CA1071188A - Cephalosporins - Google Patents
CephalosporinsInfo
- Publication number
- CA1071188A CA1071188A CA262,347A CA262347A CA1071188A CA 1071188 A CA1071188 A CA 1071188A CA 262347 A CA262347 A CA 262347A CA 1071188 A CA1071188 A CA 1071188A
- Authority
- CA
- Canada
- Prior art keywords
- sulfaminoethyl
- cephem
- compound
- tetrazol
- ylthiomethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—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, cefaclor, or cephalexine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Abstract
ABSTRACT
The compounds of this invention are cephalosporins having various acyl substituents at the 7-position and a sulfaminoalkyl substituted tetrazolylthiomethyl group at the 3-position of the cephem nucleus and intermediates for the preparation thereof.
The compounds of this invention are cephalosporins having various acyl substituents at the 7-position and a sulfaminoalkyl substituted tetrazolylthiomethyl group at the 3-position of the cephem nucleus and intermediates for the preparation thereof.
Description
1~7~38 1 This invention relates to a new series of cephalosporin compounts which have antibacterial acti~ity when administered parenterally and to intermediaees for the preparation thereof. In particular, the structures of the biologically active cephalosporin compounds of this invention are characterized by having a sulfaminoaLkyl substituted tetrazolylthiomethyl group at the 3-position of the cephe~ nucleus. Also, this invention extends to methots and compositions for treating certain bacterial infections using these new compounts as well a~ to certain chemical inter~ediates and methot~ for preparing the compounds described here~ter.
The compounts of this invention are represented by the follo~ing structural for3Lla:
" ' 1 ~ _~S ., o ~ca2S ~ ¦ ¦
: N_ N
; cooa I ~
(C~2)n~N~S03a t FOR~ULA I
in which:
Rl is an acyl group selected from the group consisting . of:
g-ca-c- , Y-C~2-C- and Z-S(O)m-Ca2-C-where:
X is thienyl, tihydrophenyl, phenyl or phenyl monosubstituted wich hydroxy, hydroxy~ethyl, for~amido, ureido or carboxymethylamino;
A is Na2, oa, cooa or S03-d; or rormyloxy when X is phenyl;
30 Y is thienyl, tetrazolyl, sydnone, cyano or aminomethylpnenyl;
.
. ~ .1 ~l ~071188 1 Z is methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyrldyl;
m i9 zero to two; ant n 19 two to five, or a non-toxic pharmaceutically acceptable salt thereof.
It wlll be recognized that the 4-carboxylic acit group of the compounts of Formula I may be reatily esterifiet by methods well known to the art. These esters include, for example, simple alkyl ant aryl esters as well as esters which are easily cleaved, within the boty, to the parent acit such as intanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycyloxymethyl esters and others. Of course, when A is COO~, this group may be similarly esterified. All ~uch esters are included within the scope of this invention.
A selected group of compounts of this invention is represented by Formula I where n is two.
Another group of compounds of this invention is represented by Formula I where n ls two, ~ ls phenyl, A is ~2 or OH, Y is thienyl or tetrazolyl, Z is trifluoromethyl and m is zero.
E~amples of representative 7-acyl substituents (RlNH) of the compounds of Formula I are listed below:
-hydroxyphenylacetamito a-aminophenylacetamito ~-amino-4-hytroxyphenylacetamito 2S trifluoromethylthioacetamito methylthioacetamido -carboxythienylacetamito a-carboxyphenylacetamito ~-sulfophenylacetamido a-amino-4-carboxymethylaminophenyl-acetamido , ~ 071~L88 } 2-aminomethylphenylacetamido 3-sytnoneacetamido tetrazolylacetamido thienylacetamido
The compounts of this invention are represented by the follo~ing structural for3Lla:
" ' 1 ~ _~S ., o ~ca2S ~ ¦ ¦
: N_ N
; cooa I ~
(C~2)n~N~S03a t FOR~ULA I
in which:
Rl is an acyl group selected from the group consisting . of:
g-ca-c- , Y-C~2-C- and Z-S(O)m-Ca2-C-where:
X is thienyl, tihydrophenyl, phenyl or phenyl monosubstituted wich hydroxy, hydroxy~ethyl, for~amido, ureido or carboxymethylamino;
A is Na2, oa, cooa or S03-d; or rormyloxy when X is phenyl;
30 Y is thienyl, tetrazolyl, sydnone, cyano or aminomethylpnenyl;
.
. ~ .1 ~l ~071188 1 Z is methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyrldyl;
m i9 zero to two; ant n 19 two to five, or a non-toxic pharmaceutically acceptable salt thereof.
It wlll be recognized that the 4-carboxylic acit group of the compounts of Formula I may be reatily esterifiet by methods well known to the art. These esters include, for example, simple alkyl ant aryl esters as well as esters which are easily cleaved, within the boty, to the parent acit such as intanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl and thienylglycyloxymethyl esters and others. Of course, when A is COO~, this group may be similarly esterified. All ~uch esters are included within the scope of this invention.
A selected group of compounts of this invention is represented by Formula I where n is two.
Another group of compounds of this invention is represented by Formula I where n ls two, ~ ls phenyl, A is ~2 or OH, Y is thienyl or tetrazolyl, Z is trifluoromethyl and m is zero.
E~amples of representative 7-acyl substituents (RlNH) of the compounds of Formula I are listed below:
-hydroxyphenylacetamito a-aminophenylacetamito ~-amino-4-hytroxyphenylacetamito 2S trifluoromethylthioacetamito methylthioacetamido -carboxythienylacetamito a-carboxyphenylacetamito ~-sulfophenylacetamido a-amino-4-carboxymethylaminophenyl-acetamido , ~ 071~L88 } 2-aminomethylphenylacetamido 3-sytnoneacetamido tetrazolylacetamido thienylacetamido
2,2,2-trifluoroethylsulfinylacetamido cyanoacetamldo methylsulfonylacetamido cyanomethylthioacetamido 4-pyrldylthioacetamido 2-pyridoneaceta~ido 4-pyridoneacetamido.
Some examples of the compounds of ~or~ula I are 7-D-mantela~ido-
Some examples of the compounds of ~or~ula I are 7-D-mantela~ido-
3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-ce hem-4-carboxylic acld, 7-(2-thlenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acidt 7-(1-tetrazolylacatamido)-3-~1-(2-sulfaminoethyL)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid and 7-trlfluoromethylthioacetamido-3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxyllc acid.
Cephalosporin derivatives having 7-acyl substituents as defined above are well documented in the prior art. Although substltutlon by variously qubstituted S-heterocyclicthiomethyl groups t-C~2S~et) at the 3-position of the cephem nucleus is also known, no compounts containing the 3-(sulfaminoalkyl substituted tetrazolyl)thiomethyl moiety discloset herein are believed to be known to the art.
The compounds of Formula I are prepared by acylating 7-aminocephalosporanic acid with an appropriately protected acylatlng agent and then displacing the 3-acetoxy group with the deslred sulfaminoalkyltetrazole thiol or its corresponding salt with subsequent removal of the protective group(s) when pre~ent.
The carboxylic acid group of the acylating agent is activated by 07~88 any of the standard methods such as conversion to the mixed anyhdrlde, acid chloride, acid imidazolide or activated ester. In addition, a reagent such as dlcyclohexylcarbodiimide can be used provided that the carboxyl group on the cephem nucleus is protected with S an easily removable protecting group such as a benzhydryl, e-butyl, trichloroethyl, benzyl, benzyloxymethyl, p-methoxybenzyl or p-nitrobenzyl eRter. ~hen A is NH2, the a-amino group of the acylating agent is, preferably, protected prior to acylation with an easily removable protective group known in the art such as t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, the methyl acetoacetate adduct or similar groups co~monly used i~ the ~ynthesis of peptides.
The sulfaminoalkyltetrazole thlols of the formula:
N - N
LS
(CH2)~-N~S0 FORMULA II
in which n is two to flve, are also ob~ects of this lnvention, being important intermediates for producing pharmaceutical end products as described herein.
Alternatively, the compoundY of Formula I are prepared by acylation of an approprlate 7-amino-3-~ulfaminoalkyltetra201ylthiomethyl cephalosporin nucleus of For~ula III:
25~ ll CoOR4 - N
(CH2)n-NHS03H
FORMULA III
~071~88 in which:
n is two to five; and - R4 is hydrogen or a protecting ester group, with an approprlate acylating agent followed by removal of the S protective groups when present.
The compounds of Formula III above are also considered as ob~ects of this invention.
The protective groups can be removed according to ! methods well known eo the art, such as with trifluoroacetic acid when t-butyl or t-butoxycarbonyl protective groups are used.
The resulting salt is converted to the zwitterionic product or to the free acid by means of an ion exchange resin such as polystyrene-amine ion exchange resin (Amberllte IR-45) or else by basification of an aqueous solution of the salt.
15The acylatin~ agents used as starting materials are either know~ or prepared by known methods.
The 7-a~ino-3-sulfaminoalkyltetrazolylthiomethyl cephalosporin starting materials of Formula III are prepared from reaction of 7-formamidocephalosporanic acid, prepared by reactio~ of 7-amino-cephalosporanlc acid with formic acid and acetlc anhydrlde, and a20 substltuted tetrazole thiol of Formula II followed by treatment with acld such as hydrochloric acld to remove ehe formyl group.
The sulfaminoalkyltetrazole thiols of Formula II are prepared by reaction of the corresponding 1-aminoalkyl-5-(2,4-dinitrophenylthio~tetrazole compounds, prepared from 2,4-dinitro-"fluorobenzene and a l-acetamidoalkyltetrazole-;-thiol followed by acid hydrolysis of the acetamido moiety, with sulfur trioxide-trimethylamine complex with subsequent cleavage of the 2,4-dinitropbenyl protecting group. The l-acetamidoalkyltetrazole-5-thiols are prepared by reaction of an acetamidoalkyldithiocarbamate such as methyl 2-acetamidoethyldithiocarbamate with an azide such 1071~88 1 as sotium azide. The aceta~ldoal~yldithiocarbamates are prepared by treatment of a N-aminoalkylacetamide such as N-(2-aminoethyl)-acetamite with carbon disulfide and an alkyl halide such as methyl iodide ln the presence of a base such as triethylamine.
Certain compounds of this invention are capable of forming sal~s with, for e~ample, the alkali metals such as sodium or potassium, the alkaline earth metals such as calcium or with the ammonium cation. When A of Formula I is ~2~ the compounds can exist as the zwitterion or as either an acid or base salt. These salts are prepared by standard methods using a wide variety of non-toxic pharmaceutically acceptable acids and bases known iQ the art. Salts of the compounds of Formulas I, II and III are constdered as ob~ects of this invention.
It will be recognized that due to the asymmetric lS ~-carbon atom in the 7-acetamido group of Formula I when Rl i9 x-ca-c-, optical isomers will e~ist. Racemic or resolved products are obtained depending upon wheeher a racemic or resolved sidechain acid i9 used as an acylating agent. The resolved sidechain acids are readily obtained from the racemic compounds by resolution according to well known methods, including fractional crystallization of a salt formed with an optically active acid or base. All of the isomers, including separated isomers and mi~tures thereof, are included ~ithin the scope of this invention.
The compounds of Formula I have antibacterial activity 2S against both Gram-positive and Gram-negative organisms. ~inimum inhibitory concentrations (MIC's) range from 0.2 to >200 ~g/ml in in vitro testing. Test results for representative compounds are given in Table 1 below. In vivo mouse protection data (ED50's) is given in Table 2. ~ames corresponding to compound numbers are given in Table 3.
1071~88 ~IC (~g/ml) in vitro i Com~ound Number Bacterla _ 1 _ 23 _ _ _ 4 S. aureuQ E~ 127 3.1, 3.1 1.6 3.1 1.6 S. aureus SR 23390 0.8, 0.8 0.4 3.1 1.6 S. villaluz Sg 70390 50, 200 25 > 200 > 200 Serep. faecali3 E~ 34358 100, 50 12.5 50 100 o E. coli SX 12140 0.8, 0.8 3.1 0.8 0.8 E. col~ E~ 33779 3.1, 1.6 12.5 0.8 1.6 Rleb. pneumo. SX 4200 1.6, 0.8 3.1 0.8 0.8 Kleb. pneumo. SX 1200 0.4, 0.2 0.8 0.4 u.2 Sal~onella ATCC 12176 0.2, 1.6 12.S 0.4 0.4 Shigella-H~ 117 0.4, 0.2 ~ 0.4 0.8 Pseudo. aerug. E~ 63 > 200, ~ 200> 200> 200 > 200 Serratia marc. ATCC 13880 100, 100> 200 200 lûO
; Protea~ morgani 1791.6, 3.1 > 200 200 > 200 Entero. aerog. ATCC 13048 50, 6.3 25 3.1 6.3 Entero. cloacae EH 31254 1.6, 1.66.3 0.8 1.6 .
1071~88 EDso (m~lkg) in vivo E. coli SR 12140 Kleb. pneumo. S~ 4200 Compount ~umber 9. C-p . O. ~ . C. p . O .
1 0.46 50 0.46 ~
2 1.02 > 50 - --3 1.56 -- --0 4 1.82 - 50 Compound Number Compount Name 1 7-D-mantel~m~do-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-caphem-4-carboxylic acit 2 7-(2-thienylacetamito)-3-~1-(2-sulfa~inoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acit 3 7-Cl-tetrazolYlacetamito)-3-[l-(2-sulfamizoethyl) tetrazol-5-ylthiomethyl]-3-cephem-4-car~oxylic acid
Cephalosporin derivatives having 7-acyl substituents as defined above are well documented in the prior art. Although substltutlon by variously qubstituted S-heterocyclicthiomethyl groups t-C~2S~et) at the 3-position of the cephem nucleus is also known, no compounts containing the 3-(sulfaminoalkyl substituted tetrazolyl)thiomethyl moiety discloset herein are believed to be known to the art.
The compounds of Formula I are prepared by acylating 7-aminocephalosporanic acid with an appropriately protected acylatlng agent and then displacing the 3-acetoxy group with the deslred sulfaminoalkyltetrazole thiol or its corresponding salt with subsequent removal of the protective group(s) when pre~ent.
The carboxylic acid group of the acylating agent is activated by 07~88 any of the standard methods such as conversion to the mixed anyhdrlde, acid chloride, acid imidazolide or activated ester. In addition, a reagent such as dlcyclohexylcarbodiimide can be used provided that the carboxyl group on the cephem nucleus is protected with S an easily removable protecting group such as a benzhydryl, e-butyl, trichloroethyl, benzyl, benzyloxymethyl, p-methoxybenzyl or p-nitrobenzyl eRter. ~hen A is NH2, the a-amino group of the acylating agent is, preferably, protected prior to acylation with an easily removable protective group known in the art such as t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, the methyl acetoacetate adduct or similar groups co~monly used i~ the ~ynthesis of peptides.
The sulfaminoalkyltetrazole thlols of the formula:
N - N
LS
(CH2)~-N~S0 FORMULA II
in which n is two to flve, are also ob~ects of this lnvention, being important intermediates for producing pharmaceutical end products as described herein.
Alternatively, the compoundY of Formula I are prepared by acylation of an approprlate 7-amino-3-~ulfaminoalkyltetra201ylthiomethyl cephalosporin nucleus of For~ula III:
25~ ll CoOR4 - N
(CH2)n-NHS03H
FORMULA III
~071~88 in which:
n is two to five; and - R4 is hydrogen or a protecting ester group, with an approprlate acylating agent followed by removal of the S protective groups when present.
The compounds of Formula III above are also considered as ob~ects of this invention.
The protective groups can be removed according to ! methods well known eo the art, such as with trifluoroacetic acid when t-butyl or t-butoxycarbonyl protective groups are used.
The resulting salt is converted to the zwitterionic product or to the free acid by means of an ion exchange resin such as polystyrene-amine ion exchange resin (Amberllte IR-45) or else by basification of an aqueous solution of the salt.
15The acylatin~ agents used as starting materials are either know~ or prepared by known methods.
The 7-a~ino-3-sulfaminoalkyltetrazolylthiomethyl cephalosporin starting materials of Formula III are prepared from reaction of 7-formamidocephalosporanic acid, prepared by reactio~ of 7-amino-cephalosporanlc acid with formic acid and acetlc anhydrlde, and a20 substltuted tetrazole thiol of Formula II followed by treatment with acld such as hydrochloric acld to remove ehe formyl group.
The sulfaminoalkyltetrazole thiols of Formula II are prepared by reaction of the corresponding 1-aminoalkyl-5-(2,4-dinitrophenylthio~tetrazole compounds, prepared from 2,4-dinitro-"fluorobenzene and a l-acetamidoalkyltetrazole-;-thiol followed by acid hydrolysis of the acetamido moiety, with sulfur trioxide-trimethylamine complex with subsequent cleavage of the 2,4-dinitropbenyl protecting group. The l-acetamidoalkyltetrazole-5-thiols are prepared by reaction of an acetamidoalkyldithiocarbamate such as methyl 2-acetamidoethyldithiocarbamate with an azide such 1071~88 1 as sotium azide. The aceta~ldoal~yldithiocarbamates are prepared by treatment of a N-aminoalkylacetamide such as N-(2-aminoethyl)-acetamite with carbon disulfide and an alkyl halide such as methyl iodide ln the presence of a base such as triethylamine.
Certain compounds of this invention are capable of forming sal~s with, for e~ample, the alkali metals such as sodium or potassium, the alkaline earth metals such as calcium or with the ammonium cation. When A of Formula I is ~2~ the compounds can exist as the zwitterion or as either an acid or base salt. These salts are prepared by standard methods using a wide variety of non-toxic pharmaceutically acceptable acids and bases known iQ the art. Salts of the compounds of Formulas I, II and III are constdered as ob~ects of this invention.
It will be recognized that due to the asymmetric lS ~-carbon atom in the 7-acetamido group of Formula I when Rl i9 x-ca-c-, optical isomers will e~ist. Racemic or resolved products are obtained depending upon wheeher a racemic or resolved sidechain acid i9 used as an acylating agent. The resolved sidechain acids are readily obtained from the racemic compounds by resolution according to well known methods, including fractional crystallization of a salt formed with an optically active acid or base. All of the isomers, including separated isomers and mi~tures thereof, are included ~ithin the scope of this invention.
The compounds of Formula I have antibacterial activity 2S against both Gram-positive and Gram-negative organisms. ~inimum inhibitory concentrations (MIC's) range from 0.2 to >200 ~g/ml in in vitro testing. Test results for representative compounds are given in Table 1 below. In vivo mouse protection data (ED50's) is given in Table 2. ~ames corresponding to compound numbers are given in Table 3.
1071~88 ~IC (~g/ml) in vitro i Com~ound Number Bacterla _ 1 _ 23 _ _ _ 4 S. aureuQ E~ 127 3.1, 3.1 1.6 3.1 1.6 S. aureus SR 23390 0.8, 0.8 0.4 3.1 1.6 S. villaluz Sg 70390 50, 200 25 > 200 > 200 Serep. faecali3 E~ 34358 100, 50 12.5 50 100 o E. coli SX 12140 0.8, 0.8 3.1 0.8 0.8 E. col~ E~ 33779 3.1, 1.6 12.5 0.8 1.6 Rleb. pneumo. SX 4200 1.6, 0.8 3.1 0.8 0.8 Kleb. pneumo. SX 1200 0.4, 0.2 0.8 0.4 u.2 Sal~onella ATCC 12176 0.2, 1.6 12.S 0.4 0.4 Shigella-H~ 117 0.4, 0.2 ~ 0.4 0.8 Pseudo. aerug. E~ 63 > 200, ~ 200> 200> 200 > 200 Serratia marc. ATCC 13880 100, 100> 200 200 lûO
; Protea~ morgani 1791.6, 3.1 > 200 200 > 200 Entero. aerog. ATCC 13048 50, 6.3 25 3.1 6.3 Entero. cloacae EH 31254 1.6, 1.66.3 0.8 1.6 .
1071~88 EDso (m~lkg) in vivo E. coli SR 12140 Kleb. pneumo. S~ 4200 Compount ~umber 9. C-p . O. ~ . C. p . O .
1 0.46 50 0.46 ~
2 1.02 > 50 - --3 1.56 -- --0 4 1.82 - 50 Compound Number Compount Name 1 7-D-mantel~m~do-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-caphem-4-carboxylic acit 2 7-(2-thienylacetamito)-3-~1-(2-sulfa~inoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acit 3 7-Cl-tetrazolYlacetamito)-3-[l-(2-sulfamizoethyl) tetrazol-5-ylthiomethyl]-3-cephem-4-car~oxylic acid
4 7-erifluoromethylchioacetamito-3-[1-(2-~ulfa~ino-ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid -1071~88 Pharmaceutical compositions havlng antibacterial activity which comprise a pharmaceueical carrier containlng an active but non-toxic quantity of a compound of Formula I as well as methots of combatting bacterial infections by administering such a composition to an infected host in a non-toxic amount sufficient to combat such infections are also ob~ects of thls inYentiOn. The administration may be by parenteral in~ectlon such as subcutaneously, intramuscularly or intravenously.
The injection of sultably prepared sterile solutions or suspensions containing an effective, non-toxic amount of the new cephalosporin compound is the preferred route of administration.
The compounds of Formula I are formulated and administered in the same manner as other cephalosporins. The dosage regimen comprises adminlstration, preferably by injection, of an active but non-toxic quantity of a compound of Formula I selected from the dosage : L5 unit range of from 100 to 1000 mg ~ith the total daily dosage regimen being from 400 mg to 6 g. The precise dosages are dependent upon the age and weight of the snb~ect and on the infection being treated and can be determined by those skilled in the art based on the data disclosed herein compared wlth that available to the art attained with know~ cephalosporins.
Also considered within the scope of this invention are the 7a-methoxy analogs of the compounds of Formula I, which compounds are represented by the following structural formula:
OC~
25 ~ ~ ~ N
O N - N
COOH
(CE2) -NHS03H
FORMULA IV
or a non-toxic pharmaceutically acceptable salt thereof, in which and n are as previously defined hereabove.
10~ 38 A selected group of the compounds of Formula IV are those where n is two.
; Representatlve of the compounds of Formula IV are 7a-methoxy-7B-(2-thlenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid, 7a-methoxy-7~-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid, 7B-D-mandelamido-7a-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid and 7-methaxy-7,~-(1-tetrazolylaceta~ido)-3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
The compounds of Formula IV are preferably prepared by displacing the 3-acetoxy group from a 7a-metho~y-7~-acylaminocephalosporanic acid or qalt thereof, suitably protected as necessary, with a substituted tetrazole thiol of Formula II, or a corresp~nding salt, ~ith subsequent removal of the protective group(s) and conversion of any salts to the corresponding free acids, all as descrlbed hereinabove. The 7~-methoxy-7~-acyla~ino-cephalosporanic acids or salts are either known to the art or are prepared by known methods.
As with the compounds of Formula I, all non-toxic pharmaceutically acceptable salts and ail isomers, including separated isomers and mixtures thereof, of the compounds represented by Formula IV are included within ehe scope of this inveneion.
The compounds of Formula IV have anti-bacterial activity against both Gra~-positive and Gram-negative organisms. They are ad~inistered and formulated in the same manner as previously described for the compounds of Formula I.
The following examples illustrate the invention but are not to be construed as limiting the scope thereof. Temperatures are in degrees Centigrade (~C.) unless otherwise stated.
EXA~PLE 1 7-D-~andelamido-3-[1-(2-sulfaminoethyl)tetrazol-;-ylthiomethyl]-3-cephem-4-carboxYlic acid 107~88 To a solution of 20.4 g (0.20 mol) of N-(2-amlnoethyl)aceeamide in 200 ml of 95~ ethanol was added 27.9 ml (0.20 mol) of triethylamine and 12.0 ml (0.20 mol) of carbon disulfide. The exothermic reaction reached reflux and then cooled to ambient temperature over a 1.5 hour period. Methyl iodide (28.4 g, 0.20 mol) was added which again produced an exothermic reaction. After 1.75 hours the reaction mi~ture was evaporated to dryness and the solid residue was dissolved in 200 ml of water. The aqueous solution was extracted twice with 250 ml portions of ethyl acetate. The extracts were combined, shaken with sodium thio3ulfate, dried (MgSO4) and evaporated to dryness to give methyl 2-acetamitoethyldithiocarbamate.
To a solution of 38.4 g (0.198 mol) of methyl 2-aceta~ido-ethyldithiocarba~ate in 100 ml of 95% ethanol was added a solution of 13.5 8 (0.208 mol) of sodium azide in 100 ml of water. The reaction mixture was refluxed for 24 hours then cooled and concentrated under reduced pressure to about half volume. The solutlon was cooled to 15 and 50 ml of 6N sulfuric acid was added. The acidic solution was filtered and the filtrate was concentrated to about 100 ml and chilled at 5 to induce crystallization of 1-(2-aceta~ldoethyl)tetrazole-5-thiol which wa~ collected by filtration, mp 139-139.5~. Additional amounts of the product were obtained by continuous extraction of the filtrate with ethyl acetate.
A solution of 9.3 8 ~0.050 mol2 of 2,4-dinitrofluorobenzene in 50 ml of acetone was added to a solution of 9.35 g (0.050 mol) of 1-(2-acetamidoethyl)eetrazole-5-thiol and 6.85 ~1 C0.050 mol2 of triethylamine in 100 ml of acetone and ehe reaction mixture was stirred for 1 hour. The solid material was colleceed by filtration and recrystallized from acetonitrile eo give 1-(2-aceeamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, mp 197-198.
A mixture of 6.5 g (0.02 mol) of 1-~2-aceta~idoethyl)-5-(2,4-dinitrophenylthio)tetrazole, 100 ~1 of 12 N hydrochloric acid and 100 ml of 95% ethanol was refluxed for 4.5 hours. The mixture was evaporated eo dryness to give a gummy residue uhich crystallized upon atditio~ of ethanoL to give 1-(2-amtnoethyl)-5-(2J4-tinitrophenylthio) tetrazole hytrochloride, mp 217-219 (d).
To a solution of 3.5 g (0.01 mol) of 1-(2-aminoethyl)-5-(2,4-dinitropherlylthio)tetrazole hydrochloride in 30 ~1 of dry ti~ethylformamide was added 1.4 g (0.01 mol) of sulfur trioxide-tri~ethylamine cple~
followed by 1.4 ml (0.01 mol) of triethylAm~ne. ~he ~isture was stirred for C.5 hour and then filtered. ~he filtrate was evaporated in vacuo~ acetoue was adted to the residue, ~he precipieate was removed by filt~ation and the ~iltrate was evaporated to dryness.
~ethanol was added to the residue and the solid material produced upon scratching ~as re~oved by filtration. The methanolic filtrate was broughe to pa 11.3 by addition of 5% methanolic sodium me~ho~ide, stirret lS for 1.25 hour~, filtered ant tlluted uith 300 ml of ~ther. The resulting solid was removet by filtraeion ant the filtrate was evaporated to dryuess to give a resitue which uas eriturated with 95% ethanol to intuce crystallization. The solid product was collected by filtration and tissolved in metha~ol and the methanolic solution was concentrate~ to 10 ml, dilutet uith 75 ml of 95% ethanol and re-concentrated to S ml to give l-(2-sulfaminoe~hyl)tetrazole-5-ehiol tisotium salt, mp 122-127~.
C3a5N503S2 2 Na 1.5 ~z Calculated: 12.16% C; 2.72% H; ~3.64X N
Found: 12.252 C; 7. 98~ H; Z.3.77~. ~
A solution of 1-(2-sulfami~oethyl)tetrazole-;-thiol disotium ~alt in water ls passet through an Amberlite ~B-L20X ion e~change resi~ column to give, after lyophilization, 1-(2-sulfaminoethyl)-tetrazole-5-thiol.
To a mixture of 2.11 g (0.006 mol) of 7-D-mantelamidocephalo-sporanic acit sotium salt and 1.18 g (0.004 mol) of 1-(2-sulfaminoethyl)-tetrazole-S-thiol disodium salt i~ 30 ml or uater was added 10~ aqueous -~
.".~
- ' ' , 1071~88 sodium hydroxide solution a~t then 5~ aqueous sodium bicarbonate solution to p~ 7.3. The reaction mixture was heated at 70 ror 2.66 hours, the~
it was coolet, covered with ethyl acetate, acidified to p~ 2.5 with 3N
hytrochloric acid and e~tracted twice wieh eehyl acetate. The aqueous phase was neutralizet to pa 7.0 by adtition of 10% aqueous sodium hydroxide and the~ 5% aquaous sodium bicarbonate solution-~ and chromatographed on gAD-7 resin ~ith water and methanol a~ eluants.
A~ter removing t~e methanol in vacuo the chr = tography fractions were lyophilized to give 7-D-mandelamido-3-~1-(2-sulfaminoethyl)tetrazol-5-ylth~omethyl]-3-cephem-4-carboxylic acid disodium salt.
Clg~lg~7ogs3-2 Na 3 ~2 Calculated: 34.08% C; 3.76~ ~; 14.64~ N
Found: 34.56% C; 3.25% ~; L3.96~ N
Ac aqueous solution of 7-D-mantelamido-3-~1-(2-sulfaminoethyl)-tetrazol-5-ylthicmeehyl]-3-cephem-4-carboxylic acid disodium salt is pas~ed through a column of Ambert~te 1~-120~ ion eYchange re~in co give the title compount.
E~A~PLE 2 7-(2-Thienylacetamido)-3-~1-(2-sulfaminoethyl~tetrazole-5-ylthiomeehyl]-3-cePhe~-4-carboxYlic acid A mixture of 1.89 g (0.064 mol) or 1-(2-su14aminoethyl)t2trazole-
The injection of sultably prepared sterile solutions or suspensions containing an effective, non-toxic amount of the new cephalosporin compound is the preferred route of administration.
The compounds of Formula I are formulated and administered in the same manner as other cephalosporins. The dosage regimen comprises adminlstration, preferably by injection, of an active but non-toxic quantity of a compound of Formula I selected from the dosage : L5 unit range of from 100 to 1000 mg ~ith the total daily dosage regimen being from 400 mg to 6 g. The precise dosages are dependent upon the age and weight of the snb~ect and on the infection being treated and can be determined by those skilled in the art based on the data disclosed herein compared wlth that available to the art attained with know~ cephalosporins.
Also considered within the scope of this invention are the 7a-methoxy analogs of the compounds of Formula I, which compounds are represented by the following structural formula:
OC~
25 ~ ~ ~ N
O N - N
COOH
(CE2) -NHS03H
FORMULA IV
or a non-toxic pharmaceutically acceptable salt thereof, in which and n are as previously defined hereabove.
10~ 38 A selected group of the compounds of Formula IV are those where n is two.
; Representatlve of the compounds of Formula IV are 7a-methoxy-7B-(2-thlenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid, 7a-methoxy-7~-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid, 7B-D-mandelamido-7a-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid and 7-methaxy-7,~-(1-tetrazolylaceta~ido)-3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
The compounds of Formula IV are preferably prepared by displacing the 3-acetoxy group from a 7a-metho~y-7~-acylaminocephalosporanic acid or qalt thereof, suitably protected as necessary, with a substituted tetrazole thiol of Formula II, or a corresp~nding salt, ~ith subsequent removal of the protective group(s) and conversion of any salts to the corresponding free acids, all as descrlbed hereinabove. The 7~-methoxy-7~-acyla~ino-cephalosporanic acids or salts are either known to the art or are prepared by known methods.
As with the compounds of Formula I, all non-toxic pharmaceutically acceptable salts and ail isomers, including separated isomers and mixtures thereof, of the compounds represented by Formula IV are included within ehe scope of this inveneion.
The compounds of Formula IV have anti-bacterial activity against both Gra~-positive and Gram-negative organisms. They are ad~inistered and formulated in the same manner as previously described for the compounds of Formula I.
The following examples illustrate the invention but are not to be construed as limiting the scope thereof. Temperatures are in degrees Centigrade (~C.) unless otherwise stated.
EXA~PLE 1 7-D-~andelamido-3-[1-(2-sulfaminoethyl)tetrazol-;-ylthiomethyl]-3-cephem-4-carboxYlic acid 107~88 To a solution of 20.4 g (0.20 mol) of N-(2-amlnoethyl)aceeamide in 200 ml of 95~ ethanol was added 27.9 ml (0.20 mol) of triethylamine and 12.0 ml (0.20 mol) of carbon disulfide. The exothermic reaction reached reflux and then cooled to ambient temperature over a 1.5 hour period. Methyl iodide (28.4 g, 0.20 mol) was added which again produced an exothermic reaction. After 1.75 hours the reaction mi~ture was evaporated to dryness and the solid residue was dissolved in 200 ml of water. The aqueous solution was extracted twice with 250 ml portions of ethyl acetate. The extracts were combined, shaken with sodium thio3ulfate, dried (MgSO4) and evaporated to dryness to give methyl 2-acetamitoethyldithiocarbamate.
To a solution of 38.4 g (0.198 mol) of methyl 2-aceta~ido-ethyldithiocarba~ate in 100 ml of 95% ethanol was added a solution of 13.5 8 (0.208 mol) of sodium azide in 100 ml of water. The reaction mixture was refluxed for 24 hours then cooled and concentrated under reduced pressure to about half volume. The solutlon was cooled to 15 and 50 ml of 6N sulfuric acid was added. The acidic solution was filtered and the filtrate was concentrated to about 100 ml and chilled at 5 to induce crystallization of 1-(2-aceta~ldoethyl)tetrazole-5-thiol which wa~ collected by filtration, mp 139-139.5~. Additional amounts of the product were obtained by continuous extraction of the filtrate with ethyl acetate.
A solution of 9.3 8 ~0.050 mol2 of 2,4-dinitrofluorobenzene in 50 ml of acetone was added to a solution of 9.35 g (0.050 mol) of 1-(2-acetamidoethyl)eetrazole-5-thiol and 6.85 ~1 C0.050 mol2 of triethylamine in 100 ml of acetone and ehe reaction mixture was stirred for 1 hour. The solid material was colleceed by filtration and recrystallized from acetonitrile eo give 1-(2-aceeamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, mp 197-198.
A mixture of 6.5 g (0.02 mol) of 1-~2-aceta~idoethyl)-5-(2,4-dinitrophenylthio)tetrazole, 100 ~1 of 12 N hydrochloric acid and 100 ml of 95% ethanol was refluxed for 4.5 hours. The mixture was evaporated eo dryness to give a gummy residue uhich crystallized upon atditio~ of ethanoL to give 1-(2-amtnoethyl)-5-(2J4-tinitrophenylthio) tetrazole hytrochloride, mp 217-219 (d).
To a solution of 3.5 g (0.01 mol) of 1-(2-aminoethyl)-5-(2,4-dinitropherlylthio)tetrazole hydrochloride in 30 ~1 of dry ti~ethylformamide was added 1.4 g (0.01 mol) of sulfur trioxide-tri~ethylamine cple~
followed by 1.4 ml (0.01 mol) of triethylAm~ne. ~he ~isture was stirred for C.5 hour and then filtered. ~he filtrate was evaporated in vacuo~ acetoue was adted to the residue, ~he precipieate was removed by filt~ation and the ~iltrate was evaporated to dryness.
~ethanol was added to the residue and the solid material produced upon scratching ~as re~oved by filtration. The methanolic filtrate was broughe to pa 11.3 by addition of 5% methanolic sodium me~ho~ide, stirret lS for 1.25 hour~, filtered ant tlluted uith 300 ml of ~ther. The resulting solid was removet by filtraeion ant the filtrate was evaporated to dryuess to give a resitue which uas eriturated with 95% ethanol to intuce crystallization. The solid product was collected by filtration and tissolved in metha~ol and the methanolic solution was concentrate~ to 10 ml, dilutet uith 75 ml of 95% ethanol and re-concentrated to S ml to give l-(2-sulfaminoe~hyl)tetrazole-5-ehiol tisotium salt, mp 122-127~.
C3a5N503S2 2 Na 1.5 ~z Calculated: 12.16% C; 2.72% H; ~3.64X N
Found: 12.252 C; 7. 98~ H; Z.3.77~. ~
A solution of 1-(2-sulfami~oethyl)tetrazole-;-thiol disotium ~alt in water ls passet through an Amberlite ~B-L20X ion e~change resi~ column to give, after lyophilization, 1-(2-sulfaminoethyl)-tetrazole-5-thiol.
To a mixture of 2.11 g (0.006 mol) of 7-D-mantelamidocephalo-sporanic acit sotium salt and 1.18 g (0.004 mol) of 1-(2-sulfaminoethyl)-tetrazole-S-thiol disodium salt i~ 30 ml or uater was added 10~ aqueous -~
.".~
- ' ' , 1071~88 sodium hydroxide solution a~t then 5~ aqueous sodium bicarbonate solution to p~ 7.3. The reaction mixture was heated at 70 ror 2.66 hours, the~
it was coolet, covered with ethyl acetate, acidified to p~ 2.5 with 3N
hytrochloric acid and e~tracted twice wieh eehyl acetate. The aqueous phase was neutralizet to pa 7.0 by adtition of 10% aqueous sodium hydroxide and the~ 5% aquaous sodium bicarbonate solution-~ and chromatographed on gAD-7 resin ~ith water and methanol a~ eluants.
A~ter removing t~e methanol in vacuo the chr = tography fractions were lyophilized to give 7-D-mandelamido-3-~1-(2-sulfaminoethyl)tetrazol-5-ylth~omethyl]-3-cephem-4-carboxylic acid disodium salt.
Clg~lg~7ogs3-2 Na 3 ~2 Calculated: 34.08% C; 3.76~ ~; 14.64~ N
Found: 34.56% C; 3.25% ~; L3.96~ N
Ac aqueous solution of 7-D-mantelamido-3-~1-(2-sulfaminoethyl)-tetrazol-5-ylthicmeehyl]-3-cephem-4-carboxylic acid disodium salt is pas~ed through a column of Ambert~te 1~-120~ ion eYchange re~in co give the title compount.
E~A~PLE 2 7-(2-Thienylacetamido)-3-~1-(2-sulfaminoethyl~tetrazole-5-ylthiomeehyl]-3-cePhe~-4-carboxYlic acid A mixture of 1.89 g (0.064 mol) or 1-(2-su14aminoethyl)t2trazole-
5-thiol tisodium salt and 2.67 8 (0.064 mol) of 7-(2-ehienyla~etamido)-cephalosporanic acit sodium salt in 40 ml of water was heated at 69 for 5.5 hours while ~aintaining the pH at 7.4 by addition of dilute aqueous sodiu~ bicarbonate solution. After cooling, ehe mi~ture was e~tracted ~S wlth ethyl acetate. The aqueous phase was neutralized, evaporated co dryness and the residue was passed through a .YAD-4 column eluting with water and methanol. The methanol was removed by evaporation and the aqueous resitue was lyophilizet to give a solid material. The solid was quspented in methanol, the insoluble material was remo~Jed by fileration and ehe filtrate was evaporated to tryness to ~ive 7-(2-thienylaceta ido)-3-[1-(2-sulfaminoethyl)t~trazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid ` ! - 14 -~07~88 disodium salt.
C17H17N707S4 2 Na 1 CH40 Calculated: 33.90% C; 3.31Z H; 15.37% N
Found: 34.04~ C; 3.57% ~; 14.74% N
7-(2-Thienylacetamido)-3-[1-(2-sulfamlnoethyl~tetrazol-5-yl-thiomethyl~-3-cephem-4-carboxyllc acid disodium salt is converted to the title compount as described in EYample 1.
E~AMPLE 3 7-(1-Tetrazolylaceta~ido)-3-~1-(2-sulfaminoethyl)tetrazole-5-yl-thlomethvl]-3-cePhem-4-carboxYlic acid 1 A mi~ture of 3.5 g (8.5 mmol) of 7-(1-tetrazolylacetamido)-cephalospor3nic acid sodium salt and 2.96 g (10 mmol) of 1-(2-sulfamino-ethyl)tetrazole-5-thiol disodium salt in 50 ml of water was stirred at 65~ for 6.5 hours while maintainin~ the p~ of the reaction mi~ture at 7.0 by addition of 5% aqueous sotium bicarbonate solution. The mixture was cooled to ambient temperature, acidified to pH 1.5 with 3N hydrochloric acid, filtered and extracted three times with ethyl acetate. The p~ of the aqueous phase was then ad~usted to 7.0 by adtition of sodium bicarbonate, the solution ~a~ chramatographed on a 2AD-2 column and the resulting product was freeze-dried to give 7-(1-tetrazolylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxyLic acit disodium salt.
C14~15N117S3 2 Na 2 a2o Calculated: 26.80% C; 3.37~ ~; 24.55% N
Fount: 27.11% C; 3.40% ~; 24.18% N
7-(1-Tetrazolylacetamido)-3-[1-(2-sulfaminoethyl)tatrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid disodium salt is converted to the title compound as described in Example 1.
EXAMæLE 4 7-Trifluoromethylthioacetamido-3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiometh~l]-3-ce~hem-4-carboxYlic acid A solution of 3.05 g (0.01 mol) of 1-(2-sulfaminoethyl)tetra-i~7~88 zole-5-thiol disodium salt ant 4.36 g (0.01 mol) of 7-trifluoromethyl-ehioacetamidocephalosporanic acid sodium salt in 50 ~1 of water was heated at 70 for 5.5 hours while maintaining the pH at 7.5 with 5%
aqueous sodium bicarbonate. The reaction mi~ture was diluted with SO
ml of water and extracted twice wlth ethyl acetate. The aqueous phase was acidified to pH 2 and extracted three times with ethyl acetate.
The aqueous layer was brought to pH 7.4 by addition of 5~ aqueous sodium bicarbonate and the solution was passed through a XAD-4 resin column while eluting with water followed by methanol. The methanol solution was evaporated to dryness and the residue was dissolved in 75 ml of water. The aqueous solution was ~Ytracted twice with ether and petroleum ether then lyophilized. The lyophilized material was dissolved in methanol, the solvent was evaporated to dryness and triturated with ether to give 7-trifluoromethylthioacetamido-3-rl-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid disodium salt.
C14H14F3N707S4-2 Na 2 H20 Calculated: 25.49~ C; 2.75% a; 14.86%
Found: 25.85Z C; 2.78% H; 14.13% ~
7-Trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid disodium salt is converted to the title compount as describet in Example 1.
E ~P~E S
7-(D-a-Aminophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-vlthiomethyl]-3-cePhem-4-carbo~Ylic acid A solution of 7.58 g (0.015 mol) of 7-(,D-a-t-butoxycarbonyl-aminophenylacetamido)cephalosporanic acid, 2.96 g (0.01 mol) of 1-(2-sulfaminoethyl~tetrazole-5-thiol disodium salt and 1.26 g (O.OlS mol) of sodium bicarbonate in 125 ml of water is stirred at 60 for 5 hours ~hile ~aintaining the pH at 7.0-7.2 by addition of sodium bicarbonate.
The mixture is cooled and e~tracted with ethyl acetate. The aqueous phasa is acidified to pH 2.5 with 3N hydrochloric acid and the acidic 07~L~88 solution i~ extracted again with ethyl acetate. The aqueous phase is brought to pH 7.1 by addltion of 5~ sodlum carbonate solution, then passed through a XAD-4 ion exchange resin column and eluted-~ith water and meehanol to give 7-(D-a-t-butosycarbonyla~inophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid disodium salt.
7-tD-a-t-ButYoxycarbonylaminophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid disodium ~alt i9 stirred at 25 with 25 ml of trifluoroacetic acid and 25 ml of 1,3-dimethoxybenzene for 2.25 ho~lrs. The misture is evaporated to dryness, ether is added to the residue and the precipitate is collected, washed with ether, stirred in acetonitrile for 2 hours and tried in vacuo to glve the title compound as the trifluoroacetic acid salt.
An aqueous solution of the trifluoroacetic acid 3alt is lS brought to p~ 5.0 by atdition of dilute aqueous sotium hydroside.
After lyophilization, the lyophilized material is dissolved in meth-anoi and ether is added to precipitate 7-(D-a-aminophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbosylic acid sodium salt. The sodium salt is dissolved in water and the aqueous solution is passed through an Amberlite IR-1208 ion exchange resin column. Lyophilization of the eluted material gives the title c~mpound.
E~ANPLE 6 Reaction of the N-t-buto~ycarbonyl derivative of the following cephalosporanic acids:
7-(-amino-4-hydro~yphenylaceta~ido~cephalosporanic acid 7-(-amino-4-formamidophenylacetamido)cephalosporanic acid 7-(a-amino-3-form~midophenylacetamido)cephalosporanic acid 7-(-amino-4-ureidophenylacetamido)cephalosporanic acid 7-(~-amino-3-ureidoph&nylacetamido)cephalosporanic acid 7-(-a~ino-4-hydroxymethlyphenylacetamido)cephalosporanic acid ^ 17 -L 7-(a-amino-1,4-cyclohexadienylacetamido~cephalosporanic acid 7-(-amino-4-carboxymethylaminophenylacetamido)cephalo-sporanic acid with 1-~2-sulfaminoethyl)tetrazole-5-thiol disodium salt as described in the procedure of Example 5 followed by removal of the protective group and conversion of the trifluoroacetic acid salts to the free acids as d2scribed therein gives the following compounds of this .! invention:
7-(a-amino-4-hydroxyphenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-formamidophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-3-formamidophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthlomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-ureidophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetsazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-3-ureidophenylacetamido-3-[1-(2-sulfamino-. ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-hydroxymethylphenylacetamido)-3-[l-(2-sulfaminoethyl)tetrazol-5-ylthlomethyl]-3-cephem-4-carboxylic acid - 7-(a-amino-1,4-cyclohexadienylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-carboxymethylaminophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
E~AMPLE 7 ~5 7-(4-aydroxymandelamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acit is prepared by reaction of 7-(4-hydroxymandelamido)cephalosporanic acid sodium salt and l-(2-sulfaminoethyl)tetrazole-5-thiol disodium .~alt followed by treatment of the product with Amberlite IR-120H ion exchange resin as described 3~
in the procedure of Example 1.
1071~88 . 1 EgAMPLE 8 - When the sodium salt of a cephalosporanic acit listed below:
7-(3-sytnoneacetamido)cephalosporanic acid 7-(2-aminomethylphenylacetamido)cephalosporanic acid is reacted with 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt ~ :
by the procedure described in Example 1 and the product is converted to the free acid as described therein, the following compounds of this invention are obtained, respectively:
7-(3-sydnoneacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthi~meehyl]-3-cephem-4-carboxylic acid 7-(2-aminomethylphenylacetamido)-3-[1-(2-sulfa~inoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
Reactlon of the sodium salt of a cPphalosporanic acid llsted below:
7-(2,2,2-trifluoroechylthioacetamido)cephalosporanic acid 7-methylthioacetamidocephalosporanic acid with 1-(2-sulfaminoethyl)tetrazole-5-chiol as described in the proceduse . of Example 4 glves, after conversion of the salts formed to the free acids, the following compounds of this invention as final products:
7-(2,2,2-trifluoroethylthioacetamido)-3-[-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid . 7-methylthioacetamido-3-~1-(2-sulfaminoethyl)tetrazol-5- 2 ylthiome~hyl~-3-cephem-4-carboxylic acid.
E~LE 10 When an equivalent amount of an N-aminoalkylacetamide listed below:
N-(3-aminopropyl)acetamide N-(4-aminobutyl)acetamide N-(5-aminopentyl)acetimide ~(~7~88 i8 used in the procedure of Example 1 in place of N-(2-aminoethyl)-acetamide and the resuLting dithiocarba~ates are treated with sodium azide to produce the corresponding l-acetamidoalkyltetrazole-5-thiols which are converted to the l-sulfaminoalkyl derivatives, all as describet therein, the following 1-sulfaminoalkyltetrazole-5-thiols are obtained:
1-~3-sulfaminopropyl)tetrazole-5-thiol 1-(4-sulfaminobutyl)tetrazole-5-thiol 1-(5-~ulfaminopentyl)tetrazole-5-thiol.
0 Reaction of the disotium salt of a l-sulfaminoalkyltetrazole-5-thiol listed above with 7-D-mandelamidocephalosporanic acid sodium salt as described in the procedure of E~ample 1 followed by conversion of the salts formed to the free acids, gives the following compounds of this ~ invention:
i 15 7-D-mandelamido-3-[1-(3-sulfaminopropyl)tetrazol-5-ylthio-methyl~-3-cephem-4-carboxylic acid 7-D-mantelamito-3-[1-(4-sulfaminobutyl)tetrazol-5-ylthio-methyl]-3-cephem-4-carboxylic acid 7-D-mandelamido-3-~1-(5-sulfa~inopentyl)tetrazol-5-ylthio-methyl]-3-cephem-4-carboxylic acid.
Likewise, reaction of the substituted tetrazol thiols or the correspondiug disodium salt listet above with any of ~he 7-acyl cephalosporanic acids mentioned herein or their corresponding salts accorting to procedures described herein gives the corresponding compounds of this invention.
E~PLE 11 Beaction of a cephalosporanic acid listed belo~ or its corresponding salt:
7-(-hydroxy-2-thienylacetamido)cephalosporanic acid 7-(a-carboxy-2-thienylacetamido~cephalosporanic acid 7-(a-sulfophenylacetamido)cephalosporanic acid with 1-(2-sulfaminoethYl)tetrazole-5-thiol disodium salt by procedures described hereinabove gives, after conversion of the product to the free acid, the followlng compounds of this invention:
7-(~-hydroxy-2-thienylacetamido)-3-[1-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(-carboxy-2-ehienylacetamido)-3-~1-(2-sulfaminoethyl)-tetrazol-5-ylthiomeehyl]-3-cephem-4-carboxylic acid 7-(a-sulfophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid.
7-Amino-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxvlic acid To a mixture of 97 g (200 ml, 2.1 mol) of formic acid, distilled from anhydrous copper sulfate, and 37.5 ml (0.4 mol) of acetic anhydride was added 25.0 g (0.1 mol) of 7-aminocephalosporanic acid. The mixture was stirred at ambient temperature for 0.5 hour, then evaporated to dryness. The residue was dissolved in ethyl acetate and the ethyl acetate solution was filtered a~d evaporated to dryness to give a residue which was recrystallized from ether-petroleum ether to give 7-for~m~docephalosporanic acid.
A mixture of 1.0 g t3.3 mmol) of 7-for~amidocephalosporanic acid and 0.7 8 (2.6 mmol~ of 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt in 15 ml of ~ater i9 stirred at 65-70~ for 3 hours while maintainin8 the p~ at 7Ø The 3ixture is cooled, acidified :!
to pa l.o with hytrochloric acid and extracted with ethyl acetate.
The extrace i9 filtered and the filtrate is evaporated to drvness to give a residue which is dissolved ln methanol. The methanol solution is filtered and ether is added to precipitate tne title compound which is collected by filtration.
EXA~PLE 13 7-(4-Pyridylthioaceta~ido)-3-l1-(2-sulfaminoethyl)tetrazol-5-vlthiomethvll-3-cePhem-4-carboxvlic acid ~o7~88 (4-Pyridylthio)acetyl chloride (0.53 g, 2.8 mmol) is dropwise added to a mixture of 1.0 g of 7-amino-3~ (2-sulfaminoethYl~tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acicl and 0.9 g (9.0 mmol) of tri-ethyla~ine in 10 ml of dry dimethylformamide. The reaction mlxture is stirred for 1.5 hour at -10~, then it is warmed to ambient température ant stirred for 1 hour. This mixture is filtered and the filtrate is diluted wlth 200 ~1 of ether-petroleum ether. The precipitate is col-lected by filtration and dissolved in methanol. The methanol solution ls filtered and the filtrate is evaporated to dryness to give the title lQ compound as itq corresponding sodium salt.
7-(4-Pyridylthioacetamido)-3-[1-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid sodium salt is converted to the title compound by procedures described above.
Acylation of 7-amino-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid with an activated derivatlve of the following acids:
cya~oacetic acid 3-pyridylthioacetic acid cyanomethylthioacetic acid 2,2,2-trifluoroethylsulfinylacetic acid methylsulfonylacetic acid 2-pyridone-~-acetic acid 4-pyritoue-N-acetic acid as describet ln the procedure of Example 13 gives the following compounds of this invention:
7-cyanoacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(3-pyridylthioacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-cyanomethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid - ~7~88 7-(2,2,2-trifluoroethylsulfinylacetamido)-3-[l-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-methylsulfonylaceta~ido-3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(2-pyridoneacetamido)-3-11-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid 7-(4-pyridoneacetamido)-3-[1-(2-sulfaminoethyl)tetrazol- -5-ylthiomethyl~-3-cephem-4-carboxylic acid.
! o 7-(D-a-Formyloxyphenylacetamido)-3-~1-(2-sulfaminoethyl)tetrazol-! l 5-ylthiomethyl]-3-cephe~-4-carboxylic acid 7-~mino-3-~1-(2-sulf2minoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid is reacted with the formate ester of D-mandeloyl chloride according to the proceture of Example 13 to give the title compound.
E~AMPLE 16 7a-Methoxy-7~-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-YlthiomethYll-3-cePhem-4-carboxylic acid A solution of 1.28 g (3 mmol) of 7a-methoxy-7~-(2-thienylace-tamido)cephalosporanic acid sodium salt is dissolved in 50 ml of water, 1.33 g (4.5 mmol) of 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt is added and the solution is heated at 70 untiL thin layer chromatography indicates consu~ption of the starting material (ca. 5 hours). The reaction mixture is chromatographed on XAD-4 ion exchange resin wlth, after washing with water, methanol as eluant. Evaporation of the methanol solution gives the title compound as t&e disodium salt.
7a-~ethoxy-7~-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)tetra-zol-5-ylthiomethyl~-3-cephem-4-car~oxylic acid disodium salt is converted to the title compound as described above.
7a-~ethoxy-7~-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-YlthiomethYl]-3-cephem-4-carboxylic acid ~07~188 To a cold solution of 5.25 g (0.012 mol) of 7B-amino-7a-methoxycephalosporanic acid benzhydryl ester in 200 ml of methylene chloride containing 1.79 8 (0.012 mol) of N,N-diethylaniline is added dropwise over a 20 minute period a solution of 1.82 g (0.012 mol) of trifluoromethylthioacetyl chloride in 50 ml of methylene chloride.
After stirring for 30 minutes, the mixture is extracted successively wlth 5Z aqueous sodium bicarbonate, 5~ aqueous hydrochloric acid and finally with brine. The organic phase is dried (MgSO4) and the solvent evaporated to give 7a-methoxy-7B-trifluoromethylthioacetamidocephalo-sporanic acid benzhydryl ester.
7a-Methoxy-7~-trifluoromethylthioacetamidocephalosporanic acid benzhydryl ester is dissolved in a cold mixture of trifluoroacetic acid-anisole (2:1) and the mixture is stirred for 1.5 hour without ex-ternal cooling. The solvent is evaporated in vacuo and the residual product is taken up in ethyl acetate, washed with water, dried (~gSO4) and concentrated _ vacuo to a small volu~e. This solution is added dropwise to stirred petroleum ether to precipieate 7a-methoxy-7B-tri-fluoromethylthioacetamidocephalosporanic acid.
7a-Methoxy-7~-crifluoromethylthioaceeamidocephalosporanic acid (2.2 g, 5 mmol) is suspended in 75 ml of water and 0.4 g of solid sodium bicarbonate is added until solution is complete. To this solution is added 2.21 g (7.5 mmol) of 1-(2-sulfaminoethyl)tetrazole-5-thiol di-sodium salt and the mixture is heated at 70 for 7 hours. The pH of the reaction mi~ture is maintained at 7.5 by dropwise addition of 3N hydro-chloric acid as necessary. Progress of the reaction is monitored by thin layer chromatography and ~udged to be complete when tlc indicates disappearance of starting material. The reaction mixture is chromato-graphed on a column of ~AD-4 resin and the product is eluted from the colu~n with methanol. Evaporation of the methanol solution gives 7a-methoxy-7~-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-3~
5-ylthiomethyl]-3-cephem-4-carboxylic acid disodium salt.
107~1~8 1 The disodium salt is convertet to the title compound by procedures described hereinabove.
E2AMoeLE 18 7~-D-Mandelamido-7a-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthio-methy~-3-cephem-4-carboxYlic acid A cold solution of 2.6 g (6 ~mol) of 73-amino-7a-methoxycephalo-sporanic acid benzhydryl ester in 100 ml of methylene chloride containing 0.9 g (6 mmol) of N,~-dlethylaniline is treated dropwise over a 15 minute period wlth a solution of 1.7 g (6 mmol) of D-0-dichloroacetyLmandeloyl chloride in 25 ml of methylene chloride. The reaction mixture is allowed to come to room temperature with stirring and then ls extracted successively with 5% aqueous sodium bicarbonater 5~ hydrochloric acid and brine. The organic phase i9 dried and evaporated in vacuo. The residue is dissolved in colt trifluoroacetic acid-anisole (2:1) and the mixture is stirred at ambient temperature for l hour. The mixture is evaporated in vacuo and the residue is dissolved in 5~ aqueous sodium bicarbonate. The pa is raised to 9-9.3 by addition of 5~ aqueous sodium carbonate and maintained there for 30 minutes to complete cleavage of the dichloroacetyl group.
The solution is cooled in ice, layered with ethyl acetate and acidified to pa 2.0 with dilute hydrochloric acid. The layers are separated and after a second extraction of the aqueous layer with ethyl acetate the organic phases are combined, dried and evaporated in vacuo to yield 7~-D-mandelamido-7a-methoxycephalosporanic acid.
7~-D-Mandelamido-7a-methoxycephalosporanic acid (2.2 g, 5 mmol) is suspented ln 75 ml of water and solid sodium bicarbonate is atded until ~5 all of the acid has dissolved. To this is added 2.21 g (7.5 ~mol) of 1-(2-sulfaminoethyl)tecrazole-5-thiol disodium salt and the mixture is heated at 70~ for 7 hours. The pH of the reaction mixture is maintained at 7.5 by addition of 3N hydrochloric acid. Chromatography of this solution on XAD-4 resin while eluting with methanol gives, upon evapo-ration of the methanol, the title compound as its disodium salt.
107~18~
7B-D-Mandelamido-7a-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carbQxylic acid disodium salt is converted to the title compount by procedures described hereinabove.
E~AMPLE 19 7-Methoxy-7B-(D-a-aminophenylacetamito)-3-[1-(2-sulfaminoethyl)tetrazol-5-~ hiomethvll-3-cephem-4-carbo~Ylic acid _ _ To a solution of 5.3 g (0.012 mol) of 7B-amino-7a-methoxycephalo-sporanic acit p-nitrobenzyl eqter in 200 ml of methylene chloride is added 3.0 g (0.012 mol) of D-a-t-butoxycarbonylaminophenylacetic acid and 2.5 g (0.012 mol) of ticyclohexylcarbodiimide. The mixture is stirred for 18 hours at ambient temperature then filtered. The filtrate is evaporated in vacuo and the residue is dissolved in methanol-cetrahydro-furan and hydrogenated over 5% palladium on carbon to give 73-(D-a-t-butoxycarbonylaminophenylacetamido)-7a-methoxycephalosporanic acid.
7B-(D-a-t-Butoxycarbonylaminophenylacetamido)-7a-methoxy-cephalosporanic acid (2.68 g, 5 mmol) is dissolved in 75 ml of water by adding 0.4 g of solid sodium bicarbonate. 1-(2-Sulfamlnoethyl)tetra-zole-5-ehiol disodium salt (2.21 g, 7.5 mmol) is added and the reaction mixture is heated at 70 until thin layer chromatography indlcates that the starting material has disappeared. The reaction mixture is chromato-graphed on ~YAD-4 resin and eluted with methanol. Evaporation of the methanol solution gives 7a-methoxy-7B-(D-a-t-butoxycarbonylaminophenyl-acetamido)-3-~1-(2-sulfaminoethyl)te~razol-5-ylthiomechyl]-3-cephem-4-carboxylic acit disodium salt.
The disodium salt is suspended in l:l trifluoroacetic acid -anisole and stirred at ambient temperature for two hours. F~cess tri-fluoroacetic acit is removed by evaporation, the residue is trituratet with ether and the resulting precipitate is collected by filtration and stirred with acetonitrile to give the title compound as its trifluoroacetic acid salt.
An aqueous solution of the trifluoroacetic acid salt is brought to pH 7 by addition of 5~ aqueous sodium bicarbonate then chromatographed 1~711~8 -:
: 1 on XAD-4 resin with methanol as elutant. ~he solid material obtained after evaporation of the methanol is dissolved in water and the aqueous solution ls passet through a cation exchange column (IR-120~). Lyophili-zation of the eluted material gives the title compound.
7a-Methoxy-7~-(1-tetrazolylacetamito)-3-[1-(2-sulf~m~noethyl)tetrazol-5-Ylthiomethyl]-3-cephem-4-carboxylic acid Substitution of an equivalent amount of l-tetrazolylacetyl chlorite in the procedure of Example 17 ~i-es 7~-methoxy-7~-(1-tetrazolyl-acetamldo)cephalosporanic acid benzhydryl ester which is converted to 7~-methoxy-7~-(1-tetrazolylacetamido)cephalosporanic acid as described therein.
Reactlon of 7-methoxy-73-(l-tetra201ylacetamido)cephalosporanic acit, 1-(2-sulfaminoethyl)tetrazole-5-thlol disodium salt ant sodium bi-carbonate as described ln Example 17 gives, after conversion of the product disodium salt to the free acid as described above, the title compound.
An injectable pharmaceutical composition is for~ed byadding sterile water or sterile saline solution (2 ml) to 500 mg of 7-D-mandelamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-~0 - 3-cephem-4-carboxylic acid disodium salt.
Pharmaceutical co~positions of the other antibacterial compounds tisclosed above may be formulated in a similar manner.
.
. .
C17H17N707S4 2 Na 1 CH40 Calculated: 33.90% C; 3.31Z H; 15.37% N
Found: 34.04~ C; 3.57% ~; 14.74% N
7-(2-Thienylacetamido)-3-[1-(2-sulfamlnoethyl~tetrazol-5-yl-thiomethyl~-3-cephem-4-carboxyllc acid disodium salt is converted to the title compount as described in EYample 1.
E~AMPLE 3 7-(1-Tetrazolylaceta~ido)-3-~1-(2-sulfaminoethyl)tetrazole-5-yl-thlomethvl]-3-cePhem-4-carboxYlic acid 1 A mi~ture of 3.5 g (8.5 mmol) of 7-(1-tetrazolylacetamido)-cephalospor3nic acid sodium salt and 2.96 g (10 mmol) of 1-(2-sulfamino-ethyl)tetrazole-5-thiol disodium salt in 50 ml of water was stirred at 65~ for 6.5 hours while maintainin~ the p~ of the reaction mi~ture at 7.0 by addition of 5% aqueous sotium bicarbonate solution. The mixture was cooled to ambient temperature, acidified to pH 1.5 with 3N hydrochloric acid, filtered and extracted three times with ethyl acetate. The p~ of the aqueous phase was then ad~usted to 7.0 by adtition of sodium bicarbonate, the solution ~a~ chramatographed on a 2AD-2 column and the resulting product was freeze-dried to give 7-(1-tetrazolylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxyLic acit disodium salt.
C14~15N117S3 2 Na 2 a2o Calculated: 26.80% C; 3.37~ ~; 24.55% N
Fount: 27.11% C; 3.40% ~; 24.18% N
7-(1-Tetrazolylacetamido)-3-[1-(2-sulfaminoethyl)tatrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid disodium salt is converted to the title compound as described in Example 1.
EXAMæLE 4 7-Trifluoromethylthioacetamido-3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiometh~l]-3-ce~hem-4-carboxYlic acid A solution of 3.05 g (0.01 mol) of 1-(2-sulfaminoethyl)tetra-i~7~88 zole-5-thiol disodium salt ant 4.36 g (0.01 mol) of 7-trifluoromethyl-ehioacetamidocephalosporanic acid sodium salt in 50 ~1 of water was heated at 70 for 5.5 hours while maintaining the pH at 7.5 with 5%
aqueous sodium bicarbonate. The reaction mi~ture was diluted with SO
ml of water and extracted twice wlth ethyl acetate. The aqueous phase was acidified to pH 2 and extracted three times with ethyl acetate.
The aqueous layer was brought to pH 7.4 by addition of 5~ aqueous sodium bicarbonate and the solution was passed through a XAD-4 resin column while eluting with water followed by methanol. The methanol solution was evaporated to dryness and the residue was dissolved in 75 ml of water. The aqueous solution was ~Ytracted twice with ether and petroleum ether then lyophilized. The lyophilized material was dissolved in methanol, the solvent was evaporated to dryness and triturated with ether to give 7-trifluoromethylthioacetamido-3-rl-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid disodium salt.
C14H14F3N707S4-2 Na 2 H20 Calculated: 25.49~ C; 2.75% a; 14.86%
Found: 25.85Z C; 2.78% H; 14.13% ~
7-Trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid disodium salt is converted to the title compount as describet in Example 1.
E ~P~E S
7-(D-a-Aminophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-vlthiomethyl]-3-cePhem-4-carbo~Ylic acid A solution of 7.58 g (0.015 mol) of 7-(,D-a-t-butoxycarbonyl-aminophenylacetamido)cephalosporanic acid, 2.96 g (0.01 mol) of 1-(2-sulfaminoethyl~tetrazole-5-thiol disodium salt and 1.26 g (O.OlS mol) of sodium bicarbonate in 125 ml of water is stirred at 60 for 5 hours ~hile ~aintaining the pH at 7.0-7.2 by addition of sodium bicarbonate.
The mixture is cooled and e~tracted with ethyl acetate. The aqueous phasa is acidified to pH 2.5 with 3N hydrochloric acid and the acidic 07~L~88 solution i~ extracted again with ethyl acetate. The aqueous phase is brought to pH 7.1 by addltion of 5~ sodlum carbonate solution, then passed through a XAD-4 ion exchange resin column and eluted-~ith water and meehanol to give 7-(D-a-t-butosycarbonyla~inophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid disodium salt.
7-tD-a-t-ButYoxycarbonylaminophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid disodium ~alt i9 stirred at 25 with 25 ml of trifluoroacetic acid and 25 ml of 1,3-dimethoxybenzene for 2.25 ho~lrs. The misture is evaporated to dryness, ether is added to the residue and the precipitate is collected, washed with ether, stirred in acetonitrile for 2 hours and tried in vacuo to glve the title compound as the trifluoroacetic acid salt.
An aqueous solution of the trifluoroacetic acid 3alt is lS brought to p~ 5.0 by atdition of dilute aqueous sotium hydroside.
After lyophilization, the lyophilized material is dissolved in meth-anoi and ether is added to precipitate 7-(D-a-aminophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbosylic acid sodium salt. The sodium salt is dissolved in water and the aqueous solution is passed through an Amberlite IR-1208 ion exchange resin column. Lyophilization of the eluted material gives the title c~mpound.
E~ANPLE 6 Reaction of the N-t-buto~ycarbonyl derivative of the following cephalosporanic acids:
7-(-amino-4-hydro~yphenylaceta~ido~cephalosporanic acid 7-(-amino-4-formamidophenylacetamido)cephalosporanic acid 7-(a-amino-3-form~midophenylacetamido)cephalosporanic acid 7-(-amino-4-ureidophenylacetamido)cephalosporanic acid 7-(~-amino-3-ureidoph&nylacetamido)cephalosporanic acid 7-(-a~ino-4-hydroxymethlyphenylacetamido)cephalosporanic acid ^ 17 -L 7-(a-amino-1,4-cyclohexadienylacetamido~cephalosporanic acid 7-(-amino-4-carboxymethylaminophenylacetamido)cephalo-sporanic acid with 1-~2-sulfaminoethyl)tetrazole-5-thiol disodium salt as described in the procedure of Example 5 followed by removal of the protective group and conversion of the trifluoroacetic acid salts to the free acids as d2scribed therein gives the following compounds of this .! invention:
7-(a-amino-4-hydroxyphenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-formamidophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-3-formamidophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthlomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-ureidophenylacetamido)-3-[1-(2-sulfamino-ethyl)tetsazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-3-ureidophenylacetamido-3-[1-(2-sulfamino-. ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-hydroxymethylphenylacetamido)-3-[l-(2-sulfaminoethyl)tetrazol-5-ylthlomethyl]-3-cephem-4-carboxylic acid - 7-(a-amino-1,4-cyclohexadienylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(a-amino-4-carboxymethylaminophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
E~AMPLE 7 ~5 7-(4-aydroxymandelamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acit is prepared by reaction of 7-(4-hydroxymandelamido)cephalosporanic acid sodium salt and l-(2-sulfaminoethyl)tetrazole-5-thiol disodium .~alt followed by treatment of the product with Amberlite IR-120H ion exchange resin as described 3~
in the procedure of Example 1.
1071~88 . 1 EgAMPLE 8 - When the sodium salt of a cephalosporanic acit listed below:
7-(3-sytnoneacetamido)cephalosporanic acid 7-(2-aminomethylphenylacetamido)cephalosporanic acid is reacted with 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt ~ :
by the procedure described in Example 1 and the product is converted to the free acid as described therein, the following compounds of this invention are obtained, respectively:
7-(3-sydnoneacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthi~meehyl]-3-cephem-4-carboxylic acid 7-(2-aminomethylphenylacetamido)-3-[1-(2-sulfa~inoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid.
Reactlon of the sodium salt of a cPphalosporanic acid llsted below:
7-(2,2,2-trifluoroechylthioacetamido)cephalosporanic acid 7-methylthioacetamidocephalosporanic acid with 1-(2-sulfaminoethyl)tetrazole-5-chiol as described in the proceduse . of Example 4 glves, after conversion of the salts formed to the free acids, the following compounds of this invention as final products:
7-(2,2,2-trifluoroethylthioacetamido)-3-[-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid . 7-methylthioacetamido-3-~1-(2-sulfaminoethyl)tetrazol-5- 2 ylthiome~hyl~-3-cephem-4-carboxylic acid.
E~LE 10 When an equivalent amount of an N-aminoalkylacetamide listed below:
N-(3-aminopropyl)acetamide N-(4-aminobutyl)acetamide N-(5-aminopentyl)acetimide ~(~7~88 i8 used in the procedure of Example 1 in place of N-(2-aminoethyl)-acetamide and the resuLting dithiocarba~ates are treated with sodium azide to produce the corresponding l-acetamidoalkyltetrazole-5-thiols which are converted to the l-sulfaminoalkyl derivatives, all as describet therein, the following 1-sulfaminoalkyltetrazole-5-thiols are obtained:
1-~3-sulfaminopropyl)tetrazole-5-thiol 1-(4-sulfaminobutyl)tetrazole-5-thiol 1-(5-~ulfaminopentyl)tetrazole-5-thiol.
0 Reaction of the disotium salt of a l-sulfaminoalkyltetrazole-5-thiol listed above with 7-D-mandelamidocephalosporanic acid sodium salt as described in the procedure of E~ample 1 followed by conversion of the salts formed to the free acids, gives the following compounds of this ~ invention:
i 15 7-D-mandelamido-3-[1-(3-sulfaminopropyl)tetrazol-5-ylthio-methyl~-3-cephem-4-carboxylic acid 7-D-mantelamito-3-[1-(4-sulfaminobutyl)tetrazol-5-ylthio-methyl]-3-cephem-4-carboxylic acid 7-D-mandelamido-3-~1-(5-sulfa~inopentyl)tetrazol-5-ylthio-methyl]-3-cephem-4-carboxylic acid.
Likewise, reaction of the substituted tetrazol thiols or the correspondiug disodium salt listet above with any of ~he 7-acyl cephalosporanic acids mentioned herein or their corresponding salts accorting to procedures described herein gives the corresponding compounds of this invention.
E~PLE 11 Beaction of a cephalosporanic acid listed belo~ or its corresponding salt:
7-(-hydroxy-2-thienylacetamido)cephalosporanic acid 7-(a-carboxy-2-thienylacetamido~cephalosporanic acid 7-(a-sulfophenylacetamido)cephalosporanic acid with 1-(2-sulfaminoethYl)tetrazole-5-thiol disodium salt by procedures described hereinabove gives, after conversion of the product to the free acid, the followlng compounds of this invention:
7-(~-hydroxy-2-thienylacetamido)-3-[1-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(-carboxy-2-ehienylacetamido)-3-~1-(2-sulfaminoethyl)-tetrazol-5-ylthiomeehyl]-3-cephem-4-carboxylic acid 7-(a-sulfophenylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxylic acid.
7-Amino-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carboxvlic acid To a mixture of 97 g (200 ml, 2.1 mol) of formic acid, distilled from anhydrous copper sulfate, and 37.5 ml (0.4 mol) of acetic anhydride was added 25.0 g (0.1 mol) of 7-aminocephalosporanic acid. The mixture was stirred at ambient temperature for 0.5 hour, then evaporated to dryness. The residue was dissolved in ethyl acetate and the ethyl acetate solution was filtered a~d evaporated to dryness to give a residue which was recrystallized from ether-petroleum ether to give 7-for~m~docephalosporanic acid.
A mixture of 1.0 g t3.3 mmol) of 7-for~amidocephalosporanic acid and 0.7 8 (2.6 mmol~ of 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt in 15 ml of ~ater i9 stirred at 65-70~ for 3 hours while maintainin8 the p~ at 7Ø The 3ixture is cooled, acidified :!
to pa l.o with hytrochloric acid and extracted with ethyl acetate.
The extrace i9 filtered and the filtrate is evaporated to drvness to give a residue which is dissolved ln methanol. The methanol solution is filtered and ether is added to precipitate tne title compound which is collected by filtration.
EXA~PLE 13 7-(4-Pyridylthioaceta~ido)-3-l1-(2-sulfaminoethyl)tetrazol-5-vlthiomethvll-3-cePhem-4-carboxvlic acid ~o7~88 (4-Pyridylthio)acetyl chloride (0.53 g, 2.8 mmol) is dropwise added to a mixture of 1.0 g of 7-amino-3~ (2-sulfaminoethYl~tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acicl and 0.9 g (9.0 mmol) of tri-ethyla~ine in 10 ml of dry dimethylformamide. The reaction mlxture is stirred for 1.5 hour at -10~, then it is warmed to ambient température ant stirred for 1 hour. This mixture is filtered and the filtrate is diluted wlth 200 ~1 of ether-petroleum ether. The precipitate is col-lected by filtration and dissolved in methanol. The methanol solution ls filtered and the filtrate is evaporated to dryness to give the title lQ compound as itq corresponding sodium salt.
7-(4-Pyridylthioacetamido)-3-[1-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid sodium salt is converted to the title compound by procedures described above.
Acylation of 7-amino-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid with an activated derivatlve of the following acids:
cya~oacetic acid 3-pyridylthioacetic acid cyanomethylthioacetic acid 2,2,2-trifluoroethylsulfinylacetic acid methylsulfonylacetic acid 2-pyridone-~-acetic acid 4-pyritoue-N-acetic acid as describet ln the procedure of Example 13 gives the following compounds of this invention:
7-cyanoacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(3-pyridylthioacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-cyanomethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid - ~7~88 7-(2,2,2-trifluoroethylsulfinylacetamido)-3-[l-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-methylsulfonylaceta~ido-3-~1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 7-(2-pyridoneacetamido)-3-11-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid 7-(4-pyridoneacetamido)-3-[1-(2-sulfaminoethyl)tetrazol- -5-ylthiomethyl~-3-cephem-4-carboxylic acid.
! o 7-(D-a-Formyloxyphenylacetamido)-3-~1-(2-sulfaminoethyl)tetrazol-! l 5-ylthiomethyl]-3-cephe~-4-carboxylic acid 7-~mino-3-~1-(2-sulf2minoethyl)tetrazol-5-ylthiomethyl~-3-cephem-4-carbo~ylic acid is reacted with the formate ester of D-mandeloyl chloride according to the proceture of Example 13 to give the title compound.
E~AMPLE 16 7a-Methoxy-7~-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-YlthiomethYll-3-cePhem-4-carboxylic acid A solution of 1.28 g (3 mmol) of 7a-methoxy-7~-(2-thienylace-tamido)cephalosporanic acid sodium salt is dissolved in 50 ml of water, 1.33 g (4.5 mmol) of 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt is added and the solution is heated at 70 untiL thin layer chromatography indicates consu~ption of the starting material (ca. 5 hours). The reaction mixture is chromatographed on XAD-4 ion exchange resin wlth, after washing with water, methanol as eluant. Evaporation of the methanol solution gives the title compound as t&e disodium salt.
7a-~ethoxy-7~-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)tetra-zol-5-ylthiomethyl~-3-cephem-4-car~oxylic acid disodium salt is converted to the title compound as described above.
7a-~ethoxy-7~-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-YlthiomethYl]-3-cephem-4-carboxylic acid ~07~188 To a cold solution of 5.25 g (0.012 mol) of 7B-amino-7a-methoxycephalosporanic acid benzhydryl ester in 200 ml of methylene chloride containing 1.79 8 (0.012 mol) of N,N-diethylaniline is added dropwise over a 20 minute period a solution of 1.82 g (0.012 mol) of trifluoromethylthioacetyl chloride in 50 ml of methylene chloride.
After stirring for 30 minutes, the mixture is extracted successively wlth 5Z aqueous sodium bicarbonate, 5~ aqueous hydrochloric acid and finally with brine. The organic phase is dried (MgSO4) and the solvent evaporated to give 7a-methoxy-7B-trifluoromethylthioacetamidocephalo-sporanic acid benzhydryl ester.
7a-Methoxy-7~-trifluoromethylthioacetamidocephalosporanic acid benzhydryl ester is dissolved in a cold mixture of trifluoroacetic acid-anisole (2:1) and the mixture is stirred for 1.5 hour without ex-ternal cooling. The solvent is evaporated in vacuo and the residual product is taken up in ethyl acetate, washed with water, dried (~gSO4) and concentrated _ vacuo to a small volu~e. This solution is added dropwise to stirred petroleum ether to precipieate 7a-methoxy-7B-tri-fluoromethylthioacetamidocephalosporanic acid.
7a-Methoxy-7~-crifluoromethylthioaceeamidocephalosporanic acid (2.2 g, 5 mmol) is suspended in 75 ml of water and 0.4 g of solid sodium bicarbonate is added until solution is complete. To this solution is added 2.21 g (7.5 mmol) of 1-(2-sulfaminoethyl)tetrazole-5-thiol di-sodium salt and the mixture is heated at 70 for 7 hours. The pH of the reaction mi~ture is maintained at 7.5 by dropwise addition of 3N hydro-chloric acid as necessary. Progress of the reaction is monitored by thin layer chromatography and ~udged to be complete when tlc indicates disappearance of starting material. The reaction mixture is chromato-graphed on a column of ~AD-4 resin and the product is eluted from the colu~n with methanol. Evaporation of the methanol solution gives 7a-methoxy-7~-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-3~
5-ylthiomethyl]-3-cephem-4-carboxylic acid disodium salt.
107~1~8 1 The disodium salt is convertet to the title compound by procedures described hereinabove.
E2AMoeLE 18 7~-D-Mandelamido-7a-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthio-methy~-3-cephem-4-carboxYlic acid A cold solution of 2.6 g (6 ~mol) of 73-amino-7a-methoxycephalo-sporanic acid benzhydryl ester in 100 ml of methylene chloride containing 0.9 g (6 mmol) of N,~-dlethylaniline is treated dropwise over a 15 minute period wlth a solution of 1.7 g (6 mmol) of D-0-dichloroacetyLmandeloyl chloride in 25 ml of methylene chloride. The reaction mixture is allowed to come to room temperature with stirring and then ls extracted successively with 5% aqueous sodium bicarbonater 5~ hydrochloric acid and brine. The organic phase i9 dried and evaporated in vacuo. The residue is dissolved in colt trifluoroacetic acid-anisole (2:1) and the mixture is stirred at ambient temperature for l hour. The mixture is evaporated in vacuo and the residue is dissolved in 5~ aqueous sodium bicarbonate. The pa is raised to 9-9.3 by addition of 5~ aqueous sodium carbonate and maintained there for 30 minutes to complete cleavage of the dichloroacetyl group.
The solution is cooled in ice, layered with ethyl acetate and acidified to pa 2.0 with dilute hydrochloric acid. The layers are separated and after a second extraction of the aqueous layer with ethyl acetate the organic phases are combined, dried and evaporated in vacuo to yield 7~-D-mandelamido-7a-methoxycephalosporanic acid.
7~-D-Mandelamido-7a-methoxycephalosporanic acid (2.2 g, 5 mmol) is suspented ln 75 ml of water and solid sodium bicarbonate is atded until ~5 all of the acid has dissolved. To this is added 2.21 g (7.5 ~mol) of 1-(2-sulfaminoethyl)tecrazole-5-thiol disodium salt and the mixture is heated at 70~ for 7 hours. The pH of the reaction mixture is maintained at 7.5 by addition of 3N hydrochloric acid. Chromatography of this solution on XAD-4 resin while eluting with methanol gives, upon evapo-ration of the methanol, the title compound as its disodium salt.
107~18~
7B-D-Mandelamido-7a-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carbQxylic acid disodium salt is converted to the title compount by procedures described hereinabove.
E~AMPLE 19 7-Methoxy-7B-(D-a-aminophenylacetamito)-3-[1-(2-sulfaminoethyl)tetrazol-5-~ hiomethvll-3-cephem-4-carbo~Ylic acid _ _ To a solution of 5.3 g (0.012 mol) of 7B-amino-7a-methoxycephalo-sporanic acit p-nitrobenzyl eqter in 200 ml of methylene chloride is added 3.0 g (0.012 mol) of D-a-t-butoxycarbonylaminophenylacetic acid and 2.5 g (0.012 mol) of ticyclohexylcarbodiimide. The mixture is stirred for 18 hours at ambient temperature then filtered. The filtrate is evaporated in vacuo and the residue is dissolved in methanol-cetrahydro-furan and hydrogenated over 5% palladium on carbon to give 73-(D-a-t-butoxycarbonylaminophenylacetamido)-7a-methoxycephalosporanic acid.
7B-(D-a-t-Butoxycarbonylaminophenylacetamido)-7a-methoxy-cephalosporanic acid (2.68 g, 5 mmol) is dissolved in 75 ml of water by adding 0.4 g of solid sodium bicarbonate. 1-(2-Sulfamlnoethyl)tetra-zole-5-ehiol disodium salt (2.21 g, 7.5 mmol) is added and the reaction mixture is heated at 70 until thin layer chromatography indlcates that the starting material has disappeared. The reaction mixture is chromato-graphed on ~YAD-4 resin and eluted with methanol. Evaporation of the methanol solution gives 7a-methoxy-7B-(D-a-t-butoxycarbonylaminophenyl-acetamido)-3-~1-(2-sulfaminoethyl)te~razol-5-ylthiomechyl]-3-cephem-4-carboxylic acit disodium salt.
The disodium salt is suspended in l:l trifluoroacetic acid -anisole and stirred at ambient temperature for two hours. F~cess tri-fluoroacetic acit is removed by evaporation, the residue is trituratet with ether and the resulting precipitate is collected by filtration and stirred with acetonitrile to give the title compound as its trifluoroacetic acid salt.
An aqueous solution of the trifluoroacetic acid salt is brought to pH 7 by addition of 5~ aqueous sodium bicarbonate then chromatographed 1~711~8 -:
: 1 on XAD-4 resin with methanol as elutant. ~he solid material obtained after evaporation of the methanol is dissolved in water and the aqueous solution ls passet through a cation exchange column (IR-120~). Lyophili-zation of the eluted material gives the title compound.
7a-Methoxy-7~-(1-tetrazolylacetamito)-3-[1-(2-sulf~m~noethyl)tetrazol-5-Ylthiomethyl]-3-cephem-4-carboxylic acid Substitution of an equivalent amount of l-tetrazolylacetyl chlorite in the procedure of Example 17 ~i-es 7~-methoxy-7~-(1-tetrazolyl-acetamldo)cephalosporanic acid benzhydryl ester which is converted to 7~-methoxy-7~-(1-tetrazolylacetamido)cephalosporanic acid as described therein.
Reactlon of 7-methoxy-73-(l-tetra201ylacetamido)cephalosporanic acit, 1-(2-sulfaminoethyl)tetrazole-5-thlol disodium salt ant sodium bi-carbonate as described ln Example 17 gives, after conversion of the product disodium salt to the free acid as described above, the title compound.
An injectable pharmaceutical composition is for~ed byadding sterile water or sterile saline solution (2 ml) to 500 mg of 7-D-mandelamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-~0 - 3-cephem-4-carboxylic acid disodium salt.
Pharmaceutical co~positions of the other antibacterial compounds tisclosed above may be formulated in a similar manner.
.
. .
Claims (38)
1. A process for preparing a compound of the formula:
in which:
W is hydrogen or methoxy;
R1 is an acyl group selected from the group consisting of:
, and where:
X is thienyl, dihydrophenyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido, ureido or carboxymethylamino;
A is NH2, OH, COOH or SO3H; or formyloxy when X
is phenyl;
Y is thienyl, tetrazolyl, sydnone, cyano or aminomethylphenyl;
Z is methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyridyl;
m is zero to two; and n is two to five, or a non-toxic pharmaceutically acceptable salt thereof, comprising reacting a compound of the formula:
where R1 and W are defined as above or a salt thereof, with a compound of the formula:
where n is defined as above or a salt thereof, or, when W is hydrogen, acylating a compound of the formula:
where n is defined as above and R4 is hydrogen or a protecting ester group, with a compound of the formula R1-OH or an activated derivative thereof, suitably protected as necessary, followed by removal of the protecting group(s) when necessary, acidifying or otherwise converting to the free acid when necessary and optionally converting the product to a non-toxic pharmaceutically acceptable salt.
in which:
W is hydrogen or methoxy;
R1 is an acyl group selected from the group consisting of:
, and where:
X is thienyl, dihydrophenyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido, ureido or carboxymethylamino;
A is NH2, OH, COOH or SO3H; or formyloxy when X
is phenyl;
Y is thienyl, tetrazolyl, sydnone, cyano or aminomethylphenyl;
Z is methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyridyl;
m is zero to two; and n is two to five, or a non-toxic pharmaceutically acceptable salt thereof, comprising reacting a compound of the formula:
where R1 and W are defined as above or a salt thereof, with a compound of the formula:
where n is defined as above or a salt thereof, or, when W is hydrogen, acylating a compound of the formula:
where n is defined as above and R4 is hydrogen or a protecting ester group, with a compound of the formula R1-OH or an activated derivative thereof, suitably protected as necessary, followed by removal of the protecting group(s) when necessary, acidifying or otherwise converting to the free acid when necessary and optionally converting the product to a non-toxic pharmaceutically acceptable salt.
2. A process as claimed in claim 1 in which n is two.
3. A process as claimed in claim 1 in which R1 is , X is phenyl and A is NH2 or OH.
4. A process as claimed in claim 3 in which W is hydrogen.
5. A process as claimed in claim 3 in which W is methoxy.
6. A process as claimed in claim 1 in which R1 is and Y is thienyl or tetrazolyl.
7. A process as claimed in claim 6 in which W is hydrogen.
8. A process as claimed in claim 6 in which W is methoxy.
9. A process as claimed in claim 1 in which R1 is , Z is trifluoromethyl and m is zero to two.
10. A process as claimed in claim 9 in which W is hydrogen.
11. A process as claimed in claim 9 in which W is methoxy.
12. A process as claimed in claim 4 for preparing 7-mandelamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7-mandelamido-cephalosporanic acid sodium salt with 1-(2-sulfaminoethyl)-tetrazole-5-thiol disodium salt and then acidifying.
13. A process as claimed in claim 5 for preparing 7.beta.-mandelamido-7.alpha.-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7.beta.-mandelamido-7.alpha.-methoxycephalosporanic acid, sodium bicarbonate and 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt and then converting to the free acid.
14. A process as claimed in claim 7 for preparing 7-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7-(2-thienylacetamido)cephalosporanic acid with 1-(2-sulfamino-ethyl)tetrazole-5-thiol disodium salt and then converting to the free acid.
15. A process as claimed in claim 7 for preparing 7-(1-tetrazolylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7-(1-tetrazolylacetamido)cephalosporanic acid sodium salt with 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt and then acidifying.
16. A process as claimed in claim 8 for preparing 7.alpha.-methoxy-7.beta.-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7.alpha.-methoxy-7.beta.-(2-thienylacetamido)cephalosporanic acid sodium salt with 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt and then converting to the free acid.
17. A process as claimed in claim 8 for preparing 7.alpha.-methoxy-7.beta.-(1-tetrazolylacetamido)-3-[1-(2-sulfaminoethyl)-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7.alpha.-methoxy-7.beta.-(1-tetrazolylacetamido)cephalosporanic acid, sodium bicarbonate and 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt and then converting to the free acid.
18. A process as claimed in claim 10 for preparing 7-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol 5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7-trifluoromethylthioacetamidocephalosporanic acid sodium salt with 1-(2-sulfaminoethyl)tetrazole-5-thiol disodium salt and then acidifying.
19. A process as claimed in claim 11 for preparing 7.alpha.-methoxy-7.beta.-trifluoromethylthioacetamido-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid comprising reacting 7.alpha.-methoxy-7.beta.-trifluoromethylthioacetamido-cephalosporanic acid, sodium bicarbonate and 1-(2-sulfamino-ethyl)tetrazole-5-thiol disodium salt and then converting to the free acid.
20. A compound of the formula:
in which:
W is hydrogen or methoxy;
R1 is an acyl group selected from the group consisting of:
, and where:
X is thienyl, dihydrophenyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido, ureido or carboxymethylamino;
A is NH2, OH, COOH or SO3H; or formyloxy when X is phenyl;
Y is thienyl, tetrazolyl, sydnone, cyano or aminomethylphenyl;
Z is methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyridyl;
m is zero to two; and n is two to five, or a non-toxic pharmaceutically acceptable salt thereof, when prepared by the process of claim 1 or its obvious chemical equivalent.
in which:
W is hydrogen or methoxy;
R1 is an acyl group selected from the group consisting of:
, and where:
X is thienyl, dihydrophenyl, phenyl or phenyl monosubstituted with hydroxy, hydroxymethyl, formamido, ureido or carboxymethylamino;
A is NH2, OH, COOH or SO3H; or formyloxy when X is phenyl;
Y is thienyl, tetrazolyl, sydnone, cyano or aminomethylphenyl;
Z is methyl, trifluoromethyl, trifluoroethyl, cyanomethyl or pyridyl;
m is zero to two; and n is two to five, or a non-toxic pharmaceutically acceptable salt thereof, when prepared by the process of claim 1 or its obvious chemical equivalent.
21. A compound of claim 20 in which n is two when prepared by the process of claim 2 or its obvious chemical equivalent.
22. A compound of claim 20 in which R1 is , X is phenyl and A is NH2 or OH when prepared by the process of claim 3 or its obvious chemical equivalent.
23. A compound of claim 20 in which R1 is , x is phenyl, A is NH2 or OH and W is hydrogen when prepared by the process of claim 4 or its obvious chemical equivalent.
24. A compound of claim 20 in which R1 is , X is phenyl, A is NH2 or OH and W is methoxy when prepared by the process of claim 5 or its obvious chemical equivalent.
25. A compound of claim 20 in which R1 is and Y is thienyl or tetrazolyl when prepared by the process of claim 6 or its obvious chemical equivalent.
26. A compound of claim 20 in which R1 is and Y is thienyl or tetrazolyl and W is hydrogen when prepared by the process of claim 7 or its obvious chemical equivalent.
27. A compound of claim 20 in which R1 is Y-CH2-C- and Y is thienyl or tetrazolyl and W is methoxy when prepared by the process of claim 8 or it obvious chemical equivalent.
28. A compound of claim 20 in which R1 is , Z is trifluoromethyl and m is zero to two when prepared by the process of claim 9 or its obvious chemical equivalent.
29. A compound of claim 20 in which R1 is , Z is trifluoromethyl, m is 0 to 2 and W is hydrogen when prepared by the process of claim 10 or its obvious chemical equivalent.
30. A compound of claim 20 in which R1 is , Z is trifluoromethyl, m is 0 to 2 and W is methoxy when prepared by the process of claim 11 or its obvious chemical equivalent.
31. The compound 7-mandelamido-3-[1-(2-sulfamino-ethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 12 or its obvious chemical equivalent.
32. The compound 7.beta.-mandelamido-7.alpha.-methoxy-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 13 or its obvious chemical equivalent.
33. The compound 7-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 14 or its obvious chemical equivalent.
34. The compound 7-(1-tetrazolylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 15 or its obvious chemical equivalent.
35. The compound 7.alpha.-methoxy-7.beta.-(2-thienylacetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 16 or its obvious chemical equivalent.
36. The compound 7.alpha.-methoxy-7.beta.-(1-tetrazolyl-acetamido)-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 17 or its obvious chemical equivalent.
37. The compound 7-trifluoromethylthioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 18 or its obvious chemical equivalent.
38. The compound 7.alpha.-methoxy-7.beta.-trifluoromethyl-thioacetamido-3-[1-(2-sulfaminoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid when prepared by the process of claim 19 or its obvious chemical equivalent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62716475A | 1975-10-30 | 1975-10-30 | |
| US66583776A | 1976-03-11 | 1976-03-11 | |
| US05/704,142 US4118491A (en) | 1976-03-11 | 1976-07-12 | 7-Acyl-3-(sulfaminoalkyl substituted tetrazolylthiomethyl)cephalosporins, antibacterial compositions containing them and methods of treating bacterial infections with them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071188A true CA1071188A (en) | 1980-02-05 |
Family
ID=27417417
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA262,347A Expired CA1071188A (en) | 1975-10-30 | 1976-09-30 | Cephalosporins |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS6053026B2 (en) |
| AT (1) | AT353957B (en) |
| AU (1) | AU505141B2 (en) |
| CA (1) | CA1071188A (en) |
| CH (1) | CH627757A5 (en) |
| DE (1) | DE2649545A1 (en) |
| DK (1) | DK463176A (en) |
| ES (1) | ES452769A1 (en) |
| FI (1) | FI60868C (en) |
| FR (3) | FR2361896A1 (en) |
| GB (3) | GB1570095A (en) |
| GR (1) | GR61667B (en) |
| IE (1) | IE44393B1 (en) |
| IL (3) | IL50546A (en) |
| LU (1) | LU76092A1 (en) |
| NL (1) | NL7612010A (en) |
| SE (3) | SE452621B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4117123A (en) * | 1977-06-09 | 1978-09-26 | Smithkline Corporation | 7-Acylamino-3-[1-(2-sulfamidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acids |
| AT383811B (en) * | 1983-09-22 | 1987-08-25 | Biochemie Gmbh | Process for the preparation of monoalkali metal salts of 7-amino-3-cephem-4-carboxylic acid derivatives |
| US4717531A (en) * | 1983-09-23 | 1988-01-05 | Westinghouse Electric Corp. | Fuel transfer system upender using translation drive |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR207752A1 (en) * | 1973-03-30 | 1976-10-29 | Fujisawa Pharmaceutical Co | PROCEDURE FOR OBTAINING 7-AMINO-SUBSTITUTED-3-THIOMETHYL SUBSTITUTED-3-CEFEM-4-CARBOXYL ACIDS |
| NL7414119A (en) * | 1973-10-31 | 1975-05-02 | Fujisawa Pharmaceutical Co | PROCESS FOR PREPARING 1H-TETRAZOL-5-THIOL DERIVATIVES AND 1-SUBSTITUATED 1H-TETRAZOL-5-THIOLS. |
| GB1449420A (en) * | 1973-11-26 | 1976-09-15 | Sankyo Co | 7alpha-methoxycephalosporing derivatives |
| NZ176206A (en) * | 1973-12-25 | 1978-03-06 | Takeda Chemical Industries Ltd | Cephalosporins |
| US4066762A (en) * | 1976-07-12 | 1978-01-03 | Smithkline Corporation | Derivatives of 7-(2-substituted-2-hydroxyiminoacetamido)-3-(1-substituted tetrazol-5-ylthiomethyl-3-cephem-4-carboxylic acid |
-
1976
- 1976-09-23 IL IL50546A patent/IL50546A/en unknown
- 1976-09-28 SE SE8006413A patent/SE452621B/en not_active IP Right Cessation
- 1976-09-28 SE SE7610722A patent/SE435291B/en not_active IP Right Cessation
- 1976-09-30 CA CA262,347A patent/CA1071188A/en not_active Expired
- 1976-10-14 DK DK463176A patent/DK463176A/en not_active Application Discontinuation
- 1976-10-14 AU AU18702/76A patent/AU505141B2/en not_active Ceased
- 1976-10-21 FR FR7631723A patent/FR2361896A1/en active Granted
- 1976-10-26 GB GB19863/79A patent/GB1570095A/en not_active Expired
- 1976-10-26 FI FI763044A patent/FI60868C/en not_active IP Right Cessation
- 1976-10-26 GB GB44441/76A patent/GB1570093A/en not_active Expired
- 1976-10-26 GB GB19786/79A patent/GB1570094A/en not_active Expired
- 1976-10-27 IE IE2377/76A patent/IE44393B1/en unknown
- 1976-10-27 ES ES452769A patent/ES452769A1/en not_active Expired
- 1976-10-28 LU LU76092A patent/LU76092A1/xx unknown
- 1976-10-29 JP JP51131157A patent/JPS6053026B2/en not_active Expired
- 1976-10-29 CH CH1369576A patent/CH627757A5/en not_active IP Right Cessation
- 1976-10-29 DE DE19762649545 patent/DE2649545A1/en not_active Ceased
- 1976-10-29 GR GR52030A patent/GR61667B/en unknown
- 1976-10-29 AT AT807276A patent/AT353957B/en not_active IP Right Cessation
- 1976-10-29 NL NL7612010A patent/NL7612010A/en not_active Application Discontinuation
-
1977
- 1977-03-22 FR FR7708505A patent/FR2337720A1/en active Granted
- 1977-03-22 FR FR7708504A patent/FR2351982A1/en active Granted
-
1979
- 1979-02-28 IL IL56757A patent/IL56757A0/en unknown
- 1979-02-28 IL IL56758A patent/IL56758A0/en unknown
-
1980
- 1980-09-12 SE SE8006414A patent/SE437025B/en not_active IP Right Cessation
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