DE2430375A1 - Antibacterial 7-amino-delta-3-cephem-4-carboxylic acid derivs. - prepd. by reacting thio amide deriv. with a 7-amino-cephem-4-carboxylic acid deriv - Google Patents

Abstract

7-Amino-delta3-cephem-4-carboxylic acid derivs. are of general formula (I): where R1, R2 and R3 are same or different aliphatic hydrocarbon, mono- or bicyclic carbocyclic aryl, aralkyl, cycloalkyl, cycloalkylalkyl, a heterocyclic group or a heterocyclic substd. alkyl; R1+R2+N and R1+R3+N may form a ring-system; or R3=H; R4=H, halogen, hydroxy, alkoxy, acyloxy, carbomoyloxy opt. substd. at one- or two-N-atoms, alkylthio, heterocyclic thio, trialkylaminonium, pyrimidinium opt. ring-substd. thioronium, amidinothio opt. alkyl(1-3C)-substd. at the N-atoms, N-substd. aminothiocarbonylthio, arylthio, alkoxythiocarbonylthio, alkarysulphonyl, acido, amino, amido, polyhydroxyphenyl, indol3-yl opt. substd. at the N-atom with alkyl(1-3C) or thiocyanoalkyl; R5=H or opt. substs. alkyl, aralkyl or acyloxymethyl. Pharmacologically-acceptable salts as well as all isomeric forms of (I) are included. (I) have high antibacterial activity with low toxicity.

Description

Description of the patent application 7-Amino- # ³-cephem-4-carboxylic acid derivatives The invention relates to new derivatives of 7-amino- # ³-cephem-4-carboxylic acid, their pharmacologically acceptable salts and processes for their preparation.

The compounds according to the invention have the general formula in R1 R2 and R3 respectively. are identical or different and each represent an aliphatic hydrocarbon radical, a mono- or bicyclic carbocyclic aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylaalkyl group, a heterocyclic group or a heterocyclically substituted alkyl group, R1 and R2 together with the nitrogen atom form a ring system, R1 and R3 together with the nitrogen and carbon atom is a ring system, also R3 is a hydrogen atom, R4 is a substituent as is known for the methyl group in the 3-position of the cephalosporin system, such as a hydrogen or halogen atom, a hydroxyalkoxy or acyloxy group, a carbamyloxy group, which is optionally substituted on one or two nitrogen atoms, an alkylthio group, a heterocyclic thio group, a trialkylammonium group, a pyrimidination group which is optionally substituted in the ring, a thiouronium group, an amidinothio group which is optionally substituted on the nitrogen atoms with alkyl groups it is substituted by 1 to 3 carbon atoms, an N-substituted aminothiocarbonylthio group, an arylthio group, an alkoxythio-carbonylthio group, an alkarylsulfonyl group, an acido-amino or amido group, a polyhydroxyphenyl group, an indol-3-yl group, which may optionally be connected to nitrogen by alkyl groups 1 to 3 carbon atoms is substituted or a thio c yanoalkyl group and R5 is a hydrogen atom or a substituted or unsubstituted alkyl, aralkyl or an acyioxymethyl group.

Preferably R1, R2 and R3 denote an aliphatic hydrocarbon group, in which the carbon chain is straight or branched, saturated or unsaturated 3ein can, for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, dodecyl, allyl, butenyl, pentenyl or propagyl group, a mono- or bicyclic aryl group, for example a phenyl or naphthyl group, an aralkyl group such as a mono- or bicyclic aralkyl group, for example a bemzyl, phanylethyl, 1- or 2-naphthylmethyl group, a cycloalkyl or Cycloalkylalkyl group in which the cycloalkyl group has 3 to 10 ring members and can be saturated or contain 4 or 2 double bonds, for example a cyclopentyl, Cyclohexyl, 1-adamentyl, 1-bicyclo (2,2,2) octyl, Cyclopentenyl, cyclohexenyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentenylethyl, Cyclohexenylmethyl group, etc., a heterocyclic group or a heterocyclic substituted alkyl group in which the heterocyclic part is more or less hydrogenated and contains 5 to 10 atoms in the ring and oxygen, sulfur or nitrogen atoms may contain, for example a pyridyl, pyrazinyl, pyrirnidyl, pyrrolidyl, Piperidyl, morpholinyl, thiazinyl, furyl, thienyl or quinolyl ring, where in any case the hetero-atoms can be located anywhere, and R1 and R2 together with the nitrogen atom and R1 and R3 together with the nitrogen atom uiid carbon atom is a heterocyclic ring with 5 to 10 atoms, which is optionally contains even more hetero atoms in the ring, such as S, OW or N atoms and more or is less hydrated, for example a piperidyl-, morpholiyl-, hexahydro-1H-azepin-1-yl or hexahydro-1- (2H) -azocinyl ring. The groups R1, R2 and R3 can be further substituted be through halogen atoms, alkyl, hydroxy, alkoxy, alkylthio, acyl, carboxyl, Carbalkoxy, carbamyl, carbamido, cyano, sulfonyl, or amino or substituted Amino groups.

R4 preferably denotes a hydrogen or halogen atom, a hydroxy, lower alkanoyloxy, carbocyclic or beterocyclic arylcarbonyloxy, aralkanoyloxy, cycloalkanecarbonyloxy, α-methoxy-p-sul foxycinnamoyloxy or α-methoxy-p-hydroxycinnamoyloxy group, a Carbamyloxy group of the formula -OOCNR6R7, in which R6 and R7 each have a hydrogen atom, a lower alkyl, halo-lower alkyl, lower alkoxycarbonyl, aryl, alkarylsulfonyl group, for example a p-toluenesulfonyl, benzhydryl group or together with the The nitrogen atom to which they are bonded denotes a heterocyclic group such as a pyrrolidinyl, piperidyl or morpholinyl group; a thio group of the formula -SR; in which it3 is a lower alkyl, aryl or heterocyclic group, such as a pyridyl, lower alkyl-thiazolyl-, 1,3,4-thiadiazol-2-yl-, 5-alkyl- 1,3,4-thiadiazol-2-yl, 2-benzothiazolyl or 4-lower alkyl-pyrimidinyl-2-group, an alkanoyl, aralkanoyl or carbocyclic or heterocyclic arylcarbonyl-tri (lower / alkyl) -ammonium or Pyridinium group of the formula in which X1 is a hydrogen or halogen atom or a trifluoromethyl, cyano, carboxy, carbamyl, N-lower-alkylcarbamyl-, N, N-di-lower-alkylcarbonyl-, carboxymethyl-, lower alkanoyl-, lower alkyl- , Denotes hydroxymethyl or sulfo group; a thiouronium group, an amidinothio group of the formula in which R9, R10 and R11 are a hydrogen atom or a lower alkyl group, an aminothiocarbonylthio group of the formula in which R12 and R13 are a hydrogen atom, a lower alkyl-hydroxy-lower-alkyl-, di- (lower alkyl) -amino-lower-alkyl-,. Morpholino-lower-alkyl-NA ryl-N-lower alkylaminoalkyl group or together with the nitrogen atom to which they are attached, a heterocyclic group such as a morpholinyl, piperidyl, pyyrolidyl or a piperazinyl group of the formula in which R14 is a lower alkyl or phenyl group, an alkoxythiocarbonylthio group of the formula in which R15 is a lower alkyl or lower cycloalkyl group; an alkarylsulE onyl, azido or a group of the formula in which R16 is a hydrogen atom or an alkyl group and R17 is a hydrogen atom, an aryl, lower alkanoyl, aralkanoyl group or R16, R17-N is an imidazole or alkylimidazole group; a polyhydroxyphenyl group, an N-lower-alkylindol-3-yl group or a thiocyano group.

When R5 is an alkyl or aralkyl group, it is preferred a lower alkyl and aryl-lower alkyl group or an alkyl group represented by Halogen or cyano groups is substituted, for example a methyl, ethyl, tert.

Butyl, benzyl, diphenylmethyl or triphenylmethyl, chloromethyl, ß, ß, ß-trichloroethyl or cyanomethyl group; in addition, R5 can be an acyloxymethyl group mean whose acyl radical is a lower aliphatic or aromatic acyl radical, for example an acetyl, propionyl, butyryl, pivaloyl, benzoyl group, etc.

The compounds of formula 1 can be isolated as such or in the form of a salt with a pharmaceutically acceptable acid such as hydrochloric acid, Phosphoric acid, nitric acid, p-tolsulfonic acid, acetic acid, propionic acid, citric acid, Tartaric acid, maleic acid, etc. When R5 is hydrogen, the compounds of the formula I can be isolated as an amphoion or zwitterion or as a salt, for example as alkali metal and ammonium or amine salts or as salts with strong acids, The invention includes all possible isomeric forms of the Ver.

bonds of the formula I Depending on the different substituents, while the 7-amino-cephem-4-carboxylic acid group has the configuration of the natural occurring cephalosporins C.

The compounds according to the invention have valuable antibacterial properties Effectiveness and low toxicity.

All natural or semi-synthetic ones produced or isolated so far Cephalosporins owned on the 7-amino group an acyl substituent and it is therefore surprising that the compounds according to the invention which are part of the 7-amino group have an amidino group, also have strong antibacterial activity against a wide range of bacteria.

For certain medicinal purposes it is beneficial to use the free acids or to use their salts, while it is more favorable for other purposes that are easy hydrolyzable esters apply that are chemically or enzymatically in the organism In other cases they can be hydrolyzed into the corresponding free acids the less easily hydrolysable esters are preferred to have a certain distribution to achieve in the body.

For example, in some cases the above-mentioned acyloxymethyl esters of formula I absorbed or resorbed more easily after oral administration than the corresponding free acids. After absorption, these esters become ours Influence of the enzymes present in the blood and tissues hydrolyzes with release the corresponding free acids, which are generally stronger antibacterial Have effectiveness than the esters.

The invention also relates to methods of making the compounds described above. In one process, the compounds are prepared by reacting a reactive derivative, an amide or a thioamide of the general formula II: in which R1, R2 and R3 have the meaning given above and Y is an oxygen or sulfur atom, with a 7-amino- # ³-cephem-4-carboxylic acid derivative of the general formula III: in which R4 and R6 have the meaning given above or R5 is an alkylated silyl group. In the last-mentioned case, the reaction must be followed by solvolysis in order to obtain the compounds according to the invention in which R5, e. is a hydrogen atom, which can also be obtained by cleavage of other esters and that by known esterifications to form esters of the formula I (R5 no hydrogen atom) can be converted.

The starting substances of the formula II are known or can be used according to known processes are produced.

The amides of the formula II can be converted into the reactive ones by known processes Derivatives are converted, such as the acid amide halides, acid amide dialkyl sulfate complexes or acid amide acetakes. The acid amide halides used are preferably the Chlorides or bromides and they can be prepared by treating the amides with halogenating agents Bs is preferred to use halogenating agents which form gaseous by-products such as phosgene and oxalyl halides during the entire reaction or thionyl halides.

However, other halides can also be used.

The reaction can be carried out in inert dry organic solvents be, for example, in ether or toluene, in which the amide halides in most Cases are insoluble and from which they are filtered off after complete conversion can be. The acid amide halides are hydroscopic and relatively unstable and are therefore preferably used for the next stage without further purification.

The acid amide dialkyl sulfate complexes can be prepared by treating the amides with dialkyl sulfate, preferably dimethyl sulfate, under known conditions. By treating the acid amide dialkyl sulfate complexes with lower sodium alcoholates, for example sodium methoxide, acid amide acetals of the general formula II a are formed: in which R1, R2 and R3 have the meaning given above and Alk is a lower alkyl group. These acetals can also be used for the next stage.

When acid thioamides can be used as starting substances a reactive derivative in the form of an acid thioamide-alkyl halide complex are prepared by treatment with alkyl halides, for example lower alkyl iodide. This reaction is known from the chemical literature.

The reaction conditions for the conversion of the hmid derivative and of the compound of formula III depend on the reactants in the Procedures are applied. When acid amide acetals for reaction with compounds of the formula III are used, the reaction temperature depends on the reactants. The reaction is carried out in inert organic solvents, for example ether.

If acid amide halides are used, the reaction will also carried out in organic solvents that are dry and free from traces of alcohol, preferably in chloroform, in which the reaction components are soluble are.

Solvent,. in which the starting materials are insoluble, for Example, ether, can, however, also be used. When dialkyl sulfate complexes or thioamide alkyl halide complexes are used, the reaction can be carried out in the above specified solvents, but also in lower alkanols. The reaction is carried out with cooling and in the presence of at least one Equivalent of a tertiary amine, for example trimethylamine-; Triethylamine, N, N-diisopropylethylamine or N-methylmorpholine.

If an equivalent of the tert. Amine is applied, becomes the reaction product obtained as a salt when an acid amide halide is used1 and in the form of a R1, R2, R3 amidino- # ³-cephem-4-carboxylic acid derivative as such when the dialkyl sulfate complexes and thioamide alkyl halide complexes can be used. If 2 or more equivalent of the tertiary amine are used, an R1, R2, R3 amidino-A3-cephem-4-carboxylic acid derivative is obtained, which can optionally be converted into a salt.

The reaction time depends on the participants in the reaction, the temperature and the solvents used in the process. When R5 is a hydrogen atom is, it is preferred to have the carboxyl group in the form of a trimethylsilyl ester or a Dimethylsilyldiester "group to protect, which after the reac-tion easily again can be split off.

This reaction is preferably carried out with an acid amide acetal reactant carried out. The silyl esters of 7-amino- # 3-cephem-4-carboxylic acids can be prepared are by silylation of a 7-amino-cephem-4-carboxylic acid with, for example Hexamethyldisilazane analogous to the preparation of the corresponding esters of 6-aminopenicillanic acid. The silyl esters of the amidino- # ³-cephalosporanic acids are preferably obtained by hydrolysis or alcoholysis cleaved under mild conditions.

In another method, the compounds of the invention can be prepared by reacting an amine, of the formula HNR1R2, with a reactive derivative of a 7-acylamino- # 3-cephalosporanic acid ester. Such reactive derivatives are obtained, for example, by reacting a compound of the formula IV: in which R3, R4 and R5 have the meaning given above with a halogenating agent, for example phosphorus pentachloride, in the presence of a tertiary organic base, for example quinoline. The reaction between this reactive derivative and the amine HNR1R2 can be carried out without isolating the intermediate product formed in the process, from which; as mentioned in the examples, it is believed to be an amide chloride of the compound of formula IV. The reaction is carried out at room temperature or below in the presence of an inert solvent such as chlorofori. Another reactive derivative of the compound of the formula -1V can be an imidoester which can be prepared by reacting the above-mentioned amide chloride with a lower aliphatic alcohol in the presence of a tertiary organic amine, for example triethylamine. The reaction products of formula I can be purified and isolated in the usual way and they can be obtained either in the free state or in the form of a salt. The free acid (R5 = H) can also be obtained from some of the esters by enzymatic hydrolysis or mild hydrogenolysis, and when the free acid is produced as a reaction product, its esters can be made by known esterification processes. The esterification can lead to the formation of a tight mixture of the E2 and a3 isomers. In such cases, the A-isomer is isolated after purification by chromatography or by other methods1 as given in the literature.

Some of the compounds of the formula III are known compounds and can be prepared by the esterification of 7-amino- # ³-cephem-4-carboxylic acid or a protected 7-amino-63-cephem-4-carboxylic acid such as the 7-trityl derivative. After the reaction, the trityl group can under conditions which the lactam ring cannot affect1 be split off. The connections can also be made by esterification of the commonly used cephalosporins, their acyl side chain then chemically or enzymatically under such conditions cleaved is that the EsLergruppe is not attacked.

These esterifications can also lead to a mixture of the - and 63-isomers Lead that separated before use in the next stage as stated above must become.

The compounds of the formula III and IV can also be prepared by nucleophilic substitution of the acetoxy group of a 7-amino-cephalosporanic acid derivative of the formula V with a suitable nucleophile to form the products of the formula VI: where nt is a hydrogen atom or an acyl group of the known cephalosporins and R ″ is a cation or has the meaning given above for R5 and R4 'has the meaning given for R4 with the exception of an acetoxy group. Such a nucleophilic substitution can be carried out with the corresponding nucleophiles: in a polar medium, preferably in the presence of a base. Suitable solvents are, for example, water, methanol, dioxane, dimethylformamide and the like. According to the definition of R4 'above, examples of suitable nucleophiles are: alkali azides, pyridine or substituted pyridines, aromatic amines such as auliline, which is optionally substituted with methyl, chlorine, nitro or sulfo groups, naphthylamine or pnminobenzoic acid, imidazole or alkylimidazole, aliphatic and aromatic thiols such as alkyl mercaptans, mercaptoacetic acid, unsubstituted and substituted Benzolthiole and Naphthalinthiole, heterocyclic thiols such Pyridinthiole, Pyrimidinthiole, Oxazolthiole, Imidazolthiole, Thiazolthiole, Pyrazolthiole, Triazolthiole, Tetrazolthiole, Oxazolthiole, Oxadiazolthiole, Thiadiazolthiole, Thflåtriazolthiole, triazinethiols, Benzimidazolthiole, Benzoxazolthiole, Benzothiazolthiole, Triazolpyridinthiole , where the heterocyclic groups can be substituted with methyl, ethyl, phenyl, benzyl, halogen, amino, methoxy, ethoxy, XthoxSyphenyl, halophenyl, halobenzyl, methoxyphenyl, dimethoxyphenyl, pyridyl or Thi enyl groups; Thioureas, which are optionally substituted by alkyl groups with 1 to 4 carbon atoms, diphenyl, dibenzyl or dinaphthyl groups, xanthates such as phenoxyethylxanthic acid, which is optionally substituted by chlorine or nitro groups, dithiocarbamates such as N, N-dialkyldithiocarbamic acid, N-alkyl-N- phenyldithiocarbamic acid N, N-dihydroxyethyldithiocarbamic acid, pyrrolidyldithiocarboxylic acid, piperidyldithiocarboxylic acid and their 2-methyl-hemologues 1-methyl-4-piperazinyldithiocarboxylic acid and their 1-ethyl-, 1-hydroxyethyl-homoic acid, 1-thiobenzyl-homoic acid, 1-thiobenzyl-homoic acid, 1-thiobenzylphynyl or 1-thiobenzylphynyl or 1-thiobenzyl-homologic acid, 1-dithiocyl-homologic acid, such as thioacetic acid, thiopropionic acid, thiobenzic acid, thiophene-2-thiocarboxylic acid, pyridine-thiocarboxylic acid or pyridine-r-thiocarboxylic acid. The above-mentioned xanthates and thiocarbamates can preferably be used in the form of their alkali salts.

Some compounds of formula VI) R ″ = R5) are made in a different way prepared, for example by acylation of a compound of formula VI in which R4 'is a hydroxy group with a reactive derivative of a carboxylic acid in the presence of a tertiary amine or an inorganic base, if necessary. Compounds are obtained in which pure lower alkanoyloxy, carbocyclic or heteroacyclic arylcarbonyloxy, aralkanoyloxy or cycloalkanecarbonyloxy groups is. When the compounds of the formula VI (R41 = OH) are reacted with isocyanates compounds of the formula VI in which R4 'is the group OOCNHR6. In implementation of compounds of the formula VI (R4, = OH) with Phosgene makes one Compound of the formula VI in which R4 'is OCOCl, which is obtained by reaction with a secondary Amine gives products of Formula VI in which R4 'is a 00CNR6R7 group.

When R 'in formula V is hydrogen, the reaction product is of Formula VI the same as Formula III.

When R 'is an acyl group of known cephalosporins, it can be like in formula IV be R3CO and in this case the intermediates to the above reaction described can be used. In other cases, R 'can be by procedure be split off as they are used in the deacylation of Ccphalosporinen for the production of 7-aminocephalosporanic acid applied free, whereby one in turn compounds of formula III receives.

The compounds of the formula I are well tolerated. When R5 is a hydrogen atom the compounds are preferably in the form for parenteral administration an aqueous sterile solution, optionally applied in the form of a suitable salt. If esters are employed, they can preferably be administered orally either as such or can be administered in the form of one of their salts and they can be with solid carriers andX or additives are mixed. In the case of such agents, the proportion of therapeutic active substance to carrier and additive in the range from 1 to 95 Va-. the Funds can either be in pharmaceutical forms such as tablets, pills, or dragees processed or they can be filled into medical containers such as capsules or bottled in the form of mixtures. Pharmaceutically acceptable organic or inorganic solid or liquid carriers which are -for oral, enteral or topical Administration are suitable, can be used for the preparation of the means.

Gelatin, lactose, starch, magnesium stearate, talc, vegetable ones and animal fats and oils, gums, polyalkylene glycol or other known carriers for drugs are suitable.

In addition, the agents can contain other pharmaceutically active ingredients included, which together with the erfindui.igsgemäße Verbinüngen for the treatment of Infectious diseases can be administered like other antibiotics.

The invention is illustrated in more detail by the following examples: Example 1 Pivaloyloxymethyl-7-amino-3-methyl-4³-cephem-4-carboxylate hydrochloride A. Pivaloyloxymethyl-benzylpenicillinate sulfoxide To a solution of 20 g of pivaloyloxymethyl-benzyl penl cillinat in 200 ml of glacial acetic acid 20 ml of 30% hydrogen peroxide were added with stirring. The solution was Maintained at room temperature for 4 h and diluted with 300 ml of water while stirring. Of the Precipitate was filtered off and mixed with 25 ml of 40% acetic acid and 50 ml of water washed.

Mp 143-143.50C.

B. pivaloyloxymethyl 7-ß-phenylacetamido-3-methyl-43-cephem-4-carboxylate 80 ml of dry benzene, 60 ml of N, N-dimethylacetamide and 0.12 ml of metanesulfonic acid were added dried by refluxing for 1/2 hour, with the water continuously was withdrawn in one trap. Then, 9.3 g of pivaloyloxymuthylbenzyl penicillinate sulfoxide was added added and heated to boiling for a further 9 h. The resulting water was with it Using a trap removed.

The benzene was removed in vacuo. The residue was in 180 ml Dissolved ethyl acetate and extracted with 2 x 30 ml of water.

The aqueous phase was extracted with 60 ml of ethyl acetate. the united organic phases were successively mixed with 2 × 60 ml of water, 50 ml of saturated aqueous Sodium bicarbonate solution, 50 ml water and 25 ml saturated aqueous sodium chloride solution washed. The organic phase was dried, treated with activated charcoal and used for Evaporated to dryness. The partially crystalline residue was triturated with 40 ml of ether and stored in the refrigerator for 16 h. The precipitate was filtered off and washed with ether washed.

Mp 164-1650C.

C. Pivaloyloxymethyl-7-amino-3-methyl- # 3 -cephem-4-carboxylate hydrochloride To a solution of 25 g of phosphorus pentachloride in 250 ml of dry alcohol-free Chloroform was added with stirring to 27 ml of quinoline and after cooling to -20 ° C. 38.8 g of pivaloyloxymethyl-7-β-phenylacetamido-3-methyl- # 3-cephem-4-carboxylate. After stirring for 15 minutes at -20 ° C, the temperature was lowered to -40 ° C and 85 ml of n-propanol were added over the course of 5 minutes.

The mixture was kept at -150 ° C. for a further min and then 85 ml saturated aqueous sodium chloride solution and 40 ml of water were added with vigorous stirring. After cooling to 500 ml, 200 ml petroleum ether were added and a further 15 min at stirred at this temperature. Then the aqueous phase was separated and the in the The precipitate formed in the organic phase was filtered off and washed with ether. After drying, the filter cake was suspended in 150 ml of isopropanol at 0.degree. The precipitate was filtered off and washed twice with 50 ml of ether.

Mp 173-17400. @ 720. +670 (C = 1, 0.1N HCl) Example 2 Pivaloyloxymethyl 7- (N, N-dimethylformamidino-N ') -3-methyl- # 3 -cephem-4-carboxylate A solution of 0.65 g of chlorodimethylformiminium chloride in 10 ml dry alcohol-free chloroform slowly wound into a solution of 1.85 g @@@@@@@@@ 7-amino-3-methyl- # 3-cephem-4-carboxylate hydrochloride and 2.6 ml of N, N-diisopropylethylamine given in 25 ml of chloroform with stirring at -50 ° C. The temperature was during Increased to 0 ° C. for 1 h and then evaporated the solution in vacuo. The residue was triturated with 100 ml of ether and the resulting solid was filtered off. That The filtrate was evaporated in vacuo and the oily residue was triturated with 25 ml of water. The resulting solid was isolated and recrystallized twice from acetone-water, an analytically pure product was obtained.

M.p. 117.5-118 ° C. #: + 55 ° (c = 1.96% ethanol).

Example 3 Pivaloyloxymethyl-7 - [(hexahydro-1H-azepin-1-yl) -methyleneaminoj7- 3-methyl-3-cephem-4-carboxylate hydrochloride 3.05 g of N-formylhexamethyleneimine dissolved in 100 ml dries ether. While stirring and cooling in an ice bath, 2.02 ml Oxalyl chloride in 20 nile dry ether was added dropwise. The mixture was at 2 1/2 h Stirred from 0 to 50C. The precipitated amide chloride was filtered off and washed with dry Ether washed.

It was kept in the desiccator.

A solution of 0.92 g of this amide chloride in 10 ml of dry alcohol-free Chloroform slowly became a solution of (pivaloyloxymethyl) 1.88 g, 7-amino-3-methyl- # 3 -cephem-4-carboxylate hydrochloride and 2.11 ml of triethylamine in 25 ml of chloroform were added at -50 ° C. with stirring. the The temperature was increased to 0 ° C. over the course of 1 h and the solution was then in vacuo evaporated.

The residue was triturated with 100 ml of ether and the undissolved Triethylamine hydrochloride filtered off. The filtrate was taken with 70 ml of water Stirring and ice-cooling extracted, the pH of the aqueous phase to approximately 2 has been reduced. The aqueous phase was separated with sodium bicarbonate made alkaline and extruded with 150 ml of ether.

The ethereal phase was dried and vacuumed to approx 50 ml evaporated. 0.4 ml of a solution of hydrogen chloride in isopropanol (8.6 n) was diluted with 5 ml of dry ether and slowly stirred and cooled with ice given to the ethereal phase. The resulting precipitate was filtered off and with ether, washed. The amorphous powder was made from tert-butyl alcohol-isopropyl ether recrystallized to give the pure compound.

Mp 189-190 ° C. / -, 720, +1430 (c = 1.96% ethanol).

Example 4 7 - [(Hexahydro-1H-azepin-1-yl) -methyleneamino] -cephalosporanic acid hydrochloride hydrate A suspension of 1.36 g of 7-aminocephalosporanic acid in 15 ml of dry chloroform was heated to boiling with 1.38 ml of hexamethyldisilazane for 1 h. The resulting solution was evaporated in vacuo. To the residue in 100 ml of dry ether became slow dry a solution of 0.98 g of 1-hexamethyleneimine carboxaldehyde dimethylacetal in 15 ml Ether added with stirring at -35 ° C. The temperature was within 15 min increased to 0 ° C. The precipitate was filtered off, washed with ether and poured into 25 ml of isopropanol suspended.

0.5 ml of an 8N solution of hydrogen chloride was added to this suspension in isopropanol with stirring and ice cooling added. The mixture was with 25 ml of isopropyl ether diluted and filtered. The precipitate was obtained from ethanol (i, sopropyl ether) recrystallized and air-dried, giving an analytically pure product received.

Mp 16500. #: +590 (c = 1.96% ethanol) ,.

Examples 5 - 7 Mech. Following the procedure of the previous examples the compounds of Table 1 were prepared according to Formula 1.

T a b e l l e 1 Example R1 R2 R3 R4 R5 No.

5 ethyl ethyl hydrogen hydrogen pivaloyloxymethyl R1R2N R3 R4 R5 6 morpholinyl-4 hydrogen hydrogen pivaloyloxymethyl 7 piperidyl-1 benzyl Hydrogen pivaloyloxymethyl T a b e l l e 2 Amide halide production Example halogen solution reaction recrystallized Fp rotation nating 20 no. medium time (h) from (° C) # medium D 5 (COCl) 2 ether 1 acetone-water 112-113 +76 1) 6 (COCl) 2 ether 19 acetone-water 118.5-119 +24 2) 7 COCl2 toluene 3 acetone-water 141-141.5 -82 3) 1) in 96% ethanol 2) in chloroform 3) in acetone example 8 7- (N, N-dimethyl-benzamidino-N ') -3- (mercaptomethyl) - # 3 -cephem-4-carboxylic acid picolinate A mixture of 1.75 g of 7-amino-3- (mercaptomethyl) - # 3-cephem-4-carboxylic acid picolinate and 1.4 ml of hexamethyldisilazane in 15 ml of dry chloroform was refluxed for 2 hours heated.

After evaporation in vacuo, the residue was dissolved in 100 ml of ether taken up and cooled to -350C. This slowly added 1.12 g of N, N-dimethylbenzamide dimethylacetal added in 15 ml of dry ether at this temperature with stirring.

The mixture was stirred at 0 ° C. for a further 3 h. The precipitate was filtered off and washed with 25 ml of ether and dried in a desiccator. It was not possible, to purify the product by recrystallization.

Example 9 7- (N-Morpholinoformamidino-N ') -3 - [(5'-methyl-1', 3 ', 4'-oxadiazol-2'-yl) -thiomethyl- # ³-cephem-4-carboxylic acid A. 4-Morpholincarboxaldehyd-dimethyl-acetal 91.5 g of N-formylmorpholine were with 75 ml of dimethyl sulfate mixed and left to stand for 18 h at room temperature. then the viscous oil was extracted with 3 x 200 ml of ether and in vacuo at room temperature evaporated. The remaining 178.5 g were added to a solution of 17 g of sodium in 220 ml of methanol at 5 to? OOC were added over the course of 1.25 h with stirring. The mixture was stirred at room temperature for 2 h and filtered.

The filtrate was vacuum distilled to give the Acetrl.

Kp 72.5 - 73.5 ° / 10 mm Hg.

B. 7- (N-Morpholinoformamidino-N ') - 3- / T5'-methyl-1E, 3', 4'-oxadiazol-2'-yl) -thiomethyl] - # ³-cephem-4-carboxylate 1.6 g of 7-amino-3- / T5'-methyl-1 ', 3 t, 4'-oxadiazol-2'-yl) -thiomethyl7-3-cephem "4-carboxylic acid and 1.38 ml of hexamethyldisilazene were 2 h in 15 ml of dry chloroform heated to reflux temperature. The solvent was removed in vacuo the residue taken up in 100 ml of ether and cooled to -350C. Then it became 0.89 g of 4-morpholine-carboxaldehyde-dimethyl-acetal in 15 ml of dry ether with stirring added dropwise at -35 0C. The temperature was slowly increased to OOC and for 2 hours at that Value held. After stirring for an additional 2 hours at room temperature, the mixture became filtered off. The precipitate was washed with dry ether and placed in a vacuum desiccator kept.

Example 10 7- (N, N-Dimethylformamidino-N ') - cephalosporanic acid-hydro chloride 1.36 g of 7-amino-cephalosporanic acid were treated with 1.38 ml of hexamethyldisilazane for 1 hour refluxed in 15 ml of dry chloroform. After evaporation in vacuo the crystalline residue was dissolved in 100 μl of ether. 0.64 g 1,1-dimethoxy-trimethylamine in 15 ml of dry ether were added dropwise with stirring at -300C. The temperature was increased to 0 ° C within 15 min. The precipitate was filtered off and washed with ether. The product was dried in a vacuum desiccator.

To 0.8 g of the crude product suspended in 10 ml of isopropanol 0.3 ml of an 8 N solution of hydrogen chloride in isopropanol were added with stirring given. 15 ml of isopropyl ether were then added and the mixture was kept at 0.degree. The 1 precipitate was filtered off and washed with isopropyl. Thin layer chromatography (Iterok Siiica Gel HF254) iu n-Butanol-Ethanol-Vasser (8: 2: 2) showed that the product was almost pure and only contaminated with a little 7-aminocephalosporanic acid (the Rf value the latter compound is three times as large as that of the product). All attempts to further clean the product led to one impure product.

Example 11 7- (N, N-Diisopropylformamidino-N ') - 3- (N-methylanilinomethyl) - # 3-cephem-4-carboxylic acid 1.6 g of 7-amino-3- (N-methylanilinomethyl) - # ³-cephem-4-carboxylic acid and 1.38 ml of hexamethyldisilazane were refluxed in 20 ml of dry chloroform for 2.5 hours. The solvent was evaporated in vacuo and the residue taken up in 125 ml of dry ether. Zero stirring was 1.05 g of N- (dimethoxymethyl) -1,1'-dimethyldia'tbylamine in 15 ml of dry ether added dropwise at -35 ° C. The temperature slowly rose to 0 ° C heated and held at this value for 3 h. The precipitate was filtered off and washed with dry ether and stored in a vacuum desiccator.

Example 12 Diphenyl-methyl- (N, N-diethyl-thiophene-2'-carboxamidino-N ') -3-ethoxy methyl- # ³-cephem-4-carboxylate To a solution of 3.7 g of N, N-diethyl-thiophene-2-carboxamide 1.7 ml of oxalyl chloride in 10 ml of dry ether were slowly added to 500 ml of dry ether added with stirring at 0 ° C. The mixture was stirred at room temperature for 3.5 h, the 'precipitate filtered off and washed with water. It was stored in the desiccator.

0.6 g of the crude amide chloride in 5 ml of dry alcohol-free chloroform slowly became a solution of 1.5 g of diphenylmethyl-7-amino-3-ethoxymethyl- # ³-cephem-4-carboxylate-p-toluenesulfonate and 1.05 ml of triethylamine in 10 ml of dry chloroform with stirring at -20 to -30 ° C given. The temperature was increased from OOC over 0.75 h. The solution was evaporated in vacuo and the.

Triturated residue with 50 ml of ether. Do the filtering that became The filtrate is extracted with 25 ml of dilute hydrochloric acid at a pH of approximately 3. The aqueous phase was on brought a p'ii value of 7.5 and extracted with 2 x 25 ml of ethyl acetate. After drying and evaporation in vacuo a residue was obtained which did not crystallize.

Example 15 tert. Butyl 7- (N, N-dimethyl-butyramidino-N ') -3-cyanomethyl- # 3 cephem-4-carboxylate hydrochloride To a solution of 2.3 g of N, N-dimethylbutyramide in 10 ml of dry toluene was slowly added a solution of <30 ml $ gt ($ lt; $ lt; 0.043 mol) >> @@@@@@@@@@@@@@@@@@@@@@@ in toluene at 0 ° C with stirring added. The reaction mixture was stirred at room temperature for 20 hours. The precipitate was filtered off and washed with ether. It was kept in the desiccator.

0.48 g of the crude amide chloride in 5 ml of dry alcohol-free chloroform were slowly added to a solution of 1.17 g of tert-butyl 7-amino-3-cyanomethyl- # ³-cephem-4-carboxylate-p-toluenesulfonate and 1.3 ml of N, N-diisopropylethylamine in dry chloroform with stirring at -5O0C admitted. The temperature was slowly increased to 0 ° C. and held at this value for 1 hour. The solvent was removed in vacuo; and the residue treated with 50 ml of ether. After filtering, the filtrate was diluted with hydrochloric acid (30 ml, pH approx 3) extracted. The aqueous phase was adjusted to pH with sodium bicarbonate before about 7.5 g and extracted with 2 x 25 ml ethyl acetate. After drying and evaporation in vacuo gave an oil which was taken up in 60 ml of ether. An "n solution of hydrogen chloride in 0.3 ml of isopropanol was added slowly with stirring added at 0 ° C. The desired product precipitated and was filtered off with ether washed and dried.

Example 14 7- (N-pyrrolidinoformamidino-N ') -3-azidomethyl- # 3-cephem-4-carboxylic acid 1.3 g of 7-amino-3-azidomethyl- # ³-cephem-4-carboxylic acid and 1.4 ml of hexamethyldisilazane were added refluxed in 20 ml of dry chloroform for 2 h. The solvent was removed in vacuo and the residue taken up in 110 ml of dry ether and on -400C cooled. At this temperature, 0.83 g of 1-pyrrolidinecarboxalidehyde dimethylacetal were obtained added dropwise in 15 ml of ether with stirring. The temperature was slowly increased to 0 ° C and stirred at 0 ° C. for a further 2.5 h. The precipitate was filtered off with ether washed and dried in a vacuum desiccator.

Example 15 Benzyl 7- [α- (hexahydro-1H-azepin-1-yl) -β-methoxyethylideneamino] -cephalosporanate A. Ethyl methoxythione acetate 37.7 g of ethyl methoxyacetimidate hydrochloride were used in -20 ° C in 45 ml of pyridine stirred. Then 17 g of hydrogen sulfide was added to the suspension initiated and then stirred for 2 h at 0 ° C, the mixture at 0 ° C in 100 ml Poured saturated aqueous sodium chloride solution and extracted with 2 x 50 ml ether. The ethereal phase was extracted with 0.1 N hydrochloric acid until the pH of the aqueous Phase was about 5.

After extraction with 2 × 50 ml of ice water, the ethereal phase became dried and distilled to give the pure formation.

Bp 60-610C / 14 mm Hg.

B. N-methoxythioacetylhexamethyleneimine 13.4 g of ethyl methoxythione acetate were added to 22.4 ml of hexamethyleneimine with stirring and cooling with ice water. The solution was left to stand at room temperature overnight and then distilled.

Bp 99-101 ° C / 0.15-0.25 mm Hg.

C. Methyl Iodide Complex of N-Methoythioacetylhexamethyleneimine One Solution of 14 g of N-methoxythioacetylhexamethyleneimine in 25 ml of acetone were slow 6.2 ml of methyl iodide were added.

The solution was kept at room temperature for 16 hours. The Kompiex was precipitated by adding a few crystals, filtered off with suction and washed with acetone and ether. The melting point of the crude product was 102-1040C.

D. Benzyl-7- [α- (hexahydro-1H-azepin-1-yl) -ß-methoxyethylideneamine, o7- cephalosporanate To a solution of 0.9 g of benzyl 7-amino-cephalosporanate and 0.87 ml of N, N-diisopropylethylamine in 10 ml of dry chloroform were 0.83 g of the at 0 ° C above-mentioned compound after stage C added. The solution was im Stored in the refrigerator. The solvent was removed in vacuo and the residue treated with 15 ml of ethyl acetate.

After filtration, the filtrate was evaporated in vacuo and the The residue is dissolved in 35 ml of ether and washed with 35 ml of dilute hydrochloric acid (pH approx 3) extracted. The aqueous phase was separated and washed with sodium bicarbonate solution brought to a pH of 7.5. When extracting with 40 ml of ether and then Drying and evaporation in vacuo gave an oily residue that was not crystallized.

Example 16 7- (N-Morpholinoformamidino-N ') - cephalosporanic acid sulfate 1.36 g of 7-amino-cephalosporanic acid in 15 ml of dry chloroform were treated with 1 for 1 hour , 38 ml of hexamethyldisilazane heated under reflux. The resulting solution was evaporated in vacuo to give a solid residue in.

Take up 100 ml of dry ether and slowly add to a solution of 0.89 g of 4-morpholine carboxaldehyde dimethyl acetal in 25 ml dry Ether was added with stirring at 0 ° C. The reaction mixture was left at 0 ° C for 1 hour stirred and filtered.

The precipitate was washed with dry ether. Mp 140-146 ° C. A suspension of 0.4 g of the crude product in 15 ml of isopropanol was added to 00C 0.55 ml of 4N sulfuric acid solution in isopropanol was added with stirring. It was stirred for a further 15 min and then the sulfate by adding 20 ml of ether failed. It can be recrystallized from chloroform ether. In thin layer chromatography (Silica Gel) in ethanol-chloroform-water-ammonium hydroxide (90: 84: 20: 6) one Rf = 0.40. 7-aminocephalosporanic acid Rf = 0.27.

Example 17 Pivaloyloxymethyl-7- (N-piperidino-ß-phenylacetamidino-N ') 3-methyl-a3-cephem-4-carboxylate To a solution of 2.1 g of phosphorus pentachlride in 20 ml of dry alcohol-free chloroform were stirred and 2.3 ml of quinoline after cooling to -100G, 4 g of pivaloxyloxymethyl-7-ß-phenylacetamido-3-methyl- # ³-cephem-carboxylate given. After stirring at 100 ° C. for 15 min, the solution became an ice-cold saturated one added aqueous solution of sodium bicarbonate with vigorous stirring. After 30 min Stirring, the organic phase was separated off and dried at 0 ° C. over magnesium sulfate. After filtering, 1.7 ml of piperidine was added to the filtrate at -150C. The solution was kept at 0 ° C. for 1 hour and evaporated in vacuo. The residue was triturated with 200 ml of ether. The solid piperidine hydrochloride was filtered off and the filtrate evaporated. The oily residue was washed with 3 × 50 ml of petroleum ether triturated and finally between 100 ml of dilute hydrochloric acid with a pH value of 3 and 50 ml of ether distributed. The aqueous phase was separated to pH brought from 7.5 and extracted with ether.

The ethereal phase was dried and evaporated in vacuo, whereby a semi-solid residue was obtained which was recrystallized from acetone-water. After recrystallization from acetone-water, an analytically pure product was obtained.

Mp 141-141.5 ° C. #: -82 ° (c = 1, acetone).

Example 18 Pivaloyloxymethyl-7 - [(hexahydro-1H-azepin-1-yl) -methyleneamino] -3-methyl- # 3 -cephem-4-carboxylate hydrochloride To a solution of 3.7 g of pivaloyloxymethyl-7-amino-3-methyl- # ³-cephen-4-carboxylate hydrochloride and 3.4 ml of N1N diisopropylethylamine in 55 ml of dry chloroform were at 0 ° C , 5 rs Qcs N-formylhexamethyleneimine dimethyl sulfate complex, which is produced according to the method of Bredereck et al (Chem. Ber. 101, 41 (1968)). To The solution was evaporated in vacuo at 0 to 5 ° C. for 20 h. The residue was with 200 ml of ether triturated and then filtered. The filtrate was with 125 ml extracted from dilute hydrochloric acid (pH approx. 2). The aqueous phase was made with sodium bicarbonate brought to a pH of about 7.5 and extracted with 275 ml of ether. To after drying, the ethereal phase was evaporated to 100 ml in vacuo and that desired hydrochloride by adding hydrogen chloride in isopropanol with stirring precipitated at 0 to 5 0C.

The precipitate was from tert. Butyl alcohol isopropyl ether recrystallized, thereby obtaining the pure compound.

Fp 1890C. The IR spectrum was the same as that of the product according to the example 3 identical.

Example 19 Sodium 7- (N-morpholino-β- (4'-chlorophenyl) acetamidino-N ') -cephslosporanate A. Methyl iodide complex of 4- (4 '-chlorophenylthioacetyl) -morpholine A solution of 10.2 g of 4- (4'-chlorophenylthioacetyl) morpholine and 3.75 ml of methyl iodide in 70 ml of acetone was stirred at room temperature for 24 h. The resulting precipitate was filtered off and washed with acetone and ether.

Mp 155-1570C.

B. 4- [4'-chloro-α- (methylthio) styryl] morpholine To an ice cold one A solution of 2.0 g of the crude complex in 20 ml of chloroform was 0.7 ml of triethylamine given. The solution was left to stand for 20 h at room temperature and salt vacuum evaporated. The residue was triturated from the triethylammonium iodide with 75 ml of ether Filtered off and evaporated, leaving an oil.

C. Sodium 7- (N-morpholino-β- (4'-chlorophenyl) acetamidino-N cephalosporanate 3.4 g of 7-aminocephalosporanic acid were mixed with 3.5 ml of hexamethyldisilazane in 35 ml of dry chloroform heated to reflux. After evaporation in vacuo was the crystalline residue was redissolved in 30 ml of chloroform at 0 to 50C.

2.6 g of the crude 4- [4'-chloro-α- (methylthio) -styryl] morpholine in dry chloroform were slowly added with stirring.

The resulting solution was evaporated in vacuo for 16 h and the residue stirred with 40 ml of chloroform. The resulting precipitate was filtered off and the filtrate evaporated in vacuo. The residue was stirred with 50 ml of ether and the crude solid collected and washed with ether.

1.5 g of the crude product were added to a solution of 0.5 g of sodium 2-ethylhexanoate is added to 12 ml of methanol.

The crude sodium salt was precipitated by adding 45 ml of ether. Bs was purified by recrystallization from methanol-ether.

Example 20 The procedure of Example 19 was repeated, wherein the appropriate reagents were used to make the following analogs : Sodium 7- (N-morpholino-ß-phenylacetamidino-N ').

cephalosporanate; Sodium 7- (N-morpholino-ß (4'-methoxyphenyl) -acetamidino-N ') - cephalosporanate ; Sodium 7- (N-morpholino-ß- (2'-methoxyphenyl) acetamidino-N ') - cephalosporanate and Sodium 7- (N, N-diethyl-2-phenoxyacetamidino-N ') - cephalosporanate.

EXAMPLES 21 to 33 Following the procedure of Examples 2, 3, 5, 6, 7, 12 and 13 and proceeding from the corresponding imides of the formula TI and esters of the R4-substituted? -Amino-3-cephem-4-aarboxylic acids of Formula III the following compounds were made: Table 1 R1 R2 R3 R4 R5 21 methyl pyrrolidylidene-2 methyl mercapto 2,2,2-trichloroethyl 22 4-chlorobenzyl methyl hydrogen acetoxy ethyl 23 hexahydro-1 (2H) -azocinyl hydrogen benzoyloxy diphenylmethyl 24 cyclopentyl methyl hydrogen 2,2-dimethyl - diphenylmethyl 1-oxopropoxy 25 1,2,3,4-tetrahydro- hydrogen isopropoxy diphenylmethyl isoquinolyl-2 26 ethyl ethyl cyclopene 2-methyl-1-diphenylmethylethyl oxopropoxy 27 methyl methyl 2-thienyl- (1-oxo-2- bute-diphenylmethyl methyl nyl) oxy 28 morpholinyl-4 4-methoxy-propoxy diphenylmethyl benzyl 29 ethyl phenethyl hydrogen acetoxy ethyl 30 4-methylpiperidyl-1 hydrogen acetoxy ethyl 31 methyl phenyl hydrogen benzoyloxy diphenylmethyl 32 morpholinyl-4 heptyl cyano tert-butyl 33 methyl Methyl tert-butyl hydrogen pivaloyloxymethyl Examples 34 to 45 Following the procedure of Examples 8, 9, 10, 11, 14 and 15 and starting from the corresponding R4-substituted 7-amino-bephem-4-carboxylic acids of the formula III (R5 = H ) and acid a The following compounds were prepared midacetals of the formula II a: Table 2 R2 R4 34 methyl methyl (1,3,4-thiadiazol-2-yl) thio 35 ethyl ethyl aminocarbonyloxy 36 propyl propyl (1-butyl-1H-tetrazol-5-yl) thio 37 ethyl isopropyl (4,5 -Dimethyl-4H-1,2,4-triazol-3-yl) thio 38 methyl butyl (5-ethyl-1,3,4-thiadiazol-2-yl) -thio 39 allyl allyl 2-chloroethylaminocarbonyloxy 40 methyl cyclohexyl propionyloxy 41 methyl cycloheptyl (5-methyl-1,3,4-oxadiazol-2-yl) -thio 42 2-methylpiperidyl-1-methylthio thio 43 3-methylpiperidyl-1 (4'-methyl-2-oxazolyl) thio 44 octahydro-1H -azonin- [(5-methylthio) -1,3,4-thiadia-1-yl zol-2-yl] thio 45 heptyl heptyl (1H-1,2,3-triazol4-yl) thio claim:

Claims (1)

Claim 7-amino- # ³-cephem-4-carboxylic acid derivatives, of the general formula in which R1, R2 and R3 are in each case, identical or different and in each case an aliphatic hydrocarbon radical, a mono- OdC) bicyclic carbocyclic aryl group, an aralkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group or a heterocyclically substituted alkyl group, R1 and R2 together with the nitrogen atom a ring system, R1 and R3 together with the nitrogen and carbon atom a ring system, also R3 a hydrogen atom, R4 a substituent, as is known for the methyl group in the 3-position of the cephalosporin system, such as c2n hydrogen or halogen atom , a hydroxyalkoxy or acyloxy group, a carbamyloxy group which is optionally substituted on one or two nitrogen atoms, an alkylthio group, a heterocyclic thio group, a trialkylmonium group, a pyrimidinium group which is optionally substituted in the ring, a thiouronium group, an amidinothio group, which is optionally an deno group Stic kstoffatomen is substituted with alkyl groups with 1 to 3 carbon atoms, an N-substituted aminothiocarbonylthio group. an arylthio group, an alkoxythiocarbonylthio group, an alkarylsulfonyl group, an acido, amino or amido group, a polyhydroxyphenyl group, an indol-3-yl group, which is optionally substituted on the nitrogen atom by alkyl groups with 1 to 3 carbon atoms, or a thiocyanoalkyl group and R5 is a Hydrogen atom or a substituted or unsubstituted alkyl, aralkyl or acyloxymethyl group and their pharmacologically acceptable salts.