NO165109B - Cephalosporin compounds. - Google Patents

Description

The present invention relates to a cephalosporin compound which is characterized by having the general formula:

where Z means Cl or I.

Preferably, Z represents chlorine.

3-formylcef-3-em compounds, which are used as intermediates in a process for the production of 3-substituted vincephalosporins, can be produced by oxidation of the corresponding 3-hydroxymethylcef-3-ems, which are obtained by enzymatic hydrolysis of the corresponding cephalosporins. This method is known from Chamberlain, US-PS 3,351,596

which, among other things, deals with compounds II and III.

Chamberlin (loe.sit.) described derivatives of the 3-CHO group with carbonyl reagents such as semicarbazide and hydroxylamine, but there was no mention of carbonylation of the 3-CHO group.

The corresponding sulfoxides are more stable and can be prepared

In better yields (Webber, GB-PS 1,341,712).

The first mention of 3-alkenyl-substituted cephalosporins was by Clark et. al.<1> 1 GB-PS 1,342,241 corresponding to US-PS 3,769,277 and 3,994,884). Compounds IV and V are discussed on pages 25 and 29 of GB-PS 1,342,241.

These compounds were prepared by reacting the corresponding 3-triphenylphosphonium methyl-cephalosporin with formaldehyde or acetaldehyde. The reverse process consisting of the reaction of a phosphoranylidene derivative of the formula R3P=CR<3>R<4> with a 3-CHO-cephalosporin is also discussed in the said patent on page 5. In US-PS 4,107,431 it is noted that the compound of formula IV is absorbed by oral administration.

Another earlier mention of compounds of this type was by Webber et.al. "J.Med.Chem." 18 (10) 986-992 (1975) and in US-PS 4,065,620, where in columns 3, 4 and 5 the substance group to which the present compounds belong is mentioned. Particularly mentioned compounds are shown in formula VI.

Other variations of this type are referred to in US-PS 4,094,978, 4,112,087, where connection points VII and VIII are discussed.

Other substituted 3-alksnyl cephalosporins are discussed in the following patents:

US-PS 3,830,700: 3-(nitrostyryl)cephalexin analogs.

US-PS 3,983,113, 4,049,806, 4,139,618: 3-(heterocyclothio)

propenyl cephalosporins,

US-PS 4,147,863: 3-(heterocyclothio)propenyl-cephalosporins, DE-OS 3,019,445: 3-(1-methyl-5-1etratoyl)vinyl-cephalosporins,

FR-PS 2,460,302: 3-(dimethylamino)vinyl-cephalexin analogues, EP-PS 30,630; 7-[(3-methanesulfonamidophenyl)-α-aminoacetamido]-3-vinylcef-3-em-4-carboxylic acid, US-PS 4,255,423 and 4,390,693: 7-(2-thienyl)acetamido- 3-(3-acetoxy-1-propenyl) and -3-(heterocyclovinyl)cef-3-em-4-carboxylic acids, and 7α-methoxy analogs.

The most important commercially available and orally active cephalosporins, which have the same application, are cefalexin, cedroxil, cefadrin and cefaklo. These compounds have the formulas IX, X, XI and XII.

These compounds are the subject of the following patents: Cephalexin: US-PS 3,507,861

Cefadroxil: US-PS 3,489,752

(Re 29 164 )

Cefaclor: US-PS 3,925,372

Cefadrine: US-PS 3,485,819

Related compounds described are 3-chloro-cefadroxil and 3-hydroxycefadroxil, respectively in US-PS 3,489,751 and GB-PS 1,472,174.

The compounds according to the present invention are used for the preparation of compounds with the general formulas XIII and

XIV

In these formulas are:

n 0 or the whole number 1,

R<1> hydrogen, OP<3>, lower alkoxy or halogen such as chlorine, bromine, fluorine and iodine,

P<1>, P^ and P<3> hydrogen atoms or conventional protecting groups, which are used in cephalosporin chemistry on amino, carboxy and hydroxy groups respectively,

R<2> hydrogen, OP<3> or lower alkoxy,

Alk is an alkylidene or alkylene group that contains from 1-4 carbon atoms and

x chlorine, bromine or iodine.

The compounds where n is P<1>, P<2> and P<3> are conventional protecting groups, are intermediates for the preparation of biologically active end products shown by the general formula XIII, when n is 0 and P<1 >, P<2> and P3 are hydrogen. These compounds are interesting as orally effective cephalosporin antibiotics with a strong activity against gram-positive bacteria and an improved spectrum of activity against gram-negative bacteria, various "picky" bacteria and anaerobes compared to cephalexin, cefadroxil, cefaclor and cefadrin. They provide a higher concentration of antibiotic in the bloodstream when administered orally and are suitable for administration to humans once or twice daily. As such, they are prescribed in doses of 100-5,000 mg per day, depending on the size of the patient and the state of the disease. They can be administered parenterally in corresponding dosage amounts.

Compounds of the general formula XIV are mainly of interest as intermediates. However, where n is 0 and , P<2> and P<3> are hydrogen, they contain antibacterial activity and are also useful as antibiotics.

In view of these properties, compounds of the general formulas XIII and XIV, where n is 0 and P<*>, P<2> and P<3> are hydrogen, are useful in the treatment of bacterial infections caused by susceptible organisms in mammals. For this purpose, they are administered orally or parenterally in antibacterially effective, non-toxic doses or in the form of their pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal or amine salts or as a pharmaceutically acceptable ester.

The pharmaceutically acceptable acid addition salts are those in which the anion does not contribute significantly to the toxicity of the salt, and which are compatible with the usual pharmaceutical carriers and adapted for oral or parenteral administration. They include the salts of compounds with the general formulas XIII and XIV, where n=0 and P<1> is hydrogen, with mineral acids such as altic acid, hydrobromic acid, phosphoric acid and sulfuric acid, with organic carboxylic acids or organic sulphonic acids such as acetic acid, cltronic acid, maleic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid and other known acids, which are used in penicillin and cephalosporin chemistry. The preparation of these salts takes place by the conventional technique which involves the reaction of one of the compounds of the general formulas XIII and XIV, where n ■ and P<1> are hydrogen, with the acid in an almost equivalent amount.

Pharmaceutically acceptable metal and amine salts are equivalent to those salts of compounds with the general formulas XIII and XIV where n is 0 and P<2> is hydrogen and which are stable in the surrounding environment, and where the cation does not contribute significantly to the salt's toxicity or biological Activity. Suitable metal salts are the sodium, potassium, barium, zinc and aluminum salts. The preferred are the sodium and potassium salts. Amine salts prepared from amines used for example with benzylpenicillin and capable of forming stable salts with the acidic carboxyl group are trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyi-p-phenethylamine, 1-epehenamine, N ,N'-dibenzylethyldiamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine and dicyclohexyamine.

Pharmaceutically acceptable esters are those esters which are active in themselves, or serve as pre-drugs by being hydrolysed in the body, thereby providing the desired antibiotics. Suitable esters of the latter type are phenacyl, acetoxymethyl, pivaloyloxymethyl, o-acetoxybenzyl, a-pivaoyloxyethyl, Q-acetoxyethyl, 3-phthalidyl, 5-indanyl, methoxymethyl, benzyloxymethyl, a-ethylbutyryloxymethyl, propionyloxymethyl, valerioxymethyl, isobutyryloxymethyl , glycoloxymethyl and others known from penicillin and cephalosporin chemistry.

The preparation of the compounds according to the invention shall be illustrated by the following examples.

Example 1

Benz yhvdrvl- 7e- rP- 2-( t- butoxxvcarbonvlamlno )- 2-( p- hvdroxv- phenvl )- acetamldo1 - 3- chloromethyl- 3- cephem- 4- carbox, vlat (Compound 3).

To a mixture of 20.7 g, 0.05 mol, benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate 2 and 20 g 0.075 mol D-2-(t-butoxycarbonylamine)-2-( p-hydroxyphenyl)-acetic acid in 500 mL dry tetrahydrofuran (THF) was added 15.45 g, 0.075 mol, N-N'-dicyclohexylcarbodiimide (DCC), and the mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue is dissolved in ethyl acetate (AcOEt), and the soluble dicyclohexylurea was removed by filtration. The filtrate was washed with an aqueous sodium bicarbinate solution, water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue is chromatographed on a silica gel column (Wakogel C-100, 500 g) by elution with 4 1 chloroform and 6 1 1 96 chloroform-methanol. The desired fractions are combined and evaporated. to dryness. The oily residue was triturated with ether-isopropyl ether to give 30.6 g of 92 <$ >, of 3.

KB r

IR: V cm-<1>: 1790, 1710, 1670, 1500, 1360, 1230, 1150.

max.

SCDC13

NMR: ppm: 1.45 (9H, s, C-CH3), 3.4 (2H, br-s,

2-H), 4.28 (2H,s,CH2Cl), 4.86 (1H, d,4.5 Hz, 6-H), 5.12 (1H, d, 6Hz, CH-CO), 5 .68 (1H, dd, 8 & 4.5, Hz, 7-H), 6.63 (2H, d, 9Hz, phenyl-H), 6.93 (1H, s, CH-Ph2). 7.08 (2H, d, 9Hz, phenyl-H), 7.0-7.5 (10H, m, phenyl-H).

The oily residue can be used in example 4 without chromatographic purification.

Example 2

Benz h. vdrvl- 7P- fD- 2- ( t-butoxxvcarbonvlamlno )- 2-( p- hvdroxv-phenyl ) acetamido1 - 3-. 1-odmetvl- 3- cephem- 4- carboxvlat

(Compound 4).

A mixture of 26.6 g (0.04 mol) of 3 and 18 g (0.12 mol) of sodium iodide in 400 ml of acetone is stirred at room temperature for 2 hours and evaporated to dryness. The residue is extracted with 400 ml of ethyl acetate, and the extract is washed with an aqueous NaCl solution. After evaporation of the solvent, the mixture is triturated with ether-isopropyl ether to form 27 g (89%) of the title product. If desired, the ethyl acetate solution can be used directly in the next step, compound 5., without isolation of compound 4.

KB r

IR: V cm-<1>: 1790, 1710, 1670, 1500, 1360, 1220,

max.

1150.

NMR: s CDCl 3

ppm: 1.47 (9H,s, C-CH3), 3.3-3.6(2H,m,2-H), 4.20 (2H,s,CH2), 4.89 (lH,d ,4.5 Hz, 6-H),5.12 (lH,d,6Hz, CH-CO), 5.68 (lH,dd,8& 4.5 Hz,7-H), 6.62 (2H , d, 9Hz, phenyl-H), 6.92 (1H, s, CHPh2). 7.08 (2H, d, 9Hz, phenyl-H), 7-7.5 (10H, m,phenyl-H).

Regarding the use of the present compounds in the production of therapeutically active cephalosporins, reference should be made to NO-PS (840334) and (850080).

Claims (2)

1. Cephalosporin compound, characterized in that it has the general formula: 2. Cephalosporin compound according to claim 1, characterized in that Z denotes Cl.