AT405180B - Novel derivatives of substituted 3-cephem-4-carboxylic acid derivatives and process for their preparation - Google Patents

Abstract

The invention relates to compounds of the formula <IMAGE> in which the substituents have the defined meanings, process for their preparation and their use as antibacterial agents.

Description

       

   <Desc / Clms Page number 1>
 



  The invention relates to compounds of the formula
 EMI1.1
 wherein R; represents hydrogen, an ester-forming group or a cation, in free form, or where such forms exist, in the form of their acid addition salts, internal salts, quaternary salts or hydrates, processes for their preparation and their use.



     R can represent hydrogen, an ester-forming group or a cation. If R 1 denotes an ester-forming group, this is preferably an ester group which is easily hydrolyzable and / or easily resorbable under physiological conditions. Such esters can be used as a prodrug, the effective antibiotic being released by hydrolysis in the body. They are preferably used orally, since this hydrolysis usually takes place under the influence of the digestive enzymes. Parenteral administration is indicated when the ester is active per se or hydrolysis takes place in the blood.

   Examples of such ester-forming groups are alkyl having 1 to 6 carbon atoms, benzyl, alkoxybenzyl, for example 4Methoxybenzyl, indanyl, phthalidyl, alkoxymethyl, for example methoxymethyl, (C1-6) alkanoyloxy (C1-6) alkyl, (C1-6) alkoxycarbonyloxy (C , -6) alkyl, glycyloxymethyl, phenylglycyloxymethyi, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methyl and other physiologically hydrolyzable known in the field of cephalosporins
 EMI1.2
 or amine salt. According to the invention, the compounds of the formula t can be obtained by a) compounds of the formula
 EMI1.3
 where either a) Rb is hydroxy and Rc and Rd together form a bond, or ss) Rd is hydrogen, a cation,

   is an ester-forming group or a silyl group and Rb and
Re together represent an oxo group, in free form or in the form of an acid addition salt with an azomethine former of the formula
 EMI1.4
 implemented by methods known per se, or b) the compounds of the formula

 <Desc / Clms Page number 2>

 
 EMI2.1
 wherein Ri has the above meaning, with a compound of the formula
 EMI2.2
 wherein X stands for a leaving group, acylated, if desired reactive groups can be protected by appropriate protective groups which are split off under the reaction conditions or after the reaction has ended, and any compounds of the formula t obtained. wherein Ri is hydrogen or a
Cation is then in compounds of the formula i,

     wherein R1 is an ester group, transferred and the compounds of formula I isolated from the reaction mixture according to methods known per se and / or optionally converted into their acid addition salts and / or quaternary salts and / or hydrates.



   Process a) according to the invention can be carried out, for example, by a compound of the formula 11 in a solvent which is inert under the reaction conditions, for example in water, in water in a mixture with a lower alcohol or dioxane, or in a dipolar aprotic solvent, for example in dimethylformamide or dimethyl sulfoxide, alone or in a mixture with an alcohol or water, at a temperature of from -20 to 50 ° C. with a compound of the formula 111, the reaction mixture optionally being added to an optimum pH for product formation by adding an organic or inorganic acid or base. Value is brought.

   The compounds of formula I obtained can be isolated from the reaction mixture by methods known per se, for example by adding an anti-solvent or by chromatography.



   Process b) can be carried out by processes customary for acylations. For example, the compounds of the formulas IV and V are dissolved or suspended in a suitable solvent, for example in a mixture of water and acetone, and are preferably allowed to react at room temperature.



   If active groups are to be protected from the reaction, it is preferable to work with silyl protective group technology, the solvent being preferably a solvent which is inert to the silylating agent, for. B. a chlorinated hydrocarbon, a nitrile such as acetonitrile, an ether such as tetrahydrofuran or mixtures of these solvents. But there are also dipolar aprotic solvents, e.g. B. N, N-dimethylformamide, suitable. Such protective groups can be split off by methods known per se.



   The compounds of the formula I obtained can be isolated from the reaction mixture by methods known per se, for example by adding an anti-solvent or by chromatography.



   In the compounds of the formula I, the substituent which is bonded to the nitrogen of the C = N group in position 3 of the ring system can be present

 <Desc / Clms Page number 3>

 a) in the Z-shape
 EMI3.1
 or / and b) in the E-form
 EMI3.2
 
According to the inventive method, the compounds of formula I are obtained in pure E form, i. H. with a maximum Z-form content of 5%, preferably a maximum of 2%. Compounds of the formula I in the form of mixtures of the E and Z forms can be separated by known methods, for example by chromotography or by fractional crystallization.



   The invention preferably relates to compounds of the formula I in the E form, i.e. H. Compounds of formula I (E).



   The starting compounds are known or can be prepared by known processes or analogously to known processes or as described in the example.



   The compounds of the formula I and their pharmacologically tolerable salts, hereinafter referred to as active compounds according to the invention, have interesting biological, in particular antimicrobial, properties with low toxicity and can therefore be used as medicaments. They have an inhibitory effect against bacteria, as can be seen in in vitro tests using the serial dilution test and in vivo tests on mice using different bacterial strains, e.g.

   B. from Pseudomonas aeruginosa, Enterobacter cloacae, Enterococcus faecalis, Moraxella catarrhalis, Haemophilus
 EMI3.3
 teus mirabilis, Klebsiella pneumoniae. This inhibitory effect was in vitro from a concentration of about 0.01 to 50 u. g / ml and in vivo from doses of 0.1 to 50 mg / kg body weight.



  In addition, the compounds of the formula (surprisingly also show high in vitro activities
 EMI3.4
 = 28, mouse models demonstrated the in vivo activity against staphylococcus aureus, E. coli and streptococcus pyogenes infections from doses of 0.1 mg / kg to 100 mg / kg. The active compounds according to the invention can therefore be used as antibacterial antibiotics.



   As active ingredients, the active compounds according to the invention can be administered alone or in suitable pharmaceutical forms together with inorganic or organic, pharmacologically indifferent auxiliaries. For example, they are used as a component of capsules, injection or instillation preparations that contain a sufficient amount of active compounds to achieve an optimal blood level, that is about 10 to 500 mg per capsule. For the application, the dose to be administered depends on the compound used and the mode of administration and the type of treatment. In larger mammals, satisfactory results are obtained when a daily dose of approximately 0.5 is administered

 <Desc / Clms Page number 4>

 up to 6 g.

   This amount can optionally be given in correspondingly smaller doses two to four times a day or in a sustained release form.



   The invention also relates to a method for treating antibacterial diseases by administering a prophylactically or therapeutically effective amount of an active substance according to the invention, and to the use of an active substance according to the invention as an antibacterial active substance. Welters also relates to a pharmaceutical composition which contains an active ingredient according to the invention together with at least one pharmaceutically acceptable carrier or diluent.

   The invention also relates to the manufacture of a medicament against antibacterial diseases by mixing together an active ingredient according to the invention with at least one pharmaceutically acceptable carrier or diluent, and to the use of an active ingredient according to the invention for the manufacture of such a medicament.



   In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all the temperatures are given in degrees Celsius.



  Example: 7- (((5-Amino-1, 2, 4-thiad) azot-3-y)) - (Z) - (fiuormethoxyimino) acety)) afnino) -3- (imino-1-pipera-
 EMI4.1
 methylhydrazono) methyl-3-cephem-4-earbonic acid. Monohydrochloride (hydroxylactone of 7 - (((5-amino-1,2,4-thiadiazol-3-yl) - (Z) - (fluoromethoxyimino) acetyl) amino) -3-formyl-3-cephem-4- carboxylic acid)
A suspension of 10 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in a mixture of 220 ml
Methylene chloride and 80 ml of acetonitrile is stirred at 0 'with 43 ml of N, 0-bis (trimethylsilyl) acetamide.



   A clear solution is obtained after 15 minutes. 15.7 g of (5-amino-1,2,4-thiadiazol-3-yl) - (Z) -2-fluoromethoxyiminoacetic acid chloride are added and the reaction mixture is stirred at 0 # for one hour. Then diluted with 1250 ml of Acetonitnl, which contains 70 ml of water, and so much 12% aqueous
Ammonia until a pH of 3.5 is reached. The solution is diluted with 2.5 liters of water and then extracted three times with 2 liters of ethyl acetate. The ethyl ester phases are combined, dried with sodium sulfate and evaporated on a Rotavapor. The residue is stirred for one hour with 100 ml of acetonitrile at 20 #, the crystalline precipitate is filtered off and dried in vacuo.

   The product consists of a mixture of diastereomers (ratio approx. 1: 1).
 EMI4.2
 
Hz, DMSO-d6): 3.65 (ml ml acetonitrile and 11 ml water suspended with a solution of 2 g 1- (1-methylhydrazino) iminomethyl) piperazine. Dihydrochloride in 4.5 m) 2N HO added. The reaction mixture is stirred for one day at room temperature and then poured into 600 ml of acetonitrile with stirring.

   The precipitated product is filtered off, washed with acetonitrile and then dried over Sicapent in a vacuum drying cabinet.
 EMI4.3
    (((5-Amino-1, 2, 4-thiadiazol-3-yl) - (Z) - (fluoromethoxylmino) acetyl) amino) -3- (imino-1-piperazinyl-0.65 g of the same as under b) obtained crude product are dissolved in 2 ml of water, and the dark clear solution is pumped onto a column with a diameter of 2.5 cm, which is filled with 50 g of RP-18 (LiChroprep RP-18, particle size 40-63 μm, Merck). It is eluted with water (flow 20 ml / min), 29 fractions being collected.

   The fractions are examined by means of analytical HPLC and the fractions 13 to 17, which contain the desired peak, are combined and lyophilized.
 EMI4.4
 

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 EMI5.1
 
2H, NH2)
The 1- (1-methylhydrazino) iminomethyl) piperazine (iminocarbonic acid (1-methylhydrazide) piperazide. Dihydrochloride) required as the starting product can be obtained as follows:
 EMI5.2
 a column filled with 1500 ml of Amberlite IRA 420 (strongly basic ion exchanger in the chloride form) was applied and then eluted with water. The fractions containing the product are lyophilized. The lyophilisate is digested with ether, filtered off and dried in vacuo. The title compound is obtained as a white solid.



    Mp: 116 # (isopropanol)
 EMI5.3
 b) Hydrochloride of the benzylidene derivative of 4-formyl-1 - ((1-methylhydrazino) iminomethyl) piperazine
A solution of 40.9 g of S-methyl-2-methylisothiosemicarbazid.Hydrochlorid in 350 ml of ethanol is with
30 g of freshly distilled formylpiperazine were added and the mixture was heated under reflux for 39 hours. The reaction mixture is then cooled to room temperature, mixed with 26. 4 ml of benzaldehyde and stirred for a further 24
Hours after. The precipitate obtained is filtered off, washed with ethanol and then dried in a vacuum drying cabinet.
 EMI5.4
 (Broad singlet. 2H, W heu c) 1- ((1-methylhydrazino) imimomethyl) piperazine. dihydrochloride
10 g of benzylidene derivative of 4-formyl-1 - ((1-methylhydrazino) iminomethyl) piperazine.

   Hydrochloride is distilled to split off the benzaldehyde, adding 48 ml of 2N HCl and adding it in about 4
Distilled 1500 ml of water for hours. The aqueous sump is concentrated to an oily residue. After standing overnight, a resinous precipitate is obtained, which one coats three times
Ethanol boils out. The ethanol-soluble part is evaporated in vacuo and the white one obtained
Solid dried in vacuo.



   'H NMR (200 MHz, DMSO-ds): 3.16 (m 7H, N-CH3 and -CH2-N-CH2-); 3.61 (m, 4H, - CH2-N + -CH2-); 6.0
 EMI5.5
 ; 8, 3 patent claims 1,3-cephemcarboxylic acid derivatives of the formula
 EMI5.6
 where R, represents hydrogen, an ester-forming group or a cation, in free form, or where such forms exist, in the form of their acid addition salts, internal salts, quaternary salts or hydrates.

** WARNING ** End of DESC field may overlap beginning of CLMS **.


    

Claims (1)

2. 3-cephemcarboxylic acid derivatives of the formula  <Desc / Clms Page number 6>    EMI6.1  wherein the substituents have the meaning defined in claim 1 and the substituent which on Nitrogen of the C = N group in position 3 of the ring system is bound, in the E form. 3. Process for the preparation of 3-cephemcarboxylic acid derivatives of the formula I, characterized in that a) compounds of the formula  EMI6.2  wherein either a) Rb is hydroxy and Re and Rd together form a bond, or ss) Rd is hydrogen, a cation, an ester-forming group or a silyl group and Rb and Rc together represent an oxo group, in free form or in the form of a Acid addition salt with an azomethine generator of the formula  EMI6.3  implemented by methods known per se, or b) the compounds of the formula  EMI6.4  wherein R, has the above meaning, with a compound of the formula  <Desc / Clms Page number 7>    EMI7.1  wherein X stands for a leaving group, acylated, if desired reactive groups can be protected by appropriate protective groups,  which are split off again under the reaction conditions or after the end of the reaction, and any compounds of the formula I obtained in which R 1 is hydrogen or a cation, then in compounds of the form! t, in which Ri represents an ester group, and the compounds of the formula) are isolated from the reaction mixture by known methods and / or, if appropriate, into their acid addition salts and / or quaternary salts and / or Transferred hydrates. 4. A pharmaceutical composition containing a compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable acid addition salt, quaternary salt or hydrate together with at least one pharmaceutically acceptable carrier or diluent. 5. A compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable acid addition salt, quaternary salt or hydrate for use as Pharmaceutical. 6. A compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable acid addition salt, primary salt or hydrate for use as an antibacterial agent. 7. A process for the preparation of a pharmaceutical composition, characterized in that a compound of the formula I as defined in claim 1 is mixed in free form or in the form of a pharmaceutically acceptable acid addition salt, quaternary salt or hydrate with at least one pharmaceutically acceptable diluent.