DE3111159A1 - (ALPHA), SS-DISUBSTITUTED ACRYLAMIDOCEPHALOSPORINE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AND VETERINE MEDICAL CONTAINERS THEREOF - Google Patents

Description

R 52 617

Registrant: FARMITAQA CARLO ERBA Sp ₀ Ac Via Carlo Imbonati 24
1-20159 Milan

α _f B-Di substituted acrylamidocephalosporins, processes for their preparation and pharmaceutical and veterinary compositions containing them

The invention relates to new 7- «, ß-disubstituted acrylamidocephalosporins, a process for their preparation and pharmaceutical and veterinary agents containing them

The compounds according to the invention have the general formula

A-C-CONH-

R ZR ₁

where mean:
Z -O- or -S-;

A is phenyl or a 5-membered or 6-membered heteromonocyclic Ring which contains at least one double bond and at least one heteroatom from the group N, S and 0, wherein the phenyl and the heteromonocyclic ring are unsubstituted or are substituted by one or more substituents, who are selected from the group:

J11115S

if

α) C ₁ -C ₆ -

b) halogen,

c) halogen-C.-C ^ -alkyl,

d) -N, wherein each of the groups R ₀ and R-, which are the same or

^R 3

can be different, hydrogen, C, -C, -alkyl, G.-Cy-acyl or one of the groups R ~ and R «is hydrogen and the other mean an amino protecting group,

e) -OR., in which R, represent hydrogen, C 1 -C 4 -alkyl, C _o -C, -alkenyl or a hydroxy protecting group, or

f) a group -0- (CH ₂ ) _ra -C00R ₅ , in which m is the number 1, 2 or 3 and Rg is hydrogen, C.-C ^ -alkyl, acetoxymethyl or a carboxy protective group;

R is hydrogen, -OCH ₃ or -SCH ₃ ;

R, hydrogen or a branched or unbranched (straight-chain) saturated or unsaturated C 1 -C, -hydrocarbyl group which is unsubstituted or substituted by one or more substituents. which are selected from hydroxy, cyano, -CONH ₂ and -COOR ₅ , in which R _{5 has} the meanings given above;

Y 1) hydrogen,

2) halogen,

3) hydroxy,

4) C, -C, alkoxy,

5) -CH ₂ -OCOCH ₃ ,

, where R, hydrogen, C.-C, -alkyl, carb-

z-

is oxy, cyano or carbamoyl, or 6) -CH ₂ -S-HSt, where Hst is

α ¹ ) a 5-membered or 6-membered heteromonocyclic ring which contains at least one double bond and at least one heteroatom from the group consisting of N, S and 0, the heteromonocyclic ring being unsubstituted or substituted by one or more substituents selected from :

a ") Hydroxy, C ^ -C, -alkoxy, halogen, aliphatic C.-C.-acyl,

b ") C.-C 1 -alkyl which is unsubstituted or substituted by one or more substituents selected from hydroxy and halogen,

c ") C ₀ -C.-alkenyl which is unsubstituted or substituted by one or more substituents selected from hydroxy and halogen,

d ") -SR ^, in which Rj is hydrogen or C, -C, -alkyl, or -S-CH ₂ COOR ¹ , in which R ^{f is} hydrogen, C« -C, -alkyl or a carboxy protective group,

e ¹¹ ) - (CH ₀ ) -C00R ·, -CH = CH-COOR ', - (CH ₀ ) -C0l <!? 2 or zn zn "^ o

- (CH ₂ ) _n -CN, in which η represents the number 0, 1, 2 or 3 and R ¹ , R ₀ and R ₀ are those given above

ζ ο

Have meanings, f ") - (CH ₀ ) -SO ₀ H, in which η has the meanings given above.

JL Π O

gen has, _p

g ") - (CH ₀₎ -NL _ wherein n, R ₀ and R ₀ The indicated above, z η κ" ζ ο

have important meanings, or

h ") a heterobicyclic ring containing at least two Contains double bonds, wherein each of the condensed heteromonocyclic rings, the same or different

may be separated, is a 5-membered or 6-membered heteromonocyclic ring which has at least one heteroatom selected from the group consisting of N, S and 0 _; contains, wherein the heterobicyclic ring is unsubstituted or substituted by one or more Su bstituenten selected from the groups (a "), (b"), (c "), (d"), (e ") given above, (f ¹¹ ) and Cg-);

M is a free or esterified carboxyl group (i.e. a carboxylic acid or ester group)

as well as the salts, in particular pharmaceutical and veterinary compatible salts of the compounds of formula (i), and all possible isomers, for example the syn and anti-isomers, ice- and träns ~ isomers, and optical isomers and their mixtures, those having antibacterial activity equipped metabolites and the metabolic precursors of the compounds of formula (i).

In particular when in the compounds of the formula (i) R Means hydrogen, the 7ß-chain can be present in the syn as well as in the anti configuration: as already stated, Both the individual syn and anti isomers of the compound of the formula (i) and their mixtures fall within the scope of the present invention. If in the compound of formula (i) A according to one of the preferred features of the invention a 2-aminothiazol-4-yl group means, it can assume one or both of the two tautomeric forms (Ia) and (Ib)!

R, N _o H

(Ia)
(Thiazoline form) (thiazole form)

each of the more authoritative forms is to be regarded as lying within the scope of formula (i). FL
Ib the meanings given above.

Formula (i) is to be viewed lying down. FL has in the formulas Ia and

Amino, hydroxy and carboxy protecting groups are the protecting groups as they are usually used in peptide chemistry · Examples of amino protective groups are formyl, an optionally Halogen-substituted aliphatic C. to C.sub.1 acyl, preferably Chloroacetyl or dichloroacetyl, tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl or trityl.

The hydroxy groups, when present, can if desired be protected.Examples of hydroxy protecting groups are formyl, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, Tetrahydropyranyl, trityl or silyl, especially trimethylsilyl or dimethyl-tert-butylsilyl.

Examples of carboxy protective groups are tert "-butyl, benzhydryl, p-methoxybenzyl, p-nitrobenzyl, trityl and trialkylsilyl.

When R. is a C. to C.sub.1 aliphatic hydrocarbon group as defined above means, it is preferably C -C -alkyl, in particular methyl, ethyl, n-propyl or Isopropyl, or around C ^ -Cg-alkenyl, preferably allyl, given

if substituted as indicated above.

When A is a 5-membered or 6-membered heteromonocyclic Means ring, it is preferably furyl, Thienyl, thiazolyl, thiadiazolyl, imidazolyl, triazolyl, pyridazinyl, in particular 2-furyl, 2-thienyl or 2-amino-4-thiazolyl, all of which are optionally substituted as indicated above.

If Y is a 5-membered or 6-membered heteromonocyclic ring as defined above, it is sxh preferably tetrazolyl or thiadiazolyl, in particular tetrazolyl, which is optionally substituted as indicated above isto

When Y is a heterobicyclic ring as defined above, so it is preferably tetrazolopyridazinyl, Tetrazolopyrazinyl, thiadiazolopyridazinyl or triazolopyridazinyl, in particular about 6-TetrazoloCl, 5-b] pyridazinyl, optionally substituted as indicated above.

The alkyl, alkenyl and acyl groups can be branched or unbranched be (straight-chain) groups. A C 1 -C 4 -alkyl group is preferably methyl or ethyl. A C 1 -C 4 -alkenyl group is preferably C 1 -C 4 alkenyl, especially allyl. One C. -C 1-4 acyl group is preferably C.sub.1 -C.sub.1 alkanoyl, in particular Acetyl or Propionyl or Benzoylo A halogen atom is preferably chlorine, fluorine or bromine. A halo-C «-C, -alkyl group is preferably a trihalo-C-C ^ -alkyl group, especially trifluoromethyl.

AWAY

If M is an esterified carboxy group, it is preferably a group of the formula -COOT, where T is one of the radicals -CH-OCR ₀ and -CH-QC-OR _1n ,

f H "f Ii ' ^υ

R ₈ 0 R ₈ 0

wherein R _{g is} hydrogen or C ^ C ^ alkyl, Q -0- or -NH-, R _{9 is} an alkyl group (e.g. C, -C, -alkyl) or a basic group, in particular an alkyl group (e.g. C, -C, - Alkyl) or an aralkyl group (e.g. benzyl group) substituted by at least one amino group, which in turn may be unsubstituted or substituted, for example, R ₀ denotes alkyl

NH-CH ₀ , aralkyl-NH-CH-, ο ο

-CH ₂ NH ₂ ; R ₁₀ means an alkyl

group, preferably a Gj-C ^ -alkyl group such as methyl, propyl or isopropyl, an aryl group, preferably phenyl, a cycloalkyl group, preferably cyclopentyl, cyclohexyl or cycloheptyl, a heteromonocyclic ring such as pyridyl, a bicyclic ring such as indanyl or aralkyl group such as benzyl _e.

The salts, in particular the pharmaceutically and veterinarily acceptable salts of the compounds of the formula (i) include salts made with inorganic acids, such as hydrochloric acid or sulfuric acid, or with organic acids, such as citric acid, tartaric acid, malic acid, maleic acid, mandelic acid, fumaric acid or methanesulfonic acid, and with inorganic ones Bases such as sodium, potassium, calcium or aluminum hydroxides and alkali metal or alkaline earth metal carbonates or •• bicarbonates, or with organic bases, such as organic

JLO

Amines such as lysine, triethylamine, procaine, Dibeηzylamiη, N-benzyl-ß-phenethylamine, N, N ^f -dibenzyl-ethylenediamine, dehydroabietylamine, N-ethyl-piperidine, diethanolamine, N-methylglucamine, tris-hydroxymethylaminomethane, and the like will. Also, the inner salts, ie _o the zwitterions are within the scope of the present invention.

A preferred class of compounds according to the invention are those of the general formula (I), in which: R is hydrogen or -S-ChL;

Z -0- or -S-;

R ₁ hydrogen, ^ -C ^ alkyl, C ^ C ₄ -AIk ₆ ηyl, - (CH ₂ ) _n -C00H,

- (CHp) -CN, - (CI-L) -CONHp, in which η is as given above Has meanings

-C-COOH or -CH = CH-COOH;
A phenyl, thienyl or * \

where R ,, hydrogen or an amino protecting group and R- « Hydrogen, hydroxy, -0 - ^ - C ^ alkyl, -0-C -C ^ -alkenyl,

-0- (CH _n ) -COOR ₀ , in which m and R ₀ are as indicated above JL m Δ Δ

have benign meanings;

Y is hydrogen, halogen, hydroxy, C ₁ -C ₃ -AIkOXy, -CH ₂ -OCOCH ₃ or -CHp-S-Het, in which Het is:

l) a tetrazolyl radical which is unsubstituted or substituted by C ^ Cg-alkyl, C ₂ -C ₄ -AIk ₀ η yl, - (CH ₂ ) _m -C00R ^f ,

-CH = CH-COOR ¹ , - (CH ₀ ) -CN, - (CH ₀ ) -CONH ₀ , - (CH ₀ ) -SO ₀ H,

Δ xn Δ m Δ Δ m ο

- (CH ₀ ) -N. _D , where m, R ', R ₀ and R "have the above given Δ m * ^ o * ■ **

Have meanings

2) a thiadiazolyl radical which is unsubstituted or substituted by C ₁ -C ₄ -AlCyI, C ^ C ^ alkenyl, -SH, -SCH ₃ ,

-SCH ₀ COOH, - (CH ₀ ) -COOH, _K1 ^ R ' _{O. Df} . _D , 2 ' ^v 2'n' -Nc ^ .2, worm R ' ₂ and R'

in each case independently of one another hydrogen or C.-C.-alkyl represent and η has the meanings given above, or

3) a heterobicyclic ring selected from tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each of which is optionally substituted by hydroxy, -SH ₇ -C0NC ^ _D 2, wherein R ₀ and

3 R_ have the meanings given above, C - C _o -alkyl, C -C ^ -alkenyl, -COOR ¹ , -S-CH ₂ COOR ¹ , -CH ₂ -COOR ', -CH = CH-COOR', in which R ^{1 has} the meanings given above, or -Nv ^^ 2, in which R «and R« have the meanings given above,

as well as the salts, especially those pharmaceutical or veterinary compatible salts thereof.

Particularly preferred compounds according to the invention are compounds of formula (i), in which:

R is hydrogen or -S-CH ₀ ,

Z -0- or -S-,

R ₁ -CH ₀ or -CH ₀ COOH, _c

R -Nv / \
A phenyl, thienyl or 11 N]> | wherein R _{11 has} the above

has given meanings and R. _{o represents} hydrogen, hydroxy or methoxy, and

Y -CH ₂ OCOCH ₃ or -CH ₂ -S-Het, in which Het substitutes tetrazolyl or tetrazolopyridazinyl substituted by methyl

KJ-

by amino, -COOH or -O ^ -COOH, and the salts, in particular the pharmaceutically or veterinarily acceptable salts thereof, ₀

Specific examples of compounds according to the invention are as follows:

1) 7-Ca-Phenyl-ß-methoxyacrylamido3-3- [(1 -methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-isomer);

2) 7- [α- (2-Thienyl) -β-methoxyacrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (syn-isomer);

3) 7- [α- (2-Thienyl) -β-methoxyacrylamido] -3 - [(i-methyl- _{1,2 /} 3 _/ 4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-isomer);

4) 7- [α- (2-Thienyl) -β-methoxyacrylamido] -3-C (tetrazolo [1,5-bJ-pyridazin-6-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-isomer);

5) 7- [α- (2-aminothiazol-4-yl) -β-methoxyacrylamido] -3-acetoxymethyl-S-cephem ^ -carboxylic acid (syn-isomer) ;.

6) 7- [α- (2-aminothiazol-4-yl) -β-methoxyacrylamidoJ-3-C (imethyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4- carboxylic acid (syn-isomer);

7) 7- [af ⁾ henyl-β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

8) 7- [α-phenyl-β- (bis-methylthio) acrylamido] -3 - [(i-methyll, 2 _/ 3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid;

9) 7- [α- (2-thienyl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

10) 7-C «- (2-thienyl) -β- (bis-methylthio) acrylaniido] -3 - [(1-methyl-1,2 , Z, 4-tetrazol-5-yl) thiomethyl] -3- cephem-4-carboxylic acid;

11) 7- [a- (2-thienyl) -ß- (bis-methylthio) acrylamido] -3-C (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl] -3-cephem-4- carboxylic acid;

12) 7 ~ [a- (2-thienyl) -ß-methylthio-ß-carboxymethylthioacrylamido] -3 - [(tetrazolo [l _f 5-b] pyridazin-6-yl) thiomethyl] -3-cephem-4- carboxylic acid;

13) 7- [α- (2-aminothiazol-4-yl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

14) 7- [a- (2-aminothiazol-4-yl) -S-S- (bis-methylthio) acrylamido] - 3 - [(l-methyl-l, 2, 3,4-tetrazol-5-yl) thiomethyl ] -3-cephem-4-carboxylic acid;

15) 7- [oc- (2-aminothttiazol-4-yl) -β- (bis-methylthio) acrylamido] -3-C (tetrazoloC1,5-b] pyridazin-6-yl) thiomethyl] -3-cephem -4-carboxylic acid;

16) 7- [α- (2-aminothiazol-4-yl) -β- (bis-methylthio) acrylamido] -3- C (8-aminotetrazoloCl, 5-b] pyridazin-6-yl) thiomethyl] -3 -cephem-4-carboxylic acid;

17) 7- [δ- (2-aminothiazol-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(8-carboxytetrazolo [l, 5-b] pyridazin-6-yl) thiomethyl] - 3-cephem-4-carboxylic acid;

18) 7-Ca- (2-aminothiazol-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(8-carboxymethyl-tetrazoloC1,5-b3-pyridazin-6-yl) -thiomethyl] -3-cephem -4-carboxylic acid;

19) 7-Ca- (2-aminothiazol-4-yl) -ß-methylthio-ß-carboxymethylthioacrylamido] -3 - [(tetrazolo [l, 5-b] pyridazin-6-yl) thiomethyl] -3- cephem-4-carboxylic acid;

IH

20) 7- [α- (2-imino-3-hydro.xythiazolin-4-yl) «" β- (bis-methylthio). acrylamido] -3 ~ acetoxymethyl-3-cephem-4-carboxylic acid;

21) 7- [a- (2-Imino-3-hydroxythiazolin-4-yl) -ß- (bis-methylthio) acrylamido] -3-C (i-methyl-1, 2,3,4-tetrazol-5-yl) thiomethylJ-S-cephem- ^ carboxylic acid;

22) 7-1 a- (2-Imino-3-hydroxythiazolin-4-yl) -ß- (bis-methylthio) acrylamido] -3-C (tetrazoloEl / 5-b] pyridazin-6-yl) -thiomethyl- 3-cephem-4-carboxylic acid;

23) 7- [α- (2-Imino-3-hydroxythiazolin-4-yl) -β-methylthio-β-carboxymethylthioacrylamido] -3 - [(tetrazoloCl, 5-b] pyridazin-6-yl) thiomethyl] -3 -cephem-4-carboxylic acid;

24) 7- [α- (2-imino-3-methoxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid;

25) 7-Ca- (2-imino-3-methoxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(l-methyl-1,2,3,4-tetrazole-5- yl) thiomethyl] -3-cephem-4-carboxylic acid;

26) 7- [Ä- (2-Imino-3-methoxythiazolin-4-yl) -ß- (bis-methylthio) acrylamido] -3-C (tetrazoloEl _/ 5-b] pyridazin-6-yl) -thiomethyl] -3-cephem-4-carboxylic acid;

27) 7-Ca :-( 2-imino-3-methoxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3- C (8-aminotetrazoloCi / 5-b] pyridazin-6-yl) thiomethyl ] -3-cephem-4-carboxylic acid;

28) 7- [α- (2-Imino-3-methoxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(8-carboxytetrazolone, 5-b] pyridazin-6-yl) thiomethyl ] -3-cephem-4-carboxylic acid as well as the salts, in particular the pharmaceutically and veterinarily acceptable salts thereof

The structural formulas of the compounds listed above are given in the following table, in which Ph = phenyl, Th = 2-thienyl and Ac = -COCH- (acetyl).

- 13 "table

binding A. R. Z - ^CH 3 Y 3 -CH-O-Ac 1 Ph H- -0- -CH ₃ NN
-CH-S A _n J ¹ N NN
-ch-s-AwJn
2 ^Ν ^ ™
Kl 2 Th H- -0- -CH ₃ -CH ₂ -O-Ac -CH ₂ -S \ jl- \ t 3 Th H- -0- -CH ₃ NN
-CH -s-iL Jn -CH 2 ~ S "S | -N-N 4th Th H- -0- -CH ₃ -CH ₂ -SJCfJ -CH-O-Ac 5 "Vl
HN- ^L H- -0- -CH ₃ -CH-O-Ac N_N 6th H- -0- -CH ₃ N_N
^ CH ₃ ; 7th Ph H ₃ CS- -S- -CH ₃ -CH-O-Ac
■ la δ Ph H ₃ CS- -S- N-N -CH ₃ 9 Th H ₃ CS- —S- -CH ₃ 10 Th H ₃ CS- -S- - ^CH 3 11 Th H ₃ CS- -S- -CH COOH
2 12th Th H ₃ CS- -S- 13th " ¹ Ls. H ₃ CS- .-S- · -CHj 14th "Vs H ₃ CS- -S-

- 14 -

Tabel - continuation -S- - ^CH 3 -CH -S-CX.il 15th HN - ^ - H ₃ CS- I I I
U) U) U)
I I I -CH ₃ COOH j
CH ₂ COOH; 16
L7
18th HN- ^
HN ^ ₅
HN. *
• Tfl
HN- ^L rc rc ac
Cj Cj'cj
OOO
I I I
CO CO CO -S- -CH ₂ COOH -CH ₂ -SJCf-I 19th H ₃ CS- -S- -CH ₃ -CH-O-Ac
Z 20th H ₃ CS- -S- -CH ₃ NN ';
C * UC -Ji Ll ί
² ^ CH ₃ 21st HON— * ~ H ₃ CS- -S- -CH ₃ I * 11
C ' H __ Q _L ί ^ Μ— - ltl 22nd HON - H ₃ CS- -S- -CH COOH
Z ΛΙΙ Q j '{J 23 HN ο H ₃ CS- -S- - ^CH 3 -CH-O-Ac
it 24 HN ς -
H ₃ CON- ¹ - H ₃ CS- -S-
-S- -CH ₃
-CH ₃ NN
- ^c V ^s "VJh ₃
-CH ₂ -S -U _n ^ _n I 'I _n ! 25th
26th H ₃ CON - ^ -
ViL
H ₃ CON- ¹¹ - rc ar
Co CJ
0 0
ι ι
U) U) -S- - ^CH 3 NH ₂
I * 'it
-CH ₉ -S " ¹ ^ - ^ N- N 27 3 ' H ₃ CS- -S- -CH ₃ COOH 28 H ₃ CON- ^L H ₃ CS-

The compounds of the invention can be prepared by a process which consists in that

a) a compound of the general formula

_O iN ^ Y _(II)

where Y and M have the meanings given above and E is amino or a group -N = C = $, where 0 is oxygen or sulfur,
or a reactive derivative thereof with a compound of the general formula

AC-COOH
Il

wherein A, R, Z and R. have the meanings given above, or with a reactive derivative thereof and desired η if the protecting groups, if any, are removed; or

b) a compound of the general formula

AC-CONH-1 ^S.

¹¹ y

CZR ₀ *

N Vj ^ - CH _{2 OCOCH 3} ^R M

wherein A, R, Z, R. and M have the meanings given above, or a reactive derivative thereof with a compound the general formula

HS-Het (V)

wherein Het has the meaning given above, or reacts a reactive derivative thereof and, if desired the protecting groups, if any, are removed to form a compound of formula (i) wherein A, R, Z, R. and M have the meanings given above and Y -CH «-S-Het means in which Het has the meanings given above; or

c) a compound of the general formula

AC-CH-CONH -, _r ->,. _x

«2 η T 1 (VI)

wherein A, M, R- and Y have the meanings given above and each of the symbols Z independently of one another means oxygen or sulfur,

or a salt thereof methylated and, if desired, the protective groups, if present, removed to provide a compound of formula (i) wherein A, M, Y and Z are those given above Have meanings and R -OCH «or -S-CH ,, and in which R- is either When starting from a compound (VI) in which R 1 is hydrogen, or a branched one is methyl or unbranched (straight-chain) saturated or unsaturated aliphatic C -C hydrocarbon group, as above in relation to the formula (i) defined when starting from a compound (VI) in which R. has a meaning other than that of hydrogen has; or

d) a compound of the general formula

311115

A-CH ^ -CONH-

J 11 ^ J- V

(VII)

² J - * ^ υ

wherein A, M and Y have the meanings given above, with a compound of the general formula

Z
HC- OR "(VIII)

wherein R "denotes C.-C, -alkyl and Z denotes those given above Has meanings

reacts and, if desired, the protective groups, if present, removed to form compounds of the formula (I) in which R and R- are both hydrogen and Z, A, M and Y have the meanings given above, and if desired, a compound of the formula (i _{), in which R 1 is} hydrogen and R, Z, A, M and Y have the meanings given above, or a salt thereof is etherified to form compounds of the formula (i) in which R 1 has the meaning given above with the exception of hydrogen and R, Z, A, M and Y have the meanings given above, and / or, if desired, a compound of the formula (i) in which M is carboxy, converted into a salt, in particular a pharmaceutically or veterinarily acceptable salt thereof, and / or if desired prepares a free compound from a salt and / or, if desired, converts a compound of the formula (I) or a salt thereof into another compound of the formula (i) or a salt thereof and / or g If desired, an isomer mixture is separated into the individual isomers.

In the compounds of the formulas (il), (Hl), (IV), (V), (Vl) and (VII) the carboxy, amino and hydroxy groups, if any

if necessary, protected in a conventional manner before the reaction is carried out. Examples for protecting groups are those commonly used in peptide synthesis, such as those mentioned above are specified. The carboxy protecting groups can be used at the end of the Reaction in a known manner, for example by mild acid hydrolysis or by catalytic hydrogenation for example with Pd / C at room pressure. The amino protecting groups can be removed in a known manner at the end of the reaction for example, the monochloroacetyl group can be removed by treatment with thiourea. The formyl and trifluoroacetyl groups can be removed by treatment with potassium carbonate in aqueous methanol and the trityl group can be removed by treatment with formic acid or with trifluoroacetic acid. The hydroxy protecting groups can be known • are removed in an analogous manner »Since, however, the compounds of the formula (i) which contain these protective groups are also removed are within the scope of the present invention, deprotection is not an essential step in the process.

The starting materials used in any of the above processes (a) to (d) can, if one or more, be asymmetric Carbon atoms are present, either optically be active or racemic compounds. In addition, the starting materials can be syn or anti isomers and their mixtures as well as cis or trans isomers and their Trade mixtures.

A reactive derivative of a compound of formula (il) can for example be an amine salt, a silyl ester or a

Τ9 -

Metal salt when M is carboxy.

A reactive derivative of a compound of formula (ill) can be, for example, an acyl halide, an anhydride or a mixed anhydride, an amide, an azide, a reactive one Ester or a salt such as a salt made with an alkali metal or alkaline earth metal, ammonia or an organic Base is formed.

A reactive ester can, for example, be a p-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl, N-hydroxysuccinimide or N-hydroxyphthalimide ester.

The reaction between a compound of formula (II) or a reactive derivative thereof and a compound of the formula (Hl) or a reactive derivative thereof can either at room temperature or with cooling, preferably at about -50 C to about +40 C in a suitable solvent, e.g. in acetone, Dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, N, N-dimethylformamide or 1,2-chloroethane or in one Mixture of water and a water-miscible solvent and, if necessary, in the presence of a base such as sodium bicarbonate, Potassium bicarbonate or a trialkylamine, or in the presence of another acid acceptor such as an alkylene oxide, such as propylene oxide, be carried out «If a compound of the formula (III) with a compound of the formula (II), where E is amino, is reacted in the form of a free acid or in the form of a salt, it is advantageous that the reaction in the presence of a condensing agent such as N, N '~ Dicyclohexylcarbodiimide. The possibly

Removal of protective groups carried out at the end of the reaction can, as indicated above, be carried out in a known manner.

The reaction between a compound of the formula (IV) or a salt thereof and a compound of the formula (V) or a reactive derivative thereof, such as, for example _, an alkali metal salt, can be carried out in water or in a mixture of water and an organic solvent such as acetone , Ethanol, dioxane or tetrahydrofuran, in the presence of about two equivalents of a base such as sodium bicarbonate. The reaction temperature is preferably within the range of about 5 to about 90 ° C. and the pH is preferably maintained at about 5 to about 7.5. If desired, a buffer such as sodium phosphate or acetate can be used. On the other hand, the same reaction can be carried out without any base and in a strictly anhydrous solvent at temperatures within the range of about 50 to about 120 C and for reaction times within the range of a few Hours to a few days. The preferred solvent is acetonitrile and an inert atmosphere (such as nitrogen) may be advisable to prevent oxidation of the heterocyclic thiol (V). The subsequent removal of the protective groups, which may be carried out, can be carried out using known methods, for example those as indicated above.

A salt of a compound of the formula (VI) can, for example its a salt with an alkali metal or an alkaline earth metal.

The methylation of a compound of the formula (VI) or one

Vi -

Salt thereof can be carried out by treatment with a methyl halide such as bromide, chloride, iodide, preferably iodide, in an organic solvent such as benzene, Toluene, xylene, dioxane, acetone or chloroform, preferably benzene, at temperatures within the range of about 20 to about 80 ° C., preferably from 50 to 70 ° C., and for reaction times which vary from 30 minutes to 2 hours. The reaction of a compound of the formula (VIl) with a compound of formula (VIII) can in the presence of a strong base, such as an alkali metal such as sodium, in a suitable anhydrous organic solvents such as diethyl ether, N, N-dimethylformamide, dioxane, tetrahydrofuran or the like Solvent, preferably in diethyl ether, at temperatures within the range from about 5 to about 40 ° C., preferably at room temperature, and for reaction times varying from 12 to 36 hours, preferably 24 hours.

The etherification of a compound of formula (i) wherein R. Is hydrogen, or a salt thereof, such as e.g. of the salt with an alkali metal or alkaline earth metal, can be carried out by reaction with a suitable compound of the formula (R ")« SO., wherein R "are those given above Has meanings in an inert aqueous or organic solvent, e.g. in ethanol, dioxane, N, N-dimethylformamide or a mixture of these solvents with water in the presence of a base such as NaOH or KOH, preferably NaOH, at temperatures within the range from about 0 C to the reflux temperature and for reaction times which from about 2 to about Hours vary, one compound of the formula (i)

22 -

hold, wherein R _{1 is} C -C ₆ -alkyl.

The same Verötherung can also be carried out by reaction with a suitable, optionally substituted halide of the formula R ¹ --X, where R ¹ . has the meanings given above for R ^ with the exception of hydrogen and X is halogen, preferably chlorine or bromine, with formation of a compound of the formula (i) in which R _{1 has} the meanings given above with the exception of hydrogen. The reaction can be carried out using approximately the same reaction conditions as given above for the methylation of a compound of the formula (VI).

Any transfer / connections that may have been carried out of the formula (i) into a salt and the conversion, if necessary, of a salt into a free compound using conventional methods, i.e. methods known per se in organic chemistry.

As indicated above, a compound of formula (i) or a salt thereof is converted into another compound of the formula (i) or a salt thereof; these conversions, if any, can also be carried out using conventional methods. The conversions carried out, if any, include the esterification of a compound of formula (i), in which M is carboxy, which can be carried out by reacting the compound of formula (i), in which the carboxy group is free or converted into a salt,

28 -

such as. in the form of a sodium, potassium, calcium or triethylammonium salt is present, with a suitable halide in an organic solvent, e.g. in acetone, tetrahydrofuran, Chloroform, methylene chloride, Ν, Ν-dimethylformamide, dimethyl sulfoxide or in a mixture of water and an organic solvent, e.g. in dioxane and acetone; the reaction temperature is within the range of about -20 to about +80 C. In addition, a compound of the formula (i) wherein M is an esterified Carboxy group means to be saponified, for example using an inorganic acid such as hydrochloric acid, or an inorganic base such as sodium or potassium hydroxide using in organic chemistry known procedures.

The separation of an isomer mixture into the individual isomers, which may be carried out, can also be carried out using conventional methods Procedure to be carried out. So can racemic Connections in the optical antipodes are separated, for example by splitting, for example. through fractional Crystallization of mixtures of diastereoisomeric salts and if desired, release of the optical antipodes from the salts * «

The cis and trans isomers or syn and anti isomers can by fractional crystallization or by chromatography, either by column chromatography or by high pressure liquid chromatography (H? LC) can be separated from their mixtures. The compounds of the formula (II) in which E is amino and Y is hydrogen, Halogen, hydroxy, C.-C, -alkyl or Cj-C, -alkoxy, represent known compounds or can be used according to known

Vt -

Process are produced. The compounds of the formula (II), where E means -N = C = JZi can be prepared, for example by reacting a compound of the formula (II) in which E is amino with phosgene or thiophosgene in the presence a hydrogen chloride acceptor using known methods.

The compounds of the formula

- COOH

(πι)

RCZR ₁

can be prepared by one of the processes (c) and (d) given above for the preparation of the compounds of the formula (i), for example (a ¹ ) by methylation of a compound of the formula

AC-COOR "
HZ-CZR (IX)

in which Z, A, R. and R "have the meanings given above, with formation of a C.-C, -alkyl ester of a compound of the formula (III) in which R is -OCH ₀ or -S-CH_, A and Z the have the meanings given above and R. is either methyl, if one starts from a compound (IX), or in which R. is hydrogen or an aliphatic C.-C, group, as defined in relation to the formula (i), if the starting point is a compound (IX) in which R- denotes such an aliphatic group be converted into another reactive derivative thereof using a process known per se,

~ 25 -

or (b ¹ ) by reacting a compound of the formula

A-CH ₂ -COOR "(X)

wherein A and R "have the meanings given above, with a Compound of formula

Z '

H-C- OR "(VIII)

to form a compound of the formula

A-C- COOR "

II (IHa)

H-C-Z-H

wherein A, Z and R ″ have the meanings given above, which can be converted either into the corresponding free acid or into another reactive derivative thereof using a process known ^{per se; or c 1} ) by etherification of a compound of the formula (purple ) or any other compound of the formula (III) in which R 1 is hydrogen, with formation of a compound of the formula (III) in which R has the meanings given above with the exception of hydrogen.

The reactions given above under (a ¹ ) / (b ¹ ) and (c ¹ ) can be carried out using the same reaction conditions as are given above for the analogous reactions which were used to prepare the compound of the formula (i) . In particular, a compound of the formula (III) in which A is the radical can be used

K ₁₂ 4-i

where R ^. and R- _{2 have} the meanings given above, according to

st

26 -

one of the following processes can be prepared a ") by reacting a compound of the formula

X-CH ₀ -CC-COOR " ² II II

where X is halogen, preferably chlorine, and R, Z, R- and R "have the meanings given above, or a reactive derivative thereof with a compound of Formula «

wherein R .. and R. ^ have the meanings given above; or

NCS-CH ₂ -CC-COOR "

b ") by reacting a compound of the formula

. \ (XIII)

R · ώ-κ ^

wherein Z, R, R ₁ and R "have the meanings given above, or a reactive derivative thereof with a compound of the formula

R ₁₂ -NH ₂ (XIV)

wherein R. ^ has the meanings given above, or a salt thereof to form a C.-C, ~ alkyl ester of a compound of the formula (III) in which A

R ₁₂ -I

- 27 -

means where R-- is hydrogen.

The reaction between a compound of formula (Xl) or a reactive derivative thereof which is, for example, a salt or an ester thereof can, and a compound of the formula (XIl) is preferably in an aprotic solvent, e.g. in Ν, Ν-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, Hexamethylphosphoric triamide or a mixture of these Solvent carried out. The reaction temperature is preferably within the range from about 0 to about +90 C.

The reaction between a compound of formula (XIIl) or a reactive derivative thereof, which can be, for example, a salt or an ester, with a Compound of formula (XIV) or a salt thereof can be dissolved in a suitable solvent, e.g. in water, methanol, ethanol, Dioxane, acetonitrile, Ν, Ν-dimethylformamide, N, N-dimethylacetamide or methylene chloride. A salt of a compound of formula (XIV) can be a salt with an inorganic Acid such as hydrochloric acid or sulfuric acid, or with an organic acid such as lemon, tartaric acid, oxalic acid or p-toluenesulfonic acid.

The reaction temperature is preferably within the range from about 0 to about 90 ° C and the pH is preferably maintained at about 1 to about 7.5.

A C - C, alkyl ester of the compounds of formula (Hl), the is obtained by the above two steps (a ") and (b"),

- 28 -

can, if desired, be incorporated into the corresponding free acid or converted into a reactive derivative thereof.

A compound of formula (Hl) wherein A

R ₁₂ -

means, in which R_ "is hydrogen and R .. has the meanings given above, can, using processes known per se, be converted into the corresponding compound in which R -, - is hydroxy and R., has the meanings given above, for example by treatment with an oxidizing agent, in particular a peracid such as perbenzoic acid, m-chloroperbenzoic acid, permaleic acid, pertrifluoroacetic acid, sodium periodate, hydrogen peroxide or a mixture thereof _/ with an inorganic or organic acid such as formic acid, acetic acid or trifluoroacetic acid. The reaction can be carried out in a solvent, for example in dioxane, methylene chloride, chloroform or methanol, at temperatures within the range from -30 to +9.degree.

A resulting compound wherein R- «is hydroxy can, if desired, be etherified using known methods to form the corresponding compound wherein R _{12 is} -OC ^ -alkyl, -O- ^ - Cj -alkenyl, or -0- (CH ₂ ) _m -C00R ₂ means, in which m and R ~ have the meanings given above »

The compounds of the formula (IV) are one special class of compounds of formula (I) and they can

- 29 -

by the same procedure (a) and the following procedures as given above for the preparation of the compounds of formula (i). For example, the compounds of the formula (IV) in which R 1 is hydrogen can be prepared by reacting a compound of the formula (VII) in which Y is -CH ^ OCOCH «with a compound of the formula (VIII) or a salt thereof and using approximately the same reaction conditions as have been given above for process step (d) _o The compounds of the formula (IV) in which R 1 has the meanings given above with the exception of hydrogen can be prepared by etherifying the corresponding compounds of the formula (IV), in which R 1 is hydrogen, using the same reaction conditions as those used for the etherification of a compound of the formula (I) in which R is hydrogen, and which have been given above.

Alternatively, the compounds of formula (IV) can be prepared by reacting a compound of formula (H), wherein Y-CHnOCOOL mean, or a derivative thereof with a compound of the formula (Hl) or with a derivative thereof under Use of the same reaction conditions as have been given above for process step (a).

The compounds of the formula (V) are known or can be prepared from known compounds by known processes will. The compounds of the formula (VE) can be prepared by reacting a compound of the formula (II) with a compound of the formula (IX) or the corresponding free acid or another reactive derivative thereof

- 30 -

Use of the same reaction conditions as have been given above for process step (a). The connections of the formula (VIl) can be prepared by reacting a compound of the formula (II) or a reactive one Derivative thereof with a compound of the formula (X) or the corresponding free acid or a reactive derivative thereof using approximately the same reaction conditions as for the above reaction for the process stage (a) have been applied. The compounds of the formulas (VIII) and (IX) are known or can be prepared by known processes will. In particular, it is possible, for example, to prepare the compounds of the formula (IX) in which R 1 is hydrogen are by reacting a compound of the formula (X) with CS_ or C0_ in the presence of a suitable base, such as potassium tert-butoxide, to form a compound of formula (IX) wherein Z and Z ,, which are the same, represent sulfur or oxygen. The reaction can be carried out in a suitable anhydrous organic solvent, e.g. in benzene ^ toluene or xylene, at temperatures varying from about -10 C to about 40 C, and for reaction times that are within the range of about 30 minutes to about 4 hours. The compounds of the formula (X) are known or can be prepared according to known Process are produced. The compounds of the formulas (XI) and (XIII) can be prepared by known processes are, for example, from the corresponding unsubstituted carboxylic acid esters, which are known compounds, and using approximately the same procedures as described above for the synthesis of compounds of formula (Hl) from compounds of the formula (X) have been given. The compounds of the formula (XIl) and (XIV) are known or can be prepared according to known

-3T-

Process can be made from known compounds.

The compounds according to the invention have a high antibacterial activity both in animals and in humans against gram-positive and gram-negative bacteria, which are normally sensitive to cephalosporins such as staphylococci, streptococci, diplococci, Klebsiella, Escherichia coli, Proteus mirabilis, Salmonella, Shigella, Haemophilus and Neisseria are. The compounds of the invention also have a high activity compared to the strong beta-lactamase forming microorganisms, such as Z ₀ B. Klebsiella aerogenes 1082 E, Escherichia CCLI Tem, Enterobacter cloacae P99 and indole-positive Proteus and the like., As well as against Pseudomonas aeruginosa strains , which are usually resistant to most cephalosporins.

Due to their high anti bacterial η activity both at The compounds according to the invention are suitable for both animals and humans against gram-positive and gram-negative bacteria for the treatment of infections caused by these microorganisms, such as infections the respiratory tract such as bronchitis, bronchopneumonia, pleurisy; Hepatobiliary and abdominal infections such as septicemia, urinary tract infections such as pyelonephritis, cystitis, obstetric and gynecological infections such as cervicitis, endometritis; Throat, nose and throat infections, such as otitis, sinusitis, parotitis.

The toxicity of the compounds according to the invention is negligible low and they can therefore be safely used in therapy

pie can be used. For example, the approximate acute toxicity in the mouse, as determined by single intravenous administrations of increasing doses and measured on the 7th day of treatment, is more than 2000 mg / kg ₀

The compounds of the invention can be administered to either humans or animals in a wide variety of dosage forms be, for example orally in the form of tablets, capsules, drops or syrups; rectally in the form of suppositories; parenterally, for example intravenously or intramuscularly

in the form of solutions or suspensions, intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; intravaginally in the form of, for example, bougies, or topically in the form of lotions, creams and ointments.

The invention also includes pharmaceutical and veterinary Agents or preparations containing at least one compound according to the invention, optionally in combination with at least a pharmaceutically or veterinarily acceptable excipient, such as a diluent or carrier, contain. These pharmaceutical or veterinary agents can be prepared in a conventional manner using the conventional carriers or diluents, as used for other cephalosporins. Examples of conventional carriers or diluents are water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and the like.

There can be daily doses within the range of about 1 to

- 33 -

about 100 mg per kg of body weight in different animal species, the exact dose depending on the age The weight and condition of the patient to be treated and the frequency and route of administration. A preferred one The method of administration of the compounds according to the invention is parenteral administration: in this case, the Compounds, for example, to adult humans in an amount within the range of about 100 to about 200 mg per Dose, preferably in an amount of about 150 mg per dose, 1 to 4 times a day, dissolved in a suitable solvent, e.g. in sterile water or in a lidocaine hydrochloride solution for intramuscular injections and sterile water, one physiological saline, dextrose or conventional intravenous fluids or electrolytes for intravenous Injections.

The compounds of the invention can be used as antibacterial agents prophylactically, e.g., in cleaning or surface disinfectants, for example at a concentration of about 0.2 to about 1 Ge \ t _e -% of these compounds, in admixture with, suspended or dissolved in conventional inert , dry or aqueous carriers for application by washing or spraying. They are also valuable supplementary feed for animal feed.

Vi

The following examples illustrate the present invention. The determination of the melting points was somewhat in some cases difficult as the compounds tended to retain the solvent. In these cases, according to the specification of the melting point to find the word "decomposition".

The IR spectra were taken in solid phase or in Nujol Determined using a Perkin-Elmer 125 spectrophotometer.

The NMR spectra were collected using a Perkin-Elmer R-24B- (60MH z) spectrometer in suitable solvents as specified below. The shifts in ppm are given with reference to (CI-L) .Si as an internal standard.

Manufacture of the raw materials

Production example 1 α ~ (2-thienyl) -β-methoxyacrylic acid

A solution of 51.5 g (0.33 mol) of methyl 2-thienyl acetate and 22.5 g (0.375 mol) of methyl formate in 50 ml of anhydrous diethyl ether was added to a suspension of 7.84 g (0.34 mol) of sodium wire in 150 ml of anhydrous diethyl ether. The temperature the mildly exothermic reaction was controlled using a water bath kept near room temperature. After stirring for 24 hours at room temperature, the mixture was cooled, carefully diluted with water and treated with 8% HCl acidified the ethereal solution was separated off, washed with a saturated aqueous sodium chloride solution, separated off, dried and evaporated to dryness, leaving a residue

- 35 -

obtained, which was triturated in petroleum throat and filtered, with formation of 48.5 g (yield 80 %) of methyl cc- (2-thienyl) i ß-hydroxyacrylate, mp 102-104 ° C.

Elemental analysis for CoHgOgS

calc .: C 52.16 H 4.37 S 17.40

found: 52.02 4.29 17.46 %

NMR S ppm (CDCl ₃ ): 3.8 (3 H ^ -CH ₃ )

7.1 (3H, m, hydrogen on the thienyl ring) 7.45 (IH, d, = CH-) 12.1 (1H, d, -OH)

To a solution of 11.04 g (0.06 mol) of the compound prepared above in 40 ml (0.08 mol) of 2η NaOH, which was cooled to 5 ° C., 5.70 ml (0.06 mol) Dimethyl sulfate added. The reaction mixture was stirred for 1 hour with cooling and then for 6 hours at room temperature. The reaction mixture was extracted twice with diethyl ether, dried, evaporated and distilled. The main fraction was .gesammelt at 110 to 113 ^O C / 0.2 mm Hg to give 9.0 g (yield 75%) of a colorless oil.

Elemental analysis for C ₉ H ₁ calculated: C 54.53 H 5.08 found: 54.35 5.01

NMR, δ ppm (CDCl ₃ )

S 16.17
15.92 ^

3.6 (3H, s -CCX) CH ₃ ) 3.85 (3H, s, -OCH ₃ ) 7.0 (3H, m, hydrogen on the thienyl ring) 7.4 (IH, s = CH-)

36 -

A solution of 10.2 g (0.051 mol) of the ester prepared above in 82 ml (0.164 mol) 2η NaOH was stirred for 20 hours at room temperature. The reaction mixture was washed with ethyl acetate, the aqueous layer was washed with dilute H 1 SO. acidified and extracted with ethyl acetate. The organic layer was evaporated to dryness. The oily residue obtained was crystallized in ethyl ether / petroleum ether, 6.48 g (yield 70 %) of a- (2-thienyl) -ß-methoxyacrylic acid, mp 134 to 136 ° C, obtained «,
Elemental analysis for CgHgO-S
calc .: C 52.16 H 4.37 S 17.40
found: 51.86 4.28 17.46 %

IR (Nujol) cm " ¹ ^ 1660 (/ C = O)

2550 (-OCH ₃ )
NMR, 5 PPm (CDCl ₃ ): 3.8 (3H, s, -OCH ₃ )

7.1 (3H, m, hydrogen on the thienyl

ring)
7.4 (IH, s _# = CH-)

11.5 (IH, br-s, -COOH). Production example 2

tt- (2 ~ thienyl) -ß-methoxyacryloyl chloride

To a solution of 1.84 g (0.01 mol) of the acid described in Preparation Example 1 and 1.4 ml (0.01 mol) of triethylamine in 50 ml of anhydrous methylene chloride (CH_C1 "), which on C was cooled, a few drops of anhydrous N, N-dimethylformamide were added (DMF) and 1 ml (0.0117 mol) of oxalyl chloride added. The mixture was stirred for 1 hour at 0 C, which was evaporated in vacuo, the residue was in

Hi

anhydrous benzene was added and then evaporated to give an oily residue which could be used without further purification was used in the next stage.

Production example 3

"- (2-Phenyl) -ß" methoxyacrylic acid

It was prepared according to the procedure given in Preparation Example 1, method F _0170-173 ° C.

IR (Nujol) cm "" ¹ - \) 1660 () c = 0) NMR, δ ppm (CDCl ₃ ): 3.75 (3H, s, -OCH ₃ )

7.2 (5H, m, H on benzene) 7.5 (IH, s, ^ CH-O) 10.6 (1H, br-s, -COOH).

Harstellunqsbeispiel 4

Potassium g- (2-thienyl) -ß- (bismethylthio) acrylate To a suspension of 28.05 g (0.25 mol) of potassium t-butoxide in 400 ml of anhydrous benzene, which was cooled to 0 ° C., was added Stir a mixture of 19.5 g (0.125 mol) methyl 2-thienyl acetate and 7.5 ml (0.125 mol) CS ^ was added. The mixture was stirred for 2 hours at room temperature (the progress of the reaction can be monitored by thin layer chromatography). Then 15.5 ml (0.25 mol) of methyl iodide were added to the suspension and the mixture was heated with stirring at 6O ⁰ C for 1 hour. After the mixture had cooled to 5 ° C., 150 ml of water were added, the organic

Layer was separated, washed with water, dried and evaporated to dryness and the oily residue was then distilled, b.p. 145 to 147 ° C / 0.15 mm Hg, giving 23/29 g (yield 71.5 %) Ä ' ethyl α- (2-thienyl) -β- (bismethylthio) acrylate.

Elemental analysis for ^ KAS-

Calc .: C 46.12 H 4.64 S 35.94

found: 46.60 4.62 35.51 %

LR. (Film) ^ 1720 cm " ¹ (/ C = O)
NMR, δ ppm (CCl ^): 2.23 (3H, s, -SCH ₃ )

2.27 (3H, s, -SCH ₃ ) 3.7 (3H, s, -OCH ₃ ) 6.8-7.2 (3H, m, hydrogen on the thienyl ring)

A mixture of 7.81 g (0.03 mol) of this ester and 60 ml of 2η ethanolic KOH was refluxed for 5 hours. The reaction mixture was taken up in a hexane / ethyl acetate mixture, the supernatant mother liquors were discarded and the residue was triturated in the hexane / ethyl acetate mixture until a solid was obtained. The solid material was filtered off and washed with petroleum ether to give 6.5 g ( 76% yield) of potassium α- (2-thienyl) -β- (bismethylthio) acrylate, which was pure enough for the next step.

39 -

Position example 5

<x- (2-Thienyl) -ß- (bismethylthio) acryloyl chloride An aqueous solution of 1.42 g (0.005 mol) of potassium a- (2-thienyl) -ß- (bismethylthio) acrylate was covered with ethyl acetate and treated with 20 Hunter H ₂ SO _{4 brought} to pH 2. After stirring for 15 minutes the organic layer was separated, dried over NOrtSO. dried and evaporated to dryness in vacuo. The free acid obtained was dissolved in 40 ml of anhydrous methylene chloride, 2 drops of anhydrous N, N-dimethylformamide were added, the mixture was cooled to 0 C and then 0.7 ml of triethylamine and 0.43 ml (0.005 mol) of oxalyl chloride were added admitted. After stirring at 0 C for 1 hour, the reaction mixture was evaporated to dryness in vacuo. The oily residue was triturated with anhydrous benzene and the solid was filtered off and then taken up in ethyl acetate to give α- (2-thienyl) -β- (bismethylthio) acryloyl chloride, which was used for the next stage without further purification.

Production example 6 Potassium α-phenyl-ß- (bismethylthio) acrylate

This compound was prepared according to the procedure given in Preparation Example 4 process, F _0264-265 ° C.

NMR, δ ppm (CCI4) 2.10 (3H, s _r -SCH ₃ )! 2.30 (3H, s, -SCH ₃ )

7.2 (5H, m, H on the benzene ring)

sz

40 -

The corresponding acyl chloride was prepared as indicated in preparation example 5 «

Production example 7

A * ethyl-tt- (2-aminothiazpl-4-yl) -β-methoxyacrylate A mixture of 20.9 g (0.1 mol) ethyl-γ-bromoacetoacetate, 10.6 g (0.1 mol) methyl orthoformate and 20.4 g (0.2 mol) of acetic anhydride was refluxed for 1 hour with stirring. The reaction mixture was evaporated to dryness in vacuo to give ethyl-α-methoxymethylene-Y-bromoacetoacetate as an oily residue, which was obtained without further purification was used for the next stage.

To an ice-cold solution of 0.1 mol of this ester in 100 ml of methanol, 7.6 g (0.1 mol) of thiourea were added and the The mixture was stirred at room temperature for 3 hours. After cooling, the precipitate was collected by filtration.

The solid was stirred with an aqueous NaHCO_ solution and filtered again, 16 g (yield 70 %) of ethyl-α- (2-aminothiazol-4-yl) -β-methoxyacrylate, mp 107-109 ° C., being obtained.

Elemental analysis for ^c o ^ i2 ^ 2 ° 3 ^

Calcd .: C 47.37 H 5.30 N 12.27 S 14.04

found: 47.10 5.13 12.29 14.18 %

N ₀ M ₀ R * ο ppm (d, -DMSO, i _e e completely deuterium-substituted dimethyl sulfoxide):

Sl

4T -

1.2 (3H, t, -OCH ₂ -OI ₃ )

3.8 (3H, s, -OCH ₃ )

4.1 (2H, q, -OCH ₀ CH-)

6.35 (IH, s, 5-H on the thiazole ring)

6.7 (2H, br-s, -NH ₂ )

, 7.35 (lH, s, = CH-)

Production example 8

Ethyl-a- (2-tritylaminothiazol-4-yl) -ß-methoxyacrylate To an ice-cold solution of 1 g (4.38 mmol) ethyl-a- (2-aminothiazol-4-yl) -ß-methoxyacrylate and 0, 58 g (5.7 mmol) of triethylamine in 25 ml of methylene chloride were added in portions to 1.47 g (5.27 mmol) of trityl chloride. After stirring for 4 hours at room temperature, the solution was shaken with water, the organic layer was separated off, dried over Na « SO. dried and evaporated to dryness in vacuo. The foamy residue was triturated with petroleum ether, 1.88 g (72 % yield) of ethyl a- (2-tritylaminothiazol-4-yl) -ß-methoxyacrylate, m.p. 68

ο
to 70 C.

NMR δ ppm (dg -DMSO): 1.2 (3H, t, -OCH ₂ CH ₃ )

3.8 (3H, s, - OCH ₃ )

4.1 (2H, q, -OCH ₀ CH-)

6.35 (IH, s, 5-H on the thiazole ring)

7.3 (16H, br-s, Ph and = CH-)

, ⁸ · 2 (lH, br-s, - NH-)

Production example 9

«- (2-Tritylaminothiazol-4 ~ yl) -ß- (bismethylthio) acrylic acid To an ice-cold suspension of 5.6 g (0.05 mol) of potassium tert-butoxide in 100 ml of anhydrous benzene, a solution of 10.7 g (0.025 mol) of ethyl (2-tritylaminothiazol-4-yl) acetate and 1.51 ml (0.025 mol) of CS ^ in 30 ml of anhydrous benzene were added. The mixture was stirred for 4 hours at room temperature (the progress of the reaction can be monitored by TLC) · There were 3.12 ml (0.05 mol) of methyl iodide was added to the suspension and the mixture was stirred for 1 hour »heated to 60 ⁰ C. After cooling to ⁰ ° C were 100 ml of water were added, the organic layer was separated, washed with water, dried over Να2 $ 0. dried and evaporated to dryness. The oily residue was purified through a silica gel column using ChLCl ^ AtOAc = 196: 4 as the eluent, 10 g (75 %) of ethyl-a- (2-tritylamino-thiazol-4-yl) -ß- (bismethylthio) acrylate, m.p. 14O ⁰ C obtained.

Elemental analysis for ^ 29 * ^ 28 ^ 2 ^ 2 ^ 3

Calc .: C 65.38 H 5.29 N 5.26 S 18.06

found: 65.86 5.43 5.12 17.70 %

IR. (Nujol) cm " ¹ <v> (1715 ^s c = 0)
NMR, _δ ppm (CCl ^: li (3H. _S , -OCH ₅ CH,)

2.1 (6H, s, -S-CH ₃ )

4.0 (2H, q, -OCH ₂ CH ₃ )

6.6 (Ih, s, 5-H on the thiazole ring)

7.1 (15H.S, Ph).

- 48 -

A solution of 2.5 g (4.7 mmol) of the above-mentioned ester and 7.05 ml (14.1 mmol) of 2 η NaOH in 50 ml of 95% ethanol was refluxed for 4 hours. The ethanol was evaporated in vacuo, 20 ml of water were added and the solution was covered with a layer of 20 ml of ethyl acetate and acidified with 8 Jäger HCl. After stirring for 1 hour at room temperature, the undissolved material was filtered off and the collected precipitate was washed with ethyl acetate and dried under vacuum at 60 ° C., 1.88 g (79.5 %) of a- (2-tritylaminothiazole-4 " »Yl) -ß- (bismethylthio) acrylic acid, mp 198 to 200 ° C, received.

Elemental analysis for ^ O7 ^ 24 ^ 2 ^ 2 ^ 3

Calc .: C 64.25 H 4.80 N 5.55 S 19.06

F _o : 63.99 4.73 5.36 18.81 %

I .R. (Nu j oil) cnf " ¹ ^ 1660 (C = O)

NMR, 6 ppm (d ₆ -DMSO): 1.92 (3H, s, -SCH ₃ )

2.05 (3H _f s, -SCH ₃ )

6.5 (lH, s, 5-H on thiazole ring)

7.1 (15H, s, -Ph). Preparation of the compounds of the formula (I)

example 1

7-Ca- (2-thienyl) -ß-methoxyacrylamido] -3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn- Isomer) (compound 3)

A suspension of 1.31 g (0.004 mol) of 7-amino-3 - [(i-methyl-1,2,3, -4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid and 3.25 g (0.016 mol) of N, O-bis (trimethylsilyl) acetamide in 80 ml of anhydrous Ethyl acetate and 20 ml of anhydrous acetonitrile was

Si

44 -

Stirred for 2 hours at 50 ° C. until all of the solid material had dissolved. In this solution, which was cooled with an ice bath, a solution of 0.002 mol of α- (2-thienyl) -β-methoxyacryloyl chloride in 25 ml of anhydrous ethyl acetate was added with stirring The mixture was stirred for 20 hours at room temperature and then an aqueous solution of NaHCO 2 was added, the organic layer was separated off, the aqueous solution was washed with dilute H 2 SO. acidified, extracted with ethyl acetate, the organic phase was washed with water, dried and evaporated to a small volume and diluted with ethyl ether. The precipitated solid was collected, whereby 7- [α- (2-thienyl) -β-methoxyacrylamido] -3-C (1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3 -cephem-4-carboxylic acid (syn-Isomeres), F «, 143 to 14 / C (Zere.).
Elemental analysis for C. "H.gN, 0 ^ S
calc .: C 43.71 H 3.67 N 16.99 S 19.45 found: 43.38 3.76 16.63 19.24 %

IR (KBr) cm " ¹ Ό 1780 OC = O β-lactam)

1680 CC = O sec .Amid) 3350 (-NH- sec .Amid ), NMR, 6 (d ₆ -DMSO): 3.85 (3H, s, ^ N-CH ₃ on the tetrazole-

ring)

3.9 (3H ₄ s, -OCH ₃ ) 7.1 (3H, m, hydrogen on the thienyl ring).

Example 2

7- [α- (2-Thienyl) -β-hiiethoxyacrylamido] -3-acetoxymethyl- "3-cephem- 4-carboxylic acid (syn-isomer) . (Compound 2) This compound was prepared using a procedure similar to that described in as described in Example 1, mp 130 to 131 ° C (Ze _r s.).

Elemental analysis for ^ iq ^ iq ^ 2 ^ 7 ^ 2

Calc .: C 49.3 H 4.14 N 6.39 S 14.63

found: 49.05 4.11 6.57 14.15 %

LR. (KBr): QiT ¹ 01780 OC = O lactam)

3300 (-NH- sec.Amid.)

NMR, δ ppm (d ₆ - DMSO): 2 (3H, s, -0-CO-CH ₃ )

3.90 (3H, s, -OCH ₃ ) 7.1 (3H _# m, H on the thiophene ring).

Example 3

7- [ot-Phenyl-ß-methoxyacrylamido3-3-C (i-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-Isomeres) (Ver binding 1)

0.64 g (3.1 mmol) of ^ N'-dicyclohexylcarbodiimide were added to a suspension of 0.55 g (3.1 mmol) of α-phenyl-β-methoxyacrylic acid in 25 ml of anhydrous acetone, while cooling to 5 ° C. After stirring the suspension at 5 ° C. for 40 minutes, a cooled solution of 1.01 g (3.1 mmol) of 7-amino-3 - [(l-methyl-1,2,3 _/ -4-tetrazole-5- yl) thiomethyl] -3-cephem-4-carboxylic acid and 0.26 g (3.1 mmol) NaHCO. added dropwise in 10 ml of acetone and 15 ml of water.

4 * - SX

The reaction mixture was stirred at 5 ° C. for 1 hour and then at room temperature for 20 hours. The acetone was evaporated in vacuo and the precipitated solid dicyclohexylurea was filtered off. The filtrate was washed with ethyl acetate, the aqueous phase was with 10 5 & ger HoSO. acidified and extracted with ethyl acetate. The organic layer was separated, washed with a saturated NaCl solution, over Na ₂ SO. dried and evaporated to dryness in vacuo. The residue was taken up in diethyl ether, the solid was filtered off, the solid was dissolved in a small amount of ethyl acetate, the undissolved material was filtered off, the filtrate was evaporated to a small volume and with the addition of diethyl ether a precipitate was obtained, whereby 7- [α-Phenyl-β-methoxyacrylamido] -3 - [(Imethyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-Isomeres), m.p. 150 ° C (Zerso), received.

I.R. (Nujol) an "Ό1780 () C = O ß-lactam)

1660 (-CONH- sec .Amid) 3300 (-NH-),

NMR, 6 ppm (CD ₃ COCD ₃ ): 3.7 (3H, s, -NCH ₃ )

3.85 (3H, s, -OCH ₃ )

7.2 (5H, m, urine benzene

ring)

7.3 (IH, s, = CH-O)

Using the same procedure, compounds 4, 5 and 6 manufactured.

Example 4

7- [a- (2-thienyl) -ß- (bismethylthio) acrylamido] -3-C (i-methyl-1,2,3 _/ 4-tetrazol-5-yl) thiomethyl] -3-cephem-4- carboxylic acid

(Compound 10)

To an ice-cold suspension of 1.64 g (0.005 mol) of 7-amino-3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid in 80 ml of anhydrous ethyl acetate and 20 ml of anhydrous acetonitrile were added with stirring 4.95 ml (0.02 mol) of N, O-bis (trimethylsilyl) acetamide. After stirring for 3 hours at 50 ° C., the reaction mixture was cooled to 0 ° C. and then was a solution of 1.32 g (0.005 mol) of α- (2-thienyl) -β- (bismethylthio) acryloyl chloride in 30 ml of anhydrous ethyl acetate was added. The mixture was stirred for 1 hour at 0 ° C. and then for 16 hours at room temperature. After cooling to 0 C, the reaction mixture was diluted with water and made neutral with an aqueous solution of NaHCO, *. The organic layer was discarded, the aqueous phase was covered with a layer of ethyl acetate and treated with 20 Jfoger H ₂ SO. brought to pH 2. The mixture was stirred for 15 minutes and the undissolved material was filtered off. The organic layer was then separated off, the aqueous phase was extracted again with ethyl acetate, the combined organic extracts were dried over Na — SO, and evaporated to a small volume in vacuo; after the addition of diethyl ether, a solid product was obtained which was filtered off and dried in vacuo at 60 ° C., 7- [a- (2-thienyl) -β- (bismethylthio) acrylamide] -3 - [(i-methyl -l, 2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid, mp 125 to 129 ° C (dec.).

yg -60

Elementary analysis for CiqH-qN.O.S, -

via _e: C 40.99 H 3.62 N 15.09 S 28.79

gef _# : 40.72 3.89 14.99 28.53 ^

TLC CCHCl ₃ : CH ₃ OHtHCOOH (180: 20:10) R = O. 54, IR (Nujol) cm " ¹ ^) 3300 (-NH-)

• 1780 (X = O ^ -lactam) '1715 (X = O acid) _s 1660 Oc = O sec.-amide),

NMR, δ ppm (d ₆ -DMS0): 2.35 (3H, s, -SCH ₃ )

2.4 (3H, s, -SCH ₃ ) 3.9 (3H, s, -NCH ₃ ) 6.9-7.2 (3H, s, m, H am 1hiophen _r ing).

Example 5

Using the procedure described in Example 4, the following compounds were prepared: 7 [α-phenyl-β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (compound 7), F «88 bis 90 C (dec.) O Elemental analysis for ^c oi ^ 22 ^N 2 ° 6 ^S 3

Calcd .: C 50.99 H 4.48 N 5.66 S 19.45

found: 50.64 4.66 5.49 18.99 %

IR (Nujol) cm " ¹ 0 3300 (-NH-)

1780 () C = 0 ß-lactam)

NMR, δ ppm (CDCl ₃ ): 1.87 (3H, s, - COCH ₃ )

2.0 (3H, s, -SCH ₃ ) 2.20 (3H, s, -SCH ₃ )

7.15 (5H, m, H on benzene ring); and

7-Ca-phenyl-ß- (bis-methylthio) acrylamido] -3 - [(l-methyl-l _/ 2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem = -4-carboxylic acid ( Compound 8), F. 115 to 12O ⁰ C (Zerso).
Elemental analysis for C ₉ -H ₉₉ NOS. ber _o : C 45.8 H 4.02 N 15.26 S 23.29

15.01 22.91 %

gef _o : 45.94 4.25 IR (Hu j oil) cin " ¹ ^

cin " ¹ ^ 3300 (-NH-]

1780 OC = 0 ß-lactam) I7I5 (-C0- acid) 1660 (-CO- sec-amide.)

rr.MR, 6ppm (d ₆ DMSO): 1.9 (3H, s, -SCH ₃ )

2.1 (3H, s, -SCH ₃ ) 3.7 (3H, s, -NCH ₃ ) 7.1 (5H, m, H on the benzene ring);

7- [α- (2-thienyl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (Compound 9), mp 105-110 ° C (dec.).

Elemental analysis for Cin ^ WV ^ S.

calc .: C 45.58 H 4.03 N 5.59 S 25.62

found: 45.35 4.22, 5.73 25.11 %

3 1 T 11 5

Bff-

TLC (CH Cl ₃ : CH ₃ OH: HCOOH- 180: 20:10) R = 0.62. rR (Nujol) cm ' ¹ * \) 3300 (-NH-)

1780 (λ> 0 β-lactam) 1715 (-CO- acid) 1660 (-CO- sec- amide), NMR, δ ppm (d ₆ -DMS0) i.7 ( _3HjSj .OCOCH ₃ )

2.22 (3H, s, -SCH ₃ ) 2.28 (3H, s, -SCH ₃ ) 6.8-7.2 (3H, m, H _{on the} thiophene ring);

7- [a- (2-thienyl) -ß- (bis-methylthio) acrylamido) -3 - [(tetra-

acid (compound 11), F ₀ 135 to 140 ° C (decomp.) o

Elementary analysis for ^ 21 ^ 19 ^ 7 ^ 4 ^ 5

calc .: C 42.48 H 3.22 N 16.51 S 27.00

gefo: 42.20 3.33 16.23 26.74%

TLC (CHCl ₃ : CH ₃ OH: HCOOH = 180: 20: 10) R _f = 0.55 , I.RiNujol) cm " ¹ ^) 3300 1 -NH- J

1780 (> C = 0 / VUctam),

! ^ 1720 (- CO- acid ^

': 1660 (- CO- sec-amide),

- 5T-

NMR, δ ppm (d ₆ -DMSO):

2.15 (3H, s, -SCH ₃ ) 2.20 (3H _f S. -SCH ₃ ) 6.8-7 (3H, m, H on the thiophene-

ring)
7.75 (IH, d, 8-H am

Piyridazine ring)

8.57 (lH, d, 7-H am

Pyridazine ring).

Example 6

7- [oc- (2-aminothiazol-4-yl) -ß- (bismethylthio) acrylamido] -3-

^ carboxylic acid (compound, T 5)

To an ice-cold solution of 4.04 g (80 mmol) of α- (2-tritylaminothiazol-4-yl) -β- (bismethylthio) acrylic acid and 1.12 ml (80 mmol) of triethylamine in 300 ml of anhydrous tetrahydrofuran (THF) 1.05 ml (80 mmol) of isobutyl chloroformate were added with stirring. After stirring for 30 minutes at 0 C, a solution of 2.93 g (80 mmol) of 7-amino-3 - [(tetrazolo [l, 5-b] pyridazin-6-yl) thiomethyl] -3-cephem- 4-carboxylic acid and 1.120 ml (80 mmol) of triethylamine in 200 ml of 50% THF were added dropwise. To 1 hour stirring at 0 C and then 18 hours Stirring at room temperature, the solvent was evaporated in vacuo, the residue was diluted with water, then covered with ethyl acetate and acidified with dilute hydrochloric acid. After stirring for 1/2 hour the The undissolved material was filtered off, the organic layer was separated, over Na SO. dried, under vacuum on a

- S2 -

evaporated to a small volume and taken up in diethyl ether. The collected precipitate was filtered off and several times washed with diethyl ether.

The solid obtained in this way was dissolved in 30 ml of 99% formic acid dissolved and stirred for 90 minutes at room temperature. The formic acid was removed under vacuum, the residue was taken up in diethyl ether and stirred for 30 minutes and the solid was filtered off and under vacuum at 60 ° C dried, 7- [a- (2-aminothiazol-4-yl) -β -. (bismethylthio) acrylamido] -3 - [(tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl] -3 -cephem-4-carbon acid (compound 15), m.p. 171 to 175 C (dec.), received.

Elemental analysis for CL ₀ Hj ₉ N ₉ O ₄ S, -ber .: C 39.39 H 3.14 N 20.67 S 26.29 found: 39.61 3.20 29.31 25.97%

■ 1 _
IR (Nujol) cm V 1780 (^ C = O ß-lactam)

1650 (} C = 0 sec-amide),

NMR, δ ppm (d ₆ -DMSO): 2.35 (3H, s, -SCH ₃ )

2.4 (3H _x S ₁ -SCH ₃ )

6.6 (lH, s, 5-H on the thiazole ring)! 7.30 (2H, br-s, NH ₂ on the thiazole ring)

7.75 (1H, d, 8-H am.. Pyridazine ring) ^; 8.57 (lH, d, 7-H on the pyridazine ring)

CS

59 -

Example 7

Following the same procedure as in Example 6, the following were made Connections made:

7- [α- (2-Aminothiazo1-4-yl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (compound 13), elemental analysis for ^ gH ₂₀ N, 0, S,
ber _o : C 41.84 H 3.90 N 10.84 S 24.83 found: 41.53 4.05 10 _r 63 24.61 %

IR (Nujol) Cm- ¹ OlVSO (^ C = O ß-lactam)

1650 (; c = 0 sec-amide),

NMR, δ ppm (cTg-DMSO): 2.0 (3H , s, -OCOCH ₃ )

2.35 (3H, s, -SCHj 2.A (3H, s, -SCH ₃ ) 6.4 (IH, s, 5-H on the thiazole ring)

7.3 (2H, br-s, -NH ₂ on the thiazole ring)

7- [a- (2-Aminothiazol-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(i-methyl-1,2,3,4-tetrazol-5-yl) -thiomethyl] -3-cephem- 4-carboxylic acid (compound 14)

Elemental analysis for Ciq ^ WW * 5

Calc .: C 37.75 H 3.52 N 19.57 S 27.99

found: 37.91 3.61 19.31 27.63%

IR, (Nujol) cm " ^{1 4} N) 1780 (/ C = O lactam)

1650 Oc = O sec-amide.)

NMR, δ ppm (d ₆ -DMS0): 2.35 (3H, s, -SCH ₃ )

.2.4 (3H, s, -SCH ₃ )

3.85 (3H, s, ^ N-CH ₃ )

6.4 (lH, s, 5-H on the thiazole ring)

7.3 (2H, br-s, -NH ₂ on the thiazole ring);

7- [a- (2-aminothiazol-4-yl) -β- (bis-methylthio) acrylamido3-3- [8-amino-tetrazolo [.1,5-b] -pyridazin-6-yl) thiomethyl] - 3-cephem-4-carboxylic acid (compound 16), elemental _{analysis for C o} _H _or .N, _0.S_ calc .: C 38.45 H 3.23 N 22.42 S 25.66

found: 38.61 3.31 22.21 25.36 %

IR (Nujol) cm " ¹ « 0 1780 (} C = 0 ß-Uctam)

1650 (/ C = O sec-amide),

NMR, δ ppm (dg-DMSO) 2.35 (3H, s, -SCH ₃ )

2.4 (3H _r s, -SCH ₃ )

6.41 (IB, s, 7-H on the pyridazine ring) _: 7.12 (lH, s _# 5-H on the TMazole ring)

7.30 (2H, br-s _f -NH ₂ on the thiazole ring) 8.02 (2H, br-s, -NH ₂ on the pyridaziru ring)

7- [oc- (2-aminothiazol-4-yl) -β- (bis-methylt hio) acrylamido] -3 - [(8-carboxytetrazolo [1,5-b] -pyridazin-6-yl) thiomethyl ] -3-cephem-4-carboxylic acid (Connection 17),

Elemental analysis for ^ οι ^ ιο ^ ο ^ Α ^ ς

Calcd .: C 38.58 H 2.93 N 19.28 S 24.52

found s 38.77 3.02 19.11 24.23 %

IR (Nujol) cm ' ¹ ^ 1780 OC = O ß-lactam)

1650 (} C = O sec -Amid)

NMR, δ ppm (d ₆ -DMSO) 2.35 (3H, s, -SCH ₃ )

2.4 (3H _{/ S} , -SCH ₃ ) 6.83 (IH, s, 5-H on the thiazole ring)

7.30 (2H, br-s, -NH ₂ on the thiazole ring) 8.02 (IH, s, 7-H on the pyridazine-

ring); and connections 18, 20, 21, .22, 24, 25, 26, 27 and

Example 8

7- [a- (2-aminothiazol-4-yl) -β- (bismethylthio) acrylamido] -3 - [(tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl] -3-cephem-

4-carbolic acid (compound 15)

To a mixture of 2.58 g (0.005 mol) of 7- [a- (2-aminothiazol-4-yl) -β- (bismethylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (prepared as indicated in Example 7) and 0.91 g (0.006 mol) of 6-mercaptotetrazolo [1,5-b] -pyridazine in 150 ml of distilled water, NaHCO _{3 was added} in small portions with stirring until a clear solution was obtained and a pH -Value of 6.5 to 7 had been reached · This solution was left on for 6.5 hours in an oil bath

- 56 -

Heated at 67 ° C (the progress of the reaction can be monitored by TLC (CHCl ₃ : CH ₃ OH: HCOOH = 160: 10:30)). After cooling to 5 ° C., a few drops of 8 point HCl were carefully added with stirring, a precipitate forming (at about pH 3). This was collected, washed with acetone and dried, yielding 7- [a ~ (2 ~ aminothiazol-4-yl) -β- (bismethylthio) acrylamido] -3 - [(tetrazolo [1,5-b] pyridazine-6 -yl) -thiomethyl] -3-cephem-4-carboxylic acid, which was identical to the acid prepared in Example 6 ·

Compounds 8, 10, 11, 12, 14, 15, 16, 17, 18, 19, 21, 22, 23, 25, 26, 27 and 28.

Example 9

To an aqueous suspension of 3.5 g of 7- [a- (2-aminothiazole-

azin-6-yl) thiomethyl] -3-cephem-4-carboxylic acid in 80 ml of water the stoichiometric amount of NaHCO- was added, whereby one received a complete dissolution of the connection. This solution was then lyophilized using the sodium salt of the above Acid received.

Manufacture of pharmaceutical preparations or agents Example 10

Injectable pharmaceutical preparations (agents) were prepared by dissolving 100 to 500 mg of sodium 7-Ca- (2-aminothiazol-4-yl) -β- (bismethylthio) acrylamido] -3 - [(tetrazolo-

CD

57 -

Cl, S-pyridazin-o-ylJthiomethyll-S-cephein- ^ carboxylate in »Sterilize water or a sterile normal saline solution (1 to 2 ml).

Claims (28)

Claims where mean:
Z -O- or -S-; A is phenyl or a 5-membered or 6-membered one. heteromonocyclic Ring which contains at least one double bond and at least one heteroatom from the group N, S and 0, wherein the phenyl and the heteromonocyclic ring are unsubstituted or are substituted by one or more substituents selected from the group: a) C.-C, -alkyl, b) halogen, c) Halogen-C.-Cj-alkyl, d) -N ^, in which each of the G _r uppen R 'and R ₃ are the same ^R 3 or can be different, represent hydrogen, C.-C6-alkyl, C.-Cy-acyl or one of the groups Rp and R ~ represent hydrogen and the other represent an amino protecting group, e) -OR, where R. is hydrogen, C - C, alkyl, C ₉ represents -C ₆ alkenyl or a hydroxy protecting group, or. f) a group -0- (CH ₉ ) -COOR., in which m is the number 1, 2 or 3, R _{5 is} hydrogen, C.-C, -alkyl / acetoxymethyl or a carboxy protective group; R is hydrogen, -OCH ₃ or -SCH ₃ ; R, hydrogen or a branched or unbranched (straight-chain), saturated or unsaturated aliphatic C, -C, -hydrocarbyl group which is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, cyano, -CONH ₉ and -COOR, ., wherein R, - has the meanings given above; Y 1) hydrogen, 2) halogen, 3) hydroxy, 4) C ₁ -C ₆ alkoxy, 5) -CH ₂ -OCOCH ₃ , 6) -Oy / \ ⁶ , where R _{5 is} hydrogen, C ^ -alkyl, Represents carboxy, cyano or carbamoyl, or 7) -CH ₂ -S-Het, wherein Het is a ') a 5-membered or 6-membered heteromonocyc- lischen ring that has at least one double bond and contains at least one heteroatom from the group consisting of N, S and 0, the heteromonocyclic ring being unsubstituted or substituted by one or more Substituents selected from the group a ") Hydroxy, C« -C.-alkoxy, halogen, aliphatic C.-C.-acyl, b ") C -C, -alkyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy and halogen, c ") C" -C, -alkenyl which is unsubstituted or substituted is by one or more substituents selected from the group hydroxy and halogen, d ^M ) -S-Ry, in which R ^ is hydrogen or C.-C, -alkyl, or -S-CH ₂ COOR ', in which R ^{1 is} hydrogen, C.-C.-alkyl or a carboxy protecting group, _n e ") - (CHj-COOR ¹ , -CH = CH-COOR ', - (CH ₂ ) -CON ^ or ^R 3 -CN, where η is the number 0, 1, 2 or 3 and R ', R ^ and R "have the meanings given above to have, f ") - (CH«) -SO-H, in which η has the meanings given above Has, g "). - (CH ₀₎ -N _D wherein n, R 'and R" have the above angegebe- Δ η ^ "κ" δ ύ have meanings, or h ") a heterobicyclic ring containing at least two Contains double bonds, wherein each of the condensed heteromonocyclic rings, the same or different - Ar - can be separated, a 5-membered or 6-membered heteromonocyclic ring which contains at least one heteroatom from the group N, S and 0, wherein the heterobicyclic ring is unsubstituted or substituted by one or more substituents selected from the above indicated groups (a "), (b ¹¹ ), (c"), (d "), (e"), (f ") and (g"); M is a carboxylic acid group or an ester group, and the salts, in particular the pharmaceutically and veterinarily acceptable salts thereof, ₀ 2. Compounds according to claim 1, characterized in that in the general formula (i): R is hydrogen or -S-CH-; Z -0- or -S-; R ₁ hydrogen, C ^ -alkyl, C ₂ -C ₄ -alkenyl, - (CH ₂ ) _n -C00H, - (CHg) _n -CN, - (CH ₂ ) _n -CONH ₂ , in which η is the number 0, 1, 2 or 3 represents -C-COOH or -CH = CH-COOH; A phenyl, thienyl or j Ij ^R i2- ^N Ll wherein R-- is hydrogen or an amino protecting group and R- «is hydrogen, hydroxy, -OC.-C 1-4 -alkyl, -0-C_-C.-Alkenyl, -0- (CH ₂ ) _m -C00R ₂ , wherein m the number 1, 2 or 3 and R «has the meanings given in claim 1; Y is hydrogen, halogen, hydroxy, C ₁ -C ₃ -AlkOXy, -CH ₂ -OCOCH ₃ or -CH ₉ -S-Het, in which Het is 1) a tetrazolyl radical which is unsubstituted or substituted by Cj-Cg-alkyl, C ₂ -C ₄ -A ^ eηyl, - (CH ₂ ) ^ COOR ¹ , -CH = CH-COOR ', - (CH ₀ ) - CN, - (CH ₀ ) -CONH ₀ , - (CH ₀ ) -SO ₀ H, Zm Δ ro Z Δ. πι ο - (CH ₉ ) -NtT / where m is the number 1, 2 or 3 ^R 3 and R ¹ , Rn and R «have the meanings given in claim 1, 2) a thiadiazolyl radical which is unsubstituted or substituted by C.-C.-alkyl, C ₀ -C. -alkenyl, -SH, -SCH ₀ , -SCH ₀ COOH, - (CH ₀ ) -COOH, A * in which R 'and R' ^R 3 each independently represent hydrogen or C.-C -C -alkyl and η represents the number 0, 1, 2 or 3, or 3) a heterobicyclic ring selected from the group consisting of tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each of which is unsubstituted or is substituted by hydroxy, -SH, / 2 -CON! wherein R ₀ and R _{0 are} those given in claim 1 ^R 3 Have meanings, ^ -Cg-alkyl, Q ^ -C ^ -alkenyl, -COOR ¹ , -S-CH ₂ COOR ¹ , -CH ₂ -COOR ¹ , -CH = CH-COOR ¹ , wherein R ¹ is in claim 1 has given meanings, or / ^R 2 -N. wherein R ₀ and R _{0 are} those given in claim 1 ^{R have} 3 meanings, Ml Q M as well as the salts, in particular pharmaceutical and veterinary compatible salts thereof. 3 «Compounds according to claim 1 or 2, characterized in that in the general formula (i) R is hydrogen or -S-CH ₃ ; Z -0- or -S-; R ₁ -CH ₃ or -CH ₂ COOH; A phenyl, thienyl or ^R ll ~ ^N y - s ^RN in which R _{11 has} the meanings given in claim 1 and R _{10 is} hydrogen, hydroxy or methoxy, and Y is -CH ₂ OCOCH or -CH ₁ JS-Het, in which Het is tetrazolyl substituted by methyl or by amino -COOH or - CH_-COOH substituted tetrazolylpyridazinyl, as well as the salts, in particular pharmaceutical and veterinary compatible salts thereof 4. Compounds according to claims 1 to 3, characterized by one of the following formulas: 1) 7-Ca-Phenyl-ß-methoxyacrylamido-3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-isomer); 2) 7-Ca- (2-thienyl) -β-methoxyacrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (syn-isomer); 3) 7- [α- (2-Thienyl) -β-methoxyacrylamido] -3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-isomer); 4) 7- [o £ - (2-thienyl) -β-methoxyacrylamido] -3-C (tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl] -3-cephem-4-carboxylic acid (syn-isomer); 5) 7- [α- (2-aminothiazol-4-yl) -β-methoxyacrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (syn-isomer); 6) 7- [oc- (2-aminothiazol-4-yl) -β-methoxyacrylamido] -3 - [(1-methyl-1,2,3,4-tetrαzol-5-yl) thiomethyl] -3-cephem -4-carboxylic acid (syn-isomer); 7) 7-Ca-phenyl-β- (bis-methylthio) acrylate-nido] -3-acetoxymethyl-3-cephem-4-carboxylic acid; 8) 7- [a-Phenyl-ß- (bis-methylthio) acrylamido] -3 - [(1-methyl-1, 2, 3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4- carboxylic acid; 9) 7- [α- (2-thienyl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid; 10) 7- [α- (2-Thienyl) -β- (bis-methylthio) acrylamido3-3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem -4-carboxylic acid; 11) 7- [α- (2-thienyl) -β- (bis-methylthio) acrylamido3-3 - [(tetrazoloCl, 5-b3pyridazin-6-yl) thiomethyl] -3-cephem-4-carboxylic acid; 12) 7- [α- (2-thienyl) -β-methylthio-β-carboxymethylthioacrylamido] -3 - [(tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl] -3-cephem- = > 4-carbons (3ure; 13) 7- [α- (2-arainothiazol-4-yl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid; 14) 7-Ca- (2-aminothiazol-4-yl) -β- (bismethylthio) acrylamido] -3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] -3 -cephem-4-carboxylic acid; 15) 7- [a- (2-aminothiazol-4-yl) -ß- (bismethylthio) acrylamido3-3 - [(tetrazolo [1,5-b] -pyridazin-6-yl) thiomethyl] -3-cephem- 4-carboxylic acid; 16) 7 [a- (2-aminothiazol-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(8-aminotetrazolo [l, 5-b] pyridazin-6-yl) thiomethyl] - 3-cephem-4-carboxylic acid; 17) 7- [a- (2-aminothiazol-4-yl) [- ß- (bis-methylthio) -acrylamido] ~ 3 - [(8-carboxytetrazolo [l, 5-b] -pyridazin-6-yl) thiomethyl] -3-cephem-4-carboxylic acid; 18) 7- [a- (2-aminothiazol-4-yl) -S-S- (bis-methylthio) -ac _r ^ yl amido] -3 - [(8-carboxymethyltetrazolon, 5-b] pyridazin-6 ~ yl ) thiomethyl] -3-cephem-4-carboxylic acid; 19) 7- [α- (2-Aminothiazol-4-yl) -β-methylthio-β-carboxymethylthioacrylamido] -3 - [(tetrazolo [1,5-b] pyridazin-6-yl) thiomethyl] -3 -cephem-4-carboxylic acid; 20) 7- [α- (2-imino-3-hydroxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid; 21) 7-C ^a - (2-imino-3-hydroxythiazolin-4-yl) -ß- (bis-methylthio) acrylamido] -3-C (l-methyl-1, 2,3, 4-tetrazole- 5-yl) thiomethyl] -3-cephem-4-carboxylic acid; 22) 7- [a- (2-Imino-3-hydroxythiazolin-4-yl) -ß- (bis-methylthio) acrylamido] -3-C (tetrazolo [l _/ 5-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid; 23) 7- [cE - (2-imino-3-hydroxythiazolin-4-yl) -ß-methylthioß-carboxymethylthioacrylamido] -3 - [(tetrazolo [l _/ 5-b3-pyridazin-6-yl) thiomethyl] -3 = -cephem-4-carboxylic acid; 24) 7- [α- (2-imino-3-methoxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid; 25) 7- [α- (2-Imino-3-methoxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(1-methyl-1,2,3,4-tetrazole-5 -yl) -thiomethyl] -3-cephem-4-carboxylic acid; 26) 7- [a- (2-imino-3-methoxythiazolin-4-yl) -S-S- (bis-methylthio) acrylamido] -3 - [(tetrazolo [l, 5-b] pyridazin-6-yl ) thiomethyl] -3-cephem-4-carboxylic acid; 27) 7- [a- (2-Imino-3-methoxythiazolin-4-yl) -β- (bis-methylthio) acrylamido] -3 - [(8-aminotetrazoloC1, 5-bü-pyridazin-6-yl) thiomethyl] -3-cephem-4-carboxylic acid; 28) 7-Cct- (2-imino-3-methoxythiazolin-4-yl) -β- (dis-methylthio) acrylamido] «= 3-C (8-carboxytetrazolo [l _/ 5-b] -pyridazine-6- yl) thiomethyl] -3-cephem-4-carboxylic acid as well as the salts, in particular pharmaceutical and veterinary compatible salts thereof " 5. Process for the preparation of the a, ß-disubstituted acrylamidocephalosporins of the formula (i) according to Claims 1 to A _1, characterized in that a) a compound of the general formula E— (f ^Sv l __ (II) in which Y and M have the meanings given in claim 1 and E is amino or the group -N = C = ^ f, in which 0 is oxygen or sulfur, or a reactive derivative thereof with a compound of the general formula A-C-COOH (III) wherein A, R, Z and R- have the meanings given in claim 1 to have, or is reacted with a reactive derivative thereof and, if desired, the protecting groups, if any, are removed; or b) a compound of the general formula A-C-CONH CZR, I lL- J-CR ^ OCOCH ₃ ( ¹ ^ wherein A, R _x Z, R ₁ and M have the meanings given in claim 1, or a reactive derivative thereof with a compound of the general formula HS-Het (V) wherein Het has the meanings given in claim 1, or a reactive derivative thereof is reacted and, if desired, the protecting groups, if any, are removed to form a compound of the general formula (i), wherein A, R, Z, R. and M are those given in claim 1 Have meanings and Y -CH ^ -S-Het means, in which Het the in Claim 1 has given meanings; or c) a compound of the general formula AC-CH ₉ -CONH wherein A, M, R .. and Y have the meanings given in claim 1 and each of the symbols Z independently of one another means oxygen or sulfur, or a salt thereof is methylated and, if desired, the protective groups, if present, are removed to form a compound of the general formula (I) in which A, M, Y and Z have the meanings given in claim 1 and R is -OCH ₃ or -S -CH ₃ and in which R is either methyl if one starts from a compound (VI) in which R. Means hydrogen, or any branched or unbranched (straight-chain) saturated or unsaturated aliphatic cal C ₁ - (^, - hydrocarbon group, as described above * in relation to I ο the formula (i) is defined, represents when one of Compound (VI) starts, wherein R ^ has a meaning other than that of hydrogen has; or d) a compound of the general formula A-CH ₀ -CONH- ... 2! I I ν (VII) wherein A, M and Y have the meanings given in claim 1, with a compound of the general formula Z H-C-OR "(VIII) wherein R "is C.-C.-alkyl and Z has the meanings given in claim 1, reacts and, if desired, the protective groups, if any, removed to form compounds of the general Formula (i), in which R and R ^ are both hydrogen and Z, A, M and Y have the meanings given in claim 1, and, if desired, a compound of the general formula (i), wherein R, denotes hydrogen and R, Z, A, M and Y have the meanings given in claim 1, or a salt thereof etherified to form a compound of the general formula (i) in which R. has the meanings given in claim 1 with the exception of hydrogen and R, Z, A, M and Y have the in - 12 - Claim 1 have the meanings given, and / or, if desired, a compound of the general formula (i), wherein M is carboxy, converted into a salt, in particular a pharmaceutically or veterinarily acceptable salt, and / or, if desired, a free compound of one Salt produces and / or, if desired, converts a compound of the general formula (I) or a salt thereof into another compound of the general formula (i) or a salt thereof and / or, if desired, a mixture of isomers into the separates individual isomers. 6. A pharmaceutical or veterinary agent, characterized in that it contains at least one α, ß-disubstituted acrylamidocephalosporin and / or at least one pharmaceutically and veterinarily acceptable salt thereof one of claims 1 to 4 and optionally at least contain a pharmaceutically and veterinarily acceptable carrier and / or diluent