US3728342A - 3-acyloxymethyl cephalosporins and method of preparation - Google Patents

3-acyloxymethyl cephalosporins and method of preparation Download PDF

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US3728342A
US3728342A US00094988A US3728342DA US3728342A US 3728342 A US3728342 A US 3728342A US 00094988 A US00094988 A US 00094988A US 3728342D A US3728342D A US 3728342DA US 3728342 A US3728342 A US 3728342A
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cephem
carboxylic acid
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hydroxymethyl
anhydride
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S Kukolja
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Eli Lilly and Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group

Definitions

  • 7-acylamido desacetoxycephalosporanic acid compounds have been found to have unique properties as antibiotics in their own right.
  • cephalexin, 7-[D-2'-phenyl 2' aminoacetamido] desacetoxycephalosporanic acid zitterion and pharmaceutically acceptable anionic and cationic salt forms thereof are useful as oral antibiotics in combatting infections caused, for example, by penicillin resistant strains of Staphylococcus aureus, and many other Gram-positive and Gram-negative micro-organisms.
  • the fermentation product includes desacetylcephalosporin C.
  • cycloalkyl groups include cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyl, cyclopentylmethyl, cyclobutylpropyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cyclopropyl, etc.
  • R groups include dioxanyl, Z-furyl, 3-fury1, imidazolyl, isoxazolyl, morpholinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, N-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidyl, N-pyrryl, 2-pyrryl, 3-pyrryl, thiazolyl, Z-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, triazinyl, triazolyl and the like; the partially and completely hydrogenated derivatives of the foregoing, such as tetrahydrofuryl, imidazolinyl, imidazolidyl, piperidyl, tetrahydropyrimidyl, pyrrolidyl and the like; as well as all of the foregoing groups which are substituted by one or more substituents including, for example, C to C al
  • Cephem refers to the cepham ring construction containing a double bond, the position of which is indicated by a prefixed A with a superscript denoting the lowest numbered carbon atom to which the double bond is connected, or by the word delta with the same number relationship.
  • penicillin V 6-phenoxymethylpenicillin
  • 7-phenoxyacetamido desacetoxycephalosporanic acid can be named as 7-phenoxyacetamido-3-methyl-A -cephem-4-carboxylic acid.
  • the position of the double bond is indicated merely by the integer before the word cephem.
  • One of the most preferred compounds of the present invention can be named 7-(2-thienylacetamido)-3-cyclobutylcar bonyloxymethyl-A -cephem-4-carboxylic acid.
  • cationic salts which can be prepared from compounds of Formula VI including for example, water-soluble salts such as the sodium, potassium, lithium, ammonium and substituted ammonium salts, as well as the less water-soluble salts such as the calcium, barium, procaine, quinine and dibenzylethylenediamine salts.
  • R is the residue of the acylamido group in the 7-position
  • R is hydrogen or the residue of an ester forming alcohol and
  • R is a C to C7 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or a cycloalkyl group ⁇ Don- CH2).
  • anhydride use can be made of any of the aliphatic carboxylic acid anhydrides containing 4--20 carbon atoms.
  • Preferred anhydrides are those having the general formula V '0 O R5-H3O( 1-R5 (XIV) wherein R is an alkyl group containing 1-7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, etc., or a cycloalkyl having the formula flH-l CHzhr- 2 CH (xv) wherein R is C to C alkylene (i.e., methylene, dimethylene, trimethylene) and m is zero or an integer from 1 to 4.
  • cycloalkyl groups include cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclo- 6 pentyl, cyclopentylethyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cyclopropyl, cyclopropylmethyl, etc.
  • the reaction between the anhydride and the desacetylcephalosporin is preferably carried out in the presence of an organic base.
  • organic bases Any of a variety of organic bases can be used for this purpose.
  • Preferred organic bases are the secondary and tertiary amines having a pK less than 8.
  • suitable bases are diethyl amine, triethyl amine, pyridine, piperidine, morpholine as well as a number of others known to those skilled in the art.
  • the reaction can be carried out in the presence of an inert organic solvent.
  • organic base is generally a liquid under normal conditions, it is usually preferred to operate without a solvent, using the organic base as the solvent.
  • reaction temperature is not critical, and can be varied within wide ranges. In general, use should be made of a reaction temperature within the range of --l0 to C., and preferably 0 to 30 C.
  • the 7-acylamido group, and the residue of the ester forming alcohol do not enter into the reaction, and thus the nature of these groups does not affect the nature of the reaction.
  • the 7-acylamido group and the R group can be any of a number of groups which are now well recognized by those skilled in the penicillin and cephalosporin arts.
  • acyl groups which can be present in the starting materials employed. in accordance i h h practice of the invention include those acyl groups having the formula wherein n is zero or an integer fnom I to 6 and R is an organic group such as HOOC-CH(NH )(CH or an aryl group or a substituted aryl group containing 6-14 carbon atoms.
  • Preferred aryl groups are those derived from benzene or naphthalene e M Q Q (XVII) gXVIII) wherein Q is hydrogen or one or more substituents ineluding, for example, C to C alkyl (e.g., methyl, ethylpropyl, isopropyl), C to C alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), a cyano group, a nitro group, a hydroxy group, halogen (e.g., chlorine, fluorine, bromine and iod ne), a trifluoromethyl group, a carboxy group, an annno group, a C to C carboxyalkyl group (e.g., carboxyrnethyl, carboxyethyl, carboxypropyl, etc.), or a C to C4, carboxamidoalkyl group [H NC(0)-alkyl] (e.g
  • acyl groups are 5 aminoadipoyl, benzoyl, phenylacetyl, beta-(phenyl)propionyl, naphthoyl, naphthylacetyl, gamma-phenyl-butyryl, p-methylbenzooyl, 2,4 dimethylphenylacetyl, S-methoxynaphthylacetyl, p-cyanophenylacetyl, 4-nitronaphthoyl, 3-nitrobenzoyl, 3, 5 dicyanonaphthylacetyl, beta-(3-nitrophenyl)-propionyl, p-hydroxybenzoyl, 4-hydroxyphenylacetyl, p-chlorophenylacetyl, m-bromobenzoyl, 3-trifluoromethylphenylacetyl,
  • o-carboxyphenylacetyl m-carboxymethylphenylacetyl, mcarboxamidomethylphenylacetyl, beta( carboxamidomethylnaphthyl)propionyl, aminobenzoyl, aminophenylacetyl as well as a number of others.
  • R can also be a cycloalkyl group containing 4-8 carbon atoms, including cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • R can also be one of the foregoing cycloalkyl groups which is substituted by one or more of the Q substituents described above.
  • acyl groups include cyclopentanoyl, cyclohexanoyl, 3 methylcyclohexanoyl, cyclobutylcarbonyl, 2 methoxycyclohexanoyl, 3-chlorocyclohexylacetyl, cyclopentylacetyl, beta-cyclopentylpropionyl, 3- methoxycyclohexylacetyl, 2-cyanocyclopentylacetyl, 3-nitrocyclohexanoyl, 3 carboxycyclohexylacetyl, 3-carboxamidomethylcyclohexylacetyl, etc.
  • R can also be a heterocyclic group wherein the heteroatom is O, S, N or any combination thereof, including dioxanyl, 2 furyl, 3-furyl, imidazolyl, isoxazolyl, morphorinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, N- pyridyl, 2 pyridyl, I l-pyridyl, pyridimidyl, N-pyrryl, 2- pyrryl, 3-pyrryl, thiazolyl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, triazinyl, triazolyl and the like;
  • the partially and completely hydrogenated derivatives of I the foregoing such as tetrahydrofuryl, imidazolinyl, imidazolidyl, piperidyl, tetrahydropyrimidyl, pyrrolidyl and the like; as well as all of the foregoing group which are substituted by one or more of the Q groups described above, as represented by the picolyls, methylfuryls, methyl thienyls, nitrofuryl, cyanofuryl, nitrobenzothienyl, nitropyridyl, cyanopyridyl, methoxypyrimidyl, bromopyridyl, trifiuoromethylpyridyl as well as others of the type described in Flynn US. Pat. No. 3,218,318.
  • acyl groups when R is heterocyclic are dioxanylacetyl, 2-fury1carbonyl, beta-pyrazinylpropionyl, 2 pyridylacetyl, 3-pyridylcarbonyl, 2-thienylacetyl, 3- benzothienylcarbonyl, piperidylacetyl, pyrrolidylcarbonyl, nitrobenzothienylacetyl, beta-(nitrofuryl)-propionyl, cyanopyridylcarbonyl, etc.
  • the acyl group forming the 7-acylamido group can further be an acyl group having the general formula R -i (XIX) wherein R is either alkyl containing 1-8 carbon atoms (e.g., methyl, .ethyl, isopropyl, n-butyl, tert-butyl, hexyl, isooctyl, etc.) or alkenyl containing 28 carbon atoms (e.g., vinyl, allyl, Z-butenyl, 3-hexenyl, etc.).
  • R can also be one of the foregoing alkyl or alkenyl groups which is substituted by one or more substituents including, for example, an amino group, a cyano group, a nitro group, a
  • halogen e.g., chlorine, fluorine, bromine
  • acyl groups are acetyl, propionyl, acrylyl, crotoyl, 2 aminoacetyl, 3-chloropropionyl, 6- heptenoyl, adipoyl, 3-hydroxypyropionoyl and S-nitrohexanoyl.
  • R is an acyl group having the formula R5(CH2)m'-X(CH2)n -C (XX) wherein n is as previously described, m is zero or an integer from 1 to 5, X is O or S and R is R (i.e., aryl, cycloalkyl or heterocyclic) as described above including substituted derivatives thereof, or R (i.e., C to C alkyl or C to C alkenyl) as described above, including substituted derivatives thereof.
  • acyl groups defined by (XX) above include tert-butoxycarbonyl, tert-butoxyacetyl, ethoxyacetyl, tert-butylmercaptocarbonyl, tert-butylmercaptoacetyl, allylmercaptoacetyl, 3 bromopropoxyacetyl,
  • the 7-acyl group can further be an acyl group having the general formula Y (XXI) wherein Y is an amino group, a protected amino group, hydroxy, C to C alkoxy (e.g., methoxy, ethoxy, etc.) carboxyl or C to C alkanoyloxy (e.g., acetoxy, propionoxy, etc.) and R isone of the groups defined by R above (i.e., aryl, heterocyclic and cycloalkyl as described in detail above).
  • Y is an amino group, a protected amino group, hydroxy, C to C alkoxy (e.g., methoxy, ethoxy, etc.) carboxyl or C to C alkanoyloxy (e.g., acetoxy, propionoxy, etc.)
  • R isone of the groups defined by R above (i.e., aryl, heterocyclic and cycloalkyl as described in detail above).
  • acyl groups are 2-phenyl 2-aminoacetyl, 2-(p-methoXyphenyl-2-aminoacetyl, 2- cyc1ohexyl-2-methoxyacetyl, 2-phenyl-Z-acetoxyacetyl, 2- *(2' pyridyl)-2-hydroxyacetyl, 2-piperidyl-2-aminoacetyl, 2 (2'-thienyl)-2-acetoxyacetyl as well as a variety of others.
  • R can be a number of other acyl groups, including, for example, phenyl-a,a-di methylacetyl and Q substituted derivatives thereof and a number of others.
  • Suitable R acyl groups are disclosed in the Behrens et al. US. Pats. Nos. 2,479; 295, 2,479,297, 2,562,407 and 2,623,876.
  • the 7 acylamido group contains an unprotected amino group
  • such amino group may be acylated by the anhydride employed.
  • this is not disadvantageous since the 7-acylamido group can easily be removed to form the corresponding 7-amino compound and reacylated as desired.
  • R be an ester residue which is easily cleaved by known means, such as by dilute aqueous base, trifiuoroacetic acid or by hydrogenation in the presence of a palladium or rhodium catalyst on a suitable carrier such as carbon, barium sulfate or alumina so that the cephalosporin is not degraded, since the ultimate product is generally used in the form of the acid.
  • R groups include 0., to C tertiary alkyl (e.g., tert-butyl, tcrt-pentyl, etc.), C to C tertiary alkenyl (e.g., tert-pentenyl, tert-hexenyl, etc.), C to C tertiary alkynyl (e.g., 1,1-dimethyl-2-pentynyl, etc.), benzyl, methoxybenzyl, phenyl, methoxyphenyl, nitrobenzyl, phenacyl, trichloroethyl, trimethylsilyl, benzhydryl, phthalirnidomethyl, succinimidomethyl as well as a number of others apparent to those skilled in the art.
  • C tertiary alkyl e.g., tert-butyl, tcrt-pentyl, etc.
  • a -desacetylcephalosporin acids and esters which can be used as the starting material in the practice of this invention include the following.
  • the A -desacetylcephalosporin starting material can be prepared by simultaneous hydrolysis and isomerization of the corresponding A -cephalosporanic acid derivative using the procedure of Cocker et al., J. Chem, Soc., sect. C, 1142 (1966)..
  • cephalothin prepared in accordance with the procedure of Flynn in the aforementioned U.S. patent can be hydrolyzed and isomerized to the corresponding A -desacetylcephalosporin as follows NaOH . I o S CHr-i INHI( H O 'N CCH2OH xxxv
  • the oxidation reaction of (XXVI) above can be carried out by, for example, the procedure described in copending application Ser. No. 764,939, filed Oct.
  • oxidizing agents such as per-acids (e.g., peracetic acid, metachloroperbenzoic acid, etc.) for oxidizing A -cephem compounds to the corresponding A -cephem sulfoxides;
  • the reduction reaction of (XXVII) above can be carried out by the use of any of a number of reducing agents, such as stannous chloride, zinc chloride or sodium dithionite, in conjunction with an acid halide activator (e.g., acetyl chloride) as described in copending application Ser. No. 764,925, filed Oct. 3, 1968.
  • reducing agents such as stannous chloride, zinc chloride or sodium dithionite
  • an acid halide activator e.g., acetyl chloride
  • the 7-acylarnido group of the products of the process of the present invention may be removed and replaced by another 7-acylamido group in the preparation of cephalosporin-type antibiotics.
  • the 7-acylamido group can be cleaved in accordance with the procedure described by Chauvette in copending application, Ser. No. 651,662, filed July 7, 1967, to form the corresponding 7-amino compound which can, in turn, be
  • the mixture is then extracted twice with ethyl acetate and the cephalosporin acid extracted with a solution of sodium bicarbonate until the pH is 7.7.
  • the resulting alkaline solution is acidified to a pH of 2.0 and extracted with ethyl acetate, the extract is washed with water and dried.
  • the product is identified as 7-(2-thienylacetamido)- 3-cyclobutylcarbonyloxymethyl A cephem-4-carboxylic acid.
  • the product is identified as 7-(2-thienylacetamido)- 3-cyclobutylcarbonyloxymethyl A cephem-l-oxide-4- carboxylic acid.
  • the product is identified as 7-(2'-thienylacetamido)-3- cyclobutylearbonyloxymethyl A cephem-4-carboxylic acid.
  • the A -compound is then oxidized with metachloroperbenzoic acid to form the corresponding sulfoxide and then reduced with sodium dithionite ina known manner.
  • the product is identified as 7-(2-furylpropionamido)-3- cyclohexylcarbonyloxymethyl-A -cephem 4 carboxylic acid.
  • the product is identified as 7-(2'-furylacetamido)-3- cyclohexylacetoxymethyl-A -cephem-4-carboxylic acid
  • the resulting A -compound is then oxidized with metachlorperbenzoic acid and reduced with stannous chloride to form 7-(2-furylacetamido)-3-cyclopentylcarbonyloxymethyl-A -cephem-4-carboxylic acid.
  • the resulting product is 7-(N'-methyl-2'-pyrrylacetamido)-3-cyclohexylacetoxymethyl-A -cephem 4 carboxylic acid which is oxidized and then reduced in accordance with the methods of Examples 2 and 3, respectively, to form 7-(N'-methyl-2'-pyrrylacetamido)-3-cyclohexylacetoxymethyl-A -cephem4-carboxylic acid.
  • EXAMPLE 7 Preparation of 7-(2'-4-dimethylthiazol- -acetamido)-3- cyclopentylearbonyloxymethyl-A -cephem 4 carboxylic acid 7-(2-4'-dimethylthiazol 5' acetamido)cephalosporanic acid prepared in accordance with the procedure in Example 13 of US. Pat. No. 3,218,318 is hydrolyzed in 14 accordance with the procedure described in Example 6 to form 7-(2-4'-dimethylthiazol-5-acetamido) 3 hydroxymethyl-A -cephem-4-carboxylic acid.
  • EXAMPLE 8 Preparation of 7-(1'- -4-triazol-.l'-acetamido)-3-cyclobutylacetoxymethyl-A -cephem-4-carboxylic acid Using the procedure described in Example 7, 7 (1'-2- '-triazol-l-acetamido)cephalosporanic acid prepared in accordance with the US. Pat. No. 3,218,318, is hydrolyzed to form the corresponding A -desacetyl compound which is reacted with cyclobutylacetic anhydride in accordance with the procedure described in Example 1.
  • the product is then oxidized and reduced to convert the A -compound to the A -compound, and the resulting product is identified as 7-(1-pyrazolacetamido)-3-cyclohexylcarbonyloxymethyl-A -cephem-4-carboxylic acid.
  • the mixture is then extracted twice with ethyl acetate, and the acid extracted with a solution of sodium bicarbonate until the pH is 7.7.
  • the alkaline solution is acidified to a pH of 2.0 and extracted with ethyl acetate, the extract being washed with water and dried.
  • the solvent is extracted and the remaining oil triturated with petroleum ether giving the powdered product (1.1 g.', 44.5%) MP. 1l0-113 dec.
  • the product is identified as 7-(2'-thienylacetamido)- 3-propionoxymethyl-A -cephem-4-carboxylic acid.
  • EXAMPLE 12 Preparation of 7-(2'-thienylacetamido) -3-butyryloxymethyl-A -cephem-4-carboxylic acid Using the procedure described in Example 11, butyric anhydride is reacted with 7 (2' thienylacetamido)-3- hydroxymethyl A cephem 4 carboxylic acid. After separation of the reactants from the reaction mixture, the product is identified as 7-(2' thienylacetamido)-3-butyryloxymethyl-A -cephem-4-carboxylic acid.
  • EXAMPLE 13 Preparation of 7-(2-thienylacetamido)-3-isobutyryloxymethyl-A -cephem-4-carboxylic acid Using the procedure described in Example 1, isobutyric anhydride is reacted with 7-(2'-thienylacetamido)-3-hydroxymethyl A cephem 4 carboxylic acid. After separation of the reactants from the reaction mixture, the product is identified as 7-(2'-thienylacetamid0) 3 isobutyryloxymethyl-A -cephem-4-carboxylic acid.
  • EXAMPLE 14 Preparation of 7-phenoxyacetamido-3-propionoxymethyl-M-cephem-l-carboxylic acid 7 phenoxyacetamido 3 hydroxymethyl-A -cephem- I-carboxylic acid is reacted with propionic anhydride in accordance with the procedures of Example 1. The resulting product is identified as 7-phenoxyacetamido-3- propionoxymethyl-A -cephem-l-carboxylic acid.
  • a process for preparing a 3-acyloxymethyl-A cephalosporin comprising reacting a 7-acylamido-3-hydroxymethyl-A -cephalosporin having the formula wherein R is the residue of the 7-acylamido group and R is selected from the group consisting of hydrogen and the residue of an ester forming alcohol which can be cleaved by dilute aqueous base, by trifluoroacetic acid or by hydrogenation in the presence of a palladium or rhodium catalyst on a carrier, with the anhydride of a saturated aliphatic carboxylic acid in which the anhydride contains 4 to 20 carbon atoms in the presence of an organic base having a pK less than 8.
  • anhydride is an anhydride having the formula wherein R is selected from the group consisting of C to 0; alkyl and cycloalkyl having the structure Ii JEEP-(0112)::-
  • n is zero or an integer from 1 to 5 and R is alkylene containing 1-5 carbon atoms.
  • R is selected from the group consisting of hydrogen, C; to C tertiary alkyl, C to C tertiary alkenyl, C to C tertiary alkynyl, benzyl, methoxybenzyl, nitrobenzyl, phenacyl, trichloroethyl trimethylsilyl, benzhydryl, phthalimidomethyl, phenyl, methoxyphenyl and succinimidomethyl.
  • acyl group in the 7-position is an acyl group selected from the group consisting of (1) an acyl group having the formula wherein n is zero or an integer from 1 to 6 and R is selected from the group consisting of monocyclic carbocyclic and bicyclic carbocylic aryl containing 6-14 carbon atoms cycloalkyl containing 48 carbon atoms and heterocyclic groups wherein the hetero atom is selected from the group consisting of O, S, N and combinations thereof, and substituted derivatives thereof wherein the substituent is selected from the group consisting of C C alkyl, C -C alkoxy, cyano, nitro, hydroxy, halogen, trifluoromethyl,
  • reaction is carried out at a temperature within the range of 10 to 100 C.
  • R is a heterocyclic group selected from the group consisting of dioxanyl, furyl, imidazolyl, isoxazoly], morpholinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrryl, thiazolyl, thienyl, benzothienyl, triazinyl, triazolyl, tetrahydrofuryl, imazolinyl, imidazolidy], piperidyl, tetrahydropyrimidyl, pyrrolidyl, and heterocyclic groups as set forth above which are substituted by one or more of the groups selected from the group consisting of C to C alkyl, C to C alkoxy, a cyano group, a nitro group, a hydroxy group, halogen, a trifluoromethyl group, a carboxy group, an amino group, a

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Abstract

3-CYCLOALKYLCARBONYLOXYMETHYL AND 3-CYCLOALYLALKANOYLOXYMETHYL $3-CEPHALOSPORINS (E.G., 7-(2''-THIENYLACETAMIDO)-3-CYCLOBUTYLCARBONYLOXYMETHYL-$3-CEPHEM4-CARBOXYLIC ACID), ARE PREPARED BY REACTION OFA 7-ACYLAMIDO-$2-DESACETYLCEPHALOSPORIN WITH THE ANHYDRIDE OF AN ALIPHATIC CARBOXYLIC ACID TO FORM THE CORRESPONDING $2-ACYLOXYMETHYL CEPHALOSPORIN WHICH CAN BE OXIDIZED AND REDUCED TO FORM THE CORRESPONDING $3-COMPOUND.

Description

United States Patent 3,728,342 3-ACYLOXYMETHYL CEPHALOSPORINS AND METHOD OF PREPARATION Stjepan Kukolja, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind. N0 Drawing. Filed Dec. 3, 1970, Ser. No. 94,988
' Int. Cl. C07d 99/24 U.S. Cl. 260-243 c 9 Claims ABSTRACT OF THE DISCLOSURE This invention relates to certain 3-cycloalkylcarbonyloxymethyl and 3-cycloalkylalkanoyloxymethyl A -cephalosporins, and to a new and improved process for their preparation from desacetylcephalosporins.
The semi-synthetic production of 7-acylamidodesacetoxycephalosporin antibiotics from penicillin starting materials has become of importance recently, due to the process invention of Morin and Jackson (U.S. Pat. 3,275,626) who describe and claim a process for converting penicillin sulfoxide esters to desacetoxycephalosporanic acid esters and to the improvements on that Morin- Jackson process by Chauvette and Flynn (U.S. application Ser. No. 574,311, filed Aug. 23, 1966) who found that certain esters of the penicillin starting materials of the resulting desacetoxycephalosporin ester products were more useful in the process in that they were more easily cleaved than those employed by Morin and Jackson. Fur ther improvements of the Morin-Jackson process were claimed by Robin D. G. Cooper (U.S. applications Ser. No. 636,629, Ser. No. 636,593, and Ser. No. 636,592, all filed May 8, 1967) who found that the use of certain solvents directed the heat rearrangement of the penicillin sulfoxide esters more specifically toward production of the corresponding desacetoxycephalosporin esters and permitted the use of lower temperatures.
Some of the 7-acylamido desacetoxycephalosporanic acid compounds have been found to have unique properties as antibiotics in their own right. For example, cephalexin, 7-[D-2'-phenyl 2' aminoacetamido] desacetoxycephalosporanic acid zitterion and pharmaceutically acceptable anionic and cationic salt forms thereof are useful as oral antibiotics in combatting infections caused, for example, by penicillin resistant strains of Staphylococcus aureus, and many other Gram-positive and Gram-negative micro-organisms.
The products produced by the penicillin ring expansion process of Morin and Jackson, and/or the Chauvette- Flynn and Cooper improvements as described above are A -desacetoxycephalosporins of the formula ll R-0-Nrr-| l 2 0=8N 4 0 CH3 It isknown t hat compounds of the above type have 3,728,342 Patented Apr. 17, 1973 effective antibiotic or antibacterial properties when the methyl group in the 3-position is substituted by an alkanoyloxy group. For example, Flynn describes and claims, in U.S. Pat. No. 3,218,318, the compound:
O (IJO'OH (II) known generically as cephalothin, a widely accepted and commercially available antibiotic.
Flynn, in the aforementioned patent, described the preparation of cephalothin by acylation of 7-aminocephalosporanic acid (7-ACA) doon (III) with Z-thienylacetyl chloride. As is known to those skilled in the art, 7-ACA is derived from. cephalosporin C C 430 OH (IV) which in turn is prepared by fermentation in accordance with known methods as described by U.S. Pat. No. 3,093,638.
At the present time, limited methods are available to the prior art for the preparation of compounds having an acyloxymethyl group in the 3-position other than the naturally occurring acetoxy group.
In addition, in the preparation of the cephalosporin C by fermentation, the fermentation product includes desacetylcephalosporin C.
certain new antibiotically active cephalosporin compounds of the formula COOH wherein R is a heterocyclic group, n is zero or an integer from 1 to 5 and R is C to C alkylene (i.e., methylene,
3 dimethylene, trimethylene). Representative of such cycloalkyl groups include cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyl, cyclopentylmethyl, cyclobutylpropyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, cyclopropyl, etc.
It has been found that compounds of the foregoing type have a wide range of antibiotic or antibacterial activity against, for example, Gram-positive and Gram-negative micro-organisms.
Representative of preferred R groups include dioxanyl, Z-furyl, 3-fury1, imidazolyl, isoxazolyl, morpholinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, N-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidyl, N-pyrryl, 2-pyrryl, 3-pyrryl, thiazolyl, Z-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, triazinyl, triazolyl and the like; the partially and completely hydrogenated derivatives of the foregoing, such as tetrahydrofuryl, imidazolinyl, imidazolidyl, piperidyl, tetrahydropyrimidyl, pyrrolidyl and the like; as well as all of the foregoing groups which are substituted by one or more substituents including, for example, C to C alkyl (e.g., methyl, ethyl, propyl, i'sopropyl), C to C alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), a cyano group, a nitro group, a hydroxy group, halogen (e.g., chlorine, fluorine, bromine and iodine), a trifluoromethyl group, a carboxy group, an amino group, a C to C carboxyalkyl group (e.g., carboxymethyl, carboxypropyl, carboxyethyl, etc.) or a C to C carboxamidoalkyl group [H N-C(O)-a1kyl] (e.g., carboxamidornethyl, carboxamidoethyl, etc.), as represented by the picolyls, methylfuryls, methyl thienyls, nitrofuryl, cyanofuryl, nitrobenzothienyl, nitropyridyl, cyanopyridyl, methoxypyrimidyl, bromopyridyl, trifluoromethylpyridyl as Well as others of the type described in Flynn US. Pat. No. 3,218,318.
For convenience, compounds of the present invention are named by the use of the cephem nomenclature system. Penarn nomenclature for the penicillins is described by Sheehan, Henery-Logan, and Johnson in the Journal of the American Chemical Society (JACS), 75, 3292, footnote 2 (1953), and has been adapted to the cephalosporins by Morin, Jackson, Flynn and Roeske [JACS, 84, 3400 (1962)]. In accordance with these systerms of. nomenclature penam and cepham refer respectively to the following saturated ring systems:
Cephem refers to the cepham ring construction containing a double bond, the position of which is indicated by a prefixed A with a superscript denoting the lowest numbered carbon atom to which the double bond is connected, or by the word delta with the same number relationship. Thus, for example, penicillin V, 6-phenoxymethylpenicillin, can be named 6-(phenoxyacetamido)- 2,2-dimethyl-penam-3-carboxylic acid, and 7-phenoxyacetamido desacetoxycephalosporanic acid can be named as 7-phenoxyacetamido-3-methyl-A -cephem-4-carboxylic acid. Sometimes the position of the double bond is indicated merely by the integer before the word cephem.
One of the most preferred compounds of the present invention can be named 7-(2-thienylacetamido)-3-cyclobutylcar bonyloxymethyl-A -cephem-4-carboxylic acid.
Illustrative of the preferred compounds of this invention include the following:
7- 2'-pyranylacetarnido -3-cyclobuty1carbonyloxyrnethyl- A -cephem-4-carboxy1ic acid 7- 3 '-pyranylacetami do 3 -cyclohexylacetoxymethyl- A -cephem-4-carboxylic acid 7- 2'-piperidylacetamido) -3-cyclohexylcarb onyloxymethyl-A -cephem-4-carboxylic acid 7- (2-piperidylacetamido) -3-cyclobutylcarbonyloxymethyl-A -cephern-4-carboxylic acid 7 2-pyridylacetamido -3 -cyclobutylcarbonyloxymethyl- A -cephern-4-carboxylic acid sodium salt 7 2-pyridylacetamido -3 -cyclohexylacetoxymethyl- A -cephem-4-carboxylic acid 7- 5 '-oxazolylacetamido) -3 -cyclopentylacetoxymethyl- A -cephem-4-carboxylic acid 7-(5'-oxazo1y1acetamido)-3-cyclopentylpropionoxymethyl-A -cephem-4-carboxylic acid 7-(4(5)imidazolylacetamido)-3-cyclobutylcarbonyloxymethyl-A -cephern-4-carboxylic acid 7 7- 2'-morpholinylacetamido -3 -cycl0butylacetoxymethyl- A -cephem-4-carboxylic acid 7 (2'-m0rph0linylacetamido) -3-cyclobutylacetoxymethy1-A -cephem-4-carboxylic acid sodium salt 7- (2-pyrazeny1acetamido -3-cyclohexylcarbonyl0xymethyl-A -cephem-4-carboxylic acid 7-( 5 -imidoazolinylacetamido -3-cyclohexylpropionoxymethyl-A -cephem-4-carboxylic acid 7- 5 '-imidoazolinylacetamido) -3 -cyclohexylacetoxymethyl-A -cephem-4-carboxylic acid 7- (2'-thienylacetamido) -3 -cyclobutylacetoxymethyl-A cephem-4-carboxylic acid potassium salt 7-(3-brorno-2'-pyridylacetamido)-3-cyclohexylcarbonyloxyrnethyl-M-cephem-4-carboxylic acid 7-( 3 '-bromo-2'-pyridylacetamido -3-cyclobutylcarbonyloxymethyl-A -cephem-4-carboxylic acid 7- 5 '-fluor0-2-pyridylpropionacetamido -3-cyclopentylpropionoxymethy1-A -cephem-4-carboxylic acid 7- 5 -pyrimidylpropionacetamido -3 -cyclobutylcarbonyl0xymethyl-A -cephem-4-carboxylic acid potassium salt 7 5 '-pyrimidylpropionacetamido) -3-cyclopentaneacetoxymethyl-A -cephem-4-carboxylic acid 7-(5-nitro-2'-thienylacetamido)3-cyclopentylpropionoxymethyl-A -cephem-4-carboxylic acid 7-(5-nitro-2'-thienylacetamido)-3-cyclopentanoyloxymethyl-A cephem-4-carboxylic acid potassium salt 7-(2'-furylbutyrylacetamido -3-cyclobutylcarbonyloxymethyl-A cephem-4-carboxylic acid 7 (2-thiazolylacetamido -3 -cyc1ohexylcarb onyloxymethyl-A -cephem-4-carboxylic acid 7 2-thienylvaleramido) -3 -cyclop entylpropionoxymethyl-A -cephem-4-carboxylic acid 7- 3 -thienylhexanoylamido) -3 -cyclopentylcarbonyloxymethy1-A -cephem-4-carboxylic acid 7 a-picolyl-3 '-acetamido) -3-cyclobutylcarbonyloxymethyl-A -cephem-4-carboxylic acid 7- (2-thienylpropionamido -3 -cyclopropylcarb onyloxymethyl-A -cephem-4-carboxylic acid 7 (2-thienylpropionamido) -3 -cyclopropylc arbonyloxymethyl-A -cephern-4-carboxylic acid 7 7- 2'-rnethyl-3 '-furylacetamido -3 -cyclobutylpropionoxymethyl-A -cephem-4-carboxylic acid 7- (2'-furyln-butylamido) -3 -cyclopentylpropionoxymethyl-A -cephem-4-carboxylic acid 7- (2-furyl-nbutylamido -3 -cyclohexylacetoxymethyl- A -cephem-4-carboxy1ic acid 7- 2'-triazinylacetamido -3-cyclopentaneacetoxymethyl- A -cephem-4-carboxylic acid 7-(5-methoxy-3-pyridylacetamido)-3-cyclohexylacetoxymethyl-A -cephern-4-carboxylic acid 7-(5-methoxy-3-pyridylacetamido)-3-cyclopropylcarbonyloxymethyl-A -cephem-4-carboxylic acid 7-(2'-triazinylacetamido)-3-cyclohexylpropionoxymethyl-A -cephem-4-carboxylic acid.
As is the case with the penicillins to which the compounds of this invention are related in some degree, numerous salts, esters, amides and like derivatives thereof can be prepared by combination withnon-toxic pharmaceutically acceptable cations, alcohols, ammonia, and amines. Such derivatives can be regarded as equivalent to the compounds disclosed, and are included within the scope of the present invention.
For purposes of illustration, there can be mentione several types of cationic salts which can be prepared from compounds of Formula VI including for example, water-soluble salts such as the sodium, potassium, lithium, ammonium and substituted ammonium salts, as well as the less water-soluble salts such as the calcium, barium, procaine, quinine and dibenzylethylenediamine salts.
Another concept of the invention resides in a new and improved process which represents a heretofore unavailable, key chemical procedure making it possible to prepare the novel compounds described above. It has been found in accordance with the practice of the process of this invention that a 7-acylamido-3-acyloxymethyl-A cephalosporin having the formula H Rr-ii-NH O 0L: ii-oHr-o-b-R;
boon, (X
wherein R, is the residue of the acylamido group in the 7-position, R is hydrogen or the residue of an ester forming alcohol and R is a C to C7 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.) or a cycloalkyl group {Don- CH2)...
CH (XII) o Brii-NH 0* N -cmon C JOORI (XIII) wherein R, and R are as defined above.
As the acid anhydride, use can be made of any of the aliphatic carboxylic acid anhydrides containing 4--20 carbon atoms. Preferred anhydrides are those having the general formula V '0 O R5-H3O( 1-R5 (XIV) wherein R is an alkyl group containing 1-7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, etc., or a cycloalkyl having the formula flH-l CHzhr- 2 CH (xv) wherein R is C to C alkylene (i.e., methylene, dimethylene, trimethylene) and m is zero or an integer from 1 to 4. Representative of the foregoing cycloalkyl groups include cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclo- 6 pentyl, cyclopentylethyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cyclopropyl, cyclopropylmethyl, etc.
Illustrative of the carboxylic acid anhydrides which can be employed in accordance with the practice of the process of this invention include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, pentanoic anhydride, hexanoic anhydride, heptanoic anhydride, cyclobutane carboxylic anhydride, cyclopentane carboxylic anhydride, cyclohexane carboxylic anhydride, cyclobutaneacetic anhydride, cyclobutanepropionic anhydride, cyclopentaneacetic anhydride, cyclohexaneacetic anhydride, cycloheptaneacetic anhydride, cyclohexanepropionic anhydride, etc.
The reaction between the anhydride and the desacetylcephalosporin is preferably carried out in the presence of an organic base. Any of a variety of organic bases can be used for this purpose. Preferred organic bases are the secondary and tertiary amines having a pK less than 8. Representative of suitable bases are diethyl amine, triethyl amine, pyridine, piperidine, morpholine as well as a number of others known to those skilled in the art.
If desired, the reaction can be carried out in the presence of an inert organic solvent. However, since the organic base is generally a liquid under normal conditions, it is usually preferred to operate without a solvent, using the organic base as the solvent.
The reaction temperature is not critical, and can be varied within wide ranges. In general, use should be made of a reaction temperature within the range of --l0 to C., and preferably 0 to 30 C.
. The 7-acylamido group, and the residue of the ester forming alcohol (R when use is made of a starting material in the form of an ester, do not enter into the reaction, and thus the nature of these groups does not affect the nature of the reaction. For this reason, the 7-acylamido group and the R group (when the latter is other thanhydrogen) can be any of a number of groups which are now well recognized by those skilled in the penicillin and cephalosporin arts.
I Illustrative of suitable acyl groups which can be present in the starting materials employed. in accordance i h h practice of the invention include those acyl groups having the formula wherein n is zero or an integer fnom I to 6 and R is an organic group such as HOOC-CH(NH )(CH or an aryl group or a substituted aryl group containing 6-14 carbon atoms.
Preferred aryl groups are those derived from benzene or naphthalene e M Q Q (XVII) gXVIII) wherein Q is hydrogen or one or more substituents ineluding, for example, C to C alkyl (e.g., methyl, ethylpropyl, isopropyl), C to C alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), a cyano group, a nitro group, a hydroxy group, halogen (e.g., chlorine, fluorine, bromine and iod ne), a trifluoromethyl group, a carboxy group, an annno group, a C to C carboxyalkyl group (e.g., carboxyrnethyl, carboxyethyl, carboxypropyl, etc.), or a C to C4, carboxamidoalkyl group [H NC(0)-alkyl] (e.g., carboxamidomethyl, carboxamidoethyl, etc.).
Representative acyl groups are 5 aminoadipoyl, benzoyl, phenylacetyl, beta-(phenyl)propionyl, naphthoyl, naphthylacetyl, gamma-phenyl-butyryl, p-methylbenzooyl, 2,4 dimethylphenylacetyl, S-methoxynaphthylacetyl, p-cyanophenylacetyl, 4-nitronaphthoyl, 3-nitrobenzoyl, 3, 5 dicyanonaphthylacetyl, beta-(3-nitrophenyl)-propionyl, p-hydroxybenzoyl, 4-hydroxyphenylacetyl, p-chlorophenylacetyl, m-bromobenzoyl, 3-trifluoromethylphenylacetyl,
o-carboxyphenylacetyl, m-carboxymethylphenylacetyl, mcarboxamidomethylphenylacetyl, beta( carboxamidomethylnaphthyl)propionyl, aminobenzoyl, aminophenylacetyl as well as a number of others.
R can also be a cycloalkyl group containing 4-8 carbon atoms, including cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In addition, R, can also be one of the foregoing cycloalkyl groups which is substituted by one or more of the Q substituents described above.
Illustrative of such acyl groups include cyclopentanoyl, cyclohexanoyl, 3 methylcyclohexanoyl, cyclobutylcarbonyl, 2 methoxycyclohexanoyl, 3-chlorocyclohexylacetyl, cyclopentylacetyl, beta-cyclopentylpropionyl, 3- methoxycyclohexylacetyl, 2-cyanocyclopentylacetyl, 3-nitrocyclohexanoyl, 3 carboxycyclohexylacetyl, 3-carboxamidomethylcyclohexylacetyl, etc.
R can also be a heterocyclic group wherein the heteroatom is O, S, N or any combination thereof, including dioxanyl, 2 furyl, 3-furyl, imidazolyl, isoxazolyl, morphorinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, N- pyridyl, 2 pyridyl, I l-pyridyl, pyridimidyl, N-pyrryl, 2- pyrryl, 3-pyrryl, thiazolyl, 2-thienyl, 3-thienyl, 2-benzothienyl, 3-benzothienyl, triazinyl, triazolyl and the like;
the partially and completely hydrogenated derivatives of I the foregoing, such as tetrahydrofuryl, imidazolinyl, imidazolidyl, piperidyl, tetrahydropyrimidyl, pyrrolidyl and the like; as well as all of the foregoing group which are substituted by one or more of the Q groups described above, as represented by the picolyls, methylfuryls, methyl thienyls, nitrofuryl, cyanofuryl, nitrobenzothienyl, nitropyridyl, cyanopyridyl, methoxypyrimidyl, bromopyridyl, trifiuoromethylpyridyl as well as others of the type described in Flynn US. Pat. No. 3,218,318.
Illustrative of acyl groups when R is heterocyclic are dioxanylacetyl, 2-fury1carbonyl, beta-pyrazinylpropionyl, 2 pyridylacetyl, 3-pyridylcarbonyl, 2-thienylacetyl, 3- benzothienylcarbonyl, piperidylacetyl, pyrrolidylcarbonyl, nitrobenzothienylacetyl, beta-(nitrofuryl)-propionyl, cyanopyridylcarbonyl, etc.
The acyl group forming the 7-acylamido group can further be an acyl group having the general formula R -i (XIX) wherein R is either alkyl containing 1-8 carbon atoms (e.g., methyl, .ethyl, isopropyl, n-butyl, tert-butyl, hexyl, isooctyl, etc.) or alkenyl containing 28 carbon atoms (e.g., vinyl, allyl, Z-butenyl, 3-hexenyl, etc.). R; can also be one of the foregoing alkyl or alkenyl groups which is substituted by one or more substituents including, for example, an amino group, a cyano group, a nitro group, a
hydroxy group, halogen (e.g., chlorine, fluorine, bromine,
iodine), a carboxy group or a carboxamide group Illustrative of these acyl groups are acetyl, propionyl, acrylyl, crotoyl, 2 aminoacetyl, 3-chloropropionyl, 6- heptenoyl, adipoyl, 3-hydroxypyropionoyl and S-nitrohexanoyl.
Also included within the scope of the invention are those desacetylcephalosporin compounds wherein R is an acyl group having the formula R5(CH2)m'-X(CH2)n -C (XX) wherein n is as previously described, m is zero or an integer from 1 to 5, X is O or S and R is R (i.e., aryl, cycloalkyl or heterocyclic) as described above including substituted derivatives thereof, or R (i.e., C to C alkyl or C to C alkenyl) as described above, including substituted derivatives thereof.
Representative of the acyl groups defined by (XX) above include tert-butoxycarbonyl, tert-butoxyacetyl, ethoxyacetyl, tert-butylmercaptocarbonyl, tert-butylmercaptoacetyl, allylmercaptoacetyl, 3 bromopropoxyacetyl,
3 hydroxypropylcarbonyl, Z-thienyloxyacetyl, piperidylmercaptoacetyl, 2 pyridyloxycarbonyl, phenoxyacetyl, naphthoxyacetyl, phenoxycarbonyl, aminophenoxyacetyl, beta-(phenoXy)-propionyl, cyclohexyloxyacetyl, chlorocyclopentyloxyacetyl, benzylacetyl, phenylmercaptoacetyl, phenylbutoxyacetyl, phenylethylmercaptopropionyl and phenylmercaptoacetyl as well as a wide variety of others.
The 7-acyl group can further be an acyl group having the general formula Y (XXI) wherein Y is an amino group, a protected amino group, hydroxy, C to C alkoxy (e.g., methoxy, ethoxy, etc.) carboxyl or C to C alkanoyloxy (e.g., acetoxy, propionoxy, etc.) and R isone of the groups defined by R above (i.e., aryl, heterocyclic and cycloalkyl as described in detail above).
Representative of the foregoing acyl groups are 2-phenyl 2-aminoacetyl, 2-(p-methoXyphenyl-2-aminoacetyl, 2- cyc1ohexyl-2-methoxyacetyl, 2-phenyl-Z-acetoxyacetyl, 2- *(2' pyridyl)-2-hydroxyacetyl, 2-piperidyl-2-aminoacetyl, 2 (2'-thienyl)-2-acetoxyacetyl as well as a variety of others. I
In addition to the foregoing, R can be a number of other acyl groups, including, for example, phenyl-a,a-di methylacetyl and Q substituted derivatives thereof and a number of others. Various other suitable R acyl groups are disclosed in the Behrens et al. US. Pats. Nos. 2,479; 295, 2,479,297, 2,562,407 and 2,623,876.
As will be appreciated by those skilled in the art, when the 7 acylamido group contains an unprotected amino group, such amino group may be acylated by the anhydride employed. However, this is not disadvantageous since the 7-acylamido group can easily be removed to form the corresponding 7-amino compound and reacylated as desired.
As indicated above, when use is made of an ester starting material, the nature of the reaction is not significantly affected by the nature of the ester protecting group or residue R It is generally preferred that R; be an ester residue which is easily cleaved by known means, such as by dilute aqueous base, trifiuoroacetic acid or by hydrogenation in the presence of a palladium or rhodium catalyst on a suitable carrier such as carbon, barium sulfate or alumina so that the cephalosporin is not degraded, since the ultimate product is generally used in the form of the acid.
Representative R groups include 0., to C tertiary alkyl (e.g., tert-butyl, tcrt-pentyl, etc.), C to C tertiary alkenyl (e.g., tert-pentenyl, tert-hexenyl, etc.), C to C tertiary alkynyl (e.g., 1,1-dimethyl-2-pentynyl, etc.), benzyl, methoxybenzyl, phenyl, methoxyphenyl, nitrobenzyl, phenacyl, trichloroethyl, trimethylsilyl, benzhydryl, phthalirnidomethyl, succinimidomethyl as well as a number of others apparent to those skilled in the art.
Examples of the A -desacetylcephalosporin acids and esters which can be used as the starting material in the practice of this invention include the following.
7- (5 '-carb oxy-5 '-valeramido) 3-hydroxymethyl- A -cephem-4-carboxylic acid 7-phenoxyacetamido-3-hydroxymethyl-A -cephem- 4carboxylic acid 7-phenylacetamido-3-hydroxymethyl-A -cephem- 4-carboxylic acid B,B,B-trichloroethyl 7-phenylmercaptoacetamido- 3-hydroxymethyl-A cephem-4-carboxylate 7-benzyloxyacetamido-3-hydroxymethyl-A -cephem- 4-carboxylic acid tert-butyl 7-(4'-methylphenylbutyrylamido)-3- hydroxymethyl-A -cephem-4-carboxylate 7- (4-propylb enzylmercaptoacetamido) -3 -hydroxymethyl-A cephem-4-carboxylic acid 1,1-dimethyl-2-pentynyl 7-(4-propylbenzy1-mercaptoacetamido) -3-hydroxymethyl-A -cephem-4-carboxylate 7-benzylmercaptopropionamido-3-hydroxymethy1- A -cephemi-carboxylic acid 7-phenylpr0pionarnido-3-hydroxymethyLM-cephem- 4-carb0xylic acid tert-butyl 7-phenylethylmercaptopropionamido-3- hydroxymethyl-A -cephem-4-carboxylate 7-phenylethylmercaptopropionamido-3-hydr0xymethyl-A -cephem-4-carboxylic acid tert-butyl 7-phenylbutoxybutyrylamido-3-hydroxymethy1-A -cephem-4-carboxylic acid 7-pheny1butoxybutyrylamido-3-hydroxymethyl-A cephem-4-carboxy1ic acid benzyl 7-phenylbutoxybutyrylamido-3-hydroxymethyl-A -cephem-4-carboxylate 7-(3'-fiuorophenoxyacetamido)-3-hydroxymethy1- A -cephemi-carboxylic acid trimethylsilyl 7-(4-br0mopheny]acetamido)-3- hydroxymethyLM-cephem-4-carboxylate 7-phenyl-a,a-dimethylacetamido-3-hydroxymethyl- A cephem-4-carboxylic acid p-nitrobenzyl 7-phenyl-a,a-dimethylacetamido-3- hydroxymethy1-A'--cephem-4-carb0xylate p-methoxybenzyl 7-(2'-ch1orobenzyloxypropionamido)- 3-hydroXymethy1-A -cephem-4-carboxylate tert-butyl 7-benzamido-3-hydroxymethy1-A -cephem- 4-carboxylate p-nitrobenzyl 7-phenylacetamido-3-hydroxymethyl- A -cepheIn-4-carb0xylate 7-(4'-nitrophenylmercaptoacetamido)-3-hydroxymethy1-A -cephem-4-carboxylic acid 7- 3 '-cyanophenylpropionami do) -3-hydroxymethy1- A cephem-4-carboxylic acid 7- (3 -trifluoromethylphenoxyacetamido -3 -hydroxymethyl-A -cephem-4-carboxylic acid 7-butyrylarnido-3-hydroxymethy1-A -cephem-4- carboylic acid tert-butyl 7-cyclohexylacetamido-3-hydroxymethyl- A -cephem-4-carboxylate 7-cyclohexy1acetamido-3-hydroxymethyl-A -cephem- 4-carboxy1ic acid succinimidomethyl 7-(beta-aminopropionamido)-3- hydroxymethyl-A -cephem-4-carboxylate 7-al1y1mercaptoacetamido-B-hydroxymethyl-A cephem-4-carboxylic acid p-methoxybenzyl 7-allylmercaptoacetamido-3- hydroxymethyl-A -cephem-4-carboxy1ate 7-(gamma-chlorocrotyhnercaptoacetamido)-3-hydroxymethyl-A -cephemkcarboxylic acid tert-butyl 7-(5'-amin0-5-carboxyvaleramido)-3- hydroxymethyl-A -cephem-4-carboxylate 7-(5'-amino-5'-carboxyvaleramido)-3-hydroxymethyl- A cephem-4-carboxylic acid 7-(2-thienylacetamido)-3-hydroxymethyl-A=-cephem- 4-carboxylic acid B,B,B-trich1oroethyl 7-(2-thienylacetamido)-3- hydroxymethyl-A -cephemi-carboxylate 7-(n-butylmercaptoacetamido)-3-hydroxymethy1-A cephem-4-carboxylic acid p-nitrobenzyl 7-(tert-but0xyacetamido)-3-hydroxy methyl-A -cephem-4-carb0xylate 7-tert-butoxyacetamido)-3-hydroxymethy1-A -cephem- 4-carboxylic acid benzyl 7-(2'-benzothienylacetamido)-3-hydroxymethyl-A -cephem-4-carboxylate 7- (3 -pyridylacetamido) -3 -hydroxymethy1A -cephen-4- carboxylic acid 7-(2'-pyranylacetamido)-3-hydroxymethyl-A -cephemicarboxylic acid 7- ('5 '-ox azolylacetamido -3 -hydroxymethyl-A -cephem- 4-carboxylic acid tert-butyl 7-(5-oxazolylacetamido)-3-hydroxymethyl- A -cephem-4-carboxylate The starting materials used in accordance with the process of this invention can be prepared by a number with citrus esterase to form desacetylcephalosporin C which can then be esterified and isomerized as illustrated below:
i C 0 0H l Citrus esterase (B0011 (XXII) I Esterification 0 (U: s ROOC-(IJH-(CHz)a- NH f 1 O-:IN -CHz-0H coon (XXIII) l Isomerization A O O R (XXIV) wherein R is the residue of the ester.
The product (XXIV) can then be reacted in accordance with the process of this invention.
Alternatively, the A -desacetylcephalosporin starting material can be prepared by simultaneous hydrolysis and isomerization of the corresponding A -cephalosporanic acid derivative using the procedure of Cocker et al., J. Chem, Soc., sect. C, 1142 (1966)..
For example, cephalothin prepared in accordance with the procedure of Flynn in the aforementioned U.S. patent can be hydrolyzed and isomerized to the corresponding A -desacetylcephalosporin as follows NaOH . I o S CHr-i INHI( H O 'N CCH2OH xxxv The oxidation reaction of (XXVI) above can be carried out by, for example, the procedure described in copending application Ser. No. 764,939, filed Oct. 3', 1968, wherein description is made of the use of oxidizing agents such as per-acids (e.g., peracetic acid, metachloroperbenzoic acid, etc.) for oxidizing A -cephem compounds to the corresponding A -cephem sulfoxides;
Similarly, the reduction reaction of (XXVII) above can be carried out by the use of any of a number of reducing agents, such as stannous chloride, zinc chloride or sodium dithionite, in conjunction with an acid halide activator (e.g., acetyl chloride) as described in copending application Ser. No. 764,925, filed Oct. 3, 1968.
'It is intended that the 7-acylarnido group of the products of the process of the present invention may be removed and replaced by another 7-acylamido group in the preparation of cephalosporin-type antibiotics. For example, the 7-acylamido group can be cleaved in accordance with the procedure described by Chauvette in copending application, Ser. No. 651,662, filed July 7, 1967, to form the corresponding 7-amino compound which can, in turn, be
12 re-acylated with, for example, a heterocyclic-containing acylating agent to prepare'the novel compounds of this invention as outlined below o (f I COOR4 (LOORt I I" ii CH2C-Ol acylation JOOR Having described the basic concepts of the invention, reference is now made to the following examples, which are provided by way of illustration, but not by way of limitation, of the practice of the invention.
EXAMPLE 1 Preparation of 7 (2' thienylacetamido) 3 cyclobutylcarbonyloxymethyl A cephem 4 carboxylic acid To a solution of 2.12 g. (mM.) of 7-(2'-thienylacetamido)-3-hydroxymethyl-A -cephem-4-carboxylic acid 81 ml. (1 m.) of pyridine, 18 mM. of cyclobutane carboxylic anhydride are added. The mixture is then stirred for 40 minutes at room temperature, andthe solution is then poured .into 500 ml. of cool 2 N HCl and cooled by stirring. The pH is 1.0.
The mixture is then extracted twice with ethyl acetate and the cephalosporin acid extracted with a solution of sodium bicarbonate until the pH is 7.7. The resulting alkaline solution is acidified to a pH of 2.0 and extracted with ethyl acetate, the extract is washed with water and dried. The product is identified as 7-(2-thienylacetamido)- 3-cyclobutylcarbonyloxymethyl A cephem-4-carboxylic acid.
EXAMPLE 2 Preparation of 7 (2 thienylacetamido) 3 cyclobutylcarbonyloxymethyl A cephem 1 oxide 4 carboxylic acid To a solution containing 1 mM. of 7'-(2-thienylacetarnido) 3 cyelobutylcarbonyloxymethyl-M-cephem- 4-carboxylic acid, prepared in Example 1, 15 ml. of CHCl 190 mg. (0.95 mM.) of 85% monochloroperbenzoic acid are added. The mixture is warmed slightly and precipitation commences. After stirring at room temperature for about 10 minutes, two-thirds of the solvent is evaporated and the product crystallized and filtered and recrystallized from alcohol.
The product is identified as 7-(2-thienylacetamido)- 3-cyclobutylcarbonyloxymethyl A cephem-l-oxide-4- carboxylic acid.
EXAMPLE 3 Preparation of 7 (2. thienylacetamido) 3 cyclobutylcarbonyl-oxyrnethyl A cephem 4 carboxylic acid 1 mM. of the 7-(2'-thienylacetamido)-3-cyclobutylcarbony1oxymethyl-A -cephem-1-oxide-4-carboxylic acid pre- 13 pared in Example 2, is dissolved in 18 ml. of dimethyl formamide and 560 mg. (2.5 mM.) of stannous chloride dihydrate and 2.5 ml. of acetyl chloride are added. The mixture is stirred at 18 C. for 15. minutes, poured into 40 ml. of cold water, and extracted 3 times with 25 ml. of
ethyl acetate. The combined extract is then washed with water and dried. The solvent is evaporated and the remaining oil dried in vacuo to yield a product having a melting point of 120122 C. dec.
. The product is identified as 7-(2'-thienylacetamido)-3- cyclobutylearbonyloxymethyl A cephem-4-carboxylic acid.
EXAMPLE 4 Preparation of 7 (2' furylpropionamido) 3 cyclohexylcarbonyloxymethyl A cephem 4 carboxylic acid 7 (2' furylpropionamido) 3 hydroxymethyl A cephem-4-carboxylic acid is prepared by hydrolysis of 7-(2'-furylpropionamido)cephalosporanic acid prepared in accordance with Example 2 of US. Pat. No. 3,218,318.
The resulting 3-hydroxymethyl compound is reacted with cyclohexane carboxylic anhydride according to the procedure of Example 1 to form 7-(2'-furylpropionamido)-3- cyclohexylcarbonyloxymethyl A cephem-4-carboxylic acid.
The A -compound is then oxidized with metachloroperbenzoic acid to form the corresponding sulfoxide and then reduced with sodium dithionite ina known manner. The product is identified as 7-(2-furylpropionamido)-3- cyclohexylcarbonyloxymethyl-A -cephem 4 carboxylic acid.
EXAMPLE 5 Preparation of 7-(2-furylacetamido)-3-cyclopentylcarbonyloxymethyl-A -cephem-4-carboxylic acid 7-(2-furylacetamido) 3 hydroxymethyl-A -cephem- 4-carboxylic acid prepared by hydrolysis of the A cephalosporanic acid is reacted with cyclopentanecarboxylic anhydride in accordance with the procedure of Example 1. The product is identified as 7-(2'-furylacetamido)-3- cyclohexylacetoxymethyl-A -cephem-4-carboxylic acid The resulting A -compound is then oxidized with metachlorperbenzoic acid and reduced with stannous chloride to form 7-(2-furylacetamido)-3-cyclopentylcarbonyloxymethyl-A -cephem-4-carboxylic acid.
EXAMPLE 6 Preparation of 7-(N'-methyl 2 pyrrylacetamido)-3- cyclohexylacetoxymethyl-A -cephem-4-canboxylic acid 7-(N-methyl 2 pyrrylacetamido)cephalosporanic acid prepared in accordance with the method described in Example 14 of US. Pat. No. 3,218,318 is hydrolyzed to form the corresponding A -desacetylcephalosporanic acid. The resulting product is 7-(N'-methyl-2-pyrrylacetamido)-3-hydroxymethyl-A -cephem 4 carboxylic acid which is reacted with cyclohexylacetic anhydride in accordance with the procedure described in Example 1.
The resulting product is 7-(N'-methyl-2'-pyrrylacetamido)-3-cyclohexylacetoxymethyl-A -cephem 4 carboxylic acid which is oxidized and then reduced in accordance with the methods of Examples 2 and 3, respectively, to form 7-(N'-methyl-2'-pyrrylacetamido)-3-cyclohexylacetoxymethyl-A -cephem4-carboxylic acid.
EXAMPLE 7 Preparation of 7-(2'-4-dimethylthiazol- -acetamido)-3- cyclopentylearbonyloxymethyl-A -cephem 4 carboxylic acid 7-(2-4'-dimethylthiazol 5' acetamido)cephalosporanic acid prepared in accordance with the procedure in Example 13 of US. Pat. No. 3,218,318 is hydrolyzed in 14 accordance with the procedure described in Example 6 to form 7-(2-4'-dimethylthiazol-5-acetamido) 3 hydroxymethyl-A -cephem-4-carboxylic acid.
This product is then reacted with cyclopentanecarboxylic anhydride in accordance with the procedure of Example 1 to form tertiary butyl 7-(2'-4-dimethylthiazol- 5'-acetamido)-3-cyclopentylcarbonyloxymethyl A -cephem-4-carboxylate.
This product is then oxidized and reduced in accordance with the procedure of Example 6 to form the corresponding 7-(2'-4'-dimethylthiazol-5-acetamido)-3-cyclopentylcarbonyloxymethyl-A -cephem-4-carboxylic acid.
EXAMPLE 8 Preparation of 7-(1'- -4-triazol-.l'-acetamido)-3-cyclobutylacetoxymethyl-A -cephem-4-carboxylic acid Using the procedure described in Example 7, 7 (1'-2- '-triazol-l-acetamido)cephalosporanic acid prepared in accordance with the US. Pat. No. 3,218,318, is hydrolyzed to form the corresponding A -desacetyl compound which is reacted with cyclobutylacetic anhydride in accordance with the procedure described in Example 1.
The resulting product is then oxidized and reduced to form 7 (1 2-4'-triazol-1-acetamido)-3-cyclobutylacetoxymethyl-A -cephem-4-carboxylic acid.
EXAMPLE 9 Preparation of 7-(1'-pyrazoleacetamido)-3-cyclohexylcarbonyloxymethyl-M-cephem-4-carboxylic acid 7 (1 pyrazolacetamido)cephalosporanic acid is hydrolyzed in accordance with the procedure described in Example 6 to form the corresponding A desacetylcephalosporanic compound, which is then reacted with cyclohexane carboxylic anhydride in accordance With the procedure described in Example 1.
The product is then oxidized and reduced to convert the A -compound to the A -compound, and the resulting product is identified as 7-(1-pyrazolacetamido)-3-cyclohexylcarbonyloxymethyl-A -cephem-4-carboxylic acid.
EXAMPLE 10 Preparation of 7-(3-thienylacetamido) 3 cyclopentyl prop1onoxymethyl-A -cephem-4-carboxylic acid potassium salt 7-(3-thienylacetamido 3 hydroxymethyl-A -cephem- 4-carboxylic acid prepared by hydrolysis of 7-(3'-thienylacetamido) cephalosporanic acid prepared in accordance with Example 5 of US. Pat. 3,218,318, is reacted with cyclopentanepropionic anhydride in accordance with the procedure described in Example 1.
The resulting product is then oxidized and reduced in accordance with the procedure described in Examples 2 and 3, respectively, to yield 7-(3-thienylacetamido)-3-cyclopentylpropionoxymethyl A -cephem-4-carboxylic acid, which is, in turn, reacted with potassium acetate to form the corresponding potassium salt.
EXAMPLE 11 Preparation of 7-(2-thienylacetamido)-3-propionoxymethyl-A -cephem-4-carboxylic acid To a solution of 2.12 g. (6 mM.) of 7-(2-thienylacetamido)-3-hydroxymethyl-A -cephem-4-carboxylic acid in 81 ml. (1 mole) of pyridine, 2.34 g. (18 mM.) of propionic anhydride are added. The mixture is then stirred 40 minutes at room temperature. Thereafter, the solution is poured into 500 ml. of cold 2 N HCl and cooled by stirring; the pH is 1.0.
The mixture is then extracted twice with ethyl acetate, and the acid extracted with a solution of sodium bicarbonate until the pH is 7.7. The alkaline solution is acidified to a pH of 2.0 and extracted with ethyl acetate, the extract being washed with water and dried. The solvent is extracted and the remaining oil triturated with petroleum ether giving the powdered product (1.1 g.', 44.5%) MP. 1l0-113 dec.
The product is identified as 7-(2'-thienylacetamido)- 3-propionoxymethyl-A -cephem-4-carboxylic acid.
Analysis.--Calcd. for c qH gNgossz (percent): 49.74; H, 4.42; N, 6.82; S, 15.64. Found (percent): C, 49.61; H, 4.40; N, 6.63; S, 15.57.
EXAMPLE 12 Preparation of 7-(2'-thienylacetamido) -3-butyryloxymethyl-A -cephem-4-carboxylic acid Using the procedure described in Example 11, butyric anhydride is reacted with 7 (2' thienylacetamido)-3- hydroxymethyl A cephem 4 carboxylic acid. After separation of the reactants from the reaction mixture, the product is identified as 7-(2' thienylacetamido)-3-butyryloxymethyl-A -cephem-4-carboxylic acid.
EXAMPLE 13 Preparation of 7-(2-thienylacetamido)-3-isobutyryloxymethyl-A -cephem-4-carboxylic acid Using the procedure described in Example 1, isobutyric anhydride is reacted with 7-(2'-thienylacetamido)-3-hydroxymethyl A cephem 4 carboxylic acid. After separation of the reactants from the reaction mixture, the product is identified as 7-(2'-thienylacetamid0) 3 isobutyryloxymethyl-A -cephem-4-carboxylic acid.
EXAMPLE 14 Preparation of 7-phenoxyacetamido-3-propionoxymethyl-M-cephem-l-carboxylic acid 7 phenoxyacetamido 3 hydroxymethyl-A -cephem- I-carboxylic acid is reacted with propionic anhydride in accordance with the procedures of Example 1. The resulting product is identified as 7-phenoxyacetamido-3- propionoxymethyl-A -cephem-l-carboxylic acid.
EXAMPLE 15 Preparation of 7-benzylmercaptoacetamido-3-is0butyrylxymethyl-A -cephem-4-carboxylic acid 7 benzylmercaptoacetamido 3 hydroxymethyl-M- cephem-4-carboxylic acid is reacted with iso'butyric anhydride in accordance with the procedures of Example 1. The product is identified as 7-benzylmercaptoacetamido- 3-isobutyryloxymethyl-A -cephem-4-carboxylic acid.
EXAMPLES 16-23 Using the procedure described in Example 1, the following 3-acyloXymethylA -compounds are prepared from the reactants as indicated.
7-phenylacetyl 3 acetoxymethyl A cephem-4-carboxylic acid from acetic anhydride and 7-phenylacetyl- 3-hydroxymethyl-A -cephem-4-carboxylic acid 7-phenylmercaptoacetamido 3 propionoxymethyl-M- cephem 4 carboxylic acid from propionic anhydride and 7-phenylmercaptoacetamido 3 hydroxymethyl- A -cephem4-carboxylic acid 7-(3'-benzylmercaptoacetamido) 3 butyryloxymethyl- A -cephem 4 carboxylic acid from butyric anhydride and 7-(3' benzylmercaptoacetamido) 3 hydroxyrnethyl-A cephem -4-carboxy1ic acid 7 cyclohexylacetamido 3 propionoxymethyl A cephem 4 carboxylic acid from propionic anhydride and 7-cyclohexylacetamido 3 hydroxymethyl- A -cephem-4-carboxylic acid 7 allylmercaptoacetamido 3 cyclopentylcarbonyloxymethyl A cephem 4 carboxylic acid from cyclopentane carboxylic anhydride and 7 allylmercaptoacetamido 3 hydroxymethyl A cephem-4-carboxylic acid B,B,B-trichloroethyl 7-(5 carboxy propionamidovaleramido) 3 propionoxymethyl 2 cephem 4- carboxylate from propionic anhydride and B,B,B-tri- It will be understood that various changes and modifications can be made in the details of procedure, formulation and use without departing from the spirit of the invention, especially as defined in the following claims.
I claim:
1. A process for preparing a 3-acyloxymethyl-A cephalosporin comprising reacting a 7-acylamido-3-hydroxymethyl-A -cephalosporin having the formula wherein R is the residue of the 7-acylamido group and R is selected from the group consisting of hydrogen and the residue of an ester forming alcohol which can be cleaved by dilute aqueous base, by trifluoroacetic acid or by hydrogenation in the presence of a palladium or rhodium catalyst on a carrier, with the anhydride of a saturated aliphatic carboxylic acid in which the anhydride contains 4 to 20 carbon atoms in the presence of an organic base having a pK less than 8.
2. A process as defined in claim 1 wherein the anhydride is an anhydride having the formula wherein R is selected from the group consisting of C to 0; alkyl and cycloalkyl having the structure Ii JEEP-(0112)::-
wherein n is zero or an integer from 1 to 5 and R is alkylene containing 1-5 carbon atoms.
3. A process as defined in claim 1 wherein the organic base is pyridine. I
4. A process as defined in claim 1 wherein R is selected from the group consisting of hydrogen, C; to C tertiary alkyl, C to C tertiary alkenyl, C to C tertiary alkynyl, benzyl, methoxybenzyl, nitrobenzyl, phenacyl, trichloroethyl trimethylsilyl, benzhydryl, phthalimidomethyl, phenyl, methoxyphenyl and succinimidomethyl.
5. A process as defined in claim 1 wherein the acyl group in the 7-position is an acyl group selected from the group consisting of (1) an acyl group having the formula wherein n is zero or an integer from 1 to 6 and R is selected from the group consisting of monocyclic carbocyclic and bicyclic carbocylic aryl containing 6-14 carbon atoms cycloalkyl containing 48 carbon atoms and heterocyclic groups wherein the hetero atom is selected from the group consisting of O, S, N and combinations thereof, and substituted derivatives thereof wherein the substituent is selected from the group consisting of C C alkyl, C -C alkoxy, cyano, nitro, hydroxy, halogen, trifluoromethyl,
17 carboxy, amino, C -C carboxy alkyl and C C carboxamido alkyl; (2) an acyl group having the formula l R7-C wherein R is selected from the group consisting of C to C alkyl, C to C alkenyl and substituted derivatives thereof wherein the substituent is selected from the group consisting of amino, cyano, nitro, hydroxy, halogen, carboxy and carboxamido; (3) an acyl group having the formula i Ra-(CHz)mX(ClIz)n-G wherein n has the meaning set forth above, In is zero or an integer from 1 to 5, X is O or S and R is selected from the group consisting of R C to C alkenyl and substituted C to C alkenyl derivatives wherein the substituent is selected from the group consisting of amino, cyano, nitro, hydroxy, halogen, carboxy and carboxamido; (4) an acyl group having the formula wherein R has the meaning defined above and Y is selected from the group consisting of amino, protected amino, hydroxy, C to C alkoxy, carboxyl, and C to C alkanoyloxy; and phenyl-a,a-dimethylacetyl and substituted derivatives thereof wherein the substituent is selected from the group consisting of C -C alkyl, C -C alkoxy, cyano, nitro, hydroxy, halogen, trifluorornethyl, carboxy, amino, C -C carboxy alkyl and (D -C carboxamido alkyl.
6. A process as defined in claim 1 wherein the reaction is carried out at a temperature within the range of 10 to 100 C.
7. A compound of the formula wherein R is a heterocyclic group selected from the group consisting of dioxanyl, furyl, imidazolyl, isoxazoly], morpholinyl, oxazolyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrryl, thiazolyl, thienyl, benzothienyl, triazinyl, triazolyl, tetrahydrofuryl, imazolinyl, imidazolidy], piperidyl, tetrahydropyrimidyl, pyrrolidyl, and heterocyclic groups as set forth above which are substituted by one or more of the groups selected from the group consisting of C to C alkyl, C to C alkoxy, a cyano group, a nitro group, a hydroxy group, halogen, a trifluoromethyl group, a carboxy group, an amino group, a C to C carboxyalkyl group and a C to C carboxamidoalkyl group; n is Zero or an integer from 1 to 5; and R is C to C alkylene and m is zero or an integer from 1 to 3, and pharmaceutically acceptable cationic salts thereof.
8. A- compound of the formula wherein R is C to C alkylene and m is zero or an integer from 1 to 3, and pharmaceutically acceptable cationic salts thereof.
9. 7 (2' thienylacetamido) 3 cyclobutylcarbonyloXymethyl-A -cephem-4-carboxylic acid.
References Cited UNITED STATES PATENTS 3,532,694 10/1970 Somerfield 260-243 C NICHOLAS S. RIZZO, Primary Examiner U.S. Cl. X.R. 424246
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017487A (en) * 1973-12-01 1977-04-12 Merck & Co., Inc. 7β-(D-5-amino-5-carboxyvaleramido)-7-methoxy-3-substituted-3-cephem-4-carboxylic acid antibiotics
US4089956A (en) * 1976-09-08 1978-05-16 Smithkline Corporation 7-Acylamino-8-oxo-3-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid derivatives and bactericidal compositions and use thereof
US4108992A (en) * 1975-05-10 1978-08-22 Beecham Group Limited Cephalosporin analogues and compositions
US4122260A (en) * 1977-10-04 1978-10-24 Yeda Research And Development Co., Ltd. Cephalosporin derivatives
US4138486A (en) * 1976-03-25 1979-02-06 Shionogi & Co., Ltd. Arylmalonamido-1-oxadethiacephalosporins
US4148998A (en) * 1977-10-04 1979-04-10 Yeda Research And Development Co., Ltd. Pyrrole cephalosporin derivatives
US4626533A (en) * 1983-04-19 1986-12-02 Biogal Gyogyszergyar 7-(2-thienylacetamido)-3-acylaminomethyl-cephalosporins
US4908444A (en) * 1986-01-23 1990-03-13 Takeda Chemical Industries, Ltd. Method of producing cephem compounds

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017487A (en) * 1973-12-01 1977-04-12 Merck & Co., Inc. 7β-(D-5-amino-5-carboxyvaleramido)-7-methoxy-3-substituted-3-cephem-4-carboxylic acid antibiotics
US4108992A (en) * 1975-05-10 1978-08-22 Beecham Group Limited Cephalosporin analogues and compositions
US4138486A (en) * 1976-03-25 1979-02-06 Shionogi & Co., Ltd. Arylmalonamido-1-oxadethiacephalosporins
US4089956A (en) * 1976-09-08 1978-05-16 Smithkline Corporation 7-Acylamino-8-oxo-3-oxa-1-azabicyclo[4.2.0]octane-2-carboxylic acid derivatives and bactericidal compositions and use thereof
US4122260A (en) * 1977-10-04 1978-10-24 Yeda Research And Development Co., Ltd. Cephalosporin derivatives
US4148998A (en) * 1977-10-04 1979-04-10 Yeda Research And Development Co., Ltd. Pyrrole cephalosporin derivatives
US4626533A (en) * 1983-04-19 1986-12-02 Biogal Gyogyszergyar 7-(2-thienylacetamido)-3-acylaminomethyl-cephalosporins
US4908444A (en) * 1986-01-23 1990-03-13 Takeda Chemical Industries, Ltd. Method of producing cephem compounds

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