DD215786A5 - METHOD FOR PRODUCING PREFERRED INFRARED AND RADIOMONIC AGENTS - Google Patents

Abstract

Cephalosporin derivatives of the general formula (see overleaf) are pharmaceutical preparations which are effective against bacterial infections and contain such cephem derivatives, processes for the preparation of the cephem derivatives and the pharmaceutical preparations and the use of cephem derivatives for controlling bacterial infections.

Description

Berlin, 27.4.1984

AP C 07-0 / 258 349 63 229/18

Process for the preparation of cephaloeporine derivatives

.... ... .., T. ':.'. Field of application of the invention

The invention relates to a process for the preparation of new cephalosporin derivatives with valuable pharmacological properties! especially with antibacterial .'effective '

The compounds prepared according to the invention are used as medicaments for the treatment of bacterial infections «

Characteristic of the known technical solutions

There is no information on which compounds have been used to treat infections so far *

the invention . .

The object of the invention is the provision of new compounds with antibacterial activity against Gram-positive and Gram-negative bacterial germs and low toxicity, which are suitable for the treatment of bacterial infections.

Explanation of the essence of the invention

The invention has for its object to find new cephalosporin derivatives and processes for their preparation! in particular polar cephem derivatives * which in the 3'-position of the cephem ring by certain pyridinium, Chlnolinium-

27.4.1984 AP C 07 D / 258 349 ~ 2 «63 229/18

and isoquinolinium residues are substituted, and which have a very good antimicrobial activity against gram-positive and gram-negative bacteria and are therefore suitable as medicaments for the treatment of microbial infections *

According to the invention cephem derivatives of the general formula I · '· -. . ' .: " ^!

C - CONH

and their physiologically acceptable acid addition salts produced «

In the formula mean: R * hydrogen is optionally substituted C ₁ -C 12 alkyl _t

optionally substituted C ₂ -CG-alkenyl, ^ ₂ -CG alkynyl, C ₃ -C ₇ -CyClOaIkyl, C ₃ -C ₇ -CyClOaIky 1- "C ₁ -CG ^ iIAlkyl, C ₄ -C ₇ -CyClOaIkenyl that Group _R 3

in which m or η can be identical or different and are each O and 1, R and R and are hydrogen, aryl, a C ₁ -C ₄ -alkyl group or together with the carbon.

27 · 4.1984 AP C 07 D / 258 349 -3 - 63 229/18

to which they are attached "form a methylene · or a C -C -cycloalkylidene group" wherein alkyl and cycloalkyl may be further substituted one or more times, R is a group -COgR > in which R is hydrogen, ^c i * * ⁰ ^ Alkyli-CH ₂ Oe ₁ -C ₄ -alkyl-CH ₂ 00C-C ₁ -C ₄ alkyl, or one equivalent of an alkali metal, alkaline earth metal, ammonium or an organic amine base; a nitrile group or a carbamoyl group -CONH ₂ , which may be monosubstituted or disubstituted by nitrogen,

/ TA a Pvridiniumrest -N ^λ ), which is substituted,

by 2 ortho-containing alkyl groups "which are closed to an optionally substituted di- to decamethylene ring in which a ring carbon atom can be errected by a heteroatom and still contain one or two double bonds * or a 1-quinoline - or a 2-Isochinollniumreet U which may each be mono- or polysubstituted by identical or different substituted by optionally substituted C ₁ -Cg -AlkYIf C ₁ -Cg-AIkOXyI halogen, trifluoro * methyl or hydroxy, and in which the R 0 group is in syn-position ·

The present invention is particularly directed to compounds in which

R is hydrogen, C 1 -C 6 -alkyl which may be monosubstituted by halogen, C 1 -C -alkylthio,

27 ^ 4 «1984

AP C 07 D / 258 349

! ..: '- 4 # ·' 63 229/18

C ₄ -C _Ä -A1kyloxy. Aryl or heteroaryl, C "-C _ft alkenyl, which may be mono- or polysubstituted by halogen" C ₂ -C ₃ -Alklnyl, C ₃ -C ₇ -CyClOaIkyl f C ₃ -C ₇ -CyCIoalkyl-C.- C - alkyl »C ₁₁ -O ₇ -cycloalkenyl and in which the

R ³ group ( ^CH 2) _n ( ^C ) m has ^{the predominant} meaning,

a Pyrldlnlunrest -N y »which is substituted

in which one ring-C-atom can be replaced by one heteroatom and furthermore also one or two double bonds may be present, mean "as possibly possible Substituents of these di- to decamethylene rings are, in particular, the following sub-substituents which may occur one or more times, but preferably simply: C -C -alkyl, C 1 -C 4 -alkoxy-hydroxymethyl, -halogeno-hydroxy, oxo-hydroxl-rino , Exomethylene »carboxy» C 1 -C 6 -alkyloxycarbonyl »cyano or carbamoyl · These sub-substituents may occur on the abovementioned rings fused to the pyridinium radical irrespective of whether the particular ring is saturated or interrupted by a heteroatom However, according to the invention, they preferably occur on fused-on saturated rings which contain no heteroatom.

The fused to the pyridinium ring ring can 2 to 10 ring members (di- to decamethylene) »preferably

April 27, 1984 AP C 07 D / 258 349 - 5.-. "63 229/18

however, they contain 3 ring members and thus represent, for example, a cyclopentenylene, cyclohexenes or cyclohepteno ring. If such a fused ring contains a double bond, examples which may be mentioned are a dehydrocyclopentadieno, dehydrocyclohexadieno, or dehydrocycloheptadieno ring. If a C atom in such rings is replaced by a heteroatom, suitable hetero atoms are, in particular, oxygen or sulfur. For example, mention is made of "ancontened rings" containing a two-carbon atom containing two or one double bonds: Furo "pyrano" dihydrofuro and dihydropyrano; as a condensed ring with a sulfur atom, the two or one double bond contains "thieno" thiopyrane "dihydrothieno" and dihydrothiopyrano. Of the rings fused to a heteroatom, "tendon" come to substitution, in particular by the abovementioned substituents "especially those rings" which contain only one double bond

R may in particular also mean

a 1-quinolium or a 2-chloro-nolinium radical "which may each be monosubstituted or polysubstituted" identically or differently by C 1 -C 6 -alkyl which may be substituted by hydroxy or C 1 -C 6 -alkoxy "by C 1 - Cg-alkoxy "halogen" trifluoromethyl or hydroxy "

and wherein also in the preferred compounds, the R O group is in syn-Positlon "Ale particular preferred are, for example, the following sub-substituents into consideration:

27, 4, 1984 AP G 07 D / 258 349 - 6 - 63 229/18

R ¹ is hydrogen C ₁ -C _{# 4 #} -AIlCyIiI such as ethyl Methylf * * Propylf isopropyl butyl, isobutyl, tert. Butyric especially methyl ethyl; by halogen! Z 'B ₉ chlorine * bromine or iodine or fluorine-substituted alkyl «in particular Trifluoräthyli 2f2 ^ 3 | ^: 3-tetrafluoropropyl; z by C.-Cg-alkyl alkylthiosubstitüiertes _e ^ B "methyl" thio, Äthylthioj by C ^ -CG-Alkyloxyeubstituiertes alkyl "i" z ₀ B _# Methy5.oxyi Äthyloxy; through aryl | Z _# B "Phenyl! ToIyI * chlorophenyl substituted alkyl, especially benzyl; substituted heteroaryl, z "B * i _t 3" thiazol-4-yl alkyl "particularly 1 ^ 3-thiazol-4-ylmethyl, C ₂ -C ₄ alkenyl, such as _# B _# vinylidene allyl, isopropenyl, methylallyl, in particular allyl, methylallyl; C ₂ -C ₄ -alkenyl-substituted by halogen, such as, for example, B ₀ chlorine or bromine, in particular S-chloro-propenyl-1-methyl-2-bromopropen-2-yl ₍ 2-chloro-propen-2-yl; C ₂ - C ₃ -Alkiny If in particular propargyl; C ₃ -C ₇ -CyClOaIkyIf such as in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, in particular cyclopentyl; C ₃ -C ₇ -CyClOaIky! Methyl V% such as in particular Cyclopropylmetnyl;

C ₄ -C ₇ -cycloalkylidene, in particular cyclopentenyl # Cyclohexenylj

the group ^(CH 2 ^ n ^ ^C ^ m · ^{R5 wherein R3 and R} are identical or

R ⁴

can be different and hydrogen, aryl! preferably phenyl, C ₁ -C ₄ -alkyl, such as "B" methyl, ethyl; Propyl, isopropyl, butyl, sec * butyl, preferably methyl methyl, in particular methyl.

27_#4_#1984 AP C 07 D / 258 349 '- 7- 63 229/18

or wherein R and R together with the carbon atom to which they are attached can form a methylene group or a C -C -cycloalkylidene group * such as "B" cyclopropy 1, cyclobutyl-cyclopentyl, cyclohexyl-cyano-heptyl, preferably Cyclopropyl, cyclobutyl, cyclo-pentyl or cyclohexyl, and where the cycloalkylidene group may be substituted z, B, by C 1 -C 4 -alkyl, preferably methyl, by halogen, and may be fluorine and chlorine or also substituted by alkylene having 3 to 6 C atoms;

m is β or 1

η * O or 1, where the sum of m and η is 1 or 2 ·,

R ³

  · "· 'Τ.

Preferred examples of the group "* are the following:

For the case »that η« O and m * 1 : ^ i -C (CH ₃ ) ₂ S -CH (C ₆ H ₅ ),

27 _# 4 _# 1984 AP C 07 D / 258 340 - 8 - 63 229/18

in the case where m 0 and η = 1: -CH ₂ - and if η and m »1 are:

R ^{5 is} the Θερρβ-COgR ⁶ I in the R ⁶ hydrogen * C ^ C ^ such as B _# methyl methyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, preferably methyl, ethyl, in particular methyl, or one equivalent of an alkali metal ^ such _# as sodium, potassium, lithium, preferably sodium and potassium, one equivalent of an alkaline earth metal, preferably calcium or magnesium, ammonium, and an equivalent of an organic Arainbase such #B, trimethylamine, diethylamine * triethylamine> Methylamine, propylamine Ν, Ν-dimethylethanolamine, trie (hydroxymethyl) aminomethane, arginine, lysine; an allyl group, a carbamoyl group which may once be substituted on the nitrogen by C ₁ -C 6 -alkyl, hydroxy-C ₁ -C 6 -alkyl, C ₁ -C 6 -alkoxycarbonyl, C ₁ -C 6 -alkylcarbonyl, carboxymethyl, C ₁ -C 6 -alkoxycarbonylmethyl, Aminocarbonylmethyl, C ₁ -C ₆ -alkylaminocarbonyl, carbamoyl, hydroxy-C ₁ -C ₆ -alkyloxy, or which may be substituted twice on nitrogen by C 1 -C -g-

27 * 4.1984 AP C 07 D / 258 349 - 9 ~ 63 229/18 ·

R is a pyridinium radical which is substituted by two alkyl groups which are closed to give a dibis decamethylene ring and which may in turn be one or more times, preferably monosubstituted and contain one or two double bonds, preferably the following fused ring systems:

Cyclopentenes, hydroxycyclopenteno, oxocyclopenteno, hydroxymethylcyclopenteno, exomethylene-cyclopenteno, carboxycyclopenteno, C ₁ -C ₄ -alkoxycarbonyl-cyclopentenoyl, in particular methoxycarbonylcyclopenteno and carbamoyl-cyclopenteno,

Cyclohexenes * hydroxycyclohexeno, oxocyclohexeno «hydroxymethylcyclohexeno, exomethylene-cyclohexeno, carboxycyclohexeno, C ₁ -C ₄ -alkoxycarbonyl-cyclohexeno, in particular methoxycarbonylcyclohexeno and carbamoyl« · cyclohexeno; Cyclohepteno, hydroxy *, chloro-i-bromo, oxo, hydroxymethyl, exomethylene or carboxy-cyclohepteno, C ^^ - C.-alkoxycarbonyl-cyclohepteno, in particular methoxycarbonyl-cyclohepteno and carbamoylcyclohepteno ^

Oehydro-cyclopenteno'i

, , ', i .

Dehydrocyclohexene and dehydrocyclohepteno ·

If a C atom is replaced by a heteroatom, in particular oxygen or sulfur, in the abovementioned fused-on ring systems, particular consideration is given to:

27 _# 4.1984 AP C 07 D / 258 349 »10« 63 229/18

2,3- and 3,4- furoi 2 ^ 3 * and 3 * 4 ~ pyrano,

2,3- and 3,4-Dlhydrofurof 2j3 * and 3 ^ 4-Oihydrppyrano *!

Methyl dihydrofurog Methoxydihydropyrano and Hydroxydihydropyranof

a quinolinium or a quinolinolium radical, which may in each case also be substituted one or more times, identically or differently by C 1 -C 4 -alkyl, such as, for example, methyl, ethyl, propyl, preferably methyl, by hydroxy -Cj-Cg-alkyl ^ such as «B _# hydroxy methyl, by C ^ -Cg-alkoxy-C ^ Cg» alkyl, such as. B "Methoxymethyli ethoxyethyl ether by ^c i"" ^c g ·· alkoxy! such as ζ, B _# methoxy, ethoxyl by halogen, trifluoromethyl or hydroxy »

The invention more particularly relates to a process for the preparation of compounds of the formula I and their physiologically tolerated acid addition salts, which is characterized by the fact that

a) a compound of general formula II

NC CONH " ^S

⁷ -ll'n \

or their salts or a reactive derivative of the compound II, wherein R has the abovementioned meaning

27.4 _# 1984 AP C 07 D / 258 349 - 11 - 63 229/18

and R is an amino or a protected amino group.

'8' indicates and R represents an interchangeable group represented by those pyridine, quinoline or isoquinoline derivatives * corresponding to the radicals R of the formula I, and is reacted with these pyridine, quinoline or isoquinoline derivatives and

"C) splits off any protective groups present and, if necessary, converts the resulting product into a physiologically tolerated acid addition salt;

or b) a 7-amino-cephem compound of general formula III

H ₂ N

Ill N

co ²

or their acid addition salts "in which PT has the abovementioned meaning and wherein the amino group may also be present in the form of a reactive derivative * with a 2 ~ (5-araino-l, 2,4-thiadiazol-3-yl) -2-synoximinoacetic acid of general formula IV

K - 12 - N) R ^{1 1} COOH 27. AP 63 4.1984 C 07 D / 258 229/18 349 R ⁷ ' and C & above aenann U 1 wherein R R ⁷ the tea euteutuna b < since

or reacted with an activated derivative of this compound and

oC) splits off an optional protective group and

B) if necessary, the resulting product in a physiologically acceptable acid addition salt leads over «*.

If the preparation of the compound of general formula I by nucleophilic replacement of R in the compounds of general formula II by said pyridine, Chino1in «or Isochinolinderivate done so come as radicals R in particular acyloxy of lower aliphatic carboxylic acids, preferably with 1 to 4 &> atoms, such as, for example, acetoxy or propionyloxy, in particular acetoxy, which may be optionally substituted, such as. B "chloroacetoxy or acetylacetoxy. For R, other groups are also suitable, such as, for example, halogen, in particular chlorine bromine or ethyl, or carbamoyloxy.

According to the invention nucleophilic exchange reaction "starting compounds of general formula II,

27 # 4.1984 AP C 07 D / 258 349 - 13 - 63 229/18

8 in which R is acetoxy, inserted, or salts thereof, such as z * B _# a · sodium 'or potassium salt · The reaction is conducted in a solvent! preferably in water, or in a mixture of water and a slightly mixed with water ·· organic solvent such. B, acetone, dioxane, acetonitrile, dimethylformamide * oimethylsulfoxide or ethanol! carried out "The reaction temperature is generally in the range of about 10 to about 100 ⁰ Og preferably between 20 and 80 ° C 'The base component is added in amounts ranging from about equimolar amounts and up to about ISfachen upper weft. The replacement of the radical R is effected by the presence of neutral salts, preferably of iodide or thiocyanate ions facilitated in the reaction medium. In particular, about 10 to about 80 equivalents of potassium iodide, sodium iodide, potassium thiocyanate or sodium thiocyanate are added. The reaction is advantageously carried out in the vicinity of the neutral point, preferably at a pH in the range from about 5 to about 8.

If the group R is present as a protected amino function, it is suitable to use, for example, amino-protecting groups. B. optionally substituted alkyl, such as tert-butyl, tert-amyl, benzyl, p-methoxybenzyl, trityl; Benzhydryl, preferably trityl trialkylallyl * such as trimethylsilyl; optionally substituted aliphatic acyl such as "B" formyl, chloroacetyl, bromoacetyl, trichloroacetyl and trifluoroacetyl, preferably formyl; or optionally substituted alkoxycarbonyl such as trichloroethoxycarbonyl, benzyloxycarbonyl or tert-butyloxycarbonyl, preferably tert-butyloxycarbonyl and benzyloxycarbonyl; or dimethylaminomethylene. ^J

27, 4, 1984 AP C 07 D / 258 349 - 14 - 63 229/18

Oils protecting group can be cleaved after the exchange reaction in a conventional manner, ζ * B ₉ the Trity! Group by means of a carboxylic acid, such as. 8 # acetic acid, trifluoroacetic acid, formic acid, or the Benzyloxycarbonylgrupp® hydrogenolytically.

The reaction products of formula I can from the reaction mixture in the usual manner, Z ₉ B * by freeze-drying the water phase * chromatography or by precipitation as sparingly soluble. Salt, for example, as a hydroiodide or Hydrothlocyanatsalz be isolated «

The nucleophilic exchange reaction on compounds of the general formula II can also be carried out in such a way that the reaction is carried out in the presence of the base component corresponding to the radicals R and of trimethyliodosilane. This variant of the exchange reaction is advantageously carried out in such a way that a mixture of the compound II and the base In a suitable solvent, trimethyliodine may also be added. "It may also be done by first reacting the compound with trimethyl iodosilane according to the reaction conditions mentioned below, and then adding the base."

Suitable solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform * dichloroethane, trichloroethane, carbon tetrachloride, or lower alkylnitriles, such as acetonitrile or propionitrile,

The base is added in at least a stoichiometric amount up to a twofold excess, preferably

27.4.1984 AP C 07 D / 258 349 - 15 - 63 229/18

worked with a five * to five tenfold excess *.

Trimethyliodosilane is also added in at least a stoichiometric amount up to a twenty-fold excess, preferably in a five- to fifteen-fold excess.

The reaction preferably is performed at temperatures between "" 5 ⁰ C and +100 ⁰ C, between 10 ° and 80 ⁰ C, executed "

Pie reaction products of formula I, after hydrolysis of the reaction mixture by addition of water or aqueous mineral acids "z, B * diluted HcIf HBr, HO or H ₂ SO ₄ I from the aqueous phase in the usual Weisef z" B _# by freeze-drying the Waeserphase, chromatography and the like. "Preferably, the polar reaction products are precipitated from the aqueous solution in the form of a sparingly soluble salt, for example after the addition of KSCN or K3Al hydrothiocyanate or hydroiodealdehyde.

In the event that R stands for a carbamoyloxy group, the Auauschauschreaktion carried out analogously «

If R stands for halogen! In particular bromine or iodine, the exchange takes place in the manner known from the literature. If compound II is present in the form of a reactive derivative, silyl derivatives, for example, which are formed in the reaction of compounds of general formula II with a silyl compound, are suitable.

April 27, 1984 AP C 07 D / 258 349 - 16 · 63 229/18

like ζ. B ₄ trimethylchlorosilane or bis-trimethylsilyl) acetamide. In this case, the reaction is conveniently carried out in the presence of a solvent such as methylene chloride or acetonitrile.

The acylation d r Compounds of general formula III or their Additionsealzen, "for example, with acid hydrogen chloride *! Hydrobromic acid, nitric acid! »Sulfuric acid, phosphoric acid! or an organic acid "such as _{# 9} methanesulfonic acid p-toluenesulfonic acid or maleic acid" is carried out with carboxylic acids of general formula IV or with a reactive derivative of such an acid. In some cases it is an advantage! to protect the amino group of 5 ** general in the compounds of formula IV before the reaction dor. The protecting groups described above for R are suitable as amino protective groups. The protective group can be cleaved off after the acylation in catfish known per se, eg. B. the Trltylgruppe by means of a carboxylic acid, such as. Formic acid or trifluoroacetic acid, or the chloro * * acetyl group using thiourea «

If the carboxylic acids of the general formula IV and their derivatives protected by the amino group themselves are used as acylating agents, it is expedient to work in the presence of a condensing agent, for example a carbodiimide such as N, N'-dicyclohexylcarbodiimide *

The activation of carboxylic acids of general formula IV can be achieved in a particularly favorable manner by treatment with be »

April 27, 1984 AP C 07 D / 258 349 m 17 - 63 229/18

Carboxylic acid amides and, for example, phosgene "Phosphorperttachlorld, tosyl chloride, thionyl chloride or oxalyl chloride take place" as described z "B _# in the German Patent 28 04 040"

Particularly suitable as activated derivatives of the carboxylic acids of the general formula IV are halides, in particular chlorides which have been added in a manner known per se by treatment with halogenating agents, such as, for example, benzoic acid. B _# Phosphorus pentachloride "phosgene or thionyl chloride under gentle conditions known for cephalosporin chemistry"

All activated derivatives of the carboxylic acids of the general formula IV are furthermore suitable for the anhydrides and mixed anhydrides, azide-activated esters and thioesters, preferably p-nitrophenol, 2,4-D-nitrophenols, methyl cyanohydrin, N-hydroxysuccinimide and N-hydroxyphthalimide , in particular, those containing 1-hydroxybenzotriazole-6-chloro-1-hydroxybenzotriazole and 2-mercaptobenzothiazole. Particularly suitable mixed anhydrides are those with lower alkanoic acids, such as "B" acetic acid, and particularly preferably those with substituted acetic acids; such as trichloroacetic acid, pivalic acid or cyanoacetic acid. However, the mixed anhydrides with carbonic acid monoesters which are obtained, for example, by reacting the carboxylic acids of the formula IV in which the amino group is protected with benzyl chloroformate, p-nitrobenzyl ester, isobutyl ether, ethyl ester or allylester wins «The activated derivatives can be converted as isolated substances, but also in situ.

j 27 «4« 1984

AP C 07 D / 258 349 ~ 18 - 63 229/18

In general, the reaction of the cephem derivatives of the general formula III with a carboxylic acid of the general formula IV or an activated derivative thereof in the presence of an inert solvent "chlorinated hydrocarbons are particularly suitable" such as preferably methylene chloride and chloroform; Ethers, such as "B _# diethyl" ätheri preferably tetrahydrofuran and Dioxanj ketone, such as acetone, and preferably Butanonj amides, preferably dimethylformamide and dimethylacetamide, or pyridine "It may also prove advantageous ^1, to use mixtures of the solvents mentioned" This It is often the case when the cephem compound of general formula III is reacted with an in situ generated activated derivative of a carboxylic acid of formula IV.

The reaction of Oephemverblndungen of formula III with carboxylic acids of the formula IV or, whose activated derivatives in a temperature range from about -60 to about +80 ° C "preferably between" 30 and +50 ⁰ Cj but especially between about "20 ⁰ C and room temperature, «

The reaction time depends on the reactants, the temperature and the solvent or the solvent mixture and is normally between about 1/4 and about 72 hours.

The reaction with Säurehalogenlden can optionally be carried out in the presence of an acid-binding agent for binding the released hydrogen halide. "As such are particularly suitable tertiary amines, such as" B "triethylamine, Dimethylanllin or pyridine, inorganic

27.4 · 1984 AP C 07 D / 258 349 - 19 - 63 229/18

Basenf ^wi ® ^ζ · ^Β · potassium carbonate or sodium carbonate, alkylene oxides, such as ζ "B _# propylene oxide * The presence of a catalyst such. B _# of dimethylaminopyridine, may be an advantage «If in the compound of general formula III the amino group is present in the form of a reactive derivative« it may be one known from the literature for aramidations « For example, silyl derivatives come into consideration, which in the implementation of compounds of. general formula are formed III with a silyl compound such as _# B _# trimethylchlorosilane or bis '' (t rime thy lsilylj-acetamide. If the reaction is activated with such "on the amino group connection performed, so it is convenient to the reaction in a inert solvent, such "B _# methylene chloride, tetrahydrofuran or dimethyl formamide · * perform *

As physiologically acceptable acid addition salts of the compounds of the general formula I may be mentioned, for example, those with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid or organic acids, such as "B, methanesulfonic acid, p-toluenesulfonic acid or maleic acid. \

The compounds of the general formula III can be obtained in a manner known per se, for example from 7-aminocephalosporanic acid or 7-aminocephalosporanic acid protected on the amino group, in the same way as described above for the nucleophilic exchange of R.

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The compounds of the general formula IV and the pyridine, quinoline and isoquinoline bases corresponding to the radicals fC are known from the literature or can be prepared by processes known from the literature.

The compounds of the general formula I obtained according to the invention and their physiologically tolerated acid addition salts exhibit remarkably good antibacterial activity against both Gram-positive and Gram-negative bacterial germs.

Also against penicillnase- and cephalosporinase-producing bacteria, the compounds of formula I are unexpectedly effective. Since they also show favorable toxicological and pharmacological properties, they are valuable chemotherapeutic agents.

The invention thus also relates to pharmaceutical preparations for the treatment of microbial infections which are characterized by a content of one or more of the compounds according to the invention.

The products according to the invention can also be used in combination with other active ingredients, for example from the series of penicillins; Cephalosporins or aminoglycosides are used «

The compounds of the general formula I and their physiologically acceptable acid addition salts can be administered orally, intramuscularly or intravenously "medicaments,

27 * 4.1984 AP C 07 D / 258 349 m 21 - 63 229/18

which contain one or more compounds of the general formula I as active ingredient can be prepared by mixing the compounds of the formula I with a plurality of pharmacologically acceptable excipients or diluents, such as, for example, B * fillers, emulsifiers, lubricants, flavoring agents or buffer substances and in a suitable galenic preparation form brings »such as tablets! Dragees «Capsules or a suspension or solution suitable for parenteral administration»

For example, tragacanth, talc, agar, polyglycols, ethanol and water are mentioned as carriers or diluents. Buffer substances are, for example, organic compounds such as, for example, N, N'-dibenzylethylenediamine, diethanolamine, ethylenediamine, N- Methylglucamine, N-Benzylphenäthylamin, diethylamine, tris (hydroxymethyl) -aminomethan »or inorganic compounds, such as« B ₀ phosphate buffer, Natriumblcarbonat »sodium carbonate · For parenteral administration are preferably suspensions or solutions in water with or without buffer substances into consideration * It is also possible to apply the active compounds as such without carrier or diluent in a suitable form, for example in capsules.

Suitable doses of the compounds of the general formula I or their physiologically acceptable acid addition salts are about 0.4 to 20 g / day, preferably 0.5 to 4 g / day for an adult of about 60 kg body weight,

Single or generally multiple doses may be administered.

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The single dose may contain the active ingredient in an amount of about 50 to 1000 mg, preferably about 100 to 500 mg.

embodiment

The following exemplary embodiments of syn compounds which can be produced according to the invention serve to further explain the invention, but do not limit it to

example 1

3-Cy clop e η t enof * l ~ py r id i π i um) me t h ν l3 * »7» »f2« »gy n-me t h οχ y-

em-4- c arboxylate

t <) A mixture of 0 _t 57 g (1 mmol) of 7-l-2- (5-amino-1,2- _t- 4-thiadiazol-3-yl) 2-methyl-7-methoxyiminoacetamido-cephalofsporanic acid -trifluoroacetate, 30 mg ascorbic acid »6 _# 65 g (40 mmol) potassium iodide, 1.8 ml (15 mmol) 2,3-cyclopenteno-pyridine» 7 ml water and 3 ml acetone is heated at 65 to 67 ^° C. for 4 hours heated with stirring «After cooling, the dark-colored solution of silica gel CLobar ~ C« column »Merck) with acetone: Waeser (2: 1) Chromatography rt _#

The product fractions are concentrated and freeze-dried. This gives 0.14 g (27 % of theory, Th,) of a colorless amorphous solid »

* 27.4 «1984

AP C 07 D / 258 349 m 23. - 63 229/18

IR (KBrJ ,: 1770 cm ^-1 (lactam-CO)

¹ H NMR (CF CO ₂ D): </ *. 2.20 ~ 2 »80 (m ₄ 2H, cyclopentene-H),

3 »10-4 _# 05 (m _f 6H, 4 cyclopentene-H and SCH ₂ ); 4 ^ 30 (s, 3H, OCH ₃ ); 5 # 20-6.25 (m _# 4H * 3-CH ₂ and 2-lactam * * H) j 7.66-8 * 70 ppm (ro, 3H, Py)

ft) To a mixture of 0.57 g (1 mmol) of 7- (2- (5-aminol, 2,4-thiadiazol-3-yl) -2-syn-methoxyimino-acetamido-1-cephalosporanic acid trifluoroacetate and I _t 07 g (9 mmol) of 2 ^5, 3-cyclopentenopyridine in 10 ml of methylene chloride is added 4 g at 5 ⁰ C 1 »(7 mmol) and then 2 Trimethyljodeilan STUN 'the refluxed" After cooling, 7 ml of 2 n HCl, stirred for 10 minutes at ca, 15 ⁰ C and adjusted by addition of solid potassium bicarbonate to pH 6.5 · The aqueous phase is separated and chromatographed over a ^M Lobar-C ^M column with acetone: water (2: 1) "After freeze-drying of the product fractions, 0.29 g (56 % dTh) of a colorless solid is obtained, identical in all properties to that described above."

404 mg (2 mmol) of 2- (5-Amlno ~ l, 2 ~ _# 4 thiadiazol-3-yl) -2-synmethoxyimino-acetic acid are dissolved in 6 ml of N _t N-Oimethylformamld dissolved "After addition of 280 mg (2, 1 mmol) of 1-hydroxybenzotriazole hydrate and 410 mg (2 mmol) of N, N'-dicyclohexylcarbodiimide are stirred for 2 hours at room temperature. From the precipitated dicyclohexylurea is filtered and to the filtrate a solution of 808 mg (2 mmol) 7 "Amlno <-3- ( 2 * 3 ·· cy clopent eno-l-pyrldlnium) with hylj «ceph-S-em ^ -ca rboxy la t-

27 * 4 * 1984 AP C 07 D / 258 349 - 24 - 63 229/18

Dihydrochloride in 10 ml of N, N-dimethylformamide and 1 ml of water. The reaction is stirred at room temperature for 3 hours, concentrated in vacuo, and the residue is dissolved in 10 ml of water. From a little undissolved, filtered and the solution passed through a Lobar CV column with acetone : Water (2: 1) chromatographed *

The product fractions are freeze-dried to give 580 mg (56 % d * Th ") of the title compound as an amorphous solid *

It is identical in all properties to the connection described above *

Analogously to Example 1, the compounds listed below are obtained as amorphous solids which correspond to the general formula I with R "methyl and as the radical R carry the substituents indicated in the second column of Table 1 »

Table 1 Example R ^{2 1} H NMR InCF ₃ CO ₂ DiZ (PPRi)

2.15-4.0 (m, 6H, 4 cyclopentene-H, SCH ₂ ); 4.30 (s, 3H, OCH ₃ ); 5.15-6.35 (m, 5H, 3-CH ₂ , cyclopentenes H, 2 lactam-H); 7 ^ 7-8.8 ppm (m, 3H, Py)

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example

R ^{2 1} H NMR in CF CO ₉ D; <f (ppm)

2.2-3.9 (m, 8H, 6 cyclopentene-H, SCH ₂ ); 4.27 (3, 3H * OCH ₃ Ji 5 * 10 6.30 (η, 4H _f 3-CH ₂ and 2 lactam H) ₁ 7.7-8.8 ppm (m, 3H ₉ 'Py )

1.7-2.4 (m, 4 cyclohexene-H); 2.8-4 * 0 (m, 6H, 4-cyclohexene-H and SCH ₂ ); 4.30 (s, 3H, OCH ₃ ); 5.15-6.20 (m ^ 4H, 3-CH ₂ and 2 lactam-H); 7.55-6.68 ppm (m, 3H _# Py)

1 ^ 8-2.35 (m, 4-cyclohexene-H; 2.7, 3.9 (m, 6H, 4-cyclohexene-H and SCH ₂ ); 4.28 (β * x 3Η> OCH ₃ ); »10-6.25 (m, 4H ^ 3-CH ₂ and 2 lactam-H); 7.6-8 * 7 (m, 3H ₁ Py)

1.8-2.4 (m, 4-cyclohexene-H), 2.58 (s, 3H, CH ₃ ); 2 ^ 8-3.9 (m, 6Hv 4 cyclohexene-H and SCH ₂ ); 4.28 (β, 3Η, OCH ₃ ); 5.15-6.30 (m, 4H, 3-CH ₂ and 2 lactam-H); 8.15 and 8.42 ppm (each 1 be, 2 Py-H)

«·» -

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example ^A H "NMR in CF ₃ CO ₂ D: ό (ppm)

1.6-2.4 (m, 6 cyclohepten-H); 3.0-4.0 (m, 6H, 4 cycloheptene H and SCH ₂ )? 4> 30 (e ^ 3Hy OCH ₃ ); 5.20-6 * 35 (m, 4H, 3 "CH ₂ and 2 lactara H); 7.6-8.7 ppm (ro, 3Hi Py)

3.43 and 3 ^ 90 (AB, a »19Hz, 2H, SCH ₂ ); 4.30 (s, V3H, OCH _3); 5.25-6.40 (m, 4H, 3 "CH ₂ and 2 lactam H) i 7.90-8.60 (m, 5H, quinoline-H); 8.90-9v40 ppm (m _# 2H _# quinoline H)

3.41 and 3 ^ 92 (AB, 3 <L9Hz, 2H> SCH _2); 4 | 28 (sv 3H, OCH ₃ ); 5 ^ 26-6 ^ 30 (mi 4H _t 3-CH ₂ and 2 lactam-H each with 1 d at 5> 42 and © ill ^ 3 »5Hzj C-6 or» C-7-H); 8iO-8 ^ 8 (m, 6H, isoquinoline-H); 9.78 ppm (bs, IH, isoquinoline-H)

3.36 and 3.88 (AB, O 2H, SCH ₂ ); 4.30 (s * OCH ₃ ); 5.25-6.40 (mi 3-CH ₂ and 2 lactam-H); 7.8-8 ^ 8 (mi 5H _t quinoline-H); 9.1 ppm (d, α »6Ηζ (1 quinoline-H) 3 ^ 17 ppm (e, 3H, CH ₃ )

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Analogously to Example 1, the precursors listed below are all obtained amorphous solids which correspond to the general formula I * (R β 2,3 cyclopenteno-l pyridinium) and as the radical R carry the substituents indicated in the second column of Table 2

Table 2

CONH

example

¹ H-NMR in CF-CO ^ D _: <f (ppm)

3 2

C ₂ H ₅ 1.42 (t> 0a7Hz / 3H, CH ₂ CH ₃ ); 2,15-2j80 m, 2H | Cyclopentene-H); 3 * 1 ·· 4,0 (m, 6H, 4 cyclopentene-H and SCH ₂ ) J 4,48 (qi 3 «7Hz, 2H, CHgCH ₃ ) 5,15 ^ 6 ^ 35 (mi 4Hy 3« CH ₂ and 2 lactam-H); 7 _# 65-8 _A 70 ppm (m _# 3H, Py)

12 CH ₂ CH ₂ CH ₃ 1.10 (t, a = 6Hz, 3H, CH ₃ ); 1, 5-2jl (m _t 2Hj CH ₂ ); 2.15-2 ^ 8 (m ^ 2H | cyclopentene-H); 3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH ₂ ) j 4.45 (t, D »6Hz ^ NOCH ₂ ); 5 * 15-6.30 (m, 4H, 3-CH ₂ and 2 lactam-H); 7 _# 6 ~ 8.7 ppm (m, 3H, Py)

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Example ¹ H-NMR in CF ₃ CO ₂ Di <f (ppm)

13

CH (CH ₃ J ₂ 1 → 40 and 1.50 (di 0 = 6Hzi 6H »2 CH ₃ ), 2.2-2.8 (m, 2 cyclopentenes H) j, 3.10-4.00 (m , 6H, 4 cyclopentene-H and SCH ₂ ) ι 4.73 (m, IH, CH) j 5.20-6 * 30 (in, 4H, 3-CH ₂ and 2 lactam «H) j 7.65- 8.72 ppm (ra, 3H, Py)

14 CH ₂ CH * CH ₂ 2.2-2.8 (m, 2H, cyclopentene-H); 3.1-4.0 (m, 6H * 4 cyclopentenes H and SCH ₂ ) J 4.80-6.42 (m, 9H, S ^ allyl H, 3-CH ₂ and 2 lactam H); 7.65-8.70 ppm (m, 3H, Py)

15, 2.2-2.8 (m, 5H, 2 cyclopentene-H and SCH ₃ ); 3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH ₂ ) j 5.15 * 6.30 (m, 6H, CHgSj 3 -CH ₂ and 2 lactam-H); 7.67-8.72 ppm (mV 3H, Py)

16

CH,

lil-1.7 (m, 5H * cyclopropyl-H) j 2y2 ~ 2.8 (m, 2H, cyclopentene-H); 3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH ₂ ) J 4.25 (d, α "χ7Η2, 2Hj NOCH ₂ ); 5 ^ 2O-6V3O (m, 4H> 3, CH ₂ and 2 lactam-H); 7.66-8.70 ppm (m, 3H, Py)

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example

¹ H-NMR in CF-CO-D: if (ppm)

3 2

17

1.3-2.8 (m _# - 1OH, 2 cyclopentene-H, 8 cyclopentyl-H); 3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH ₂ ); 5.15-6.25 (m, 4H, 3-CH ₂ and 2 lactam-H); 7.6-8.7 ppm (m, 3H _t Py)

18 - CH ₂ CO ₂ CH ₃ 2.2-2.8 (m, 2H, cyclopentene-H); 3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH ₂ ) J 3.95 (β, 3H, CH ₃ ); 5 * 05 (S ₉ 2HV NOCH ₂ ) I 5.2-6V4 (m, 4H-f 3 -CH ₂ and 2 lactam-H); 7 ^ 65-8 »7ppm (ro, 3H, Py)

- CH ₂ CONH ₂ 2.2-2.8 (m, 2HV cyclopentene-H); 3.1-4.0 (m, 6H, 4 cyclopentene-H and SCH ₂ ); 4.90-6v35 (m, 6H ₁ NpCH ₂ V 3 -CH ₂ and 2 lactam-H); 7.65-8.70 ppm (m, 3H, Py)

20

-CH ₂ COOH 2,15-28 (m, 2H ^ cyclopentene-H) ί 3,1-3 * 9 (ι, 6H _# 4 cyclopentene-H and SCH ₂ ); 5.08 (β, 2Η, OCH ₂ ); 5 * 15-6.25 (m, 4H, 3-CH ₂ and 2 lactam-H); 7.65-8.70 ppm (m, 3H, Py)

21 1.80 (β, 6H, 2 X CH ₃ ); 2.10-2.8 (m * 2H, cyclopentene-H); 3.1-3.9 (m, 6H, SCH ₂ , 4 cyclopentene-H); 5.20-6.30 (m, 4H _t 3 -CH ₂ and 2 lactam-H); 7.68-8 * 72 ppm (ro, 3H, Py)

example

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¹ H-NMR in CF-COpD: / (ppm)

22

-CH ₂ CCOOH

CH

2. · (mV 2H | cyclopentenes); 3gi-3i9 (ro, 6H, 4 cyelopene-H and SCH); 5.1-6.40 (m, 6H, NOCH ₂ 3 <-CHg and 2 lactam H); 6 (ro, 2H ^ C * CH ₂ ) J 7 * 66-8; 70 ppm (Ϊ 3H-Py)

23

-.C-COOH

l _t 5-2j8 (ro, 6H, 2 cyclopentene-H, 4-cyclopropyl-H); 3.1-3 * 9 (m _f 6H | 4 cyclopentene-H and SCHg); 5.15-6.30 (B ^ 4Hi 3 -CH ₂ and 2 lactam-H); 7.66-8 ^ 70 ppm (mv 3Hv Py)

24

-C-COOH

2 ^ 0-4.0 (ro, 14Hi 6 cyclobutyl-H, 6 cyclopentene-H and SCH ₂ ); 5.15-6.40 (m, 4H, 3-CH ₂ and 2 lactam H) ι 7.60-8.70 ppm (m, 3H, Py)

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Analogously to Example 1, the compounds listed below are obtained as amorphous solids which "correspond to the general formula I with R" methyl and carry as the remainder Fr the sub-substituents indicated in the second column of Table 3 »

example

R ^{2 1} H-NMR in CF-CO ₉ D: / "(ppm)

-CO 119-2.45 (iti ♦ 2Hi pyran-H) j 2.65-3.25 (m, 2H, pyran * H); 3.42 and 3.75 (AB, 3 »19Hz, 2Hi SCH ₂ Ji 4.26 (β, 3Η, OCH ₃ ); 4.4-4.8 (m, 2H, pyran-H) i 4.85 -6.20 (m, 4H, CH ₃ Py and 2 lactam-4); 7.25 (d, 0 * 7Hz, Py-H); 8.2-8.6 (m, 2H, Py)

3 ^ 45 and 3j85 (AB ^ 0 = 19Hz, 2H, SCH ₂ ) I 4,22 (s, 3H, OCH ₃ ); 5.2-6.45 (m, 4H _f CH ₂ Py and 2 Uactam-H); 7.3 (m, IHO, 8.0-8.3 (m, 2H), 8.88 (d, 3 "7Ηζ, IH) and 9.43 (s, IH) furo-pyridine-H

27

3.47 and 3.85 (AB, 0 2H, SCH ₂ ); 4.22 (s, 3H, OCH ₃ ); 5.25-6.5 (m, 4H, CHgPy and lactam-H); 7.90 and 8.18 (one each d, D = 5Hz, 2 thiophene H); 8.35-8.8 (m, 2H, Py), 9.50 (β, IH, Py)

«32 -

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Example 1 H-NMR in CF ₃ CO ₂ D:

(Ppm)

28

-N 3.50 and 3 i 86 (AB, 3 = 19Hz, 2H, SOH ₂ ); 4.21 (s, 3H, OCH ₃ ) j 5.3-6.5 (m, 4H »CHgPy and 2 lactam ^ -H); 7.85 (d, 0 = 5Hz, 1 thiophene H, 8.2-8.8 (m, 3H) j 9.63 (s, IH, Py)

29

CH 3.26 (8, 3H, CH _3); 3.40 and 3 * 72 (AB, 0al9H2, 2H _{# SCH3)} · 4.23 (si 3H, _OCH3); 5.25-6.45 (m, 4H, CH ₂ Py and 2 lactam H); 7.75 (d, 3 = 5Hz, thiophene-H); 8.0-8.7 (iü, 3H, thienopyridine)

30

3.46 and 3.75 (AB, 0 «19Ηζ, 2Η, SCH ₂ ); 4 → 21 (s, 3H, OCH ₃ ); 5.2-6.5 (m, 4Hg CHgPy and 2 lactam-H); 7.6 ~ 8i2 (in, 3H) and 8.5-9.3 (in, 2H), thienopyridine

Claims (3)

27 _# 4 _# 1984 AP C 07 D / 258 349 - 33 - 63 229/18 ferfindunqsanspruch It is a process for the preparation of Oephemderivaten the general formula I. -. CONH
OR ¹ and their physiologically acceptable acid addition salts, wherein mean R Wa see ret off, optionally substituted .j * ^{c "c} _ß ~ alkyl, optionally substituted Cg-Cg-Alkeny C ₂ -C ₆ -alkynyl" C ₃ -C ₇ -CyCloalkyI ^ C ₃ -C ₇ C ₄ -CyClOaIkyl -C ₇ -CyClOalkenyl the group R ³ ic ( ^c H ₂ ) _n ( ^c ) _m ^R i in which m or η are each O or 1, and R may be the same or different and hydrogen »aryl, a C ^ -C ₄ alkyl group, or together with the carbon * to which they are attached, form a methylene or a C ₃ -C ₇ -cycloalkyl group; and cycloalkyl can be further mono- or polysubstituted "R is a group -C0 ₂ R ⁶ i in the R ^{6 is} hydrogen * C ₁ -C ₄ -alkyl * -CH ₂ OC ₁ -C ₄ -alkyl; -CH ₂ OOC-C ₁ -C ₄ -alkyl or a 27.4 * 1984 AP C 07 D / 258 349 «34 ~ 63 229/18 Equivalent of an alkali metal, alkaline earth metal, ammonium or an organic amine base; a nitrile group or a carbamoyl group "CONHg which may be substituted once or twice on nitrogen." R is a pyridinium radical Hv M ¹ S which is substituted * by 2 ortho-pendent alkyl groups "which are closed to an 'optionally substituted Di" to decamethylene * ring "in which a 0" atom may be replaced by a heteroatom and still contain one or two double bonds, "or a 1-quinolinium "Or eine2-Isochinoliniumrest" which may each be mono- or polysubstituted, identical or Various substituted by optionally substituted C ^ CgwAlkyl "C ^ -Cg-alkoxy, halogen, trifluoromethyl or hydroxy" and in which the R O group in syn -Pesition stands »characterized by« one a) a compound of general formula II N ι - C ^ - * CONH H N "0R ^J <Γ Ny ^ L CO ₂ H or their salts or a reactive derivative of compound II, wherein R is the abovementioned April 27, 1984 AP C 07 D / 258 349 - 35 ~ 63 229/18 and R is an amino or a protected amino group and R is a by those pyridines, quinolines or Isochinollnderivate «the Reets R of formula I correspond» exchangeable group, with these pyridine, quinoline or Isochinollnderivaten and splits off an optional protective group and ß) if necessary, "the product obtained is converted into a physiologically acceptable acid addition salt" or b) a 7-amino-cephem compound of the general formula III or their acid addition salts, in which R has the abovementioned meaning and where the amino group may also be in the form of a reactive derivative, with a 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-syn -oximinoacetic acid of the general formula IV April 27, 1984 AP C 07 D / 258 349 - 36 - 63 229/18 N ________ C _COOH N N IV, 17
wherein R and R have the abovementioned meaning * or reacted with an activated derivative of this compound and an optional protecting group splits off and ß) if necessary, the product obtained is converted into a physiologically acceptable acid addition salt. 2 «Method according to item 1», characterized in that the nucleophilic exchange of the substituent R in the presence of neutral salt ions, in particular of oxyde or thiocyanate ions · 3. The method according to item 1, characterized in that the 8 nucleophilic replacement of the substituent R in the presence of the radical R underlying base and of trimethyl * iodosilane takes place.