Claims
- 1. A cephalosporin compound substituted by an imidazolium ring in 3-position of cephem having the formula (I) or (II) ##STR119## wherein R.sup.1 is ##STR120## wherein R.sup.9 is C.sub.2 -C.sub.6 alkenyl or C.sub.2 -C.sub.6 alkynyl; R.sup.2 is hydrogen or methoxy; R.sup.4 is C.sub.2 -C.sub.12 alkenyl or C.sub.2 -C.sub.12 alkynyl; and n is 0 to 1.
- 2. A compound according to claim 1, wherein R.sup.2 is hydrogen and n is 0.
- 3. A compound according to claim 2, wherein R.sup.9 is --CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 C.tbd.CH
- 4. A compound according to claim 2, wherein R.sub.4 is --CH.sub.2 CH.dbd.CH.sub.2, --CH.sub.2 C.tbd.CH or --CH.dbd.CH.sub.2.
- 5. A pharmaceutical composition for preventing and treating bacterial infections, said composition comprising an anti-bacterially effective amount of a cephalosporin compound of claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.
- 6. A method of preventing or treating bacterial infections in a patient in need of such therapy, said method comprising administering to said patient an anti-bacterially effective amount of a cephalosporin compound of claim 1.
Priority Claims (2)
| Number |
Date |
Country |
Kind |
| 60-194385 |
Sep 1985 |
JPX |
|
| 61-107262 |
May 1986 |
JPX |
|
Parent Case Info
This application is a continuation of Ser. No. 902,878, file Sept. 2, 1986, now abandoned.
The present invention relates to a novel cephalosporin compound substituted by imidazolium ring in C-3' position of cephem having the following formula (I) and having an anti-bacterial activity, pharmaceutically acceptable salt thereof, process thereof and pharmaceutical composition containing the derivative, ##STR2## wherein R.sup.1 is an organic residue known in .beta.-lactam antibiotics, R.sup.2 is hydrogen atom or methoxy, n is 0 or 1, A is the following nitrogen-containing group constituting imidazolium ring ##STR3## B is the following carbon-containing group constituting imidazolium ring ##STR4## R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen atom, substituted or unsubstituted C.sub.1 -C.sub.12 alkyl, substituted or unsubstituted C.sub.2 -C.sub.12 alkenyl, substituted or unsubstituted C.sub.2 -C.sub.12 alkynyl, substituted or unsubstituted C.sub.3 -C.sub.7 cycloalkyl, substituted or unsubstituted C.sub.1 -C.sub.6 lower alkoxyl, substituted or unsubstituted lower alkanoyl, carboxy lower alkyl, alkylcarbonylalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, lower alkylthio, carbamoyl, thiocarbamoyl, amino, amino lower alkyl, ureido, hydroxyl, halogen atom, mercapto, nitro, cyano, carboxyl, thienyl, furyl or pyridyl, X.sup..crclbar. is halogen atom or acid residue.
In a cephalosporin compound having the following formula (I), and pharmaceutically acceptable salt thereof ##STR5## wherein R.sup.1, R.sup.2, R.sup.3, n, A and B are same as above, there may be at least one stereoisomers such as optical isomers due to the presence of asymmetric carbon atom(s) in the molecule. The present invention includes such isomers.
Examples of useful salts of the present compound (I) are those which are pharmaceutically acceptable such as alkali metal salts (sodium salt, potassium salt, etc), alkaline earth metal salts (calcium salt, magnesium salt, etc), ammonium salt, organic amine salts (triethylamine salt, pyridinium salt, etc), inorganic acid addition salts (hydrochloride, hydrobromide, etc), organic acid addition salts (formate, trichloroacetic acid salt, methanesulfonic acid salt, etc), salts with a basic or acidic amino acid (arginine salt, aspartic acid salt, glutamic acid salt, etc).
In the present compound of the formula (I), examples of R.sup.1, which are organic residue known in .beta.-lactam antibiotics, are organic residues having 4 to 6 membered heterocyclic ring containing 1 to 4 of each of sulfur, nitrogen or oxygen atom.
Examples of such organic residues are ##STR6## wherein D is oxygen atom or sulfur atom, R.sup.15 is substituted or unsubstituted amino, R.sup.9 is hydrogen atom; methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and like C.sub.1 -C.sub.6 alkyl; vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl and like C.sub.2 -C.sub.6 alkenyl; acetylenyl, propargyl and like C.sub.2 -C.sub.6 alkynyl; cyclopropyl, cyclobutyl, cyclopentyl and like C.sub.3 -C.sub.7 cycloalkyl; cyclopentenyl, cyclohexenyl and like C.sub.4 -C.sub.7 cycloalkenyl; alkyl or alkenyl substituted by chlorine, bromine, iodine or fluorine; alkyl substituted by methylthio, ethylthio or propylthio; alkyl substituted by phenyl or benzyl; thienyl, furyl, thiazolyl and like heterocyclic ring; ##STR7## wherein R.sup.10 and R.sup.11 are same or different and are each hydrogen atom; methyl, ethyl, propyl, isopropyl, butyl and like C.sub.1-6 alkyl, and preferably hydrogen atom, methyl or ethyl. R.sup.12 is hydrogen atom; monovalent alkali metal such as sodium, potassium or lithium, preferably sodium or potassium; divalent alkaline earth metal such as calcium or magnesium; organic amine salts such as trimethylamine, triethylamine, methylamine, propylamine, N,N-dimethylethanolamine; a protective group for carboxyl such as tert-butyl, benzhydryl, 2,2,2-trichloroethyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, diphenylmethane or phenacyl.
Other examples of organic residues represented by R.sup.1 are ##STR8## wherein D is oxygen atom or sulfur atom, R.sup.15 is substituted or unsubstituted amino, R.sup.13 is methyl, ethyl, propyl and like C.sub.1-6 lower alkyl; vinyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, acetylenyl, propargyl and like C.sub.2-6 lower unsaturated alkyl; cyclopropyl, cyclobutyl, cyclopentenyl and like C.sub.3-7 cycloalkyl; nicotine, isonicotine, thienyl, furyl and like heterocyclic ring; carboxyl or esterified carboxyl; halogen atom; nitro; amino; hydroxyl; cyano; substituted or unsubstituted phenyl or benzyl; ##STR9## wherein R.sup.15 is same as above, ##STR10##
In case R.sup.1 is an organic residue having substituted or unsubstituted aromatic phenyl, examples thereof are ##STR11##
When R.sup.1 is an organic residue having substituted or unsubstituted alkyl, examples thereof are ##STR12##
When R.sup.1 is an organic residue having substituted or unsubstituted alkyl, examples thereof are ##STR13##
In the invention, R.sup.2 is hydrogen atom or methoxy, R.sup.14 is hydrogen atom; metal atom such as sodium, potassium, etc; ester residue; salt-forming cation; or anion charge when COO- forms intra- or inter-molecular salt with cation pair. Examples of ester residues are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and like C.sub.1-6 lower alkyl; 2,2,2-trichloroethyl and like lower haloalkyl; benzyl, p-methoxybenzyl, trimethoxybenzyl, trimethoxydichlorobenzyl, p-nitrobenzyl, benzhydryl, and like substituted or unsubstituted phenylalkyl; a protective group for carboxyl such as diphenylmethyl, trityl, ditolylmethyl, phenyl-p-methoxyphenylmethyl, .alpha.-p-methoxyphenylethyl, .alpha.-p-methoxyphenyl-.beta.-trichloroethyl, .alpha.-diphenylethyl, trimethylsilyl, benzyloxymethyl or phenacyl.
R.sup.3 to R.sup.8 are hydrogen atom; substituted or unsubstituted, straight-chain or branched-chain C.sub.1 -C.sub.12 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decanyl, undecanyl, dodecanyl, etc; substituted or unsubstituted, C.sub.2 -C.sub.6 alkenyl such as vinyl, allyl, isopropenyl, butenyl, methallyl, etc; C.sub.2 -C.sub.12 alkynyl such as propargyl, etc; substituted or unsubstituted, C.sub.3 -C.sub.7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc; lower alkoxyl such as methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl and like C.sub.1 -C.sub.6 alkoxyl; substituted or unsubstituted lower alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, etc; carboxy lower alkyl such as carboxymethyl, carboxyethyl, etc; alkylcarbonylalkyl such as methylcarbonylmethyl, ethylcarbonylmethyl, methylcarbonylethyl, ethylcarbonylethyl, etc; substituted or unsubstituted phenyl such as phenyl, tolyl, xylyl, hydroxyphenyl, acetylphenyl, etc; substituted or unsubstituted benzyl such as benzyl, tolylmethyl, etc; lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc; amino lower alkyl such as aminomethyl, aminoethyl, etc; halogen atom such as chlorine, bromine, fluorine, iodine, etc; carbamoyl; thiocarbamoyl; amino; ureido; hydroxyl; mercapto; nitro; cyano; carboxyl; heterocyclic ring such as thienyl, furyl, pyridyl, etc. These may have further substituent(s).
The cephalosporin compounds (I) and salts thereof of the invention can be prepared by various methods. Preferred methods are shown by the following two synthetic routes. ##STR14## wherein R.sup.1 and R.sup.2 are same as above, R.sup.14 is hydrogen atom, metal atom, ester residue, salt-forming cation, or anion charge when COO- forms intra- or iter-molecular salt with cation pair, n is 0 or 1, X is a group which can be replaced by a substituted or unsubstituted imidazole compound.
Compound (II) or salt thereof can be obtained by reacting Compound (VII), a reactive derivative in amino group or salt thereof and Compound (VI), a reactive derivative in carboxyl group or salt thereof. As salts of Compounds (VII) and (VI) are used the same salts enumerated with respect to Compound (I). Examples of reactive derivatives of Compound (VII) in amino group are a silyl derivative obtained from Compound (VII) and a silyl compound [e.g., bis(trimethylsilyl)acetamide, trimethylsilyl chloride, etc], a derivative obtained from Compound (VII) and an isocyanate or isothiocyanate compound, a Schiff base or its enamine-type tautomer formed by the reaction of Compound (VII) and a carbonyl compound [e.g., acetaldehyde, benzaldehyde and like aldehydes, acetone, methyl ethyl ketone and like ketones], etc.
Examples of reactive derivatives of Compound (VI) in carboxyl group are an acid chloride, acid bromide and like acid halides; an acid anhydride or symmetric acid anhydride with a substituted phosphoric acid, dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonate, organic carboxylic acid and like acids; an activated acid amide with an imidazole, dimethyl pyrazole, etc; an activated ester such as p-nitrophenyl ester, phenylthioester, carboxymethyl thioester, an ester with an N-hydroxypiperidine, N-hydroxysuccinimide, N-hydroxyphthalimide and like N-hydroxyl compounds; etc.
In the reaction are usable a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, benzene, ethyl acetate, N,N-dimethylformamide, pyridine, hexane, etc, which does not affect the reaction. The solvent can be used singly or in admixture. The reaction temperature is not particularly limited and the reaction can be conducted under cooling or heating and preferably at about -20.degree. to +40.degree. C.
The reaction can be conducted in the presence of an organic or inorganic base. Examples of useful bases are lithium, sodium, potassium and like alkali metals; calcium, magnesium and like alkaline earth metals; sodium hydroxide and like alkali metal hydroxides; sodium hydride and like alkali metal hydrides; calcium hydride and like alkaline earth metal hydrides; sodium carbonate and like alkali metal carbonates; potassium hydrogen carbonate and like alkali metal hydrogen carbonates; sodium ethoxide and like alkali metal alkoxides; triethylamine and like trialkylamine; pyridine, picoline, quinoline and like nitrogen-containing heterocyclic compounds; etc. Among these bases, preferably used are trialkylamine and nitrogen-containing heterocyclic compound. The amounts of the base to be used are not particularly limited but are usually up to 25 equivalents, preferably 0.25 to 4 equivalents per equivalent of Compound (VII).
In the above reaction, the proportions of Compound (VII) and Compound (VI) to be used are not particularly limited and are selected from a wide range. However, it is preferable to use in the equivalent ratio of the former: the latter of 1:5 to 5:1, more preferably of 1:2 to 2:1.
In case Compound (VI) is used in the form of free acid or salt thereof, the reaction is conducted preferably in the presence of a condensing agent. Examples of useful condensing agents are N,N'-dicyclohexyl carbodiimide and like carbodiimide compounds; diphenyl ketene-N-cyclohexylimine and like ketene-imine compounds; ethoxyacetylene, .beta.-chlorovinyl ethyl ether and like unsaturated alkyl ether compounds; sulfonic acid ester of N-hydroxybenzotriazole derivative [e.g., 1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole etc]; trialkylphosphite or triphenylphosphine with carbon tetrachloride, ethyl polyphosphate, phosphorus trichloride and like phosphorus compounds; thionyl chloride; Vilsmeyer reagent (formed from the reaction of N,N-dimethyl formamide, N-methyl formamide and like amide compound and thionyl chloride, phosphoryl chloride, phosgene and like halogen compound); etc. The above condensing agent is used usually in an amount of up to 25 equivalents, preferably 0.25 to 4 equivalents per equivalent of Compound (VII). ##STR15## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.14, A, B, X.sup..crclbar. and n are same as above.
The reaction of replacing C-3' position of Compound (II) by substituted or unsubstituted imidazoles (III) is preferably conducted in water or an organic solvent in the presence of a base or propylene oxide. Examples of organic solvents are acetonitrile, methanol, acetone, N,N-dimethyl formamide, tetrahydrofuran, etc. and these are used singly or in mixture thereof. The base includes sodium carbonate, sodium hydrogen carbonate, triethylamine, etc. The reaction temperature is not particularly limited but the reaction is carried out usually under cooling or heating and preferably at a temperature of about -10.degree. to 40.degree. C.
When R.sup.1 or R.sup.14 in Compound (IV) is amino-protecting group or carboxyl-protecting group, or when n is 1, Compound (I) is obtained by the reaction of removing amino-protecting group or carboxyl-protecting group, or by the reduction, respectively. The elimination reaction and reduction can be conducted by a usual manner such as by hydrolysis, reduction, etc. as shown below.
(A) Hydrolysis
The hydrolysis is conducted preferably in the presence of an acid. Examples of useful acids are hydrochloric acid, hydrobromic acid, sulfuric acid and like inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid and like organic acids.
The hydrolysis is usually conducted in water, methanol, tetrahydrofuran, N,N-dimethyl formamide, dioxane, benzene, hexane and the like, or mixtures of such solvents, and which does not affect the reaction. In case the acid is liquid, the acid can be used as a solvent.
The reaction temperature is not particularly limited but the hydrolysis is preferably conducted under cooling or heating.
(B) Reduction
The reduction includes usual methods such as chemical reduction, catalytic reduction, etc.
Examples of chemical reducing agents are a combination of metal or metallic compound such as tin, zinc, iron, chromium chloride, chromium acetate and organic or inorganic acid such as formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid; phosphorus tribromide; etc.
Catalysts used in the catalytic reduction include usual one containing a heavy metal such as platinum, palladium, rhodium, nickel, copper, cobalt, iron, etc.
The catalytic reduction is usually conducted in water, methanol, N,N-dimethyl formamide, hexane, benzene, dioxane and the like, or mixtures of such solvents, and which does not affect the reaction. In case the acid is liquid, the acid can be used as a solvent.
The reaction temperature is not particularly limited but the catalytic reduction is preferably conducted under cooling or heating. ##STR16## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.14, A, B, X.sup..crclbar. and n are same as above.
Compound (IV) or salt thereof can be obtained by reacting Compound (V), a reactive derivative in amino group or salt thereof and Compound (VI), a reactive derivative in carboxyl group or salt thereof. As salts of Compounds (V) and (VI) are used the same salts enumerated with respect to Compound (I). Examples of reactive derivatives of Compound (V) in amino group are same compounds which are mentioned with respect to Compound (VII) in Synthetic route-1.
As reactive derivatives of Compound (VI) in carboxyl group are enumerated the same compounds as above.
In the reaction are used the same solvents as described in the above Synthetic route-1. The reaction temperature is not particularly limited and the reaction can be conducted under cooling or heating and preferably at about -20.degree. to +40.degree. C.
The reaction can be conducted in the presence of an organic or inorganic base. As the bases are used the same compounds as mentioned in the above Synthetic route-1. The amounts of the base to be used are not particularly limited but are usually up to 25 equivalents, preferably 0.25 to 4 equivalents per equivalent of Compound (V).
In the above reaction, the proportions of Compound (V) and Compound (VI) to be used are not particularly limited and are selected from a wide range. However, it is preferable to use in the equivalent ratio of the former: the latter of 1:5 to 5:1, more preferably of 1:2 to 2:1.
In case Compound (VI) is used in the form of free acid or salt thereof, the reaction is conducted preferably in the presence of a condensing agent. As the condensing agents are employed the same compounds as described in the above Synthetic route-1. The above condensing agent is used usually in an amount of up to 25 equivalents, preferably 0.25 to 4 equivalents per equivalent of Compound (V).
When R.sup.1 or R.sup.3 in Compound (IV) is amino-protecting group or carboxyl-protecting group, or when n is 1, Compound (I) is obtained by the reaction of removing amino- or carboxyl-protecting group, or by the reduction, respectively. As the elimination reaction or reduction is conducted the same reaction as mentioned in the above Synthetic route-1.
The present Compound (I) has an excellent anti-bacterial activity and is useful for an agent for preventing and treating bacterial infections.
For preventing and treating is used a usual preparation containing, as an effective component, the present Compound (I) or a salt thereof and a pharmaceutically acceptable carrier such as an organic, inorganic, solid or liquid adjuvant suitable to oral, parenteral or local administration. The preparation may be in the form of a tablet, granule, powder, capsule and like solid form, or solution, suspension, syrup, emulsion, lemonade and like liquid form. To the preparation is added as required an auxiliary substance, stabilizer, lubricant, and other usual additives such as lactose, magnesium stearate, kaolin, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, etc.
The dosage of Compound (I) varies depending on age and situation of a patient, kind of disease or compound to be administered, etc. Usually, about 1 to 4000 mg or more of Compound (I) can be daily administered to a patient. For treating bacterial infections is administered Compound (I) in an average dosage per one time of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg.
The invention will be described with reference to Examples and Test Example which are not to be construed as limiting the scope of the invention. In the following, Tr is trityl group, tBu tertiary butyl group.
US Referenced Citations (3)
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Oct 1982 |
EPX |
| 0137442 |
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EPX |
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Continuations (1)
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Number |
Date |
Country |
| Parent |
902878 |
Sep 1986 |
|
Patent Grant
4906623
