,4-thiadiazoI-3-yl) -2-cyclopentyIoxyiminoesacetic acid in 3 ml of trifluoroacetic acid is left for 1 h at room temperature stand. The reaction mixture is concentrated

Preparation 28 BenzotriazoI-l-yI-2- (5-amino-1,2A-thiadiazol-3-yl) -2-meth-oxyiminoacetate 30 A mixture of 1-hydroxybenzotriazole (2.7g, 20mmol) and dicyclohexylcarbodiimide (4.12 g, 20 mmol) in 65 ml DMF is stirred at room temperature. After 15 min, the mixture is added with stirring at 0 C III-1 (4.04 g, 20 mmol) and then stirred for a further 3 h. The reaction mixture is filtered to remove the insoluble urea and the filter cake is washed with a small volume of DMF. The filtrate and the wash water are combined and poured into 800 ml of ice water. The precipitate is filtered off, 5.24 g (82%) of the title compound being obtained as 40 pale gray powder. Melting point: 189 -192 C (decomposition).

1R: v ^ Br cm ■ '1815, 1620, 1540, 1415, 1090, 1060, 1005,

ITI ci X

45 945, 865, 740.

UV: X! S? 5 ° H) nm (E1 cm) 246 (580) <283sh (228) '

Claims (41)

669 197 PATENT CLAIMS 1. Compounds of general formula I: n r-w I, [TU R ^ -EN ^ ^ OR2 • conh- r \ CK cod ^ © ■ ch = ch-ch2-n = q (X) wherein te alkyl group with 1 to 4 carbon atoms, a cycloal- R1 is a hydrogen atom or an amino protecting group kyl or cycloalkenyl group with 3 to 6 carbon atoms means men R2 represents a hydrogen atom, a straight-chain or branched 15 or a radical of the general formulas: R '3 -c-ch = ch-r U r4 I -c-cooh Â5 I 3 -c-c = c-rj Ì5 cooh or means what R3 represents a hydrogen atom, a lower alkyl or carboxyl group, X represents a halogen atom, a hydroxy or lower alkoxy group and R4 and R5 each independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring having 3 to 5 carbon atoms, and © 30th -N = Q represents a quaternary ammonio group; or their non-toxic, pharmaceutically acceptable salts, solvates or esters. 2. Compounds according to claim 1, wherein ®N = Q is selected from © * -N 13 R k15 14 (CH2Jn and where R13, R14 and R15, which may be the same or different, are a lower alkyl, lower alkenyl, amino lower alkyl group with the proviso that the amino group is not on the a carbon atom, or a hydroxy lower alkyl group with the proviso that the Hydroxy group is not on the a carbon atom mean; R15 is a hydrogen atom, a lower alkyl, lower alkoxy, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, formylamino, lower alkanoylamino, carboxy, hydroxy, carboxy-lower alkyl, carboxy-lower-rigalkylthio, hydroxy-lower alkyl, Halogen-lower alkyl, amino lower alkyl, lower alkoxy lower alkyl, carbamoyl or N-lower alkyl carbamoyl group or a divalent alkyl group having 3 to 5 carbon atoms. R17 for a lower alkyl, lower alkoxy lower alkyl, 55 halogen lower alkyl, allyl, hydroxy lower alkyl group with the proviso that the hydroxyl group is not on the a carbon atom, an amino lower alkyl group with the proviso that the amino group is not on the a carbon atom, or represents a phenyl-lower alkyl-60 grappe; R18 is a hydrogen atom, a lower alkyl, lower alkoxy, lower alkoxy, lower alkyl, lower alkylthio, amino, lower alkylamino, di lower alkylamino, carboxy, hydroxy, carboxy lower alkyl, hydroxy lower alkyl, 65 amino lower alkyl, formylaminolamo, lower noalkanyl -, carbamoyl or an N-lower alkyl carbamoyl group; n represents an integer from 1 to 3 inclusive; TL is CH2 or, if n is 2, also S, O or N-R'1 ', where R19 is a hydrogen atom or a lower-rigalkyl group; and • R2 "and R: |, which can be the same and different, are a hydrogen atom, a lower alkyl, lower alkoxy, lower alkylthio *, amino, lower alkylamino, di-lower alkylamino, carboxy, hydroxy, hydroxy lower alkyl, amino lower alkyl, Lower alkoxy lower alkyl, carboxy lower alkyl, carboxy lower alkylamino, lower alkanoylamino, carboxy lower alkanoylamino, carbamoyl or an N -N lower alkyl carbamoyl group. 3. Compounds according to claim 2, wherein R2 is a lower rigalkyl group with 1-4 C atoms, cycloalkyl group with 3 to 5 carbon atoms, 1-carboxycycloalk-l-yl with 3 to 5 carbon atoms in the cycloalkyl radical, allyl, propargyl or 1 -Carboxy-1-yl-lower alkyl group with up to 5 carbon atoms in the alkyl radical. 4. Compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3-tri-methylammonio) -1-propene 1-yl] -3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 5. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (l-methylpyrrolidinio) -1-propene - 1-yl] -3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 6. Compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3-pyridinio-1-propene-1 -yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, for example Hydrate. 7. A compound according to claim 3 which is 7- [2- (5-amino-1,2,2-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- 3- (3-aminopyridinio) -1-propene - 1-yl] -3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 8. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-formylaminopyridinio) -1-propene - 1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, for example Hydrate. 9. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- (3-aminomethylpyridinio) -1-propene - 1-yl] - 3-cephem-4-carb-oxylate or a non-toxic, pharmaceutically acceptable salt or solvate. e.g. Hydrate. 10. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (3-carbamoylpyridinio) -1 -propen- 1-yl] - 3-cephem- 4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, for example Hydrate. 11. A compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) - 1 -propen- 1-yl] - 3-cephem- 4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, for example Hydrate. 12. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (2-methylthiazolio) -1 -propen- 1-yl] - 3-cephem- 4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, for example Hydrate. 13. A compound according to claim 3 which is 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-ce- 3,669,197 phem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 14. A compound according to claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- s (4-hydroxymethylpyridinio) - 1-propen-1-yl] -3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate or ester thereof. 15. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- 10 (3-hydroxymethylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate or ester thereof. 16. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- [3- 15 (4-jN-methylcarbamoylj pyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 17. A compound according to claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- 20 (2,3-propylene pyridinio) - 1-propen-1-yl] - 3-cephem-4-carb-oxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 18. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] - 3- [3- 25 (4-carbamoylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carb-oxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 19. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetami- 30 do] - 3- [3- (4-carbamoylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 20. The compound of claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] - 3- [3- 35 (4-carbamoylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 21. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetamido] - 40 3- [3- (4-carbamoylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt or solvate, e.g. Hydrate. 22. A compound according to claim 3 which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- [3- 45 (4-carboxypyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxy-lat or a non-toxic, pharmaceutically acceptable salt, solvate, e.g. Hydrate or ester thereof. 23. A compound according to claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-ethoxyiminoacetamido] -3- [3- 50 (4-carboxypyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt, solvate, e.g. Hydrate or ester thereof. 24. A compound according to claim 3, which is 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- 55 (3-carboxymethylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt, solvate, e.g. Hydrate or ester thereof. 25. Compound according to claim 3, namely 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- [3- 60 (4-carboxymethylthiopyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate or a non-toxic, pharmaceutically acceptable salt, solvate, e.g. Hydrate or ester thereof. 26. A process for the preparation of compounds of general formula I according to any one of claims 1 to 25 669 197 4th r hn J conh- ^ NdR2 N \ ^^ CH == CH-CH2 ^ NSQ cocß wherein kyl or cycloalkenyl group with 3 to 6 carbon atoms R1 represents a hydrogen atom, R2 is a hydrogen atom, a straight-chain or branched or a radical of the general formulas: te alkyl group with 1 to 4 carbon atoms, a cycloal r4 I 3 -c-ch-ch-r r5 , 4th . <> c = c-r cooh or -c-cooh i5 means in which 25 R3 represents a hydrogen atom, a lower alkyl or carboxyl group, X represents a halogen atom, a hydroxy or lower alkoxy group and R4 and R5 each "independently represents a hydrogen atom, a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring having 3 to 5 carbon atoms, and 35 © -H ~ Q a quaternary ammonio group means: 30 and the non-toxic, pharmaceutically acceptable salts and esters thereof, characterized in that a compound of the general formula: TP n. -conh b -hn ^^ s ^ \ 2 'OR COOB h = ch-ch2z where R2 'has the same meanings as R2 or for a residue of the formulas: B 'represents a carboxyl protecting group. coob r4 or coob, in which X. R4 and R5 have the meanings given above. N- R1® " « I H. . conh ^ Ndr2 ✓ ^ CH = CH-ch2-N = Q B2 represents a hydrogen atom or an amino protecting group, Z represents a chlorine, bromine or iodine atom and m represents zero or 1, 50 with a tertiary amine of the formula Q = N or in succession with a secondary amine of the formula RR'NH and a compound of the formula R "Z, the radical -NRR'R" corresponding to the radical -®N = Q and. if m stands for 1, the sulfoxide is reduced and then all protective groups are removed. 27. Process for the preparation of compounds of general formula i © where 65 th alkyl group with 1 to 4 carbon atoms, a cycloal- R1 is a hydrogen atom or an amino protecting group kyl- or cycloalkenyl group with 3 to 6 carbon «to- means. men, R2 represents a hydrogen atom, a straight-chain or branched or a radical of the general formulas: 5 669 197 r4 -c-ch-ch-r3, r5 ? 3rd -ç-c = c-r, Ì5 coob or R I -c-coob, means in which B represents a hydrogen atom or a carboxy 1 protective group, R3 represents a hydrogen atom, a lower alkyl or carboxyl group, X represents a halogen atom, a hydroxy or lower alkoxy group and R4 and R5 each independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring having 3 to 5 carbon atoms, and © represents a quaternary ammonio group; and the non-toxic, pharmaceutically acceptable salts and esters thereof, characterized in that a compound of the general formula: with an acid of the general formula: nrr £ cooh > XX1- r b hn 0r or an acylating derivative thereof, in which R2 has the above meanings and B2 represents a hydrogen atom or an amino protective group. 28. The method according to claim 26 for the preparation of the following compounds a-v: a) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (trimethylammonio) - 1-propen-1-yl] -3- cephem-4-carboxylate, b) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-noacetamido] - 3- [3- (l-methylpyrrolidinio) - 1-propen-1-yl ] - 3-cephem-4-carboxylate, c) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3-pyridinio-1-propen-1-yl] - 3-cephem- 4-carboxylate, d) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-noacetamido] - 3- [3- (3-aminopyridinio) -1-propen-1-yl ] -3-cephem-4-carboxylate, e) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (3-formylaminopyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate, 15 f) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (3-aminomethylpyridinio ) - 1-propen-1-yl] - 3-cephem-4-carboxylate, g) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-noacetamido] - 3- [3- (3-carbamoylpyridinio) -1-propen-1-yl ] - 20 3-cephem-4-carboxylate, h) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimino-noacetamido] - 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl ] -3-cephem-4-carboxylate, i) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyimi-25 noacetamido] - 3- [3- (2-methylthiazolio) -1-pi'open- 1-yl] - 3-cephem-4-carboxylate, j) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (2-amino-5-thiazolo [4,5-c] pyridinio) -1-propene-1-yl] - 3-cephem- 4-carboxylate, 30 k) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- [3- (4-hydroxymethylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate, 1) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyimino-noacetamido] - 3- [3- (3-hydroxymethylpyridinio) - 1-propene-35 l - yl] -3-cephem-4-carboxylate, m) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] - 3- [3- (4-N-methylcarbamoylpyridinio) -1-propen-1-yl ] - 3-cephem-4-carboxylate, n) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-methoxyimi-40 noacetamido] - 3- [3- (2,3-propylene pyridinio) -1-propene - I-yl] -3-cephem-4-carboxylate, o) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-ethoxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) - 1-propen-1-yl] - 3-cephem-4-carboxylate, 45 p) 7- [2- (5 ~ amino-1,2,4-thiadiazol-3-yl) - 2-cyclopentyl-oxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) - 1-propen- 1- yl] - 3-cephem-4-carboxylate, q) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-allyloxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl -] - 50 3-cephem-4-carboxylate, r) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-propargyloxyiminoacetamido] - 3- [3- (4-carbamoylpyridinio) -1-propen-1-yl ] - 3-cephem-4-carboxylate, s) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyimi-55 noacetamido] - 3- [3- (4-carboxypyridinio) - 1-propen- 1- yl] -3-cephem-4-carboxylate, t) 7- [2- (5-Amino-1,2,4-thiadiazol-3-yl) -2-ethoxyimino-acetamido] - 3- [3- (4-carboxypyridinio) -1-propenyl-yl ] -3-ce-phem-4-carboxylate, 60 u) 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 v) 7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] - 3- [3- (4-carboxymethyIthiopyridinio) - 1-per-65 pen-1-yl] - 3-cephem-4-carboxylate. 29. Compounds of the general formula: 669 197 6 n j-c ^ OR2 -comi — r '-S ^ h-ch-ch22 coob wherein te alkyl group with 1 to 4 carbon atoms, a cycloal- R1 represents a hydrogen atom or an amino protecting group alkyl or cycloalkenyl group having 3 to 6 carbon atoms, 10 or a radical of the general formulas: R2 is a hydrogen atom, a straight-chain or branched 4 4 r r cooh i 3 1 3 -c-ch * ch-r, -c-chc-r, I5 '5 R R or î4 -c-cooh r5 means what R3 represents a hydrogen atom, a lower alkyl or carboxyl group, X represents a halogen atom, a hydroxy or lower alkoxy group and R4 and R5 each independently represent a hydrogen atom, a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring having 3 to 5 carbon atoms, B1 represents a carboxyl protecting group and Z represents a chlorine, bromine or iodine atom; as starting materials for carrying out the method according to claim 26. 30. Starting materials according to claim 29, wherein Z represents a chlorine or iodine atom and R2 for lower alkyl with 1-4 C atoms, cycloalkyl with 3 to 5 carbon atoms, 1-carboxycycloalk-l-yl with 3 to 5 carbon atoms in the cycloalkyl radical, allyl, propargyl or 1-carboxy-l-yl-lower alkyl having 1-5 C atoms in the alkyl radical. 31. Starting materials according to claim 30, wherein R2 denotes a methyl, ethyl, cyclopentyl, allyl or propargyl group. 32. Starting materials according to claim 31, wherein B1 denotes a benzhydryl group and R1 denotes a hydrogen atom or a trityl group. 33. Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetamido] -3- (3-iodo-1-propen-1-yl) -3- cephem-4-carboxylate, Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-ethoxyiminoacetamido] - 3- (3-iodo-1-propen-1-yl) - 3-cephem-4-carboxylate, Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-cyclopentyloxyiminoacetamido] - 3- (3-iodine-1-propen-1-yl) - 3-cephem-4-carboxylate, Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 25 2-allyloxyiminoacetamido] - 3- (3-iodo-1-propen-1-yl) - 3-ce-phem-4-carboxylate, Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-propargyloxyiminoacetamido] - 3- (3-iodine-1-propen-1-yl) - 3-cephem-4-carboxylate, 30 diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-methoxyiminoacetamido] -3- (3-chloro-1-propen- 1-yl) - 3-cephem-4-carboxylate, Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-ethoxyiminoacetamido] -3- (3-chloro-1-propen-l-yl) -3-ce-35 phem-4-carboxylate, Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) -2-cyclopentyloxyiminoacetamido] - 3- (3-chloro-1-propene 1-yl) - 3-cephem-4-carboxylate, diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 40 2-allyloxyiminoacetamido] - 3- (3-chloro-1-propen-1-yl) - 3-ce-phem-4-carboxylate, or Diphenylmethyl-7- [2- (5-amino-1,2,4-thiadiazol-3-yl) - 2-propargyloxyiminoacetamido] - 3- (3-chloro-1-propen- 1-yl) - 3-cephem-4-carboxylate, as starting materials according to Claim 45. 34. Compounds of the general formula XXII: wherein ®-N = Q is a quaternary ammonio group, 55 as starting materials for carrying out the process according to claim 27. 35. Starting materials according to claim 34, wherein ®-N = Q 6C is selected under 7 669 197 ^ r13 i * 15 © -n , 16th , 17th © -n- , 18th "{.CVn and in what R13, R14 and R15, which may be the same or different, are a lower alkyl, lower alkenyl, amino lower alkyl group with the proviso that the amino group is not on the a carbon atom, or a hydroxy lower alkyl group with the proviso that the Hydroxy group is not on the a carbon atom mean; R16 is a hydrogen atom, a lower alkyl, lower alkoxy, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, formylamino, lower alkanoylamino, carboxy, hydroxy, carboxy-lower alkyl, carboxy-lower-rigalkylthio, hydroxy-lower alkyl, Halogen-lower alkyl, amino lower alkyl, lower alkoxy lower alkyl, carbamoyl or N-lower alkyl carbamoyl group or a divalent alkyl group having 3 to 5 carbon atoms. R17 for a lower alkyl, lower alkoxy lower alkyl, halogen lower alkyl, allyl, hydroxy lower alkyl group with the proviso that the hydroxyl group is not on the a carbon atom, an amino lower alkyl group with the proviso that the amino group is not on the a carbon atom, or for is a phenyl-lower alkyl group; R's is a hydrogen atom, a lower alkyl, lower alkoxy, lower alkoxy lower alkyl, lower alkylthio, amino, lower alkylamino, di lower alkylamino, carboxy, hydroxy, carboxy lower alkyl, hydroxy lower alkyl, Amino lower alkyl, formylamino, lower alkanoylamino, carbamoyl or an N-lower alkyl carbamoyl group; n represents an integer from 1 to 3 inclusive; 20 Z is CH2 or, if n is 2, also S, O or N-R19, where R'9 is a hydrogen atom or a lower-rigalkyl group; and R20 and R21, which may be the same and different, are a hydrogen atom, a lower alkyl, lower alkoxy, lower 25-alkylthio, amino, lower alkylamino, di-lower alkylamino, carboxy, hydroxy, hydroxy lower alkyl, amino lower alkyl ", Lower alkoxy lower alkyl, carboxy lower alkyl, carboxy lower alkylamino, lower alkanoylamino, carboxy lower alkanoylamino, carbamoyl or a 30 N lower alkyl carbamoyl group 36. Starting materials according to claim 34, wherein ®-neq for 1-methyl-pyrrolidinio, pyridinio, 2-amino-5-thiazo-lo [4,5-c] pyridinio, trimethyl-ammonio, 3-amino-pyridinio, 3-formylamino-pyridinio, 3-carbamoyl-pyridinio, 4-carb-35 amoyl-pyridinio, 3-aminomethyl-pyridinio, 2-methyl-thia zolio, 3-hydroxymethyl-pyridinio, 4-hydroxymethyl-pyridi-nio, 4- (N-methyl-carbamoyl) pyridinio, 4-carboxypyridinio, 2,3-propylene-pyridinio, 3-carboxymethyl-pyridinio, or 4-carboxymethyl-thiopyridinio is. 40 37. Process for the preparation of the starting materials according to one of claims 29-33 of the general formula: R1Hir ^ - II "CONH ^ OR2 c ^ "N coob h = ch-ch2z wherein te alkyl group with 1 to 4 carbon atoms, a cycloal- R1 represents a hydrogen atom or an amino protective group 50 kyl or cycloalkenyl group having 3 to 6 carbon atoms, or a radical of the general formulas: R2 is a hydrogen atom, a straight-chain or branched I 3 -cs ch «ch-r B5 R I -c-cooh R I 3 -ç-csc-r i5 cooh or 65 means what R3 represents a hydrogen atom, a lower alkyl or carboxyl group. X represents a halogen atom, a hydroxy or lower alkoxy group and R4 and R5 are each independently a water 669 197 8th Substance atom, mean a methyl or ethyl group or together with the carbon atom to which they are attached form a cycloalkylidene ring with 3 to 5 carbon atoms, B1 denotes a carboxyl protective group and 5 Z represents a chlorine atom; characterized in that conh CH = P (Ph) 3, • coob man A) a compound of the general formula: H2Nn -M A coo.b1 with a compound of the general formula: r-COOH implements E) and the compounds thus obtained are reacted with CICH2CHO. 38. Process for the preparation of the starting materials according to one of claims 29-33 of the general formula: ch = chch2 z. R ^ n XP coob XOR2 20 in which the radicals R1, R2 and B1 have the meaning given in claim 37 and Z is bromine or iodine, characterized in that the process is carried out according to claim 37 and then one of the so obtained wherein in these formulas R1, R2 and B1 the Compounds with sodium iodide or potassium iodide given above have meanings to form a compound which is generally reacted with sodium bromide or potassium bromide. 39. Process for the preparation of the starting materials of the general formula XXII according to claims 34 to 36 NEN formula: n YY ■ c- II N ■ conh " r 30th H2N- COOB ch ^ cl r © ch »ch-ch2-n = u XXII implements B) then the compounds thus obtained with sodium iodide or potassium iodide to give a compound of the general formula: 35 cocß r! hn ' ■ CONH No. 2 wherein ®-N sQ is a quaternary ammonio group, characterized in that A) the compound of the formula: 40 -O- CHO ch..i coob iS with the compound of the formula: implements C) the compounds thus obtained with triphenylphosphine to a compound of the general formula: ? l n \ 2 S 'OR conh '(Ph) H2N ' 50 0- CH2C1 3 55 COOCH (Ph) 2 to a compound of the formula: coob o -CH = N-f S N where Ye is an anion, or x '' '' B1) reacting a compound obtained according to stage A) with tri-phenylphosphine to form one of the compounds obtained according to stage C), D) reacting a reaction obtained according to stages C) or B1), Bonds with a base to a compound of general B) then the compound thus obtained with sodium NEN formula: Umjodid or potassium iodide to a compound of the formula: N \ JJ ^ CH2C1 COOCH (Ph) 2 9 669 197 COOCH (Ph) 2 implements C) then the compound thus obtained or the compound obtained in step A) with triphenylphosphine to give the compound of the formula: COOCH (Ph) where Ye is an anion, D) the compound thus obtained with a base to give the compound of the formula: & Nvs ^^ CH-P (Ph) 3 COOCH (Ph) 2 implements E) the compound thus obtained with CICHUCHO to the compound of the formula: implements F) then the compound thus obtained with sodium iodide or potassium iodide to give the compound of the formula: > 'CH = CH-CH, I COOCH (Ph) 2 implements G) the compound thus obtained then with a secondary amine R HN < R ' wherein R and R 'each represent a methyl group or together form a pyrrolidine ring, to a compound of the general formula: CH = N ' r COOCH (Ph) 2 implements H) then the compounds thus obtained with a compound R "Y, where the radical -NRR'R" corresponds to the radical Q = N®- and Y represents a chlorine, bromine or iodine atom, to give a compound of the general formula: : h = n : h = chch, Ì ^ = Q cooch (Ph) 2 implements, or Eq) reacting the compound obtained according to stage F) with a tertiary amine Q = N to give a compound obtained according to stage H), I) one of the compounds obtained according to stages H) or Eq) is reacted with Girard reagent T or HCl to give compound XXII. 40. Pharmaceutical composition containing an antibacterially effective amount of at least one compound according to one of claims 1 to 25 together with a pharmaceutically acceptable carrier.