Claims
- 1. A compound of the formula: ##STR61##wherein Z is a nitrogen atom or a methylene group, the ring A is a benzene, pyrazole, thiazole, imidazole, pyrazine, pyridazine or pyrimidine ring when Z is a nitrogen atom or a methylene group, or a pyridine ring when Z is a nitrogen atom, the ring A being unsubstituted on being substituted with one on more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, lower haloalkyl, lower alkylenedioxy, halogen, hydroxyl, nitro, amino, lower alkoxycarbonylamino, lower alkylamino, di(lower)alkylamino and lower alkanoylamino, R.sub.1 is hydroxyl, lower alkanoxyloxy, lower alkoxycarbonyloxy or benzyloxycarbonyloxy, R.sub.2 and R.sub.3 are each hydrogen or halogen, X is oxygen or sulfur and Y is hydrogen, lower alkoxycarbonyl or lower alkanoyl, the Y-X- group being present on the carbon atom adjacent to the carbon atom to which the 6-(.alpha.-aminoacylamido)penicillanic acid moiety is linked, and non-toxic pharmaceutically acceptable salts thereof.
- 2. The compound according to claim 1, wherein Y is a hydrogen atom.
- 3. The compound according to claim 1, wherein R.sub.1 is a hydroxyl group, a C.sub.1-C.sub.6 alkoxycarbonyloxy group or a benzyloxycarbonyl group and R.sub.2 and R.sub.3 are each a hydrogen atom or a chlorine atom.
- 4. The compound according to claim 1, wherein the ring A is an unsubstituted benzene ring or a benzene ring having one or more substituents selected from the group consisting of chlorine, trifluoromethyl, nitro, benzyloxycarbonyl amino and methylenedioxy.
- 5. The compound according to claim 4, wherein R.sub.1 is a hydroxyl group or an ethoxycarbonyloxy group and R.sub.2 and R.sub.3 are each a hydrogen atom or a chlorine atom.
- 6. A compound of the formula: ##STR62##wherein the ring A is a benzene, pyrazole, thiazole, imidazole, pyrazine, pyridazine or pyrimidine ring, said ring being unsubstituted or substituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 alkylthio, C.sub.1-C.sub.8 haloalkyl, C.sub.1-C.sub.3 alkylenedioxy, halogen, nitro, free or protected amino, C.sub.1-C.sub.8 alkylamino, di(C.sub.1-C.sub.8)alkylamino and C.sub.1-C.sub.9 alkanoylamino, R.sub.1 is a free or protected hydroxyl group and R.sub.2 and R.sub.3 are each a hydrogen atom or a halogen atom, and non-toxic, pharmaceutically acceptable salts thereof.
- 7. A compound of the formula: ##STR63##wherein R.sub.1 is a free or protected hydroxyl group and R.sub.2 and R.sub.3 are each a hydrogen atom or a halogen atom.
- 8. A compound of the formula: ##STR64##
- 9. D-.alpha.-(7-Chloro-4-hydroxyquinoline-3-carboxamido)-p-ethoxycarbonyloxybenzylpenicillin and non-toxic, pharmaceutically acceptable salts thereof.
- 10. D-.alpha.-(4-Ethoxycarbonyloxyquinoline-3-carboxamido)-p-ethoxycarboxyloxybenzylpenicillin and non-toxic, pharmaceutically acceptable salts thereof.
- 11. D-.alpha.-(4-Hydroxyquinoline-3-carboxamido)-m-chloro-p-hydroxybenzylpenicillin and non-toxic, pharmaceutically acceptable salts thereof.
- 12. D-.alpha.-{8-Hydroxypyrido[3,2-d]pyrimidine-7-carboxamido}-p-hydroxybenzylpenicillin and non-toxic, pharmaceutically acceptable salts thereof.
- 13. D-.alpha.-{2,4-Dimethyl-8-hydroxypyrido[3,2-d]-pyrimidine-7-carboxamido}-p-hydroxybenzylpenicillin and non-toxic, pharmaceutically acceptable salts thereof.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 47-126634 |
Dec 1972 |
JA |
|
Parent Case Info
This application is a division of copending application Ser. No. 424,271, filed on Dec. 13, 1973 now U.S. Pat. No. 3,954,753.
The present invention relates to novel penicillins and their preparation. More particularly, it relates to novel penicillins and their non-toxic, pharmaceutically acceptable salts, which are useful as antimicrobial agents having a broad antimicrobial spectrum including Pseudomonas, and to their preparation.
It is well known that 6-(.alpha.-aminoacylamido)penicillanic acid derivatives such as 6-(.alpha.-amino-phenylacetamido)penicillanic acid (Ampicillin), 6-(.alpha.-amino-p-hydroxyphenylacetamido)penicillanic acid (Amoxycillin), 6-(.alpha.-amino-thienylacetamido)penicillanic acid, 6-(1-amino-cyclohexane)carboxamidopenicillanic acid (Cyclacillin), 6 -(.alpha.-amino-isothiazolylacetamido)penicillanic acid and 6-[.alpha.-amino-2-(1,4-hexadienylacetamido)]penicillanic acid (Epicillin) inhibit the growth of various gram-positive and gram-negative bacteria. Particularly, ampicillin is one of the excellent chemotherapeutics. These compounds, however, do not exert any appreciable antimicrobial activity against Pseudomonas. In U.S. Pat. No. 3,433,784, there are described some N-acyl derivatives of ampicillin as showing a minimal inhibitory concentration of 125 to 250 .mu.g/ml against Pseudomonas pyocinea A or R 59, when determined by the standard test method. The anit-Pseudomonas activity of the compounds as described in the working examples is, however, not so high and the antimicrobial activity against other gram-positive and gram-negative bacteria is considerably low. Thus, it may be said that the N-acyl derivatives of ampicillin are less valuable than ampicillin itself from the practical viewpoint.
As the result of the study seeking novel penicillins which have a broad antimicrobial spectrum and are highly active against gram-positive and gram-negative bacteria including Pseudomonas, it has been found that, among various compounds, the penicillins of the following formula characteristically exhibit a noticeable antimicrobial activity against Pseudomonas and a broad antimicrobial spectrum: ##STR2## wherein the ring A is a benzene ring or a 5 or 6-membered heteroaromatic ring containing one or two nitrogen atoms as the hetero atom, on which one or more of lower alkyl, lower alkoxy, lower alkylthio, lower haloalkyl, lower alkylenedioxy, halogen, hydroxyl, nitro, free or protected amino, lower alkylamino, di(lower)alkylamino and lower alkanoylamino may be present, Z is a nitrogen atom or a methylene group, X is an oxygen atom or a sulfur atom, Y is a hydrogen atom, a lower alkoxycarbonyl group or a lower alkanoyl group, R.sub.1 is a free or protected hydroxyl group and R.sub.2 and R.sub.3 are each a hydrogen atom or a halogen atom.
Accordingly, a main object of the present invention is to provide novel penicillins (I) and their non-toxic salts, which are useful as antimicrobial agents. Another object of this invention is to provide a process for preparing the penicillins (I) and their non-toxic salts. A further object of the invention is to provide a use of the penicillins (I) and their non-toxic salts as antimicrobial agents. These and other objects of the invention will be apparent to those conversant with the art from the foregoing and subsequent descriptions.
As to the significances of the symbols in the said formula (I) and in any other formula as hereinafter shown, the term "lower alkyl" is intended to mean generally both straight and branched chain aliphatic hydrocarbon groups having not more than eight carbon atoms (preferably not more than five carbon atoms) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl and isoamyl. Similarly where the term "lower" is used as a part of the description of any other group (e.g. lower alkoxy, lower alkylthio, lower haloalkyl, lower alkylamino, di(lower)alkylamino), it refers to the alkyl portion of such group. Thus, the terms "lower alkanoyl" and "lower alkoxycarbonyl" means respectively alkanoyl and alkoxycarbonyl having not more than nine carbon atoms (preferably not more than six carbon atoms). Exceptionally, however, the term "lower alkylenedioxy" indicates alkylenedioxy having not more than three carbon atoms. The halogen atom includes the chlorine atom, bromine atom, iodine atom and fluorine atom.
The protected amino group and the protected hydroxyl group indicate respectively an amino group and a hydroxyl group which are protected by any protective group conventionally employed for the protection of amino or hydroxyl. Examples of the protected amino group include lower alkanoylamino and lower alkoxycarbonylamino. Examples of the protected hydroxyl group include lower alkanoyloxy and lower alkoxycarbonyloxy.
The 5 or 6-membered heteroaromatic ring containing one or two nitrogen atoms may be, for example, a pyrazole ring, a thiazole ring, an imidazole ring, a pyridine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, etc. Among them, preferred are a pyrazole ring, a thiazole ring, a pyrazine ring and a pyrimidine ring, particularly a pyridine ring.
The non-toxic, pharmaceutically acceptable salts of the penicillins (I) are, for instance, the alkali metal salts (e.g. sodium, potassium salts), the alkaline earth metal salts (e.g. calcium, magnesium salts), the arginine salt, the substituted and unsubstituted ammonium salts, etc. Examples of the substituted ammonium salts include the salts of triethylamine, procaine, dibenzylamine, N-benzyl-.beta.-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabiethylamine, N,N'-bis-dehydroabiethylethylenediamine, etc.
One of the structural characteristics of the penicillins (I) of the invention is that the residue ##STR3## bears thereon the substituent --X--Y linked to a carbon atom adjacent to the carbon atom to which a 6-(.alpha.-aminoacylamido)penicillanic acid moiety is linked. The compounds wherein the residue ##STR4## bears no such substituent are antimicrobially much less active than those bearing the substituent and exhibit only the same low antimicrobial activity as those disclosed in U.S. Pat. No. 3,433,784 against Pseudomonas as well as other gram-positive and gram-negative bacteria.
Another structural characteristic of the penicillins (I) is the presence of the substituent R.sub.1. The serum and urinary concentrations in mice and rats of the compounds wherein the phenyl group bears the substituent R.sub.1 are higher than those of the compounds not having such substituent.
According to the present invention, the penicillin (I) can be produced by reacting a carboxylic acid of the formula: ##STR5## wherein A, Z, X, Y, R.sub.1, R.sub.2 and R.sub.3 are each as defined above and n is 0 or 1, or its reactive derivative with an amine of the formula: ##STR6## wherein R.sub.1, R.sub.2, R.sub.3 and n are each as defined above, or its derivative, if necessary, followed by hydrolysis, reduction or acylation of the resulting product and/or elimination of any protective group.
The reaction can be carried out in a conventional coupling method and/or by the use of a conventional coupling reagent in the related art field, i.e. in the synthesis of peptides, penicillins, cephalosphorins and the like.
The compound (II) may be used as such, i.e. in a free or salt form, or as the reactive derivative. Examples of salts of the compound (II) are the salts of alkali metals, alkaline earth metals, ammonia and organic bases (e.g. trimethylamine, triethylamine, dicyclohexylamine).
The reactive derivatives of the compound (II) on the carboxyl group include, e.g. acid halides, acid anhydrides, active amides, acid azides and active esters. Among the acid halides, the use of an acid chloride is the most favorable. Examples of the acid anhydrides are mixed acid anhydrides and symmetric acid anhydrides prepared by the use of acids such as toluenesulfonic acid, an alkylcarbonic acid and an aliphatic carboxylic acid (e.g. pivalic acid). Examples of the active amides are those obtained by using imidazole, dimethylpyrazole, triazole, tetrazole or the like. Examples of the active esters are those prepared by using p-nitrophenol, pentachlorophenol, p-nitrothiophenol, N,N'-dimethylhydroxylamine, 1-hydroxy-2(1H)-pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide.
When the compound (II) wherein Y is hydrogen or its reactive derivative is used, the hydroxyl group may be protected with any protective group as is conventionally employed in the related art field.
Illustrating some of the reactive derivatives of the compound (II) wherein n is 0 in detail, the mixed acid anhydride of the formula: ##STR7## wherein A, Z and X are each as defined above and Y represents acyl or alkoxycarbonyl can be prepared by the reaction of the compound (II) wherein Y is hydrogen and n is 0 with an acyl halide or an alkyl halocarbonate. Thus, the reaction of 1 molar amount of the compound (II) with a 2 molar amount of an acyl halide (e.g. pivaloyl chloride) or an alkyl halocarbonate (e.g. ethyl chlorocarbonate, isobutyl chlorocarbonate) in the presence of a 2 molar amount of a basic substance may afford the compound (IV) in an excellent yield. (The process using the thus obtained mixed acid anhydride (IV) as the reactant will be referred to as the "mixed anhydride process".)
Another type of the reactive derivative is the compound of the formula: ##STR8## wherein A, Z and X are each as defined above, which may be prepared by the reaction of 1 molar amount of the compound (II) wherein Y is hydrogen and n is 0 with 1 molar amount of phosgene in the presence of a 2 molar amount of a basic substance. The similar type of the reactive derivative may be also prepared by the use of thionyl chloride, phosphorus trichloride or the like in place of phosgene. (The process using the above cyclic compound (V) or any similar compound thereto as the reactant will be referred to as the "phosgene process".)
Examples of the basic substance in the acid reactions are an inorganic base (e.g. sodium hydroxide, potassium hydroxide) and an organic base (e.g. triethylamine, pyridine, dimethylaniline, lutidine, N-methylmorpholine and N-methylpiperidine).
Since the reactive derivatives described above are usually very reactive and unstable to isolate, they may be used in the form of the reaction mixture for the reaction with the compound (III) wherein n is 0.
The derivatives of the compound (III) may be the alkali metal salts (e.g. sodium, potassium salts), the alkaline earth metal salts (e.g. calcium, barium salts), the organic base salts (e.g. trimethylamine, triethylamine salts), the organic sulfonic acid salts (e.g. toluenesulfonic acid, naphthalenesulfonic acid, tetrahydronaphthalenesulfonic acid salts), the esters, the N-substituted derivatives, etc.
Specific examples of the derivatives of the compound (III) wherein n is 0 include the following compounds: ##STR9## wherein R.sub.1, R.sub.2 and R.sub.3 are each as defined above and R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are each a lower alkyl group.
These esters can be advantageously used in the coupling reaction, because of their higher solubility in an ordinary solvent to be used as the reaction medium and of their higher reactivity with the compound (II) than those of the corresponding free acids.
Further examples of the ester unit in the esters of the compound (III) are as follows: toluenesulfonylethyl ester, p-nitrobenzyl ester, benzyl ester, phenacyl ester, diphenylmethyl ester, substituted diphenylmethyl ester, trityl ester, benzoyloxymethyl ester, lower alkanoyloxymethyl ester, dimethylmethyleneamino ester, p-nitrophenyl ester, methylsulfonylphenyl ester, methylthiophenyl ester, t-butyl ester, 3,5-di-t-butyl-4-hydroxybenzyl ester, trichloroethyl ester etc. These ester units are all conventionally employed as a group protecting a carboxylic acid radical in the related art field.
The esters which can be prepared commercially from penicillin-G are particularly preferable. Examples of the preparation for such esters are illustratively shown in the following scheme: ##STR10## wherein R.sub.1, R.sub.2 and R.sub.3 are each as defined above and -COOE means an ester part.
The above illustrated E ester of the compound (III) can be employed for the coupling reaction in the form of a salt with an organic or inorganic acid. Examples of the organic or inorganic acid part in such salt are toluenesulfonic acid, naphthalenesulfonic acid, tetralinesulfonic acid, hydrochloric acid, etc.
The coupling reaction of the compound (II) or its reactive derivative with the compound (III) or its derivative is usually carried out at a temperature below about 80.degree. C, e.g. at a temperature of -50.degree. to 80.degree. C, but this is not limitative.
The coupling reaction is normally effected in the presence of an inert solvent. As the inert solvent, there may be used a polar solvent (e.g. dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, acetonitrile, methylisobutylketone, ethanol, dimethylformamide) or a non-polar solvent (e.g. benzene, toluene, petroleum ether, n-hexane). Water or a water-containing organic solvent is also utilizable depending on the type of starting materials used.
In case that the compound (II) is subjected to coupling in a free form or a salt form, the reaction may be carried out preferably in the presence of a conventional coupling reagent (e.g. N,N'-dicyclohexylcarbodiimide, diphenyl phosphorous acid).
In the compound (II), the substituent --X--Y may represent either a free hydroxyl or sulfhydryl group or a protected hydroxyl or sulfhydryl group. When the compound (II) wherein the substituent --X--Y represents a protected hydroxyl or sulfhydryl group is employed in the coupling reaction, the penicillin (I) wherein Y is hydrogen may be often obtained as the result of simultaneous elimination of the protective group. When the protective group is not eliminated in the course of the coupling reaction, it may be eliminated thereafter by a conventional procedure under such a mild condition that the opening of the lactam ring in the penicillin nucleus is not caused. The elimination of the protective group can be accomplished, for instance, by treating the product in the coupling reaction with an inorganic or organic basic substance (e.g. sodium carbonate, potassium carbonate, sodium hydroxide, aqueous ammonia solution, triethylamine, methylamine, dimethylamine, diethylamine, morpholine, piperidine, potassium acetate, sodium acetate, potassium 2-ethylhexanoate). In such treatment, the penicillin (I) wherein Y is hydrogen can be obtained even in an acidic condition, but the protective group is more smoothly eliminated by treatment under a basic condition.
In case that the compound (II) wherein n is 0 and Y is lower alkoxycarbonyl or lower alkanoyl and the compound (III) wherein n is O and R.sub.1 is hydroxyl are subjected to coupling, there may be sometimes obtained the penicillin (I) wherein Y is hydrogen and R.sub.1 is lower alkoxycarbonyl or lower alkanoyl. Further, the coupling reaction of the compound (III) wherein n is O and R.sub.1 is protected hydroxyl (e.g. ethoxycarbonyloxy, benzyloxycarbonyloxy) with the compound (II) wherein n is O and Y is lower alkoxycarbonyl or lower alkanoyl may afford the penicillin (I) wherein Y is lower alkoxycarbonyl or lower alkanoyl and R.sub.1 is protected hydroxyl.
When the compound (II) wherein Y is hydrogen is subjected to coupling, it may be favorably employed, for instance, in the form of the reactive ester or the acid halide on the carboxyl group whereby the penicilline (I) wherein Y is hydrogen is obtainable as the product.
The penicillin (I) wherein the ring A is substituted with an amino group may be produced from the corresponding penicillin (I) wherein the ring A is substituted with a nitro group or a protected amino group. For example, the reduction of the penicillin (I) wherein the ring A bears a nitro group or a benzyloxycarbonylamino group under such a mild condition that the opening of the lactam ring in the pencillin nucleus is not caused gives the penicillin (I) wherein the ring A bears an amino group. Further, for example, the hydrolysis of the penicillin (I) wherein the ring A bears a protected amino group (e.g. enamine) under a mild condition as above results in the elimination of the protective group to give the penicillin (I) wherein the ring a bears an amino group.
Alternatively, the penicillin (I) having an amino group on the ring a may be produced by the said coupling reaction wherein the compound (II) is used in the form of the acid halide on the carboxyl group.
When any protective group is present in the product of the coupling reaction, it may be eliminated by a per se conventional procedure such as catalytic reduction or hydrolysis, favorably under a mild condition.
The production of the penicillin (I) may be identified by thin layer chromatography, iodometry, infrared absorption spectrum and so on. The characteristic infrared absorption due to the lactam ring is at 1750 - 1800 cm.sup.-.sup.1. A particularly effective identifying method is NMR analysis, since the signals attributed to the proton Ha of the amide bond in the following structure for the penicillin (I) appear in a very low-field, which is due to the presence of the substituent --X--Y: ##STR11##
When measured in hexadeuterodimethylsulfoxide at 60 MHz using an NMR-spectral instrument, Ha and Hb signals in case of Y being a lower alkanoyl group or a lower alkoxycarbonyl group appear respectively at 540 - 570 Hz and at 630 - 680 Hz. In case of Y being a hydrogen atom, Ha and Hb signals appear respectively at 650 - 690 Hz and at 540 - 570 Hz. Ha and Hb signals in case of Y being a hydrogen atom appear in a lower field than those of Y being a lower alkanoyl group or a lower alkoxycarbonyl group.
The produced penicillin (I) may be, if desired, converted into its non-toxic pharmaceutically acceptable salt in a per se conventional manner.
Still, the compound (II) wherein n is l can be prepared easily by a conventional procedure, for instance, by reacting the reactive derivative of the compound (II) wherein n is O with an amino acid of the formula: ##STR12## wherein R.sub.1, R.sub.2 and R.sub.3 are each as defined above, or its ester in water or an organic solvent in the presence of a basic substance.
The amino acid may be any of the DL-, D- and L-configurations. The esters may be, for example, trialkylsilyl ester, lower alkyl ester, p-nitrophenyl ester, benzyl ester, phenylthiophenyl ester, N-hydroxysuccinimide ester, etc. These esters may be derived from the corresponding acid chlorides or prepared by any other conventional method. As the organic solvent, a polar or non-polar organic solvent (e.g. dioxane, tetrahydrofuran, dichloromethane, benzene, dimethylformamide, dimethylsulfoxide) is utilizable. Examples of the basic substance are sodium hydroxide, potassium hydroxide, triethylamine, N-methylmorpholine, dimethylaniline, etc.
When the ester is employed in the above reaction, the protective group of the resulting N-acylamino acid ester may be eliminated by a conventional procedure to give the compound (II) wherein n l. When desired, the obtained active ester salt of the compound (II) wherein n l may be employed in the coupling reaction with the compound (III) wherein n is l to produce the penicillin (I).
US Referenced Citations (6)
Divisions (1)
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Number |
Date |
Country |
| Parent |
424271 |
Dec 1973 |
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Patent Grant
4003887
