DE3045343A1 - N-SUBSTITUTED THIAZOLYL DERIVATIVES OF 7-AMINO-CEPHALSOSPORANIC ACID, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING PHARMACEUTICAL AND VETERINE MEDICAL AGENTS - Google Patents

Description

52 498-BR

Applicant: Farmitctlia Carlo Erba SpA
Via Carlo Imbonati 24
1-20159 Milan

N-substituted thiazolyl derivatives of Z-amino-cephalosporanic acid, Process for their preparation and pharmaceutical containing sio

and veterinary medication

The invention relates to new N-substituted thiazolyl derivatives of 7-amino-cephalosporanic acid, a process for their preparation and pharmaceutical and veterinary preparations containing them.

The novel N-substituted compounds forming an object of the invention Thiazolyl derivatives of 7-Amino-cephalosporanstiure have the general formula

l-CONH,,

whatir. mean:

A -C- or -CH-, where R _{0 is} a hydrogen αto «or a free or

Ml *

0 R ₂

130035 / OSOO

represents protected hydroxy group;

R l) -OR ", where R" represents hydrogen or a branched or unbranched (straight-chain) saturated or unsaturated aliphatic C.-C, hydrocarbon group which is unsubstituted or substituted by one or more substituents selected from (a) cyano, (b) -COOR ¹ , in which R * is hydrogen, C -C ₆ -alkyl or a carboxy protective group, (c) -C0-NC ^ _R 4 _f in which each of the groups R- and Rc, which can be identical or different , _rt for a hydrogen atom, a C.-C, "alkyl group or an aliphatic C -C.-acyl group, or wherein when R is hydrogen, R, - can also be a Arainoschutzgruppe; or

2) -NC ^ _R 4, where R ₁ , and R 1. have the meanings given above; R. Hydrogen or an amino protecting group; η is the number 0, 1 or 2;

Y fe ¹ ) hydrogen; (b ¹ ) halogen; (c ¹ ) hydroxy; (d ¹ ) C 1-4 alkoxy; (e ¹ ) C ₁ -C ₆ AUCyI; (f) -CH ₂ OCOCH ₃ ; (g ') the group

where R "is hydrogen, C -C -alkyl, carboxy, cyano

or can be carbamoyl; (h ¹ ) the group -CH ^ -S-Hot, in which Het is:

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

13003B / 0500

Choose

a ") Hydroxy, C 1 -C, -alkoxy, halogen, aliphatic C 1 -C 6 -Acy.l; b ") C - C, ~ alkyl which is unsubstituted or substituted by one or more substituents selected from hydroxy and

Halogen; c ") C_-C, -alkenyl which is unsubstituted or substituted by one or more substituents selected from hydroxy and

Halogen; d ") -SR ₆ , wherein R _{6 is} hydrogen or Cj - ^ - alkyl, -S-CH ₀ COOR ', in which R * has the meanings given above;

e ^H ) - (CHj -CX) OR ¹ , -CH = CH-COOR ', - (CH ₀ ) -CONH ₀ or - (CH ₀ ) -CN, Z- ta ζ ta ζ ζ m

in which m represents the number 0, 1, 2 or 3 and R ^{1 has} the meanings given above; f ") - (CH ₀ ) SO ₀ H, in which m has the meanings given above;

Z R) «J

or

g ^M ) - (CH ₀ ) -N: ^ _D 4, in which m, R. and R _{fi have} the meanings given above; or

2) a heterobicyclic ring which contains at least two double bonds, each of the fused heteromonocyclic rings, which can be identical or different, being a 5- or 6- membered heteromonocyclic ring which contains at least one heteroatom selected from N, S and 0, contains, the heterobicyclic ring being unsubstituted or substituted by one or more substituents selected from (a "), (b"), (c "), (d ^M ), (e"), (f ") and (g ") f as indicated above;

X is a free or esterified carboxy group,

with the hatred that when R is -0R ₀ and A is the group -CH-,

«* F

R ₂

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where R _{n is} hydrogen, R _{0 is} not hydrogen «

The present invention also encompasses the salts, in particular the pharmaceutically and veterinarily acceptable salts of the compounds of the formula (I) and all possible isomers, for example the cis and trans isomers and the optical isomers and their Mixtures containing metabolites exhibiting antibacterial activity and the metabolic precursors of the compounds of formula (I).

When η = 1, the resulting compounds are Sulfoxides and they can be in the R or S * »configuration. When η = 2, the compounds are sulfones.

Amino and carboxy protecting groups can, for example, be the protecting groups as they are commonly used in peptide chemistry. Examples of amino protecting groups are formyl, an optionally Halogen-substituted "aliphatic C" -C, -acyl, preferably Chloroacetyl or dichloroacetyl, tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl or trityl. Examples of carboxy protecting groups are tert-butyl, Benzhydryl, p-methoxybenzyl, p-nitrobenzyl, trityl and trialkylsilyl.

If A is -CH- and R _{9 is} a hydroxyl group, this group can be for _{-R 2}

be protected, for example, by a formyl, acetyl, chloroacetyl, Dichloroacetyl, trifluoroacetyl, tetrahydropyranyl, trityl or silyl group, in particular through trimethylsilyl or dimethyl-tert-butylsilyl.

An aliphatic Crt-C ^ acyl group is preferably

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around a Cp-C ^ -alkanuyl group, in particular around acetyl.

If X is an esterified carboxy group, it is preferably a group of the formula -COOM, where M is a recto -CK-OC-Ro and -CH-QC-OR-, where R _{7 is} hydrogen or R ₇ 0 R ₇ 0

C -C ^ -alkyl, Q for -0- or -NH-, R _g for an alkyl group (e.g. C.-C, -alkyl) or a basic group, in particular an alkyl (e.g., C.-Cf-alkyl) - Or aralkyl (e.g. benzyl) group which is substituted by at least one amino group, which in turn may be unsubstituted or substituted, in which Rg is, for example, alkyl-NH-CHg, ÄraItCyI-NH-CH ₃ ,

Alkyl-NH- / ~~ \, -CH- / ~ A, -CH ₀ NH ₀ , R _{0 stands} for an Al! Iyl _C group,

in particular a C.-C.-Aikylgruppo, for example methyl, propyl, Isopropyl, an aryl group, especially phenyl, eir.e cycloalkyl group, especially cyclopentyl, cyclohexyl and cycloheptyl, a hoteromonocyclic A ring such as pyridyl, a bicyclic ring such as indanyl, an aralkyl group such as benzyl.

Particularly preferred compounds are those of the formula (i) in which mean:

R. Hydrogen or an amino protecting group; R -OC ^ C ^ alkyl, -O-Cg-C ^ alkenyl, -0- (CH ₂ ) _w -COOR ¹ , in which R * has the meanings given above and m is the number 1, 2 or 3, amino , -NHCH ₃ , -N (CHg) ₂ , -NHCOCH ₃ or NHCOO-tert-butyl; A -CH ₀ -, -C or -CH-;

^ Ml

0 OH

Y is hydrogen, halogen (preferably chlorine), hydroxy, C.-C6 alkoxy (preferably methoxy), methyl, -CH ₂ OCOCH ₃ or OL-S-Hot, in which Het is:

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1) a tetrazo} yl radical which is unsubstituted or substituted by C ₁ -C, »alkyl, C ₀ -C. Alkenyl, - (CH ₀ ) -COOR ¹ , in which Hi ₁

and R ^{1 has} the meanings given above _f -CH = CH-COOR ¹ , in which R * has the meanings given above, - (CH ₀ ) -GM,

- (CH _n ) -CONH ₀ , - (CH ₀ ) -SO ₀ H, in which m. The Zm- c / L χα given above. ο ι

R has meanings, odor - (CH ₀ ) ~ ^ Cj> ^ ι where in., R. and R ₅

1 5 have the meanings given above;

2) a thiadiazolyl radical which is unsubstituted or substituted by C.-C ^ alkyl, C ^^ - alkenyl, -SH, -SCH ₃ , -S-CH ₂ COOH, - (CH ₀ ) -COOH, in which m is the above has given meanings,

Ai in which Rl and RV represent hydrogen or C 1-4 alkyl; or

3) a heterobicyclic ring selected from tetrazolopyridazinyl, tetrazolopyrazinyl ,. Thiadiazolopyridazinyl and triazolopyridazinyl, each of which is optionally substituted by

Hydroxy, -SH, -CO-N ^ _R , 4, wherein R ¹ ^ and RV are those given above

Have meanings, -COOR ¹ , in which R ^{1 has} the meanings given above, C ^ Cg-alkyl, C ₀ -C ₄ -alkonyl, -S-CHgCOOR ', -CH ₂ COOR' or -CH = CH-COOR ', wherein R * has the meanings given above, or Dl

-N ^^ p, 4, where R \ and RV have the meanings given above

The salts, in particular the pharmaceutically and veterinarily acceptable salts, of the compounds of the formula (i) are those with inorganic acids, such as hydrochloric acid, sulfuric acid, or those with organic acids, such as citric acid, Tartaric acid, malic acid, maleic acid, mandelic acid, fumaric acid and methanesulfonic acid, or those with inorganic bases such as sodium, potassium,

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^ß AD ORIGINAL

Calcium or Alurdniunihydroxiden and alkali metal · or Erdalkalimeta Hear bonaten or bicarbonates , or those rait organic bases, such as organic amines, for example «lysine, triethylamine, procaine, Dibenfcylamin, N-benzyl-ß-phenylamine, N, N'- Dibenzyl-ethylenedioinine, dchydroabiotylamine, N-At hy! Piperidine, di-titan ο la min, N-methylglucamine, tris-hydroxymethyl-arainoisiethan and the like.

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

1) 7β- [2- (2-Imino-3-ra6thoxy-4-thiazolinyl) -acetai, iido] '- 3-c6phom-4 · - carboxylic acid; .

2) 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -2-hydroxy-icetamido] -5-cephom-4-carboxylic acid;

3) 7β -. [2- (2 ~ imino-3 "> m3thoxy-i-thiai: olinyl) -2-oxoacetamido3 ~ 3-cephem-4-carboxylic acid;

4) 7β-C2- (2-imino-3-omino-4-thiazolinyl) -acetamido3-3-cephera «-4-carboxylic acid;

5) 7β-C2- (2-Injino-3-amino-4-thiazolinyl) -2-oxoacetaroido] -3-cephem-4-carboxylic acids;

6) 7β- [2- (2-imino-3-amino-4-thiazolinyl) -2-oxoacetamido] -3-cephein-4-carboxylic acid;

7) 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetamido] -3-acetoxymethyl-S-cephem - ^ - carbon acid;

8) 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -2-hydroxy-acetamido] -3-acetoxy-methyl-3-cephem-4-carboxylic acid;

9) 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -2-oxoacetamido3-3-acetoxy-methyl-3-cephem-4-carboxylic acid;

10) 7β- [2- (2-linino-.3-ynethoxy-4-thiazolinyl) acetainido] -1 (S) -OXO-S-acetoxy-methyl-o-cephera- ^ carboxylic acid;

Π) 7β ~ [2 ~ (2-Iraino-3-methoxy-4-thiazolinyl) -acetamido] -i (R) -oxo-S-acetoxy-ethyl-S-cephem ^ -carboxylic acid;

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BATH ORIGINAL

12) 7β-C2- (2-J.mino-3-raethoxy-4-thiazolinyl) -acetamido] -1-dioxo-3-acetoxy-pethyl-3-ccphem-4-carboxylic acid;

13) 7β- [2 ~ (2-Itnino-3 "umino ~ 4-thiazolinyl) -acetaiTiido] -1-c {ioxo-3-acotoxymethyl ~ 3 ~ cephem ~ 4-cirboxylic acid;

14) 7β- [2 ~ (2 ~ Imino-3-methoxy-4-thiazolinyl) -acetamido] -3 - [(i-iP5thyl-1,2,3,4-tetrazol-5-yl) -thiomethyl] ~ 3-cephem-4-carboxylic acid;

15) 7β ~ [2 ~ (2-Imino-3-methoxy-4-thiazolinyl) -acetamido] -3-L (i- (2-cyanoethyl) ~ 1,2 _/ 3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid;.! re;

Ιό) 7ß-C2- (2-imino-3-methoxy-4-thiazolinyl) -acetamido] -3-C (5 ~ methyl-1 _/ 3 _f 4-thiadiazol-2- ^ l) -thiom © thyl] - 3-cephem-4-carboxylic acid;

17) 7β ~ [2- (2.-Iniino ~ 3-mothoxy-4-thiazo.linyl) -acetan5ido] -3 - [(tetraÄO.lo ~ [1 , S-bDpyridazin-o-ylJ-thiomethylD-S -cephem ^ -carboxylic acid;

18) 7β ~ [2- (2-Imino-3-mc-ithoxy-4-thiazolinyl) acetamido] -3 - [(8 ~ amiiiotetrazoloCi, 5-b] pyridazin-6-yl) thiomethyl] -3 -cephem-4-carbon ~ acid;

19) 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetamido3-3 - [(8 "carboxytetrazolo [1,5-b] -pyridazin-6-yl) -thiomethyl] -3" -cepheni-4 « carboxylic acid;

20) 7β ~ [2 ~ (2-Itnino-3-methoxy-4-thiazolinyl) -acotarnido] -3 - [(8-carboxymethyl-tetrazoloCi, 5-b] -pyridazin-6-yl) -thiomethyl] -3 -cephera ~ 4-carboxylic acid;

21) 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -2-oxoacotamido [-3 ~ [(imethyl-1,2,3,4-tetrazol-5-yl) -thioraethyl] - 3-cephem-4-carboxylic acid;

22) 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -2-hydroxy-acetainido] -3 - [(i-

23) 7β- [2- (2-Imino-3-amino-4-thiazolinyl) -acetamido] -3- C (i-raethyl-1,2-3,4-totrazol-5-yl) -thioraethyl3-3 -cephem-4-carboxylic acid;

24) 7β- [2 "(2-imino-3-amino-4-thiazolinyl) -acetamido] -3-C (tetrazolo-Ci _f S-bD-pyridazin-o-ylI-thiomethylD ^ -cephem ^ -carboxylic acid;

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25) 7β- [2- (2-Iraino-3-amino-4-thiazolinyl) ~ acetamic) o] -3 - [(8-carboxy- · tetrazolo ~ Ci _/ 5-b] pyridazin-6 ~ yl) - thio8! ethyl] -3 "-cephei" -4 "gcrbonsi5ux'o;

26) 7β- [2- (2-Iraino-3-amino-4-thiazolinyl) -2-oxoacetamidoJ ~ 3 ~ C (i ~ methyl ~ 1,2 _/ 3 _f 4-tctrozol-5-yl) ~ thiomethyl] -3-ccphera-4-carbonsHuro;

27) 7β-C2- (2-Iraino-3-amino-4-thiazolinyl) -2-hydroxy-acetamido] ~ 3 ~ [(l-ethyl-1 _/ .2 _/ 3 _/ 4-tetrazole «-5 ~ yl) thiomethyl] -3-cephcm-4 ~ carboni; auro;

28) 7β- [2- (2-Imino-3-amino-4-thiazolinyl) -2-hydroxy-acstamido] ~ 3 - [(l ~ (2-cyanoethyl) -1, 2,3 _/ 4-tetrazole- 5 ~ yl) thiomei: hyl3-3-cephem ~ 4-carboxylic acid;

29) 7β-C2- (2-imino-3-araino-4-thiazolinyl) -2-hydroxy-acetamido] -3 - C (8-omino-tetrazolone, 5-b] -pyridazin-6-yl) -thiomothyl3-3-c0piw5: i-4 ~ carboxylic acid;

30) 7β- [2- (2-Linino-3-amirio-4-thiazolinyl) -. 2-hydroxy-acetainido] -3 "[8 ~ carboxy-tetrozoloCi, 5-b] -pyridazin-6-yl) -thiomethyl3-3 ~ cophem-4-carboxylic acid

and their salts, in particular their pharmaceutically and veterinarily acceptable salts, especially their hydrochlorides.

The structural formulas of the above compounds are in order their progressive numbering is given in the following table 2

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-xr-

30453A3

Tabel

Co O
ο
co
cn
-s.
ο

CTI

Connection no.

1 2

4 5

7 8

10 11 12 13 14

15 16

17th

R. R. A. η X H -OCH ₃ -CH ₂ zero -COOH H -OCH ₃ —CH-
OH zero -COOH H -OCH ₃ O = O zero -COOH H -NH ₂ -CH ₂ - zero -COOH H -NH ₂ -9H-
OH zero -COOH H -NH ₂ O = O zero -COOH H -OCH ₃ -CH ₂ zero -COOH H -OCH ₃ "-CH-
OH zero -COOH H -OCH ₃ —C— zero -COOH H -OCH ₃ -CH ₂ - Ks) -COOH H -OCH ₃ -CH- KR) -COOH H -OCH ₃ -CH ₂ - CVl -COOH H -NK ₂ -CH ₂ - 2 -COOH H -OCH ₃ -CH ₂ - zero -COOH H -CCH -CH ₂ - zero -COOH H -OCH ₃ -CH ₂ -. zero -COOK H -OCH ₃ K-Il -COOH

H
H

H
• H

-CH ₂ O-COCH ₃ -CH ₂ O-COCH

-CH ₂ O-COCH

-CH ₂ O-COCH ₃ -CK ₂ O-COCH ₃ -CH ₂ O-COCH ₃ -CH ₂ D-COCH ₃

-CH ₂ -S-JI _n Jj

N ^ -N

- W-

Table ~ continuation.

• H R. ² A. η • zero X Y 18th -OH -NH ₂ -CH - zero zero -COOH pu cJ !, il
~ ^CH 2-S ^-4 ^ NN H COOH 19th -OCH ₃ -CH ₂ zero -COOH -CH ₂ -S -ζΧ-ζ H zero CHoCOOH 20th -OCH ₃ -CH ₂ - zero -COOH -CH ₂ -SC ^ i! H zero N-N • 21 -0.CH ₃ d zero -COOH —PH _ς Ji '!.
° ^H 2 K $ _H - H zero N-N 22nd -OCH ₃ -CH-
. OH zero -COOH H zero N-N 23 H -NH ₂ -CH ₂ - -COOH -CH -SJLJN
* ^N CH ₃ 24 -NH ₂ -CH ₂ - NuJl -COOH -CH -sjQi'U COOH H zero 25th -CH ₂ - -COOH " ^CH 2" ^S ^ "NN ' > H N-N 26th -NH ₂ 0 -COOH -CH-S-IIuJk
* ^N CH ₃ H N-yN 27 -NH ₂ - -CH- -COOH —PH "C _J ['II H OH ^S CH ₃ 28 •. -NH ₂ -CH- -COOH NN
-CH-S-JI _n ^ H ■ OH ' ² J ^ CH ₂ CH ₂ CN 29 -NH -CH- -COOH * ^ λ ^^ XJ »ίΝ" "" "Γι H OH COOH 30th ! -CH- -COOP. -CH ₂ -S VÖ ; OH

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The compounds according to the invention can after a further Process forming the subject of the invention, which is characterized in that

a) a compound of the general formula

* ⁿ (H)

in which n, X and Y have the meanings given above and E is amino or the group N = C = O or -N = C = S means, or a reactive derivative thereof with a compound of general formula

-COOH

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

b) a compound of the general formula

HC-S-CH ₂ -CA-CONh - ^ _(IV)

wherein A, n, X and Y have the meanings given above, or a reactive derivative thereof with a compound of the general formula

R-NH ₂ (V)

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wherein R has the meanings given above, or a salt thereof is reacted and, if desired, the protecting group which may be present is removed; or

c) a compound of the general formula

(0) Vn

B-CH -CA-CONH- ² Il

wherein A, n, X and Y have the meanings given above and B Halogen means

or a reactive derivative thereof with a compound of the general formula

R ₁ NH

i / HW * (VII)

wherein R and R, have the meanings given above, reacted and if desired, removing the protecting groups, if any will; or

d) a compound of the general formula

B-CH _n -CA-CONH

² Il

(VIII)

wherein B, R, A, n, X and Y have the meanings given above, reacted with thiocyanic acid or a salt thereof and, if desired, the protective groups, if any, are removed; or

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e) a compound dor the general formula

, R-N

(ix)

in which R, R., A, η and X have the meanings given above, or a salt thereof with a compound of the general formula

HS-Het (X)

where feces have the meanings given above, or a reactive derivative thereof and, if desired, the protective groups, if present, are removed and / or, if desired, a compound of the formula (i) in which X is carboxy is converted into a salt, in particular a pharmaceutically or veterinarily acceptable salt, and / or if desired a free compound is prepared from a salt and / or, if desired, a compound of the formula (i) or a salt thereof is converted into another Compound of the formula (i) or a salt thereof is converted.

If in the compounds of formulas (II), (IV), (VI), (VIII) and (IX) X represents a free carboxy group, the carboxy group may, if necessary, be protected in a conventional manner before the reaction is carried out * Examples of protective groups are those as commonly used in peptide synthesis, such as tert-butyl, benzhydryl, p-methoxybenzyl, p-nitrobenzyl, trityl and Trialkylsilyl.

The protective groups are then at the end of the reaction in a known manner, removed for example by mild acid hydrolysis or by catalytic hydrogenation, for example with Pd / C at room pressure.

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- a - ■ · - · ■■

Since the pre-compounds of the formula (i), which contain the protective groups, are also within the scope of the present invention, removal of the protecting groups is not an essential step in the process.

Those used in each of the above methods (a) to (e) When one or more asymmetric carbon atoms are present, starting materials can be optically active or racemic compounds be.

A reactive derivative of the compound of Foxmel (II) can be obtained from ~ be for example an amine salt, a silyl ester or a metal salt, when X is carboxy.

A reactive derivative of the compound of the formula (Hl) is, for example, an acyl halide, an anhydride or a mixed an ~ hydride, an amide, an AzId, a reactive ester or a salt, such as the salts formed with alkali or alkaline earth metals, ammonia or an organic base.

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

The reaction between the compound of the formula (II) or a reactive derivative thereof under the compound of the formula (III) or a reactive derivative thereof can be either at room temperature or with cooling, preferably at about -50 to about +40 C in a suitable solvent, e.g. in acetone, dioxane, tetrahydrofuran, Acetonitrile, chloroform, methylene chloride, dimethylformamide, 1,2-

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Dichloruthan or in a mixture of water and one with water miscible solvents 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 Alkylene oxides such as propylene oxide can be carried out.

When the compound of the formula (Hl) with the compound of the formula (II), in which E is amino, in the form of a free acid or in the form of a salt is reacted, it is advantageous that the reaction in the presence of a condensing agent, such as N, N '»dicyclohexylcarbo ~ diimide, is carried out

Any removal of the protective groups carried out at the end the reaction can be carried out in a known manner. For example, the tert-butoxycarbonyl group can be removed by treatment with an aqueous solution of an acid (such as CF «, COOH or HCOOH) and the Monochloroacetyl group can be removed by treatment with thiourea. The forinyl and trifluoroacetyl groups can be removed by treatment with potassium carbonate in aqueous methanol; the tetrahydropyranyl group can be removed by treatment with dilute Hydrochloric acid and the trityl group can be removed by treatment with formic acid or trifluoroacetic acid.

The reaction between the compound of formula (IV) or a reactive derivative thereof which is, for example, a salt or an ester »A can, with a compound of the formula (V) or a salt thereof, can in a suitable solvent, e.g. in water, methanol, ethanol, dioxane, acetonitrile, dimethylformamide, dimethylacetamide or Meihylenechlorid.

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A salt of the compound of formula (V) can be either a salt with inorganic acids, such as hydrochloric acid odor Sulfuric acid, or a salt with organic acids, such as citric acid ,. Tartaric acid, oxalic acid or p-toluenesulfonic acid.

The reaction temperature is preferably within the range of about 0 to about 90 C and the pH is preferably about 1 to held about 7.5. Any subsequent removal of the protective groups can be carried out using known methods, for example those as indicated above.

In the compounds of the formulas (VI) and (VIII), B preferably stands for chlorine or bromine.

The reaction between the compound of formula (VI) or a reactive derivative thereof, which is, for example, a Sal2 or an ester, and the compound of formula (VII) is preferably in an aprotic solvent, e.g. in N, N '~ Dimethylformamide, Ν, Ν'-dimethylacetamide, dimethyl sulfoxide, acetonitrile, Hexamethylphosphoric triamide or a mixture of these solvents carried out. The reaction temperature is preferably within of the range from about 0 to about +90 C. The subsequent removal, if necessary, of the protective groups that may are present can be carried out as indicated above.

The reaction of a compound of formula (VIII) with thiocyanic acid or a salt thereof, for example an alkali metal such as potassium thiocyanate, in an inert solvent, preferably in a dipolar aprotic solvents such as acetonitrile or dimethylacetamide can be carried out.

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A salt of a prebond of the formula (IX) is, for example to a salt, in particular an alkali metal salt, a A compound of the formula (IX) in which X is carboxy. A Sulz one Compound of formula (X) can, for example, the salt with a Alkali metal, such as sodium.

The reaction between the compound of formula (IX) or a salt thereof and the compound of the formula (X) or a reactive one Derivative thereof, for example a metal salt thereof, can be dissolved in water or in a mixture of water and an organic solvent such as acetone, ethanol, dioxane or tetrahydrofuran in the presence of about 2 equivalents of a base such as sodium bicarbonate will.

The reaction temperature is preferably within the range of about 5 to about 90 C and the pH is preferably about 5 to held about 7.5. If desired, a buffer such as sodium phosphate or sodium acetate can be used.

Alternatively, the same reaction can be carried out without any base and in an absolute anhydrous solvent at temperatures within the range of about 50 to about 120 C and for reaction times within from a few hours to a few days. The preferred solvent is acetonitrile and an inert one Atmosphere (such as nitrogen) may be advisable to prevent oxidation of the heterocyclic thiol (Χ) to prevent. The subsequent, if necessary Removal of the protecting groups carried out can be carried out using known methods, for example such as are given above, take place.

130035/0500

The transfer of the connection to the Formula (I) into a salt thereof as well as that optionally carried out Conversion of a salt to a free compound can be carried out using conventional methods, i.e. using methods such as they are already known in organic chemistry.

As indicated above, a compound of formula (i) or a Salt thereof are converted into another compound of the formula (I) or a salt thereof; including any conversions that may have been carried out can be done using conventional methods. For example, a compound of the formula (i) in which R -OH means into the corresponding compound of the formula (i) in which R -OR "denotes, where R" is different from hydrogen, with the addition usual etherification reactions are transferred.

Other conversions carried out, if any, can also be the Esterification of a compound of the formula (i) in which X is carboxy, which can be carried out by reacting the compound of formula (i) in which the carboxy group is free or in a salt, for example in a sodium, potassium, calcium or triethyl ammonium salt, transferred is, with the appropriate halide in an organic solvent, e.g. in acetone, tetrahydrofuran, chloroform, methylene chloride, dimethylformamide, dimethyl sulfoxide, or in a mixture of water and a organic solvents such as dioxane and acetone; the reaction tempera " door is within the range from about -20 to about +80 C, In addition, a compound of the formula (i) wherein X is an esterified Carboxy group means to be saponified using, for example an inorganic acid, such as hydrochloric acid, or an inorganic base, such as sodium or potassium hydroxide, as in the organic Chemistry known per se.

13003S / 0500 _oiMAI

BATH ORIGINAL

- SS) -

The compounds of formula (i) where η = 1, and wherein the sulfoxide is present in the S-configuration may preferably be prepared from the corresponding compounds of formula (i) wherein η = O, are prepared by treating with an oxidizing agent, in particular a Peracid, such as perbozoic acid, m-chloroperbenzoic acid, permaline acid, sodium periodate, hydrogen peroxide or a mixture thereof with an inorganic acid such as formic acid, acetic acid or trifluoroacetic acid. The reaction can be carried out in a solvent, for example in dioxane, tetrahydrofuran, chloroform, methylene chloride, formic acid, acetic acid, benzene, Ν, Ν-dimethylformamide, Κ ', Ν-dimethylacotaniide or the like. ₍ The reaction temperature is preferably about -30 up to about + 90 ° C.

To prepare the sulfoxide with the R configuration, it is preferred to carry out the same oxidation reaction with the intermediate products, preferably with the compounds of the formula (II) in which E is amino, after first this amino group by the formation of a Schiffsche Base has been protected.

The Schiff base can be prepared by known methods, for example by treating the amine of formula (II) with a Aldehyde such as benzaldehyde, salicylaldehyde or p-nitrobenzaldehyde; at the end of the oxidation reaction the free amino group can be obtained, for example, by treatment with a hydrazine derivative such as Phenylhydrazine, 2,4-dinitrophenylhydrazine, or a Girard reagent. The carboxy group is preferably protected during the oxidation reaction using, for example, protecting groups as they are given above.

The conversion of a sulfide to a sulfoxide, that is, the conversion

130035/0500

30453A3

a compound of formula (i) in which η = 0 to the corresponding compound in which η β 1 can be effected using 1 to 1.2 molar equivalents of the oxidizing agent per mole of the compound to be oxidized.

The conversion of a sulfide into a sulfon, i.e. the conversion of a Compound of formula (I), in which η = 0, into the corresponding connection Formation of the formula (i), where η = 2, can be made using the same Oxidizing agents, as they have been used to prepare the sulfoxides, take place, in which case at least two molikjuivalents of the oxidizing agent per mole of the compound to be oxidized be used*

Any separation of a mixture of isomers into the individual isomers can also be carried out using conventional methods Methods are carried out. For example, racemic compounds can be separated into the optical antipodes, for example by separation, for example by fractional crystallization of mixtures of diastereoisomeric salts, and if desired by releasing the optical antipodes from the salts.

The compounds of the formula (II) in which E is amino and Y is hydrogen, Halogen, hydroxy, C.-C, -alkyl or C .- (λ, -alkoxy denote, represent known compounds or can be prepared by known processes.

The compounds of the formula (II) in which E is -N = C = O or -N = C = S, 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 of a hydrochloric acid acceptor

13003B / 0500

BATH ORIGINAL

Use of known procedures.

The compounds of the formula (Hl) can be prepared according to one of the following Procedure to be produced:

1.) By reacting a compound of the general formula

NC-S-CH ₂ -CA-COOR ', _{χ] [} ν

wherein A and R ^{1 have} the meanings given above, with a compound of the formula (V) using reaction conditions / which are analogous to those as are used for the reaction between the compound of the formula (IV) and the compound of the formula (V ) have been specified; the compounds of the formula (Xl) are known compounds or can be prepared by known processes /

2.) by reacting a compound of the formula

B-CH ₉ -CA-COOR ¹

5 (XII)

wherein B, A and R * have the meanings given above with a compound of the formula (VIl) using reaction conditions analogous to those used for the reaction between the compound of the formula (VI) and the compound of the formula (VII) have been specified;

3.) by reacting a compound of the general formula

B-CH _n -CA-COOR ¹

Il

'2 ι,

(XIII) R

130035/0600

- 23 -.

wherein B, R _f A and R 'have the meanings given above, _r with thiocyanic acid or a salt thereof using reaction conditions analogous to those just given for the reaction between the compound of formula (VIII) and thiocyanic acid are;

4.) by treating a compound of formula (III) in which R H bodeutet and the carboxy group is a free or esterified or protected carboxy group, with an N-aminating agent such as O-mesitylenesulfonylhydroxylamine, with formation of the ammonium mesityJon · « sulfonate salt of a compound of formula (III) in which R -NHp means from which the free base can be obtained in a conventional manner «

The reaction can in an inert solvent such as chloroform, methylene chloride, at temperatures within the range of -30 to +40 ⁰ C are performed;

&) by treating a compound of the formula (III), in which R is hydrogen, with an oxidizing agent, in particular a peracid, such as perbenzoic acid, m-chloroperbenzoic acid, permaleic acid, Pertrifluoroacetic acid, sodium periodate, hydrogen peroxide or one Mixture thereof with an inorganic or organic acid such as formic acid, acetic acid, or trifluoroacetic acid to form a compound of the formula (III) in which R is hydroxy, which in turn can be etherified to form a compound of the formula (III), in which R is -ORo, in which R ~ has the meanings given above with the exception of hydrogen.

130035/0500 bad original

30A53A3

The oxidation reaction can be carried out in a solvent, e.g. in dioxane, Methylene chloride, chloroform or methanol, at a temperature are preferably carried out between about -30 and about 90.degree. The dietary response can be applied in a conventional manner known methods, for example by treatment with the appropriate alkyl halides or diazoalkanes;

6.) by rearrangement of a compound of the general formula

(XIV)

N;

in which A and R ~ have the meanings given above, with formation of a compound of the formula (Hl) in which R is amino and R _{1 is} hydrogen.

The reaction can be carried out by heating the compound (XIV) in an acid medium, e.g. in hydrochloric acid, sulfuric acid, Formic acid and the like. Removal of any carboxy protective groups that may be present can take place during this reaction.

The compounds of the formula (XIV) are known compounds.

The compound of the formula (IV) can be selected from a compound of the formula (VE) are produced by reaction with thiocyanic acid or a Salt thereof, for example calcium thiocyanate, in an inert solvent, preferably a dipolar solvent such as acetonitrile or Ν, Ν-dimethylacetamide.

The compounds of the formula (V) represent or are known compounds

130035/0500

can be prepared by known methods.

The compounds of the formulas (VI) and (VIl) are known compounds or can be prepared by known processes.

The compounds of the formula (VIII) can be selected from compounds of the formula (VI) are prepared by reaction with a compound of the formula (V) using reaction conditions which are analogous to are those given for the reaction between the compound of the formula (IV) and the compound of the formula (V) are.

The compounds of formula (IX) in which η = O can be prepared are for example by reaction of 7-amino-cephalospornic acid or a salt thereof with a compound of the formula (Hl) or a reactive derivative thereof using reaction conditions analogous to those described above for the reaction between the compound of the formula (II) and the compound of the formula (Hl) have been given.

The compounds of the formula (X) represent or are known compounds can be prepared by known methods.

The compounds of the formulas (III), (IV), (VI), (VIII) and (IX) in which η = 1 or 2 can be prepared by oxidizing the corresponding compounds in which η = 0, as above for the analogous Conversions given for the compounds of formula (i).

The compounds according to the invention have a high level of antibacterial properties Activity (effectiveness) both in animals and in humans against

130035/0500

- 26 -

30A5343

About large-positive and large-negative bacteria that normally * are sensitive to cephalosporins, such as staphylococci, Streptococci, Diplococci, Klebsiella, Escherichia coil, Proteus mirabi-lis, Salmonella, Shigella, Haemophilus and Neieseria ,.

The compounds according to the invention are therefore valuable for the treatment of infections caused by these microorganisms such as respiratory infections such as bronchitis, bronchopneumonia, Pleurisy; Hepatobiliary and abdominal infections, such as Cholecystitis, peritonitis; Blood and cardiovascular infections, such as e.g. blood poisoning; Urinary tract infections, such as pyelonephritis, Cystitis; obstetric and gynecological infections such as cervicitis, endometritis; Ear, 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 used safely in therapy.

The compounds according to the invention can be applied to humans and animals in the a wide variety of dosage forms are administered, for example orally in the form of tablets, capsules, drops or syrups; rectal in Form of suppositories; parenterally, for example intravenously or intramuscularly, in the form of solutions or suspensions, the intravenous Administration in emergency situations is preferred; by inhalation in the form of aerosols or solutions for nebulizers; intravaginal, in In the form of, for example, bougies; or topically in the form of lotions, creams and ointments.

The pharmaceuticals forming a further subject of the invention

13003S / 0600

-27 ~

. 30453A3

or veterinary agents (preparations) containing the compounds of the invention can be based on conventional ones Manner, optionally using conventional carriers and / or diluents such as are used for the other cephalosporins.

Examples of conventional carriers or diluents are water, Gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and the like.

In various animal species, daily doses within the range of about 1 to about 100 rag per kg of body weight can be used, the exact dose being dependent on the age, weight and condition of the patient being treated and the frequency and route of administration depend. A preferred mode of administration of the invention Compounds is parenteral administration; in this case, for example, the compounds can be applied to adult humans in an amount within the range of about 100 to about 200 mg per dose, preferably from about 150 mg per dose, 1 to 4 eels a day, dissolved in a suitable solvent, e.g. in sterile water or in a Lidocaine hydrochloride solution for intramuscular injections and in sterile water, in a physiological saline solution, in a dextrose solution or in conventional intravenous fluids or electrolytes for intravenous injections.

In addition, the compounds according to the invention can be used as antibacterial Agents are used prophylactically, for example in cleaning or surface disinfectant preparations, for example in a Concentration of about 0.2 to about 1 weight percent of these compounds in Mixture with, suspended or dissolved in conventional inert

130035/0600

^ßAD

- 28 ~

if

dry or aqueous carriers for application by washing oa'er Spray on.

They are also suitable as supplementary feed for animal feed

The determination of the melting point was somewhat difficult in some cases because the compounds tend to retain the solvent. In these cases, the word "decomposition" (abbreviated "decomposition") is added after the melting point.

The IR spectra were determined in the solid phase using a Pex'kin-Elmer 125 spectrophotometer. The NMR spectra were in DM50 (Dimethyl sulfoxide) using a Perkin Elmer R 24-B (60 MHz) spectrometer with (CfO / Si determined as internal standard.

D.io invention is explained in more detail by the following examples, without however, to be limited to that.

Manufacture η as ei spie1 1

Ethyl 2-imino-3-hydroxy-thiazoline-4-acetate hydrochloride To a solution of 4.94 g of ethyl chloroacetoacetate in 30 ml of acetonitrile was added 2.91 g of potassium thiocyanate and the mixture was stirred at room temperature for 12 hours. The precipitated KCl was filtered off and the solution was evaporated to dryness in vacuo. 2.085 g of hydroxylamine hydrochloride were added to the residue, which was dissolved in 10 ml of Ν, Ν-dimethylacetamide, and the solution was stirred at room temperature overnight. 40 ml of ethyl ether were added to the solution, the precipitated solid was filtered off, 6.0 g (83.5 %) of the title compound, mp 168 ° to 170 ° C. (decomp.), Being obtained.

130035 / OSOO BAD ORIGINAL

NMR (DMSO-d ₆ ): 1.27 (3Η, t, -OCH ₂ CJi) \

3.89 (2H, s, -CH ₂ -) "4.64 (2H; q, -OCH ₀ -CH ₀ ) 6.85 (lH, s, SH on the thiazoline ring) 9.5 (3H, br-s, -NH ₀ ⁺ , and - OH)

The tert-butyl-2-iniino-3 ~ hydroxythiazoline-acetate hydrochloride and benzhydryl-2-iinino-3-hydrojiythiazoline-4-acetate hydrochloride manufactured.

Production example 2

ft-Imino-S-amino-thiozoline ^ -acetic acid hydrochloride A mixture of 2.3 g of ethyl-2-amino-OH-1,3,4-thiodiazine-S-acetate-iiydro-

chiori (in 7 ml of 37 J & ger HCl was heated to 60 to 70 ° C. for 20 minutes. After cooling, the precipitate obtained was filtered off and then crystallized in methanol, 1.75 g (86 %) of the title compound, mp 213 - 215 ° C (dec.).

NMR (DMS0-d ₆ ): 3.82 (2H, s, -CH ₉ -)

6.12 (2H ₇ s, -N-JJh ₂ ) 6.85 (lH, s, 5-H on the thiazoline ring) 9.7 (3H, "br-s, -OH and = NH ⁺ ) ·

Yy

ι ' - · _t

The free base was obtained by treating the hydrochloride with Sodium hydroxide, m.p. 205-207 ° C (dec.).

Production example 3

2-Imino-3-a ^ nino-tl ^ iazolin-4-acetic acid hydΓochlorid A mixture of 2 g thiosemicarbazide and 3.6 g ethyl chloroacetoacetate

130035/0500 BADORLGiNAL

COPt

in 15 ml of 37% HCl the mixture was heated to 60 ° C. for 3 hours, the white hydrochloride precipitating on cooling. The product was filtered off and crystallized from methanol, giving 2.64 g (58 %) of the title compound, which was identical to the compound described in Preparation 2.

Production example 4

To a suspension of 1.7 g of 2- (N-chloroacetyl) imino-thiazoline-4-acetic acid in 20 ml of acetonitrile was a solution of 1.41 g of diphenyldiazomethane in 20 ml of acetonitrile with cooling at 0 C «- drips. The reaction mixture was left for 3 hours at room temperature touched. The solution was then evaporated to dryness under vacuum, the residue was taken up in ethyl acetate, the solution was washed with aqueous sodium bicarbonate and then dried. After evaporation, 2.2 g of the benzhydryl ester were obtained.

To a solution of 1.6 g of the above-mentioned ester in 10 ml of chloroform became a solution of 0.97 g of m-chloroperbenzoic acid in 20 ml Chloroform added with cooling at 0C. The reaction mixture was then stirred for 3 hours at room temperature. Then became Ethyl ether was added, the precipitated solid was filtered off and washed with ethyl ether, 1.2 g of the benzhydryl ester which received 2- (N-chloroacetyl) imino-3-hydroxy-thiazoline-4-acetic acid. A solution of 1 g of this ester in 25 ml of trifluoroacetic acid (TFA) was stirred for 1 hour at 0 C and then under vacuum to dryness evaporated. The residue was taken up in ethyl ether and then filtered, 0.6 g of 2- (N-chloroacetyl) imino-3-hydroxy-thiazoline-4-oacetic acid, M.p. 185 to 187 ° C (dec.).

13.0035 / 0500

copy

NMR (D, MSO-d ₆ ): 3.S2 (2H, _s , -CH -)

4.5 (2H, _{S /} -C-CH _- (

₂ ;

7.1 (IH, s _r 5-H _{on the} thiazole ring)

8.2 (2H, br-s, -OH and -COOH)

Herstoll »example 5

_{0.450 g of NaHCO 3 were} added to a suspension of 2.25 g of the benzhydryl ester of 2 ~ (N ~ chloxacetyl) imi »o-3 ~ hydroxy-thiazoline-4-acetic acid in 25 ml of dimethylformamide and 2.5 ml of water the mixture was stirred at room temperature for 2 hours, then 1.5 ml of CHqI were added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was prediluted with water and extracted with ethyl acetate, the organic layer was washed with water, dried and evaporated to dryness under vacuum, whereby 2.0 g of the benzhydryl ester of 2- (N-chloroacetyl) -imino- 3 ~ methoxy-thiazoline ~ 4-acetic acid.

The ester was then treated with TFA as in Preparation 4 indicated, hydrolyzed to give the title compound «

NMR (DMSO-d ^): 3.B (2H, s, -CH -)

4.15 (3H, s, -OMe)

A.5 (2H, s, -CO-CH ₀ -Cl) w ■ - - ■

6.7 (lH, s, 5-ii on the thiazoline ring)

Manufacturing example 6 Xt hyl-2-i mi η o-3-a mi η pt hio zo lin -4-a ce ta t - hydr oc hlor i d To a solution of 4.94 g of ethyl chloroacetoacetate in 30 ml of acetonitrile

130035/0500

-n-

Is

were 2.91 g of potassium! added cyanate and the mixture was stirred for 12 hours at room temperature. The precipitated KCl was abfiltriex-t and the solution was evaporated under vacuum to T _r ockne. 2.09 g of N ^ H..HCl were added to the residue, which was dissolved in 10 ml of Ν, Ν-dimethylacetamide, and the solution was stirred at room temperature overnight. 40 ml of ethyl ether were added to the solution, the precipitated solid was filtered off, 5.0 g of the title compound being obtained.

NMR (DMS0-d ₆ ): 1.27 (3H, t, -0-CH-C ₁ H ₃ ) ".

3.89 (2Ή, s, -CH-)

it

4.64 (2H, q, -0-CH _n -CHj

• 2

. .6.12 (2H, s, -N-NH.)

6.85 (IH, s, 5-H on the thiazoline ring) i 9.7 (2H, br-s, -NH ⁺ )

The tert-butyl-2-imino-3-amino ~ thiazoline - ^ - acetate hydrochloride and the benzhydryl-2-imino-3-aminothiazoline ^ -acetate hydrochloride manufactured.

example 1

7β ~ [2- (2-imino-3-methoxy-4-thiazolinyl) acetamido] -3-acetoxymethyl-

3-cgphem-4-carboxylic acid (7)

To a suspension of 2.4 g of 2- (N-chloroacetyl) imino-3-methoxythiazoline-4-acetic acid in 150 ml of anhydrous totrahydrofuran, 2.91 g / -amino-cephalosporonic acid tert-butyl ester were added with cooling 5 C was added and then a solution of 1.92 g of dicyclohexylcarbodiimide was added in 30 nsl of anhydrous tetrahydrofuran was added dropwise. the Reaction mixture was stirred for 3 hours at room temperature,

130035 / OSOO

then it was filtered and the filtrate was concentrated under vacuum Evaporated to dryness. The residue was taken up in ethyl acetate, the solid was filtered off, the filtrate was evaporated, the residue was taken up in ethyl ether and the precipitated Product was filtered off and washed with ethyl ether, whereby one 4.65 g of the tert-butyl ester of 7ß-C2 ~ (2 ~ N-C! Tloracotyl ~ 5.mino-3 · - roethoxy-4-thiazolinyl) acetamido3-3 ~ acetoxymet hy l-3 ~ cepheni ~ 4-carboxylic acid received

A solution of 1.495 g of this ester and 0.188 g of thiourea in 10 ml Ν, Ν-dimethylacetamide was for 2 hours at room temperature touched. The solution was then diluted with ethyl acetate, whereby a resinous (rubbery) material precipitated, the supernatant Solvent was discarded and the residue was carefully triturated with fresh ethyl acetate until a powder was obtained. The product was collected by filtration, 1.1 g of the tert-butyl ester of 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) acetamidoD-S-acetoxymethyl-S-cephem- ^ - carboxylic acid received.

A solution of 0.8 g of this compound in 15 ml of trifluorosetic acid was stirred for 70 minutes at room temperature. Then the solvent was evaporated under reduced pressure, the residue was taken up in acetone, the undissolved material was filtered off, the filtrate was evaporated to dryness and the residue was in Triturated ethyl ether, 0.50 g of the title compound being obtained.

130035/0500

~ 45 3045543

UR. (KBr): 332θ -3ΐ3θ cm " ¹ NH

Ι76Ο cm ") C = O (p-Lactomj 1520 cm" ¹ -CONH (sec.Amid) NMΠ. (DMSO-d.) Ppm: 2.00 (3H, s, -C-CiL)

3.74 (2H, dd, -CH-yn -2) 3.89 (2H, s, -CH ₂ -) 4.15 (3H, _{S /} -OCH ₃ ) 4.8 (2H, _{q /} -CH-O-CO) 5.20 (IH , d, 6-H) 5.83 (IH, dd, 7-H) 6.82 (IH, s, SH

• - '' 9.4 (IH, br-s, = NH)

9.69 (IH, d, -CONH) Example 2

The following compounds were prepared in a manner analogous to Example 1:
7ß-C2- (2-imino-3-methoxy-4-thiazolinyl) -acetamido] -3-cephem-4-

carboxylic acid;
7β- [2- (2-Iuino-3-tr.ethoxy-4-thiazolinyl) -2-hydroxy-acetamido] -3-cephem-4-carboxylic acid;
7ß-C2- (2-imino ~ 3-methoxy-4-thiazolinyl) -2-oxoacetamido] -3-cephem-

4-carboxylic acid;
7β- [2- (2-Itnino-3-methoxy-4-thiazolinyl) -2-hydroxy-acetamido] -3-α-acetoxy-methyl-S-cephem- ^ - carboxylic acid; 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -2-oxoacetamido3-3-acetoxy-methyl-3-cephem-4-carboxylic acid; 7β-C2- (2-imino-3-methoxy-4-thiazolinyl) -acetamido3-1 (S) -oxo-3-acetoxy-methyl-3-cephem-4-carboxylic acid; 7β- [2- (2-quinino-3-methoxy-4-thiazolinyl) -acetamido] -l (R) -oxo-3-ocetoxymethyl-3-cephem-4-carboxylic acid ©;

BATH ORIGINAL

130035/0500

7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -acotamido3-lo; io-3-acetoxymethyl-3-cephem-4-carboxylic acid; 7β- [2- (2-imino-3-amino-4-thiazolinyl) -acetaraido3-l-dioxo-3-acetoxy-methyl-3-cephem-4-carboxylic acid; 7β- [2- (2-Imino-3-ynethoxy-4-thiazolinyl) -acetamido3 ~ 3-C (iwet hy 1-1,2,3,4-ietrazol-5 ~ yl) -thiomethyl3-3-cephem ~ 4-carboxylic acid; 7ß- [2- (2-Iidno-3-methoxy-4-thiazolinyl) ^ cetainido3-3 - [0- (2-cyano-ethyl) -l _/ 2 _/ 3 _/ 4-tetrazol-5-yl) - thiomethyl] -3 ~ cephem-4-corboxylic acid;

7ß- [2- (2-Iraino-3-methoxy-4-thiazolinyl) -acetainido3 ~ 3 - [(5-methyl-1 _{# 3/4} "thiadiazol-2-yl) ~ thiomethyl] -3-cephem-4 ~ -carboxylic acid; 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetainido3-3 - [(totrazolo-[1,5-b3pyridazin-6-yl) -thiomethyl3-3-cephem-4-carboxylic acid; 7β-C2- (2-imino-3-methoxy-4-thiazolinyl) -acetaroido3-3-C (0-aiainotetrazoloC1,5-b3pyridazin-6-yl) -thiomethyl3-3-cephera-4-carboxylic acid; 7ß-C2- (2-imino-3-methoxy-4-thiazolinyl) -aceta (nido3-3 - [(8-carboxy-tetrazoloEi, 5-b3pyridazin-6-yl) -thioir.ethyl] -3-cephem- 4-carboxylic acid;

7β-C2- (2-imino-3-methoxy-4-thiazolinyl) -acetaroido3-3-C (8-carboxymethyl-tetrazoloCl, 5-b3pyridazin-6-yl) -thiomethyl3-3-cephera-4-carboxylic acid;

7β- [2- (2-Iraino-3-methoxy-4-thiazolinyl) -2-oxoacetamido3-3 - [(imethy1-1,2,3,4-tetrazol-5-yl) -thiomethyl3-3-cephem ~ 4-carboxylic acid; 7β- [2- (2-I «ino-3-methoxy-4-thiazolinyl) -2-hydroxy-acetamido3-3 - [(1-methy 1-1,2,3,4-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid.

130035/0500

Example 3

7β- [2- (2-imino-3-methoxy-4-thiazolinyl) acetamido] -3-C (l-methyl-1 _< 2.3,4-totrnzol-F> ~ vl) thiQmethyl] "3-'cepheni -4'-car bonstiuro ( 14) To a solution containing 5.48 g of 2- (N-chloroacetyl) imino ~ 3-methoxy-thiazo ~ lin-4-acetic acid and 2.8 g of triethyiamine in 120 ml of anhydrous acetone , a few drops of N-methylmorpholine were added. The mixture was cooled to -10 C and then 2.44 ml of pivaloyl chloride dissolved in 30 ml of anhydrous acetone was added with stirring and then after stirring for 30 minutes at -10 C a solution containing 6.56 g of 7-amino ~ 3 - [(1-methyl-1,2,3,4-tetrazol-5-yl) -thiomethylll-S-cephenwi-carboxylic acid and 2.8 ml of triethyiamine in 240 ml of 50% acetone and cooled to -20.degree was added after 30 minutes. The mixture was then stirred for 1 hour at -20 ° C. and then for 2 hours at room temperature. The acetone was evaporated under vacuum. The residue was taken up in water ,, partitioned with ethyl acetate in two layers and the pH of the mixture was brought to 40 jSiger HJ ⁵ O. 2.5. After filtration, the ethyl acetate was separated off and the organic phase was washed with water, dried over Na ^ SO, and evaporated to a small volume. Ethyl ether was added to give a solid which was filtered off and mixed with ethyl ether. The solid was filtered off again, 7.4 g of 7β- [2- (2-N-chloroacetyl-imino-3-methoxy-4-thiazolinyl) acetamido] -3-C (1-methyl-! ^, S ^ Tetrazol-S-ylJthiomethylJ-S-cephem-i-carboxylic acid Treatment of this product with thiourea as indicated in Example 1 removed the imino protecting groups to give the title prebond.

BATH ORIGINAL

130035/0500

~ 3G45343

IR (KBr) 17.60 cm " ¹ > C = 0 (p-lactam)

1520 cm " ¹ sec. Amide

NMR ^ '(DMSO-d ₆ ) 3.68 (2H, q,' -CH -in-2)

3.89 (2H, s, -CH ₂ ) 3.94 (3H, s, ~ CH "-N) 4.15 (3H, s, -OCH ₃ ) 4.31 (2 !!, q, -CH ₂ -S) • '5.10 ( IH, d, -6-H) j 5.63 (IH, dd, 7-H) 6.82 (IH, s, 5-H 9.2 (IH, d, -CON !!)

9.4 (2H, br-s, = NH) Example 4

In an analogous manner to Example 3, the following compounds were obtained manufactured:

7β-C2- (2-imino-3-methoxy-4-thiazolinyl) -acetamido] -3-cephem-4-carboxylic acid;

7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -2-hydroxy-acetamido3-3-cep hem-4-carboxylic acid;

7β- [2- (2-Imino-3-raethoxy-4-thiazolinyl) -2-oxoacetamido] -3-cephem-4-carboxylic acid;

7β-C2- (2-imino-3-methoxy-4-t-hiazolinyl) -a ceta tnido] -3-acetoxymethyl-S-cepheo ^ -carboxylic acid;

7ß- [2- (2-Iraino-3-methoxy-4-thiazolinyl) -2-hydroxy-acetamido] -S-acetoxy-methyl ^ -cephem ^ -carboxylic acid; 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -2-oxoacetamido] -3-acetoxy-methyl-S-cephsm - ^ - carboxylic acid; 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetamido] -1 (S) -oxo-S-acetoxy-methyl-S-cephem ^ -carboxylic acid;

130035 / OBOO

7β-C2- (2-lmino-3-r.; Othoxy-4-thiazo.linyl) -. Acetamido] -1 (R) -oxo-3-acotoxymethyl-3-cephem »4-carboxylic acid; 7β- [2 ~ (2-linino ~ 3 ~ methoxy-4-thiazolinyl) -acetamido] -l-dioxo-3-acetoxy-methyl-3 ~ cepliera ~ 4-carboxylic acid; 7β- [2 ~ (2-imino ~ 3-an: ino ~ 4-thiazolxnyl) -acetaroido3-1-dioxo-S-acetoxymethyl-S-cephem- ^ - carboxylic acid; 7β- [2- (2-> Imino-3-methoxy-4-thiazolinyl) -acetamido] -3 - [(1- (2-cyano-ethyl) -1,2 _/ 3 _f 4-tetrazol-5-yl ) -thiomethyl] ~ 3-cepherii-4 ~ carboxylic acid;

7β- [2- (2-imino-3-methoxy-4-thiazolinyl] -acetamidoD-S-CCS-methyl-1,3 _f 4-thiadiazol-2-yl) -thiomethyl3-3-cephem-4-carboxylic acid; 7ß- [2- (2-imino-3-methoxy-4-thiazolinyl) acetamido] -3 - [(tetrazolo _[1/5 ~ b] pyridazin-6-yl) thiomethyl] -3-cephem- 4-carboxylic acid; 7β- [2- (2-Imino-3-raethoxy-4-thiazolinyl) -acetamido] -3-C (8-aminotetrazoloCl, 5-b] pyridazin-6-yl) thiotethyl] -3-cephem-4-carboxylic acid ; 7β- [2 ~ (2-Imino-3-methoxy-4-thiazolinyl) -acetamido3-3 - [(8-carboxy-tetrazoloCi, 5-b] pyridazin ~ 6-yl) -thiomethyl3-3-cephem- 4- carboxylic acid;

7ß- [2- (2 ~ imino-3-methoxy-4-thiazolinyl) -acetamido] ~ 3 - [(8-carboxy-methyl-tetrazoloCi, 5-b] pyridazin-6-yl) -thiomoethyl3- 3-cephem ~ 4-carboxylic acid;

7ß- [2- (2-Imino-3-methoxy-4-thiazolinyl) -2-oxoacetamido3-3-C (l-methyl-1,2 _/ 3,4-tetrazol-5-yl) -thiomethyl3-3- cephem-4-carboxylic acid;

7β-C2- (2-imino-3-methoxy-4-thiazolinyl) -2-hydroxy-ocetamido3-3-C (1-methyl-1,2 _/ 3 _f 4-tetrazol-5-yl) ~ thiomethyl3-3 -cephew-4- carboxylic acid ©.

BATH ORIGINAL 130035/0500

Example 5

7β- [2- (2-Iraino-3-amino ~ 4 ~ thiazolinyi) acetamido] ~ 3 ~ [(i-methyl ~ 1,2,3,4-tetr0 £ ol ~ 5 ~ yl) tiuoriiethyl3-3 ~ ceph9m ~ 4 ~ carbonj £ i ure-hydro-

Chloride (a company of the association (23))

To a solution containing 3 g of 2- (N-chloroacetyl) imino-3- (N-chloroacetyl) -amino-thiazoline-4-acetic acid contained in 60 ml of anhydrous acetone and 1.24 ml of triethylamine and had been cooled to -10 C, 1.7 ml of isobutyl chloroformate, dissolved in 16 ml of anhydrous acetone, under Stirring added. Stirring was continued for 30 minutes at -10 C, then the mixture was cooled to -30.degree. A solution, the 2.8 g of 7 ^ mino-3 - [(i-methyl-1,2,3,4 ~ tetrazol-5-yl) thiomethyl] -3 ~ cephem-4-carboxylic acid and 4 ml of triethylamine in 120 ml of 50 years Acetone containing was then added and the resulting mixture was stirred for 1 hour at a temperature between -20 and -30 C and then stirred for 1 hour at a temperature between -5 and 0 C and finally for 3 hours at room temperature. The acetone was filtered off and evaporated in vacuo, the residue was taken up in 200 ml of water and extracted twice with 100 ml of ethyl ether. After the separation, the aqueous solution with 10 JSiger Hydrochloric acid brought to pH 2.5 and extracted with ethyl acetate. The organic phase was washed with water, dried over Na ^ SO ^ dried, concentrated to a small volume and poured into cyclohexane, the 7β- [2- (2-N-chloroacetylimino-3-N-chloroacetylamino-4-thiazolinyl) acetamido] -3-C (l-methyl-1, 2,3,4-tetrazol-5-yl) thioRiethyl] -3-cephem-4-carboxylic acid received. By treating this compound with thiourea as indicated in Example 1, were the protecting groups were removed to give the title compound.

BATH ORIGINAL 130035/0500

lR (KBr): 1760 cm " ¹ ) O = 0 (p-lactam)

1520 cm "sec. Amide

NHR (DH5O-d ₆ ) 3.68 (2H, q, -CH ₂ -in-2)

. 3.89 (2H, s, -CH ₂ -)

3.94 (3H, s, -CH ₃ -N) ^: 4.31 (2H, q, -CH ₂ -S)

5.10 (IH, d, 6-H) 5.63 ^ (IH .. 6-d, 7-H). '' 6.12 (2H, s, -N-NH ₂ )

6.82 (IH, s, -5-H on the thiazoline ring) • 9.2 (2H, broad / -CONH and = NH)

In game 6

In an analogous manner to Example 5, the following compounds were obtained manufactured:

7β- [2- (2-Imino-3-amino-4-thiazolinyl) -acetamido] -3-cephem-4-carboxylic acid;

7β- [2- (2-Imino-3-amino-4-thiazolinyl) -2-hydroxy-acetarnido] -3-cephem-4-carboxylic acid;

7β- [2 "(2-imino-3-amino-4-thiazolinyl) -2-oxoacetatenido] -3-cephem · -4-carboxylic acid;
7β- [2- (2 «imino-3-amino-4-thiazolinyl) -acetamido3-3 - [(tetrazolo- [1,543] pyridazin-6-yl) -thioynethyl] -3-cephera-4-carboxylic acid; 7β- [2- (2-Imino-3-amino-4-thiazolinyl) -acetamido] -3-C (8-carboxy- [1,5-b] pyridazin-6-yl) -thiomethyl] -3-cephem -4-carboxylic acid; 7β- [2- (2-Imino ~ 3-amino-4-thiazolinyl) -2-oxoacetamido] -3 - [(i-

130035/0500

7β-C2 ~ (2-imino-3-araino-4-ihiazolinyl) ~ 2-hydroxy-acetamido] -3 ~ C (1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl3-3-3 cep!) Em-4-carboxylic acid;

7β ~ C2- (2-imino-3-ai! Iino "4-thiazolinyl) -2-hydro« y'-acetamido3-3-C (i- (2-cyanoethyl) -1, 2 _/ 3,4-tetrazole -5-yl) -thiomethyl3-3-cephcm-4-carboxylic acid;

7ß-E2- (2-imino-3-amino-4-thiazolinyl) -2-hydroxy-acetami.do] ~ 3 ~ C (8-anjino-tetrazolo [1 _/ 5-b] pyrida2in-o ~ yl) - thioriethyl3-3-cophem-4- carboxylic acid;

7β ~ [2- (2 ~ imino-3 ~ amino-4 ~ thiazolinyl) -2-hydroxy ~ acetamido3-3-C (8-carboxy-tetra2: oloCl, 5-b3pyridazin-6-yl) -thiomethyl3'-3 -cepheni ~ 4-carboxylic acid.

example 7th

7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) acetamido3-3-C (8-aminotetrazolo [l _/ 5-b3pyrida2in-6-yl) thiomethyl3-3-cephem-4-carboxylic acid

(18) \

To a solution of 3.80 g of 7-amino-3-C (tetrazoloCi, 5-b3pyrida2in-8-ainino-6-yl) thiomethyl3-3-cephem-4-carboxylic acid and 2 g of NaHCO ₃ in 60 ml of 50% aqueous acetone, which had been cooled to 0 C, a solution of 2- (N-chloroacotyl) imino-3-methoxy-thiazolinyi-4-acetic acid chloride (obtained from the acid by reaction with oxalyl chloride in dimethylformamide at 0 C) in 30 ml of acetone were added with stirring. The mixture was stirred at a temperature between 0 and 5 ° C. for 20 minutes. The acetone was evaporated, ethyl acetate was added to the resulting aqueous solution, then the solution was acidified to pH 2 with 8% hydrochloric acid. The organic phase was washed with water and dried

130035/0500

• S3 ·

and evaporated under vacuum. The residue was with ethyl ether treated and filtered. The product obtained was dissolved in N, N-dimethylacetamide dissolved and then treated with thiourea as described in Example 1 to give the title compound.

IR (KBr) 1760 cm " ¹ ) c = 0 (ß-lactam)

1520 cm "sec. Amide

NMR (DMSO-CJ ₆ ) 3.74 (2H, q, -CH ₀ -in-2)

3.89 (2H, s, -CH ^ -) 4.15 (3H, s, -OCH.) 4.36 (2H, dd, -CH-S): 5.20 (2H, d, 6-H)
_; 5.83 (IH, dd, 7-U)
6.41 (IH, s, 7-H on the pyridazine ring) 6.32 (IH, s, SH _{on the} thioline ring) p.02 (2H, broad s, -NH _{3 on the pyrid Q2} ring) ^ 9.4-9.69 (2H, broad , -CONH and -NH)

7β- [2- (2-Linino-3-methoxy-4-thiazolinyl) acetainido] -3 - [(8-aminotetrazoloCl ^ -bjpyridazin-o-ylJthiomethylD-S-cephem ^ -car boric acid

To a solution containing 5.1 g of the sodium salt of 7β- [2 ~ (2-imino-3-methoxy ~ 4-thiazolinyl) -acetamido3-3-acetoxymethyl-3-cephem-4-carbon acid in 40 ml of acetone and 200 ml of a phosphate buffer (pH 7), 1.9 g of 6-mercapto-8-amino-tetrazolo [1,5-b] pyridazine were obtained. and 1.84 g of NaHCO were added and .the mixture was for 6 hours stirred at 60.degree. Then it was cooled, washed with ethyl acetate in separated two layers and acidified with 10 pointer HCl until the pH was brought to 2 The 2-phase system was filtered,

130035/0500

the organic phase was separated off, the aqueous phase was with 10 jSigem NhL brought to pH 4.5 and extracted with ethyl acetate The organic phase was washed with water, dried and to Evaporated dry to give the title compound which was identical to that described in Example 7.

In an analogous manner, the others listed above were also invented according to the invention 3-heterocyclic thiomethyl compounds produced.

Example 9

7β- [2 ~ (2-imino ~ 3 ~ raethoxy ^ M; hiazolinyl) acetamido] -3 - [(iH * ethy.l ~ 1.2,3 _> 4-tetrazole "5» yl) thiomethylJ ^ -cephew ^ - carbonic acid , (H) To a suspension which contained 2.9 g of 2- (N-chloroacetyl) imino-3-methoxy-thiazoline-4-acetic acid in 200 ml of anhydrous tetrahydrofuran, which had been cooled to 0 ° C. g of dicycloh & xylcarbodiimide was added. The reaction mixture was stirred for 10 minutes at 0 C and then for 40 minutes at room temperature. This solution was then added to a solution cooled to -5 C which contained 3.7 g of 7-Arrtino-3-C (l- methyl-l, 2,3,4-tetrazol-5-yl) thiomethyl3-3-cephem-4 ~ carboxylic acid and 9 g of Ν, Ο-bis-trimethylsilylacetandd in a mixture of 260 ml of anhydrous tetrahydrofuran, 4 »1 dimethylformamide and 100 The mixture was stirred for 20 minutes at 0 ° C. and then for 30 minutes at room temperature, while still being evaporated to dryness under reduced pressure, the residue was treated with 300 ml of water and 400 ml of ethyl acetate Layer was separated, the undissolved material was filtered off and treated again with 400 ml of ethyl acetate. The combined organic layers were evaporated to a low volume to give a product which, after dissolving in Ν, Ν-dimsthylacetamide as in

130035/0500 ^BA & origjnal

Hei »pi el 1 indicated was treated with thiourea with formation the TitoI prebond, which is identical to that described in Example 3 was. "■

Example 10

Piva, loyloxymethyl-7β- [2 ~ (2-imino-3-methoxy-4-thiazoliiiyl) acet ~ amido-3-C8 ~ OKdno-tetrazolotl / 5-b] pyridazin-6-yl) thiomethy.l] -3 "

To a suspension of 2.74 g of the sodium salt of 7ß- [2- (2-Itnino-S-methoxy - ^ - thiazolinyl-acetamidoJ-S-CCS-amino-tetrazolo- [!, ö-bJpyridazin-o-ylJthiomethylJ- S-cephetfWt-carbonsüurG in 40 sril of acetone was a 10 $ solution of sodium iodide in water (0.4 ral) and chloromethyl pivalate (0.72 ml) were added. The suspension was 3 Refluxed for hours and after cooling to 5 ° C the solid was filtered off and the resulting solution would evaporated under vacuum. The oily residue was dissolved in 50 ml of ethyl acetate yellow, the resulting solution was aqueous with a 5 / say NaHCOg solution and then washed with water, dried and evaporated to dryness, the Pivaloyloxymothylester dor 7β ~ [2 ~ (2 "Imino-3 ~ methoxy-4-thiazolinyl) acetomido] -3-C (8-aminotetrazoloCi, 5 ~ b] pyridazin-6-yl) thiomethyl] -3-cephera-4 ~ carboxylic acid received.

In an analogous manner, the pivaloyloxymethyl esters were those in the preceding Examples of compounds according to the invention described manufactured.

BATH ORIGINAL

130035/0500

Claims (1)

ar - 4 T 52 498-BR Applicant: Farmitalia Carlo Erba S, pA
Via Carlo Imbonati 24
1-20159 Milan Claims 1. N-substituted thiazolyl derivatives of Z-amino-cephalosporanic acid, characterized by the general formula in where mean: A -C- or -CH-, where R ₄ . represents a hydrogen atom or a free or O R ₂ protected hydroxy group; R i) -OR ", where R" represents hydrogen or a branched or unbranched (straight-chain), saturated or unsaturated aliphatic C -C -hydrocarbon group which is unsubstituted or substituted by one or more substituents which are selected from (a) Cyano, (b) -COOR ¹ , where R ^{1 is} hydrogen, Cj-C ^ -alkyl or a carboxy protecting group, 130035/0500 ORIGINAL INSPECTED R. (c) -CO-NC ^, ^ ·, wherein each of the groups R ^. and rg that are equal to or 5 can be different, a hydrogen atom, a C, -C, -alkyl- Represent group or an aliphatic CL-C.-acyl group or wherein when R. is hydrogen, then Rg can also represent an amino protecting group; or 2) -N ^ _D 4, in which R. and R _{K have} the meanings given above; 5 R, hydrogen or an amino protecting group; η is the number 0, 1 or 2; Y fc ¹ ) hydrogen; (b ¹ ) halogen; (c ¹ ) hydroxy; (d ¹ ) C ₁ ^ alkoxy; (e ¹ ) C ₁ -C ₆ alkYl; (f) -CH ₂ OCOCH ₃ ; (g ¹ ) the group , where R "is hydrogen, C ^ C ^ alkyl, carboxy, Can be cyano or carbamoyl; (h ¹ ) the group -CH ^ -S-Het, in which Het is: 1) a 5- or 6-membered heteromonocyclic ring containing at least one double bond and at least one heteroatom from N, S and 0, wherein the ring can be unsubstituted or substituted by one or more substituents which are selected from (a ") Hydroxy, C 1 -C 4 alkoxy, halogen, aliphatic Cn -C 4 acyl, (b ^M ) C 1 -C 4 alkyl which is unsubstituted or substituted by one or more substituents which are selected from hydroxy and halogen; (c ") C 1 -C 6 alkenyl which is unsubstituted or substituted by one or more substituents selected from hydroxy 130035/0500 3Q45343 and Ha] CQCn; (d ") -SR ,, in which R _{6 is} hydrogen or C ^ -C ^ alkyl, -S-Cl-LCOOFi ¹ , in which R ^{1 has} the meanings given above; (e") - (CH ₀ ) -COOR ' , -CH = CH-COOR ¹ , - (CH ₀ ) -CONH ₉ or - (CIL) -CN, in which n> denotes the number 0, 1, 2 or 3 and R ^{1 has} the meanings given above; (f ") - (CH ₀ ) So ₀ H, in which m has the meanings given above; or ζ m ο ^V9 - (CH ₂ ) -NC ^ Dt, where m, R. and R- are those given above 5 Have meanings; or 2) a heterobicyclic ring which has at least two double bonds, each of the fused heteromonocyclic rings of the same being the same or different 5- or 6-membered heteromonocyclic ring (s) containing ( contain) at least one heteroatom selected from N, S and 0, the heterobicyclic ring being unsubstituted or substituted by one or more substituents selected from (a "), (b"), (c ^M ), (d " ), (e "), (f") and (g ") as defined above; X is a free or esterified carboxy group; with the proviso that when A is a -ChL group, R is not stands for -OH, as well as the salts, in particular pharmaceutical and veterinary compatible salts thereof. 2. Compounds according to claim 1, characterized in that in the general formula (I) mean: 130 0 35/0600 30A53A3 R- hydrogen or an amino protecting group; R -OC.-C.-alkyl, -OC ^ C.-alkenyl, -0- (CH ₀ ) -COOR ¹ , wherein R ¹ IO ZO / L Π>. has the meanings given in claim 1 and m represents the number 1, 2 or 3; NH ₂ , -NHCH ₃ ; -N (CHg) ₂ ; -NHCOCH ₃ or NHC00-C (CH ₃ ) ₃ , A -CH ₀ -, -C- or -CH-; O OH Y is hydrogen, halogen, hydroxy, C .- ^ - alkoxy, methyl, -CH ₂ OCOCH ₃ or CH _O -S-Het, in which Het is: i) a tetrazolyl radical which is unsubstituted or substituted by C ₁ -C ₃ -A ^ yI, C ₂ -C ₄ -alkenyl _f - (CH, ^ -COOR ¹ , wherein 1 ^ the has the meaning given above and R * has the meaning given in claim 1, -CH = CH-COOR ¹ , where R ^{1 has} the meaning given in claim, - (CH ₀ ) -CN, - (CH ₀ ) -CONH ₀ , - (CH ₀ ) -SO "H, wherein R ». has the meaning given above, or - (CH ₀ ) -NC ^ _O 4, in which 1 ο R. has the meaning given above and R ^ and R, - the claim 1 have given meanings; 2) a thiadiazolyl radical which is unsubstituted or substituted by C ^ -alkyl, C ₂ -C ₄ -alkenyl _f -SH, -SCH ₃ , -S-CH ₂ COOH, - (CH ₀ ) -COOH, wherein in the meanings given in claim 1 ^m / R · / R has, -Nv ^ p, 4, where R ¹ . and R ' _{5 is} hydrogen or C.-Cg-alkyl 5 represent; or 3) a heterobicyclic ring selected from tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each of which is unsubstituted or substituted by 130035/0600 Hydroxy, -SH, ~ CO-N. ^ _, 4, where R ¹ . and R ¹ ~ those given above 5
Have meanings, -COOR ¹ , in which R ^{1 has} the meanings given in claim 1, C.-Cg-alkyl, C ₂ -C ₄ -alkenyl, -S-CH ₂ COOR ¹ , -CH ₉ COOR ¹ , -CHsCH- COOR ', in which R ^{1 has} the meanings given in claim 1, or -N: C ^ _R , 4, in which R', and R'g have the above 5
have given meanings. 3. 7β- [2- (2-Itnino-3-methoxy-4-thiazolinyl) -acetamido3-3-cephem-4-carboxylic acid · 4. 7β-r.2- (2-Itnino-3-methoxy-4-thiazolinyl) -2-hydroxyH3cetamido] ~ 3-cephem-4-carboxylic acid. 5. 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -2-oxoacetqraido] -3-cephem-4-carboxylic acid. 6. 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetamido3-3-acetoxy methyl-3-cephem-4-carboxylic acid ♦ 7. 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -2-hydroxy-acetamido] -3-acetoxy-methyl-3-cephem-4-carboxylic acid. 8. 7β- [2- (2-Itnino-3-raethoxy-4-thiazolinyl) -2-oxoacetamido] -S-acetoxy-methyl-S-cephem - ^ - carboxylic acid. 9. 7β- [2- (2-Imino-3-raethoxy-4-thiazolinyl) -acetamido] -1 (S) -oxo-3-acetoxy-methyl-S-cephem - ^ - carboxylic acid · 10. 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetamido] -1 (R) oxo-S-acetoxy-methyl-S-cephem - ^ - carboxylic acid. 130035/0500 3Q45343 Π. 7β- [2- (2-Imino-3-methoxy-4-thinzolinyl) -acetamido3-1-dioxo-S-acetoxy-methyl-S-cephem3-carbon acid. 12. 7β-C2- (2-imino ~ 3-methoxy-4- «thiazolinyl) acetainido] ~ 3 - [(l-n ', otliyl ~ 1,2,3,4-t (trozol-5-yl) -thioiT: 8thyl] -3-cephom-4-carbonic acid. 13. 7β- [2- (2-Iniino-3-methoxy-4-thiazolinyl) -acetamido] -3 - [(1- (2-cyanoethyl) - !, 2,3,4-tetrazol-5-yl) ~ thiomethyl3-3-cephem-4 ~ carbonic acid ©. 14. 7β- [2- (2-Imino-3-niethoxy-4-thiazolinyl) -Gcetamido] -3 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl3-3 «Ccphera-4-carboxylic acid. 15. 7β- [2- (2-I «nino ~ 3 ~ Rictfioj; y-4-thiazolinyl) -acetcmido] -3- {Jte" trazolo- [1,5-b] -pyridazin-6-yl) - thiomethyl] -3-cephem-4-carboxylic acid. 16. 7β- [2- (2-Iraino-3-methoxy-4-thiazolinyl) acetamido] -3 - [(8-amino ~ tetrazolo-C ^ ö-bJ-pyridazin-o-yl) ^ hi omethyl] -3-cephem-4-carboxylic acid. 17. 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetaraido] -3 - [(0-carboxytetrazolo- [l _f 5-b] -pyridazin-6-yl) -thiomethyl] - 3-cephGm-4-carboxylic acid. 18. 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -acetaroido] -3 - [(8-carboxy .. methyl-tetrazolo-Cl, 5-bJ-pyridazin-6-yl) - thiomethyl] -3-cepheiJi-4- carboxylic acid. 19. 7β- [2- (2-Imino-3-methoxy-4-thiazolinyl) -2-oxoacetainido] -3 - [(lwethyl-1,2,3 _/ 4-tetrazol-5-yl) -thioraethyi3-3 -cephet8-4-carboxylic acid. 20. 7β- [2- (2-imino-3-methoxy-4-thiazolinyl) -2-hydroxy-aceta (nido3-3 - [(imethyl-1 _/ 2 _f 3 _f 4-tetrazol ~ 5-yl) - thiomethyl3-3-cphem-4-carboxylic acid. 130035/0500
COPY 21. Salts, including pharmaceutical and veterinary compatible © salts of the compound according to one of claims 3 to 20 « 22. 7β- [2- (2-Linino-3-amino-4-thiazolinyl) -acetamido] -3-cephom-4-carboxylic acid. 23. 7β .- [2- (2-Inuno-3-amino-4-thiazolinyl) -2-hydroxy-acetainido] -3-cephem-4-carboxylic acid. 24. 7β ~ [2 ~ (2-Imino-3-amino-4-thiazolinyl) -2-oxoacetamido3-3-cephein-4-carboxylic acid. 25. 7β- [2 ~ (2-Imino ~ 3-amino-4-thiazolinyl) -acetamido] -! - dioxo-3-acetoxymethyl-S-cephem - ^ - carboxylic acid. 26. 7β- [2- (2-Imino-3-amino-4-thiazolinyl) -acetamido] -3- [(i-niethyl "l, 2-3 _/ 4-tetrazol-5-yl) -thiomethyl] - 3-cephem-4-carboxylic acid. 27. 7β- [2- (2-Imino-3-amino-4-thiazolinyl) -acetamido] -3-C (tetrazolo- [!, ö -bl-pyridaziri-o-ylI-thiomethylj-S-cephefn- ^ -carboxylic acid. 28. 7β- [2- (2-Imino-3-amino-4-thiazolinyl) -acetamido] -3 - [(8-carboxytetrazolo-Π , 5-b] -pyridazin-6-yl) -thiojnethyl] -3-cephem-4-carboxylic acid. 29. 7β- [2- (2-Irnino-3-amino-4-thiQzolinyl) -2-oxoacetanddo] -3 ~ C (Imethyl-l ^^^ - tetrazole-Sy ^ -thiomethyll-S-cephem ^ -carboxylic acid . 30. 7β- [2- (2-Imino-3-Qmino-4-thiazolinyl) -2-hydroxy-acetamido] -3 - [(imet hyl-1,2,3,4-tetrazol-5-yl) -t hiomet hylj-S-cephem ^ -carboxylic acid. 130035/0500
COPY 31. 7β-C2- (2-imino-3-amino-4-thiazolinyl) - '2-hydroxy-acetaniidoj-3-r (l ~ (2-cyanoöthyl) ™ · !, 2,3,4-tetrazol-5-yl) -thioia6thyl] -3-cep ho ra-4-carboxylic acid · 32. 7β- [2- (2-Imino-3-aniino-4-thiazolinyl) -2-hydroxy-acotamido] -3-L (0 ~ amino-tetrazolo-Ci, 5-b] -pyridazin-6-yl) -thioraethyl] -3-cephem-4 "corbo-acid. 33. 7β- [2- (2-Imino-3-aßiino-4-thiazolinyl) -2-hydroxy-acetamido] -3-C (8-carboxy-tetrazolo- [l _/ 5-b] ~ pyridazine-6- yl) thiomethyl] -3 ~ cophem-4-carboxylic acid. 34.7β-C2 ~ (2-iitiino-3-a "inO" 4-thiozolinyl) '«2« hydroxy-acGtaiKido] ~ 3 * - [(8-carboxy-tetrazolo- [1,5-b] -pyridazin-o-yl) -thioRiethyl] -3-cephem-4-carboxylic acid. 35. Salts, in particular pharmaceutical and veterinary Compatible salts of the compound according to any one of claims 22 to 34. 36. Process for the preparation of the N-substituted thiazolyl derivatives the 7-amino-cephalosporanic acid according to any one of claims 1 to 35, characterized in that a) a compound of the general formula (ID wherein n, X and Y have the meanings given in claim 1 and E is amino, -N = C = O or -N = C = S, or a reactive derivative thereof with a compound of 130035 / OSOO general formula J '-A-COOH (ΙΠ) wherein R, R ₁ and A have the meanings given in claim 1, or a reactive derivative thereof is reacted and, if desired, the protective groups, if any, are removed; or b) a compound of the general formula NC-S-CH-CA-CONIi. ^{ς (} ^ ² Il 0 wherein A, n, X and Y have the meanings given in claim 1, or a reactive derivative thereof with a compound of the general formula R-NH ₂ (V) wherein R has the meanings given in claim 1, or a salt thereof reacted and, if desired, the protecting groups, if present, be removed; or c) a compound of the general formula N 0 1 30035 / OSOO wherein A, η, X and Y have the meanings given in claim 1 hnb «? n and B Kalogen means or a reactive derivative thereof with a compound of all « common formula R NHv ¹ Vs / M-K (VII) ■ R wherein R and R. have the meanings given in claim 1, implemented and, if desired, the protective groups, if present, be removed; or d) a compound of the general formula t ⁿ (VIII) N ^^ - Y B-CH-CA-CONH ' ^{S 2} !!
N R ^x wherein B, R, A, n, X and Y have the meanings given in claim 1 own, reacted with thiocyanic acid or a salt thereof and if desired the protecting groups, if any, are removed; or e) a compound of the general formula A-CONH (ix) FLOCOCH,
* ο wherein R, R-, A, n and X have the meanings given in claim 1 to have, 130035/0500 or a salt thereof with a compound of the general formula HS-Het (X) where Hot has the meanings given above, or a reactive derivative thereof and, if desired, the protective groups, if present, are removed and / or if desired, a compound of the formula (i) in which X is carboxy means converted into a salt, in particular a pharmaceutically or veterinarily acceptable salt, and / or if desired a free compound prepared from a salt and / or, if desired, a compound of the formula (I) or a salt thereof into another Compound of the formula (i) or a salt thereof is converted. 37. Pharmaceutical or veterinary agent, characterized in that it contains at least one N-substituted thiazolyl derivative of 7-amino-cephalosporanic acid according to one of claims 1 to 35, optionally together with at least one pharmaceutically or veterinarily acceptable carrier and / or diluent _f . 13003S / 0500