Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• This invention relates to new cephem compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
• the present invention relates to new cephem compounds and pharmaceutically acceptable salts thereof. More particularly, it relates to new cephem compounds and pharmaceutically acceptable salts thereof, which have antimicrobial activities, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a method for treating infectious diseases in human being and animals. Accordingly, one object of the present invention is to provide the cephem compounds and pharmaceutically acceptable salts thereof, which are highly active against a number of pathogenic microorganisms.
• Another object of the present invention is to provide processes for the preparation of the cephem compounds and salts thereof.
• R is amino or protected amino
• Z is N or CH
• 3 R is hydroxy or protected hydroxy.
• the object compound (I) of the present invention can be prepared by the following processes.
• R J R 2, R3 and Z are each as defined above,
• R is protected carboxy(lower)alkyl
• R, 2 is carboxy(lower)alkyl
• Ra is protected hydroxy
• X is a leaving group
• the starting compounds (Ila) and (V) can be prepared by the following Processes. - 6 -
• R 3, R3 a_. and X are each as defined above,
• R is amino or protected ammo, and is protected ammo
• syn isomer means one geometrical isomer having the partial structure represented by the following formula :
• anti isomer means the other geometrical isomer having the partial structure represented by the following formula :
• Suitable “protected amino” may include an acylamino or an amino group substituted by a conventional protecting group such as ar(lower)alkyl which may have suitable substituent(s) (e.g. benzyl, trityl, etc.) or the like.
• suitable "acyl moiety" in the term “acylamino” may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic or heterocyclic ring.
• suitable examples of the said acyl may be lower alkanoyl (e.g.
• acyl moiety as stated above may have suitable substituent(s) such as halogen (e.g. chlorine, bromine, iodine or fluorine) or the like.
• halogen e.g. chlorine, bromine, iodine or fluorine
• Suitable “organic group” may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.), mono(or di or tri)halo(lower)alkyl (e.g. chloromethyl, dichloromethyl, trichloromethyl,.
• lower alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.
• mono(or di or tri)halo(lower)alkyl e.g. chloromethyl, dichloromethyl, trichloromethyl,.
• lower alkenyl e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.
• lower alkynyl e.g.
• aryl e.g., phenyl, naphthyl, etc.
• ar(lower)alkyl such as phenyl(lower)alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.
• Suitable "protected carboxy” and “protected carboxy moiety" in the term “protected carboxy(lower)alkyl” may include esterified carboxy and the like.
• suitable examples of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); lower alkoxyalkyl ester (e.g., methoxymethyl ester, ethoxy ethyl ester, isopropoxymethyl ester,
• mono(or di or tri)halo(lower)alkyl ester e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.
• lower alkanoyloxy(lower)alkyl ester e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.
• lower alkanesulfonyl(lower)alkyl ester e.g.
• ar(lower)alkyl ester for example, phenyl(lower)alkyl ester which may have one or more suitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may have one or more suitable substituent(s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chloroph
• Suitable “protective group” in the “protected hydroxy” may include acyl as mentioned above, phenyl(lower)alkyl which may have one or more su table substituent(s) (e.g. benzyl, 4-methoxybenzyl, etc.), tetrahydropyranyl and the like.
• Suitable “leaving group” may be halogen [e.g. chlorine, bromine, iodine, etc. ] , acyloxy such as sulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, mesyloxy, etc.], lower alkanoyloxy [e.g. acetyloxy, propionyloxy, etc. ] or the like.
• halogen e.g. chlorine, bromine, iodine, etc.
• acyloxy such as sulfonyloxy [e.g. benzenesulfonyloxy, tosyloxy, mesyloxy, etc.], lower alkanoyloxy [e.g. acetyloxy, propionyloxy, etc. ] or the like.
• Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt [e.g. - 13 -
• an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
• an ammonium salt e.g. calcium salt, magnesium salt, etc.
• an organic base salt e.g. trimethylamine salt, triethyla ine salt, .pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt etc.
• an organic acid salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
• an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.]
• a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
• Preferred embodiments of the object compound (I) are as follows.
• R is amino or protected amino [more preferably acylamino] ,
• Z is N or CH
• R is lower alkyl, carboxy(lower)alkyl or protected carboxy(lower)alkyl [more preferably esterified carboxy(lower)alkyl, most preferably lower alkoxycarbonyl(lower)alkyl]
• 3 R is hydroxy or protected hydroxy [more preferably phenyl(lower)alkyloxy which may have one or more suitable substituent(s) ] .
• the compound (I) or a salt thereof can be prepared by reacting the compound (Ila) or its reactive derivative at the amino group, or a salt thereof with the compound (III) - 14 -
• Suitable reactive derivative at the amino. group of the compound (Ila) may ' include Schiff's base type imino or its tautomeric enamine type ' isomer formed by the reaction of the compound (Ila) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Ila) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide [e.g.
• Suitable reactive derivative at the carboxy group of the compound (III) may include a conventional one uses in a ⁇ -lactam chemistry, an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
• Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g.
• dialkylphosphoric acid phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.
• dialkylphosphorous acid sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.]
• aliphatic carboxylic acid e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.
• aromatic carboxylic acid e.g.
• benzoic acid etc.
• a symmetrical acid anhydride an activated amide with imidazole, 1-hydroxy-lH-benzotriazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.
• the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, ethylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
• a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, ethylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
• a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloro
• the reaction when the compound (III) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodii ide; N,N' -diethylcarbodiimide, N ,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N'-carbonyl-bis(2-methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy
• the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
• an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
• the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
• the compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.
• the present reaction may be carried out in a solvent such as acetone, chloroform, acetonitrile, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction.
• a solvent such as acetone, chloroform, acetonitrile, methylene chloride, ethylene chloride, formamide, N,N-dimethylformamide, methanol, ethanol, diethyl ether, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent which does not adversely affect the reaction.
• the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
• the reaction is usually carried out in the presence of an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.],
• diisopropylethylamine etc. a diisopropylethylamine etc.] picoline, alkali metal alkanoate [e.g. sodium 2-ethylhexanoate, etc.], N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.
• alkali metal alkanoate e.g. sodium 2-ethylhexanoate, etc.
• N-(lower)alkylmorpholine N,N-di(lower)alkylbenzylamine, or the like.
• the compound (lb) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to elimination reaction of the carboxy protective group. Suitable method of this elimination reaction may include conventional one such as hydrolysis, reduction and the like.
• the hydrolysis is preferably carried out in the presence of.a base or an acid including Lewis acid.
• Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, l,5-diazabicyclo[4.3.0]- non-5-ene, 1,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
• Suitable acid may include an organic acid [e.g.
• trichloroacetic acid e.g. trichloroacetic acid, trifluoroacetic acid, etc.
• cation trapping agents e.g. anisole, phenol, etc.
• the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], - 18 -
• a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], - 18 -
• reaction temperature is not critical and the reaction is usually carried " out under cooling to warming.
• Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
• Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobro ic acid, etc.).
• a metal e.g. tin, zinc, iron, etc.
• metallic compound e.g. chromium chloride, chromium acetate, etc.
• organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobro ic acid,
• Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.) copper catalysts (e.g.
• platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
• palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon
• the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.
• a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture ⁇ hereof.
• the reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
• the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the hydroxy protective group.
• This reaction can be carried out in a similar manner to that of the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g. solvent, reaction temperature, etc.) can be referred to those of the Process (3) .
• the compound (V) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the amino group, or a salt thereof with the compound (VII) or its reactive derivative at the carboxy group, or a salt thereof.
• This reaction can be carried out in a similar manner to that of the aforementioned Process (1) , and therefore the reagents to be used and the reaction conditions (e.g. solvent, reaction temperature, etc.) can be referred to those of the Process (1).
• the reaction conditions e.g. solvent, reaction temperature, etc.
• the compound (II) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (V) or a salt thereof.
• the reaction is usually carried out in a conventional solvent such as alcohol (e.g., methanol, ethanol. - 2 -
• reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
• the reaction is usually carried out in the presence of an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, tri(lower)alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine etc.], picoline, or the like.
• an alkali metal e.g. sodium, potassium, etc.
• an alkaline earth metal e.g. magnesium, calcium, etc.
• tri(lower)alkylamine e.g. trimethylamine, triethylamine, diisopropylethylamine etc.
• the compound (lie) or a salt thereof can be prepared by subjecting the compound (lib) or a salt thereof to elimination reaction of the hydroxy protective group.
• This reaction can be carried out in a similar manner to that of the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g. solvent, reaction temperature, etc.) can be referred to those of the Process (3) .
• the reaction conditions e.g. solvent, reaction temperature, etc.
• the compound (Ila) or a salt thereof can be prepared by subjecting the compound (lid) or a salt thereof to elimination reaction of the amino protective group.
• This reaction can be carried out in a similar manner to that of the aforementioned Process (3) , and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3) . '
• the object compound (I) and pharmaceutically acceptable salts thereof are novel and exhibit high antimicrobial activity, inhibiting the growth of a wide variety of pathogenic microorganisms including Gram-positive and Gram-negative microorganisms and are useful as antimicrobial agents.
• test data on MIC minimum inhibitory concentration
• representative compound of this invention are shown in the following.
• Test method In vitro antibacterial activity was determined by the two-fold agar-plate dilution method as described below. One loopful of an overnight culture of each test
• Test compound 7 ⁇ -[2-(5-Amino-l,2,4-thiadiazol-3-yl)-2-(1-carboxy-l- methylethoxyimino)acetamido]-3-[3- ⁇ (5-hydroxy-4-oxo-l,4- dihydropyridin-2-yl)carbonylamino ⁇ -l-pyridinio]methyl-3- cephem-4-carboxylate (syn isomer)
• the object compound (I) and pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
• pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
• the pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
• auxiliary substances such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
• dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amounts between 1 mg and about 4,000 mg or even more per day may be administered to a patient.
• An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg of the object compound (I) of the present invention may be used in treating diseases infected by pathogenic microorganisms.
• the powder (27.9 g) was dissolved in water (279 ml) by adjustment to pH 8 with IN sodium hydroxide, and the solution was adjusted to pH 6.5 with IN hydrochloric acid, and the resulting precipitate was removed by filtration, and the filtrate was subjected to column chromatography on Diaion HP-20 (140 ml) and eluted with water.
• the eluate (1290 ml) was adjusted to pH 1 with 6N hydrochloric acid, and the resulting precipitate was removed by filtration, and - the filtrate was subjected to column chromatography on Diaion HP-20 (420 ml). The column was washed with water (4.2 I ) .
• the desired product was eluted with 30% aqueous tetrahydrofuran, and the eluate (1.26 SL ) was evaporated to 850 ml and cooled to 7°C.
• the resulting powder was - ⁇ -) ⁇ -
• the desired product was eluted with 35% aqueous methanol, and the eluate was lyophilized to give 7 ⁇ -[2-(5-amino-l,2,4-thiadiazol-3-yl)- 2-(1-carboxy-1-methylethoxyimino)aceta ido]-3-[3- ⁇ (5- hydroxy-4-oxo-l,4-dihydropyridin-2-yl)carbonylamino ⁇ -l- pyridinio]methyl-3-cephem-4-carboxylate (syn isomer) (79 mg) .

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• 1991
  • 1991-05-28 GB GB919111406A patent/GB9111406D0/en active Pending
• 1992
  • 1992-05-23 TW TW081104045A patent/TW202454B/zh active
  • 1992-05-27 JP JP4509891A patent/JPH06510523A/ja active Pending
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