FI86731B - REFERENCE FOR THERAPEUTIC PREPARATION OF THERAPEUTIC ANALYSIS 7 - / (2-AMINO-4-THIAZOLYL) -2- (SUBSTITUTES IN IMINO) ACETYLAMINO / -2-CARBOXY-3- (SUBSTITUTES IN PROPENYL) -8-OXO-4-OXO-4-OXO-4-OXO /4.2.0/OKT-2-ENDERIVAT I SYN-FORM. - Google Patents

Abstract

The derivatives in question are the products of formula I <IMAGE> R = either <IMAGE> Ra = an organic group; <IMAGE> R'A and R'B are either a hydrogen atom or an alkyl radical; ZA = single bond, sulphur, optionally oxidised, or oxygen, R3A = in particular, aryl, optionally substituted, quaternary ammonium, acetyl, carbamoyl, alkoxycarbonyl, alkyl, haloalkyl, nitrile or azido; R4 = H or OCH3; A = in particular, H, alkali metal equivalent, ester or CO2A; CO2<(-)>; n2 = integer equal to 0, 1 or 2; and the salts of the products of formula IA with inorganic or organic acids.

Description

1 86731

Process for the preparation of therapeutically useful 7 - [(2-amino-4-thiazolyl) -2- (substituted imino) acetylamino] -2-carboxy-3- (substituted propenyl) -8-oxo-4-thia-1-azabic for the preparation of the syn-form of cyclo [4.2.0] oct-2-ene derivatives FR Patent Publication No. 2,559,486, filed February 13, 1984, describes novel derivatives of 1-detia-2-thia-cephalosporinic acid and their salts, their preparation -10 method and their applications as drugs.

The general formula of the compounds described in the above-mentioned patent publication is „* 4 Λ (0) n, ÄX, co2a where R is either the radical Ra-C-NH-, where Ra is an organic 20 (!)

R 1 is a radical, or the radical N-CH = N-, in which the same or different R 1 and R 1 represent a hydrogen atom or an aliphatic or aromatic hydrocarbon radical, a heterocyclic radical, or R 1 and R 2 form an optionally substituted cyclic radical with the nitrogen atom to which they are attached. are bonded, or the radical Rb-NH-, wherein Rb is an optionally substituted carbocyclic or heterocyclic aryl radical,

Rx is either: a) the radical -Z-R2, in which R2 is an optionally substituted or heteroatom-containing alkyl, alkenyl-35 or alkynyl radical and Z is an optionally oxidized sulfur atom, selenium, oxygen or -NH-, 2 86731 b) the radical Za -R 3, wherein R 3 is an optionally substituted carbocyclic or heterocyclic aryl radical or an optionally substituted quaternary ammonium and Za is a methylene radical, sulfur, selenium, oxygen or -NH, or Za represents a single bond, or Za represents a -CH 2 -S- radical, c) an optionally substituted or heteroatom-containing alkyl, alkenyl or alkynyl radical having 2 to 8 carbon atoms, d) a halogen atom, a nitrile radical, an azido, a thiocyanate or an isothiocyanate, e) an azidomethyl radical, an amino or mono- or disubstituted thiocyanate methyl, isothiocyanate methyl or carbamyloxymethyl, R4 represents a hydrogen atom or a methoxy radical, A represents a hydrogen atom, an alkali metal equivalent, an alkaline earth metal such as magnesium, ammonium or an aminated organic base, or A represents an ester group or CO2A represents a CO2 * group, and n2 represents an integer of 0, 1 or 2.

Products corresponding to the above general formula may exist in racemic or optically active form.

A group of compounds with particularly interesting pharmacological properties has now been discovered.

The invention relates to a process for the preparation of therapeutically useful 7 - [(2-amino-4-thiazolyl) -2- (substituted imino) acetylamino] -2-carboxy-3- (substituted propenyl) -8-oxo-4-thia-1- to prepare the syn-form of azabicyclo [4.2.0] oct-2-ene derivatives of formula (IA) 30 NH.

A

S

-C0NH

Τ 'w% (I *> N 1 sl 7 -1 "

\ A- Λ k 3A

35 0 O |

'CC ^ A

3,86731 wherein A is a hydrogen atom, an alkali metal equivalent, an alkaline earth metal equivalent, a magnesium equivalent, an ammonium equivalent, an aminated organic base equivalent or an ester-5 group such as a t-butyl group, or CO 2 A represents a CO 2 'group R' is alkyl having up to 6 carbon atoms a radical which may be substituted by halogen atoms or carboxy, or R 'is an alkenyl radical having up to 6 carbon atoms, ZA is a single bond, a sulfur atom or an oxygen atom; and A) when ZA is a single bond, R '3A is a thienopyridinium, thiazolopyridinium, imidazopyridinium, cyclohexenopyridinium, tetrahydroquinolinium, isoquinolinium, trimethylammonium, diazabicyclooctyl, imidazolyl or tetrazolyl group , which may be substituted by C 1-4 alkyl or amino, B) when ΖΛ is a sulfur atom,

Rf 3A is a pyridinium, thiazolopyridinyl, triazolyl, tetrazolyl, thiadiazolyl, purinyl or thiazolopyridinyl group which may be substituted by C 1-4 alkyl, trifluoromethyl or thiomethyl, or R'3a is

25 / N ^ N — N .N - N N — N

, - (i, 4s5-f-CH2 C = O I c = o c = o ^ H3CTNo> “3C® ^

30 HO

JM-N

- ('Voh 35 or Λ -f <°

Cl 4 86731 and C) when ZA is an oxygen atom, R'3a is an acetyl, carbonyl or carbamoyl group, and for the preparation of their salts with inorganic and organic acids.

All the compounds of the invention have antibiotic activity due to the cephem core.

FI patent application 85 0583 describes compounds containing a 2-thiacephem core. However, the compounds according to the invention are more active than the compounds known from said FI publication.

DE-A-3 404 615 (= GB 2 134 522) describes cephalosporin derivatives containing a propenyl chain at the 3-position. These compounds also contain 15 sulfur atoms in the 1-position, whereas the compounds of the invention instead contain a sulfur atom in the 2-position.

Among the products of formula (IA) in which ZA represents a sulfur atom or oxygen and R'3A represents quaternary ammonium, those products in which ZA is not directly bound to a nitrogen atom are preferred.

The products of formula (IA) may exist in racemic or optically active form.

Among the values of A are sodium, potassium, lithium, calcium, magnesium, ammonium or organic base equivalents. Organic bases include methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzine, benzine, benzine, benzine histidine and N-methylglucamine.

Other readily removable ester group residues which may represent A include methoxymethyl, ethoxymethyl, isopropyloxymethyl, α-methoxyethyl, α-ethoxyethyl, methylthiomethyl, 5,66731 ethylthiomethyl, isopropylthiomethyl, pivalyloxymethyl, acetyloxymethyl, acetyl butyryloxymethyl, isobutyryloxymethyl, valeroxymethyl, isovaleroxymethyl, tert-butylcarbonyloxymethyl, hexadecanyloxymethyl, propionyloxyethyl, isovaleryloxyethyl, 1-acetyloxyethyl, 1-propionyloxyethyl, 1-buty acetyloxypropyl, 1-hexadecanyloxyethyl, 1-propionyloxypropyl, 1-methoxycarbon-10-yloxyethyl, methoxycarbonyloxymethyl, 1-acetyloxybutyl, 1-acetyloxyhexyl, 1-acetyloxyheptyl, phthalidyl, 5,6-dimethoxyphthalidyl, 5,6-dimethoxyphthalidyl carbonylmethyl, allyl, 2-chloroallyl, methoxycarbonylmethyl, benzyl li or tert-butyl.

Mention may also be made of other ester group residues which may represent A, such as methoxyethoxymethyl, dimethylaminoethyl, cyanomethyl, tert-butyloxycarbonymethyl, 2,2-ethylenedioxymethyl, cyanoethyl, 2,2-dimethoxyethyl, 2-chloroethoxymethyl. , 2-hydroxy-20-ethoxyethyl, 2,3-epoxypropyl, 3-dimethylamino, 2-hydroxypropyl, 2-hydroxyethyl, 2-methylaminoethoxymethyl, 2-aminoethoxymethyl, 3-methoxy-2,4-thidiazol-5-yl, 2-tetrahydropyranyl, 2-methoxyprop-2-yl, 1-hydroxyprop-2-yl, isopropyl, carbamylmethyl, chloro-methyl, 2-chloroethyl, acetylmethyl, 2-methylthioethyl or thiocyanate methyl.

Mention may also be made, of other ester group residues which may represent A, of 2-chloro-1-acetyloxyethyl, 2-bromo-1-acetyloxyethyl, 2-fluoro-1'-acetyloxyethyl, 2-methoxy-1-acetyloxyethyl, 2 - methyl-1-acetyloxypropyl, 2-acetyloxyprop-2-yl, 1-methoxyacetyloxyethyl, 1-acetylcarbonyloxyethyl, 1-hydroxyacetyloxyethyl, 1-formylcarbanoyloxyethyl, 1- (2-thienyl) carbonyloxyethyl, 1- (2-35 furyl) carbonyloxyethyl, 1- (5-nitro-2-furyl) carbocarboxyethyl, 1- (2-pyrrolyl) carbonyloxyethyl, 1- (propionyloxycarbonyloxy) ethyl ±, 1- (propyloxycarbonyloxy) ethyl, 1- (Isopropyloxycarbonyloxy) -ethyl, 1- (methoxyethoxycarbonyloxy) ethyl, 1- (allyloxy-5-carbonyloxy) ethyl, 1- (2,3-epoxy) propyloxycarbonyloxyethyl, 1- (2-furyl) methyloxycarbonyloxyethyl , 1- (fluoro) ethyloxycarbonyloxyethyl, 1- (methoxycarbonyloxy) propyl, (2-methoxycarbonyloxy) prop-2-yl, (methoxy aronyloxy) chloromethyl, 1- (methoxycarbonyloxy) 2-chloroethyl, 1- (methoxycarbonyloxy) 2-methoxyethyl or 1- (methoxycarbonyloxy) 1-allyl.

A may also represent a group: 15 ογ -ch2-o CH3 20 The products of formula (IA) may also exist in the form of salts of organic acids or mineral acids.

Acids which form a salt with the amino group or amino groups or quaternary ammonium group of the products of formula (I) may include, but are not limited to, acetic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid phosphoric acid, sulfuric acid, hydrochloric acid, bromive-30 blank acid or hydroiodic acid.

Among the values of A, ester groups of the following formula may be mentioned in particular:

-CH-O-C-D

35 A h 7 66751 wherein B represents a linear or branched alkyl radical of 1 to 5 carbon atoms, optionally substituted, and D represents 1 to 15 carbon atoms, and in particular an alkyl radical of 5 to 5 carbon atoms or a linear or branched alkoxy radical, optionally substituted, and more particularly ester groups in which B represents a hydrogen atom or a methyl radical or an ethyl radical and D represents a methyl radical, an ethyl radical, a methoxy radical or an ethoxy radical.

Of the values of 10 A, mention may also be made of the radical -CH 2 - (j: = CHRy Rx where Rx is hydrogen, alkyl, in particular methyl or ethyl, halogen, in particular chlorine, and Ry is hydrogen, halogen or aryl, in particular phenyl, optionally substituted methyl, nitroxy or halogen, or Ry is alkyl, optionally substituted with alkoxy, alkoxycarbonyl or halogen.

Among the values of A, mention may be made of the radical 20 Lc-CH2 'C = C where Rx is as defined above and alc2 R * ^ alc2 and alc2, identical or different, represent an alkyl radical comprising 1 to 4 carbon atoms.

Of the above products of formula (IA), those in which R 'represents a methyl radical or an isopropyl radical, optionally substituted by a carboxy radical, a difluoromethyl radical or a trifluoromethyl radical, or an allyl radical, are preferred, and products in which ZA represents a single radical and R optionally substituted.

Preferred products include those shown in the Examples below, and in particular the following 35 products: 8b 6 7 31 (6S) (7S) -7- [3- [7 - [[(2-amino-4-thiazolyl) 2 - [Z- (trifluoromethoxy) imino] acetyl] amino] 2-carboxy-8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] 2- (E) -propenyl] thieno- [2,3-b] pyridinium inner salt; Syn- (6S) (7S) -5- [3- [7 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-carboxy-8-oxo-4-thia -1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -2-methyl-thiazolo [4,5-c] pyridinium inner salt; (6S) (7S) -7- [3- [7 - [[(2-amino-4-thiazolyl) 2- (Z) - (methoxy-10imino) acetyl] amino] 2-carboxy-8-oxo- 4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] propen-2- (E) -yl] thieno [2,3-b] pyridinium inner salt;

Syn- (6S) (7S) -7 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3 - [[3- (1,3,4-thiadiazol-2- yl) thio] 1- (E) -15 propenyl] 8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid inner salt; Z- (6S) (7S) -5- [3- [7 - [[(2-amino-4-thiazolyl) (difluoromethoxy) imino] acetyl] amino] 2-carboxy-8-oxo-4 -thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -2-methyl-thiazolo [4,5-c] pyridinium inner salt.

The process according to the invention is characterized in that a) a compound of formula (X ') 25 NHC (C6H5) 3 ✓4s.

S

The N-S

N I A (X ') 30 \ 0 0 ^ ΝγΛ ^' \ ^ ΟΗ

\ i C02A

wherein R 'and A are as defined above, is reacted with a compound containing a group R'3A, such as a halide or anhydride, after which the aramino protecting group is removed to give a compound of formula (IA) wherein Z is an oxygen atom, i.e. the formula is (XI'A) 9 86731 5

NH

A

‘-L ^ CONH

J

Or b) compound (X ') is reacted with a hydroxy group activating agent such as trifluoromethylsulfonic anhydride, followed by a compound containing a group R'3A such as trifluoroethylsulfonic anhydride. with a halide or anhydride, after which the amino protecting group is removed to give a compound of formula (IA) 20 wherein Z is a single bond, i.e. of formula (XI'B) NH „Λ

25 S N

V ^ ZJ ^^ CONH

j V-f ^ S (χι'Β)

x0 0 ^ 3A

or c) the compound (X ') is reacted with a hydroxy group activating compound such as trifluoromethylsulfonic anhydride followed by a compound of formula HS-R'3A or a reactive derivative thereof.

10 86731 after which the amino protecting group is removed to give a compound of formula (IA) wherein Z is a sulfur atom, i.e. of formula (Xl'c) 5 NH «Λ

S

- ^^, C0NH

10 \ BXv / »·», xi'c)

O 0 | ^ V / JA

The conversion of products of formula X 'into products of formula XI'A is carried out by classical methods.

The derivative of the group R'3A used may, for example, be a halide derivative of an optionally substituted carbocyclic or heterocyclic aryl radical. In this case, fluoride is preferably used when R3A represents, for example, an acetyl radical or a carbamoyl radical. It is preferably carried out in the presence of a reactive derivative such as an anhydride or halide.

The conversion of products of formula X 'to products of formula XI'B is preferably carried out under the following conditions: an activated derivative of a hydroxyl radical is formed, for example, by the action of a sulfonic acid derivative such as trifluoromethylsulfonic anhydride. Operates at low temperature or room temperature.

When R 3a does not represent quaternary ammonium, it is preferably carried out in the presence of a base.

The conversion of products of formula X to products of formula 35 XI'c is carried out under similar conditions.

il B 6 7 31

An activated derivative of the hydroxyl group is first formed under the above conditions, especially from trifluoromethylsulfonic anhydride. The reaction of the product of formula HZR3A is preferably carried out in the presence of an organic base such as 2,6-dimethylpyridine and a soluble iodide source. In this case, it is preferably carried out in the presence of tetraalkylammonium iodide.

The products of formulas XI'A, XI'B and XI'c form products of formula IA when they do not contain any protecting groups and when A does not represent the easily removable ester to be removed.

In other cases, the effect of one or more hydrolysing agents, hydrogenolysing agents or thioureas on the products of formulas XI'A, XI'B or XI'c is intended to eliminate the protecting group or groups which may be present in the various products.

The nature of the reagents used in each case is well known to those skilled in the art. Examples of such reactions are given later in the experimental section.

The following is a non-limiting list of substances that can be used to eliminate various groups.

Elimination of the protecting group or groups can be accomplished by hydrolysis, when acidic or basic, or by the use of hydrazine.

Preferably, acid hydrolysis is used to eliminate optionally substituted alkoxy groups and cyclocarbonyl groups such as tert-pentyloxycarbonyl or tert-butyloxycarbonyl, optionally substituted aralkoxycarbonyl groups such as benzyloxycarbonyl group butyl group, trityl group, benzhydryl group, benzhydryl group.

Preferably, the acid used may be selected from the group consisting of hydrochloric acid, benzenesulfonic acid or para-toluenesulfonic acid, formic acid or trifluoroacetic acid. However, other mineral acids or organic acids can also be used.

Alkaline hydrolysis is preferably used to eliminate acyl groups such as trifluoroacetyl.

The preferred base used is a mineral base such as sodium or potassium hydroxide. Magnesium oxide, barium oxide or alkali metal carbonate or acidic alkali metal carbonate such as sodium or potassium carbonate or acidic sodium or potassium carbonate or other bases may also be used.

Sodium or potassium acetate can also be used.

Hydrazine hydrolysis is preferably used to eliminate phthalyl-type groups.

Some groups can also be eliminated with a zinc acetic acid system (for a trichlorethyl group), the benzhydrylbenzyloxycarbonyl groups are preferably eliminated with hydrogen in the presence of a catalyst.

The chloroacetyl group is eliminated by the action of thiourea in a neutral or acidic environment by a reaction similar to that described in MASAKI J.A.C.S., 90, 4508, (1968).

Other deprotection methods known in the literature may also be used.

Preferred groups include formyl, acetyl, ethoxycarbonyl, mesyl, trifluoroacetyl, chloroacetyl and trityl. The radicals trityl and chloroacetyl are particularly preferred.

The acid used is preferably trifluoroacetic acid. The salt formation of the products can be carried out by conventional methods.

The salt formation can be carried out, for example, by treating the product in acid form or as a solvate, for example as an ethanol solution or as an acid hydrate with a mineral base such as sodium or potassium hydroxide, sodium or potassium carbonate, or acidic sodium or potassium carbonate. Acidic mineral salts such as trisodium phosphate may also be used. Salts of organic acids can also be used.

As the salts of organic acids, mention may be made, for example, of the sodium salts of linear or branched saturated or unsaturated aliphatic carboxylic acids having 1 to 18, preferably 2 to 10, carbon atoms. These aliphatic radicals may contain one or more heteroatoms, such as oxygen or sulfur, or may be substituted by an aryl radical, such as phenyl, thienyl, furyl, or by one or more hydroxyl radicals or by one or more halogen atoms, such as fluorine, chlorine or bromine, , one or more lower alkoxycarboxyl or carbonyl radicals, preferably methoxycarbonyl, ethoxycarbonyl or propyloxycarbonyl, or one or more aryloxy radicals, preferably phenoxy.

In addition, sufficiently soluble aromatic acids, such as benzoic acids, preferably substituted with lower alkyl radicals, can be used as the organic acid.

Examples of such organic acids are: formic acid, acetic acid, acrylic acid-25 po, butyric acid, adipic acid, isobutyric acid, n-caproic acid, isocaproic acid-ethyl-acetic acid, ethyl-acetic acid, crotonic acid-2-acetic acid, phenylacetic acid, phenylacetic acid , glutaric acid, monoethyl ester of adipic acid, hexanoic acid, heptanoic acid-30 po, decanoic acid, oleic acid, stearic acid, palmitic acid, 3-hydroxypropionic acid, 3-methoxypropionic acid, propionic acid, 4-chlorobutyric acid, 4-chlorobutyric acid, 4-phenylivo .

Sodium acetate, sodium 2-ethylhexanoate or sodium diethyl acetate are also preferably used as sodium salts.

i4 8 6 7 31

Salt formation can also be performed by an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) aminomethane, methylamine, ethanolamine, pyridine, pyridine, picoline, picoline, and benzylamine.

It can also be performed with arginine, lysine, procaine, histidine or N-methylglucamine-10.

This salt formation is preferably carried out in a solvent or solvent mixture such as water, ethyl ether, methanol, ethanol or acetone.

The salts are obtained in amorphous or crystalline form according to the reaction conditions used.

The crystalline salts are preferably prepared by reacting the free acids with a salt of an aliphatic carboxylic acid mentioned above, preferably sodium acetate.

20 The conversion of products into salts by means of mineral acids or organic acids is carried out under normal conditions.

The preparation of the starting materials is described in FR patent 2,559,486.

The products of general formula (I), as well as their pharmaceutically acceptable salts, have very good antibiotic activity against gram (+) bacteria, such as staphylococci, and in particular penicillin-resistant staphylococci. Their efficacy against gram (-) bak-30 bacteria, in particular coliform bacteria, klebsiella, salmonella and Proteus bacteria, is particularly remarkable.

Such properties allow the use of the above products as medicaments for the treatment of disease states caused by sensitive microbes, and in particular in staphylococcal disease states such as staphylococcal sepsis, malignant staphylococcal infection of the face or skin, wet sepsis, wet dermatitis, -5 sa, dehydration, rose, acute primary or post-influenza staphylococcal infection, catarrh pneumonia, and purulent pneumonia.

These products can also be used as medicaments for colic infections and the like, proteus, klebsiella and Salmonella infections, as well as other conditions caused by gram (-) bacteria.

The compounds of formula IA, as well as their pharmaceutically acceptable salts, can be used in the preparation of pharmaceutical compositions in which the compounds are active ingredients.

These compositions may be administered orally, reactively, parenterally, intramuscularly or topically to the skin or mucous membranes.

In particular, those products of formula (I) in which 20 A represents a removable ester group, such as propionyloxymethyl, may be administered orally.

They may be in solid form or in solution, and may be in the form of pharmaceutically acceptable forms, such as ordinary or coated tablets, pills, granules, suppositories, injections, ointments, creams, gels; they are prepared using conventional methods. The active ingredient (s) may be incorporated with excipients conventionally used in pharmaceutical compositions such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous media, animal or vegetable fats and emulsifiers or dispersants, dispersants, preservatives.

35 In particular, these products may be in the form of a powder which can be dissolved directly in a suitable medium, for example sterile, pyrogen-free water.

The dose to be administered may vary depending on the condition being treated, the individual being treated, the mode of administration and the product being used. It can be formed, for example, from 0.500 to 1 g three times a day administered intramuscularly using the products of Examples 1 or 2.

The products of formula (I) can also be used for disinfecting surgical instruments.

Pharmacological research on the products of the invention

In vitro activity, dilution method in aqueous medium

Prepare a series of tubes in which an equal volume of sterile medium is placed. A growth amount of test product is dispensed into each tube 15, after which each tube is inoculated with the bacterial strain. Incubate for 24 hours or 48 hours at 37 ° C, after which the growth is assessed by X-ray allowing the lowest inhibitory concentration (PIK) at pg / cm 3.

lv 86731

The following results were obtained:

I I l I

. Eg.3 product Eg 10 b I I 'product'

I Kannat I I I

| | 24 H: 48 H | 24 H: 48 H | | Staphylococcus aureus SG 511 | 0.08: 0.15 0.08: 0.15 10 | Staphylococcus aureus 285 | 0.15: 0.3 0.08: 0.15 | Staphylococcus aureus 54146 | 0.15: 0.15 0.15: 0.3 | Streptococcus pyogenes A 561 | <1 0.01: 40.01 | 4 0.01: 40.01 | | Streptococcus pyogenes 77 A | - $ · 0.01: 40.01 | 40.01: ^ 0.01 | I Escherichia Coli 1894 | 4 0.01: ^ 0.01 | 4 0.01: 4 0.01 | 15 I "" 078 I 4 0.01: 40.01 140.01: 40.01 | | "" TEM | 4 0.01: 0.04 0.04: 0.08 | "" 1507 E | 4 0.01: 40.01 | 40.01: 40.01 | | "" OCO | 4 0.01: 0.02 0.02: 0.04 | "" DC2 | N <0.01: 40.01 140.01: 4 0.01 | 20 | Salmonella typhimurium MZ 11 | 4 0.01: 40.01 | 0.04: 0.04 | Klebsiella pneumoniae 52145 | 0.04: 0.04 0.04: 0.04 | Klebsiella aerogenes 1522 E | 0.08: 0.08 0.15: 0.15 | Enterobacter cloacae 1321 E | 4 0/01: 4 0.01 | 0.02: 0.02 | Proteus mirabilis A 235 0.02: 0.02 0.04: 0.04 25 I Proteus vulgaris A 232 0.08: 0.3 0.08: 0.08 is 86731

I> I,, I

. I Eg 30 products .Ex. 19.

I> 'product' I Strains I _________________ ι ________________ i

5 I I 24 H: 48 H I 24 H: 48 H I

I_I _: _ 1 _: _ I

I Staphylococcus aureus SG 511 | 0.3: 0.3 0.6: 0.6 | Staphylococcus aureus 285 | 0.3: 0.3 0.6: 0.6 | Staphylococcus aureus 54146 | 0.3: 0.6 0.6: 1.2 10 I Streptococcus pyogenes A 561 | 0.01: ^ 0.01 1 ^ .0.01: v <0.01 | | Streptococcus pyogenes 77 A | ^ 0.01: ^ 0.01 | ^ 0.01: ^ 0.01 | | Escherichia Coli 1894 | ^ 0.01: ^ 0.01 1 ^ 0.01: ^ 0.01 | | "” 078 | ^ 0,01: ^ 0,01 | 0,04: 0,04 || "TEN | 0,02: 0,02 | 0,15: 0,15 | 15 I" "1507 E | N <0,01: x <0,01 | ^ 0,01: N <0,01 || "DC0 | 0,04: 0,04 | 0,15: 0,15 || DC2 | N <0.01: ^ 0.01 | <.0.01: ^ 0.01 | j Salmonella typhimurium MZ 11 | 0.02: 0.02 | 0.15: 0.15 || Klebsiella pneumoniae 52145 | 0, 02: 0.02 | 0.3: 0.3 | 20 | Klebsiella aerogenes 1522 E | 0.04: 0.04 | 0.3: 0.3 | | Enterobacter cloacae 1321 E | ^ 0.01: 0, 01 j 0,04: 0,08 || Proteus mirabilis A 235 | 0,02: 0,04 | 0,08: 0,08 | | Proteus vulgaris A 232 | 0,02: 0,04 | 0,04: 0.04 | | _ | _: _ j _: _ | i9 86 731

Reference Example A:

Syn, cis-racemic 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-4-thia-3-methoxymethyl-1-azabicyclo [4.2.0] oct-2 -ene-2-carboxylic acid 5 Step A: methoxyacetaldehyde

Boil under reflux 100 cm3 of methoxyacetaldehyde dimethyl ketal, 100 cm3 of water and 3.2 cm3 of concentrated hydrochloric acid, followed by several fractional distillations to give 8.7 g of the expected product.

Step B: Tert-butyl 2-chloro-3-methoxymethyloxirane carboxylate Cool a mixture of 2.106 g of methoxyacetaldehyde, 3.8 cm3 of tert-butyl dichloroacetate and 25 cm3 of tetrahydrofuran to -20 ° C. After 15 minutes, 29 cm3 of potassium tert-butylate in tetrahydrofuran (0.9 M / l) are added and the reaction is allowed to proceed for 1 hour and 20 minutes. Add 25 cm3 of ether and 24 cm3 of water and extract with ether. Wash the organic phase with water saturated with sodium chloride, dry and concentrate to dryness under reduced pressure. The residue obtained is chromatographed on silica, eluting with methylene chloride to give 1.44 g of the expected product.

Step C: 1,1-Dimethylethyl 7- [2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-2-hydroxy-3-methoxymethyl-4 -thia-1-azabicyclo [4.2.0] octane-2-carboxylate

1.38 g of 1,1-dimethylethyl 2-chloro-3-methoxymethyloxiran carboxylate, 2.736 g of 4-mercaptomethyl-3- [2- (2-tritylaminothiazol-4-yl) -2-methoxy) are stirred. siiminoacetamido] 2-oxo-1-azetidine (cis, syn-racemic) prepared by the method of BE patent 894,795 and 12 cm 3 of dimethylformamide. After 10 minutes, 458 g of lithium carbonate are added and the mixture is stirred for 2 hours and 50 minutes. Pour the reaction mixture 100 into 35 cm3 of water and 60 cm3 of ethyl acetate. Extract with 2o 8 6 7 31 ethyl acetate, wash the organic phase with water, dry and concentrate to dryness under reduced pressure. Take up the residue again in ether to give 3.058 g of the expected product.

Analysis: C30H41O7N5S2: 743.91

Calculated: C% 61.35, H% 5.56, N% 9.41, S% 8.62 Found: 61.1 5.7 8.9 8.4

Gear D: 1,1-Dimethylethyl 7- [2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-3-10 methoxymethyl-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

4.44 g of diphosphoric tetraiodide in 35 cm3 of pyridine are added to the suspension, shaken for 5 minutes and 3.058 g of 1,1-dimethylethyl 7- [2- (2-tritylamino-15-thiazol-4-yl) -2-methoxyimino- acetamido] -8-oxo-2-hydroxy-3-methoxymethyl-4-thia-1-azabicyclo [4.2.0] octane-2-carboxylate and stirred for 2 hours 40 min. Distill off the pyridine, take up the residue in 50 cm3 of ethyl acetate, filter, add 50 cm3 of 1N hydrochloric acid to the filtrate, mix vigorously and decant the organic phase, wash with water and concentrate to dryness under reduced pressure. The residue is chromatographed on silica with a mixture of methylene chloride and ethyl acetate (85:15). Concentrate the interesting fractions to dryness, crystallize from ethanol and give 703 mg of the desired product.

Analysis: C38H3906N5S2: 725.89

Calculated: C% 62.88, H% 5.41, N% 9.65, S% 8.83 Found: 62.7 5.4 9.6 8.8

Step E: Syn, cis-racemic 7 - [- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-4-thia-3-methoxymethyl-1-azabicyclo [4.2. O] oct-2-ene-2-carboxylic acid 246 mg of 1,1-dimethylethyl 7- [2- (2-triethylaminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo are dissolved. 3-Methoxy-methyl-4-thia-1-azabicyclo [4.2.0] oct-2-35 ene-2-carboxylate in 1 cm3 of trifluoroacetic acid and 2i 86731 are left to react for 50 min. at room temperature. 12 cm3 of isopropyl ether are added, the precipitate formed is filtered off and 176 mg of crude trifluoroacetate are obtained, which is dissolved in ethanol. Add 2 drops of pyridine, allow to crystallize for 1 hour to give 88 mg of the desired product. Analysis: C15H1706N5S2: 427.46

Calculated: C% 42.15, H% 4.01, N% 16.38, S% 15.00 Found: 42.2 4.0 16.2 15.0

Reference Example B: 10 Syn, cis-racemic 7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-3 - [(1-methyl-1H-tetrat -sol-5-yl) thio-methyl] -4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Step A: 2- (1,1-Dimethylethyl) dimethyloxysilyl / ethanol at 20 ° C under nitrogen: 18 g of tert-butyldimethylsilyl chloride, 150 cm 3 of dichloromethane, 17.5 cm 3 of dimethylformamide, 20 33.6 ethylene glycol.

After complete dissolution, add 5 min. 20.1 cm 3 of triethylamine, followed by the addition of 1.8 g of 4-dimethylaminopyridine. After stirring for 2 hours 45 minutes, the solution is poured into 120 cm3 of water and neutralized with 1N hydrochloric acid (about 40 cm3) to give a pH of 3. Decant, extract again the aqueous phase with 20 cm3 of pentane and wash the organic phase 60 cm3 of water and extract again with 20 cm3 of pentane. The organic phase is dried and distilled under reduced pressure. After distillation of Vä-30, 13.9 g of the desired product are isolated.

Eb 16 mm / Hg = 82 ° -86 ° C.

Step B: 2 - [(1,1-dimethylethyl) dimethyloxysilyl] acetaldehyde Dissolve with stirring under nitrogen a mixture of 4.71 cm 3 of oxalyl chloride in 120 cm 3 of dichloromethane. Cool to 22 86731 to -70 ° C and add at 12 ° C, maintaining the temperature at -65 ° C, a solution containing 8 cm 3 of dimethyl sulphoxide and 26 cm 3 of dichloromethane. After 10 min of reaction at this temperature, the following solution containing 8.81 g of 2- (1,1-dimethylethyl) dimethyloxysilyl / ethanol obtained in step A, 50 cm3 of di- chloromethane and 8.86 cm 3 of pyridine. After 15 min of reaction at this temperature, 35 cm3 of triethylamine are added in 8 min at -65 ° C. At + 13 [deg.] C., neutralize with 1N chloro-10 hydrochloric acid to give a pH of 4. Decant, extract again with 50 cm <3> of dichloromethane, dry the organic phase and distill under reduced pressure. The crude product is chromatographed on silica eluting with dichloromethane. Finally, 7.95 g of the desired product are isolated.

Step C: 1,1-Dimethylethyl 2-chloro-3- (tert-butyl-dimethyloxysilylmethyl) oxirane carboxylate

Proceed as in Reference Example A, Step B, taking care not to add potassium-20 tert-butylate solution and 7.95 g of the aldehyde obtained in Step B at -20 ° C to 1,1-dimethylethyl dichloroacetate solution simultaneously, and after silica chromatography (eluent: hexane-dichloromethane 6: 4) 9.4 g of the expected product.

Step D: 1,1-Dimethylethyl 7- [2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-2-hydroxy-3 - [(1 (1-dimethylethyl) dimethyloxysilylmethyl] -4-thia-1-azabicyclo [4.2.0] octane-2-carboxylate Proceed as in Step C of Reference Example A 16 with a reaction time of 30 hours. After chromatography on silica and elution with dichloromethane-ethyl acetate (75:25), 4-mercaptomethyl 3- [2- (2-tritylaminothiazol-4-yl) -2-methoxy) is isolated from 8.31 g of cis, syn racem. iminoacetamido] -2-oxo-1-azetidine and 9.09 g of cyclic product from the product obtained above.

23 86731

Step E: 1,1-Dimethylethyl 7- [2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -8-oxo-3 - [(1,1-dimethylethyl) dimethyl -oxysilylmethyl] -4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 5 Proceed as in Step D of Reference Example A.

The reaction time is reduced to 55 min. The reaction solution is poured into 2N hydrochloric acid in acidified water to pH 1.4 and extracted with ethyl acetate. From 9.09 g of the product obtained above, 4 g of ha-10 product are isolated after chromatography.

UV spectrum in ethanol ref .: 233 nm Ej: 364 ref .: 265 nm E *: 173 max: 302 nm E *: 229 £ = 18900

Step F: 1,1-Dimethylethyl 7- [2- (2-tritylamino-thiazol-4-yl) -2-methoxyimino-acetamido] -8-oxo-3-hydroxymethyl-4-thia-1- azabicyclo [4.2.0] oct-2-ene-2-carboxylate 20 Suspend 2.595 g of the silyl derivative obtained in step E in 30 cm3 of acetone and 4.7 cm3 of 1N hydrochloric acid. The solution gradually becomes clear and, after stirring for 3 hours, 7.7 cm3 of bicarbonate-saturated water are added and the acetone is distilled off under reduced pressure. 20 cm3 of dichloromethane are added, stirred, decanted, extracted again and the organic phase is dried and distilled under reduced pressure. The gummy residue is dissolved in 5.5 cm3 of ethyl acetate to which 43 cm3 of ether are added. After stirring for 3 hours 15 minutes, the crystals formed are filtered off, rinsed and dried. Thus, 2.232 g of the desired product are isolated.

Lie G: 1,1-Dimethylethyl 7- [2- (2-tritylamino-thiazol-4-yl) -2-methoxyimino-acetamido] -8-oxo-3-chloromethyl-4-thia-1- azabicyclo [4.2.0] oct-2-ene-2-carb-35 carboxylate 24 8 6 7 31

Dissolve 623 cm3 of the alcohol obtained in step F in 8 cm3 of dichloromethane with 834 mg of tosyl chloride and add in 20 minutes a solution containing 534 mg of 4-dimethylaminopyridine and 5 cm3 of dichloromethane. After stirring for 1 hour, 2.2 cm3 of 1N hydrochloric acid are added, the mixture is stirred, decanted and the organic phase is dried. After distillation under reduced pressure, the residue is chromatographed on silica, eluting with dichloromethane-ethyl acetate (9: 1). The desired product crystallizes out in ether to give 245 mg.

UV spectrum in EtOH ref .: 224 nm e [: 441 £ = 38200 ref .: 264 nm E *: 179 nm ref .: 271 nm E \: 164 max .: 306 nm Ej: 222 £, = 19200

Step H: 1,1-Dimethylethyl 7- [2- (2-tritylamino-thiazol-4-yl) -2-methoxyimino-acetamido] -8-oxo-3-yl-methyl-1H-tetrazole- 5-yl) -thiomethyl] -8-oxo-4-thia-20'-azabicyclo [4.2.0] oct-2-ene-2-carboxylate.

Dissolve 301 mg of the product obtained in step G and 114 mg of sodium 1-methyl-5-mercapto-1,2,3,4-tetrazole in 3 cm3 of dimethylformamide. After stirring for 1 hour 40 minutes, the solution is poured into 30 cm3 of water and extracted with ethyl acetate. The organic phase is dried and distilled under reduced pressure. The resin obtained is dissolved in ethyl acetate (2 cm3) and ether is added just above the solubility limit. After filtration, the crystals obtained are filtered off after 45 minutes, rinsed with ether and dried to give 283 mg of the desired derivative in two portions.

Step I: 7- [2- (2-Aminothiazol-4-yl) -2-methoxyimino-acetamido] -8-oxo-3 - [(1-methyl-1H-tetrazol-5-yl) -thiomethyl] -4-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 35 Proceed as in Example 1, Step E, but dissolve the crude product in bicarbonate water and adjust the pH to 4 86731, and filter when high some of the water is distilled off. From 371 g of the product of step H, 61 mg of the desired product are isolated.

UV spectrum 5 1) in EtOH max: 302nm e \: 295 £ = 15100 2) in EtOH / HCl N / 10 ref .: 273nm E \: 304 max .: 285nm E \: 318 £ = 16300 10 ref .: 292nm E \: 312 £ = 16000 ta .: 309nra e \: 245 ¢, = 12500

The corresponding optically active products are prepared and in particular syn- (6S) (7S) -1,1-dimethylethyl-7- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -8-15 oxo -3-hydroxymethyl-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, acting as in Reference Example A, starting from cis, syn- (3S) (4S) -4-mercaptomethyl-3- [2- (2-tritylamino-thiazol-4-yl) -2-methoxyimino-acetamido] -2-oxo-1-azetidine as disclosed in FR Patent Application 20 2,538,389.

The product obtained has the following physicochemical properties: F = 180 ° C.

UV: 1) in ethanol: ref .: 222 nm E * = 444 ref .: 237 nm E * = 352 max: 302 nm E * = 223; £ = 15900 2) in ethanol and 0.1 N HCl ref .: 221 nm E * = 464 ref .: 263 nm E * = 204 ref .: 285 nm E * = 294 max: 293 nm E ^ = 340; £ = 22000 ref .: 300 nm E = 299 ref .: 310 nm E * = 230

Reference Example C: (6S) (7S) -7 [[(2-triphenylmethylamino-thiazol-4-35-yl) -2- (Z) -methoxyimino) acetyl] amino] -2 - [(1,1 -Dimethyl-26 86 731 (ethyl) oxycarbonyl-8-oxo-4-thia-1-azabicyclo [4.2.0] octen-3-yl-1-methyl] triphenylphosphonium chloride

2.182 g of 1,1-dimethylethyl (6S, 7S) -7- [-2- (2-trilylamino-thiazol-4-yl) -2-methoxyimino-5-acetamido] -8-oxo-3-chloromethyl-4 thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate prepared as in Step G of the Reference Example and 1.679 g of triphenylphosphine in 24 cm 3 of tetrahydrofuran are added 14.1 g silica, distill tetrahydrofuran under reduced pressure for 2 hours, cooled, stirred for 26 hours at 20 ° C, chromatographed on silica (eluent dichloromethane-methanol 9: 1) to give 1.89 g of the expected product. Example 1 (6S) (7S) -Syn-7- [3 - [- 7 - [[2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-carboxy-8-oxo -4-Thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] propen-2- (E) -yl] thieno [2,3-b] pyridine trifluoromethanesulfonate

Step A: 1,1-Dimethylethyl (6S) (7S) -7 - [[- 2- (2-triphenylmethylamino-thiazol-4-yl] -2- (Z) -methoxyimino-20-acetyl] ] amino-3- [3 - [(1,1-dimethylethyl) dimethylsilyl] oxy] propen-1-yl] -8-oxo-4-thia-1-azabicyclo [4.2.0] octene. 2-ene-2-carboxylate

1.89 g of 1,1-dimethylethyl 7 - [[2- (2-triphenylmethylamino-thiazol-4-yl] -2- (Z) -methoxyimino-25-acetyl] amino] -3-methyl- triphenylphosphoninium] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, 30 cm3 of dichloromethane, 0.68 cm3 of 2- [1,1-dimethyl- ethyl dimethylsilyloxy] acetaldehyde, 0.53 cm 3 triethylamine, stirred at + 20 ° C for 14 hours, chromatographed on silica eluting with a mixture of dichloromethane and ethyl acetate (9/1) and isolating the product obtained containing the isomers. E (2/3) and Z (1/3) mixture.

NMR Spectrum (CDCl 3) δ 0.90 - 0.92 ppm SitBu; 1.50 - 1.52 ppm CO 2 tBu; 2.95 - 3.11 27 8 6 7 31 ppm CH 2 S; 4.05 ppm OCH 3; 4.31 - 4.37 ppm CH2 4.11 ppm H6; 5.4 to 5.5 ppm H7 5.75 to 5.87 ppm and 6.11 to 6.24 ppm Z (1/3); 6.17 to 6.34 ppm and 6.97 to 7.16 ppm E (2/3); 6.50 to 6.56 ppm H5 thiazolyl syn; 7.34 ppm 03.

Lie B: 1,1-Dimethylethyl 7 - [[- 2- (2-triphenylmethylamino-thiazol-4-yl] -2- (Z) -methoxyiminoacetyl] -amino] -3 - [(3- hydroxypropen-1- (E) -yl)] - 8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate and 1,1-dimethylethyl 7 - [ [-2- (2-triphenylmethylamino-thiazol-10-yl] -2- (Z) -methoxyiminoacetyl] amino] -3- [3-hydroxy-propen-1- (Z) -yl] -8- oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

Dissolve 1.305 g of the product obtained in step A of Example 1 in 15 cm3 of acetone, add 2 cm3 of 1N hydrochloric acid solution, stir for 2 hours and 30 minutes, concentrate to dryness by distillation under reduced pressure, add bicarbonate water, extract with dichloromethane, concentrate to dryness by distillation under vacuum. chromatograph the residue on silica eluting with a mixture of dichloromethane and ethyl acetate (1/1) and isolate: 536 mg of isomer E and 369 mg of isomer Z of the desired product.

(E) -isomeria-controls.

IR spectrum (chloroform) 3607 cm-1 OH; 3405 cm-1 amide NH; 1684 cm-1 C = O; 1515 cm-1 amide II; 1772 cm-1 lactam C = 0; 1595 cm-1 1544 cm-1; 1527 cm-1: aromatic thiazole, conjugated system; 1700 cm-1 tert-butyl ester; 1370 cm-1; CH 3; 1154 cm-1 C-O-C; 30 28 cm-1 OMe; 1049 cm-1 C = N-OR.

UV spectrum: ethanol

Max 231 nm E {= 479 £ = 32200 tait. 258 nm Ej = 290; Tait. 264 nm Ej = 264; 35 tait. 270 nm Ej = 240;

Max 320 nm Ej = 245; Ε = 18100 28 δ 6731 NMR spectrum (CDCl 3) 1.51 ppm tBu; 3.05 ppm CH 2 S; 4.02 ppm OCH3; 4.28 ppm CH2OH; 5.84 ppm: H7; 6.24 to 6.41 and 6.97 to 7.13 ppm H ethylene; AEJ = 15 Hz; 7.29 ppm O 3; 6.53 ppm H5 thiazole "syn".

5 Z-isomeria control

Ir spectrum (chloroform) 3605 cm -1 OH; 3405 cm-1 amide NH; 1685 cm-1 C = 0; 1505 cm-1 amide II; 1773 cm-1 β-lactam C = 0; 1704 cm-1 tert-butyl ester; 1368 cm-1 Me; 1154 cm-1 C-O- C; aromatic thiazo-10I, conjugated system; 2820 cm-1 C = N-OMe; 1050 cm-1 C = N-OR.

UV spectrum: (ethanol) turning point 230 nm E | = 411; Tait. 260 nm λ = 220; turning point 265 nm E = 198; Tait. 271 nm e = 176; Max 308 nm E {= 194 = 14300 NMR spectrum (CDCl 3) 1.49 ppm tBu; 3.06 ppm S-CH2; 4.04 ppm OMe; 4.27 ppm CH 2 OH; 5.84 ppm H7; 5.85 to 5.98 ppm and 6.21 to 6.34 ppm H ethylene; ΔΖJ = 11 Hz; 6.56 ppm H5 thiazole syn; 7.29 ppm 03.

Step C: (6S) (7S) -7 - [- 3 - [- 7 - [[- 2- (2-triphenylmethylaminothiazol-4-yl) -2- (Z) -methoxyimino] acetyl] amino] -2 - [[- 1,1-dimethylethyl] oxy] carbonyl] 8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-3-yl] propen-2 - (E) -yl] thieno [2,3-b] pyridinium trifluoromethanesulfonate 25 Dissolve 22 mg of the E-isomer obtained in step B of Example 1 in 4.8 cm3 of dichloromethane, add 3 cm3 of a solution containing 536 mg of thieno [2,3-b] pyridine in 10 cm3 of methylene chlorine, cooled to -70 ° C, 2.7 cm3 of a solution of trifluoromethanesulphonic acid-30 polyanhydride containing 0.42 cm3 of methylene chloride in 10 cm3 are added dropwise slowly To + 20 ° C, concentrate to dryness by distillation under reduced pressure, add ethyl acetate, wash with water containing 0.7 cm 3 of 1N hydrochloric acid, decant, wash with water, extract with 35 ethyl acetate, concentrate to dryness by distillation under reduced pressure, 29 86 731, chromatograph the residue on silica. eluting with dichloromethane-methanol (92/8) and isolating 236 mg of the desired compound (E-isomer).

Step C ': (6S) (7S) -7 - [- 3 - [- 7 - [[- 2- (2-triphenyl-5-methylaminothiazol-4-yl) -2- (Z) -methoxyimino " ) acetyl] amino] -2 - [[1,1-dimethylethyl] oxy] carbonyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] propen-2 - (Z) -yl] thieno [2,3-b] pyridinium trifluoromethanesulfonate 145 mg of the 10 Z-isomer obtained in step B of Example 1 are dissolved in 5 cm3 of dichloromethane, 120 l of thieno [2,3-b] are added. ] pyridine, cooled to -70 ° C, 1.76 cm3 of a solution of trifluoromethanesulphonic anhydride in methylene chloride containing 0.42 cm3 of anhydride in 10 cm3 of methylene chloride are added dropwise, the mixture is slowly warmed to 15 +20 ° C, the solution is chromatographed on silica eluting with dichloromethane-methanol (92/8) and 157 mg of the desired compound (E-isomer) are isolated.

Step D: (6S) (7S) -Syn-7 - [- 3 - [- 7 - [[- 2-amino-thiazol-4-yl) methoxyimino] acetyl] amino] -2-carboxy- 8-oxo-20-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] propen-2- (E) -yl] thieno [2,3-b] pyridinium trifluoromethanesulfonate

221 mg of the isomer (E) obtained in step C of Example 1 are mixed with 2.5 mg of 33% formic acid (aqueous solution), heated to 65 ° C for 55 min, cooled, diluted with water, filtered, washed with ether, and the aqueous phase is concentrated to dryness. by distillation under reduced pressure, add water, centrifuge, dry to give 93 mg of the desired product.

IR spectrum (nujol) δ 1760 cm -1 β-lactam C; 1660 cm -1; 1550 and 1535 cm "1 aro-

OF

0 amate + amide II + thiazole + conjugated system; 1030 cm * 1 CF3SO3 UV spectrum (ethanol) 35 Max 238 nm E} = 625 £ = 44200

Max. 307 nm E1 = 251 £, = 17700 30 86 7 31 Turning point 318 nm E3 = 232 Turning point 338 nm E3 = 166 NMR spectrum (DMSO) 3.83 ppm: OCH3; 5.55 - 6.44 ppm CH 2 N *; 107: 1H ethylene; Δ 6.81 ppm: H5 thiazole; 7.23 ppm NH2; 7.84 to 9.24 ppm aromatic.

The Z-isomer is completely hydrolyzed by formic acid hydrolysis to the E-isomer (isomerization).

Example 2: (6S) (7S) -Syn- [7 - [[- 2- (2-aminothiaz-10-sol-4-yl) -2- (Z) -methoxyimino) acetyl] amino] - 3 - [[- 3- [1-methyl-1H, 1,2,3,4-tetrazol-5-ylthio] propen (E) -yl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic boksyy1ihappo

Step A: 1,1-Dimethylethyl [7 - [[2- (2-triphenyl-15-methylamino-thiazol-4-yl) -2- (Z) -methoxyimino) acetyl] amino] -3 - [ [-3- (1-methyl-1H-1,2,3,4-tetrazol-5-ylthio] propen- (E) -yl] -8-oxo-4-thia-1-azabicyclo [4.2. 0] oct-2-ene-2-carboxylate

37 mg of 1,1-dimethylethyl [7 - [[2- (2-20 triphenylmethylaminothiazol-4-yl) -2- (Z) -methoxyimino) acetyl] amino] -3 - [[( 3-hydroxy)] propen- (E) -yl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, 24 mg ammonium tetrabutyl iodide, 0, 8 cm3 of methylene chloride, 23 μΐ of lutidine, are cooled to -70 ° C, 0.25 cm3 of a trichloromethanesulphonic anhydride solution containing 0.42 cm3 of anhydride in 10 cm3 of methylene chloride are added dropwise at a time, 14 mg of 1- methyl 5-mercapto-1,2,3,4-tetrazole sodium salt and 0.5 cm 3 of dimethylformamide, stirred at 20 ° C, concentrated to dryness, chromatographed the residue on silica eluting with a mixture of methylene chloride and ethyl acetate (9/1 ) and isolate the desired product.

Step B: [7 - [[- 2- (2-Amino-thiazol-4-yl) -2- (Z) -methoxyimino-acetyl] amino] -3 - [[- 3 - [- 1-methyl -1H, -35 1,2,3,4-tetrazol-5-ylthio] propen- (E) -yl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2- ene-2-carboxylic acid 31 ft 6 7 31

Mix 329 mg of the compound obtained in step A of Example 2 with 9.6 cm3 of a 33% aqueous formic acid solution, heat for 1 hour 15 min at +65 ° C, cool, dilute with water, filter, concentrate to dryness by distillation under reduced pressure, take up the residue in water. , the insoluble form is eliminated by filtration, concentrated to dryness and 142 mg of the desired product are isolated.

IR spectrum (nujol) 3410 cm -1; 3300 cm-1; 3210 cm -1 OH / NH absorption 1775 cm -1; 10 1770 cm β-lactam C; 1665 cm-1 other carbonyls; 0 1626 cm'1 aromatic conjugated system NH2 UV spectrum: (ethanol, 0.1N HCl)

Max 239 nm E = 390 £ = 21000; Λ max 266 nm λ = 414 ε = 22300; Turning point 280 nm E1 = 390;

Max 329 nm E1 = 304 £ = 16300 NMR spectrum (DMSO)

3.86 and 3.94 ppm NCH 3 and OMe 20 4.03-4.10 ppm = C-CH 2 S

5.56 - 5.73 ppm H H7 β-lactam (cis)

B

6.07 - 6.39 ppm ethylene ΔΕ 25 CH 2

B

6.88-7.05 ppm

B

6.84 ppm H5 thiazole syn 7.2 ppm: NH2

9.17 - 9.27 ppm NHCO

Example 3: (6S) (7S) -Syn-7 - [- 3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -2-carboxy- 8-35 Oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] propen-2- (E) -yl] -thieno [2,3-b] pyridinium inner salt 32 86 7 31

281 mg of the product obtained in step C of Example 1 are dissolved in 3.17 cm3 of 66% formic acid and heated at 65 ° C for 2 hours. Dilute with 3.2 cm3 of water, filter and concentrate the filtrate to dryness under reduced pressure. Dissolve the residue in 1.3 cm3 of 1M aqueous triethylamine carbonate solution and 1.3 cm3 of acetonitrile, chromatograph on silica (eluent: aqueous acetonitrile 9/1 and 85/15). 77 mg of the desired product are obtained.

NMR Spectrum (DMSO) δ 3.83 ppm (s): OCH 3 5.49 ppm: H7 β-lactam cis 5.88 - 7.48 ppm: H ethylene 6.80 ppm (s): H5 thiazole syn IR- spectrum (nujol) 15 NH / OH β-lactam C = 0: 1760 cm-1 amide C = 0: 1665 cm-1 NH2 def, aromatic, COO ", amide II thiazole: 1635 cm-1, 1600 cm-1, 1558 cm -1, 1540 cm -1, 20 C = N OR 1035 cm -1

Example 4: Syn- (6S 7S) 7 - [- 2- (2-amino-thiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-acetoxy) -1- (E ) - propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxyl trifluoroacetate Step A: 1,1-Dimethylethyl 7 - [- 2- (2- tritylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetamido] -3 - [(3-acetoxy) propen-1- (E) -yl] -8-oxo-4-thia-1 -azabicyclo [4.2.0] oct-2-ene-2-carboxylate

300 mg of the E-isomer obtained in step 1B of Example 30, 1.5 cm3 of pyridine and 0.75 cm3 of acetic anhydride are stirred for 2 hours at room temperature. Add 20 cm3 of water and 10 cm3 of 1N hydrochloric acid and extract with methylene chloride. 395 mg of crude product are obtained, which is chromatographed on silica eluting with methylene chloride-ethyl acetate 35 (6/4). 255 mg of the desired product are obtained. Mp 170 ° C

33 86 731

Step B: Syn- (6S), (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(3-acetoxy) -1- (E) -propenyl] -8-oxo-4-thia-1-α Sabicyclo [4.2.0] oct-2-ene-2-carboxytrifluoroacetate 5 Stir for 55 min at room temperature 210 mg of the product obtained above and 1.05 cm3 10% trifluoroacetic acid. 5 cm3 of ether are added and the mixture is stirred for a further 1 hour, centrifuged to give 133 mg of the expected product.

Nuclear Magnetic Resonance Spectrum (DMSO) δ 6.92 ppm, H5 thiazole 9.27 - 9.37 ppm: H amide 5.63 - 5.68 ppm: H7 4.02 - 4.08 ppm: H6 6.22 - 6 , 3 and 7.09 to 6.93 ppm: H ethylene 15 2.07 ppm: H acetyl IR spectrum (nujol)

Absorption OH / NH β-lactam C = 0: 1767 cm -1, 1740 cm -1, 1698 cm -1, 1667 cm -1, 1640 cm -1 Strong absorption: 1140 cm -1, 1250 cm -1 UV- spectrum

1) EtOH

max 236 nm E1 = 387 δ = 23100 ref. 260 nm Ej = 256 max 320 nm Ej = 320 £ = 15500 2) EtOH + 0.1 N HCl max 238 nm Ej = 291 £ = 17300 max 266 nm E1 = 331 £ = 19700 ta. 283 nm Ej = 289 30 max 324 nm E} = 234 t = 13900

Example 5: Syn- (6S 7S) -3 - [- 7 - [- 2- (2-amino-thiazol-4-yl) -2-methoxyimino) acetamido] -2-carboxy-8-oxo - 4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (Z) -propenyl-trimethylammonium trifluoromethanesulfonate and (E) -35 propenyl isomer 34 86 731

Step A: Syn- (6S) (7S) -3 - [- 7 - [- 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -2 - [(1,1 -dimethyllethoxy) carbonyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] propen-2- (E) -yl-trimethyl Ammonium 5-trifluoromethanesulfonate and propen-2- (Z) -yl isomer

282 mg of tert-butyl-7 - [- 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -3- [-3-hydroxy-1- (E + Z ) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene carboxylate to 3 cm3 of methylene chloride. Cool to -70 ° C and add 1.6 cm 3 of a solution of 1.53 mmol of trimethylamine trifluoromethanesulphonic anhydride and stir at -70 ° C for 30 min. 7 cm3 of methylene chloride and 5 cm3 of 0.1N hydrochloric acid are added. Heat the solution, isolate the organic phase, dry and chromatograph on silica. Elution with methylene chloride-methanol (95/5) gives the desired products 108 mg of the Z-isomer (30%), 117 mg of the E-isomer (33%) and 53 mg of a mixture of E and Z.

Step B: Syn- (6S) (7S) -3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -2-carboxy-8-oxo- 4-Thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (Z) -propenyl trimethylammonium trifluoromethanesulfonate and the 2- (E) -propenyl isomer.

Dissolve 108 mg of the product obtained (Z-isomer) in 2 cm3 of 66% formic acid and stir for 2 hours at 65 ° C. Cool and dilute with 2 cm3 of water. Wash the reaction mixture with ether and methylene chloride. Evaporate the aqueous phase. Take the residue 3 times in 5 cm3 of gun-30 tonitrile and 1 cm3 of methanol. Add 5 cm3 of methylene chloride to the residue, stir for 1 hour, centrifuge to give 55 mg of the desired product.

NRM spectrum (DMSO) 3.06 ppm (s): N® (CH 3) 3 35 3.86 ppm (s): OCH 3 35 86731 ~ 4.10 ppm (m): CH 2 -14 ^ 3.02 - 3.27 ppm: S-CH2 6.72 ppm: - @> = CH-CH2 ΔΖ 6.81 ppm: H5 thiazole syn

Δ 9.3 ppm: NHCO

UV spectrum

1) EtOH

max 231 nm Ej = 336 £ = 21200 max 302 nm Ej = 202 £ = 12700 10 2) EtOH + 0.1 N HCl max 232 nm E * = 257 £. = 16200 max 261 nm E * = 250 £, = 15800 max 284 nm Ej = 237 £ = 14900 fold. 310 nm Ej = 179 Starting from the E-isomer obtained in step A, proceed as above to give 56 mg of the desired product. Nuclear Magnetic Resonance Spectrum (DMSO) 3.02 ppm: N 2 Me) δ 3.87 ppm (s): OMe 3 4 4.11 ppm: O2-ίΦ 5.61 - 5.78 ppm: H7 cis 6.73 ppm: H5 thiazole syn 5 , 94 - 6.22 ppmΊ

V H ethylene ΔΕ 25 7.11 - 7.28 ppm J

UV spectrum 1) EtOH

max 235 nm Ej = 381 £ = 24000 max 325 nm E3 = 244 £ = 15400 2) EtOH + 0.1 N HCl. 245 nm E3 = 299 max 263 nm E \ = 318 £ = 20100 max 332 nm Ej = 212 £ = 13400

Example 6: Syn- (6S) (7S) -3 - [[- 3 - [[- 7- (2-aminothiaz-35-sol-4-yl) -2-methoxyiminoacetamido] -2-carboxy- 8-Oxo-36 86 731 4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] oxycarbonyl] -1-methylpyridinium inner salt Step A: (6S) (7S) -1,1-Dimethylethyl 7 - [- 2- (2-tritylaminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido-5-yl] -3- [-3- (nicotinyloxy) -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

1.5 g of nicotinic acid in 1.8 cm3 of thionyl chloride are refluxed for 1 hour 30 min. Take up in toluene, evaporate, triturate the residue in ether, dry and give 2.12 g of nicotinyl chloride hydrochloride. 258 mg of the E-isomer obtained in step B of Example 1 are dissolved in 1 cm 3 of pyridine and 93 mg (0.525 mM) of freshly prepared nicotinyl chloride hydrochloride are added and stirred for 2 hours under normal pressure. Dilute with 10 cm3 of methylene chloride, wash with 1N hydrochloric acid and sodium bicarbonate solution. Dry, evaporate, chromatograph the residue on silica, elute with methylene chloride-diacetone (9/1) to give 232 mg of the expected product.

Step B: (6S) (7S) -AE-3-3 - [- 7 - [- 2- (2-tritylaminothiazol-4-yl-2- (Z) -methoxyimino-acetamido] -2 - (1,1-dimethylethoxycarbonyl) -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -1- (E) -propenyloxycarbonyl-1-methylpyridinium Iodide 25 Dissolve 225 mg of the product obtained above in 1 cm3 of dimethyl sulphoxide, add 0.168 cm3 of methyl iodide and stir for 5 hours Evaporate the dimethyl sulphoxide under reduced pressure at 40 [deg.] C., chromatograph the residue on silica (eluent: methylene chloride-methanol 92/8) 187 mg of the desired product.

Step C: (6S) (7S) -3 - [[- 3 - [[- 7- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -2-carboxy-8-oxo-4 -thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] oxycarbonyl] -1-methylpyridinium inner salt 35 Dissolve 187 mg of the product obtained in Step B 1 cm3 of trifluoroacetic acid and left at room temperature 37 86731 for 10 min. Mix the product with 10 cm3 of isopropyl ether. Centrifuge, dissolve the residue in 5 cm3 of hot ethanol, concentrate to about 1 cm3, redissolve the product while heating and add 0,05 cm3 of pyridine. Cool, stir for 10 min, centrifuge, wash with ethanol and ether to give 34 mg of the desired product. Nuclear Magnetic Resonance Spectrum (DMSO) 3.78 - 4.86 ppm (s): OCH 3 4.05 ppm (m): H 6 4.37 - 4.44 ppm: 1 m): H7 6.24 ppm (t, d): = @ - CH2 7.15 ppm (d): - @ = CH-CH2 6.82 ppm: H5 thiazole syn 7.23 ppm: NH2

8.06 to 9.57 ppm: H pyridine and free H

Example 7: (6S) (7S) -1 - [- 3 - [- 7 - [[- 2- (aminothiazol-4-yl) -2- (methoxyimino) acetamido] -2-carboxy] -8- oxo-4-20 thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (Z) -propenyl] -1,4-diazabicyclooctane trifluoroacetate trifluoromethanesulfonate

Step A: 1,1-Dimethylethyl 7 - [- 2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [- 3- (1,4-25 diazabicyclo octane) -1- (Z) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene carboxylate

300 mg of 1,1-dimethylethyl- (6S) (7S) -7 - [[-2- (2-tritylaminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [- 3- hydroxy-1- (Z) -propenyl] -8-oxo-4-thia-30'-azabicyclo [4.2.0] oct-2-ene carboxylate, 6 cm3 of methylene chloride and 179 mg of 1,4-diazabicyclooctane . Cool to -70 ° C and add dropwise 0.114 cm 3 of trifluoromethanesulfonate anhydride with stirring for 25 minutes at this temperature. Leave at -15 ° C for 15 minutes, stir and add 20 cm3 of water and 6 cm3 of 0.1N chloro-38 86731 hydrochloric acid. Extract with methylene chloride, dry and concentrate to dryness to give 350 mg of crude product, which is chromatographed on silica, eluting with a methylene chloride-methanol mixture (9/1). 240 mg of the desired product 5 are obtained.

Step B: (6S) (7S) -1 - [- 3 - [- 7 - [[- 2 - (- 2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -2-carboxy- 8-Oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (Z) -propenyl] -1,4-diazabicyclooctane trifluoroacetate trifluoro -10 methanesulfonate.

Stir for 60 minutes 190 mg of the product obtained above and 1 cm3 of 10% trifluoroacetic acid. Precipitate with 6 cm3 of ether, filter, dry to give 146 mg of the desired product. F = 190 ° C.

NMR Spectrum (DMSO) 6.88 ppm: H5 thiazole 9.3-9.4 ppm: H amide 5.58-5.73 ppm: H6 6.73-6.87 ppm 1. . . _

'' L: H ethylene δ Z

20 5.86-6.11 ppm j

UV spectrum 1) EtOH

max 231 nm E} = 236 £ = 18800 max 303 nm E3 = 150 £ = 12000 2) EtOH + 0, 1N HCl max 233 nm E3 176 £ = 14000 max 261 nm E3 = 177 £ = 14000 fold . 283 nm Ej = 164 tait. 291 nm Ej = 157 30 tait. 311 nm E3 = 119

Example 8: Syn- (6S) (7S) -4 - [- 3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -2-carboxy -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -2-methylthiazolo [5,4-b] pyridinium internal 35 salt 39 8 6 7 31

Step A: Syn- (6S) (7S) -4 - [[- 7 - [- 2- (2-tritylamino-thiazol-4-yl-2- (Z) -methoxyimino-acetamido] -2- ( 1,1-Dimethylethyloxycarbonyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -2-methyl- thiat-5 Solo [5,4-b] pyridinium) Cool to -70 ° C 350 mg of the Z-isomer obtained in step B of Example 1 in 10 cm 3 of methylene chloride and 356 mg of methylthiazolo [5,4-b] pyridine Add 2.34 cm3 of a solution containing 0.5 cm3 of trifluorosulphonic-10-hydride in 10 cm3 of methylene chloride, shake for 5 min at -70 ° C under nitrogen and allow to warm to 20 ° C, dilute with methylene chloride, wash with water , dried and dried to dryness under reduced pressure, chromatograph the residue on silica (eluent: methylene chloride-methanol 9: 1, and methylene chloride-methanol 92: 8).

347 mg of the desired product are obtained.

Step B: Syn- (6S) (7S) -4 - [- 3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -2-carboxy -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl-20-yl] -2-methyl-thiazolo [5,4-g] bJpyridinium inner salt

Proceed as in Example 3, starting from 330 mg of the product obtained above. Elute with distilled water containing 5% acetonitrile, then 10% and finally 20%. Evaporate the acetonitrile, take up the residue in 1 cm3 of acetone, isolate and rinse with as little acetone as possible by centrifugation to give 98 mg of the expected product.

NMR spectrum 3.84 ppm: OCH 3 δ 6.80 ppm: H5 thiazole 5.58 ppm: H7 β-lactam cis 5.93 and 7.41 ppm: H ethylene ΔΕ

UV spectrum 1) EtOH

35 max 225 nm E3 = 598 € = 34200 fold. 260 nm = 332 40 86731 ta.295 ran E \ = 306 max. 304 ran E * 333 £ = 19000 tait. 320 ran Ej = 256 2) EtOH + 0.1 IN HCl 5 max 220 ran Ej 526 £ = 30100 max 265 ran Ej 413 £ = 23600 tait. 280 nm E | = 381 times. 289 nm Ej = 357 tait. 299 ran Ej = 316 10 max 331 nm E} = 200 £ = 11400

Example 9: Syn- (6S) (7S) -1 - [- 3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -2-carboxy- 8-Oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -5,6,7,8-tetrahydroquinolinium inner salt 15 Step A : Syn- (6S) (7S) -1 - [- 3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -2- (1, 1-Dimethylethyloxycarbonyl) -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -5,6,7,8 -tetrahydroquinolinium 20 Proceed as in Example 8, Step A, using 162 μΐ of 2,3-cyclohexenopyridine to give 73 mg of the desired product.

Step B: Syn- (6S) (7S) -1 - [- 3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -2-carboxy -8-oxo-25 4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -5,6,7,8-tetrahydroquinoline internal salt

Dissolve 136 mg of the product obtained above in 1.5 cm3 of 66% formic acid and proceed as in Example 3 to give 25 mg of the desired product.

NMR Spectrum (DMSO) 3.84 ppm: OCH 3 5.46 ppm: H7 β-lactam (cis) 6.8 ppm: H5 thiazole syn 7.09 ppm: H ethylene ΔΕ 35 41 B 6 7 31

UV spectrum in EtOH

max 232 nm E3 = 411 £ = 22800 tait. 264 nm Ej = 290 tait. 274 nm eJ = 269 δ tait. 282 nm E * = 239 max 317 nm E * = 277 £ = 15400

Example 10; Syn (6S) (7S) -7 - [- 3 - [- 7 - [- 2- (2-Amino-thiazol-4-yl) -2-difluoromethoxy-imino-acetamido] -2-carboxylic, ester 8-Oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -10 2- (E) -propenyl] thieno [2,3-b] pyridinium inner salt

Proceed as in Example 5, starting from 2.527 g of 1,1-dimethylethyl 7 - [- 2- (2-tritylaminothiazol-4-yl) -2- (Z) -difluoromethoxyiminoacetamido] -3- (3-hydroxy- (E + Z) -propen-1-yl-8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl-2-carboxylate prepared by conventional methods and 1.89 cm 3 of thieno [2,3-b] pyridine and, after formic acid hydrolysis, 813 mg of the expected product are obtained: [α] D = 132.5 ° ± 2 ° (c = 1% in H 2 O-CH 3 CN (1-1) NMR Spectrum (DMSO) 2.89 - 3.06 ppm: S-CH2 5.51 ppm: H7 β-lactam (cis) 7.06 ppm: H5 thiazole syn 7.48 ppm: H ethylene ΔΕ 25 UV- spectrum ethanol - 0.1N HCl max 240 nm E3 = 614 £ = 36400 refr. 260 nm E * = 316 refr. 280 nm Ej = 296 refractory 300 nm E * = 258 30 max 329 E * = 238 £ = 14100

Example 11: (6S) (7S) -4 - [- 3 - [- 7 - [- 2- (2-aminothiazol-4-yl) -2-difluoromethoxyiminoacetamido] -2-carboxy- 8-Oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] thieno [3,2-b] pyridinium inner salt 35 Proceed as in Example 5 starting from 300 mg of 1,2-dimethylethyl 7 - [- 2- (2-tritylaminothiazol-4-4263731) -2- (Z) -difluoromethoxyiminoacetamido] -3 - [[-3-hyd -roxy- (E) -propen-1-yl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2-carboxylate and 210 mg thieno [3,2-b] pyridine. After treatment with formic acid and treatment with tri-fluoroacetic acid, 117 mg of product are obtained, which is taken up in 0.5 cm3 of acetonitrile and 0.5 cm3 of triethylamine carbonate, chromatographed on silica, eluting first with 5% water, then 10% and finally with 15% water. %. 43 mg of the desired product are obtained.

UV spectrum EtOH - 0.1 N HCl max 239 nm E3 = 569 = 33700 fold. 260 nm Ej = 274 max 290 nm Ej = 260 £ - = 15400 15 max 327 nm E \ = 254 6- = 15100

Example 12: Syn- (6S) (7S) -7 - [- 3 - [- 7 - [- 2- (2-amino-thiazol-4-yl) -2-propenyloxyiminoacetamido] -2-carb -Boxy-8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] -thieno [3,2-b] pyridinium trifluoromethane-20 sulfonate

Proceed as in Example 5, starting from 160 mg of 1,1-dimethylethyl 7 - [- 2- (2-tritylaminothiazol-4-yl) -2- (Z) -propenyloxyiminoacetamido] -3- [3-hydroxy- (E) -propenyl) -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-25 en-3-yl] -2-carboxylate and 2.2 cm3 of a thienylpyridine solution (266 mg / 5 cm3 CH2Cl2) · After formic acid hydrolysis, 53 mg of the desired product are obtained.

Nuclear Magnetic Resonance Spectrum (DMSO) 6.80 ppm: H5 thiazole-6.33 ppm H ethylene trans 7.18 ppm 5.95 ppm: -CH = CH2 7.88 ppm: H3 "8.27 ppm: H2 O 8 , 14 ppm: H6 y aromatic bicycle

9.08 ppm: H5 I

9.22 ppm: H7 I

«86731 UV spectrum

1) EtOH

max 239 run E3 = 686 έ = 50600 fold. 260 run Ej = 263 δ max 306 nm E3 = 264 έ = 19500 2) EtOH + 0.1 N HCl max 240 nm E3 = 612 έ- = 45200 max 270 nm E3 = 363 £ = 25,500 talt. 280 nm e {= 333 10 tait. 291 nm Ej = 288 tait. 301 nm E3 = 237 max 330 nm E3 = 218 & = 16100

Example 13: Syn- (6S) (7S) -7 - [[- 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl] amino] -3 - [- 3 - [- 5- (methyl-15H) -1,3,4-thiadiazol-2-yl] thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2 -ene-2-carboxylic acid Step A: 1,1-Dimethylethyl syn- (6S) (7S) -7 - [[(2-triphenylmethylaminothiazol-4-yl) -2- (methoxyimino) acetylamino] -3 - [- 3 - [- 5- (methyl) -1,3,4-thiadiad-20-sol-2-yl] thio] -1- (E) -propenyl] -8-oxo-4-thia -1-azabicyclo [4.2.0] oct-2-ene carboxylate Cool to -70 ° C 184.5 mg of the E-isomer obtained in step B of Example 1 in 4 cm 3 of methylene chloride anhydride, 120 mg. tetrabutylammonium iodide and 116 in silicon 2,6-lutidine. Add 620 μ20 of trifluoromethanesulphonic anhydride in methylene chloride (0.609 M / l) drop by drop. After 10 min at -70 [deg.] C., the temperature is allowed to rise to 20 [deg.] C., the solvent is evaporated off under reduced pressure and 66.1 mg of 5-methyl-2-mercapto-1,3,3,4-thiadiazole, 2.5 cm <3> of dimethylformamide are gradually added with stirring. and 104 mg of potassium carbonate anhydride. Stir for half an hour at 20-25 ° C and pour into 10 cm3 of 1N hydrochloric acid and extract with ethyl acetate. Wash with 5% sodium bicarbonate solution, then with water, dry and evaporate to dryness under reduced pressure. Chromatograph the residue on silica, eluting with ethyl acetate-methylene chloride (15:85) to give 147 mg of the desired product.

44 86731

Step B: Syn- (6S) (7S) -7 - [[- 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl] amino] -3 - [-3- [- 5 - (methyl) -1,3,4-thiadiazol-2-yl] thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid

118 mg of the above product and 2.3 cm3 of trifluoroacetic acid are stirred for 20 minutes at room temperature. Add 10 drops at a time of 25 cm3 of anhydride ether, centrifuge, take up the precipitate in 5 cm3 of ether, centrifuging twice each time to dryness under reduced pressure. Take the product in 1 to 5 cm3 of ethanol and 100 .mu.l of pyridine ethanol solution (1M / l), centrifuge, take twice the precipitate in 1 cm3 of ether each time by centrifugation. After drying, 52 mg of the desired product are obtained.

Nuclear Magnetic Resonance Spectrum (DMSO) 6.81 ppm: H5 thiazole 5.64 ppm: H7 4.01 ppm: H6 6.96 and 6.19 ppm: H, ethylene 7.23 ppm: H amino 3.85 ppm: H methoxy 2.68 ppm: H thiadiazole methyl 25 UV spectrum EtOH - 0.1N HCl inflection point 243 nm Ej = 430 max. 267 nm E * = € 580 = 29300 max. 329 nm Ej = 340 <£ = 18800 IR- spectra (nujol)

30 General absorption NH / OH

β-lactam: C = 0: 1759 cm -1 other C = 0: 1660 cm -1 range C = C; C = N 1: 1630 cm-1 amide II J: 1540 cm-1 35 45 86731

Example 14: (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido] -3- [-3- (1H-tetrazole -1-yl-1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and (6S) (7S) -7- [2- (2-5-aminothiazol-4-yl) -2- (Z) -methoxyimino) acetamido] -3- [3- (2H-tetrazol-1-yl) -1- (E) -propenyl] -8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Step A: 1,1-Dimethylethyl 7 - [[(2-tritylamino-thiazol-4-yl) -2- (Z) -methoxyimino) acetamido] -3 - [- 3- (1H-10 tetrazol-1 -yl) -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate and 1,1-dimethylethyl 7 - [[ (2-tritylaminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido] -3 - [- 3- (2H-tetrazol-1-yl) -1- (E) - propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate

230 mg of the isomer obtained in step B of Example 1 are dissolved in 149 mg of tetrabutylammonium iodide and 0.143 cm3 of 2,6-lutidine in 5 cm3 of dichloroethane. Cool to -70 ° C and add dropwise 1.7 cm3 of tri-20-fluoromethylsulfonic anhydride solution (0.42 cm3 of anhydride per 10 cm3 of CH2Cl2). Allow the temperature to rise to 20 [deg.] C., evaporate the solvent and add 44 mg of 1H-tetrazole, 131 mg of potassium carbonate and 3 cm <3> of dimethylformamide.

After stirring for 1 hour and 10 minutes, the solution is poured into water containing 1.5 cm3 of 2N hydrochloric acid and extracted with ethyl acetate. Wash the organic phase with water containing an excess of 0.2N thiosulfate, dry, concentrate to dryness on a silica column, elute with methylene chloride-ethyl acetate, first (75:25), then 30 (50:50). 90 mg of the second isomer (point 2) and 99 mg of the second isomer (point 1) are isolated.

Step B: (6S) (7S) -7- [2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido] -3- [-3- (1H-tetrazole- 1-yl) -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-35 ene-2-carboxylic acid 46 86731

Dissolve 99 mg of the isomer (1-point) in 1.2 cm3 of 66% formic acid. Heat at 65 ° C for 2 hours, cool, dilute with 1.5 cm 3 of water, filter, concentrate the filtrate to dryness, take up the residue in water, filter, rinse with water, then ether to give 49 mg of the desired product.

Nuclear Magnetic Resonance Spectrum (DMSO) 3.87 ppm: H OCH 3 6.11 - 6.41 and δ 6.84-7.0 ppm: H ethylene ΔΕ 6.84 ppm: H5 thiazole syn 5.61 - 5.76 ppm: H7 β-lactam cis UV spectrum EtOH + 0.1 N HCl max 238 nm Ei = 377 £ = 18500 15 max 263 nm Ej = 419 = 20600 ref. 280 nm Ej = 356 max 325 nm Ej = 299 £. = 14700

Step C: (6S) (7S) -7 - [- 2- (2-Arinothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido] -3- [-3- (2H-tetrazole) -1-yl) -20 1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Proceed as in step B starting from 90 mg of the isomer (point 2) to give 31 mg of the desired product.

NRM spectrum (DMSO) δ 3.88 ppm: H 0CH 3 6.11-6.44 and 6.9-7.07 ppm: H ethylene ΔΕ 6.87 ppm: H5 thiazole syn 5.7 ppm: H7 β-lactam cis

30 UV spectrum in EtOH

max 234 nm E3 = 470 £ = 23400 tait. 260 nm E3 = 302 max 320 nm E3 = 303 £ = 15100

Example 15: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido] -3 - [- 3- ( 2-Methyl-47,86731 (1H-imidazol-1-yl) -1- (E) -propenyl] -8-oxo-4-1ia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Step A: 1,1-Dimethylethyl syn- (6S) (7S) -7 - [- 2- (2-tritylaminothiazol-4-yl) -2- (Z) - (methoxyimino) acet-5-amido] - 3 - [- 3- (2-methylimidazol-1-yl) -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic salicylate

Proceed as in Example 13, Step A, starting from 62 mg of 2-methylimidazole to give 82 mg of the desired product 10.

Step B: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) acetamido] -3 - [- 3- (2 -methyl-1H-imidazol-1-yl) 1- (E) -propenyl] -8-oxo-4-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 15 Heated above the product obtained and 1 cm3 of 66% other monetary acid for 3 hours at 60-65 [deg.] C., evaporated to dryness at 30 [deg.] C. under reduced pressure, take up twice the residue in 5 cm <3> of water, evaporate to dryness. Take up the residue in 7 cm3 of ether, stir for half an hour, centrifuge at 20 to give 41.5 mg of the expected product.

Nuclear Magnetic Resonance Spectrum (DMSO) 3.85 ppm: OCH 3 6.55 - 6.61 ppm (dJ = 16): H ethylene ΔΕ 25 5.58-5.64 ppm (m): H 7 β-lactam cis 7.13 ppm: H5 thiazole UV spectrum EtOH + 0.1N HCl ref. 217 nm max 238 nm £. = 17300 max 264 nm £ = 19100 tait. 281 nm max 327 nm ε = 13100

Example 16: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [[(5-thiomethyl) -35 L , 3,4-Thiadiazol-2-yl] thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 48 B 6 7 31

Proceed as in Example 13 starting from 2-mercapto-5-thiomethyl-1,3,4-thiadiazole, eluting by chromatography with methylene chloride / ethyl acetate (95: 5) and then (9: 1). After deblocking and purification of the functional groups, 69 mg of the desired product are obtained.

NMR spectrum (DMSO) 6.81 ppm: H5 thiazole syn 3.85 ppm: OCH3 5.64 ppm: H7 β-lactam cis 6.18 and 6.98 ppm: H ethylene trans 2.74 ppm: S-CH3 UV spectrum 1) EtOH + (1 cm 3 DMSO) max 298 nm λί = 378 £ = 22100 δ. 320 nm e \ = 350 £ = 20500 2) EtOH - 0.1 N HCl max 280 nm E * = 469 £ = 27500 max 330 nm E3 = 310 £. = 18200

Example 17: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetarido] -3 - [[-3- (5-methylthio) ) - 1,3,4-thiadiazol-2-yl] thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2- karboksyy1ihappo

Proceed as in Example 13 starting from 184.5 mg of the E-isomer obtained in Step B of Example 1 using 66.6 mg of 2-amino-5-mercapto-1,3,4-thiadiazole in dimethylformamide. Elute by silica chromatography with methylene chloride-ethyl acetate (1: 1). The trifluoroacetic acid blocked functional groups are liberated to give 60.5 mg of the desired product.

NMR Spectrum (DMSO) 6.82 ppm: H5 thiazole 3.86 ppm: OCH3 5.64 ppm: H7 β-lactam cis 6.90 ppm (dJ-1.5) δ 6.15 ppm (d- + J = 7.5 and 15): H ethylene ΔΕ 49 86 731 UV spectrum

1) EtOH

max 287 nm E * = 411 £ = 22800 tait. 282 nm E * = 309 δ max 322 nm E {= 312 £ = 17300 2) EtOH - 0.1N HCl max 271 nm Ej 472 £ = 26200 max 330 nm Ej = 285 = 15800

Example 18: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [[- 3- (9H-purine)] -6-yl) thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Proceed as in Example 13 using 76 mg of 6-mercaptopurine. Chromatograph the product on silica, eluting first with methylene chloride-ethyl acetate (75:25), then with ethyl acetate only and finally with methyl chloride-methanol (95: 5). Deprotect to give 76 mg of the desired product.

NMR spectrum (DMSO) δ 6.82 ppm (s): H5 thiazole 5.64 ppm: H7 β-lactam cis 6.26 ppm). AT, y: H ethylene ΔΕ 7.06 ppmj UV spectrum

1) EtOH 0 2 cm3 DMSO

max 240 nm E3 = 401 £ = 23000 max 292 nm Ei = 423 £ = 24300 max 320 nm Εϊ = 311 L · = 17800 fold. 257, 410 nm 2) EtOH - 0.1N HCl. 240 nm Ej = 319 tait. 264 nm Ei = 375 max 287 nm = 475 £ = 27200 max 323 nm Εί = 286 £ = 16400 so 86731

Example 19: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [[-3- (1,3, 4-Thiadiazol-2-yl) thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 5 Proceed as in Example 13 using 59.1 mg of 5-mercapto-1,3,4-thiadiazole to give 47.1 mg of the desired product.

Nuclear Magnetic Resonance Spectrum (DMSO) 6.85 ppm: H5 thiazole 3.87 ppm: OCH3 5.65 ppm: β-lactam cis 6 f 01 ppm "V,. H ethylene ΔΕ

7.06 ppm J

UV spectrum 15 EtOH - 0.1N HCl. 241 nm Ej = 335 max 269 nm Ej = 425 £ = 22900 max 329 nm E} = 278 £ = 15000

Example 20: Syn- (6S) (7S) -7- [2- (2-aminothiazol-4-20 yl) -2- (methoxyimino) acetamido] -3 - [[- 3- (1,2, 3-Triazol-5-yl) thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Proceed as in Example 13 starting from 5-mercapto-1,2,3-triazole using sodium thiolate without the addition of potassium carbonate. Chromatography is eluted with methylene chloride-ethyl acetate (75:25). Deprotection is carried out with formic acid: 2 cm3 (66%) for 149 mg of protected product. Stir for 3 hours at 60-65 ° C, remove formic acid at 30 ° C under reduced pressure, take up in water twice and evaporate each time. Triturate the residue with ether, centrifuge to give 89 mg of product, which is dissolved in 6 cm3 of tetrahydrofuran and 1 cm3 of methanol. Add this solution drop by drop to 100 cm3 of ether, shaking vigorously, centrifuge to give 69.5 mg of the desired product.

s1 86731 NMR Spectrum (DMSO) 6.81 ppm (s): H5 thiazole syn 3.85 ppm (s): OCH3 5.63 ppm: H7 β-lactam cis δ 6.76 ppm 1: H ethylene ΔΕ

6.08 ppm J

UV spectrum EtOH - N / 10 HCl max 240 nm E3 = 396 f- = 20700 max 266 nm Ej = 416 £ = 21700 10 ref. 282 nm E3 = 387 max 328 nm E3 = 320 t- = 16700

Example 21; Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [- 3 - [[- 4-methyl-5- Trifluoromethyl-4H-1,2,4-triazol-3-yl] thio] -1- (E) -prop-15-phenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2 ene-2-carboxylic acid

Proceed as in Example 13 using 90 mg of 4-methyl-5-trifluoromethyl-4H-1,2,4-triazole-3-1-ion. Chromatograph on silica, eluting with methylene chloride-20-diethyl acetate (75:25). After 66% formic acid treatment, 78 mg of the desired product are obtained.

NMR Spectrum (DMSO) 3.67 and 3.85 ppm: N-CH3 and O-CH3 5.64 ppm: H7 β-lactam cis 6.2 and 6.89 ppm: H ethylene ΔΕ 6.81 ppm: H5 thiazole UV- spectrum of EtOH - 0.1N HCl. 240 nm E * = 328 max 260 nm Ei = 345 £ = 20900 30 ta. 280 nm e = 303 max 326 nm Ej = 215 £, = 13000

Example 22: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [- 3 - [(thiazolo [5 (4-b] pyridin-2-yl) thio] -1- (E) -propenyl] -8-oxo-4-thia-35'-azabicyclo [4.2.0] oct-2-ene-2- carboxylic acid 52 86731

Proceed as in Example 13 using 205 mg of 2-mercapto-thiazolo [5,4-b] pyridine. Chromatograph and elute with methylene chloride-acetone (9: 1). Deprotection is performed with 150 mg of the product obtained with formic acid to give 67 mg of crude product. Chromatograph on silica 45 mg of the latter, eluting with ethyl acetate, and acetone-ethylacetyl-water (5: 4: 1). 17 mg of the desired product are obtained.

NMR spectrum (DMSO) δ 6.79 ppm: H5 thiazole 3.84 ppm: 0CH3 5.54 ppm: H7 β-lactam 5.98 and 7.27 ppm: H-ethylene IR spectrum (nujol)

15 General absorption in the OH / NH range

^ C = 0 β-lactam: 1754 cm-1 fold. : 1660 cm-1 max: 1650 cm-1

In the range -C = C, ^ C = N "Λ strong abs.

20 aromatic C 1580 cm -1, 1620 cm -1, NH def. amide II and 1535 cm -1 in the range -CH = CH-: 975 cm -1

Example 23: Syn- (6S) (7S) -7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [- 3 - [[- 1H-1 , 2,4-25 triazol-3-yl] thio] -1- (E) -propenyl] -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Proceed as in Example 21 using 50 mg of 1H-1,2,4-triazole-3-thione to give 62 mg of the desired product. NMR Spectrum (DMSO) δ 5.56-5.71 ppm: H7 β-lactam cis 6.04 - 6.4 ppm ia]. „Ethylene ΔΕ

6.84 - 7.02 ppm J

6.84 ppm: H5 thiazole syn

UV spectrum in EtOH

35 max 234 nm Ej = 481 £ = 25100 max 320 nm E} = 323 £ = 16900 53 86731

Example 24: Syn- (6S) (7S) -2 - [- 3-7 - [- 2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -2-carboxy- 8-Oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] -2- (E) -propenyl] isoquinolinium inner salt 5 Proceed as in Example 21 from 148 mg the E-isomer obtained in Step B of Example 1. After addition of trifluoromethanesulphonic anhydride and distillation of the solvent, 5 cm3 of acetonitrile and 52 μΐ of isoquinoline are added. After 1 hour and 15 minutes, the acetones are evaporated off, the residue is taken up in ethyl acetate, washed with water containing an excess of 0.2N sodium thiosulphate, washed with water, dried and concentrated to dryness. Chromatograph the residue on silica, elute with methylene chloride-methanol (92: 8) and isolate 83 mg of the protected intermediate. After treatment with 66% formic acid and evaporation of the solvent, the residue obtained is taken up in 1 cm3 of acetonitrile and 1 cm3 of 1M triethylamine solution and chromatographed on silica, eluting first with aqueous acetonitrile (9: 1) and then (85:15). 16.76 mg of the desired product are obtained.

Nuclear Magnetic Resonance Spectrum (DMSO) 3.83 ppm: OCH 3 5.45 ppm: H7 and CH2-1 ^ 6.79 ppm: H5 thiazole 5.91 to 7.42 ppm: H ethylene ΔΕ

UV spectrum in EtOH

max 224 nm λί = 951 L · = 52400 tait. 232 nm E3 = 840 nm. 262 nm λ = 296 30 tait. 277 nm E3 = 252 max 289 nm E3 = 226 £ = 12400 max 323 nm E3 = 280 £. = 15400

Examples 25-39:

The products in the tables below have also been obtained by the process of the invention.

54 8 6 7 31

L ·. I I II I

E.g.

I n: o I R I I n2 I CO2A 1-L ~ = t-1-1-1-1 51 IΛ. 1 11 1

I I \ szJ COW- I I o I CO2H I

, I jj I 0 II I

I I No I II I

1! 1! ! ! "! -! ! - ^!

II II I

. 27 I I I "I CO Θ I

1, j © K. · »Ill III 11 1

15 I 1 I II I

1 28 1 2 3 »» CO.H

I I I I I 2 I

I I 1 1 1 1 1 11 11 1 20 I 29 '"^ ^' CO H '

1 I I I I 2 I

I I I «is« se® I I I

j I I II I

30 I "I I" I co ® I

95 I I I 0 ^^ CH, I I 2 I

2

I I I II I

3

II I

III II I

I 1_I_I- I_I

55 86731 i i i i j i

| Eg | R | R. I n, | CO, A I

n: o.

I I I I I I

.31 I V ^^ CONH- I I Q I co2H I

I I w I fr0 I I I

5 I X 1 1 1

| l ίΗΗ @ 11 I

I I I II I

I I I w-n I I I

, I I I I I

I 32 I '· I & I ·· I co h I

1 I I Mil I

I I I »C Ϊ" I I I

I I I HO- <0) -C = 0, I I

I 1 (W_N

33 I .. I v ^ x'S-C ^ S-tHi I., I CO H I

15 I I J '° I I I

1 I I 3 Ö) 2> I I I

I I I H3c-fr ° I I I

t I I 0 || I

I I I 5 _ * - * 1 1 1

20 I 34 I "I 5 c = 0! - I CO h I

I I 'I * *

I I I J Θ "-7 I I I

I © 1 1 ‘^ -NgVs 1 1 1

2 5 i 35 I W, rMNH- I KAch I m I co 'I

I I X I II I

I I ° N <^ I II I

ill II I

II II I

30 I I »X I m_n I I I

• 36 I Q COMH- I I "I C02H I

I I If I CKJ I 1 I

I I \ I II I

I CW | I I I

35 I I. 1

I_I_I_I_I

56 86731 i j i | j |

I R | R, I nj | C02A I

I_I_I_I I_I

I 37 I 54 £ 1 I I I I

5 I I I I 0 | co2h I

I I I I I I

I | 2 CH3 I || I

III II I

II I <&> I I I

10 I 38 I "I I" I CO H I

• I I u ^ o £> I I I

l || II I

III II 1 is li r * · I ii i

I I 5 'N I JJ - "* I I I

I 'L = i .C3NH- I' V-OH I "I CO H I

I! ! I I I I

I I \ I ^ I I I

,, «3, I, I

I_1_I I_I

Claims (10)

57 86731 Claim A process for the preparation of therapeutically useful 7 - [(2-amino-4-thiazolyl) -2- (substituted imino) acetylamino] -2-carboxy-3- (substituted propenyl) -8-oxo-4-thia- For the preparation of the syn-form of 1-azabicyclo [4.2.0] oct-2-ene derivatives of formula (IA) NHO 10 Λ S CONH (Ia> v N | -rs o cr | 15 ^ R1 C ° 2A where A is a hydrogen atom , an alkali metal equivalent, an alkaline earth metal equivalent, a magnesium equivalent, an ammonium equivalent, an aminated organic base equivalent or an ester group such as a t-butyl group, or CO 2 A represents a CO 2 "group R 'is an alkyl radical having up to 6 carbon atoms which may be substituted with halogen atoms or carboxy, or R * is an alkenyl radical having up to 6 carbon atoms, ZA is a single bond, a sulfur atom or an oxygen atom, and A) when ZA is a single bond, R'3a is thienopyridinium, thiazolopyridinium, imid azopyridinium, cyclohexenopyridinium, tetrahydroquino-30 linium, isoquinolinium, trimethylammonium, diazabicyclooctyl, tetrazolyl or imidazolyl group which may be substituted by C 1-4 alkyl or amino, B) when ZA is a sulfur atom, r, 3a is pyridinium, thiazolopyridinyl, triazole 35 yl, tetrazolyl, thiadiazolyl, purinyl or 58,867,731 thiazolopyridinyl groups which may be substituted by C 1-4 alkyl, trifluoromethyl or thiomethyl, or R? 3A On 5, NN-NN-NM-MA Ah 'As ^ f- cii2> <. JO L> * x λκ S I ^ N g I c = 0 I oo c = o A ch2 | _I O] C = 0 H3C (n_'a ^ / 0V) H3C'NO) 10 NH 0 3- '- ho «3C-CC 2 <00 ° 0 N-N 15 VoH O A-ci and C) when ΖΛ is an oxygen atom, R'3r is an acetyl, carbonyl or carbamoyl group, and for the preparation of their salts with inorganic and organic acids, characterized in that a) a compound of formula (X ') NHC (C6H5) 3 S '^ N τη ^^ ^ CONH T VO \ A- nvAA OH oo I ^ R. CO 2 A 35 59 8 6 7 31 In which R 'and A have the same meaning as above, is reacted with a compound containing a group R'3a, such as a halide or anhydride, after which the amino protecting group is removed to give a compound of formula (IA) 5 in which Z is an oxygen atom, i.e. of the formula (XI'A) NH-AS 10 - (^ 'CONH \ o ^ A ^ V- ° R'3A (XI'A> CO 2 A react with a hydroxy activating compound such as trifluoromethylsulfonic anhydride and then with a compound containing R'3a such as a halide or anhydride, after which the amino protecting group is removed to give a compound of formula (IA) wherein Z is a single bond, i.e. (XI'B) 25 NH _ sa; Or c) compound (X ') is reacted with a hydroxy group activating compound such as trifluoromethylsulfonic acid anhydride 60 86731 followed by a compound of formula HS-R'3A or with its reactive derivative, after which the amino protecting group is removed to give a compound of formula (IA) wherein Z is a sulfur-5 atom, i.e., of formula (XI'C) NH-AS-A ^^ conh / SR, 3a (XI ' c) 0. I - 1 - R (C02A) not 86731 For the preparation of therapeutically active compounds 7 - [(2-amino-4-thiazolyl) -2- (substituted amino) -5-acetylamino] -2-carboxy-3- (substituted) propenyl) -8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-ender with formyl (IA) syn-form, NH-I 2 10 S '' 'N \ - = - i ^ CONH i) —rs (ia) Nv, / 1 ^ .Z ^ -R' \ Nn / W A 3A 0 o | \. CO _A 15 R 2 for A is an atomic atom, an alkali metal equivalent, an alkali metal equivalent, an magnesium equivalent, an ammonium equivalent, an amine organic base equivalent or an ester group, a t-butyl group, or a C02A alkyl group C02 ', R' is in alkyl radicals having up to 6 colaters, which may be substituted by halogen atoms or carboxy, or R 'is in alkenyl radicals, 25 A is not a publication, which is a hydrogen or a cyanogen, and A) A is a publication, which is R'3a and thienopyridinium, thiazolopyridinium, imidazopyridinium, cyclohexenopyridinium, tetrahydroquinolinium, isoquinolinium, trimethylamine diazabicyclooctyl, tetrazolyl or imidazolyl, a single substituent of C 1-4 alkyl or amino, B) a ZA is an envelope atom, an R'3a is pyridinium, thiazolopyridinyl, triazol-35-yl, tetrazolyl , thiadiazolyl, purinyl or thiazolopyr- 62 86731 ridinyl, an active substituent of C 1-4 alkyl, trifluoromethyl or thiomethyl, or R'3A is N-NN-NF ~ C = 0 IC = 0 C = 0 (°) P "--'ΗΞι> NH - 'I HoC-CO I © H Cl NH J II 10 ho-h (^ Vc = o 0 NN —V-OH 1 * 15 (0> -ci och C) to ZA is a cyanogen atom, is R '3A to an acetyl-, carbonyl- or carbamoyl group, the same is obtained with organic and organic syrups, 20 kännetecknat därav, att a) en förening med formeln (X') NHC (C6H5) 3 25 H / CONH ^ T vos (X,) \ J— -OH 0 o | co2a 30 of R 'och A a betecknar samma som ovan, omsätts med en fö-rening, somehehehlener Gruppen R'3A, säsom en halogenid ell anhydride, varefter aminooskydsgruppen avlägsnas förställning av en sädan förening med formeln (IA), där en syreatom och som har formeln (XI'A) 63 86731 NH_ Λ S c .CONH vr * \ 0 ^ ~ NYi ^ \ ^ 0R'3A (XI'A> \> co2a 10 eller b) föreningen (X ') omsätts in the case of compounds having an hydroxyl group, a trifluoromethylsulfonic anhydride group, and a further mixture of compounds having a group R'3A, halogenated halides or anhydrides, a different amino acid group from the formulation ), in which case there is an encapsulation and some form (XI'B) 20 ^ 'H2 Λ S ^ - = - ί .CONH ΊΓ VO <xrB »co2A or c) föreningen (X') omsätts med en förening, som 30 active hydroxyl groups, such as trifluoromethylsulfonic anhydride, and further prepared with the formula HS-R'3a, or and that the reaction cable is derived from a group of amino acids in the form of a compound of formula (IA), a mixture of compounds of formula (35'C) 64 86731 NH Λ SN Ί Cl qR, (χΐ ' α> \ Jr- / SR 3Δ 0. j '"“ ri C02A 10