CA1049504A - Penicillins and their production - Google Patents
Penicillins and their productionInfo
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- CA1049504A CA1049504A CA166,058A CA166058A CA1049504A CA 1049504 A CA1049504 A CA 1049504A CA 166058 A CA166058 A CA 166058A CA 1049504 A CA1049504 A CA 1049504A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
PENICILLINS AND THEIR PRODUCTION
Abstract of the Disclosure Penicillins of the formula:
(IA) wherein is a six-membered heteroaromatic ring containing 1 or 2 hetero nitrogen atoms, R is phenyl, p-hydroxyphenyl, C1-C4 alkyl, cyclohexadienyl, thienyl or isothiazolyl, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano or R1 and R2 linked together represent a lower alkylene chain optionally substituted with an oxo group, and non-toxic, pharmaceutically acceptable salts thereof are prepared by reacting a compound of the formula:
wherein R is as defined above, or a derivative thereof, with a carboxylic acid of the formula:
wherein
Abstract of the Disclosure Penicillins of the formula:
(IA) wherein is a six-membered heteroaromatic ring containing 1 or 2 hetero nitrogen atoms, R is phenyl, p-hydroxyphenyl, C1-C4 alkyl, cyclohexadienyl, thienyl or isothiazolyl, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano or R1 and R2 linked together represent a lower alkylene chain optionally substituted with an oxo group, and non-toxic, pharmaceutically acceptable salts thereof are prepared by reacting a compound of the formula:
wherein R is as defined above, or a derivative thereof, with a carboxylic acid of the formula:
wherein
Description
o~
This invention re]ates to penicillins and their production. More particularly, it relates to novel derivatives _ of 6-(~-aminophenylacetamido)-penicillanic acid and 6~(~-amino-thienylacetamido)-penicillanic acid and to processes for their production.
As is well known, 6-(~-aminophenylacetamido)-penicillanic acid (i.e. ampicillin) inhibits the growth of various gram-positive and gram-negative bateria but does not exert any appreciable antimicrobial activity against Pseudomonas. In U.S. patent No.
3,433,784, certain N-acyl derivatives of ampicillin are described as showing a minimal inhibitory concentration of 125 to 250~ ~g/ml against Pseudomonas pyocinea A or R 59, when determined by the standard test method. The anti-Pseudomonas activity of the compounds described in the working examples is, however, not so high and the antimicrobial activity against other gram-positive and gram-negative bacteria is considerably lower. Thus, it may be concluded that these N-acyl derivatives of ampicillin are actually less valuable from the practical viewpoint.
As the result of studies seeking novel penicillins which have a broad antimicrobial spectrum and are highly active against gram-positive and gram-negative bacteria including Pseudomonas, it has now been found that penicillins of the following formula characteristically exhibit noticeable antimicrobial activity against Pseudomonas and a broad antimicrobial spectrum:
OY
l ~ \C-~ONH-CH-CO~I-CH-CII C ~CH~ (I) C ~ 0~,C- N - CH-~OOH
wherein ( Ç is a six-membered heteroaromatic ring selected from A -pyridine, pyrimidine, pyridazine and pyrazine, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and Rl and R2 are each hy-drogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano or R
. .
', ~ ; J
~4~51~4 and R2 linked together represent cyclopenteno, cyclohexeno or cyclohepteno optionally substituted with an oxo group.
The term "lower alkyl" as used herein means straight or branched chain saturated aliphatic hydrocarbon having from one to eight carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl or isoamyl. Similarly, where the term "lower" is used as a part of the description of any other group (e.g. lower alkoxy, lower alkanoyl, lower alkylmercapto), it refers to the alkyl portion of such group. The heteroaromatic ring may be, pyridine, pyrimidine, pyridazine or pyrazine.
The structural characteristics of the new penicillins of the present invention of general formula (I) are such that the residue ( `C carries an -O-Y group which is linked to a carbon atom adjacent to the carbon atom to which an ampicillin unit is linked. Compounds wherein the residue ( \ C
bears no -O-Y group are antimicrobially much less active than those bearing an -0-Y group and exhibit only the same low anti-microbial activity as those disclosed in U.S. patent 3,433,784 against Pseudomonas as well as other gram-positive and gram- `
negative bacteria.
Among the penicillins (I), particularly effective compounds include D-~-(4-hydroxypyridine-3-carboxamidc)-benzylpenicillin, D-~-(2,4-dihydroxypyrimidine-5-carboxamido)-benzylpenicillin, D-~-(3-hydroxypyridazine-4-carboxamido)-benzylpenicillin, D-~-(3-hydroxypyridine-2-carboxamido)-benzylpenicillin, D-~-(2-hydroxypyridine-3-carboxamido)-benzylpenicillin and D-~-(2-hydroxypyrazine-3-carboxamido)-benzylpenicillin.
According to the present invention, the penicillins (I) can be produced by reacting 6-t~-aminophenylacetamido)-penicillanic acid of the formula:
..
.
9S~4 / \ /CH3 H2N-CH-CON~I-fH-fH C ~CH
~ O,C -N - CH-COOEI (I~) or a derivative thereof with a carboxylic acid of the formula:
.
R ~i 1 ~ -COOH (III) ,., R2 wherein ~ ~C, Y, Rl and R2 are each as defined above, or a salt or reactive derivative thereof, if necessary, followed by hydrolysis or acylation of the resulting product and/or elimination of any protective group.
The derivative of the compound (II) may be, for example, a salt ester or N-substituted derivative thereof. Examples of suitable salts are salts of alkali metals (e.g. sodium or potassium), alkaline earth metals (e.g. calcium or barium), organic bases (e.g. trimethylamine or triethylamine) and organic sulfonic acids ~e.g. toluenesulfonic acid, naphthalenesulfonic acid or tetrahydro-naphthalenesulfonic acid). Examples of suitable esters and N-substituted derivatives are compounds having the following formulae:
H2N-CH-CONH~ICH-fH C ~CH3 R
~ O~,C- N CH-COOSi- R4 R~-- SiHN-CH-cONH-fH_fH ~C~ 3 , N CH-COOSi-R4 :-, - :
, , ~L~495G~
H2N-CH-CONEl-CH-Cf~ ~C ~ 3 ~,C- N CH-COOSn -R4 CH CO
l l ~S\ jCH
NH N IH_lH f ~CH3 R6 \R 1I H-C00H
CH-~CO
I I ~ S \ ~CH
NH N-fH~IH j ~CH3 / R3 / \ C -/- CH-COOSi- R4 wherein R3, R4, R5~ R6 and R7 are each lower alkyl, Further examples of the ester unit for constructing suitable esters of the compound (II) are toluenesulfonylethylester, p-nitrobenzylester, benzylester, phenacylester, diphenylmethylester, substituted diphenylmethylester, tritylester, benzoyloxymethylester, lower alkanoyloxymethylester, dimethylmethyleneaminoester, p-nitrophenylester, methylsulfonylphenylester, methylthiophenylester,t~butylester, 3,5-di-t-butyl-4-hydroxybenzylester and trichloro-ethylester. These ester units have all been conventionally employed as groups for protecting a carboxylic acid radical in the fields of penicillin, cephalosporin and peptide chemistry.
Furthermore, the salts of the above mentioned esters of the compound (II) can also be employed, for example, hydrochloric acid and organic sulfonic acid (e.g. toluenesulfonic acid, naphthalenesu].fonlc acid or tetrahydronaphthalenesulfonic acid) salts. In thls case esters derived from penicillin G by well-known methods are preferred.
The compound (III) may be used as such, i.e. in a free ~(~4~5~D~
or salt form, or in the form of a reactive derivative thereof.
Examples of suitable salts of compound (III) includealkali metal, alkaline earth metal, ammonium and organic base (e.g. trimethylamine, triethylamine or dicyclohexylamine) salts.
Reactive derivatives of compound (III) on the carboxyl group thereof include acid halides, acid anhydrides, active amides, acid azides and active esters.
Among the acid halides, the use of an acid ch]oride is most favorable. Examples of suitable acid anhydrides are mixed acid anhydrides and symmetrical acid anhydrides prepared by the use of acids such as toluenesulfonic acid, an alkylcarbonic acid or an aliphatic carboxylic acid (e.g. pivalic acid). Examples of active amldes are those obtained by using imidazole, dimethyl-pyra~ole, triaæole or tetra~ole. Examples of active esters are those prepared by using p-nitrophenol. pentachlorophenol, p-nitrothiophenol, N,N'-dimethylhydroxylamine, l-hydroxy-2(1H)-pyridone, N-hydroxy-succinimide or N-hydroxyphthalimide.
When a compound (III) wherein Y is hydrogen, or a reactive derivative of such compound is used, the hydroxyl group may be protected with any protecting group conventionally employed in this field.
Illustrating some of the suitable reactive derivatives of compound (III), the mixed acid anhydride of the formula:
C \ Rl ~ \ C-Cooy (IV) wherein ( ~C, Rl and R2 are each as defined above, and Y
represents acyl or alkoxycarbonyl, can be prepared by reacting a compound (III) wherein Y is hydrogen with an acyl halide or an alkyl halocarbonate. Thus, the reaction of 1 mole of- compound (III) with 2 moles of an acyl halide (e.g. pivaloyl chloride) or an alkyl halocarbonate (e.g. ethyl chlorocarbonate or isobutyl -~L95~
chlorocarbonate) in the presence of 2 moles of a basic subs~ance affords the compo~lnd (IV) in an excellent yield. The process using the thus obtained mixed acid anhydride (IV) as reactant will be referred to herein as the "mixed anhydride process".
Another type of reactive derivative is a compound of the formula:
Il . , 0~ ~O : .
Rl~c\c~b~o (v) ~:
This invention re]ates to penicillins and their production. More particularly, it relates to novel derivatives _ of 6-(~-aminophenylacetamido)-penicillanic acid and 6~(~-amino-thienylacetamido)-penicillanic acid and to processes for their production.
As is well known, 6-(~-aminophenylacetamido)-penicillanic acid (i.e. ampicillin) inhibits the growth of various gram-positive and gram-negative bateria but does not exert any appreciable antimicrobial activity against Pseudomonas. In U.S. patent No.
3,433,784, certain N-acyl derivatives of ampicillin are described as showing a minimal inhibitory concentration of 125 to 250~ ~g/ml against Pseudomonas pyocinea A or R 59, when determined by the standard test method. The anti-Pseudomonas activity of the compounds described in the working examples is, however, not so high and the antimicrobial activity against other gram-positive and gram-negative bacteria is considerably lower. Thus, it may be concluded that these N-acyl derivatives of ampicillin are actually less valuable from the practical viewpoint.
As the result of studies seeking novel penicillins which have a broad antimicrobial spectrum and are highly active against gram-positive and gram-negative bacteria including Pseudomonas, it has now been found that penicillins of the following formula characteristically exhibit noticeable antimicrobial activity against Pseudomonas and a broad antimicrobial spectrum:
OY
l ~ \C-~ONH-CH-CO~I-CH-CII C ~CH~ (I) C ~ 0~,C- N - CH-~OOH
wherein ( Ç is a six-membered heteroaromatic ring selected from A -pyridine, pyrimidine, pyridazine and pyrazine, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and Rl and R2 are each hy-drogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano or R
. .
', ~ ; J
~4~51~4 and R2 linked together represent cyclopenteno, cyclohexeno or cyclohepteno optionally substituted with an oxo group.
The term "lower alkyl" as used herein means straight or branched chain saturated aliphatic hydrocarbon having from one to eight carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl or isoamyl. Similarly, where the term "lower" is used as a part of the description of any other group (e.g. lower alkoxy, lower alkanoyl, lower alkylmercapto), it refers to the alkyl portion of such group. The heteroaromatic ring may be, pyridine, pyrimidine, pyridazine or pyrazine.
The structural characteristics of the new penicillins of the present invention of general formula (I) are such that the residue ( `C carries an -O-Y group which is linked to a carbon atom adjacent to the carbon atom to which an ampicillin unit is linked. Compounds wherein the residue ( \ C
bears no -O-Y group are antimicrobially much less active than those bearing an -0-Y group and exhibit only the same low anti-microbial activity as those disclosed in U.S. patent 3,433,784 against Pseudomonas as well as other gram-positive and gram- `
negative bacteria.
Among the penicillins (I), particularly effective compounds include D-~-(4-hydroxypyridine-3-carboxamidc)-benzylpenicillin, D-~-(2,4-dihydroxypyrimidine-5-carboxamido)-benzylpenicillin, D-~-(3-hydroxypyridazine-4-carboxamido)-benzylpenicillin, D-~-(3-hydroxypyridine-2-carboxamido)-benzylpenicillin, D-~-(2-hydroxypyridine-3-carboxamido)-benzylpenicillin and D-~-(2-hydroxypyrazine-3-carboxamido)-benzylpenicillin.
According to the present invention, the penicillins (I) can be produced by reacting 6-t~-aminophenylacetamido)-penicillanic acid of the formula:
..
.
9S~4 / \ /CH3 H2N-CH-CON~I-fH-fH C ~CH
~ O,C -N - CH-COOEI (I~) or a derivative thereof with a carboxylic acid of the formula:
.
R ~i 1 ~ -COOH (III) ,., R2 wherein ~ ~C, Y, Rl and R2 are each as defined above, or a salt or reactive derivative thereof, if necessary, followed by hydrolysis or acylation of the resulting product and/or elimination of any protective group.
The derivative of the compound (II) may be, for example, a salt ester or N-substituted derivative thereof. Examples of suitable salts are salts of alkali metals (e.g. sodium or potassium), alkaline earth metals (e.g. calcium or barium), organic bases (e.g. trimethylamine or triethylamine) and organic sulfonic acids ~e.g. toluenesulfonic acid, naphthalenesulfonic acid or tetrahydro-naphthalenesulfonic acid). Examples of suitable esters and N-substituted derivatives are compounds having the following formulae:
H2N-CH-CONH~ICH-fH C ~CH3 R
~ O~,C- N CH-COOSi- R4 R~-- SiHN-CH-cONH-fH_fH ~C~ 3 , N CH-COOSi-R4 :-, - :
, , ~L~495G~
H2N-CH-CONEl-CH-Cf~ ~C ~ 3 ~,C- N CH-COOSn -R4 CH CO
l l ~S\ jCH
NH N IH_lH f ~CH3 R6 \R 1I H-C00H
CH-~CO
I I ~ S \ ~CH
NH N-fH~IH j ~CH3 / R3 / \ C -/- CH-COOSi- R4 wherein R3, R4, R5~ R6 and R7 are each lower alkyl, Further examples of the ester unit for constructing suitable esters of the compound (II) are toluenesulfonylethylester, p-nitrobenzylester, benzylester, phenacylester, diphenylmethylester, substituted diphenylmethylester, tritylester, benzoyloxymethylester, lower alkanoyloxymethylester, dimethylmethyleneaminoester, p-nitrophenylester, methylsulfonylphenylester, methylthiophenylester,t~butylester, 3,5-di-t-butyl-4-hydroxybenzylester and trichloro-ethylester. These ester units have all been conventionally employed as groups for protecting a carboxylic acid radical in the fields of penicillin, cephalosporin and peptide chemistry.
Furthermore, the salts of the above mentioned esters of the compound (II) can also be employed, for example, hydrochloric acid and organic sulfonic acid (e.g. toluenesulfonic acid, naphthalenesu].fonlc acid or tetrahydronaphthalenesulfonic acid) salts. In thls case esters derived from penicillin G by well-known methods are preferred.
The compound (III) may be used as such, i.e. in a free ~(~4~5~D~
or salt form, or in the form of a reactive derivative thereof.
Examples of suitable salts of compound (III) includealkali metal, alkaline earth metal, ammonium and organic base (e.g. trimethylamine, triethylamine or dicyclohexylamine) salts.
Reactive derivatives of compound (III) on the carboxyl group thereof include acid halides, acid anhydrides, active amides, acid azides and active esters.
Among the acid halides, the use of an acid ch]oride is most favorable. Examples of suitable acid anhydrides are mixed acid anhydrides and symmetrical acid anhydrides prepared by the use of acids such as toluenesulfonic acid, an alkylcarbonic acid or an aliphatic carboxylic acid (e.g. pivalic acid). Examples of active amldes are those obtained by using imidazole, dimethyl-pyra~ole, triaæole or tetra~ole. Examples of active esters are those prepared by using p-nitrophenol. pentachlorophenol, p-nitrothiophenol, N,N'-dimethylhydroxylamine, l-hydroxy-2(1H)-pyridone, N-hydroxy-succinimide or N-hydroxyphthalimide.
When a compound (III) wherein Y is hydrogen, or a reactive derivative of such compound is used, the hydroxyl group may be protected with any protecting group conventionally employed in this field.
Illustrating some of the suitable reactive derivatives of compound (III), the mixed acid anhydride of the formula:
C \ Rl ~ \ C-Cooy (IV) wherein ( ~C, Rl and R2 are each as defined above, and Y
represents acyl or alkoxycarbonyl, can be prepared by reacting a compound (III) wherein Y is hydrogen with an acyl halide or an alkyl halocarbonate. Thus, the reaction of 1 mole of- compound (III) with 2 moles of an acyl halide (e.g. pivaloyl chloride) or an alkyl halocarbonate (e.g. ethyl chlorocarbonate or isobutyl -~L95~
chlorocarbonate) in the presence of 2 moles of a basic subs~ance affords the compo~lnd (IV) in an excellent yield. The process using the thus obtained mixed acid anhydride (IV) as reactant will be referred to herein as the "mixed anhydride process".
Another type of reactive derivative is a compound of the formula:
Il . , 0~ ~O : .
Rl~c\c~b~o (v) ~:
2 , wherein ( ~C, Rl and R2 are each as defined above, which may be prepared by reacting 1 mole of compound (III) with 1 mole of phosgene in the presence of 2 moles of a basic substance. A
similar type of reactive derivative may be also prepared by the use of thionyl chloride or phosphorus trichloride in place of phosgene. The process using the above cyclic compound (V) or any similar compound as reactant will be referred to herein as the ~phosgene process~'.
Examples of basic substances suitable for use in said reactions are inorganic bases (e.g. sodium hydroxide and potassium hydroxide) and organic bases (e.g. triethylamine, pyridine, dimethylaniline, lutidine, N-methylmorpholine and N-methylpiperi~
dine).
The above described reactive derivatives are usually so reactive and unstable as to be difficultly isolatable and they are normally left in their reaction mixture for the reaction with the compound (II) to produce the compound (I).
Suitable compounds (III) include pyridine carboxylic acids of the formula:
O-Y
R9 ~ ~ C00~1 (VI) ,`' ., , '' ,. , :
~(~495~V4 wherein Y is as defined above, R8 is hydrogen or lower alkyl and Rg is lower alkyl, lower alkanoyl, cyano, hydroxy(lower)alkyl or benzoyl, or R8 and R9 are linked together to form lower alkylene, which compounds (VI) may be prepared by condensing a ketone of the formula:
wherein R8 and Rg are each as defined above, with diethyl amino-methylenemalonate of the formula:
H2N-CH=C(COOC2H5)2 and cyclizing the resultant condensation product, followed by hydrolysis. The said compound (VI) may be also produced by condensing an unsaturated amine of the formula: ` ~~-R9-cH-c (NH2) -R8 wherein R8 and Rg are each as defined above, with diethyl ethoxymethylenemalonate of the formula:
C2H50-CH=C(COOC2H5)2 and cyclizing the resultant condensation product, followed by hydrolysis.
A compound (VI) wherein R9 is lower alkanoyl may be reduced to give a compound (VI) wherein Rg is hydroxy(lower)alkyl.
Furthermore, a compound (VI) wherein Y is hydrogen may be acylated by a conventional procedure to give a compound (VI) wherein Y is lower alkanoyl or lower alkoxycarbonyl.
Specific examples of compounds (III) are as follows:
4-Hydroxy-2,3-cyclopentenopyridine-5-carboxylic acid, m.p. 263 - 264C (decomp.) 4-Hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid, m.p. 285C (decomp.) 4-Hydroxy-2,3-cycloheptenopyridine-5-carboxylic acid, m.p. 248 - 249C (decomp.) 2-Methyl-3-acetyl-4-hydroxypyridine-5-carboxylic acid, m.p. 260 - 263C (decomp.) 4-Hydroxy-2-methyl-3-benæoylpyridine-5-carboxylic acid, .-.. , ~ : . .
~0495~)g~
m.p. >360C
2-Methyl-3-~-hydroxyethyl)-4-hydroxypyridine-5-carboxylic acid, m.p. >360C
4-Hydroxy-6,7-dihydro-5-oxo-5H-cyclopenta[b3pyridine-3-carboxylic acid, m.p. >300C
2-Methyl-3-cyano-6-hydroxypyridine-5-carboxylic acid, m.p. 247 - 248C.
The reaction between the compound (II) or its derivative and the compound (III) or its reactive derivative is usually carried out in an inert solvent, such as a polar solvent (e.g. dichloro-methane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile,`~ -methylisobutylketone, ethyl alcohol or dimethylformamide), a non-polar solvent (e.g. benæene, toluene, petroleum ether or n-hexane) or a mixture thereof. In some cases, an aqueous medium may be used. The reaction temperature is not critical but is usually below 50C, preferably from -80 to 50C.
When the compound (III) is employed in the form of a free acid or a salt, a coupling reagent such an N,N'-dicyclohexyl-carbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, triphenylphosphine or 2-ethyl-5-(m-sulfonyl)-isoxazolium hydroxide inner salt is preferably used in the reaction with the compound (II). When using such a coupling reagent, the reaction often proceeds through the activated state of the carboxyl group in the compound (III), or the activated state of the amino group in the compound (II).
When a compound (I) wherein Y is lower alkanoyl or lower alkoxycarbonyl is produced, it may be further hydrolyzed in the presence of an inorganic base (e.g~ sodium carbonate, potassium carbonate, sodium hydroxide or ammonia), an organic base (e.g. methylamine, dimethylamine, diethylamine, triethylamine, benzylamine, morpholine, plperidine, potassium 2-ethylhexanoate or sodium 2-ethylhexanoate), an inorganic acid (e.g. hydrochloric acid or sulfuric acid) or an organic acid (e.g. formic acid, .. . . . : ..
~049S~
trifluoroacetic acid or ~ethanesulfonic acid) to give the corres-ponding co~pound (I) wherein Y is hydrogen.
Nhen any protective group i5 present in the resulting product, it may be eliminated by a p~ se conventional procedure such as catalytic reduction or hydrolysis, favorably under mild conditions.
The penicillin (I) produced may, if desired, be converted into a non-toxic pharmaceutically acceptable salt thereof in a per se conventional manner. Examples of ~uitable salts are salts of alkali metals (e~g. sodium or potassium), salts of alkaline earth metals (e.g. calcium or ~agnesium), an ammonium salt, substituted ammonium salts, amine salts (e.g. triethylamine, procaine, dibenzylamine, ~-benzyl-~-phenethylamine, l-ephenamine, N,N'-diben~ylethylenediamine, dehydroabietylamine or N,N'-bis-dehydroabietylethylenediamine salts), or an arginine salt.
Practical and presently preferred embodiments of the present invention are illustratively shown in the following Examples.
.. . .
ExamPl~ 1 . .
. Preparation of D-a-(4-ethoxycarbonyloxy-2,3-cyclo-pentenopyri.dine-5-carboxamido)-benzylpenicillin:~
OCOOC2H5 ' ' -f ~ CO~I CH CO~I-CEI-CÉI C CH3 ~ J ~ C -N - CH-COOEi To 4-hydroxy-2,3-cyclopentenopyrid.ine-5-carboxylic acid (m,p. 26~ - 264C, deco~p.) (1 g) are added dic~oro-methrlne (50 ml) and triethylamine (1.07 ~)) and the resultin~
mixturc is cooled do~.~ to -10C. ~thyl chlorocarbollate (1.16 g) is added to the mixture which is subsequently stirred at the sa~e t~?erature for 10 minutes. a-Aminob~nzylpenicillin .. , .. , .
950~
triethylamine aalt (2.51 g) is added thereto, and the result-ing mixture is kept at -10 to 5C for 3 hours. On completion o~ the reaction, a solution of sodium ~icarbonate (0.89 g) in water (25 ml~ and ethyl acetate (200 ml) are added thereto.
The organic layer is separated from the aqueous layer and washed with water (25 ml). The aqueous layer and the wash-ings are combined together~ washed twice with 50 ml portions of ethyl aceta-te, and then cooled with ice. The aqueous solu-tion is adjusted to pH 2 by the addition of dilute aqueous 10hydroch~D acid and extrac-ted with ethyl acetate (100 ml). ' , The extract is washed with water, dried over anhydrous magne-sium sulfate and concentrated under reduced pressure. The residue is recrystalli~ed from ether to give the objective penicillin. Yield, 2.07 g. Purity (determined by iodometry), 93%.
Example 2 Preparation of D-~a(4-hydroxy 2,3-cyclopentenopyri-dine-5-carboxamido)-benzylpenicillin:-CONH-CH-CONH-CH-CH ~ C~ C 3 ~ C- N - CH-COOH
O ~ :
To the p~nicillin (0.9 g) obtained in Example 1 is added a solution of potassium carbonate (0.39 g) in water (9 ml), and the resulting solution is stirred at room temperature for 1 hour and then adjusted to pH 2 with dilute ~ydrochloric acid while cooling with ice. Separated white crystals are collected by filtration, washed with water and dried under re-duced pressure to give the objective penicillin. Yield, 0.6 g.
Purity (determined by iodometry), 87%.
.. . . . ~ . - , :' ' ' ' : ' ' -~0495~4 .
.xam~le 3 Preparation of D-~(~-hydroxy~2,~-cyclohexenopyridine-5-carboxamido)-benzylpenicillin:-OEI
[~3-coNH-cH-col~i-c~I-cH f ~ 3 N ~ C - N CH-COOH
To 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid (hemihydrate, m.p. 285C, decomp.) (0.9 g) are added di-chloromethane (20 ml) and triethylamine (0.9 g), and a 10 ~o solution of phosgene in dichloromethane (4-4 g) is added there-to at -30C. After stirring for 20 minutes, a-aminobenzylpeni-cillin triethylamine salt (2 g) is added, and the resulting ~olution i~ stirred at the same temperature for 3 hours and then at -5 to 0C for i hour. A solution of potassium carbo-nate (0.615 g) in water (25 ml) and ethyl acetate (200 ml) are added thereto. The aqueous layer is separated and washed ... . :
with ethyl acetate~ The aqueous solut:Lon is adjusted to pH
2 ~th dilute hydrochloric acid whïle cooling with ice, and the seprated crystals are collected by filtration, washed with water and dried under reduced pressure to gi~e the ob-~ Jective penicillin. Yield, 1.52 g. ~urity (determined by iodometry), 90.5 ~.
Example 4 `
Preparation o-f D-a-(3-acetyl-4-hydroxy-2-methyl-pyridlne-5-carboxamido)-benzylpeniciLlin:-.
,, ~:
- 11 - .
. ~ . . .
.' 1~
~,. .. . . .
QH
H3CO~ ~ ~ \ ~ CH3 ~ ~ ONH-CH-CONH-CH-fH I ~ CH3 H3 ~ ~ ~ C_ N - CH-COOH
O
(1) To 3-acetyl-4-hydroxy-2-methylpyridine-5-car-boxylic acid (2.38 g~ are added dichloromethane (40 ml) and triethylamine (2.5 g), and ethyl chlorocarbonate (2166 g~ is added thereto at -20C. After 15 minutes, a solution of ~-aminobenzylpenicillin triethylamine salt (5.5 g) in dic~loro-methane(25 ml) is added thereto at the same temperature.
After kept at -10C for 4 hours, dichloromethaneis distille~
off under reduced pressure, and the residue is dissolved in a solution of potassium carbonate (1.66 g) in water (100 ml) and ethyl acetate (50 ml). The aqueous layer is separated 9 allowed to stand at room temperature for 1 to 2 hours, cooled with ice, a~justed to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove ethyl ac~tate. The residue is crystallized from petroleum ether to give the objective penicil~in. ~ield, 5 g. Purity (determined by iodometry~, 89%.
(2) To 3~acetyl-4-hydroxy-2-methylpyridine-5-car-boxylic acid (2.38 g) are added dichloromethane(40 ml) and triethylamine (2.5 g), and ethyl chlorocarbonate (2.66 g) is added thereto at ~5C. After stirring for 30 minutes, the solution is added at 0 to -5C to a solu-tion of ¢-aminobenzyl-penicillin trimethylsi~l ester in dichloromethar.eprepared by adding trimethylchlorosilane (1.33 g) to a solution of -12~
0~9~04 aminobenzylpenicillin triethylamine salt (5.5 g) in dichloro-methane (30 ml). The resulting mixture is kept at the same temperature for 5 hours. After removal of dichloromethane under reduced pressure, water (70 ml) is added to the residue, and the resulting mixture is adjusted to pH 2 with concentrat-ed hydrochloric acid while stirring. The precipitate is ex-~racted with ethyl acetate, and the extract is washed with water, dried over an~drous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in a solu-tion of potassium carbonate (1.66 g) in water (70 ml) and ethyl acetate (50 ml). The aqueous layer is separated and treated as in the above (1) to give the objective penicillin.
Example S
Preparation of D-~-(2,3-cyclohexeno-4-pivaloyloxy-pyridine-S-carboxamido)-benzylpenicillin:-OOOC(CH3)3 CONH-CH-CONH-OH- ~ C
N ~ C- N CH-COOH
To 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid (0.9 g) are added dichloromethane (30 ml) and triethyl-amine (0.9 g)~ and pivaloyl chloride (1.22 g) is ~dded drop-wise thereto at -10C. After stirring for 30 minutes,~ -amino-benzylpenicillin sodium salt (1.65 g~ is added thereto at the same temperature. The resulting mixture is kept overnight at the same temperature, and cold water (30 ml) and ethyl acetate (200 ml) are added thereto. The aqueous layer is sepa~ated at 0 to 5C, wabhed with cold ethyl acetate, ad~usted to pH
2 with dilute hydrochloric acid and extracted with cold ethyl LOD~9504 acetate. The extract is washed with cold water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue is crystallized from ether to give the objective penicillin. Yield, 0.8 g. Purity (deter-mined by iodometry), 88~3%.
Example 6 Preparation of D-~-(4-ethyoxycarbonyloxy-2,3-cyclo-hexenopyridine-5-carboxamido) benzylpenicillin:-oCooc2H5 ~ N ~ C - N CH-COOH
To 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid (0O9 g) are added dichloromethane (40 ml) and triethyl-amine (0.9 g), and ethyl chlorocarbonate (0.975 g) is added thereto at -20 to -15C. After stirring for 20 minutes at the same temperature, ~-aminobenzylpenicillin sodium salt (1.8 g~ is added to the resulting mixture which is kept sub-sequently for ~ hours at the same temperature. The reaction mixture is treated as in Example 1 to gi~e the objective peni-cillin (0.7 g). Purity (determined by iodometry), 94~.
Example_7 Preparation of D-~-(2,4-dihydroxypyrimidine-5-carboxamido?-benzylpenicillin:-OH
HO ~ ~ CONH-CH-CONH-CH-CH f ~CH
N ~ CH-COOH
~ O ,., 495()~
a) Uracil-5;carboxylic acid (1.0 g) is dissolved in dry pyridine (20 ml) under heating. p-Nitrophenyl trifluoro-acetate (1.8 g) is added to the solution whichis ~ubsequently stirred at 45C for 30 minutes. Then, the solution is concen-trated to dryness under reduced pressure, and the crystals thus obtained are washed with chloroform and then acetone to give the active ester, i.e. p-nitrophenyl 2,~-dihydroxypyrimidine-5-carboxylate (1.16 g). M~Po 298 - 299C (decomp.) b) To a solution of ~-aminobenzylpenicillin tri-ethylamine salt (1.5 g) in dichloromethane ~30 ml) are addedthe active ester (1.01 g) anddimethylformamide (50 ml) at room temperature. The resulting mixture is stirred at room temperature for 2.5 hours and concentrated under reduced pres~
sure. Dichloromethane (40 ml) is added to the residue, and the solution is extracted three times with 60 ml portions of an aqueous solution of sodium bicarbonate. The extracts are combined together and admixed with ethyl acetate ~50 ml).
The mixture is adjusted to pH 2 with lN hydrochloric acid.
The ethyl acetate layer is separated, and the aqueous layer is extracted twice with ethyl acetate. The ethyl acetate layer and -the ethyl ace~ate extrac-t are combined together~
wabhed with an aqueous solution of sodium chloride and dried over magnesium sulfata. To the dried ethyl acetate solution is added dropwise a mixture of a 50~ solution of potassium 2-ethylhexanoate (1.2 g) in n-butanol with ether (30 ml).
The white precipitate is collected by filtration, washed with ether and dried over phosphorus pe~toxide under reduced pres-sure to ~ive the objeetive penicillin as ~he potassium salt (0.7 g). Purity (determin~d by iodometry), 90~.
~)49S~4 Example 8 Preparation of D-~-(3-hydroxypyridazine-4-carboxamido)-benzylpenicillin:-OH
CONH CH-CONH-CH-CH C~ CH
~ C -N CH-COOH
(1) ~-Aminobenzylpenicillin triethylamine salt (3.0 g~ is disso~ed in dichloromethane (50 ml), and p-nitrophenyl
similar type of reactive derivative may be also prepared by the use of thionyl chloride or phosphorus trichloride in place of phosgene. The process using the above cyclic compound (V) or any similar compound as reactant will be referred to herein as the ~phosgene process~'.
Examples of basic substances suitable for use in said reactions are inorganic bases (e.g. sodium hydroxide and potassium hydroxide) and organic bases (e.g. triethylamine, pyridine, dimethylaniline, lutidine, N-methylmorpholine and N-methylpiperi~
dine).
The above described reactive derivatives are usually so reactive and unstable as to be difficultly isolatable and they are normally left in their reaction mixture for the reaction with the compound (II) to produce the compound (I).
Suitable compounds (III) include pyridine carboxylic acids of the formula:
O-Y
R9 ~ ~ C00~1 (VI) ,`' ., , '' ,. , :
~(~495~V4 wherein Y is as defined above, R8 is hydrogen or lower alkyl and Rg is lower alkyl, lower alkanoyl, cyano, hydroxy(lower)alkyl or benzoyl, or R8 and R9 are linked together to form lower alkylene, which compounds (VI) may be prepared by condensing a ketone of the formula:
wherein R8 and Rg are each as defined above, with diethyl amino-methylenemalonate of the formula:
H2N-CH=C(COOC2H5)2 and cyclizing the resultant condensation product, followed by hydrolysis. The said compound (VI) may be also produced by condensing an unsaturated amine of the formula: ` ~~-R9-cH-c (NH2) -R8 wherein R8 and Rg are each as defined above, with diethyl ethoxymethylenemalonate of the formula:
C2H50-CH=C(COOC2H5)2 and cyclizing the resultant condensation product, followed by hydrolysis.
A compound (VI) wherein R9 is lower alkanoyl may be reduced to give a compound (VI) wherein Rg is hydroxy(lower)alkyl.
Furthermore, a compound (VI) wherein Y is hydrogen may be acylated by a conventional procedure to give a compound (VI) wherein Y is lower alkanoyl or lower alkoxycarbonyl.
Specific examples of compounds (III) are as follows:
4-Hydroxy-2,3-cyclopentenopyridine-5-carboxylic acid, m.p. 263 - 264C (decomp.) 4-Hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid, m.p. 285C (decomp.) 4-Hydroxy-2,3-cycloheptenopyridine-5-carboxylic acid, m.p. 248 - 249C (decomp.) 2-Methyl-3-acetyl-4-hydroxypyridine-5-carboxylic acid, m.p. 260 - 263C (decomp.) 4-Hydroxy-2-methyl-3-benæoylpyridine-5-carboxylic acid, .-.. , ~ : . .
~0495~)g~
m.p. >360C
2-Methyl-3-~-hydroxyethyl)-4-hydroxypyridine-5-carboxylic acid, m.p. >360C
4-Hydroxy-6,7-dihydro-5-oxo-5H-cyclopenta[b3pyridine-3-carboxylic acid, m.p. >300C
2-Methyl-3-cyano-6-hydroxypyridine-5-carboxylic acid, m.p. 247 - 248C.
The reaction between the compound (II) or its derivative and the compound (III) or its reactive derivative is usually carried out in an inert solvent, such as a polar solvent (e.g. dichloro-methane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile,`~ -methylisobutylketone, ethyl alcohol or dimethylformamide), a non-polar solvent (e.g. benæene, toluene, petroleum ether or n-hexane) or a mixture thereof. In some cases, an aqueous medium may be used. The reaction temperature is not critical but is usually below 50C, preferably from -80 to 50C.
When the compound (III) is employed in the form of a free acid or a salt, a coupling reagent such an N,N'-dicyclohexyl-carbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, triphenylphosphine or 2-ethyl-5-(m-sulfonyl)-isoxazolium hydroxide inner salt is preferably used in the reaction with the compound (II). When using such a coupling reagent, the reaction often proceeds through the activated state of the carboxyl group in the compound (III), or the activated state of the amino group in the compound (II).
When a compound (I) wherein Y is lower alkanoyl or lower alkoxycarbonyl is produced, it may be further hydrolyzed in the presence of an inorganic base (e.g~ sodium carbonate, potassium carbonate, sodium hydroxide or ammonia), an organic base (e.g. methylamine, dimethylamine, diethylamine, triethylamine, benzylamine, morpholine, plperidine, potassium 2-ethylhexanoate or sodium 2-ethylhexanoate), an inorganic acid (e.g. hydrochloric acid or sulfuric acid) or an organic acid (e.g. formic acid, .. . . . : ..
~049S~
trifluoroacetic acid or ~ethanesulfonic acid) to give the corres-ponding co~pound (I) wherein Y is hydrogen.
Nhen any protective group i5 present in the resulting product, it may be eliminated by a p~ se conventional procedure such as catalytic reduction or hydrolysis, favorably under mild conditions.
The penicillin (I) produced may, if desired, be converted into a non-toxic pharmaceutically acceptable salt thereof in a per se conventional manner. Examples of ~uitable salts are salts of alkali metals (e~g. sodium or potassium), salts of alkaline earth metals (e.g. calcium or ~agnesium), an ammonium salt, substituted ammonium salts, amine salts (e.g. triethylamine, procaine, dibenzylamine, ~-benzyl-~-phenethylamine, l-ephenamine, N,N'-diben~ylethylenediamine, dehydroabietylamine or N,N'-bis-dehydroabietylethylenediamine salts), or an arginine salt.
Practical and presently preferred embodiments of the present invention are illustratively shown in the following Examples.
.. . .
ExamPl~ 1 . .
. Preparation of D-a-(4-ethoxycarbonyloxy-2,3-cyclo-pentenopyri.dine-5-carboxamido)-benzylpenicillin:~
OCOOC2H5 ' ' -f ~ CO~I CH CO~I-CEI-CÉI C CH3 ~ J ~ C -N - CH-COOEi To 4-hydroxy-2,3-cyclopentenopyrid.ine-5-carboxylic acid (m,p. 26~ - 264C, deco~p.) (1 g) are added dic~oro-methrlne (50 ml) and triethylamine (1.07 ~)) and the resultin~
mixturc is cooled do~.~ to -10C. ~thyl chlorocarbollate (1.16 g) is added to the mixture which is subsequently stirred at the sa~e t~?erature for 10 minutes. a-Aminob~nzylpenicillin .. , .. , .
950~
triethylamine aalt (2.51 g) is added thereto, and the result-ing mixture is kept at -10 to 5C for 3 hours. On completion o~ the reaction, a solution of sodium ~icarbonate (0.89 g) in water (25 ml~ and ethyl acetate (200 ml) are added thereto.
The organic layer is separated from the aqueous layer and washed with water (25 ml). The aqueous layer and the wash-ings are combined together~ washed twice with 50 ml portions of ethyl aceta-te, and then cooled with ice. The aqueous solu-tion is adjusted to pH 2 by the addition of dilute aqueous 10hydroch~D acid and extrac-ted with ethyl acetate (100 ml). ' , The extract is washed with water, dried over anhydrous magne-sium sulfate and concentrated under reduced pressure. The residue is recrystalli~ed from ether to give the objective penicillin. Yield, 2.07 g. Purity (determined by iodometry), 93%.
Example 2 Preparation of D-~a(4-hydroxy 2,3-cyclopentenopyri-dine-5-carboxamido)-benzylpenicillin:-CONH-CH-CONH-CH-CH ~ C~ C 3 ~ C- N - CH-COOH
O ~ :
To the p~nicillin (0.9 g) obtained in Example 1 is added a solution of potassium carbonate (0.39 g) in water (9 ml), and the resulting solution is stirred at room temperature for 1 hour and then adjusted to pH 2 with dilute ~ydrochloric acid while cooling with ice. Separated white crystals are collected by filtration, washed with water and dried under re-duced pressure to give the objective penicillin. Yield, 0.6 g.
Purity (determined by iodometry), 87%.
.. . . . ~ . - , :' ' ' ' : ' ' -~0495~4 .
.xam~le 3 Preparation of D-~(~-hydroxy~2,~-cyclohexenopyridine-5-carboxamido)-benzylpenicillin:-OEI
[~3-coNH-cH-col~i-c~I-cH f ~ 3 N ~ C - N CH-COOH
To 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid (hemihydrate, m.p. 285C, decomp.) (0.9 g) are added di-chloromethane (20 ml) and triethylamine (0.9 g), and a 10 ~o solution of phosgene in dichloromethane (4-4 g) is added there-to at -30C. After stirring for 20 minutes, a-aminobenzylpeni-cillin triethylamine salt (2 g) is added, and the resulting ~olution i~ stirred at the same temperature for 3 hours and then at -5 to 0C for i hour. A solution of potassium carbo-nate (0.615 g) in water (25 ml) and ethyl acetate (200 ml) are added thereto. The aqueous layer is separated and washed ... . :
with ethyl acetate~ The aqueous solut:Lon is adjusted to pH
2 ~th dilute hydrochloric acid whïle cooling with ice, and the seprated crystals are collected by filtration, washed with water and dried under reduced pressure to gi~e the ob-~ Jective penicillin. Yield, 1.52 g. ~urity (determined by iodometry), 90.5 ~.
Example 4 `
Preparation o-f D-a-(3-acetyl-4-hydroxy-2-methyl-pyridlne-5-carboxamido)-benzylpeniciLlin:-.
,, ~:
- 11 - .
. ~ . . .
.' 1~
~,. .. . . .
QH
H3CO~ ~ ~ \ ~ CH3 ~ ~ ONH-CH-CONH-CH-fH I ~ CH3 H3 ~ ~ ~ C_ N - CH-COOH
O
(1) To 3-acetyl-4-hydroxy-2-methylpyridine-5-car-boxylic acid (2.38 g~ are added dichloromethane (40 ml) and triethylamine (2.5 g), and ethyl chlorocarbonate (2166 g~ is added thereto at -20C. After 15 minutes, a solution of ~-aminobenzylpenicillin triethylamine salt (5.5 g) in dic~loro-methane(25 ml) is added thereto at the same temperature.
After kept at -10C for 4 hours, dichloromethaneis distille~
off under reduced pressure, and the residue is dissolved in a solution of potassium carbonate (1.66 g) in water (100 ml) and ethyl acetate (50 ml). The aqueous layer is separated 9 allowed to stand at room temperature for 1 to 2 hours, cooled with ice, a~justed to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove ethyl ac~tate. The residue is crystallized from petroleum ether to give the objective penicil~in. ~ield, 5 g. Purity (determined by iodometry~, 89%.
(2) To 3~acetyl-4-hydroxy-2-methylpyridine-5-car-boxylic acid (2.38 g) are added dichloromethane(40 ml) and triethylamine (2.5 g), and ethyl chlorocarbonate (2.66 g) is added thereto at ~5C. After stirring for 30 minutes, the solution is added at 0 to -5C to a solu-tion of ¢-aminobenzyl-penicillin trimethylsi~l ester in dichloromethar.eprepared by adding trimethylchlorosilane (1.33 g) to a solution of -12~
0~9~04 aminobenzylpenicillin triethylamine salt (5.5 g) in dichloro-methane (30 ml). The resulting mixture is kept at the same temperature for 5 hours. After removal of dichloromethane under reduced pressure, water (70 ml) is added to the residue, and the resulting mixture is adjusted to pH 2 with concentrat-ed hydrochloric acid while stirring. The precipitate is ex-~racted with ethyl acetate, and the extract is washed with water, dried over an~drous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in a solu-tion of potassium carbonate (1.66 g) in water (70 ml) and ethyl acetate (50 ml). The aqueous layer is separated and treated as in the above (1) to give the objective penicillin.
Example S
Preparation of D-~-(2,3-cyclohexeno-4-pivaloyloxy-pyridine-S-carboxamido)-benzylpenicillin:-OOOC(CH3)3 CONH-CH-CONH-OH- ~ C
N ~ C- N CH-COOH
To 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid (0.9 g) are added dichloromethane (30 ml) and triethyl-amine (0.9 g)~ and pivaloyl chloride (1.22 g) is ~dded drop-wise thereto at -10C. After stirring for 30 minutes,~ -amino-benzylpenicillin sodium salt (1.65 g~ is added thereto at the same temperature. The resulting mixture is kept overnight at the same temperature, and cold water (30 ml) and ethyl acetate (200 ml) are added thereto. The aqueous layer is sepa~ated at 0 to 5C, wabhed with cold ethyl acetate, ad~usted to pH
2 with dilute hydrochloric acid and extracted with cold ethyl LOD~9504 acetate. The extract is washed with cold water, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue is crystallized from ether to give the objective penicillin. Yield, 0.8 g. Purity (deter-mined by iodometry), 88~3%.
Example 6 Preparation of D-~-(4-ethyoxycarbonyloxy-2,3-cyclo-hexenopyridine-5-carboxamido) benzylpenicillin:-oCooc2H5 ~ N ~ C - N CH-COOH
To 4-hydroxy-2,3-cyclohexenopyridine-5-carboxylic acid (0O9 g) are added dichloromethane (40 ml) and triethyl-amine (0.9 g), and ethyl chlorocarbonate (0.975 g) is added thereto at -20 to -15C. After stirring for 20 minutes at the same temperature, ~-aminobenzylpenicillin sodium salt (1.8 g~ is added to the resulting mixture which is kept sub-sequently for ~ hours at the same temperature. The reaction mixture is treated as in Example 1 to gi~e the objective peni-cillin (0.7 g). Purity (determined by iodometry), 94~.
Example_7 Preparation of D-~-(2,4-dihydroxypyrimidine-5-carboxamido?-benzylpenicillin:-OH
HO ~ ~ CONH-CH-CONH-CH-CH f ~CH
N ~ CH-COOH
~ O ,., 495()~
a) Uracil-5;carboxylic acid (1.0 g) is dissolved in dry pyridine (20 ml) under heating. p-Nitrophenyl trifluoro-acetate (1.8 g) is added to the solution whichis ~ubsequently stirred at 45C for 30 minutes. Then, the solution is concen-trated to dryness under reduced pressure, and the crystals thus obtained are washed with chloroform and then acetone to give the active ester, i.e. p-nitrophenyl 2,~-dihydroxypyrimidine-5-carboxylate (1.16 g). M~Po 298 - 299C (decomp.) b) To a solution of ~-aminobenzylpenicillin tri-ethylamine salt (1.5 g) in dichloromethane ~30 ml) are addedthe active ester (1.01 g) anddimethylformamide (50 ml) at room temperature. The resulting mixture is stirred at room temperature for 2.5 hours and concentrated under reduced pres~
sure. Dichloromethane (40 ml) is added to the residue, and the solution is extracted three times with 60 ml portions of an aqueous solution of sodium bicarbonate. The extracts are combined together and admixed with ethyl acetate ~50 ml).
The mixture is adjusted to pH 2 with lN hydrochloric acid.
The ethyl acetate layer is separated, and the aqueous layer is extracted twice with ethyl acetate. The ethyl acetate layer and -the ethyl ace~ate extrac-t are combined together~
wabhed with an aqueous solution of sodium chloride and dried over magnesium sulfata. To the dried ethyl acetate solution is added dropwise a mixture of a 50~ solution of potassium 2-ethylhexanoate (1.2 g) in n-butanol with ether (30 ml).
The white precipitate is collected by filtration, washed with ether and dried over phosphorus pe~toxide under reduced pres-sure to ~ive the objeetive penicillin as ~he potassium salt (0.7 g). Purity (determin~d by iodometry), 90~.
~)49S~4 Example 8 Preparation of D-~-(3-hydroxypyridazine-4-carboxamido)-benzylpenicillin:-OH
CONH CH-CONH-CH-CH C~ CH
~ C -N CH-COOH
(1) ~-Aminobenzylpenicillin triethylamine salt (3.0 g~ is disso~ed in dichloromethane (50 ml), and p-nitrophenyl
3-hydroxypyridazine-4-carboxylate (M~Po 233C, decomp.) (1.90 g~ and dimethylformamide (30 ml) are added thereto in o~der while stirring at room temperature. Stirring is continued at room temperature for 17 hours. The separated crystals are collected by filtration, washed with ether and driPd under reduced pressure to give the objective penicillin as the tri-ethylamine salt t2.9 g). Purity (determined by iodometry), 93%, (2) ~ -Aminobenzylpenicillin 3,5-dit-butyl-4-hydroxy-benzyl ester (3.72 g), prepared from benzylpenicillin 3,5-di-t-butyl-4-hydroxybenzyl ester via 3,5-di-t-b~tyl-4-hydroxy-benzyl ester of 6-aminopenicillanic acid, is dissolved in di-chloromethane (50 ml). To the resulting solution is added at room temperature p-nitrophenyl 3-hydroxypyridazine-4-carboxy-late (1.90 g~, and dimethylformamide (30 ml) is added thereto.
The mixture is kept overnight at room temperature while stir~
ring and evaporated under reduced pressure to remove dichloro-methane. The residual solution is added to cold water (200 ml).
The precipitate is collected by filtration, dried and added to a mixture of dimethylformamide (30 ml) and sodium thipphenolate .
~4~S~4 ~1.15 g). The resulting solution i9 poured onto acetone (200 ml) and heated at 50 to 55C while stirring. The precipitate is collected by filtration while hot, washed with acetone and dissolved in water (50 ml). The solution is adjusted to pH 2 with hydrochloric acid. The separated crystals are collected by ~ -filtration, washed with cold water and dried over phosphorus pentoxide under reduced pressure to give the objective penicillin.
Purity (determined by iodometry), 89.5%.
Examples 9 to 26 10The new penicillins shown in the following Table 1 are obtained by similar procedures to those described in the above Examples. ~~
The penicillins of Examples 9 to 26 each have the general formula:
~ S ~ ~ CH3 Z-Co~l-CH-COi~-f~I-clH f ~C~3 ~ ~ C- N CH-COOM
, ~ I ' , in which Z and M have the meanings indicated in the Table.
. ~ --~495C34 Tclbl~
. _ , _ Exa~nple Subs t:L tuents Purity (5~) . . . _ I (iodometry) OII
. 9 ~ H - 85 _ ~C2EI5 H 92.5 ¦~
()~f H . . .
11 H3C_ElC ~, E 92 . M~ .
13 ~H E 92 . 5 ¦~1 K ¦ 9 1~l ~ Ll ~
CR l~ ¦ H ¦ 82 , ,_,. . .
17 . _ K 91 . .
L~ 1 ' - ~.
95~
Table 1 contin~led . - . , .. _ . _ _ Example Substituents Purity (~0) . _ _ _; __ (iodometry) . . . _ . . _. _ . _ 19 H jC-HC~ K 89 ¦~ I &~ --~ K ¦ 8 . .
22 ~ OH K 90.5 r- ~ ~
24 [~N~ Na 85 25~OOC2H ¦ N ~ 80 . ¦
.'' _ . -26~`NIJ . K 89 When determined according to the agar dilution method, the penicillins of the above Examples 1 to 26 afford the minimal inhibitory concentration as shown in the following Table 2.
: .
.
The mixture is kept overnight at room temperature while stir~
ring and evaporated under reduced pressure to remove dichloro-methane. The residual solution is added to cold water (200 ml).
The precipitate is collected by filtration, dried and added to a mixture of dimethylformamide (30 ml) and sodium thipphenolate .
~4~S~4 ~1.15 g). The resulting solution i9 poured onto acetone (200 ml) and heated at 50 to 55C while stirring. The precipitate is collected by filtration while hot, washed with acetone and dissolved in water (50 ml). The solution is adjusted to pH 2 with hydrochloric acid. The separated crystals are collected by ~ -filtration, washed with cold water and dried over phosphorus pentoxide under reduced pressure to give the objective penicillin.
Purity (determined by iodometry), 89.5%.
Examples 9 to 26 10The new penicillins shown in the following Table 1 are obtained by similar procedures to those described in the above Examples. ~~
The penicillins of Examples 9 to 26 each have the general formula:
~ S ~ ~ CH3 Z-Co~l-CH-COi~-f~I-clH f ~C~3 ~ ~ C- N CH-COOM
, ~ I ' , in which Z and M have the meanings indicated in the Table.
. ~ --~495C34 Tclbl~
. _ , _ Exa~nple Subs t:L tuents Purity (5~) . . . _ I (iodometry) OII
. 9 ~ H - 85 _ ~C2EI5 H 92.5 ¦~
()~f H . . .
11 H3C_ElC ~, E 92 . M~ .
13 ~H E 92 . 5 ¦~1 K ¦ 9 1~l ~ Ll ~
CR l~ ¦ H ¦ 82 , ,_,. . .
17 . _ K 91 . .
L~ 1 ' - ~.
95~
Table 1 contin~led . - . , .. _ . _ _ Example Substituents Purity (~0) . _ _ _; __ (iodometry) . . . _ . . _. _ . _ 19 H jC-HC~ K 89 ¦~ I &~ --~ K ¦ 8 . .
22 ~ OH K 90.5 r- ~ ~
24 [~N~ Na 85 25~OOC2H ¦ N ~ 80 . ¦
.'' _ . -26~`NIJ . K 89 When determined according to the agar dilution method, the penicillins of the above Examples 1 to 26 afford the minimal inhibitory concentration as shown in the following Table 2.
: .
.
4';~5~4 Table 2 .
inimal Inhlbitory Conc~ntratlon (MIC) a~ainst PathoF,enic Microorganisms (ln vi~ro).
_ . . .
~mpl~ MIC ( ~Ig/ml ) St~phy- Escheri- Proteus Prot~u~, hlebsiell~ P~udo-lococcus chia mirabilis ~ulgaris pneumoni~e mon~s aureus coli GN2425 HXl9 602 ~eru~i-209P NIHJ 104a . _ .
1 0.~9 12,5 3.13 0,05 6,25 6,25 2 0.39 25 - 12,5 0.39 12.5 12~5 3 ~.78 12.5 6,25 0.39 6 ~25 12,5 0.78 12.5 6.25 0.39 12.5 12,5.
0,78 12,5 6,25 0.39 6,25 12,5 6 0.78 12,5 6,25 0.39 6,25 12,5 7 0.39 12,5 6,25 '5 25 3]3 8 0.39 12,5 6,25 0~05 6.25 3.13 : 9 0,78 25 6.25' 0.78 3.13 12,5 0,78 25 6.25 0.78 3.1~ 25 11 0,78 25 12,5 0,39 12.5 6.25 12 1.56 12.5 6,25 0.2 ~ 25 1~ 0.39 12,5 50 0,39 25 3.13 14 0.78 50 12.5 0,2 25 6,23 I5 0.78 25 3 O 13 0.05 50 3013 16 0,78 50 12.5 0,1 50 6.25 l? -39 25 12.5 0;05 100 3.13 18 0.2 12.5 50 0.39- 25 12.5 19 0,78 6.25 12.5 0.2 ~5 12.5 0.78 6.25 3.13 0.057 50 12.5 21 0.78 12.5 5P 0.'~8 100 12.5 22 0.2 6.25 25 0.2 . 25 6.25 23 -39 12.5 ?5 0.2 25 6.~5 2~ 0.78 25 25 0.78 25 ~.13 0.78 25 3.1-S 0.05 25 6.25 26 0.39 12.5 12.5 0.2 12.5 ~
I 0.78 100 50 0.39 50 5o 1 I 0.78 100 100 0.78 100 50 ' cilli n ' 1 6.26 1,56 1,56 50 ? 200 .
`- 10~9e504 Comp~unds Nos. I and II are penicilllns of the following formulae disclos~d in U.S. patent 3,433,784:
No. I. ~
~N~LCOI~-CH-CO~-CH-fH `f-- -S
. ~ C -N - CII-COONa NoO II ~ CO~ CH-CO~I-CH-CH ~C ~CH~
~ N - C~I~COONn :
.
. :
: ' ' , ,:, -. .
- , -'~
, ..
.~ , .
- 21 - . .
. , :. ;, : ., . :
~, , . .. . : .
inimal Inhlbitory Conc~ntratlon (MIC) a~ainst PathoF,enic Microorganisms (ln vi~ro).
_ . . .
~mpl~ MIC ( ~Ig/ml ) St~phy- Escheri- Proteus Prot~u~, hlebsiell~ P~udo-lococcus chia mirabilis ~ulgaris pneumoni~e mon~s aureus coli GN2425 HXl9 602 ~eru~i-209P NIHJ 104a . _ .
1 0.~9 12,5 3.13 0,05 6,25 6,25 2 0.39 25 - 12,5 0.39 12.5 12~5 3 ~.78 12.5 6,25 0.39 6 ~25 12,5 0.78 12.5 6.25 0.39 12.5 12,5.
0,78 12,5 6,25 0.39 6,25 12,5 6 0.78 12,5 6,25 0.39 6,25 12,5 7 0.39 12,5 6,25 '5 25 3]3 8 0.39 12,5 6,25 0~05 6.25 3.13 : 9 0,78 25 6.25' 0.78 3.13 12,5 0,78 25 6.25 0.78 3.1~ 25 11 0,78 25 12,5 0,39 12.5 6.25 12 1.56 12.5 6,25 0.2 ~ 25 1~ 0.39 12,5 50 0,39 25 3.13 14 0.78 50 12.5 0,2 25 6,23 I5 0.78 25 3 O 13 0.05 50 3013 16 0,78 50 12.5 0,1 50 6.25 l? -39 25 12.5 0;05 100 3.13 18 0.2 12.5 50 0.39- 25 12.5 19 0,78 6.25 12.5 0.2 ~5 12.5 0.78 6.25 3.13 0.057 50 12.5 21 0.78 12.5 5P 0.'~8 100 12.5 22 0.2 6.25 25 0.2 . 25 6.25 23 -39 12.5 ?5 0.2 25 6.~5 2~ 0.78 25 25 0.78 25 ~.13 0.78 25 3.1-S 0.05 25 6.25 26 0.39 12.5 12.5 0.2 12.5 ~
I 0.78 100 50 0.39 50 5o 1 I 0.78 100 100 0.78 100 50 ' cilli n ' 1 6.26 1,56 1,56 50 ? 200 .
`- 10~9e504 Comp~unds Nos. I and II are penicilllns of the following formulae disclos~d in U.S. patent 3,433,784:
No. I. ~
~N~LCOI~-CH-CO~-CH-fH `f-- -S
. ~ C -N - CII-COONa NoO II ~ CO~ CH-CO~I-CH-CH ~C ~CH~
~ N - C~I~COONn :
.
. :
: ' ' , ,:, -. .
- , -'~
, ..
.~ , .
- 21 - . .
. , :. ;, : ., . :
~, , . .. . : .
5~
SUPPLEMENTARY DISCLOSURE
It has now been further found that penicilllns of the formula:
.. OY ., R~ j S j ~CH~
-COl~H~fH-CONH-IH-~ ~C ~ (IA) ~2 R ~ -N - C~-C00H
. ~ O
wherein ( C-, R1, R2 and Y are as defined in the principal disclosure and R is p-hydroxyphenyl, Cl-C4 alkyl, cyclohexadienyl, thienyl or isothiazolyl, also exhibit a noticeable antimicrobial activity against Pseudomonas and a broad antimicrobial spectrum -~
without serious side effects.
10The pharmaceutical characteristics of the penicillins of the formula (IA) are their strong antimicrobial activity against Pseudomonas, broad antimicrobial spectrum low toxicity and hlgh solubility in water, which is desirable in the preparation of iniectable solutions.
The structural characteristics of the new penicillins -of formula (IA) are that the residue ( JC bears thereon an -O-Y
group which is linked to a carbon atom adjacent the carbon atom to which an N-acylpenicillin unit is linked. Compounds wherein the residue ( \ C bears no -O-Y group are antimicrobially much less active than those bearing an -O-Y group and exhibit only the same low antimicrobial activity as those disclosed in U.S.
Patent 3,433,784 against Pseudomonas as well as other gram-positive and gram-negative bacteria.
In the case of Z being phenyl and ( \C representing a pyridine ring, the preferred penicillins (IA) are those wherein Rl and R2 a~e each hydrogen, lower alkyl (particularly methyl), cyano, hydroxy(lower)alkyl (particularly a-hydroxyethyl), lower alkanoyl (particularly acetyl) or benzoyl or they are linked ther so that R ~ \C represents a C8 C10 y ' ..' ~9S~4 :
ring (e.g. cyclopentenopyridine, cyclohexenopyiidine, cyclohepteno-pyridine) which may be substituted by an oxo group, and Y is hydrogen, ethoxycarbonyl or t-butanoyl. In the case of Z being phenyl and ( ~ C representing a pyrimidine ring, the preferred penicillins (IA3 are those wherein Rl and R2 are each hydrogen, hydroxyl, mercapto or lower alkylthio (particularly methylthio) and Y is hydrogen or ethoxycarbonyl. In the case of Z being phenyl and ( C representing a pyridazine ring, the preferred A-~penicillins (IA) are those wherein Rl and R2 are each hydrogen, halogen (particularly chlorine) or lower alkyl (particularly methyl) and Y is hydrogen.
~ urther penicillins (IA) which are particularly effec-tive include D-~-(4-hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin and D-a-(2-hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin. The penicillins (IA) can be prepared -by reacting a compound of the formula:
. ~ , ..
~cK co~T~_c~_c~ f ~CH3 (IIA) O~C N CX-COOH
wherein K is as defined above or a derivative thereof, with a carboxylic acid of the formula:
1Y ' Rl ~ \ C-COOH (IIIA) ~-C\
wherein ( JC- Rl, R2 and Y are as defined in the principal disclosure or a reactive derivative thereof, if necessary, followed by hydrolysis or acylation of the resulting product and/or elimination of any protective group.
Suitable derivatives of the compounds (IIA) and (IIIA) ;
which may be employed are the same as those outlined in detail in the principal disclosure for compounds (II) and (III~.
, - 23 -..
~95~4 The reaction is conventionally carried out ln an inert solvent such as a polar solvent (e.g. dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, ethanol, dimethylformamide), a non-polar solvent (e.g. benzene, toluene, petroleum ether, n-hexane) or a mixture thereof. The reaction temperature is usually below 50C, preferably from 50 to -80C.
Other optional and preferred reaction conditions which may be employed in particular cases are similar to those outlined in the principal disclosure for compounds wherein R is replaced by phenyl.
The produced penicillin (IA) may, if desired, be converted into a non toxic pharmaceutically acceptable salt thereof in a per se conventional manner. Examples of suitable -salts are salts of alkali metals (e.g. sodium or potassium), salts of alkaline earth metals ~e.g. calcium or magnesium), ammonium salts, substituted ammonium salts, amine salts (e.g.
triethylamine, procaine, dibenzylamine, N-benzyl-~-phenethylamine, l-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine and N,N'-bis-dehydroabietylethylenediamine salts), and arginine salts.
The subject matter of this supplementary disclosure is illustrated by the following Examples.
Exam~le 1 Preparation of D-~ -hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin:- -OH ~S~
~COI~E-ICH-CO~H-CH--fE ~CHE3 ~C N CH-COOH
(1) D-~-amino-p-hydroxybenzylpenicillin triethylamine salt (1.17 g) is dissolved in dimethylformamide (25 ml), and p-nitrophenyl 4-hydroxypyridine-3-carboxylate (M.P. 256-258C, ~~Y--. .. , ~
:~
s~ :
decomp.) (0.65 g) and triethylamine (0.5 g) are successively added thereto while stirring at room -temperature. Stirring is continued at room temperature for 4 hours. Ts the resulting solution i5 added acetone (125 ml), and the separated crystals are collected by filtration, washed with acetone and dissolved in water (50 ml).
The solution is adjusted to pH 2 with hydrochloric acid while cooling. The separated crystals are collected by filtration, washed wi-th cold water and drie~ over phosphorus pentoxide under redu~ed pressure to give the objective penicillin (0.77 g).
(2) The D-a~(4hydroxypyridi~-3-carboxamido)-p-hydroxybenzylpenicillin (0.77 g) is dissolved in a solu-tion of dimethylformamide (8 ml) and acetone (35 ml). A solution of sodium 2-ethylhexanoate (0.256 g) in ace-tone (8 ml) is added thereto while stirring at room temperature. Stirring is continued at room temperature for 20 minutes. The separated crystals are collected by filtration, washed with acetone and dried under -~
reduced pressure to give the objective penicillin as the sodium salt (0.75 g). Purity (determined by iodometry), 88%.
Example 2 Preparation of D-~-(2-hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin:
/ \ CH3 ~_CONHCHCONH-CH - CH C
H ~ C N CH-cooH
OH
(1) To D-~-amino-p-hydroxybenzylpenicillin tri~ydra-te -(0.84 g) were added molecular sieve powder 3A (1 g) and tri-ethylamine (~.4 g). After s~irring at room temperature for 20 minutes, the resulting mixture was filtered. To the filtrate, there was added p-nitrophenyl-2-hydroxypyridine-3-carboxylate (MrP~ 234 to 238C) (0.52 g) while stirring at room temperature.
Stirring was continued a* room temperature for 3 hours. To the 30 resulting solution, there was added ether (200 ml), and the ; ~
` 104951)~
pre~ipitate~ crystals were collected by filtration, washed with ether and dissolved in water (50 ml). The solution was adjusted to pH 2 with hydrochloric acid while cooling. The precipitated cryst~ls were collected by filtration, washed with cold water and dried over phosphorus pentoxide under re-duced pressure to give the objective penicillin (0.69 g).
(2) The D-~-(2-hvdroxypyridine-3-carboxamido)~p-hydroxy-benzylpenicillin (Q.69 g) was dissolved in a solution of di-methylformamide (7 m].) and acetone (15 ml). ~ solution of sodium 2-theylhexanoate (0.266 g) in acetone (15 ml) was added thereto while stirring at room temperature. Stirring was continued at room tempe~ature for 20 minutes. The pre-cipitated crystals were collected by filtration, washed with acetone and dried under ~educed pressure to give the objective penicillin as the sodium salt (0.705 g). Purity (determined by iodometry), 90%, Example 3 Preparation of D-~-(4-hydroxypyridine-3-carboxamido)-1,4-cyclohexadienylmethylpenicillin:
OH
CONH-CHCONH-CH C~ \C~ CH3 ,C _ N _1H-COOH
(1) To 4-hydroxypyridine-3-oarboxylic acid (3.0 g), there were added dichloromethane (150 ml) and triethylamine (4.60 g), and isobutylchloroformate (6.50 g) ~as added thereto at 20C. After stirring for 30 minutes; D-~-amino-1,4-cyclo-hexadienylmethylpenicillin triethylamine salt (9.7 g) was added to the resulting mixture, which was subsequently kept for 4 hours at -20C. On completion of the reaction, a solution of sodium bicarbonate (4.3 g) in water (200 ml) and ethyl acetate (400 ml) were added thereto. The organic layer was separated from the aqueous layer and washed with water (25 ml). The ~495V4 aqueous layer and the washin~s were combined ~o~ethcr; ~Jashed twice ~rith ethylacetate and then cooled trith ice. The aqueous ~olution ~ras adjusted to p~I 2 by the addition of dilute aqueous hydrochloric acid and extracted ~Tith ethylacetate (200 ml).
The extract wa~ washed ~rith water, dried over anhydrous mag-nesium sulfate and concentrated under reduced pressure, The re~idue was recrystalized from a mixture o~ ether and ethyl - acetate to give n-a (~-isobutoxycarbonyloxyp~ridine-3-carbox-amido)~l,4-hexadienylmethylpenicillin (8 g)O
~2) ~a) To the D-a-~4-isobutoxycarbonyloxypyridine- -3-carboxami~o)-1,4-hexadienylmethylpenicilli~ ~4 g)~ there ~as added a solution o~ sodium 2-ethylhexanoate (1.37 g) i~ di-methylforma~ide (20 ml~ while stirring at room temperature.
Stirring was continued for 20 minutes, ~o the resulting so-lution, there wa~ added ether tlOO ml), and the precipitated crystals ~rere collected by filtration, washed ~rith ether and dried under red~ced pressure to give the oDjective penicillin as the sodiun salt (2.9 g). Purity (deter~ined by iodometry), 91 ~o.
(b) ~o the D-a-(4~isobutoxycarbonyloxypyridine-3-carboxa~idc)~1,4-hexadienylmethylpenicillin (4 g), there ~ras addcd a solution of pOtassium carbonate (1.5 g) in ~rater (40 ~1), ~ld the resulting solution was stirred at room tem-perature for 1 hour and ~hen adjusted to pH 2 with dilute hydrochloric acid uhile cool~lg ~rith ice. Precipitated ~rhite crystals ~Jere collected by Iiltration~ washed ~rith ~later and dried ~dcr redllced pressure to give the objcc~ive penicillin, Yicld, ~
Examples 4 to 11 The new penicillins as shown in Table 1 were prepared by procedures equlvalent to those described in Examples 1 to 3.
~ ' '.
..... .
r /s Z-CONH-CH-CONH-CH--IH C ~CH3 R ~, _ N--CH-~OOM .
Table ].
... .. .
Example Compound Purity (C/o) No . _. .. . . ~ ( iodo-Z R M metry) -- OH . _ 4 ~ ~ . Na 90 _ ..... ..... ._ _ ........... ...
0~ ~ . .
S ~ ~--CH-CH2- Na 82 _~. OH
. 6 ~ 3 CE-CH2- . Na 86 . .. ..OH . . _____ . .
7 ~ . ~ . Na 89 : . . , . ._._ OH . .; __ ~ __ _ ~
.~ 8 ~ ~ ~a ag.5 _ OH __ ~ ~ .
: N~ . . ~ Na 83 _ OH . . . .. . ~ . . . . . .
10 ~ [~L ;. Na 88 .
H _ , _ 1~ ~r ! ~ ~188 1 :
.. ,~ ~ :.
.. . ~ . . . .... : ...... . .
~04~.~5~3L~Jt.
When determlned according to the agar dilution method, the penicillins of the above Examples exhibited minim~l inhibitory concentrations as shawn in Table 2.
Table 2 Minimal inhlbitory concentrations (MIC) against pathogenic_microorganisms (in vitro).
_ , .
. MIC (~g/~l) _ . . _ ~
Staplly- Escheri- Proteus Proteus Klebsiellal~seudo-.
lococcus chia mirabilis ~llgaris pneumoniae~monas Example aureus coli GN2425 ~19 602 aerugi-209P liIHJ nosa ,, . .
l 0.78 12.5 6.25 0.2 100 3.13 2 1.56 12.5 12.5 0.2 100 6.25 : 3 0~9 25 12.5 0.2 12.5 6.25 4 0.2 12.5 12.5 0.05 3.13 3.13 0.39 12.5 25 0-39 25 12.5
SUPPLEMENTARY DISCLOSURE
It has now been further found that penicilllns of the formula:
.. OY ., R~ j S j ~CH~
-COl~H~fH-CONH-IH-~ ~C ~ (IA) ~2 R ~ -N - C~-C00H
. ~ O
wherein ( C-, R1, R2 and Y are as defined in the principal disclosure and R is p-hydroxyphenyl, Cl-C4 alkyl, cyclohexadienyl, thienyl or isothiazolyl, also exhibit a noticeable antimicrobial activity against Pseudomonas and a broad antimicrobial spectrum -~
without serious side effects.
10The pharmaceutical characteristics of the penicillins of the formula (IA) are their strong antimicrobial activity against Pseudomonas, broad antimicrobial spectrum low toxicity and hlgh solubility in water, which is desirable in the preparation of iniectable solutions.
The structural characteristics of the new penicillins -of formula (IA) are that the residue ( JC bears thereon an -O-Y
group which is linked to a carbon atom adjacent the carbon atom to which an N-acylpenicillin unit is linked. Compounds wherein the residue ( \ C bears no -O-Y group are antimicrobially much less active than those bearing an -O-Y group and exhibit only the same low antimicrobial activity as those disclosed in U.S.
Patent 3,433,784 against Pseudomonas as well as other gram-positive and gram-negative bacteria.
In the case of Z being phenyl and ( \C representing a pyridine ring, the preferred penicillins (IA) are those wherein Rl and R2 a~e each hydrogen, lower alkyl (particularly methyl), cyano, hydroxy(lower)alkyl (particularly a-hydroxyethyl), lower alkanoyl (particularly acetyl) or benzoyl or they are linked ther so that R ~ \C represents a C8 C10 y ' ..' ~9S~4 :
ring (e.g. cyclopentenopyridine, cyclohexenopyiidine, cyclohepteno-pyridine) which may be substituted by an oxo group, and Y is hydrogen, ethoxycarbonyl or t-butanoyl. In the case of Z being phenyl and ( ~ C representing a pyrimidine ring, the preferred penicillins (IA3 are those wherein Rl and R2 are each hydrogen, hydroxyl, mercapto or lower alkylthio (particularly methylthio) and Y is hydrogen or ethoxycarbonyl. In the case of Z being phenyl and ( C representing a pyridazine ring, the preferred A-~penicillins (IA) are those wherein Rl and R2 are each hydrogen, halogen (particularly chlorine) or lower alkyl (particularly methyl) and Y is hydrogen.
~ urther penicillins (IA) which are particularly effec-tive include D-~-(4-hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin and D-a-(2-hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin. The penicillins (IA) can be prepared -by reacting a compound of the formula:
. ~ , ..
~cK co~T~_c~_c~ f ~CH3 (IIA) O~C N CX-COOH
wherein K is as defined above or a derivative thereof, with a carboxylic acid of the formula:
1Y ' Rl ~ \ C-COOH (IIIA) ~-C\
wherein ( JC- Rl, R2 and Y are as defined in the principal disclosure or a reactive derivative thereof, if necessary, followed by hydrolysis or acylation of the resulting product and/or elimination of any protective group.
Suitable derivatives of the compounds (IIA) and (IIIA) ;
which may be employed are the same as those outlined in detail in the principal disclosure for compounds (II) and (III~.
, - 23 -..
~95~4 The reaction is conventionally carried out ln an inert solvent such as a polar solvent (e.g. dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, ethanol, dimethylformamide), a non-polar solvent (e.g. benzene, toluene, petroleum ether, n-hexane) or a mixture thereof. The reaction temperature is usually below 50C, preferably from 50 to -80C.
Other optional and preferred reaction conditions which may be employed in particular cases are similar to those outlined in the principal disclosure for compounds wherein R is replaced by phenyl.
The produced penicillin (IA) may, if desired, be converted into a non toxic pharmaceutically acceptable salt thereof in a per se conventional manner. Examples of suitable -salts are salts of alkali metals (e.g. sodium or potassium), salts of alkaline earth metals ~e.g. calcium or magnesium), ammonium salts, substituted ammonium salts, amine salts (e.g.
triethylamine, procaine, dibenzylamine, N-benzyl-~-phenethylamine, l-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine and N,N'-bis-dehydroabietylethylenediamine salts), and arginine salts.
The subject matter of this supplementary disclosure is illustrated by the following Examples.
Exam~le 1 Preparation of D-~ -hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin:- -OH ~S~
~COI~E-ICH-CO~H-CH--fE ~CHE3 ~C N CH-COOH
(1) D-~-amino-p-hydroxybenzylpenicillin triethylamine salt (1.17 g) is dissolved in dimethylformamide (25 ml), and p-nitrophenyl 4-hydroxypyridine-3-carboxylate (M.P. 256-258C, ~~Y--. .. , ~
:~
s~ :
decomp.) (0.65 g) and triethylamine (0.5 g) are successively added thereto while stirring at room -temperature. Stirring is continued at room temperature for 4 hours. Ts the resulting solution i5 added acetone (125 ml), and the separated crystals are collected by filtration, washed with acetone and dissolved in water (50 ml).
The solution is adjusted to pH 2 with hydrochloric acid while cooling. The separated crystals are collected by filtration, washed wi-th cold water and drie~ over phosphorus pentoxide under redu~ed pressure to give the objective penicillin (0.77 g).
(2) The D-a~(4hydroxypyridi~-3-carboxamido)-p-hydroxybenzylpenicillin (0.77 g) is dissolved in a solu-tion of dimethylformamide (8 ml) and acetone (35 ml). A solution of sodium 2-ethylhexanoate (0.256 g) in ace-tone (8 ml) is added thereto while stirring at room temperature. Stirring is continued at room temperature for 20 minutes. The separated crystals are collected by filtration, washed with acetone and dried under -~
reduced pressure to give the objective penicillin as the sodium salt (0.75 g). Purity (determined by iodometry), 88%.
Example 2 Preparation of D-~-(2-hydroxypyridine-3-carboxamido)-p-hydroxybenzylpenicillin:
/ \ CH3 ~_CONHCHCONH-CH - CH C
H ~ C N CH-cooH
OH
(1) To D-~-amino-p-hydroxybenzylpenicillin tri~ydra-te -(0.84 g) were added molecular sieve powder 3A (1 g) and tri-ethylamine (~.4 g). After s~irring at room temperature for 20 minutes, the resulting mixture was filtered. To the filtrate, there was added p-nitrophenyl-2-hydroxypyridine-3-carboxylate (MrP~ 234 to 238C) (0.52 g) while stirring at room temperature.
Stirring was continued a* room temperature for 3 hours. To the 30 resulting solution, there was added ether (200 ml), and the ; ~
` 104951)~
pre~ipitate~ crystals were collected by filtration, washed with ether and dissolved in water (50 ml). The solution was adjusted to pH 2 with hydrochloric acid while cooling. The precipitated cryst~ls were collected by filtration, washed with cold water and dried over phosphorus pentoxide under re-duced pressure to give the objective penicillin (0.69 g).
(2) The D-~-(2-hvdroxypyridine-3-carboxamido)~p-hydroxy-benzylpenicillin (Q.69 g) was dissolved in a solution of di-methylformamide (7 m].) and acetone (15 ml). ~ solution of sodium 2-theylhexanoate (0.266 g) in acetone (15 ml) was added thereto while stirring at room temperature. Stirring was continued at room tempe~ature for 20 minutes. The pre-cipitated crystals were collected by filtration, washed with acetone and dried under ~educed pressure to give the objective penicillin as the sodium salt (0.705 g). Purity (determined by iodometry), 90%, Example 3 Preparation of D-~-(4-hydroxypyridine-3-carboxamido)-1,4-cyclohexadienylmethylpenicillin:
OH
CONH-CHCONH-CH C~ \C~ CH3 ,C _ N _1H-COOH
(1) To 4-hydroxypyridine-3-oarboxylic acid (3.0 g), there were added dichloromethane (150 ml) and triethylamine (4.60 g), and isobutylchloroformate (6.50 g) ~as added thereto at 20C. After stirring for 30 minutes; D-~-amino-1,4-cyclo-hexadienylmethylpenicillin triethylamine salt (9.7 g) was added to the resulting mixture, which was subsequently kept for 4 hours at -20C. On completion of the reaction, a solution of sodium bicarbonate (4.3 g) in water (200 ml) and ethyl acetate (400 ml) were added thereto. The organic layer was separated from the aqueous layer and washed with water (25 ml). The ~495V4 aqueous layer and the washin~s were combined ~o~ethcr; ~Jashed twice ~rith ethylacetate and then cooled trith ice. The aqueous ~olution ~ras adjusted to p~I 2 by the addition of dilute aqueous hydrochloric acid and extracted ~Tith ethylacetate (200 ml).
The extract wa~ washed ~rith water, dried over anhydrous mag-nesium sulfate and concentrated under reduced pressure, The re~idue was recrystalized from a mixture o~ ether and ethyl - acetate to give n-a (~-isobutoxycarbonyloxyp~ridine-3-carbox-amido)~l,4-hexadienylmethylpenicillin (8 g)O
~2) ~a) To the D-a-~4-isobutoxycarbonyloxypyridine- -3-carboxami~o)-1,4-hexadienylmethylpenicilli~ ~4 g)~ there ~as added a solution o~ sodium 2-ethylhexanoate (1.37 g) i~ di-methylforma~ide (20 ml~ while stirring at room temperature.
Stirring was continued for 20 minutes, ~o the resulting so-lution, there wa~ added ether tlOO ml), and the precipitated crystals ~rere collected by filtration, washed ~rith ether and dried under red~ced pressure to give the oDjective penicillin as the sodiun salt (2.9 g). Purity (deter~ined by iodometry), 91 ~o.
(b) ~o the D-a-(4~isobutoxycarbonyloxypyridine-3-carboxa~idc)~1,4-hexadienylmethylpenicillin (4 g), there ~ras addcd a solution of pOtassium carbonate (1.5 g) in ~rater (40 ~1), ~ld the resulting solution was stirred at room tem-perature for 1 hour and ~hen adjusted to pH 2 with dilute hydrochloric acid uhile cool~lg ~rith ice. Precipitated ~rhite crystals ~Jere collected by Iiltration~ washed ~rith ~later and dried ~dcr redllced pressure to give the objcc~ive penicillin, Yicld, ~
Examples 4 to 11 The new penicillins as shown in Table 1 were prepared by procedures equlvalent to those described in Examples 1 to 3.
~ ' '.
..... .
r /s Z-CONH-CH-CONH-CH--IH C ~CH3 R ~, _ N--CH-~OOM .
Table ].
... .. .
Example Compound Purity (C/o) No . _. .. . . ~ ( iodo-Z R M metry) -- OH . _ 4 ~ ~ . Na 90 _ ..... ..... ._ _ ........... ...
0~ ~ . .
S ~ ~--CH-CH2- Na 82 _~. OH
. 6 ~ 3 CE-CH2- . Na 86 . .. ..OH . . _____ . .
7 ~ . ~ . Na 89 : . . , . ._._ OH . .; __ ~ __ _ ~
.~ 8 ~ ~ ~a ag.5 _ OH __ ~ ~ .
: N~ . . ~ Na 83 _ OH . . . .. . ~ . . . . . .
10 ~ [~L ;. Na 88 .
H _ , _ 1~ ~r ! ~ ~188 1 :
.. ,~ ~ :.
.. . ~ . . . .... : ...... . .
~04~.~5~3L~Jt.
When determlned according to the agar dilution method, the penicillins of the above Examples exhibited minim~l inhibitory concentrations as shawn in Table 2.
Table 2 Minimal inhlbitory concentrations (MIC) against pathogenic_microorganisms (in vitro).
_ , .
. MIC (~g/~l) _ . . _ ~
Staplly- Escheri- Proteus Proteus Klebsiellal~seudo-.
lococcus chia mirabilis ~llgaris pneumoniae~monas Example aureus coli GN2425 ~19 602 aerugi-209P liIHJ nosa ,, . .
l 0.78 12.5 6.25 0.2 100 3.13 2 1.56 12.5 12.5 0.2 100 6.25 : 3 0~9 25 12.5 0.2 12.5 6.25 4 0.2 12.5 12.5 0.05 3.13 3.13 0.39 12.5 25 0-39 25 12.5
6 0.78 25 25 0.39 5o 12.5
7 0.39 12.5 6.25 0.05 12.5 3.13
8 . 0.7~ 25 . 12.5 0.2 25 6.23 .
.9 0.39 25 6.25 0.05- 50 3.13 I0 0-39 12.5 6.25 0.05 12.5 3.13 11 0.39 12.5 6.25 0.05 25_ 6.25 :- ~ ' . ' , .~.,,~, .
.: - : , . . . ~ , .. : .
.
- . ~ -,
.9 0.39 25 6.25 0.05- 50 3.13 I0 0-39 12.5 6.25 0.05 12.5 3.13 11 0.39 12.5 6.25 0.05 25_ 6.25 :- ~ ' . ' , .~.,,~, .
.: - : , . . . ~ , .. : .
.
- . ~ -,
Claims (61)
1. A process for preparing a penicillin of the formula:
wherein is a six-membered heteroaromatic ring selected from pyridine, pyrimidine, pyridazine and pyrazine, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmer-capto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano, or R1 and R2 linked together represent cyclopenteno, cyclohexeno or cyclohepteno optionally substituted with an oxo group, or a non-toxic, pharmaceutically acceptable salt thereof, which comprises reacting 6-(.alpha.-aminophenylacetamido)-penicillanic acid or a derivative thereof with a carboxylic acid of the formula:
wherein , Y, R1 and R2 are each as defined above, or a reactive derivative thereof, if necessary, hydrolyzing or acylating the resulting product and/or eliminating any protective group, and, if necessary, converting the product to a non-toxic pharma-ceutically acceptable acid addition salt thereof.
wherein is a six-membered heteroaromatic ring selected from pyridine, pyrimidine, pyridazine and pyrazine, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmer-capto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano, or R1 and R2 linked together represent cyclopenteno, cyclohexeno or cyclohepteno optionally substituted with an oxo group, or a non-toxic, pharmaceutically acceptable salt thereof, which comprises reacting 6-(.alpha.-aminophenylacetamido)-penicillanic acid or a derivative thereof with a carboxylic acid of the formula:
wherein , Y, R1 and R2 are each as defined above, or a reactive derivative thereof, if necessary, hydrolyzing or acylating the resulting product and/or eliminating any protective group, and, if necessary, converting the product to a non-toxic pharma-ceutically acceptable acid addition salt thereof.
2. A process according to claim 1, wherein the reactive derivative of the carboxylic acid is an active ester.
3. A process for preparing a penicillin according to claim 1 in which Y represents hydrogen, which comprises hydrolyzing a product of the formula:
wherein Y is lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each as defined in claim 1, to give the corres-ponding hydroxyl compound.
wherein Y is lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each as defined in claim 1, to give the corres-ponding hydroxyl compound.
4. A process according to claim 1, 2 or 3, wherein the reaction is carried out in an inert solvent.
5. A process according to claim 1, 2 or 3, wherein the reaction is carried out at a temperature of from -50 to 80°C.
6. A process according to claim 1, 2 or 3, wherein the reaction is carried out in the presence of a basic substance.
7. A process according to claim 1, wherein the product is isolated in D(-)configuration.
8. A process according to claim 1, wherein Y represents hydrogen.
9. A process according to claim 1 wherein Y, R1 and R2 each represent hydrogen.
10. A process according to claim 1, wherein represents a pyridazine ring and Y, R1 and R2 are each hydrogen.
11. A process according to claim 1, wherein represents a pyrimidine ring and Y, R1 and R2 are each hydrogen.
12. A process according to claim 1, wherein represents a pyrazine ring and Y, R1 and R2 are each hydrogen.
13. A process according to claim 1, wherein represents a pyridine ring and Y, R1 and R2 are each hydrogen.
14. A process according to claim 1 wherein represents
15. A process according to claim 1 wherein represents
16. A process according to claim 1 wherein represents
17. A process according to claim 1 wherein represents
18. A process according to claim 1 wherein represents
19. A process according to claim 1 wherein represents
20. A process according to claim 1 wherein represents
21. A process according to claim 1 wherein represents
22. A process according to claim 1 wherein represents
23. A penicillin of the formula;
wherein is a six-membered heteroaromatic ring selected from pyridine, pyrimidine, pyridazine and pyrazine, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkyl-mercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano, or R1 and R2 linked together represent cyclopenteno, cyclohexeno or cyclohepteno optionally substituted with an oxo group, or a non-toxic pharmaceutically acceptable salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
wherein is a six-membered heteroaromatic ring selected from pyridine, pyrimidine, pyridazine and pyrazine, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkyl-mercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano, or R1 and R2 linked together represent cyclopenteno, cyclohexeno or cyclohepteno optionally substituted with an oxo group, or a non-toxic pharmaceutically acceptable salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
24. A penicillin according to claim 23, having the D(-)-configuration, whenever prepared by the process claimed in claim 7, or by an obvious chemical equivalent thereof.
25. A penicillin according to claim 23, wherein Y is hydrogen, whenever prepared by the process claimed in claim 8, or by an obvious chemical equivalent thereof.
26. A penicillin of the formula:
wherein R1 and R2 are each hydrogen and is as defined in claim 9, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.
wherein R1 and R2 are each hydrogen and is as defined in claim 9, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.
27. A penicillin of the formula:
wherein is a pyridazine ring and R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 10, or by an obvious chemical equivalent thereof.
wherein is a pyridazine ring and R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 10, or by an obvious chemical equivalent thereof.
28. A penicillin of the formula:
wherein is a pyrimidine ring R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 11, or by an obvious chemical equivalent thereof.
wherein is a pyrimidine ring R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 11, or by an obvious chemical equivalent thereof.
29. A penicillin of the formula:
wherein is a pyrazine ring and R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 12, or by an obvious chemical equivalent thereof.
wherein is a pyrazine ring and R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 12, or by an obvious chemical equivalent thereof.
30. A penicillin of the formula:
wherein is a pyridine ring and R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 13, or by an obvious chemical equivalent thereof.
wherein is a pyridine ring and R1 and R2 are each hydrogen, and non-toxic, pharmaceutically acceptable salts thereof, whenever prepared by the process claimed in claim 13, or by an obvious chemical equivalent thereof.
31. D-.alpha.-(4-Hydroxypyridine-3-carboxamido)-benzylpenicillin, whenever prepared by the process claimed in claim 14, or by an obvious chemical equivalent thereof.
32. D-.alpha.-(2,4-Dihydroxypyrimidine-5-carboxamido)-benzylpenicillin, whenever prepared by the process claimed in claim 15, or by an obvious chemical equivalent thereof.
33. D-.alpha.-(3-Hydroxypyridazine-4-carboxamido)-benzylpenicillin, whenever prepared by the process claimed in claim 16, or by an obvious chemical equivalent thereof.
34. D-.alpha.-(3-Hydroxypyridine-2-carboxamido)-benzylpenicillin, whenever prepared by the process claimed in claim 17, or by an obvious chemical equivalent thereof.
35. D-.alpha.-(2-Hydroxypyridine-3-carboxamido)-benzylpenicillin, whenever prepared by the process claimed in claim 18, or by an obvious chemical equivalent thereof.
36. D-.alpha.-(2-Hydroxypyrazine-3-carboxamido)-benzylpenicillin, whenever prepared by the process claimed in claim 19, or by an obvious chemical equivalent thereof.
37. D-.alpha.-[2-Methyl-3-(.alpha.-hydroxyethyl)-4-hydroxypyridine-5-carboxamido]-benzylpenicillin, whenever prepared by the process claimed in claim 20, or by an obvious chemical equivalent thereof.
38. D-.alpha.-[3-(.alpha.-Hydroxyethyl)-4-hydroxypyridine-5-carboxamido]-benzylpenicillin, whenever prepared by the process claimed in claim 21, or by an obvious chemical equivalent thereof.
39. D-.alpha.-(4-Hydroxypyridazine-5-carboxamido)-benzylpenicillin, whenever prepared by the process claimed in claim 22, or by an obvious chemical equivalent thereof.
Claims Supported By the Supplementary Disclosure
Claims Supported By the Supplementary Disclosure
40. A process for preparing a penicillin of the formula:
(IA) wherein is a six-membered heteroaromatic ring containing 1 or 2 hetero nitrogen atoms, R is phenyl, p-hydroxyphenyl, C1-C4 alkyl, cyclohexadienyl, thienyl or isothiazolyl, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl halogen or cyano or R1 and R2 linked together represent a lower alkylene chain optionally substituted with an oxo group, or a non-toxic, pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula:
(IIA) wherein R is as defined above, or a derivative thereof, with a carboxylic acid of the formula:
wherein , Y, R1 and R2 are each as defined above, or a reactive derivative thereof, if necessary, hydrolyzing or acylating the resulting product and/or eliminating any protective group, and, if necessary, converting the product to a non-toxic pharma-ceutically acceptable acid addition salt thereof.
(IA) wherein is a six-membered heteroaromatic ring containing 1 or 2 hetero nitrogen atoms, R is phenyl, p-hydroxyphenyl, C1-C4 alkyl, cyclohexadienyl, thienyl or isothiazolyl, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl halogen or cyano or R1 and R2 linked together represent a lower alkylene chain optionally substituted with an oxo group, or a non-toxic, pharmaceutically acceptable salt thereof, which comprises reacting a compound of the formula:
(IIA) wherein R is as defined above, or a derivative thereof, with a carboxylic acid of the formula:
wherein , Y, R1 and R2 are each as defined above, or a reactive derivative thereof, if necessary, hydrolyzing or acylating the resulting product and/or eliminating any protective group, and, if necessary, converting the product to a non-toxic pharma-ceutically acceptable acid addition salt thereof.
41. A process according to claim 40 wherein represents and R represents p-hydroxyphenyl.
42. A process according to claim 40, wherein represents and R represents p-hydroxyphenyl.
43. A process according to claim 40, wherein represents and R represents 1,4-cyclohexadienyl.
44. A process according to rlaim 40, wherein represents and R represents .
45. A process according to claim 40, wherein represents and R represents .
46. A process according to claim 40, wherein represents and R represents .
47. A process according to claim 40, wherein represents and R represents .
48. A process according to claim 40, wherein represents and R represents .
49. A process according to claim 40, wherein represents and R represents .
50. A penicillin of the formula (IA) wherein is a six-membered heteroaromatic ring containing 1 or 2 hetero nitrogen atoms, R is phenyl, p-hydroxyphenyl, C1-C4 alkyl, cyclohexadienyl, thienyl or isothiazolyl, Y is hydrogen, lower alkanoyl or lower alkoxycarbonyl and R1 and R2 are each hydrogen, lower alkyl, lower alkanoyl, benzoyl, lower alkylmercapto, hydroxyl, mercapto, hydroxy(lower)alkyl, halogen or cyano or R1 and R2 linked together represent a lower alkylene chain optionally substituted with an oxo group, or a non-toxic, pharmaceutically acceptable salt thereof, whenever prepared by the process claimed in claim 40, or by an obvious chemical equivalent thereof.
51. D-.alpha.-(4-Hydroxypyridine-3-carboxamido)-p-hydroxy-benzylpenicillin, whenever prepared by the process claimed in claim 41, or by an obvious chemical equivalent thereof.
52. D-.alpha.-(2-Hydroxypyridine-3-carboxamido)-p-hydroxy-benzylpenicillin, whenever prepared by the process claimed in claim 42, or by an obvious chemical equivalent thereof.
53. D-.alpha.-(4-Hydroxypyridine-3-carboxamido)-1,4-cyclo-hexadienylmethylpenicillin, whenever prepared by the process claimed in claim 43, or by an obvious chemical equivalent thereof.
54. D-.alpha.-(3-Hydroxypyridazine-4-carboxamido)-1,4-cyclohexadienylmethylpenicillin, whenever prepared by the process claimed in claim 44, or by an obvious chemical equivalent thereof.
55. D-.alpha.-(3-Hydroxypyridazine-4-carboxamido)-3-thienyl-methylpenicillin, whenever prepared by the process claimed in claim 45, or by an obvious chemical equivalent thereof.
56. 6-[D-.alpha.-(4-Hydroxypyridine-3-carboxamido)-4-isothiazolylacetamido]penicillanic acid, whenever prepared by the process claimed in claim 46, or by an obvious chemical equivalent thereof.
57. D-.alpha.-(4-Hydroxypyrimidine-5-carboxamido)-3-thienylmethylpenicillin, whenever prepared by the process claimed in claim 47, or by an obvious chemical equivalent thereof.
58. D-.alpha.-(3-Hydroxypyridazine-4-carboxamido)-2-thienylmethylpenicillin, whenever prepared by the process claimed in claim 48, or by an obvious chemical equivalent thereof.
59. 6-[D-.alpha.-(3-Hydroxypyridazine-4-carboxamido)-4-isothiazolylacetamido]penicillanic acid, whenever prepared by the process claimed in claim 49, or by an obvious chemical equivalent thereof.
60. A process for preparing a penicillin of the formula which comprises reacting 6-(.alpha.-aminophenylacetamido) penicillanic acid or a derivative thereof with a carboxylic acid of the formula or a reative derivative thereof.
61. A penicillin of the formula whenever prepared by the process of claim 60.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2675972A JPS569511B2 (en) | 1972-03-15 | 1972-03-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1049504A true CA1049504A (en) | 1979-02-27 |
Family
ID=12202194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA166,058A Expired CA1049504A (en) | 1972-03-15 | 1973-03-14 | Penicillins and their production |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS569511B2 (en) |
| CA (1) | CA1049504A (en) |
| CH (1) | CH590290A5 (en) |
| DE (1) | DE2312976A1 (en) |
| FR (1) | FR2181818B1 (en) |
| GB (1) | GB1409177A (en) |
| HU (1) | HU168866B (en) |
| NL (1) | NL7303660A (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR208171A1 (en) * | 1972-09-29 | 1976-12-09 | Ciba Geigy Ag | PROCEDURE FOR OBTAINING NEW DERIVATIVES OF CEF-3-EM-4-CARBOXYL ACID |
| JPS587637B2 (en) * | 1973-12-27 | 1983-02-10 | 住友化学工業株式会社 | Shinkipenicillin no Seihou |
| US3954734A (en) * | 1974-01-21 | 1976-05-04 | Parke, Davis & Company | Novel antibacterial amide compounds and process means for producing the same |
| JPS5761760B2 (en) * | 1974-02-04 | 1982-12-25 | Sumitomo Chemical Co | |
| JPS5346997A (en) * | 1976-10-06 | 1978-04-27 | Bristol Myers Co | Antiibacterial agent |
| JPS54119484A (en) * | 1978-03-07 | 1979-09-17 | Mitsui Toatsu Chem Inc | Novel penicillin and antibracterial containing the same as the active ingredient |
| JPS55111489A (en) * | 1979-02-19 | 1980-08-28 | Eisai Co Ltd | Penicillin derivative, its preparation, and antibacterial agent comprising it |
| JPS55120566A (en) * | 1979-03-09 | 1980-09-17 | Mitsui Toatsu Chem Inc | New quinoline derivative |
| US4231928A (en) * | 1979-04-24 | 1980-11-04 | Bristol-Myers Company | Antibacterial agents |
| JPS57129218U (en) * | 1981-02-09 | 1982-08-12 | ||
| JPS57168819U (en) * | 1981-04-20 | 1982-10-23 | ||
| JPH0110726Y2 (en) * | 1981-05-12 | 1989-03-28 | ||
| JPS5875309U (en) * | 1981-11-13 | 1983-05-21 | 東芝電池株式会社 | Self-propelled record cleaner |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4872189A (en) * | 1971-12-29 | 1973-09-29 | ||
| JPS5017994A (en) * | 1973-06-19 | 1975-02-25 |
-
1972
- 1972-03-15 JP JP2675972A patent/JPS569511B2/ja not_active Expired
-
1973
- 1973-03-14 CH CH371573A patent/CH590290A5/xx not_active IP Right Cessation
- 1973-03-14 FR FR7309153A patent/FR2181818B1/fr not_active Expired
- 1973-03-14 CA CA166,058A patent/CA1049504A/en not_active Expired
- 1973-03-15 DE DE2312976A patent/DE2312976A1/en active Pending
- 1973-03-15 NL NL7303660A patent/NL7303660A/xx unknown
- 1973-03-15 HU HUSU806A patent/HU168866B/hu unknown
- 1973-03-15 GB GB1258073A patent/GB1409177A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NL7303660A (en) | 1973-09-18 |
| FR2181818B1 (en) | 1976-07-02 |
| GB1409177A (en) | 1975-10-08 |
| FR2181818A1 (en) | 1973-12-07 |
| HU168866B (en) | 1976-07-28 |
| DE2312976A1 (en) | 1973-09-27 |
| JPS569511B2 (en) | 1981-03-02 |
| CH590290A5 (en) | 1977-07-29 |
| JPS4892391A (en) | 1973-11-30 |
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